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Wang H, Heizhati M, Li N, Gan L, Yao L, Li M, Cai L, Li X, Aierken X, Yu D, Liu M, Maitituersun A, Nuermaimaiti Q, Nusufujiang A, Hong J. The use of statins are associated with an increased risk of new-onset diabetes in patients with hypertension and obstructive sleep apnoea, a longitudinal study. Diabetol Metab Syndr 2025; 17:121. [PMID: 40205492 PMCID: PMC11980143 DOI: 10.1186/s13098-025-01682-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 03/25/2025] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND Statins, a kind of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are first-line cholesterol-lowering drugs that are widely used in the primary and secondary prevention of coronary atherosclerotic heart disease (CAD). However, the safety of statins has been in the spotlight as recent studies have shown that statins may increase the incidence of diabetes. Therefore, we conducted a study of statins use and new-onset diabetes(NODM) in people with hypertension and obstructive sleep apnea (OSA) to better understand the relationship and to provide guidance for future clinical management. METHODS We conducted a retrospective cohort study using data from the Urumchi Hypertension Database (UHDATA), including patients aged ≥ 18 years diagnosed with hypertension and obstructive sleep apnoea treated at our Hypertension Centre between 2015 and 2019. The study was followed until November 2023 and the primary endpoint was new onset diabetes during the follow-up period. The hazard ratio (HR) and 95% confidence interval (CI) were calculated using the Cox proportional hazards model. Sensitivity analyses were performed by excluding those with pre-diabetes at baseline. RESULTS 8755 patients with hypertension and OSA, and 80.1% were followed up. During median follow-up of 31 months, 740 patients developed NODM. The incidence of NODM per 1000 person-years was 53.1. In Cox regression analysis, the risk of diabetes is significantly higher in patients who continue to take statins (HR = 1.77, 95% CI, 1.34-2.34, P < 0.001), and the results remain significant in sensitive analysis. CONCLUSIONS In patients with OSA and hypertension, continuous statins use increases the risk of diabetes and physicians should be vigilant about monitoring blood glucose levels when using statins in this patients.
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Affiliation(s)
- Hui Wang
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Mulalibieke Heizhati
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Nanfang Li
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China.
- Xinjiang Hypertension Institute, Urumqi, 830001, China.
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China.
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China.
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China.
| | - Lin Gan
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Ling Yao
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Mei Li
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Li Cai
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Xiufang Li
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Xiayire Aierken
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Dan Yu
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Miaomiao Liu
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Adalaiti Maitituersun
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Qiaolifanayi Nuermaimaiti
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Aketilieke Nusufujiang
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
| | - Jing Hong
- Hypertension Center of People's Hospital of Xinjiang Uygur, Autonomous Region, Xinjiang Hypertension Institute, Urumqi, 830001, China
- Xinjiang Hypertension Institute, Urumqi, 830001, China
- NHC Key Laboratory of Hypertension Clinical Research, Urumqi, 830001, China
- Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Urumqi, 830001, China
- Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, 830001, China
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Schwartz GG, Szarek M, Jukema JW, Cobbaert CM, Reijnders E, Bittner VA, Schwertfeger M, Bhatt DL, Fazio S, Garon G, Goodman SG, Harrington RA, White HD, Steg PG. Risk of Incident Diabetes Related to Lipoprotein(a), LDL Cholesterol, and Their Changes With Alirocumab: Post Hoc Analyses of the ODYSSEY OUTCOMES Randomized Trial. Diabetes Care 2025; 48:596-604. [PMID: 39913634 PMCID: PMC11932820 DOI: 10.2337/dc24-2110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 01/13/2025] [Indexed: 03/23/2025]
Abstract
OBJECTIVE Previous genetic and clinical analyses have associated lower lipoprotein(a) and LDL cholesterol (LDL-C) with greater risk of new-onset type 2 diabetes (NOD). However, PCSK9 inhibitors such as alirocumab lower both lipoprotein(a) and LDL-C without effect on NOD. RESEARCH DESIGN AND METHODS In a post hoc analysis of the ODYSSEY OUTCOMES trial (NCT01663402), we examined the joint prediction of NOD by baseline lipoprotein(a), LDL-C, and insulin (or HOMA-insulin resistance [HOMA-IR]) and their changes with alirocumab treatment. Analyses included 8,107 patients with recent acute coronary syndrome on optimized statin therapy, without diabetes at baseline, assigned to alirocumab or placebo with median follow-up 2.4 years. Splines were estimated from logistic regression models. RESULTS Lower baseline lipoprotein(a) and higher baseline insulin or HOMA-IR independently predicted 782 cases of NOD; baseline LDL-C did not predict NOD. Alirocumab reduced lipoprotein(a) and LDL-C without affecting insulin or NOD risk (odds ratio [OR] vs. placebo 0.998; 95% CI 0.860-1.158). However, in logistic regression, decreased lipoprotein(a) and LDL-C on alirocumab were independent, opposite predictors of NOD. OR for NOD for 25% and 50% lipoprotein(a) reductions on alirocumab were 1.12 (95% CI 1.01-1.23) and 1.24 (1.02-1.52). OR for NOD for 25% and 50% LDL-C reductions on alirocumab were 0.88 (95% CI 0.80-0.97) and 0.77 (0.64-0.94). CONCLUSIONS Baseline lipoprotein(a) was inversely associated with risk of NOD. Alirocumab-induced reductions of lipoprotein(a) and LDL-C were associated with increased and decreased risk of NOD, respectively, without net effect on NOD. Ongoing trials will determine the impact of larger and longer lipoprotein(a) reductions on NOD.
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Affiliation(s)
- Gregory G. Schwartz
- Division of Cardiology, University of Colorado School of Medicine, Aurora, CO
| | - Michael Szarek
- Division of Cardiology, University of Colorado School of Medicine, Aurora, CO
- CPC Clinical Research, Aurora, CO
- State University of New York Downstate Health Sciences University, Brooklyn, NY
| | - J. Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
- Netherlands Heart Institute, Utrecht, the Netherlands
| | - Christa M. Cobbaert
- Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Esther Reijnders
- Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Vera A. Bittner
- Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL
| | | | - Deepak L. Bhatt
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY
| | | | | | - Shaun G. Goodman
- Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada
- St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
| | | | - Harvey D. White
- Green Lane Cardiovascular Research Unit, Te Whatu Ora–Health New Zealand and University of Auckland, Te Toka Tumai, New Zealand
| | - Philippe Gabriel Steg
- Université Paris-Cité, INSERM-UMR1148, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, French Alliance for Cardiovascular Trials, Institut Universitaire de France, Paris, France
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Wang Y, Courcelles E, Peyronnet E, Porte S, Diatchenko A, Jacob E, Angoulvant D, Amarenco P, Boccara F, Cariou B, Mahé G, Steg PG, Bastien A, Portal L, Boissel JP, Granjeon-Noriot S, Bechet E. Credibility assessment of a mechanistic model of atherosclerosis to predict cardiovascular outcomes under lipid-lowering therapy. NPJ Digit Med 2025; 8:171. [PMID: 40108310 PMCID: PMC11923190 DOI: 10.1038/s41746-025-01557-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 03/09/2025] [Indexed: 03/22/2025] Open
Abstract
Demonstrating cardiovascular (CV) benefits with lipid-lowering therapy (LLT) requires long-term randomized clinical trials (RCTs) with thousands of patients. Innovative approaches such as in silico trials applying a disease computational model to virtual patients receiving multiple treatments offer a complementary approach to rapidly generate comparative effectiveness data. A mechanistic computational model of atherosclerotic cardiovascular disease (ASCVD) was built from knowledge, describing lipoprotein homeostasis, LLT effects, and the progression of atherosclerotic plaques leading to myocardial infarction, ischemic stroke, major acute limb event and CV death. The ASCVD model was successfully calibrated and validated, and reproduced LLT effects observed in selected RCTs (ORION-10 and FOURIER for calibration; ORION-11, ODYSSEY-OUTCOMES and FOURIER-OLE for validation) on lipoproteins and ASCVD event incidence at both population and subgroup levels. This enables the future use of the model to conduct the SIRIUS programme, which intends to predict CV event reduction with inclisiran, an siRNA targeting hepatic PCSK9 mRNA.
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Affiliation(s)
| | | | | | | | | | | | - Denis Angoulvant
- Cardiology department, Hôpital Trousseau, CHRU de Tours & UMR Inserm 1327 ISCHEMIA "Membrane Signaling and Inflammation in Reperfusion Injuries" Université de Tours, F37000, Tours, France
| | - Pierre Amarenco
- Department of Neurology and Stroke center, APHP, Bichat Hospital, Université Paris-Cité, Paris, France and McMaster University, Population Health Research Institute, Hamilton, ON, Canada
| | - Franck Boccara
- Sorbonne Université, GRC n°22, C2MV-Complications Cardiovasculaires et Métaboliques chez les patients vivant avec le Virus de l'immunodéficience humaine, Inserm UMR_S 938, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), Cardiologie, Hôpital Saint Antoine AP-HP, Paris, France
| | - Bertrand Cariou
- Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, F-44000, Nantes, France
| | - Guillaume Mahé
- Vascular Medicine Unit, CHU Rennes, Univ Rennes, CIC1414, M2S-EA 7470, Rennes, France
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Li CY, Wang WT, Ma SH, Lo LW, Wu CY, Chang WC, Chen YJ, Chen TL. Association of proprotein convertase subtilisin/kexin type-9 inhibitors with risk of nonmelanoma skin cancer: a retrospective cohort study. Br J Dermatol 2025; 192:697-705. [PMID: 39585798 DOI: 10.1093/bjd/ljae438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 11/03/2024] [Accepted: 11/03/2024] [Indexed: 11/27/2024]
Abstract
BACKGROUND Growing evidence has shown that cholesterol metabolism abnormalities involve carcinogenesis. Proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors have been reported to inhibit tumour progression and prevent ultraviolet-related skin damage. OBJECTIVES To investigate the association of PCSK9 inhibitors with the risk of nonmelanoma skin cancer (NMSC). METHODS This retrospective cohort study analysed data from the US Collaborative Network in the TriNetX database. Adults aged ≥ 40 years with atherosclerotic cardiovascular disease (ASCVD) under statin therapy between 2016 and 2022 were identified. A target trial design was used to compare the risk of NMSC, including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), in patients also treated with PCSK9 inhibitors or continuing statin treatment (the control group). Each head-to-head comparison involved propensity score matching. Hazard ratios (HRs) were estimated using Cox proportional hazard models. Stratified analyses based on age, sex, Fitzpatrick skin type and immune status were also performed. RESULTS A total of 73 636 patients with ASCVD were analysed. Compared with the control group, patients with ASCVD initiating PCSK9 inhibitors had lower risks of developing NMSC [HR 0.78, 95% confidence interval (CI) 0.71-0.87], BCC (HR 0.78, 95% CI 0.69-0.89) and cSCC (HR 0.79, 95% CI 0.67-0.93). Subanalyses revealed a reduced risk of NMSC with each PCSK9 inhibitor, namely evolocumab and alirocumab. Stratified analyses showed similar results in patients aged 65-79 years, those older than 80 years and in men. CONCLUSIONS Our study indicated that patients with ASCVD taking PCSK9 inhibitors have a lower risk of incident NMSC than those not taking PCSK9 inhibitors.
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Affiliation(s)
- Cheng-Yuan Li
- Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chao Tung University, Taipei, Taiwan
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Ting Wang
- School of Medicine, National Yang Ming Chao Tung University, Taipei, Taiwan
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taiwan
| | - Sheng-Hsiang Ma
- Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chao Tung University, Taipei, Taiwan
- Department of Public Health, Institute of Public Health, National Yang Ming Chao Tung University, Taipei, Taiwan
| | - Li-Wei Lo
- Cardiovascular Center, Department of Internal Medicine, Taipei Veterans General Hospital, Taiwan
- Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chen-Yi Wu
- Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chao Tung University, Taipei, Taiwan
- Department of Public Health, Institute of Public Health, National Yang Ming Chao Tung University, Taipei, Taiwan
| | - Wei-Chuan Chang
- Epidemiology and Biostatistics Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yi-Ju Chen
- Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Tai-Li Chen
- Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chao Tung University, Taipei, Taiwan
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Sriphrapradang C, Thakkinstian A, Chinthammit R, Nayak G. Characterization of treatment intensified (add-on to metformin) adults with type 2 diabetes in Thailand: A cross-sectional real-world study (CONVERGE). J Diabetes Investig 2025. [PMID: 40077899 DOI: 10.1111/jdi.14409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/24/2024] [Accepted: 01/07/2025] [Indexed: 03/14/2025] Open
Abstract
OBJECTIVE The CONVERGE (Cardiovascular Outcomes and Value in the Real-World with GLP-1RAs) study characterized demographics, clinical characteristics, and medication use in treatment-intensified (add-on to metformin) adults with type 2 diabetes (T2D) in Thailand. METHODS A retrospective cross-sectional study of data from medical records (Jul 26, 2013, to Dec 31, 2017) was descriptively summarized for overall population and subgroups defined by glucose-lowering agent (GLA) classes. RESULTS Data from 1,000 adults were collected in reverse chronological order. At baseline, the mean (SD) age was 60 (12) years, HbA1c was 8.0%, and the median (IQR) T2D duration was 1.0 (0.2-2.4) years. Patients taking SGLT2-is (sodium glucose cotransporter-2 inhibitors) had a longer T2D duration (1.8 years, 0.8-3.2), GLP-1RAs (glucagon-like peptide-1 receptor agonists) had a higher body mass index of 32.0 (8.84) kg/m2, and insulin subgroup had a higher HbA1c 8.5% (7.5-10.1). The utilization of GLP-1 RAs/SGLT-2is was low (1.5% and 6%, respectively). Among the subgroups, most patients in the GLP-1RA (80.0%) and insulin subgroup (81.3%) receiving 3/≥4 GLAs. The most frequently prescribed GLAs post-metformin were sulfonylureas (45.2%) and dipeptidyl peptidase-4 inhibitors (39.4%). Overall, 90% received ≥1 cardiovascular (CV) medication; lipid-lowering agents (78%) were the most prescribed. CONCLUSIONS These results indicate low utilization of GLAs with CV benefits, attributed to a lack of CV benefit data during the study period and partial reimbursement implementation. Future studies must identify barriers to adoption and estimate the usage of these GLAs with CV benefits as more evidence becomes available on positive CV outcomes to improve patient care in Thailand.
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Affiliation(s)
- Chutintorn Sriphrapradang
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Ammarin Thakkinstian
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Di Fusco SA, Volpe M, Nardi F, Matteucci A, Aquilani S, Marino G, Aiello A, Colivicchi F. Reducing LDL-Cholesterol to Very Low Levels: Sailing Between Established Benefits and Potential Risks. High Blood Press Cardiovasc Prev 2025; 32:139-149. [PMID: 39998740 DOI: 10.1007/s40292-025-00708-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
In view of the growing evidence supporting more marked reductions of low-density lipoprotein cholesterol (LDL-C), according to the concept of "the lower is better" and with the availability of powerful and well tolerated lipid-lowering drugs, physicians are facing today with the clinical management of patients with very low LDL-C levels. The fear of potential risks linked to extreme reductions of LDL-C down to very low levels may lead to the de-escalation of treatments with consequent paradoxical unfavorable consequences due to the exposure to a higher cardiovascular risk. The aim of this review is to point out evidence of very low LDL-C clinical impact, with a focus on potential adverse effects. Research on cholesterol homeostasis has identified complex mechanisms which guarantee cell functions even when circulating cholesterol levels are very low. The almost complete self-sufficiency of the human body in terms of cholesterol needs is confirmed by evidence derived from genetically determined models with very low LDL-C levels. Studies on the potential harm of lowering LDL-C to very low concentrations do not confirm an increased risk of cancer or neurodegenerative disease attributable to lipid-lowering treatments, whereas evidence suggests a potential benefit in these settings. A potential increased risk of hemorrhagic stroke has been reported, suggesting tight monitoring and control of blood pressure should be implemented in patients with very low LDL-C levels. With regard to statin treatment, a dose-dependent increased risk of newly diagnosed diabetes has been reported. This adverse effect has not been found with more recently approved lipid-lowering drugs.
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Affiliation(s)
- Stefania Angela Di Fusco
- Clinical and Rehabilitation Cardiology Unit, Emergency Department, San Filippo Neri Hospital, ASL Rome 1, Rome, Italy.
- Clinical and Rehabilitation Cardiology Unit, San Filippo Neri Hospital, Via Martinotti 20, 00135, Rome, Italy.
| | - Massimo Volpe
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Via di Grottarossa 1035, 00189, Rome, Italy
- IRCCS San Raffaele Roma, Rome, Italy
| | | | - Andrea Matteucci
- Clinical and Rehabilitation Cardiology Unit, Emergency Department, San Filippo Neri Hospital, ASL Rome 1, Rome, Italy
| | - Stefano Aquilani
- Clinical and Rehabilitation Cardiology Unit, Emergency Department, San Filippo Neri Hospital, ASL Rome 1, Rome, Italy
| | - Gaetano Marino
- Clinical and Rehabilitation Cardiology Unit, Emergency Department, San Filippo Neri Hospital, ASL Rome 1, Rome, Italy
| | - Alessandro Aiello
- Clinical and Rehabilitation Cardiology Unit, Emergency Department, San Filippo Neri Hospital, ASL Rome 1, Rome, Italy
| | - Furio Colivicchi
- Clinical and Rehabilitation Cardiology Unit, Emergency Department, San Filippo Neri Hospital, ASL Rome 1, Rome, Italy
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Da Dalt L, Baragetti A, Norata GD. Targeting PCSK9 beyond the liver: evidence from experimental and clinical studies. Expert Opin Ther Targets 2025; 29:137-157. [PMID: 40110803 DOI: 10.1080/14728222.2025.2482545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 03/06/2025] [Accepted: 03/18/2025] [Indexed: 03/22/2025]
Abstract
INTRODUCTION PCSK9 has been widely studied as a target for lipid-lowering as its inhibition increases LDLR recycling on the surface of hepatocytes, which promotes the catabolism of LDL particles. PCSK9 can be synthesized in extra-hepatic tissues, including in the brain, the pancreas, and the heart, and in immune cells. It is of interest to understand whether the extra-hepatic effects observed when PCSK9 is genetically inhibited by naturally occurring mutations are also recapitulated by pharmacology. AREA COVERED Genetics studies reported an increased risk of developing new-onset diabetes, ectopic adiposity, and reduced immune-inflammatory responses with PCSK9 deficiency. However, these aspects were not observed in clinical trials and data from real-world medicine with monoclonal antibodies (mAbs) and gene silencing approaches targeting PCSK9. EXPERT OPINION It is possible that the biological adaptations occurring when PCSK9 is inhibited lifelong, as in the case of genetic studies, could explain the discrepancy with the data obtained by clinical studies testing the pharmacological inhibition of PCSK9. Also, PCSK9 mAbs have been in use for 12 years; thus, probably, in this time window, a pharmacological reduction of circulating PCSK9 up to 80-90% does not lead to changes other than the impressive reduction in LDL-C and in CVD events.
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Affiliation(s)
- Lorenzo Da Dalt
- Department of Pharmacological Sciences 'Rodolfo Paoletti', University of Milan, Milano, Italy
| | - Andrea Baragetti
- Department of Pharmacological Sciences 'Rodolfo Paoletti', University of Milan, Milano, Italy
| | - Giuseppe Danilo Norata
- Department of Pharmacological Sciences 'Rodolfo Paoletti', University of Milan, Milano, Italy
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Moura FA, Kamanu FK, Wiviott SD, Giugliano RP, Udler MS, Florez JC, Ellinor PT, Sabatine MS, Ruff CT, Marston NA. Type 2 diabetes genetic risk and incident diabetes across diabetes risk enhancers. Diabetes Obes Metab 2025; 27:1287-1295. [PMID: 39696834 DOI: 10.1111/dom.16123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/22/2024] [Accepted: 11/25/2024] [Indexed: 12/20/2024]
Abstract
AIMS To evaluate the predictive value of a contemporary type 2 diabetes (T2D) polygenic score (PGS) in detecting incident diabetes across a range of diabetes risk factors. MATERIALS AND METHODS We analysed participants in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial (ClinicalTrials.gov, number NCT0176463), which compared the efficacy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab versus placebo in lowering cardiovascular outcomes in participants with stable atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg/dL (1.8 mmol/L) or higher who were receiving statin therapy. Genetic risk was characterized using a previously validated T2D PGS based on ~1.2 million single-nucleotide polymorphisms. PGS was analysed continuously and categorically as high (top 20% of the PGS) and low to intermediate (lower 80% of the PGS). The effect of evolocumab on incident diabetes in patients without diabetes at baseline was also assessed. HbA1c was measured at baseline and every 24 weeks thereafter, while FPG was measured at baseline, week 12, week 24 and every 24 weeks thereafter. Potential cases of incident diabetes were adjudicated centrally. Hazards ratios (HRs) for incident diabetes were adjusted for baseline characteristics and ancestry. RESULTS Among 9388 participants, the mean age was 63 ± 9 years and 22.7% were women, with median HbA1c 39 mmol/mol (36 mmol/mol - 41 mmol/mol; 5.7% [5.4%-5.9%]) and mean body mass index (BMI) 28.7 ± 5 kg/m2. Diabetes developed in 690 participants (7.3%) during 2.3 years of median follow-up. T2D PGS predicted incident T2D (HR per 1-SD 1.22, 95% CI 1.14-1.32, p < 0.001). The rates of incident T2D in the high and low to intermediate genetic risk categories were 12.1% versus 6.8%, respectively (HR 1.43 95% CI 1.20-1.70, p < 0.001). Notably, high T2D genetic risk had greater predictive strength among individuals with lower HbA1c (P-int = 0.0499) and lower BMI (P-int = 0.004). CONCLUSIONS The T2D polygenic score serves as an independent predictor of incident diabetes, particularly among individuals with lower distribution of traditional risk factors.
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Affiliation(s)
- Filipe A Moura
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
- VA Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Frederick K Kamanu
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Stephen D Wiviott
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Robert P Giugliano
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Miriam S Udler
- Center for Genomic Medicine and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Jose C Florez
- Center for Genomic Medicine and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Patrick T Ellinor
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Marc S Sabatine
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Christian T Ruff
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Nicholas A Marston
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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9
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Nicholls SJ, Nelson AJ. Achieving More Optimal Lipid Control with Non-Statin Lipid Lowering Therapy. Curr Atheroscler Rep 2025; 27:32. [PMID: 39954169 PMCID: PMC11829850 DOI: 10.1007/s11883-025-01280-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2025] [Indexed: 02/17/2025]
Abstract
PURPOSE OF REVIEW The use of statins has transformed approaches to the prevention of cardiovascular disease. However, many patients remain at a major risk of experiencing cardiovascular events, due to a range of factors including suboptimal control of low-density lipoprotein cholesterol (LDL-C). Accordingly, there is an ongoing need to develop additional strategies, beyond the use of statins, to achieve more effective reductions in cardiovascular risk. RECENT FINDINGS Genomic studies have implicated the causal role of LDL in atherosclerosis and identified that polymorphisms influencing factors involved in lipid metabolism influence both the level of LDL-C and cardiovascular risk. These findings have highlighted the potential for cardiovascular benefit from development of therapies targeting these factors and incremental benefit when used in combination with statins. Clinical trials have demonstrated that these new agents have favourable effects on both atherosclerotic plaque and cardiovascular events. Additional work has sought to improve intensification of statin therapy and adherence with lipid lowering therapy, to achieve more effective cardiovascular prevention via lipid lowering. Emerging therapies, beyond statins, have the potential to optimise lipid levels and play an effective role in the prevention of cardiovascular disease.
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Affiliation(s)
- Stephen J Nicholls
- Victorian Heart Institute, Monash University, 631 Blackburn Rd, Clayton, Melbourne, Australia.
| | - Adam J Nelson
- Victorian Heart Institute, Monash University, 631 Blackburn Rd, Clayton, Melbourne, Australia
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10
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Tomlinson B, Chan P. Exploring emerging pharmacotherapies for type 2 diabetes patients with hypertriglyceridemia. Expert Opin Pharmacother 2025; 26:279-289. [PMID: 39794291 DOI: 10.1080/14656566.2025.2451752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 01/07/2025] [Indexed: 01/13/2025]
Abstract
INTRODUCTION Atherogenic dyslipidemia with increased triglycerides, low high-density lipoprotein cholesterol levels and increased small dense low-density lipoprotein (LDL) particles is a major risk factor contributing to the increased cardiovascular (CV) risk in patients with type 2 diabetes (T2D). This is regarded as a residual risk after achieving target levels of LDL cholesterol. AREAS COVERED This article reviews the novel therapies to reduce triglycerides in patients with T2D. These were identified by a PubMed search and mainly focus on pemafibrate and the drugs targeting apolipoprotein C3 (apoC3) and angiopoietin-like 3 (ANGPTL3). EXPERT OPINION Current therapies to reduce triglycerides in patients with T2D include fibrates and omega-3 fatty acids but these are often not sufficient and the evidence for CV benefits is limited. Pemafibrate was effective in reducing triglycerides in patients with T2D but did not reduce CV events in the PROMINENT study. Inhibitors of apoC3 are effective in reducing triglycerides even in familial chylomicronaemia syndrome and olezarsen and plozasiran in this group are being studied in patients with combined hyperlipidemia. The ANGPTL3 inhibitor evinacumab has been approved for homozygous familial hypercholesterolemia, and other ANGPTL3 inhibitors may prove to be useful to reduce triglycerides in T2D.
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Affiliation(s)
- Brian Tomlinson
- Faculty of Medicine, Macau University of Science & Technology, Macau, China
| | - Paul Chan
- Division of Cardiology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
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11
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Pedro-Botet J, Arrieta F, Botana M, Gimeno-Orna JA, Martínez-Montoro JI, Ortega-Martínez de Victoria E, Ribalta J, Sánchez-Margalet V, Pérez-Pérez A. Lipid-lowering drug therapy for reducing cardiovascular risk in diabetes. A clinical view of the Cardiovascular Disease Working Group of the Spanish Diabetes Society. ENDOCRINOL DIAB NUTR 2025; 72:101523. [PMID: 39924389 DOI: 10.1016/j.endien.2025.101523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/21/2024] [Accepted: 09/03/2024] [Indexed: 02/11/2025]
Abstract
Patients with type 2 diabetes mellitus (T2DM) managed in both hospital and out-ofhospital settings usually have a high/very high cardiovascular risk, with a high burden of cardiovascular disease. All this justifies that the reduction of low-density lipoprotein cholesterol is the main therapeutic goal in T2DM. However, residual cardiovascular risk is very prevalent in T2DM, and is usually associated with atherogenic dyslipidemia and hyperlipoproteinemia(a); therefore, it is also necessary to reverse these lipoprotein abnormalities to achieve effective cardiovascular prevention. Given the considerable armamentarium of lipid-lowering drugs currently available, the Cardiovascular Disease Working Group of the Spanish Diabetes Society has considered it appropriate to carry out a narrative review and update of the effectiveness of these lipid-lowering drugs in the population with T2DM taking into account their effect on the lipoprotein profile and their potential impact on glycemic control.
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Affiliation(s)
- Juan Pedro-Botet
- Unidad de Lípidos y Riesgo Vascular, Hospital del Mar, Barcelona, Spain; Departamento de Medicina, Universidad Autónoma de Barcelona, Barcelona, Spain.
| | - Francisco Arrieta
- Servicio de Endocrinología y Nutrición, Hospital Universitario Rey Juan Carlos, Madrid, Spain
| | - Manuel Botana
- Sección de Endocrinología, Hospital Universitario Lucus Augusti, Lugo, Spain
| | - José A Gimeno-Orna
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - José I Martínez-Montoro
- Servicio de Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Málaga, Spain; Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma Bionand, Málaga, Spain
| | - Emilio Ortega-Martínez de Victoria
- Servicio de Endocrinología y Nutrición, Hospital Clínic, Madrid, Spain; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Josep Ribalta
- Departament de Medicina i Cirurgia, Unitat de Recerca en Lípids i Arteriosclerosi (URLA), Universitat Rovira i Virgili, Reus, Spain; Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Víctor Sánchez-Margalet
- Departamento de Bioquímica Médica y Biología Molecular, e Inmunología, Facultad de Medicina, Hospital Universitario Virgen Macarena, Universidad de Sevilla, Sevilla, Spain
| | - Antonio Pérez-Pérez
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Servicio de Endocrinología y Nutrición, Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
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12
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Alraddadi SI, Almodaimegh H, Kharbosh A, Alharbi H, Fathelrahman AI, Alsheikh MY, Alfehaid L. Evolocumab safety and efficacy in hypercholesteremia patients with or without diabetes: a retrospective real-world analysis. Diabetol Metab Syndr 2025; 17:41. [PMID: 39891190 PMCID: PMC11783923 DOI: 10.1186/s13098-025-01587-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 01/10/2025] [Indexed: 02/03/2025] Open
Abstract
BACKGROUND Proprotein convertase subtilisin/kexin type 9 inhibitors effectively reduce LDL cholesterol and adverse cardiovascular events with a safety profile comparable to a placebo. Limited real-world data exists on their effectiveness in different patient groups. This study evaluated evolocumab's efficacy and safety in hypercholesteremia patients with and without diabetes. METHOD In a large tertiary hospital in Saudi Arabia, patients aged 18 and above who initiated evolocumab therapy were screened for eligibility between January 2017 and July 2023. All patients who had been on maximally tolerated statin and ezetimibe therapy for at least 4 months before starting evolocumab were included. The included participants were then divided into diabetic and non-diabetic groups and assessed for evolocumab's efficacy and safety. Efficacy was measured by LDL-C reduction and target achievement, while safety was assessed by examining glycemic control changes, new-onset diabetes (NOD) and hepatic enzyme levels. Data analysis included descriptive and comparative methods, with significance set at p < 0.05. RESULTS A total of 151 patients were included, with an average age of 51.77 years. The majority of patients were male (67.6%) and obese (81.5%). Around 55% had diabetes, and 63% had established atherosclerotic cardiovascular disease at baseline. During a mean follow-up period of 13.17 months, the average reduction in LDL-C from baseline was - 34.21, - 28.66, and - 39.61% for the overall cohort, non-diabetic patients, and diabetic patients, respectively. In the overall cohort, 34.4 and 24.5% reached the target LDL-C levels of less than 1.4 mmol/L (55 mg/dL) and less than 1.8 mmol/L (70 mg/dL), respectively. Worsening of glycemic control (HbA1C increase > 0.5) was observed in 25.83% of the overall cohort, 16.18% of non-diabetics, and 33.74% of diabetics. An HbA1C increase > 1 was observed in 13.25% of the overall cohort, 2.94% in non-diabetics and 21.69% in diabetics. Five patients (3.3%) developed NOD. CONCLUSION The study demonstrated that the addition of evolocumab to maximally tolerated statin and ezetimibe therapy reduced LDL-C levels but with a smaller average reduction and a lower proportion of patients achieving recommended LDL-C targets than in landmark clinical trials. Additionally, there was a potential negative effect on glycemic control, warranting further investigation.
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Affiliation(s)
- Sultan Ibrahim Alraddadi
- Pharmaceutical Care Department, King Abdulaziz Medical City, Prince Mutib Ibn Abdullah Ibn Abdulaziz Rd, Ar Rimayah,, 11426, Riyadh, Saudi Arabia.
- Department of Pharmacy Practice, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
| | - Hind Almodaimegh
- Pharmaceutical Care Department, King Abdulaziz Medical City, Prince Mutib Ibn Abdullah Ibn Abdulaziz Rd, Ar Rimayah,, 11426, Riyadh, Saudi Arabia
- Department of Pharmacy Practice, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Abdullah Kharbosh
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Hadeel Alharbi
- Pharmaceutical Care Department, King Abdulaziz Medical City, Prince Mutib Ibn Abdullah Ibn Abdulaziz Rd, Ar Rimayah,, 11426, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | | | - Mona Yaser Alsheikh
- Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Lama Alfehaid
- Pharmaceutical Care Department, King Abdulaziz Medical City, Prince Mutib Ibn Abdullah Ibn Abdulaziz Rd, Ar Rimayah,, 11426, Riyadh, Saudi Arabia
- Department of Pharmacy Practice, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
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13
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Xu L, Cao Y. The impact of body mass index on the relationship between psoriasis and Osteopenia: a mediating analysis based on NHANES (2003-2006). Arch Dermatol Res 2025; 317:268. [PMID: 39821427 DOI: 10.1007/s00403-025-03805-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 12/09/2024] [Accepted: 01/03/2025] [Indexed: 01/19/2025]
Abstract
The relationship between psoriasis and osteopenia remains undetermined. Patients with psoriasis tend to have a higher Body Mass Index (BMI) compared to those without the condition. While it appears plausible that BMI could mediate this association, further study is required to confirm this hypothesis. The objective of this study is to ascertain whether BMI plays a role in influencing the impact of psoriasis on osteopenia. This study encompassed 2,624 participants from the National Health and Nutrition Examination Survey (NHANES) conducted between 2003 and 2006. The condition of psoriasis was self-reported, while osteopenia was assessed based on bone mineral density (BMD) range and self-reported osteoporosis. BMI was derived from NHANES body measurement data. Weighted logistic regression analyses and mediation analysis were utilized to elucidate the relationship. Subgroup differences were further explored in the absence of a clear relationship. A positive correlation was observed between psoriasis and osteopenia. Furthermore, BMI was positively related to psoriasis and negatively related to osteopenia. Additionally, BMI served as a mediator in the relationship between psoriasis and osteopenia, accounting for 20.8% of the variance. Specifically, the mediating influence of BMI exhibited variations based on diabetes status and gender. In conclusion, Controlling BMI could potentially mitigate the impact of psoriasis on osteopenia. Therefore, we advocate for a rigorous focus on bone health in individuals with psoriasis, particularly among males and non-diabetic populations.
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Affiliation(s)
- Lan Xu
- First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310000, China
| | - Yi Cao
- Department of Dermatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, Zhejiang, 310006, China.
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14
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Kim S, Subramanian S. Approach to Lipid Management in the Patient with Diabetes. J Clin Endocrinol Metab 2025:dgaf018. [PMID: 39797609 DOI: 10.1210/clinem/dgaf018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 12/13/2024] [Accepted: 01/09/2025] [Indexed: 01/13/2025]
Abstract
Diabetes is associated with increased atherosclerotic cardiovascular disease (ASCVD) risk, a leading cause of morbidity and mortality. Disordered lipid metabolism is a major contributor to ASCVD risk in diabetes. Dyslipidemia in type 2 diabetes is characterized by hypertriglyceridemia, low HDL cholesterol and the presence of small, dense LDL particles. Statins have demonstrated longstanding benefit for reducing ASCVD risk in individuals with diabetes. Newer agents for add-on therapies to statins are now available for additional cardiovascular risk reduction. In this clinical overview, we review the pathogenesis of dyslipidemia in both types 1 and 2 diabetes and provide an update on the management of lipids in the individual with diabetes. We discuss the importance of appropriate risk stratification, individualized treatment selection, and the need to avoid therapy inertia to mitigate cardiovascular risk. We will also address lipid-related effects of glycemic lowering therapies.
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Affiliation(s)
- Stephanie Kim
- Clinical Assistant Professor, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle WA
| | - Savitha Subramanian
- Professor of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle WA
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15
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Brandts J, Müller-Wieland D. Debate: Lipid-lowering Therapies and Diabetes Development. Curr Atheroscler Rep 2025; 27:24. [PMID: 39775321 PMCID: PMC11711849 DOI: 10.1007/s11883-024-01270-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 01/11/2025]
Abstract
PURPOSE OF REVIEW This review explores the relationship between lipid-lowering therapies, particularly statins, and the risk of new-onset diabetes (NOD). It examines the underlying mechanisms and evaluates whether other lipid-lowering agents present similar risks. RECENT FINDINGS Recent meta-analyses further underscore a dose-dependent increase in NOD risk with statin therapy, particularly with high-intensity statins. In contrast to other LDL-cholesterol lowering drugs and their impact on lipid metabolism in the liver, genetic and experimental studies indicate that statins may impair insulin secretion through various mechanisms, including alterations in small G protein function, calcium signaling, and cholesterol homeostasis in pancreatic beta cells. This might contribute to the increased risk of NOD. Statins effectively reduce cardiovascular events but increase the risk of NOD, potentially via intracellular pathways affecting liver and beta-cell function. Despite the cardiovascular benefits of statins, personalized treatment strategies and alternative lipid-lowering therapies may offer safer options for patients at risk of diabetes, potentially shaping future clinical guidelines and therapeutic approaches.
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Affiliation(s)
- Julia Brandts
- Department of Internal Medicine I, University Hospital Aachen, Pauwelsstraße, 30 52074, Aachen, Germany
- Imperial Centre for Cardiovascular Disease Prevention, School of Public Health, Imperial College London, London, UK
| | - Dirk Müller-Wieland
- Department of Internal Medicine I, University Hospital Aachen, Pauwelsstraße, 30 52074, Aachen, Germany.
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16
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Rosoff DB, Wagner J, Jung J, Pacher P, Christodoulides C, Davey Smith G, Ray D, Lohoff FW. Multiomic Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations. Diabetes 2025; 74:120-130. [PMID: 39418486 DOI: 10.2337/db24-0451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024]
Abstract
The prevalence of type 2 diabetes (T2D) varies among populations of different races/ethnicities. The influence of genetically proxied LDL cholesterol lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA reductase (HMGCR) on T2D in non-European populations is not well established. A drug target Mendelian randomization approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and Europe (EUR). Our study did not find relationships between genetically proxied PCSK9 inhibition and T2D risk in the EAS (odds ratio [OR] 1.02; 95% CI 0.95-1.10), SAS (1.05; 0.97-1.14), HISP (1.03; 0.94-1.12), or EUR population (1.04; 0.98-1.11). However, in the AFR population, primary analyses suggested an increased risk of T2D resulting from PCSK9 inhibition (OR 1.53; 95% CI 1.058-2.22; P = 0.024), although this was not supported in sensitivity analyses. Genetically proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR 1.44; 95% CI 1.30-1.61; P = 9.8 × 10-12), EAS (1.36; 1.22-1.51; P = 4.2 × 10-10), and EUR populations (1.52; 1.21-1.90; P = 3.3 × 10-4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-EUR populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in SAS, EAS, and EUR cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Daniel B Rosoff
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K
| | - Josephin Wagner
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
| | - Jeesun Jung
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
| | - Constantinos Christodoulides
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K
| | - George Davey Smith
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K
| | - David Ray
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K
- National Institute for Health and Care Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, U.K
| | - Falk W Lohoff
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
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17
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ElSayed NA, McCoy RG, Aleppo G, Balapattabi K, Beverly EA, Briggs Early K, Bruemmer D, Das SR, Echouffo-Tcheugui JB, Ekhlaspour L, Garg R, Khunti K, Kosiborod MN, Lal R, Lingvay I, Matfin G, Pandya N, Pekas EJ, Pilla SJ, Polsky S, Segal AR, Seley JJ, Stanton RC, Bannuru RR. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2025. Diabetes Care 2025; 48:S207-S238. [PMID: 39651970 PMCID: PMC11635050 DOI: 10.2337/dc25-s010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2024]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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18
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Zhang Q, Miao M, Cao S, Liu D, Cao Z, Bai X, Yin Y, Jin S, Dong L, Zheng M. PCSK9 promotes vascular neointimal hyperplasia through non-lipid regulation of vascular smooth muscle cell proliferation, migration, and autophagy. Biochem Biophys Res Commun 2025; 742:151081. [PMID: 39632291 DOI: 10.1016/j.bbrc.2024.151081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/18/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
We aim to explore the impact of Proprotein convertase subtilisin-kexin type 9 (PCSK9) and its inhibitor evolocumab on neointimal hyperplasia. Wild type and PCSK9 knockout (PCSK9-/-) mice were subjected to ligation of the common carotid artery, with or without subcutaneous injection of evolocumab. Mouse aortic vascular smooth muscle (MOVAS) cells were pretreated with evolocumab or under siRNA-mediated suppression of PCSK9, and then exposed to platelet-derived growth factor type BB(PDGF-BB), a major promoter of MOVAS transformation to a proliferative phenotype. PCSK9 was upregulated in ligated carotid arteries and PDGF-BB-treated MOVAS cells. PCSK9-/- mice showed decreased intimal area and intimal/media area ratio, downregulation of proliferation and autophagy, which was coincidence with wild-type mice treated with evolocumab. In MOVAS cells fortified with evolocumab or silencing of PCSK9, PCNA, Beclin1, p62, LC3 were downregulated, additionally, EdU-positive cells decreased, cell viability reduced, migration ability was weakened, and the number of autophagosomes and autolysosomes decreased after the treatment. We also identified the PI3K/AKT/mTOR signaling molecules as potential PCSK9 targets mediating proliferative effect in MOVAS cells. To sum up, our results suggest that PCSK9 has intrinsic properties to promote proliferation, migration and autophagy in VSMCs independent of its lipid-regulating role. The proliferative effects of PCSK9 may be mediated by the PI3K/AKT/mTOR signaling pathway. These data provide additional evidence for PCSK9i in cardiovascular disease beyond the low-density lipoprotein (LDL)-lowering benefit.
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MESH Headings
- Animals
- Autophagy
- Cell Proliferation
- Proprotein Convertase 9/metabolism
- Proprotein Convertase 9/genetics
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Cell Movement
- Neointima/metabolism
- Neointima/pathology
- Mice
- Hyperplasia/metabolism
- Hyperplasia/pathology
- Antibodies, Monoclonal, Humanized/pharmacology
- Male
- Mice, Knockout
- Mice, Inbred C57BL
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Becaplermin/metabolism
- Becaplermin/pharmacology
- Signal Transduction
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Affiliation(s)
- Qian Zhang
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, Hebei, China; Hebei Key Laboratory of Heart and Metabolism, Shijiazhuang, 050031, Hebei, China
| | - Mengdan Miao
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, Hebei, China; Hebei Key Laboratory of Heart and Metabolism, Shijiazhuang, 050031, Hebei, China; Department of Cardiology, Handan First Hospital, Handan, 056000, Hebei, China
| | - Shanhu Cao
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, Hebei, China; Hebei Key Laboratory of Heart and Metabolism, Shijiazhuang, 050031, Hebei, China
| | - Da Liu
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, Hebei, China; Hebei Key Laboratory of Heart and Metabolism, Shijiazhuang, 050031, Hebei, China
| | - Zelong Cao
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, Hebei, China; Hebei Key Laboratory of Heart and Metabolism, Shijiazhuang, 050031, Hebei, China
| | - Xiaoyu Bai
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, Hebei, China; Hebei Key Laboratory of Heart and Metabolism, Shijiazhuang, 050031, Hebei, China
| | - Yajuan Yin
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, Hebei, China; Hebei Key Laboratory of Heart and Metabolism, Shijiazhuang, 050031, Hebei, China
| | - Sheng Jin
- Department of Physiology, Hebei Medical University, 361 zhongshan Road, Shijiazhuang, 050017, China
| | - Lihua Dong
- Department of Biochemistry and Molecular Biology, Hebei Medical University, 050017, Shijiazhuang, China
| | - Mingqi Zheng
- Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, Hebei, China; Hebei Key Laboratory of Heart and Metabolism, Shijiazhuang, 050031, Hebei, China.
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19
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Lan NSR, Dwivedi G, Fegan PG, Game F, Hamilton EJ. Unravelling the cardio-renal-metabolic-foot connection in people with diabetes-related foot ulceration: a narrative review. Cardiovasc Diabetol 2024; 23:437. [PMID: 39696281 PMCID: PMC11657306 DOI: 10.1186/s12933-024-02527-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 11/26/2024] [Indexed: 12/20/2024] Open
Abstract
Diabetes-related foot ulceration (DFU), a serious but preventable complication of diabetes, is a leading cause of hospitalisation, lower extremity amputation and disability worldwide. People with DFU have a greater burden of cardiovascular risk factors, heart failure and chronic kidney disease, resulting in over two-fold higher risk of cardiovascular death compared with people with diabetes without DFU. Here, we propose a "cardio-renal-metabolic-foot" connection in people with diabetes based on shared pathophysiological mechanisms linking DFU with cardiovascular and renal disease. Whilst these mechanistic links remain to be fully elucidated, systemic inflammation and infection in the context of DFU are postulated as key mediators in the development, and progression of, cardiovascular and renal disease. However, cardiovascular and renal disease are also implicated in the pathogenesis of DFU, highlighting the multi-directional interplay between conditions. The impact of screening, prevention, and early management of cardiovascular complications associated with DFU requires further research. Multi-modality cardiac imaging could play a role in unravelling disease mechanisms leading to novel therapeutic strategies, as well as facilitating personalised risk assessment and management. Recent clinical trials have transformed the therapeutic landscape for people with type 2 diabetes, by demonstrating that sodium glucose co-transporter 2 inhibitors, glucagon-like peptide-1 agonists and non-steroidal mineralocorticoid receptor antagonists improve cardiovascular and renal outcomes. Although dedicated research in people with DFU is warranted, these therapies could target multiple facets of the "cardio-renal-metabolic-foot" connection. The holistic, person-centred approach to managing DFU should incorporate new multidisciplinary models of care focusing on the prevention and management of cardiovascular and kidney disease.
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Affiliation(s)
- Nick S R Lan
- Centre of Excellence for Cardiometabolic Health, Fiona Stanley Hospital, Perth, Australia
- Department of Cardiology, Fiona Stanley Hospital, Perth, Australia
- Medical School, The University of Western Australia, Perth, Australia
- Harry Perkins Institute of Medical Research, Perth, Australia
| | - Girish Dwivedi
- Centre of Excellence for Cardiometabolic Health, Fiona Stanley Hospital, Perth, Australia
- Department of Cardiology, Fiona Stanley Hospital, Perth, Australia
- Medical School, The University of Western Australia, Perth, Australia
- Harry Perkins Institute of Medical Research, Perth, Australia
| | - P Gerry Fegan
- Centre of Excellence for Cardiometabolic Health, Fiona Stanley Hospital, Perth, Australia
- Medical School, Curtin University, Perth, Australia
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia
| | - Fran Game
- Department of Diabetes and Endocrinology, University Hospitals of Derby and Burton NHS Foundation Trust, Derby, UK
| | - Emma J Hamilton
- Medical School, The University of Western Australia, Perth, Australia.
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia.
- Centre of Excellence Multidisciplinary Diabetes Foot Ulcer Service, Fiona Stanley and Fremantle Hospitals Group, 11 Robin Warren Drive, Murdoch, Perth, Australia.
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20
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Barcia Durán JG, Das D, Gildea M, Amadori L, Gourvest M, Kaur R, Eberhardt N, Smyrnis P, Cilhoroz B, Sajja S, Rahman K, Fernandez DM, Faries P, Narula N, Vanguri R, Goldberg IJ, Fisher EA, Berger JS, Moore KJ, Giannarelli C. Immune checkpoint landscape of human atherosclerosis and influence of cardiometabolic factors. NATURE CARDIOVASCULAR RESEARCH 2024; 3:1482-1502. [PMID: 39613875 PMCID: PMC11634783 DOI: 10.1038/s44161-024-00563-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 10/21/2024] [Indexed: 12/01/2024]
Abstract
Immune checkpoint inhibitor (ICI) therapies can increase the risk of cardiovascular events in survivors of cancer by worsening atherosclerosis. Here we map the expression of immune checkpoints (ICs) within human carotid and coronary atherosclerotic plaques, revealing a network of immune cell interactions that ICI treatments can unintentionally target in arteries. We identify a population of mature, regulatory CCR7+FSCN1+ dendritic cells, similar to those described in tumors, as a hub of IC-mediated signaling within plaques. Additionally, we show that type 2 diabetes and lipid-lowering therapies alter immune cell interactions through PD-1, CTLA4, LAG3 and other IC targets in clinical development, impacting plaque inflammation. This comprehensive map of the IC interactome in healthy and cardiometabolic disease states provides a framework for understanding the potential adverse and beneficial impacts of approved and investigational ICIs on atherosclerosis, setting the stage for designing ICI strategies that minimize cardiovascular disease risk in cancer survivors.
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Grants
- R35HL135799 U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- R01HL084312 U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- P30 CA016087 NCI NIH HHS
- 23POST1029885 American Heart Association (American Heart Association, Inc.)
- R35 HL135799 NHLBI NIH HHS
- R01 HL153712 NHLBI NIH HHS
- 20SFRN35210252 American Heart Association (American Heart Association, Inc.)
- R01HL165258 U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- 965509 American Heart Association (American Heart Association, Inc.)
- R01HL153712 U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- R01 HL165258 NHLBI NIH HHS
- R01 HL084312 NHLBI NIH HHS
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
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Affiliation(s)
- José Gabriel Barcia Durán
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Dayasagar Das
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Michael Gildea
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Letizia Amadori
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Morgane Gourvest
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Ravneet Kaur
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Natalia Eberhardt
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Panagiotis Smyrnis
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Burak Cilhoroz
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Swathy Sajja
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Karishma Rahman
- Division of Cardiology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dawn M Fernandez
- Division of Cardiology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Peter Faries
- Department of Surgery, Vascular Division, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Navneet Narula
- Department of Pathology, New York University Grossman School of Medicine, New York University Langone Health, New York, NY, USA
| | - Rami Vanguri
- Division of Precision Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Ira J Goldberg
- Division of Endocrinology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Edward A Fisher
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
- Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA
| | - Jeffrey S Berger
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Kathryn J Moore
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA.
- Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA.
| | - Chiara Giannarelli
- NYU Cardiovascular Research Center, Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA.
- Department of Pathology, New York University Grossman School of Medicine, New York University Langone Health, New York, NY, USA.
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21
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Planchat A, Gencer B, Degrauwe S, Musayeb Y, Roffi M, Iglesias JF. Secondary prevention therapies following percutaneous coronary intervention or acute coronary syndrome in patients with diabetes mellitus. Front Cardiovasc Med 2024; 11:1436332. [PMID: 39650149 PMCID: PMC11621092 DOI: 10.3389/fcvm.2024.1436332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 11/04/2024] [Indexed: 12/11/2024] Open
Abstract
Diabetes mellitus (DM) promotes atherosclerosis, leading to increased risk for cardiovascular morbidity and mortality. Diabetics represent a challenging subset of patients undergoing percutaneous coronary intervention (PCI) or who have experienced an acute coronary syndrome (ACS), a subset characterized by higher rates of recurrent ischemic events compared with non-diabetics. These events are caused by both patient-related accelerated atherosclerotic disease progression and worse stent-related adverse clinical outcomes translating into a higher risk for repeat revascularization. In addition, DM is paradoxically associated with an increased risk of major bleeding following PCI or an ACS. Secondary prevention therapies following PCI or an ACS in diabetic patients are therefore of paramount importance. This mini review focuses on the currently available evidence regarding short- and long-term secondary prevention treatments for diabetic patients undergoing PCI or who have experienced an ACS.
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Affiliation(s)
- Arnaud Planchat
- Department of Cardiology, Geneva University Hospitals, Geneva, Switzerland
| | - Baris Gencer
- Department of Cardiology, Lausanne University Hospital, Lausanne, Switzerland
| | - Sophie Degrauwe
- Department of Cardiology, Geneva University Hospitals, Geneva, Switzerland
| | - Yazan Musayeb
- Department of Cardiology, Geneva University Hospitals, Geneva, Switzerland
| | - Marco Roffi
- Department of Cardiology, Geneva University Hospitals, Geneva, Switzerland
| | - Juan F. Iglesias
- Department of Cardiology, Geneva University Hospitals, Geneva, Switzerland
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22
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Cavender MA, Smith SC. How Can We Increase the Utilization of Evidence-Based Medication After Myocardial Infarction? JAMA Netw Open 2024; 7:e2447075. [PMID: 39602126 DOI: 10.1001/jamanetworkopen.2024.47075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2024] Open
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23
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Elshorbagy A, Lyons AR, Vallejo-Vaz AJ, Stevens CA, Dharmayat KI, Brandts J, Catapano AL, Freiberger T, Hovingh GK, Mata P, Raal FJ, Santos RD, Soran H, Watts GF, Abifadel M, Aguilar-Salinas CA, Alhabib KF, Alkhnifsawi M, Almahmeed W, Alonso R, Al-Rasadi K, Al-Sarraf A, Ashavaid TF, Banach M, Binder CJ, Bourbon M, Brunham LR, Chlebus K, Corral P, Cruz D, Davletov K, Descamps OS, Ezhov M, Gaita D, Groselj U, Harada-Shiba M, Holven KB, Kayikcioglu M, Khovidhunkit W, Lalic K, Latkovskis G, Laufs U, Liberopoulos E, Lima-Martinez MM, Lin J, Maher V, Marais AD, März W, Mirrakhimov E, Miserez AR, Mitchenko O, Nawawi H, Nordestgaard BG, Panayiotou AG, Paragh G, Petrulioniene Z, Pojskic B, Postadzhiyan A, Reda A, Reiner Ž, Reyes X, Sadiq F, Sadoh WE, Schunkert H, Shek AB, Stroes E, Su TC, Subramaniam T, Susekov AV, Tilney M, Tomlinson B, Truong TH, Tselepis AD, Tybjærg-Hansen A, Vázquez AC, Viigimaa M, Vohnout B, Wang L, Yamashita S, Arca M, Averna M, Schreier L, Pang J, Ebenbichler C, Dieplinger H, Innerhofer R, Winhofer-Stöckl Y, Greber-Platzer S, Krychtiuk K, Speidl W, Toplak H, Widhalm K, Stulnig T, Huber K, Höllerl F, Rega-Kaun G, Kleemann L, Mäser M, Scholl-Bürgi S, Säly C, Mayer FJ, Sperone A, Tanghe C, Gérard AC, Pojskic L, Sisic I, Durak Nalbantic A, Ejubovic M, Jannes CE, Pereira AC, Krieger JE, Petrov I, Goudev A, Nikolov F, Tisheva S, Yotov Y, Tzvetkov I, Baass A, Bergeron J, Bernard S, Brisson D, Brunham LR, Cermakova L, Couture P, Francis GA, Gaudet D, Hegele RA, Khoury E, Mancini GJ, McCrindle BW, Paquette M, Ruel I, Iatan I, Cuevas A, Wang X, Meng K, Song X, Yong Q, Jiang T, Liu Z, Duan Y, Hong J, Ye P, Chen Y, Qi J, Liu Z, Li Y, Zhang C, Peng J, Yang Y, Yu W, Wang Q, Yuan H, Cheng S, Jiang L, Chong M, Jiao J, Wu Y, Wen W, Xu L, Zhang R, Qu Y, He J, Fan X, Wang Z, Chow E, Pećin I, Perica D, Symeonides P, Vrablik M, Ceska R, Soska V, Tichy L, Adamkova V, Franekova J, Cifkova R, Kraml P, Vonaskova K, Cepova J, Dusejovska M, Pavlickova L, Blaha V, Rosolova H, Nussbaumerova B, Cibulka R, Vaverkova H, Cibickova L, Krejsova Z, Rehouskova K, Malina P, Budikova M, Palanova V, Solcova L, Lubasova A, Podzimkova H, Bujdak J, Vesely J, Jordanova M, Salek T, Urbanek R, Zemek S, Lacko J, Halamkova H, Machacova S, Mala S, Cubova E, Valoskova K, Burda L, Benn M, Bendary A, Daoud I, Emil S, Elbahry A, Rafla S, Sanad O, Kazamel G, Ashraf DM, Sobhy M, El-Hadidy A, Shafy MA, Kamal S, Bendary M, Talviste G, Christmann J, Dressel A, Fath F, Ferraro C, Frenzke L, Gopon A, Klein I, Pienkowska D, Sietmann T, Sonntag A, Adjan O, Bahrmann P, Baessler A, Barkowski R, Beckerdjian R, Berr C, Birkenfeld A, Böll G, Carstensen A, Demuth I, Finkernagel H, Gouni-Berthold I, Hahmann H, Hamerle M, Halder J, Heide M, Julius U, Kassner U, Katzmann JL, Kirschbaum A, Klose G, Könemann S, König C, König W, Krämer B, Kuprat G, Koschker AC, Krämer B, Kilic Ö, Laufs U, Lindenmeier G, Van de Loo I, Lorenz B, Lorenz E, Löhr B, McChord J, Maslarska M, Methe H, Merkel M, Moussaoui Z, Müller-Kozarez I, Olivier CB, Ong P, Otte B, Parhofer K, Partsch CJ, Paulus M, Pehlivanli S, Pflederer T, Pusl T, Richter V, Rosner S, Sanin V, Schäfer S, Schäfer C, Schatz U, Schirmer S, Schmidt C, Seeger W, Sisovic S, Spens A, Jablonski KS, Stadelmann A, Steinhagen-Thiessen E, Stürzebecher P, Tafelmeier M, Tillack D, Tselmin S, Tünnemann-Tarr A, Vogt A, Beckerath JV, Wilke A, Wolf U, Zemmrich C, Rizos CV, Skoumas I, Tziomalos K, Rallidis L, Kotsis V, Doumas M, Athyros V, Skalidis E, Kolovou G, Kolovou V, Garoufi A, Bilianou E, Koutagiar I, Kiouri E, Antza C, Zacharis E, Attilakos A, Sfikas G, Koumaras C, Anagnostis P, Anastasiou G, Liamis G, Koutsogianni AD, Petkou E, Milionis H, Koulouri A, Prodromiadou E, Karányi Z, Harangi M, Bajnok L, Audikovszky M, Márk L, Benczúr B, Reiber I, Nagy G, Nagy A, Reddy LL, Shah SAV, Ponde CK, Dalal JJ, Sawhney JP, Verma IC, Altaey M, Al-Jumaily K, Rasul D, Abdalsahib AF, Jabbar AA, Al-ageedi M, Abdalsahib AF, Al-ageedi M, Dhamin M, AlFil S, Khadhim F, Miahy S, Agar R, Catapano AL, Arca M, Averna M, Calandra S, Tarugi P, Casula M, Galimberti F, Olmastroni E, Sarzani R, Ferri C, Repetti E, Piro S, Suppressa P, Meregalli G, Borghi C, Muntoni S, Calabrò P, Cipollone F, Purrello F, Pujia A, Passaro A, Marcucci R, Pecchioli V, Pisciotta L, Mandraffino G, Pellegatta F, Mombelli G, Branchi A, Fiorenza AM, Pederiva C, Werba JP, Parati G, Carubbi F, Iughetti L, Fortunato G, Iannuzzi A, Iannuzzo G, Cefalù AB, Biasucci G, Zambon S, Pirro M, Sbrana F, Trenti C, D'Erasmo L, Federici M, Ben MD, Bartuli A, Giaccari A, Pipolo A, Citroni N, Guardamagna O, Lia S, Benso A, Biolo G, Maroni L, Lupi A, Bonanni L, Rinaldi E, Zenti MG, Matsuki K, Hori M, Ogura M, Masuda D, Kobayashi T, Nagahama K, Al-Jarallah M, Radovic M, Lunegova O, Bektasheva E, Abilova S, Erglis A, Gilis D, Nesterovics G, Saripo V, Meiere R, Skudrina G, Terauda E, Jambart S, Ayoub C, Ghaleb Y, Aliosaitiene U, Kutkiene S, Abdul Kadir SHS, Kasim NAM, Nor NSM, Abdul Hamid H, Abdul Razak S, Al-Khateeb A, Abd Muid S, Abdul Rahman T, Kasim SS, Radzi ABM, Ibrahim KS, Rosli MM, Razali R, Chua YA, Razman AZ, Nazli SA, Aziz N, Rosman A, Abdul Murad N, Jalaludin MA, Abdul Latif AZ, Azzopardi C, Mehta R, Martagon AJ, Ramirez GAG, Villa NEA, Vazquez AV, Elias-Lopez D, Retana GG, Rodriguez B, Macías JJC, Zazueta AR, Alvarado RM, Portano JDM, Lopez HA, Sauque-Reyna L, Herrera LGG, Mendia LES, Aguilar HG, Cooremans ER, Aparicio BP, Zubieta VM, Gonzalez PAC, Ferreira-Hermosillo A, Portilla NC, Dominguez GJ, Garcia AYR, Cazares HEA, Gonzalez JR, Valencia CVM, Padilla FG, Prado RM, Ibarra MODLR, Villicaña RDA, Rivera KJA, Carrera RA, Alvarez JA, Martinez JCA, Bustillo MDLRB, Vargas GC, Chacon RC, Andrade MHF, Ortega AF, Alcala HG, de Leon LEG, Guzman BG, Garcia JJG, Cuellar JCG, Cruz JRG, Garcia AH, Almada JRH, Herrera UJ, Sobrevilla FL, Rodriguez EM, Sibaja CM, Rodriguez ABM, Oyervides JCM, Vazquez DIP, Rodriguez EAR, Osorio MLR, Saucedo JR, Tamayo MT, Talavera LAV, Arroyo LEV, Carrillo EAZ, Stroes ES, Defesche J, Zuurbier L, Reeskamp L, Ibrahim S, Roeters van Lennep J, Wiegman A, Isara A, Obaseki DE, Al-Waili K, Al-Zadjali F, Al-Zakwani I, Al-Kindi M, Al-Mukhaini S, Al-Barwani H, Rana A, Shah LSU, Al-Nouri F, Starostecka E, Konopka A, Bielecka-Dabrowa A, Lewek J, Sosnowska B, Gąsior M, Dyrbuś K, Jóźwiak J, Pajkowski M, Romanowska-Kocejko M, Żarczyńska-Buchowiecka M, Chmara M, Wasąg B, Stróżyk A, Michalska-Grzonkowska A, Medeiros AM, Alves AC, Silva F, Lobarinhas G, Palma I, de Moura JP, Rico MT, Rato Q, Pais P, Correia S, Moldovan O, Virtuoso MJ, Araujo F, Salgado JM, Colaço I, Dumitrescu A, Lengher C, Mosteoru S, Meshkov A, Ershova A, Rozhkova T, Korneva V, Yu KT, Zafiraki V, Voevoda M, Gurevich V, Duplyakov D, Ragino Y, Chubykina U, Shaposhnik I, Alkaf F, Khudari A, Rwaili N, Al-Allaf F, Alghamdi M, Batais MA, Almigbal TH, Kinsara A, AlQudaimi AHA, Awan Z, Elamin OA, Altaradi H, Popovic L, Singh S, Rasulic I, Petakov A, Lalic NM, Lam C, Le TJ, Siang ELT, Dissanayake S, I-Shing JT, Shyong TE, Jin TCS, Ting SPL, Ming JHK, Drum CL, Nastar FA, Jia LW, Ya NKS, Jie MCW, Dalan R, Wei YQ, sian TY, Keong YK, Rong SK, Jin DSE, Ming IKJ, Chang TH, Peng FYK, Vasanwala RF, Raslova K, Balinth K, Buganova I, Fabryova L, Kadurova M, Klabnik A, Kozárová M, Sirotiakova J, Battelino T, Cevc M, Debeljak M, Torkar AD, Fras Z, Jug B, Cugalj BK, Kovac J, Mlinaric M, Sikonja J, Pilcher GJ, Blom DJ, Wolmarans KH, Brice BC, Muñiz-Grijalvo O, Díaz-Díaz JL, de Isla LP, Fuentes F, Badimon L, Martin F, Miserez EB, Shipton JL, Ganokroj P, Chattranukulchai P, Jiamjarasrungsi W, Thongtang N, Krittayaphong R, Vathesatogkit P, Sriphrapradang C, Phimphilai M, Leelawattana R, Anthanont P, Suraamornkul S, Deerochanawong C, Senthong V, Torpongpun A, Suteerayongprasert P, Pengpong N, Sathavarodom N, Sunanta U, Porntharukchareon T, Kiatpanabhikul P, Kaewkrasaesin C, Kongkit J, Umphonsathien M, Akbulut M, Alici G, Bayram F, Can LH, Celik A, Ceyhan C, Coskun FY, Demir M, Demircan S, Dogan V, Durakoglugil E, Dural İE, Gedikli O, Hacioglu A, Ildizli M, Kilic S, Kirilmaz B, Kutlu M, Oguz A, Ozdogan O, Onrat E, Ozer S, Sabuncu T, Sahin T, Sivri F, Sonmez A, Temizhan A, Topcu S, Tokgozoglu L, Tuncez A, Vural M, Yenercag M, Yesilbursa D, Yigit Z, Yildirim AB, Yildirir A, Yilmaz MB, Atallah B, Traina M, Sabbour H, Abdul Hay D, Luqman N, Elfatih A, Abdulrasheed A, Manla Y, Kwok S, DellOca N, Alieva RB, Fozilov KG, Hoshimov SU, Nizamov UI, Kan LE, Kim AR, Abdullaeva GJ, Abdullaev AA, Do DL, Nguyen MNT, Kim NT, Le TT, Le HA, Ray KK. Association of BMI, lipid-lowering medication, and age with prevalence of type 2 diabetes in adults with heterozygous familial hypercholesterolaemia: a worldwide cross-sectional study. Lancet Diabetes Endocrinol 2024; 12:811-823. [PMID: 39374602 DOI: 10.1016/s2213-8587(24)00221-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 07/05/2024] [Accepted: 07/15/2024] [Indexed: 10/09/2024]
Abstract
BACKGROUND Statins are the cornerstone treatment for patients with heterozygous familial hypercholesterolaemia but research suggests it could increase the risk of type 2 diabetes in the general population. A low prevalence of type 2 diabetes was reported in some familial hypercholesterolaemia cohorts, raising the question of whether these patients are protected against type 2 diabetes. Obesity is a well known risk factor for the development of type 2 diabetes. We aimed to investigate the associations of known key determinants of type 2 diabetes with its prevalence in people with heterozygous familial hypercholesterolaemia. METHODS This worldwide cross-sectional study used individual-level data from the EAS FHSC registry and included adults older than 18 years with a clinical or genetic diagnosis of heterozygous familial hypercholesterolaemia who had data available on age, BMI, and diabetes status. Those with known or suspected homozygous familial hypercholesterolaemia and type 1 diabetes were excluded. The main outcome was prevalence of type 2 diabetes overall and by WHO region, and in relation to obesity (BMI ≥30·0 kg/m2) and lipid-lowering medication as predictors. The study population was divided into 12 risk categories based on age (tertiles), obesity, and receiving statins, and the risk of type 2 diabetes was investigated using logistic regression. FINDINGS Among 46 683 adults with individual-level data in the FHSC registry, 24 784 with heterozygous familial hypercholesterolaemia were included in the analysis from 44 countries. 19 818 (80%) had a genetically confirmed diagnosis of heterozygous familial hypercholesterolaemia. Type 2 diabetes prevalence in the total population was 5·7% (1415 of 24 784), with 4·1% (817 of 19 818) in the genetically diagnosed cohort. Higher prevalence of type 2 diabetes was observed in the Eastern Mediterranean (58 [29·9%] of 194), South-East Asia and Western Pacific (214 [12·0%] of 1785), and the Americas (166 [8·5%] of 1955) than in Europe (excluding the Netherlands; 527 [8·0%] of 6579). Advancing age, a higher BMI category (obesity and overweight), and use of lipid-lowering medication were associated with a higher risk of type 2 diabetes, independent of sex and LDL cholesterol. Among the 12 risk categories, the probability of developing type 2 diabetes was higher in people in the highest risk category (aged 55-98 years, with obesity, and receiving statins; OR 74·42 [95% CI 47·04-117·73]) than in those in the lowest risk category (aged 18-38 years, without obesity, and not receiving statins). Those who did not have obesity, even if they were in the upper age tertile and receiving statins, had lower risk of type 2 diabetes (OR 24·42 [15·57-38·31]). The corresponding results in the genetically diagnosed cohort were OR 65·04 (40·67-104·02) for those with obesity in the highest risk category and OR 20·07 (12·73-31·65) for those without obesity. INTERPRETATION Adults with heterozygous familial hypercholesterolaemia in most WHO regions have a higher type 2 diabetes prevalence than in Europe. Obesity markedly increases the risk of diabetes associated with age and use of statins in these patients. Our results suggest that heterozygous familial hypercholesterolaemia does not protect against type 2 diabetes, hence managing obesity is essential to reduce type 2 diabetes in this patient population. FUNDING Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi-Sankyo, and Regeneron.
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Lovegrove CE, Howles SA, Furniss D, Holmes MV. Causal inference in health and disease: a review of the principles and applications of Mendelian randomization. J Bone Miner Res 2024; 39:1539-1552. [PMID: 39167758 PMCID: PMC11523132 DOI: 10.1093/jbmr/zjae136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 07/04/2024] [Accepted: 08/19/2024] [Indexed: 08/23/2024]
Abstract
Mendelian randomization (MR) is a genetic epidemiological technique that uses genetic variation to infer causal relationships between modifiable exposures and outcome variables. Conventional observational epidemiological studies are subject to bias from a range of sources; MR analyses can offer an advantage in that they are less prone to bias as they use genetic variants inherited at conception as "instrumental variables", which are proxies of an exposure. However, as with all research tools, MR studies must be carefully designed to yield valuable insights into causal relationships between exposures and outcomes, and to avoid biased or misleading results that undermine the validity of the causal inferences drawn from the study. In this review, we outline Mendel's laws of inheritance, the assumptions and principles that underlie MR, MR study designs and methods, and how MR analyses can be applied and reported. Using the example of serum phosphate concentrations on liability to kidney stone disease we illustrate how MR estimates may be visualized and, finally, we contextualize MR in bone and mineral research including exemplifying how this technique could be employed to inform clinical studies and future guidelines concerning BMD and fracture risk. This review provides a framework to enhance understanding of how MR may be used to triangulate evidence and progress research in bone and mineral metabolism as we strive to infer causal effects in health and disease.
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Affiliation(s)
- Catherine E Lovegrove
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Sarah A Howles
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Dominic Furniss
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom
| | - Michael V Holmes
- Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, United Kingdom
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25
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Zhang YY, Chen BX, Wan Q. Association of lipid-lowering drugs with the risk of type 2 diabetes and its complications: a mendelian randomized study. Diabetol Metab Syndr 2024; 16:240. [PMID: 39367514 PMCID: PMC11451088 DOI: 10.1186/s13098-024-01477-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 09/23/2024] [Indexed: 10/06/2024] Open
Abstract
BACKGROUND The pathogenesis of type 2 diabetes mellitus is somewhat associated with lipid metabolism. We aim to assess the impact of lipid-lowering drugs (HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors) on type 2 diabetes mellitus and its complications through a two-sample Mendelian randomization (MR) study. METHOD We identified suitable genetic instruments from the GWAS database that represent the expression levels of three genes, interpreting reduced genetically proxied gene expression as indicative of lipid-lowering drug use. We evaluated the causal relationships among these variables employing a two-sample Mendelian randomization approach, with the Inverse Variance Weighted (IVW) analysis serving as the primary method. Coronary artery disease was utilized as a positive control to validate the reliability of the selected genetic instruments. RESULT Increased genetically proxied HMGCR expression is significantly associated with a reduced risk of type 2 diabetes mellitus (OR = 0.64, 95%CI = 0.55-0.74), which was replicated in the FinnGen study with consistent results (OR = 0.65, 95%CI = 0.53-0.80). Increased genetically proxied HMGCR expression is associated with a reduced risk of diabetic retinopathy (OR = 0.23, 95%CI = 0.12-0.44) and diabetic nephropathy (OR = 0.35, 95%CI = 0.17-0.71). In contrast, increased genetically proxied PCSK9 expression is associated with a decreased risk of diabetic coma (OR = 0.70, 95%CI = 0.50-0.98), diabetic neuropathy (OR = 0.24, 95%CI = 0.14-0.42), diabetic retinopathy (OR = 0.67, 95%CI = 0.48-0.96), diabetic cardiovascular diseases (OR = 0.62, 95%CI = 0.38-0.99), and diabetic nephropathy (OR = 0.62, 95%CI = 0.41-0.95). CONCLUSIONS This Mendelian randomization study suggests an association between HMGCR and the pathogenesis of type 2 diabetes mellitus, with increased genetically proxied HMGCR expression reducing the risk of type 2 diabetes mellitus, while PCSK9 and NPC1L1 show no significant association with type 2 diabetes mellitus. These findings may offer more reasonable lipid-lowering drug options for patients with dyslipidemia.
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Affiliation(s)
- Yue-Yang Zhang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, China
- Sichuan Clinical Research Center for Diabetes and Metabolism, Luzhou, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, 646000, China
| | - Bing-Xue Chen
- Department of Ultrasound Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Qin Wan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, China.
- Sichuan Clinical Research Center for Diabetes and Metabolism, Luzhou, 646000, China.
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, China.
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, 646000, China.
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26
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Weir MR. Cardiovascular risk reduction in type 2 diabetes: What the non-specialist needs to know about current guidelines. Diabetes Obes Metab 2024; 26 Suppl 5:14-24. [PMID: 38987977 DOI: 10.1111/dom.15764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/10/2024] [Accepted: 06/19/2024] [Indexed: 07/12/2024]
Abstract
In the US, approximately 11% of the population have diagnosed diabetes and nearly 40% have prediabetes. In addition, chronic kidney disease (CKD) affects 14% of the US population including up to 40% of those with diabetes. Cardiovascular disease (CVD) remains the leading cause of death worldwide where it affects approximately half of adults. The presence of CKD or diabetes doubles the risk of cardiovascular events. When both CKD and diabetes occur in the same patient the risks are further increased. The clinical problems of hypertension, hyperglycemia, and hyperlipidemia are all closely related with obesity, metabolic syndrome, Type 2 diabetes, CKD, atherosclerotic cardiovascular disease, heart failure and non-alcoholic fatty liver disease and metabolic dysfunction-associated steatohepatitis. The increasing frequency of obesity has driven increases in all of these medical comorbidities. These conditions frequently cluster together in the same patient exacerbating the risk of morbidity and mortality. They are also associated with cognitive dysfunction/dementia, pulmonary diseases, cancers, gastrointestinal diseases, immune system abnormalities, and inflammatory disorders. Only 6.8% of adults in US meet all targets for cardiovascular risk management with significant disparities based on race and ethnicity. Given the complexity of these multisystem problems in people with diabetes and obesity, it would seem reasonable to attempt to diagnose and treat many of the comorbidities earlier in the course of disease rather than wait for substantial end organ dysfunction to occur. The American Diabetes Association (ADA) has recently published a consensus statement recommending early screening for the diagnosis of heart failure, CKD and diabetes, recognizing both the frequency and gravity of this combination. Likewise, there are recommendations in the guidelines to facilitate screening for microalbuminuria, blood pressure, glycemic control and lipids earlier in patients at risk rather than wait and treat as a secondary prevention program. Thus, the general principle is to facilitate earlier recognition and diagnosis and provide treatment before downstream target organ complications occur. This review will focus on CVD and risk management based on newest recommendations and standards of care in people with diabetes by the ADA. The main considerations in the treatment of people with diabetes are glycemic control, blood pressure, lipids, and the use of medications with proven cardiorenal disease progression capability to prevent or delay.
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Affiliation(s)
- Matthew R Weir
- Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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27
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Jamadade P, Nupur N, Maharana KC, Singh S. Therapeutic Monoclonal Antibodies for Metabolic Disorders: Major Advancements and Future Perspectives. Curr Atheroscler Rep 2024; 26:549-571. [PMID: 39008202 DOI: 10.1007/s11883-024-01228-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2024] [Indexed: 07/16/2024]
Abstract
PURPOSE OF REVIEW Globally, the prevalence of metabolic disorders is rising. Elevated low-density lipoprotein (LDL) cholesterol is a hallmark of familial hypercholesterolemia, one of the most prevalent hereditary metabolic disorders and another one is Diabetes mellitus (DM) that is more common globally, characterised by hyperglycemia with low insulin-directed glucose by target cells. It is still known that low-density lipoprotein cholesterol (LDL-C) increases the risk of cardiovascular disease (CVD). LDL-C levels are thought to be the main therapeutic objectives. RECENT FINDINGS The primary therapy for individuals with elevated cholesterol levels is the use of statins and other lipid lowering drugs like ezetimibe for hypercholesterolemia. Even after taking statin medication to the maximum extent possible, some individuals still have a sizable residual cardiovascular risk. To overcome this proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors-monoclonal antibodies (mAbs) are a novel class of systemic macromolecules that have enhanced LDL-C-lowering efficacy. Along with this other inhibitor are used like Angiopoeitin like 3 inhibitors. Research on both humans and animals has shown that anti-CD3 antibodies can correct autoimmune disorders like diabetes mellitus. Individuals diagnosed with familial hypercholesterolemia (FH) may need additional treatment options beyond statins, especially when facing challenges such as statin tolerance or the inability of even the highest statin doses to reach the desired target cholesterol level. Here is the summary of PCSK9, ANGPTL-3 and CD3 inhibitors and their detailed information. In this review we discuss the details of PCSK9, ANGPTL-3 and CD3 inhibitors and the current therapeutic interventions of using the monoclonal antibodies in case of the metabolic disorder. We further present the present studies and the future prospective of the same.
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Affiliation(s)
- Pratiksha Jamadade
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Export Promotions Industrial Park (EPIP), Vaishali, Hajipur, 844102, Bihar, India
| | - Neh Nupur
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Export Promotions Industrial Park (EPIP), Vaishali, Hajipur, 844102, Bihar, India
| | - Krushna Ch Maharana
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Export Promotions Industrial Park (EPIP), Vaishali, Hajipur, 844102, Bihar, India
| | - Sanjiv Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Export Promotions Industrial Park (EPIP), Vaishali, Hajipur, 844102, Bihar, India.
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Lamia TH, Shah-Riar P, Khanam M, Khair F, Sadat A, Tania MK, Haque SM, Saaki SS, Ferdausi A, Naurin SA, Tabassum M, Rahie RET, Hasan R. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors as Adjunct Therapy to Statins: A New Frontier in Cardiovascular Risk Reduction. Cureus 2024; 16:e71365. [PMID: 39539858 PMCID: PMC11558015 DOI: 10.7759/cureus.71365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2024] [Indexed: 11/16/2024] Open
Abstract
Lowering low-density lipoprotein cholesterol (LDL-C) plasma levels is crucial for the prevention of primary and secondary cardiovascular diseases (CVDs). Many patients struggle to obtain goal LDL-C levels, despite the availability of several lipid-lowering medications, because of limited efficaciousness and unfavorable side effects. Proprotein convertase subtilisin/kexin type 9 (PCSK9) targeting has drawn interest recently as a novel approach to further lower cardiovascular (CV) risk. The number of receptors accessible to remove LDL-C from the bloodstream is reduced when PCSK9 attaches to LDL-C receptors and directs them toward lysosomal destruction. LDL receptor activity is increased by PCSK9 inhibition, which attracts therapeutic intervention. Despite concurrent statin therapy, phase 3 clinical trials have demonstrated encouraging outcomes with monoclonal antibodies against PCSK9, such as evolocumab and alirocumab, resulting in significant reductions in LDL-C levels. This study intends to investigate recent advancements in the field to evaluate PCSK9 inhibitors' safety, effectiveness, and potential for preventing CVD. The investigation will also review potential future paths and wider effects of using PCSK9 inhibitors in therapeutic settings.
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Affiliation(s)
| | - Prince Shah-Riar
- Internal Medicine, Doctors Hospital at Renaissance (DHR) Health, Edinburg, USA
| | - Mousumi Khanam
- Internal Medicine, Dhaka Medical College and Hospital, Dhaka, BGD
| | - Farzana Khair
- Internal Medicine, Bangladesh Medical College, Dhaka, BGD
| | - Anahita Sadat
- Internal Medicine, Dhaka Medical College and Hospital, Dhaka, BGD
| | - Maksuda Khan Tania
- Internal Medicine, Ibrahim Medical College and Birdem General Hospital, Dhaka, BGD
| | - Siddiqi M Haque
- Internal Medicine, University of California, Riverside School of Medicine, Riverside, USA
| | - Shaila S Saaki
- Internal Medicine, Dhaka Medical College and Hospital, Dhaka, BGD
| | | | | | - Maliha Tabassum
- Internal Medicine, Holy Family Red Crescent Medical College, Dhaka, BGD
| | | | - Rashedul Hasan
- Internal Medicine, Desert Valley Hospital, Victorville, USA
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Sinha T, Gul U, Babar NN, Israr F, Butt AA, Chaudhari SS, Maqbool H, Amin A. The Comparison of the Effectiveness of Dapagliflozin and Empagliflozin in the Prevention of Cardiovascular Outcomes in Patients With Type 2 Diabetes: A Network Meta-Analysis. Cureus 2024; 16:e69711. [PMID: 39429324 PMCID: PMC11490073 DOI: 10.7759/cureus.69711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2024] [Indexed: 10/22/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a significant risk factor for cardiovascular diseases, prompting research into treatments that can mitigate this risk. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, particularly dapagliflozin and empagliflozin, have shown promising cardiovascular benefits in T2DM patients. This meta-analysis aimed to directly compare the cardiovascular outcomes of these two drugs. To achieve this, we conducted a comprehensive literature search across multiple databases up to August 5, 2024, including both randomized controlled trials (RCTs) and observational studies. The primary outcomes of interest were major adverse cardiovascular events (MACE), atrial fibrillation (AF), cardiovascular mortality, myocardial infarction (MI), and hospitalization for heart failure (HF). Twelve studies met the inclusion criteria for this meta-analysis. The pooled analysis revealed several key findings. Notably, dapagliflozin demonstrated superior efficacy in preventing atrial fibrillation compared to empagliflozin. However, no significant differences were observed between the two drugs in terms of MACE, cardiovascular mortality, hospitalization for heart failure (HHF), or myocardial infarction. When compared to placebo, both dapagliflozin and empagliflozin showed greater effectiveness in preventing adverse cardiovascular outcomes in T2DM patients. These results reinforce the cardiovascular benefits of both dapagliflozin and empagliflozin in patients with T2DM. The comparable efficacy in most outcomes suggests that clinicians have flexibility in prescribing either of these SGLT2 inhibitors. However, the lower risk of atrial fibrillation associated with dapagliflozin may be a crucial factor in treatment decisions, especially for patients with a history of or at high risk for atrial fibrillation.
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Affiliation(s)
- Tanya Sinha
- Internal Medicine, Tribhuvan University, Kathmandu, NPL
| | - Ushna Gul
- Internal Medicine, Khyber Medical College, Peshawar, PAK
| | - Nawabzada Nadir Babar
- Internal Medicine, Combined Military Hospital (CMH) Lahore Medical College and Institute of Dentistry, Lahore, PAK
| | - Farhan Israr
- Medicine, Khyber Medical College, Peshawar, PAK
- Internal Medicine, Lady Reading Hospital, Peshawar, PAK
| | - Aqsa A Butt
- Internal Medicine, Allama Iqbal Medical College, Lahore, PAK
| | - Sandipkumar S Chaudhari
- Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, USA
- Family Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, USA
| | - Hamza Maqbool
- Internal Medicine, Continental Medical College, Lahore, PAK
| | - Adil Amin
- Cardiology, Pakistan Navy Ship (PNS) Shifa, Karachi, PAK
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30
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Xiao Y, Yu B, Chao C, Wang S, Hu D, Wu C, Luo Y, Xie L, Li C, Peng D, Zhou Z. Chinese expert consensus on blood lipid management in patients with diabetes (2024 edition). J Transl Int Med 2024; 12:325-343. [PMID: 39360162 PMCID: PMC11444477 DOI: 10.2478/jtim-2024-0014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024] Open
Abstract
Diabetes is a significant independent risk factor for atherosclerotic cardiovascular disease (ASCVD), with dyslipidemia playing a critical role in the initiation and progression of ASCVD in diabetic patients. In China, the current prevalence of dyslipidemia in diabetes is high, but the control rate remains low. Therefore, to enhance lipid management in patients with diabetes, the Endocrinology and Metabolism Physician Branch of the Chinese Medical Doctor Association, in collaboration with the Experts' Committee of the National Society of Cardiometabolic Medicine, has convened experts to develop a consensus on the management of dyslipidemia in patients with type 1 or type 2 diabetes. The development of this consensus is informed by existing practices in lipid management among Chinese diabetic patients, incorporating contemporary evidence-based findings and guidelines from national and international sources. The consensus encompasses lipid profile characteristics, the current epidemiological status of dyslipidemia, ASCVD risk stratification, and lipid management procedures in diabetic patients. For the first time, both low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol have been recommended as primary targets for lipid intervention in diabetic patients. The consensus also includes a summary and recommendations for lipid management strategies in special diabetic populations, including children and adolescents, individuals aged 75 years and older, patients with chronic kidney disease, metabolic-associated fatty liver disease, and those who are pregnant. This comprehensive consensus aims to improve cardiovascular outcomes in diabetic patients by contributing to the dissemination of key clinical advancements and guiding clinical practice.
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Affiliation(s)
- Yang Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - Bilian Yu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - Chen Chao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - Shuai Wang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - Die Hu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - Chao Wu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - Yonghong Luo
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - Lingxiang Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - Chenyu Li
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - Daoquan Peng
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - Endocrinology and Metabolism Physician Branch of the Chinese Medical Doctor Association
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
| | - National Society of Cardiometabolic Medicine
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha410011, Hunan Province, China
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Wang Z, Zhang J, Jiao F, Wu Y, Han L, Jiang G. Genetic association analyses highlight apolipoprotein B as a determinant of chronic kidney disease in patients with type 2 diabetes. J Clin Lipidol 2024; 18:e787-e796. [PMID: 39278771 DOI: 10.1016/j.jacl.2024.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 07/05/2024] [Accepted: 07/10/2024] [Indexed: 09/18/2024]
Abstract
BACKGROUND Blood lipid levels were associated with chronic kidney disease (CKD) in patients with type 2 diabetes (T2D), but the genetic basis and causal nature remain unclear. OBJECTIVE This study aimed to investigate the relationships of lipids and their fractions with CKD in patients with T2D. METHODS Our prospective analysis involved 8,607 White participants with T2D but no CKD at baseline from the UK Biobank. Five common lipid traits were included as exposures. Weighted genetic risk scores (GRSs) for these lipid traits were developed. The causal associations between lipid traits, as well as lipid fractions, and CKD were explored using linear or nonlinear Mendelian randomization (MR). The 10-year predicted probabilities of CKD were evaluated via integrating MR and Cox models. RESULTS Higher GRS of apolipoprotein B (ApoB) was associated with an increased CKD risk (hazard ratio (HR) [95% confidence interval (CI)]:1.07[1.02,1.13] per SD; P = 0.008) after adjusting for potential confounders. Linear MR indicated a positive association between genetically predicted ApoB levels and CKD (HR [95% CI]:1.53 [1.12,2.09]; P = 0.008), but no evidence of associations was found between other lipid traits and CKD in T2D. Regarding 12 ApoB- containing lipid fractions, a significant causal association was found between medium very-low-density lipoprotein particles and CKD (HR[95% CI]:1.16[1.02,1.32];P = 0.020). Nonlinear MR did not support nonlinearity in these causal associations. The 10-year probability curve showed that ApoB level was positively associated with the risk of CKD in patients with T2D. CONCLUSION Lower ApoB levels were causally associated with a reduced risk of CKD in patients with T2D, positioning ApoB as a potential therapeutic target for CKD prevention in this population.
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Affiliation(s)
- Zhenqian Wang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang); School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang)
| | - Jiaying Zhang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang); School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang)
| | - Feng Jiao
- Guangzhou Centre for Applied Mathematics, Guangzhou University, Guangzhou, China (Dr Jiao)
| | - Yueheng Wu
- Medical Research Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China (Dr Wu)
| | - Liyuan Han
- Department of Global Health, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China (Dr Han)
| | - Guozhi Jiang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang); School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang); Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen, Guangdong, China (Dr Jiang).
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Safarova M, Bimal T, Soffer DE, Hirsh B, Shapiro MD, Mintz G, Cha A, Gianos E. Advances in targeting LDL cholesterol: PCSK9 inhibitors and beyond. Am J Prev Cardiol 2024; 19:100701. [PMID: 39070027 PMCID: PMC11278114 DOI: 10.1016/j.ajpc.2024.100701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 06/07/2024] [Accepted: 06/22/2024] [Indexed: 07/30/2024] Open
Abstract
There is a direct relationship between the duration and level of exposure to low density lipoprotein cholesterol (LDL-C) levels over one's lifespan and cardiovascular events. Early treatment to lower elevated LDL-C is crucial for better outcomes with multiple therapies currently available to reduce atherogenic lipoproteins. Statins remain the foundation of LDL-C lowering therapy as one of the most cost-effective drugs to reduce atherosclerotic events (ASCVD) and mortality. Nonetheless, LDL-driven goal attainment remains suboptimal globally, highlighting a considerable need for non-statin therapies to address residual risk related to statin intolerance, non-adherence, and inherited lipoprotein disorders. LDL-C lowering interventions beyond statins include ezetimibe, PCSK9 monoclonal antibodies, inclisiran and bempedoic acid with specific guideline recommendations as to when to consider each. For patients with homozygous familial hypercholesterolemia requiring more advanced therapy, lomitapide and evinacumab are available, providing mechanisms that are not LDL receptor dependent. Lipoprotein apheresis remains an effective option for clinical familial hypercholesterolemia as well as elevated lipoprotein (a). There are investigational therapies being explored to add to our current armamentarium including CETP inhibitors, a third-generation PCSK9 inhibitor (small recombinant fusion protein oral PCSK9 inhibitor) and gene editing which aims to directly restore or disrupt genes of interest at the DNA level. This article is a brief review of the pharmacotherapy options beyond statins for lowering LDL-C and their impact on ASCVD risk reduction. Our primary aim is to guide physicians on the role these therapies play in achieving appropriate LDL-C goals, with an algorithm of when to consider each based on efficacy, safety and outcomes.
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Affiliation(s)
- Maya Safarova
- Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI USA
| | - Tia Bimal
- Northwell, New Hyde Park, NY, Cardiovascular Institute, Lenox Hill Hospital, USA
| | - Daniel E. Soffer
- Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Benjamin Hirsh
- Department of Cardiology, Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, Hempstead, NY, USA
- Northwell, New Hyde Park, NY, Cardiovascular Institute, Sandra Atlas Bass Heart Hospital, USA
| | - Michael D. Shapiro
- Center for the Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Guy Mintz
- Department of Cardiology, Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, Hempstead, NY, USA
- Northwell, New Hyde Park, NY, Cardiovascular Institute, Sandra Atlas Bass Heart Hospital, USA
| | - Agnes Cha
- Northwell/Vivo Health Pharmacy, Ambulatory Pharmacy Services, Lake Success, NY, USA
| | - Eugenia Gianos
- Northwell, New Hyde Park, NY, Cardiovascular Institute, Lenox Hill Hospital, USA
- Department of Cardiology, Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, Hempstead, NY, USA
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Dutka M, Zimmer K, Ćwiertnia M, Ilczak T, Bobiński R. The role of PCSK9 in heart failure and other cardiovascular diseases-mechanisms of action beyond its effect on LDL cholesterol. Heart Fail Rev 2024; 29:917-937. [PMID: 38886277 PMCID: PMC11306431 DOI: 10.1007/s10741-024-10409-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/11/2024] [Indexed: 06/20/2024]
Abstract
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a protein that regulates low-density lipoprotein (LDL) cholesterol metabolism by binding to the hepatic LDL receptor (LDLR), ultimately leading to its lysosomal degradation and an increase in LDL cholesterol (LDLc) levels. Treatment strategies have been developed based on blocking PCSK9 with specific antibodies (alirocumab, evolocumab) and on blocking its production with small regulatory RNA (siRNA) (inclisiran). Clinical trials evaluating these drugs have confirmed their high efficacy in reducing serum LDLc levels and improving the prognosis in patients with atherosclerotic cardiovascular diseases. Most studies have focused on the action of PCSK9 on LDLRs and the subsequent increase in LDLc concentrations. Increasing evidence suggests that the adverse cardiovascular effects of PCSK9, particularly its atherosclerotic effects on the vascular wall, may also result from mechanisms independent of its effects on lipid metabolism. PCSK9 induces the expression of pro-inflammatory cytokines contributing to inflammation within the vascular wall and promotes apoptosis, pyroptosis, and ferroptosis of cardiomyocytes and is thus involved in the development and progression of heart failure. The elimination of PCSK9 may, therefore, not only be a treatment for hypercholesterolaemia but also for atherosclerosis and other cardiovascular diseases. The mechanisms of action of PCSK9 in the cardiovascular system are not yet fully understood. This article reviews the current understanding of the mechanisms of PCSK9 action in the cardiovascular system and its contribution to cardiovascular diseases. Knowledge of these mechanisms may contribute to the wider use of PCSK9 inhibitors in the treatment of cardiovascular diseases.
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Affiliation(s)
- Mieczysław Dutka
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland.
| | - Karolina Zimmer
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland
| | - Michał Ćwiertnia
- Department of Emergency Medicine, Faculty of Health Sciences, University of Bielsko-Biala, 43-309, Bielsko-Biała, Poland
| | - Tomasz Ilczak
- Department of Emergency Medicine, Faculty of Health Sciences, University of Bielsko-Biala, 43-309, Bielsko-Biała, Poland
| | - Rafał Bobiński
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland
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Vroom MM, Dodart JC. Active Immunotherapy for the Prevention of Alzheimer's and Parkinson's Disease. Vaccines (Basel) 2024; 12:973. [PMID: 39340005 PMCID: PMC11435640 DOI: 10.3390/vaccines12090973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/23/2024] [Accepted: 08/26/2024] [Indexed: 09/30/2024] Open
Abstract
Neurodegenerative diseases (ND) give rise to significant declines in motor, autonomic, behavioral, and cognitive functions. Of these conditions, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent, impacting over 55 million people worldwide. Given the staggering financial toll on the global economy and their widespread manifestation, NDs represent a critical issue for healthcare systems worldwide. Current treatment options merely seek to provide symptomatic relief or slow the rate of functional decline and remain financially inaccessible to many patients. Indeed, no therapy has yet demonstrated the potential to halt the trajectory of NDs, let alone reverse them. It is now recognized that brain accumulation of pathological variants of AD- or PD-associated proteins (i.e., amyloid-β, Tau, α-synuclein) begins years to decades before the onset of clinical symptoms. Accordingly, there is an urgent need to pursue therapies that prevent the neurodegenerative processes associated with pathological protein aggregation long before a clinical diagnosis can be made. These therapies must be safe, convenient, and affordable to ensure broad coverage in at-risk populations. Based on the need to intervene long before clinical symptoms appear, in this review, we present a rationale for greater investment to support the development of active immunotherapy for the prevention of the two most common NDs based on their safety profile, ability to specifically target pathological proteins, as well as the significantly lower costs associated with manufacturing and distribution, which stands to expand accessibility to millions of people globally.
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Affiliation(s)
- Madeline M Vroom
- Vaxxinity, Inc., Space Life Sciences Lab, 505 Odyssey Way, Merritt Island, FL 32953, USA
| | - Jean-Cosme Dodart
- Vaxxinity, Inc., Space Life Sciences Lab, 505 Odyssey Way, Merritt Island, FL 32953, USA
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Leiter LA, Raal FJ, Schwartz GG, Koenig W, Ray KK, Landmesser U, Han J, Conde LG, Wright RS. Inclisiran in individuals with diabetes or obesity: Post hoc pooled analyses of the ORION-9, ORION-10 and ORION-11 Phase 3 randomized trials. Diabetes Obes Metab 2024; 26:3223-3237. [PMID: 38757725 DOI: 10.1111/dom.15650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 05/18/2024]
Abstract
AIMS To conduct a pooled analysis of Phase 3 trials investigating the efficacy and safety of inclisiran across glycaemic and body mass index (BMI) strata. MATERIALS AND METHODS Participants were randomized 1:1 to receive 300 mg inclisiran sodium or placebo twice yearly, after initial and 3-month doses up to 18 months, with background oral lipid-lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2). Co-primary endpoints were percentage and time-adjusted percentage change in low-density lipoprotein (LDL) cholesterol from baseline. Safety was also assessed. RESULTS Baseline characteristics were balanced between treatment arms and across strata. Percent LDL cholesterol change (placebo-corrected) with inclisiran from baseline to Day 510 ranged from -47.6% to -51.9% and from -48.8% to -54.4% across glycaemic/BMI strata, respectively. Similarly, time-adjusted percentage changes after Day 90 and up to Day 540 ranged from -46.8% to -52.0% and from -48.6% to -53.3% across glycaemic/BMI strata, respectively. Inclisiran led to significant reductions in proprotein convertase subtilisin/kexin type 9 and other atherogenic lipids and lipoproteins versus placebo across the glycaemic/BMI strata. The proportions of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata. Across the glycaemic/BMI strata, a higher proportion of individuals had mild/moderate treatment-emergent adverse events (TEAEs) at the injection site with inclisiran (2.8%-7.7%) versus placebo (0.2%-2.1%). CONCLUSION Inclisiran provided substantial and sustained LDL cholesterol lowering across glycaemic/BMI strata, with a modest excess of transient mild-to-moderate TEAEs at the injection site.
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Affiliation(s)
- Lawrence A Leiter
- Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Frederick J Raal
- Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Gregory G Schwartz
- Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Wolfgang Koenig
- Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
| | - Kausik K Ray
- Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK
| | - Ulf Landmesser
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Charité University Medicine Berlin, Friede Springer Cardiovascular Prevention Center od Charité, Berlin Institute of Health, DZHK, Partner Site Berlin, Berlin, Germany
| | - Jackie Han
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | | | - R Scott Wright
- Division of Preventive Cardiology and Department of Cardiology, Mayo Clinic, Rochester, Minnesota, USA
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36
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Chen T, Liu N. How safe are proprotein convertase subtilisinekexin type 9 inhibitors in diabetes? Curr Opin Lipidol 2024; 35:187-194. [PMID: 38527426 DOI: 10.1097/mol.0000000000000934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
PURPOSE OF REVIEW To examine the safety of proprotein convertase subtilisinekexin type 9 (PCSK9) inhibitors in patients with diabetes, specifically focusing on their impact on glucose metabolism. RECENT FINDINGS Patients with diabetes often require intensified lipid-lowering therapy. PCSK9 inhibitors can reduce low-density lipoprotein cholesterol (LDL-C) concentrations by approximately 60%, and significantly reduce cardiovascular risk when added to statin therapy. Some studies have suggested an association between low LDL-C levels and an increased risk of new-onset diabetes, and genetics has almost consistently shown an increased glucose concentration and risk of diabetes. Most clinical trials have not demonstrated a deterioration in glycaemic control in patients with diabetes after the use of PCSK9 inhibitors, and they do not lead to other significant treatment-emergent adverse events. SUMMARY Although the majority of patients with diabetes are undergoing background statin therapy, which may mask potential adverse effects of PCSK9 inhibitors on glycaemic control, current data suggest that the benefits outweigh the risks for diabetic patients using PCSK9 inhibitors. Considering the different nature of genetic studies and of clinical trials, close monitoring of glucose parameters is necessary, especially in individuals with prediabetes.
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Affiliation(s)
- Tian Chen
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
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JI LN, CHEN YD. Consensus on glycemic management for patients with coronary heart disease and type 2 diabetes. J Geriatr Cardiol 2024; 21:689-702. [PMID: 39183955 PMCID: PMC11341531 DOI: 10.26599/1671-5411.2024.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024] Open
Abstract
The prevalence of patients with coronary heart disease (CHD) and diabetes mellitus is notably high, posing significant residual cardiovascular risks even after routine interventions such as antihypertensive, lipid-lowering, and antithrombotic treatments. Recent studies have demonstrated that certain glucose-lowering medications confer cardiovascular benefits for patients with type 2 diabetes. However, a survey indicates that cardiologists may not be fully acquainted with the optimal screening timing, indicators, and diagnostic criteria for type 2 diabetes, and there is insufficient awareness and a low rate of prescription of novel glucose-lowering medications with proven cardiovascular efficacy, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i). In this context, based on domestic and international guidelines or consensus and the latest evidence-based evidence, this consensus aims to standardize the glycemic management for patients with acute coronary syndrome, chronic coronary syndrome, and perioperative management for percutaneous coronary intervention. It highlights the key points of screening and diagnosis of type 2 diabetes, and the comprehensive management of cardiovascular risk in patients with CHD. The consensus elaborates on the principles and algorithms of glycemic management for CHD patients, without involving acute complications of diabetes, clarifies the clinical practice of glucose-lowering medications with cardiovascular benefits, and promotes the standardized use of these medications in cardiovascular and other related specialty fields. Additionally, it addresses the glucose-lowering treatment to comprehensively reduce cardiovascular risks.
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Kounatidis D, Tentolouris N, Vallianou NG, Mourouzis I, Karampela I, Stratigou T, Rebelos E, Kouveletsou M, Stamatopoulos V, Tsaroucha E, Dalamaga M. The Pleiotropic Effects of Lipid-Modifying Interventions: Exploring Traditional and Emerging Hypolipidemic Therapies. Metabolites 2024; 14:388. [PMID: 39057711 PMCID: PMC11278853 DOI: 10.3390/metabo14070388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/14/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and secondary prevention by effectively reducing cardiovascular risk through lipid profile enhancements. Beyond their primary lipid-lowering effects, extensive research indicates that these therapies exhibit pleiotropic actions, offering additional health benefits. These include anti-inflammatory properties, improvements in vascular health and glucose metabolism, and potential implications in cancer management. While statins and ezetimibe have been extensively studied, newer lipid-lowering agents also demonstrate similar pleiotropic effects, even in the absence of direct cardiovascular benefits. This narrative review explores the diverse pleiotropic properties of lipid-modifying therapies, emphasizing their non-lipid effects that contribute to reducing cardiovascular burden and exploring emerging benefits for non-cardiovascular conditions. Mechanistic insights into these actions are discussed alongside their potential therapeutic implications.
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Affiliation(s)
- Dimitris Kounatidis
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.K.); (N.T.); (E.R.); (M.K.)
| | - Nikolaos Tentolouris
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.K.); (N.T.); (E.R.); (M.K.)
| | - Natalia G. Vallianou
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece;
| | - Iordanis Mourouzis
- Department of Pharmacology, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Irene Karampela
- Second Department of Critical Care, Attikon General University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Theodora Stratigou
- Department of Endocrinology and Metabolism, Evangelismos General Hospital, 10676 Athens, Greece;
| | - Eleni Rebelos
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.K.); (N.T.); (E.R.); (M.K.)
| | - Marina Kouveletsou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.K.); (N.T.); (E.R.); (M.K.)
| | | | - Eleni Tsaroucha
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece;
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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Zac-Varghese S, Mark P, Bain S, Banerjee D, Chowdhury TA, Dasgupta I, De P, Fogarty D, Frankel A, Goldet G, Karalliedde J, Mallik R, Montero R, Sharif A, Wahba M, Dhatariya K, McCafferty K, Lioudaki E, Winocour P. Clinical practice guideline for the management of lipids in adults with diabetic kidney disease: abbreviated summary of the Joint Association of British Clinical Diabetologists and UK Kidney Association (ABCD-UKKA) Guideline 2024. BMC Nephrol 2024; 25:216. [PMID: 38971750 PMCID: PMC11227212 DOI: 10.1186/s12882-024-03664-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 07/01/2024] [Indexed: 07/08/2024] Open
Abstract
The contribution of chronic kidney disease (CKD) towards the risk of developing cardiovascular disease (CVD) is magnified with co-existing type 1 or type 2 diabetes. Lipids are a modifiable risk factor and good lipid management offers improved outcomes for people with diabetic kidney disease (DKD).The primary purpose of this guideline, written by the Association of British Clinical Diabetologists (ABCD) and UK Kidney Association (UKKA) working group, is to provide practical recommendations on lipid management for members of the multidisciplinary team involved in the care of adults with DKD.
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Affiliation(s)
| | | | | | | | | | | | - Parijat De
- Birmingham City Hospital, Birmingham, UK
| | - Damian Fogarty
- Belfast Health and Social Care Trust, Belfast, Northern Ireland
| | | | | | - Janaka Karalliedde
- Guy's and St Thomas NHS Foundation Trust, London, UK
- Kings College London, London, UK
| | | | | | | | | | | | - Kieran McCafferty
- Barts Health NHS Trust, London, UK
- Queen Mary University of London, London, UK
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Chait A, Eckel RH, Vrablik M, Zambon A. Lipid-lowering in diabetes: An update. Atherosclerosis 2024; 394:117313. [PMID: 37945448 DOI: 10.1016/j.atherosclerosis.2023.117313] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/11/2023] [Accepted: 09/22/2023] [Indexed: 11/12/2023]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) is accelerated in people with diabetes. Dyslipidemia, hyperglycemia, oxidative stress, and inflammation play a role via a variety of mechanisms operative in the artery wall. In addition, some unique features predispose people with type 1 diabetes to accelerated atherosclerosis. Various organizations have created guidelines that provide advice regarding screening, risk assessment, and roadmaps for treatment to prevent ASCVD in diabetes. Management of dyslipidemia, especially with statins, has proven to be of immense benefit in the prevention of clinical CVD. However, since many patients fail to attain the low levels of low-density lipoproteins (LDL) recommended in these guidelines, supplemental therapy, such as the addition of ezetimibe, bempedoic acid or PCSK9 inhibitors, is often required to reach LDL goals. As a result, the upfront use of combination therapies, particularly a statin plus ezetimibe, is a rational initial approach. The addition to statins of drugs that specifically lower triglyceride levels has not proven beneficial, although the addition of icosapent-ethyl has been shown to be of value, likely by mechanisms independent of triglyceride lowering. Newer treatments in development, including apoC-III and ANGPTL3 inhibitors, seem promising in further reducing apoB-containing lipoproteins.
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Affiliation(s)
- Alan Chait
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, WA, USA
| | - Robert H Eckel
- Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Michal Vrablik
- 3rd Department of Internal Medicine, General University Hospital and 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alberto Zambon
- Department of Medicine - DIMED, University of Padova, and IRCCS Multimedica Milan, Italy.
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Moon JS, Kang S, Choi JH, Lee KA, Moon JH, Chon S, Kim DJ, Kim HJ, Seo JA, Kim MK, Lim JH, Song YJ, Yang YS, Kim JH, Lee YB, Noh J, Hur KY, Park JS, Rhee SY, Kim HJ, Kim HM, Ko JH, Kim NH, Kim CH, Ahn J, Oh TJ, Kim SK, Kim J, Han E, Jin SM, Bae J, Jeon E, Kim JM, Kang SM, Park JH, Yun JS, Cha BS, Moon MK, Lee BW. 2023 Clinical Practice Guidelines for Diabetes Management in Korea: Full Version Recommendation of the Korean Diabetes Association. Diabetes Metab J 2024; 48:546-708. [PMID: 39091005 PMCID: PMC11307112 DOI: 10.4093/dmj.2024.0249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 06/20/2024] [Indexed: 08/04/2024] Open
Affiliation(s)
- Jun Sung Moon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Shinae Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Han Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Kyung Ae Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju, Korea
| | - Joon Ho Moon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Suk Chon
- Department of Endocrinology and Metabolism, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University Hospital, Ajou University School of Medicine, Suwon, Korea
| | - Hyun Jin Kim
- Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Korea
| | - Ji A Seo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Mee Kyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Hyun Lim
- Department of Food Service and Nutrition Care, Seoul National University Hospital, Seoul, Korea
| | - Yoon Ju Song
- Department of Food Science and Nutrition, The Catholic University of Korea, Bucheon, Korea
| | - Ye Seul Yang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Hyeon Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - You-Bin Lee
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Junghyun Noh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Kyu Yeon Hur
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong Suk Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Youl Rhee
- Department of Endocrinology and Metabolism, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University Hospital, Ajou University School of Medicine, Suwon, Korea
| | - Hyun Min Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Jung Hae Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Nam Hoon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Chong Hwa Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea
| | - Jeeyun Ahn
- Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Tae Jung Oh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Soo-Kyung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Jaehyun Kim
- Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Eugene Han
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Sang-Man Jin
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jaehyun Bae
- Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea
| | - Eonju Jeon
- Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea
| | - Ji Min Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Seon Mee Kang
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Jung Hwan Park
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Jae-Seung Yun
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Bong-Soo Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Min Kyong Moon
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Grejtakova D, Boronova I, Bernasovska J, Bellosta S. PCSK9 and Lipid Metabolism: Genetic Variants, Current Therapies, and Cardiovascular Outcomes. Cardiovasc Drugs Ther 2024:10.1007/s10557-024-07599-5. [PMID: 38907775 DOI: 10.1007/s10557-024-07599-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/12/2024] [Indexed: 06/24/2024]
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the modulation of lipid metabolism as a critical negative regulator of hepatic low-density lipoprotein receptor (LDLR) levels and circulating low-density lipoprotein (LDL) clearance. Numerous gain-of-function (GOF) mutations in PCSK9 have been identified as causing familial hypercholesterolemia (FH) by reducing LDLR levels, and loss-of-function (LOF) mutations associated with a hypercholesterolemia phenotype protective against atherosclerosis. PCSK9 represents an example of successful translational research resulting in the identification of PCSK9 as a major drug target for a lipid-lowering therapy. To explore the genetic constitution of PCSK9 and its biologic role, in this review, we summarize the current evidence of clinically significant PCSK9 genetic variants involved in lipid metabolism as well as emphasize the importance of PCSK9 inhibition for the improvement of cardiovascular outcomes by conducting a meta-analysis of the available data on the incidence of cardiovascular disease events.
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Affiliation(s)
- Daniela Grejtakova
- Laboratory of Molecular Genetics, Department of Biology, Faculty of Humanities and Natural Sciences, University of Presov, 17 November 1, Presov, 08001, Slovakia.
| | - Iveta Boronova
- Laboratory of Molecular Genetics, Department of Biology, Faculty of Humanities and Natural Sciences, University of Presov, 17 November 1, Presov, 08001, Slovakia
| | - Jarmila Bernasovska
- Laboratory of Molecular Genetics, Department of Biology, Faculty of Humanities and Natural Sciences, University of Presov, 17 November 1, Presov, 08001, Slovakia
| | - Stefano Bellosta
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università Degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy
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Béliard S, Mourre F, Valéro R. Hyperlipidaemia in diabetes: are there particular considerations for next-generation therapies? Diabetologia 2024; 67:974-984. [PMID: 38376536 PMCID: PMC11058750 DOI: 10.1007/s00125-024-06100-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 12/07/2023] [Indexed: 02/21/2024]
Abstract
Dyslipidaemias are major cardiovascular risk factors, especially in people with diabetes. In this area, next-generation therapies targeting circulating lipoparticle metabolism (LDL, VLDL, chylomicrons, HDL) have recently been approved by the European and US medical agencies, including anti- proprotein convertase subtilisin/kexin 9 (PCSK9) antibodies; an siRNA targeting PCSK9; bempedoic acid, which targets ATP citrate lyase; an antisense oligonucleotide targeting apolipoprotein C-III; an anti-angiopoietin-like 3 antibody; and a purified omega-3 fatty acid, icosapent ethyl. Other therapies are in different phases of development. There are several important considerations concerning the link between these new lipid-lowering therapies and diabetes. First, since concerns were first raised in 2008 about an increased risk of new-onset diabetes mellitus (NODM) with intensive statin treatment, each new lipid-lowering therapy is being evaluated for its associated risk of NODM, particularly in individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Second, people with diabetes represent a large proportion of those at high or very high cardiovascular risk in whom these lipid-lowering drugs are currently, or will be, prescribed. Thus, the efficacy of these drugs in subgroups with diabetes should also be closely considered, as well as any potential effects on glycaemic control. In this review, we describe the efficacy of next-generation therapies targeting lipoprotein metabolism in subgroups of people with diabetes and their effects on glycaemic control in individuals with diabetes and prediabetes and in normoglycaemic individuals.
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Affiliation(s)
- Sophie Béliard
- APHM (Assistance Publique-Hôpitaux de Marseille), Department of Nutrition, Metabolic Diseases, Endocrinology, La Conception Hospital, Marseille, France.
- Inserm, INRAE (Institut National de Recherche pour l'agriculture, l'Alimentation et l'Environnement), C2VN (Centre de recherche en CardioVasculaire et Nutrition), Aix Marseille University, Marseille, France.
| | - Florian Mourre
- APHM (Assistance Publique-Hôpitaux de Marseille), Department of Nutrition, Metabolic Diseases, Endocrinology, La Conception Hospital, Marseille, France
- Inserm, INRAE (Institut National de Recherche pour l'agriculture, l'Alimentation et l'Environnement), C2VN (Centre de recherche en CardioVasculaire et Nutrition), Aix Marseille University, Marseille, France
| | - René Valéro
- APHM (Assistance Publique-Hôpitaux de Marseille), Department of Nutrition, Metabolic Diseases, Endocrinology, La Conception Hospital, Marseille, France
- Inserm, INRAE (Institut National de Recherche pour l'agriculture, l'Alimentation et l'Environnement), C2VN (Centre de recherche en CardioVasculaire et Nutrition), Aix Marseille University, Marseille, France
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Mhaimeed O, Burney ZA, Schott SL, Kohli P, Marvel FA, Martin SS. The importance of LDL-C lowering in atherosclerotic cardiovascular disease prevention: Lower for longer is better. Am J Prev Cardiol 2024; 18:100649. [PMID: 38576462 PMCID: PMC10992711 DOI: 10.1016/j.ajpc.2024.100649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 02/25/2024] [Accepted: 03/09/2024] [Indexed: 04/06/2024] Open
Abstract
Cumulative exposure to low-density lipoprotein cholesterol (LDL-C) is a key driver of atherosclerotic cardiovascular disease (ASCVD) risk. An armamentarium of therapies to achieve robust and sustained reduction in LDL-C can reduce ASCVD risk. The gold standard for LDL-C assessment is ultracentrifugation but in routine clinical practice LDL-C is usually calculated and the most accurate calculation is the Martin/Hopkins equation. For primary prevention, consideration of estimated ASCVD risk frames decision making regarding use of statins and other therapies, and tools such as risk enhancing factors and coronary artery calcium enable tailoring of risk assessment and decision making. In patients with diabetes, lipid lowering therapy is recommended in most patients to reduce ASCVD risk with an opportunity to tailor therapy based on other risk factors. Patients with primary hypercholesterolemia and familial hypercholesterolemia (FH) with baseline LDL-C greater than or equal to 190 mg/dL are at elevated risk, and LDL-C lowering with high-intensity statin therapy is often combined with non-statin therapies to prevent ASCVD. Secondary prevention of ASCVD, including in patients with prior myocardial infarction or stroke, requires intensive lipid lowering therapy and lifestyle modification approaches. There is no established LDL-C level below which benefit ceases or safety concerns arise. When further LDL-C lowering is required beyond lifestyle modifications and statin therapy, additional medications include oral ezetimibe and bempedoic acid, or injectables such as PCSK9 monoclonal antibodies or siRNA therapy. A novel agent that acts independently of hepatic LDL receptors is evinacumab, which is approved for patients with homozygous FH. Other emerging agents are targeted at Lp(a) and CETP. In light of the expanding lipid treatment landscape, this manuscript reviews the importance of early, intensive, and sustained LDL-C-lowering for primary and secondary prevention of ASCVD.
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Affiliation(s)
- Omar Mhaimeed
- Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, United States
| | - Zain A Burney
- Department of Medicine, Cleveland Clinic, Cleveland, OH, United States
| | - Stacey L Schott
- Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, United States
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Payal Kohli
- Department of Cardiology, University of Colorado Anschutz, Aurora, CO, United States
- Department of Cardiology, Veterans Affairs Hospital, Aurora, CO, United States
- Cherry Creek Heart, Aurora, CO, United States
- Tegna Broadcasting, MD, United States
| | - Francoise A Marvel
- Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, United States
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Seth S Martin
- Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, United States
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Manolis AA, Manolis TA, Mikhailidis DP, Manolis AS. Are We Using Ezetimibe As Much As We Should? Biomark Insights 2024; 19:11772719241257410. [PMID: 38827240 PMCID: PMC11143858 DOI: 10.1177/11772719241257410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 05/09/2024] [Indexed: 06/04/2024] Open
Abstract
Lipid-lowering therapies, particularly non-statin regimens, are underutilized as ~2/3 of patients with atherosclerotic cardiovascular (CV) disease (CVD) are not optimally managed, and do not attain target low-density lipoprotein cholesterol (LDL-C) concentrations, despite statin treatment. Statins have been the mainstay of hypolipidemic therapies; however, they are plagued by adverse effects, which have partly hindered their more widespread use. Ezetimibe is often the first added mode of treatment to attain LDL-C goals as it is efficacious and also allows the use of a smaller dose of statin, while the need for more expensive therapies is obviated. We herein provide a comprehensive review of the effects of ezetimibe in lipid lowering and reducing CV events and improving outcomes. Of the hypolipidemic therapies, oral ezetimibe, in contrast to newer agents, is the most convenient and/or affordable regimen to be utilized as mono- or combined therapy supported by data from CV outcomes studies attesting to its efficacy in reducing CVD risk and events. When combined with a statin, the statin dose could be lower, thus curtailing side-effects, while the hypolipidemic effect is enhanced (by ~20%) as the percentage of patients with target level LDL-C (<70 mg/dL) is higher with combined treatment versus a high-intensity statin. Ezetimibe could also serve as an alternative treatment in cases of statin intolerance. In conclusion, ezetimibe has an excellent safety/tolerability profile; it is the first added treatment to a statin that can attain LDL-C targets. In the combined therapy, the hypolipidemic effect is enhanced while the dose of statin could be lower, thus limiting the occurrence of side-effects. Ezetimibe could also serve as an alternative mode of treatment in cases of statin intolerance.
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Affiliation(s)
| | | | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK
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Natale F, Franzese R, Marotta L, Mollo N, Solimene A, Luisi E, Gentile C, Loffredo FS, Golino P, Cimmino G. Evolving Concepts of the SCORE System: Subtracting Cholesterol from Risk Estimation: A Way for a Healthy Longevity? Life (Basel) 2024; 14:679. [PMID: 38929662 PMCID: PMC11204887 DOI: 10.3390/life14060679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 05/17/2024] [Accepted: 05/23/2024] [Indexed: 06/28/2024] Open
Abstract
The role of cholesterol, mainly low-density lipoproteins (LDL-C), as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) is now established and accepted by the international scientific community. Based on this evidence, the European and American guidelines recommend early risk stratification and "rapid" achievement of the suggested target according to the risk estimation to reduce the number of major cardiovascular events. Prolonged exposure over the years to high levels of LDL-C is one of the determining factors in the development and progression of atherosclerotic plaque, on which the action of conventional risk factors (cigarette smoking, excess weight, sedentary lifestyle, arterial hypertension, diabetes mellitus) as well as non-conventional risk factors (gut microbiota, hyperuricemia, inflammation), alone or in combination, favors the destabilization of the atherosclerotic lesion with rupture/fissuration/ulceration and consequent formation of intravascular thrombosis, which leads to the acute clinical manifestations of acute coronary syndromes. In the current clinical practice, there is a growing number of cases that, although extremely common, are emblematic of the concept of long-term exposure to the risk factor (LDL hypercholesterolemia), which, not adequately controlled and in combination with other risk factors, has favored the onset of major cardiovascular events. The triple concept of "go lower, start earlier and keep longer!" should be applied in current clinical practice at any level of prevention. In the present manuscript, we will review the current evidence and documents supporting the causal role of LDL-C in determining ASCVD and whether it is time to remove it from any score.
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Affiliation(s)
- Francesco Natale
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (R.F.); (L.M.); (N.M.); (A.S.); (E.L.); (C.G.); (F.S.L.); (P.G.)
| | - Rosa Franzese
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (R.F.); (L.M.); (N.M.); (A.S.); (E.L.); (C.G.); (F.S.L.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Luigi Marotta
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (R.F.); (L.M.); (N.M.); (A.S.); (E.L.); (C.G.); (F.S.L.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Noemi Mollo
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (R.F.); (L.M.); (N.M.); (A.S.); (E.L.); (C.G.); (F.S.L.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Achille Solimene
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (R.F.); (L.M.); (N.M.); (A.S.); (E.L.); (C.G.); (F.S.L.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Ettore Luisi
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (R.F.); (L.M.); (N.M.); (A.S.); (E.L.); (C.G.); (F.S.L.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Carmine Gentile
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (R.F.); (L.M.); (N.M.); (A.S.); (E.L.); (C.G.); (F.S.L.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Francesco S. Loffredo
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (R.F.); (L.M.); (N.M.); (A.S.); (E.L.); (C.G.); (F.S.L.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Paolo Golino
- Vanvitelli Cardiology Unit, Monaldi Hospital, 80131 Naples, Italy; (F.N.); (R.F.); (L.M.); (N.M.); (A.S.); (E.L.); (C.G.); (F.S.L.); (P.G.)
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Giovanni Cimmino
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
- Cardiology Unit, AOU Luigi Vanvitelli, 80138 Naples, Italy
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Chen S, Zhang M, Yang P, Guo J, Liu L, Yang Z, Nan K. Genetic Association between Lipid-Regulating Drug Targets and Diabetic Retinopathy: A Drug Target Mendelian Randomization Study. J Lipids 2024; 2024:5324127. [PMID: 38757060 PMCID: PMC11098603 DOI: 10.1155/2024/5324127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 03/20/2024] [Accepted: 04/06/2024] [Indexed: 05/18/2024] Open
Abstract
Background Diabetic retinopathy (DR) is a diabetic microvascular complication and a leading cause of vision loss. However, there is a lack of effective strategies to reduce the risk of DR currently. The present study is aimed at assessing the causal effect of lipid-regulating targets on DR risk using a two-sample Mendelian randomization (MR) study. Method Genetic variants within or near drug target genes, including eight lipid-regulating targets for LDL-C (HMGCR, PCSK9, and NPC1L1), HDL-C (CETP, SCARB1, and PPARG), and TG (PPARA and LPL), were selected as exposures. The exposure data were obtained from the IEU OpenGWAS project. The outcome dataset related to DR was obtained from the FinnGen research project. Inverse-variance-weighted MR (IVW-MR) was used to calculate the effect estimates by each target. Sensitivity analyses were performed to verify the robustness of the results. Results There was suggestive evidence that PCSK9-mediated LDL-C levels were positively associated with DR, with OR (95% CI) of 1.34 (1.02-1.77). No significant association was found between the expression of HMGCR- and NPC1L1-mediated LDL-C levels; CETP-, SCARB1-, and PPARG-mediated HDL-C levels; PPARA- and LPL-mediated TG levels; and DR risk. Conclusions This is the first study to reveal a genetically causal relationship between lipid-regulating drug targets and DR risk. PCSK9-mediated LDL-C levels maybe positively associated with DR risk at the genetic level. This study provides suggestive evidence that PCSK9 inhibition may reduce the risk of DR.
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Affiliation(s)
- Shengnan Chen
- Department of Joint Surgery, HongHui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi, China
- Medical Department of Xi'an Jiaotong University, Xi'an, Shaanxi 710048, China
| | - Ming Zhang
- Department of General Practice, HongHui Hospital, Xi'an Jiao Tong University, Xi'an 710054, Shaanxi, China
| | - Peng Yang
- Department of Joint Surgery, HongHui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi, China
| | - Jianbin Guo
- Department of Joint Surgery, HongHui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi, China
| | - Lin Liu
- Department of Joint Surgery, HongHui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi, China
| | - Zhi Yang
- Department of Joint Surgery, HongHui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi, China
| | - Kai Nan
- Department of Joint Surgery, HongHui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi, China
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Si PEH, Parker S, Abdelhafiz D, Summerbell A, Muzulu S, Abdelhafiz AH. Cardiovascular risk reduction in older people with type 2 diabetes mellitus-a comprehensive narrative review. Diabetes Res Clin Pract 2024; 211:111662. [PMID: 38599285 DOI: 10.1016/j.diabres.2024.111662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 04/01/2024] [Accepted: 04/07/2024] [Indexed: 04/12/2024]
Abstract
Metabolic targets are controversial in older people with type 2 diabetes due to functional heterogeneity and morbidity burden. Tight blood pressure and metabolic control appears beneficial in fit individuals who are newly diagnosed with type 2 diabetes and have fewer comorbidities. The benefits of low blood pressure and tight metabolic control is attenuated with the development of comorbidities, especially frailty. Guidelines consider frail older people as one category and recommend relaxed targets. However, sarcopenic obese frail individuals may benefit from tight targets and intensification of therapy due to their unfavourable metabolic profile, accelerated diabetes trajectory and high cardiovascular risk. In addition, the early use of sodium glucose transporter-2 inhibitors and glucagon like peptide-1 receptor agonists may be beneficial in this frailty phenotype due to their cardio-renal protection, which is independent of glycaemic control, provided they are able to engage in resistance exercise training to avoid loss of muscle mass. In the anorexic malnourished frail individual, early use of insulin, due to its weight gain and anabolic properties, is appropriate. In this phenotype, targets should be relaxed with deintensification of therapy due to significant weight loss, decelerated diabetes trajectory and increased risk of medication side effects.
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Affiliation(s)
- Pann Ei Hnynn Si
- Sheffield Kidney Institute, Sheffield Teaching Hospitals, Herries Road, Sheffield S5 7AU, UK
| | - S Parker
- Translational Health Sciences, Bristol Medical School, Bristol, BS8 1QU
| | - D Abdelhafiz
- Lancaster Medical School, Lancaster, LA1 4YG, UK
| | - A Summerbell
- Department of Geriatric Medicine, Rotherham General Hospital, Moorgate Road, Rotherham S60 2 UD, UK
| | - S Muzulu
- Department of Diabetes and Endocrinology Rotherham General Hospital, UK
| | - Ahmed H Abdelhafiz
- Department of Geriatric Medicine, Rotherham General Hospital, Moorgate Road, Rotherham S60 2 UD, UK.
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Yasin A, Nguyen M, Sidhu A, Majety P, Spitz J, Asgharpour A, Siddiqui MS, Sperling LS, Quyyumi AA, Mehta A. Liver and cardiovascular disease outcomes in metabolic syndrome and diabetic populations: Bi-directional opportunities to multiply preventive strategies. Diabetes Res Clin Pract 2024; 211:111650. [PMID: 38604447 DOI: 10.1016/j.diabres.2024.111650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 03/26/2024] [Accepted: 04/01/2024] [Indexed: 04/13/2024]
Abstract
The incidence and prevalence of metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are rising globally. MetS and T2DM are associated with significant morbidity and mortality, which is partly related to liver and cardiovascular disease. Insulin resistance is central to MetS and T2DM pathophysiology, and drives ectopic fat deposition in the liver, also known as metabolic dysfunction-associated steatotic liver disease (MASLD). MetS and T2DM are not only risk factors for developing MASLD but are also independently associated with disease progression to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In addition to the risk of liver disease, MetS and T2DM are independent risk factors for cardiovascular disease (CVD), including coronary artery disease (CAD) and heart failure (HF). Importantly, there is a bidirectional relationship between liver and CVD due to shared disease pathophysiology in patients with MetS and T2DM. In this review, we have described studies exploring the relationship of MetS and T2DM with MASLD and CVD, independently. Following this we discuss studies evaluating the interplay between liver and cardiovascular risk as well as pragmatic risk mitigation strategies in this patient population.
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Affiliation(s)
| | | | - Angad Sidhu
- Virginia Commonwealth University, Richmond, VA, US
| | | | - Jared Spitz
- Inova Heart and Vascular Institute, Fairfax, VA, US
| | | | | | | | - Arshed A Quyyumi
- Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia
| | - Anurag Mehta
- Virginia Commonwealth University, Richmond, VA, US.
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Stevens PE, Ahmed SB, Carrero JJ, Foster B, Francis A, Hall RK, Herrington WG, Hill G, Inker LA, Kazancıoğlu R, Lamb E, Lin P, Madero M, McIntyre N, Morrow K, Roberts G, Sabanayagam D, Schaeffner E, Shlipak M, Shroff R, Tangri N, Thanachayanont T, Ulasi I, Wong G, Yang CW, Zhang L, Levin A. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int 2024; 105:S117-S314. [PMID: 38490803 DOI: 10.1016/j.kint.2023.10.018] [Citation(s) in RCA: 515] [Impact Index Per Article: 515.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 10/31/2023] [Indexed: 03/17/2024]
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