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Mondal S, Pramanik S, Khare VR, Fernandez CJ, Pappachan JM. Sodium glucose cotransporter-2 inhibitors and heart disease: Current perspectives. World J Cardiol 2024; 16:240-259. [PMID: 38817648 PMCID: PMC11135334 DOI: 10.4330/wjc.v16.i5.240] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 04/08/2024] [Accepted: 04/28/2024] [Indexed: 05/23/2024] Open
Abstract
Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.
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Affiliation(s)
- Sunetra Mondal
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Multispecialty Hospitals, Siliguri 734010, West Bengal, India
| | - Vibhu Ranjan Khare
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Cornelius James Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, United Kingdom.
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Eckert AJ, Zimny S, Altmeier M, Dugic A, Gillessen A, Bozkurt L, Götz G, Karges W, Wosch FJ, Kress S, Holl RW. Factors associated with diabetic foot ulcers and lower limb amputations in type 1 and type 2 diabetes supported by real-world data from the German/Austrian DPV registry. J Diabetes 2024; 16:e13531. [PMID: 38403299 PMCID: PMC10894714 DOI: 10.1111/1753-0407.13531] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/09/2023] [Accepted: 12/27/2023] [Indexed: 02/27/2024] Open
Abstract
AIMS Diabetic foot ulcer (DFU) is a leading cause of lower limb amputations in people with diabetes. This study was aimed to retrospectively analyze factors affecting DFU using real-world data from a large, prospective central-European diabetes registry (DPV [Diabetes-Patienten-Verlaufsdokumentation]). MATERIALS AND METHODS We matched adults with type 1 (T1D) or type 2 diabetes (T2D) and DFU to controls without DFU by diabetes type, age, sex, diabetes duration, and treatment year to compare possible risk factors. Cox regression was used to calculate hazard ratios for amputation among those with DFU. RESULTS In our cohort (N = 63 464), male sex, taller height, and diabetes complications such as neuropathy, peripheral artery disease, nephropathy, and retinopathy were associated with DFU (all p < .001). Glycated hemoglobin (HbA1c) was related to DFU only in T1D (mean with 95% confidence interval [CI]: 7.8 [6.9-9.0] % vs 7.5 [6.8-8.5] %, p < .001). High triglycerides and worse low-density lipoprotein/high-density lipoprotein ratio were also associated with DFU in T1D, whereas smoking (14.7% vs 13.1%) and alcohol abuse (6.4% vs 3.8%, both p < .001) were associated with DFU in T2D. Male sex, higher Wagner grades, and high HbA1c in both diabetes types and insulin use in T2D were associated with increased hazard ratios for amputations. CONCLUSIONS Sex, body height, and diabetes complications were associated DFU risk in adults with T1D and T2D. Improvement in glycemic control and lipid levels in T1D and reduction of smoking and drinking in T2D may be appropriate interventions to reduce the risk for DFU or amputations.
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Affiliation(s)
- Alexander J Eckert
- Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm, Germany
- German Center for Diabetes Research (DZD), Munich, Germany
| | - Stefan Zimny
- Department of General Internal Medicine, Endocrinology and Diabetology, Helios Clinic Schwerin, Schwerin, Germany
| | - Marcus Altmeier
- Klinik für Diabetologie, Klinikum Dortmund, Dortmund, Deutschland
| | - Ana Dugic
- Medical Clinic I, Klinikum Bayreuth Friedrich-Alexander-University Erlangen-Nürnberg, Bayreuth, Germany
| | - Anton Gillessen
- Department of Internal Medicine, Herz-Jesu-Hospital, Muenster, Germany
| | - Latife Bozkurt
- Department of Internal Medicine III and Karl Landsteiner Institute for Metabolic Disorders and Nephrology, Clinic Hietzing, Vienna Health Care Group, Vienna, Austria
| | - Gabriele Götz
- Department of Internal Medicine, Diabetes, Gastroenterology, Tumor Medicine, and Palliative Care, Academic Teaching Hospital Nürtingen, Tübingen, Germany
| | - Wolfram Karges
- Clinic for Gastroenterology, Metabolic Disorders and Internal Intensive Medicine (Medical Clinic III), Department of Endocrinology and Diabetology, University Hospital Aachen, Aachen, Germany
| | | | - Stephan Kress
- Diabetes, Sport and Physical Activity Working Group of the DDG, Unna, Germany
- Department of Internal Medicine I, Vinzentius Hospital Landau, Landau, Germany
| | - Reinhard W Holl
- Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm, Germany
- German Center for Diabetes Research (DZD), Munich, Germany
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Park S, Jeong HE, Bea S, Yu OHY, Cho YM, You SC, Man KKC, Shin JY. Safety of sodium-glucose co-transporter-2 inhibitors on amputation across categories of baseline cardiovascular disease and diuretics use in patients with type 2 diabetes. Diabetes Obes Metab 2023; 25:3248-3258. [PMID: 37503763 DOI: 10.1111/dom.15221] [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: 05/01/2023] [Revised: 06/28/2023] [Accepted: 07/04/2023] [Indexed: 07/29/2023]
Abstract
AIM To assess the risk of amputation associated with sodium-glucose co-transporter-2 inhibitors (SGLT2is) among patients with type 2 diabetes, across categories of baseline cardiovascular disease (CVD) and diuretic use (DU). MATERIALS AND METHODS We conducted an active comparator, new-user cohort study using Korea's nationwide claims data (2015-2020). The study cohort consisted of patients with type 2 diabetes who initiated SGLT2is or dipeptidyl peptidase-4 inhibitors (DPP4is). Cohort entry was defined by first prescription date. We then classified patients into four discrete subcohorts based on their baseline status of CVD and DU as (1) CVD+/DU+, (2) CVD+/DU-, (3) CVD-/DU+ and (4) CVD-/DU-. We performed 1:1 propensity score (PS) matching within each cohort and estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of amputation with SGLT2is versus DPP4is using Cox models. RESULTS We identified 219 900 PS-matched pairs of SGLT2is and DPP4is (CVD+/DU+, n = 11 719; CVD+/DU-, n = 26 092; CVD-/DU+, n = 26 894; and CVD-/DU-, n = 155 195), with well-balanced baseline covariates across all cohorts. Significantly lower risks of amputation with SGLT2is versus DPP4is were found in CVD+/DU+ (HR 0.36, 95% CI 0.14-0.90), CVD+/DU- (0.45, 0.21-0.99) and CVD-/DU- (0.48, 0.33-0.70), but not in CVD-/DU+ (0.54, 0.26-1.12). Consistent trends in estimates were found across various sensitivity analyses. CONCLUSIONS Initiating SGLT2is against DPP4is did not increase the risk of amputation across patient populations of varying vulnerability. These findings based on routine practice will reassure clinicians of the safety of SGLT2is with regard to amputation risk in selected high-risk patients with type 2 diabetes.
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Affiliation(s)
- Sohee Park
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
- Research Department of Practice and Policy, UCL School of Pharmacy, London, UK
| | - Han Eol Jeong
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
- Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, Republic of Korea
| | - Sungho Bea
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Oriana H Y Yu
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
- Division of Endocrinology and Metabolism, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
| | - Young Min Cho
- Department of Internal Medicine Seoul National University College of Medicine, Seoul, South Korea
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
- Institute on Aging, Seoul National University, Seoul, South Korea
| | - Seng Chan You
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kenneth K C Man
- Research Department of Practice and Policy, UCL School of Pharmacy, London, UK
- Centre for Medicines Optimisation Research and Education, University College London Hospitals NHS Foundation Trust, London, UK
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong
| | - Ju-Young Shin
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
- Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, Republic of Korea
- Department of Clinical Research Design & Evaluation, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Republic of Korea
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Mizutani G, Horii T, Oikawa Y, Atsuda K, Shimada A. Real-world risk of lower-limb amputation associated with sodium-glucose cotransporter 2 inhibitors versus metformin: A propensity score-matched model analysis in Japan. J Diabetes Investig 2022; 13:2000-2009. [PMID: 36124433 DOI: 10.1111/jdi.13906] [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: 05/21/2022] [Revised: 08/11/2022] [Accepted: 09/01/2022] [Indexed: 11/29/2022] Open
Abstract
AIMS/INTRODUCTION We aimed to clarify the real-world risk of lower-limb amputation and identify factors related to increased risk in Japanese patients with type 2 diabetes using sodium-glucose cotransporter 2 inhibitors (SGLT2is). MATERIALS AND METHODS We carried out a retrospective observational cohort study utilizing the Japanese Medical Data Vision, a diagnosis procedure combination database. We identified 107,296 patients with type 2 diabetes who were initiated on SGLT2is or metformin (control; n = 53,648 per group) using 1:1 propensity score matching from April 2014 to October 2019. The hazard ratio (HR) for the risk of lower-limb amputation was analyzed using a Cox proportional hazards model adjusted for patients' baseline characteristics and use of concomitant medical agents. RESULTS Of the 107,296 patients, 66 (0.06%); that is, 41 (0.08%) in the SGLT2is group and 25 (0.05%) in the metformin group, underwent amputation, with no significant difference in the proportions between the groups. There was no significant difference in the risk of amputation between the SGLT2is and metformin groups (HR 1.34, 95% confidence interval [CI] 0.80-2.24). However, female sex (HR 2.78, 95% CI 1.12-6.94) and use of strong statins (HR 2.68; 95% CI 1.18-8.20) were significantly associated with a higher risk of amputation in the SGLT2is group than in the metformin group. CONCLUSIONS SGLT2is might not be related to an increased risk of lower-limb amputation in patients with type 2 diabetes in real-world clinical practice. The possible increased risk of SGLT2is-associated amputation in female patients with type 2 diabetes and patients with type 2 diabetes requiring strong statins is notable.
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Affiliation(s)
- Gen Mizutani
- Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Saitama, Japan
| | - Takeshi Horii
- Research and Education Center for Clinical Pharmacy, Division of Clinical Pharmacy, Laboratory of Pharmacy Practice and Science 1, Kitasato University School of Pharmacy, Kanagawa, Japan.,Department of Pharmacy, Faculty of Pharmacy, Musashino University, Tokyo, Japan
| | - Yoichi Oikawa
- Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Saitama, Japan
| | - Koichiro Atsuda
- Research and Education Center for Clinical Pharmacy, Division of Clinical Pharmacy, Laboratory of Pharmacy Practice and Science 1, Kitasato University School of Pharmacy, Kanagawa, Japan
| | - Akira Shimada
- Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Saitama, Japan
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Lee YC, Dong YH, Yang WS, Wu LC, Lin JW, Chang CH. Risk of major adverse limb events in patients with type 2 diabetes mellitus receiving sodium glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists: A population-based retrospective cohort study. Front Pharmacol 2022; 13:869804. [PMID: 36176438 PMCID: PMC9513310 DOI: 10.3389/fphar.2022.869804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 08/10/2022] [Indexed: 12/03/2022] Open
Abstract
Background: Both sodium glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular protective effects in patients with type 2 diabetes mellitus. However, the comparative risk of GLP-1RA versus SGLT-2i for major adverse limb events remains unknown. Materials and methods: We studied a nationwide cohort involving 123,048 diabetes patients 20–100 years of age who initiated a SGLT-2i or GLP-1RA during 2012 and 2017. The patients in the two groups were matched by propensity score (PS), and incidence rates for hospitalization for major adverse limb events, critical limb ischemia (CLI) and lower extremity amputation (LEA), were assessed. Cox proportional hazards regression was applied to estimate hazard ratios (HRs) between patients receiving SGLT-2i as compared with GLP-1RA. The modification effects of age, a history of established cardiovascular disease, and chronic kidney disease were examined. In addition, use of dipeptidyl peptidase-4 inhibitor (DPP-4i) was chosen as a second active comparator. Results: After PS-matching, a total of 13,378 SGLT-2i and 13,378 GLP-1RA initiators were identified. Use of SGLT-2i was not associated with an increased risk for hospitalization for CLI and LEA, either compared with GLP-1RA (HR, 1.13; 95% CI, 0.77–1.65 and 1.27; 95% CI, 0.63–2.55, respectively) or compared with DPP-4i use (HR, 1.06; 95% CI, 0.75–1.50 and HR, 0.80; 95% CI, 0.42–1.53, respectively). Although the study was underpowered to explore potential effect modification, a trend of higher risks for LEA was noted among SGLT-2i users with cardiovascular disease as compared with either GLP-1RA or DPP-4i. Conclusion: Use of SGLT-2i was not associated with higher risks for hospitalization for CLI and LEA as compared with reference drugs. Further large-scale studies are needed for a precise risk estimation.
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Affiliation(s)
- Yen-Chieh Lee
- Department of Family Medicine, Cathay General Hospital, Taipei, Taiwan
- Department of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Yaa-Hui Dong
- Department of Pharmacy, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Public Health, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Hospital and Health Care Administration, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Shun Yang
- Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City, Taiwan
- The Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan
| | - Li-Chiu Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jou-Wei Lin
- Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Douliu City, Taiwan
- Cardiovascular Center, National Taiwan University Hospital Yunlin Branch, Douliu City, Taiwan
- Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- *Correspondence: Jou-Wei Lin, ; Chia-Hsuin Chang,
| | - Chia-Hsuin Chang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- *Correspondence: Jou-Wei Lin, ; Chia-Hsuin Chang,
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Marchiori E, Rodionov RN, Peters F, Magnussen C, Nordanstig J, Gombert A, Spanos K, Jarzebska N, Behrendt CA. SGLT2 Inhibitors and Peripheral Vascular Events. Heart Fail Clin 2022; 18:609-623. [DOI: 10.1016/j.hfc.2022.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Xu B, Li S, Kang B, Zhou J. The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management. Cardiovasc Diabetol 2022; 21:83. [PMID: 35614469 PMCID: PMC9134641 DOI: 10.1186/s12933-022-01512-w] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic, complex metabolic disease characterized by chronic hyperglycemia causing from insufficient insulin signaling because of insulin resistance or defective insulin secretion, and may induce severe complications and premature death. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are oral drugs used to reduce hyperglycemia in patients with T2DM, including empagliflozin, ertugliflozin, dapagliflozin and canagliflozin. The primary objective of this article is to examine the clinical benefit, safety, and tolerability of the four SGLT2 inhibitors approved by the US FDA. SGLT2 inhibitors increase urinary glucose excretion via inhibiting SGLT2 to decrease renal reabsorption of filtered glucose and reduce the renal threshold for glucose. Rather than stimulating insulin release, SGLT2 inhibitors improve β-cell function by improving glucotoxicity, as well as reduce insulin resistance and increase insulin sensitivity. Early clinical trials have confirmed the beneficial effects of SGLT2 in T2DM with acceptable safety and excellent tolerability. In recent years, SGLT2 inhibitors has been successively approved by the FDA to decrease cardiovascular death and decrease the risk of stroke and cardiac attack in T2DM adults who have been diagnosed with cardiovascular disease, treating heart failure (HF) with reduced ejection fraction and HF with preserved ejection fraction, and treat diabetic kidney disease (DKD), decrease the risk of hospitalization for HF in T2DM and DKD patients. SGLT2 inhibitors are expected to be an effective treatment for T2DM patients with non alcoholic fatty liver disease. SGLT2 inhibitors have a similar safety profile to placebo or other active control groups, with major adverse events such as Ketoacidosis or hypotension and genital or urinary tract infections.
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Affiliation(s)
- Bo Xu
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Shaoqian Li
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Bo Kang
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Jiecan Zhou
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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Alexander JT, Staab EM, Wan W, Franco M, Knitter A, Skandari MR, Bolen S, Maruthur NM, Huang ES, Philipson LH, Winn AN, Thomas CC, Zeytinoglu M, Press VG, Tung EL, Gunter K, Bindon B, Jumani S, Laiteerapong N. Longer-term Benefits and Risks of Sodium-Glucose Cotransporter-2 Inhibitors in Type 2 Diabetes: a Systematic Review and Meta-analysis. J Gen Intern Med 2022; 37:439-448. [PMID: 34850334 PMCID: PMC8811049 DOI: 10.1007/s11606-021-07227-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 10/19/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are a recent class of medication approved for the treatment of type 2 diabetes (T2D). Previous meta-analyses have quantified the benefits and harms of SGLT2Is; however, these analyses have been limited to specific outcomes and comparisons and included trials of short duration. We comprehensively reviewed the longer-term benefits and harms of SGLT2Is compared to placebo or other anti-hyperglycemic medications. METHODS We searched PubMed, Scopus, and clinicaltrials.gov from inception to July 2019 for randomized controlled trials of minimum 52 weeks' duration that enrolled adults with T2D, compared an SGLT2I to either placebo or other anti-hyperglycemic medications, and reported at least one outcome of interest including cardiovascular risk factors, microvascular and macrovascular complications, mortality, and adverse events. We conducted random effects meta-analyses to provide summary estimates using weighted mean differences (MD) and pooled relative risks (RR). The study was registered a priori with PROSPERO (CRD42018090506). RESULTS Fifty articles describing 39 trials (vs. placebo, n = 28; vs. other anti-hyperglycemic medication, n = 12; vs. both, n = 1) and 112,128 patients were included in our analyses. Compared to placebo, SGLT2Is reduced cardiovascular risk factors (e.g., hemoglobin A1c, MD - 0.55%, 95% CI - 0.62, - 0.49), macrovascular outcomes (e.g., hospitalization for heart failure, RR 0.70, 95% CI 0.62, 0.78), and mortality (RR 0.87, 95% CI 0.80, 0.94). Compared to other anti-hyperglycemic medications, SGLT2Is reduced cardiovascular risk factors, but insufficient data existed for other outcomes. About a fourfold increased risk of genital yeast infections for both genders was observed for comparisons vs. placebo and other anti-hyperglycemic medications. DISCUSSION We found that SGLT2Is led to durable reductions in cardiovascular risk factors compared to both placebo and other anti-hyperglycemic medications. Reductions in macrovascular complications and mortality were only observed in comparisons with placebo, although trials comparing SGLT2Is vs. other anti-hyperglycemic medications were not designed to assess longer-term outcomes.
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Affiliation(s)
- Jason T Alexander
- Department of Medicine, University of Chicago, Chicago, IL, USA.
- , Chicago, USA.
| | - Erin M Staab
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Wen Wan
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Melissa Franco
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | | | - M Reza Skandari
- Centre for Health Economics and Policy Innovation, Imperial College Business School, London, UK
| | - Shari Bolen
- Department of Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Nisa M Maruthur
- Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elbert S Huang
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | | | - Aaron N Winn
- Department of Clinical Sciences, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | | | - Valerie G Press
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | | | - Kathryn Gunter
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Brittany Bindon
- Department of Medicine, National Jewish Health, Denver, CO, USA
| | - Sanjay Jumani
- Department of Medicine, University of Chicago, Chicago, IL, USA
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Lower Limb Amputation Rates in Germany. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58010101. [PMID: 35056409 PMCID: PMC8780615 DOI: 10.3390/medicina58010101] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 11/17/2022]
Abstract
Background and Objectives: The current epidemiology of lower limb amputations is unknown. Therefore, the purpose of this study was to determine (1) lower extremity amputation rates as a function of age, gender, and amputation level between 2015 and 2019, (2) main diagnoses indicating amputation, (3) revision rates after lower extremity amputation. Materials and Methods: Lower extremity amputation rates were quantified based on annual Operation and Procedure Classification System (OPS) and International Classifications of Disease (ICD)-10 codes from all German medical institutions between 2015 through 2019, provided by the Federal Statistical Office of Germany (Destatis). Results: In 2019, 62,016 performed amputations were registered in Germany. Out of these 16,452 procedures (26.5%) were major amputations and 45,564 patients (73.5%) underwent minor amputations. Compared to 2015, the incidence of major amputations decreased by 7.3% to 24.2/100,000 inhabitants, whereas the incidence of minor amputation increased by 11.8% to 67.1/100,000 inhabitants. Highest incidence was found for male patients aged 80-89 years. Patients were mainly diagnosed with peripheral arterial disease (50.7% for major and 35.7% for minor amputations) and diabetes mellitus (18.5% for major and 44.2% for minor amputations). Conclusions: Lower limb amputations remain a serious problem. Further efforts in terms of multidisciplinary team approaches and patient optimization strategies are required to reduce lower limb amputation rates.
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Augusto GA, Cassola N, Dualib PM, Saconato H, Melnik T. Sodium-glucose cotransporter-2 inhibitors for type 2 diabetes mellitus in adults: An overview of 46 systematic reviews. Diabetes Obes Metab 2021; 23:2289-2302. [PMID: 34142426 DOI: 10.1111/dom.14470] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 06/02/2021] [Accepted: 06/14/2021] [Indexed: 12/11/2022]
Abstract
AIMS To summarize the evidence from systematic reviews (SRs) of randomized controlled trials (RCTs) evaluating the efficacy and safety of sodium-glucose cotransporter-2 (SGLT2) inhibitors versus placebo or active comparators for type 2 diabetes mellitus. MATERIALS AND METHODS We searched six databases between 2014 and 2021. We assessed the quality of evidence using Assessment of Multiple Systematic Reviews (AMSTAR 2) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) and summarized the main outcome results according to their evidence of benefit (PROSPERO ID: CRD42019132431). RESULTS We included 46 SRs, comprising 175 RCTs and 136 096 participants. The results showed "clear evidence of benefit" in relation to: myocardial infarction (odds ratio [OR]/hazard ratio [HR] 0.85 to 0.91); cardiovascular mortality (OR/HR 0.67 to 0.86); heart failure (OR/HR 0.64 to 0.69); albuminuria progression and composite renal outcome (relative risk [RR]/HR 0.55 to 0.63); glycated haemoglobin (HbA1c) versus placebo (mean difference [MD] -0.49% to -0.77% [5.4 to 8.4 mmol/mol]); and weight versus placebo (MD -1.09 kg to -2.99 kg). "Possible benefit" was observed in relation to major adverse cardiovascular events (OR/HR 0.80 to 0.89), all-cause mortality and nonalcoholic fatty liver disease. SGLT2 inhibitors showed "clear evidence of no effect or equivalence" in relation to stroke and fractures. "Clear evidence of harm" was observed in relation to genital infections (RR/OR 2.06 to 5.25) and ketoacidosis (HR/OR 1.36 to 2.20). Regarding amputation risk and urinary tract infections, we found "no conclusions possible due to lack of evidence". CONCLUSIONS Our results showed that SGLT2 inhibitors have beneficial effects in relation to renal and cardiovascular outcomes (except for stroke), HbA1c and weight. Further studies are needed to assess urinary infections and amputation risk.
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Affiliation(s)
- Gustavo A Augusto
- Brazilian Cochrane Centre, Universidade Federal de São Paulo (UNIFESP), Sao Paulo, Brazil
| | - Nicolle Cassola
- Brazilian Cochrane Centre, Universidade Federal de São Paulo (UNIFESP), Sao Paulo, Brazil
| | - Patrícia M Dualib
- Diabetes Centre of the Endocrinology Division, Universidade Federal de São Paulo (UNIFESP), Sao Paulo, Brazil
| | - Humberto Saconato
- Brazilian Cochrane Centre, Universidade Federal de São Paulo (UNIFESP), Sao Paulo, Brazil
| | - Tamara Melnik
- Brazilian Cochrane Centre, Universidade Federal de São Paulo (UNIFESP), Sao Paulo, Brazil
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11
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Htet ZM, Karim M. Sodium-glucose co-transporter 2 inhibitors: game changers when handled with care? J R Soc Med 2021; 114:351-358. [PMID: 33945350 PMCID: PMC8415814 DOI: 10.1177/01410768211011109] [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: 06/10/2020] [Accepted: 03/31/2021] [Indexed: 11/15/2022] Open
Abstract
Recent years have seen a paradigm shift in the management of patients with diabetes mellitus. Rather than good glycaemic control being the sole primary aim, the therapeutic focus has broadened to consider potential additional cardiovascular and renal benefits. Sodium-glucose co-transporter 2 inhibitors, such as empagliflozin, canagliflozin and dapagliflozin, have gained increasing prominence, with evidence suggesting significant improvement in outcomes in patients with established cardiovascular and renal disease. Here, we discuss the benefits and relative risks of these novel agents and highlight important clinical issues of relevance to general physicians.
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Affiliation(s)
- Zay M Htet
- Norfolk and Norwich University Hospital NHS Trust, Norwich NR4 7UY, UK
| | - Mahzuz Karim
- Norfolk and Norwich University Hospital NHS Trust, Norwich NR4 7UY, UK
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12
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Paul SK, Bhatt DL, Montvida O. The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium-glucose cotransporter type-2 inhibitors: real-world study. Eur Heart J 2021; 42:1728-1738. [PMID: 33289789 DOI: 10.1093/eurheartj/ehaa956] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/18/2020] [Accepted: 11/12/2020] [Indexed: 01/14/2023] Open
Abstract
AIMS The aim of this study was to evaluate the temporal pattern of amputations in patients with type 2 diabetes mellitus (T2DM), the risk of amputations by new and older anti-diabetic drugs (ADDs), and the interplay of peripheral artery disease (PAD) with therapy and amputation risk. METHODS AND RESULTS Using Centricity Electronic Medical Records from USA, 3 293 983 patients with T2DM were identified: 169 739 received sodium-glucose cotransporter type-2 inhibitors (SGLT-2i; no exposure to incretins); 149 826 received glucagon-like peptide 1 receptor agonists [GLP-1RA, no SGLT-2i or dipeptidyl peptidase-4 inhibitor (DPP-4i) exposure]; 448 225 received DPP-4i (no exposure to GLP-1RA or SGLT-2i); and 1 954 353 received other ADDs. The proportion of incident amputations per 10 000 adults ranged between 4.7 and 6.8 during 2000-08 and significantly increased to 12.3 in 2017. Over 17 211 719 person-years follow-up post T2DM diagnosis, the rates per 1000 person-years of any and lower limb amputations (LLAs) were similar between SGLT-2i and incretins [95% confidence interval (CI) range: 1.06-1.67], and significantly higher in other groups (95% CI range: 1.96-2.29). In propensity score-adjusted pairwise analyses, the risk of LLA was not higher in SGLT-2i vs. GLP1-RA [hazard ratio (HR) (95% CI): 0.88 (0.73, 1.05)], and lower in SGLT-2i vs. DPP-4i/other ADD [HR (95% CI): 0.65 (0.56, 0.75)/0.43 (0.37, 0.49)]. The rate of LLA was similar in patients treated with canagliflozin, empagliflozin, or dapagliflozin. Patients with PAD had more than four-fold higher LLA risk (range of 95% CI of HR: 3.6-6.0). CONCLUSION The risk of amputation in patients treated with SGLT-2i and incretins was not higher compared with other ADDs. Pre-existing PAD was the greatest driver of amputation risk.
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Affiliation(s)
- Sanjoy K Paul
- Melbourne EpiCentre, University of Melbourne, The Royal Melbourne Hospital - City Campus, 7 East, Main Building, Grattan Street, Parkville Victoria 3050, Australia
| | - Deepak L Bhatt
- Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Olga Montvida
- Melbourne EpiCentre, University of Melbourne, The Royal Melbourne Hospital - City Campus, 7 East, Main Building, Grattan Street, Parkville Victoria 3050, Australia
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13
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Montada-Atin T, Prasad GVR. Recent advances in new-onset diabetes mellitus after kidney transplantation. World J Diabetes 2021; 12:541-555. [PMID: 33995843 PMCID: PMC8107982 DOI: 10.4239/wjd.v12.i5.541] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/05/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
A common challenge in managing kidney transplant recipients (KTR) is post-transplant diabetes mellitus (PTDM) or diabetes mellitus (DM) newly diagnosed after transplantation, in addition to known pre-existing DM. PTDM is an important risk factor for post-transplant cardiovascular (CV) disease, which adversely affects patient survival and quality of life. CV disease in KTR may manifest as ischemic heart disease, heart failure, and/or left ventricular hypertrophy. Available therapies for PTDM include most agents currently used to treat type 2 diabetes. More recently, the use of sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and dipeptidyl peptidase 4 inhibitors (DPP4i) has cautiously extended to KTR with PTDM, even though KTR are typically excluded from large general population clinical trials. Initial evidence from observational studies seems to indicate that SGLT2i, GLP-1 RA, and DPP4i may be safe and effective for glycemic control in KTR, but their benefit in reducing CV events in this otherwise high-risk population remains unproven. These newer drugs must still be used with care due to the increased propensity of KTR for intravascular volume depletion and acute kidney injury due to diarrhea and their single-kidney status, pre-existing burden of peripheral vascular disease, urinary tract infections due to immunosuppression and a surgically altered urinary tract, erythrocytosis from calcineurin inhibitors, and reduced kidney function from acute or chronic rejection.
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Affiliation(s)
- Tess Montada-Atin
- Kidney Transplant Program, St. Michael's Hospital, Toronto M5C 2T2, Ontario, Canada
| | - G V Ramesh Prasad
- Kidney Transplant Program, St. Michael's Hospital, Toronto M5C 2T2, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto M5C 2T2, Canada
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14
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Grachev VG, Vedenskaya SS, Smolenskaya OG. Features of Risk Stratification, Diagnosis and Secondary Prevention in Patients with Multifocal Arterial Disease. Part 2: Treatment Options. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2021. [DOI: 10.20996/1819-6446-2021-03-02] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The similarity of the pathogenesis of atherosclerosis and atherothrombotic complications, regardless of their location, makes the approaches to secondary prevention similar, which include lifestyle modification, pharmacotherapy of hemodynamic disorders, metabolic changes and hemostasis. Secondary prophylaxis in patients with multifocal arterial lesions using antihypertensive, antithrombotic and lipid-lowering therapy provides a more pronounced decrease in the incidence of cardiovascular complications than in lesions of single vascular lesions due to a higher initial risk. However, these treatments do not reduce the risk to the level that is achieved by treating patients with less atherosclerotic lesion. In this regard, it is of interest to use the currently available new methods and regimens of drug therapy in patients with multifocal arterial lesions, which make it possible to more intensively influence the mechanisms of atherosclerosis progression and more effectively prevent the development of its complications.
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15
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Grachev VG, Vedenskaya SS, Smolenskaya OG. Features of Antithrombotic Therapy in Patients with Multifocal Arterial Disease. ACTA ACUST UNITED AC 2021; 61:87-95. [PMID: 33849424 DOI: 10.18087/cardio.2021.3.n1498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/26/2021] [Accepted: 02/25/2021] [Indexed: 12/24/2022]
Abstract
Multifocal arterial injury is common in patients with atherosclerotic cardiovascular diseases and is associated with increased risk of cardiovascular complications and death. Administration of more intensive antithrombotic therapy, particularly combinations of acetylsalicylic acid and a "vascular" dose of rivaroxaban, in patients with multifocal arterial injury is characterized by a beneficial ratio of efficiency and safety due to a pronounced decrease in the risk of cardiovascular complications. Detection of peripheral artery diseases in patients with ischemic heart disease and atherosclerotic cerebrovascular pathology makes it possible to improve the risk stratification, optimize the diagnostic tactics and clarify indications for more intensive antithrombotic therapy.
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Affiliation(s)
- V G Grachev
- Urals State Medical University of Ministry Healthcare of Russian Federation, Yekaterinburg
| | - S S Vedenskaya
- Urals State Medical University of Ministry Healthcare of Russian Federation, Yekaterinburg
| | - O G Smolenskaya
- Urals State Medical University of Ministry Healthcare of Russian Federation, Yekaterinburg
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16
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Werkman NCC, Nielen JTH, van den Bergh JPW, Ejskjaer N, Røikjer J, Schaper NC, Rossi B, Klungel O, Vestergaard P, de Vries F, Driessen JHM. Use of Sodium-Glucose Co-Transporter-2-Inhibitors (SGLT2-Is) and Risk of Lower Limb Amputation. Curr Drug Saf 2021; 16:62-72. [PMID: 32767909 DOI: 10.2174/1574886315666200805103053] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/03/2020] [Accepted: 06/16/2020] [Indexed: 01/02/2023]
Abstract
BACKGROUND Treatment with sodium-glucose co-transporter-2-inhibitors (SGLT2-Is), such as canagliflozin, has been associated with an increased risk of lower limb amputations (LLAs) in type 2 diabetes mellitus (T2DM). However, conflicting results have been reported for different SGLT2-Is and the underlying mechanism is unclear. OBJECTIVE To investigate the risk of LLA and diabetic foot ulcer with SGLT2-I use compared to other anti-diabetic drugs and to explore hypovolemia as a potential underlying mechanism. METHODS A cohort study was conducted using data from the Clinical Practice Research Datalink GOLD (2013-2019). The study population (N=51,847) consisted of T2DM patients over 18 years of age with at least one prescription of a non-insulin anti-diabetic drug. Concomitant diuretic use and the presence of signs of hypovolemia were determined to assess the potential underlying mechanism. Cox proportional hazard models were used to estimate the hazard ratio (HR) for LLA in current SGLT2-I use versus current sulphonylurea (SU) use. Analyses were adjusted for lifestyle variables, comorbidities, and concomitant drug use. RESULTS Current SGLT2-I use was not associated with an increased risk of LLA compared to current SU use (fully adjusted HR 0.70; 95% confidence interval 0.38-1.29). Concomitant use of diuretics and the presence of signs of hypovolemia were not associated with an increased risk of LLA. CONCLUSION Use of SGLT2-Is, with or without signs of hypovolemia, was not associated with an increased risk of LLA or DFU versus current SU use. Future studies powered to detect potential differences between individual SGLT2-Is are required to rule out a canagliflozin-specific effect.
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Affiliation(s)
- Nikki C C Werkman
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
| | - Johannes T H Nielen
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center+, Maastricht, Netherlands
| | - Joop P W van den Bergh
- School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands
| | - Niels Ejskjaer
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Johan Røikjer
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Nicolaas C Schaper
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
| | - Bernardette Rossi
- Directorate Pharmaceutical Affairs, Department for Policy in Health, Ministry for Health, Valletta, Malta
| | - Olaf Klungel
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, Netherlands
| | - Peter Vestergaard
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Frank de Vries
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
| | - Johanna H M Driessen
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
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17
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Biscetti F, Nardella E, Rando MM, Cecchini AL, Gasbarrini A, Massetti M, Flex A. Outcomes of Lower Extremity Endovascular Revascularization: Potential Predictors and Prevention Strategies. Int J Mol Sci 2021; 22:2002. [PMID: 33670461 PMCID: PMC7922574 DOI: 10.3390/ijms22042002] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 01/02/2023] Open
Abstract
Peripheral artery disease (PAD) is a manifestation of atherosclerosis, which may affect arteries of the lower extremities. The most dangerous PAD complication is chronic limb-threatening ischemia (CLTI). Without revascularization, CLTI often causes limb loss. However, neither open surgical revascularization nor endovascular treatment (EVT) ensure long-term success and freedom from restenosis and revascularization failure. In recent years, EVT has gained growing acceptance among all vascular specialties, becoming the primary approach of revascularization in patients with CLTI. In clinical practice, different clinical outcomes after EVT in patients with similar comorbidities undergoing the same procedure (in terms of revascularization technique and localization of the disease) cause unsolved issues that need to be addressed. Nowadays, risk management of revascularization failure is one of the major challenges in the vascular field. The aim of this literature review is to identify potential predictors for lower extremity endovascular revascularization outcomes and possible prevention strategies.
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Affiliation(s)
- Federico Biscetti
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (M.M.R.); (A.G.); (M.M.); (A.F.)
- Cardiovascular Internal Medicine Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy
| | - Elisabetta Nardella
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (E.N.); (A.L.C.)
| | - Maria Margherita Rando
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (M.M.R.); (A.G.); (M.M.); (A.F.)
- Cardiovascular Internal Medicine Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy
| | - Andrea Leonardo Cecchini
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (E.N.); (A.L.C.)
| | - Antonio Gasbarrini
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (M.M.R.); (A.G.); (M.M.); (A.F.)
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (E.N.); (A.L.C.)
| | - Massimo Massetti
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (M.M.R.); (A.G.); (M.M.); (A.F.)
- Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy
| | - Andrea Flex
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (M.M.R.); (A.G.); (M.M.); (A.F.)
- Cardiovascular Internal Medicine Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (E.N.); (A.L.C.)
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18
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Qiu M, Ding LL, Zhang M, Zhou HR. Comparison of the risk of SGLT2is and NonSGLT2is in leading to amputation: A network meta-analysis. J Diabetes Complications 2021; 35:107803. [PMID: 33293207 DOI: 10.1016/j.jdiacomp.2020.107803] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 10/31/2020] [Accepted: 11/06/2020] [Indexed: 11/29/2022]
Abstract
OBJECTIVE Whether sodium-glucose cotransporter 2 inhibitors (SGLT2is) increase the risk of amputation or not remains controversial. We aimed to evaluate the relative risk of different SGLT2is and Non-SGLT2i antihyperglycemic drugs (NonSGLT2is) in leading to amputation by network meta-analysis of large sample studies. METHODS We searched Embase and PubMed for relevant large sample studies. We conducted Bayesian network meta-analysis using random-effects model. Effect size was presented as hazard ratio (HR) and 95% confidence interval (CI). RESULTS Seventeen large studies involving 1 million SGLT2i users and 3 million NonSGLT2i users were included in network meta-analysis. SGLT2is [HR (95% CI): 1.38 (1.02, 1.91)] versus NonSGLT2is significantly increased the amputation risk, whereas SGLT2is [HR (95% CI): 1.45 (0.94, 2.17)] versus placebo did not. Compared with glucagon-like peptide 1 receptor agonists (GLP1RAs), canagliflozin [HR (95% CI): 1.5 (1.01, 2.33)] along with incorporative SGLT2is [HR (95% CI): 1.64 (1.07, 2.53)] significantly increased the amputation risk, whereas empagliflozin [HR (95% CI): 1.46 (0.83, 2.67)] and dapagliflozin [HR (95% CI): 1.22 (0.7, 2.23)] did not due to the wide 95% CIs of HRs. CONCLUSION Although SGLT2is versus placebo do not significantly increase the amputation risk, SGLT2is (especially, canagliflozin) versus NonSGLT2is (especially, GLP1RAs) significantly increase that risk.
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Affiliation(s)
- Mei Qiu
- Department of General Medicine, Shenzhen Longhua District Central Hospital, Shenzhen 518110, China
| | - Liang-Liang Ding
- Department of Endocrinology, First Affiliated Hospital of Yangtze University, Jingzhou 434000, China
| | - Miao Zhang
- Department of Nephrology, Shenzhen Hospital of Beijing University of Chinese Medicine, Shenzhen 518116, China
| | - Hai-Rong Zhou
- Department of General Medicine, Shenzhen Longhua District Central Hospital, Shenzhen 518110, China.
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19
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Tang H, Yang K, Li X, Song Y, Han J. Pancreatic safety of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Pharmacoepidemiol Drug Saf 2021; 29:161-172. [PMID: 32017292 DOI: 10.1002/pds.4943] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 11/07/2019] [Accepted: 11/25/2019] [Indexed: 12/26/2022]
Abstract
PURPOSE This study aimed to systematically evaluate the association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and pancreatic safety in patients with type 2 diabetes mellitus (T2DM). METHODS Electronic databases were searched before September 2019 to include randomized controlled trials (RCTs) of SGLT2 inhibitors that reported any event on pancreatitis or pancreatic cancer among patients with T2DM. Peto odds ratio (OR) with 95% confidence interval (CI) was used to pool the data. The GRADE framework was introduced to assess the quality of evidence. RESULTS Of the 35 trials involving 44 912 patients with T2DM included, 41 events of acute pancreatitis (19 trials; 32 932 patients), 72 events of overall pancreatitis (including acute pancreatitis, chronic pancreatitis, or nonspecific pancreatitis; 26 trials; 36 688 patients), and 40 events of pancreatic cancer (18 trials; 27 806 patients) were reported during a median follow-up of 52 weeks. SGLT2 inhibitors were not associated with an increased risk of acute pancreatitis compared to controls (placebo or other active drugs; Peto OR, 1.13; 95% CI, 0.60-2.13; moderate quality evidence). A similar result was found for risk of overall pancreatitis (Peto OR, 1.08; 95% CI, 0.67-1.75; moderate quality evidence) and pancreatic cancer (Peto OR, 1.34; 95% CI, 0.71-2.54; very low-quality evidence). CONCLUSIONS Moderate quality evidence from RCTs shows no significantly increased risk of acute pancreatitis associated with SGLT2 inhibitors, while there is very low-quality evidence suggesting no significant association between SGLT2 inhibitors and pancreatic cancer among patients with T2DM.
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Affiliation(s)
- Huilin Tang
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indiana
| | - Keming Yang
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indiana
| | - Xin Li
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indiana
| | - Yiqing Song
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indiana
| | - Jiali Han
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indiana.,Melvin and Bren Simon Cancer Center, Indiana University, Indiana
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20
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Sodium–Glucose Cotransporter-2 Inhibitors and the Risk of Amputation: What Is Currently Known? Am J Ther 2021; 28:e96-e110. [DOI: 10.1097/mjt.0000000000001164] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Giorgino F, Vora J, Fenici P, Solini A. Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovasc Diabetol 2020; 19:196. [PMID: 33222693 PMCID: PMC7680601 DOI: 10.1186/s12933-020-01163-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/29/2020] [Indexed: 02/07/2023] Open
Abstract
Approximately half of all patients with type 2 diabetes (T2D) develop a certain degree of renal impairment. In many of them, chronic kidney disease (CKD) progresses over time, eventually leading to end-stage kidney disease (ESKD) requiring dialysis and conveying a substantially increased risk of cardiovascular morbidity and mortality. Even with widespread use of renin-angiotensin system blockers and tight glycemic control, a substantial residual risk of nephropathy progression remains. Recent cardiovascular outcomes trials investigating sodium-glucose cotransporter 2 (SGLT2) inhibitors have suggested that these therapies have renoprotective effects distinct from their glucose-lowering action, including the potential to reduce the rates of ESKD and acute kidney injury. Although patients in most cardiovascular outcomes trials had higher prevalence of existing cardiovascular disease compared with those normally seen in clinical practice, the proportion of patients with renal impairment was similar to that observed in a real-world context. Patient cardiovascular risk profiles did not relevantly impact the renoprotective benefits observed in these studies. Benefits were observed in patients across a spectrum of renal risk, but were evident also in those without renal damage, suggesting a role for SGLT2 inhibition in the prevention of CKD in people with T2D. In addition, recent studies such as CREDENCE and DAPA-CKD offer a greater insight into the renoprotective effects of SGLT2 inhibitors in patients with moderate-to-severe CKD. This review outlines the evidence that SGLT2 inhibitors may prevent the development of CKD and prevent and delay the worsening of CKD in people with T2D at different levels of renal risk.
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Affiliation(s)
- Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Policlinico, Piazza Giulio Cesare, 11, 70124, Bari, Italy.
| | - Jiten Vora
- Diabetes and Endocrinology, University of Liverpool, Liverpool, UK
| | | | - Anna Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
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Hassanein M, Bashier A, Randeree H, Abouelmagd M, AlBaker W, Afandi B, Abu Hijleh O, Shaltout I, Ei-Sharkawy M, Dagdelen S, Assaad Khalil S. Use of SGLT2 inhibitors during Ramadan: An expert panel statement. Diabetes Res Clin Pract 2020; 169:108465. [PMID: 32971151 DOI: 10.1016/j.diabres.2020.108465] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 08/31/2020] [Accepted: 09/16/2020] [Indexed: 01/17/2023]
Abstract
Fasting from dawn to sunset, during the holy month of Ramadan, constitutes one of the five main pillars in Islam and is observed by the majority of Muslims. Owing to important physiological changes, Ramadan fasting holds a crucial place in the context of diabetes management. Approximately one-fifth of the world's Muslim population resides in the Middle East and Africa (MEA) region. To discuss the challenges and management of diabetes during Ramadan fasting in the MEA region, a panel of 12 experts in the field of diabetes from across the MEA region attended two expert committee meetings held in Dubai. The key point of discussion was the safety and efficacy of the use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) during Ramadan, based on outcomes of the recent clinical trials with SGLT2i. This is the first consensus recommendation on the management of diabetes with SGLT2i across the MEA region during Ramadan. The document summarizes expert views and opinions on the current management of diabetes with SGLT2i during Ramadan and aims to enhance the current knowledge and understanding on the issue of diabetes management during Ramadan. This will aid the physicians of the MEA region with appropriate decision-making for their patients during Ramadan.
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Affiliation(s)
- Mohamed Hassanein
- Consultant Endocrinology, Dubai Hospital, Dubai, United Arab Emirates.
| | | | | | | | - Waleed AlBaker
- Associate Professor of Medicine, University of Immam Abdulrahman Bin Faisal, Saudi Arabia
| | - Bachar Afandi
- Division Chief, Endocrinology (Diabetic Clinic - Medical Affairs, Tawam Hospital), Abu Dhabi, United Arab Emirates
| | - Omar Abu Hijleh
- Senior Consultant Endocrinologist, Jordan Center for Thyroid, Endocrine Diseases and Diabetes, Jordan Hospital Medical Center, Jordan
| | | | - Magdy Ei-Sharkawy
- Professor, Internal Medicine and Nephrology, Ain Shams University, Cairo, Egypt
| | - Selcuk Dagdelen
- Department of Endocrinology and Metabolism, Hacettepe University School of Medicine, Turkey
| | - Samir Assaad Khalil
- Professor of Endocrinology, Medicine, Alexandria University, Alexandria, Egypt
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23
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Muzurović EM, Mikhailidis DP. Diabetes Mellitus and Noncardiac Atherosclerotic Vascular Disease-Pathogenesis and Pharmacological Treatment Options. J Cardiovasc Pharmacol Ther 2020; 26:25-39. [PMID: 32666812 DOI: 10.1177/1074248420941675] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Diabetes mellitus (DM) is also a cause of cardiovascular (CV) disease (CVD). Addressing the atherosclerotic CVD (ASCVD) burden in DM should reduce premature death and improve quality of life. Diabetes mellitus-associated ASCVD can lead to complications in all vascular beds (carotids as well as coronary, lower extremity, and renal arteries). This narrative review considers the diagnosis and pharmacological treatment of noncardiac atherosclerotic vascular disease (mainly in patients with DM). Based on current knowledge and the fact that modern DM treatment guidelines are based on CV outcome trials, it should be noted that patients with noncardiac CVD may not have the same benefits from certain drugs compared with patients who predominantly have cardiac complications. This leads to the conclusion that in the future, consideration should be given to conducting well-designed trials that will answer which pharmacological treatment modalities will be of greatest benefit to patients with noncardiac ASCVD.
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Affiliation(s)
- Emir M Muzurović
- Department of Internal Medicine, Endocrinology Section, 274294Clinical Centre of Montenegro, Ljubljanska bb, Podgorica, Montenegro.,Faculty of Medicine, University of Montenegro, Kruševac bb, Podgorica, Montenegro
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom
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24
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Ni L, Yuan C, Chen G, Zhang C, Wu X. SGLT2i: beyond the glucose-lowering effect. Cardiovasc Diabetol 2020; 19:98. [PMID: 32590982 PMCID: PMC7320582 DOI: 10.1186/s12933-020-01071-y] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 06/16/2020] [Indexed: 02/06/2023] Open
Abstract
Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are a new type of glucose-lowering drug that can reduce blood glucose by inhibiting its reabsorption in proximal tubules and by promoting urinary glucose excretion. SGLT2i are widely used in the clinical treatment of type 2 diabetes mellitus (T2DM). In recent studies, SGLT2i were found to not only reduce blood glucose but also protect the heart and kidney, which can significantly reduce cardiovascular events, delay the progression of renal failure, greatly improve the quality of life of patients, and reduce medical expenses for families and society. As adverse cardiac and renal events are the most common and serious complications of T2DM, it is very important to understand the cardio- and renoprotective mechanisms of SGLT2i. This article reviews the historical development, pharmacological mechanism, heart and kidney protection and safety of SGLT2i. The information presented provides a theoretical basis for the clinical prevention and treatment of diabetes and its complications and for the development of new glucose-lowering drugs.
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Affiliation(s)
- Lihua Ni
- Department of Nephrology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei, 430071, China
| | - Cheng Yuan
- Department of Gynecological Oncology, Zhongnan Hospital, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Guopeng Chen
- Institute of Model Animal, Wuhan University, Wuhan, 430071, China.,School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Changjiang Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Zhang Road No. 99, Wuhan, Hubei, 430060, China. .,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China. .,Hubei Key Laboratory of Cardiology, Wuhan, 430060, People's Republic of China. .,Cardiovascular Disease Center, Enshi Central Hospital, Enshi, 445000, People's Republic of China.
| | - Xiaoyan Wu
- Department of Nephrology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei, 430071, China.
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25
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Miyashita S, Kuno T, Takagi H, Sugiyama T, Ando T, Valentin N, Shimada YJ, Kodaira M, Numasawa Y, Kanei Y, Bangalore S. Risk of amputation associated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of five randomized controlled trials. Diabetes Res Clin Pract 2020; 163:108136. [PMID: 32272190 DOI: 10.1016/j.diabres.2020.108136] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/27/2020] [Accepted: 03/26/2020] [Indexed: 12/17/2022]
Abstract
Amputation has been known to be a rare adverse event of sodium glucose co-transporter-2 (SGLT2) inhibitors. It remains unclear whether the SGLT2 inhibitor as a class or specific categories of the SGLT2 inhibitors are linked with an increased risk of amputation. The objective of this meta-analysis was to investigate the association between the amputation risk and the use of SGLT2 inhibitors. The main outcome measure was the risk of amputation. Multiple databases were searched up to February 2020 and data extraction was performed. Inclusion criteria were randomized controlled trials (RCTs) which reported risk of amputation with SGLT2 inhibitors over non-SGLT2 inhibitors or placebo. The risk of bias was assessed by Cochrane bias tool. The initial search yielded 1,873 citations and a total of five RCTs were included in the meta-analysis. The five included studies evaluated a total of 39,067 patients with diabetes mellitus, including 21,395 patients on SGLT2 inhibitors. The incidence rate of amputation ranged from 0.36 to 3.18% in the SGLT2 inhibitor group and from 0% to 2.87% in the control group. Follow up duration ranged from 24 weeks to 4.2 years. Use of SGLT2 inhibitors was not associated with significant increase in the risk of amputation as compared with controls (OR: 1.31, 95% CI: 0.92-1.87, I2 = 75%). Subgroup analysis showed that neither canagliflozin, empagliflozin, nor dapagliflozin was associated with increased risk of amputation. In conclusion, our meta-analysis showed that neither canagliflozin nor other SGLT2 inhibitors increase the risk of amputation.
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Affiliation(s)
- Satoshi Miyashita
- Department of Medicine, Mount Sinai Beth Israel Medical Center, NY, USA
| | - Toshiki Kuno
- Department of Medicine, Mount Sinai Beth Israel Medical Center, NY, USA.
| | - Hisato Takagi
- Department of Cardiovascular Surgery, Shizuoka Medical Center, Shizuoka, Japan
| | - Takehiro Sugiyama
- Diabetes and Metabolism Information Center, Research Institute, Center for Global Health and Medicine, Tokyo, Japan; Department of Health Services Research, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Public Health/Health Policy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomo Ando
- Department of Cardiology, Detroit Medical Center, MI, USA
| | - Nelson Valentin
- Department of Medicine, Mount Sinai Beth Israel Medical Center, NY, USA
| | - Yuichi J Shimada
- Division of Cardiology, Department of Medicine, Columbia University Medical Center, NY, USA
| | - Masaki Kodaira
- Department of Cardiology, Japanese Red Cross Ashikaga Hospital, Ashikaga, Japan
| | - Yohei Numasawa
- Department of Cardiology, Japanese Red Cross Ashikaga Hospital, Ashikaga, Japan
| | - Yumiko Kanei
- Department of Cardiology, Mount Sinai Beth Israel Medical Center, NY, USA
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26
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Effect of empagliflozin beyond glycemic control: Cardiovascular benefit in patients with type 2 diabetes and established cardiovascular disease. Rev Port Cardiol 2020; 38:721-735. [PMID: 31892455 DOI: 10.1016/j.repc.2019.02.008] [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: 06/04/2018] [Revised: 01/16/2019] [Accepted: 02/03/2019] [Indexed: 11/22/2022] Open
Abstract
The prevalence of type 2 diabetes (T2D) continues to increase, and its association with cardiovascular (CV) disease has led to the inclusion of CV endpoints in clinical trials on the treatment of T2D. This article explores the various trials already performed and under development in this field, with particular focus on the EMPA-REG OUTCOME trial. In this trial, empagliflozin, a sodium-glucose co-transporter 2 inhibitor, demonstrated a reduction in CV risk in patients with T2D and established CV disease, in addition to CV safety and a decrease in glycated hemoglobin. This represents a paradigm shift that has led to changes in the international guidelines for the treatment of T2D. These results were maintained in subsequent subgroup analysis for heart failure, chronic kidney disease and peripheral arterial disease, although there are many questions concerning the mechanisms involved in these effects, including whether they are hemodynamic, metabolic or due to decreased myocardial cytoplasmic sodium concentrations. With this reduction in risk for major CV events in patients with T2D, the EMPA-REG OUTCOME trial demonstrated CV protection from a hypoglycemic drug for the first time, and opened a new era in the treatment and management of T2D. This study has led to the development of ongoing trials that will establish which patients will benefit most from this therapy, particularly with regard to comorbidities.
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27
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Bagherpour A, Saleem A, Gill G, Walser EM. Revascularization. IMAGE-GUIDED INTERVENTIONS 2020:111-124.e3. [DOI: 10.1016/b978-0-323-61204-3.00014-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
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28
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McGill JB, Subramanian S. Safety of Sodium-Glucose Co-Transporter 2 Inhibitors. Am J Cardiol 2019; 124 Suppl 1:S45-S52. [PMID: 31741440 DOI: 10.1016/j.amjcard.2019.10.029] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 08/06/2019] [Indexed: 12/17/2022]
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have a well-defined safety profile based on data obtained from numerous clinical trials, including cardiovascular outcomes trials (CVOTs) and postmarketing pharmacovigilance reporting. Adverse events including risk of genital mycotic infection and volume depletion-related events are consistent with the mechanism of action of this drug class. However, several emergent (albeit infrequent) serious safety issues have also been reported. In their respective CVOTs, the proportion of patients with reported diabetic ketoacidosis was similar in empagliflozin or canagliflozin compared with their placebo groups, but it was higher for dapagliflozin. Canagliflozin may be associated with an increased risk of bone fracture and lower limb amputation; however, data are inconclusive. There is no evidence linking SGLT2 inhibitors with an increased risk of cancer, but these agents, particularly dapagliflozin, should be used with caution in patients with hematuria or a history of bladder cancer. Postmarketing reports of acute kidney injury have occurred in patients receiving SGLT2 inhibitors, and cases identified in recent CVOTs occurred with similar frequency in SGLT2 inhibitor and placebo groups. Common adverse events associated with SGLT2 inhibitors (such as genital infections or volume depletion) are generally mild and manageable by patients or by primary care physicians, and the risk of rare events (such as ketoacidosis) can be minimized by appropriate patient selection and early recognition of symptoms. When selecting treatment, it is important that clinicians weigh the known risks of SGLT2 inhibitors against their proven benefits, including the reduction of adverse cardiovascular and renal outcomes.
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Affiliation(s)
- Janet B McGill
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Mo.
| | - Savitha Subramanian
- Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle
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29
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McCoy RG, Dykhoff HJ, Sangaralingham L, Ross JS, Karaca-Mandic P, Montori VM, Shah ND. Adoption of New Glucose-Lowering Medications in the U.S.-The Case of SGLT2 Inhibitors: Nationwide Cohort Study. Diabetes Technol Ther 2019; 21:702-712. [PMID: 31418588 PMCID: PMC7207017 DOI: 10.1089/dia.2019.0213] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background: High-quality diabetes care is evidence-based, timely, and equitable. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are the most recently approved class of glucose-lowering medications with additional cardio- and renal-protective benefits and low risk of hypoglycemia. Cardiovascular and kidney disease are among the most common chronic diabetes complications, whereas hypoglycemia is the most prevalent adverse effect of glucose-lowering therapy. We examine the sociodemographic and clinical factors associated with early SGLT2i initiation and appropriateness of use based on contemporaneous scientific evidence. Materials and Methods: Retrospective analysis of medical and pharmacy claims data from OptumLabs® Data Warehouse for commercially insured and Medicare Advantage adult beneficiaries with diabetes types 1 and 2, who filled any glucose-lowering medication between January 1, 2013 and December 31, 2016. Demographic (age, sex, race, income), clinical (comorbidities), and insurance-related factors affecting first prescription for a SGLT2i were examined using multivariable logistic regression. Results: Among 1,054,727 adults with pharmacologically treated diabetes, 7.2% (n = 75,500) initiated a SGLT2i. Patients with prior myocardial infarction (MI) (odds ratio [OR]: 0.94, 95% confidence interval [CI]: 0.91-0.96), heart failure (HF) (OR: 0.93, 95% CI: 0.91-0.94), kidney disease (OR: 0.80, 95% CI: 0.78-0.81), and severe hypoglycemia (OR: 0.96, 95% CI: 0.94-0.98) were all less likely to start a SGLT2i; P < 0.001 for all. SGLT2i were also less likely to be started by patients ≥75 years (OR: 0.57, 95% CI: 0.55-0.59, vs. 18-44 years), Black patients (OR: 0.93, 95% CI: 0.91-0.95, vs. White), and those with Medicare Advantage insurance (OR: 0.63, 95% CI: 0.62-0.64, vs. commercial). Conclusions: Younger, healthier, non-Black patients with commercial health insurance were most likely to start taking SGLT2i. Patients with MI, HF, kidney disease, and prior hypoglycemia were less likely to use SGLT2i, despite evidence supporting their preferential use in these patients. Efforts to address this treatment-risk paradox may help improve health outcomes among patients with type 2 diabetes.
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Affiliation(s)
- Rozalina G. McCoy
- Division of Community Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota
- Division of Health Care Policy and Research, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Rochester, Minnesota
| | - Hayley J. Dykhoff
- Division of Health Care Policy and Research, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Rochester, Minnesota
| | - Lindsey Sangaralingham
- Division of Health Care Policy and Research, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Rochester, Minnesota
| | - Joseph S. Ross
- National Clinician Scholars Program, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
- Section of General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
- Department of Health Policy and Management, Yale School of Medicine, New Haven, Connecticut
- Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, Connecticut
| | - Pinar Karaca-Mandic
- Carlson School of Management, University of Minnesota, Minneapolis, Minnesota
- National Bureau of Economic Research, Cambridge, Massachusetts
| | - Victor M. Montori
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic, Rochester, Minnesota
- Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, Minnesota
| | - Nilay D. Shah
- Division of Health Care Policy and Research, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Rochester, Minnesota
- OptumLabs, Cambridge, Massachusetts
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30
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Papadokostaki E, Rizos E, Tigas S, Liberopoulos EN. Canagliflozin and Amputation Risk: Evidence So Far. INT J LOW EXTR WOUND 2019; 19:21-26. [DOI: 10.1177/1534734619878090] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The CANVAS program detected a 2-fold increased risk of lower limb amputation in patients treated with canagliflozin compared with those with placebo. This adverse effect was not confirmed in the CREDENCE trial. Moreover, randomized controlled trials with other agents in this class, dapagliflozin and empagliflozin, did not detect increased risk of amputation. Observational studies, cohort studies, and pharmacovigilance reports with sodium-glucose cotransporter 2 inhibitor (SGLT2i) have reported conflicting results. Whether this adverse event is a drug effect specific to canagliflozin, or a SGLT2i class effect, remains controversial. Until more evidence emerges, clinicians should avoid using SGLT2i, especially canagliflozin, in patients with previous amputations or existing foot ulceration.
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Affiliation(s)
| | - Evangelos Rizos
- European University Cyprus, Nicosia, Cyprus
- University of Ioannina, Ioannina, Greece
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31
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Nagahisa T, Saisho Y. Cardiorenal Protection: Potential of SGLT2 Inhibitors and GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes. Diabetes Ther 2019; 10:1733-1752. [PMID: 31440988 PMCID: PMC6778572 DOI: 10.1007/s13300-019-00680-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Indexed: 02/06/2023] Open
Abstract
Recent large clinical trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, with the aim of verifying cardiovascular safety, have revealed that these medications have a preventative advantage on adverse cardiovascular outcomes, including worsening of heart failure and deterioration of nephropathy, in patients with type 2 diabetes (T2D). These observed benefits do not seem to correlate with the glucose-lowering effect, and the underlying mechanism is being intensively investigated. Given the results from recent studies, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that patients with T2D and clinical cardiovascular disease (CVD) with inadequate glucose control despite treatment with metformin should receive an SGLT2 inhibitor or GLP-1 receptor agonist. In this review we summarize the results of recent cardiovascular outcome trials and discuss the potential clinical advantage of SGLT2 inhibitors and GLP-1 receptor agonists. We also present practical implications of these glucose-lowering agents for reducing the risk of adverse cardiovascular events and progressive renal comorbidity in patients with T2D and CVD.
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Affiliation(s)
- Taichi Nagahisa
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yoshifumi Saisho
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
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32
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Monteiro P, Aguiar C, Matos P, Silva-Nunes J, Birne R, Branco P, Calado J, Melo M, Polónia J. Effect of empagliflozin beyond glycemic control: Cardiovascular benefit in patients with type 2 diabetes and established cardiovascular disease. REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2019. [DOI: 10.1016/j.repce.2019.02.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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33
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Tentolouris A, Vlachakis P, Tzeravini E, Eleftheriadou I, Tentolouris N. SGLT2 Inhibitors: A Review of Their Antidiabetic and Cardioprotective Effects. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:2965. [PMID: 31426529 PMCID: PMC6720282 DOI: 10.3390/ijerph16162965] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 08/10/2019] [Accepted: 08/12/2019] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes mellitus is a chronic metabolic disease associated with high cardiovascular (CV) risk. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the latest class of antidiabetic medication that inhibit the absorption of glucose from the proximal tubule of the kidney and hence cause glycosuria. Four SGLT2i are currently commercially available in many countries: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. SGLT2i reduce glycated hemoglobin by 0.5%-1.0% and have shown favorable effects on body weight, blood pressure, lipid profile, arterial stiffness and endothelial function. More importantly, SGLT2i have demonstrated impressive cardioprotective and renoprotective effects. The main mechanisms underlying their cardioprotective effects have been attributed to improvement in cardiac cell metabolism, improvement in ventricular loading conditions, inhibition of the Na+/H+ exchange in the myocardial cells, alteration in adipokines and cytokines production, as well as reduction of cardiac cells necrosis and cardiac fibrosis. The main adverse events of SGLT2i include urinary tract and genital infections, as well as euglycemic diabetic ketoacidosis. Concerns have also been raised about the association of SGLT2i with lower limb amputations, Fournier gangrene, risk of bone fractures, female breast cancer, male bladder cancer, orthostatic hypotension, and acute kidney injury.
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Affiliation(s)
- Anastasios Tentolouris
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece
| | - Panayotis Vlachakis
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece
| | - Evangelia Tzeravini
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece
| | - Ioanna Eleftheriadou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece
| | - Nikolaos Tentolouris
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece.
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34
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Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitridge R, Mills JL, Ricco JB, Suresh KR, Murad MH, Aboyans V, Aksoy M, Alexandrescu VA, Armstrong D, Azuma N, Belch J, Bergoeing M, Bjorck M, Chakfé N, Cheng S, Dawson J, Debus ES, Dueck A, Duval S, Eckstein HH, Ferraresi R, Gambhir R, Gargiulo M, Geraghty P, Goode S, Gray B, Guo W, Gupta PC, Hinchliffe R, Jetty P, Komori K, Lavery L, Liang W, Lookstein R, Menard M, Misra S, Miyata T, Moneta G, Munoa Prado JA, Munoz A, Paolini JE, Patel M, Pomposelli F, Powell R, Robless P, Rogers L, Schanzer A, Schneider P, Taylor S, De Ceniga MV, Veller M, Vermassen F, Wang J, Wang S. Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia. Eur J Vasc Endovasc Surg 2019; 58:S1-S109.e33. [PMID: 31182334 PMCID: PMC8369495 DOI: 10.1016/j.ejvs.2019.05.006] [Citation(s) in RCA: 890] [Impact Index Per Article: 148.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
GUIDELINE SUMMARY Chronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on definition, evaluation, and management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD) in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI) is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR) hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen) has not been established. Regenerative medicine approaches (eg, cell, gene therapies) for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative.
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Affiliation(s)
- Michael S Conte
- Division of Vascular and Endovascular Surgery, University of California, San Francisco, CA, USA.
| | - Andrew W Bradbury
- Department of Vascular Surgery, University of Birmingham, Birmingham, United Kingdom
| | - Philippe Kolh
- Department of Biomedical and Preclinical Sciences, University Hospital of Liège, Wallonia, Belgium
| | - John V White
- Department of Surgery, Advocate Lutheran General Hospital, Niles, IL, USA
| | - Florian Dick
- Department of Vascular Surgery, Kantonsspital St. Gallen, St. Gallen, and University of Berne, Berne, Switzerland
| | - Robert Fitridge
- Department of Vascular and Endovascular Surgery, The University of Adelaide Medical School, Adelaide, South Australia, Australia
| | - Joseph L Mills
- Division of Vascular Surgery and Endovascular Therapy, Baylor College of Medicine, Houston, TX, USA
| | - Jean-Baptiste Ricco
- Department of Clinical Research, University Hospitalof Poitiers, Poitiers, France
| | | | - M Hassan Murad
- Mayo Clinic Evidence-Based Practice Center, Rochester, MN, USA
| | - Victor Aboyans
- Department of Cardiology, Dupuytren, University Hospital, France
| | - Murat Aksoy
- Department of Vascular Surgery American, Hospital, Turkey
| | | | | | | | - Jill Belch
- Ninewells Hospital University of Dundee, UK
| | - Michel Bergoeing
- Escuela de Medicina Pontificia Universidad, Catolica de Chile, Chile
| | - Martin Bjorck
- Department of Surgical Sciences, Vascular Surgery, Uppsala University, Sweden
| | | | | | - Joseph Dawson
- Royal Adelaide Hospital & University of Adelaide, Australia
| | - Eike S Debus
- University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, Germany
| | - Andrew Dueck
- Schulich Heart Centre, Sunnybrook Health, Sciences Centre, University of Toronto, Canada
| | - Susan Duval
- Cardiovascular Division, University of, Minnesota Medical School, USA
| | | | - Roberto Ferraresi
- Interventional Cardiovascular Unit, Cardiology Department, Istituto Clinico, Città Studi, Milan, Italy
| | | | - Mauro Gargiulo
- Diagnostica e Sperimentale, University of Bologna, Italy
| | | | | | | | - Wei Guo
- 301 General Hospital of PLA, Beijing, China
| | | | | | - Prasad Jetty
- Division of Vascular and Endovascular Surgery, The Ottawa Hospital and the University of Ottawa, Ottawa, Canada
| | | | | | - Wei Liang
- Renji Hospital, School of Medicine, Shanghai Jiaotong University, China
| | - Robert Lookstein
- Division of Vascular and Interventional Radiology, Icahn School of Medicine at Mount Sinai
| | | | | | | | | | | | | | - Juan E Paolini
- Sanatorio Dr Julio Mendez, University of Buenos Aires, Argentina
| | - Manesh Patel
- Division of Cardiology, Duke University Health System, USA
| | | | | | | | - Lee Rogers
- Amputation Prevention Centers of America, USA
| | | | - Peter Schneider
- Kaiser Foundation Hospital Honolulu and Hawaii Permanente Medical Group, USA
| | - Spence Taylor
- Greenville Health Center/USC School of Medicine Greenville, USA
| | | | - Martin Veller
- University of the Witwatersrand, Johannesburg, South Africa
| | | | - Jinsong Wang
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shenming Wang
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Katsiki N, Dimitriadis G, Hahalis G, Papanas N, Tentolouris N, Triposkiadis F, Tsimihodimos V, Tsioufis C, Mikhailidis DP, Mantzoros C. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) use and risk of amputation: an expert panel overview of the evidence. Metabolism 2019; 96:92-100. [PMID: 30980838 DOI: 10.1016/j.metabol.2019.04.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 04/03/2019] [Accepted: 04/06/2019] [Indexed: 12/12/2022]
Abstract
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are oral antidiabetic agents that exert their glucose-lowering effect by increasing renal excretion of glucose. These drugs have been reported to beneficially affect cardiovascular (CV) and renal outcomes. However, concerns have recently been raised in relation to increased risk of lower-extremities amputation with canagliflozin and it remains unclear whether and to what extent this side effect could also occur with other SGLT2i. The present expert panel overview focuses on the three SGLT2i available and widely used in the US and Europe, i.e. empagliflozin, canagliflozin and dapagliflozin and only refers briefly to other SGLT2i for which less data are available. The results of large CV outcome trials with these SGLT2i are presented, focusing specifically on the data in relation to amputation risk. The potential pathophysiological mechanisms involved in this side effect are discussed. Furthermore, available data reporting amputation cases in SGLT2i users are critically reviewed. The expert panel concludes that, based on current data, increased amputation risk seems to be related only to canagliflozin, thus representing a drug-effect rather than a SGLT2i class-effect. The exact pathways underlying this drug-induced adverse event, possibly related to off-target drug effects rather than SGLT2 inhibition per se, should be elucidated in future studies. Continuous monitoring and pharmacovigilance is necessary and head to head trials would also be essential to provide definitive conclusions.
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Affiliation(s)
- Niki Katsiki
- First Department of Internal Medicine, Division of Endocrinology and Metabolism, Diabetes Center, Medical School, AHEPA University Hospital, Thessaloniki, Greece.
| | - George Dimitriadis
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, "Attikon" University hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George Hahalis
- Department of Cardiology, University of Patras Medical School, Patras, Greece
| | - Nikolaos Papanas
- Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
| | - Nikolaos Tentolouris
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | | | - Vasilios Tsimihodimos
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece
| | - Costas Tsioufis
- First Cardiology Clinic, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL), London, UK.
| | - Christos Mantzoros
- Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
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36
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Monteiro-Soares M, Ribeiro-Vaz I, Boyko EJ. Canagliflozin should be prescribed with caution to individuals with type 2 diabetes and high risk of amputation. Diabetologia 2019; 62:900-904. [PMID: 30941448 DOI: 10.1007/s00125-019-4861-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 03/08/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Matilde Monteiro-Soares
- Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Porto, Portugal
| | - Inês Ribeiro-Vaz
- Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine, University of Porto, Porto, Portugal
- Porto Pharmacovigilance Center, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Edward J Boyko
- Veterans Affairs Puget Sound Health Care System (S-123-PCC), 1660 S. Columbian Way, Seattle, WA, 98108, USA.
- University of Washington School of Medicine, Seattle, WA, USA.
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Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitridge R, Mills JL, Ricco JB, Suresh KR, Murad MH. Global vascular guidelines on the management of chronic limb-threatening ischemia. J Vasc Surg 2019; 69:3S-125S.e40. [PMID: 31182334 PMCID: PMC8365864 DOI: 10.1016/j.jvs.2019.02.016] [Citation(s) in RCA: 876] [Impact Index Per Article: 146.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Chronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on definition, evaluation, and management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD) in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI) is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR) hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen) has not been established. Regenerative medicine approaches (eg, cell, gene therapies) for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative.
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Affiliation(s)
- Michael S Conte
- Division of Vascular and Endovascular Surgery, University of California, San Francisco, Calif.
| | - Andrew W Bradbury
- Department of Vascular Surgery, University of Birmingham, Birmingham, United Kingdom
| | - Philippe Kolh
- Department of Biomedical and Preclinical Sciences, University Hospital of Liège, Wallonia, Belgium
| | - John V White
- Department of Surgery, Advocate Lutheran General Hospital, Niles, Ill
| | - Florian Dick
- Department of Vascular Surgery, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Robert Fitridge
- Department of Vascular and Endovascular Surgery, The University of Adelaide Medical School, Adelaide, South Australia
| | - Joseph L Mills
- Division of Vascular Surgery and Endovascular Therapy, Baylor College of Medicine, Houston, Tex
| | - Jean-Baptiste Ricco
- Department of Clinical Research, University Hospitalof Poitiers, Poitiers, France
| | | | - M Hassan Murad
- Mayo Clinic Evidence-Based Practice Center, Rochester, Minn
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Abstract
INTRODUCTION Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are recommended after metformin for a large spectrum of patients with type 2 diabetes, because of a favorable benefit/risk profile despite a variety of adverse events. AREAS COVERED This narrative review discusses the safety profile of SGLT2is: initial concerns (cardiovascular safety, acute renal failure, hypoglycemia, urinary and genital infections, volume depletion, bladder cancer), further concerns (euglycemic ketoacidosis, bone fractures) and more recent concerns (lower limb amputation, Fournier's gangrene). EXPERT OPINION Overall, the safety profile of SGLT2is is good. The only increased adverse event that was consistently reported in clinical trials and observational studies is genital mycotic infections, with only a borderline increase in urinary tract infections. Among clinical trials, only the CANVAS program reported an unexpected increase in bone fractures and peripheral amputations. A variety of rare adverse events have been described as case reports, including ketoacidosis, amputations and Fournier gangrene, which led to specific warnings by regulatory agencies. Identifying predisposing patient's characteristics and/or precipitating clinical conditions would help prevent the most severe complications. These adverse events should not mask the overall cardiovascular and renal benefit of SGLT2is, especially in patients with type 2 diabetes at high cardiovascular risk.
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Affiliation(s)
- André J Scheen
- a Division of Clinical Pharmacology , Center for Interdisciplinary Research on Medicines (CIRM), Liège University , Liège , Belgium.,b Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine , CHU Liège , Liège , Belgium
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Abstract
In recent years the surgical treatment of metabolic diseases has become established as an effective alternative to conservative treatment. The new S3 guidelines address these changes and give clear indications for obesity surgery. One of the core points of the new guidelines is the differentiation between obesity surgery and metabolic surgery. In obesity surgery the primary aim of treatment is weight loss whereas for metabolic indications the aim is an improvement of comorbidities independent of the body mass index (BMI). With respect to the selection of procedures sleeve gastrectomy (SG) and the traditional Roux-en-Y gastric bypass (RYGB) can be used as safe and evidence-based operative procedures. The RYGB has better metabolic effects but higher complication and reintervention rates. More recent procedures, such as the one anastomosis gastric bypass (OAGB) and single anastomosis duodeno-ileal (SADI) bypass possibly have slightly stronger metabolic effects, however, the risk of malnutrition and vitamin deficiency is higher.
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Affiliation(s)
- A T Billeter
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsklinik Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Deutschland
| | - B P Müller-Stich
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsklinik Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Deutschland.
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40
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Tang H, Yang K, Song Y, Han J. Meta-analysis of the association between sodium-glucose co-transporter-2 inhibitors and risk of skin cancer among patients with type 2 diabetes. Diabetes Obes Metab 2018; 20:2919-2924. [PMID: 30039616 DOI: 10.1111/dom.13474] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 07/11/2018] [Accepted: 07/15/2018] [Indexed: 12/24/2022]
Abstract
A slight increase in melanoma risk was observed among sodium-glucose co-transporter-2 (SGLT-2) inhibitor users in the regular reports. However, the association remains uncertain. To address this issue, we performed a systematic search of electronic databases up to May 2, 2018 and a meta-analysis of 21 randomized controlled trials (RCTs) involving 20 308 patients. We did not find a significant increase in risk of melanoma among SGLT-2 inhibitor users (Peto odds ratio [OR], 2.17; 95% confidence interval [CI], 0.80-5.89; I2 , 0%). Similar results were observed in the subgroup analyses according to the type of SGLT-2 inhibitor, type of control, ages of patients, race/ethnicity, and trial durations. For non-melanoma skin cancer risk, no significant difference was observed when all trials were combined (Peto OR, 0.70; 95% CI, 0.47-1.07; I2 , 0%), while a significantly decreased risk was observed among trials with duration <52 weeks (Peto OR, 0.12; 95% CI, 0.02-0.59; I2 , 0%). No evidence of publication bias was detected in the analyses. Current evidence from RCTs did not support a significantly increased risk of skin cancer associated with SGLT-2 inhibitors.
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Affiliation(s)
- Huilin Tang
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana
| | - Keming Yang
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana
| | - Yiqing Song
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana
| | - Jiali Han
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana
- Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana
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Chatterjee S, Bandyopadhyay D, Ghosh RK, Majumdar U, Aneja A, Lavie CJ, Deedwania P. SGLT-2 Inhibitors and Peripheral Artery Disease: A Statistical Hoax or Reality? Curr Probl Cardiol 2018; 44:207-222. [PMID: 30195639 DOI: 10.1016/j.cpcardiol.2018.06.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 06/29/2018] [Indexed: 12/14/2022]
Abstract
Inhibitors of sodium-glucose cotransporters type-2 are the most recent addition to the armamentarium of oral antidiabetic agents. This class of drugs has shown promising results in glycemic control and most importantly to reduce cardiovascular disease (CVD) mortality risk. Despite the encouraging data, there is concern regarding their potential for causing or worsening peripheral artery disease (PAD), which may increase the risk of lower extremity amputations. Following the publication of results of CANVAS and CANVAS-R trials, which revealed that leg and mid-foot amputations occurred about twice as often in patients treated with canagliflozin compared to placebo, the Food and Drug Administration (FDA) in the United States issued a black box warning of leg and foot amputations associated with canagliflozin use. In this article, our main aim is to review the available evidence in preclinical and clinical studies regarding SGLT-2 inhibitors and PAD events, the possible mechanisms related to increased risk of amputation, to evaluate whether it is a class effect or individual drug effect, and most importantly, implications for their continued use as antidiabetic agents. It also raises the issue of including PAD events among the end-points when assessing future antihyperglycemic agents. Thus, we also tried to analyze whether outcomes of SGLT2 inhibitors trials mostly focused on stroke, myocardial infarction, heart failure, and peripheral vascular disease-related outcomes remained underrated.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, CHU Liège, Liège, Belgium.
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
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