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Kao DP, Martin JL, Aquilante CL, Shalowitz EL, Leyba K, Kudron E, Reusch JEB, Regensteiner JG. Sex-differences in reporting of statin-associated diabetes mellitus to the US Food and Drug Administration. BMJ Open Diabetes Res Care 2024; 12:e004343. [PMID: 39638563 PMCID: PMC11624814 DOI: 10.1136/bmjdrc-2024-004343] [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: 05/28/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024] Open
Abstract
INTRODUCTION Diabetes mellitus (DM) is increasingly recognized as a possible consequence of statin therapy. Secondary analysis of randomized clinical trials and limited observational cohort analyses have suggested that women may be more likely than men to experience statin-associated DM. No analyses of real-world drug safety data addressing this question have been published. RESEARCH DESIGN AND METHODS This was a retrospective pharmacovigilance analysis of spontaneously reported adverse drug events (ADEs) submitted to the Food and Drug Administration Adverse Event Reporting System between January 1997 through December 2023. We analyzed cases that mentioned atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin in aggregate as well as cases reporting atorvastatin, pravastatin, rosuvastatin, simvastatin individually. DM events were identified using the Medical Dictionary for Regulatory Activities. We used the proportional reporting ratio to identify increased rates of statin-associated DM events in women and men compared with all other medications, and the reporting OR to compare reporting rates in women versus men. RESULTS A total of 18,294,814 ADEs were reported during the study period. Among statin-associated ADEs, 14,874/519,209 (2.9%) reports mentioned DM in women compared with 7,411/489,453 (1.5%) in men, which were both significantly higher than background (0.6%). Statins were the primary-suspected or secondary-suspected cause of the ADE significantly more often in women than men (60 vs 30%), and reporting rates were disproportionately higher in women than in men for all statins. (reporting OR 1.9 (95% CI 1.9 to 2.0)). The largest difference in reporting of statin-associated DM between women and women was observed with atorvastatin. CONCLUSIONS Analysis of post-marketing spontaneous ADE reports demonstrated a higher reporting rate of DM-associated with statin use compared with other medications with a significantly higher reporting rate in women compared with men. Future studies should consider mechanisms of statin-associated DM moderated by sex.
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Affiliation(s)
- David P Kao
- Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Ludeman Family Center for Women's Health Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - James L Martin
- Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Christina L Aquilante
- Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Elise L Shalowitz
- Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Katarina Leyba
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Elizabeth Kudron
- Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Medicine, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Jane E B Reusch
- Ludeman Family Center for Women's Health Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Judith G Regensteiner
- Ludeman Family Center for Women's Health Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Medicine, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Menon B, Syed R, Yadav PK, Menon M. Diabetes and Stroke—A Focused Review. JOURNAL OF DIABETOLOGY 2024; 15:247-257. [DOI: 10.4103/jod.jod_46_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 05/21/2024] [Indexed: 01/06/2025] Open
Abstract
Abstract
Globally, diabetes mellitus (DM) and stroke are two common chronic illnesses that have a substantial impact on rates of morbidity and mortality. There is significant evidence linking diabetes to an increased risk of stroke in terms of incidence, severity, and mortality. This extensive review looks at shared risk factors, underlying pathophysiological mechanisms, epidemiological trends, and evidence-based therapy approaches to give a thorough analysis of the causal relationship between diabetes mellitus and stroke. Studies using epidemiological data regularly show that people with diabetes have a higher incidence of stroke than people without the disease. Furthermore, diabetes is linked to a less favorable outcome following a stroke, as well as an elevated chance of stroke recurrence. Determining the pathophysiological pathways that connect diabetes and stroke is essential to understanding their relationship. Key pathophysiological processes associated with these disorders include endothelial dysfunction, inflammation, oxidative stress, hyperglycemia, and dyslipidemia. Due to microvascular complications, these mechanisms raise the risk of hemorrhagic stroke and predispose diabetics to an increased risk of ischemic stroke by creating a prothrombotic and atherosclerotic milieu. Diabetes and stroke are linked due to shared risk factors like smoking, obesity, dyslipidemia, hypertension, and poor glycemic control. Lifestyle changes, blood pressure control, lipid-lowering therapy, antiplatelet medicines, and a nutritious diet are essential for stroke risk reduction. Reducing the risk of stroke in people with diabetes requires the implementation of management techniques that focus on both diabetes control and stroke prevention. Optimizing results and lowering the frequency of stroke-related complications in diabetics requires multidisciplinary care. The intricate interactions between diabetes mellitus and stroke are highlighted in this review’s conclusion, which also highlights the value of patient education, risk factor treatment, the effect of antidiabetic therapy on stroke, and integrated care in lowering the incidence of stroke in people with diabetes.
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Affiliation(s)
- Bindu Menon
- Department of Neurology, Apollo Speciality Hospitals, Nellore, Andhra Pradesh, India
| | - Rizwana Syed
- Department of Neurology, Apollo Speciality Hospitals, Nellore, Andhra Pradesh, India
| | - Praveen Kumar Yadav
- Sri Ramakrishna Mission Medical College (SRIMS), Durgapur, West Bengal, India
| | - Medha Menon
- Department of Medicine, Kasturba Medical College, Manipal, India
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Kaya HK, Demirtas B, Yokus B, Kesim DA, Tasdemir E, Sermet A. Comparative effects of pravastatin and rosuvastatin on carbohydrate metabolism in an experimental diabetic rat model. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2024; 74:117-130. [PMID: 38554383 DOI: 10.2478/acph-2024-0001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/22/2023] [Indexed: 04/01/2024]
Abstract
Statin treatment may increase the risk of diabetes; there is insufficient data on how statins affect glucose regulation and glycemic control and the effects of statins on liver enzymes related to carbohydrate metabolism have not been fully studied. Therefore, we aimed to compare the effects of the statin derivatives, pravastatin, and rosuvastatin, on carbohydrate metabolism in an experimental diabetic rat model. Female Wistar albino rats were used and diabetes was induced by intraperitoneal injection of streptozotocin. Thereafter, 10 and 20 mg kg-1 day-1 doses of both pravastatin and rosuvastatin were administered by oral gavage to the diabetic rats for 8 weeks. At the end of the experiment, body masses, the levels of fasting blood glucose, serum insulin, insulin resistance (HOMA-IR), liver glycogen, and liver enzymes related to carbohydrate metabolism were measured. Both doses of pravastatin significantly in creased the body mass in diabetic rats, however, rosuvastatin, especially at the dose of 20 mg kg-1 day-1 reduced the body mass signi ficantly. Pravastatin, especially at a dose of 20 mg kg-1 day-1, caused significant increases in liver glycogen synthase and glucose 6-phosphate dehydrogenase levels but significant decreases in the levels of glycogen phosphorylase, lactate dehydrogenase, and glucose-6-phosphatase. Hence, pravastatin partially ameliorated the adverse changes in liver enzymes caused by diabetes and, especially at the dose of 20 mg kg-1 day-1, reduced the fasting blood glucose level and increased the liver glycogen content. However, rosuvastatin, especially at the dose of 20 mg kg-1 day-1, significantly reduced the liver glycogen synthase and pyruvate kinase levels, but increased the glycogen phosphorylase level in diabetic rats. Rosuvastatin, 20 mg kg-1 day-1 dose, caused significant decreases in the body mass and the liver glycogen content of diabetic rats. It can be concluded that pravastatin, especially at the dose of 20 mg kg-1 day-1 is more effective in ameliorating the negative effects of diabetes by modulating carbohydrate metabolism.
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Affiliation(s)
- Hacer Kayhan Kaya
- Department of Physiology, Dicle University, Faculty of Medicine Diyarbakır, Turkey
| | - Berjan Demirtas
- Plant and Animal Production Department, Equine and Training Program, Vocational School of Veterinary Medicine, İstanbul University-Cerahpaşa, İstanbul, Turkey
| | - Beran Yokus
- Department of Biochemistry Faculty of Veterinary Medicine Dicle University Diyarbakır Turkey
| | - Dilek Aygün Kesim
- Department of Physical Medicine and Rehabilitation, Dicle University, Faculty of Medicine Diyarbakır, Turkey
| | - Ezel Tasdemir
- Department of Internal Medicine Medicalpark Hospitals, Antalya Turkey
| | - Abdurrahman Sermet
- Department of Physiology, Dicle University, Faculty of Medicine Diyarbakır, Turkey
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Khedr A, Hennawi HA, Khan MK, Elbanna M, Jama AB, Proskuriakova E, Mushtaq H, Mir M, Boike S, Rauf I, Eissa A, Urtecho M, Koritala T, Jain N, Goyal L, Surani S, Khan SA. Effect of fibrinolytic therapy on ST-elevation myocardial infarction clinical outcomes during the COVID-19 pandemic: A systematic review and meta-analysis. World J Cardiol 2023; 15:309-323. [PMID: 37397830 PMCID: PMC10308269 DOI: 10.4330/wjc.v15.i6.309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 03/30/2023] [Accepted: 05/19/2023] [Indexed: 06/26/2023] Open
Abstract
BACKGROUND ST-elevation myocardial infarction (STEMI) is the result of transmural ischemia of the myocardium and is associated with a high mortality rate. Primary percutaneous coronary intervention (PPCI) is the recommended first-line treatment strategy for patients with STEMI. The timely delivery of PPCI became extremely challenging for STEMI patients during the coronavirus disease 2019 (COVID-19) pandemic, leading to a projected steep rise in mortality. These delays were overcome by the shift from first-line therapy and the development of modern fibrinolytic-based reperfusion. It is unclear whether fibrinolytic-based reperfusion therapy is effective in improving STEMI endpoints.
AIM To determine the incidence of fibrinolytic therapy during the COVID-19 pandemic and its effects on STEMI clinical outcomes.
METHODS PubMed, Google Scholar, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were queried from January 2020 up to February 2022 to identify studies investigating the effect of fibrinolytic therapy on the prognostic outcome of STEMI patients during the pandemic. Primary outcomes were the incidence of fibrinolysis and the risk of all-cause mortality. Data were meta-analyzed using the random effects model to derive odds ratios (OR) and 95% confidence intervals. Quality assessment was carried out using the Newcastle-Ottawa scale.
RESULTS Fourteen studies including 50136 STEMI patients (n = 15142 in the pandemic arm; n = 34994 in the pre-pandemic arm) were included. The mean age was 61 years; 79% were male, 27% had type 2 diabetes, and 47% were smokers. Compared with the pre-pandemic period, there was a significantly increased overall incidence of fibrinolysis during the pandemic period [OR: 1.80 (1.18 to 2.75); I2= 78%; P = 0.00; GRADE: Very low]. The incidence of fibrinolysis was not associated with the risk of all-cause mortality in any setting. The countries with a low-and middle-income status reported a higher incidence of fibrinolysis [OR: 5.16 (2.18 to 12.22); I2 = 81%; P = 0.00; GRADE: Very low] and an increased risk of all-cause mortality in STEMI patients [OR: 1.16 (1.03 to 1.30); I2 = 0%; P = 0.01; GRADE: Very low]. Meta-regression analysis showed a positive correlation of hyperlipidemia (P = 0.001) and hypertension (P < 0.001) with all-cause mortality.
CONCLUSION There is an increased incidence of fibrinolysis during the pandemic period, but it has no effect on the risk of all-cause mortality. The low- and middle-income status has a significant impact on the all-cause mortality rate and the incidence of fibrinolysis.
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Affiliation(s)
- Anwar Khedr
- Department of Internal Medicine, BronxCare Health System, Bronx, NY 10457, United States
| | - Hussam Al Hennawi
- Department of Internal Medicine, Jefferson Abington Hospital, Abington, PA 19001, United States
| | - Muhammed Khuzzaim Khan
- Department of Internal Medicine, Dow University of Health Science, Karachi 74200, Pakistan
| | - Mostafa Elbanna
- Department of Internal Medicine, Rochester Regional Health, Rochester, NY 14621, United States
| | - Abbas B Jama
- Department of Critical Care, Mayo Clinic Health System, Mankato, MN 56001, United States
| | | | - Hisham Mushtaq
- Department of Internal Medicine, St. Vincent's Medical Center, Bridgeport, CT 06606, United States
| | - Mikael Mir
- Department of Medicine, University of Minnesota, Minneapolis, MN 55455, United States
| | - Sydney Boike
- Department of Medicine, University of Minnesota, Minneapolis, MN 55455, United States
| | - Ibtisam Rauf
- Department of Medicine, St. George's University, School of Medicine, St George SW17 0RE, Grenada
| | - Aalaa Eissa
- Department of Medicine, KFS University, KFS 33511, Egypt
| | - Meritxell Urtecho
- Department of Medicine, Robert D and Patricia E. Kern Center of Health Care Delivery, Mayo Clinic, Rochester, MN 55905, United States
| | - Thoyaja Koritala
- Department of Hospital Medicine, Mayo Clinic Health System, Mankato, MN 56001, United States
| | - Nitesh Jain
- Department of Medicine, Mayo Clinic Health System, Mankato, MN 56001, United States
| | - Lokesh Goyal
- Department of Hospital Medicine, Christus Sphon Hospital-shoreline, Corpus Christo, TX 78404, United States
| | - Salim Surani
- Department of Pulmonary, Critical Care & Sleep Medicine, Texas A&M University, College Station, TX 77843, United States
| | - Syed A Khan
- Department of Critical Care Medicine, Mayo Clinic Health System, Mankato, MN 56001, United States
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Yu JM, Chen WM, Shia BC, Wu SY. Long-term outcomes of statin dose, class, and use intensity on primary prevention of cardiovascular mortality: a national T2DM cohort study. Eur J Clin Pharmacol 2023; 79:687-700. [PMID: 37010535 DOI: 10.1007/s00228-023-03488-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 03/27/2023] [Indexed: 04/04/2023]
Abstract
PURPOSE To investigate how statins reduce cardiovascular mortality in patients with type 2 diabetes (T2DM) in a dose-, class-, and use intensity-dependent manner. METHODS We used an inverse probability of treatment-weighted Cox hazards model, with statin use status as a time-dependent variable, to estimate the effects of statin use on cardiovascular mortality. RESULTS Adjusted hazard ratio [aHR; 95% confidence interval (CI)] for cardiovascular mortality was 0.41 (0.39-0.42). Compared with nonusers, pitavastatin, pravastatin, simvastatin, rosuvastatin, atorvastatin, fluvastatin, and lovastatin users demonstrated significant reductions in cardiovascular mortality [aHRs (95% CIs) = 0.11 (0.06, 0.22), 0.35 (0.32, 0.39), 0.36 (0.34, 0.38), 0.39 (0.36, 0.41), 0.42 (0.40, 0.44), 0.46 (0.43, 0.49), and 0.52 (0.48, 0.56), respectively]. In Q1, Q2, Q3, and Q4 of cDDD-year, our multivariate analysis demonstrated significant reductions in cardiovascular mortality [aHRs (95% CIs) = 0.63 (0.6, 0.65), 0.44 (0.42, 0.46), 0.33 (0.31, 0.35), and 0.17 (0.16, 0.19), respectively; P for trend < 0.0001]. The optimal statin dose daily was 0.86 DDD, with the lowest aHR for cardiovascular mortality of 0.43. CONCLUSIONS Persistent statin use can reduce cardiovascular mortality in patients with T2DM; in particular, the higher is the cDDD-year of statin, the lower is the cardiovascular mortality. The optimal statin dose daily was 0.86 DDD. The priority of protective effects on mortality are pitavastatin, rosuvastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, and lovastatin for the statin users compared with non-statin users.
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Affiliation(s)
- Jung-Min Yu
- Department of Cardiovascular Surgery, Taichung Tzu Chi Hospital, Taichung, Taiwan
- Department of Surgery, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Wan-Ming Chen
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan
- Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei, Taiwan
| | - Ben-Chang Shia
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan.
- Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei, Taiwan.
- , No. 83, Nanchang St., Luodong Township, Luodong, Yilan County, 265, Taiwan.
| | - Szu-Yuan Wu
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan.
- Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei, Taiwan.
- Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
- Division of Radiation Oncology, Lotung Poh-Ai Hospital, Lo-Hsu Medical Foundation, Yilan, Taiwan.
- Big Data Center, Big Data & Cancer Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan.
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan.
- Cancer Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan.
- Centers for Regional Anesthesia and Pain Medicine, Taipei Municipal Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
- Department of Management, College of Management, Fo Guang University, Yilan, Taiwan.
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Yu JM, Chen WM, Chen M, Shia BC, Wu SY. Effects of Statin Dose, Class, and Use Intensity on All-Cause Mortality in Patients with Type 2 Diabetes Mellitus. Pharmaceuticals (Basel) 2023; 16:507. [PMID: 37111264 PMCID: PMC10144141 DOI: 10.3390/ph16040507] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/10/2023] [Accepted: 03/24/2023] [Indexed: 04/29/2023] Open
Abstract
PURPOSE to examine the impact of statins on reducing all-cause mortality among individuals diagnosed with type 2 diabetes. This investigation explored the potential correlations between dosage, drug classification, and usage intensity with the observed outcomes. METHODS The research sample consisted of individuals aged 40 years or older diagnosed with type 2 diabetes. Statin usage was determined as a frequent usage over a minimum of one month subsequent to type 2 diabetes diagnosis, where the average statin dose was ≥28 cumulative defined daily doses per year (cDDD-year). The analysis employed an inverse probability of treatment-weighted Cox hazard model, utilizing statin usage status as a time-varying variable, to evaluate the impact of statin use on all-cause mortality. RESULTS The incidence of mortality was comparatively lower among the cohort of statin users (n = 50,804 (12.03%)), in contrast to nonusers (n = 118,765 (27.79%)). After adjustments, the hazard ratio (aHR; 95% confidence interval (CI)) for all-cause mortality was estimated to be 0.32 (0.31-0.33). Compared with nonusers, pitavastatin, rosuvastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, and lovastatin users demonstrated significant reductions in all-cause mortality (aHRs (95% CIs) = 0.06 (0.04-0.09), 0.28 (0.27-0.29), 0.29 (0.28-0.31), 0.31 (0.30-0.32), 0.31 (0.30-0.32), 0.36 (0.35-0.38), and 0.48 (0.47-0.50), respectively). In Q1, Q2, Q3, and Q4 of cDDD-year, our multivariate analysis demonstrated significant reductions in all-cause mortality (aHRs (95% CIs) = 0.51 (0.5-0.52), 0.36 (0.35-0.37), 0.24 (0.23-0.25), and 0.13 (0.13-0.14), respectively; p for trend <0.0001). Because it had the lowest aHR (0.32), 0.86 DDD of statin was considered optimal. CONCLUSIONS In patients diagnosed with type 2 diabetes, consistent utilization of statins (≥28 cumulative defined daily doses per year) was shown to have a beneficial effect on all-cause mortality. Moreover, the risk of all-cause mortality decreased as the cumulative defined daily dose per year of statin increased.
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Affiliation(s)
- Jung-Min Yu
- Department of Cardiovascular Surgery, Taichung Tzu Chi Hospital, Taichung 427213, Taiwan
- Department of Surgery, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan
| | - Wan-Ming Chen
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei 242062, Taiwan
- Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei 242062, Taiwan
| | - Mingchih Chen
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei 242062, Taiwan
- Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei 242062, Taiwan
| | - Ben-Chang Shia
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei 242062, Taiwan
- Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei 242062, Taiwan
| | - Szu-Yuan Wu
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei 242062, Taiwan
- Artificial Intelligence Development Center, Fu Jen Catholic University, Taipei 242062, Taiwan
- Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan
- Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan 265501, Taiwan
- Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan 265501, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan
- Cancer Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan 265501, Taiwan
- Centers for Regional Anesthesia and Pain Medicine, Taipei Municipal Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Department of Management, College of Management, Fo Guang University, Yilan 26247, Taiwan
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Alvarez-Jimenez L, Morales-Palomo F, Moreno-Cabañas A, Ortega JF, Mora-Rodríguez R. Effects of statin therapy on glycemic control and insulin resistance: A systematic review and meta-analysis. Eur J Pharmacol 2023; 947:175672. [PMID: 36965747 DOI: 10.1016/j.ejphar.2023.175672] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 03/27/2023]
Abstract
AIMS To update the evidence about the diabetogenic effect of statins. METHODS We searched for randomized-controlled trials reporting the effects of statin therapy on glycosylated hemoglobin (HbA1c) and/or homeostatic model insulin resistance (i.e., HOMA-IR) as indexes of diabetes. Studies were classified between the ones testing normal vs individuals with already altered glycemic control (HbA1c ≥ 6.5%; and HOMA-IR ≥ 2.15). Furthermore, studies were separated by statin type and dosage prescribed. Data are presented as mean difference (MD) and 95% confidence intervals. RESULTS A total of 67 studies were included in the analysis (>25,000 individuals). In individuals with altered glycemic control, statins increased HbA1c levels (MD 0.21%, 95% CI 0.16-to-0.25) and HOMA-IR index (MD 0.31, 95% CI 0.24-to-0.38). In individuals with normal glycemic control, statin increased HbA1c (MD 1.33%, 95% CI 1.31-to-1.35) and HOMA-IR (MD 0.49, 95% CI 0.41-to-0.58) in comparison to the placebo groups. The dose or type of statins did not modulate the diabetogenic effect. CONCLUSIONS Statins, slightly but significantly raise indexes of diabetes in individuals with adequate or altered glycemic control. The diabetogenic effect does not seem to be influenced by the type or dosage of statin prescribed.
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Affiliation(s)
- Laura Alvarez-Jimenez
- Exercise Physiology Lab at Toledo, Sports Science Department, University of Castilla-La Mancha, 45004, Toledo, Spain
| | - Felix Morales-Palomo
- Exercise Physiology Lab at Toledo, Sports Science Department, University of Castilla-La Mancha, 45004, Toledo, Spain
| | - Alfonso Moreno-Cabañas
- Exercise Physiology Lab at Toledo, Sports Science Department, University of Castilla-La Mancha, 45004, Toledo, Spain
| | - Juan F Ortega
- Exercise Physiology Lab at Toledo, Sports Science Department, University of Castilla-La Mancha, 45004, Toledo, Spain
| | - Ricardo Mora-Rodríguez
- Exercise Physiology Lab at Toledo, Sports Science Department, University of Castilla-La Mancha, 45004, Toledo, Spain.
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Yang XH, Zhang BL, Cheng Y, Fu SK, Jin HM. Statin use and the risk of CVD events, stroke, and all-cause mortality in patients with diabetes: A systematic review and meta-analysis. Nutr Metab Cardiovasc Dis 2022; 32:2470-2482. [PMID: 36064686 DOI: 10.1016/j.numecd.2022.07.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/06/2022] [Accepted: 07/22/2022] [Indexed: 10/31/2022]
Abstract
AIMS Considering the lack of evidence on statin use and the risk of cardiovascular disease (CVD) in patients with diabetes in primary and secondary prevention, this study aimed to evaluate the effect of statin use in individuals with diabetes for primary and secondary prevention. DATA SYNTHESIS The MEDLINE, Web of Science, Embase, ClinicalTrials.gov, and Cochrane Central Register for Controlled Trials databases were searched. We included studies that assessed the effect of statin use in individuals with diabetes for at least 1 year. The outcomes included CVD, all-cause mortality, and stroke. A total of 24 studies including 2,152,137 patients with diabetes were included in the meta-analysis. Compared with statin non-users, patients who received statins showed a lower risk of CVD events (primary prevention: risk ratio [RR] = 0.80, 95% confidence interval [CI] 0.69-0.94, P = 0.006; secondary prevention: RR = 0.75, 95% CI 0.65-0.87, P < 0.0001). No association was observed between statin and non-statin users and the risk of all-cause mortality. The pooled results also revealed that statin use reduced the risk of ischemic stroke in patients with diabetes (primary prevention: RR = 0.83, 95% CI 0.70-0.97, P = 0.020; secondary prevention: RR = 0.74, 95% CI 0.63-0.85, P < 0.0001). CONCLUSIONS Statin use significantly reduced the risk of CVD events and stroke, but not all-cause mortality, in individuals with diabetes undergoing both primary and secondary prevention. More data are required to verify the effects of statins in patients with diabetes. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42021281132.
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Affiliation(s)
- Xiu Hong Yang
- Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gong Wei Road, Shanghai, China.
| | - Bao Long Zhang
- The Institutes of Biomedical Sciences (IBS), Fudan University, 130 Dongan Road, Shanghai, China.
| | - Yun Cheng
- Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gong Wei Road, Shanghai, China.
| | - Shun Kun Fu
- Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gong Wei Road, Shanghai, China.
| | - Hui Min Jin
- Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gong Wei Road, Shanghai, China.
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Davies MJ, Drexel H, Jornayvaz FR, Pataky Z, Seferović PM, Wanner C. Cardiovascular outcomes trials: a paradigm shift in the current management of type 2 diabetes. Cardiovasc Diabetol 2022; 21:144. [PMID: 35927730 PMCID: PMC9351217 DOI: 10.1186/s12933-022-01575-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 05/14/2022] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with type 2 diabetes (T2D). Historical concerns about cardiovascular (CV) risks associated with certain glucose-lowering medications gave rise to the introduction of cardiovascular outcomes trials (CVOTs). Initially implemented to help monitor the CV safety of glucose-lowering drugs in patients with T2D, who either had established CVD or were at high risk of CVD, data that emerged from some of these trials started to show benefits. Alongside the anticipated CV safety of many of these agents, evidence for certain sodium-glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revealed potential cardioprotective effects in patients with T2D who are at high risk of CVD events. Reductions in 3-point major adverse CV events (3P-MACE) and CV death have been noted in some of these CVOTs, with additional benefits including reduced risks of hospitalisation for heart failure, progression of renal disease, and all-cause mortality. These new data are leading to a paradigm shift in the current management of T2D, with international guidelines now prioritising SGLT2 inhibitors and/or GLP-1 RAs in certain patient populations. However, clinicians are faced with a large volume of CVOT data when seeking to use this evidence base to bring opportunities to improve CV, heart failure and renal outcomes, and even reduce mortality, in their patients with T2D. The aim of this review is to provide an in-depth summary of CVOT data-crystallising the key findings, from safety to efficacy-and to offer a practical perspective for physicians. Finally, we discuss the next steps for the post-CVOT era, with ongoing studies that may further transform clinical practice and improve outcomes for people with T2D, heart failure or renal disease.
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Affiliation(s)
- Melanie J Davies
- Diabetes Research Centre, University of Leicester, Leicester, UK
- NIHR Leicester Biomedical Research Centre, Leicester, UK
- University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Heinz Drexel
- Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Landeskrankenhaus Feldkirch, Feldkirch, Austria
| | - François R Jornayvaz
- Service of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, WHO Collaborating Centre, Geneva University Hospital/Geneva University, Geneva, Switzerland
| | - Zoltan Pataky
- Service of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, WHO Collaborating Centre, Geneva University Hospital/Geneva University, Geneva, Switzerland
| | - Petar M Seferović
- University of Belgrade, Faculty of Medicine, Belgrade, Serbia.
- Serbian Academy of Sciences and Arts, Belgrade, Serbia.
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Neves JS, Newman C, Bostrom JA, Buysschaert M, Newman JD, Medina JL, Goldberg IJ, Bergman M. Management of dyslipidemia and atherosclerotic cardiovascular risk in prediabetes. Diabetes Res Clin Pract 2022; 190:109980. [PMID: 35787415 DOI: 10.1016/j.diabres.2022.109980] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/26/2022] [Accepted: 06/29/2022] [Indexed: 11/03/2022]
Abstract
Prediabetes affects at least 1 in 3 adults in the U.S. and 1 in 5 in Europe. Although guidelines advocate aggressive management of lipid parameters in diabetes, most guidelines do not address treatment of dyslipidemia in prediabetes despite the increased atherosclerotic cardiovascular disease (ASCVD) risk. Several criteria are used to diagnose prediabetes: impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and HbA1c of 5.7-6.4%. Individuals with prediabetes have a greater risk of diabetes, a higher prevalence of dyslipidemia with a more atherogenic lipid profile and an increased risk of ASCVD. In addition to calculating ASCVD risk using traditional methods, an OGTT may further stratify risk. Those with 1-hour plasma glucose ≥8.6 mmol/L (155 mg/dL) and/or 2-hour ≥7.8 mmol/L (140 mg/dL) (IGT) have a greater risk of ASCVD. Diet and lifestyle modification are fundamental in prediabetes. Statins, ezetimibe and PCSK9 inhibitors are recommended in people requiring pharmacotherapy. Although high-intensity statins may increase risk of diabetes, this is acceptable because of the greater reduction of ASCVD. The LDL-C goal in prediabetes should be individualized. In those with IGT and/or elevated 1-hour plasma glucose, the same intensive approach to dyslipidemia as recommended for diabetes should be considered, particularly if other ASCVD risk factors are present.
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Affiliation(s)
- João Sérgio Neves
- Department of Endocrinology, Diabetes and Metabolism, São João University Hospital Center, Porto, Portugal; Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal.
| | - Connie Newman
- Division of Endocrinology, Diabetes and Metabolism, New York University Grossman School of Medicine, New York, NY, USA
| | - John A Bostrom
- Section of Cardiovascular Medicine, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
| | - Martin Buysschaert
- Department of Endocrinology and Diabetology, Université Catholique de Louvain, University Clinic Saint-Luc, Brussels, Belgium
| | - Jonathan D Newman
- Division of Cardiology and the Center for the Prevention of Cardiovascular Disease, New York University Grossman School of Medicine, New York, NY, USA
| | | | - Ira J Goldberg
- Division of Endocrinology, Diabetes and Metabolism, New York University Grossman School of Medicine, New York, NY, USA
| | - Michael Bergman
- Division of Endocrinology, Diabetes and Metabolism, New York University Grossman School of Medicine, New York, NY, USA; Department of Population Health, New York University Grossman School of Medicine, New York, NY, USA
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11
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Alvarez-Jimenez L, Morales-Palomo F, Moreno-Cabañas A, Ortega JF, Mora-Rodriguez R. Statins effect on insulin resistance after a meal and exercise in hypercholesterolemic pre-diabetic individuals. Scand J Med Sci Sports 2022; 32:1346-1355. [PMID: 35612762 PMCID: PMC9541393 DOI: 10.1111/sms.14193] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 11/28/2022]
Abstract
Aim To study if statins, a widely prescribed, inexpensive medication to prevent coronary artery diseases may cause insulin resistance (IR). Methods Fasted (HOMA‐IR) and post‐meal insulin resistance were assessed in 21 pre‐diabetic hypercholesterolemic individuals treated with statins (STA trial). Measurements were compared to another trial conducted 96 h after statin withdrawal using placebo pills (PLAC trial). Trials were duplicated 16–18 h after a bout of moderate‐intensity exercise (500 kcal of energy expenditure) to reduce IR and better appreciate statin effects (EXER+STA and EXER+PLAC trials). Results Statin withdrawal did not affect fasting (HOMA‐IR; 2.35 ± 1.05 vs. 2.18 ± 0.87 for STA vs. PLAC trials; p = 0.150) or post‐meal insulin resistance (i.e., Matsuda‐index, STA 6.23 ± 2.83 vs. PLAC 6.49 ± 3.74; p = 0.536). A bout of aerobic exercise lowered post‐meal IR (p = 0.043), but statin withdrawal did not add to the exercise actions (p = 0.564). Statin withdrawal increased post‐meal plasma free glycerol concentrations (0.136 ± 0.073 vs. 0.185 ± 0.090 mmol·L−1 for STA vs. PLAC trials; p < 0.001) but not plasma free fatty acids or fat oxidation (p = 0.981, and p = 0.621, respectively). Post‐meal fat oxidation was higher in the exercise trials (p = 0.002). Conclusions Withdrawal of statin medication does not affect fasting or post‐meal insulin resistance in pre‐diabetic hypercholesterolemic individuals. Furthermore, statin use does not interfere with the beneficial effects of exercise on lowering IR.
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Affiliation(s)
| | - Felix Morales-Palomo
- Exercise Physiology Lab at Toledo, University of Castilla-La Mancha, Toledo, Spain
| | | | - Juan Fernando Ortega
- Exercise Physiology Lab at Toledo, University of Castilla-La Mancha, Toledo, Spain
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12
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Otten J, Tavelin B, Söderberg S, Rolandsson O. Fasting C-peptide at type 2 diabetes diagnosis is an independent risk factor for total and cancer mortality. Diabetes Metab Res Rev 2022; 38:e3512. [PMID: 34780669 DOI: 10.1002/dmrr.3512] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 10/22/2021] [Accepted: 11/02/2021] [Indexed: 11/12/2022]
Abstract
AIMS We assessed the association between insulin resistance and blood glucose concentrations at type 2 diabetes diagnosis and future development of diabetes-related complications and mortality. MATERIALS AND METHODS This retrospective cohort study included 864 individuals with type 2 diabetes (median age 60 years) whose fasting C-peptide and HbA1c were measured at diabetes diagnosis. The median follow-up time until death or study end was 16.4 years (interquartile range 13.3-19.6). The association between C-peptide and mortality/complications was estimated by Cox regression adjusted for sex, age at diabetes diagnosis, smoking, hypertension, BMI, total cholesterol, and HbA1c. C-peptide and HbA1c were converted to Z scores before the Cox regression analysis. RESULTS An increase by one standard deviation in fasting C-peptide at diabetes diagnosis was associated with all-cause (hazard ratio [HR] 1.33; 95% confidence intervals [CI] 1.12-1.58; p = 0.001) and cancer mortality (HR 1.51; 95% CI 1.13-2.01; p = 0.005) in the fully adjusted model. An increase by one standard deviation in HbA1c at diabetes diagnosis was associated with all-cause mortality (HR 1.24; 95% CI 1.07-1.44; p = 0.005), major cardiovascular events (HR 1.20; 95% CI 1.04-1.39; p = 0.015), stroke (HR 1.36; 95% CI 1.09-1.70; p = 0.006), and retinopathy (HR 1.54; 95% CI 1.34-1.76; p < 0.0001) in the fully adjusted model. CONCLUSIONS Fasting C-peptide at type 2 diabetes diagnosis is an independent risk factor for total and cancer-related mortality. Thus, treatment of type 2 diabetes should focus not only on normalising blood glucose levels but also on mitigating insulin resistance.
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Affiliation(s)
- Julia Otten
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Björn Tavelin
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
| | - Stefan Söderberg
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Olov Rolandsson
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
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Liao L, Liu Y, Zheng C, Xiang Y, Zhang Z, Cheng X, Bai Y. Association of statins with mortality in type 2 diabetes patients with intensive glycemic therapy. Diabetes Res Clin Pract 2021; 179:109005. [PMID: 34391828 DOI: 10.1016/j.diabres.2021.109005] [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: 01/24/2021] [Revised: 07/14/2021] [Accepted: 08/04/2021] [Indexed: 11/21/2022]
Abstract
AIMS Intensive glycemic therapy could lead to increased mortality in patients with type 2 diabetes mellitus (T2DM). But it remains unclear whether statins use improves prognosis in T2DM patients with intensive glycemic therapy. METHODS Using data from Action to Control Cardiovascular Risk in Diabetes trial and performing propensity score matching and Cox proportional hazards regression, we explored the relationship between statin use and the risk of mortality in intensive-therapy group. RESULTS In the intensive-therapy group, total mortality (TM) in patients with statins treatment is lower than those without statins (hazard ratio (HR), 0.68; 95% confidence interval (CI) 0.49-0.95; P = 0.022); the effects of statins on cardiovascular mortality (CM) and primary outcomes (PO), however, were negligible (CM: HR 0.96; 95% CI 0.61-1.51; P = 0.854; PO: HR 0.88; 95% CI 0.65-1.19; P = 0.415). Besides, the risk of TM, CM and PO in patients with the intensive therapy combined with statins use was similar to those in the standard group (TM: P = 0.445; CM: P = 0.362; PO: P = 0.637). CONCLUSIONS Statins may alleviate the risk of TM in T2DM patients receiving intensive glycemic therapy.
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Affiliation(s)
- Longsheng Liao
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yamei Liu
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chunxiang Zheng
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuan Xiang
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhe Zhang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, Shandong, China
| | - Xunjie Cheng
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Yongping Bai
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Eckel RH, Bornfeldt KE, Goldberg IJ. Cardiovascular disease in diabetes, beyond glucose. Cell Metab 2021; 33:1519-1545. [PMID: 34289375 PMCID: PMC8411849 DOI: 10.1016/j.cmet.2021.07.001] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/21/2021] [Accepted: 07/01/2021] [Indexed: 02/06/2023]
Abstract
Despite the decades-old knowledge that diabetes mellitus is a major risk factor for cardiovascular disease, the reasons for this association are only partially understood. While this association is true for both type 1 and type 2 diabetes, different pathophysiological processes may be responsible. Lipids and other risk factors are indeed important, whereas the role of glucose is less clear. This lack of clarity stems from clinical trials that do not unambiguously show that intensive glycemic control reduces cardiovascular events. Animal models have provided mechanisms that link diabetes to increased atherosclerosis, and evidence consistent with the importance of factors beyond hyperglycemia has emerged. We review clinical, pathological, and animal studies exploring the pathogenesis of atherosclerosis in humans living with diabetes and in mouse models of diabetes. An increased effort to identify risk factors beyond glucose is now needed to prevent the increased cardiovascular disease risk associated with diabetes.
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Affiliation(s)
- Robert H Eckel
- Divisions of Endocrinology, Metabolism and Diabetes, and Cardiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
| | - Karin E Bornfeldt
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, and Department of Laboratory Medicine and Pathology, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA, USA
| | - Ira J Goldberg
- Division of Endocrinology, Diabetes and Metabolism, NYU Grossman School of Medicine, New York, NY, USA
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15
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Lee SM, Son YK, Kim SE, Kim YH, Park Y, An WS. Effect of pravastatin on erythrocyte membrane fatty acid contents in patients with chronic kidney disease. Kidney Res Clin Pract 2021; 40:392-400. [PMID: 34078022 PMCID: PMC8476301 DOI: 10.23876/j.krcp.20.247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/21/2021] [Indexed: 12/03/2022] Open
Abstract
Background Statin treatment has decreased the risk of cardiovascular events in patients with chronic kidney disease (CKD). Erythrocyte membrane oleic acid level is higher in patients with acute coronary syndrome. This study aimed to evaluate the effect of pravastatin on the erythrocyte membrane fatty acid (FA) contents in patients with CKD. Methods Sixty-two patients were enrolled from January 2017 to March 2019 (NCT02992548). Pravastatin was initially administered at a dose of 20 mg for 24 weeks. The pravastatin dose was increased to 40 mg after 12 weeks if it was necessary to control dyslipidemia. The primary outcome was change in erythrocyte membrane FA, including oleic acid, after pravastatin treatment for 24 weeks. Results Forty-five patients finished this study, and there was no adverse effect related to pravastatin. Compared with baseline, total cholesterol and low-density lipoprotein cholesterol levels were significantly decreased after pravastatin treatment. Compared with baseline, saturated FA, oleic acid, and arachidonic acid levels were significantly increased and polyunsaturated FA and linoleic acid (LA) levels were significantly decreased after pravastatin treatment. There was also a decrease in eicosapentaenoic acid after pravastatin treatment in CKD patients with estimated glomerular filtration rate < 60 mL/min/1.73 m2. Conclusion Administration of pravastatin in patients with CKD leads to a decrease in FA known to be protective against the risk of CVD. Omega-3 FA or LA supplementation might be necessary to recover changes in erythrocyte membrane FA contents when pravastatin is used for treating dyslipidemia in patients with CKD.
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Affiliation(s)
- Su Mi Lee
- Department of Internal Medicine, Dong-A University, Busan, Republic of Korea
| | - Young Ki Son
- Department of Internal Medicine, Dong-A University, Busan, Republic of Korea
| | - Seong Eun Kim
- Department of Internal Medicine, Dong-A University, Busan, Republic of Korea
| | - Yeong Hoon Kim
- Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - Yongsoon Park
- Department of Food and Nutrition, Hanyang University, Seoul, Republic of Korea
| | - Won Suk An
- Department of Internal Medicine, Dong-A University, Busan, Republic of Korea
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16
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Kim YS, Han YE, Choi EA, You NY, Lee JW, You HS, Kim Y, Kim J, Kang HT. Statin use increased new-onset diabetes in hypercholesterolemic individuals: Data from the Korean National Health Insurance Service-National Health Screening Cohort database (NHIS-HEALS). Prim Care Diabetes 2020; 14:246-253. [PMID: 31548127 DOI: 10.1016/j.pcd.2019.08.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 08/17/2019] [Accepted: 08/28/2019] [Indexed: 01/08/2023]
Abstract
AIM We investigated the association between statin use and new-onset diabetes (NODM) in Korean adults with hypercholesterolemia. METHODS This study performed based on data from the National Health Insurance Service-National Health Screening Cohort for the years from 2002 to 2015. Statin users classified as high- or low- users according to medication possession ratio. Statin non-users consisted of hypercholesterolemic participants who never used statin over the entire follow-up period. 21,469 participants (10,880 statin users, 10,589 statin non-users) with a median follow-up period of 12.5 years were included. We estimated the NODM risk based on the survival analyses. In particular, to adjust for confounding effects, we considered Cox proportional hazards regression models over three stages. RESULTS Compared to non-users, statin users had a significantly higher risk for NODM. The fully adjusted hazard ratios (aHRs) (95% confidential intervals [95% CIs]) of statin users for NODM were 1.43 (1.31-1.57) in men, and 1.86 (1.66-2.10) in women, respectively after adjusted confounding factors including age and lifestyle factors. Compared to high-users, aHRs (95% CIs) of low-users for NODM were 1.16 (1.03-1.30) and 1.28 (1.16-1.43) in men and women, respectively. CONCLUSIONS In hypercholesterolemic patients, statin users have a higher risk of NODM than non-users.
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Affiliation(s)
- Ye-Seul Kim
- Department of Family Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Ye-Eun Han
- Department of Information & Statistics, Chungbuk National University, Cheongju, Republic of Korea
| | - Eun-A Choi
- Department of Information & Statistics, Chungbuk National University, Cheongju, Republic of Korea
| | - Na-Young You
- Department of Information & Statistics, Chungbuk National University, Cheongju, Republic of Korea
| | - Jae-Woo Lee
- Department of Family Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Hyo-Sun You
- Department of Family Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Yonghwan Kim
- Department of Family Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Joungyoun Kim
- Department of Information & Statistics, Chungbuk National University, Cheongju, Republic of Korea.
| | - Hee-Taik Kang
- Department of Family Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea; Department of Family Medicine, Chungbuk National University College of Medicine, Cheongju, Chungbuk, Republic of Korea.
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Na E, Cho S, Kim DJ, Choi J, Han E. Time-varying and dose-dependent effect of long-term statin use on risk of type 2 diabetes: a retrospective cohort study. Cardiovasc Diabetol 2020; 19:67. [PMID: 32416728 PMCID: PMC7231413 DOI: 10.1186/s12933-020-01037-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 05/09/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND We evaluated the effect of statin use on new-onset type 2 diabetes among individuals without atherosclerotic cardiovascular disease (ASCVD) using nationally representative South Korean claims data (2002-2013, N = 1,016,820). METHODS A total of 13,698 patients (statin users 5273, non-statin users 5273) aged 40-74 years, newly diagnosed with dyslipidemia but without any history of diabetes or ASCVD, were selected in 2005. We followed up the final sample until 2013 and evaluated the cumulative incidence of type 2 diabetes. We used extended Cox regression models to estimate the time-varying adjusted hazard ratios of statin use on new-onset type 2 diabetes. We performed further analyses based on the cumulative defined daily dose of statin received per year to evaluate the degree of risk compared to non-statin users. RESULTS Over the mean follow-up period of 7.1 years, 3034 patients developed type 2 diabetes; the number of statin users exceeded that of non-users, demonstrating that statin use significantly increased the risk of new-onset type 2 diabetes. The risk of new-onset type 2 diabetes differed among statin users according to cDDD per year (adjusted HR = 1.31 [95% CI 1.18-1.46] for less than 30 cDDD per year; 1.58 [1.43-1.75] for 30-120 cDDD per year; 1.83 [1.62-2.08] for 120-180 cDDD per year; and 2.83 [2.51-3.19] for more than 180 cDDD per year). The diabetogenic effect of pitavastatin was not statistically significant, but the risk was the largest for atorvastatin. Long-term exposure (≥ 5 years) to statins was associated with a statistically significant increase in the risk of new onset type 2 diabetes in all statin subtypes explored, with the highest magnitude for simvastatin (HR = 1.916, 95% CI 1.647-2.228) followed by atorvastatin (HR = 1.830, 95% CI 1.487-2.252). CONCLUSIONS Statin use was significantly associated with an increased risk of new-onset type 2 diabetes. We also found a dose-response relationship in terms of statin use duration and dose maintenance. Periodic screening and monitoring for incident type 2 diabetes may be warranted in long-term statin users.
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Affiliation(s)
- Eonji Na
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences Research, College of Pharmacy, Yonsei University, 162-1 Songdo-dong, Yeonsu-gu, Incheon, South Korea
| | - Sunyoung Cho
- Department of Pharmaceutical Medicine and Regulatory Sciences, College of Medicine and Pharmacy, Yonsei University, Incheon, South Korea
- Integro Medi Lab Co., Ltd., Seoul, South Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South Korea
| | - Junjeong Choi
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences Research, College of Pharmacy, Yonsei University, 162-1 Songdo-dong, Yeonsu-gu, Incheon, South Korea
| | - Euna Han
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences Research, College of Pharmacy, Yonsei University, 162-1 Songdo-dong, Yeonsu-gu, Incheon, South Korea.
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Maini J, Rehan HS, Yadav M, Gupta LK. Exploring the role of adipsin in statin-induced glucose intolerance: a prospective open label study. Drug Metab Pers Ther 2020; 35:/j/dmdi.ahead-of-print/dmpt-2020-0101/dmpt-2020-0101.xml. [PMID: 32229661 DOI: 10.1515/dmpt-2020-0101] [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: 01/09/2020] [Accepted: 02/17/2020] [Indexed: 06/10/2023]
Abstract
Background Evidence from the literature, highlights the increased risk of developing glucose intolerance and type 2 diabetes mellitus (T2DM) with statin therapy. In addition, few animal studies demonstrate that adipsin secreted from adipocytes plays a crucial role in insulin secretion and the development of T2DM. Methods To further explore the role of serum adipsin, in this prospective open label study, 55 newly diagnosed dyslipidemic patients were enrolled. Before starting statin therapy, liver function test (LFT), kidney function test (KFT), lipid profile, glycemic parameters [glycated hemoglobin A (HbA1c), fasting blood sugar (FBS), and postprandial blood sugar (PPBS)], serum insulin, and serum adipsin were estimated. Then these patients were prescribed statin (i.e. atorvastatin, rosuvastatin, or pitavastatin) and after 12 weeks of therapy, all the above investigations were repeated. Results After 12 weeks of statin therapy, the LFT and KFT values remained unchanged and lipid parameters showed significant improvement. But the glycemic parameters deranged significantly (p < 0.001), i.e. FBS, PPBS, and HbA1c increased by 12.49% (102.99 ± 20.76 mg/dL), 24.72% (147.71 ± 47.29 mg/dL), and 21.43% (6.38 ± 1.34%), respectively. On the other hand, the baseline adipsin (2.73 ± 1.99 ng/mL) and insulin (16.13 ± 12.50 mIU/L) levels reduced significantly (p < 0.0001) to 1.43 ±1.13 ng/mL and 6.91 ± 5.93 mIU/L, respectively. The reduction in serum adipsin also showed a positive correlation with reduction in serum insulin (r = 0.85; p < 0.0001). None of the patients experienced any significant adverse effect or reaction leading to discontinuation of therapy. Conclusions There might be an association between reduction in adipsin and development of glucose intolerance by statin therapy.
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Affiliation(s)
- Jahnavi Maini
- Department of Pharmacology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
| | - Harmeet Singh Rehan
- Department of Pharmacology, Lady Hardinge Medical College and Associated Hospitals, New Delhi-110001,India, Phone: +91 9811694040
| | - Madhur Yadav
- Deaprtment of Medicine, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
| | - Lalit Kumar Gupta
- Department of Pharmacology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
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Shutta R, Nakatani D, Sakata Y, Hikoso S, Mizuno H, Suna S, Kitamura T, Okada K, Dohi T, Kojima T, Oeun B, Sunaga A, Kida H, Sato H, Hori M, Komuro I, Nishino M, Sakata Y. Hydrophilic vs. Lipophilic Statins in Diabetic Patients - Comparison of Long-Term Outcomes After Acute Myocardial Infarction. Circ Rep 2020; 2:280-287. [PMID: 33693242 PMCID: PMC7925312 DOI: 10.1253/circrep.cr-20-0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background:
Studies comparing the cardiac consequences of hydrophilic and lipophilic statins in experimental and clinical practice settings have produced inconsistent results. In particular, evidence focusing on diabetic patients after acute myocardial infarction (AMI) is lacking. Methods and Results:
From the Osaka Acute Coronary Insufficiency Study (OACIS) registry database, 1,752 diabetic patients with AMI who were discharged with a prescription for statins were studied. Long-term outcomes were compared between hydrophilic and lipophilic statins, including all-cause death, recurrent myocardial infarction (re-MI) and admission for heart failure (HF) and a composite of these (major adverse cardiac events; MACE). During a median follow-up period of 1,059 days, all-cause death, non-fatal re-MI, admission for HF, and MACE occurred in 95, 89, 112 and 249 patients, respectively. Although there was no significant difference between statins in the risk of all-cause death, re-MI and MACE, the risk of HF admission was significantly lower in patients with hydrophilic than lipophilic statins before (adjusted hazard ratio [aHR], 0.560; 95% CI: 0.345–0.911, P=0.019) and after (aHR, 0.584; 95% CI: 0.389–0.876, P=0.009) propensity score matching. Hydrophilic statin use was consistently associated with lower risk for HF admission than lipophilic statins across the subgroup categories. Conclusions:
In the present diabetic patients with AMI, hydrophilic statins were associated with a lower risk of admission for HF than lipophilic statins.
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Affiliation(s)
- Ryu Shutta
- Division of Cardiology, Osaka Rosai Hospital Sakai Japan
| | - Daisaku Nakatani
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita Japan
| | - Yasuhiko Sakata
- Department of Evidence-based Cardiovascular Medicine and Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine Sendai Japan
| | - Shungo Hikoso
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita Japan
| | - Hiroya Mizuno
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita Japan
| | - Shinichiro Suna
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita Japan
| | - Tetsuhisa Kitamura
- Division of Environmental Medicine and Population Sciences, Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University Suita Japan
| | - Katsuki Okada
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita Japan
| | - Tomoharu Dohi
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita Japan
| | - Takayuki Kojima
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita Japan
| | - Bolrathanak Oeun
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita Japan
| | - Akihiro Sunaga
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita Japan
| | - Hirota Kida
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita Japan
| | - Hiroshi Sato
- School of Human Welfare Studies, Kwansei Gakuin University Nishinomiya Japan
| | - Masatsugu Hori
- Osaka Prefectural Hospital Organization Osaka International Cancer Institute Osaka Japan
| | - Issei Komuro
- Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine Tokyo Japan
| | - Masami Nishino
- Division of Cardiology, Osaka Rosai Hospital Sakai Japan
| | - Yasushi Sakata
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita Japan
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20
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Chattopadhyay S, George A, John J, Sathyapalan T. Pre-diabetes mellitus newly diagnosed after myocardial infarction adversely affects prognosis in patients without known diabetes. Diab Vasc Dis Res 2019; 16:489-497. [PMID: 31044609 DOI: 10.1177/1479164119845561] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Effect of pre-diabetes mellitus on post-myocardial infarction prognosis is unclear. METHODS Retrospective cohort analysis of 1056 myocardial infarction survivors with fasting plasma glucose and 2-h post-load plasma glucose measured. Major adverse cardiovascular events included death, non-fatal reinfarction and ischaemic stroke. Cox proportional hazard regression identified predictors of event-free survival. Continuous net reclassification improvement and integrated discrimination improvement determined the added predictive value of glycaemic indices. RESULTS Major adverse cardiovascular events occurred in 25.1% and 16.4% patients with and without pre-diabetes mellitus (hazard ratio with pre-diabetes mellitus: 1.56; 95% confidence interval: 1.17-2.08; p = 0.003) in the whole cohort and in 24.1% and 17.2% patients (hazard ratio with pre-diabetes mellitus, 1.43; 95% confidence interval: 1.03-1.98; p = 0.033) in the matched cohort, respectively. Pre-diabetes mellitus predicted major adverse cardiovascular events-free survival in whole (hazard ratio: 1.39; 95% confidence interval: 1.03-1.89; p = 0.033) and matched cohorts (hazard ratio: 1.42; 95% confidence interval: 1.01-1.99; p = 0.043). The 2-h post-load plasma glucose, but not fasting plasma glucose, predicted major adverse cardiovascular events-free survival in the whole (hazard ratio: 1.16; 95% confidence interval: 1.07-1.26; p < 0.0001) and matched cohorts (hazard ratio: 1.20; 95% confidence interval: 1.09-1.31; p < 0.0001). Adding 2-h post-load plasma glucose to models containing fasting plasma glucose, significantly improved net reclassification improvement and integrated discrimination improvement for both cohorts, but not vice versa. CONCLUSION Pre-diabetes mellitus predicts major adverse cardiovascular events after myocardial infarction. The 2-h post-load plasma glucose predicts prognosis better than fasting plasma glucose in these patients.
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Affiliation(s)
| | - Anish George
- Department of Cardiology, Scunthorpe General Hospital, Scunthorpe, UK
| | - Joseph John
- Department of Cardiology, Castle Hill Hospital, Cottingham, UK
| | - Thozhukat Sathyapalan
- Department of Academic Endocrinology, Diabetes and Metabolism, Hull York Medical School, University of Hull, Hull, UK
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21
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Huff JM, Falter RA, Scheinberg N. Retrospective Comparison of Appropriate Statin Use Between Patients With Diabetes in the Primary Care Setting Managed by Pharmacists or Internal Medicine Providers. Diabetes Spectr 2019; 32:349-354. [PMID: 31798293 PMCID: PMC6858076 DOI: 10.2337/ds18-0067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE The purpose of this study was to compare statin prescribing practices according to the American Diabetes Association's Standards of Medical Care in Diabetes-2017 between diabetes patients managed by pharmacists versus those managed by internal medicine providers. DESIGN AND METHODS A retrospective observational study was completed using the electronic health record of a multispecialty private practice. A total of 176 patients were included in the study, with 88 each in the pharmacy and internal medicine groups. Patients were ≥40 years of age with diabetes and managed by an internal medicine provider or a pharmacist between January and December 2017. Descriptive statistics, χ2, and unpaired t tests were used to describe between-group differences. RESULTS More pharmacy than internal medicine patients were prescribed appropriate statin therapy (47.7 vs. 34.1%, P = 0.092), particularly those needing high-intensity statins (44.3 vs. 27.4%, P = 0.03). Females, patients 40-75 years of age, and patients with no history of atherosclerotic cardiovascular disease in the pharmacy group were more likely to receive appropriate treatment (37.5 vs. 15.0%, P = 0.022; 46.8 vs. 29.7%, P = 0.039; and 45.3 vs. 23.5%, P = 0.015, respectively). Overall, more males than females were prescribed appropriate statin therapy (53.1 vs. 26.3%, P = 0.001). CONCLUSION Although there were no overall significant differences in statin prescribing between the pharmacy and internal medicine groups, patients needing high-intensity statins, those who were female, and those who were younger were more likely to receive appropriate therapy when managed by a pharmacist. Appropriate statin prescribing remains low among diabetes patients, and optimization of this therapy should be prioritized.
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Affiliation(s)
- Jamie M Huff
- Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA
| | - Rebecca A Falter
- Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA
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22
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Hsu H, Hsu P, Cheng MH, Ito Y, Kanda E, Schaefer EJ, Ai M. Lipoprotein Subfractions and Glucose Homeostasis in Prediabetes and Diabetes in Taiwan. J Atheroscler Thromb 2019; 26:890-914. [PMID: 30726792 PMCID: PMC6800394 DOI: 10.5551/jat.48330] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 01/14/2019] [Indexed: 12/13/2022] Open
Abstract
AIMS Prediabetes and diabetes are associated with increased insulin resistance and decreased insulin production, dyslipidemia, and increased cardiovascular disease (CVD) risk. Our goals were to assess lipoprotein subfractions using novel assays in such subjects. METHODS Fasting normal, prediabetic, and diabetic Taiwanese men and women (n=2,049) had their serum glucose, glycosylated hemoglobin, insulin, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), HDL3-C, apolipoprotein E-HDL-C, direct low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), LDL-TG, and remnant lipoprotein cholesterol (RLP-C) levels measured using novel assays. HDL2-C, LDL-C, and large-buoyant LDL-C (lbLDL-C) were calculated. RESULTS Prediabetic male and female subjects had significantly higher levels of TG, RLP-C, sdLDL-C, the sdLDL-C/LDL-C ratio, and LDL-TG than normal subjects, and statin treatment abolished this effect in men, but not in women. Diabetic male and female subjects had significantly higher TG and sdLDL-C/LDL-C ratios, and significantly lower levels of HDL-C, HDL2-C, HDL3-C, and apoE HDL-C than normal subjects, as did prediabetic women. Median direct LDL-C levels were ＞100 mg/dL in all groups, even in those receiving statin therapy. Calculated LDL-C significantly underestimated direct LDL-C by ＞10% in diabetic subjects. CONCLUSIONS Our data indicate that prediabetic subjects were more likely to have significantly elevated RLP-C, sdLDL-C, and LDL-TG, while diabetic subjects were more likely to have significantly decreased HDL-C, HDL2-C, HDL3-C, and apoE HDL-C than normal subjects, and calculated LDL-C significantly underestimated their direct LDL-C. In our view, direct LDL-C and sdLDL-C should be measured and optimized in both diabetic and prediabetic subjects to reduce CVD risk.
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Affiliation(s)
- Hung Hsu
- Department of Insured Medical Care Management, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Powen Hsu
- Department of General Internal Medicine, Lo-Hsu Medical Foundation Lotung Poh-Ai Hospital, Lotung, Yilan, Taiwan
| | - Ming-Hui Cheng
- Department of Laboratory Medicine, Lo-Hsu Medical Foundation Lotung Poh-Ai Hospital, Lotung, Yilan, Taiwan
| | - Yasuki Ito
- Research and Development Center, Denka-Seiken Company, Ltd., Tokyo, Japan
| | - Eiichiro Kanda
- Department of Medical Science, Kawasaki Medical School, Kurashiki, Japan
| | - Ernst J Schaefer
- Cardiovascular Nutrition Laboratory, Human Nutrition Research Center on Aging at Tufts University, and Tufts University School of Medicine, Boston, MA, USA
| | - Masumi Ai
- Department of Insured Medical Care Management, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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23
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Abstract
The 2013 ACC/AHA guidelines on blood cholesterol management were a major shift in the delineation of the main patient groups that could benefit from statin therapy and emphasized the use of higher-intensity statin therapies. In 2016, an expert consensus panel from the ACC recommended the use of nonstatin therapies (ezetimibe and PCSK9 inhibitors) in addition to maximally tolerated statin therapy in individuals whose LDL-cholesterol and non-HDL-cholesterol levels remained above certain thresholds after statin treatment. Given the substantial benefits of statin therapies in both primary and secondary prevention of cardiovascular disease, their long-term safety has become a concern. The potential harmful effects of statin therapy on muscle and liver have been known for some time, but new concerns have emerged regarding the risk of new-onset diabetes mellitus, cognitive impairment and haemorrhagic stroke associated with the use of statins and the risks of achieving very low levels of LDL cholesterol. The increased media attention on the adverse events associated with statins has unfortunately led to statin therapy discontinuation, nonadherence to therapy or concerns about initiating statin therapy. In this Review, we explore the safety of statin therapy in light of the latest evidence and provide clinicians with reassurance about the safety of statins. Overwhelming evidence suggests that the benefits of statin therapy far outweigh any real or perceived risks.
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Affiliation(s)
- Bhavin B Adhyaru
- Division of General Internal Medicine & Geriatrics, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
| | - Terry A Jacobson
- Division of General Internal Medicine & Geriatrics, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA. .,Lipid Clinic and Cardiovascular Risk Reduction Program, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
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24
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Domecq JP, Prutsky G, Elraiyah T, Wang Z, Mauck KF, Brito JP, Undavalli C, Sundaresh V, Prokop LJ, Montori VM, Murad MH. Medications affecting the biochemical conversion to type 2 diabetes: A systematic review and meta-analysis. J Clin Endocrinol Metab 2019; 104:3986-3995. [PMID: 31365088 DOI: 10.1210/jc.2019-01269] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 06/05/2019] [Indexed: 02/13/2023]
Abstract
BACKGROUND The extent to which some pharmacological interventions reduce or increase the risk of biochemical conversion to T2DM in at-risk individuals is unclear. METHODS We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Scopus through August 24, 2017, for randomized controlled trials evaluating the effect of drugs suspected to modify the risk of biochemical conversion to T2DM. RESULTS We included 43 trials with 192,156 subjects (mean age 60 years; 56% men; mean BMI 30.4 kg/m2). Alpha-glucosidase inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, metformin, orlistat, phentermine-topiramate and pioglitazone significantly reduced the risk of biochemical conversion to T2DM, whereas statins and nateglinide increased the risk. There was insufficient direct evidence regarding the effects of sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter-2 inhibitors. Most trials were brief and evaluated this outcome during treatment without a withdrawal or washout period. CONCLUSIONS Several drugs modify the risk of biochemical conversation to T2DM, although whether this effect is persistent and clinically relevant is unclear. Future studies need to focus on cardiovascular disease prevention, mortality and patient-important outcomes instead of biochemical conversion to T2DM.
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Affiliation(s)
| | | | - Tarig Elraiyah
- Evidence Based Practice Center, Mayo Clinic, Rochester, MN
- Division of Nephrology, Department of Medicine, Drexel University College of Medicine, Philadelphia, PA
| | - Zhen Wang
- Evidence Based Practice Center, Mayo Clinic, Rochester, MN
| | - Karen F Mauck
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN
| | - Juan Pablo Brito
- Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, MN
- Division of Endocrinology, Mayo Clinic, Rochester, MN
| | | | | | - Larry J Prokop
- Evidence Based Practice Center, Mayo Clinic, Rochester, MN
| | - Victor M Montori
- Evidence Based Practice Center, Mayo Clinic, Rochester, MN
- Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, MN
- Division of Endocrinology, Mayo Clinic, Rochester, MN
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25
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Hammad MA, Abdo MS, Mashaly AM, Syed Sulaiman SA, Alghamdi S, Mangi AA, Mohamed Noor DA. The statins effects on HbA1c control among diabetic patients: An umbrella review of systematic reviews and meta-analyses of observational studies and clinical trials. Diabetes Metab Syndr 2019; 13:2557-2564. [PMID: 31405676 DOI: 10.1016/j.dsx.2019.07.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 07/08/2019] [Indexed: 10/26/2022]
Abstract
Statins have impacts on the metabolism of glucose that might influence the progress of diabetes in non-diabetics or affect glycemic control in patients with existing diabetes. Experimental proof has been contradictory about whether some statins display beneficial properties while others indicate harmful impressions. Some systematic reviews of statins had stated conflicting findings on the concern of glucose metabolism. The current study investigates the published systematic reviews and meta-analyses to combine their results and give a clear situation regarding the influence of statins therapy on glycated hemoglobin (HbA1c). This study has valuable strength points; long follow-up period and big sample size.
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Affiliation(s)
- Mohamed Anwar Hammad
- Department of Clinical Pharmacy, Pharmacy School, Universiti Sains Malaysia, Penang, Malaysia.
| | - Mahmoud Saeed Abdo
- Department of Clinical Pharmacy, Pharmacy School, Universiti Sains Malaysia, Penang, Malaysia.
| | - Abdalla Mohamed Mashaly
- Department of Clinical Pharmacy, Pharmacy School, Universiti Sains Malaysia, Penang, Malaysia.
| | | | - Saleh Alghamdi
- Department of Clinical Pharmacy, Faculty of Clinical Pharmacy, Al Baha University, Al Baha, Saudi Arabia; Faculty of Pharmacy, Gomal University, DI-Khan KPK, Pakistan.
| | - Altaf A Mangi
- Faculty of Pharmacy, Gomal University, DI-Khan KPK, Pakistan
| | - Dzul Azri Mohamed Noor
- Department of Clinical Pharmacy, Pharmacy School, Universiti Sains Malaysia, Penang, Malaysia.
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26
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Zykov MV. [The problem of safety of lipid-lowering therapy]. ACTA ACUST UNITED AC 2019; 59:13-26. [PMID: 31221072 DOI: 10.18087/cardio.2505] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Indexed: 11/18/2022]
Abstract
This study focused on analysis of current publications evaluating safety of lipid-lowering therapy. Search for literature was performed on websites of cardiological societies and online databases, including PubMed, EMBASE, and eLibrary by the following key words: statins, statin intolerance, lipid-lowering therapy, statin safety, and statin аdverse effects. The focus is on statins, in view of the fact that they are the most commonly prescribed, highly effective and safe drugs for primary and secondary cardiovascular prophylaxis. This review consistently summarized information about myopathies, hepatic and renal dysfunction, potentiation of DM, and other possible adverse effects of lipid-lowering therapy. The author concluded that despite the high safety of statins acknowledged by all international cardiological societies, practicing doctors still continue unreasonably cancel statins, exposing the patient under even greater danger. Information about the corresponding author.
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Affiliation(s)
- M V Zykov
- Research Institute for Complex Issues of Cardiovascular Diseases
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27
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Su X, Kong Y, Peng D. Evidence for changing lipid management strategy to focus on non-high density lipoprotein cholesterol. Lipids Health Dis 2019; 18:134. [PMID: 31170997 PMCID: PMC6554877 DOI: 10.1186/s12944-019-1080-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 05/31/2019] [Indexed: 12/17/2022] Open
Abstract
Low-density lipoprotein cholesterol (LDL-C) has been recommended as the primary treatment target on lipid management in coronary heart disease (CHD) patients for past several decades. However, even by aggressive LDL-C lowering treatment, patients still present a significant residual risk of major adverse cardiovascular events (MACE). Non-high-density lipoprotein cholesterol (non-HDL-C) contained all the atherogenic lipoproteins, such as chylomicron, very-low density lipoprotein (VLDL), LDL, intermediate density lipoprotein (IDL). Many prospective observation studies have found that non-HDL-C was better than LDL-C in predicting risks of MACE. Since non-HDL-C appears to be superior for risk prediction beyond LDL-C, current guidelines have emphasize the importance of non-HDL-C for guiding cardiovascular prevention strategies and have flagged non-HDL-C as a co-primary therapeutic target. The goals of non-HDL-C were recommended as 30 mg/dl higher than the corresponding LDL-C goals, but the value seemed inappropriate. This review provide evidence for changing lipid management strategy to focus on non-HDL-C and appropriate values for adding to LDL-C goals would be proposed.
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Affiliation(s)
- Xin Su
- Department of Cardiovascular Medicine, the Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Yi Kong
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Daoquan Peng
- Department of Cardiovascular Medicine, the Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
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28
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Bahrambeigi S, Rahimi M, Yousefi B, Shafiei-Irannejad V. New potentials for 3-hydroxy-3-methyl-glutaryl-coenzymeA reductase inhibitors: Possible applications in retarding diabetic complications. J Cell Physiol 2019; 234:19393-19405. [PMID: 31004363 DOI: 10.1002/jcp.28682] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 03/25/2019] [Accepted: 04/05/2019] [Indexed: 12/12/2022]
Abstract
The prevalence of diabetes mellitus is increasing all over the world and it is apparent that treatment of diabetic complications has the same importance as primary diabetes treatment and glycemic control. Diabetic complications occur as a result of prolonged hyperglycemia and its consequences, such as advanced glycation end products and reactive oxygen species. Impairment of lipid profile is also contributed to worsening diabetic complications. Therefore, it seems that the application of lipid-lowering agents may have positive effects on reversing diabetic complications besides glycemic control. Statins, a group of lipid-lowering compounds, have been shown to exert antioxidant, immunomodulatory, anti-inflammatory, and antiproliferative properties beyond their lipid-lowering effects. Furthermore, they have been reported to improve diabetic complications with different pathways. In this review, we will discuss the clinical importance, molecular biology of the most important microvascular/macrovascular diabetic complications, possible application of statins and their mechanism of action in retarding these complications.
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Affiliation(s)
- Saman Bahrambeigi
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Mahdi Rahimi
- Ageing Research Institute, Physical Medicine and Rehabilitation Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Ageing Research Institute, Physical Medicine and Rehabilitation Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Shafiei-Irannejad
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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29
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Thomson SR, Chogtu B, Shetty R, Devasia T. Analysis of glycemic status in diabetes-naïve patients on statins: A hospital-based cross-sectional study. Indian J Pharmacol 2019; 50:320-325. [PMID: 30783324 PMCID: PMC6364334 DOI: 10.4103/ijp.ijp_132_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION: Randomized controlled trials, observational studies, and meta-analysis suggest risk of hyperglycemia in patients on statins, and this association is being viewed with renewed interest globally. The present study has tried to explore the possible diabetogenic effect of statins, the mechanism of this effect, and various comorbidities associated with this causation. MATERIALS AND METHODS: This cross-sectional study was carried out at the Department of Cardiology from October 2015 to March 2017. Patients on statins for at least 1 year and normoglycemic at the time of statin initiation were recruited in the study. The outcome of the present study was development of new-onset diabetes mellitus (NODM). Blood glucose levels and insulin levels were estimated. Other adverse reactions of statins and associated comorbidities in the patients were recorded. Descriptive statistics were used to analyze adverse drug reactions. RESULTS: A total of 104 patients met the inclusion criteria, of which eight patients (7.7%) developed NODM and 4 (3.8%) developed prediabetes. Atorvastatin 40 mg was most commonly prescribed statin. About 25% of patients taking atorvastatin 80 mg developed diabetes CONCLUSION: Statins have a mild-to-moderate risk of developing NODM. The dose of statins is an important factor that increases the risk of diabetes in statin users
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Affiliation(s)
- Sereen Rose Thomson
- Department of Pharmacology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Bharti Chogtu
- Department of Pharmacology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Ranjan Shetty
- Department of Cardiology, Manipal Hospital, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Tom Devasia
- Department of Cardiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
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30
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Djoussé L, Song RJ, Cho K, Gaziano JM, Gagnon DR. Association of statin therapy with incidence of type 2 diabetes among US Veterans. JOURNAL OF CLINICAL CARDIOLOGY AND CARDIOVASCULAR THERAPY 2019; 1:10.31546/JCCCVT.1002. [PMID: 31660540 PMCID: PMC6816272 DOI: 10.31546/jcccvt.1002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
AIMS While some but not all trial data have suggested an elevated risk of type 2 diabetes with statin use, limited data are available on the relation of statin treatment with glycaemia and risk of type 2 diabetes among Veterans. We examined whether statin use was associated with a higher incidence of type 2 diabetes and secondarily, if statin use was associated with high plasma glucose. METHODS Prospective analysis based on electronic health records of 3,390,799 US Veterans from 2000 to 2012. We used the Veteran Administration Corporate Data Warehouse to obtain information on random plasma glucose. Statin use was captured using the pharmacy database. type 2 diabetes was defined as having at least one inpatient diagnosis or at least two outpatient diagnoses of type 2 diabetes using International Classification of Disease version 9 codes 250.xx, or the use of hypoglycemic agents. We used multi-level derived propensity score and inverse probability weighting to address confounding by indication and Cox regression to estimate relative risk of type 2 diabetes. RESULTS The mean age was 62±11.9 years; 93.3% were men and 82.7% were white. During a median follow-up of 3.0 years, 443,104 new cases of type 2 diabetes occurred. Compared to no statin use, multivariable adjusted hazard ratio (95% CI) for type 2 diabetes was 1.21 (1.19-1.24) for low statin potency, 1.22 (1.21-1.23) for medium statin potency, and 1.34 (1.32-1.36) for high statin potency (p linear trend <0.0001). In secondary analysis, statin use was not associated with higher plasma glucose. CONCLUSIONS Our data show a positive association between statin use and incidence of type 2 diabetes among US Veterans.
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Affiliation(s)
- Luc Djoussé
- Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA
- The Division of Aging, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Rebecca J Song
- Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA
- Department of Biostatistics, Boston University School of Public Health, Boston, MA
| | - Kelly Cho
- Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA
- The Division of Aging, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - J Michael Gaziano
- Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA
- The Division of Aging, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - David R Gagnon
- Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA
- Department of Biostatistics, Boston University School of Public Health, Boston, MA
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Sheng Z, Cao JY, Pang YC, Xu HC, Chen JW, Yuan JH, Wang R, Zhang CS, Wang LX, Dong J. Effects of Lifestyle Modification and Anti-diabetic Medicine on Prediabetes Progress: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2019; 10:455. [PMID: 31354627 PMCID: PMC6639788 DOI: 10.3389/fendo.2019.00455] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 06/24/2019] [Indexed: 01/03/2023] Open
Abstract
Background: Pre-diabetes is a risk factor for full-blown diabetes; it presents opportunities to prevent the actual diseases. It is therefore essential to identify effective preventive strategies, and to clarify the direction of future research. Methods: PubMed, Embase and Cochrane Central Register of Controlled Trials were searched using key terms (Supplementary Table 1). We applied network meta-analysis to multiple comparisons among various diabetic preventive strategies, including lifestyle and pharmacological interventions; traditional meta-analysis for the synthesis of basal metabolic changes after interventions; and trial sequential analysis for determinations as to whether analysis conclusions meet expectations. Results: We included 32 randomized controlled trials comprising 43,669 patients and 14 interventions in the meta-analysis. Both lifestyle modifications and anti-diabetic medications improved physical conditions, including weight loss, blood glucose, and blood pressure. Network meta-analysis suggested that the progression of diabetes could be delayed to varying degrees by lifestyle and pharmacological interventions, except for angiotensin-converting enzyme inhibitors, statins, sulfonylureas and vitamin D. The risk ratios (RR) [95% credible interval (CrI)] compared with control were: GLP-1RAs 0.28 (0.15, 0.50), Orlistat 0.33 (0.18, 0.55), TZM 0.33 (0.16, 0.63), TZD 0.39 (0.27, 0.53), LST 0.54 (0.32, 0.88), lifestyle 0.58 (0.49, 0.67), LSM 0.62 (0.45, 0.80), GI 0.66 (0.46, 0.88), SU 0.67 (0.40, 1.00), Vitamin D 0.91 (0.59, 1.40), ACEI 0.93 (0.62, 1.40), statins 1.20 (0.84, 1.60). Conclusions: In adults with pre-diabetes, firm evidence supports the notion that lifestyle modifications and metformin reduces the incidence of diabetes with an average of 20% relative risk reduction, while statins increase the relative risk 20%. We found that lifestyle modifications, promising long-term strategies involving three factors (nutrition, exercise, and weight loss) contribute to health by reducing BMI, body weight, waist and hip circumference, systolic and diastolic pressure, fasting, and 2-h postprandial blood glucose, total cholesterol and by increasing HDL. We made this determination using TSA, avoiding further waste of experimental resources.
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Affiliation(s)
- Zhi Sheng
- Clinical Medicine Department, Medical College, Qingdao University, Shandong, China
| | - Jia-Yu Cao
- Clinical Medicine Department, Medical College, Qingdao University, Shandong, China
| | - Ying-Chang Pang
- Clinical Medicine Department, Medical College, Qingdao University, Shandong, China
| | - Hang-Cheng Xu
- Clinical Medicine Department, Medical College, Qingdao University, Shandong, China
| | - Jing-Wen Chen
- Clinical Medicine Department, Medical College, Qingdao University, Shandong, China
| | - Jun-Hua Yuan
- Special Medicine Department, Medical College, Qingdao University, Shandong, China
| | - Rui Wang
- Special Medicine Department, Medical College, Qingdao University, Shandong, China
| | - Cai-Shun Zhang
- Special Medicine Department, Medical College, Qingdao University, Shandong, China
| | - Liu-Xin Wang
- Special Medicine Department, Medical College, Qingdao University, Shandong, China
| | - Jing Dong
- Special Medicine Department, Medical College, Qingdao University, Shandong, China
- Physiology Department, Medical College, Qingdao University, Shandong, China
- *Correspondence: Jing Dong
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Gupta KK, Ali S, Sanghera RS. Pharmacological Options in Atherosclerosis: A Review of the Existing Evidence. Cardiol Ther 2018; 8:5-20. [PMID: 30543029 PMCID: PMC6525235 DOI: 10.1007/s40119-018-0123-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Indexed: 12/11/2022] Open
Abstract
Coronary heart disease (CHD) is the leading cause of mortality worldwide and high low-density lipoprotein (LDL) cholesterol levels have been shown to be key in the pathogenesis of this condition. Lipid control has therefore been the subject of decades of research and has led to many large and robust randomized controlled trials, as well as the highest grossing drug of all time—Lipitor (atorvastatin). Statin therapy has long been indicated for secondary and more recently primary prevention. However, despite the large-scale use of statins, CHD prevalence remains high, and some patients do not respond to statin therapy. There has been a large push to find and test alternative lipid-lowering agents, these include fibrates, cholesterol absorption inhibitors, and proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors. It is the aim of this review to assess the literature surrounding each of these groups of drugs.
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Affiliation(s)
| | - Shair Ali
- St George's Hospital NHS Trust, London, UK
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33
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Meneilly GS, Knip A, Miller DB, Sherifali D, Tessier D, Zahedi A. Diabetes in Older People. Can J Diabetes 2018; 42 Suppl 1:S283-S295. [PMID: 29650107 DOI: 10.1016/j.jcjd.2017.10.021] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Indexed: 12/15/2022]
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Tun NN, Arunagirinathan G, Munshi SK, Pappachan JM. Diabetes mellitus and stroke: A clinical update. World J Diabetes 2017; 8:235-248. [PMID: 28694925 PMCID: PMC5483423 DOI: 10.4239/wjd.v8.i6.235] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Revised: 02/26/2017] [Accepted: 05/05/2017] [Indexed: 02/05/2023] Open
Abstract
Cardiovascular disease including stroke is a major complication that tremendously increases the morbidity and mortality in patients with diabetes mellitus (DM). DM poses about four times higher risk for stroke. Cardiometabolic risk factors including obesity, hypertension, and dyslipidaemia often co-exist in patients with DM that add on to stroke risk. Because of the strong association between DM and other stroke risk factors, physicians and diabetologists managing patients should have thorough understanding of these risk factors and management. This review is an evidence-based approach to the epidemiological aspects, pathophysiology, diagnostic work up and management algorithms for patients with diabetes and stroke.
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Sehra D, Sehra S, Sehra ST. Cardiovascular pleiotropic effects of statins and new onset diabetes: is there a common link: do we need to evaluate the role of KATP channels? Expert Opin Drug Saf 2017; 16:823-831. [PMID: 28571494 DOI: 10.1080/14740338.2017.1338269] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Statins are considered the main stay of treatment in the prevention of cardio-vascular morbidity and mortality. They have multiple pleiotropic effects, like stabilization of atherosclerotic plaques, inhibition of platelet aggregation, and vascular smooth muscle proliferation; in addition to their lipid lowering action. Statins manifest these pleiotropic effects because they activate KATP channels in the cardiac and vascular tissue. Simultaneous activation of the KATP channels by statins in β cells of pancreas may inhibit insulin release which may lead to diabetes. Areas covered: Literature published between 1980 and 2016 on cholesterol biosynthesis, new onset diabetes and on the pleiotropic effects of statins, was reviewed. A comprehensive search on PubMed, Embase and Cochrane databases was carried out. Expert opinion: Statins exert their beneficial pleiotropic effects on the cardiovascular system by activating KATP channels in the cardiac and vascular tissue. However, simultaneous activation of KATP channels in the beta cells of pancreas leads to inhibition of insulin release. This disturbs the carbohydrate metabolism and probably leads to diabetes. In our opinion, use of stains should be more judicious and restricted to secondary prevention only.
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Affiliation(s)
- Devindra Sehra
- a Internal Medicine , Sehra Medical Centre , New Delhi , India
| | - Sudhish Sehra
- a Internal Medicine , Sehra Medical Centre , New Delhi , India.,b Medicine , Sri Balaji Action Medical Institute , New Delhi , India
| | - Shiv Tej Sehra
- c Department of Medicine , Mount Auburn Hospital , Cambridge , MA , USA
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Rahal AJ, ElMallah AI, Poushuju RJ, Itani R. Do statins really cause diabetes? A meta-analysis of major randomized controlled clinical trials. Saudi Med J 2017; 37:1051-60. [PMID: 27652354 PMCID: PMC5075367 DOI: 10.15537/smj.2016.10.16078] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Objectives: To investigate and establish the relationship between the use of statin therapy and the risk of development of diabetes. Methods: PubMed and the Cochrane Central Register of Controlled Trials was searched for randomized controlled end-point trials of statins, with more than 1000 subjects and a minimum of one-year follow-up period, published until August 2015. The odds ratio (OR) of diabetes incidence with overall statin therapy as well as with different statins in question was calculated through random effect meta-analysis model. Results: Fourteen studies were included in the analysis with a total of 94,943 participants. Of these, 2392 subjects developed incident diabetes in the statin and 2167 in the placebo groups during a 4-year follow-up. The OR of diabetes incidence with statin therapy was significantly higher as compared with the placebo group (OR=1.11; 95% confidence interval = 1.0 to 1.2; p=0.007). There was an insignificant level of heterogeneity between the included trials (Cochran Q= 19.463, p=0.109, I2=33.20). Subgroup analysis showed that only 2 statins namely, atorvastatin (OR= 1.29; p=0.042) and rosuvastatin (OR = 1.17; px=0.01) were significantly associated. Conclusion: Statin therapy can slightly increase risk of incident diabetes in subjects with hypercholesterolemia.
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Affiliation(s)
- Alaa J Rahal
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon. E-mail.
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37
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Casula M, Mozzanica F, Scotti L, Tragni E, Pirillo A, Corrao G, Catapano AL. Statin use and risk of new-onset diabetes: A meta-analysis of observational studies. Nutr Metab Cardiovasc Dis 2017; 27:396-406. [PMID: 28416099 DOI: 10.1016/j.numecd.2017.03.001] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 01/11/2017] [Accepted: 03/02/2017] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIMS Meta-analyses of randomized control trials investigating the association between incident diabetes and statin use showed an increased risk of new-onset diabetes (NOD) from 9% to 13% associated with statins. However, short follow-up period, unpowered sample size, and lack of pre-specified diagnostic criteria for diabetes detection could be responsible of an underestimation of this risk. We conducted a meta-analysis of published observational studies to evaluate the association between statins use and risk of NOD. METHODS AND RESULTS PubMed, EMBASE and MEDLINE databases were searched from inception to June 30, 2016 for cohort and case-control studies with risk of NOD in users vs nonusers, on ≥1000 subjects followed-up for ≥1 year. Two review authors assessed study eligibility and risk of bias and undertook data extraction independently. Pooled estimates were calculated by a random-effects model and between-study heterogeneity was tested and measured by I2 index. Furthermore, stratified analyses and the evaluation of publication bias were performed. Finally, the meta-analysis included 20 studies, 18 cohort and 2 case-control studies. Overall, NOD risk was higher in statin users than nonusers (RR 1.44; 95% CI 1.31-1.58). High between-study heterogeneity (I2 = 97%) was found. Estimates for all single statins showed a class effect, from rosuvastatin (RR 1.61; 1.30-1.98) to simvastatin (RR 1.38; 1.19-1.61). CONCLUSIONS The present meta-analysis confirms and reinforces the evidence of a diabetogenic effect by statins utilization. These observations confirm the need of a rigorous monitoring of patients taking statins, in particular pre-diabetic patients or patients presenting with established risk factors for diabetes.
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Affiliation(s)
- M Casula
- Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy.
| | - F Mozzanica
- Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy
| | - L Scotti
- Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca, Via Bicocca degli Arcimboldi 8, 20126, Milan, Italy
| | - E Tragni
- Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy
| | - A Pirillo
- Center for the Study of Atherosclerosis, E. Bassini Hospital, Via M. Gorki 50, Cinisello Balsamo, 20092, Milan, Italy
| | - G Corrao
- Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca, Via Bicocca degli Arcimboldi 8, 20126, Milan, Italy
| | - A L Catapano
- Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy; IRCCS MultiMedica, Via Milanese 300, 20099, Sesto S. Giovanni (MI), Italy
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Abstract
Over the last several decades, the global incidence and prevalence of diabetes mellitus has increased significantly. The raised incidence rate is projected to continue as greater numbers of persons adopt a Western lifestyle and diet. Patients with diabetes mellitus are at heightened risk of both adverse microvascular and cardiovascular events. Moreover, once cardiovascular disease develops, diabetes mellitus exacerbates progression and worsens outcomes. The medical management of patients with diabetes mellitus mandates comprehensive risk factor modification and antiplatelet therapy. Recent clinical trials of new medical therapies continue to inform the care of patients with diabetes mellitus to reduce both cardiovascular morbidity and mortality.
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Affiliation(s)
- Joshua A Beckman
- From the Department of Medicine, Section of Vascular Medicine, Cardiovascular Division, Vanderbilt University School of Medicine, Nashville, TN (J.A.B.); and Department of Medicine, Heart and Vascular Center, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH (M.A.C.).
| | - Mark A Creager
- From the Department of Medicine, Section of Vascular Medicine, Cardiovascular Division, Vanderbilt University School of Medicine, Nashville, TN (J.A.B.); and Department of Medicine, Heart and Vascular Center, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH (M.A.C.)
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Millán Núñez-Cortés J, Cases Amenós A, Ascaso Gimilio JF, Barrios Alonso V, Pascual Fuster V, Pedro-Botet Montoya JC, Pintó Sala X, Serrano Cumplido A. Consensus on the Statin of Choice in Patients with Impaired Glucose Metabolism: Results of the DIANA Study. Am J Cardiovasc Drugs 2017; 17:135-142. [PMID: 27837448 PMCID: PMC5340834 DOI: 10.1007/s40256-016-0197-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Introduction and Objectives Despite the recognized clinical benefit of statins on cardiovascular prevention, providing correct management of hypercholesterolaemia, possible adverse effects of their use cannot be disregarded. Previously published data shows that there is a risk of developing diabetes mellitus or experiencing changes in glucose metabolism in statin-treated patients. The possible determining factors are the drug characteristics (potency, dose), patient characteristics (kidney function, age, cardiovascular risk and polypharmacy because of multiple disorders) and the pre-diabetic state. Methods In order to ascertain the opinion of the experts (primary care physicians and other specialists with experience in the management of this type of patient) we conducted a Delphi study to evaluate the consensus rate on diverse aspects related to the diabetogenicity of different statins, and the factors that influence their choice. Results Consensus was highly significant concerning aspects such as the varying diabetogenicity profiles of different statins, as some of them do not significantly worsen glucose metabolism. There was an almost unanimous consensus that pitavastatin is the safest statin in this regard. Conclusions Factors to consider in the choice of a statin regarding its diabetogenicity are the dose and patient-related factors: age, cardiovascular risk, diabetes risk and baseline metabolic parameters (which must be monitored during the treatment), as well as kidney function.
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Affiliation(s)
- Jesús Millán Núñez-Cortés
- Internal Medicine Department, Hospital General Universitario Gregorio Marañón, School of Medicine of the Universidad Complutense, Madrid, Spain.
- Cátedra-Servicio de Medicina Interna, Hospital General Universitario Gregorio Marañón, Facultad de Medicina de la Universidad Complutense, Calle del Dr. Esquerdo, 46, 28007, Madrid, Spain.
| | | | | | - Vivencio Barrios Alonso
- Cardiology Department, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, Spain
| | | | | | - Xavier Pintó Sala
- Unit of Lipids and Vascular Risk, Hospital Universitario de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
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Parida S, Swain TR, Routray SN, Maiti R. Effect of Atorvastatin on Glycaemic Parameters in Normoglycaemic and Prediabetic Subjects: A Prospective, Panel Study. J Clin Diagn Res 2017; 11:FC04-FC09. [PMID: 28384881 DOI: 10.7860/jcdr/2017/23741.9427] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 11/17/2016] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Type 2 diabetes is associated with obesity and dyslipidemia, which are risk factor for cardiovascular disease. With recent FDA approved indications for statins being widened because of its lipid lowering and pleiotropic effects, statins are currently amongst the most widely used drugs in patients with or without diabetes. Although cardiovascular risk is reduced by statin therapy, its association with the development of diabetes is disputed. AIM This study was conducted to evaluate the effect of Atorvastatin on glycaemic status of normoglycaemic and prediabetic individuals. MATERIALS AND METHODS An observational, prospective panel study was conducted on 75 subjects who were on Atorvastatin therapy. After baseline data collection and investigations, subjects were recruited depending on their glycaemic status into three groups: normoglycaemic, Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) group. Atorvastatin therapy was continued and the subjects were followed every 6 months up to 18 months. At every follow up all glycaemic parameters were evaluated and subjects were assessed for continuation of statin therapy, dosing schedule and possible adverse drug reactions. RESULT All three groups as a whole, irrespective of dose of Atrovastatin therapy, showed a statistically significant (p<0.0001) increase in all glycaemic parameters. In normoglycaemic group with low dose Atorvastatin, there was no significant change in 2-hour Post Prandial Blood Sugar (PPBS) but change in HbA1c% (p=0.0004) and FBS (p<0.0001) was significant, whereas, with high dose, changes in 2-hr PPBS and HbA1c % were significant from 6 months onwards. In IFG group, both with low and high dose of Atorvastatin, there was significant change in all glycaemic parameters from 12 months onwards. In case of IGT, especially with high dose Atorvastatin, significant changes were evident from 6 months onwards. CONCLUSION Atorvastatin therapy especially with higher dose was found to be associated with glucose intolerance in normoglycaemics and also caused progression towards diabetes in prediabetic individuals.
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Affiliation(s)
- Sansita Parida
- Senior Resident, Department of Pharmacology, All India Institute of Medical Sciences (AIIMS) , Bhubaneswar, Odisha, India
| | - Trupti Rekha Swain
- Associate Professor, Department of Pharmacology, Sri Ram Chandra Bhanja Medical College and Hospital , Cuttack, Odisha, India
| | - Satya Narayan Routray
- Professor, Department of Cardiology, Sri Ram Chandra Bhanja Medical College and Hospital , Cuttack, Odisha, India
| | - Rituparna Maiti
- Associate Professor, Department of Pharmacology, All India Institute of Medical Sciences (AIIMS) , Bhubaneswar, Orissa, India
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Association between reductions in low-density lipoprotein cholesterol with statin therapy and the risk of new-onset diabetes: a meta-analysis. Sci Rep 2017; 7:39982. [PMID: 28071756 PMCID: PMC5223121 DOI: 10.1038/srep39982] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 11/30/2016] [Indexed: 12/21/2022] Open
Abstract
A recent meta-analysis demonstrated that statin therapy was associated with a risk of diabetes. The present study investigated whether the relative reduction in low-density lipoprotein cholesterol (LDL-c) was a good indicator of the risk of new-onset diabetes. We searched the PubMed, Embase, Cochrane Central Register, Lilacs, Food and Drug Administration, and European Medicines Agency databases for randomized controlled trials of statins. Fourteen trials were included in the study. Eight trials with target LDL-c levels ≤100 mg/dL (2.6 mmol/L) or LDL-c reductions of at least 30% were extracted separately. The results showed that the overall risk of incident diabetes increased by 11% (OR = 1.11; 95% CI 1.03–1.20). The group with intensive LDL-c-lowering statin had an 18% increase in the likelihood of developing diabetes (OR = 1.18; 95% CI, 1.10–1.28). Furthermore, the risks of incident diabetes were 13% (OR = 1.13; 95% CI 1.01–1.26) and 29% (OR = 1.29; 95% CI 1.13–1.47) in the subgroups with 30–40% and 40–50% reductions in LDL-c, respectively, suggesting that LDL-c reduction may provide a dynamic risk assessment parameter for new-onset diabetes. In conclusion, LDL-c reduction is positively related to the risk of new-onset diabetes. When LDL-c is reduced by more than 30% during lipid-lowering therapy, blood glucose monitoring is suggested to detect incident diabetes in high-risk populations.
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Alshehry ZH, Mundra PA, Barlow CK, Mellett NA, Wong G, McConville MJ, Simes J, Tonkin AM, Sullivan DR, Barnes EH, Nestel PJ, Kingwell BA, Marre M, Neal B, Poulter NR, Rodgers A, Williams B, Zoungas S, Hillis GS, Chalmers J, Woodward M, Meikle PJ. Plasma Lipidomic Profiles Improve on Traditional Risk Factors for the Prediction of Cardiovascular Events in Type 2 Diabetes Mellitus. Circulation 2016; 134:1637-1650. [PMID: 27756783 DOI: 10.1161/circulationaha.116.023233] [Citation(s) in RCA: 197] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 09/29/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND Clinical lipid measurements do not show the full complexity of the altered lipid metabolism associated with diabetes mellitus or cardiovascular disease. Lipidomics enables the assessment of hundreds of lipid species as potential markers for disease risk. METHODS Plasma lipid species (310) were measured by a targeted lipidomic analysis with liquid chromatography electrospray ionization-tandem mass spectrometry on a case-cohort (n=3779) subset from the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation). The case-cohort was 61% male with a mean age of 67 years. All participants had type 2 diabetes mellitus with ≥1 additional cardiovascular risk factors, and 35% had a history of macrovascular disease. Weighted Cox regression was used to identify lipid species associated with future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) and cardiovascular death during a 5-year follow-up period. Multivariable models combining traditional risk factors with lipid species were optimized with the Akaike information criteria. C statistics and NRIs were calculated within a 5-fold cross-validation framework. RESULTS Sphingolipids, phospholipids (including lyso- and ether- species), cholesteryl esters, and glycerolipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model (14 traditional risk factors and medications) to predict cardiovascular events increased the C statistic from 0.680 (95% confidence interval [CI], 0.678-0.682) to 0.700 (95% CI, 0.698-0.702; P<0.0001) with a corresponding continuous NRI of 0.227 (95% CI, 0.219-0.235). The prediction of cardiovascular death was improved with the incorporation of 4 lipid species into the base model, showing an increase in the C statistic from 0.740 (95% CI, 0.738-0.742) to 0.760 (95% CI, 0.757-0.762; P<0.0001) and a continuous net reclassification index of 0.328 (95% CI, 0.317-0.339). The results were validated in a subcohort with type 2 diabetes mellitus (n=511) from the LIPID trial (Long-Term Intervention With Pravastatin in Ischemic Disease). CONCLUSIONS The improvement in the prediction of cardiovascular events, above traditional risk factors, demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes mellitus. CLINICAL TRIAL REGISTRATION URL: https://clinicaltrials.gov. Unique identifier: NCT00145925.
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Affiliation(s)
- Zahir H Alshehry
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Piyushkumar A Mundra
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Christopher K Barlow
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Natalie A Mellett
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Gerard Wong
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Malcolm J McConville
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - John Simes
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Andrew M Tonkin
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - David R Sullivan
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Elizabeth H Barnes
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Paul J Nestel
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Bronwyn A Kingwell
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Michel Marre
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Bruce Neal
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Neil R Poulter
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Anthony Rodgers
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Bryan Williams
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Sophia Zoungas
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Graham S Hillis
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - John Chalmers
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Mark Woodward
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.)
| | - Peter J Meikle
- From Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (Z.H.A., P.A.M., C.K.B., N.A.M., G.W., P.J.N., B.A.K., P.J.M.); King Fahad Medical City, Riyadh, Saudi Arabia (Z.H.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia (Z.H.A., M.J.M., P.J.M.); NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia (J.S., E.H.B.); School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (A.M.T., S.Z.); Royal Prince Alfred Hospital, Sydney, NSW, Australia (D.R.S.); Hópital Bichat-Claude Bernard and Université Paris 7, Paris, France (M.M.); George Institute for Global Health, Sydney, NSW, Australia (B.N., N.R.P., S.Z., G.S.H., J.C., M.W.); University College London and National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK (B.W.); Department of Cardiology, Royal Perth Hospital/University of Western Australia, Perth, WA, Australia (G.S.H.); George Institute for Global Health, University of Oxford, Oxford, UK (M.W.); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.).
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Lee J, Noh Y, Shin S, Lim HS, Park RW, Bae SK, Oh E, Kim GJ, Kim JH, Lee S. Impact of statins on risk of new onset diabetes mellitus: a population-based cohort study using the Korean National Health Insurance claims database. Ther Clin Risk Manag 2016; 12:1533-1543. [PMID: 27785041 PMCID: PMC5066992 DOI: 10.2147/tcrm.s117150] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Statin therapy is beneficial in reducing cardiovascular events and mortalities in patients with atherosclerotic cardiovascular diseases. Yet, there have been concerns of increased risk of diabetes with statin use. This study was aimed to evaluate the association between statins and new onset diabetes mellitus (NODM) in patients with ischemic heart disease (IHD) utilizing the Korean Health Insurance Review and Assessment Service claims database. Among adult patients with preexisting IHD, new statin users and matched nonstatin users were identified on a 1:1 ratio using proportionate stratified random sampling by sex and age. They were subsequently propensity score matched further with age and comorbidities to reduce the selection bias. Overall incidence rates, cumulative rates and hazard ratios (HRs) between statin use and occurrence of NODM were estimated. The subgroup analyses were performed according to sex, age groups, and the individual agents and intensities of statins. A total of 156,360 patients (94,370 in the statin users and 61,990 in the nonstatin users) were included in the analysis. The incidence rates of NODM were 7.8% and 4.8% in the statin users and nonstatin users, respectively. The risk of NODM was higher among statin users (crude HR 2.01, 95% confidence interval [CI] 1.93–2.10; adjusted HR 1.84, 95% CI 1.63–2.09). Pravastatin had the lowest risk (adjusted HR 1.54, 95% CI 1.32–1.81) while those who were exposed to more than one statin were at the highest risk of NODM (adjusted HR 2.17, 95% CI 1.93–2.37). It has been concluded that all statins are associated with the risk of NODM in patients with IHD, and it is believed that our study would contribute to a better understanding of statin and NODM association by analyzing statin use in the real-world setting. Periodic screening and monitoring for diabetes are warranted during prolonged statin therapy in patients with IHD.
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Affiliation(s)
- Jimin Lee
- Division of Clinical Pharmacy, College of Pharmacy, Ajou University, Suwon, South Korea
| | - Yoojin Noh
- Division of Clinical Pharmacy, College of Pharmacy, Ajou University, Suwon, South Korea
| | - Sooyoung Shin
- Division of Clinical Pharmacy, College of Pharmacy, Ajou University, Suwon, South Korea
| | - Hong-Seok Lim
- Department of Cardiology, School of Medicine, Ajou University, Suwon, South Korea
| | - Rae Woong Park
- Department of Biomedical Informatics, School of Medicine, Ajou University, Suwon, South Korea
| | - Soo Kyung Bae
- Division of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea
| | - Euichaul Oh
- Division of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea
| | - Grace Juyun Kim
- Division of Biomedical Informatics, College of Medicine, Seoul National University, Seoul, South Korea
| | - Ju Han Kim
- Division of Biomedical Informatics, College of Medicine, Seoul National University, Seoul, South Korea
| | - Sukhyang Lee
- Division of Clinical Pharmacy, College of Pharmacy, Ajou University, Suwon, South Korea
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Impact of statin therapy on plasma adiponectin concentrations: A systematic review and meta-analysis of 43 randomized controlled trial arms. Atherosclerosis 2016; 253:194-208. [DOI: 10.1016/j.atherosclerosis.2016.07.897] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Revised: 06/12/2016] [Accepted: 07/12/2016] [Indexed: 11/21/2022]
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Mccallum RW, Fisher M. From 4S to FIELD and PROactive: 10 years of CV trials in people with diabetes. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/14746514050050040701] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
he last ten years have seen a rapid expansion in the evidence-base for the reduction of cardiovascular risk in people with diabetes.in Following the landmark Scandinavian Simvastatin Survival Study (4S), several other studies have shown the benefits of statins in people with diabetes, but much less data are available for the benefit of fibrates, and the main evidence to date comes from subgroup analysis of the Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial (VA-HIT). The Hypertension in Diabetes Study (HDS), nested within the United Kingdom Prospective Diabetes Study (UKPDS), proved that tight control of hypertension reduced microvascular and macrovascular events in people with diabetes, and the Heart Outcomes Prevention Evaluation (HOPE) and MICRO-HOPE studies suggested a benefit in reducing cardiovascular events with angiotensin-converting enzyme (ACE) inhibition, additional to blood pressure lowering effects. With regards to glycaemic therapy, the UKPDS has shown the benefit of metformin in reducing myocardial infarctions. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) studies will be presented later this year and will give information on the role of fenofibrate and pioglitazone respectively in reducing cardiovascular events in people with diabetes.
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Affiliation(s)
| | - Miles Fisher
- Wards 4 & 5, Glasgow Royal Infirmary, 84 Castle Street, Glasgow, G4 0SF, UK?
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Abstract
iabetes can be considered as a cardiovascular disease leading to the premature death of patients. The increase in cardiovascular risk has been extensively investigated and is associated with a cluster of adverse factors. The effects of various treatments used to affect the pathogenesis of the atherosclerotic process have been investigated in many large trials. A number of issues make the interpretation and comparison of these trials complicated, and in particular the use of a single primary end point such as mortality has been replaced with composite end points. The effects of risk factors and interventions on coronary heart disease (CHD) risk has been converted to cardiovascular disease (CVD) risk for understandable reasons, but this makes the interpretation and comparison of results even more complex. This review provides a critical analysis of outcome studies, highlighting differences in design, end points, patient inclusion and definitions in recent cardiovascular diabetology trials, and examines the potential pitfalls in making unjustified comparisons. Br J Diabetes Vasc Dis 2006; 6:111—18
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Affiliation(s)
- Roland W Mccallum
- Department of Medicine and Diabetes, Royal Alexandra Hospital, Corsebar Road, Paisley, PA2 9PN, UK
| | - Miles Fisher
- Wards 4 & 5, Glasgow Royal Infirmary, 84 Castle Street, Glasgow, G4 0SF, UK,
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Thakker D, Nair S, Pagada A, Jamdade V, Malik A. Statin use and the risk of developing diabetes: a network meta-analysis. Pharmacoepidemiol Drug Saf 2016; 25:1131-1149. [PMID: 27277934 DOI: 10.1002/pds.4020] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 03/14/2016] [Accepted: 04/01/2016] [Indexed: 11/06/2022]
Abstract
PURPOSE Randomized controlled trials have shown mixed findings regarding the association of statins and diabetes. This systematic literature review and network meta-analysis (NMA) was performed to update evidence on this association to possibly assist clinicians in making more informed treatment choices. METHODS We identified studies relevant to our NMA by performing study searches in databases like Embase, Cochrane, and PubMed, published between August 2010 and June 2014. Pre-2010 studies were identified from bibliography of previously published meta-analyses. Unpublished study data were found from clinicaltrial.gov. Data synthesis was performed by pairwise meta-analysis and NMA within a Frequentist framework. RESULTS Twenty nine trials in which 1 63 039 participants had been randomized were included in this review; among these 1 41 863 were non-diabetic patients. The direct meta-analysis showed that statins, as a class, significantly increased the likelihood of developing diabetes by 12% (pooled OR 1.12; 95%CI 1.05-1.21; I2 36%; p = 0.002; 18 RCTs). In the NMA, atorvastatin 80 mg was associated with a highest risk of diabetes, with OR of 1.34 (95%CI 1.14-1.57) followed by rosuvastatin (OR: 1.17; 95%CI: 1.02-1.35). The ORs (95%CIs) for simvastatin 80 mg, simvastatin, atorvastatin, pravastatin, lovastatin and pitavastatin were 1.21 (0.99-1.49), 1.13 (0.99-1.29), 1.13 (0.94-1.34), 1.04 (0.93-1.16), 0.98 (0.69-1.38) and 0.74 (0.31-1.77), respectively. High-dose atorvastatin increased the odds of developing diabetes even when compared with pravastatin, simvastatin and low-dose atorvastatin in the NMA. CONCLUSIONS Based on the results, statins, as a class, increased the risk of diabetes significantly in the pairwise meta-analysis. Overall, there appears to be a small increased risk of incident diabetes, particularly with more intensive statin therapy, although more data would be valuable to increase the robustness of this interpretation, given that the lower confidence intervals of our study analyses are close to, or just crossing one. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Divyesh Thakker
- Knowledge Services (Health Research & Consulting), Capita, India
| | - Sunita Nair
- Knowledge Services (Health Research & Consulting), Capita, India.
| | - Amit Pagada
- Knowledge Services (Health Research & Consulting), Capita, India
| | - Vinayak Jamdade
- Knowledge Services (Health Research & Consulting), Capita, India
| | - Anuradha Malik
- Knowledge Services (Health Research & Consulting), Capita, India
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Castro MR, Simon G, Cha SS, Yawn BP, Melton LJ, Caraballo PJ. Statin Use, Diabetes Incidence and Overall Mortality in Normoglycemic and Impaired Fasting Glucose Patients. J Gen Intern Med 2016; 31:502-8. [PMID: 26850412 PMCID: PMC4835368 DOI: 10.1007/s11606-015-3583-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 09/18/2015] [Accepted: 12/16/2015] [Indexed: 12/25/2022]
Abstract
BACKGROUND The association between the use of statins and the risk of diabetes and increased mortality within the same population has been a source of controversy, and may underestimate the value of statins for patients at risk. OBJECTIVE We aimed to assess whether statin use increases the risk of developing diabetes or affects overall mortality among normoglycemic patients and patients with impaired fasting glucose (IFG). DESIGN AND PARTICIPANTS Observational cohort study of 13,508 normoglycemic patients (n = 4460; 33% taking statins) and 4563 IFG patients (n = 1865; 41% taking statin) among residents of Olmsted County, Minnesota, with clinical data in the Mayo Clinic electronic medical record and at least one outpatient fasting glucose test between 1999 and 2004. Demographics, vital signs, tobacco use, laboratory results, medications and comorbidities were obtained by electronic search for the period 1999-2004. Results were analyzed by Cox proportional hazards models, and the risk of incident diabetes and mortality were analyzed by survival curves using the Kaplan-Meier method. MAIN MEASURES The main endpoints were new clinical diagnosis of diabetes mellitus and total mortality. KEY RESULTS After a mean of 6 years of follow-up, statin use was found to be associated with an increased risk of incident diabetes in the normoglycemic (HR 1.19; 95% CI, 1.05 to 1.35; p = 0.007) and IFG groups (HR 1.24; 95%CI, 1.11 to 1.38; p = 0.0001). At the same time, overall mortality decreased in both normoglycemic (HR 0.70; 95% CI, 0.66 to 0.80; p < 0.0001) and IFG patients (HR 0.77, 95% CI, 0.64 to 0.91; p = 0.0029) with statin use. CONCLUSION In general, recommendations for statin use should not be affected by concerns over an increased risk of developing diabetes, since the benefit of reduced mortality clearly outweighs this small (19-24%) risk.
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Affiliation(s)
- M Regina Castro
- Department of Medicine, Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
| | - Gyorgy Simon
- Institute for Health Informatics, University of Minnesota, Minneapolis, MN, USA
| | - Stephen S Cha
- Department of Health Sciences Research, Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN, USA
| | - Barbara P Yawn
- Department of Research, Olmsted Medical Center, Rochester, MN, USA
| | - L Joseph Melton
- Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
| | - Pedro J Caraballo
- Department of Medicine, Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA. .,Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Bernardi A, Rocha VZ, Faria-Neto JR. Use of statins and the incidence of type 2 diabetes mellitus. Rev Assoc Med Bras (1992) 2016; 61:375-80. [PMID: 26466221 DOI: 10.1590/1806-9282.61.04.375] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 07/16/2015] [Indexed: 01/18/2023] Open
Abstract
INTRODUCTION the use of statins is associated with reduced cardiovascular risk in studies of primary and secondary prevention, and the reduction is directly proportional to the reduction of LDL-cholesterol. Recent evidence suggests that statins may be associated with a higher incidence of new cases of diabetes. The aim of this review is to explore this possibility, identifying factors associated with the increase in risk and the potential diabetogenic mechanisms of statins. In addition, we evaluated if the risk of diabetes interferes with the reduction in cardiovascular risk achieved with statins. METHODS we reviewed articles published in the Scielo and Pubmed databases, which assessed or described the association between use of statins and risk of diabetes up to June 2015. RESULTS use of statins is associated with a small increase in the incidence of new cases of diabetes. Age, potency of statin therapy, presence of metabolic syndrome, impaired fasting blood glucose, overweight and previously altered glycated hemoglobin levels are associated with increased risk of diabetes, but there is no consensus about the possible diabetogenic mechanisms of statins. In patients candidate to hypolipemiant drug therapy, the benefit of reducing cardiovascular risk outweighs any risk increase in the incidence of diabetes. CONCLUSION statins are associated with a small increase in incidence of diabetes in patients predisposed to glycemic alteration. However, since the benefit of cardiovascular risk reduction prevails even in this group, there is no evidence to date that this finding should change the recommendation of starting statin therapy.
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Affiliation(s)
- André Bernardi
- Centro de Epidemiologia e Pesquisa Clínica, Escola de Medicina, Pontifícia Universidade Católica do Paraná, Curitiba, PR, BR
| | | | - José Rocha Faria-Neto
- Centro de Epidemiologia e Pesquisa Clínica, Escola de Medicina, Pontifícia Universidade Católica do Paraná, Curitiba, PR, BR
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Lin ZF, Wang CY, Shen LJ, Hsiao FY, Lin Wu FL. Statin Use and the Risk for Incident Diabetes Mellitus in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: A Population-Based Retrospective Cohort Study in Taiwan. Can J Diabetes 2016; 40:264-9. [PMID: 26992286 DOI: 10.1016/j.jcjd.2015.12.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 11/07/2015] [Accepted: 12/21/2015] [Indexed: 01/08/2023]
Abstract
OBJECTIVES The purpose of this study was to examine the association between statin use by individuals and the risk for incident diabetes mellitus in patients with acute coronary syndrome (ACS) following percutaneous coronary intervention (PCI). METHODS We conducted a retrospective cohort study of patients who were hospitalized for ACS between January 1, 2006, and December 31, 2010, and who had undergone PCI (n=30,665); the data were retrieved from the Taiwan National Health Insurance Research Database. A propensity score technique was used to establish a 1:1 matched cohort for statin users and non-statin users (n=9043 for each group). The risk for incident diabetes mellitus in statin users compared to non-statin users for patients with ACS after PCI was estimated by the multivariable Cox proportional hazards regression model. RESULTS Statin use was associated with a significant increase of 27% in the risk for new-onset diabetes mellitus (adjusted hazard ratio [HR] 1.27, 95% CI 1.14 to 1.41) compared to non-statin use in the matched cohort. The matched cohort analysis indicated that almost all individual statins were associated with a statistically significant increase in the risk for new-onset diabetes mellitus compared to those without statin use. CONCLUSIONS Our study indicated an association between increased risk for new-onset diabetes mellitus and statin use. Because the benefits of statins in prevention of morbidity and mortality in patients with ACS are well-established, clinical decision making should not be changed for patients with existing cardiovascular disease in whom statin therapy is recommended.
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Affiliation(s)
- Zhen-Fang Lin
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Yu Wang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Li-Jiuan Shen
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan
| | - Fei-Yuan Hsiao
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan.
| | - Fe-Lin Lin Wu
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan.
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