Statins and Risk for Diabetes Mellitus. Background

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1 Statins and Risk for Diabetes Mellitus Kevin C. Maki, PhD, FNLA Midwest Center for Metabolic & Cardiovascular Research and DePaul University, Chicago, IL 1 Background In 2012 the US Food and Drug Administration added a statement to the labels of statin medications indicating that increases in glycated hemoglobin (HbA 1C ) and fasting glucose levels have been reported with statin use. The Diabetes Subpanel of the National Lipid Association Expert Panel on Statin Safety reviewed the published evidence relating statin use to the hazard for diabetes mellitus or worsening glycemia, with the aims of summarizing the results and providing practical guidance on how to manage this issue in clinical practice. 2

2 Maki et al. J Clin Lipidol. 2014;8:S17 S29. 3 WOSCOPS Statin Treatment Associated with Lower Risk for T2DM Multivariate HR = 0.70 (95% CI 0.50 to 0.99), P = Freeman et al. Circulation. 2001;103:

3 JUPITER Increased Risk for T2DM with Rosuvastatin Treatment Event Placebo Rosuvastatin Difference P Value New T2DM (All)* 270 (3.0%) 216 (2.4%) New T2DM (0 DM RF)* 12 (0.2%) 12 (0.2%) New T2DM ( 1 DM RF)* 204 (1.7%) 258 (2.1%) HR (95% CI) 0 DM RF 0.99 ( ) HR (95% CI) 1 DM RF 1.28 ( ) *8901 subjects were allocated to each group overall; of the 17,802 participants, 6095 had no major diabetes mellitus (DM) risk factors (RF) and 11,508 1 DM RF; DM RFs included metabolic syndrome, impaired fasting glucose, body mass index 30 kg/m 2 and glycated hemoglobin >6% Ridker et al. Lancet. 2012;380: JUPITER Lower Risk for Primary CVD Endpoint with Rosuvastatin Treatment Event Placebo Rosuvastatin Difference P Value 1 o CVD EP (All)* 251 (2.8%) 142 (1.6%) 109 < o CVD EP (0 DM RF)* 91 (1.5%) 44 (0.7%) 47 < o CVD EP ( 1 DM RF)* 157 (1.3%) 96 (0.8%) 61 < HR (95% CI) 0 DM RF 0.48 ( ) 52% HR (95% CI) 1 DM RF 0.61 ( ) 39% *8901 subjects were allocated to each group overall; of the 17,802 participants, 6095 had no major diabetes mellitus (DM) risk factors (RF) and 11,508 1 DM RF; DM RFs included metabolic syndrome, impaired fasting glucose, body mass index 30 kg/m 2 and glycated hemoglobin >6% Ridker et al. NEJM. 2008;359: ; Ridker et al. Lancet. 2012;380:

4 Statin Therapy and Incident Diabetes in 13 CVD Endpoint Trials Sattar et al. Lancet. 2010;375: Number Needed to Treat Sattar Meta-Analysis The number of patients that would need to be treated for 4 years to produce one excess case of T2DM is 255 Based on the CTT analysis, a 1 mmol/l (38.7 mg/dl) reduction in LDL-C over 4 years would prevent 5.4 CHD events would be prevented in those 255 patients CHD includes myocardial infarction and fatal CHD, but does not include revascularization or stroke, which account for about half of all major adverse CVD events Thus, 5-10 CVD events and revascularizations might be prevented for each excess case of T2DM associated with use of statin therapy Sattar et al. Lancet. 2010;375:

5 Incident Diabetes Intensive vs. Moderate Statin Therapy: Diabetes and CVD Outcomes Incident CVD Preiss et al. JAMA. 2011;305: Number Needed to Treat Preiss Meta-Analysis The number of patients that would need to be treated for one year with intensive statin therapy vs. moderate-dose statin therapy to produce an excess case of T2DM is 498 The number patients that would need to be treated to prevent one CVD event in a year is 155 (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization). Thus, if 498 patients were treated for one year with high-intensity statin therapy rather than moderate intensity statin therapy, this would be expected to produce one excess case of T2DM but to prevent 3.2 CVD events Preiss et al. JAMA. 2011;305:

6 T2DM Risk by Baseline Statin Use and 3-year Follow-up in the Women s Health Initiative (WHI) Culver et al. Arch Intern Med. 2012;172: Effect of Adherence to Statin Therapy on the HRs for Diabetes Corrao et al. Diabetes Care DOI: /dc

7 T2DM Risk in Men by Statin Treatment During 5.9 Year Follow-up (METSIM Cohort) Adjusted HR = 1.46 (95% CI 1.22 to 1.74) P < Statin treatment at baseline No statin treatment at baseline Cederberg et al. Diabetologia. 2015; 58: T2DM Risk by in Men Statin Treatment During 5.9 Year Follow-up (METSIM Cohort) Simvastatin Atorvastatin High (40 or 80 mg/d) High (20 or 40 mg/d) Low (10 or 20 mg/d) Low (10 mg/d) None None High vs. none: HR = 1.44 (95% CI 1.23 to 1.68) Low vs. none: HR = 1.28 (95% CI 1.01 to 1.62) High vs. none: HR = 1.37 (95% CI 1.14 to 1.65) Cederberg et al. Diabetologia. 2015; 58:

8 Association of Simvastatin and Atorvastatin Use at Baseline and Insulin Sensitivity Cederberg et al. Diabetologia. 2015; 58: Association of Simvastatin and Atorvastatin Use at Baseline and Insulin Secretion Cederberg et al. Diabetologia. 2015; 58:

9 Key Findings of the METSIM Cohort Study Statin therapy was associated with: 46% greater risk of T2DM Worsened glycemia, particularly 2-hour plasma glucose 24% insulin sensitivity, 7-12% insulin secretion (beta-cell function) Simvastatin and atorvastatin use were dose-dependently associated with reduced insulin sensitivity and beta-cell function Findings suggest risk for T2DM associated with statin use is higher than previously believed based on RCT data RCTs using either FPG or physician-reported diagnosis of diabetes may substantially underestimate risk In the METSIM cohort, 56.5% of diabetes diagnoses were made using 2-hour plasma glucose and/or HbA1c 17 NLA Expert Panel Conclusions Statin therapy should continue to be recommended where appropriate for the reduction of cardiovascular disease event risk. Lifestyle modification should be emphasized to all patients for whom statin therapy is recommended to reduce cardiovascular risk, and to attenuate the increase in diabetes risk. Patients with risk factors for diabetes should be screened with fasting glucose or glycated hemoglobin (HbA1c), ideally prior to starting statin therapy, within one year of initiation, and at intervals no longer than 3 years thereafter. 18

10 Conclusions Statin use is associated with an increase in risk for newonset type 2 diabetes mellitus, compared with placebo or usual care. Intensive statin therapy appears to increase diabetes risk beyond that of moderate-dose statin therapy. Excess risk for diabetes with statin use is most clearly evident in those with major risk factors for diabetes. JUPITER, the hazard for T2DM was increased by 28% for those with T2DM risk factors and by 0% in those without risk factors The cardiovascular benefits of statin therapy outweigh the potential risk for diabetes development, although risk for T2DM associated with statin use may be greater than initially estimated. 19