Predictors of New-Onset Diabetes in Patients Treated With Atorvastatin
Predictors of New-Onset Diabetes in Patients Treated With Atorvastatin
Objectives We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin.
Background Statin therapy might modestly increase the risk of new-onset T2DM.
Methods We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM.
Results In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69).
Conclusions High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials.
An increased risk of new-onset type 2 diabetes mellitus (T2DM) has been described with a wide variety of drugs, including thiazide diuretics, beta-blockers, glucocorticoids, niacin, and protease inhibitors. In a recently published meta-analysis of 13 statin trials with 91,140 participants, statin therapy was associated with a slightly higher incidence of new-onset T2DM (hazard ratio [HR]: 1.09, 95% confidence interval [CI]: 1.02 to 1.17). Little heterogeneity was found between trials, and meta-regression showed that the risk of developing diabetes with statins was highest in trials with older participants but that neither baseline body mass index (BMI) nor change in low-density lipoprotein (LDL) cholesterol concentrations accounted for residual variation in risk. However, other clinical predictors were not examined, and only 1 of the 13 trials in this analysis involved atorvastatin, compared with 6 with pravastatin and 3 with rosuvastatin.
The purpose of this report is to describe the incidence of new-onset T2DM in 3 additional large randomized trials: the TNT (Treating to New Targets) trial, in which 80 mg and 10 mg/day of atorvastatin were compared in patients with stable coronary disease; the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, in which atorvastatin 80 mg was compared with simvastatin 20 mg/day in post-myocardial infarction (MI) patients; and the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, in which 80 mg/day of atorvastatin was compared with placebo in patients with a recent stroke or transient ischemic attack. Within each trial, we examined baseline clinical predictors of incident diabetes. In addition, we compared the subsequent event rate after the development of new-onset T2DM with the event rate for patients who did not develop this complication.
Abstract and Introduction
Abstract
Objectives We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin.
Background Statin therapy might modestly increase the risk of new-onset T2DM.
Methods We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM.
Results In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69).
Conclusions High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials.
Introduction
An increased risk of new-onset type 2 diabetes mellitus (T2DM) has been described with a wide variety of drugs, including thiazide diuretics, beta-blockers, glucocorticoids, niacin, and protease inhibitors. In a recently published meta-analysis of 13 statin trials with 91,140 participants, statin therapy was associated with a slightly higher incidence of new-onset T2DM (hazard ratio [HR]: 1.09, 95% confidence interval [CI]: 1.02 to 1.17). Little heterogeneity was found between trials, and meta-regression showed that the risk of developing diabetes with statins was highest in trials with older participants but that neither baseline body mass index (BMI) nor change in low-density lipoprotein (LDL) cholesterol concentrations accounted for residual variation in risk. However, other clinical predictors were not examined, and only 1 of the 13 trials in this analysis involved atorvastatin, compared with 6 with pravastatin and 3 with rosuvastatin.
The purpose of this report is to describe the incidence of new-onset T2DM in 3 additional large randomized trials: the TNT (Treating to New Targets) trial, in which 80 mg and 10 mg/day of atorvastatin were compared in patients with stable coronary disease; the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, in which atorvastatin 80 mg was compared with simvastatin 20 mg/day in post-myocardial infarction (MI) patients; and the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, in which 80 mg/day of atorvastatin was compared with placebo in patients with a recent stroke or transient ischemic attack. Within each trial, we examined baseline clinical predictors of incident diabetes. In addition, we compared the subsequent event rate after the development of new-onset T2DM with the event rate for patients who did not develop this complication.
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