Predictors of New-Onset Diabetes in Patients Treated With Atorvastatin: Results From 3 Large Randomized Clinical Trials
What are the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within three large randomized trials with atorvastatin?
The investigators used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. They identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM. Major cardiovascular events in patients with and without new-onset T2DM were assessed with an extensive time-dependent Cox proportional hazard analysis.
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], 0.94-1.29; 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, 0.98-1.43; 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, 1.08-1.75; p = 0.011). In each of the three trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the three 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, 0.77-1.35; p = 0.69).
The authors concluded that high-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM.
This study suggests that the use of high-dose atorvastatin is associated with a slight increase in the risk of new-onset T2DM, although the strongest predictors of new-onset T2DM remain baseline fasting glucose and other features of the metabolic syndrome. The mechanism underlying the small increase in new-onset T2DM in patients treated with statins is unknown. It is possible that statins decrease insulin sensitivity in liver or muscle, but there is no direct experimental evidence to support this. Although any potential increased risk of new-onset T2DM with atorvastatin warrants careful monitoring, the benefits of atorvastatin clearly outweigh the risks in patients with coronary or cerebrovascular disease, and it remains uncertain as to whether new-onset T2DM itself increases risk.
Keywords: Pyrroles, Cholesterol, Blood Glucose, Diabetes Mellitus, Type 2, Insulin Resistance, Triglycerides, Hypertension, Glucose
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