Statin Therapy and Risk for Diabetes: Deconstructing a Flawed Study

Michael Mogadam, MD

Disclosures

February 24, 2012

In This Article

Other Supportive Studies

Even if we accept the notion that statins may increase the risk for dysglycemia or diabetes, there is no data to suggest that they increase the risk for cardiovascular disease and micro- or macrovascular diseases or that negate the benefits of statin therapy.

Yeboah and colleaguesused data from the Multi-Ethnic Study of Atherosclerosis (MESA) baseline and follow-up examinations to assess the associations of impaired fasting glucose (IFG) with type 2 diabetes and cardiovascular disease (CVD).[2] During 7.5 years of follow-up, IFG was not associated with incident CV events in multivariate model compared with normal fasting glucose. However, IFG was strongly associated with progression to and development of type 2 diabetes. Thus the association between IFG and CVD risk is not due to IFG but its progression to diabetes and the coexistence of other major CVD risk factors in persons with IFG. Thus the development of diabetes in patients with IFG who are treated with statins may be misunderstood and mislabeled as "statin-induced diabetes." These findings also suggest that the threshold of fasting blood glucose level that is independently associated with CVD risk may be as high as the threshold for the diagnosis of diabetes.

What about previous reports of statin-associated hyperglycemia, dysglycemia, or "diabetes"? Waters and colleagues examined the incidence and clinical predictors of new-onset type 2 diabetes within 3 large randomized trials that used atorvastatin.[3] They used a standard definition of diabetes (2 elevated fasting blood glucose levels) and excluded patients with prevalent diabetes, but not those with IFG, at baseline.

  1. In the TNT (Treating to New Targets) trial,[4] 351 of 3798 patients randomized to 80 mg of atorvastatin and 308 of 3797 randomized to 10 mg developed new-onset type 2 diabetes mellitus (T2DM) (9.24% vs 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94-1.29, P = .226).

  2. In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial,[5] 239 of 3737 patients randomized to atorvastatin 80 mg/day and 208 of 3724 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 = .072).

  3. In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial,[6] new-onset T2DM developed in 166 of 1905 patients randomized to atorvastatin 80 mg/day and in 115 of 1898 patients in the placebo group (8.71% vs 6.06%, adjusted HR: 1.37, 95% CI: 1.08-1.75, P = .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, there was no difference in the major cardiovascular events, which were 11.3% in patients with and 10.8% in patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77-1.35, P = .69). The authors did find that high-dose atorvastatin treatment compared with placebo in the SPARCL trial was associated with a slightly increased risk for new-onset T2DM.

In a meta-analysis of 13 clinical trials with 91,140 participants, Sattar and colleagues examined the possible association of statins with development of diabetes.[7] Among the 91,140 participants without diabetes, 4278 developed incident diabetes over a mean study follow-up of about 4 years. The rate of diabetes in individual trials varied substantially. In the combined data, 174 more cases of incident diabetes occurred in the groups assigned to statin treatment than in the placebo or standard-care groups, representing a 9% increase in the likelihood of development of diabetes during follow-up. The investigators estimated that this amounted to 1 additional case of diabetes per 255 patients treated with statins over 4 years. The results were nearly identical when the analyses were restricted to placebo-controlled trials. Although the association between statin therapy and risk for incident diabetes was stronger in trials with older participants, baseline BMI and percent change in LDL cholesterol did not seem to be important factors.

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