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Statins may raise blood glucose: Should we be concerned?
by Ronald M. Goldenberg, MD, FRCPC, FACE
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KEY MESSAGES
• Statin therapy has been associated with a small increased risk of new onset diabetes or a small rise in glucose levels.
• Statins have been proven to significantly reduce the risk of major cardiovascular events.
• The benefit of statin therapy in reducing cardiovascular events outweighs the small risk of worsening glycemia or new onset diabetes.
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On February 28, 2012, the US Food and Drug Administration (FDA) approved new safety label changes for the statin class of cholesterol-lowering drugs (1). These changes included a statement regarding the effect of statins on blood glucose. The FDA stated that “increases in blood sugar levels have been reported with statin use.” However, they also indicated that “the cardiovascular benefits of statins outweigh these small increased risks.”
What is the evidence that statins can raise blood glucose or increase the risk of diabetes, and how can we interpret this information so that we can advise our patients? Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) reported a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated patients compared to placebo-treated patients, but the absolute risk increase was small, with new onset diabetes reported in 2.4% of those on placebo and in 3.0% of those treated with rosuvastatin (2). There was a small but statistically significant difference in median A1C levels in JUPITER after 24 months of therapy: 5.9% in the statin-treated group and 5.8% in the placebo group (2). The small rise in A1C suggests a mild progression of dysglycemia with statin therapy.
A meta-analysis by Sattar et al was published in the Lancet in 2010 (3). They reviewed 13 statin trials with 91,140 participants and reported that statin therapy was associated with a small 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% confidence interval [CI] 1.02-1.17). This translated into one additional case of diabetes per 255 patients taking statin therapy for 4 years. In contrast, data from the Cholesterol Treatment Trialists (CTT) meta-analysis of statin trials in 71,370 participants demonstrated that statin therapy was associated with a reduction in major coronary events of 5.4 events per 255 patients treated for 4 years compared with control therapy for a 1mmol/L reduction in LDL-cholesterol concentration. Therefore, for every 255 patients treated with statins for 4 years, there will be one additional case of diabetes but 5.4 less coronary events (see figure below). The benefit of statin therapy outweighing the risk of diabetes would be expected to be even greater when accounting for the effect of statins on strokes and the need for revascularisation, in addition to the reduction in coronary events.
A further meta-analysis examined the effect of intensive-dose versus moderate-dose statin therapy on the risk of diabetes (4). In 5 statin trials with 32,752 participants, intensive-dose statin therapy was associated with a 12% increased risk for incident diabetes (OR 1.12; 95% CI 1.04-1.22) and a 16% decreased risk for cardiovascular events (OR 0.84; CI, 0.75-0.94). As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events.
In the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) post-hoc substudy, an increase of 0.5% in A1C occurred in 28% of subjects taking pravastatin 40 mg, compared with 44% of patients on atorvastatin 80 mg (5). Among the 3,382 patients without pre-existing diabetes, A1C increased by 0.12% in patients treated with pravastatin and by 0.30% in patients treated with atorvastatin (p<0.0001).
The mechanism for statins increasing the risk of diabetes or worsening glycemia has not been clearly elucidated. The effect of statins on insulin resistance has been inconsistent in various reports.3
What does all these mean for our diabetes patients or those at risk of diabetes being treated with statins? There are inherent risks and benefits with any pharmacotherapy. While there is evidence that statins can increase the risk of diabetes or raise glucose levels, the absolute risk is quite small. The benefits of statin therapy in reducing cardiovascular events far outweigh the small risk of worsening glycemic control. The Canadian Diabetes Association suggests that people with diabetes who are currently taking a statin continue their medication unless instructed otherwise by their healthcare provider. Stopping statin therapy is not recommended based on the recent FDA warnings especially because the risk of ongoing statin therapy is small and discontinuation of statin therapy may increase the risk of vascular events.
References
1. Food and Drug Administration. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. February 28,2012.
Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
2. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359: 2195–207.
3. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735-742.
4. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive- dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011; 305(24):2556-2564.
5. Sabatine MS, Wiviott SD, Morrow DA, McCabe CH, Cannon CP. High-dose atorvastatin associated with worse glycemic control: a PROVE-IT TIMI 22 substudy. Circulation. 2004;110(Suppl III):S834.
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