Cardiovascular Benefits and Diabetes Risks of Statin Therapy in Primary Prevention: An Analysis From the JUPITER Trial

Abstract

Conclusion: The cardiovascular mortality benefits of statin therapy exceed the potential diabetes hazard induced by statins. Summary: Recent trial data and meta-analysis have suggested that statins confer an increase risk for development of diabetes (Ridker PM, et al, N Engl J Med 2008;359:2195-207; and Sattar N, et al, Lancet 2010;375:735-42). Recognition of the increased risk of diabetes with statin therapy has lead to questions on the balance of benefit and risk of statin drugs for primary prevention. The authors, therefore, analyzed data from participants from the JUPITER trial to address the balance of vascular benefits and diabetes hazards with statin use. In the JUPITER trial, 17,603 men and women without previous cardiovascular disease were randomly assigned to rosuvastatin (20 mg/d) or placebo and were monitored for 5 years for the primary end point of myocardial infarction, stroke, admission to the hospital for unstable angina, arterial revascularization, or cardiovascular death. Prespecified secondary end points of the trial included venous thromboembolism, incident of physician-reported diabetes, and all-cause mortality. With respect to diabetes development, patients were stratified on the basis of having none or at least one of the major four risk factors for developing diabetes: metabolic syndrome, impaired fasting glucose, body mass index ≥30 kg/m2, or glycated hemoglobin A1c >6%. There were 11,508 trial participants with one or more major diabetes risk factors. In individuals with one or more diabetes risk factors, statin allocation was associated with a 39% reduction in the primary end point (hazard ratio [HR], 0.61, 95% confidence interval [CI], 0.47-0.79, P = .0001), a 36% reduction in venous thromboembolism (HR, 0.64; 95% CI, 0.39-1.06; P = .08), a 17% reduction in total mortality (HR, 0.83; 95% CI, 0.64-1.0; P = .15), and a 28% increase in diabetes (HR, 1.28; 95% CI, 1.07-1.54, P = .01). For those with diabetes risk factors, 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. For trial participants with no major diabetes risk factors, statin allocation was associated with a 52% reduction in the primary end point (HR, 0.48; 95% CI, 0.33-0.68; P = .001), a 53% reduction in venous thromboembolism (HR, 0.47; 95% CI, 0.21-1.03; P = .05), a 22% reduction in total mortality (HR, 0.78l; 95% CI, 0.59-1.03; P = .08), and no increase in diabetes (HR, 0.99; 95% CI, 0.45-2.21; P = .99). In patients without diabetes risk factors, 86 vascular events were avoided, with no new cases of diabetes diagnosed. In the 486 participants in the trial who developed diabetes in the follow-up (270 on rosuvastatin vs 216 on placebo; HR, 1.25, 95% CI, 1.05-1.49; P = .01), the point estimate of cardiovascular risk reduction associated with statin therapy (HR, 0.63; 95% CI, 0.25-1.06) was consistent with that for the trial as a whole (HR, 0.56; 95% CI, 0.46-0.69). Compared with placebo, statin accelerated the average time to diagnosis of diabetes by 5.4 weeks (83.3 [standard deviation, 47.8] weeks on rosuvastatin vs 89.7 [50.4] weeks on placebo). Comment: Three meta-analyses were published between 2009 and 2011 indicating an increase risk of type 2 diabetes in patients taking a statin medication. In addition, intensive-dose statin therapy appeared to be associated with higher risk than lower-dose therapy (Preiss D, et al, JAMA 2011;305:2556-64). This prompted the Food and Drug Administration to recommend safety label changes to statin drugs (http://www.FDA.gov/drugs/drugsaftey/ucm293101.htm). This report, while confirming the increased risk of diabetes in patients on statin medications, suggests that in the setting of primary prevention, even in the face of risk factors for development of diabetes, the use of statin medications has a favorable overall effect on mortality and cardiovascular events, despite an increased risk of diabetes. The authors believe the data provide reassurance for patients and physicians with regard to lipid-lowering agents as adjuncts to smoking sensation, exercise, and diet in the prevention of major cardiovascular events.