Cardiovascular Benefits and Diabetes Risks of Statin Therapy

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationships relevant to this field of study.

Synopsis: In the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceeded the diabetes hazard, including patients at high risk of developing diabetes.

Source: Ridker PM, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: An analysis from the JUPITER trial. Lancet 2012;380:565-571.

It has been clearly demonstrated by the results of many previous studies that statin therapy effectively reduces cardiovascular events in both men and women. Recently, data from several studies have suggested that statin therapy also presented an increased risk for developing incident type 2 diabetes1-3 and intensive statin doses may be associated with a higher risk for this complication than lower doses.4 Therefore, the FDA added a warning about the possible diabetes risk to the labels of all statin agents.5 These regulatory changes have been widely publicized in the lay and medical press and most articles have concluded that the cardiovascular benefits of statin treatment exceed the diabetes risk, particularly in primary prevention.

The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) analyzed the clinical outcomes of 17,603 men and women focusing on the balance between vascular benefits and diabetes hazard of statin use.6 In those individuals with one or more major coronary artery disease (CAD) risk factors, statin therapy was associated with a 36% reduction in venous thromboembolism, a 17% reduction in total mortality, a 39% reduction in the primary endpoint (myocardial infarction, stroke, admission to hospital for unstable angina, arterial revascularization, or cardiovascular death), and a 28% increase in diabetes. For trial participants with no major diabetes risk factors, statin allocation was associated with a 52% reduction in the primary endpoint, a 53% reduction in venous thromboembolism, a 22% reduction in total mortality, and there were no new cases of diabetes diagnosed. The trial found that the cardiovascular mortality benefits of statin therapy far exceeded the diabetes hazard, including in participants at high risk of developing diabetes.

Commentary

The JUPITER trial using rosuvastatin was the first placebo-controlled statin trial to formally report an increased risk of developing diabetes.1 Post-hoc evaluations of other previously completed trials have also revealed a small increased risk of developing diabetes for all statins.3-4 There seems to be little question that when considering secondary prevention in high-risk CAD patients, the diabetes risk associated with statin therapy is low in absolute terms and is of minimal importance, especially when considering the significant reduction in subsequent cardiovascular events observed in the patients receiving statin therapy. Therefore, the recent major concern regarding statin therapy has been directed toward the use of statins in patients for the primary prevention of complications of CAD. In the JUPITER trial, which was a primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceeded the diabetes hazard in the trial population as a whole as well as in the participants at increased risk of developing diabetes. In fact, it appears that monitoring of glucose concentrations when starting statin therapy might not be needed for those primary prevention patients who have normal pretreatment glucose concentrations or who do not have the multiple characteristics of the metabolic syndrome since the risk of developing diabetes in this group of patients is extremely low.

In summary, in primary prevention of CAD, the cardiovascular mortality benefits of statin therapy far exceed the diabetes hazard even when participants at high risk of developing diabetes are included. Therefore, statin therapy should be administered to the appropriate primary prevention subjects (as well as to secondary prevention subjects) when these drugs are properly prescribed for cardiovascular risk reduction as an adjunct to dietary discretion, increased exercise, hypertension control, and smoking cessation. Additional research is needed into the yet unknown mechanism by which statin therapy increases diabetes risk in certain individuals and not in others.

References

1. Ridker PM, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207.

2. Rajpathak SN, et al. Statin therapy and risk of developing type 2 diabetes: A meta-analysis. Diabetes Care 2009;32:1924-1929.

3. Sattar N, et al. Statins and risk of incident diabetes: A collaborative meta-analysis of randomized statin trials. Lancet 2010;375:735-742.

4. Preiss D, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy. JAMA 2011;305:2556-2564.

5. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. Accessed November 9, 2012.

6. Ridker PM, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: An analysis from the JUPITER trial. Lancet 2012;380:565-571.