Diabetes Care: Should Statins Be the Only Treatment?

The most recent American Heart Association/American College of Cardiology guidelines recommend statin treatment for all diabetic patients between the ages of 40-75, including high-intensity statin therapy for those diabetics with an estimated 10-year risk of cardiovascular disease(CVD) > 7.5%.¹ I know statins are good for primary and more definitely secondary cardiovascular disease (CVD) prevention. How did statin therapeutic guidelines evolve?

Before discussing statins, there are many other therapeutic choices when treating dyslipidemia in diabetic patients, including ezetimibe, fibrates, niacin, bile acid sequestering agents, and fish oils, among others. Evidence for the benefits of fibrates in lowering CVD risk in diabetic patients is generally lacking.^2-3 In the ACCORD trial, the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes.

Fish oils have yet to be proven to reduce CVD in diabetics; however, they have been shown to reduce CVD risk factors in diabetics.⁴ Ezetimibe, another non-statin lipid-lowering therapy, is still being studied for CVD reduction.⁵ Its final evaluation is still pending.

Statins are currently the gold standard in dyslipidemia diabetic patients. I recall the 4S study results (Scandinavian Simvastatin Survival Study) being touted among colleagues as the study confirming statins’ potent impact on lowering CVD risk in all study patients, including the diabetes subgroup. Among those with diabetes, patients on simvastatin enjoyed a 55% reduction in risk for major CVD events and a 43% reduction in overall death.⁶

Next, the Cholesterol and Recurrent Events (CARE) trial, focusing on recurrent CVD events in patients with a history of MI 3 to 20 months prior to the start of the study. The diabetic subgroup and all other study participants benefited from pravastatin therapy, resulting in a 25% reduction in both CVD events and revascularization procedures.⁷

Other studies demonstrating statin benefit in diabetic patients have confirmed statins’ CVD protective effects, including the Heart Protection Study, the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm, and the Collaborative Atorvastatin Diabetes Study, among others.^8-10

Even though there is proof of statins’ efficacy in CVD reduction, the results can be viewed in a different light when assessing absolute risk reduction. For example, in the ASCOT LLA trial, relative risk reduction (RRR) was 36% but absolute risk reduction (ARR) was 0.5%. In effect you would have to treat 100 patients for 1 year to prevent 0.5 events. Patients in this study were high risk with hypertension and an average of an additional 3.6 risk factors.⁹ In the West of Scotland Coronary Prevention Study Group (WOSCOPS), the numbers were as follows: RRR -31%, ARR 0.4% -- or a 1 year Numbers Needed to Treat (NNT) of 250. One would have to treat 250 patients for one year to prevent an event with no mortality reduction.¹¹

In the JUPITER trial with 20 mg Crestor, researchers reported RRR 55% and ARR of 0.6%/year, and a one year NNT of 167.¹² In the 4 S trial with 20 mg Zocor, analysis of the data showed RRR of 42%, ARR of 3.4% over 5.4 years, and a 5.4 year NNT of 30, meaning approximately 150 patients would have to treated for one year to prevent an event.⁶

Now that the target goal for LDL reduction no longer hovers around 70mg/dl, as was once recommended,¹³ I am beginning to wonder whether every diabetic adult should be on a statin, either for primary or secondary prevention of CVD. Taking into account patient benefits, risk of medication adverse effects, drug-drug interactions, among others, will help guide you in your decision making. Ultimately, most diabetic patients will benefit from statins.

References:

1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 pt B):2889-2934.

2. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563-74.

3. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005 Nov 26;366(9500):1849-61.

4. De Luis DA, Conde R, Aller R, et al. Effect of omega-3 fatty acids on cardiovascular risk factors in patients with type 2 diabetes mellitus and hypertriglyceridemia: an open study. Eur Rev Med Pharmacol Sci. 2009 Jan-Feb;13(1):51-5.

5. Blazing MA, Giugliano RP, Cannon CP, et al. Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: Final baseline characteristics of the IMPROVE-IT study population. American Heart Journal. August 2014;168(2):205—212.e1.

6. Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol Lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 1997;20:614-620.

7. Goldberg RB, Mellies MJ, Sacks FM, et al. The Care Investigators. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation. 1998;98:2513-2519.

8. Collins R, Armitage J, Parish S, et al. Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet. 2003;361:2005-2016.

9. Sever PS, Poulter NR, Dahlof B, et al. Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial-Lipid lowering arm (ASCOT-LLA). Diabetes Care. 2005;28:1151-1157.

10. Colhoun HM, Betteridge DJ, Durrington PN, et al. CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicenter randomized placebo-controlled trial. Lancet. 2004;364:685-696.

11. Shepherd J. The West of Scotland Coronary Prevention Study: a trial of cholesterol reduction in Scottish men. See comment in PubMed Commons below Am J Cardiol. 1995 Sep 28;76(9):113C-117C.

12. Ridker PM, Danielson E, Fonseca FAH, Genest J, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med 2008; 359:2195-2207.

13. Brunzell JD, Davidson M, Furberg CD, et al. American Diabetes Association; American College of Cardiology Foundation. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008;31:811-822.