Diabetic Dyslipidemia: Fenofibrate plus Statin

Adding fenofibrate to statins may decrease cardiovascular disease (CVD) events in certain patients with T2DM, according to findings from the ACCORD Follow-On Study (ACCORDION) study, a long-term follow-up sub-study of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The study was published online in JAMA.¹

While the findings failed to show an overall difference in CVD events between fenofibrate and placebo (both added to simvastatin), they did suggest a benefit in patients who started out with baseline hypertriglyceridemia and low HDL. 

“These findings support the hypothesis that individuals with diabetic dyslipidemia may benefit from add-on fenofibrate therapy,” wrote first author Marshall Elam, PhD, and colleagues with the ACCORDION Study.

Diabetic dyslipidemia is characterized by increased triglyceride levels, low HDL, and accumulation of small dense LDL. 

The ACCORDION study included data from a subset of patients in the ACCORD trial, a multicenter, randomized, placebo-controlled trial in patients with T2DM at high risk for CVD. 

The initial sub-study, called the ACCORD-lipid trial, took place at 77 community and academic outpatient clinics in the US and Canada. It included 4644 participants who had T2DM and CVD or CVD risk factors: hypertriglyceridemia, high LDL, and/or low HDL.

Participants were randomized to open label simvastatin (20 mg-40 mg daily) plus masked fenofibrate, or open label simvastatin plus masked placebo. After a follow-up of almost five years, results showed that adding fenofibrate did not decrease CVD events compared to simvastatin alone. However, subgroup analyses suggested a benefit for combined therapy in participants who started out with high triglycerides and low HDL. Results also suggested a benefit in men and possible harm for women. Whether or not the results were due to relatively short study duration was unclear.²

The ACCORDION trial extended follow-up by an additional five years. The primary outcome was a composite of major CV events (fatal and nonfatal MI and nonfatal stroke).

Key results over a median of 9.7 years:

• 4.3% of participants continued fenofibrate after finishing the ACCORD trial.

• Primary outcome:

♦ Confirmed ACCORD lipid study’s overall neutral results

♦ Overall similar annual rates: 2.38% for fenofibrate vs 2.55% placebo (HR 0.93; 95% CI, 0.83-1.05; P=0.25)

• Primary outcome significantly different with baseline dyslipidemia vs without (P=0.05)

♦ Dyslipidemia: 27% lower with fenofibrate vs placebo (HR 0.73; 95% CI, 0.56-0.95)

♦ No dyslipidemia: 1% lower with fenofibrate vs placebo (HR 0.99; 95% CI, 0.86-1.13)

• Primary outcome significantly different in women vs men (P=0.003)

♦ Women: 30% higher with fenofibrate vs placebo (HR 1.30; 95% CI, 1.10-1.68)

♦ Men: 16% lower with fenofibrate vs placebo (HR 0.84; 95% CI, 0.73-0.96)

The authors noted that the results for patients with baseline dyslipidemia and women vs men were nearly identical to earlier results from the ACCORD lipid trial. While the results for triglyceridemia are not wholly unexpected, those suggesting sex differences in treatment effect are. The findings remain unexplained, though the authors suggested that they may be due to chance because of low numbers of women and low event rates in women treated with placebo.

They also pointed out that the subgroup analyses should be considered hypothesis generating, and were based on relatively small numbers of events in some cases.

Also, they emphasized that the safety profile of combining fenofibrate with simvastatin seems to be acceptable, without increased muscle or liver toxicity. They pointed out that these results contrast with studies of combining gemfibrozil with a statin, which showed increased risk of myopathy.

“Our findings support the hypothesis that patients with diabetic dyslipidemia may derive some benefit from add-on triglyceride lowering therapy. Randomized trials testing the cardiovascular efficacy of fibrate as well as other triglyceride-lowering treatments in this specific patient population are needed,” they concluded.

Take-home Points

• Results from the ACCORD Follow-On Study (ACCORDION) study showed that major CV events over almost 10 years’ follow-up were similar for fenofibrate vs placebo, when both were added to simvastatin.

• Major CVD events were decreased in patients with baseline hypertriglyceridemia who were randomized to fenofibrate.

• Major CVD events were increased in women and decreased in men who were randomized to fenofibrate.

• The results are hypothesis-generating and require further study.

The ACCORD and ACCORDION trials were supported by the National, Heart, Lung, and Blood Institute.

Dr Largay is an employee of AstraZeneca. One or more authors reports grants, personal fees, board membership XX from one or more of the following: National Institutes of Health/National Heart, Lung, and Blood Institute during the conduct of the study, AstraZeneca, Sanofi Aventis, Takeda, Vivus, Andromeda, Boehringer Ingelheim, GI Dynamics, Halozyme, Hoffman-LaRoche, Immune Tolerance Network, Johnson and Johnson, Lexicon, Lilly, Medtronic, Merck, Novo Nordisk, Orixigen, Phase Bio, National Institute of Allergy and Infectious Diseases, Sanofi Aventis, Takeda, Tolerx,  Quadrant Healthcare, Medical Logix, Creative Educational Concepts, Institute for Medical and Nursing Education, Global Academy for Medical Education, Aegerion, Amgen, AstraZeneca, Eli Lilly, Janssen,  Servier, GlaxoSmithKline, Pfizer, Bristol-Myers Squibb, GI Dynamics, Amylin, Orexigen, Liposcience, Elcylex, Metavention, vTv Pharma (formerly Transtech Pharma), Dance Biopharm, Quest, Medtronic Minimed, PhaseBio, Osiris, Halozyme, Pfizer, Johnson and Johnson, Andromeda, Astellas, MacroGenics, Intarcia Therapeutics, Scion NeuroStim, American Diabetes Association, Diabetes Sisters, Taking Control of Your, Diabetes, AstraZeneca Healthcare Foundation, Bristol-Myers Squib Together on Diabetes Foundation, the National Diabetes Education Program, Jansen, Abbott, Berlin Chemie, Kaneq Bioscience, Roche, National Institutes of Health, Thermalin Diabetes, and/or COVANCE.

References:

1. Elam MB, et al. for the ACCORDION Study Investigators. Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes. JAMA Cardiol. 2016 Dec 28.

2. Ginsberg HN, et al. ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563-1574.