fenofibrate: not so effective

There was extended followup of ACCORD-Lipid study for 5 years after the study ended, which confirmed the original conclusions that adding fenofibrate to simvastatin in diabetic patients did not improve cardiovascular outcomes, and that the assessment of prespecified outcomes also found that the subgroup with low HDL/high triglycerides did better with fenofibrate, but women overall did worse (see lipids fenofibrate not help diabet jamacardiol2016 in dropbox, or doi:10.1001/jamacardio.2016.4828 )

Details:

--4644 patients (90% of surviving participants) agreed to the 5-year followup of the ACCORD-lipid trial, after the fenofibrate vs placebo intervention was finished (all patients received simvastatin)

--this cohort was similar to the original study (these are the pre-trial baselines): 31% women, 66% white/14% black/7% Hispanic, 35% previous cardiovascular event, 4% heart failure, 14% current smoker/46% former, BMI 32, 11 year duration of diabetes, A1c=8.25, LDL 100, HDL 42 in women/37 men, TG 188

Results:

--simvastatin treatment (20 or 40mg dose, titrated) did lead to a mean decrease of LDL to 80 mg/dl, which basically continued in the post-trial period. The TG (triglycerides) decreased to 145 in those on fenofibrate and 170 on placebo, with both achieving 161 mg/dL in the post-trial period. HDL increased during the ACCORD trial to about 41 mg/dl in both groups, and pretty much stayed the same in the post-trial period.

--primary outcome (nonfatal MI, nonfatal stroke, fatal CV event): essentially the same non-significant 7% difference as found in the trial

--secondary outcomes (individual components of the primary outcome, plus revascularization, hospitalization for heart failure, all-cause mortality): all continued to be nonsignficant

--prespecified subgroups, primary outcome in all of them were nonsignificant, other than in:

    --female: 30% increase, HR 1.30 (1.01-1.68)

    --male: 16% decrease, HR 0.84 (0.73-0.96)

                

Commentary:

--this trial adds to several others suggesting that fenofibrate does not have much cardiovascular benefit, including the large FIELD trial. Gemfibrozil, however, either singly or in addition to statins, did confer clinical benefit in several studies. i am unaware of any trials directly comparing different fibrates, but one meta-analysis of fibrates and CAD outcomes did find significant clinical benefit with gemfibrozil (23% decrease) vs none with fenofibrate or benzafibrate (see Lancet 2010; 375:1875)

--on secondary analyses, however, there is some consistency in other trials in finding that fenofibrate is clinically helpful in those with diabetic dyslipidemia (low HDL, high TG), which occurs in up to 35% of diabetic patients (though only 17% of the ACCORD cohort)

--the male/female difference found here is concerning, though was not found in the FIELD trial, which did have more female participants. And I am unaware of any male/female differences in trials with other fibrates

--the above "legacy" study is important, since it does show that using fenofibrate for a pretty long trial (4.7 years) did not show any residual benefit 5 years later. Several other trials, such as the Coronary Drug Project, did show benefit on longer-term followup after the trial ended (with niacin, in the case of the CDP), confirming the utility of these legacy trials (and they might also show delayed adverse events).​

--so, one concern is what agent to add when a statin does not give adequate cardioprotection, especially in diabetics with dyslipidemia and very high triglycerides? The fact that 2 trials did find some benefit for fenofibrate in this subgroup is reassuring, but not definitive since this was a subgroup analysis (though prespecified).  It does seem that gemfibrozil is a more potent fibrate, though there is the concern of drug-drug interactions with statins: increased myopathy/ rhabdomyolysis. A recent article, however, did suggest that this consideration may be overblown (see http://gmodestmedblogs.blogspot.com/2016/11/cardiac-drug-interactions-with-statins.html​ )which looks at drug-drug interactions, suggesting that it is safe to use either atorvastatin or rosuvastatin with gemfibrozil, though perhaps best at lower doses. And that may well be the best alternative…