Wider Fibrate Use Urged in Mild to Moderate CKD

November 14, 2012

SYDNEY, Australia — A new meta-analysis shows that fibrate therapy improves lipid profiles and prevents cardiovascular events in people with chronic kidney disease (CKD), cutting CV deaths by 40% [1]. The findings also show that despite increasing serum creatinine--a long-known side effect of fibrates--the drug class caused no harm to the kidneys in the long run and may even provide some renal benefits, say Dr Min Jun (George Institute for Global Health, Sydney, Australia) and colleagues in their paper published online October 17, 2012 in the Journal of the American College of Cardiology.

"The major finding is the CV benefit," senior author Dr Vlado Perkovic (George Institute for Global Health) told heartwire . "While fibrates reduce CV risk by about 9% in the general population, in our study they seem to be much more potent in people with kidney disease, and this is important." This is likely because CKD patients typically have high triglycerides and low levels of HDL, and this is the lipid profile that appears to particularly benefit from fibrates, he notes.

The major finding is the CV benefit. Fibrates seem to be much more potent in people with kidney disease, and this is important.

Thus, overall, the results suggest that fibrates could be used more broadly in patients with mild to moderate CKD to prevent cardiovascular disease, say the researchers. Perkovic says doctors shouldn't be afraid of using fibrates in renal patients. Any spike in creatinine seen on starting therapy "will reverse," he says, and the meta-analysis shows fibrates reduced proteinuria, so "they may even be protective" for the kidney, he reiterates.

Writing in an accompanying editorial [2], Dr Peter A McCullough (St John Providence Health System, Warren, MI) and Dr Michael J Di Loreto (St John Hospital and Medical Center, Detroit, MI) agree. "In general, fibrates are some of the best-tolerated drugs to treat dyslipidemia, and the paper by Jun and coworkers supports their use in patients with CKD."

No Evidence That Fibrates Harm the Kidney, and They May Even Protect It

Jun and colleagues explain that cardiovascular disease is the leading cause of death in patients with CKD. While dyslipidemia is a risk factor for progressive kidney disease, the tendency for fibrates to cause an acute elevation of creatinine has resulted in concerns about the safety of this therapy in this patient population, and there have been conflicting reports regarding the impact of fibrate therapy on kidney function.

Hence, they conducted a search of MEDLINE, EMBASE, and the Cochrane Library from 1950 to January 2012 for prospective randomized controlled trials assessing the effects of fibrate therapy compared with placebo in people with CKD or on kidney-related outcomes. "These were mainly subsets of large clinical trials that had people with relatively early kidney disease," explained Perkovic.

Ten studies including 16 869 participants were identified. Fibrates improved lipid profiles in patients with mild to moderate CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2).

Specifically, fibrates lowered total cholesterol [-0.32 mmol/L, p=0.05] and triglyceride levels [-0.56 mmol/L, p=0.03] but not LDL cholesterol [-0.01 mmol/L, p=0.83]. They increased HDL cholesterol [0.06 mmol/L, p=0.001].

Fibrates reduced the risk of major cardiovascular events by 30% (RR 0.70, p=0.004) and cardiovascular death by 40% (RR 0.60, p=0.03) in those with mild to moderate CKD but did not affect all-cause mortality.

There were no clear safety concerns specific to people with CKD.

In people with diabetes, fibrates reduced the risk of albuminuria progression by about 14% (p=0.02). Serum creatinine was elevated by fibrates, however, by around 25% (p<0.001), and calculated GFR was reduced (-2.67 mL/min/1.73 m2, p=0.01), but there was no detectable effect on the risk of end-stage kidney disease (RR 0.85, p=0.575).

Thus there "were no clear safety concerns specific to people with CKD," Jun et al state.

Perkovic said that there was not enough information on people with advanced kidney disease to draw any firm conclusions regarding the use of fibrates in these patients. "There is no particular reason to think things are going to be different, but it would be reassuring to have the data before using fibrates widely in that population," he commented.

There May Be Dual Cardiorenal Benefits of Fibrates

In their editorial, McCullough and Di Loreto say that while the authors did not report the baseline triglyceride concentration of the CKD patients, it is expected that they would have had a higher triglyceride concentration than the general population, "so this report provides further support and clarity on the cardiovascular benefit of fibrates" and indicates "there is no evidence of long-term adverse effects on kidney function in any population studied," they note.

"Furthermore, there appears to be a cardiorenal benefit of this class of drugs in reducing renal blood flow and, to an extent, attenuating glomerular hyperfiltration and microalbuminuria. Future trials should plan a priori cardiorenal end points for lipid-lowering therapy when off-target pharmacologic effects are possible. In some cases such as fibrates, there can be dual benefits," they conclude.

Perkovic has received grants for clinical trials from Baxter, Johnson & Johnson, Novartis, Roche, and Servier; consulting fees from Vitae Pharmaceuticals, Abbott, and Boehringer Ingelheim; and lecture fees from Abbott, AstraZeneca, Roche, and Servier. Disclosures for the coauthors are listed in the paper. The editorialists report no conflicts of interest.