Does Fenofibrate Help or Hurt Renal Function?

I saw a patient years ago (August 2002) for triglycerides (TGs) of 759 mg/dL despite pravastatin 20 mg daily. I started him on fenofibrate 145 mg daily, and he decreased his TGs to 300 mg/dL. The TGs got even better with high dose atorvastatin. He recently returned to see me prior to a lung transplant for advanced pulmonary fibrosis, but he had not yet been accepted for the transplant, because his creatinine was 1.4 mg/dL. I stopped his fenofibrate and his creatinine decreased to 1.1 mg/dl 3 weeks later.

Many clinicians are unaware that fenofibrate can cause a reversible increase in creatinine because it interferes with creatinine excretion in the kidney. Creatinine values in the 5-year Fenofibrate Intervention and Event Lowering in Diabetes or FIELD study increased 12% soon after fenofibrate was started.(1) A sub-study of 661 FIELD participants (shown below) demonstrated that creatinine increased when study drug was started in both groups, remained high in the fenofibrate group but fell promptly in the fenofibrate group when fenofibrate was stopped at the end of the 5-year study. The creatinine was actually lower in the fenofibrate group after the study demonstrating that fenofibrate improves renal function in diabetics. What a paradox…higher creatinine levels on the drug, but ultimately better renal function.(2) (See Figures)

Fig — Changes in creatinine for 661 subjects from baseline to 8 weeks after the study. Solid line is fenofibrate group. Dashed line is placebo.

Fenofibrate is not the only lipid-lowering agent that raises creatinine. The new LDL cholesterol lowering drug, bempedoic acid, also increases creatinine by interfering with the organic anion transporter or OAT in the kidney. Bempedoic acid increases uric acid as well by a similar mechanism.

Please remember this increase in creatinine with fenofibrate and now with bempedoic acid. I have seen multiple patients over the years, who were told they were headed for dialysis, whose creatinine normalized after stopping the fenofibrate.

Some may ask why I use fenofibrate at all because the FDA now requires that the package insert for fenofibrate products state that “The effect of (fenofibrate) on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established”.(3) This is based primarily on the results of the Action to Control Cardiovascular Risk in Diabetes or ACCORD Trial.4 ACCORD assigned statin-treated diabetics to either fenofibrate or placebo. There was no significant reduction in cardiovascular events with fenofibrate, but my gripe with ACCORD is that the subjects’ median baseline TG level was 162 with an interquartile mean of 113–229 mg/dl. I would not have treated many of these subjects with fenofibrate because their TGs were not high enough. If you look at the subgroup with TGs >203 and HDL-C’s 35 mg/dl, however, there was a reduction in events, but the p value was “not statistically significant” at 0.06, so not below the vaulted 0.05.(4) So close but no cigar.

Concentrated fish oil is my first choice for treating TGs because the Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia or REDUCE-IT trial demonstrated a 4.8% absolute reduction in cardiovascular events with icosapent ethyl,(5) but I still use fenofibrate for very high (fasting TGs >500 mg/dl) in combination with concentrated fish oil. Also, fenofibrate may have small vessel benefits, at least in diabetics. In FIELD fenofibrate reduced amputations especially minor amputations, such as toes, and especially in individuals without large-vessel disease suggesting a small vessel benefit.(6) (I would not consider losing my toes minor, but that’s their definition.) Similar to the reduced reduction in GFR noted above for FIELD, fenofibrate reduced both the need for first eye laser treatments and the progression of diabetic retinopathy in FIELD and ACCORD, respectively.(7) Perhaps fenofibrate has a small (vessel) story to tell.

So, the take home messages — Fenofibrate:

1. Can cause reversible elevations in serum creatinine.

2. May have cardiovascular benefit in diabetic patients with high TGs and low HDL-Cs.

3. Is useful to reduce TGs in patients with very high TG levels.

4. May reduced small vessel disease which causes kidney, peripheral vascular and eye problems in diabetic patients.

1. Ting RD, Keech AC, Drury PL, et al. Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment: The FIELD study. Diabetes Care. 2012;35(2):218–225. doi: 10.2337/dc11–1109 [doi].

2. Davis TM, Ting R, Best JD, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: The fenofibrate intervention and event lowering in diabetes (FIELD) study. Diabetologia. 2011;54(2):280–290. doi: 10.1007/s00125–010–1951–1 [doi].

3. Https://Www.accessdata.fda.gov/drugsatfda_docs/label/2019/021656s029lbl.pdf — accessed 4 Nov 2020. .

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

5. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22. doi: 10.1056/NEJMoa1812792 [doi].

6. Rajamani K, Colman PG, Li LP, et al. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): A prespecified analysis of a randomised controlled trial. Lancet. 2009;373(9677):1780–1788. doi: 10.1016/S0140–6736(09)60698-X [doi].

7. Wright AD, Dodson PM. Medical management of diabetic retinopathy: Fenofibrate and ACCORD eye studies. Eye (Lond). 2011;25(7):843–849. doi: 10.1038/eye.2011.62 [doi].