Are there medicines I should avoid if I am taking fibrates to lower my cholesterol?

Fibrates are a class of medication recommended to treat elevated triglycerides (TG) and low levels of high-density lipoprotein cholesterol (HDL-C) in order to lower the risk of cardiovascular events, like heart attack and stroke.^1,2 Fibrates approved for use in the US include gemfibrozil and fenofibrate.^3–5

Drug-drug interactions can occur between fibrates and other medicines. Gemfibrozil is metabolized by the CYP450 enzyme system, and other drugs that are metabolized in the same pathway may be affected when the drugs are taken together.⁶ This includes the co-administration of gemfibrozil with certain statin medications, such as simvastatin and lovastatin, for patients with hyperlipidemia. When these drugs are given together, excess levels of statin can result, leading to an increased risk of statin-associated myopathy.⁷ Fenofibrate generally does not interfere with most statins and is the preferred fibrate to use when statins and fibrates are both indicated.⁸

Evidence about the safety of fibrates when co-administered with ezetimibe is incomplete. Because fibrates and ezetimibe both increase the risk of cholelithiasis, the effect of co-administration has been studied.^7,9,10 McKenney et al. conducted a randomized, double-blind placebo-controlled study of 576 patients over 48 weeks who took either ezetimibe 10 mg, fenofibrate 160 mg, the same drugs in combination, or placebo.¹¹ The study results reported 1 planned or performed cholecystectomy in the 236 patients receiving fenofibrate alone (0.4%), compared with 4 planned or performed cholecystectomies in the 340 patients receiving the combination (1.2%), a difference that was not statistically significant. However, individuals with a history of gallbladder disease were excluded from the study, and the study was considered too small in retrospect to evaluate the gallbladder disease risk. The ezetimibe package insert warns against co-administration of ezetimibe and fibrates other than fenofibrate. ¹² Fibrates are contraindicated in any patient with a history of gallbladder disease.^4,5

Bellosta et al. reviewed what is known about fibrates’ interaction with PCSK9-inhibitors.¹³ Compared to monotherapy with alirocumab, a combination of alirocumab and fenofibrate results in a 35% lower plasma concentration of alirocumab. However, this drug-drug interaction is not a contraindication to combination therapy, and its therapeutic goal of low-density lipoprotein cholesterol reduction is maintained when the drugs are co-administered.

Leonard et al. conducted a cohort study of Medicaid patients to study the effects of combining oral hypoglycemics with fibrates.¹⁴ Sulfonylureas are hypoglycemic agents that are used to treat type 2 diabetes. The study set out to estimate the magnitude of risk of severe hypoglycemia that occurs when drugs from these two classes were co-administered. Hazard ratios (HR) for the incidence of severe hypoglycemia when fibrates were combined with a sulfonylurea were consistently elevated compared to sulfonylurea monotherapy. Patients exposed to both glyburide + gemfibrozil (n=13,772) had a HR of 1.50 (95% confidence interval [CI] [1.24 – 1.81]); glipizide + gemfibrozil (n= 13,271) had a HR of 1.37 (95% CI [1.11 – 1.69]); glipizide + fenofibrate (n=7,767) had a HR of 1.63 (95% CI [1.29 – 2.06]). The risk for severe hypoglycemia was most notable after the first month of combined therapy. In the same study when metformin, a non-sulfonylurea oral hypoglycemic drug, was co-administered with fenofibrate, there was a 60% increased rate of severe hypoglycemia, but the findings did not reach statistical significance.

The manufacturer’s package insert for gemfibrozil specifically recommends against the concomitant use of gemfibrozil with repaglinide, another oral diabetes medication that is not a sulfonylurea, due to potential hypoglycemic effects.³ While other hypoglycemic medications are not listed as specific contraindications for the use of fibrate therapy, the elevated risk of severe hypoglycemia should be discussed with patients taking both medications.^3-5

The manufacturer’s package inserts for gemfibrozil and fenofibrate also recommend caution when co-administering with anticoagulants, specifically warfarin.^3-5 Dosage adjustments of the warfarin and frequent prothrombin testing may be needed to achieve the desired prothrombin level to prevent bleeding complications.

Cyclosporine and other immunosuppressants can lead to renal toxicity when given in combination with fenofibrate.^4,5 Benefits and risks of combination therapy should be weighed, and the lowest effective dosage of each drug employed. Caution should also be employed when co-administering fenofibrate with colchicine as cases of rhabdomyolysis have been reported when these drugs were given together. Bile acid sequestrants can bind to some drugs when given simultaneously. For this reason, it is recommended that fenofibrate be given one hour before or four to six hours after a bile acid sequestrant.

^References

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5. Fenoglide (fenofibrate) [package insert]. San Diego, CA: Santarus, Inc; 2012.
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9. 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; 366 (9500): 1849-1861.
10. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317 (20): 1237-1245.
11. Mckenney JM, Harm PD, Farnier M, et al. Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia. J Am Coll Cardiol 2006; 47 : 1584-1587.
12. Ezetimibe [package insert]. Whitehouse Station , NJ: Merck & Co, Inc; 2007.
13. Bellosta S, Corsini A. Statin drug interactions and related adverse reactions: an update. Expert Opin Drug Saf 2018; 17 (1): 25-37.
14. Leonard CE, Bilker WB, Brensinger CM, et al. Severe hypoglycemia in users of sulfonylurea antidiabetic agents and antihyperlipidemics. Clin Pharmacol Ther 2016; 99 (5): 538-547.