Statin and Fibrate Combinations: What Does the Evidence Say?

Nancy Hope Goodbar, PharmD


July 16, 2013


Which patients may benefit from combination statin and fibrate therapy?

Response from Nancy Hope Goodbar, PharmD
Assistant Professor of Pharmacy Practice, Presbyterian College School of Pharmacy, Clinton, South Carolina

Statin therapy has a proven and well-documented mortality benefit in patients with elevated low-density lipoprotein (LDL) cholesterol, as this parameter is the primary treatment target in lipid management.[1,2,3,4] Statins are considered first-line therapy for LDL-cholesterol lowering and provide patients with cardiovascular disease (CVD) risk reduction for primary and secondary prevention.[3,4] Evidence for utilization of other cholesterol-lowering agents, specifically fibrates, as monotherapy or in combination with statins is not as compelling. Therefore, optimal treatment strategies for mixed dyslipidemias are sometimes difficult to elucidate. Although fibrates do not have a proven cardiovascular benefit, their use with statins is recommended in certain subsets of patients with hypertriglyceridemia.

The FIELD study[5] evaluated the effects of fenofibrate on CVD. Patients with type 2 diabetes (T2D), both with and without the metabolic syndrome, were included in the study. Criteria for the metabolic syndrome were met if the patient had T2D with at least 2 of the following: increased blood pressure either on antihypertensive therapy or with an average blood pressure ≥ 130/85, high-density lipoprotein (HDL) cholesterol level < 40 mg/dL for men or < 50 mg/dL for women, triglyceride (TG) level > 150 mg/dL, or increased waist circumference.

The study found that in patients with and those without metabolic syndrome, the effects of fenofibrate on cardiovascular risk reduction were similar. However, when the effects of fenofibrate compared with placebo were analyzed in patients with both decreased HDL cholesterol levels and TG levels ≥ 204 mg/dL, a statistically significant decrease was found in the CVD event rate. This outcome supported the findings of previous studies.[6,7]

The ACCORD Lipid Trial[8] compared statin monotherapy with a statin plus fibrate on CVD event rate in patients with T2D. The primary outcome was the first occurrence of a major cardiovascular event in patients randomly assigned to receive simvastatin plus placebo compared with simvastatin plus fenofibrate. The fenofibrate group compared with the placebo group showed no significant decrease in major cardiovascular events, with an annual event rate of 2.2% and 2.4%, respectively. Subgroup analysis showed that patients with TG levels ≥ 204 mg/dL and HDL cholesterol levels ≤ 34 mg/dL benefited the most from fenofibrate therapy, with a trend for an interaction for treatment. This analysis also showed a significant interaction for treatment effect in the sex subgroup, with men having a 16% lower event rate vs a 38% higher event rate in women.[9]

To date, no trial has provided statistically or clinically compelling evidence to routinely recommend addition of a fibrate to statin therapy in patients with T2D. Evaluation of the current literature on this topic suggests that after a patient has been maximized on statin therapy, it would be an appropriate alternative to add a fibrate for TG levels > 200 mg/dL and HDL cholesterol levels < 35 mg/dL. It would be prudent to keep in mind the possible negative effects that fibrates may have on women, per the ACCORD trial. These recommendations are reflected in both the National Cholesterol Education Program Adult Treatment Panel III guidelines[3] and the Endocrine Society clinical practice guidelines.[4]


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