Practical Pearls: Statins and Fibrates: A Re-Interpretation of the Data

On April 18, 2016, the FDA announced retraction of prior approvals related to the combination of a statin with fenofibrate.1 This decision was prompted by the results of the ACCORD Lipid Trial, which failed to show reduction in cardiovascular events in diabetics when fenofibrate was routinely added to a statin.2 The question now is whether this failure applies to all patients or might there be a group that does benefit from a fibrate-statin combination?

We will review the fibrate monotherapy literature, including subgroup analysis, and see if there is a group that consistently benefited from a fibrate. If so, we’ll then see if this subset may also benefit from the addition of a fibrate to a statin.

Fibrate Monotherapy Trials

1. Helsinki Heart Study (HHS) (1987): 4,087 asymptomatic men treated with gemfibrozil versus placebo, and followed for five years.3 There was a 34 percent reduction in cardiac endpoints in this primary prevention study. An unplanned post-hoc analysis suggested that most of this was due to the 75 percent reduction seen in the group with triglycerides (TG) > 204 mg/dL and high-density lipoprotein cholesterol (HDL-C)<42 mg/dL.4 In an 18- year follow up, those with the metabolic syndrome — those in the highest BMI and highest TG tertile — had a 71 percent reduction in coronary artery disease mortality.5

2. VA High-Density Lipoprotein Trial (VAHIT) (1999): 2,531 men, with known coronary heart (CHD) and low levels of HDL-C and low-density lipoprotein cholesterol (LDL-C), were randomized to gemfibrozil or placebo and followed for five years. This resulted in a 22 percent reduction in CHD events in the gemfibrozil group.6 The average TG was 153 mg/dL and the average HDL-C 31 mg/dL. Those with TG levels >180 mg/dL had the highest CHD event rate.7 The benefit from gemfibrozil was primarily in patients with diabetes, or non-diabetics with an elevated insulin level.8

3. Bezafibrate Infarction Prevention Study (BIP) (2000): 3,090 patients, with a previous MI or stable angina, were randomized to placebo or bezafibrate, and followed for 6.2 years.9 There was no overall reduction in event rates, but the primary incidence rate of the placebo group slowed down toward the end of the study. This change was consistent with the decline in LDL-C in that group, possibly due to more patients in the placebo group receiving open-labeled lipid-modifying drugs than in the bezafibrate group.

In a planned post-hoc analysis, there was a 40 percent reduction (p= 0.02) in the subgroup with TG ≥ 200 mg/dL and HDL-C < 42 mg/dL.

In an unplanned post-hoc analysis, patients with at least three components of metabolic syndrome had a 29 percent reduction in MI (p=0.02), while there was no significant benefit in those patients without metabolic syndrome.10

4. FIELD Study (2005): 9,795 participants, with diabetes mellitus (22 percent with prior cardiovascular disease) and not taking a statin at entry, were randomized to placebo versus fenofibrate and followed for five years.11 During that time, 17 percent of placebo patients versus 8 percent of fenofibrate patients went on a statin. Fenofibrate reduced cardiovascular events by 11 percent, which was not significant (p=0.16). Only 38 percent of the entire population had both low HDL-C (<40 mg/ dL for males and <50 mg/dL for females) and high TG levels (>150 mg/dL). A posthoc analysis found that those with TG levels ≥ 200 mg/dL and HDL-C < 42 mg/ dL had a 27 percent reduction in event rate (p=0.005).12

Conclusion: These studies suggest a specific patient subset that benefits from fibrate monotherapy (see Table 1):13

1. Evidence of insulin resistance: elevated insulin level, metabolic syndrome, or diabetes.

2. Elevated triglyceride: ≥ 200 mg/dL.

3. Low HDL-C: <40 mg/dL for male, and < 50 mg/dL for female.

Proposal: Only the patient group that benefited from fibrate monotherapy will get benefit from the addition of a fibrate to statin therapy.

ACCORD Lipid Trial (2010): 5,518 patients with diabetes, being treated with simvastatin, were randomized to placebo versus fenofibrate, and followed for 4.7 years.14 The combination did not reduce CV events as compared to simvastatin alone. The conclusion was that these results did not support the routine use of combination therapy with fenofibrate and a statin to reduce CV risk.

The results from fibrate monotherapy studies, though, supported the use of fibrates in individuals with high TG (>200 mg/dL) and low HDL-C. In ACCORD, this group was termed the “subgroup with dyslipidemia” (see Table 2). Seventy-nine percent of the ACCORD population did not fit in this category and had no benefit with the addition of a fibrate. The other 21 percent not only had a much higher CV event rate, but as proposed, had a reduction in CV events with addition of fenofibrate (p=0.057) (see Table 2). In the discussion regarding ACCORD, the authors suggest that it is possible that certain subgroups did benefit from combination therapy, but that the subgroups that did not benefit may have diluted the overall effect.2

 The authors further state: “Our subgroup results and those of previous studies (HHS, BIP, FIELD) support the view that the addition of fenofibrate to a statin may benefit patients with type 2 diabetes who have a substantial dyslipidemia.”2

 In a 9.7 year post-randomization follow up of ACCORD, with only 4.3 percent of participants still on fenofibrate, there was continued evidence that prior treatment with fenofibrate in patients with TG levels >204 mg/dL and HDL-C <34 mg/dL, reduced cardiovascular disease events.17

 In conclusion, a current hypothesis based on post-hoc analysis is that fibrates, when routinely added to statin therapy in patients with metabolic syndrome or diabetes, appear to be ineffective unless they are given to the appropriate subset: high triglyceride (>200 mg/dL) and low HDL-C (<40 mg/dL in male and <50 mg/dL in female). Further studies of combination therapy with fibrates and statins should be considered but in the appropriate group as defined above.

Practical pearl: As a way to further reduce CV events in patients with metabolic syndrome or diabetes, consider adding a fibrate to those on statin therapy that still have both high TG levels (>200mg/dL) and low HDL (<40 mg/dL in males, <50 mg/ dL in females).

Disclosure statement: Dr. Moran is a speaker for Amgen, Sanofi, and Regeneron. References are listed on page 36.