Fibrates for CV prevention
References: ACCORD Lipid, FIELD
Bottom-line:
In patients taking a statin, the addition of a fibrate does not significantly reduce the risk of CV events.
In patients at intermediate-to-high CV risk who are absolutely not able to take a statin, fibrate therapy reduces the relative risk of non-fatal, but not fatal, CV events by ~20%.
- In my opinion, ezetimibe & bile-acid sequestrants (& soon possibly PCSK9 inhibitors) should be considered before fibrates in these patients.
Patients
Intervention
- FIELD: Fenofibrate vs matching placebo
- Fenofibrate given as 200 mg (micronized formulation) PO once daily
- Non-study lipid-lowering drug: Fenofibrate group 8%, placebo group 17%
- ~20% in each group discontinued study drug by end of study
- ACCORD Lipid: Fenofibrate + simvastatin vs simvastatin + matching placebo
- Fenofibrate given as 160 mg PO once daily
- Average dose of simvastatin 20 mg/d in both groups (open-label, adjusted to lipid targets)
- Fenofibrate discontinued in 22%, placebo discontinued in 19% by end of study; ~20% in each group discontinued simvastatin by end of study
Results @ ~5 years
Internal validity
- Both trials at low risk of bias (including allocation, performance, detection, & attrition bias)
- Central randomization
- Patients, clinicians, investigators, adjudicators all blinded to treatment allocation
- Loss-to-follow-up <1%
- Analyzed using intention-to-treat principles
Generalizability
- FIELD represents the effects of fibrate monotherapy in a population with type 2 diabetes at mostly intermediate risk of CV events (estimated ~10-12% over 10 years)
- Mechanistically, primarily testing the mechanistic effect of lowering triglycerides by ~30% over placebo, as effect on both LDL & HDL modest
- ACCORD Lipid represents the effects of adding a fibrate to a statin in a higher-risk population of patients with type 2 diabetes (estimated ~25% over 10 years without statin)
- Again, primarily testing the mechanistic effect of lowering triglycerides, as no discernible effect on LDL or HDL
Other fibrate studies
- VA-HIT: In 2531 men with CAD not receiving a statin, gemfibrozil lowered trigs by ~30% more than placebo. At a median 5.1 years, this resulted in a 4.4% absolute risk reduction in MI or coronary death (NNT 23).
- BIP: In 3090 men with CAD not receiving a statin, bezafibrate increased HDL & lowered trigs by ~15% more than placebo. At a mean 6.2 years, this did not result in a statistically significant effect on MI or sudden death.
- Subgroup analyses from these various trials have provided more confusion than clarity. For example, some studies demonstrate an interaction by baseline triglycerides (VA-HIT, BIP), but not others (FIELD, ACCORD Lipid). The ACCORD Lipid study, but not the BIP trial, found a subgroup interaction based on the combination of low HDL and high trigs.
- A systematic review of 18 fibrate trials, including the ones already mentioned here, found results largely consistent with the FIELD trial:
- No reduction in death or fatal CV events;
- Reduction in CV events, entirely driven by non-fatal coronary events (i.e. non-fatal MI & coronary revascularization): Relative risk 0.81 (0.75-0.89);
- 5% relative risk reduction in coronary events per 0.1 mmol/L reduction in triglycerides;
- Notably, ACCORD Lipid was the only trial included in this systematic review which had routine statin administration.