Fibrates for CV prevention

in , ,

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.