Fibrates for CV prevention

References: ACCORD Lipid, FIELD


  • 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.



  • 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


  • 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.

Reducing LDL & improving CV outcomes - systematic review

Silverman MG, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: A systematic review and meta-analysis. JAMA 2016;316:1289-97.

Clinical question: Does reduction of CV outcomes with lipid-lowering therapy correlate with degree of LDL-lowering?

Bottom line:

  • The value of this study is mechanistic; it does not provide clinical guidance. 

  • The analysis demonstrates that CV outcome reduction of proven lipid-lowering drugs is closely associated with degree of LDL-lowering. This supports the lipid hypothesis, i.e. that lipid-lowering drugs which lower CV risk outcomes (statins, bile acid sequestrants, & ezetimibe) do so primarily by lowering LDL.

  • This study does not validate a particular lipid target, nor does it support using interventions with neutral, harmful or conflicting evidence (fibrates, niacin, or CETP inhibitors) to achieve a lipid target.



  • Databases: MEDLINE, Embase
  • Timeframe: 1966 to July 2016
  • Inclusion criteria:
    • Randomized controlled trials (RCTs)
    • Compared (1) LDL-lowering intervention to control/placebo or (2) more vs less intensive statin therapy
    • Reported cardiovascular outcomes including MI
    • Duration of at least 6 months
    • At least 50 events
  • Exclusion criteria: Trial with populations with "significant competing risks", including heart failure & chronic kidney disease
  • Additional measures for comprehensiveness:
    • References lists of identified studies, review and meta-analyses
    • Reviewed abstracts of major cardiovascular meetings held in past 2 years (no mention of which)
    • Contacted content experts

Results of systematic review

  • Included 49 RCTs (n=312,175)
    • Statin (25 trials)
    • Fibrate (9 trials)
    • Diet (4 trials)
    • CETP inhibitor (3 trials)
    • Niacin (3 trials)
    • Bile acid sequestrants (2 trials)
    • PCSK9 inhibitor (2 trials)
    • Ezetimibe (1 trial)
    • Ileal bypass surgery (1 trial)

Results of the meta-analysis

  • Mean follow-up 4.3 years
  • Mean ~absolute reduction in LDL vs placebo in trials
    • PCSK9 inhibitor -1.85 mmol/L
    • Ileal bypass -1.6 mmol/L
    • Bile acid sequestrant -0.90 mmol/L
    • Statin -0.85 mmol/L (all drugs & doses pooled)
    • Diet -0.75 mmol/L
    • Niacin -0.35 mmol/L
    • Ezetimibe -0.3 mmol/L
    • Fibrate -0.25 mmol/L
  • ~23% relative risk reduction (RRR) in major vascular events per 1 mmol/L reduction in LDL with any interventions except CETP inhibitors

Considerations & limitations

  • Generalizability & internal validity
    • Investigators excluded studies that included patients with "significant competing risk", which includes some of the landmark "negative" statin trials (CORONA, GISSI-HF, 4D, etc)
      • Results of this analysis don't apply to the subpopulations of these studies (primarily heart failure & chronic kidney disease)
      • The analysis may overestimate the true relative risk reduction since this exclusion criterion primarily excluded "negative" studies.
    • Numerous differences in populations between trials, including
      • Era (e.g. 1st fibrate/niacin trial conducted in 60s, most statin trials conducted in 1990s-2000s)
      • Primary vs secondary prevention
      • LDL before initiation of study treatment & background CV therapies
  • Results
    • Although interventions produced comparable RRRs in CV outcomes per 1-mmol/L reduction in LDL, actual achievable LDL reduction & therefore realistic CV reductions with each agent are quite different
    • This study evaluated a composite CV outcome, which bundles together outcomes of different severity & importance to patients. Different interventions may have the same effect on a composite CV outcome, but not specific components. For example, statins reduce every type of CV event (death, MI, stroke, revascularization), whereas fibrates only reduce non-fatal MI, but not death or stroke.