Fenofibrate

What it is

Fenofibrate is a synthetic fibric-acid derivative taken by mouth, given as a prodrug that is hydrolysed to fenofibric acid. Its US label describes it as a peroxisome proliferator-activated receptor (PPAR) alpha agonist used alongside diet for lipid disorders. Its absorption depends on food: the label states the extent of absorption is about 35% greater when tablets are taken with a meal.

What the research says

The literature supports fenofibrate as a triglyceride-lowering drug whose effect on hard cardiovascular outcomes is unsettled. A meta-analysis of 18 randomised trials of fibrates found a reduction in coronary events but no effect on all-cause mortality, cardiovascular death or stroke; the two big fenofibrate trials in type 2 diabetes (FIELD, ACCORD Lipid) both missed their primary endpoints. The more consistent randomised signal is for slowing diabetic retinopathy progression.

Evidence grade: Disputed.

How it works

Drug class: Fibric acid derivative (fibrate); peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonist

Fenofibrate switches on a nuclear receptor called PPAR-alpha in the liver and elsewhere. That increases the activity of lipoprotein lipase, which strips triglyceride out of circulating lipoproteins, and increases production of the main HDL proteins. The net effect measured in trials is a large fall in triglycerides, a rise in HDL cholesterol and a smaller, variable change in LDL cholesterol. (Source 1)

What it is used for

• The label's approved use is to change lipid numbers, not outcomes. Fenofibrate reliably lowers triglycerides and raises HDL cholesterol; that is what the approval rests on. Evidence: established. (Source 2)
• Approved for adults with severe hypertriglyceridaemia. The evidence is for lowering the triglyceride number; the label also says excess weight and excess alcohol should be addressed first. Evidence: limited. (Source 2)
• Both major randomised trials in type 2 diabetes missed their primary endpoint, and the US label carries an explicit limitation of use saying this was not shown. A class meta-analysis found fewer coronary events but no effect on death or stroke. Evidence: not-supported. (Source 3)
• This is the most consistent randomised signal. LENS reported less progression of retinopathy or maculopathy on fenofibrate, and FIELD and ACCORD-EYE reported absolute reductions of 5.0% over 5 years and 3.7% over 4 years. It is not an approved use in the US label. Evidence: limited. (Source 4)

Interactions

• Warfarin and other coumarin anticoagulants (label): Fenofibrate can potentiate coumarin anticoagulants, lengthening clotting time and raising the INR. (Source 5)
• Statins (case reports): Combining a fibrate with a statin raises the risk of severe muscle breakdown (rhabdomyolysis). The signal is strongest for gemfibrozil rather than fenofibrate. (Source 5)
• Red yeast rice (supplement containing monacolin K) (theoretical): Red yeast rice supplements that contain meaningful amounts of monacolin K are chemically the same as the statin lovastatin, so NCCIH states they carry statin-type side effects and statin-type drug interactions. That places the fibrate-plus-statin muscle risk on the table for someone taking both. (Source 6)
• Ciclosporin (cyclosporine) and tacrolimus (label): Both these immunosuppressants damage the kidney, and fenofibrate is cleared by the kidney, so the label warns the combination can worsen kidney function. (Source 5)
• Food (any meal) (pharmacokinetic study): Food raises how much fenofibrate gets absorbed, so tablets are meant to be taken with a meal. This is a measured pharmacokinetic effect, not a theoretical one. (Source 2)
• Alcohol (label): The label does not describe a direct pharmacological clash, but names heavy drinking as a cause of high triglycerides that should be dealt with before drug treatment is started. (Source 2)

Stopping it

• Creatinine rises caused by fenofibrate are described as reversible: the label states they tend to return to baseline after the drug is stopped. (Source 5)
• StatPearls describes stopping or dose reduction as the response to a clinically significant creatinine rise, once other causes have been excluded. There is no described withdrawal syndrome or rebound for fibrates. (Source 1)
• LiverTox reports that fenofibrate-related liver enzyme abnormalities often settle even if the drug is continued, but that monitoring and stopping are advised if enzymes stay above three times the upper limit of normal or symptoms appear. (Source 7)

What goes wrong

Fibrates roughly doubled the chance of a significant rise in serum creatinine in randomised trials. (Source 8)

• Meta-analysis, Moderate certainty.
• Size: 18 RCTs, 45,058 participants.
• Who: Adults in fibrate trials.
• How long: As above.
• Result: RR 1.99 (95% CI 1.46 to 2.70) for increases in serum creatinine concentrations. The abstract does not give the absolute rates.
• Funding: not stated.

There were statistically significant increases in serum creatinine concentrations in fibrate groups (RR 1.99, 95% CI 1.46 to 2.70)

Fenofibrate causes liver enzyme rises in a substantial minority and has caused clinically apparent liver injury, sometimes chronic. (Source 7)

• Case series, Low certainty.
• Size: Multiple published case reports plus trial monitoring data.
• Who: Patients taking fenofibrate.
• How long: Acute hepatitis-like injury within weeks to months; chronic hepatitis and cirrhosis after more than 6 months or years.
• Result: Aminotransferase elevations in up to 20% of patients, above 3 times normal in 3% to 5%. LiverTox assigns fenofibrate a likelihood score of B (a likely cause of clinically apparent liver injury).
• Funding: independent (NIDDK)

Mild, transient serum aminotransferase elevations develop in up to 20% of patients receiving fenofibrate, but values above 3 times normal in only 3% to 5%.

Fibrates carry a small increase in muscle injury, gallstones and venous thrombosis. (Source 1)

• Expert review, not systematic, Low certainty.
• Size: Not stated in this review.
• Who: Patients taking fibrates.
• How long: not stated.
• Result: Described as a slightly increased risk, less than 1.0%, of myopathy, cholelithiasis and venous thrombosis.
• Funding: not stated.

fibrates can cause a slightly increased risk (less than 1.0%) of myopathy, cholelithiasis, and venous thrombosis.

What the evidence supports

Pooled across 18 randomised trials, fibrates reduced coronary events but the reduction in major cardiovascular events only just reached significance. (Source 8)

• Meta-analysis, Moderate certainty.
• Size: 18 RCTs, 45,058 participants; 2,870 major cardiovascular events.
• Who: Adults in fibrate trials, mostly with dyslipidaemia, diabetes or established coronary disease.
• How long: Trial durations varied; sample sizes 81 to 10,627.
• Result: Major cardiovascular events RR 0.90 (95% CI 0.82 to 1.00); coronary events RR 0.87 (95% CI 0.81 to 0.93); non-fatal coronary events RR 0.81 (95% CI 0.75 to 0.89). The abstract reports relative risks only, without absolute risk reductions or NNTs.
• Funding: not stated.

There was a statistically significant reduction in risk of cardiovascular events (RR 0.90, 95% CI 0.82 to 1.00; five RCTs), coronary events (RR 0.87, 95% CI 0.81 to 0.93; 16 RCTs)

In the LENS randomised trial, fenofibrate reduced progression of diabetic retinopathy or maculopathy compared with placebo. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 1,151 randomised (576 fenofibrate, 575 placebo), as reported in this review.
• Who: Adults with diabetes and early retinopathy.
• How long: Median about 4 years.
• Result: Progression 32.1% versus 40.2%; hazard ratio 0.74 (95% CI 0.61 to 0.90). Absolute difference 8.1 percentage points, about 12 people treated per progression avoided. Macular oedema 3.8% versus 7.5%; hazard ratio 0.50 (95% CI 0.30 to 0.84).
• Funding: independent (LENS was funded by the UK National Institute for Health and Care Research; this commentary does not state its own funding)

maculopathy were n = 185 (32.1%) vs. n = 231 (40.2%); hazard ratio, 0.74; 95% CI, 0.61

Older trials reported absolute reductions in retinopathy progression of 5.0% over 5 years (FIELD) and 3.7% over 4 years (ACCORD-EYE). (Source 4)

• Randomized trial, Low certainty.
• Size: FIELD 9,795 randomised (retinopathy substudies smaller); ACCORD-EYE 1,593 evaluated.
• Who: Adults with type 2 diabetes.
• How long: 5 years and 4 years respectively.
• Result: Absolute reductions of 5.0% over 5 years (p = 0.022, FIELD) and 3.7% over 4 years (p = 0.006, ACCORD-EYE); first laser treatment reduced by 31% (p = 0.0002).
• Funding: FIELD industry-funded; ACCORD independent (NHLBI). Not stated on this page.

the progression of DR with absolute reductions of 5.0% over 5 years

What the evidence does not support

The same meta-analysis found no effect of fibrates on death from any cause, cardiovascular death or stroke. (Source 8)

• Meta-analysis, Moderate certainty.
• Size: 18 RCTs, 45,058 participants; 3,880 deaths.
• Who: Adults in fibrate trials.
• How long: As above.
• Result: No statistically significant difference for stroke, all-cause mortality, cardiovascular death, sudden death, non-vascular death or serious drug-related adverse events.
• Funding: not stated.

No statistically significant differences between groups were found for the following outcomes: stroke; all-cause mortality; cardiovascular death; sudden death; non-vascular death; and serious drug-related adverse events.

In FIELD, fenofibrate did not reduce the primary endpoint of coronary death or non-fatal myocardial infarction in people with type 2 diabetes. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 9,795 people with type 2 diabetes.
• Who: Adults with type 2 diabetes, 22% with prior cardiovascular disease, median HbA1c 6.9%.
• How long: 5 years.
• Result: Primary endpoint HR 0.89 (95% CI 0.75-1.05, p = 0.16). Total mortality 7.3% versus 6.6% (p = 0.18), numerically higher on fenofibrate. Statin drop-in was commoner in the placebo arm (17% versus 8%, p < 0.0001), which the summary notes may have diluted any difference.
• Funding: industry-funded (the FIELD trial was funded by Laboratoires Fournier, per the published trial report; the ACC summary page does not state funding)

There was no difference in the primary composite endpoint of CHD death or nonfatal myocardial infarction (MI) (hazard ratio [HR] 0.89, 95% confidence interval 0.75-1.05, p = 0.16).

In ACCORD Lipid, adding fenofibrate to simvastatin did not reduce cardiovascular events in the trial population as a whole. (Source 9)

• Randomized trial, Moderate certainty.
• Size: 5,518 people with type 2 diabetes on simvastatin.
• Who: Adults with type 2 diabetes at high cardiovascular risk, all on simvastatin.
• How long: Mean 4.7 years.
• Result: 2.24% per year on fenofibrate versus 2.41% per year on placebo; hazard ratio 0.92 (95% CI 0.79-1.08; p = 0.32). Absolute difference about 0.17 percentage points per year.
• Funding: independent (ACCORD was funded by the US National Heart, Lung, and Blood Institute; this review article does not state its own funding)

Over an average of 4.7 years of treatment, the rate of CVD events was 2.24% per year in the fenofibrate group versus 2.41% per year in the placebo group

Where the evidence is mixed

The review flagged that the trials it pooled were of variable and often poorly reported quality. (Source 8)

• Meta-analysis, Moderate certainty.
• Size: 18 RCTs.
• Who: As above.
• How long: As above.
• Result: Completion rates ranged from 19% to 100%; Jadad scores ranged from 0 to 4.
• Funding: not stated.

Trial quality was variable and poor reporting of criteria was widespread; this was particularly the case for randomisation, allocation concealment and use of intention-to-treat analysis.

In FIELD the secondary composite of total cardiovascular events was lower on fenofibrate, an absolute difference of 1.4 percentage points. (Source 3)

• Randomized trial, Low certainty.
• Size: 9,795.
• Who: Adults with type 2 diabetes.
• How long: 5 years.
• Result: 12.5% versus 13.9% (p = 0.035); absolute risk reduction 1.4 percentage points over 5 years, about 71 people treated for 5 years per event avoided. Driven by non-fatal MI (HR 0.76, p = 0.01) and revascularisation (5.9% versus 7.4%, p = 0.004). This was a secondary endpoint after the primary was null.
• Funding: industry-funded (as above)

The secondary composite endpoint of total cardiovascular disease events was lower in the fenofibrate group (12.5% vs. 13.9%, p = 0.035), due primarily to a reduction in nonfatal MI (HR 0.76, p = 0.01) and coronary revascularization (5.9% vs. 7.4%, p = 0.004).

A post-hoc ACCORD subgroup with high triglycerides and low HDL cholesterol showed a lower event rate, but this was a subgroup analysis and not the trial's answer. (Source 10)

• Randomized trial, Low certainty.
• Size: Subgroup of the 5,518 ACCORD Lipid participants.
• Who: Participants with both high baseline triglycerides and low baseline HDL cholesterol.
• How long: Mean 4.7 years.
• Result: Primary outcome 12.4% on fenofibrate versus 17.3% on placebo, an absolute difference of 4.9 percentage points (about 20 treated per event avoided over the trial); described by the commentary as a 28% crude hazard ratio reduction. The interaction test in the main trial was not significant at the conventional level.
• Funding: not stated.

the primary outcome rate was 12.4% in the fenofibrate group, versus 17.3% in the placebo group (28% crude HR reduction, CI less than 1, e.g. statistically significant findings).

Where the research disagrees

Whether fenofibrate prevents cardiovascular events in type 2 diabetes

• US prescribing information for fenofibrate (label revised August 2022), position, resting on the FIELD and ACCORD trials: Limitations of Use: Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus. (Source 2)
• Jun and colleagues, meta-analysis of 18 fibrate trials (2010), as summarised by CRD, meta-analysis of randomised trials: There was a statistically significant reduction in risk of cardiovascular events (RR 0.90, 95% CI 0.82 to 1.00; five RCTs), coronary events (RR 0.87, 95% CI 0.81 to 0.93; 16 RCTs) (Source 8)
• Commentary in Cardiovascular Diabetology (2010) on ACCORD Lipid, narrative commentary on a subgroup analysis: In contrast, in patients without atherogenic dyslipidemia this favorable effect was not demonstrated. (Source 10)

How much

• Reference intake: There is no reference intake for a prescription drug; the dose is set by the prescriber. As a position, the US label (revised August 2022) states an initial dose of 160 mg once daily for primary hypercholesterolaemia or mixed dyslipidaemia, and 54 mg once daily in renal impairment. (Source 2)
• Upper limit: As a position, the US label (revised August 2022) states a maximum dose of 160 mg once daily. (Source 2)
• Studied: We could not reach a page giving the exact daily dose used in FIELD or ACCORD Lipid in verbatim form; the ACC trial summary and the ACCORD review we did reach do not state it. The dose range on the current US label is 54 mg to 160 mg once daily, taken with meals. (Source 2)

A common belief, and what the research shows

The belief: Fenofibrate lowers triglycerides, so it must prevent heart attacks and deaths the way statins do.

What the research shows: Lowering a blood number is not the same as preventing an event. The class meta-analysis found no effect on death: "No statistically significant differences between groups were found for the following outcomes: stroke; all-cause mortality; cardiovascular death; sudden death; non-vascular death; and serious drug-related adverse events." In FIELD, "There was no difference in the primary composite endpoint of CHD death or nonfatal myocardial infarction (MI) (hazard ratio [HR] 0.89, 95% confidence interval 0.75-1.05, p = 0.16)." The US label itself records that the drug "was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus."

Questions and answers

What is it?

Fenofibrate is a prescription tablet or capsule from the fibrate family. The US label describes it as a PPAR-alpha agonist used as an add-on to diet in adults. It is not a vitamin or a food component; it exists only as a manufactured medicine. (Source 2)

What does it do in the body?

It switches on the PPAR-alpha receptor, which increases the activity of lipoprotein lipase, the enzyme that clears triglyceride from the blood. It also increases production of the proteins that make up HDL particles. The result measured in trials is lower triglycerides and higher HDL cholesterol. (Source 1)

Is it good or bad for you?

It depends entirely on what you are asking it to do. For lowering triglycerides it works, and the randomised evidence for slowing diabetic retinopathy is reasonably consistent. For preventing heart attacks and deaths in type 2 diabetes the two large trials were null, and the pooled trial evidence shows fewer coronary events but no effect on dying. It also carries real harms: creatinine rises, liver injury, muscle problems and gallstones. (Source 8)

How do you get more of it?

Fenofibrate is available only on prescription, so more of it means a prescriber changing the dose. One thing that does change how much reaches the bloodstream is food: the label says tablets should be taken with meals because absorption is about 35% higher when fed than fasting. (Source 2)

If it is harmful, what reduces it?

Fenofibrate has no described withdrawal syndrome; it is cleared by the kidneys and its effects fade after stopping. Where it has caused a problem such as a rising creatinine, the documented response is stopping or reducing the dose after other causes are ruled out, and the label states creatinine rises tend to return to baseline afterwards. (Source 1)

Why might someone be low in it or missing it?

This question does not apply in the usual sense: nobody is naturally low in fenofibrate, because the body does not make it. People stop or never start it for reasons documented in the label and literature, including a creatinine rise, liver enzyme abnormalities, muscle symptoms, or kidney impairment requiring a lower dose. The label also flags that heavy drinking and excess weight should be addressed before drug treatment for high triglycerides. (Source 2)

Which whole foods contain it or feed it?

No whole food contains fenofibrate. Food matters only because it changes absorption: the label records that the extent of absorption is about 35% greater when tablets are taken with a meal than fasting, which is why it is given with meals. (Source 2)

What happens if you do not have it?

Not taking fenofibrate is the ordinary state for almost everyone. What the trials show is what you forgo: in type 2 diabetes the placebo groups had the same rate of coronary death and heart attack as the fenofibrate groups, and the same death rate. What placebo groups did show more of was retinopathy progression, at 40.2% versus 32.1% in LENS. (Source 4)

How can you test for it?

There is no routine blood level test used in practice. What is monitored instead is harm: liver enzymes at baseline and periodically, with stopping advised if they stay above three times the upper limit of normal, and serum creatinine, which fibrates raise roughly twofold in trials and which usually falls back after stopping. (Source 7)

References

1. StatPearls Publishing, NCBI Bookshelf. Fibrate Medications - StatPearls. 2023. PMID 31424832. Read the source
2. DailyMed, US National Library of Medicine. FENOFIBRATE tablet, film coated - US prescribing information (label revised August 2022; DailyMed page updated 6 December 2024). 2024. Read the source
3. American College of Cardiology. Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) - clinical trial summary of Keech A et al., Lancet 2005. 2014. PMID 16310551, DOI 10.1016/S0140-6736(05)67667-2. Read the source
4. Eye (Nature Publishing Group). Fenofibrate therapy in reducing the progression of diabetic retinopathy: revisiting the FIELD and ACCORD-EYE studies through the LENS trial. 2025. DOI 10.1038/s41433-024-03410-9. Read the source
5. DailyMed, US National Library of Medicine. FENOFIBRATE tablet, film coated - US prescribing information, warnings and drug interactions sections. 2024. Read the source
6. National Center for Complementary and Integrative Health (NCCIH), NIH. Red Yeast Rice: What You Need To Know. 2024. Read the source
7. National Institute of Diabetes and Digestive and Kidney Diseases, NCBI Bookshelf. Fenofibrate - LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2020. PMID 31643176. Read the source
8. Centre for Reviews and Dissemination, Database of Abstracts of Reviews of Effects (DARE), NCBI Bookshelf. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis (CRD/DARE structured abstract of Jun M, Foote C, Lv J, et al., Lancet 2010). 2010. PMID 20462635, DOI 10.1016/S0140-6736(10)60656-3. Read the source
9. Clinical Lipidology (PubMed Central author manuscript). The ACCORD-Lipid study: implications for treatment of dyslipidemia in Type 2 diabetes mellitus. 2011. PMID 26207146, DOI 10.2217/clp.10.84. Read the source
10. Cardiovascular Diabetology. "If it ain't broke, don't fix it": a commentary on the positive-negative results of the ACCORD Lipid study. 2010. PMID 20550659, DOI 10.1186/1475-2840-9-24. Read the source