- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- ACR - American College of Rheumatology
- AHA - American Heart Association
- ALT - Alanine aminotransferase
- AST - Aspartate aminotransferase
- CAD - Coronary artery disease
- CrCl - Creatinine clearance
- CVD - Cardiovascular disease
- GI - Gastrointestinal
- ULN - Upper limit of normal
- DRUGS IN CLASS
- Fenofibrates
- Fenofibrate (Antara®, Fenoglide®, Lipofen®, Lofibra®, Tricor®, Triglide®)
- Fenofibric acid
- Fenofibric acid (Trilipix®)
- NOTE: Fenofibric acid is the active metabolite of fenofibrate
- Other
- Gemfibrozil (Lopid®)
- MECHANISM OF ACTION
- PPARɑ receptors are found on liver cells
- Stimulating PPARɑ receptors increases the metabolism of triglycerides and enhances the production of HDL
- Fibrates stimulate PPARɑ receptors [6]
- FDA-APPROVED INDICATIONS
- Fenofibrate (Antara®, Fenoglide®, Lipofen®, Lofibra®, Tricor®, Triglide®)
- Dyslipidemia - to decrease total cholesterol, LDL, triglycerides, and apolipoprotein B, and to increase HDL
- Severe hypertriglyceridemia (≥ 1000 mg/dl)
- Important limitations - has not been proven to reduce CVD morbidity or mortality
- Fenofibric acid (Trilipix®)
- Dyslipidemia - to decrease total cholesterol, LDL, triglycerides, and apolipoprotein B, and to increase HDL
- Severe hypertriglyceridemia (≥ 1000 mg/dl)
- Important limitations - has not been proven to reduce CVD morbidity or mortality
- Gemfibrozil (Lopid®)
- Severe hypertriglyceridemia (≥ 1000 mg/dl)
- Primary prevention of coronary heart disease in Type IIB patients with low HDL and elevated LDL and triglycerides
- CHOLESTEROL EFFECTS
- Overview
- The effects of fenofibrates on lipid parameters varies according to the baseline lipid values
- The first table shows the effects of fenofibrate on lipid parameters in patients with moderate hypertriglyceridemia (175 - 499 mg/dl) and high LDL levels. The second table shows the effects in patients with very high triglycerides (> 500 mg/dl).
Fenofibrate at recommended dosing for 3 - 6 months | ||
---|---|---|
Lipid parameter (average baseline value) |
Fenofibrate (N=361) |
Placebo (N=285) |
Total (307 mg/dl) |
-19% | 0% |
LDL (214 mg/dl) |
-21% | -2% |
Triglycerides (191 mg/dl) |
-29% | +8% |
HDL (52 mg/dl) |
+11% | +1% |
Fenofibrate at recommended dosing for 8 weeks | ||
---|---|---|
Lipid parameter (average baseline value) |
Fenofibrate (N=48) |
Placebo (N=44) |
Total (267 mg/dl) |
-14% | 0% |
LDL (101 mg/dl) |
+45% | -4% |
Triglycerides (718 mg/dl) |
-55% | +7% |
HDL (28 mg/dl) |
+23% | +5% |
- CVD OUTCOMES
- Overview
- Several large studies have evaluated the effect of fibrates on CVD outcomes
- The VA-HIT trial evaluated gemfibrozil in patients with heart disease. It was published in 1999 and took place before the widespread use of statins.
- The ACCORD trial evaluated the addition of a fenofibrate to statin therapy in diabetics
- The VA-HIT trial enrolled 2531 men with coronary artery disease
Main inclusion criteria
- Age < 74 years
- Documented CAD
- HDL ≤ 40 mg/dl
- LDL ≤ 140 mg/dl
- Triglycerides ≤ 300 mg/dl
Main exclusion criteria
- Serious coexisting medical condition
Baseline characteristics
- Average age 64 years
- Diabetes - 25%
- Previous CABG or PCI - 56%
- Average LDL - 112 mg/dl
- Average HDL - 32 mg/dl
- Average triglycerides - 160 mg/dl
Randomized treatment groups
- Group 1 (1267 patients) - Placebo twice a day
- Group 2 (1264 patients) - Gemfibrozil 600 mg twice a day
Primary outcome: Composite of nonfatal myocardial infarction or death from coronary heart disease (defined as sudden death,
death due to myocardial infarction, death due to congestive heart failure, and death as a complication of invasive cardiac procedures)
Results
Duration: Median of 5.1 years | |||
Outcome | Placebo | Gemfibrozil | Comparisons |
---|---|---|---|
Primary outcome | 21.7% | 17.3% | RR 0.78, 95%CI [0.65 - 0.93], p=0.006 |
Nonfatal myocardial infarction | 14.5% | 11.6% | RR 0.77, 95%CI [0.62 - 0.96], p=0.02 |
Death due to heart disease | 9.3% | 7.4% | RR 0.78, 95%CI [0.59 - 1.02], p=0.07 |
Stroke | 6% | 4.6% | RR 0.75, 95%CI [0.53 - 1.06], p=0.10 |
Overall mortality | 17.4% | 15.7% | RR 0.89, 95%CI [0.73 - 1.08], p=0.23 |
Dyspepsia | 34% | 40% | p=0.002 |
Average HDL at one year | 32 mg/dl | 34 mg/dl | p<0.001 |
Average triglycerides at one year | 166 mg/dl | 115 mg/dl | p<0.001 |
Average LDL at one year | 113 mg/dl | 113 mg/dl | p>0.05 |
Findings: Gemfibrozil therapy resulted in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level. The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.
- The ACCORD trial enrolled 5518 patients with type 2 diabetes
Main inclusion criteria
- Type 2 diabetes
- HgA1C ≥ 7.5%
- Age 40 - 79 years with CVD or age 55 - 79 with 2 risk factors for CVD
- LDL of 60 - 180 mg/dl
- HDL < 55 mg/dl (women and blacks), < 50 mg/dl (all others)
- Triglycerides < 750 mg/dl (no lipid therapy), < 400 mg/dl (lipid therapy)
Main exclusion criteria
- BMI > 45
- Serum creatinine > 1.5 mg/dl
- History of myopathy
- History of gallbladder disease
Baseline characteristics
- Average age 62 years
- Previous CVD event - 37%
- Taking statin - 60%
- Average HgA1C - 8.3%
- Median duration of diabetes - 9 years
- Average LDL - 100 mg/dl
- Average HDL - 38 mg/dl
- Median triglycerides - 162 mg/dl
Randomized treatment groups
- Group 1 (2765 patients) - Fenofibrate 160 mg + simvastatin once daily
- Group 2 (2753 patients) - Placebo + simvastatin once daily
- The protocol for simvastatin and fenofibrate dosing changed over the course of the trial
- The average dose of simvastatin was 22 mg in both groups
Primary outcome: Composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes
Results
Duration: Average of 4.7 years | |||
Outcome | Fenofibrate | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 10.5% | 11.3% | RR 0.92, 95%CI [0.79 - 1.08], p=0.32 |
Nonfatal myocardial infarction | 6.3% | 6.8% | RR 0.91, 95%CI [0.74 - 1.12], p=0.39 |
Stroke | 1.8% | 1.7% | RR 1.05, 95%CI [0.71 - 1.56], p=0.80 |
Overall mortality | 7.3% | 8% | RR 0.91, 95%CI [0.75 - 1.10], p=0.33 |
ALT ever > 5 X ULN | 0.6% | 0.2% | p=0.03 |
Serum creatinine > 1.3 mg/dl in women | 28% | 19% | p<0.001 |
Serum creatinine > 1.5 mg/dl in men | 37% | 19% | p<0.001 |
Incidence of microalbuminuria | 38% | 42% | p=0.01 |
Average LDL at end of study | 81 mg/dl | 80 mg/dl | p=0.16 |
Average HDL at end of study | 41.2 mg/dl | 40.5 mg/dl | p=0.01 |
Average triglycerides at end of study | 147 mg/dl | 170 mg/dl | p<0.0001 |
Drug discontinuation | 22.7% | 18.7% | N/A |
Findings: The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes.
- Professional recommendations
- See cholesterol treatment guidelines for recommendations from various professional organizations
- Summary
- The VA-HIT trial was performed before the widespread use of statins, and it showed a benefit with gemfibrozil
- The ACCORD trial found that the addition of fenofibrate to a statin did not improve outcomes when compared to a statin alone
- After the ACCORD trial was published, the use of fibrates to treat dyslipidemia fell out of favor. Statins, which also lower triglycerides, are now recommended for most patients. Fibrates may be necessary in patients with severe hypertriglyceridemia (> 1000 mg/dl).
- GOUT
- Overview
- Gout is an inflammatory joint disease caused by elevated uric acid levels
- Fenofibrate promotes uric acid excretion in the kidneys and therefore may be beneficial in the treatment of gout
- Studies
- The effect of fenofibrate on uric acid levels has been evaluated in several studies
- Study 1 - 14 patients with gout who were receiving allopurinol (200 mg twice a day) were given fenofibrate 300 mg a day for 2 months. Uric acid levels decreased from an average of 6.1 mg/dl to 5.2 mg/dl. [PMID 12759298]
- Study 2 - 25 patients without gout who had an average uric acid level of 7.6 mg/dl were given fenofibrate 200 mg a day for 4 weeks. The average uric acid level decreased to 5.6 mg/dl. [PMID 10413068]
- Study 3 - a post-hoc analysis of the FIELD study showed that patients randomized to fenofibrate (200 mg daily) had a 20% decrease in their uric acid levels at one-year when compared to placebo. Patients on fenofibrate also had a lower incidence of first gout events (2% vs 3%) over 5 years. [PMID 29496472]
- Professional recommendations
- SIDE EFFECTS
- Gastrointestinal side effects (gemfibrozil)
- Gemfibrozil may cause gastrointestinal side effects (upset stomach, abdominal pain). In one study, gastrointestinal complaints occurred in 34% of gemfibrozil-treated patients compared to 24% of placebo-treated patients. The incidence of gastrointestinal side effects with other fibrates is similar to placebo. [5,6,7]
- Hepatotoxicity
- Fenofibrates can be toxic to the liver. Everything from mild liver enzyme elevations to rare cases of liver failure has been reported. In trials, liver enzyme elevations ≥ 3 X ULN have occurred in up to 13% of fenofibrate-treated patients. Rare cases of liver injury that have led to liver transplantation and death have been reported within the first few weeks of starting therapy and after several months of treatment. In many patients, toxicity resolved after discontinuation of the fenofibrate. Symptoms of fenofibrate-induced hepatotoxicity include elevated liver function tests, dark urine, abnormal stool, jaundice, malaise, abdominal pain, myalgia, weight loss, pruritus, and nausea.
- Liver enzymes should be checked before starting therapy and periodically thereafter. Fenofibrates should be discontinued if symptoms of liver injury develop or if persistent liver enzyme elevations > 3 X ULN occur. Therapy should also be discontinued if any enzyme elevation is accompanied by an elevated bilirubin. [1]
- Serum creatinine increase
- In trials, patients on fibrates typically had a slight increase in serum creatinine levels
- In the FIELD study, patients on fenofibrate had an average serum creatinine level that was 0.12 mg/dl higher than the placebo group [11]
- In the ACCORD study, patients on fenofibrate had an average serum creatinine level that was 0.08 mg/dl higher than the placebo group [12}
- A cohort study in the Annals of Internal Medicine found that fibrates raised the average serum creatinine level by 0.2 mg/dl in elderly patients when compared to pre-fibrate levels [14]
- Professional recommendations
- The AHA 2013 cholesterol treatment guidelines state that serum creatinine should be checked before, within 3 months of initiation, and every 6 months thereafter in patients receiving fenofibrates
- If GFR is < 30 ml/min, fenofibrates should not be used. If GFR is 30 - 59 ml/min, the dose of fenofibrate should not exceed 54 mg/day [19]
- Summary
- Fenofibrates may cause a slight increase in serum creatinine levels
- An increase in end-stage kidney disease in patients taking fibrates has not been seen, and in some trials, fenofibrates have been shown to significantly decrease the progression of albuminuria (protein in the urine) [11,12,13]
- The effect of fenofibrates on serum creatinine levels may be related to an inhibitory action of fenofibrates on organic cation transporter 2 [15]
- Muscle toxicity
- Fibrates may increase the risk of muscle toxicity including myopathy and rhabdomyolysis. The risk appears to be greatest in patients with diabetes, renal insufficiency, hypothyroidism, and advanced age. Creatine phosphokinase (CPK) levels should be checked in any patient who complains of unusual muscle weakness or pain. If CPK levels are elevated, fibrates should be discontinued.
- Concomitant statin therapy may increase the risk of myopathy. This is particularly true of gemfibrozil, and it is contraindicated with statins. Fenofibrates, on the other hand, have been combined with statins in a number of trials and had no apparent effect on muscle-related events.
- Cases of myopathy have been reported when fibrates are combined with colchicine, and caution should be used when prescribing together [1,10,11,12,13]
- Gallstones
- FIbrates can increase the concentration of cholesterol in the gallbladder. This may lead to gallstones.
- An older fibric acid, clofibrate, was associated with an increased risk of gallstones, and it was eventually pulled from the market
- After clofibrate, other fibrates have been scrutinized closely for gallstone risk
- Across randomized trials, the risk of gallstone disease in the fibrate group has not been consistently greater than the placebo group (with the caveat that gallstones often do not cause symptoms and may go undiagnosed) [10,11,12]
- Summary
- It is unclear if fibrates promote gallstone formation
- Risks for gallstones include high triglycerides and low HDL levels. It may be that people at high-risk for gallstones are more likely to be prescribed fibrates.
- Data from randomized controlled trials is reassuring
- If fibrates promote gallstone formation, the risk is most likely very small
- When fibrates are taken with ezetimibe (Zetia®), the risk may be higher (see drug interactions below)
- CONTRAINDICATIONS
- All fibrates
- Severe kidney disease
- Active liver disease, including primary biliary cirrhosis and unexplained persistent liver function abnormalities
- Preexisting gallbladder disease
- Nursing mothers
- Known hypersensitivity
- Gemfibrozil (Lopid®)
- Do not take with dasabuvir (Viekira pak™)
- Do not take with repaglinide (Prandin®)
- Do not take with simvastatin (Zocor®)
- Do not take with cerivastatin
- PRECAUTIONS
- Kidney disease
- AHA recommendations
- The AHA 2013 cholesterol treatment guidelines state that serum creatinine should be checked before, within 3 months of initiation, and every 6 months thereafter in patients receiving fenofibrates. If GFR is < 30 ml/min, fenofibrates should not be used. If GFR is 30 - 59 ml/min, the dose of fenofibrate should not exceed 54 mg/day [19]
- Antara®
- CrCl 30 - 89 ml/min: starting dose is 43 mg/day. Titrate as tolerated.
- CrCl < 30 ml/min: DO NOT USE
- Fenoglide®
- CrCl 30 - 89 ml/min: starting dose is 40 mg/day. Titrate as tolerated.
- CrCl < 30 ml/min: DO NOT USE
- Lipofen®
- CrCl 30 - 89 ml/min: starting dose is 50 mg/day. Titrate as tolerated.
- CrCl < 30 ml/min: DO NOT USE
- Lofibra® capsule
- CrCl 30 - 89 ml/min: starting dose is 67 mg/day. Titrate as tolerated.
- CrCl < 30 ml/min: DO NOT USE
- Lofibra® tablet
- CrCl 30 - 89 ml/min: starting dose is 54 mg/day. Titrate as tolerated.
- CrCl < 30 ml/min: DO NOT USE
- Lopid®
- CrCl 30 - 89 ml/min: has not been studied
- CrCl < 30 ml/min: DO NOT USE
- Tricor®
- CrCl 30 - 89 ml/min: starting dose is 48 mg/day. Titrate as tolerated.
- CrCl < 30 ml/min: DO NOT USE
- Triglide®
- CrCl ≤ 89 ml/min: DO NOT USE
- Trilipix®
- CrCl 30 - 89 ml/min: starting dose is 45 mg/day. Titrate as tolerated.
- CrCl < 30 ml/min: DO NOT USE
- Liver disease
- Fibrates have not been studied in liver disease and are contraindicated in patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities
- Gallbladder disease
- Fibrates have been associated with the formation of gallstones (see gallstones above)
- Fibrates should not be taken by patients with suspected gallbladder disease [5,6,7]
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All fibrates
- Bile Acid Sequestrants (Questran®, Welchol®) - bile acid sequestrants may interfere with the absorption of fibrates. Fibrates should be taken 1 hour before or 4 hours after bile acid sequestrants. [5,6,7]
- Colchicine (Colcrys®) - muscle toxicity including rhabdomyolysis has been reported in patients taking fenofibrates with colchicine. Use caution when prescribing together.
- Ezetimibe (Zetia®) - ezetimibe and fibrates increase cholesterol excretion into the bile, raising the risk of gallstones in susceptible patients. Furthermore, gemfibrozil and fenofibrate increase ezetimibe exposure. Use caution when combining.
- Immunosuppressants - immunosuppressants such as cyclosporine and tacrolimus can be nephrotoxic and may reduce the elimination of fibrates. Use caution when combining.
- Warfarin (Coumadin®) - fibrates may interfere with warfarin therapy. Monitor INR levels when adding fibrates to warfarin. [5,6,7]
- Gemfibrozil (Lopid®)
- CYP2C8 substrates - gemfibrozil is a CYP2C8 strong inhibitor, and it may increase exposure to CYP2C8 substrates
- Dasabuvir (Viekira Pak™) - DO NOT COMBINE. Gemfibrozil increases dasabuvir exposure.
- Enzalutamide (Xtandi®) - gemfibrozil increases enzalutamide exposure, raising the risk of seizures. The enzalutamide dose should be reduced when taken with gemfibrozil.
- Glitazones (pioglitazone, rosiglitazone, Actos®, Avandia®) - gemfibrozil increases pioglitazone and rosiglitazone exposure. The pioglitazone dose should not exceed 15 mg when taken with gemfibrozil.
- OATP1B1 substrates - gemfibrozil is an OATP1B1 inhibitor, and it may increase exposure to OATP1B1 substrates.
- Repaglinide (Prandin®) - DO NOT COMBINE. Gemfibrozil increases repaglinide exposure.
- Selexipag (Uptravi®) - DO NOT COMBINE. Gemfibrozil has been shown to double selexipag levels and increase exposure to its active metabolite 11-fold.
- Statins (Lipitor®, Zocor®, Crestor®, etc)
- Simvastatin: DO NOT COMBINE
- Rosuvastatin: Gemfibrozil should not be taken with rosuvastatin. If concomitant use cannot be avoided, rosuvastatin dosing should start at 5 mg once daily and not exceed 10 mg/day.
- Other statins: combining gemfibrozil with a statin increases the risk of muscle toxicity (rhabdomyolysis) and should generally be avoided. If a statin-fibrate combination is necessary, fenofibrates are preferred, as they have been used safely with statins several trials. [11,12]
- Metabolism and clearance
- Gemfibrozil (Lopid®)
- CYP2C8 - strong inhibitor
- CYP2C9 - inhibitor
- CYP2C19 - inhibitor
- CYP1A2 - inhibitor
- OATP1B1 - inhibitor
- UGT1A1 and 1A3 - inhibitor
- Fenofibrate (Antara®, Fenoglide®, Lipofen®, Lofibra®, Tricor®, Triglide®)
- CYP2C9 - mild-moderate inhibitor
- CYP2C8 - weak inhibitor
- CYP2C19 - weak inhibitor
- CYP2A6 - weak inhibitor
- Fenofibric acid (Trilipix®)
- LONG-TERM SAFETY
- Fibrates have been widely prescribed since the 1980s
- They have been found to be safe in long-term use [1,2,3]
- DOSING
- BIBLIOGRAPHY
- 1 - Fenofibrate PI
- 2 - PMID 16310551
- 3 - PMID 3313041
- 4 - PMID 20228404
- 5 - Gemfibrozil PI
- 6 - Fenofibrate PI
- 7 - Fenofibric acid PI
- 8 - PMID 15653014
- 9 - PMID 12485966
- 10 - PMID 10438259
- 11 - PMID 16310551
- 12 - PMID 20228404
- 13 - PMID 20462635
- 14 - PMID 22508733
- 15 - PMID 22473497
- 16 - PMID 12759298 - Gout study
- 17 - PMID 10413068 Hyperuricemia study
- 18 - PMID 29496472 - Effect of fenofibrate on uric acid and gout in type 2 diabetes: a post-hoc analysis of the randomised, controlled FIELD study, Lancet Diabetes Endocrinol (2018)
- 19 - PMID 24222016 - PMID 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, Circulation (2013)