What is the use of Lopid (gemfibrozil) in treating hyperlipidemia?

Lopid (Gemfibrozil) in Treating Hyperlipidemia

Primary FDA-Approved Indications

Gemfibrozil (Lopid) is FDA-approved for two specific clinical scenarios: severe hypertriglyceridemia (Types IV and V hyperlipidemia) with triglycerides typically >2000 mg/dL to prevent pancreatitis, and reducing coronary heart disease risk in Type IIb patients without existing coronary disease who have the triad of low HDL-C, elevated LDL-C, and elevated triglycerides after failing other therapies. 1

Severe Hypertriglyceridemia (Primary Indication)

• Gemfibrozil is indicated as adjunctive therapy to diet for adult patients with very high serum triglyceride elevations (Types IV and V hyperlipidemia) who present a risk of pancreatitis and do not respond adequately to dietary control 1
• Patients who typically benefit have serum triglycerides over 2000 mg/dL with elevations of VLDL-cholesterol and fasting chylomicrons (Type V hyperlipidemia) 1
• Subjects with total serum triglycerides consistently below 1000 mg/dL are unlikely to present pancreatitis risk 1
• Gemfibrozil therapy may be considered for patients with triglyceride elevations between 1000-2000 mg/dL who have a history of pancreatitis or recurrent abdominal pain typical of pancreatitis 1
• Drug therapy is NOT indicated for Type I hyperlipoproteinemia patients who have elevated chylomicrons and plasma triglycerides but normal VLDL levels 1

Coronary Heart Disease Risk Reduction (Secondary Indication)

• Gemfibrozil reduces the risk of developing coronary heart disease ONLY in Type IIb patients without history or symptoms of existing coronary disease 1
• These patients must have had inadequate response to weight loss, dietary therapy, exercise, and other pharmacologic agents (bile acid sequestrants and nicotinic acid) 1
• Patients must have the specific triad: low HDL-cholesterol (consistently below 35 mg/dL) PLUS elevated LDL-cholesterol PLUS elevated triglycerides 1

Mechanism of Action and Lipid Effects

• Gemfibrozil decreases serum triglycerides and VLDL cholesterol while increasing HDL cholesterol 1
• The drug inhibits peripheral lipolysis and decreases hepatic extraction of free fatty acids, reducing hepatic triglyceride production 1
• Gemfibrozil inhibits synthesis and increases clearance of VLDL carrier apolipoprotein B, leading to decreased VLDL production 1
• Triglycerides may be reduced by as much as 74% in some patients 2
• In Type V hyperlipidemia, gemfibrozil produced a 74% reduction in total plasma triglycerides (21.03 vs 5.50 mmol/L compared to placebo) and virtually abolished chylomicronemia 3

Important Lipid Response Patterns

• While modest decreases in total and LDL cholesterol may occur, treatment of Type IV hyperlipoproteinemia patients often results in a RISE in LDL-cholesterol 1
• In Type IIb patients with elevations of both LDL-cholesterol and triglycerides, LDL-cholesterol levels are generally minimally affected, but gemfibrozil usually raises HDL-cholesterol significantly 1
• Gemfibrozil increases HDL subfractions HDL2 and HDL3, as well as apolipoproteins AI and AII 1
• In patients with significantly elevated triglycerides, gemfibrozil treatment is associated with a significant increase in LDL-cholesterol in some cases 1

Clinical Trial Evidence: Helsinki Heart Study

• The primary prevention component studied 4081 male patients aged 40-55 with serum non-HDL-cholesterol over 200 mg/dL and no previous coronary heart disease 1
• Over five years, the gemfibrozil group experienced a 1.4% absolute (34% relative) reduction in serious coronary events (sudden cardiac deaths plus fatal and nonfatal myocardial infarctions) compared to placebo, p=0.04 1
• There was a 37% relative reduction in nonfatal myocardial infarction, equivalent to 13.1 events per thousand persons 1
• Deaths from any cause totaled 44 (2.2%) in the gemfibrozil group and 43 (2.1%) in the placebo group 1

Type IIb Subgroup Benefit

• The greatest reduction in serious coronary events occurred in Type IIb patients with elevations of both LDL-cholesterol and total plasma triglycerides 1
• Type IIb patients had 26 fewer coronary events per thousand persons over five years with gemfibrozil compared to placebo 1
• The difference in coronary events was substantially greater for patients with the triad of LDL-cholesterol >175 mg/dL, triglycerides >200 mg/dL, and low HDL-cholesterol 1
• The mean increase in HDL-cholesterol among Type IIb patients was 12.6% compared to placebo 1

Critical Contraindications and Warnings

Lack of Benefit in Secondary Prevention

The secondary prevention component of the Helsinki Heart Study showed NO BENEFIT from gemfibrozil in 628 middle-aged males with known coronary disease—the hazard ratio for cardiac events was 1.47 (95% CI 0.88-2.48, p=0.14), and there were 17 cardiac deaths in the gemfibrozil group versus 8 in placebo (hazard ratio 2.18, p=0.06). 1

• Gemfibrozil has shown benefit ONLY in selected dyslipidemic patients WITHOUT suspected or established coronary heart disease 1
• No efficacy in patients with established coronary disease was observed during the Coronary Drug Project with the chemically related drug clofibrate 1

Major Safety Concerns from FDA Label

• BECAUSE OF POTENTIAL TOXICITY INCLUDING MALIGNANCY, GALLBLADDER DISEASE, ABDOMINAL PAIN LEADING TO APPENDECTOMY AND OTHER ABDOMINAL SURGERIES, AN INCREASED INCIDENCE IN NON-CORONARY MORTALITY, AND THE 44% RELATIVE INCREASE IN AGE-ADJUSTED ALL-CAUSE MORTALITY SEEN WITH CLOFIBRATE, THE POTENTIAL BENEFIT OF GEMFIBROZIL IN TREATING TYPE IIA PATIENTS WITH ELEVATIONS OF LDL-CHOLESTEROL ONLY IS NOT LIKELY TO OUTWEIGH THE RISKS 1
• Gemfibrozil is NOT indicated for treatment of patients with low HDL-cholesterol as their only lipid abnormality 1
• In patients with above-median HDL-cholesterol values at baseline (>46.4 mg/dL), the incidence of serious coronary events was similar for gemfibrozil and placebo 1

Combination with Statins: Critical Safety Issue

• The 2002 ACC/AHA/NHLBI Clinical Advisory specifically warned that rhabdomyolysis was reported most frequently when cerivastatin was used in combination with gemfibrozil, contributing to cerivastatin's market withdrawal 4
• Gemfibrozil should be avoided in diabetic patients and when combining with statins due to increased myopathy risk 4
• Fenofibrate has a better safety profile than gemfibrozil when combined with statins 4
• Gemfibrozil is contraindicated with lovastatin, pravastatin, and simvastatin 5
• When combining fibrates with statins, fenofibrate is strongly preferred over gemfibrozil due to significantly lower rhabdomyolysis risk—approximately 15 times lower (0.58 vs 8.6 cases per million prescriptions) 5

Current Clinical Context: Gemfibrozil vs. Modern Alternatives

Why Gemfibrozil Use Has Declined

• The use of gemfibrozil has decreased over the years, with muscle-associated adverse effects being the predominant and most clinically relevant reason 2
• The 2008 ADA guidelines noted that gemfibrozil decreased CVD events in non-diabetic subjects, but fenofibrate failed to reduce overall cardiovascular outcomes in diabetic patients 4
• Gemfibrozil inhibits statin glucuronidation, creating dangerous drug interactions that fenofibrate does not 5

When Gemfibrozil Might Still Be Considered

• Despite safety concerns, there are situations where gemfibrozil in combination with a statin may be necessary 2
• Understanding the metabolism of gemfibrozil and the degree of interaction with various statins will assist providers to optimize safety when this combination is clinically indicated 2
• For severe hypertriglyceridemia to reduce pancreatitis risk, gemfibrozil monotherapy remains appropriate, though evidence is limited 6

Pharmacokinetics and Dosing Considerations

• Gemfibrozil is well absorbed from the gastrointestinal tract with peak plasma levels occurring in 1-2 hours and a plasma half-life of 1.5 hours following multiple doses 1
• Both rate and extent of absorption are significantly increased when administered 0.5 hour before meals 1
• Average AUC was reduced by 14-44% when gemfibrozil was administered after meals compared to 0.5 hour before meals 1
• Approximately 70% of the administered dose is excreted in urine, mostly as glucuronide conjugate, with less than 2% excreted as unchanged gemfibrozil 1
• Gemfibrozil is highly bound to plasma proteins with potential for displacement interactions with other drugs 1

Comparative Efficacy: Historical Perspective

• In comparative studies with clofibrate, similar reductions in plasma lipid levels were observed, though changes tend to be more favorable overall with gemfibrozil 7
• Gastrointestinal symptoms and rash are the only side effects produced more frequently with gemfibrozil than placebo 7
• Although gemfibrozil is hepatotoxic in male rats, drug-induced pathological liver changes have not been reported in humans 7
• A once-daily extended-release formulation showed comparable improvements to twice-daily dosing: mean percent changes in triglycerides, HDL-C, and LDL-C were -32%, +10%, and -10% for extended release versus -36%, +11%, and -10% for twice daily 8

Bottom Line: Modern Clinical Role

In contemporary practice, gemfibrozil has been largely superseded by fenofibrate for most indications due to superior safety profile when combined with statins, which are the cornerstone of cardiovascular risk reduction. 5, 6 Gemfibrozil retains a role only in severe hypertriglyceridemia (>1000-2000 mg/dL) as monotherapy to prevent pancreatitis when fenofibrate is unavailable or contraindicated, and should be avoided in patients requiring statin therapy due to unacceptable myopathy risk. 4, 5, 2