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Gemfibrozil for the Secondary Prevention of Coronary Heart Disease in Men with Low Levels of High-Density Lipoprotein Cholesterol
Open accessAbstract
BACKGROUND: Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary heart disease is beneficial, there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein (HDL) cholesterol. METHODS: We conducted a double-blind trial comparing gemfibrozil (1200 mg per day) with placebo in 2531 men with coronary heart disease, an HDL cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or less, and an LDL cholesterol level of 140 mg per deciliter (3.6 mmol per liter) or less. The primary study outcome was nonfatal myocardial infarction or death from coronary causes. RESULTS: The median follow-up was 5.1 years. At one year, the mean HDL cholesterol level was 6 percent higher, the mean triglyceride level was 31 percent lower, and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group. LDL cholesterol levels did not differ significantly between the groups. A primary event occurred in 275 of the 1267 patients assigned to placebo (21.7 percent) and in 219 of the 1264 patients assigned to gemfibrozil (17.3 percent). The overall reduction in the risk of an event was 4.4 percentage points, and the reduction in relative risk was 22 percent (95 percent confidence interval, 7 to 35 percent; P=0.006). We observed a 24 percent reduction in the combined outcome of death from coronary heart disease, nonfatal myocardial infarction, and stroke (P< 0.001). There were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer. CONCLUSIONS: 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.
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“However, the mean reduction in plasma triglyceride concentration in the fibrate trials was only 20 mg/dL to 50 mg/dL, a fraction of what would be needed to significantly reduce the risk of major vascular events within a shortterm trial.”
From Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease (2019) · cites this paper as [30]
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Experimental — accuracy not yet measuredThe cited source doesn’t support the claim as written.
In the citing paper
“Treatment with gemfibrozil versus placebo reduced the primary endpoint of death or nonfatal MI by 32% (P = 0.004), mortality by 41% (P = 0.02), and stroke by 40% (P = 0.046).”
From 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia (2021) · cites this paper as [33]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Evidence supporting the prescription of fibrates for cardiovascular prevention remains debated.”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [93]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Fibrates decrease triglyceride levels by 30 -50% and sometimes increase HDL cholesterol (165-168).”
From Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline (2012) · cites this paper as [166]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“A sub study was conducted on patients with diabetes participating in the VA-HIT Trial (n=627) compared to those without diabetes (n=142). Following 5 years of treatment with gemfibrozil the investigators observed an average reduction of TG levels by 31% and a corresponding increase in HDLC of 6%. More importantly, these changes were associated with a, statistically significant 22% reduction in”
From Fenofibrate and metabolic syndrome (2010) · cites this paper as [72]
Experimental — accuracy not yet measured
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In the citing paper
“Clinical and epidemiological studies have demonstrated that triglyceride (TG) elevation is an independent risk factor for increased cardiovascular (CV) events”
From Rationale and design of REDUCE‐IT : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Epidemiological, biological, and genetic studies have provided robust evidence of a strong association between elevated TG levels and higher rates of CV events.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11”
From Rationale and design of REDUCE‐IT : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [7]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Previous fibrate studies in subjects with diabetes10,11 or in those without diabetes13–15 did not address the role of such drugs in patients receiving statin therapy.”
From Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus (2010) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“The ACCORD, LEADER and VA-COOP trials could not confirm that fibrates reduce the incidence of MACE at a 5% significance level, whilst a significant MACE reduction was observed in the FIELD and VA-HIT trials [91–94].”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [93]
The cited source says what the claim attributes to it.
In the citing paper
“Studies to date have not demonstrated an overall benefit of fibrates for reduction of cardiovascular or total mortality (165-169).”
From Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline (2012) · cites this paper as [166]
The cited source says what the claim attributes to it.
In the citing paper
“For example, the VA-HIT Trial, with a total of 2,531 men with a history of CHD who had low HDLC levels (mean, 32 mg/dl) and low LDLC levels (mean, 111 mg/dl), assigned subjects to receive either 1,200 mg/day of gemfibrozil or placebo. After a 5 year follow-up, treatment with gemfibrozil resulted in a significant 22% reduction in the combined incidence of nonfatal myocardial infarction (MI) and CHD”
From Fenofibrate and metabolic syndrome (2010) · cites this paper as [72]
The cited source says what the claim attributes to it.
In the citing paper
“However, randomized data from large outcome studies across broad populations regarding pharmacological TG lowering and effect on CV outcomes have been mixed (Table 4).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24”
From Rationale and design of REDUCE‐IT : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, TG reduction lowers several inflammatory markers associated with CV risk, and subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG‐lowering therapy.3, 4, 5, 6, 7, 8, 9, 10, 11”
From Rationale and design of REDUCE‐IT : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“Again, there was no significant difference in allcause mortality”
From The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk (2019) · cites this paper as [136]
The cited source says what the claim attributes to it.
In the citing paper
“The results of this study may also help to explain why prior randomized trials evaluating fibrates, which lower plasma triglyceride levels at least partially through the LPL pathway, have failed to consistently demonstrate that lowering triglyceride levels reduces the risk of cardiovascular events.[29][30][31][32][33]”
From Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease (2019) · cites this paper as [30]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Furthermore, TG reduction lowers several inflammatory markers associated with CV risk, and subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG‐lowering therapy.3, 4, 5, 6, 7, 8, 9, 10, 11”
From Rationale and design of REDUCE‐IT : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [7]
Experimental — accuracy not yet measuredIn the citing paper
“Additionally, qualitative changes in LDL cholesterol may be present in the form of small, dense LDL particles which are more atherogenic and may be associated with higher risk of CVD [58-60].”
From The case for low carbohydrate diets in diabetes management (2005) · cites this paper as [60]
In the citing paper
“As monotherapy, fibrates likely reduce ASCVD risk.43–45”
From Clinical review on triglycerides (2020) · cites this paper as [45]
In the citing paper
“In the Helsinki Heart Study (HHS) [4] and the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) [5], administration of gemfibrozil significantly reduced CV event rate, the primary endpoints of the trials.”
From Pemafibrate, a new selective PPARα modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases (2020) · cites this paper as [5]
In the citing paper
“In some studies, an increase of patient-reported neurocognitive effects has been described [293].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [293]
In the citing paper
“However, the data on other outcome parameters have remained equivocal.”
From ESC/EAS Guidelines for the management of dyslipidaemias (2011) · cites this paper as [125]
In the citing paper
“The data from these trials have shown consistent decreases in the rates of non-fatal MI (although often as a result of post-hoc analyses), the effect being most robust in subjects with elevated TG/low HDL-C levels.”
From ESC/EAS Guidelines for the management of dyslipidaemias (2011) · cites this paper as [125]
In the citing paper
“The clinical benefits of fibrates in monotherapy are primarily illustrated by four prospective, randomized, placebo-controlled, clinical trials: Helsinki Heart Study (HHS), Veterans Affairs Highdensity lipoprotein Intervention Trial (VA-HIT), Bezafibrate Infarction Prevention study (BIP), and FIELD.124 -127”
From ESC/EAS Guidelines for the management of dyslipidaemias (2011) · cites this paper as [125]
In the citing paper
“Although the Helsinki Heart Study reported a significant reduction in CVD outcomes with gemfibrozil, neither the FIELD nor the ACCORD study showed a reduction in total CVD outcomes.”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [266]
In the citing paper
“The results of ESTABLISH642), JAPAN-ACS643), the ZEUS study644), and PRECISE-IVUS645) have shown that in cases stratified into a high-risk category even in secondary prevention, such as ACS or ACS complicated by DM, controlling the LDL-C at a target level of < 70 mg/dL is useful for plaque regression.”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [645]
In the citing paper
“It was reported in the recent PRECISE-IVUS study that decreasing the LDL-C level to < 70 mg/dL using a combination of statin and ezetimibe resulted in a marked plaque volume regression in patients with ACS, compared to those who were treated with statins only645).”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [645]
In the citing paper
“Gemfibrozil has been shown to decrease rates of CVD events in subjects without diabetes (195,196) and in the diabetic subgroup in one of the larger trials (195).”
From Standards of Medical Care in Diabetes—2009 (2009) · cites this paper as [195]
In the citing paper
“However, additional adjustment for HDL-C and the ratio of apo B to apo AI decreased the predictive ability of on-treatment triglyceride levels, and further adjustment for baseline glucose, BMI, hypertension, T2DM, and smoking eliminated the association.501”
From Triglycerides and Cardiovascular Disease: A Scientific Statement From the American Heart Association (2011) · cites this paper as [501]
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Metadata
- Authors
- Rubins, H. B., Robins, S. J., Collins, D., Fye, C. L., Anderson, J. W., Elam, M. B., Faas, F. H., Linares, E., Schaefer, E. J., Schectman, G., Wilt, T. J., & Wittes, J.
- Affiliations
- Boston University (US)
- West Haven Cooperative Studies Program Coordinating Center (US)
- Veterans Health Administration (US)
- Memphis VA Medical Center (US)
- Tufts University (US)
- Minneapolis VA Medical Center (US)
- Statistics Collaborative (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 1999-08-05
- Volume
- 341
- Issue
- 6
- Pages
- 410-418
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2328529137
- Semantic Scholar
- c59834b2e2f45268e79b64cd3316445882b86f66
- Cited by
- 3,439
- References
- 40
- Citations by year
- 2026: 22 · 2025: 29 · 2024: 38 · 2023: 52 · 2022: 41 · 2021: 44 · 2020: 46 · 2019: 56 · 2018: 54 · 2017: 62 · 2016: 69 · 2015: 80 · 2014: 93 · 2013: 129 · 2012: 114
- FWCI
- 242.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Keywords
- gemfibrozil, secondary prevention, coronary artery disease, low HDL cholesterol, HDL cholesterol, triglycerides, LDL cholesterol, nonfatal myocardial infarction, coronary heart disease mortality, stroke, fibrates, men
- MeSH terms
- Aged, Hypolipidemic Agents, Coronary Disease, Double-Blind Method, Follow-Up Studies, Humans, Hypolipoproteinemias, Cholesterol, HDL, Cholesterol, LDL, Male, Middle Aged, Myocardial Infarction, Risk, Triglycerides, Gemfibrozil, Incidence, Proportional Hazards Models
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