The Lancet NOVEMBER 26, 2005

Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial

Anthony C. Keech, Russell J. Scott, John Simes, et al. (The FIELD Study Investigators)

Bottom Line

The FIELD study found that while long-term fenofibrate therapy in patients with type 2 diabetes significantly reduced total cardiovascular events, it did not significantly reduce the primary composite outcome of coronary heart disease death or nonfatal myocardial infarction.

Key Findings

1. The primary outcome (coronary heart disease death or nonfatal myocardial infarction) was reduced by 11% in the fenofibrate group compared to placebo, but this result did not reach statistical significance (hazard ratio 0.89, 95% CI 0.75–1.05; P=0.16).

2. Fenofibrate therapy produced a statistically significant 11% reduction in total cardiovascular events (hazard ratio 0.89, 95% CI 0.80–0.99; P=0.035).

3. There was a significant 21% reduction in coronary revascularization procedures (P=0.003) and a significant 24% reduction in nonfatal myocardial infarctions (P=0.01), although these benefits were partially offset by a nonsignificant increase in coronary heart disease mortality.

4. A subgroup analysis in patients with metabolic syndrome, particularly those with marked dyslipidemia (triglycerides ≥2.3 mmol/l and low HDL cholesterol), showed a 27% relative risk reduction in cardiovascular events (P=0.005), suggesting targeted benefits for these high-risk profiles.

Study Design

Design

RCT

Double-Blind

Sample

9,795

Patients

Duration

5 yr

Median

Setting

Multicenter, international

Population Men and women aged 50–75 years with type 2 diabetes and total cholesterol levels between 3.0-6.5 mmol/L (if triglycerides 1.0-5.0 mmol/L) or 3.0-5.0 mmol/L (if triglycerides <1.0 mmol/L).

Intervention Oral fenofibrate 200 mg (micronized) daily

Comparator Matching placebo

Outcome Composite of coronary heart disease death or nonfatal myocardial infarction

Study Limitations

• The primary endpoint of major coronary events was not met, and the observed non-significant increase in coronary heart disease mortality complicates the interpretation of overall coronary benefit.

• The study was impacted by a high 'drop-in' rate of statin therapy, which was more frequent in the placebo group (17%) than the fenofibrate group (8%), potentially masking the true therapeutic effect of fenofibrate.

• The trial population included a mix of primary and secondary prevention, and the inconsistent effects across these subgroups limit the ability to generalize the findings to all type 2 diabetes patients.

• The increase in coronary deaths was not linked to any specific identifiable mechanism and may be due to chance, but it prevents definitive claims regarding mortality benefits.

Clinical Significance

The FIELD study suggests that while fenofibrate is not a universal cardiovascular protective agent in type 2 diabetes, it may offer specific clinical benefits—particularly in reducing coronary revascularization and events—for patients presenting with the classic 'atherogenic dyslipidemia' phenotype (high triglycerides and low HDL). However, it does not support fenofibrate as a routine substitute for statin-based cardiovascular prevention in this population.

Historical Context

The FIELD study was one of the largest and most influential randomized controlled trials designed to assess whether the lipid-modifying effects of fibrates (specifically PPAR-alpha agonists) could translate into hard cardiovascular outcomes in a large cohort of patients with type 2 diabetes, a population historically at high risk for vascular complications.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the primary molecular mechanism by which fenofibrate regulates lipid levels in patients with type 2 diabetes?

Key Response

Fenofibrate is a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist. Activation of PPAR-alpha increases the expression of lipoprotein lipase (LPL) and apolipoproteins A-I and A-II, while decreasing apolipoprotein C-III. This leads to a significant reduction in plasma triglycerides and a modest increase in HDL cholesterol.

Resident

Given the results of the FIELD study, why might a clinician still consider fenofibrate for a patient with type 2 diabetes and dyslipidemia who is already on a statin?

Key Response

While the primary composite endpoint for macrovascular events was non-significant, FIELD (and later ACCORD) suggested that fenofibrate significantly reduces microvascular complications, particularly the progression of diabetic retinopathy and the need for laser therapy. Furthermore, subgroup analyses indicate that patients with 'atherogenic dyslipidemia' (high triglycerides and low HDL) derive the greatest cardiovascular benefit.

Fellow

The FIELD study observed a rise in serum creatinine and homocysteine levels in the fenofibrate group. How should these laboratory changes be interpreted regarding renal function and cardiovascular risk?

Key Response

Fenofibrate characteristically causes a reversible increase in serum creatinine that is not typically associated with a decrease in the actual glomerular filtration rate (GFR), but rather changes in creatinine production or tubular secretion. The rise in homocysteine was also observed, but it did not appear to negate the overall reduction in total cardiovascular events seen in secondary endpoints.

Attending

To what extent did the 'statin drop-in' phenomenon in the FIELD study likely influence the trial's failure to reach significance for its primary macrovascular endpoint?

Key Response

During the trial, more patients in the placebo group (17%) were started on statins by their primary physicians compared to the fenofibrate group (8%). This 'drop-in' therapy reduced the LDL-cholesterol gap between the two arms, potentially diluting the treatment effect of fenofibrate and biasing the results toward the null for the primary endpoint of CHD death and nonfatal MI.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the use of a composite primary endpoint in the FIELD study in the context of its statistical power and the observed results for individual components.

Key Response

The primary endpoint combined CHD death and nonfatal MI. While nonfatal MI showed a significant reduction, the lack of effect on CHD death (and a non-significant trend toward an increase) resulted in a non-significant composite. This highlights the risk of combining endpoints with potentially different biological responses to a specific pharmacological mechanism, which can mask benefit if the components move in opposite directions.

Journal Editor

How should the manuscript's reporting of the 'significant reduction in total cardiovascular events' be handled when the primary endpoint failed to reach statistical significance?

Key Response

As a reviewer, one must ensure the authors do not 'spin' the results. Because the primary endpoint was non-significant (p=0.16), all subsequent secondary analyses are technically exploratory or hypothesis-generating due to the hierarchical nature of statistical testing. The editor should insist that the failure of the primary endpoint is prominently featured in the abstract and conclusion.

Guideline Committee

How do the FIELD study results compare to current ADA and AHA/ACC guidelines regarding the use of fibrates for cardiovascular risk reduction in type 2 diabetes?

Key Response

Current guidelines (e.g., ADA Standards of Care) prioritize statins (Level A) for macrovascular risk reduction. Based on FIELD and ACCORD Lipid, fibrates are not recommended as first-line therapy for macrovascular prevention but may be considered for microvascular benefits—specifically for slowing retinopathy progression (Level B)—or for patients with severe hypertriglyceridemia (TG >500 mg/dL) to prevent pancreatitis.

Clinical Landscape

Noteworthy Related Trials

2001

BIP Study

n = 3,090 · Circulation

Tested

Bezafibrate

Population

Patients with coronary artery disease

Comparator

Placebo

Endpoint

Incidence of myocardial infarction or sudden death

Key result: Bezafibrate did not significantly reduce the primary endpoint in the overall study population, although some subgroup benefits were noted.

2010

ACCORD-Lipid Trial

n = 5,518 · NEJM

Tested

Fenofibrate plus Simvastatin

Population

T2DM patients already treated with Simvastatin

Comparator

Simvastatin plus Placebo

Endpoint

First occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death

Key result: The addition of fenofibrate to statin therapy did not significantly reduce the rate of major cardiovascular events in patients with type 2 diabetes.

2013

HPS2-THRIVE Trial

n = 25,673 · NEJM

Tested

Extended-release niacin/laropiprant

Population

High-risk patients with pre-existing cardiovascular disease

Comparator

Placebo

Endpoint

Major vascular events

Key result: Addition of niacin/laropiprant to statin therapy failed to significantly reduce the risk of major vascular events and increased the risk of serious side effects.

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