The New England Journal of Medicine September 28, 2017

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

The HPS3/TIMI55–REVEAL Collaborative Group (Bowman L, Hopewell JC, Chen F, et al.)

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Bottom Line

In patients with atherosclerotic vascular disease receiving intensive statin therapy, the CETP inhibitor anacetrapib significantly but modestly reduced the risk of major coronary events compared to placebo, likely driven by reductions in non-HDL cholesterol.

Key Findings

1. At the trial midpoint, anacetrapib increased mean HDL cholesterol by 43 mg/dL (a 104% relative increase) and decreased mean non-HDL cholesterol by 17 mg/dL (an 18% relative decrease) compared to placebo.

2. The primary composite outcome (first major coronary event) occurred in 10.8% of the anacetrapib group versus 11.8% of the placebo group (rate ratio, 0.91; 95% CI, 0.85 to 0.97; P=0.004).

3. The clinical benefit was primarily driven by reductions in myocardial infarction (4.4% vs. 5.1%; P=0.007) and coronary revascularization (8.2% vs. 9.1%), with no significant difference in coronary death (2.5% vs. 2.8%; P=0.25).

4. There were no significant between-group differences in the risk of all-cause mortality or cancer.

5. The incidence of new-onset diabetes was marginally lower in the anacetrapib group compared to placebo (5.3% vs. 6.0%; P=0.05).

6. Anacetrapib was associated with small off-target effects, including a slight increase in systolic blood pressure (0.7 mmHg) and minor reductions in kidney function.

Study Design

Design

RCT

Double-Blind

Sample

30,449

Patients

Duration

4.1 yr

Median

Setting

Multinational

Population Adults aged >50 years with established atherosclerotic vascular disease (coronary, cerebrovascular, or peripheral arterial disease) who were receiving intensive atorvastatin therapy.

Intervention Anacetrapib 100 mg once daily

Comparator Matching placebo once daily

Outcome First major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization

Study Limitations

• The absolute risk reduction was very modest (1.0 percentage point difference over 4.1 years), resulting in a number needed to treat (NNT) of approximately 100.

• Anacetrapib accumulates extensively in adipose tissue, creating a long-terminal half-life that raised unresolvable concerns regarding long-term safety.

• The study did not evaluate whether the massive increase in HDL-C contributed any independent clinical benefit, although the magnitude of risk reduction aligned with the degree of non-HDL-C lowering.

• Due to the drug's limited clinical efficacy compared to its development cost and safety profile concerns, the manufacturer abandoned it, meaning the trial results could not directly translate into clinical practice.

Clinical Significance

The REVEAL trial was a landmark study because it was the first to demonstrate that a CETP inhibitor could successfully reduce major adverse cardiovascular events, breaking a string of failures by other drugs in its class (torcetrapib, dalcetrapib, evacetrapib). However, the trial simultaneously marked the end of the line for anacetrapib. The cardiovascular benefit (a 9% relative risk reduction) was deemed too small to justify regulatory approval, especially given the compound's profound accumulation in body fat. Consequently, the trial reinforced the 'LDL/non-HDL hypothesis' over the 'HDL hypothesis', suggesting that the marginal benefit observed was likely mediated by the drug's modest non-HDL cholesterol lowering rather than its massive HDL-raising effect.

Historical Context

Cholesteryl ester transfer protein (CETP) inhibitors were originally developed to dramatically raise HDL cholesterol ('good cholesterol') with the expectation that this would significantly reduce cardiovascular events. Early trials of CETP inhibitors were disastrous: torcetrapib increased mortality (ILLUMINATE, 2007), dalcetrapib lacked efficacy (dal-OUTCOMES, 2012), and evacetrapib was stopped early for futility (ACCELERATE, 2017). REVEAL, an enormous and lengthy trial, was the last major test for the class. While it uniquely achieved a statistically significant cardiovascular benefit, it ultimately confirmed that raising HDL via CETP inhibition is not a highly effective strategy for cardiovascular risk reduction in the modern statin era.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action of CETP inhibitors like anacetrapib, and why did the REVEAL trial suggest that its cardiovascular benefits were driven more by changes in non-HDL cholesterol rather than the massive increases in HDL cholesterol?

Key Response

This tests foundational knowledge of lipid metabolism. CETP transfers cholesteryl esters from HDL to VLDL/LDL in exchange for triglycerides. The REVEAL trial reinforced the modern paradigm that raising HDL pharmacologically does not reliably reduce cardiovascular events, whereas lowering atherogenic apoB-containing lipoproteins (non-HDL cholesterol) is the primary driver of risk reduction.

Resident

Resident

For a patient with atherosclerotic vascular disease already on high-intensity statin therapy, how does the magnitude of cardiovascular risk reduction seen with anacetrapib in the REVEAL trial compare to currently approved non-statin therapies like ezetimibe and PCSK9 inhibitors?

Key Response

Residents must contextualize trial data with standard-of-care. Anacetrapib demonstrated a modest 9% relative risk reduction (similar in magnitude to ezetimibe in IMPROVE-IT) but significantly less than the 15-20% relative risk reduction seen with PCSK9 inhibitors, highlighting why anacetrapib's clinical utility would be limited.

Fellow

Fellow

Previous CETP inhibitors such as torcetrapib, dalcetrapib, and evacetrapib failed to show cardiovascular benefit or caused harm. What pharmacological properties and trial design elements, specifically regarding follow-up duration, explain why anacetrapib succeeded in the REVEAL trial where evacetrapib failed?

Key Response

Fellows need to understand class effects versus drug-specific effects. Torcetrapib had off-target toxicity (aldosterone increase), and dalcetrapib only raised HDL without lowering LDL. Evacetrapib lowered LDL but its trial was terminated early for futility; REVEAL succeeded largely because its extended median follow-up (4.1 years) allowed time for the delayed separation of event curves characteristic of lipid-lowering therapies.

Attending

Attending

Despite the REVEAL trial meeting its primary efficacy endpoint, the manufacturer decided not to seek regulatory approval for anacetrapib. What does this teach us about the modern threshold for clinical meaningfulness versus statistical significance in cardiovascular outcome trials?

Key Response

Focuses on high-level clinical decision-making and pharmacology. A statistically significant but clinically modest benefit (approx 1% absolute risk reduction), combined with the drug's concerning pharmacokinetic profile (massive accumulation in adipose tissue with a multi-year half-life), did not justify commercialization, reminding clinicians that not all 'positive' trials yield viable drugs.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

PhD

The REVEAL trial demonstrated a delayed separation of the Kaplan-Meier event curves, with benefits only apparent after the first year. How does this finding align with Mendelian randomization studies of CETP variants, and what are the implications for designing future lipid-lowering trials?

Key Response

Tests deep methodological knowledge. Mendelian randomization shows lifetime exposure to lower non-HDL via CETP variants reduces CV risk. The delayed curve separation in REVEAL illustrates that pharmacological lipid lowering requires time (often >1-2 years) to translate into plaque stabilization, emphasizing that outcome trials must have sufficiently long follow-up to avoid false-negative results.

Journal Editor

Journal Editor

Given anacetrapib's extremely long terminal half-life and significant accumulation in adipose tissue, how does this unique pharmacokinetic profile complicate the interpretation of safety data and the assessment of long-term validity in the REVEAL trial?

Key Response

A critical peer reviewer would flag that while in-trial safety was acceptable, a drug with a half-life of several years presents a latent threat for delayed adverse events. Standard trial durations and conventional post-market surveillance are poorly equipped to capture safety signals that might emerge years after drug discontinuation.

Guideline Committee

Guideline Committee

If anacetrapib had been brought to market, how would its data from the REVEAL trial dictate its positioning within the 2018 AHA/ACC Multi-Society Guideline on the Management of Blood Cholesterol, particularly concerning the hierarchy of non-statin therapies?

Key Response

The 2018 guidelines strongly prioritize ezetimibe (Class I) and PCSK9 inhibitors (Class IIa) as add-on therapies for secondary prevention. Due to anacetrapib's modest absolute benefit, lack of long-term safety data regarding adipose accumulation, and delayed onset of benefit, a guideline committee would likely have relegated it to a weak Class IIb recommendation, reserved only for patients intolerant to all other proven non-statin therapies.

Clinical Landscape

Noteworthy Related Trials

2007

ILLUMINATE Trial

n = 15,067 · NEJM

Tested

Torcetrapib plus Atorvastatin

Population

Patients with high cardiovascular risk

Comparator

Placebo plus Atorvastatin

Endpoint

Time to first major cardiovascular event

Key result: Torcetrapib resulted in an increased risk of mortality and cardiovascular events despite raising HDL cholesterol and lowering LDL cholesterol.

2012

dal-OUTCOMES Trial

n = 15,871 · NEJM

Tested

Dalcetrapib 600mg daily

Population

Patients with recent acute coronary syndrome

Comparator

Placebo

Endpoint

Composite of CHD death, nonfatal MI, ischemic stroke, unstable angina, or cardiac arrest

Key result: Dalcetrapib significantly increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events.

2017

ACCELERATE Trial

n = 12,092 · NEJM

Tested

Evacetrapib 130mg daily

Population

Patients with high-risk vascular disease

Comparator

Placebo

Endpoint

Composite of cardiovascular death, MI, stroke, coronary revascularization, or hospitalization for unstable angina

Key result: Evacetrapib had no significant effect on the rate of major cardiovascular events despite profoundly lowering LDL cholesterol and raising HDL cholesterol.

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