New England Journal of Medicine July 17, 2014

Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients (HPS2-THRIVE)

HPS2-THRIVE Collaborative Group

Bottom Line

In high-risk patients with atherosclerotic vascular disease already receiving statin-based therapy, the addition of extended-release niacin with laropiprant did not reduce the risk of major vascular events but significantly increased the risk of serious adverse events.

Key Findings

1. Assignment to niacin-laropiprant compared with placebo had no significant effect on the incidence of the primary outcome of major vascular events (13.2% vs. 13.7%; rate ratio [RR] 0.96; 95% CI 0.90-1.03; P=0.29).

2. During a median follow-up of 3.9 years, the intervention successfully lowered LDL cholesterol by an average of 10 mg/dL and raised HDL cholesterol by an average of 6 mg/dL compared to placebo, but this did not translate to clinical benefit.

3. Niacin-laropiprant significantly increased the incidence of serious disturbances in diabetes control compared to placebo (absolute excess, 3.7 percentage points; P<0.001) and new diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001).

4. The treatment was associated with unexpected and significant increases in severe adverse events, including infections (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001).

5. Other serious adverse events significantly elevated in the niacin-laropiprant group included gastrointestinal (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal (absolute excess, 0.7 percentage points; P<0.001), and skin-related issues (absolute excess, 0.3 percentage points; P=0.003).

Study Design

Design

RCT

Double-Blind

Sample

25,673

Patients

Duration

3.9 yr

Median

Setting

Multicenter, Global

Population Adults 50 to 80 years of age with clinically manifest atherosclerotic vascular disease (coronary, cerebrovascular, or peripheral).

Intervention 2 g of extended-release niacin and 40 mg of laropiprant daily.

Comparator Matching placebo daily.

Outcome First major vascular event (composite of nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization).

Study Limitations

• The study used a specific combination of niacin and laropiprant (an anti-flushing agent), making it difficult to definitively isolate whether some of the unexpected adverse events (such as bleeding and infections) were driven by niacin itself or by the prostaglandin receptor antagonist laropiprant.

• The trial employed an active prerandomization run-in phase where patients intolerant to the study drug were excluded; this means the high rate of adverse events observed likely underestimates the true rate of intolerance in the general population.

• Patients enrolled already had well-controlled LDL cholesterol on statins (baseline mean of 63 mg/dL), potentially minimizing the absolute risk reduction that could be achieved via further lipid modification.

Clinical Significance

HPS2-THRIVE definitively demonstrated that adding extended-release niacin to effective statin therapy in high-risk patients provides no cardiovascular benefit while causing substantial harm. Alongside the AIM-HIGH trial, it effectively ended the routine clinical practice of prescribing niacin to raise HDL cholesterol for cardiovascular risk reduction and dealt a major blow to the 'HDL hypothesis'.

Historical Context

For decades, niacin was a cornerstone of lipid-lowering therapy due to its potent ability to raise HDL cholesterol and lower triglycerides. However, the 'HDL hypothesis' (the idea that pharmacologically raising HDL causally reduces cardiovascular events) was increasingly questioned following the failure of torcetrapib. HPS2-THRIVE was launched to provide a definitive, massive-scale answer, utilizing laropiprant to mitigate niacin's notorious flushing side effect. The profoundly negative results, revealing previously unrecognized severe safety signals, prompted the global withdrawal of the niacin-laropiprant combination (Tredaptive) and drastically altered lipid management guidelines.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism by which niacin improves the lipid profile, and what is the specific role of laropiprant in this combination therapy evaluated in the HPS2-THRIVE trial?

Key Response

Niacin inhibits lipolysis in adipose tissue, reducing the flux of free fatty acids to the liver, which decreases hepatic VLDL synthesis and subsequently lowers LDL and triglycerides while raising HDL. Laropiprant is a selective prostaglandin D2 receptor 1 (DP1) antagonist; it specifically blocks the prostaglandin-mediated vasodilation pathway responsible for the cutaneous flushing that typically limits patient tolerance to high-dose niacin therapy.

Resident

A 65-year-old patient with coronary artery disease on optimal high-intensity statin therapy notes their HDL is 32 mg/dL and asks to start niacin to raise their 'good cholesterol'. Based on the findings of the HPS2-THRIVE trial, how would you counsel this patient regarding efficacy and safety?

Key Response

You should counsel against adding niacin. The HPS2-THRIVE trial demonstrated that adding niacin-laropiprant to optimal statin therapy provides no incremental cardiovascular benefit (no reduction in major vascular events). Furthermore, it significantly increases the risk of severe adverse effects, including new-onset diabetes, myopathy, gastrointestinal bleeding, and infections. Therefore, targeting HDL numbers with niacin in statin-treated patients is clinically inappropriate and potentially harmful.

Fellow

The HPS2-THRIVE trial revealed an unexpected increase in non-cardiovascular serious adverse events, including bleeding and severe infections. What pathophysiologic mechanisms might explain these off-target toxicities, and how do these findings collectively impact the validity of the 'HDL hypothesis'?

Key Response

The increased bleeding risk may be linked to laropiprant's antagonism of prostaglandin pathways, which can interfere with normal platelet function. The increased infection rate is less clear but may relate to niacin's metabolic disruptions (such as worsening glycemic control) or unknown immunomodulatory effects of DP1 antagonism. Alongside AIM-HIGH and CETP inhibitor trials, these findings effectively dismantled the 'HDL hypothesis,' proving that therapeutically raising HDL does not intrinsically confer cardiovascular protection and can introduce pleiotropic harms.

Attending

HPS2-THRIVE precipitated a paradigm shift in lipidology, essentially ending the routine use of niacin. As an attending teaching clinical reasoning to residents, how do you use this trial to illustrate the danger of treating surrogate markers instead of focusing on hard clinical outcomes?

Key Response

This trial serves as a classic teaching example of the 'surrogate endpoint fallacy.' Niacin predictably and favorably alters the lipid panel by raising HDL and lowering triglycerides, which observational data suggests should improve outcomes. However, HPS2-THRIVE proves that correcting a physiologic number on paper does not guarantee clinical benefit and can actually induce harm. It emphasizes to trainees that evidence-based medicine must rely on randomized trials powered for hard clinical endpoints rather than biologic plausibility alone.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The HPS2-THRIVE study design incorporated an active run-in phase where patients who experienced unacceptable side effects to the niacin-laropiprant combination were excluded prior to randomization. What specific bias does this design choice introduce when evaluating the drug's safety profile and tolerability?

Key Response

An active run-in phase creates an 'enriched' population of patients who are already known to tolerate the drug. This systematic exclusion of early non-responders or those susceptible to immediate side effects (like severe flushing or GI distress) leads to an underestimation of the true incidence of adverse events in the general population. Consequently, the significantly high rates of serious adverse events observed during the trial likely represent a 'best-case scenario' for the drug's safety profile.

Journal Editor

A major critical appraisal challenge in the HPS2-THRIVE trial is the use of a combination pill without a standalone niacin control arm. As a reviewer assessing the manuscript's internal validity, how does this structural limitation affect the attribution of the observed adverse events?

Key Response

Because the trial compared niacin-laropiprant directly to placebo, there is no way to definitively isolate which agent caused the unexpected harms (such as bleeding and infections). A rigorous editorial review would flag that while myopathy and diabetes are known niacin toxicities, the novel adverse events could be entirely attributable to laropiprant, high-dose niacin, or a synergistic interaction between the two, making it impossible to render a final verdict on niacin's independent safety profile from this dataset alone.

Guideline Committee

In the wake of the HPS2-THRIVE and AIM-HIGH trials, how did major lipid management guidelines (such as the AHA/ACC guidelines) update their recommendations regarding the use of niacin for secondary prevention in patients with atherosclerotic cardiovascular disease on statins?

Key Response

Following these trials, guideline committees drastically downgraded niacin. Current AHA/ACC guidelines give the addition of niacin to statin therapy a Class III recommendation (No Benefit/Harm), stating it should not be used routinely for cardiovascular risk reduction. The guidelines shifted the paradigm for managing residual risk away from HDL-raising strategies entirely, focusing instead on further lowering LDL-C with non-statin therapies like ezetimibe and PCSK9 inhibitors, or addressing triglycerides with icosapent ethyl.

Clinical Landscape

Noteworthy Related Trials

2010

ACCORD-Lipid Trial

n = 5,518 · NEJM

Tested

Fenofibrate

Population

Patients with type 2 diabetes at high risk for cardiovascular disease on simvastatin

Comparator

Placebo

Endpoint

First occurrence of nonfatal MI, nonfatal stroke, or cardiovascular death (3-point MACE)

Key result: Adding fenofibrate to simvastatin did not significantly reduce the rates of major cardiovascular events compared to simvastatin alone.

2011

AIM-HIGH Trial

n = 3,414 · NEJM

Tested

Extended-release niacin (1500-2000 mg/day)

Population

Patients with cardiovascular disease, low HDL-C, and high triglycerides on statin therapy

Comparator

Placebo

Endpoint

Composite of CHD death, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven revascularization

Key result: The trial was stopped early because extended-release niacin added to statin therapy did not reduce the risk of cardiovascular events and showed an unexplained increase in ischemic stroke.

2015

IMPROVE-IT Trial

n = 18,144 · NEJM

Tested

Ezetimibe 10 mg daily

Population

Patients stabilized after an acute coronary syndrome with LDL-C levels within guideline recommendations

Comparator

Placebo

Endpoint

Composite of cardiovascular death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke

Key result: The addition of ezetimibe to statin therapy significantly reduced the risk of cardiovascular events compared to statin therapy alone.

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