New England Journal of Medicine JULY 17, 2014

Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients

The HPS2-THRIVE Collaborative Group

Bottom Line

In high-risk patients receiving intensive background statin therapy, the addition of extended-release niacin with laropiprant failed to reduce the rate of major vascular events while significantly increasing the incidence of serious adverse side effects.

Key Findings

1. The primary outcome of a first major vascular event occurred in 13.2% of the niacin-laropiprant group compared to 13.7% in the placebo group (rate ratio, 0.96; 95% CI, 0.90 to 1.03; P = 0.29), indicating no statistically significant clinical benefit.

2. Treatment with niacin-laropiprant led to a significant increase in the risk of serious adverse events, including gastrointestinal, musculoskeletal, and dermatological complications.

3. Unexpected increases were observed in the incidence of serious infections and bleeding events in patients receiving the study medication.

4. The therapy was associated with a significant increase in risks concerning diabetes control and the development of new-onset diabetes.

5. Niacin-laropiprant increased the risk of statin-induced myopathy by approximately 4-fold, with a markedly higher risk observed in Chinese participants compared to European participants.

Study Design

Design

RCT

Double-Blind

Sample

25,673

Patients

Duration

3.9 yr

Median

Setting

Multicenter, six countries

Population Patients aged 50-80 years with pre-existing occlusive arterial disease, already receiving effective background statin therapy.

Intervention Extended-release niacin (2 g) plus laropiprant (40 mg) daily.

Comparator Matching placebo.

Outcome Time to first major vascular event (composite of non-fatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization).

Study Limitations

• The inclusion of a run-in phase designed to ensure tolerability may have introduced selection bias, potentially excluding patients who would have been most representative of clinical practice.

• The addition of laropiprant to neutralize flushing effects complicates the ability to isolate the specific cardiovascular effects of niacin alone.

• The study population was heavily weighted toward patients already achieving low LDL-C levels, potentially masking the marginal benefits of further lipid modulation.

• The higher rate of treatment discontinuation due to side effects (approximately 25%) may have influenced long-term outcomes and assessment of efficacy.

Clinical Significance

The trial findings strongly suggest that the addition of niacin to effective, high-intensity statin therapy does not improve cardiovascular outcomes in high-risk patients and carries a significant burden of serious adverse events, leading to a major shift away from the routine clinical use of niacin for cardiovascular risk reduction.

Historical Context

Niacin had long been used as a lipid-modifying agent based on its ability to raise HDL-C and lower LDL-C; however, early evidence from the Coronary Drug Project predated modern statin therapy, leaving the clinical utility of niacin in the contemporary era uncertain, a question definitively addressed by HPS2-THRIVE and the concurrent AIM-HIGH trial.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism by which niacin affects lipid levels, and why did the study use laropiprant in conjunction with extended-release niacin?

Key Response

Niacin (Vitamin B3) inhibits hepatic diacylglycerol acyltransferase-2, leading to decreased VLDL and LDL production while increasing HDL by inhibiting its hepatic uptake. Laropiprant is a selective prostaglandin D2 receptor 1 (DP1) antagonist added specifically to reduce the prostaglandin-mediated cutaneous flushing that frequently limits patient adherence to niacin therapy.

Resident

In patients already optimized on statin therapy, what were the most clinically significant 'serious adverse events' identified in the HPS2-THRIVE trial that should preclude the routine addition of niacin?

Key Response

The trial found a significant increase in non-fatal but serious adverse events, including a 3.7% absolute increase in new-onset diabetes, a 1.4% increase in serious infections (particularly opportunistic and skin infections), and significant increases in gastrointestinal ulceration and bleeding. These findings suggest that the risk-benefit ratio for niacin is unfavorable in the context of modern intensive statin therapy.

Fellow

Considering the results of HPS2-THRIVE and the earlier AIM-HIGH trial, what do these findings suggest about the clinical utility of the 'HDL-cholesterol hypothesis' in the setting of aggressive LDL-lowering?

Key Response

Both trials demonstrated that pharmacologically raising HDL-C (by 6% in HPS2-THRIVE and 25% in AIM-HIGH) failed to provide incremental cardiovascular benefit in patients with well-controlled LDL-C. This suggests that either the magnitude of HDL increase was insufficient, or more likely, that HDL-C is a marker rather than a causal mediator of risk, or that niacin's adverse metabolic effects counteract any potential vascular benefits of increased HDL.

Attending

How does the failure of niacin-laropiprant in HPS2-THRIVE inform your approach to managing 'residual risk' in high-risk patients who have reached LDL targets but remain hypertriglyceridemic or have low HDL?

Key Response

This trial was practice-changing because it moved niacin from a 'reasonable second-line agent' to one that is generally avoided. It reinforces the priority of LDL-C lowering as the primary therapeutic target and suggests that for residual risk, clinicians should look toward other evidence-based interventions like icosapent ethyl (REDUCE-IT) or intensified lifestyle modifications rather than targeting surrogate HDL levels.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The HPS2-THRIVE study utilized a 'run-in period' where all patients received the active drug before randomization. How might this design choice impact the interpretation of the study's safety data and its generalizability to real-world populations?

Key Response

The 5-8 week run-in period excluded patients who could not tolerate niacin due to early side effects (like flushing or GI upset). Consequently, the study likely underestimated the true incidence of adverse events that would occur in a general clinical population. This 'enrichment' for tolerant patients makes the significant increase in serious adverse events in the randomized phase even more striking and concerning.

Journal Editor

The study cohort included approximately 10,000 participants from China and 15,000 from the UK. What are the potential implications of this geographic distribution on the reported rates of myopathy and other side effects?

Key Response

A key concern for reviewers is the interaction between ethnicity and drug metabolism. In HPS2-THRIVE, the rate of myopathy was significantly higher in the Chinese cohort compared to the European cohort. This raises questions about whether the safety signals were driven by specific sub-populations, potentially complicating the global applicability of the safety findings while simultaneously providing a high-powered look at ethnic differences in drug response.

Guideline Committee

Based on the HPS2-THRIVE data, what strength of recommendation should be assigned to the use of niacin as an adjunct to statins for the prevention of major vascular events in the next guideline update?

Key Response

Current AHA/ACC guidelines give a 'Class III: No Benefit' (or even 'Harm') recommendation for the addition of niacin to statins. HPS2-THRIVE provided the definitive high-level evidence (Level A) showing that the lack of efficacy in reducing MACE, coupled with the significant increase in serious adverse events (diabetes, infection, bleeding), makes niacin an inappropriate choice for secondary prevention in patients achieving low LDL-C on statins.

Clinical Landscape

Noteworthy Related Trials

2002

Heart Protection Study (HPS)

n = 20,536 · Lancet

Tested

Simvastatin 40mg daily

Population

Patients at high risk of coronary disease

Comparator

Placebo

Endpoint

All-cause mortality

Key result: Simvastatin significantly reduced the risk of heart attack, stroke, and revascularization regardless of initial cholesterol levels.

2010

ACCORD-Lipid Trial

n = 5,518 · NEJM

Tested

Fenofibrate plus simvastatin

Population

Patients with type 2 diabetes at high cardiovascular risk

Comparator

Simvastatin alone

Endpoint

First occurrence of major cardiovascular events

Key result: The addition of fenofibrate to simvastatin did not significantly reduce the rate of cardiovascular events compared to simvastatin monotherapy.

2011

AIM-HIGH Trial

n = 3,414 · NEJM

Tested

Extended-release niacin

Population

Patients with established cardiovascular disease

Comparator

Placebo on top of statin therapy

Endpoint

Composite of death, MI, stroke, hospitalization for ACS, or revascularization

Key result: The addition of niacin to statin therapy did not significantly reduce the risk of cardiovascular events despite significant increases in HDL cholesterol and decreases in triglycerides.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis