Potential Uses of Niacin: Flushing Out The Results of HPS2-THRIVE

Written By

Michael S. Kelly, PharmD
Evan M. Sisson, PharmD, MSHA, CDE

Reviewed By

Dawn Fuke, Pharm.D., BCPS
Sarah L. Anderson, Pharm.D., BCPS


HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203-212

Current cholesterol guidelines promote the use of statins as first line therapy in primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) events. Despite the impressive risk reduction associated with statins, a 60% to 80% residual risk of vascular events remains. Does adding niacin to statin treatment reduce residual risk?  Or does statin therapy alone offer optimal benefit?


Primary prevention trials of statins have shown they can reduce the risk of major vascular events by nearly 40%.1,2 Secondary prevention trials in patients with established vascular disease have also demonstrated that statins can prevent another ASCVD event. But despite treatment with high-intensity statin therapy and achieving a mean low-density lipoprotein cholesterol (LDL-C) of 62 mg/d, nearly a quarter of patients still experienced a major vascular event in the TNT study.3 This residual risk may be due to atherogenic dyslipidemia -  characterized by low high-density lipoprotein cholesterol (HDL-C) and/or elevated triglycerides.4


Niacin is an attractive addition to statin therapy because it positively addresses atherogenic dyslipidemia by lowering LDL-C and triglycerides while increasing HDL-C. Moreover, in previous studies niacin has been shown to reduce cardiovascular events.5,6 The Coronary Drug Project (CDP), which randomized men with a previous myocardial infarction to receive niacin 3g or placebo for a mean follow-up of 6.2 years, reported a significant reduction in cardiovascular events in patients who received niacin.5 In the HATS trial, a small study that enrolled patients with cardiovascular disease and HDL-C < 40 mg/dL, simvastatin plus niacin significantly reduced coronary stenosis and the risk of first major cardiovascular event by 90% (RR = 0.10, [95% CI: 0.01 – 0.81; p=0.003]).6


More recently, two large randomized control trials have attempted to assess the benefit of adding niacin to statin therapy in patients with cardiovascular disease.7,8 The most recent of these studies, HPS2-THRIVE, was a double-blind, multinational trial that randomized 25,673 patients between age 50 to 80, with previous vascular disease, to either extended-release niacin plus laropiprant or placebo.8  Laropiprant, a prostaglandin D2 antagonist, was added to niacin to reduce flushing and improve tolerability.


Prior to randomization, patients entered a run-in phase and received simvastatin 40 mg, with the addition of ezetimibe 10 mg if total cholesterol was ≥ 135 mg/dL after 4-weeks. Patients then received 1 gram of extended-release niacin in combination with 20 mg laropiprant for 4 weeks and the dose was doubled for an addition 3 to 6 weeks. During the ER niacin/laropiprant run-in phase, nearly 25% of patients withdrew from the study due to adverse events. Patients able to tolerate ER niacin/laropiprant were then randomized to either continue ER niacin/laropiprant or switched to a matching placebo.


At baseline, LDL-C was well below 70mg/dL in both groups  (see Table 1). After a median follow-up of 3.9 years, ER niacin/laropiprant resulted in an average LDL-C reduction of 10 mg/dL and an increase in HDL-C of 6 mg/dL compared to placebo. The primary outcome of first major vascular event was not statistically different between the ER niacin/laropiprant and placebo groups (13.2% and 13.7%; RR= 0.96; 95% CI [0.90 to 1.03]; p = 0.29). Likewise, stroke and major coronary events were not different. However, treatment with ER niacin/laropiprant resulted in a modest but significant 10% reduction of any revascularization procedures compared to placebo (6.3% vs. 7.0%; RR= 0.90; 95% CI [0.82 to 0.99]; p = 0.03). Modest improvements in blood pressure and lipoprotein(a) were also associated with ER niacin/laropiprant.


Several known adverse events of niacin (gastrointestinal, musculoskeletal, and skin-related events) occurred significantly more often in patients treated with ER niacin/laropiprant. ER niacin/laropiprant was also associated with an increased risk of infection and bleeding events. Patients with pre-existing diabetes mellitus were more likely to have disturbed glycemic control and new-onset diabetes was more common in those treated with ER niacin/laropiprant versus placebo (8.1% and 7.3%; RR= 1.27; 95% CI [1.14 to 1.41]; p< 0.0001).


For every 1000 patients treated with ER niacin/laropiprant for 4 years, an excess of 18 cases of new diabetes, 14 cases of infection, and 7 cases of bleeding were seen.  One revascularization event would be avoided for every 143 patients treated with ER niacin/laropiprant. HPS2-THRIVE authors concluded that the addition of niacin/laropiprant to statin therapy does not reduce the residual risk of major vascular events in patients with previous cardiovascular disease and may result in increased adverse events. While the authors of HPS2-THRIVE state there is no benefit in adding niacin to statin therapy, this conclusion contradicts previous studies.


Table 1: Comparison of trials investigating niacin added to statin therapy.


HATS (2001)

AIM-HIGH (2011)

HPS2-THRIVE (2014)

Type of prevention

Secondary prevention

Secondary prevention

Secondary prevention

Patient Population

Patients with CVD and

HDL-C < 40 mg/dL


Patients with CVD and

HDL-C < 50 mg/dL


Patients with CVD















Baseline Lipid Values (mg/dL)

Total Cholesterol




























Lipid Values at study end (mg/dL)

Total Cholesterol





-5 vs. placebo






-33 vs. placebo






-10 vs. placebo






+6 vs. placebo

Clinical Outcomes

Composite of CV death, MI, stroke, or revascularization:

9 events (placebo) vs. 1 event (simva-niacin)

RR = 0.10
[95% CI 0.01 – 0.81; p=0.03]

Composite of CV death, MI, stroke, revascularization, hospitalization for ACS:

HR = 1.02
[95% CI 0.87 – 1.21; p=0.79]

Composite of CV death, MI, stroke, or revascularization:

RR = 0.96
[95% CI 0.9 – 1.03; p=0.29]

ACS: acute coronary syndrome; CVD: cardiovascular disease; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; MI: myocardial infarction


One possible explanation for the lack of benefit seen in HPS2-THRIVE is that patients’ lipid values were well controlled before randomization (see Table 1). Patients with very-high ASCVD risk, such as those with prior cardiovascular disease, should be treated to a non-HDL-C goal of less than 100 mg/dL and LDL-C of less than 70 mg/dL.9 Patients enrolled in HPS2-THRIVE had already achieved these lipid values with statin therapy (mean non-HDL-C of 84 mg/dL and LDL-C of 63 mg/dL) prior to the addition of niacin/laropiprant or placebo. The addition of non-statin cholesterol lowering therapies in patients with optimal lipid parameters may not offer additional cardiovascular-risk reduction. This concept was acknowledged by HPS2-THRIVE authors and they concede that niacin may be beneficial in patients with elevated LDL-C.8


Subgroup analysis of HPS2-THRIVE suggests several groups may benefit from niacin therapy. Patients from Europe had a higher LDL-C at baseline and a numerically greater reduction in LDL-C (12% vs. 7%) compared to patients from China. And Europeans who took niacin-ER/laropiprant were less likely to experience a major vascular event compared to patients from China (p=0.06). The higher incidence of myopathy that occurred in Chinese patients who received niacin/laropiprant suggests that patients from China may be more sensitive to this combination when it's used with statin therapy. Further subgroup analysis identified significant risk reduction trends in patients randomized to niacin/laropiprant who were current smokers, those with high alcohol intake, and patients with LDL-C greater than 76 mg/dL at baseline.  Clearly that’s a lot of patients!


Despite the reduction in major cardiovascular events associated with statin therapy, considerable residual risk remains. Based on the results of HPS2-THRIVE, adding niacin/laropiprant to statin therapy in patients with optimal lipid parameters does not reduce cardiovascular risk further and may increased the risk of serious adverse events. However, in patients who remain at high ASCVD risk due to elevated non-HDL-C and LDL-C values, adding niacin to statin therapy is still a good option. The American Diabetes Association’s (ADA) recent position statement affirms our view that niacin should be considered in patients with low HDL-C values and elevated LDL-C, despite statin therapy.10   When would you consider using niacin in your practice?



This was great review of the trial. I agree that patients who are at their non-HDL goal in the NLA guidelines will not likely benefit from the addition of niacin. The question is what do we do with patients in clinic who don't respond or don't tolerate their statin therapy? We probably won't ever have a randomized controlled trial to answer this, but there is some evidence such as the subgroup analysis of HPS2-thrive to support second line therapy in selected patients. I think as clinicians we need to use a patient-centered approach to optimize risk reduction not just settle for statin therapy.

I most respectfully submit that the evidence presented in this well-written summary do not support the final conclusion. If indeed no strong evidence of niacin's benefit was demonstrated, why do we cling to the notion that when risk remains high, we should still default to treating with a drug we desperately want to do SOMETHING? It seems illogical and uncommitted to trusting the information we ourselves have studied. Just my 2 cents.