Individuals with prior cardiovascular disease are at risk for subsequent events despite aggressive LDL-lowering with statins. Helping to lower the residual risk of cardiovascular disease is often explored by addressing the other lipoproteins, HDL cholesterol and triglycerides (TG).1-3 Niacin’s effects in raising HDL and lowering TG along with moderate reductions in LDL have been evaluated in various trials with mixed results.1,3 Niacin use has often been limited due to adverse effects, including prostaglandin D2-mediated flushing. Laropiprant is an antagonist of the prostaglandin D2 receptor (DP1) and has been shown to reduce flushing and thus improve tolerability and adherence to niacin.2,3 The HPS2-THRIVE study sought to investigate the effect of adding extended release (ER) niacin with laropiprant to statin therapy in high-risk patients with prior vascular disease.
Landray and colleagues performed a randomized, multicenter, double-blind study to evaluate the effects of ER niacin with laropiprant in patients at high risk for vascular disease to evaluate the effect on major coronary events (e.g., nonfatal myocardial infarction or death from cardiac cause, stroke, or coronary or noncoronary revascularization).2 Inclusion criteria included a history of myocardial infarction, cerebrovascular disease, peripheral arterial disease or diabetes with evidence of symptomatic coronary disease. Patients taking LDL-therapy more effective than simvastatin 40mg plus ezetimibe 10mg daily were excluded. All patients took simvastatin 40mg daily with or without ezetimibe 10mg daily. The average LDL was 63mg/dL and HDL 44mg/dL prior to randomization. Eligible patients were randomized to a dose of niacin ER 2gm and laropiprant 40mg per day after slow titration to minimize side effects, or placebo and were followed for a median of 3.9 years.2
A total of 25,673 patients were randomized with 78.4% having coronary disease. There was no significant difference in major vascular or coronary events with niacin/laropiprant compared with placebo (13.2% vs 13.7%; 95% CI, 0.9-1.03, P=0.29, respectively).2 Compliance with niacin/laropiprant was 89.1% during the first year of therapy, and fell to 69.9% by the third year. Niacin/laropiprant decreased LDL by 10mg/dL and triglycerides by 33mg/dL, and increased HDL 6mg/dL. Adverse reactions were the reason for discontinuation in 25.4% of patients in the treatment arm compared to 16.6% in the placebo arm (P<0.001). Most of the adverse reactions leading to discontinuation with niacin/laropiprant were due to known effects of niacin (e.g., skin-related, gastrointestinal, musculoskeletal or diabetes-related). Overall, there were significantly more fatal and nonfatal serious adverse events with niacin/laropiprant (55.6% vs. 52.7% with placebo, P<0.001). Niacin/laropiprant led to a 55% worsening in glycemic control in pre-existing diabetics (11.1% vs. 7.5% with placebo) and resulted in a 32% increase in the diagnosis of diabetes (P<0.001). Other significant adverse drug reactions associated with niacin/laropiprant included gastrointestinal disturbances (bleeding, peptic ulceration, dyspepsia, diarrhea), musculoskeletal (myopathy, gout), skin-related, infection, and general bleeding.2
The findings of HPS2-THRIVE along with other recent trials have not demonstrated a benefit with niacin therapy and raising HDL for cardiovascular events, and has raised concerns about the safety of using niacin (with or without laropiprant).1,2 There were a large number of dropouts (33%) in the trial to fully assess the effect, and the dropouts and adverse reactions question the benefit of adding laropiprant to only minimize the flushing side effect.2 Minimal data is currently available for tolerability of laropiprant, however Krishna and coworkers indicated it was well tolerated.4 With the new evidence regarding niacin showing no benefit on cardiovascular events and increased risk for severe adverse drug reactions, the role of extended-release niacin with ...