The safety, tolerability and biochemical efficacy of extended release niacin and laropiprant in a major randomised clinical trial

Thesis

Niacin has been in clinical use for over 50 years and was the first drug shown in a randomized trial to improve outcomes after MI, but substantial uncertainty remains about its efficacy and safety in the context of current standard medical therapy.

This thesis explores the biochemical efficacy, tolerability and safety of extended release (ER) niacin/laropiprant in the large, randomized HPS2-THRIVE trial. Laropiprant is a prostaglandin D₂ receptor (DP1) antagonist which reduces the main adverse effect of niacin, namely “flushing” (an unpleasant cutaneous vasodilation) that makes a large trial of niacin practicable.

ER niacin/laropiprant increases high density lipoprotein cholesterol (HDL-C) and apolipoprotein A1, and reduces low density lipoprotein cholesterol (LDL-C), apolipoprotein B, triglycerides and lipoprotein (a), consistent with previous studies of ER niacin.

The reasons for stopping ER niacin/laropiprant reflected the known adverse effect profile of ER niacin, although unlike previous trials flushing was not the most frequent reason for stopping. Skin (pruritus and rash), gastrointestinal (nausea, pain and diarrhoea) and diabetes-related (hyperglycaemia) adverse events were the most common reasons for stopping ER niacin/laropiprant during 3.9 years’ follow-up.

The analyses presented here identified three major previously unknown hazards of ER niacin. ER niacin/laropiprant increased the risk of statin-related myopathy almost five-fold, and this effect was greater among participants in China than Europe. ER niacin/laropiprant also increased the risk of bleeding (intracranial, gastrointestinal and other sites) and infection. Compared to placebo there was an absolute excess of 3.1% of serious adverse events (excluding cancer and major vascular events [MVEs]) among participants assigned ER niacin/laropiprant.

ER niacin/laropiprant did not significantly reduce MVEs. These findings suggest that the use of niacin to reduce vascular risk should now be reconsidered.

Authors: Haynes, R

• Publication date: 2013
• DOI: 10.5287/ora-z5g15gp98
• Type of award: DM
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: cardiovascular disease; niacin; lipids; safety
• Subjects: Cardiovascular disease