Nicotinic Acid: Mechanism of Action, Effect on Lipid Profile and Cardiovascular Risk

General Description

Nicotinic acid, or niacin, exerts its effects on lipid profile and cardiovascular risk through various mechanisms, including activation of GPR109A, inhibition of adenylyl cyclase activity, and modulation of lipid synthesis pathways. It reduces triglycerides and LDL cholesterol levels while increasing HDL cholesterol levels. Nicotinic acid also impacts apoB degradation, LDL particle formation, and CETP activity, leading to improved lipid profiles. Clinical studies have shown its benefits in reducing cardiovascular events and mortality. However, recent trials like AIM-HIGH have questioned its efficacy when combined with statins. Ongoing research, such as HPS2-THRIVE, aims to provide further insights into the role of nicotinic acid in managing cardiovascular risk in patients with varying lipid profiles.

Figure 1. Nicotinic Acid

Mechanism of Action

Nicotinic acid operates through various mechanisms to achieve its beneficial effects, though some aspects of its action remain unclear. Primarily, Nicotinic acid decreases triglyceride and LDL cholesterol levels, although the data regarding this reduction are debated. One significant mechanism of Nicotinic acid involves binding and activating the adipose tissue G-protein receptor-109A (GPR109A). Activation of GPR109A in adipose tissue leads to inhibition of adenylyl cyclase activity via a Gi-mediated pathway, resulting in decreased levels of cyclic adenosine monophosphate (cAMP). As cAMP typically promotes lipolysis, its reduction results in decreased circulating free fatty acids, subsequently limiting hepatic very low-density lipoprotein (VLDL) production and reducing plasma LDL cholesterol and triglyceride levels. Additionally, Nicotinic acid inhibits hepatic triglyceride synthesis by targeting diacylglycerol acyl transferase 2, a key enzyme in this process. Furthermore, Nicotinic acid influences transcription and translation pathways, favoring protease-mediated intracellular degradation of apolipoprotein B (apoB), thereby reducing LDL particle formation. Nicotinic acid also affects HDL particles, extending their plasma residence time by inhibiting cholesterol ester transfer protein (CETP) activity, reducing HDL clearance, and enhancing cholesterol efflux from macrophages. Moreover, NA increases apoA1 levels by promoting its production and decreasing hepatic removal, further contributing to HDL stability. In summary, Nicotinic acid employs multiple pathways to enhance HDL and apoA1 plasma residence time, ultimately reducing LDL cholesterol and triglyceride levels. ¹

Effect on lipid profile and cardiovascular risk

Nicotinic acid has a significant impact on lipid profile and cardiovascular risk. When taken at a dose of 1000 mg/day, Nicotinic acid leads to a reduction of approximately 20% in triglyceride levels, a 5% decrease in LDL cholesterol levels, and a 17% increase in HDL cholesterol levels. To achieve the full lipid-modifying effects of Nicotinic acid, a dose escalation to 2000 mg/day is required, resulting in even greater reductions in triglycerides and LDL cholesterol, along with a potential 25% increase in HDL cholesterol levels. Additionally, Nicotinic acid has been linked to a reduction in lipoprotein (a) levels, further contributing to its beneficial effects on lipid profile. Extended-release Nicotinic acid (ER-NA) is primarily recommended for dyslipidemic patients who are already on statin therapy but have not reached their target LDL or non-HDL cholesterol levels as per guidelines. It can also be used as an adjunctive therapy in combination with fibrates, statins, or omega-3 fatty acids for individuals with severe hypertriglyceridemia at risk of pancreatitis. In cases of statin intolerance or contraindication, ER-NA monotherapy is a viable option, as well as for patients with severe hypertriglyceridemia who cannot tolerate fibrates. While previous studies have shown a reduction in cardiovascular events and mortality with Nicotinic acid use, recent trials like AIM-HIGH have raised questions about its efficacy in combination with statins for high-risk cardiovascular patients. The AIM-HIGH trial did not demonstrate additional benefits of adding ER-NA to statin therapy in patients with established cardiovascular disease, high triglycerides, and low HDL cholesterol levels. However, the trial had limitations, including a small difference in HDL cholesterol levels between the treatment and placebo groups, which may have impacted the overall outcomes. Ongoing studies like HPS2-THRIVE aim to provide further insights into the potential benefits of combining statins with Nicotinic acid/laropiprant in preventing cardiovascular events in patients with vascular disease. The results of these trials will be crucial in determining the role of NA in managing cardiovascular risk in different patient populations with varying lipid profiles. ²

Reference

1. Kei A, Elisaf MS. Nicotinic acid: clinical considerations. Expert Opin Drug Saf. 2012; 11(4): 551-564.

2. Kamanna VS, Vo A, Kashyap ML. Nicotinic acid: recent developments. Curr Opin Cardiol. 2008; 23(4): 393-398.