Novel Niacin Receptor Agonists: A Promising Strategy for the Treatment of Dyslipidemia.

Background: Hyperlipidemia is characterized by high level of cholesterol and triglycerides in blood. Various classes of drugs like statins, fibrates, niacin etc. are used for treatment of hyperlipidaemia. Objective: Niacin, which is one of the beneficial anti-hyperlipidemic agents, helps to lower LDL cholesterol by 20 to 40% and causes increase of HDL cholesterol by 20 to 35%. However cutaneous flushing, loss of glucose tolerance, liver toxicity are the reported side effects of niacin therapy responsible for decreased patient compliance. Very recently, the G protein coupled receptor (GPCR); GPR109A located on the adipocytes has been identified as the receptor for activation of niacin. Method: In-vitro studies have demonstrated that GPR109A receptor having high affinity for niacin. The present review attempts to provide a systematic presentation of the various chemical classes of compounds that have been reported as novel niacin receptor agonists including pyrazole-3-carboxylic acids, urea derivatives, anthranilic acids, biaryl anthranilides, tetrahydro anthranilic acid, xanthines, barbituric acid, bicyclic pyrazole carboxylic acids, pyrido pyrimidinones, pyrazolyl propionyl cyclohexenamides, pyrazole acids etc. Results : As the design of GPR109A receptor agonists offers a promising solution for treatment of dyslipidemia, this review will be beneficial for medicinal and drug discovery chemists to expediate the process of discovery of new class of antihyperlipidemic agent with favorable lipid lowering profile with increase in HDL levels. Conclusion: This review explains about novel GPR109A receptor agonist for the treatment of dyslipidemia.

Extended-Release Niacin Therapy and Risk of Ischemic Stroke in Patients With Cardiovascular Disease

Background and Purpose— In Atherothrombosis Intervention in Metabolic Syndrome with low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial, addition of extended-release niacin (ERN) to simvastatin in participants with established cardiovascular disease, low high-density lipoprotein cholesterol, and high triglycerides had no incremental benefit, despite increases in high-density lipoprotein cholesterol. Preliminary analysis based on incomplete end point adjudication suggested increased ischemic stroke risk among participants randomized to ERN. Methods— This final analysis was conducted after complete AIM-HIGH event ascertainment to further explore potential relationship between niacin therapy and ischemic stroke risk. Results— There was no group difference in trial primary composite end point at a mean 36-month follow-up among 3414 patients (85% men; mean age, 64±9 years) randomized to simvastatin plus ERN (1500–2000 mg/d) versus simvastatin plus matching placebo. In the intention-to-treat analysis, there were 50 fatal or nonfatal ischemic strokes: 18 (1.06%) in placebo arm versus 32 (1.86%) in ERN arm (hazard ratio [HR], 1.78 [95% confidence interval {CI}, 1.00–3.17; P =0.050). Multivariate analysis showed independent associations between ischemic stroke risk and >65 years of age (HR, 3.58; 95% CI, 1.82–7.05; P =0.0002), history of stroke/transient ischemic attack/carotid disease (HR, 2.18; 95% CI, 1.23–3.88; P =0.0079), elevated baseline Lp(a) (HR, 2.80; 95% CI, 1.25–6.27 comparing the middle with the lowest tertile; HR, 2.31; 95% CI, 1.002–5.30 comparing the highest with the lowest tertile; overall P =0.042) but a nonsignificant association with ERN (HR, 1.74; 95% CI, 0.97–3.11; P =0.063). Conclusions— Although there were numerically more ischemic strokes with addition of ERN to simvastatin that reached nominal significance, the number was small, and multivariable analysis accounting for known risk factors did not support a significant association between niacin and ischemic stroke risk. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00120289.