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Vitamins and Supplements: Evidence in the Prevention and Treatment of Cardiovascular Disease
Published in James M. Rippe, Lifestyle Medicine, 2019
Jenna M. Holzhausen, Aaron D. Berman
More recent studies, however, have cast doubt on niacin’s ability to decrease hard endpoints of cardiovascular morbidity and mortality. The AIM-HIGH study36 examined effects of niacin in patients already on intensive statin therapy with target LDL levels of <70 mg/dL. Addition of niacin had no effect on the composite endpoint of death from coronary heart disease, nonfatal MI, ischemic stroke, hospitalization for unstable coronary syndrome, or coronary or cerebral revascularization despite significant decreases in LDL and triglycerides, and increases in HDL. The statin used in this study was simvastatin, with ezetimibe added to achieve LDL < 80 mg/dL if needed. One shortcoming of this study was the mean treatment time of only three years, which perhaps was not long enough to show benefits. The HPS2-THRIVE study,37 published in 2014, further brought the use of niacin into question. Niacin plus laropiprant (to reduce flushing) was compared with placebo in over 25,000 patients with vascular disease. Patients receiving lipid-lowering therapy more potent than in the AIM-HIGH trial (simvastatin 40 mg with ezetimibe 10 mg) were excluded. Again, niacin (with laropiprant) had no effect on cardiovascular outcome but was associated with an increased risk of diabetes and diabetic complications. Complications, such as GI disturbance, bleeding, infection, and others, were also higher in the treatment group; although, it is unclear if these are attributable to niacin or laropiprant.
Disorders of lipid metabolism
Published in Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich, Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Laropiprant was used in HPS2-THRIVE to inhibit the most common side effect of niacin: prostaglandin-mediated flushing. The extent of off-target effects of laropiprant is uncertain. Flushing may also be prevented or minimized by aspirin and avoidance of alcohol, monosodium glutamate, hot beverages, and spicy foods. Other side effects from high-dose niacin include a small increase in the serum glucose, a moderate increase in the serum uric acid level, and a small reduction in the serum phosphorus level.
The Role of Nutrition and Nutritional Supplements in the Treatment of Dyslipidemia
Published in Stephen T. Sinatra, Mark C. Houston, Nutritional and Integrative Strategies in Cardiovascular Medicine, 2015
The recent THRIVE trial of 26,000 patients using 2 g of extended-release niacin plus the antiflushing agent laropiprant daily or placebo on top of a background therapy of simvastatin with or without ezetimibe did not reduce CV events despite an increased HDL of 17% and decreased LDL of 20%. 68,69 Whether the inhibition of flushing by laropiprant or some other unknown effect of this agent interfered with the HDL function and the CV outcomes is not clear. However, the recommendation by some not to use niacin in face of other positive studies is clearly premature.
Lipoprotein(a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options
Published in Annals of Medicine, 2020
Andreja Rehberger Likozar, Mark Zavrtanik, Miran Šebeštjen
Niacin (i.e. vitamin B3) was for a long time the only approved lipid-lowering drug that showed potent reductions in Lp(a) levels [10]. Niacin lowers Lp(a) by silencing apo(a) gene expression in hepatocytes, which encodes glycoprotein apo(a), a crucial element in the Lp(a) structure [91]. The effects of niacin were dose-dependent and led to 25 and 38% decreases in Lp(a) levels with 2 and 4 g niacin daily, respectively [92]. A similar efficacy of niacin was seen in a meta-analysis of extended-release niacin preparations [93]. However, despite large reductions in Lp(a) levels, the treatment effects of niacin have not been mirrored in any overall reduction of CV events [70, 72]. Indeed, a randomized double-blind trail of niacin in patients with low HDL cholesterol levels who were receiving intensive statin therapies (i.e. AIM-HIGH) found no differences in a comparison of simvastatin with placebo or with extended-release niacin in patients with established CVD, in terms of the endpoint of CV events [73]. Also, addition of laropiprant to extended-release niacin did not improve the outcomes in the ‘Effects of extended-release niacin with laropiprant in high-risk patients’ (HPS2-THRIVE) study [71]. Another limitation of the wider prescription of niacin is the high prevalence of side-effects. In particular, at the higher doses that are effective in reducing Lp(a) levels, niacin is poorly tolerated, and is often discontinued by patients.
Pharmacological treatment options for severe hypertriglyceridemia and familial chylomicronemia syndrome
Published in Expert Review of Clinical Pharmacology, 2018
Rabia Chaudhry, Adie Viljoen, Anthony S. Wierzbicki
Niacin has the ability to reduce TGs by 20% – only slightly less than fibrates in patients with moderate hypertriglyceridemia. Niacin has been used to treat hypertriglyceridemia as it reduces peripheral lipolysis through the hydroxycarboxylic receptor type 3 (HCAR3 also known as the niacin receptor HM74A or G-protein coupled receptor 109A (GPR109A) mimicking the action of beta-hydroxybutyrate, the physiological ligand. Niacin decreases the activity of hepatic diacyl-glycerol-acyl-transferase (DGAT)-2 involved in VLDL assembly [47]. More recently it has been suggested that its main action is to reduce the amount of apoC-3 by decreasing activity of PPAR-gamma co-activator-1 beta [48], interacting with the sterol-receptor binding protein-1c and PPAR-α pathways involved in TG metabolism with a secondary action on DGAT1 and DGAT2 [49]. The HCAR3 receptor is involved in free fatty flux and in the flushing side-effect of niacin [50] but specific partial agonists/antagonists (e.g. MK-0354) reduced FFA flux but did not affect lipids [51]. Niacin can cause significant hyperglycemia and needs to be used cautiously in patients with diabetes [52]. Niacin is additive to fibrates in the treatment of hypertriglyceridemia. There are few data on the specific use of niacin in FCS but case reports show that is successful in reducing TGs in type V hyperlipidemia [53] with the effects being mediated through reductions in CM production (apoB48) [54]. Niacin-laropiprant has been withdrawn worldwide but there is some limited availability of other niacin preparations outside Europe.
Dyslipidaemia in the elderly: to treat or not to treat?
Published in Expert Review of Clinical Pharmacology, 2018
Niki Katsiki, Genovefa Kolovou, Pablo Perez-Martinez, Dimitri P. Mikhailidis
Niacin has been reported to decrease TG and LDL-C, increase HDL-C levels, and improve the quality of LDL-C [187,188]. In this context, niacin represented an attractive therapeutic option, used either as monotherapy or in combination with a statin, for the treatment of mixed atherogenic dyslipidemia. Flushing was a common niacin-induced side effect that limited its clinical use. Extended-release niacin (combined with laropiprant) was developed in order to reduce this adverse event [189]. Other niacin-related adverse events included gastrointestinal effects, insulin resistance, and minor worsening of glycemic control as well as hepatotoxicity (mainly in relation to higher doses of sustained-release niacin) [189]. Despite the positive initial data from clinical trials regarding a potential CVD benefit from niacin therapy, two major RCTs, that is, The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial [190] and the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial [191] did not find significant reductions in CVD events or mortality in statin-treated patients with established CVD on niacin compared with placebo. Furthermore, there were reports of serious adverse events induced by niacin treatment including bleeding, infection, liver, and musculoskeletal effects. These findings led to the withdrawal of niacin from the EU market and greatly limited its clinical use in USA.