Safety assessment of niacin in the US Food and Drug Administration's mini‐sentinel system

Purpose

The Heart Protection Study 2—Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2‐THRIVE) trial found higher incidence rates of adverse reactions, including bleeding, in patients receiving the combination of extended‐release niacin and laropiprant versus placebo. It is not known whether these adverse events are attributable to laropiprant, not approved in the USA, or to extended‐release niacin. We compared rates of major gastrointestinal bleeding and intracranial hemorrhage among initiators of extended‐release niacin and initiators of fenofibrate.

Methods

We used Mini‐Sentinel (now Sentinel) to conduct an observational, new user cohort analysis. We included data from 5 Data Partners covering the period from January 1, 2007 to August 31, 2013. Individuals who initiated extended‐release niacin were propensity score‐matched to individuals who initiated fenofibrate. Within the matched cohorts, we used Cox proportional hazards models to compare rates of hospitalization for major gastrointestinal bleeding events and intracranial hemorrhage assessed using validated claims‐based algorithms.

Results

A total of 234 242 eligible extended‐release niacin initiators were identified, of whom 210 389 (90%) were 1:1 propensity score‐matched to eligible fenofibrate initiators. In propensity score‐matched analyses, no differences were observed between exposure groups in rates of major gastrointestinal bleeding (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.82 to 1.18) or intracranial hemorrhage (HR, 1.21; 95% CI, 0.66 to 2.22). Results were similar in pre‐specified sensitivity and subgroup analyses.

Conclusions

We did not observe evidence for an association between extended‐release niacin versus fenofibrate and rates of major gastrointestinal bleeding or intracranial hemorrhage.     

Combination drug therapy for hyperlipidemia

Low-dose combination hypolipidemic therapy may be the best approach to achieve the stringent target low-density lipoprotein cholesterol (LDL-C) levels recommended by the latest National Cholesterol Education Program guidelines in patients with multiple risk factors or existing coronary heart disease. Three randomized, double-blind clinical trials have investigated the efficacy and safety of low-dose fluvastatin, a new, wholly synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, in combination with bile acid sequestrants, fibric acid derivatives, and niacin, respectively. Low-dose fluvastatin coupled with low-dose cholestyramine proved to be significantly more effective than higher doses of either agent alone in reducing LDL-C levels in patients with hypercholesterolemia. The combination was well tolerated, with most adverse events attributable to the gastrointestinal effects of cholestyramine. In patients with heterozygous familial hypercholesterolemia and severely elevated LDL-C and triglyceride (TG) levels, the combination of fluvastatin with bezafibrate was equivalent to fluvastatin plus cholestyramine in lowering LDL-C levels but was superior in raising high-density lipoprotein cholesterol (HDL-C) levels and reducing TG levels. Bezafibrate was considerably better tolerated than cholestyramine. Neither regimen was associated with untoward elevations in hepatic transaminase or creatine phosphokinase levels. Combination therapy with fluvastatin and niacin reduced LDL-C levels by more than 30% in 90% of hypercholesterolemic subjects studied and decreased these levels by more than 40% in 60% of these subjects. The combination also increased HDL-C levels by 36.4%, decreased TG levels by 32%, and reduced lipoprotein (a) levels by 37%. These modifications were achieved without adverse hepatic or myopathic effects. In summary, low-dose fluvastatin can be safely and effective combined with either bile acids, fibrates, or niacin to achie greater reductions in LDL-C than standard monotherapy.     

2015年中国15个省（自治区、直辖市）65岁及以上居民膳食维生素B1、维生素B2和烟酸摄入状况

目的了解中国15个省(自治区、直辖市)65岁及以上居民膳食维生素B1、维生素B2和烟酸的摄入情况和危险因素。方法利用2015年中国居民营养状况变迁的队列研究资料,选择有完整连续3天24小时膳食调查数据的3222名65岁及以上的居民为研究对象,分析膳食维生素B1、维生素B2和烟酸的摄入状况和食物来源,并与中国居民膳食维生素B1、维生素B2和烟酸的推荐摄入量进行比较。采用多因素Logistic回归模型分析维生素摄入不足的危险因素。结果老年居民每天摄入维生素B1、维生素B2、烟酸的中位数分别为:男性0.8、0.7和12.8 mg,女性0.7、0.6和10.9 mg。南方老年居民维生素B1摄入不足的危险性高于北方老年居民。80岁及以上老年居民维生素B1摄入不足的危险性高于65~79岁老年居民。农村教育程度低的老年居民维生素B2摄入不足的危险性高于城市教育程度高的老年居民。男性80岁及以上、教育程度低、北方、农村和收入水平低的老年居民烟酸摄入不足的危险性更高,女性教育程度低、北方和农村的老年居民烟酸摄入不足的危险性更高。结论 2015年中国15个省(自治区、直辖市)约80%以上的老年居民存在膳食维生素B1和维生素B2摄入不足风险。不同年龄、教育程度、地区、城乡、收入的老年居民维生素B1、维生素B2和烟酸摄入情况不同。     

Serious Adverse Effects of Extended-release Niacin/Laropiprant: Results From the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial

PurposeThe Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial of patients at high risk of vascular disease found that adding extended-release niacin-laropiprant to intensive statin-based LDL-lowering therapy had no benefit on cardiovascular outcomes. However, the trial also identified previously unrecognized serious adverse effects (including new-onset diabetes, bleeding, and infection). Our objective was to explore the safety profile of niacin-laropiprant and examine whether any patients were at lower (or higher) risk of its adverse effects.MethodsHPS2-THRIVE was a randomized, double-blind trial of niacin-laropiprant (2000/40 mg/d) versus placebo among 25,673 patients at high risk of vascular disease. Information on all serious adverse events was collected during a median of 3.9 years of study treatment. Effects of niacin-laropiprant on new-onset diabetes, disturbances of diabetes control, bleeding, infection, and gastrointestinal upset were estimated by (1) time after randomization, (2) severity, (3) baseline characteristics, (4) baseline risk of the adverse event of interest, and (5) risk of major vascular event.FindingsThe hazard ratio (HR) for new-onset diabetes with niacin/laropiprant was 1.32 (95% CI, 1.16–1.51; P < .001), which corresponded to an absolute excess of 4 people (95% CI, 2–6) developing diabetes per 1000 person-years in the study population as a whole. Among the 8299 participants with diabetes at baseline, the HR for serious disturbances in diabetes control was 1.56 (95% CI, 1.35–1.80), corresponding to an absolute excess of 12 (95% CI, 8–16) per 1000 person-years. The HR was 1.38 (95% CI, 1.17–1.63; P < .001) for serious bleeding, corresponding to an absolute excess of 2 (95% CI, 1–3) per 1000 person-years and 1.22 (95% CI, 1.11–1.34; P < .001) for serious infection, corresponding to an absolute excess of 4 (95% CI, 2–6) per 1000 person-years. The excess risks of these serious adverse events were larger in the first year after starting niacin-laropiprant therapy than in later years (except for the excess of infection, which did not appear to attenuate with time), and the risks of nonfatal and fatal events were similarly increased. The absolute excesses of each of these adverse effects were similar regardless of the baseline risk of the outcome.ImplicationsPractitioners or patients considering the use of niacin (in addition to, or instead of, a statin) despite the lack of evidence of cardiovascular benefits (at least when added to effective statin therapy) should take account of the significant risks of these serious adverse effects when making such decisions. ClinicalTrials.gov identifier: NCT00461630.     

Design and Evaluation of Niacin Microspheres

Present study aims to prepare and evaluate niacin microspheres. Niacin-ethyl cellulose microspheres were prepared by water-in-oil-in-oil double emulsion solvent diffusion method. Spherical, free flowing microspheres having an entrapment efficiency of 72% were obtained. The effect of polymer-drug ratio, surfactant concentration for secondary emulsion process and stirring speed of emulsification process were evaluated with respect to entrapment efficiency, in vitro drug release behavior and particle size. FT-IR and DSC analyses confirmed the absence of drug-polymer interaction. The in vitro release profile could be altered significantly by changing various processing and formulation parameters to give a controlled release of drug from the microspheres. The percentage yield was 85%, particle size range was 405 to 560 μm. The drug release was controlled for 10 h. The in vitro release profiles from optimized formulations were applied on various kinetic models. The best fit with the highest correlation coefficient was observed in Higuchi model, indicating diffusion controlled principle. The in vitro release profiles of optimized formulation was studied and compared with commercially available niacin extended release formulation.     

阿托伐他汀联用烟酸对冠状动脉粥样硬化斑块的影响

目的评价阿托伐他汀不同剂量及联合烟酸缓释片对冠状动脉粥样硬化斑块的影响。方法将冠状动脉造影确诊冠心病并经彩超检查发现颈动脉斑块的患者123例随机分为3组,A组给予阿托伐他汀10 mg口服,B组给予阿托伐他汀80 mg口服,C组给予阿托伐他汀10 mg联合烟酸缓释片1.0 g口服。疗程均为12个月,治疗前后分别测定TC、LDL-C、TG、HDL-C、ALT、CPK及肌酐;治疗后再用彩超测定颈动脉内膜中层厚度(IMT),并计算斑块积分。结果 3组TC、LDL-C、TG均明显降低,B组和C组降低幅度明显大于A组。C组HDL-C升高幅度明显大于A组和B组。A组颈动脉IMT及斑块积分下降不明显,B组及C组则下降明显。结论在他汀治疗基础上加用烟酸可以达到全面调脂,明显缩小粥样硬化斑块的目的,不良反应较小,有良好应用前景。     

The comparative bioavailability of an extended-release niacin and lovastatin fixed dose combination tablet versus extended-release niacin tablet, lovastatin tablet and a combination of extended-release niacin tablet and lovastatin tablet

Lovastatin and extended-release (ER) niacin in a fixed dose combination (Advicor) is approved for the treatment of dyslipidemia. Since both drugs are extensively metabolized, this study investigated the bioavailability and pharmacokinetics of their co-administration following single-dose administration. In a 4-way crossover study 40 subjects received: two 1000/20 Advicor tablets (ADV), two 1000 mg niacin ER tablets (NSP), two 20mg lovastatin tablets (Mevacor; MEV), and two niacin ER 1000 mg tablets with two lovastatin 20mg tablets (NSP+MEV). Plasma was assayed for niacin, nicotinuric acid (NUA), lovastatin, lovastatin acid and HMGCoA reductase inhibition. Urine was assayed for niacin and its metabolites, NUA, N-methylnicotinamide and N-methyl-2pyridone-5-carboxamide. Least square mean ratios and 90% confidence intervals for C(max) and AUC((0-t)) were determined for NSP+MEV versus MEV or NSP, ADV versus MEV or NSP, and ADV versus NSP+MEV. Co-administration of niacin and lovastatin did not significantly influence C(max) and AUC((0-t)) of lovastatin, niacin, NUA and total urinary recovery of niacin and metabolites. A 22 to 25% decrease in lovastatin acid C(max) was observed while lovastatin acid AUC((0-t)) was not affected. The HMGCoA reductase inhibition C(max) and AUC((0-t)) were not affected indicating that the difference in lovastatin acid C(max) was not clinically relevant.     

Acyl hydroxypyrazoles as novel agonists for high-affinity nicotinic acid receptor GPR109A: WO2008051403

Background: Acyl hydroxypyrazoles were discovered and claimed by Merck as novel agonists for the high-affinity nicotinic acid receptor, G-protein coupled receptor 109A (GPR109A). The fused bicyclic core contains a hydroxypyrazole that mimics the anthranilide moiety described in their earlier patents and patent publications. Objective: This article evaluates new GPR109A receptor agonists disclosed by Merck in the recent patent WO2008051403. Conclusion: The aim of this invention was to provide potential therapy to reduce free fatty acids (FFA), low-density lipoprotein cholesterol (LDL-C), total cholesterol, and serum triglycerides (TG), and to raise high-density lipoprotein cholesterol (HDL-C). Thus, these agonists could – potentially – be used to treat dyslipidemia, atherosclerosis, and metabolic syndromes such as diabetes.     

Present-day uses of niacin: effects on lipid and non-lipid parameters

Existing guidelines for the prevention and treatment of coronary artery disease focus on lowering low-density lipoprotein cholesterol (LDL-C) as the primary lipid target. However, there has been increasing interest in raising high-density lipoprotein cholesterol (HDL-C) due to strong evidence linking low HDL-C levels with an increased risk of atherosclerosis. Raising HDL-C levels with lifestyle changes and pharmacologic interventions appear to reduce the risk of coronary artery disease beyond that of lowering LDL-C alone. Niacin has a substantial HDL-C raising effect, and also may beneficially alter total cholesterol, LDL-C and triglyceride levels. Niacin also exhibits antioxidant, anti-inflammatory and other beneficial effects on atherosclerosis. Niacin is safe and effective to use in women, in patients with diabetes mellitus and/or metabolic syndrome, and when used in combination with statins. Niacin has the promise of being a powerful pharmacologic agent in the fight against atherosclerotic disease, although additional clinical studies are required to examine this further.     

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