L-shaped association between dietary niacin intake and chronic kidney disease among adults in the USA: a cross-sectional study.

BACKGROUND: Chronic kidney disease (CKD), which has become a global public health issue, is associated with mitochondrial dysfunction. Niacin is a necessary coenzyme for mitochondrial energy metabolism. However, the association between dietary niacin intake and CKD remains uncertain. This study aimed to investigate the association between dietary niacin intake and CKD in American adults. METHODS: This is a cross-sectional study. 25,608 individuals aged ≥20 years from the National Health and Nutrition Examination Survey from 2007 to 2018 were involved.Dietary niacin intake was estimated based on 24-hour dietary recalls conducted by trained personnel. CKD was determined by an estimated glomerular filtration rate (eGFR) (<60 ml/min/1.73 m2) or a urinary albumin-to-creatinine ratio (ACR) (≥30mg/g). The association between dietary niacin intake and CKD was investigated using multivariable logistic regression analysis. RESULTS: Of 25,608 participants, 17.14% (4388/25,608) had CKD. Compared to individuals with lower niacin intake (quartile [Q]1, ≤15.30 mg/day), those with higher niacin intake in Q2 (15.31-22.07 mg/day), Q3 (22.08-31.09 mg/day), and Q4 (≥31.10 mg/day) exhibited adjusted odds ratios for CKD of 0.89 (95% confidence interval [CI]:0.81-0.99, p = 0.024), 0.83 (95% CI:0.75-0 .92, p < 0 .001), and 0.83 (95% CI:0.75-0.93, p = 0.001) respectively. The relationship between dietary niacin intake and CKD among U.S. adults follows an L-shaped pattern, with an inflection point at approximately 28.04 mg/day. CONCLUSIONS: These results suggest an L-shaped association between dietary niacin intake and CKD. Individuals with low dietary niacin intake levels should be alert to the risk of CKD.

Cholestatic Drug-Induced Liver Injury in a Patient Taking High-Dose Niacin for Hyperlipidemia.

Niacin, an important component of a balanced diet, is central to lipid metabolism. Occasionally used to treat hyperlipidemia, niacin is widely available without a prescription, making its use often unknown to treating physicians. Severe hepatotoxicity has been reported with niacin use. In the following report, we describe a case of hospitalization for acute decompensated cirrhosis with cholestatic morphology in a patient taking self-initiated large quantities of extended-release niacin. Despite medical management and support, the patient unfortunately expired on day 16 of hospitalization. Given ease of access and unclear long-term benefit in hyperlipidemia, the current case serves to raise awareness of niacin's potential hepatotoxicity through highlighting a severe outcome. Although mode of liver injury remains unknown, the use of extended-release niacin formulations and prolonged high-dose supplementation is associated with enhanced hepatotoxicity. Careful review and counseling of commonly available supplements remains an important task of both hospital and primary care physicians.

Immunomodulatory Effects of Combined Nicotinic Acid and Prednisolone in Adjuvant-induced Arthritis.

BACKGROUND: The combination of two drugs may lead to better results while reducing the need for each medication. OBJECTIVE: This study aimed to explore the synergistic benefits of combination therapy by suboptimal dose of niacin (Nic.) and prednisolone (Pred.) in an experimental model of Rheumatoid arthritis (RA). METHODS: About 50 male Wistar rats (weighing 150 - 160 grams) were randomly divided into five groups of ten, including healthy and RA groups treated with Nic. (80 mg/kg-orally), or Pred. (2 mg/kg-orally), and/or co-administration of Nic. and Pred. (half doses with each one-orally). RA was induced by the injection of complete Freund's adjuvant into the hind paw of each rat. All treatments were initiated on the fifth day following the induction and continued until day 30 post-induction. RESULTS: The combined Nic. and Pred. at half doses promoted a significant regression in the severity of the established RA, which is more pronounced than full doses of either drug alone. Combination therapy promoted a reduction in some hematological and biochemical RA parameters, like neutral red uptake by phagocytic cells, myeloperoxidase, nitric oxide, and C-reactive protein, more profound than each drug alone. Combined treatment caused a greater decrease in IFN-γ expression than other treatments in the area of plantar joints. All treatments were effective in increasing the expression of the IL-10 in the area of plantar joints. Prednisolone was less effective in reducing the expression of the TNF-α in the area of plantar joints than the other group. CONCLUSION: This combination may be a useful approach to controlling RA.

Association of niacin intake with constipation in adult: result from the National Health and Nutrition Examination.

BACKGROUND: Although dietary intake is believed to be associated with constipation, there is currently a lack of research exploring the relationship between niacin intake and constipation. Therefore, the aim of this study is to investigate the association between niacin intake in adults and constipation using data from the National Health and Nutrition Examination Survey (NHANES). METHODS: This study included 5170 participants (aged ≥ 20 years) from the NHANES survey conducted between 2009 and 2010. Participants who reported experiencing constipation "always", "most of the time", or "sometimes" in the past 12 months were defined as constipation cases. The daily niacin intake was obtained from dietary recall and dietary supplement recalls of the patients. Weighted multivariate logistic regression analysis, restricted cubic spline regression, subgroup analysis, and interaction analysis were used to assess the correlation between niacin intake and constipation. RESULTS: After adjustment for covariates, the multivariate logistic regression model showed that low niacin intake was associated with a higher risk of constipation (Model 1: OR: 0.917, 95% CI 0.854-0.985, P = 0.023; Model 2: OR: 0.871, 95% CI 0.794-0.955, P = 0.01). After dividing niacin intake into four groups, a daily intake of 0-18 mg niacin was associated with a higher risk of constipation (Model 1: OR: 1.059, 95% CI 1.012-1.106, P = 0.019; Model 2: OR: 1.073, 95% CI 1.025-1.123, P = 0.013). The restricted cubic spline regression analysis also showed a non-linear relationship between niacin intake and the risk of constipation. CONCLUSION: The findings of this study suggested that daily intake of 0-18 mg of niacin was associated with a higher risk of constipation compared to a daily intake of 18-27 mg of niacin.

Adverse drug reactions of non-statin antihyperlipidaemic drugs in China from 1989 to 2019: a national database analysis.

OBJECTIVE: This study aims to understand the adverse drug reactions (ADRs) for non-statin antihyperlipidaemic drugs included in the China Anti-hyperlipidemic Drug Database. DESIGN: An approach of Chinese national database analysis was employed to screen clinical trials involving non-statin antihyperlipidaemic drugs from 1989 to 2019. SETTING: The database was provided by the China National Medical Products Administration Information Centre. PARTICIPANTS: In total, 117 clinical studies with 8800 patients were selected from 2650 clinical trials of the Anti-hyperlipidemic Drug Database. INTERVENTIONS: The non-statin antihyperlipidaemic drugs were divided into three groups: (1) fibrates (fenofibrate, gemfibrozil, bezafibrate, etofylline clofibrate); (2) nicotinic acid and derivatives (niacin, acipimox) and (3) others (probucol, cholestyramine). RESULTS: The results of this study show that first, gastrointestinal symptoms were the most common reactions (6.975%), which account for approximately 50% of the reported cases with ADRs. Second, cholestyramine (16.418%) and gemfibrozil (13.158%) were the most common gastrointestinal side effect-causing non-statin antihyperlipidaemic drugs, which account for one-third of the population. Third, niacin (7.879%) and gemfibrozil (5.000%) were the most likely cause of liver disease symptoms. Finally, niacin (10.909%) and acipimox (18.847%) were the major non-statin antihyperlipidaemic drugs with skin symptoms. CONCLUSION: This study revealed that gastrointestinal symptoms were the most common ADRs of fibrates, probucol and cholestyramine in the Chinese population. For nicotinic acid and derivatives, the ADRs of skin symptoms were the most common in China.

Dietary niacin intake and risk of dyslipidemia: A pooled analysis of three prospective cohort studies.

BACKGROUND & AIMS: Although the pharmacological effect of niacin in lowering blood cholesterol and triglyceride levels has been demonstrated in several clinical studies, information regarding the effect of dietary niacin intake is uncertain, and the longitudinal association between dietary niacin intake and the risk of dyslipidemia has not been adequately studied. METHODS: We analyzed data from three community-based cohort studies in Korea, including 211,567 participants aged ≥40 years. Dietary niacin intake was estimated using a validated semi-quantitative food frequency questionnaire, and the occurrence of dyslipidemia was confirmed through surveys during the follow-up period. We applied Cox proportional hazard regression to calculate the cohort-specific hazard ratio (HR) and 95% confidence interval (CI) for dyslipidemia and pooled the results using the fixed-effects method. RESULTS: Higher dietary niacin intake was associated with a reduced risk of dyslipidemia (pooled, multivariable-adjusted HR: 0.71, 95% CI: 0.62-0.82). Compared with the group whose dietary niacin intake was above the recommended dietary allowance in Korea, the risk of dyslipidemia increased by 32% (pooled, multivariable-adjusted HR: 1.32, 95% CI: 1.19-1.46) in the group below the estimated average requirement in Korea. Spline regression showed a dose-response linear relationship between dietary niacin intake and the risk of dyslipidemia (all p-values for nonlinearity >0.05). CONCLUSION: Consumption of foods with high niacin levels may help prevent or delay the onset of dyslipidemia.

The efficacy of niacin supplementation in type 2 diabetes patients: Study protocol of a randomized controlled trial.

BACKGROUND: Dyslipidemia is a main risk factor of cardiovascular disease in the diabetic patients. Niacin was found acutely to decrease the plasma concentration of free fatty acids by inhibiting their mobilization from adipose tissue. This present study is a double blinded, randomized, and prospective trial to determine the effect of niacin during dyslipidemia in type 2 diabetic patients. METHODS: This randomized controlled, double-blinded, single center trial is carried out according to the principles of Declaration of Helsinki. This present study was approved in institutional review committee of the Second Affiliated Hospital of Dalian Medical University. All the patients received the informed consent. Diabetic patients were randomized (1:1) to receive 3-month treatment with extended-release niacin or matching placebo. The major outcome of our present study was the change in the level of HbA1c from the baseline to week 12. Secondary outcome measures contained the levels of fasting blood glucose, the concentrations of serum transaminase, the other laboratory variables, and self-reported adverse events. The P < .05 was regarded as statistically significant. RESULTS: We assumed that adding the niacin to the medication in patients with type 2 diabetes would reduce dyslipidemia and achieve target lipid levels. TRIAL REGISTRATION: This study protocol was registered in Research Registry (researchregistry5925).

Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA2 -mediated adverse reactions? A combined epidemiological-experimental approach.

AIM: Dimethyl fumarate and nicotinic acid activate the hydroxy-carboxylic acid receptor 2 (HCA2 ) and induce flushing. It is not known whether HCA2 mediates other adverse drug reactions (ADRs) to these two substances. This study aims to compare ADRs associated with dimethyl fumarate and nicotinic acid, and to discuss whether they are HCA2 -mediated. METHODS: We identified spontaneous reports of suspected ADRs to dimethyl fumarate and nicotinic acid in the European Adverse Drug Reaction Database (EudraVigilance). These reports were analysed at different hierarchical levels of the Medical Dictionary for Regulatory Activities (MedDRA). In addition, we screened murine organs for HCA2 expression. RESULTS: Similarities in the ADR profile of dimethyl fumarate and nicotinic acid included "gastrointestinal signs and symptoms" (odds ratio [OR] 0.8 [0.6-1.1]), "hepatobiliary investigations" (OR 1.3 [0.7-2.5]) and "anxiety disorders and symptoms" (OR 0.9 [0.3-2.2]) in High Level Group Terms; "diarrhoea (excluding infective)" (OR 1.2 [0.7-1.8]) and "liver function analyses" (OR 1.3 [0.7-2.6]) in High Level Terms; and "diarrhoea" (OR 1.2 [0.7-2.0]) and "vomiting" (OR 0.9 [0.4-1.7]) in Preferred Terms. In analogy, HCA2 was expressed in the gastrointestinal tract, liver and central nervous system (CNS) of murine organs. A discrepant ADR profile was seen for "lymphopenia" (n = 777) at the preferred term level (only reported for dimethyl fumarate) and "blood glucose increased" (more often reported for nicotinic acid; OR 0.1 [0.0-0.5]). CONCLUSION: The gastrointestinal ADRs common to both substances may be mediated by HCA2 . Other ADRs not common to both substances are compound or indication-specific reactions and likely do not involve HCA2 .

Effectiveness of Levoamlodipine Maleate for Hypertension Compared with Amlodipine Besylate: a Pragmatic Comparative Effectiveness Study.

PURPOSE: Antihypertensive treatment is the most important method to reduce the risk of cardiovascular events in hypertensive patients. However, there is scant evidence of the benefits of levoamlodipine maleate for antihypertensive treatment using a head-to-head comparison in the real-world. This study aims to examine the effectiveness of levoamlodipine maleate used to treat outpatients with primary hypertension compared with amlodipine besylate in a real-world setting. METHODS: This was a pragmatic comparative effectiveness study carried out at 110 centers across China in outpatients with primary hypertension treated with levoamlodipine maleate or amlodipine besylate, with 24 months of follow-up. The primary outcomes used for evaluating the effectiveness were composite major cardiovascular and cerebrovascular events (MACCE), adverse reactions, and cost-effectiveness. RESULTS: Among the included 10,031 patients, there were 482 MACCE, 223 (4.4%) in the levoamlodipine maleate group (n = 5018) and 259 (5.2%) in the amlodipine besylate group (n = 5013) (adjusted hazard ratio = 0.90, 95%CI: 0.75-1.08, P = 0.252). The levoamlodipine maleate group had lower overall incidences of any adverse reactions (6.0% vs. 8.4%, P < 0.001), lower extremity edema (1.1% vs. 3.0%, P < 0.001) and headache (0.7% vs. 1.1%, P = 0.045). There was a nearly 100% chance of the levoamlodipine maleate being cost-effective at a willingness to pay threshold of 150,000 Yuan per quality-adjusted life years (QALYs) gained, resulting in more QALYs (incremental QALYs: 0.00392) and cost savings (saving 2725 Yuan or 28.8% reduction in overall costs) per patient. CONCLUSION: In conclusion, levoamlodipine maleate could reduce cost by 29% with a similar MACCE incidence rate and lower occurrence of adverse reactions (especially edema and headache) compared with amlodipine besylate. TRIAL REGISTRATION: Clinicaltrials.gov NCT01844570 registered at May 1, 2013.

Pellagra secondary to selective eating in a child with autism.

Once a significant cause of morbidity and mortality, health care providers rarely see primary pellagra in developed countries where fortification of foods with niacin is commonplace and niacin-rich foods are generally widely available. We report a ten-year-old boy with autism spectrum disorder who presented with photosensitive dermatitis which resolved after vitamin supplementation and dietary changes. In this child, the pellagra developed as the result of a long-term pattern of selective eating. Restricted diets, even to the point of nutrient deficiencies, are well-documented among children with autism spectrum disorders (ASD).

An association between niacin skin flush response and plasma triglyceride levels in patients with schizophrenia.

The available data suggest that abnormalities of arachidonic acid-related signaling may be of relevance in attenuated niacin-induced flush responses and lipid and glucose metabolism disturbances, which are all common among individuals with schizophrenia. We previously demonstrated attenuated skin flush responses to niacin in patients with schizophrenia. Here we investigated whether these niacin responses might be associated with elevated plasma lipid and glucose concentrations in this patient group. We found that higher plasma triglyceride levels were associated with higher total volumetric niacin response (VNR) values and that the VNR accounted for ~14.2% of the variability in triglyceride levels. Triglyceride levels were significantly higher in patients with a positive niacin skin flush response compared to those with absent niacin skin flushing at the 5-minute interval with niacin concentrations of 0.1 and 0.01 M, and at the 10- and 15-minute intervals with a niacin concentration of 0.001 M.

Activation of HCAR2 by niacin: benefits beyond lipid lowering.

Niacin (nicotinic acid) is a potent lipid-lowering agent that has been used for prevention of coronary heart disease. Niacin activates the HCAR2 receptor found on adipocytes, macrophages and various immune cells throughout the body. Activation of the HCAR2 receptor by niacin results in beneficial anti-inflammatory effects that are independent of lipid lowering. This review summarizes the use of niacin in treatment of dyslipidemia, the pharmacogenetics of niacin response and the potential role of HCAR2 signaling in the treatment of a variety of inflammatory and metabolic diseases.

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.

PURPOSE: The 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. METHODS: HPS2-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. FINDINGS: The 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. IMPLICATIONS: Practitioners 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.

Looking at Lp(a) and Related Cardiovascular Risk: from Scientific Evidence and Clinical Practice.

PURPOSE OF REVIEW: A considerable body of data from genetic and epidemiological studies strongly support a causal relationship between high lipoprotein(a) [Lp(a)] levels, and the development of atherosclerosis and cardiovascular disease. This relationship is continuous, unrelated to Lp(a) threshold, and independent of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels. Unfortunately, the mechanism(s) through which Lp(a) promotes atherosclerosis are not clarified yet. Suggested hypotheses include: an increased Lp(a)-associated cholesterol entrapment in the arterial intima followed by inflammatory cell recruitment, abnormal upload of proinflammatory oxidized phospholipids, impaired fibrinolysis by inhibition of plasminogen activation, and enhanced coagulation, through inhibition of the tissue factor pathway inhibitor. This review is aimed at summarizing the available evidence on the topic. RECENT FINDINGS: There are two clinical forms, isolated hyperlipidemia(a) [HyperLp(a)] with acceptable LDL-C levels (< 70 mg/dL), and combined elevation of Lp(a) and LDL-C in plasma. To date, no drugs that selectively decrease Lp(a) are available. Some novel lipid-lowering drugs can lower Lp(a) levels, but to a limited extent, as their main effect is aimed at decreasing LDL-C levels. Significant Lp(a) lowering effects were obtained with nicotinic acid at high doses. However, adverse effects apart, nicotinic acid is no longer prescribed and available in Europe for clinical use, after European Agency of Medicines (EMA) ban. The only effective therapeutic option for now is Lipoprotein Apheresis (LA), albeit with some limitations. Lastly, it is to be acknowledged that the body of evidence confirming that reducing plasma isolated elevation of Lp(a) brings cardiovascular benefit is still insufficient. However, the growing bulk of clinical, genetic, mechanistic, and epidemiological available evidence strongly suggests that Lp(a) is likely to be the smoking gun.

Nicotinic acid suppresses sebaceous lipogenesis of human sebocytes via activating hydroxycarboxylic acid receptor 2 (HCA2 ).

Nicotinic acid (NA) activates hydroxycarboxylic acid receptor 2 (HCA2 ), and it is widely used in treating dyslipidaemias. Since its side effects include skin dryness, whereas its deficiency can be accompanied by dyssebacia, characterized by sebaceous gland enlargement, we asked if HCA2 is expressed on human sebocytes, and if NA influences sebocyte functions. By using human immortalized SZ95 sebocytes, we found that non-cytotoxic (≤100 µmol/L; MTT-assay) concentrations of NA had no effect on the homeostatic sebaceous lipogenesis (SLG; Nile Red), but normalized excessive, acne-mimicking SLG induced by several lipogenic agents (arachidonic acid, anandamide, linoleic acid + testosterone; Nile Red; 48-hr treatments). Moreover, it exerted significant anti-proliferative actions (CyQUANT-assay), and increased [Ca2+ ]IC (Fluo-4 AM-based Ca2+ -measurement). Although NA did not prevent the lipopolysaccharide-induced pro-inflammatory response (up-regulation [Q-PCR] and release [ELISA] of several pro-inflammatory cytokines) of the sebocytes, collectively, these data support the concept that NA may be effective in suppressing sebum production in vivo. While exploring the mechanism of the sebostatic actions, we found that sebocytes express HCA2 (Q-PCR, immunofluorescent labelling), siRNA-mediated silencing of which prevented the NA-induced Ca2+ -signal and the lipostatic action. Collectively, our data introduce NA, and HCA2 activators in general, as novel, potent and most likely safe sebostatic agents, with possible anti-acne potential.