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BACKGROUND - We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.
METHODS - Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.
RESULTS - The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.
CONCLUSIONS - Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
BACKGROUND & AIMS - Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation.
METHODS - Global G protein-coupled bile acid receptor-1 null (Tgr5) and intestinal-specific farnesoid X receptor null (Fxr) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r) mice on chow diet were characterized following GB-IL.
RESULTS - GB-IL induced weight loss and improved oral glucose tolerance in Tgr5, but not Fxr mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r mice.
CONCLUSIONS - Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
Treatment of Sprague-Dawley rats with AY9944, an inhibitor of 3β-hydroxysterol-Δ(7)-reductase (Dhcr7), leads to elevated levels of 7-dehydrocholesterol (7-DHC) and reduced levels of cholesterol in all biological tissues, mimicking the key biochemical hallmark of Smith-Lemli-Opitz syndrome (SLOS). Fourteen 7-DHC-derived oxysterols previously have been identified as products of free radical oxidation in vitro; one of these oxysterols, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), was recently identified in Dhcr7-deficient cells and in brain tissues of Dhcr7-null mouse. We report here the isolation and characterization of three novel 7-DHC-derived oxysterols (4α- and 4β-hydroxy-7-DHC and 24-hydroxy-7-DHC) in addition to DHCEO and 7-ketocholesterol (7-kChol) from the brain tissues of AY9944-treated rats. The identities of these five oxysterols were elucidated by HPLC-ultraviolet (UV), HPLC-MS, and 1D- and 2D-NMR. Quantification of 4α- and 4β-hydroxy-7-DHC, DHCEO, and 7-kChol in rat brain, liver, and serum were carried out by HPLC-MS using d(7)-DHCEO as an internal standard. With the exception of 7-kChol, these oxysterols were present only in tissues of AY9944-treated, but not control rats, and 7-kChol levels were markedly (>10-fold) higher in treated versus control rats. These findings are discussed in the context of the potential involvement of 7-DHC-derived oxysterols in the pathogenesis of SLOS.
AIMS - To assess the efficacy and safety of ezetimibe/simvastatin (E/S) plus extended-release niacin (N) in hyperlipidaemic patients with diabetes mellitus (DM), metabolic syndrome (MetS) without DM (MetS/non-DM) or neither (non-DM/non-MetS).
METHODS - A subgroup analysis of a double-blind, 64-week trial of 1220 randomized patients who received E/S (10/20 mg) + N (to 2 g) or E/S (10/20 mg) for 64 weeks, or N (to 2 g) for 24 weeks then E/S (10/20 mg) + N (2 g) or E/S (10/20 mg) for 40 additional weeks. The evaluable populations of this analysis included n = 765 patients at 24 weeks and n = 574 at 64 weeks. Among those receiving N, only those who attained the 2-g dose were included in the analysis.
RESULTS - E/S+N improved levels of low-density lipoprotein cholesterol, other lipids and lipoprotein ratios compared with N and E/S at 24 weeks and E/S at 64 weeks. The combination increased high-density lipoprotein cholesterol and apolipoprotein AI comparably to N and more than E/S. E/S+N reduced high-sensitivity C-reactive protein (hsCRP) levels more effectively than N and similarly to E/S. E/S+N was generally well tolerated. Discontinuations due to flushing with N and E/S+N were comparable and greater than E/S in all subgroups. Fasting glucose trended higher for N vs. E/S. Glucose elevations from baseline to 12 weeks were highest for patients with DM (24.9 mg/dl for N, 21.2 mg/dl for E/S+N, 17.5 mg/dl for E/S); fasting glucose then declined to pretreatment levels at 64 weeks in all subgroups. New-onset DM was more frequent among MetS patients than those without MetS during the first 24 weeks and trended higher among those assigned to N-containing regimens [n = 5(5.1%) for N, n = 2(1.7%) for E/S, n = 21(8.8%) for E/S+N]; during the 24-64 week extension study, diabetes was diagnosed in five additional patients in the E/S(cumulative incidence of 5.9%) and one in the E/S+N (cumulative incidence of 9.2%). Treatment-incident elevations in uric acid levels were increased among subjects assigned to N-containing regimens, but there were no effects on symptomatic gout.
CONCLUSION - Combination E/S+N is a safe treatment option for hyperlipidaemic patients including those with DM and MetS, but requires monitoring of glucose and potentially uric acid levels.
© 2010 Blackwell Publishing Ltd.
BACKGROUND AND AIMS - Some nutraceuticals are prescribed as lipid-lowering substances. However, doubts remain about their efficacy. We evaluated the effects of a nutraceutical combination (NC), consisting of 500 mg berberine, 200mg red yeast rice and 10mg policosanols, on cholesterol levels and endothelial function in patients with hypercholesterolemia.
METHODS AND RESULTS - In this single centre, randomized, double-blind, placebo-controlled study, 50 hypercholesterolemic patients (26 males and 24 females, mean age 55±7 years, total cholesterol 6.55±0.75 mmol/l, BMI 28±3.5) were randomized to 6 weeks of treatment with a daily oral dose of NC (25 patients) or placebo (25 patients). In a subsequent open-label extension of 4 weeks, the whole sample received NC. The main outcome measure was decrease total cholesterol (C) levels in the NC arm. Secondary outcome measures were decreased low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and improved endothelial-dependent flow-mediated dilation (FMD) and insulin sensitivity in relation to NC. Evaluation of absolute changes from baseline showed significant reductions in NC versus placebo for C and LDL-C (C: -1.14±0.88 and -0.03±0.78 mmol/l, p<0.001; LDL-C: -1.06±0.75 and -00.4±0.54 mmol/l, p<0.001), and a significant improvement of FMD (3±4% and 0±3% respectively, p<0.05). After the extension phase, triglyceride levels decreased significantly from 1.57±0.77 to 1.26±0.63 mmol/l, p<0.05 and insulin sensitivity improved in a patient subgroup with insulin resistance at baseline (HOMA: from 3.3±0.4 to 2.5±1.3, p<0.05). No adverse effect was reported.
CONCLUSIONS - This NC reduces cholesterol levels. The reduction is associated with improved endothelial function and insulin sensitivity.
Copyright © 2009 Elsevier B.V. All rights reserved.
CONTEXT - Endometriosis is a common condition associated with infertility and pelvic pain in women. Recent in vitro studies have shown that statins decrease proliferation of endometrial stroma (ES) and inhibit angiogenesis.
OBJECTIVE - The aim was to evaluate effects of simvastatin on development of endometriosis in a nude mouse model.
METHODS - Proliferative phase human endometrial biopsies were obtained from healthy donors and established as organ cultures or used to isolate ES cells. To establish endometriosis in the nude mouse, endometrial tissues were maintained in 1 nm estradiol (E) for 24 h and subsequently injected into ovariectomized nude mice. Mice (n = 37) were treated with E (8 mg, SILASTIC capsule implants; made in author laboratory) alone or with E plus simvastatin (5 or 25 mg/kg x d) for 10 d beginning 1 d after tissue injection (from three donors). Mice were killed and examined for disease. Effects of simvastatin on matrix metalloproteinase-3 (MMP-3) were evaluated in cultures of ES cells.
PRIMARY OUTCOME - The number and size of endometriotic implants were measured.
RESULTS - Simvastatin induced a dose-dependent decrease of the number and size of endometrial implants in mice. At the highest dose of simvastatin, the number of endometrial implants decreased by 87%, and the volume by 98%. Simvastatin also induced a concentration-dependent decrease in MMP-3 in the absence and presence of inflammatory challenge (using IL-1alpha).
CONCLUSIONS - Simvastatin exerted a potent inhibitory effect on the development of endometriosis in the nude mouse. Mechanisms of action of simvastatin may include inhibition of MMP-3. The present findings may lead to the development of novel treatments of endometriosis involving statins.
Hyperlipidemia is common after renal transplantation. On the basis of current lipid guidelines, the majority of renal transplant recipients should have plasma low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL. Even with statin (HMG-CoA [3-hydroxy-3-methylglutaryl CoA] reductase inhibitor) therapy, a significant number of renal transplant recipients have LDL-C levels >100 mg/dL. We report that ezetimibe, a novel inhibitor of intestinal cholesterol absorption, was well tolerated and effectively reduced the LDL-C level to <100 mg/dL in our cohort of renal transplant recipients with persistently elevated LDL-C levels during treatment with maximally tolerated statin medications.
Hyperlipidemia affects the majority of renal transplant patients. Multiple risk factors contribute to elevated serum cholesterol including the use of certain immunosuppressant agents. HMG-Co A reductase inhibitors have become the preferred class of cholesterol-lowering medication with an increasing body of evidence to support their safety, efficacy, and outcomes in both the normal and renal transplant populations. New guidelines recommend lowering previous LDL-c goals as outcomes appears to continually improve. As a result, ezetimibe has been added to patients with persistently elevated triglycerides and/or LDL-c in individuals who possessed a renal transplant and were deemed to be on a maximum safe dose of statin agent. After the addition of ezetimibe, total cholesterol, LDL-c, and triglycerides fell by 21%, 31%, and 13%, respectively. Creatinine phosphokinase, liver enzyme serum levels, and renal function were not affected to any level of clinical significance with the addition of ezetimibe. Large interpatient variability of measurable immunosuppressant levels was seen but no serious adverse events were attributed to a change in levels.
Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors that form obligate heterodimers with retinoid X receptors (RXRs). These nuclear receptors play crucial roles in the regulation of fatty acid metabolism: LXRs activate expression of sterol regulatory element-binding protein 1c (SREBP-1c), a dominant lipogenic gene regulator, whereas PPARalpha promotes fatty acid beta-oxidation genes. In the current study, effects of PPARs on the LXR-SREBP-1c pathway were investigated. Luciferase assays in human embryonic kidney 293 cells showed that overexpression of PPARalpha and gamma dose-dependently inhibited SREBP-1c promoter activity induced by LXR. Deletion and mutation studies demonstrated that the two LXR response elements (LXREs) in the SREBP-1c promoter region are responsible for this inhibitory effect of PPARs. Gel shift assays indicated that PPARs reduce binding of LXR/RXR to LXRE. PPARalpha-selective agonist enhanced these inhibitory effects. Supplementation with RXR attenuated these inhibitions by PPARs in luciferase and gel shift assays, implicating receptor interaction among LXR, PPAR, and RXR as a plausible mechanism. Competition of PPARalpha ligand with LXR ligand was observed in LXR/RXR binding to LXRE in gel shift assay, in LXR/RXR formation in nuclear extracts by coimmunoprecipitation, and in gene expression of SREBP-1c by Northern blot analysis of rat primary hepatocytes and mouse liver RNA. These data suggest that PPARalpha activation can suppress LXR-SREBP-1c pathway through reduction of LXR/RXR formation, proposing a novel transcription factor cross-talk between LXR and PPARalpha in hepatic lipid homeostasis.