The relationship between Lp(a) and CVD outcomes: a systematic review

Summary of QUIPS quality assessment domains (60 studies). (DOCX 54 kb

Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data

Background Patients with type 2 diabetes mellitus (T2DM) have elevated cardiovascular risk. PCSK9 monoclonal antibodies have been shown to reduce LDL-C and other lipids, but specific efficacy for patients with diabetes is unknown. Methods We studied the effect of the PCSK9 inhibitor evolocumab on lipid parameters (LDL-C, non-HDL-cholesterol, total cholesterol, triglycerides, lipoprotein(a), HDL-C) in patients with and without T2DM. We searched Medline and EMBASE (2012-2015) to identify 12-week phase 3 trials of subcutaneous evolocumab therapy once every 2 weeks or once monthly versus placebo or ezetimibe. We used random effects meta-analyses to combine data. Subgroups of T2DM patients (by glycaemia, insulin use, renal function and cardiovascular disease status) were also compared. Findings Data were available for 413 patients with, and 2,119 without, T2DM in three trials. After 12 weeks of evolocumab therapy, mean (95% CI) reductions in LDL-C were 60% (51-69%) versus placebo and 39% (32-47%) versus ezetimibe in patients with T2DM. Reductions were 66% (62-70%) and 40% (36-45%), respectively, in patients without T2DM. In patients with T2DM, reductions observed with evolocumab compared with placebo and ezetimibe were 55% (47-63%) and 34% (26-41%) for non-HDL-cholesterol, 38% (32-44%) and 24% (16-31%) for total cholesterol, 31% (25-37%) and 26% (16-35%) for lipoprotein(a), respectively; increases in HDL-C of 8% (4-11%) and 8% (4-13%), respectively, were also observed. Findings across diabetes subgroups were comparable. Interpretation Evolocumab markedly reduces atherogenic lipoproteins in T2DM, an effect consistent across T2DM subgroups, and comparable to changes in patients without T2DM. Cardiovascular outcomes trials are ongoing

Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab in patients with type 2 diabetes: a meta-analysis

Background: Patients with type 2 diabetes have increased cardiovascular risk. PCSK9 monoclonal antibodies have been shown to reduce LDL cholesterol and other lipids, but specific efficacy for patients with diabetes is unknown. We compared the effect of the PCSK9 inhibitor evolocumab on lipid parameters in patients with and without type 2 diabetes. Methods: We did a random-effects meta-analysis of randomised clinical trials comparing the efficacy of evolocumab, placebo, and ezetimibe to improve lipid parameters in adult patients (age 18–80 years) with or without type 2 diabetes. We searched MEDLINE and Embase to identify eligible 12-week, phase 3 trials published between Jan 1, 2012, and Feb 28, 2015. We excluded trials that included patients who had homozygous familial hypercholesterolaemia. All analyses were based on individual participant data. We used DerSimonian and Laird random-effects meta-analyses to compare the mean changes from baseline in concentrations of LDL cholesterol, non-HDL cholesterol, total cholesterol, triglycerides, lipoprotein(a), and HDL cholesterol at 12 weeks for evolocumab, placebo, and ezetimibe. We also assessed the effect of evolocumab therapy compared with placebo across subgroups of patients based on glycaemia, insulin use, renal function, and cardiovascular disease status at baseline. Results: Three trials met our inclusion criteria, and included 413 patients with type 2 diabetes and 2119 patients without type 2 diabetes. In patients with type 2 diabetes evolocumab caused mean reductions in LDL cholesterol concentration that were 60% (95% CI 51–69) versus placebo and 39% (32–47) versus ezetimibe. In patients without type 2 diabetes, evolocumab caused mean reductions in LDL cholesterol that were 66% (62–70) versus placebo and 40% (36–45) versus ezetimibe. In patients with type 2 diabetes, evolocumab was associated with reductions in non-HDL cholesterol (55% [47–63] vs placebo and 34% [26–41] vs ezetimibe), total cholesterol (38% [32–44] vs placebo and 24% [16–31] vs ezetimibe), and lipoprotein(a) (31% [25–37] vs placebo and 26% [16–35] vs ezetimibe), and an increase in HDL cholesterol (7% [4–11] vs placebo and 8% [4–13] vs ezetimibe). Findings were similar across diabetes subgroups based on glycaemia, insulin use, renal function, and cardiovascular disease status. Interpretation: Evolocumab markedly reduces atherogenic lipoproteins in patients with type 2 diabetes, an effect that is consistent across subgroups and similar to that seen in patients without type 2 diabetes. Results from ongoing cardiovascular outcome trials of PCSK9 inhibitors will provide additional data to inform the use of these drugs in patients with type 2 diabetes

Abstract 16955: Effects of Evolocumab (AMG 145) as a Monotherapy or in Combination with Statins on Lipoprotein Particles and Subclasses

Background: Evolocumab (AMG 145) reduces LDL-C alone or in combination with statins. We evaluated the effect of evolocumab on lipoprotein particles from subjects receiving evolocumab as monotherapy or combined with statins using biomarker samples collected from 2 clinical studies. Methods: Exploratory biomarker samples, taken before and after evolocumab treatment from a phase 1b study evaluating evolocumab combined with statins in hypercholesterolemic (HCL) subjects and from a phase 2 study evaluating evolocumab as a monotherapy in HCL subjects, were analyzed by NMR at LipoScience, Inc. Lipoprotein particle concentrations and size were determined using the LP-3 module. Results: Evolocumab alone or in combination with statins significantly reduced total, small, and large LDL-P in a dose-dependent manner. As shown in the table, evolocumab monotherapy reduced total LDL-P by 45% and 54%, small LDL-P by 36% and 35%, and large LDL-P by 68% and 84%, after 140 mg and 420 mg doses, respectively. LDL-P values were reduced slightly less than LDL-C (52% at 140 mg and 62% at 420 mg), but LDL-P reductions were similar to those seen for ApoB. IDL-P, total VLDL-P, and small VLDL-P were also reduced. Total HDL-P increased, primarily due to increases in large HDL-P. Similar results were obtained when evolocumab was given combined with statins, but with greater reductions in total, small, and large LDL-P. Notably, greater reductions in LDL-P or LDL-C were correlated with higher concentrations of total LDL-P, small LDL-P, triglycerides, smaller LDL size, and lower HDL-C at baseline. Conclusion: Evolocumab either alone or in combination with statins affected lipoprotein particles similarly. In both treatment regimens, LDL-C and total LDL-P were significantly reduced and large LDL-P were reduced, on average, to a greater extent than small LDL-P. Total LDL-P was reduced to a lesser extent than LDL-C. Additionally, reductions in VLDL-P and IDL-P were observed along with increases in HDL-P. </jats:p

Plasma eicosanoids as noninvasive biomarkers of liver fibrosis in patients with nonalcoholic steatohepatitis.

BackgroundEicosanoid and related docosanoid polyunsaturated fatty acids (PUFAs) and their oxygenated derivatives have been proposed as noninvasive lipidomic biomarkers of nonalcoholic steatohepatitis (NASH). Therefore, we investigated associations between plasma eicosanoids and liver fibrosis to evaluate their utility in diagnosing and monitoring NASH-related fibrosis.MethodsOur analysis used baseline eicosanoid data from 427 patients with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), and longitudinal measurements along with liver fibrosis staging from 63 patients with NASH and stage 2/3 fibrosis followed for 24 weeks in a phase II trial.ResultsAt baseline, four eicosanoids were significantly associated with liver fibrosis stage: 11,12-DIHETE, tetranor 12-HETE, adrenic acid, and 14, 15-DIHETE. Over 24 weeks of follow up, a combination of changes in seven eicosanoids [5-HETE, 7,17-DHDPA, adrenic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA), 16-HDOHE, and 9-HODE) had good diagnostic accuracy for the prediction of ⩾1 stage improvement in fibrosis (AUROC: 0.74; 95% CI: 0.62-0.87), and a combination of four eicosanoids (7,17-DHDPA, 14,15-DIHETRE, 9-HOTRE, and free adrenic acid) accurately predicted improvement in hepatic collagen content (AUROC: 0.72; 95% CI: 0.50-0.77).ConclusionThis study provides preliminary evidence that plasma eicosanoids may serve as noninvasive biomarkers of liver fibrosis and may predict liver fibrosis improvement in NASH