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Dyslipidemia in diabetes mellitus and cardiovascular disease.

ABSTRACT: Patients with diabetes have a high residual risk for cardiovascular disease (CVD) and adverse outcomes despite statin therapy and lifestyle modifications. Particular to individuals with diabetes is the pattern of elevated triglycerides, small dense low density lipoprotein cholesterol, and reduced levels of high density lipoprotein cholesterol, described as dyslipidemia of diabetes. The role of combination therapy with an additional agent such as niacin, ezetimibe, fenofibrate, and n-3 fatty acids has been studied; however, at the same time, these agents have come under criticism for their limitations. We performed a review of key trials assessing the benefit of combination therapy to reduce CVD risk from dyslipidemia. Of the currently available agents that can be used in combination with statins, ezetimibe has the most favorable risk profile, with a recent trial demonstrating modest incremental benefit when given in addition to statins. PCSK9 inhibitors are a promising category, although clinical outcome data in individuals with diabetes are pending.

SUBMITTER: Warraich HJ

PROVIDER: S-EPMC6768535 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Dyslipidemia in diabetes mellitus and cardiovascular disease.

Warraich Haider J HJ Rana Jamal S JS

Cardiovascular endocrinology 20170215 1

Patients with diabetes have a high residual risk for cardiovascular disease (CVD) and adverse outcomes despite statin therapy and lifestyle modifications. Particular to individuals with diabetes is the pattern of elevated triglycerides, small dense low density lipoprotein cholesterol, and reduced levels of high density lipoprotein cholesterol, described as dyslipidemia of diabetes. The role of combination therapy with an additional agent such as niacin, ezetimibe, fenofibrate, and n-3 fatty acid ...[more]

PMID: 31646116

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Project description:Background Metabolic dyslipidemia (high triglyceride) and low high-density lipoprotein cholesterol (HDL-C) is highly prevalent in type 2 diabetes mellitus (T2DM). The extent to which diabetes mellitus-related abnormalities in the triglyceride-HDL-C profile associates with cardiovascular disease (CVD) risk is incompletely understood. We evaluated the associations of triglyceride and HDL-C status with CVD outcomes in individuals with T2DM. Methods and Results We analyzed data from 4199 overweight/obese adults with T2DM free of CVD with available data on triglyceride and HDL-C at baseline (2001-2004) in the Look AHEAD (Action for Health in Diabetes) study. We used Cox proportional models to estimate hazard ratios (HRs) and 95% CIs of: (1) composite CVD outcome (myocardial infarction, stroke, hospitalization for angina, and/or death from cardiovascular causes); (2) coronary artery disease events; and (3) cerebrovascular accidents (stroke). Of the 4199 participants, 62% (n=2600) were women, with a mean age of 58 years (SD, 7), and 40% (n=1659) had metabolic dyslipidemia at baseline. Over a median follow-up of 9.5 years (interquartile range, 8.7-10.3), 500 participants experienced the composite CVD outcome, 396 experienced coronary artery disease events, and 100 experienced stroke. Low HDL-C was associated with higher hazards of the composite CVD outcome (HR, 1.36; 95% CI, 1.12-1.64 [P=0.002]) and coronary artery disease events (HR, 1.46; 95% CI, 1.18-1.81 [P=0.001]) but not stroke (HR, 1.38; 95% CI, 0.90-2.11 [P=0.140]). Compared with patients with normal triglyceride and normal HDL, participants with metabolic dyslipidemia had higher risks of the composite CVD outcome (HR, 1.30; 95% CI, 1.03-1.63 [P=0.025]) and coronary artery disease events (HR, 1.48; 95% CI, 1.14-1.93 [P=0.003]) but not stroke (HR, 1.23; 95% CI, 0.74-2.05 [P=0.420]). Conclusions In a large sample of overweight/obese individuals with T2DM, metabolic dyslipidemia was associated with higher risks of CVD outcomes. Our findings highlight the necessity to account for metabolic dyslipidemia in CVD risk stratification among patients with T2DM. Registration URL: https://www.lookaheadtrial.org; Unique identifier: NCT00017953.

Project description:BACKGROUND:Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). METHODS:In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C???100 mg/dL; n?=?413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C???70 mg/dL; n?=?441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin?<?9% (DM-DYSLIPIDEMIA) or?<?10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was???70 mg/dL (DM-INSULIN) or non-HDL-C was???100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. RESULTS:This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C?<?100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB?<?80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P?<?0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls. CONCLUSIONS:Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015.

Project description:BackgroundHypertension (HTN), diabetes mellitus (DM), and dyslipidemia (DL) are well-known risk factors of cardiovascular disease (CVD), but not all patients develop CVDs. Studies have been limited investigating genetic risk of CVDs specific to individuals with metabolic diseases. This study aimed to identify disease-specific and/or common genetic loci associated with CVD susceptibility in chronic metabolic disease patients.MethodsWe conducted a genome-wide association study (GWAS) of a multiple case-control design with data from the City Cohort within Health EXAminees subcohort of the Korean Genome and Epidemiology Study (KoGES_HEXA). KoGES_HEXA is a population-based prospective cohort of 173,357 urban Korean adults that had health examinations at medical centers. 42,393 participants (16,309 HTN; 5,314 DM; 20,770 DL) were analyzed, and each metabolic disease group was divided into three CVD case-controls: coronary artery disease (CAD), ischemic stroke (IS), and cardio-cerebrovascular disease (CCD). GWASs were conducted for each case-control group with 7,975,321 imputed single nucleotide polymorphisms using the Phase 3 Asian panel from 1000 Genomes Project, by logistic regression and controlled for confounding variables. Genome-wide significant levels were implemented to identify important susceptibility loci.ResultsTotaling 42,393 individuals, this study included 16,309 HTN (mean age [SD], 57.28 [7.45]; 816 CAD, 398 IS, and 1,185 CCD cases), 5,314 DM (57.79 [7.39]; 361 CAD, 153 IS, and 497 CCD cases), and 20,770 DL patients (55.34 [7.63]; 768 CAD, 295 IS, and 1,039 CCD cases). Six genome-wide significant CVD risk loci were identified, with relatively large effect sizes: 1 locus in HTN (HTN-CAD: 17q25.3/CBX8-CBX4 [OR, 2.607; P = 6.37 × 10-9]), 2 in DM (DM-IS: 4q32.3/MARCH1-LINC01207 [OR, 5.587; P = 1.34 × 10-8], and DM-CCD: 17q25.3/RPTOR [OR, 3.511; P = 1.99 × 10-8]), and 3 in DL (DL-CAD: 9q22.2/UNQ6494-LOC101927847 [OR, 2.282; P = 7.78 × 10-9], DL-IS: 3p22.1/ULK4 [OR, 2.162; P = 2.97 × 10-8], and DL-CCD: 2p22.2/CYP1B1-CYP1B1-AS1 [OR, 2.027; P = 4.24 × 10-8]).ConclusionsThis study identified 6 susceptibility loci and positional candidate genes for CVDs in HTN, DM, and DL patients using an unprecedented study design. 1 locus (17q25.3) was commonly associated with CAD. These associations warrant validation in additional studies for potential therapeutic applications.

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Dyslipidemia in diabetes mellitus and cardiovascular disease.

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Dyslipidemia in diabetes mellitus and cardiovascular disease.

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