Dataset Information

Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease.

ABSTRACT:

Objective

Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome.

Research design and methods

In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4-12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A_1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A_1c ?6.5%, or a combination of at least two measurements of serum glucose ?7.0 mmol/L (fasting) or ?11.1 mmol/L (random).

Results

At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68-0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes.

Conclusions

In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.

SUBMITTER: Schwartz GG

PROVIDER: S-EPMC7171952 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease.

Schwartz Gregory G GG Leiter Lawrence A LA Ballantyne Christie M CM Barter Philip J PJ Black Donald M DM Kallend David D Laghrissi-Thode Fouzia F Leitersdorf Eran E McMurray John J V JJV Nicholls Stephen J SJ Olsson Anders G AG Preiss David D Shah Prediman K PK Tardif Jean-Claude JC Kittelson John J

Diabetes care 20200306 5

<h4>Objective</h4>Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome.<h4>Research design and methods</h4>In the dal-OUTCOMES trial, 15,871 patients were random ...[more]

PMID: 32144166

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Project description:AimsHigh-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular (CV) events and thus an attractive therapeutic target. However, in spite of marked elevations in HDL-C, the first cholesterol transport protein (CETP) inhibitor torcetrapib raised blood pressure (BP), impaired endothelial function, and increased CV mortality and morbidity. Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib. As HDL stimulates nitric oxide (NO), suppresses inflammation, and exerts protective CV effects, we investigated the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers, and lipids in patients with, or at risk of, coronary heart disease (CHD) in a double-blind randomized placebo-controlled trial (clinicaltrials.gov number NCT00655538).Methods and resultsPatients with target low-density lipoprotein cholesterol (LDL-C) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of standard therapy (including statins). The primary outcome measures were the change from baseline of flow-mediated dilatation (%FMD) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring (ABPM) at week 4. Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks, changes in HDL-C, LDL-C, triglycerides, CETP activity, as well as standard safety parameters. Four hundred seventy-six patients were randomized. Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4% with placebo or dalcetrapib, respectively and did not change significantly from placebo after 12 and 36 weeks (P = 0.1764 and 0.9515, respectively). After 4, 24, and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51, 53, and 56% (placebo corrected, all P < 0.0001), while at weeks 4, 12, and 36 HDL-C increased by 25, 27, and 31% (placebo corrected, all P < 0.0001). Low-density lipoprotein cholesterol levels did not change. At baseline, ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group (P = 0.3372 and 0.1248, respectively, placebo-corrected change from baseline) and did not change for up to 36 weeks. Biomarkers of inflammation, oxidative stress, and coagulation did not change during follow-up except for Lp-PLA(2) mass levels which increased by 17% (placebo corrected). Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event (11 events with dalcetrapib and 12 events with placebo).ConclusionThe dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD. Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function, blood pressure, or markers of inflammation and oxidative stress. The dal-OUTCOMES trial (NCT00658515) will show whether dalcetrapib improves outcomes in spite of a lack of effect on endothelial function.

Project description:BackgroundAlthough ischemic coronary artery disease (CAD) is the most common etiology of heart failure (HF), the extent to which patients with new-onset HF actually undergo an ischemic work-up and/or revascularization is not well defined.ObjectivesThis study sought to analyze the patterns of testing for ischemic CAD and revascularization in patients with new-onset HF.MethodsThis was a retrospective cohort study using Truven Health MarketScan Commercial and Medicare databases from 2010 to 2013. The occurrence of noninvasive and invasive ischemic CAD testing and revascularization procedures were examined among patients with new inpatient HF diagnoses during the index hospitalization and within 90 days of admission.ResultsAmong 67,161 patients identified with new-onset HF during an inpatient hospitalization, only 17.5% underwent testing for ischemic CAD during the index hospitalization, increasing to 27.4% at 90 days. Among patients with new-onset HF, only 2.1% underwent revascularization during the index hospitalization for HF; by 90 days, the revascularization rate had increased to 4.3%. Of the tests performed for ischemic CAD, stress testing (nuclear stress testing or stress echocardiography) was performed in 7.9% of new-onset HF patients during the index hospitalization (14.6% within 90 days), whereas coronary angiography was performed in 11.1% of patients during the index hospitalization (16.5% within 90 days). In adjusted analyses, HF patients carrying a baseline diagnosis of CAD had greater odds of noninvasive ischemic testing (odds ratio: 1.25; 95% confidence interval: 1.17 to 1.33; p < 0.0001), as well as invasive ischemic testing (odds ratio: 1.93; 95% confidence interval: 1.83 to 2.05; p < 0.0001), at the index hospitalization than those without baseline CAD.ConclusionsThe majority of patients hospitalized for new-onset HF did not receive testing for ischemic CAD either during hospitalization or within 90 days, which suggests significant underutilization of ischemic CAD assessment in new-onset HF patients.

Project description:BackgroundThe pathological basis of coronary heart disease (CHD) is atherosclerosis. BTNL2 can inhibit the activation of T cells. We aimed to explore the association between BTNL2 genetic variants and CHD risk in the southern Chinese Han population.MethodsWe recruited 1419 participants to perform an association analysis between missense variants in BTNL2 and CHD risk through SNPStats online software. Genotyping of all candidate SNPs were completed by the Agena MassARRAY. In addition, we used false-positive report probability analysis to detect whether the positive findings were noteworthy observations. We also used Haploview 4.2 software and SNPStats online software to conduct the haplotype analysis and analysis of linkage disequilibrium (LD). Finally, the interaction of SNP-SNP in CHD risk was evaluated by multi-factor dimensionality reduction (MDR).ResultsThe results showed that BTNL2-rs35624343, -rs117896888, -rs41441651, -rs41417449, -rs28362680 and -rs2076523 were significantly associated with the CHD susceptibility. Especially for BTNL2-rs28362680, the allele A (OR = 0.68, p < 0.0001), genotype AA (OR = 0.40, p = 0.001) or GA (OR = 0.68, p < 0.0001) were associated with the reducing CHD risk. And -rs28362680 significantly reduced the CHD risk under all genetic models (dominant: OR = 0.64, p < 0.0001; recessive: OR = 0.47, p = 0.003; overdominant: OR = 0.73, p = 0.004; log-additive: OR = 0.66, p < 0.0001). And -rs28362680 was also closely associated with CHD risk reduction in all stratified analyses (age, gender, smoking, drinking, hypertension and diabetes). In addition, haplotype analysis showed that the "Crs117896888Crs41441651Trs41417449Ars28362680" (OR = 0.65, p < 0.0001) and "Grs117896888Trs41441651Crs41417449Ars28362680" (OR = 0.68, p = 0.013) may reduce CHD risk.ConclusionMissense variants (rs35624343, rs117896888, rs41441651, rs41417449, rs28362680, rs2076523) may be protective factors for the CHD risk. In particular, there were sufficient evidences that BTNL2-rs28362680 can protective CHD risk.

Project description:AimTo analyze the risk of coronary heart disease in patients with type 2 diabetes mellitus (T2DM) receiving standard medical treatment.MethodsWe performed a retrospective chart analysis of 269 middle-aged patients (age 45-64 years, mean age, 53.9 ± 5.5 years) with T2DM and without atherosclerotic cardiovascular events who underwent typing to determine their apolipoprotein E (apoE) isoforms. The apoE isoforms were determined using isoelectric focusing, followed by immunoblotting. We retrospectively evaluated the charts of the 269 patients, recorded between their first visit to the hospital (the study's start point, between 1987 and 1992) and the occurrence of an atherosclerotic cardiovascular event (the study's endpoint) or January 2004, whichever came first. The age-adjusted mean values and the prevalences of covariates were calculated to compare the laboratory data among the apoE phenotypes. To investigate the association of risk factors with the incidence of coronary heart disease during the follow-up period, monovariate and multivariate Cox regression models were used.ResultsAt enrollment, the mean serum low density lipoprotein (LDL) cholesterol levels were lowest (2.92 ± 0.89 mmol/L) among the subjects with apoE2 (apoE2/2 or apoE2/3) and highest (3.52 ± 0.77 mmol/L) among the subjects with apoE4 (apoE3/4 or apoE4/4). No significant differences in mean age or the percentage of smokers were observed among the three groups. Furthermore, no significant differences were observed in the systolic and diastolic blood pressures, body mass index, HbA1c level or serum triglyceride levels among the three groups. There were 47 cases of coronary heart disease over 3285 person-years of follow-up. An age-adjusted multivariate Cox proportional model identified diabetic retinopathy (hazard ratio, 2.38, 95% CI: 1.28-4.43, P = 0.006), a high systolic blood pressure (hazard ratio, 1.04, 95% CI: 1.02-1.06, P < 0.001) and high HbA1c values (hazard ratio, 1.19, 95% CI: 1.02-1.38, P = 0.0029), but not the LDL cholesterol value at enrollment (hazard ratio, 1.01, 95% CI: 0.97-1.05, P = 0.77) nor the specific apoE isoform, as significant predictors of coronary heart disease.ConclusionUnder standard medical treatment of diabetes, including the control of LDL cholesterol levels, the apoE4 isoform was not associated with coronary heart disease among T2DM patients.

Dataset Information

Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease.

Objective

Research design and methods

Results

Conclusions

Publications

Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease.

Similar Datasets

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