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Major adverse cardiovascular events with basal insulin peglispro versus comparator insulins in patients with type 1 or type 2 diabetes: a meta-analysis.

ABSTRACT: To identify possible differences in cardiovascular (CV) risk among different insulin therapies, we performed pre-specified meta-analyses across the clinical program for basal insulin peglispro (BIL), in patients randomized to treatment with BIL or comparator insulin [glargine (IG) or NPH].One phase 2 (12-week) and 6 phase 3 (26 to 78-week) randomized studies of BIL compared to IG or NPH, in patients with type 1 or type 2 diabetes, were included. The participants were diverse with respect to demographics, baseline glycemic control, and concomitant disease or medications, but treatment groups were comparable in each study. For any potential CV or neurovascular event, relevant medical information was provided to a blinded external clinical events committee (C5Research, Cleveland Clinic, Cleveland, OH, USA) for adjudication. Cox regression analysis was used to compare treatment groups. The primary endpoint was a composite of adjudicated MACE+ [CV death, myocardial infarction (MI), stroke, or hospitalization for unstable angina].The pooled population included 5862 patients in the safety evaluation, with randomization to BIL:IG:NPH of 3578:2072:212. Mean age was 54.1 years, 27 % had type 1 diabetes, 56 % were male, and 88 % were white. Baseline demographic and clinical characteristics, including use of statins or other lipid-lowering drugs, were comparable between BIL and comparators. A total of 83 patients experienced at least 1 MACE+ and 70 patients experienced at least 1 MACE (CV death, MI, or stroke). Overall, there were no treatment-associated differences in time to MACE+ [hazard ratio (HR) for BIL versus comparator insulin (95 % CI): 0.82 (0.53-1.27)] or MACE [0.83 (0.51-1.33)]. In 4297 patients with type 2 diabetes, there were 71 MACE+ events [HR: 1.02 (95 % CI: 0.63-1.65), p = 0.94]. In 1565 patients with type 1 diabetes, there were only 12 MACE+ [0.24 (0.07-0.85), p = 0.027]. There were no differences in all-cause death between BIL and comparators. Sub-group analyses did not identify any sub-population with increased risk with BIL versus comparator insulins.Treatment with BIL versus comparator insulin in patients with type 1 diabetes or type 2 diabetes was not associated with increased risk for major CV events in the studies analyzed.

SUBMITTER: Hoogwerf BJ

PROVIDER: S-EPMC4869328 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Major adverse cardiovascular events with basal insulin peglispro versus comparator insulins in patients with type 1 or type 2 diabetes: a meta-analysis.

Hoogwerf Byron J BJ Lincoff A Michael AM Rodriguez Angel A Chen Lei L Qu Yongming Y

Cardiovascular diabetology 20160517

<h4>Background</h4>To identify possible differences in cardiovascular (CV) risk among different insulin therapies, we performed pre-specified meta-analyses across the clinical program for basal insulin peglispro (BIL), in patients randomized to treatment with BIL or comparator insulin [glargine (IG) or NPH].<h4>Methods</h4>One phase 2 (12-week) and 6 phase 3 (26 to 78-week) randomized studies of BIL compared to IG or NPH, in patients with type 1 or type 2 diabetes, were included. The participant ...[more]

PMID: 27188479

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Project description:Importance:The comparative cardiovascular safety of analogue and human insulins in adults with type 2 diabetes who initiate insulin therapy in usual care settings has not been carefully evaluated using machine learning and other rigorous analytic methods. Objective:To examine the association of analogue vs human insulin use with mortality and major cardiovascular events. Design, Setting, and Participants:This retrospective cohort study included 127 600 adults aged 21 to 89 years with type 2 diabetes at 4 health care delivery systems who initiated insulin therapy from January 1, 2000, through December 31, 2013. Machine learning and rigorous inference methods with time-varying exposures were used to evaluate associations of continuous exposure to analogue vs human insulins with mortality and major cardiovascular events. Data were analyzed from September 1, 2017, through June 30, 2018. Exposures:On the index date (first insulin dispensing), participants were classified as using analogue insulin with or without human insulin or human insulin only. Main Outcomes and Measures:Overall mortality, mortality due to cardiovascular disease (CVD), myocardial infarction (MI), stroke or cerebrovascular accident (CVA), and hospitalization for congestive heart failure (CHF) were evaluated. Marginal structural modeling (MSM) with inverse probability weighting was used to compare event-free survival in separate per-protocol analyses. Adjusted and unadjusted hazard ratios and cumulative risk differences were based on logistic MSM parameterizations for counterfactual hazards. Propensity scores were estimated using a data-adaptive approach (machine learning) based on 3 nested covariate adjustment sets. Sensitivity analyses were conducted to address potential residual confounding from unmeasured differences in risk factors across delivery systems. Results:The 127 600 participants (mean [SD] age, 59.4 [12.6] years; 68 588 men [53.8%]; mean [SD] body mass index, 32.3 [7.1]) had a median follow-up of 4 quarters (interquartile range, 3-9 quarters) and experienced 5464 deaths overall (4.3%), 1729 MIs (1.4%), 1301 CVAs (1.0%), and 3082 CHF hospitalizations (2.4%). There were no differences in adjusted hazard ratios for continuous analogue vs human insulin exposure during 10 quarters for overall mortality (1.15; 95% CI, 0.97-1.34), CVD mortality (1.26; 95% CI, 0.86-1.66), MI (1.11; 95% CI, 0.77-1.45), CVA (1.30; 95% CI, 0.81-1.78), or CHF hospitalization (0.93; 95% CI, 0.75-1.11). Conclusions and Relevance:Insulin-naive adults with type 2 diabetes who initiate and continue treatment with human vs analogue insulins had similar observed rates of major cardiovascular events, CVD mortality, and overall mortality.

Project description:Soluble TNF-like weak inducer of apoptosis (sTWEAK) is a proinflammatory cytokine belonging to the TNF superfamily. sTWEAK concentrations have been associated with the presence of CKD and cardiovascular disease (CVD). We hypothesized that sTWEAK levels may relate to a higher prevalence of atherosclerotic plaques, vascular calcification, and cardiovascular outcomes observed in patients with CKD.A 4-year prospective, multicenter, longitudinal study was conducted in 1058 patients with CKD stages 3-5D (mean age =58±13 years old; 665 men) but without any history of CVD from the NEFRONA Study (a study design on the prevalence of surrogate markers of CVD). Ankle-brachial index and B-mode ultrasound were performed to detect the presence of carotid and/or femoral atherosclerotic plaques together with biochemical measurements and sTWEAK assessment. Patients were followed for cardiovascular outcomes (follow-up of 3.13±1.15 years).Patients with more advanced CKD had lower sTWEAK levels. sTWEAK concentrations were independently and negatively associated with carotid intima-media thickness. sTWEAK levels were lower in patients with carotid atherosclerotic plaques but not in those with femoral plaques. After adjustment by confounders, the odds ratio (OR) for presenting carotid atherosclerotic plaques in patients in the lowest versus highest tertile of sTWEAK was 4.18 (95% confidence interval [95% CI], 2.89 to 6.08; P<0.001). Furthermore, sTWEAK levels were lower in patients with calcified carotid atherosclerotic plaques. The OR for presenting calcified carotid plaques was 1.77 (95% CI, 1.06 to 2.93; P=0.02) after multivariable adjustment. After the follow-up, 41 fatal and 68 nonfatal cardiovascular events occurred. In a Cox model, after controlling for potential confounding factors, patients in the lowest tertile of sTWEAK concentrations had a higher risk of fatal and nonfatal cardiovascular events (hazard ratio [HR], 2.40; 95% CI, 1.33 to 4.33; P=0.004) and cardiovascular mortality (HR, 2.67; 95% CI, 1.05 to 6.76; P=0.04).Low sTWEAK levels were associated with the presence of carotid atherosclerotic plaques in patients with CKD. Additionally, lower sTWEAK levels were associated with a higher risk of cardiovascular morbidity and mortality.

Project description:ImportancePatients with stroke due to nontraumatic (spontaneous) intracerebral hemorrhage (ICH) often harbor vascular risk factors and comorbidities, but it is unclear which major adverse cardiovascular events (MACEs) occur more frequently among patients with a prior ICH than the general population.ObjectiveTo evaluate the risk of a MACE for patients with a prior ICH compared with the general population.Design, setting, and participantsThis cohort study identified 8991 patients with a first ICH in the Danish Stroke Registry from January 1, 2005, to June 30, 2018, who were aged 45 years or older and survived more than 30 days after an ICH. Patients in this ICH cohort were matched 1:40 on age, sex, and ICH-onset date with a comparison cohort of 359 185 individuals from the general population without a prior ICH. Both cohorts were followed up for 6 months or more until December 31, 2018, for outcomes using registry data. Data were analyzed from October 1, 2021, to July 19, 2022.ExposuresIntracerebral hemorrhage identified by a nationwide clinical database.Main outcomes and measuresThe main outcomes were ICH, ischemic stroke, myocardial infarction, and a composite of MACEs. For each outcome, a case-control study nested within the cohorts was also performed, adjusting for time-varying exposures and potential confounders. Crude absolute event rates per 100 person-years, adjusted hazard ratios (aHRs) and 95% CIs and, in the nested case-control analyses, crude and adjusted odds ratios and 95% CIs were calculated.ResultsThe ICH cohort (n = 8991; 4814 men [53.5%]; mean [SD] age, 70.7 [11.5] years) had higher event rates than the comparison cohort (n = 359 185; 192 256 men [53.5%]; mean [SD] age, 70.7 [11.5] years) for MACEs (4.16 [95% CI, 3.96-4.37] per 100 person-years vs 1.35 [95% CI, 1.33-1.36] per 100 person-years; aHR, 3.13 [95% CI, 2.97-3.30]), ischemic stroke (1.52 [95% CI, 1.40-1.65] per 100 person-years vs 0.56 [95% CI, 0.55-0.57] per 100 person-years; aHR, 2.64 [95% CI, 2.43-2.88]), and ICH (1.44 [95% CI, 1.32-1.56] per 100 person-years vs 0.06 [95% CI, 0.06-0.07] per 100 person-years; aHR, 23.49 [95% CI, 21.12-26.13]) but not myocardial infarction (0.52 [95% CI, 0.45-0.60] per 100 person-years vs 0.48 [95% CI, 0.47-0.49] per 100 person-years; aHR, 1.12 [95% CI, 0.97-1.29]). Nested case-control analyses returned risk estimates of similar magnitude as the cohort analyses.Conclusions and relevanceThe findings of this cohort study suggest that Danish patients with a prior ICH had statistically significantly higher rates of MACEs than the general population, indicating a need for attention to optimal secondary prevention with blood pressure lowering and antithrombotic and statin therapies after an ICH in clinical research and practice.

Dataset Information

Major adverse cardiovascular events with basal insulin peglispro versus comparator insulins in patients with type 1 or type 2 diabetes: a meta-analysis.

Publications

Major adverse cardiovascular events with basal insulin peglispro versus comparator insulins in patients with type 1 or type 2 diabetes: a meta-analysis.

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