Dataset Information

Comparison of Mortality and Major Cardiovascular Events Among Adults With Type 2 Diabetes Using Human vs Analogue Insulins.

ABSTRACT: 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.

SUBMITTER: Neugebauer R

PROVIDER: S-EPMC6991251 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Comparison of Mortality and Major Cardiovascular Events Among Adults With Type 2 Diabetes Using Human vs Analogue Insulins.

Neugebauer Romain R Schroeder Emily B EB Reynolds Kristi K Schmittdiel Julie A JA Loes Linda L Dyer Wendy W Desai Jay R JR Vazquez-Benitez Gabriela G Ho P Michael PM Anderson Jeff P JP Pimentel Noel N O'Connor Patrick J PJ

JAMA network open 20200103 1

<h4>Importance</h4>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.<h4>Objective</h4>To examine the association of analogue vs human insulin use with mortality and major cardiovascular events.<h4>Design, setting, and participants</h4>This retrospective cohort study included 127 600 adults aged 21 to 89 ...[more]

PMID: 31977057

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Project description:BackgroundTo 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].MethodsOne 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].ResultsThe 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.ConclusionsTreatment 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.

Project description:ImportanceType 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease.ObjectiveTo evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events.Design, setting, and participantsRandomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018.InterventionsPatients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines.Main outcomes and measuresPrimary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline.ResultsOf 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m2; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, -0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P < .001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P = .62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis.Conclusions and relevanceAmong adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years.Trial registrationClinicalTrials.gov Identifier: NCT01897532.

Project description:ImportanceBefore 2016, safety concerns limited metformin use in patients with kidney disease; however, the effectiveness of metformin on clinical outcomes in patients with reduced kidney function remains unknown.ObjectiveTo compare major adverse cardiovascular events (MACE) among patients with diabetes and reduced kidney function who continued treatment with metformin or a sulfonylurea.Design, setting, and participantsRetrospective cohort study of US veterans receiving care within the national Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016. There were 174 882 persistent new users of metformin and sulfonylureas who reached a reduced kidney function threshold (estimated glomerular filtration rate <60 mL/min/1.73 m2 or creatinine ≥1.4 mg/dL for women or ≥1.5 mg/dL for men). Patients were followed up from reduced kidney function threshold until MACE, treatment change, loss to follow-up, death, or study end (December 2016).ExposuresNew users of metformin or sulfonylurea monotherapy who continued treatment with their glucose-lowering medication after reaching reduced kidney function.Main outcomes and measuresMACE included hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death. The analyses used propensity score weighting to compare the cause-specific hazard of MACE between treatments and estimate cumulative risk accounting for the competing risks of changing therapy or noncardiovascular death.ResultsThere were 67 749 metformin and 28 976 sulfonylurea persistent monotherapy users; the weighted cohort included 24 679 metformin and 24 799 sulfonylurea users (median age, 70 years [interquartile range {IQR}, 62.8-77.8]; 48 497 men [98%]; and 40 476 white individuals [82%], with median estimated glomerular filtration rate of 55.8 mL/min/1.73 m2 [IQR, 51.6-58.2] and hemoglobin A1c level of 6.6% [IQR, 6.1%-7.2%] at cohort entry). During follow-up (median, 1.0 year for metformin vs 1.2 years for sulfonylurea), there were 1048 MACE outcomes (23.0 per 1000 person-years) among metformin users and 1394 events (29.2 per 1000 person-years) among sulfonylurea users. The cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75-0.86) compared with sulfonylureas, yielding an adjusted rate difference of 5.8 (95% CI, 4.1-7.3) fewer events per 1000 person-years of metformin use compared with sulfonylurea use.Conclusions and relevanceAmong patients with diabetes and reduced kidney function persisting with monotherapy, treatment with metformin, compared with a sulfonylurea, was associated with a lower risk of MACE.

Project description:ImportanceWhether optimal cardiovascular health metrics may counteract the risk of cardiovascular events among patients with prediabetes or diabetes is unclear.ObjectiveTo investigate the associations of ideal cardiovascular health metrics (ICVHMs) with subsequent development of cardiovascular disease (CVD) among participants with prediabetes or diabetes as compared with participants with normal glucose regulation.Design, setting, and participantsThe China Cardiometabolic Disease and Cancer Cohort Study was a nationwide, population-based, prospective cohort study of 20 communities from various geographic regions in China. The study included 111 765 participants who were free from CVD or cancer at baseline. Data were analyzed between 2011 and 2016.ExposuresPrediabetes and diabetes were defined according to the American Diabetes Association 2010 criteria. Seven ICVHMs were adapted from the American Heart Association recommendations.Main outcomes and measuresThe composite of incident fatal or nonfatal CVD, including cardiovascular death, myocardial infarction, stroke, and hospitalized or treated heart failure.ResultsOf the 111 765 participants, 24 881 (22.3%) had normal glucose regulation, 61 024 (54.6%) had prediabetes, and 25 860 (23.1%) had diabetes. Mean (SD) age ranged from 52.9 (8.6) years to 59.4 (8.7) years. Compared with participants with normal glucose regulation, among participants with prediabetes, the multivariable-adjusted hazard ratio for CVD was 1.34 (95% CI, 1.16-1.55) for participants who had 1 ICVHM or less and 0.57 (95% CI, 0.43-0.75) for participants who had at least 5 ICVHMs; among participants with diabetes, the hazard ratios for CVD were 2.05 (95% CI, 1.76-2.38) and 0.80 (95% CI, 0.56-1.15) for participants who had 1 ICVHM or less and at least 5 ICVHMs, respectively. Such pattern of association between ICVHMs and CVD was more prominent for participants younger than 55 years (prediabetes and at least 5 ICVHMs: hazard ratio [HR], 0.32; 95% CI, 0.16-0.63; 1 ICVHM or less: HR, 1.58; 95% CI, 1.13-2.21; diabetes and at least 5 ICVHMs: HR, 0.99; 95% CI, 0.44-2.26; 1 ICVHM or less: HR, 2.46; 95% CI, 1.71-3.54; compared with normal glucose regulation) than for participants 65 years or older (prediabetes and at least 5 ICVHMs: HR, 0.80; 95% CI, 0.50-1.26; 1 ICVHM or less: HR, 1.01; 95% CI, 0.79-1.31; diabetes and at least 5 ICVHMs: HR, 0.79; 95% CI, 0.46-1.35; 1 ICVHM or less: HR, 1.73; 95% CI, 1.36-2.22, compared with normal glucose regulation; P values for interaction ≤.02). Additionally, the hazard ratio for CVD per additional ICVHM was 0.82 (95% CI, 0.79-0.86) among participants with prediabetes and was 0.85 (95% CI, 0.80-0.89) among participants with diabetes.Conclusions and relevanceParticipants with prediabetes or diabetes who had 5 or more ICVHMs exhibited lower or no significant excess CVD risks compared with the participants with normal glucose regulation.

Project description:BackgroundPeople with kidney failure have a high incidence of major surgery, though the risk of perioperative outcomes at a population-level is unknown. Our objective was to estimate the proportion of people with kidney failure that experience acute myocardial infarction (AMI) or death within 30 days of major non-cardiac surgery, based on surgery type.MethodsIn this retrospective population-based cohort study, we used administrative health data to identify adults from Alberta, Canada with major surgery between April 12,005 and February 282,017 that had preoperative estimated glomerular filtration rates (eGFRs) < 15 mL/min/1.73m2 or received chronic dialysis. The index surgical procedure for each participant was categorized within one of fourteen surgical groupings based on Canadian Classification of Health Interventions (CCI) codes applied to hospitalization administrative datasets. We estimated the proportion of people that had AMI or died within 30 days of the index surgical procedure (with 95% confidence intervals [CIs]) following logistic regression, stratified by surgery type.ResultsOverall, 3398 people had a major surgery (1905 hemodialysis; 590 peritoneal dialysis; 903 non-dialysis). Participants were more likely male (61.0%) with a median age of 61.5 years (IQR 50.0-72.7). Within 30 days of surgery, 272 people (8.0%) had an AMI or died. The probability was lowest following ophthalmologic surgery at 1.9% (95%CI: 0.5, 7.3) and kidney transplantation at 2.1% (95%CI: 1.3, 3.2). Several types of surgery were associated with greater than one in ten risk of AMI or death, including retroperitoneal (10.0% [95%CI: 2.5, 32.4]), intra-abdominal (11.7% [8.7, 15.5]), skin and soft tissue (12.1% [7.4, 19.1]), musculoskeletal (MSK) (12.3% [9.9, 15.5]), vascular (12.6% [10.2, 15.4]), anorectal (14.7% [6.3, 30.8]), and neurosurgical procedures (38.1% [20.3, 59.8]). Urgent or emergent procedures had the highest risk, with 12.1% experiencing AMI or death (95%CI: 10.7, 13.6) compared with 2.6% (1.9, 3.5) following elective surgery.ConclusionsAfter major non-cardiac surgery, the risk of death or AMI for people with kidney failure varies significantly based on surgery type. This study informs our understanding of surgery type and risk for people with kidney failure. Future research should focus on identifying high risk patients and strategies to reduce these risks.

Dataset Information

Comparison of Mortality and Major Cardiovascular Events Among Adults With Type 2 Diabetes Using Human vs Analogue Insulins.

Publications

Comparison of Mortality and Major Cardiovascular Events Among Adults With Type 2 Diabetes Using Human vs Analogue Insulins.

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