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Importance: Few cardiovascular outcomes trials have been conducted for obesity treatments. Withdrawal of 2 marketed drugs has resulted in controversy about the cardiovascular safety of obesity agents.Objective: To determine whether the combination of naltrexone and bupropion increases major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) compared with placebo in overweight and obese patients.Design, Setting, and Participants: Randomized, multicenter, placebo-controlled, double-blind noninferiority trial enrolling 8910 overweight or obese patients at increased cardiovascular risk from June 13, 2012, to January 21, 2013, at 266 US centers. After public release of confidential interim data by the sponsor, the academic leadership of the study recommended termination of the trial and the sponsor agreed.Interventions: An Internet-based weight management program was provided to all participants. Participants were randomized to receive placebo (n=4454) or naltrexone, 32 mg/d, and bupropion, 360 mg/d (n=4456).Main Outcomes and Measures: Time from randomization to first confirmed occurrence of a MACE. The primary analysis planned to assess a noninferiority hazard ratio (HR) of 1.4 after 378 expected events, with a confidential interim analysis after approximately 87 events (25% interim analysis) to assess a noninferiority HR of 2.0 for consideration of regulatory approval.Results: Among the 8910 participants randomized, mean age was 61.0 years (SD, 7.3 years), 54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes, with a median body mass index of 36.6 (interquartile range, 33.1-40.9). For the 25% interim analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropion-treated patients (0.8%; HR, 0.59; 95% CI, 0.39-0.90). After 50% of planned events, MACE occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57-1.34). Adverse effects were more common in the naltrexone-bupropion group, including gastrointestinal events in 14.2% vs 1.9% (P < .001) and central nervous system symptoms in 5.1% vs 1.2% (P < .001).Conclusions and Relevance: Among overweight or obese patients at increased cardiovascular risk, based on the interim analyses performed after 25% and 50% of planned events, the upper limit of the 95% CI of the HR for MACE for naltrexone-bupropion treatment, compared with placebo, did not exceed 2.0. However, because of the unanticipated early termination of the trial, it is not possible to assess noninferiority for the prespecified upper limit of 1.4. Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial.Trial Registration: clinicaltrials.gov Identifier: NCT01601704. [ABSTRACT FROM AUTHOR]

Objective: To determine which one of the two most common metabolic surgical procedures is associated with greater reduction in risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) and obesity.Research Design and Methods: A total of 13,490 patients including 1,362 Roux-en-Y gastric bypass (RYGB), 693 sleeve gastrectomy (SG), and 11,435 matched nonsurgical patients with T2DM and obesity who received their care at the Cleveland Clinic (1998-2017) were analyzed, with follow-up through December 2018. With multivariable Cox regression analysis we estimated time to incident extended MACE, defined as first occurrence of coronary artery events, cerebrovascular events, heart failure, nephropathy, atrial fibrillation, and all-cause mortality.Results: The cumulative incidence of the primary end point at 5 years was 13.7% (95% CI 11.4-15.9) in the RYGB groups and 24.7% (95% CI 19.0-30.0) in the SG group, with an adjusted hazard ratio (HR) of 0.77 (95% CI 0.60-0.98, P = 0.04). Of the six individual end points, RYGB was associated with a significantly lower cumulative incidence of nephropathy at 5 years compared with SG (2.8% vs. 8.3%, respectively; HR 0.47 [95% CI 0.28-0.79], P = 0.005). Furthermore, RYGB was associated with a greater reduction in body weight, glycated hemoglobin, and use of medications to treat diabetes and cardiovascular diseases. Five years after RYGB, patients required more upper endoscopy (45.8% vs. 35.6%, P < 0.001) and abdominal surgical procedures (10.8% vs. 5.4%, P = 0.001) compared with SG.Conclusions: In patients with obesity and T2DM, RYGB may be associated with greater weight loss, better diabetes control, and lower risk of MACE and nephropathy compared with SG. [ABSTRACT FROM AUTHOR]

Objective: To construct and internally validate prediction models to estimate the risk of long-term end-organ complications and mortality in patients with type 2 diabetes and obesity that can be used to inform treatment decisions for patients and practitioners who are considering metabolic surgery.Research Design and Methods: A total of 2,287 patients with type 2 diabetes who underwent metabolic surgery between 1998 and 2017 in the Cleveland Clinic Health System were propensity-matched 1:5 to 11,435 nonsurgical patients with BMI ≥30 kg/m2 and type 2 diabetes who received usual care with follow-up through December 2018. Multivariable time-to-event regression and random forest machine learning models were built and internally validated using fivefold cross-validation to predict the 10-year risk for four outcomes of interest. The prediction models were programmed to construct user-friendly web-based and smartphone applications of Individualized Diabetes Complications (IDC) Risk Scores for clinical use.Results: The prediction tools demonstrated the following discrimination ability based on the area under the receiver operating characteristic curve (1 = perfect discrimination and 0.5 = chance) at 10 years in the surgical and nonsurgical groups, respectively: all-cause mortality (0.79 and 0.81), coronary artery events (0.66 and 0.67), heart failure (0.73 and 0.75), and nephropathy (0.73 and 0.76). When a patient's data are entered into the IDC application, it estimates the individualized 10-year morbidity and mortality risks with and without undergoing metabolic surgery.Conclusions: The IDC Risk Scores can provide personalized evidence-based risk information for patients with type 2 diabetes and obesity about future cardiovascular outcomes and mortality with and without metabolic surgery based on their current status of obesity, diabetes, and related cardiometabolic conditions. [ABSTRACT FROM AUTHOR]

Importance: Although metabolic surgery (defined as procedures that influence metabolism by inducing weight loss and altering gastrointestinal physiology) significantly improves cardiometabolic risk factors, the effect on cardiovascular outcomes has been less well characterized.Objective: To investigate the relationship between metabolic surgery and incident major adverse cardiovascular events (MACE) in patients with type 2 diabetes and obesity.Design, Setting, and Participants: Of 287 438 adult patients with diabetes in the Cleveland Clinic Health System in the United States between 1998 and 2017, 2287 patients underwent metabolic surgery. In this retrospective cohort study, these patients were matched 1:5 to nonsurgical patients with diabetes and obesity (body mass index [BMI] ≥30), resulting in 11 435 control patients, with follow-up through December 2018.Exposures: Metabolic gastrointestinal surgical procedures vs usual care for type 2 diabetes and obesity.Main Outcomes and Measures: The primary outcome was the incidence of extended MACE (composite of 6 outcomes), defined as first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation. Secondary end points included 3-component MACE (myocardial infarction, ischemic stroke, and mortality) and the 6 individual components of the primary end point.Results: Among the 13 722 study participants, the distribution of baseline covariates was balanced between the surgical group and the nonsurgical group, including female sex (65.5% vs 64.2%), median age (52.5 vs 54.8 years), BMI (45.1 vs 42.6), and glycated hemoglobin level (7.1% vs 7.1%). The overall median follow-up duration was 3.9 years (interquartile range, 1.9-6.1 years). At the end of the study period, 385 patients in the surgical group and 3243 patients in the nonsurgical group experienced a primary end point (cumulative incidence at 8-years, 30.8% [95% CI, 27.6%-34.0%] in the surgical group and 47.7% [95% CI, 46.1%-49.2%] in the nonsurgical group [P < .001]; absolute 8-year risk difference [ARD], 16.9% [95% CI, 13.1%-20.4%]; adjusted hazard ratio [HR], 0.61 [95% CI, 0.55-0.69]). All 7 prespecified secondary outcomes showed statistically significant differences in favor of metabolic surgery, including mortality. All-cause mortality occurred in 112 patients in the metabolic surgery group and 1111 patients in the nonsurgical group (cumulative incidence at 8 years, 10.0% [95% CI, 7.8%-12.2%] and 17.8% [95% CI, 16.6%-19.0%]; ARD, 7.8% [95% CI, 5.1%-10.2%]; adjusted HR, 0.59 [95% CI, 0.48-0.72]).Conclusions and Relevance: Among patients with type 2 diabetes and obesity, metabolic surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident MACE. The findings from this observational study must be confirmed in randomized clinical trials.Trial Registration: ClinicalTrials.gov Identifier: NCT03955952. [ABSTRACT FROM AUTHOR]

Background: The failure of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib was associated with off target increased plasma aldosterone levels (PAL). The potent CETP inhibitor evacetrapib failed to show clinical benefit in a large randomized control trial. We sought to evaluate the impact of evacetrapib on PAL in a subset of the ACCELERATE trial and determine the association between PAL and major adverse cardiovascular outcomes (MACE). Methods: We included all patients who had a central laboratory measured PAL drawn per study protocol. We determined the impact of evacetrapib exposure compared to placebo on PAL levels following 12 months of exposure. Utilizing baseline and post-exposure aldosterone levels, a Kaplan-Meier hazards model generated hazard ratios (HR) for the risk of MACE (composite of cardiovascular death (CV), non-fatal myocardial infarction (MI), stroke, hospitalization for unstable angina, and revascularization) with increasing quartile of baseline PAL and percent change in PAL at follow-up. Results: Amongst 12,092 patients in ACCELERATE, 1,624 patients had a PAL drawn. The average age of the study population was 65.2 years and 75.7% male with a mean body mass index of 31.9. At baseline, 93.7% were hypertensive, 73.3% were diabetic, and 57.6% had a prior MI. Baseline PAL (85.2 [43, 150] vs. 86.8 [43, 155] pmol/L, p=0.81) and follow-up percent change (13.6% [-29, 88] vs. 17.9% [-24, 87], p=0.23) were similar between those who received evacetrapib and placebo. During a median follow-up of 28 months, the primary endpoint occurred in 263 patients (16.2%) with all-cause mortality occurring in 78 patients (4.8%). The HR for increasing quartile of the log of baseline PAL or percent change in PAL at follow-up were not significant for MACE (Table 1). Conclusions: Exposure to evacetrapib did not result in significant change in PAL compared to placebo. Among patients with high risk vascular disease, PAL was not a predictor for CV events. [ABSTRACT FROM AUTHOR]

Objective Guidelines exist for the use of low-dose aspirin in the general population for primary cardiovascular (CV) prevention, but the risk-benefit considerations may differ in RA. While RA confers an increased CV risk, such patients more likely use NSAIDs and corticosteroids. Methods We conducted a cohort study to assess potential risks and benefits of low-dose aspirin. We estimated incidence rates and hazard ratios (HRs) using Cox regression among subjects with RA but no known CV disease in the Prospective Randomized Evaluation of Celecoxib Integrated Safety Vs Ibuprofen Or Naproxen trial. The primary exposure of interest was low-dose aspirin, and all enrolled patients were provided open-label esomeprazole. The primary composite outcome was major NSAID toxicity, including major adverse CV event (MACE), clinically significant gastrointestinal events, renal events and all-cause mortality. Results We found 1852 subjects with RA in Prospective Randomized Evaluation of Celecoxib Integrated Safety Vs Ibuprofen Or Naproxen without known CV disease; 540 reported using low-dose aspirin for CV prevention and 1312 did not. Any major NSAID toxicity was observed in 79 (6.0%) non-aspirin users and 37 (6.9%) aspirin users (P = 0.50). Aspirin users experienced all components of the primary outcome at a similar rate to non-users. In fully adjusted models, the risk for major NSAID toxicity was similar between aspirin exposure groups (HR = 1.08, 95% CI: 0.69, 1.69). The risk for MACE was also similar between exposure groups in age- and gender-adjusted models (HR = 1.23, 95% CI: 0.72, 2.10). Conclusion RA patients using low-dose aspirin with chronic NSAIDs and esomeprazole had a similar risk of major NSAID toxicity and MACE as patients who did not. [ABSTRACT FROM AUTHOR]

A correction to the article "Predicting 10-Year Risk of End-Organ Complications of Type 2 Diabetes With and Without Metabolic Surgery: A Machine Learning Approach" is presented.