Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes and Obesity

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Aminian reported receiving grants from Medtronic. Dr Arterburn reported receiving grants from the National Institutes of Health (NIH) and the Patient-Centered Outcomes Research Institute and receiving nonfinancial support from International Federation for the Surgery of Obesity and Metabolic Disorders Latin America Chapter. Dr Brethauer reported receiving grants from Medtronic and GI Windows. Dr Schauer reported receiving grants from Medtronic, Ethicon, and Pacira and receiving personal fees from Medtronic, GI Dynamics, WL Gore and Associates, Becton Dickinson Surgical, and Global Academy for Medical Education. Dr Kattan reported receiving grants from Medtronic and Novo Nordisk. Dr Nissen reported receiving a grant from Medtronic for the current study and receiving research support from Amgen, AbbVie, AstraZeneca, Cerenis, Eli Lilly, Esperion Therapeutics, Novo-Nordisk, The Medicines Company, Orexigen, Pfizer, and Takeda and consulting for a number of pharmaceutical companies without financial compensation (all honoraria, consulting fees, or any other payments from any for-profit entity are paid directly to charity, so neither income nor any tax deduction is received). No other disclosures were reported.

Figures

Figure 1.. Identification of Eligible Patients for Inclusion

Details of cohort construction and International Classification of Diseases and Current Procedural Terminology codes are available in Supplement 1. Application of enrollment criteria resulted in a total of 2287 surgical patients and 39 267 nonsurgical patients with type 2 diabetes medllitus and body mass index (BMI) 30 or greater before matching. Afterward, each surgical patient was matched with a propensity score to 5 nonsurgical patients based on 7 a priori–identified potential confounders including the index date, age at index date, sex, BMI at index date, location, insulin use, and presence of end-organ complications of diabetes. ED indicates emergency department. aSome patients met multiple exclusion criteria. bPatients with glycated hemoglobin values less than 6.5% and not taking diabetes medications at the index date were excluded.

Figure 2.. Eight-Year Cumulative Incidence Estimates (Kaplan-Meier) for 2 Composite End Points

The primary end point was the incidence of extended major adverse cardiovascular events (MACE; composite of 6 outcomes), defined as first occurrence of coronary artery events, cerebrovascular events, heart failure, atrial fibrillation, nephropathy, and all-cause mortality, recording the first occurrence after the index date as the event date. The secondary composite end points included 3-component MACE (all-cause mortality, myocardial infarction, and ischemic stroke), recording the first occurrence after the index date as the event date. For both end points, the median observation time was 4.0 years (interquartile range [IQR], 2.1-6.1) for nonsurgical patients and 3.3 years (IQR, 1.2-6.3) for surgical patients. HR indicates hazard ratio.

Figure 3.. Eight-Year Cumulative Incidence Estimates (Kaplan-Meier) for 6 Individual End Points

For each 5 individual outcomes (except all-cause mortality), any patient with a history of that outcome prior to the index date was eliminated from risk assessment only for that outcome. For all-cause mortality, median observation time was 4.0 years (interquartile range [IQR], 2.1-6.1) in the nonsurgical group and 3.3 years (IQR, 1.2-6.3) in the surgical group; for heart failure, 4.1 years (IQR, 2.2-6.2) and 3.3 years (IQR, 1.1-6.4); for coronary artery disease, 4.0 years (IQR, 2.1-6.1) and 3.3 years (IQR, 1.1-6.4); for nephropathy, 4.1 years (IQR, 2.2-6.2) and 3.3 years (IQR, 1.1-6.3); for cerebrovascular disease and atrial fibrillation, 4.0 years (IQR, 2.1-6.1) and 3.3 years (IQR, 1.1-6.3). HR indicates hazard ratio.

Figure 4.. Mean Trend Curves of Weight Loss and HbA1c Values Over 8 Years of Follow-up

Smoothed mean trends of percent weight lost from baseline and absolute glycated hemoglobin (HbA1c) values (%) in surgical and nonsurgical patients during follow-up. Shaded areas indicate 95% CIs. Mean difference in total weight loss at 8 years and mean difference in HbA1c changes from baseline at 8 years between groups were estimated from a flexible regression model with a 4-knot spline on time, since the index date interacted with the treatment group. Statistical comparison and sample size at different time points have been reported in eTable 8 and eTable 9 in Supplement 1.

Figure 5.. Proportions of Patients Taking Diabetes and Cardiovascular Drugs Over 8 Years of Follow-up

Proportions over time with 95% point-wise confidence intervals by surgical and nonsurgical patients. Shaded areas indicate 95% CIs. P values from a Fisher exact test are also displayed comparing the proportion of surgical and nonsurgical patients taking drug at 8 years after the index date. The proportion of patients taking each drug were computed every tenth of a year starting at the index date through 8 years of follow-up. Renin-angiotensin system inhibitors include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Statistical comparison and sample size at different time points have been reported in eTable 8 and eTable 10 in Supplement 1.