Macrovascular and Microvascular Morbidity and Mortality After Metabolic Surgery Versus Medicines (M6)

Macrovascular and Microvascular Outcomes in Patients With Type 2 Diabetes and Obesity: Comparison of Metabolic Surgery Versus GLP-1 Receptor Agonists

The goal of this study is to compare the impact of metabolic surgery and a class of anti-diabetes medications (Glucagon-like peptide-1 receptor agonists,GLP-1 RAs) on occurrence of diseases involving small and large vessels such as heart disease, kidney disease, and disease of the retina (a part of the eye), as well as deaths.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Obesity; Type 2 Diabetes Mellitus; Nephropathy; All Cause Mortality; Retinopathy; Major Adverse Cardiovascular Events; Microvascular Disease; Macrovascular Disease

• Study Type: Observational
• Enrollment (Actual): 3932

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients with obesity (defined by body mass index [BMI] ≥30 kg/m^2) and T2DM who underwent metabolic surgery at Cleveland Clinic Health System (CCHS) from 2010 to 2017 were compared with similar patients who continuously received GLP-1 RA for at least 2 years. The study used Cleveland Clinic electronic health records (EHR), including Surescripts dispensed prescription records. Follow-up ended on December 31, 2022. To minimize the effects of confounding factors, a doubly robust estimation combining the overlap weighting and outcome regression will be utilized to compare primary and secondary end points in surgical and GLP-1RA groups.

Description

Inclusion Criteria:

• BMI>=30 kg/m^2
• Type 2 Diabetes Mellitus
• 18-75 y/o
• Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) (Surgical Cohort) at CCHS hospitals in Florida and Ohio between January 1, 2010, and December 31, 2017

For the GLP-1RA Group:

• Follow-up of at least 30 days after the assigned index date
• Did not meet any of the exclusion criteria for surgical patients (see below)
• Did not have metabolic surgery prior to assigned index date.
• Continuously received GLP-1 RA for ≥2 years (prescription order for GLP-1 RA placed between January 1, 2010, and December 31, 2017, as well as ≥ 3 documented prescription fills within 1 year before their assigned index date and ≥ 3 fills within 1 year after their index date)

Exclusion Criteria:

• History of solid organ transplant
• Cardiac ejection fraction <20% any time before index date
• Active cancer
• Cancer code within 1 year before index date
• ED admission within 5 days before index date
• Dialysis or estimated glomerular filtration rate (eGFR) <20 before index date.
• Received care in CCHS locations other than in Ohio and Florida.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Metabolic Surgery; Patients aged 18 years to 75 years, who had a BMI ≥30 and T2DM at the time of surgery, and who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) at Cleveland Clinic Health System(CCHS) hospitals in Florida and Ohio between January 1, 2010, and December 31, 2017.
GLP-1 RAs; Non-surgical patients at CCHS who at randomly assigned index dates had T2DM and obesity, follow-up of at least 30 days after the assigned index date, did not meet any of the exclusion criteria for surgical patients, and did not have metabolic surgery prior to the assigned index date, who continuously received GLP-1 RA for ≥2 years, defined by prescription order for GLP-1 RA placed between January 1, 2010, and December 31, 2017, as well as ≥ 3 documented prescription fills within 1 year before their assigned index date and ≥ 3 fills within 1 year after their index date.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Mortality Rate	Death from all causes percentage	After surgical or assigned index date to Dec 31, 2022

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of MACE	Incident major adverse cardiovascular events (MACE, composite of 4 outcomes), defined as the first occurrence of coronary artery events (unstable angina, myocardial infarction, or coronary intervention/surgery), cerebrovascular events (ischemic stroke, hemorrhagic stroke, or carotid intervention/surgery), heart failure, or atrial fibrillation.	After surgical or assigned index date to Dec 31, 2022
Incidence of Nephropathy	Onset of ≥40% sustained decline in eGFR compared with baseline (calculated using the 2021 CKD-EPI equation), onset of sustained eGFR <15 mL/min/1.73 m^2, initiation of dialysis, or kidney transplant.	After surgical or assigned index date to Dec 31, 2022
Incidence of Retinopathy	(1) First occurrence of retinopathy in patients who did not have such events at baseline or (2) progression to a more severe form of retinopathy in those with baseline retinopathy	After surgical or assigned index date to Dec 31, 2022

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Components of MACE Separately	Incidence of each of the following MACE components separately: the first occurrence of coronary artery events (unstable angina, myocardial infarction, or coronary intervention/surgery), cerebrovascular events (ischemic stroke, hemorrhagic stroke, or carotid intervention/surgery), heart failure, or atrial fibrillation.	After surgical or assigned index date to Dec 31, 2022
Change in weight percentage	Relative change in weight percentage at follow up compared to index date	After surgical or assigned index date to Dec 31, 2022
Change HBA1c percentage	Absolute change HBA1c percentage at follow up compared to index date	After surgical or assigned index date to Dec 31, 2022
Trends of prescription and dispenses of medications for T2DM and cardio-vascular conditions	Using dates of prescription orders and dispenses of medications for T2DM and cardio-vascular conditions	After surgical or assigned index date to Dec 31, 2022
Progression of Chronic Kidney Disease (CKD) in Patients with CKD stages 3 and 4 at baseline	Defined as onset of ≥ 50% sustained decline in eGFR compared with baseline, onset of sustained eGFR <15 mL/min/1.73 m2, initiation of dialysis, or kidney transplant after the index date.	After surgical or assigned index date to Dec 31, 2022
Cost-effectiveness of Metabolic Surgery vs GLP-1RAs	Defined as the cost per life year and the cost per quality adjusted life year (QALY) in the surgical and nonsurgical patients.	After surgical or assigned index date to Dec 31, 2022
Incidence of Adverse Events After Metabolic Surgery	Serious complications following surgery include bleeding requiring transfusion, pulmonary adverse events, venous thromboembolism, cardiac events, renal failure requiring dialysis, gastrointestinal leak, bowel obstruction requiring surgery, gastric/anastomotic stricture or ulcer, and sepsis.	90 days after surgical index date

Collaborators and Investigators

• Sponsor: Ali Aminian

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2010
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): May 20, 2024

Study Registration Dates

• First Submitted: March 29, 2024
• First Submitted That Met QC Criteria: April 3, 2024
• First Posted (Actual): April 9, 2024

Study Record Updates

• Last Update Posted (Actual): May 21, 2024
• Last Update Submitted That Met QC Criteria: May 20, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Diabetes Mellitus, Type 2; Obesity
• Other Study ID Numbers: IRB #19-066

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No