Bariatric Surgery vs. Semaglutide vs. Tirzepatide

Phase 4

Recruiting

• Conditions: Obesity and Obesity-related Medical Conditions
• Interventions: Procedure: Bariatric Surgery; Drug: Semaglutide; Drug: Tirzepatide

• Registration Number: NCT06803888
• Lead Sponsor: Ali Aminian

Brief Summary

The recent introduction of the new generation of anti-obesity medications (AOMs) will change the future of obesity treatment. These highly effective medications, such as high-dose semaglutide and tirzepatide, are hormone analogues that augment the incretin function and exert multiple physiological effects by activating glucagon-like peptide-1 (GLP-1) and/or glucose-dependent insulinotropic polypeptide (GIP) distributed in various organs. These medications provide an average of 15-22% weight reduction in one-year trials, which had not been seen in the past with medical therapy. While the literature suggests that bariatric surgery is superior to these new highly effective medications, there is no head-to-head comparison between the most common bariatric operations (Roux-en-Y gastric bypass \[RYGB\] and sleeve gastrectomy \[SG\]) with semaglutide (once weekly) and tirzepatide (once weekly). The goal of this Randomized Clinical Trial (RCT) is to compare these effective therapies in patients with severe obesity to provide the best evidence to inform clinical decisions in treating patients with obesity.

Detailed Description

This is a randomized, non-blinded, controlled efficacy/safety study with 3 parallel groups who will either receive bariatric surgery (RYGB or SG), semaglutide, or tirzepatide. The study has 2 phases: the first 12 months for the assessment of the primary endpoint ( mean percentage weight loss) and the second 12 months as the extension phase of the study to mimic the real-life setting. Findings at the end of each phase will be separately reported.

A randomized trial of 125 patients with a BMI of 35-65 kg/m2 who sought treatment for obesity at Cleveland Clinic will be performed. Patients who meet the ASMBS/IFSO 2022 guidelines for bariatric surgery will be invited for possible enrollment. Interested and eligible patients will be randomized to receive their already chosen bariatric surgery (RYGB or SG), tirzepatide. or semaglutide in 2:2:1 ratio.

The study is not intended to compare RYGB vs SG head-to-head. RYGB and SG constitute one group as a bariatric surgery group. The assignment of RYGB or SG is not based on a randomized design. Each patient and surgical team will make a shared decision about the most appropriate surgical procedure. The study is also not intended to compare semaglutide vs tirzepatide head-to-head.

In the second or extension phase of the study, participants are followed from month 12 to month 24, regardless of the treatment that they receive. In this phase, the study medications (semaglutide and tirzepatide) will not be provided by the study. The goal of this phase is to provide valuable insights into A) access to AOMs and the durability of effects in the real-life setting, B) cross-over from AOMs to bariatric surgery, and C) adjuvant pharmacotherapy after bariatric surgery.

Study Timeline

• Study First Submitted: 2025-01-14
• Study First Submitted QC: 2025-01-28
• Study Start: 2025-01-29
• Study First Posted: 2025-01-31
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-15
• Last Update Posted: 2025-04-17
• Primary Completion: 2027-07-01
• Study Completion: 2027-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 125

Inclusion Criteria

Entry into the study would require that the patient:

1. Is a candidate for general anesthesia
2. Is eligible for bariatric surgery (RYGB or SG) based on ASMBS/IFSO 2022 guidelines
3. Is ≥18 and ≤70 years old (both inclusive)
4. has a BMI ≥35 and ≤65 kg/m2 (both inclusive)
5. Patients with and without T2DM are eligible for the study. Patients with T2DM should have been on a stable dose of anti-diabetic medication (including insulin but not semaglutide or tirzepatide) for at least 3 months prior to entry, with HbA1c ≤12%.
6. No weight loss > 20 lbs. in 3 months before screening (self-reported)
7. Has the ability and willingness to participate in the study, provide informed consent, and agree to any of the arms involved in the study.
8. Is able to understand the options and to comply with the requirements of each arm.
9. Has a negative urine pregnancy test at randomization visit for women of childbearing potential.
10. Women of childbearing age must agree to use reliable method of contraception for 2 years.

Exclusion Criteria

1. Significant cardiac or atherosclerotic disease (planned to undergo cardiac, coronary, carotid, or peripheral artery revascularization procedures in the next 12 months)

2. Severe uncompensated cardiopulmonary disease leading to American Society of Anesthesiologists Class IV or V

3. Classified as New York Heart Association Class IV

4. Left ventricular ejection fraction <25% at the time of screening (if already known)

5. Myocardial infarction, unstable angina, stroke, transient ischemic attack, heart surgery, coronary stent placement in the past 6 months

6. Prior bariatric surgery of any kind

   • Intragastric balloon that has been removed at least 6 months prior to the first study visit is allowed.

7. History of solid organ transplant

8. Type 1 diabetes or autoimmune diabetes

9. eGFR < 30 mL/min/1.73 m2 or being on dialysis

10. History of deep vein thrombosis, pulmonary embolism, or venous thromboembolism

11. On therapeutic dose of anticoagulants such as warfarin or direct oral anticoagulants (DOACs)

12. Decompensated cirrhosis characterized by presence of ascites, hepatic encephalopathy, portal hypertension, or esophageal varices.

13. History of severe anemia defined as hemoglobin less than 8 g/dL

14. Use of investigational therapy

15. Liver transaminase level or alkaline phosphatase >200 U/L

16. Significant alcohol use (average >2 drinks/day)

17. Presence of active malignancy (except non-melanoma skin cancer)

18. Life expectancy less than 3 years due to concomitant diseases

19. Major mental health, psychological disorders, or substance abuse disorders that in the opinion of the investigators could disqualify the patient from bariatric surgery

20. Any condition or major illness that, in the investigator's judgment, places the subject at undue risk by participating in the study

21. Unable to understand the risks, benefits and compliance requirements of study

22. Lack capacity to give informed consent

23. Plans to move outside the primary location of study (northeast Ohio) within the next 12 months

24. Pregnant, breast-feeding or the intention of becoming pregnant or not using adequate contraceptive measures

25. Hypothalamic obesity

26. Continuous treatment with semaglutide (once weekly) or tirzepatide (once weekly) <60 days before screening

27. History of semaglutide (once weekly) or tirzepatide (once weekly) use in the past for obesity with lack of clinical response

28. Chronic use of systemic steroids

29. Uncontrolled thyroid disease: thyroid stimulating hormone (TSH) > 6.0 mIU/L or < 0.1 mIU/L

    • Note: Patients receiving treatment for hypothyroidism can be included if their thyroid hormone replacement dose has been stable for at least 3 months.

30. Acute pancreatitis < 180 days before screening

31. History or presence of chronic pancreatitis

32. History of Crohn's disease

33. Known or suspected allergy to semaglutide, tirzepatide, excipients, or related products

34. A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)

35. Previous participation in this trial and got randomized to one of the study groups but did not proceed.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bariatric Surgery	Bariatric Surgery	Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG)
Semaglutide	Semaglutide	Semaglutide, which is an incretin-based medication that has been approved for the treatment of obesity, will be used for this arm.
Tirzepatide	Tirzepatide	Tirzepatide, which is an incretin-based medication that has been approved for the treatment of obesity, will be used for this arm.

Primary Outcome Measures

Name	Time	Method
The mean percentage weight loss	First 52 weeks of the study	The mean percentage weight loss at 52 weeks for the following 2 comparisons: * Bariatric surgery (RYGB and SG) vs tirzepatide; * Bariatric surgery (RYGB and SG) vs semaglutide

Secondary Outcome Measures

Name	Time	Method
Change in body composition (via Seca mBCA 554 Bioimpedance Analysis)	First 52 weeks of the study	Change in body composition (% fat mass and % fat-free mass) as measured by Seca mBCA 554 Bioimpedance Analysis to assess whether that weight loss is primarily caused by reduction in fat mass or not.
Percentage of Participants Achieving Weight Loss Milestones (Body weight related end points)	First 52 weeks of the study	Percentage of participants achieving ≥5%, ≥10%, ≥15%, ≥20%, ≥25%, ≥30%, and ≥35% weight loss from baseline
Absolute Change in Weight (Body weight related end points)	First 52 weeks of the study	Mean absolute change in weight measured in kilograms from baseline to 52 weeks
Absolute Change in BMI (Body weight related end points)	First 52 weeks of the study	Absolute change in BMI measured in kg/m\^2 from baseline to 52 weeks
Excess Weight Loss Percentage (Body weight related end points)	First 52 weeks of the study	Percentage of excess weight loss, calculated by dividing the difference between initial BMI and final BMI by the difference between initial BMI and a target BMI of 25
Change in Waist Circumference (Body weight related end points)	First 52 weeks of the study	Change in waist circumferential measurement above the level of the iliac crests measured in centimeters from baseline to 52 weeks
Systolic blood pressure trends	First 52 weeks of the study	Mean and change in systolic blood pressure measured in mmHg
Mean and change from baseline in lipid panel	First 52 weeks of the study	Mean and change from baseline in total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides
Changes in glucose homeostasis markers in T2DM patients	First 52 weeks of the study	Mean and change from baseline in blood glucose and HbA1c in patients with T2DM
Percentage of patients with T2DM meeting predefined HbA1c targets	First 52 weeks of the study	Percentage of patients meeting different HbA1c targets, for example: * HbA1c \<6.5% (without diabetes medications); * HbA1c \<7% (irrespective of taking diabetes medications or not)
Changes in inflammatory marker, CRP	First 52 weeks of the study	Mean and change from baseline in C-Reactive Protein (CRP) measured in mg/L
Changes in Lipoprotein(a)	First 52 weeks of the study	Mean and change from baseline in Lipoprotein(a) measured in mg/dL
Change in cardiovascular and diabetes medications	First 52 weeks of the study	Change in the number of cardiovascular and diabetes medications prescribed
Change from baseline in quality of life metrics	First 52 weeks of the study	Change from baseline in score of The 36-Item Short Form Health Survey (SF-36) (physical and mental components). Each item is given a score ranging from 0-100. Lower scores indicating poor outcomes. Final score is an average of all the items that were answered. Unanswered questions are not included in the final average. Research coordinator completes the survey with the patient.
Mean change in liver fat content (via MRI-PDFF)	First 52 weeks of the study	Mean change from baseline in liver fat content as assessed by MRI-PDFF measured as a percentage
Percentage of Participants Achieving ≥5%, ≥30%, ≥50% Absolute Reduction in Liver Fat Content (via MRI-PDFF)	First 52 weeks of the study	Percentage of participants achieving at least 5%, 30%, or 50% relative reduction in liver fat content from baseline
Percentage of Participants Achieving MRI-PDFF Normalization (via MRI-PDFF)	First 52 weeks of the study	Percentage of participants achieving MRI-PDFF normalization, defined as a liver fat content of \<5%, at week 52

Trial Locations

Locations (1)

The Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States