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Should Weight Loss Influence Our Recommendations for Antidiabetes Treatment?

Robert S. Zimmerman, MD

Vice Chairman
Director, Cleveland Clinic Diabetes Center
Department of Endocrinology
Cleveland Clinic
Cleveland, Ohio

Robert Zimmerman, MD, has disclosed that he has received funds for research support from Bayer, Merck, and Novo Nordisk; has ownership interest in Baxter, Bristol Myers Squibb, Pfizer, and Procter & Gamble; and received fees for non-CME/CE services from Bayer and Merck.

View ClinicalThoughts from this Author

Released: October 26, 2020

Obesity and type 2 diabetes (T2D) often coexist, so should the degree of potential weight loss influence our recommendations for antidiabetes treatment? For me, the answer is yes. When choosing an agent for greatest weight reduction while treating diabetes, semaglutide appears to have the greatest impact. Here’s why.

As a class, the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with improved glucose control, reduced cardiovascular events, and weight loss. In reviewing clinical trials of patients with diabetes—being careful to include only studies that have specifically compared weight reduction in the same patient population—these agents appear to vary in their potency to produce weight reduction.

Exenatide: Weekly vs Daily
The first trial comparing 2 GLP-1 RAs was a 24-week, randomized, open-label trial of weekly exenatide vs twice-daily exenatide as monotherapy or add-on therapy to existing oral antidiabetic agents in patients with T2D and inadequate glycemic control. Both weekly exenatide and twice-daily exenatide led to weight reduction, though the magnitude was greater with the extended-release formulation (-2.3 kg vs -1.4 kg). A second trial by Drucker and colleagues comparing weekly exenatide with twice-daily exenatide showed similar weight reduction between the groups after 30 weeks of treatment.

Liraglutide, Lixisenatide, and Dulaglutide
Liraglutide appears to have an even more potent effect on weight loss, not just at the doses approved as an antiobesity agent, but even at doses used for glycemic control. In the randomized, open-label DURATION-6 trial, patients with T2D treated with lifestyle modification and oral antihyperglycemic drugs were randomly assigned to receive injections of once-daily liraglutide or weekly exenatide. Both treatments were associated with progressive decreases in body weight. Over 26 weeks, patients in the liraglutide group lost approximately 3.5 kg, and those receiving weekly exenatide lost approximately 2.7 kg (P < .0005).  

In separate randomized, open-label trials, once-daily liraglutide was compared with other GLP-1 RAs in patients with T2D receiving metformin who did not achieve glycemic control. Compared with once-daily lixisenatide, liraglutide promoted similar body weight decreases by Week 26 (approximately -4 kg for both groups; P = .23). Compared with weekly dulaglutide, liraglutide led to greater weight loss over 26 weeks (2.9 vs 3.6 kg, respectively; P < .05). Taken together, these data suggest that both lixisenatide and liraglutide have potent weight loss benefits, while dulaglutide is a weaker agent for weight reduction at doses approved for diabetes management.

Regarding semaglutide, data from the phase III SUSTAIN program demonstrate that once-weekly semaglutide is approximately twice as potent at reducing weight as other GLP-1 RAs. In the randomized, open-label SUSTAIN 7 trial, patients with T2D receiving metformin experienced dose-dependent reductions in weight with both semaglutide and dulaglutide, but semaglutide was superior to dulaglutide at both low (estimated treatment difference [ETD]: -2.26 kg; P < .0001) and high (ETD: -3.55 kg; P < .0001) doses. In the randomized, open-label SUSTAIN-10 trial, semaglutide led to mean body weight reductions of -5.8 kg vs -1.9 kg with liraglutide (ETD: -3.83; P < .0001).

Furthermore, a network meta-analysis of 26 studies showed that once-weekly semaglutide combined with 1 or 2 oral antidiabetic drugs is more efficacious than other GLP-1 RAs regarding both glycemic control and weight loss.

What about the oral formulation of semaglutide? In the randomized, double-blind PIONEER 4 trial, oral semaglutide resulted in superior weight loss compared with liraglutide (ETD: -1.2 kg; P = .0003) and placebo (ETD: -3.8 kg; P < .0001) at Week 26.

Taken together, these data support semaglutide as the most potent weight reduction agent currently available for patients with diabetes.

To summarize, although there are few head-to-head trials comparing weight reduction, there appears to be a hierarchy of GLP-1 RAs regarding potency in causing weight loss. At doses used to treat diabetes, semaglutide seems to be the most potent, with oral semaglutide associated with greater weight reduction than the subcutaneous formulation. Liraglutide is less potent than semaglutide, but more potent than other GLP-1 RAs. Dulaglutide and lixisenatide are less potent than liraglutide and semaglutide, whereas exenatide once weekly is more potent than exenatide. 

My Practice
In my own practice, I prefer semaglutide, either orally or as a once-weekly injection, for patients with T2D who also have weight issues. Because of the strong evidence supporting its potency for weight reduction, I favor semaglutide as first-line treatment for achieving glycemic control and weight loss, and I choose this agent when a patient’s insurance will cover the cost. Indeed, the weight loss benefits are a primary reason I choose GLP-1 RAs, as so many patients with diabetes are overweight or obese

Your Thoughts?
How do you choose among GLP-1 RAs for patients with T2D who are overweight or obese? Answer the polling question and join the discussion by posting a comment below. And for more support on selecting the ideal GLP-1 RA, I encourage you to visit the Interactive Decision Support Tool, Choosing Among GLP-1 Receptor Agonists for Patients With Type 2 Diabetes, which I developed with my colleagues, Martin J. Abrahamson, MD, FACP; Zachary T. Bloomgarden, MD, MACE; Anne Peters, MD; and Richard E. Pratley, MD. In this online tool, you can enter the details of your patient and learn how 5 experts would proceed.

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