Trial Supports GLP-1 After Underwhelming Metabolic Surgery

Adding a GLP-1 receptor agonist to lifestyle intervention helped to bolster weight loss in patients with poor outcomes following primary metabolic surgery, the BARI-OPTIMISE randomized trial found.

Looking at 70 individuals who experienced suboptimal weight loss and GLP-1 response after undergoing one of two established metabolic procedures, those who started taking 3-mg liraglutide (Saxenda) experienced significantly greater weight loss than those assigned a placebo injection, reported Rachel Batterham, MBBS, PhD, of the University College London Centre for Obesity Research, and colleagues.

Over 24 weeks, postsurgical patients who started injectable liraglutide lost 8.82% of their body weight from baseline compared with a loss of 0.54% for those on placebo (P<0.001). Weight loss for those on liraglutide was still trending downward at the 24-week mark, suggesting even more weight loss was likely.

This translated to a 9.49 kg [20.9 lb] loss on average for liraglutide-treated patients versus a 0.39 kg [0.86 lb] loss with placebo, the group reported in JAMA Surgery.

At this time-point, 71.9% of liraglutide-treated patients lost at least 5% of their body weight — the threshold for clinically significant weight loss — versus only 8.8% of placebo patients.

“Although metabolic surgery remains the most effective and durable therapy for severe obesity and associated comorbidities, one in four patients experience poor weight loss outcomes,” Batterham’s groups pointed out. The 70 patients in the trial were at least 1 year out of their Roux-en-Y gastric bypass (7% of patients) or sleeve gastrectomy (93%) procedure.

In the trial, the benefits of adding liraglutide to the mix after metabolic surgery went beyond just weight loss. At 24 weeks, those on liraglutide saw greater fat mass loss (adjusted mean difference -4.85 kg, 95% CI -7.18 to -2.53) along with a slew of other metabolic improvements:

• Glucose: -0.51 mmol/L [-9.2 mg/dL] (95% CI -0.86 to -0.17)
• HbA1c: -0.24% (95% CI -0.32 to -0.16)
• Systolic blood pressure: -9.05 mm Hg (95% CI -16.24 to -1.85)
• Total cholesterol: -0.42 mmol/L (95% CI -0.68 to -0.15)
• HDL cholesterol: -0.12 mmol/L (95% CI -0.23 to -0.01)

Lean mass dropped more in the liraglutide arm (adjusted mean difference -3.22 kg, 95% CI -4.80 to -1.64), while no differences between groups were seen for bone density, heart rate, diastolic blood pressure, C-reactive protein, LDL cholesterol, and triglycerides.

Those treated with liraglutide saw higher marks for quality of life, particularly in the physical functioning domain, though other quality-of-life aspects like self-esteem, sex life, public distress, and work didn’t differ greatly.

As expected with a GLP-1 receptor agonist, those on liraglutide experienced more adverse events, mostly being gastrointestinal-related. Over half of liraglutide patients experienced nausea versus 20% of the placebo patients. Constipation was also far more common with liraglutide (26% vs 6%). No patients in either group experienced a serious adverse event.

Praising the study, accompanying commentary authors Paulina Salminen, MD, PhD, of Turku University Hospital in Finland, and Ali Aminian, MD, of the Cleveland Clinic in Ohio, said the findings support adding newer weight-loss medications as part of an “all-hands-on-deck approach” to treating severe obesity.

However, they weren’t impressed by the fact that nearly all patients in the trial opted for laparoscopic sleeve gastrectomy (LSG), saying that while long-term weight loss “can be good and sustainable” with this particular procedure, “it should be noted that there are safe and more effective surgical options that can be considered in patients with suboptimal initial clinical response or recurrent weight gain after LSG, e.g., conversion to Roux-en-Y gastric bypass, duodenal switch, or single-anastomosis duodeno-ileal bypass.”

Salminen and Aminian were hopeful that the practice of combination surgical and pharmacological therapy will become more common given the newer anti-obesity medications on the market (semaglutide [Wegovy]), on the horizon (tirzepatide), and in development (orforglipron, retatrutide, survodutide, etc.).

From 2018 to 2020, BARI-OPTIMISE randomized 70 adult patients at two sites in London to liraglutide or placebo on top of diet and lifestyle counseling — with the aim of a 500-kcal energy deficit and 150 minutes of moderate to vigorous exercise per week.

The average age of participants was 47.6 years, and as expected with metabolic surgery, the majority were women (74%). A little under two-thirds were white (63%), one-fifth were Black, and 7% were Asian.

Patients had an average weight of 119.8 kg (264.1 lb) at the start of the trial, and 57% had a baseline BMI of 40 or greater. Only 13% of patients had type 2 diabetes. On average, individuals were 52 months out from their metabolic surgery.

Suboptimal weight loss response to surgery for trial eligibility was defined as 20% or less total body weight loss from the day of surgery, which the authors acknowledged is only one accepted criteria. Suboptimal GLP-1 response was measured as a twofold or less increase in circulating active GLP-1 between 0 and 30 minutes following a 500-kcal test meal.

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