A Triple Gut Hormone Infusion (GLP-1 + Oxyntomodulin + PYY) Improved Weight and Blood Sugar Better Than Gastric Bypass for Glucose Control | Research

The takeaway

A 4-week infusion of three gut hormones — GLP-1, oxyntomodulin, and PYY — produced significant weight loss and better glucose control than gastric bypass surgery in obese patients with diabetes or prediabetes.

Better glucose control than surgery
Despite less total weight loss, the triple hormone infusion achieved superior glucose tolerance and reduced glycemic variability compared to gastric bypass and very low-calorie diet

What the researchers found

Four weeks of subcutaneous GOP infusion produced significantly greater weight loss than placebo (-4.4 kg vs -2.5 kg, p=0.025) and substantially greater improvement in fructosamine levels (-44.1 vs -11.7 µmol/L, p=0.0026), a marker of medium-term blood sugar control.

The most striking finding was the comparison with gastric bypass (RYGB) and very low-calorie diet (VLCD). Despite causing less total weight loss than either comparator, GOP achieved superior glucose tolerance after a mixed meal and reduced glycemic variability on continuous glucose monitoring. This suggests the three-hormone combination has direct glucose-regulating effects independent of weight loss alone.

Why it matters

Gastric bypass is the most effective treatment for obesity with diabetes, but it's invasive and irreversible. This study showed that infusing the same hormones the gut produces after bypass surgery can replicate — and even exceed — its glucose control benefits. This provides proof-of-concept for developing drug cocktails that mimic the hormonal effects of bariatric surgery, potentially offering patients the metabolic benefits without the surgical risks.

How the study worked

Single-blinded, placebo-controlled randomized study. 26 obese patients with prediabetes or type 2 diabetes were randomized to receive subcutaneous GOP infusion (n=15) or saline placebo (n=11) for 4 weeks. Two unblinded comparator groups were also studied: 21 post-RYGB patients and 22 patients on a very low-calorie diet. Outcomes included body weight, fructosamine levels, glucose and insulin during mixed meal tests, energy expenditure, energy intake, and continuous glucose monitoring.

What this study cannot tell us

Small sample size (26 randomized patients) limits statistical power. The study was single-blinded, not double-blinded. GOP was delivered by continuous subcutaneous infusion, which isn't practical for long-term clinical use. The RYGB and VLCD comparator groups were unblinded and not randomized, making direct comparisons less reliable. Only 4 weeks of treatment was studied — long-term effects and sustainability are unknown.

How to read the evidence

This is a randomized, placebo-controlled clinical trial in humans — strong study design. However, the small sample size (26 patients), single-blinding, short duration (4 weeks), and unblinded comparator groups limit the strength of the conclusions.

When this study was published

Published in 2019 in Diabetes Care, a top diabetes journal. The concept of multi-hormone therapy for obesity and diabetes continues to be actively pursued, making this foundational study still highly relevant.

The bigger picture

This study is part of the 'medical bypass' concept — recreating the hormonal changes of bariatric surgery with drugs. While current GLP-1 agonists like semaglutide target a single hormone, this research suggests that combining multiple gut hormones may unlock even better metabolic outcomes, particularly for glucose control. The finding that GOP outperformed surgery on glucose metrics despite less weight loss highlights that the next generation of obesity drugs may work by directly improving metabolism, not just reducing body weight.

Questions still open

Could the GOP combination be developed into a practical injectable drug (like semaglutide) rather than requiring continuous infusion?
Would longer-term GOP treatment produce even greater weight loss while maintaining its superior glucose control?
Which of the three hormones contributes most to the glucose benefits seen beyond weight loss effects?

Common questions

What are GLP-1, oxyntomodulin, and PYY?

These are three hormones naturally produced by your gut after eating. GLP-1 stimulates insulin release and suppresses appetite. Oxyntomodulin reduces appetite and increases energy burning. PYY signals fullness to the brain. After gastric bypass surgery, levels of all three surge dramatically, which is thought to be a major reason the surgery is so effective for weight loss and diabetes.

Why was the glucose control better than gastric bypass even with less weight loss?

This suggests the three hormones have direct effects on blood sugar regulation beyond what weight loss alone would explain. GLP-1 directly stimulates insulin production, and the combination of all three hormones may work together to stabilize blood sugar in ways that simply eating less (as with a very low-calorie diet) or having surgery cannot fully replicate.

Read the original research

Combined GLP-1, Oxyntomodulin, and Peptide YY Improves Body Weight and Glycemia in Obesity and Prediabetes/Type 2 Diabetes: A Randomized, Single-Blinded, Placebo-Controlled Study.

Diabetes care, 42(8), 1446-1453

View on PubMed ↗Publisher’s paper ↗

Citation

Behary, Preeshila; Tharakan, George; Alexiadou, Kleopatra; Johnson, Nicholas; Wewer Albrechtsen, Nicolai J; Kenkre, Julia; Cuenco, Joyceline; Hope, David; Anyiam, Oluwaseun; Choudhury, Sirazum; Alessimii, Haya; Poddar, Ankur; Minnion, James; Doyle, Chedie; Frost, Gary; Le Roux, Carel; Purkayastha, Sanjay; Moorthy, Krishna; Dhillo, Waljit; Holst, Jens J; Ahmed, Ahmed R; Prevost, A Toby; Bloom, Stephen R; Tan, Tricia M. (2019). Combined GLP-1, Oxyntomodulin, and Peptide YY Improves Body Weight and Glycemia in Obesity and Prediabetes/Type 2 Diabetes: A Randomized, Single-Blinded, Placebo-Controlled Study.. Diabetes care, 42(8), 1446-1453. https://doi.org/10.2337/dc19-0449