Combined Glp-1, Oxyntomodulin, And Peptide Yy Improves Glycaemia And Body Weight In Obesity And Type 2 Diabetes: A Randomized, Single-Blinded Study

Background: Roux-en-Y gastric bypass (RYGB) is a successful treatment for diabetes and obesity, possibly because it augments post-prandial secretion of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and peptide YY (PYY). Subcutaneous infusion of GLP-1, OXM and PYY (GOP) mimicking hormone levels observed after RYGB reduces food intake. We hypothesized that GOP given for 4 weeks to patients with diabetes and obesity would improve glycaemia and body weight in comparison to placebo. Methods: 26 patients were randomized to a single-blinded GOP or Saline infusion. We also studied 21 patients who had RYGB, and 22 patients on a 800 kcal/day very low calorie diet (VLCD). Outcome measures were: (a) fructosamine levels; (b) body weight; (c) glucose and insulin during mixed meal test (MMT); (d) energy expenditure (EE); (e) energy intake (EI); (f) glucose variability. Findings: GOP infusion was well tolerated and led to a significantly greater mean reduction in fructosamine of -44·1 [95% CI 62·7, -25·5] µmol/L vs. Saline -11·7 [-18·9, -4·5] (difference in treatment effect 32·4 [12·9, 51·9], p=0·002). RYGB and VLCD also led to improvements (-34·0 [-45·6, -22.4] and -28·5 [-40.4, -16.7] respectively). The weight loss with GOP was -4·4 [-5·4, -3·5] kg compared to -2·5 [-4·1, -0·9] with Saline, -10·3 [-11·8, -8·8] with RYGB and -8·3 [-9·5, -7·1] with VLCD. Strikingly, there were key differences in glucose and insulin dynamics during the MMT. After RYGB there was an early glucose peak followed by marked insulin secretion, whereas GOP led to a flat euglycaemic response with no sharp insulin peak. The improvement in glucose tolerance with GOP was superior to VLCD. Interpretation: GOP infusion improves glycaemia and reduces body weight, supporting triple agonism of GLP-1, glucagon and peptide YY receptors as a treatment strategy for diabetes with obesity. Disclosure P. Behary: None. G. Tharakan: None. K. Alexiadou: None. N.A. Johnson: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. J. Cuenco: None. D. Hope: None. W. Dhillo: None. J.S. Minnion: None. G. Frost: Consultant; Self; Heptares, Nestlé. C. le Roux: Advisory Panel; Self; GI Dynamics, Inc., Herbalife International of America, Inc., Janssen Pharmaceuticals, Inc., Johnson & Johnson, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. S. Purkayastha: None. K. Moorthy: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. A. Ahmed: None. T. Prevost: None. S. Bloom: None. T.M.M. Tan: Other Relationship; Self; Novo Nordisk A/S. Funding Medical Research Council UK; Imperial Biomedical Research Centre