EMERGING THERAPIES: DRUGS AND REGIMENS Diabetes Care 1 Preeshila Behary,1 George Tharakan,1 Combined GLP-1, Oxyntomodulin, Kleopatra Alexiadou,1 Nicholas Johnson,2 Nicolai J. Wewer Albrechtsen,3,4 and Peptide YY Improves Julia Kenkre,1 Joyceline Cuenco,1 David Hope,1 Oluwaseun Anyiam,1 Body Weight and Glycemia in Sirazum Choudhury,1 Haya Alessimii,1 Ankur Poddar,1 James Minnion,1 Obesity and Prediabetes/Type Chedie Doyle,1 Gary Frost,1 Carel Le Roux,1,5 Sanjay Purkayastha,6 Krishna Moorthy,6 2 Diabetes: A Randomized Waljit Dhillo,1 Jens J. Holst,7 Ahmed R. Ahmed,6 A. Toby Prevost,2 Single-Blinded Placebo Stephen R. Bloom,1 and Tricia M. Tan1 Controlled Study https://doi.org/10.2337/dc19-0449 OBJECTIVE 1Section of Investigative Medicine, Imperial Col- Roux-en-Y gastric bypass (RYGB) augments postprandial secretion of glucagon-like lege London, London, U.K. 2Imperial Clinical Trials Unit, Imperial College peptide 1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY). Subcutaneous London, London, U.K. infusion of these hormones (“GOP”), mimicking postprandial levels, reduces energy 3Department of Clinical Biochemistry, Rigshospi- intake. Our objective was to study the effects of GOP on glycemia and body weight talet, Copenhagen, Denmark 4 when given for 4 weeks to patients with diabetes and obesity. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Den- RESEARCH DESIGN AND METHODS mark In this single-blinded mechanistic study, obese patients with prediabetes/diabetes 5School of Medicine, University College Dublin, were randomized to GOP (n = 15) or saline (n = 11) infusion for 4 weeks. We also Dublin, Ireland 6 studied 21 patients who had undergone RYGB and 22 patients who followed a very Department of Surgery and Cancer, Imperial College Healthcare National Health Service Trust, low-calorie diet (VLCD) as unblinded comparators. Outcomes measured were 1) London, U.K. body weight, 2) fructosamine levels, 3) glucose and insulin during a mixed meal test 7Panum Institute, Department of Biomedical (MMT), 4) energy expenditure (EE), 5) energy intake (EI), and 6) mean glucose and Sciences and the Novo Nordisk Foundation Center measures of glucose variability during continuous glucose monitoring. for Basic Metabolic Research, University of Co- penhagen, Copenhagen, Denmark RESULTS Corresponding author: Tricia M. Tan, t.tan@ imperial.ac.uk GOP infusion was well tolerated over the 4-week period. There was a greater weight P 2 2 2 Received 5 March 2019 and accepted 25 April loss ( = 0.025) with GOP (mean change 4.4 [95% CI 5.3, 3.5] kg) versus saline 2019 2 2 2 P ( 2.5 [ 4.1, 0.9] kg). GOP led to a greater improvement ( = 0.0026) in fructosamine Clinical trial reg. no. NCT01945840, clinicaltrials (244.1 [262.7, 225.5] mmol/L) versus saline (211.7 [218.9, 24.5] mmol/L). Despite a .gov smaller weight loss compared with RYGB and VLCD, GOP led to superior glucose This article contains Supplementary Data online tolerance after a mixed-meal stimulus and reduced glycemic variability compared at http://care.diabetesjournals.org/lookup/suppl/ with RYGB and VLCD. doi:10.2337/dc19-0449/-/DC1. P.B. and G.T. contributed equally. CONCLUSIONS © 2019 by the American Diabetes Association. GOP infusion improves glycemia and reduces body weight. It achieves superior Readers may use this article as long as the work glucose tolerance and reduced glucose variability compared with RYGB and VLCD. is properly cited, the use is educational and not for profit, and the work is not altered. More infor- GOP is a viable alternative for the treatment of diabetes with favorable effects on mation is available at http://www.diabetesjournals body weight. .org/content/license. Diabetes Care Publish Ahead of Print, published online June 8, 2019 2 GOP Combination in Obesity and Type 2 Diabetes Diabetes Care Bariatric surgery, in particular Roux-en-Y of analogs possessing extended pharma- Dutch Eating Behavior Questionnaire gastric bypass (RYGB), remains the most cokinetics. Lastly, continuous subcuta- (DEBQ) questionnaires (18–20). efficacious treatment for obesity and neous infusions are commonplace in type 2 diabetes (T2DM). Glycemic im- diabetes treatment, demonstrating its Interventions provement after RYGB is superior to practicality in daily life. Infusion Groups (GOP or Saline) intensive medical management and is We therefore hypothesized that a GOP GLP-1 (7-36) amide, PYY (3-36) amide, sustained, with diabetes remission rates infusion, given for 4 weeks in “free living” and OXM were manufactured to Good of 26–29% at 5 years (1). Mechanistic conditions, would reduce body weight Manufacturing Practice standards (Am- studies have shown an early improve- and improve glycemia compared with bioPharm). They were mixed under ster- ment in hepatic insulin sensitivity and a placebo of 0.9% saline (hereafter re- ile conditions and freeze-dried in single later in peripheral insulin sensitivity as ferred to as Saline) infusion. To compare vials. Visually identical vials containing well as b-cell function (2). Proposed mech- the metabolic effects of GOP with those freeze-dried 0.9% Saline were also man- anisms include early postsurgical calorie of RYGB, we studied a group of patients ufactured. Vials were reconstituted with restriction; postprandial secretion of the who underwent surgery. To compare the sterile water for injections and added to satiety gut hormones glucagon-like pep- effects of GOP with simple dietary re- 0.9% Saline. Reconstituted peptides were fi tide 1 (GLP-1), oxyntomodulin (OXM), striction, we studied a group of patients veri ed to be stable for over 12 h at 37°C and peptide YY (PYY), reduced secretion who followed an 800 kcal/day very low- by high-performance liquid chromatog- of the orexigenic hormone ghrelin, bypass calorie diet (VLCD). raphy (Supplementary Fig. 1). A Cane of the proximal small bowel and reduced Crono Infusion pump (Applied Medical secretion of an “anti-incretin,” changes in RESEARCH DESIGN AND METHODS Technology) and an infusion set (Med- bile acid metabolism, changes in gut tronic) was used to deliver the subcuta- Study Design and Participants neous infusion of GOP at a dose of 4/4/ microbiota composition, reprogramming This mechanistic study took place at the 0.4 pmol/kg/min, respectively (5). Vol- of intestinal glucose metabolism, and in- National Institute for Health Research (NIHR) unteers were allocated to receive the crease in energy expenditure, among Imperial Clinical Research Unit Facility GOP or Saline infusion for 28 days by others (3). However, the exact contribu- at Hammersmith Hospital, London, from simple randomization performed by an tions from each mechanism are not clear. July 2016 to October 2018. It was a single- independent investigator. Volunteers’ GLP-1, OXM, and PYY are released blinded randomized controlled study usual treatment for diabetes was sus- from the L cells of the small intestine comparing two infusion groups (GOP pended for the duration of the study. and colon, and their postprandial secre- or Saline) in patients with obesity and Only volunteers remained blinded to the tion is augmented several-fold after prediabetesorT2DM.Twofurthersimilar nature of the infusion from allocation RYGB (4,5). GLP-1 is insulinotropic and nonblinded groups of patients under- until the end of the 28-day infusion period. reduces food intake. Its analogs are an going RYGB and patients following a They were instructed to run the infusion established treatment for diabetes (6) as VLCD diet were recruited. Potential vol- for 12 h/day, beginning 1 h before break- well as obesity (7). OXM is a dual agonist unteers for the GOP, Saline, and VLCD fast and disconnecting after their last meal of the GLP-1 and glucagon receptors (8), groups were recruited from clinics at the of the day. On study days, the infusions which reduces food intake (9) and in- Imperial Weight Centre (IWC) or from were commenced at least 2 h before any creases energy expenditure (10), leading newspaper advertising, whereas patients study procedures. All volunteers also re- to weight loss (11). PYY acts to reduce already listed for surgery at the IWC were appetite and food intake postprandially ceived dietetic advice on healthy eating recruited to form the RYGB group. fi (12,13). Combinations of GLP-1 and PYY and weight loss from a quali ed dietitian. (14,15), OXM and PYY (16), and GLP-1 and Inclusion and Exclusion Criteria RYGB Group glucagon (17) have synergistic effects on Key eligibility criteria were male or fe- Volunteers undergoing RYGB attended food intake. male participants aged between 18 and the research unit for a baseline visit before Replicating the postprandial gut hor- 70 years, meeting the U.K. National surgery and were reviewed at 2, 4, and 12 mone levels after RYGB is possible using Health Service (NHS) criteria for bariatric weeks after surgery. RYGB surgery was a continuous subcutaneous infusion of surgery, and with a diagnosis of predi- performed laparoscopically according to combination of GLP-1, OXM, and PYY abetes (impaired fasting glucose, im- standardized techniques by three desig- (“GOP”). This is safe, acceptable, and paired glucose tolerance, or HbA1c of nated surgeons at IWC. led to a reduction in total ad libitum 6.0–6.4% [42–47 mmol/mol]) or T2DM VLCD Group energy intake compared with placebo according to World Health Organization Volunteers attended the research unit for over a 10.5-h infusion (5). A continuous criteria. Patients who had diabetes had a baseline visit, before starting a complete subcutaneous infusion obviates the de- a stable HbA1c of #9.0% (75 mmol/mol) meal replacement VLCD of 800 kcal/day velopment of sharp peaks and leads to a either on diet or a single oral hypogly- for 4 weeks (Cambridge Weight Plan).