TY - JOUR
T1 - The effects of empagliflozin, dietary energy restriction, or both on appetite-regulatory gut peptides in individuals with type 2 diabetes and overweight or obesity
T2 - The SEESAW randomized, double-blind, placebo-controlled trial
AU - Sargeant, Jack A.
AU - King, James A.
AU - Yates, Thomas
AU - Redman, Emma L.
AU - Bodicoat, Danielle H.
AU - Chatterjee, Sudesna
AU - Edwardson, Charlotte L.
AU - Gray, Laura J.
AU - Poulin, Benoit
AU - Waheed, Ghazala
AU - Waller, Helen L.
AU - Webb, David R.
AU - Willis, Scott A.
AU - Wilding, John P.H.
AU - Khunti, Kamlesh
AU - Stensel, David J.
AU - Davies, Melanie J.
N1 - Funding Information:
JAS and TY report funding in the form of an investigator‐initiated trial from AstraZeneca. DRW has received honoraria as a speaker for AstraZeneca, Sanofi‐Aventis and Lilly, and has received research funding support from Novo Nordisk. JPHW reports receiving consultancy fees (paid to University of Liverpool) in relation to obesity and type 2 diabetes in the last 12 months from AstraZeneca, Boehringer Ingelheim, Janssen Pharmaceuticals, Lilly, Mundipharma, Napp, Novo Nordisk, Rhythm Pharmaceuticals, Sanofi and Saniona; personal fees honoraria/lecture fees from AstraZeneca, Boehringer Ingelheim, Lilly, Napp, Mundipharma, Sanofi and Takeda; and research grant funding (via University of Liverpool) from AstraZeneca and Novo Nordisk. KK has acted as consultant, advisory board member and speaker for Abbott, Amgen, Astrazeneca, Bayer, NAPP, Lilly, Merck Sharp and Dohme, Novartis, Novo Nordisk, Roche, Berlin‐Chemie AG/Menarini Group, Sanofi‐Aventis, Servier and Boehringer Ingelheim; and has received EACME grants from Boehringer Ingelheim, AstraZeneca, Novartis, Novo Nordisk, Sanofi‐Aventis, Lilly, Merck Sharp & Dohme. MJD has acted as consultant, advisory board member and speaker for Novo Nordisk, Sanofi, Lilly and Boehringer Ingelheim, an advisory board member and speaker for AstraZeneca, an advisory board member for Janssen, Lexicon, Servier and Gilead Sciences Ltd and as a speaker for Napp Pharmaceuticals, Mitsubishi Tanabe Pharma Corporation and Takeda Pharmaceuticals International Inc. She has received grants in support of investigator and investigator initiated trials from Novo Nordisk, Sanofi‐Aventis, Lilly, Boehringer Ingelheim, AstraZeneca and Janssen. JAK, ELR, DHB, SC, CLE, LJG, BP, GW, HLW, SAW and DJS have no conflicts of interest to declare.
Funding Information:
This research was funded by an investigator‐initiated grant from Boehringer‐Ingelheim. The funder had no role in collection, analysis or interpretation of data, nor writing of the manuscript. They commented on initial trial design and reviewed the manuscript, but final decisions were made by the investigator team. This study was supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre and the NIHR Applied Research Collaboration East Midlands. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Funding information
Funding Information:
information This research was funded by an investigator-initiated grant from Boehringer-Ingelheim. The funder had no role in collection, analysis or interpretation of data, nor writing of the manuscript. They commented on initial trial design and reviewed the manuscript, but final decisions were made by the investigator team. This study was supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre and the NIHR Applied Research Collaboration East Midlands. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.We would like to thank the participants for volunteering their time to participate in this study. We also thank all staff who supported aspects of trial set-up, management and delivery, particularly Natasha Wileman (Senior Trials Manager, Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust).
Publisher Copyright:
© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
PY - 2022/8
Y1 - 2022/8
N2 - Aim: To assess the impact of the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin (25 mg once-daily), dietary energy restriction, or both combined, on circulating appetite-regulatory peptides in people with type 2 diabetes (T2D) and overweight or obesity. Materials and Methods: In a double-blind, placebo-controlled trial, 68 adults (aged 30-75 years) with T2D (drug naïve or on metformin monotherapy; HbA1c 6.0%-10.0% [42-86 mmol/mol]) and body mass index of 25 kg/m2 or higher were randomized to (a) placebo only, (b) placebo plus diet, (c) empagliflozin only or (d) empagliflozin plus diet for 24 weeks. Dietary energy restriction matched the estimated energy deficit elicited by SGLT2 inhibitor therapy through urinary glucose excretion (~360 kcal/day). The primary outcome was change in postprandial circulating total peptide-YY (PYY) during a 3-hour mixed-meal tolerance test from baseline to 24 weeks. Postprandial total glucagon-like peptide-1 (GLP-1), acylated ghrelin and subjective appetite perceptions formed secondary outcomes, along with other key components of energy balance. Results: The mean weight loss in each group at 24 weeks was 0.44, 1.91, 2.22 and 5.74 kg, respectively. The change from baseline to 24 weeks in postprandial total PYY was similar between experimental groups and placebo only (mean difference [95% CI]: −8.6 [−28.6 to 11.4], 13.4 [−6.1 to 33.0] and 1.0 [−18.0 to 19.9] pg/ml in placebo-plus diet, empagliflozin-only and empagliflozin-plus-diet groups, respectively [all P ≥.18]). Similarly, there was no consistent pattern of difference between groups for postprandial total GLP-1, acylated ghrelin and subjective appetite perceptions. Conclusions: In people with T2D and overweight or obesity, changes in postprandial appetite-regulatory gut peptides may not underpin the less than predicted weight loss observed with empagliflozin therapy. Clinical Trials Registration: NCT02798744, www.ClinicalTrials.gov; 2015-001594-40, www.EudraCT.ema.europa.eu; ISRCTN82062639, www.ISRCTN.org.
AB - Aim: To assess the impact of the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin (25 mg once-daily), dietary energy restriction, or both combined, on circulating appetite-regulatory peptides in people with type 2 diabetes (T2D) and overweight or obesity. Materials and Methods: In a double-blind, placebo-controlled trial, 68 adults (aged 30-75 years) with T2D (drug naïve or on metformin monotherapy; HbA1c 6.0%-10.0% [42-86 mmol/mol]) and body mass index of 25 kg/m2 or higher were randomized to (a) placebo only, (b) placebo plus diet, (c) empagliflozin only or (d) empagliflozin plus diet for 24 weeks. Dietary energy restriction matched the estimated energy deficit elicited by SGLT2 inhibitor therapy through urinary glucose excretion (~360 kcal/day). The primary outcome was change in postprandial circulating total peptide-YY (PYY) during a 3-hour mixed-meal tolerance test from baseline to 24 weeks. Postprandial total glucagon-like peptide-1 (GLP-1), acylated ghrelin and subjective appetite perceptions formed secondary outcomes, along with other key components of energy balance. Results: The mean weight loss in each group at 24 weeks was 0.44, 1.91, 2.22 and 5.74 kg, respectively. The change from baseline to 24 weeks in postprandial total PYY was similar between experimental groups and placebo only (mean difference [95% CI]: −8.6 [−28.6 to 11.4], 13.4 [−6.1 to 33.0] and 1.0 [−18.0 to 19.9] pg/ml in placebo-plus diet, empagliflozin-only and empagliflozin-plus-diet groups, respectively [all P ≥.18]). Similarly, there was no consistent pattern of difference between groups for postprandial total GLP-1, acylated ghrelin and subjective appetite perceptions. Conclusions: In people with T2D and overweight or obesity, changes in postprandial appetite-regulatory gut peptides may not underpin the less than predicted weight loss observed with empagliflozin therapy. Clinical Trials Registration: NCT02798744, www.ClinicalTrials.gov; 2015-001594-40, www.EudraCT.ema.europa.eu; ISRCTN82062639, www.ISRCTN.org.
KW - SGLT2 inhibitors
KW - compensation
KW - energy balance
KW - energy restriction
KW - gut hormones
UR - http://www.scopus.com/inward/record.url?scp=85129797291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129797291&partnerID=8YFLogxK
U2 - 10.1111/dom.14721
DO - 10.1111/dom.14721
M3 - Article
C2 - 35441435
AN - SCOPUS:85129797291
SN - 1462-8902
VL - 24
SP - 1509
EP - 1521
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
IS - 8
ER -