The effects of empagliflozin, dietary energy restriction, or both on appetite-regulatory gut peptides in individuals with type 2 diabetes and overweight or obesity: The SEESAW randomized, double-blind, placebo-controlled trial

Abstract

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.

Keywords: SGLT2 inhibitors; compensation; energy balance; energy restriction; gut hormones.

Conflict of interest statement

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.

© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Study consort diagram

FIGURE 2

Difference between experimental groups and placebo‐only at each time point (open symbols) and across follow‐up (filled symbols) in A, Total body weight, B, Resting energy expenditure, C, Daily steps and, D, HbA1c. Data are presented as adjusted mean difference (experimental group minus placebo‐only) with 95% CI. All analyses were adjusted for age, BMI (both categorized as per randomization) and baseline value of the outcome, with analyses of daily steps additionally adjusted for accelerometer wear time. * Denotes comparison with placebo‐only group was statistically significant after application of Holm's sequential Bonferroni procedure to account for multiple comparisons. GEE analyses across follow‐up can be inferred as the summary intervention effect. BMI, body mass index; GEE, generalized estimating equations

FIGURE 3

Difference between experimental groups and placebo‐only at each time point (open symbols) and across follow‐up (filled symbols) in appetite‐regulatory gut peptides: A, Postprandial total PYY, B, Postprandial acylated ghrelin, C, Postprandial total GLP‐1, and D, Fasting leptin. Data are presented as adjusted mean difference (experimental group minus placebo‐only) with 95% CI. Postprandial responses were assessed as time‐averaged area under the concentration‐time curve during the standardized 3‐hour mixed meal tolerance test. All analyses were adjusted for age, BMI (both categorized as per randomization) and baseline value of the outcome. * Denotes comparison with placebo‐only group was statistically significant after application of Holm's sequential Bonferroni procedure to account for multiple comparisons. GEE analyses across follow‐up can be inferred as the summary intervention effect. BMI, body mass index; GEE, generalized estimating equations; GLP‐1, glucagon‐like peptide‐1; PYY, peptide YY