Roux-en-Y gastric bypass (RYGB) results in rapid weight loss, reduced adiposity, and improved glucose metabolism. These effects are not simply attributable to decreased caloric intake or absorption, ...but the mechanisms linking rearrangement of the gastrointestinal tract to these metabolic outcomes are largely unknown. Studies in humans and rats have shown that RYGB restructures the gut microbiota, prompting the hypothesis that some of the effects of RYGB are caused by altered host-microbial interactions. To test this hypothesis, we used a mouse model of RYGB that recapitulates many of the metabolic outcomes in humans. 16S ribosomal RNA gene sequencing of murine fecal samples collected after RYGB surgery, sham surgery, or sham surgery coupled to caloric restriction revealed that alterations to the gut microbiota after RYGB are conserved among humans, rats, and mice, resulting in a rapid and sustained increase in the relative abundance of Gammaproteobacteria (Escherichia) and Verrucomicrobia (Akkermansia). These changes were independent of weight change and caloric restriction, were detectable throughout the length of the gastrointestinal tract, and were most evident in the distal gut, downstream of the surgical manipulation site. Transfer of the gut microbiota from RYGB-treated mice to nonoperated, germ-free mice resulted in weight loss and decreased fat mass in the recipient animals relative to recipients of microbiota induced by sham surgery, potentially due to altered microbial production of short-chain fatty acids. These findings provide the first empirical support for the claim that changes in the gut microbiota contribute to reduced host weight and adiposity after RYGB surgery.
The goal of this study was to understand the mechanisms of greater weight loss by gastric bypass (GBP) compared to gastric banding (GB) surgery. Obese weight- and age-matched subjects were studied ...before (T0), after a 12 kg weight loss (T1) by GBP (n = 11) or GB (n = 9), and at 1 year after surgery (T2). peptide YY3–36 (PYY3–36), ghrelin, glucagon-like peptide-1 (GLP-1), leptin, and amylin were measured after an oral glucose challenge. At T1, glucose-stimulated GLP-1 and PYY levels increased significantly after GBP but not GB. Ghrelin levels did not change significantly after either surgery. In spite of equivalent weight loss, leptin and amylin decreased after GBP, but not after GB. At T2, weight loss was greater after GBP than GB (P = 0.003). GLP-1, PYY, and amylin levels did not significantly change from T1 to T2; leptin levels continued to decrease after GBP, but not after GB at T2. Surprisingly, ghrelin area under the curve (AUC) increased 1 year after GBP (P = 0.03). These data show that, at equivalent weight loss, favorable GLP-1 and PYY changes occur after GBP, but not GB, and could explain the difference in weight loss at 1 year. Mechanisms other than weight loss may explain changes of leptin and amylin after GBP.
Background: Antihyperglycemic medication (AHM) may influence body weight causing weight gain or weight reduction. In SURMOUNT-2, tirzepatide, a once weekly GIP/GLP-1 receptor agonist, resulted in ...significantly greater weight reduction compared to placebo in participants with BMI ≥27 kg/m2 and type 2 diabetes. We conducted a subgroup analysis to explore the association between the weight-reduction efficacy of tirzepatide and concomitant AHMs at randomization categorized as promoting weight loss (WL), weight gain (WG), or weight neutral (WN). Methods: A mixed model for repeated measures assessed the change in body weight from randomization to endpoint (week 72). Logistic regression was conducted to analyze the proportion of participants achieving ≥5%, ≥10%, and ≥15% weight reduction targets at endpoint. Results: At baseline, mean weight was 95.7, 100.6, and 101.8 kg and BMI was 34.5, 36.0, and 36.4 kg/m2 in the WL, WG, and WN subgroups, respectively. Tirzepatide resulted in significantly greater weight reduction than placebo in all AHM subgroups (all p<0.001). No differences were observed among tirzepatide-treated AHM subgroups in the percent change in body weight and the proportion of participants achieving weight reduction targets. Conclusion: Tirzepatide was superior to placebo for weight reduction and showed similar weight reduction efficacy across AHM subgroups. Disclosure S. Machineni: Research Support; Eli Lilly and Company. Advisory Panel; Eli Lilly and Company. Consultant; Novo Nordisk. Research Support; Rhythm Pharmaceuticals, Inc. Consultant; Rhythm Pharmaceuticals, Inc. F. Jaouimaa: Employee; Eli Lilly and Company. R. Griffin: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M.X. Zhang: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J. Fraseur Brumm: None. Funding Eli Lilly and Company
Background: Obesity increases the risk of multiple co-morbidities. Little is known about the impact of this multimorbidity on weight reduction outcomes. This post hoc analysis of data from the ...SURMOUNT-1 trial was undertaken to explore the association between obesity-related multimorbidity and the weight-reduction efficacy of tirzepatide, a novel GIP/GLP-1 receptor agonist. Methods: Adults with a BMI ≥30 kg/m2, or ≥27 kg/m2 and at least one diagnosed weight-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease), excluding diabetes, received tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks. History of obesity-related complications (ORC) was determined at baseline by participant self-report; 10 ORC were evaluated for these analyses, excluding prediabetes. SURMOUNT-1 participants were grouped by number of baseline ORC 0 (n=944; 37%), 1 (n=686; 27%), or ≥2 (n=909; 36%). Analysis of the percent change in body weight from baseline was conducted using mixed model repeated measure with treatments by ORC groups interaction on the efficacy estimand. Results: At week 72, there was no statistically significant interaction (p=0.373) between tirzepatide treatment and number of ORC at baseline. The percent body weight reduction in tirzepatide groups vs. placebo was: -13.5, -13.5 and -13.6 for 5 mg dose, -20.4 -18.4, and -17.8 for 10 mg dose, and -20.2, -18.9, and -20.7 for 15 mg dose, for participants in the 0, 1, and ≥ 2 baseline ORC groups, respectively. Thus, treatment differences in percent reduction from baseline in body weight for each of the 3 doses of tirzepatide vs. placebo were consistent across all ORC groups. Conclusions: Regardless of the number ORC at baseline, all the tirzepatide doses resulted in greater reduction in body weight compared with placebo in SURMOUNT-1. These results are consistent with the overall study results.
The effects of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, on weight reduction after successful intensive lifestyle intervention are ...unknown. This double-blind, placebo-controlled trial randomized (1:1) adults with body mass index ≥30 or ≥27 kg/m
and at least one obesity-related complication (excluding diabetes), who achieved ≥5.0% weight reduction after a 12-week intensive lifestyle intervention, to tirzepatide maximum tolerated dose (10 or 15 mg) or placebo once weekly for 72 weeks (n = 579). The treatment regimen estimand assessed effects regardless of treatment adherence in the intention-to-treat population. The coprimary endpoint of additional mean per cent weight change from randomization to week 72 was met with changes of -18.4% (standard error (s.e.) 0.7) with tirzepatide and 2.5% (s.e. 1.0) with placebo (estimated treatment difference -20.8 percentage points (95% confidence interval (CI) -23.2%, -18.5%; P < 0.001). The coprimary endpoint of the percentage of participants achieving additional weight reduction ≥5% was met with 87.5% (s.e. 2.2) with tirzepatide and 16.5% (s.e. 3.0) with placebo achieving this threshold (odds ratio 34.6%; 95% CI 19.2%, 62.6%; P < 0.001). The most common adverse events with tirzepatide were gastrointestinal, with most being mild to moderate in severity. Tirzepatide provided substantial additional reduction in body weight in participants who had achieved ≥5.0% weight reduction with intensive lifestyle intervention. ClinicalTrials.gov registration: NCT04657016 .
Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic ...polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes.
This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m2 or higher and glycated haemoglobin (HbA1c) of 7–10% (53–86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003.
Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years SD 10·6, 476 51% were female, 710 76% were White, and 561 60% were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m2 (SD 6·6), and HbA1c 8·02% (SD 0·89; 64·1 mmol/mol SD 9·7). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was –12·8% (SE 0·6) and –14·7% (0·5), respectively, and –3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of –9·6% percentage points (95% CI –11·1 to –8·1) with tirzepatide 10 mg and –11·6% percentage points (–13·0 to –10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79–83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator.
In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management.
Eli Lilly and Company.
In a 13-week, randomized trial involving persons 6 to 79 years of age with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction in the glycated hemoglobin level than ...standard care.
Objective
Obesity is a growing global concern compounded by limited availability of effective treatment options. The SURMOUNT development program aims to evaluate the efficacy and safety of ...tirzepatide as an adjunct to lifestyle intervention compared with placebo on chronic weight management in adults with BMI ≥ 27 kg/m2 with or without type 2 diabetes.
Methods
The SURMOUNT program includes four global phase 3 trials NCT04184622 (SURMOUNT‐1), NCT04657003 (SURMOUNT‐2), NCT04657016 (SURMOUNT‐3), and NCT04660643 (SURMOUNT‐4). Participants are randomized to once‐weekly subcutaneous tirzepatide versus placebo in a double‐blind manner. The primary end point in all trials is the percentage change in body weight from randomization to end of treatment. Results for the primary end point for SURMOUNT‐1 were published recently and results for the other trials are expected in 2023.
Results
Across trials, participants have a mean age of 44.9 to 54.2 years, are mostly female (50.7% to 69.7%), and have a mean BMI of 36.1 to 38.9.
Conclusions
The extensive assessment of once‐weekly tirzepatide in the global SURMOUNT program will detail the clinical effects of this first‐in‐class glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 receptor agonist in chronic weight management.
This analysis of 3,375 adults with overweight/obesity across the Semaglutide Treatment Effect in People with obesity (STEP) 1, 3, and 4 trials evaluated whether more participants with prediabetes had ...normoglycemia after 68 weeks' treatment with once-weekly semaglutide 2.4 mg plus lifestyle intervention versus placebo and assessed changes in glucose metabolism in participants with prediabetes.
STEP 1, 3, and 4 were phase 3, 68-week, randomized, placebo-controlled, multinational trials; STEP 4 had a 20-week semaglutide run-in and 48-week randomized period. Analyses included changes (week 0-68; before the washout period) in glycemic status (prespecified: STEP 1 and 3; post hoc: STEP 4), and in HbA1c, fasting plasma glucose (FPG), and HOMA insulin resistance (HOMA-IR) among participants with prediabetes (post hoc).
Significantly more participants with baseline (week 0) prediabetes (n = 1,536) had normoglycemia at week 68 with semaglutide versus placebo (STEP 1, 84.1% vs. 47.8%; STEP 3, 89.5% vs. 55.0%; STEP 4, 89.8% vs. 70.4%; all P < 0.0001). Fewer participants with baseline normoglycemia had prediabetes at week 68 with semaglutide versus placebo (STEP 1, 2.9% vs. 10.9%; STEP 3, 3.2% vs. 5.8%; STEP 4, 1.1% vs. 5.0%). Semaglutide resulted in greater improvements in HbA1c, FPG, and HOMA-IR than placebo among participants with baseline prediabetes (all P < 0.01).
STEP 1, 3, and 4 collectively provide a robust assessment of the effects of semaglutide on glucose metabolism and prediabetes in a large cohort of adults with overweight/obesity while on treatment. Among participants with baseline prediabetes, 68 weeks' treatment with semaglutide versus placebo led to significant improvements in glucose metabolism and a higher likelihood of normoglycemia.
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