Semaglutide

BackgroundWith the increasing use of GLP-1 receptor agonists and dual GIP/GLP-1 agonists for managing obesity and type 2 diabetes, understanding their real-world effectiveness and safety is essential. This TriNetX analysis directly compares clinical outcomes among patients treated with tirzepatide vs semaglutide.MethodWe utilized data from the TriNetX Research Network, identifying patients aged > 40 years or with obesity ("BMI ≥ 30 kg/m2") and type 2 diabetes (HbA1c ≥ 6.5% or fasting glucose.≥ 125 mg/dL). Qualifying events were restricted to May 1, 2022, through November 21, 2024. We established two cohorts: one initiating tirzepatide and another semaglutide, ensuring each patient had at least three prescriptions and no prior exposure to the comparator drug or other GLP-1 receptor agonists. The index date was defined as the first co-occurrence of the obesity/diabetes criteria and the respective drug prescription. To ensure comparability, we performed 1:1 propensity matching, resulting in 47,804 patients in each cohort. Outcomes, including all-cause mortality, MACE, heart failure exacerbation, ischemic stroke/TIA, hospitalization/ED use, dementia, UTI, adverse Gastrointestinal (GI) effects, and changes in HbA1c, were assessed within a 1-year window after the index date.ResultsOur matched cohort had a mean age of 75 years, with 45% male patients and 74% identified as white. Patients treated with tirzepatide experienced a significantly lower incidence of MACE at "("3.7% vs 4.1% (RR 0.918, 95% CI 0.862-0.978). All-cause mortality was also lower with tirzepatide (0.2% vs. 0.4%; Risk Ratio 0.436, 95% CI 0.338-0.562). The tirzapetide group achieved better glycemic control with a lower mean HbA1c (6.565% vs. 6.848%; p < 0.001) during the follow-up. There was no significant difference in heart failure exacerbation or UTI incidence. GI side effects were slightly less frequent in the tirzepatide cohort (9.8% vs. 10.2%; Risk Ratio 0.959, 95% CI 0.924-0.997), while hospitalization or emergency visits were comparable between the two groups.ConclusionIn this propensity matched cohort of patients with obesity and type 2 diabetes, tirzepatide demonstrated improved cardiometabolic outcomes compared to semaglutide, including lower all-cause mortality and lower HbA1c. These findings support the cardiovascular safety and efficacy of tirzapetide and highlight the need for further studies to evaluate its effectiveness in broader clinical populations.

BACKGROUND: Evidence suggests that glucagon-like peptide 1 receptor agonists (GLP-1RAs) might have pro-cognitive effects. No prior study has evaluated the efficacy and safety of a GLP-1RA for the treatment of cognitive dysfunction in adults with major depressive disorder (MDD) in a randomized clinical trial. METHODS: This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345). Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese. Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide. The primary outcome was an executive function composite score comprising the digit symbol substitution test, the Stroop test, and the n-back test. Secondary outcomes included a global cognition composite score, measures of functioning, depressive symptom severity, suicidality, and body weight. FINDINGS: 72 participants were randomized to oral semaglutide (n = 35) or placebo (n = 37). Semaglutide did not improve executive function (adjusted Z score difference [semaglutide - placebo]: 0.32, 95% confidence interval [CI]: -0.92 to 1.58, p = 0.60). Preplanned secondary analysis showed treatment effects for global cognition (2.39, 95% CI: 0.19 to 4.60, p = 0.03) and body weight (kg) (adjusted mean difference -6.03, 95% CI: -8.76 to -3.29, p < 0.001). Treatment did not affect depressive symptom severity or the frequency of suicidal ideation. Gastrointestinal side effects were common in the semaglutide group, with no serious adverse events. CONCLUSION: Semaglutide did not improve executive function; results from secondary analyses suggested effects on specific domains of cognition. Semaglutide was safe for patients with MDD. FUNDING: This work was supported by the Physicians' Services Incorporated Foundation.

OBJECTIVE: We aimed to compare the effectiveness and safety of semaglutide 1.0 mg versus dulaglutide 1.5 mg and liraglutide 1.8 mg in patients with type 2 diabetes mellitus (T2DM) under routine clinical care. METHODS: This multicenter, retrospective, real-world study enrolled Chinese adults with T2DM who initiated GLP-1 receptor agonist therapy in endocrinology clinics between January 1, 2022, and August 31, 2024. We compared the effectiveness of these agents on HbA1c and weight loss, with safety as a key exploratory endpoint. Additionally, the UK Prospective Diabetes Study Outcomes Model 2.1 was utilized to project long-term health outcomes. RESULTS: This multicenter retrospective study included 111, 74, and 107 patients treated with semaglutide 1.0 mg, dulaglutide 1.5 mg, and liraglutide 1.8 mg, respectively. After 1:1 propensity score matching, semaglutide demonstrated significantly greater HbA1c reduction compared to both dulaglutide (-0.27% ± 0.70%, p = 0.008) and liraglutide (-0.39% ± 0.87%, p < 0.001), along with higher glycemic target achievement rates. Semaglutide was associated with improved outcomes in all death, cardiovascular death, and other death endpoints. No significant differences in safety profiles were observed among the three treatment groups. CONCLUSIONS: Semaglutide demonstrated superior glycemic control and weight loss compared to both dulaglutide and liraglutide, whereas dulaglutide and liraglutide exhibited comparable clinical efficacy.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, is a candidate for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). METHODS: In this ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled trial, we assigned 1197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. The results of a planned interim analysis conducted at week 72 involving the first 800 patients are reported here (part 1). The primary end points for part 1 were the resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis. RESULTS: Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% confidence interval [CI], 21.1 to 36.2; P<0.001). A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001). Results for the three secondary outcomes that were included in the plan to adjust for multiple testing were as follows: combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% of the patients in the semaglutide group and in 16.1% of those in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P<0.001). The mean change in body weight was -10.5% with semaglutide and -2.0% with placebo (estimated difference, -8.5 percentage points; 95% CI, -9.6 to -7.4; P<0.001). Mean changes in bodily pain scores did not differ significantly between the two groups. Gastrointestinal adverse events were more common in the semaglutide group. CONCLUSIONS: In patients with MASH and moderate or advanced liver fibrosis, once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT04822181.).

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of semaglutide 2.4 mg, a glucagon-like peptide-1 receptor agonist, by race and ethnicity, across three phase 3 trials. METHODS: The Semaglutide Treatment Effect in People with Obesity (STEP) clinical trials evaluated the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg. Here, STEP 1 and 3 data were pooled for analysis; STEP 2 data were examined separately. All analyses were conducted using data from racial and ethnic subgroups. The primary outcome was the estimated treatment difference in percent body weight change for semaglutide 2.4 mg versus placebo. RESULTS: Participants reported race as White (STEP 1 and 3, 75.3%; STEP 2, 59.4%), Black (8.8%; 8.9%), Asian (10.6%; 27.3%), or other racial group (5.3%; 4.4%); and ethnicity as Hispanic or Latino (13.9%; 11.9%) or not Hispanic or Latino (83.9%; 88.1%). There were no significant interactions between treatment effect and race (STEP 1 and 3: p ≥ 0.07; STEP 2: p ≥ 0.15) or ethnicity (p ≥ 0.40; p ≥ 0.85). The safety of semaglutide 2.4 mg was consistent across subgroups. CONCLUSIONS: The treatment effect of semaglutide was statistically significant versus placebo and clinically relevant across all racial and ethnic subgroups in STEP 1 and 3 and STEP 2. All subgroups across both samples demonstrated good tolerability.

INTRODUCTION: Glucagon-like peptide 1 receptor agonists (GLP1Ras) have emerged as pivotal agents in diabetes management and organ protection. However, their use is limited due to the necessity for injectable administration. The advent of the first oral GLP1Ra (oral semaglutide) in Japan since 2021 is expected to expand its usage. The aim of this study is to survey the efficacy and tolerability of oral semaglutide in clinical practice. MATERIALS AND METHODS: We retrospectively analyzed 120 outpatients diagnosed with type 2 diabetes mellitus who had received oral semaglutide for >6 months. Changes in clinical parameters during oral semaglutide treatment from baseline to 12 months were analyzed. The inverse probability weighting method using the propensity score was used to evaluate the differences in clinical parameters at 6 months after treatment, based on the patients' obesity levels. RESULTS: Body weight (BW), glycated hemoglobin A1c (HbA1c), and alanine aminotransferase (ALT) levels at baseline decreased significantly after treatment compared with those at 12 months (P < 0.001, P < 0.001, and P = 0.03, respectively). The patients were divided into two groups using a cutoff baseline body mass index (BMI) of 30.3 kg/m2. Although no significant difference was observed, changes in body weight and HbA1c indicated a potentially greater decrease in the BMI ≧ 30.3 group than that in the BMI < 30.3 group (P = 0.07 and 0.13, respectively). Among 206 registered patients, 25 (12.1%) discontinued oral-semaglutide treatment owing to adverse effects, including gastrointestinal symptoms. CONCLUSIONS: Oral semaglutide treatment demonstrates efficacy and tolerability for managing type 2 diabetes mellitus in Japan. Significant improvements in metabolic factors induced by oral semaglutide are anticipated, particularly in obese patients.