Daily Endocrinology Research Analysis

BACKGROUND: Elecoglipron is an oral, small molecule glucagon-like peptide (GLP)-1 receptor agonist currently in development for the management of type 2 diabetes. Elecoglipron is orally administered once daily with no food or fluid restrictions. SOLSTICE, a phase 2b study, evaluated the efficacy, safety, and tolerability of elecoglipron versus placebo in participants with type 2 diabetes. METHODS: This phase 2b, randomised, double-blind, placebo-controlled trial was conducted in medical research centres and hospitals across nine countries, Canada, Germany, Hungary, Japan, Poland, Slovakia, Spain, the UK, and the USA. Sites were selected based on their capacity to fulfil protocol requirement, including, but not limited to, regulatory and ethics approvals, appropriate infrastructure and personnel, and access to the target patient population. Participants aged 18 years and older with a BMI of 23 kg/m FINDINGS: From Oct 8, 2024, to June 6, 2025, 863 individuals were screened for study inclusion, 457 were excluded as they did not meet the inclusion criteria or met the exclusion criteria, 406 were enrolled and randomly assigned to one of the eight treatment groups, and 404 participants received at least one dose of trial treatment. Among those who received at least one dose of trial treatment, mean (SD) baseline characteristics were: age 58·4 years (10·7); HbA INTERPRETATION: Once-daily oral elecoglipron showed reductions in glycaemia and a safety and tolerability profile consistent with the GLP-1 receptor agonist class at a similar phase of development, supporting continued development with phase 3 trials for people living with type 2 diabetes. FUNDING: AstraZeneca.

Although the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibition in heart failure (HF) have been well established, it is unknown whether SGLT2 inhibition confers benefit in carriers of rare variants in cardiomyopathy-associated genes. Here we evaluated whole-exome sequencing data from the randomized DECLARE-TIMI 58 trial, in which adults with type 2 diabetes and increased cardiovascular risk were randomized to dapagliflozin or placebo treatment. Pathogenic or likely pathogenic variants (P/LP) in high-confidence cardiomyopathy genes were identified, and treatment effects on hospitalization for HF (HHF) were compared between carriers of such variants and noncarriers. Among 12,685 patients for whom sequence data were obtained, 121 carried a cardiomyopathy variant (76 dilated cardiomyopathy, 25 hypertrophic cardiomyopathy and 25 arrhythmogenic cardiomyopathy). Over a median follow-up of 4.2 years, dapagliflozin lowered the risk of HHF more strongly in carriers (hazard ratio 0.18, 95% confidence interval 0.04-0.86) than in noncarriers (hazard ratio 0.70, 95% confidence interval 0.57-0.86; P interaction 0.03). Absolute risk reduction was 13.0% in carriers and 1.0% in noncarriers (P interaction 0.03). Most carriers (82%) had no prior HF, and in carriers without prior HF, treatment with dapagliflozin reduced the absolute risk of HHF by 12.8%, compared with a reduction of 0.6% in noncarriers (P interaction 0.01). The findings from this cohort of older and high-risk patients raise the possibility that SGLT2 inhibitor treatment should be started early to prevent HF in individuals who carry P/LP cardiomyopathy variants. These results need to be confirmed in a prospective, dedicated trial of preventive HF treatments in carriers of P/LP cardiomyopathy-associated variants.

BACKGROUND: Adolescents with severe obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) lack prospective comparative evidence to select between bariatric surgery and intensive lifestyle intervention. AIMS: To compare 52-week histological and cardiometabolic outcomes of vertical sleeve gastrectomy (VSG) versus comprehensive lifestyle intervention (CLI). METHODS: Single-centre, prospective, parallel-arm study of adolescents aged 12-19 with severe obesity and biopsy-confirmed MASLD with NAFLD Activity Score (NAS) ≥ 3. The primary endpoint was NAS ≥ 2-point decrease without fibrosis worsening; secondary endpoints included MASH resolution, fibrosis regression, MRI proton density fat fraction (MRI-PDFF) and elastography (MRE). Overlap-weighted adjusted analysis addressed baseline imbalance. Conservative unadjusted intention-to-treat analogue analyses treated missing Week 52 histology as nonresponse and missing continuous outcomes as no change. RESULTS: Forty-two adolescents enrolled (VSG = 17; CLI = 25) and 27 (64%) completed paired Week 52 histology. In the adjusted analysis, VSG was associated with a higher probability of NAS improvement (risk difference [RD] 0.68, 95% CI 0.45-0.91), fibrosis improvement (RD 0.36, 95% CI 0.12-0.59) and complete MASLD resolution (RD 0.49, 95% CI 0.26-0.72) when compared to CLI. VSG produced greater reductions in percent weight (-19.6%, 95% CI -30.0 to -9.1), percentage of the 95th percentile BMI (-27.6%, 95% CI -42.6 to -12.7), ALT (-54.0 U/L, 95% CI -80.8 to -27.1) and MRI-PDFF (-8.0%, 95% CI -13.0 to -2.9). Findings were directionally consistent in conservative unadjusted intention-to-treat and paired-biopsy completer analyses. CONCLUSION: In this prospective cohort of adolescents with severe obesity and biopsy-confirmed MASLD, VSG achieved greater 52-week histological improvement, including steatosis and fibrosis, than CLI. TRIAL REGISTRATION: ClinicalTrials.gov identifier: (NCT02412540).