Daily Endocrinology Research Analysis
Analyzed 124 papers and selected 3 impactful papers.
Summary
Analyzed 124 papers and selected 3 impactful articles.
Selected Articles
1. Survodutide Once Weekly for the Treatment of Adults with Obesity.
In a 76-week, double-blind phase 3 trial, once-weekly survodutide (3.6 or 6.0 mg) produced mean weight loss of approximately 12–13% versus 5.4% with placebo in adults with obesity without diabetes. Gastrointestinal adverse events were common and dose-related but mostly mild-to-moderate.
Impact: This is a pivotal phase 3 trial of a dual glucagon/GLP-1 agonist demonstrating clinically meaningful and sustained weight loss, potentially expanding therapeutic options beyond current GLP-1 monotherapies.
Clinical Implications: Survodutide may become a viable option for adults with obesity without diabetes, achieving double-digit weight loss; clinicians should monitor gastrointestinal tolerability and counsel regarding lifestyle alongside pharmacotherapy.
Key Findings
- Mean weight change at week 76: −12.2% (3.6 mg), −13.0% (6.0 mg) vs −5.4% (placebo).
- ≥5% weight loss achieved by 72.6% (3.6 mg), 71.9% (6.0 mg), and 46.3% (placebo).
- Gastrointestinal adverse events were most common (80.9% at 3.6 mg; 89.7% at 6.0 mg; 47.9% placebo), typically mild-to-moderate.
- Trial used a treatment-regimen estimand accounting for discontinuation and prohibited medications.
Methodological Strengths
- Randomized, double-blind, placebo-controlled phase 3 design with two active-dose arms
- Long duration (76 weeks) and estimand framework capturing real-world treatment effects
Limitations
- No head-to-head comparison with other approved incretin therapies within this trial
- Cardiometabolic outcome data and durability post-discontinuation were not assessed
Future Directions: Head-to-head trials versus high-dose semaglutide or tirzepatide, cardiometabolic outcomes, and weight maintenance strategies post-treatment discontinuation.
BACKGROUND: Although medications with glucagon-like peptide-1 (GLP-1) receptor agonist activity have transformed the management of obesity and shown substantial cardiometabolic benefits, unmet needs remain. Survodutide, an investigational glucagon receptor-GLP-1 receptor dual agonist, led to substantial weight reduction in a phase 2 trial involving adults with obesity without diabetes. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher, or 27 or higher with at least one obesity-related complication (excluding diabetes), in a 1:1:1 ratio to receive once-weekly survodutide administered subcutaneously at a dose adjusted up to 3.6 mg or 6.0 mg or placebo, in addition to counseling for lifestyle modification. The two primary end points were the percent change in body weight and a reduction in body weight of at least 5% from baseline to week 76. The primary efficacy analysis was conducted according to the treatment-regimen estimand, which incorporates the effects of any early discontinuation of survodutide or placebo, the use of protocol-prohibited obesity medications, and a prolonged dose-escalation period. RESULTS: Among 725 participants (241 in the 3.6-mg survodutide group, 242 in the 6.0-mg survodutide group, and 242 in the placebo group), the mean age was 47.1 years; 294 participants (40.6%) were men. At baseline, the mean BMI was 37.9, and the mean body weight was 108.8 kg. At week 76, the mean change in body weight from baseline according to the treatment-regimen estimand was -12.2% (95% confidence interval [CI], -13.6 to -10.8) in the 3.6-mg group, -13.0% (95% CI, -14.4 to -11.6) in the 6.0-mg group, and -5.4% (95% CI, -6.9 to -4.0) in the placebo group; 72.6%, 71.9% and 46.3% of the participants, respectively, had weight reduction of at least 5% (P<0.001 for all comparisons with placebo). The most common adverse events were gastrointestinal symptoms (typically mild to moderate), which occurred in 80.9% of the participants in the 3.6-mg group, in 89.7% of those in the 6.0-mg group, and in 47.9% of those in the placebo group. No deaths were reported. CONCLUSIONS: Survodutide led to significantly greater reductions in body weight than placebo in adults with obesity without diabetes. (Funded by Boehringer Ingelheim; SYNCHRONIZE-1 ClinicalTrials.gov number, NCT06066515.).
2. Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study.
In this 30-country, double-blind phase 3 trial (n=2713), fixed-dose cagrilintide-semaglutide (2.4 mg each) achieved superior HbA1c reduction and greater weight loss compared with semaglutide 2.4 mg in adults with type 2 diabetes and overweight/obesity. Safety was consistent with incretin and amylin-based therapies.
Impact: This large head-to-head phase 3 study demonstrates superiority of a dual amylin/GLP-1 approach over semaglutide alone, potentially redefining standards for glycemic and weight management in T2D.
Clinical Implications: CagriSema could enable greater A1c and weight targets in T2D than semaglutide alone, informing therapy selection especially for patients prioritizing weight loss; monitoring for GI adverse effects remains essential.
Key Findings
- Cagrilintide-semaglutide (2.4 mg each) was superior to semaglutide 2.4 mg for HbA1c reduction.
- Weight loss was greater with cagrilintide-semaglutide than with semaglutide alone.
- Study enrolled 2713 adults across 30 countries; 95.7% completed the study and 87.6% remained on treatment at week 68.
- Safety profile aligned with known effects of incretin and amylin pathways.
Methodological Strengths
- Large, multinational, double-blind, active- and placebo-controlled phase 3 design
- Direct head-to-head comparison with semaglutide enabling superiority assessment
Limitations
- Numerical effect sizes and detailed safety by subgroup not provided in the abstract
- Long-term cardiovascular and renal outcomes not yet reported
Future Directions: Assess durability, cardiovascular-renal outcomes, and comparative effectiveness versus other co-agonists; evaluate real-world adherence and tolerability.
BACKGROUND: The amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide have complementary effects on glycaemic control and bodyweight. We aimed to investigate the efficacy and safety of a fixed-dose combination of cagrilintide and semaglutide (cagrilintide-semaglutide; known as CagriSema) versus semaglutide or cagrilintide for glycaemic control in people with type 2 diabetes and overweight or obesity. METHODS: REIMAGINE 2 was a randomised, double-blind, placebo-controlled and active-controlled, parallel-group study conducted in 30 countries (trial sites included university hospitals, health-care centres, research centres, and other centres). Participants aged 18 years or older with inadequately controlled type 2 diabetes (HbA FINDINGS: From Oct 10, 2023, to July 29, 2024, 3593 people were screened for eligibility, 2713 of whom were randomly assigned to cagrilintide-semaglutide (2·4 mg each; n=603), semaglutide 2·4 mg (n=605), cagrilintide 2·4 mg (n=152), cagrilintide-semaglutide (1·0 mg each; n=595), semaglutide 1·0 mg (n=609), or placebo (pooled 2·4 mg and 1·0 mg; n=149). 1164 (42·9%) of 2713 were female, 1549 (57·1%) were male, and 2207 (81·3%) were White. Of the randomly assigned participants, 2595 (95·7%) completed the study and 2376 (87·6%) were on treatment at week 68. Mean baseline HbA INTERPRETATION: Cagrilintide-semaglutide (2·4 mg each) was superior to semaglutide 2·4 mg in reducing HbA FUNDING: Novo Nordisk.
3. Continuing Glucagon-Like Peptide-1 Receptor Agonists Into the First Trimester of Pregnancy and Pregnancy Outcomes : A Target Trial Emulation Study Using Claims Information.
Using 2011–2024 U.S. claims data and a target-trial emulation of 3572 pregnancies exposed to GLP-1RAs preconception, continuation into the first trimester was not associated with definitively higher risks of nonlive birth, SGA, LGA, or major congenital malformations. Precision was limited for MCM and SGA estimates.
Impact: Provides urgently needed pregnancy safety data for GLP-1RAs using modern causal-inference methods, informing counseling for inadvertent early exposure.
Clinical Implications: For patients who conceive while on GLP-1RAs, findings are somewhat reassuring but support shared decision-making; current practice to discontinue upon recognition of pregnancy remains prudent pending more precise estimates.
Key Findings
- Nonlive birth risk: 29.7% (continuation) vs 27.1% (noncontinuation); adjusted risk ratio 1.09 (95% CI, 0.98–1.23).
- Among linked live births, weighted prevalence ratios for continuation vs noncontinuation: SGA 1.29 (0.82–2.06), LGA 1.08 (0.84–1.40), MCM 1.21 (0.83–1.82).
- No definitive increase in adverse outcomes with early continuation, but precision was limited for MCM and SGA.
- Target-trial emulation on MarketScan claims (2011–2024) minimized design bias relative to conventional cohorts.
Methodological Strengths
- Target-trial emulation with explicit treatment strategies and weighted analyses
- Large, contemporary U.S. claims data spanning 2011–2024
Limitations
- Residual confounding (e.g., glycemic control) and exposure misclassification possible with claims data
- Imprecise estimates for MCM and SGA limit firm safety conclusions
Future Directions: Linkage to registries and EHRs for refined phenotyping, prospective registries, and international pooled analyses to enhance precision for congenital outcomes.
BACKGROUND: Glucagon-like peptide-1 receptor agonist (GLP-1RA) use has increased among women of reproductive age, but limited data exist on safety in pregnancy. OBJECTIVE: To estimate the risk for nonlive birth, abnormal fetal growth, and major congenital malformation (MCM) with GLP-1RA dispensing in early pregnancy. DESIGN: In an observational cohort of pregnant women aged 16 to 55 years with a GLP-1RA dispensation in the 90 days before the last menstrual period (LMP), a target trial with 2 treatment strategies was emulated: continuation of dispensing into the first trimester (≥1 further dispensation), or noncontinuation. SETTING: Merative MarketScan U.S. insurance claims data (2011 to 2024). PARTICIPANTS: 3572 pregnancies (41.1% [ MEASUREMENTS: Risk for nonlive birth was estimated using a weighted Kaplan-Meier estimator. Among live-birth pregnancies linked to infants, the weighted prevalence of MCM, small for gestational age (SGA), and large for gestational age (LGA) was estimated. RESULTS: The weighted risk for nonlive birth was 29.7% with continuation and 27.1% with noncontinuation (adjusted risk ratio, 1.09 [95% CI, 0.98 to 1.23]). Among 2529 live-birth pregnancies, 1443 (57.1%) received at least 1 GLP-1RA dispensation after LMP and 1499 (829 continuers) were linked to an infant. Weighted prevalence ratios for continuation versus noncontinuation were 1.29 (CI, 0.82 to 2.06) for SGA, 1.08 (CI, 0.84 to 1.40) for LGA, and 1.21 (CI, 0.83 to 1.82) for MCM. LIMITATION: Potential residual confounding by prior glycemic control. CONCLUSION: Risks for nonlive birth, SGA, LGA, and MCM were not definitively higher with continuation of GLP-1RAs into early pregnancy. However, estimates for MCM and SGA were imprecise and were compatible with both no increased risk and clinically relevant differences in risk. PRIMARY FUNDING SOURCE: National Institutes of Health.