Daily Endocrinology Research Analysis
Analyzed 84 papers and selected 3 impactful papers.
Summary
Analyzed 84 papers and selected 3 impactful articles.
Selected Articles
1. Efficacy and safety of co-administered cagrilintide and semaglutide versus semaglutide alone in adults with overweight or obesity with or without type 2 diabetes in Japan and Taiwan (REDEFINE 5): a multicentre, randomised, active-controlled, phase 3a trial.
In this double-blind phase 3a trial in Japan and Taiwan (n=331), fixed-dose cagrilintide 2.4 mg plus semaglutide 2.4 mg produced greater weight loss at 68 weeks versus semaglutide 2.4 mg alone (−18.4% vs −11.9%; ETD −6.5 percentage points; p<0.0001). Safety was comparable between groups, with gastrointestinal adverse events most common.
Impact: This is a high-quality randomized trial demonstrating clinically meaningful additional weight loss with an incretin–amylin combination in an East Asian population, addressing a major therapeutic gap.
Clinical Implications: For adults with overweight or obesity (with or without type 2 diabetes), cagrilintide–semaglutide may offer superior weight loss versus semaglutide alone, informing therapeutic selection and counseling about expected efficacy and GI tolerability.
Key Findings
- At week 68, mean bodyweight change was −18.4% with cagrilintide–semaglutide vs −11.9% with semaglutide; ETD −6.5 percentage points (95% CI −8.4 to −4.6; p<0.0001).
- Adverse events occurred in 87% vs 84% (combination vs semaglutide), predominantly gastrointestinal disorders.
- Trial enrolled 331 adults in Japan/Taiwan, including 24% with type 2 diabetes; discontinuation rates were 10% vs 6%.
Methodological Strengths
- Multicentre, double-blind, randomized, active-controlled phase 3a design
- Prespecified fixed-dose combination versus standard-of-care comparator with 68-week follow-up
Limitations
- Conducted only in Japan and Taiwan, which may limit generalizability to other populations
- Single fixed cagrilintide dose; study not powered for rare safety outcomes
Future Directions: Head-to-head trials across diverse populations, dose-ranging studies for cagrilintide, and long-term cardiovascular and renal outcomes are warranted.
BACKGROUND: The combination of cagrilintide and semaglutide has been shown in global studies to induce reductions in bodyweight. We assessed the efficacy and safety of a fixed-dose combination of cagrilintide 2·4 mg and semaglutide 2·4 mg versus semaglutide 2·4 mg for weight management in an east Asian population. METHODS: This double-blind, parallel-group, phase 3a trial (REDEFINE 5) was conducted across 21 sites (community, hospital) in Japan and one site in Taiwan. We included participants aged at least 18 years with a BMI of at least 27 kg/m FINDINGS: Between April 3, 2023, and Sept 15, 2023, we screened 355 individuals; 331 were randomly assigned to cagrilintide-semaglutide (n=164) or semaglutide (n=167). 226 (68%) participants were male and 105 (32%) were female; 80 (24%) had type 2 diabetes. 17 (10%) participants discontinued cagrilintide-semaglutide and ten (6%) discontinued semaglutide. The estimated mean change in bodyweight from baseline to week 68 was -18·4% (SE 0·7) in the cagrilintide-semaglutide group versus -11·9% (0·7) in the semaglutide group (estimated treatment difference [ETD] -6·5 percentage points [95% CI -8·4 to -4·6]; p<0·0001). Adverse events were reported by 143 (87%) of 164 participants in the cagrilintide-semaglutide group and 141 (84%) of 167 in the semaglutide group, the most common of which were gastrointestinal disorders (87 [53%] of 164 participants in the cagrilintide-semaglutide group vs 85 [51%] of 167 in the semaglutide group). One death was reported in the semaglutide 2·4 mg group, which was not judged to be treatment related by the investigator. INTERPRETATION: These findings support the efficacy and safety of cagrilintide-semaglutide for weight management in individuals from east Asia with overweight or obesity, with or without type 2 diabetes. FUNDING: Novo Nordisk. TRANSLATIONS: For the Japanese and Mandarin translations of the abstract see Supplementary Materials section.
2. Association of GLP-1 Receptor Agonist Use With Chronic Kidney Disease Risk in Type 2 Diabetes: Multicenter Emulated Target Trials.
In an emulated target trial of 24,510 matched pairs of T2D patients without CKD, initiating GLP-1 receptor agonists versus DPP-4 inhibitors was associated with lower risks of incident CKD, dialysis (HR 0.53), AKI, MACE, and all-cause mortality (HR 0.55). Benefits were consistent across subgroups and corroborated by Kaplan–Meier curves.
Impact: This large, rigorously emulated target trial provides real-world evidence that GLP-1 receptor agonists confer kidney and survival benefits in T2D patients before CKD onset, informing earlier therapeutic positioning.
Clinical Implications: When selecting glucose-lowering therapy in T2D without CKD, GLP-1 receptor agonists should be prioritized for renal and cardiovascular risk reduction alongside glycemic control.
Key Findings
- GLP-1 RA initiation vs DPP-4i was associated with lower composite kidney outcomes (HR 0.85; 95% CI 0.82–0.87) and incident CKD (HR 0.85; 95% CI 0.82–0.88).
- Marked reductions were observed for dialysis (HR 0.53; 95% CI 0.43–0.64), AKI (HR 0.81; 95% CI 0.76–0.86), MACE (HR 0.84; 95% CI 0.81–0.88), and all-cause mortality (HR 0.55; 95% CI 0.50–0.59).
- Results were consistent across multiple subgroups and supported by Kaplan–Meier analyses.
Methodological Strengths
- Emulated target trial with new-user, active-comparator design and propensity score matching of 24,510 pairs
- Large, multicenter EHR network with comprehensive outcomes and subgroup analyses
Limitations
- Observational design susceptible to residual confounding and misclassification
- Medication adherence and over-the-counter use not fully captured in EHR data
Future Directions: Pragmatic randomized trials to confirm renal protection in CKD-free T2D, head-to-head comparisons across drug classes, and mechanistic studies on kidney benefits are needed.
OBJECTIVE: To determine whether glucagon-like peptide-1 receptor agonist (GLP-1 RA) initiation is associated with reduction of incident renal outcomes compared with dipeptidyl peptidase-4 inhibitors (DPP-4is) in patients with type 2 diabetes (T2D) without pre-existing chronic kidney disease (CKD). METHODS: This study identified 370,636 patients with T2D from the TriNetX Collaborative Network database between January 1, 2015, and June 30, 2023. An emulated target trial was constructed, comprising 24,510 propensity score-matched pairs of new users of GLP-1 RAs and DPP-4is. Composite CKD events (defined as a combination of CKD diagnosis, estimated glomerular filtration rate <60 mL/min per 1.73 m RESULTS: Participants were 57.6±12.0 years of age and 48.9% were male. Compared with DPP-4i users, GLP-1 RA users had significantly reduced risks of composite kidney outcomes (HR, 0.85; 95% CI, 0.82 to 0.87), incident CKD (HR, 0.85; 95% CI, 0.82 to 0.88), dialysis (HR, 0.53; 95% CI, 0.43 to 0.64), acute kidney injury (HR, 0.81; 95% CI, 0.76 to 0.86), major adverse cardiac events (HR, 0.84; 95% CI, 0.81 to 0.88), and all-cause mortality (HR, 0.55; 95% CI, 0.50 to 0.59). Kaplan-Meier analyses confirmed lower cumulative incidence of these outcomes in GLP-1 RA users. Subgroup analyses confirmed consistent benefits across various patient groups. CONCLUSION: In patients with T2D and no prior CKD, GLP-1 RA use was associated with lower risks of renal complications, incident CKD, cardiovascular events, and death compared with DPP-4is.
3. Associations of Semaglutide With Skeletal Outcomes in People With Obesity, With and Without Type 2 Diabetes: A Target Trial Emulation.
Using a large federated EHR and target trial emulation, semaglutide initiation in people with obesity and T2D was associated with lower 3-year major osteoporotic fracture risk versus empagliflozin (HR 0.69), glipizide (HR 0.72), and usual care (HR 0.84). No significant associations were observed in those without T2D, and osteoporosis diagnoses largely did not differ.
Impact: Addresses an important safety domain for GLP-1 therapy by providing comparative, real-world skeletal outcomes across multiple active comparators and diabetes strata.
Clinical Implications: Semaglutide does not appear to increase fracture risk and may reduce major osteoporotic fractures in people with obesity plus T2D, supporting its use without added skeletal concern in this subgroup.
Key Findings
- With T2D, semaglutide initiation was linked to lower MOF risk vs empagliflozin (HR 0.69; 95% CI 0.61–0.77), glipizide (HR 0.72; 0.63–0.83), and usual care (HR 0.84; 0.76–0.93) over 3 years.
- Without T2D, semaglutide showed no significant association with MOF across comparators over 2 years (all p>0.05).
- Osteoporosis diagnosis rates did not significantly differ in most comparisons; exploratory osteoarthritis/gout outcomes were inconsistent.
Methodological Strengths
- Large federated EHR with 1:1 propensity score matching on 215 covariates and multiple active comparators
- Stratified target trial emulation by T2D status with predefined skeletal outcomes
Limitations
- Observational design with potential residual confounding and outcome misclassification
- Heterogeneous follow-up (2–3 years) and reliance on coded diagnoses for MOF and osteoporosis
Future Directions: Prospective studies and pragmatic trials to clarify skeletal effects by diabetes status, bone density/turnover assessments, and evaluation across other GLP-1/GIP agonists.
AIMS: To evaluate the associations between semaglutide initiation and long-term skeletal outcomes in people with obesity, stratified by type 2 diabetes (T2D) status, using target trial emulation. MATERIALS AND METHODS: This retrospective cohort study used the TriNetX federated electronic health record network. People with obesity initiating semaglutide were matched 1:1 via propensity score matching (215 covariates) to those initiating active comparators or usual care. The with-T2D cohort (n = 19 824-93 519 matched pairs per comparison) was followed for 3 years; the without-T2D cohort (n = 10 323-56 225 pairs) for 2 years. The primary outcome was major osteoporotic fracture (MOF). Secondary outcomes included osteoporosis diagnosis; exploratory outcomes included osteoarthritis and gout. RESULTS: In the with-T2D cohort, semaglutide initiation was associated with a lower risk of MOF compared with empagliflozin (HR 0.69; 95% CI 0.61-0.77), glipizide (HR 0.72; 0.63-0.83) and usual care (HR 0.84; 0.76-0.93). In the without-T2D cohort, no significant associations with MOF were observed across any comparison (all p > 0.05). Osteoporosis risk did not differ significantly in most comparisons in either cohort. Exploratory analyses of osteoarthritis and gout showed inconsistent patterns across comparators. CONCLUSIONS: Among people with obesity and T2D, semaglutide initiation was associated with a lower risk of MOF over 3 years compared with other glucose-lowering agents and usual care. This association was not observed in people with obesity without T2D. These findings support further investigation of the skeletal effects of GLP-1 receptor agonists.