Daily Endocrinology Research Analysis
Analyzed 27 papers and selected 3 impactful papers.
Summary
Three phase 3 randomized trials in endocrinology highlight rapid advances in metabolic therapeutics. A triple-agonist (retatrutide) improved glycemic control and reduced body weight as monotherapy; a dual GLP-1/glucagon agonist (mazdutide) achieved approximately 17% weight loss in Chinese adults; and an oral GLP-1RA (orforglipron) added to titrated insulin glargine significantly lowered HbA1c and weight without increasing hypoglycemia.
Research Themes
- Incretin-based poly-agonists for metabolic disease
- Oral GLP-1 receptor agonists combined with basal insulin
- Global obesity pharmacotherapy efficacy and tolerability
Selected Articles
1. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.
In a 40-week, multicenter, double-blind phase 3 RCT (n=537), retatrutide monotherapy significantly improved glycemic control and reduced body weight versus placebo in adults with type 2 diabetes inadequately controlled by diet and exercise. Adverse events were consistent with GLP-1 agonist class effects, primarily gastrointestinal.
Impact: This trial provides phase 3 evidence that triple-receptor agonism can deliver robust glycemic and weight benefits in type 2 diabetes, opening a new therapeutic class beyond current incretin therapies.
Clinical Implications: If approved, retatrutide may offer a potent monotherapy for patients needing both glycemic and weight reduction, with class-typical GI tolerability considerations and need for long-term safety and CV outcome data.
Key Findings
- 40-week, double-blind, placebo-controlled phase 3 RCT across 48 sites randomized 537 adults to retatrutide 4, 9, or 12 mg or placebo.
- Retatrutide significantly improved glycemic control (HbA1c) and reduced body weight versus placebo.
- Adverse events were consistent with GLP-1 agonists, predominantly gastrointestinal.
Methodological Strengths
- Randomized, double-blind, placebo-controlled phase 3 design
- Multicenter, multinational execution with prespecified endpoints
Limitations
- Effect sizes for HbA1c and weight are not detailed in the abstract segment provided
- Duration limited to 40 weeks; long-term safety and cardiovascular outcomes remain unknown
Future Directions: Head-to-head comparisons versus established GLP-1/GIP agents, durability and CV outcome trials, and optimization of dosing/tolerability.
BACKGROUND: Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of retatrutide as a monotherapy in people with type 2 diabetes that is inadequately controlled by diet and exercise alone. METHODS: In this 40-week, phase 3, randomised, double-blind, placebo-controlled trial at 48 sites in the USA, Mexico, and India, we recruited adults (aged ≥18 years) with type 2 diabetes that is inadequately controlled by diet and exercise alone, glycated haemoglobin (HbA FINDINGS: Between April 10, 2024, and April 21, 2025, 930 participants were screened and 537 (296 [55%] female and 241 [45%] male) were randomly assigned: 134 to retatrutide 4 mg, 133 to retatrutide 9 mg, 136 to retatrutide 12 mg, and 134 to placebo. Baseline mean age was 48·8 years (SD 12·1), mean HbA INTERPRETATION: Retatrutide showed significant improvements in glycaemic control and bodyweight reduction as a monotherapy in adults with type 2 diabetes that is inadequately controlled with diet and exercise alone, with an adverse event profile consistent with molecules with GLP-1 agonist activity, supporting its potential as an effective treatment for type 2 diabetes. FUNDING: Eli Lilly and Company.
2. Treatment With 9-mg Mazdutide for Weight Reduction in Chinese Adults With Obesity: The GLORY-2 Randomized Clinical Trial.
In a 60-week, double-blind, phase 3 trial in Chinese adults with obesity (n=461 analyzed), once-weekly 9 mg mazdutide produced a mean −16.65% weight loss versus −1.50% with placebo and 84.3% achieved ≥5% weight loss versus 33.1% with placebo. Gastrointestinal adverse events were common but mostly mild to moderate; discontinuation occurred in 2.9% with mazdutide.
Impact: This pivotal phase 3 trial demonstrates large, clinically meaningful weight loss with a dual GLP-1/glucagon agonist in an underrepresented population, supporting generalizability and expanding therapeutic options.
Clinical Implications: Mazdutide may serve as an effective pharmacotherapy for obesity with substantial weight loss; clinicians should counsel regarding frequent GI symptoms and monitor cardiometabolic parameters, especially in patients with coexisting type 2 diabetes.
Key Findings
- Mean percent weight change at week 60 was −16.65% with mazdutide versus −1.50% with placebo (between-group difference −15.15%; P<.001).
- ≥5% weight loss was achieved by 84.3% in the mazdutide group versus 33.1% with placebo (P<.001).
- GI adverse events (vomiting 53.1%, nausea 46.9%, diarrhea 39.4%) were common but mostly mild to moderate; discontinuation due to AEs was 2.9%.
Methodological Strengths
- Double-blind, placebo-controlled phase 3 RCT with prespecified co-primary endpoints
- Lifestyle run-in and standardized adjunctive counseling across 27 hospitals
Limitations
- Conducted exclusively in Chinese adults, which may limit generalizability to other ethnicities and healthcare settings
- No active comparator against established incretin-based therapies; GI AEs were frequent
Future Directions: Head-to-head trials versus semaglutide and tirzepatide, evaluation of cardiometabolic outcomes and long-term safety, and dose-ranging studies to optimize efficacy-tolerability balance.
IMPORTANCE: Obesity is a worldwide problem and a major public health issue in China. OBJECTIVE: To evaluate the efficacy and safety of mazdutide (a once-weekly glucagon and glucagon-like peptide-1 receptor dual agonist) in Chinese adults with obesity (defined as a body mass index of ≥30). DESIGN, SETTING, AND PARTICIPANTS: A double-blind, placebo-controlled, phase 3, randomized clinical trial including Chinese adults with or without type 2 diabetes that was conducted at 27 hospitals from December 2023 to November 2025. INTERVENTIONS: Participants were randomized in a 2:1 ratio to receive a once weekly, 9-mg dose of mazdutide administered subcutaneously (n = 308) or placebo (n = 154) as an adjunct to a reduced calorie diet and increased physical activity for 60 weeks. MAIN OUTCOMES AND MEASURES: The coprimary outcomes were the percentage change in body weight from baseline and a weight reduction of at least 5% at week 60. The efficacy and safety analyses were performed in participants who received at least 1 dose of the study treatment. RESULTS: A total of 461 participants (295 [64.0%] female; 16.1% with type 2 diabetes; mean age, 33.9 [SD, 8.4] years; body weight, 94.0 [SD, 13.8] kg; BMI, 34.3 [SD, 3.2]) received the study treatment (307 in the mazdutide group and 154 in the placebo group) and were included in the analyses. At week 60, the mean percentage change in body weight from baseline was -16.65% (95% CI, -18.19% to -15.12%) in the mazdutide group compared with -1.50% (95% CI, -3.43% to 0.43%) in the placebo group (between-group difference, -15.15% [95% CI, -17.22% to -13.09%]; P < .001). At week 60, 84.3% of participants in the mazdutide group had a body weight reduction of 5% or greater compared with 33.1% in the placebo group (between-group difference, 51.6% [95% CI, 43.0% to 60.1%]; P < .001). Adverse events leading to study treatment discontinuation were reported in 2.9% of participants in the mazdutide group compared with 0% in the placebo group. The most common adverse events were vomiting (53.1% in the mazdutide group vs 1.3% in the placebo group), nausea (46.9% vs 3.2%, respectively), and diarrhea (39.4% vs 6.5%); most of the adverse events were mild to moderate in severity. CONCLUSIONS AND RELEVANCE: Mazdutide provided clinically meaningful weight reduction in Chinese adults with moderate to severe obesity compared with placebo, but participants receiving the drug experienced gastrointestinal adverse reactions compared with those receiving placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06164873.
3. Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes: The ACHIEVE-5 Randomized Clinical Trial.
In a global 40-week, double-blind phase 3 RCT (n=546), adding oral orforglipron (3, 12, or 36 mg daily) to titrated insulin glargine reduced HbA1c by −1.58% to −1.88% versus −0.79% with placebo and produced −2.6% to −5.4% weight loss versus +0.2% with placebo. Gastrointestinal adverse events were common, and clinically significant hypoglycemia was not increased.
Impact: This is the first phase 3 evidence that an oral nonpeptide GLP-1RA can be effectively and safely combined with basal insulin, delivering significant HbA1c and weight benefits without added hypoglycemia.
Clinical Implications: For insulin-treated type 2 diabetes, orforglipron offers an oral add-on that improves glycemia and weight without increasing hypoglycemia, potentially delaying prandial insulin initiation.
Key Findings
- At week 40, HbA1c decreased by −1.58%, −1.88%, and −1.82% with orforglipron 3, 12, and 36 mg vs −0.79% with placebo; all doses were superior (P<.001).
- Proportions achieving HbA1c targets (<7.0% and ≤6.5%) and reductions in body weight (−2.6% to −5.4% vs +0.2% placebo) favored orforglipron.
- Gastrointestinal adverse events were the most common and mostly mild-to-moderate; no increase in clinically significant hypoglycemia vs placebo.
Methodological Strengths
- Randomized, double-blind, placebo-controlled phase 3 design across 72 sites and multiple countries
- Dose-ranging evaluation with high completion rate (92.9%) and prespecified endpoints
Limitations
- Duration limited to 40 weeks; long-term durability and cardiovascular outcomes remain unknown
- No active comparator against injectable GLP-1RAs or other incretin-based therapies
Future Directions: Head-to-head comparisons with injectable GLP-1RAs and tirzepatide, assessment of cardiovascular outcomes, and real-world adherence and tolerability studies.
IMPORTANCE: The effects of orforglipron, an oral, nonpeptide glucagon-like peptide 1 receptor agonist, added to insulin glargine for treatment of type 2 diabetes have not been described. OBJECTIVE: To assess efficacy and safety of orforglipron added to titrated insulin glargine in adults with type 2 diabetes and inadequate glycemic control. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, phase 3 study conducted at 72 sites across the US, Brazil, China, Japan, and Romania between November 10, 2023, and September 15, 2025, in adults with type 2 diabetes taking insulin glargine with or without metformin and/or sodium-glucose cotransporter 2 inhibitors over 40 weeks. INTERVENTIONS: Participants were randomized (1:1:1:1) to receive once-daily 3-mg (n = 137), 12-mg (n = 132), or 36-mg (n = 136) dosages of orforglipron or placebo (n = 141), in addition to titrated insulin glargine. MAIN OUTCOMES AND MEASURES: The primary outcome was mean hemoglobin A1c (HbA1c) change from baseline to week 40 (for the 12-mg once daily and 36-mg once daily dosages of orforglipron). Key secondary outcomes were mean HbA1c change from baseline (for the 3-mg once daily dosage of orforglipron), proportion of participants achieving HbA1c targets of lower than 7.0% and 6.5% or lower, and mean body weight change and percentage change from baseline to week 40. RESULTS: Among 546 randomized participants (median age, 61.0 [IQR, 26-95] years; 52.9% male; median duration of type 2 diabetes, 14.6 [IQR, 0.1-40.7] years; mean HbA1c, 8.50% [SD, 0.95%]; mean body mass index, 30.8 [SD, 6.1]), 507 (92.9%) completed the trial. At week 40, the mean changes from baseline in HbA1c were -1.58%, -1.88%, and -1.82% with orforglipron, 3 mg, 12 mg, and 36 mg once daily, respectively, vs -0.79% with placebo. Each dosage of orforglipron was superior to placebo (estimated treatment differences: 3 mg once daily, -0.78% [95% CI, -1.02% to -0.55%]; 12 mg once daily, -1.08% [95% CI, -1.33% to -0.83%]; 36 mg once daily, -1.03% [95% CI, -1.28% to -0.77%]; P < .001 for all). All key secondary outcomes demonstrated statistically significant differences in favor of orforglipron compared with placebo. Mean percentage body weight change from baseline was -2.6%, -4.8%, and -5.4% with orforglipron, 3 mg once daily, 12 mg once daily, and 36 mg once daily, respectively, vs 0.2% with placebo. The most frequent adverse events with orforglipron were gastrointestinal (mild to moderate). Orforglipron did not increase the risk of clinically significant hypoglycemia vs placebo. CONCLUSIONS AND RELEVANCE: In participants with type 2 diabetes inadequately controlled by insulin glargine, addition of oral orforglipron significantly improved glycemic control and body weight, without increasing hypoglycemia risk, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06109311.