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...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.
Gao L, Jiang H, Cai H
… +19 more, Tian J, Shi B, Qiu W, Huang C, Han J, Zhang S, Pang S, Bi Y, Chen L, Gu X, Han J, Ma Q, Deng H, Wang Y, Li L, Han-Zhang H, Qian L, Ji L, GLORY-2 Trial Investigators
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)...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.
IMPORTANCE: The Inflation Reduction Act capped out-of-pocket costs for insulin at $35 per 30-day supply for Medicare beneficiaries in 2023; the impact on insulin access and use is not known. OBJECTIVE: To measure changes...IMPORTANCE: The Inflation Reduction Act capped out-of-pocket costs for insulin at $35 per 30-day supply for Medicare beneficiaries in 2023; the impact on insulin access and use is not known. OBJECTIVE: To measure changes in insulin cost and use after the cap, overall and for insulin users with previously high out-of-pocket cost. DESIGN, SETTING, AND PARTICIPANTS: Interrupted time series analysis using data from the United States from January 2021 through December 2023 to measure the additional changes experienced by insulin users with Medicare Part D insurance after the cap (2023) compared with before the cap (2021-2022). EXPOSURE: The $35 out-of-pocket cap. MAIN OUTCOMES: Out-of-pocket cost per 30-day insulin supply (average and within-year range), 30-day insulin fills, adherence (proportion of days covered with basal insulin), and persistence (no days without basal insulin). RESULTS: The study cohort included 2 860 394 insulin users (mean age, 70.7 years; 52% female). In 2023, almost no insulin fills exceeded the cap; in comparison, 13% of fills would have exceeded the cap in 2021-2022. Cost per 30-day supply of insulin was $22.95 before the policy and decreased to $18.16 after the policy (difference, -$4.79 [95% CI, -$4.84 to -$4.74]; relative reduction, 21%), and the within-year range declined from $22.73 to $11.77 (difference, -$10.96 [95% CI, -$11.07 to -$10.84]; relative reduction, 48%). Insulin fills, adherence, and persistence to basal insulin did not increase for the full cohort but did for people with high baseline cost for insulin. For people with baseline costs in the top decile (ie, above $58 on average per 30-day supply of insulin), 30-day insulin fills per year increased from 10.4 to 11.2 (difference, 0.8 fills [95% CI, 0.7 to 0.8]; relative increase, 8%), proportion of days covered increased from 59.7% to 62.4% (difference, 2.7 percentage points [95% CI, 2.5 to 2.8 percentage points], relative increase, 5%), and persistence increased from 7.5% to 8.5% (difference, 1 percentage point [95% CI, 0.8 to 1.2 percentage points]; relative increase, 13%). CONCLUSIONS AND RELEVANCE: The Medicare $35 insulin out-of-pocket cap decreased and stabilized insulin out-of-pocket cost, increasing insulin use for people with previously high out-of-pocket cost. These findings can inform the design of policies to boost insulin access among users with high out-of-pocket cost.
Neuen BL, Perkovic V, Agarwal R
… +33 more, Cherney DZI, Lam CSP, Wanner C, Tuttle KR, Sarafidis P, Barratt J, Burgner A, Chen X, Chew-Wong A, Dobronravov VA, Floege J, McCafferty K, Nangaku M, Packham D, Papachristou E, Pergola PE, Speeckaert MM, Subbiah A, Tang SCW, Tang S, Yeo SC, Jongs N, Smeijer JD, Berger M, Brinker M, Dayoub R, Elliott J, Li N, Mueller K, Rethemeier N, Finkelsztein MY, Heerspink HJL, FIND-CKD Investigators
IMPORTANCE: Glomerular diseases are a leading cause of chronic kidney disease (CKD) and kidney failure. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces the risk of kidney function loss in CKD, b...IMPORTANCE: Glomerular diseases are a leading cause of chronic kidney disease (CKD) and kidney failure. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces the risk of kidney function loss in CKD, but its effects in individuals with CKD due to glomerular diseases are uncertain. OBJECTIVES: To evaluate the efficacy and safety of finerenone in patients with glomerular diseases. DESIGN, SETTING, AND PARTICIPANTS: Prespecified exploratory subgroup analysis of a phase 3, randomized, double-blind, placebo-controlled trial conducted across 24 countries and regions, focusing on participants with an investigator-reported glomerular disease diagnosis. The overall trial enrolled adults with nondiabetic CKD and an estimated glomerular filtration rate (eGFR) of either (1) at least 25 to less than 60 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 200 mg/g to less than 500 mg/g or (2) an eGFR of at least 25 to less than 90 mL/min/1.73 m2 and urinary albumin to creatinine ratio of at least 500 mg/g to less than 3500 mg/g. INTERVENTION: Finerenone 10 mg or 20 mg taken orally once daily (n = 446) vs matching placebo (n = 457). MAIN OUTCOMES AND MEASURES: Annualized rate of eGFR decline (total eGFR slope) from baseline to month 32 (primary outcome of the main trial); percent change in albuminuria to 12 months; and a composite outcome of kidney failure or sustained 40% or more decline in eGFR (prespecified exploratory outcomes). RESULTS: Of 1584 participants, 903 (57.0%) had investigator-reported glomerular disease, including 416 (46.1%) with immunoglobulin A nephropathy, 215 (23.8%) with focal segmental glomerulosclerosis, and 90 (10.0%) with membranous nephropathy. Participants with glomerular disease (mean [SD] age, 51.1 [13.6] years; 362 female [40.1%]; 558 Asian [61.9%]) had a mean eGFR of 48.8 mL/min/1.73 m2 and median urinary albumin to creatinine ratio of 839.6 mg/g. The total eGFR slope up to 32 months was -3.50 mL/min/1.73 m2 per year with finerenone and -4.23 mL/min/1.73 m2 per year with placebo (0.73 mL/min/1.73 m2 per year difference; 95% CI, 0.22-1.24). Finerenone reduced albuminuria at month 12 by 42% (95% CI, 35%-48%) and lowered the risk of kidney failure or 40% or more eGFR decline (7.42 vs 9.60 events per 100 patient-years; hazard ratio, 0.74; 95% CI, 0.57-0.97). CONCLUSIONS AND RELEVANCE: In this exploratory analysis, treatment with finerenone slowed kidney function decline, reduced albuminuria, and lowered the risk of kidney failure or substantial loss of kidney function in patients with glomerular diseases. These findings suggest an important role for finerenone in preserving kidney function in this population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05047263.