Cardiovascular Outcomes Associated with GLP-1 Receptor Agonist Use among Adults with Type 1 Diabetes and Overweight or Obesity: A Target Trial Emulation Using Real-World EHR Data

Authors: Yixue Shao, et al.

This target trial emulation study evaluated the association between glucagon-like peptide-1 receptor agonist (GLP-1RA) use and cardiovascular outcomes in adults with type 1 diabetes (T1D) and overweight or obesity. Using electronic health records from the Epic COSMOS database, researchers compared 23,527 adults with T1D who initiated a GLP-1RA between 2020 and 2024 with 102,676 matched nonusers. The mean age of participants was 52.1 years, 55.9% were female, and 21% had pre-existing cardiovascular disease at baseline. The primary outcome was major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or all-cause mortality. GLP-1RA use was associated with a 31% lower risk of MACE compared with nonuse (hazard ratio [HR] 0.69; 95% confidence interval [CI]: 0.63–0.76; p<0.001). Significant reductions were also observed in the risk of atrial fibrillation (AF) (HR 0.82; 95% CI: 0.70–0.96) and heart failure (HF) (HR 0.83; 95% CI: 0.74–0.94). However, no significant association was found between GLP-1RA use and peripheral vascular disease (PVD) (HR 1.04; 95% CI: 0.94–1.16).

These data suggest the potential value of GLP-1RAs as a targeted therapeutic option for reducing macrovascular events in high-risk T1D populations, aligning with current standards of care in type 2 diabetes.

Effect of the Dual GLP-1/GIP Receptor Agonist Tirzepatide on Circulating Proteins Associated with ESKD Risk in Patients with Type 2 Diabetes

Authors: Eiichiro Satake, et al.

This post-hoc analysis of the SURPASS-4 trial evaluated the effect of tirzepatide (TZP) on circulating kidney disease-related biomarkers in patients with type 2 diabetes (T2D) who were at high cardiovascular risk. In the original SURPASS-4 trial, once-weekly TZP treatment was associated with substantial weight loss, slower decline in kidney function, and reduced albuminuria compared with insulin glargine. The current analysis examined changes in 21 circulating proteins included in the Joslin Kidney Panel (JKP), a group of biomarkers strongly associated with the risk of end-stage kidney disease in diabetes. Plasma samples from patients treated with TZP (n=104) or insulin glargine (n=106) were analyzed at baseline and after 52 weeks using the custom Joslin OLINK proteomics platform version 2. Changes in JKP protein concentrations over 52 weeks were compared between the two treatment groups. Baseline concentrations of JKP proteins were similar in both groups. After 52 weeks of treatment, concentrations of 7 of the 21 JKP proteins were reduced in the TZP group compared with the insulin glargine group. Differences in protein changes between treatments were greater and more statistically significant among patients with higher baseline urinary albumin-to-creatinine ratio (UACR).

Overall, TZP treatment significantly reduced concentrations of 12 of the 21 circulating JKP version 2 proteins in patients with T2D.

Triple Therapy for Type 1 Diabetes with Insulin, Semaglutide, and Dapagliflozin (TTT1): A Phase 3 Clinical Trial

Authors: Husam A Ghanim et al.

This study evaluated the efficacy and safety of adding semaglutide and dapagliflozin to insulin therapy in overweight adults with type 1 diabetes (T1D) and suboptimal glycemic control. Hypoglycemia and ketosis are known risks of adjunct non-insulin therapies. A total of 78 participants (mean age 45 years, 51% female, mean HbA1c 8.3%, mean body mass index [BMI] 33 kg/m²) were randomized during the first 26 weeks to receive standard insulin therapy alone or insulin plus semaglutide, titrated up to 1.0 mg weekly. During Weeks 26–52, participants receiving semaglutide were further randomized to dapagliflozin 10 mg daily or placebo. During the first 26 weeks, semaglutide significantly improved glycemic control, reducing HbA1c by 0.45% compared with standard care (95% confidence interval [CI]: −0.78 to −0.13; p=0.0072). Semaglutide also produced substantial weight loss, with a mean reduction of 10.2 kg compared with standard care (95% CI: −12.8 to −7.7; p<0.0001). In the second treatment period, adding dapagliflozin to semaglutide resulted in an additional HbA1c reduction of 0.46% compared with placebo (95% CI: −0.78 to −0.14; p=0.003), meeting the primary endpoint. However, no significant additional weight reduction was observed (−1.0 kg; p=0.2219). Over the full 52-week study period, participants receiving both semaglutide and dapagliflozin achieved a greater HbA1c reduction than those receiving standard care alone (−0.36%; 95% CI: −0.67 to −0.05; p=0.0235). Time spent below the target glucose range was not affected by either treatment. However, semaglutide was associated with a higher rate of Level 2 hypoglycemia during the first 26 weeks compared with standard care (17 vs 9 events per patient-year; incidence rate ratio 2.6; 95% CI: 1.4–5.0; p=0.0047). One episode of diabetic ketoacidosis occurred during the study, in a participant receiving placebo during the second treatment period.

Overall, semaglutide improved glycemic control and reduced body weight in overweight adults with T1D, while the addition of dapagliflozin provided further HbA1c reduction without additional significant weight loss.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Orforglipron: A Multiple Dose Titration Study in Chinese Participants with Obesity or Overweight with Weight-Related Comorbidities

Authors: Shobha Bhattachar, et al.

This Phase 1 randomized, placebo-controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orforglipron, an oral non-peptide glucagon-like peptide-1 receptor agonist (GLP-1RA), in Chinese adults with obesity or overweight and weight-related comorbidities. A total of 24 participants with stable body weight were enrolled and received escalating doses of orforglipron for up to 16 weeks (maximum 12 mg) or 24 weeks (maximum 36 mg). Participants had a mean (range) age of 30.1 (19-48) years, mean body mass index (BMI) of 32.0 (29.1-34.9) kg/m², and 50% were female. No serious adverse events or deaths were reported in the orforglipron group. One participant discontinued treatment because of mild diarrhea. Most treatment-emergent adverse events were mild, with no severe adverse events reported. Decreased appetite was the most frequently reported adverse event, and gastrointestinal disorders were the most commonly reported adverse event category. The pharmacokinetic profile of orforglipron in Chinese participants was consistent with that observed in global studies. Within the 1–36 mg dose range, both AUC₀–₂₄ (42.7–2620 ng·h/mL) and Cmax (3.1–159 ng/mL) showed an approximately proportional increase with increasing dose. Treatment with orforglipron was associated with reductions from baseline in body weight (−10.21 kg), BMI (−3.48 kg/m²), waist circumference (−11.66 cm), fasting glucose (−0.52 mmol/L), and glycated hemoglobin (HbA1c) (−0.36%).

Overall, orforglipron demonstrated a favorable safety and tolerability profile, pharmacokinetic characteristics consistent with those observed globally, and was associated with meaningful reductions in weight and metabolic parameters in Chinese participants with obesity or overweight and weight-related comorbidities.

GLP-1RA Discontinuation in People with Obesity: Real-World Insights Across Disease Burden Subgroups

Authora: Jaime Almandoz, et al.

This real-world cohort study using Truveta data from the United States evaluated discontinuation of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) among adults with obesity, including those with type 2 diabetes (T2D), cardiovascular disease (CVD), or metabolic dysfunction-associated steatotic liver disease (MASLD). The analysis included 201,391 new users of semaglutide, tirzepatide, or liraglutide from 2021 to 2025. Discontinuation was defined as treatment cessation, identified by the absence of a prescription refill within the permissible gap period in the Truveta database. The median age was 53 years, with 51% aged 45-64 years in which 68% were female, and 46% had T2D, 23% had T2D + CVD, and 5% had T2D + MASLD. Semaglutide was the most commonly prescribed GLP-1 RA (68%), followed by tirzepatide (26%). At 12 months, the cumulative probability of treatment discontinuation was 55% in the overall obesity cohort, 49% among patients with obesity and T2D, 51% among those with obesity, T2D, and CVD, and 47% among those with obesity, T2D, and MASLD. In the overall obesity group, discontinuation rates at 12 months were 57% for semaglutide and 43% for tirzepatide. Patients with greater cardiometabolic disease burden remained on treatment longer. Median treatment duration was 68 days longer in patients with obesity, T2D, and MASLD than in the overall obesity cohort.

Overall, discontinuation of GLP-1 RA therapy was common in routine clinical practice, although treatment persistence was higher among patients with multiple cardiometabolic comorbidities.

Variation in A1C in Asian American, Native Hawaiian, and Pacific Islander (AANHPI) Populations with and without Diabetes by Age and BMI: The PANACHE Study

Authors: Yihe Goh Daida, et al.

This study examined mean predicted mean predicted glycated hemoglobin (A1c) levels across Asian American, Native Hawaiian, and Pacific Islander (AANHPI) populations and Non-Hispanic White (NHW) adults, assessing differences by age, body mass index (BMI), sex, and diabetes status. The analysis included 792,905 adults aged 30 years or older from Kaiser Permanente Northern California and Hawaii between 2012 and 2022. Participants had no prior cardiovascular disease. A1c levels were evaluated after adjusting for education, income, hypertension, dyslipidemia, smoking, and glucose-lowering medications where applicable. Native Hawaiian and Pacific Islander (NHPI) adults had the highest prevalence of obesity (58%) and dyslipidemia (51%), while Filipino adults had the highest prevalence of hypertension (52%) and diabetes mellitus (35%). Among individuals with diabetes, NHPI adults had the highest adjusted A1c levels across all age and BMI categories. The greatest racial variation in A1c was observed among underweight men with diabetes. Among individuals without diabetes, all AANHPI subgroups had higher adjusted mean A1c levels than NHW adults across normal-weight, overweight, and obese BMI categories and across ages 30–84 years. The highest A1c levels were observed among NHPI, Filipino, and South Asian adults.

Overall, A1c levels differed across AANHPI subpopulations independent of diabetes status, age, sex, and BMI, suggesting the need for population-specific approaches to diabetes screening and management.

C. elegans PDF-1 and the Evolutionary Origin of Incretin-Like Peptides in Treatment of Diet-Induced Obesity

Authors: Yoshiyuki Watanabe, et al.

This study investigated the metabolic effects of pigment dispersing factor-1 (PDF1), a peptide originally identified in Caenorhabditis elegans (C. elegans), which shares structural similarities with glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and their receptors. Researchers evaluated the effects of synthetic PDF1-derived peptides in diet-induced obese mice and in muscle cell experiments at doses of 100 or 200 nmol/kg/day. In mice, treatment with a 37-amino acid PDF1-derived peptide significantly reduced body weight gain (P=0.029) and food intake (P=0.037), although the effects were less pronounced than those observed with tirzepatide. Treatment was also associated with increased expression of brown fat activity markers, including Cidea and Ucp1. PDF1 peptide treatment improved glucose metabolism, resulting in significantly lower plasma glucose levels at 30 and 60 minutes during an oral glucose tolerance test (both P<0.05). Fasting insulin levels and insulin responses during the oral glucose tolerance test were also significantly reduced (both P<0.05). In addition, insulin resistance, assessed using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), was markedly improved and approached normal levels (P<0.001). In cultured C2C12 muscle cells, PDF1-derived peptides significantly increased glucose uptake at concentrations of 10 nM and 100 nM (both P<0.01).

Overall, PDF1-derived peptides produced modest reductions in food intake and weight gain but substantially improved insulin sensitivity and glucose metabolism in preclinical models. These findings indicate that PDF1 may serve as the ancestral precursor of GLP-1 and GIP and could provide a novel framework for the development of new therapeutic agents for diabetes and obesity.

Achieving at Least 15% Weight Loss within 2 Years of T2D Diagnosis is Associated with a Lower Long-Term Risk of Micro- and Macrovascular Disease: A UK Cohort Study

Presenter: Naveed Sattar, et al.

This retrospective cohort study assessed the impact of substantial weight loss on vascular outcomes in adults with newly diagnosed type 2 diabetes (T2D) and obesity using UK Clinical Practice Research Datalink (CPRD) data. Individuals who achieved at least 15% weight loss within 2 years of T2D diagnosis were propensity score matched 1:4 with controls who maintained stable weight (<2% weight change). The matched cohort included 13,658 individuals in the weight-loss group and 54,632 controls. Matching accounted for factors such as age, sex, ethnicity, body mass index (BMI), glycated hemoglobin (HbA1c), smoking status, diabetes medications, and comorbidities. Compared with controls, individuals achieving ≥15% weight loss had a 13% lower risk of microvascular events (hazard ratio [HR] 0.87; 95% confidence interval [CI] 0.82–0.91) and a 10% lower risk of macrovascular events (HR 0.90; 95% CI 0.84–0.95). Glycemic outcomes were also better in the weight-loss group, with a substantially higher proportion of individuals achieving HbA1c targets of ≤6.5% and <5.7% compared with controls.

Overall, achieving at least 15% weight loss within 2 years of type 2 diabetes diagnosis was associated with lower risks of both microvascular and macrovascular complications, as well as improved glycemic control, supporting the value of early weight-loss interventions in T2D management.

When HbA1c Lies: Hypertriglyceridemia and Obesity Drive Multisystem Complications in “Well-Controlled” Type 2 Diabetes

Presenter: Shubhashree Patil, et al.

This study evaluated the prevalence of complications among patients with type 2 diabetes mellitus (T2DM) who had achieved glycated hemoglobin (HbA1c) levels below 7%. Among 400 patients assessed, 168 had HbA1c <7% (mean 6.4%). Despite achieving glycemic targets, 44% (74/168) had multisystem complications, defined as involvement of at least two of the following: bone disease, neuropathy, or dyslipidemia. The prevalence of bone loss, neuropathy, and dyslipidemia was 58%, 35%, and 62%, respectively. Patients with multisystem complications had significantly higher triglyceride (TG) levels (198 vs 118 mg/dL; p<0.001) and body mass index (BMI) (29.8 vs 24.2 kg/m²; p<0.001) than those without complications, while HbA1c levels were similar (6.4% vs 6.3%; p=0.68). Elevated TG levels (>200 mg/dL) were associated with a 6.2-fold higher odds of multisystem complications (odds ratio [OR] 6.24; 95% confidence interval [CI] 2.84–13.71; p<0.001), while BMI >28 kg/m² was associated with a 4.8-fold higher odds (OR 4.78; 95% CI 2.31–9.89; p<0.001). Patients with both TG >200 mg/dL and BMI >28 kg/m² had a substantially higher complication rate than those with TG <150 mg/dL and BMI <25 kg/m² (82% vs 12%; p<0.001). Even among patients with HbA1c ≤6% (n=42), 38% had multisystem complications, all of whom had elevated TG levels (>180 mg/dL) or BMI (>27 kg/m²).

In conclusion, these findings suggest that factors beyond glycemic control, particularly hypertriglyceridemia and obesity, are associated with complication burden in patients with T2DM.

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