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.

Comparing Adverse Event Rates among GLP-1/GIP Therapy Switchers vs. Continuous Use Groups in a Real-World Telehealth Cohort

Authors: Lauren Broffman, et al.

This study evaluated real-world adverse event (AE) reporting among patients with overweight or obesity who received glucagon-like peptide-1 (GLP-1)-based therapies, comparing those who remained on a single treatment with those who switched between therapies. Electronic health record data were analyzed from GLP-1-naive patients treated with semaglutide (Wegovy), tirzepatide (Zepbound), or those who switched between the two therapies. A total of 1,500 patients were randomly selected for each treatment group, with a minimum of 90 days of enrolment. Adverse events were identified through mandatory monthly reporting, unprompted app-based reporting, and provider communications. Data collected through December 30, 2025 were included in the analysis. Baseline demographic characteristics were similar across the treatment groups.

Patients who switched therapies reported significantly higher overall rates of adverse events than those who remained on a single treatment. The observed adverse events included nausea, upset stomach, constipation, diarrhea, heartburn, abdominal cramps, injection-site reactions, hair loss, and other symptoms.

Higher rates were also observed across individual adverse event categories among switchers (all p<0.001). Hair loss was the only adverse event category that did not differ significantly between groups.

Overall, the lowest treatment tolerability was observed among patients who switched therapies. The authors noted that additional research is needed to determine whether switching is primarily driven by adverse events or by other factors, such as insurance coverage changes or differences in treatment effectiveness.

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.

Glucagon-Like Peptide 1 Receptor Agonist (GLP-1RA) or GLP-1RA/Glucose-Dependent Insulinotropic Polypeptide RA (GLP-1/GIPRA) Effects in Youth/Young Adults (Y/YA) with Type 1 Diabetes and Characteristics of Nonresponders

Authors: Lauren Anne Waterman, et al.

This retrospective review evaluated the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonists (GLP-1/GIPRAs) in youth and young adults (Y/YA) with type 1 diabetes (T1D), and explored characteristics associated with nonresponse. The analysis included 48 participants with a mean age of 18.6 years, mean T1D duration of 8.3 years, and mean glycated hemoglobin (HbA1c) of 8.0%. Most participants were female (72.9%). Clinical data, including body mass index (BMI), glycemic measures, insulin use, and gastrointestinal adverse events, were evaluated for up to 18 months after treatment initiation. Treatment with GLP-1RAs or GLP-1/GIPRAs was associated with significant improvements in glycemic control and body weight, along with reductions in insulin requirements compared with baseline (p<0.05). Nonresponse, defined as less than 5% weight loss and less than 0.4% reduction in HbA1c, was observed in 32% of participants. Nonresponse was significantly associated with the onset of overweight or obesity before puberty (p=0.0275) and with having tried only one GLP-1RA or GLP-1/GIPRA therapy (p=0.004).

Overall, GLP-1RAs and GLP-1/GIPRAs improved weight, glycemic control, and insulin requirements in Y/YA with T1D, though responses varied. Further prospective studies are needed to define optimal use and identify patients most likely to benefit.

Reduction in Glomerular Hyperfiltration with Tirzepatide in Youth-Onset T2D

Author: Petter Bjornstad, et al.

This analysis from the SURPASS-PEDS trial evaluated the effect of tirzepatide on kidney function and glomerular hyperfiltration in children and adolescents with youth-onset type 2 diabetes (YT2D). Participants aged 10 to less than 18 years receiving metformin and/or basal insulin were randomized to tirzepatide 5 mg (n=32), tirzepatide 10 mg (n=33), or placebo (n=34) for 30 weeks. Estimated glomerular filtration rate (eGFR) was calculated using the Zappitelli creatinine-cystatin C equation, and hyperfiltration was defined as eGFR ≥126.8 mL/min/1.73 m². At baseline, the mean age was 14.7 years and 18% of participants had hyperfiltration. Mean eGFR was 142 mL/min/1.73 m² in participants with hyperfiltration compared with 104 mL/min/1.73 m² in those with normal filtration. After 30 weeks, tirzepatide treatment was associated with a reduction in eGFR, with reductions being more than twice as large in participants who had hyperfiltration at baseline. The proportion of participants with hyperfiltration decreased from 18.6% to 5.5% in the pooled tirzepatide group, whereas it increased from 16.1% to 21.9% in the placebo group (p<0.05).

In conclusion, amongst participants with YT2D, tirzepatide reduced eGFR and was associated with a lower prevalence of glomerular hyperfiltration after 30 weeks of treatment.

Relative and Absolute Risk Reduction for MACE in Cardiovascular Outcomes Trials with GLP-1 Receptor Agonists in Female vs. Male People with Type 2 Diabetes

Authors: Young Hee Lee-Barkey, et al.

This pooled analysis evaluated whether the cardiovascular outcomes with glucagon-like peptide-1 receptor agonists (GLP-1RAs) differ between women and men with type 2 diabetes (T2D). Data were analyzed from eight cardiovascular outcomes trials (CVOTs), including LEADER, SUSTAIN-6, EXSCEL, HARMONY Outcomes, REWIND, PIONEER-6, AMPLITUDE-O, and SOUL. The analysis included 22,859 women (35.9%) and 40,803 men. Major adverse cardiovascular events (MACE) rates were compared between GLP-1RA and placebo groups, and results were normalized to a 3-year follow-up period. GLP-1RA treatment was associated with similar relative reductions in MACE risk in women (odds ratio [OR] 0.82; 95% confidence interval [CI], 0.75–0.89) and men (OR 0.86; 95% CI, 0.81–0.91). Absolute risk reductions were also comparable between women (1.66%; 95% CI, 1.45–1.87) and men (1.60%; 95% CI, 1.46–1.73). The number needed to treat (NNT) to prevent one MACE event was similar in women (60; 95% CI, 54–69) and men (63; 95% CI, 58–68). However, the baseline risk of MACE in the placebo group was higher in men than in women (4.3 vs. 3.3 events per 100 person-years of observation).

Overall, GLP-1 receptor agonists provided comparable reductions in major adverse cardiovascular events in women and men with type 2 diabetes, with similar absolute risk reductions and numbers needed to treat.

Relative and Absolute Risk Reduction for MACE in Cardiovascular Outcomes Trials with GLP-1 Receptor Agonists in Type 2 Diabetes Patients with and without ASCVD at Baseline

Authors: Michael Albrecht Nauck, et al.

This pooled analysis evaluated whether the cardiovascular outcomes with glucagon-like peptide-1 receptor agonists (GLP-1RAs) differ between patients with and without atherosclerotic cardiovascular disease (ASCVD) at baseline. Data were analyzed from seven cardiovascular outcomes trials: LEADER, SUSTAIN-6, EXSCEL, REWIND, PIONEER-6, AMPLITUDE-O, and SOUL. The analysis included 38,642 participants with ASCVD and 13,409 without ASCVD at baseline. Major adverse cardiovascular events (MACE) rates were compared between GLP-1RA and placebo groups, with results normalized to a 3-year follow-up period. GLP-1RAs produced similar relative reductions in MACE risk among participants with ASCVD (odds ratio [OR] 0.83; 95% confidence interval [CI], 0.78–0.88) and those without ASCVD (OR 0.89; 95% CI, 0.79–1.00). However, absolute risk reduction was significantly greater in participants with ASCVD than in those without ASCVD (2.12% vs. 0.92%). Accordingly, the number needed to treat (NNT) to prevent one MACE event was lower in the ASCVD group (47; 95% CI, 44–51) than without non-ASCVD group (109; 95% CI, 88–144). Participants receiving placebo had a higher baseline risk of MACE if they had ASCVD compared with those without ASCVD (4.7 vs. 3.0 events per 100 person-years of observation).

Overall, GLP-1 receptor agonists provided comparable relative reductions in major adverse cardiovascular events regardless of baseline ASCVD status; however, patients with established ASCVD experienced greater absolute risk reductions and lower numbers needed to treat.

Impact of GLP-1RA Initiation on Medical Expenditures in Medicare Beneficiaries with Type 2 Diabetes

Authors: Yu Wang, et al.

This study assessed the impact of glucagon-like peptide-1 receptor agonist (GLP-1 RA) initiation on healthcare expenditures among Medicare beneficiaries with type 2 diabetes (T2D). Using Medicare fee-for-service claims from 2015–2023, researchers compared new GLP-1 RA users with matched non-users. The analysis included 32,494 beneficiaries aged 67 years or older with T2D. Healthcare expenditures were tracked for up to 20 quarters after treatment initiation using a difference-in-differences approach. Medical expenditures increased over time in both groups. Compared with matched controls, initiation of a GLP-1 RA was associated with an average increase of $1,279 in total quarterly healthcare expenditures. This increase was primarily driven by higher prescription drug spending, which increased by $1,260 per quarter. Non-prescription medical expenditures increased only slightly by $19 per quarter. Cardiovascular disease (CVD)- and chronic kidney disease (CKD)-related expenditures decreased modestly following GLP-1 RA initiation, with an average reduction of $15 per quarter.

Overall, GLP-1 RA use was associated with higher Medicare spending, largely due to increased medication costs. Although small reductions in CVD- and CKD-related expenditures were observed, these savings did not offset the increase in prescription spending, suggesting a potentially substantial net economic burden for healthcare payers.

Real-World Evidence on Efficacy and Safety of Semaglutide in Patients with Type 2 Diabetes and Advanced Chronic Kidney Disease

Authors: Salma Elnour, et al.

This retrospective study evaluated the effectiveness and safety of semaglutide in patients with type 2 diabetes mellitus (T2DM) and advanced chronic kidney disease (CKD stages 4–5) although, evidence for GLP-1 RA use in advanced CKD is limited. A total of 45 patients were followed for 12 months after starting semaglutide. The mean age of participants was 69.1 years, and 57.8% were female. At baseline, mean glycated hemoglobin (HbA1c) was 8.3%, estimated glomerular filtration rate (eGFR) was 25.5 mL/min/1.73 m², and body weight was 77.6 kg. After 12 months of treatment, semaglutide significantly reduced HbA1c by 0.71% (P<0.001), indicating improved glycemic control. Kidney function remained stable, with no significant change in eGFR (change: −0.22 mL/min/1.73 m²; P=0.305). Body weight decreased by 0.43 kg, although this change was not statistically significant (P=0.496). The discontinuation rate was 13.3%, with most discontinuations attributed to gastrointestinal adverse events.

Overall, semaglutide improved glycemic control while maintaining stable kidney function in patients with advanced CKD and demonstrated an acceptable safety profile. However, these findings warrant confirmation in prospective studies.

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