In overweight or obesity without diabetes, weekly semaglutide vs. daily liraglutide increased weight loss at 68 wk

Source Citation Rubino DM, Greenway FL, Khalid U, et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA. 2022;327:138-50. 35015037

Antihypertensive drugs reduced risk for new-onset type 2 diabetes; effect varies by antihypertensive class

Source Citation Nazarzadeh M, Bidel Z, Canoy D, et al. Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis. Lancet. 2021;398:1803-10. 34774144

Annals Graphic Medicine - Not the Needle! A Day in the Life of Someone Living With Diabetes

Methodological Approaches to Real-World Evidence Generation for Glucagon-like Peptide-1–Based Therapies: Synopsis of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped the clinical approach to managing obesity and type 2 diabetes. As approved indications have expanded, use of GLP-1RAs has increased rapidly in the United States. Although randomized trials demonstrate strong efficacy, many questions remain about their optimal use in clinical practice. Real-world data (RWD) from electronic health records, registries, insurance claims, and other sources offer a promising avenue to address these questions. However, concerns about data quality, selection bias, and incomplete ascertainment of medication use and outcomes pose significant challenges to the validity of the resulting evidence. In May 2025, the National Institute of Diabetes and Digestive and Kidney Diseases convened experts from regulatory agencies, payer organizations, and academia to explore these challenges. This second of 2 synopsis articles on the workshop summarizes the discussion around the strengths and limitations of various RWD sources and methodological approaches to strengthen causal inference and generalizability. Presenters highlighted pragmatic clinical trials and target trial emulation as strategies to generate stronger real-world evidence (RWE) that is relevant to both clinical practice and policy. The workshop underscored that careful attention to study design, data limitations, and analytic approach is essential to yield RWE that informs clinicians, patients, payers, and policymakers.

Tirzepatide Versus Intensified Conventional Care After 2 Years of Treatment in Early Type 2 Diabetes: A Randomized Clinical Trial: Annals of Internal Medicine: Vol 179, No 7

Background: Initiation of treatment with tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist (GLP-1RA), early after a diagnosis of type 2 diabetes (T2D) may establish better and more durable glycemic control than current treatment approaches per guidelines and clinical practice. Objective: To assess the efficacy and safety of tirzepatide versus intensified conventional care (ICC) in participants with early T2D who have inadequate glycemic control with diet, exercise, and metformin. Design: Randomized, open-label, parallel-group, phase 4 trial (SURPASS-EARLY). (ClinicalTrials.gov: NCT05433584) Setting: 78 sites in 10 countries. Participants: 794 adults with at most 4 years of T2D history treated with metformin. Intervention: Tirzepatide (15 mg or maximum tolerated dose) or ICC (including GLP-1RAs but excluding tirzepatide) used in clinical practice and supported by local treatment guidelines. Measurements: The primary objective was to show the noninferiority of tirzepatide to ICC for change in hemoglobin A1c (HbA1c) from baseline to 2 years. Secondary objectives were to show the superiority of tirzepatide for change in HbA1c, weight, and waist circumference. Results: Tirzepatide was superior to ICC for mean changes from baseline to 2 years in HbA1c (−1.99 percentage points [95% CI, −2.12 to −1.87 percentage points] vs. −1.32 percentage points [CI, −1.44 to −1.19 percentage points]; estimated treatment difference [ETD], −0.68 percentage points [CI, −0.84 to −0.51 percentage points]; P < 0.001), weight (ETD, −8.0 kg [CI, −9.39 to −6.50 kg]; P < 0.001), and waist circumference (ETD, −6.2 cm [CI, −7.54 to −4.93 cm]; P < 0.001) (treatment regimen estimand). More participants achieved normoglycemia (HbA1c <5.7%) with tirzepatide (60.2%) than ICC (24.0%). The most common adverse events were gastrointestinal in both groups. Limitation: Open-label design. Conclusion: In participants with early T2D uncontrolled with metformin, tirzepatide treatment resulted in superior reductions in HbA1c, weight, and waist circumference, and more participants achieved normoglycemia (HbA1c <5.7%) with tirzepatide than ICC after 2 years. Primary Funding Source: Eli Lilly and Company.

Leveraging Real-World Evidence to Inform Regulatory, Clinical, and Coverage Decisions Related to Glucagon-Like Peptide-1–Based Therapies: Synopsis of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed obesity and diabetes management, with rapidly expanding indications and use among U.S. adults. Despite their promise, key questions remain about optimal treatment pathways, long-term safety, effectiveness across diverse populations, adherence, and economic impact. Real-world evidence (RWE) derived from electronic health records, claims, and other data sources could address these gaps, but unique challenges complicate its use, such as inconsistent insurance coverage, high discontinuation rates, medication shortages, compounded formulations, and off-label prescribing. To explore these issues, the National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop in May 2025 with experts from regulatory agencies, guideline committees, payers, and academia. Discussions focused on identifying knowledge gaps in GLP-1RA use, evaluating how RWE informs practice, assessing limitations of real-world data, and strategies to reduce bias in RWE. Presentations emphasized RWE’s potential to complement randomized trials by capturing rare adverse events, long-term outcomes, and effectiveness in routine care. However, persistent challenges include data reliability, confounding, and incomplete capture of medication use and outcomes, particularly in pediatric and underserved populations. Coverage decisions remain heterogeneous across Medicare, Medicaid, and private payers and across time, underscoring the need for rigorous cost–benefit analyses. The workshop concluded that robust RWE is essential for developing value-based coverage policies and optimizing GLP-1RA use. Continued investment in high-quality data infrastructure and analytic methods will be critical to inform regulatory, clinical, and economic decisions as utilization expands.

Comparative Effectiveness of Glucagon-like Peptide-1 Receptor Agonists Versus Oral Agents for Insulin Discontinuation in Type 2 Diabetes: A Target Trial Emulation: Annals of Internal Medicine: Vol 179, No 8

Background: Addition of glucagon-like peptide-1 receptor agonists (GLP-1RAs) to basal insulin can decrease insulin requirements, but whether it permits insulin discontinuation is unclear. Objective: To compare rates of insulin discontinuation among patients with type 2 diabetes (T2D) receiving basal insulin who initiated treatment with a GLP-1RA, sodium–glucose cotransporter-2 inhibitor (SGLT-2i), or dipeptidyl peptidase-4 inhibitor (DPP-4i) between 2020 and 2022. Design: Target trial emulation. Setting: U.S. Veterans Health Administration electronic health record (EHR) data. Participants: Veterans with T2D receiving basal insulin. Measurements: Insulin discontinuation, defined as the first gap in insulin prescription fills of 12 months or more over 3 years of follow-up. Results: Among 8869 matched sets of GLP-1RA (76.6% semaglutide, 15.2% dulaglutide, 7.9% liraglutide, and 0.3% exenatide), SGLT-2i (99.7% empagliflozin), and DPP-4i (95.9% alogliptin) initiators, 63% were 65 years or older, 93% were male, 70% were White, and 48% had a hemoglobin A1c (HbA1c) level of 9% or more. Over 3 years of follow-up, 1480 (16.7%) GLP-1RA initiators compared with 1585 (17.9%) SGLT-2i initiators and 1517 (17.1%) DPP-4i initiators discontinued insulin therapy in the intention-to-treat analysis (risk ratio, 0.93 [95% CI, 0.86 to 1.01] and 0.98 [CI, 0.87 to 1.09] for the GLP-1RA arm compared with the SGLT-2i and DPP-4i arms, respectively). Results were not substantively different in a modified per protocol analysis. None of the subgroups showed a comparative advantage of GLP-1RAs with respect to insulin discontinuation over SGLT-2is or DPP-4is. Limitation: Possible residual confounding; misclassification of exposure and outcome using EHRs may bias associations toward the null. Conclusion: Among veterans with T2D receiving basal insulin therapy, addition of GLP-1RA did not increase the chances of stopping insulin therapy compared with SGLT-2i or DPP-4i therapy. Primary Funding Source: U.S. Department of Veterans Affairs.

Weekly and Biweekly Treatment With Bofanglutide Versus Semaglutide in Chinese Patients With Type 2 Diabetes: A Phase 2b Randomized Clinical Trial: Annals of Internal Medicine: Vol 179, No 8

Background: Bofanglutide is a novel glucagon-like peptide-1 receptor agonist under development for type 2 diabetes mellitus (T2DM) and overweight and obesity. Objective: To evaluate the efficacy and safety of bofanglutide compared with semaglutide. Design: Phase 2b, randomized, open-label, active-controlled trial. (ClinicalTrials.gov: NCT06256549) Setting: Multicenter (37 sites in China). Participants: Adults with T2DM who were drug-naive or receiving stable oral antidiabetic drugs (glycated hemoglobin A1c [HbA1c], 7.0% to 11.0%). Intervention: Participants were randomly assigned 1:1:1:1:1 to 1 of 5 treatment groups: bofanglutide titrated to targets of 12, 18, or 24 mg (biweekly [once every 2 weeks; Q2W]); bofanglutide titrated to 24 mg (once weekly [QW]); or semaglutide titrated to 1 mg QW. Measurements: Change in HbA1c level from baseline to week 24 (primary end point), secondary efficacy end points, and safety. Results: Overall, 272 participants were enrolled, with a mean age of 50.8 years, HbA1c level of 8.35%, and body mass index of 27.9 kg/m2. At week 24, HbA1c level change from baseline was −1.87% (95% CI, −2.11% to −1.63%), −2.28% (CI, −2.54% to −2.03%), and −1.94% (CI, −2.19% to −1.69%) for bofanglutide 12, 18, 24 mg Q2W, respectively; −2.32% (CI, −2.57% to −2.06%) for bofanglutide 24 mg QW; and −1.60% (CI, −1.85% to −1.35%) for 1 mg of semaglutide QW. Corresponding treatment differences versus semaglutide were −0.27% (CI, −0.61% to −0.08%), −0.68% (CI, −1.04% to −0.33%), −0.34% (CI, −0.70% to 0.02%), and −0.72% (CI, −1.08% to −0.36%), respectively. Gastrointestinal adverse events (GIAEs) (mostly grade 1 or 2 in severity) occurred in 81.8% to 87.3% and 51.9% of participants in the bofanglutide and semaglutide groups, respectively. Hypoglycemia occurred in 0% to 3.8% versus 1.9%, with no severe hypoglycemia. Limitation: Open-label, short duration, only Chinese participants. Conclusion: Meaningful reductions in HbA1c levels were seen with bofanglutide in patients with T2DM; GIAEs were the most common and generally manageable. Primary Funding Source: Gan & Lee Pharmaceuticals.

In adults with obesity but without type 2 diabetes, tirzepatide increased weight loss at 72 wk compared with semaglutide

Clinical Impact Ratings GIM/FP/GP: 6 out of 7 Endocrinology: 6 out of 7

Correction: Comparison of an Energy-Reduced Mediterranean Diet and Physical Activity Versus an Ad Libitum Mediterranean Diet in the Prevention of Type 2 Diabetes