Semaglutide Falls Short in Alzheimer Disease, Tirzepatide Shows Promise in T1D

In this episode, hosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, breakdown recent trial news from the 2 most popular incretin therapies: semaglutide and tirzepatide. First, hosts breakdown the November 24, 2025 announcement from Novo Nordisk disclosing their evoke and evoke+ trials of oral semaglutide in early symptomatic Alzheimer Disease failed to slow disease progression. Next, hosts break down the TIRTLE study, which examined use of tirzepatide in patients with type 1 diabetes. Semaglutide Misses Mark in Alzheimer Disease Novo Nordisk announced top-line results from the evoke and evoke+ phase 3 trials showing oral semaglutide 14 mg did not slow disease progression over 2 years in adults with early symptomatic Alzheimerdisease, with no significant difference in CDR-SB change versus placebo. Despite improvements in Alzheimer-related biomarkers across both studies, neither trial demonstrated a slowing of clinical decline. evoke was a global, randomized, double-blind, placebo-controlled trial enrolling 1,855 participants aged 55–85 with amyloid-positive CDR 0.5 MCI or CDR 1.0 mild dementia, treated 1:1 with semaglutide or placebo for 104 weeks plus a planned 52-week extension. evoke+ mirrored this design, randomizing 1,953 participants with the same eligibility criteria to daily semaglutide 14 mg or placebo for a total planned duration of 156 weeks. Findings from the trials will be presented at the 2025 Clinical Trials in Alzheimer’s Disease (CTAD) conference on December 3, 2025. The lack of efficacy led to discontinuation of the planned 1-year extension period across both trials, though safety and tolerability remained consistent with prior semaglutide experience in diabetes and obesity. TIRTLE: Tirzepatide Shows Benefit in Type 1 Diabetes In a 12-week, double-blind, placebo-controlled phase 2 trial of 24 adults with type 1 diabetes and BMI >30 kg/m², tirzepatide produced a 10.3-kg mean weight loss versus 0.7 kg on placebo, an −8.7-kg treatment difference (P < 0.0001) corresponding to 8.8% total body weight reduction. All tirzepatide-treated participants achieved ≥5% weight loss, and 45% achieved ≥10%, compared with 9% and 0% in the placebo group. Eligibility criteria required patients to be 18 years of age or older, with confirmed type 1 diabetes, obesity (BMI >30), and stable insulin therapy. Tirzepatide also improved glycemic control, reducing HbA1c by 0.4%, and decreased total daily insulin dose by 35% relative to placebo (−24.2 vs −0.3 units/day). Safety data suggested no significant adverse events occurred, with 22 of the 24 participants completing the study. Relevant disclosures for Isaacs include Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott Diabetes Care, Dexcom, Medtronic, and others. Relevant disclosures for Bellini include Abbott Diabetes Care, MannKind, Provention Bio, and others. References: Novo Nordisk. Novo Nordisk A/S: Evoke phase 3 trials did not demonstrate a statistically significant reduction in Alzheimer’s disease progression. Novo Nordisk. November 24, 2025. Accessed November 24, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916462. Snaith JR, Frampton R, Samocha-Bonet D, Greenfield JR. Tirzepatide in Adults With Type 1 Diabetes: A Phase 2 Randomized Placebo-Controlled Clinical Trial. Diabetes Care. Published online November 20, 2025. doi:10.2337/dc25-2379

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