Moderate · human
This systematic review and meta-analysis (PRISMA 2020, PROSPERO-registered) pooled three randomized controlled trials (N = 13,590 adults with type 2 diabetes) comparing once-weekly tirzepatide — a dual GIP/GLP-1 receptor agonist — against dulaglutide (a GLP-1 receptor agonist) over at least 26 weeks. The primary safety outcome was overall adverse event incidence, which the study found did not differ significantly between treatments (RR 1.04; moderate-certainty evidence). However, discontinuation due to adverse events was consistently higher with tirzepatide (RR 1.32; high-certainty evidence), suggesting a tolerability-persistence trade-off. Glycemic target achievement (HbA1c) was population-dependent: tirzepatide showed consistent benefit at the primary threshold in treatment-naïve patients receiving lower-dose dulaglutide, while the advantage narrowed in patients with established cardiovascular disease on higher-dose dulaglutide; heterogeneity was extreme at the strictest threshold. Weight-loss threshold achievement favored tirzepatide, though evidence certainty was very low due to substantial heterogeneity. Serious adverse events did not differ significantly. Key limitations include only three included trials, high heterogeneity for several outcomes, and restricted generalizability across patient subgroups. GRADE certainty ranged from very low to high across outcomes.
Healthcare (Basel, Switzerland) · Mar 2026DOI ↗ Moderate · human
This secondary analysis pooled data from two randomized, double-blind, placebo-controlled crossover trials to examine whether the GLP-1 receptor agonist (RA) dulaglutide affects copeptin — a stable surrogate marker for vasopressin (antidiuretic hormone) — in euvolemic individuals. A total of 54 participants were included: 34 with primary polydipsia and 20 healthy volunteers. Participants received three weeks of either subcutaneous dulaglutide or saline placebo once weekly before crossing over. Fasting blood samples for copeptin were collected after each treatment phase. The study found that dulaglutide was associated with a statistically significant suppression of copeptin levels, with a median within-subject difference of −0.7 pmol/L (p = .047), representing approximately a 12% reduction relative to placebo. This effect was not significantly correlated with dulaglutide-related changes in blood pressure, BMI, or nausea frequency. The authors suggest this finding may help explain GLP-1's known role in fluid and sodium homeostasis. Key limitations include the secondary-analysis design (not pre-specified as the primary outcome), modest sample size, a mixed population (healthy and polydipsic participants), and the reliance on copeptin as a proxy rather than directly measured vasopressin.
European journal of endocrinology · Feb 2026DOI ↗ Moderate · human
This post hoc analysis of the AWARD-7 randomized controlled trial examined how dulaglutide (a GLP-1 receptor agonist) affects plasma concentrations of 21 Joslin Kidney Panel (JKP) proteins—biomarkers previously linked to end-stage kidney disease (ESKD) risk—in adults with type 2 diabetes and moderate-to-severe chronic kidney disease (CKD). Researchers used the Joslin OLINK proteomic platform to compare changes in protein concentrations from baseline to 6 months between participants receiving once-weekly dulaglutide (n=124) and those receiving insulin glargine (n=125). The study found that 14 of the 21 JKP proteins increased in the insulin glargine group but decreased in the dulaglutide group, with statistically significant between-group differences. The most notable differences involved 8 TNF-receptor superfamily members, which play roles in inflammation and apoptosis. Additional proteins—including CD160, WFDC2, DLL1, LAYN, SYND1, and EPHA2—also differed significantly between groups. Effects were more pronounced in participants with lower kidney function, higher albuminuria, higher HbA1c, or higher BMI at baseline. The authors suggest these proteomic changes may help explain the kidney-protective effects observed with dulaglutide in AWARD-7. Key limitations include the post hoc, exploratory design, the 6-month follow-up window, and lack of adjustment for multiple comparisons.
Kidney international reports · Jan 2026DOI ↗ Moderate · human
This Phase III randomized controlled trial evaluated mazdutide, a novel once-weekly dual glucagon and GLP-1 receptor agonist, compared to dulaglutide in 731 Chinese adults with type 2 diabetes (T2D) on background oral anti-diabetic therapy. Participants were randomized 1:1:1 to one of two mazdutide doses or dulaglutide (1.5 mg) for 28 weeks. The study found that both mazdutide doses demonstrated non-inferiority and superiority to dulaglutide in reducing HbA1c from baseline, with least-squares mean treatment differences of -0.24% and -0.30% for the lower and higher doses, respectively. Mazdutide also produced significantly greater reductions in body weight than dulaglutide, with differences of -3.78% and -5.76% for the two doses. The safety profile was generally acceptable, though gastrointestinal adverse events occurred more frequently with mazdutide than dulaglutide. Limitations include the relatively short 28-week duration, restriction to a Chinese population, and the lack of a placebo arm, which may limit generalizability of findings.