Background: Cotadutide, a dual glucagon-like peptide (GLP-1) and glucagon receptor agonist, is in development for NASH and T2DM with DKD. GLP-1 receptor agonists have been shown to delay the onset of macroalbuminuria in DKD. The glycemic and renal effects of cotadutide were assessed in a phase 2a, randomized, controlled trial (NCT03550378).

Methods: The trial enrolled 41 patients with T2DM (HbA1c 6.5-10.5%) and CKD stage 3 (eGFR 30-59 mL/min/1.73 m2), on insulin and/or oral glucose-lowering therapy and BMI 25-45 kg/m2. Patients were randomized to once-daily subcutaneous cotadutide (n = 21) titrated up to 300 µg or placebo (PBO; n = 20) for 32 days. Endpoints included glucose response during a mixed meal tolerance test (MMTT), time spent within a target glucose range over a 7-day period on continuous glucose monitoring (CGM) and body weight. Exploratory measures included eGFR, UACR, C-peptide and NT-proBNP.

Results: After 32 days, cotadutide compared with PBO reduced MMTT glucose AUC (-26.7%; 90% CI -34.6% to -18.8%; 7-day mean glucose -47.9 mg/dL vs. PBO) and increased CGM time spent in target range over 32 days by 36.0% vs. PBO to 78.7% (both p ≤ 0.003). Cotadutide was associated with 35.2% reduction in insulin dose, 0.88 µg/L increase in C-peptide and 3.7% reduction in body weight (all p ≤ 0.012). There was no change in eGFR. In patients with baseline micro- or macroalbuminuria (n = 18), UACR was reduced by 50.6% (p = 0.0504 vs. PBO). In addition, NT-proBNP level was reduced with cotadutide vs. PBO (-79.7 ng/L vs. -9.42 ng/L, p = 0.040). Safety and tolerability findings were consistent with the known mechanism of action of GLP-1 receptor agonists. There were no episodes of severe hypoglycemia, and CGM time < 54 mg/dL was 1.65% with cotadutide vs. 0.82% with PBO.

Conclusion: In patients with T2DM and DKD, short term treatment with cotadutide had robust effects on glucose lowering. The reduction in albuminuria suggests that cotadutide has renoprotective potential in DKD, but further evaluation is warranted.


V. E. Parker: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. H. L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Mitsubishi Corporation Life Sciences Limited, Mundipharma International, Novo Nordisk, Retrophin, Inc., Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC. R. J. Mccrimmon: Advisory Panel; Self; Novo Nordisk Inc., Sanofi-Aventis, Board Member; Self; Novo Nordisk Foundation, Research Support; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. T. Hoang: None. H. Schlichthaar: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk. F. W. Gibb: Speaker’s Bureau; Self; Abbott Diabetes. B. Wenzel: None. M. G. Posch: None. Y. Chang: None. M. Petrone: None. L. Hansen: Employee; Self; AstraZeneca.

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