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Abstract: PO1018

Efficacy and Safety of Cotadutide, a Dual GLP-1 and Glucagon Receptor Agonist, for Patients with Type 2 Diabetes Mellitus and CKD

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Parker, Victoria Er, AstraZeneca, Cambridge, United Kingdom
  • Hoang, Thuong, AstraZeneca, Cambridge, United Kingdom
  • Schlichthaar, Heike, Study Center, SMO.MD GmbH, Magdeburg, Germany
  • Chang, Yi-Ting, AstraZeneca, Gaithersburg, Maryland, United States
  • Petrone, Marcella, AstraZeneca, Cambridge, United Kingdom
  • Hansen, Lars, AstraZeneca, Gaithersburg, Maryland, United States
  • Ambery, Philip D., AstraZeneca, Gothenburg, Sweden
  • L Heerspink, Hiddo Jan, University Medical Center, Groningen, Netherlands
  • Mccrimmon, Rory, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom
  • Jermutus, Lutz, AstraZeneca, Cambridge, United Kingdom
Background

Cotadutide is in development for nonalcoholic steatohepatitis and type-2 diabetes mellitus (T2DM). GLP-1 analogues have been shown to delay the development of macroalbuminuria in patients (pts) with T2DM. The glycemic and renal effects of cotadutide were assessed in a phase 2a, randomized, controlled trial.

Methods

The trial enrolled 41 pts with T2DM (HbA1c: ≥6.5—≤10.5%) and chronic kidney disease (CKD) stage G3 (estimated glomerular filtration rate [eGFR]: ≥30–<60 mL/min/1.73m2), on insulin and/or oral therapy, with a BMI of 25—45 kg/m2. Pts 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 via mixed meal tolerance test (MMTT), HbA1c, body weight (BW), eGFR, urinary albumin creatinine ratio (UACR), and C-peptide levels. The trial was powered based on a 2-sided alpha of 0.1.

Results

Cotadutide significantly reduced MMTT glucose AUC vs baseline (-26.7%, 90% CI: -34.6 to -18.8) and vs PBO (3.7%, 90% CI: -3.8 to 11.2; P<0.001), with a 35.2% reduction in insulin dose (P=0.012). Cotadutide significantly reduced BW (-3.7%) and HbA1c (-0.7%; both P<0.001). After 32 days of cotadutide treatment, no significant changes were observed in eGFR or blood pressure. Fasting C-peptide levels in the cotadutide group increased significantly vs PBO (LS mean change: 0.88 µg/L, 90% CI: 0.57 to 1.19, P<0.001). In pts with baseline micro- or macroalbuminuria (n=18), UACR was reduced by 50.6% vs PBO (P=0.0504). Serious adverse events (AEs) were balanced between treatment arms; treatment-related AEs were more frequent with cotadutide (71%) vs PBO (35%). The most common AEs were nausea (cotadutide, 33%; PBO, 20%) and vomiting (cotadutide, 24%; PBO, 5%). Pulse rate was significantly increased (11 beats per minute; P<0.001) by day 32.

Conclusion

In pts with T2DM and CKD, cotadutide improved overall glycemic control and glucose responses to an MMTT with acceptable tolerability. Improvements in albuminuria suggest that cotadutide may be beneficial in this population to slow long-term progression of CKD. Further exploration of this effect is warranted.

Funding

  • Commercial Support –