Cotadutide Confers Renoprotective Benefits in Patients with CKD and T2D

The leading cause of chronic kidney disease (CKD) and kidney failure is type 2 diabetes (T2D). Treatment of patients with T2D and CKD focuses on slowing the progression of loss of kidney function and reducing the increased risk of cardiovascular disease by optimizing glycemic control. Standard management strategies include lifestyle interventions that target weight, lipid, and blood pressure control by introducing lipid-lowering agents as well as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. 

Other treatment plans may include the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors and finerenone, a nonsteroidal mineralocorticoid receptor antagonist. Although these strategies have shown improved patient outcomes, there are concerns regarding residual risk of kidney and cardiovascular events. 

The recent emergence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) may represent an additional drug class with renoprotective effects. GLP-1RAs are approved for weight management as well as for T2D, and some have a proven cardiovascular benefit. Results of post hoc analyses of cardiovascular outcome trials have suggested that the use of those agents may be associated with delay in the onset of new macroalbuminuria, as well as reductions in decline in estimated glomerular filtration rate (eGFR) and the risk of adverse kidney outcomes. 

Cotadutide is a GLP-1 and glucagon receptor agonist. In a phase 2 study of 18 patients with T2D and elevated albuminuria, cotadutide reduced albuminuria by 51%. Researchers, led by Viknesh Selvarajah, PhD, and Hiddo J. L. Heerspink, PhD, conducted a phase 2b trial designed to examine the dose-response relationships between cotadutide and urinary albumin-to-creatinine ratio (UACR). Results were reported in Kidney International. 

The primary objective of the randomized, double-blind, placebo-controlled phase 2b trial with an open-label comparator was the effect of cotadutide versus placebo on UACR after 14 weeks of treatment. Secondary objectives were changes in UACR at week 26, glycemic control, body weight, and safety and tolerability. 

The study cohort included adults 18 to 79 years of age with BMI (calculated as weight in kilograms divided by height in meters squared) of 25 kg/m² or higher (>23 for patients enrolled in Japan), confirmed T2D (glycated HbA1c of 6.5%-12.5%, with glucose control managed with any insulin and/or oral combination therapy with no major changes in dose), and CKD (eGFR ≥20 and <90 mL/min/1.73 m²) and UACR of greater than 50 mg/mL (or >5.7 mg/mmol). Participants were randomized 1:1:1:1:1 to receive daily cotadutide 100 µg, 300 µg, or 600 µg (double-blind); matched placebo (double-blind); or weekly semaglutide 1 mg (open-label) via subcutaneous injection. Randomization was stratified by region (Japan vs other regions) and use of SGLT2 inhibitor therapy at screening. 

A total of 416 patients were screened between August 2020 and April 2022. Of those, 247 were randomized to receive cotadutide (100 µg: n=52; 300 µg: n=48; or 600 µg: n=51), placebo (n=51), or semaglutide (n=45). One patient in the 300 µg arm did not receive treatment. A total of 235 patients completed the study. Thirty-eight participants did not complete treatment. 

The treatment arms were generally well balanced in baseline demographics and patient characteristics. In the group of 248 enrolled participants, median age was 68.0 years, 19% (n=47) were female, and 76.6% (n=190) were White. The geometric mean UACR was 205.5 mg/g and was lower in the cotadutide 600 µg and semaglutide arms than in the other groups. At baseline, mean eGFR was 55.3 mL/min/1.73 m2, and mean BMI was 32.6; 116 participants (46.8%) were receiving an SGLT2 inhibitor. 

Dose-dependent percentage reductions in UACR from baseline to the end of week 14 were associated with cotadutide treatment. The reductions were statistically significant for cotadutide 300 µg (–43.9%; 95% CI, –54.7% to –30.6%; P=0.001) and cotadutide 600 µg (–49.9%; 95% CI, –59.3% to –38.4%; P<0.001) versus placebo (–12.9%; 95% CI, –29.3% to 7.2%). Treatment ratios versus placebo were 0.64 (95% CI, 0.50-0.84) for cotadutide 300 µg and 0.58 (95% CI, 0.45-0.74) for cotadutide 600 µg. Those effects were sustained at week 26. 

There were no differences between treatment arms in eGFR change from baseline to week 14 or in changes in cystatin C eGFR. Significant reductions in HbA1c were observed from baseline to week 14 and week 26 across all dose levels of cotadutide compared with placebo. The largest reduction in HbA1c was seen in the semaglutide arm. There were reductions in fasting glucose from baseline to week 26 with cotadutide versus placebo, as well as reductions in continuous glucose monitoring measures of glycemic control to the end of week 14 and the end of week 26 with cotadutide versus placebo. 

There were dose-dependent reductions in body weight from baseline to the end of week 14 versus placebo and into follow-up. After adjustment for changes in insulin dose, the reductions in body weight to week 26 were clinically and statistically significant. There were significant reductions in systolic blood pressure in the group receiving cotadutide 600 µg from baseline to week 26 when measured by ambulatory blood pressure monitoring. 

At all cotadutide dose levels, there were improvements in Kidney Disease Quality of Life-36 (KDQOL-36) scores from baseline to week 26. There was a clinically significant improvement in the score on the KDQOL-36 burden of kidney disease scale from baseline to week 26 with cotadutide 600 µg versus placebo and semaglutide. There were also improvements in Diabetes Treatment Satisfaction Questionnaire scores in the cotadutide 300 µg and 600 µg arms versus placebo; the improvements were comparable to those in the semaglutide arm. 

Safety and tolerability findings with cotadutide 600 µg were comparable to those with semaglutide and consistent with previous studies of cotadutide. Serious adverse events were balanced across arms. 

Limitations to the study findings cited by the authors included underrepresentation of Black and female patients, absence of data on patient preference for once-daily subcutaneous formulation compared with competitor products, and lack of collection of 24-hour urine samples to assess effects of urinary albumin and creatinine excretion. 

In summary the researchers said, “Overall, our findings suggest that cotadutide has the potential to be a beneficial therapy in CKD with T2D, driving improvements in albuminuria alongside holistic effects, including improvements in glycemic control, blood pressure, body weight, and insulin dose reduction versus placebo. Furthermore, despite daily injections, patients reported improvements in quality of life with cotadutide versus placebo. We believe that the results indicate an added kidney benefit of combining GLP-1 and glucagon receptor agonism versus GLP-1 receptor agonism alone. However, larger studies with longer follow-up are needed to confirm the benefits for kidney outcomes.” 

Source: Kidney International