Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Diabetic kidney disease (DKD) is a common complication of type 2 diabetes mellitus and an important cause of end-stage renal disease. Metabolic dysfunction, albuminuria, and chronic low-grade inflammation characterize early DKD, leading to progressive renal impairment. To date, SGLT2 inhibitors and GLP-1 receptor agonists are known to provide renoprotective and metabolic benefits; however, there is limited evidence available regarding the combined use of these treatments in early DKD. Objectives: This study evaluated the short-term effects of canagliflozin and semaglutide, administered alone or in combination, on renal function, metabolic parameters, and systemic inflammatory markers in patients with early-stage DKD. Methods: In this randomized controlled trial, 120 patients with early-stage diabetic kidney disease were randomly allocated (1:1:1:1) to four groups (n = 30 each): canagliflozin (100 mg orally once daily), semaglutide (0.25 mg once weekly with escalation to 1.0 mg after 4 weeks), combination treatment, or placebo/control. Participants: All participants were provided standard background care. Treatment continued for 24 weeks. The main renal outcomes were urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Glycemic control, insulin resistance, lipid parameters, and inflammatory biomarkers (HbA1c, fasting glucose, HOMA-IR, TNF-?, IL-6, CRP) were considered as secondary outcomes. Safety assessment was conducted using binary safety assessment. Results: At 24 weeks, combination therapy achieved significantly greater reductions in UACR compared with monotherapy and placebo (P < 0.05). Across treatment groups, a small reduction in eGFR was observed without significant between-group differences. Measurements of HbA1c, fasting glucose, HOMA-IR, lipid parameters, and inflammatory markers showed better results in the combination therapy group compared to single-agent therapy (P < 0.05). Rates of adverse events were similar between the groups. Conclusion: Combined canagliflozin and semaglutide therapy demonstrated superior short-term benefits in reducing albuminuria, improving metabolic control, and attenuating systemic inflammation in early DKD, supporting further long-term evaluation of renal and cardiovascular outcomes.