Effectiveness and Safety of Combined Semaglutide and Dapagliflozin Therapy in Type 2 Diabetes: A Retrospective Cohort Study

Background: Combination therapy with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors may provide complementary metabolic, cardiovascular, and renal benefits in type 2 diabetes mellitus (T2DM). However, real-world evidence from Middle Eastern populations remains limited. This study evaluated the effectiveness and safety of combined semaglutide and dapagliflozin therapy in routine clinical practice. Methods: This retrospective cohort study included adults (≥18 years) with T2DM treated with concurrent semaglutide and dapagliflozin for at least 12 months at a specialized primary care clinic in King Abdulaziz Medical City, Jeddah, Saudi Arabia. Clinical and laboratory data were extracted from electronic medical records. The primary outcome was a change in glycated hemoglobin (HbA1c). Secondary outcomes included changes in the lipid profile, renal parameters (estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR)), and adverse events. Paired comparisons were performed using the Wilcoxon signed-rank test. Multivariable linear regression was used to identify predictors of HbA1c reduction. Results: A total of 291 patients were included (mean age 58.6 ± 9.5 years; 49.8% male; mean diabetes duration 12.9 ± 9.5 years). Median HbA1c decreased from 8.20% to 7.20% (Z = −10.323; P < 0.001). Significant reductions were also observed in total cholesterol, LDL cholesterol, and triglycerides (all P < 0.001), while the UACR decreased significantly (P < 0.001). eGFR remained stable (P = 0.376). Most patients (90.4%) experienced no documented adverse events; hypoglycemia occurred in 6.2%. In multivariable analysis, higher baseline HbA1c (B = 0.552; P < 0.001), hypertension (B = 0.413; P = 0.016), and dyslipidemia (B = 0.381; P = 0.021) were associated with greater HbA1c reduction, whereas insulin use was associated with a smaller reduction (B = −0.612; P < 0.001). The model explained 43.2% of the variability in HbA1c change. Conclusions: In routine clinical practice, combined semaglutide and dapagliflozin therapy was associated with significant improvements in glycemic control, lipid profile, and albuminuria, with stable renal function and a favorable safety profile. These findings support the effectiveness of this combination in real-world settings and highlight the need for prospective comparative studies to confirm long-term outcomes and define optimal patient selection.