Recommended Citation
Ezeano C, Essien E, Alpizar-Rivas R. Combination Therapy Versus Monotherapy and the Risk of Diabetic Ketoacidosis Among Patients on SGLT2 Inhibitors and GLP-1 Receptor Agonists. Presented at Scientific Day; May 20, 2026; Milwaukee, WI.
Abstract
Background/Significance:
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce cardiovascular and renal events but carry a recognized risk of diabetic ketoacidosis (DKA), including euglycemic presentations. Whether combining SGLT2i with glucagon-like peptide-1 receptor agonists (GLP-1RA) modifies DKA risk compared with monotherapy remains unclear. We evaluated 1-year DKA risk among adults with type 2 diabetes treated with combination therapy versus either agent alone.
Purpose:
To compare the 1-year incidence and hazard of DKA across three treatment strategies: (1) SGLT2i + GLP-1RA vs GLP-1RA alone; (2) SGLT2i + GLP-1RA vs SGLT2i alone; and (3) SGLT2i alone vs GLP- 1RA alone.
Methods:
We conducted a retrospective multicenter cohort study using the TriNetX Global Collaborative Network (17 healthcare organizations). Adults ≥18 years with type 2 diabetes (ICD-10 E11) initiating study medications were included. Exclusions were type 1 diabetes, pregnancy, total pancreatectomy, or prior to DKA. The primary outcome was DKA within 365 days (ICD-10 E11.1/E13.1). Propensity-score matching (1:1) adjusted for age, sex, HbA1c, BMI, diabetes duration, insulin use, eGFR, hypertension, ASCVD, heart failure, and CKD. Effect measures included risk difference (RD), risk ratio (RR), and hazard ratio (HR) using Kaplan–Meier and Cox proportional hazards analyses.
Results:
Combination vs GLP-1RA alone (matched n=16,673 vs 16,660): DKA risk 0.5% vs 0.4% (RR 1.35, 95% CI 0.98–1.85; HR 1.53, 95% CI 1.11–2.11). Combination vs SGLT2i alone (n=16,673 vs 16,711): DKA risk 0.5% vs 0.6% (RR 0.92, 95% CI 0.69–1.22; HR 1.02, 95% CI 0.76–1.35). SGLT2i alone vs GLP-1RA alone (n=213,160 vs 212,923): DKA risk 0.5% vs 0.4% (RR 1.41, 95% CI 1.29– 1.55). Absolute risks were low (approximately 0.5–0.6% at 1 year).
Conclusion:
Combination therapy did not reduce 1-year DKA risk versus SGLT2i monotherapy by either risk-based or time-to-event analyses. Compared with GLP-1RA alone, combination therapy was associated with a higher DKA hazard. SGLT2i monotherapy carried significantly higher DKA risk than GLP-1RA monotherapy. Although absolute risks were low (~0.5–0.6% over 1 year), the relative differences are clinically meaningful in high-risk populations. GLP-1RA monotherapy demonstrated the lowest 1-year risk of DKA. Adding GLP-1RA to SGLT2i did not lower risk below SGLT2i alone, challenging the assumption that GLP-1RA mitigates SGLT2i-associated DKA. These findings should inform drug sequencing, shared decision-making, and risk counseling for patients who are predisposed to ketosis.
Presentation Notes
Presented at Scientific Day; May 20, 2026; Milwaukee, WI.
Full Text of Presentation
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Document Type
Oral/Podium Presentation
Combination Therapy Versus Monotherapy and the Risk of Diabetic Ketoacidosis Among Patients on SGLT2 Inhibitors and GLP-1 Receptor Agonists
Background/Significance:
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce cardiovascular and renal events but carry a recognized risk of diabetic ketoacidosis (DKA), including euglycemic presentations. Whether combining SGLT2i with glucagon-like peptide-1 receptor agonists (GLP-1RA) modifies DKA risk compared with monotherapy remains unclear. We evaluated 1-year DKA risk among adults with type 2 diabetes treated with combination therapy versus either agent alone.
Purpose:
To compare the 1-year incidence and hazard of DKA across three treatment strategies: (1) SGLT2i + GLP-1RA vs GLP-1RA alone; (2) SGLT2i + GLP-1RA vs SGLT2i alone; and (3) SGLT2i alone vs GLP- 1RA alone.
Methods:
We conducted a retrospective multicenter cohort study using the TriNetX Global Collaborative Network (17 healthcare organizations). Adults ≥18 years with type 2 diabetes (ICD-10 E11) initiating study medications were included. Exclusions were type 1 diabetes, pregnancy, total pancreatectomy, or prior to DKA. The primary outcome was DKA within 365 days (ICD-10 E11.1/E13.1). Propensity-score matching (1:1) adjusted for age, sex, HbA1c, BMI, diabetes duration, insulin use, eGFR, hypertension, ASCVD, heart failure, and CKD. Effect measures included risk difference (RD), risk ratio (RR), and hazard ratio (HR) using Kaplan–Meier and Cox proportional hazards analyses.
Results:
Combination vs GLP-1RA alone (matched n=16,673 vs 16,660): DKA risk 0.5% vs 0.4% (RR 1.35, 95% CI 0.98–1.85; HR 1.53, 95% CI 1.11–2.11). Combination vs SGLT2i alone (n=16,673 vs 16,711): DKA risk 0.5% vs 0.6% (RR 0.92, 95% CI 0.69–1.22; HR 1.02, 95% CI 0.76–1.35). SGLT2i alone vs GLP-1RA alone (n=213,160 vs 212,923): DKA risk 0.5% vs 0.4% (RR 1.41, 95% CI 1.29– 1.55). Absolute risks were low (approximately 0.5–0.6% at 1 year).
Conclusion:
Combination therapy did not reduce 1-year DKA risk versus SGLT2i monotherapy by either risk-based or time-to-event analyses. Compared with GLP-1RA alone, combination therapy was associated with a higher DKA hazard. SGLT2i monotherapy carried significantly higher DKA risk than GLP-1RA monotherapy. Although absolute risks were low (~0.5–0.6% over 1 year), the relative differences are clinically meaningful in high-risk populations. GLP-1RA monotherapy demonstrated the lowest 1-year risk of DKA. Adding GLP-1RA to SGLT2i did not lower risk below SGLT2i alone, challenging the assumption that GLP-1RA mitigates SGLT2i-associated DKA. These findings should inform drug sequencing, shared decision-making, and risk counseling for patients who are predisposed to ketosis.
Affiliations
Aurora Sinai Medical Center, Aurora St. Luke’s Medical Center