Early GLP-1 Receptor Agonist and SGLT2 Inhibitor Add-On Strategies in Adults With Obesity, Type 2 Diabetes, Cardiovascular-Kidney-Metabolic Syndrome Stage 2-3, and Metabolic Dysfunction-Associated Steatotic Liver Disease

Early GLP-1 Receptor Agonist and SGLT2 Inhibitor Add-On Strategies in Adults With Obesity, Type 2 Diabetes, Cardiovascular-Kidney-Metabolic Syndrome Stage 2-3, and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Target Trial Emulation

This retrospective observational target-trial emulation uses electronic health record data from the TriNetX US Collaborative Network to compare early treatment intensification strategies in adults with obesity, type 2 diabetes, cardiovascular-kidney-metabolic syndrome stage 2-3, and metabolic dysfunction-associated steatotic liver disease who initiate a GLP-1 receptor agonist or an SGLT2 inhibitor as background therapy. Within each background-therapy cohort, patients who added the complementary class within 90 days of initiation were compared against patients who did not, with prespecified comparisons against both the overall non-complementary cohort and the analytical subset who initiated usual-care add-on therapy (DPP-4 inhibitors, sulfonylureas, or insulin) within the same window. The primary outcome is all-cause mortality over 60 months, with major adverse cardiovascular, kidney, and liver outcomes also evaluated. Propensity-score matching is used to reduce bias from nonrandom treatment selection.

Inclusion Criteria:

• Adults aged 18 years or older.
• BMI ≥27 kg/m², or diagnosis codes consistent with obesity
• Type 2 diabetes mellitus
• Cardiovascular-kidney-metabolic syndrome stage 2-3
• Metabolic dysfunction-associated steatotic liver disease
• New initiation of GLP-1 receptor agonist therapy or SGLT2 inhibitor therapy during the study period as background therapy
• No prescription of either GLP-1 receptor agonist or SGLT2 inhibitor within the 6-month washout window before background therapy initiation

Exclusion Criteria:

• Type 1 diabetes mellitus, or other specified diabetes types that are not type 2 diabetes
• Human immunodeficiency virus infection
• Other chronic, alcohol-related, or secondary liver diseases
• Prior bariatric surgery
• Prior solid-organ transplantation
• Hepatocellular carcinoma or liver transplant within 1 year before background therapy initiation
• Major cardiovascular, kidney, or liver event within the 6-month window before background therapy initiation
• Transplant-related complications