Glycaemic and Cardiometabolic Outcomes of Empagliflozin Versus Sitagliptin Added to Metformin in T2DM: Insights From a Systematic Review and Meta-Analysis.

BACKGROUND

Type 2 diabetes mellitus (T2DM) often requires combination therapy when metformin alone becomes insufficient. Empagliflozin (SGLT2 inhibitor) and sitagliptin (DPP-4 inhibitor) are commonly used add-on agents with differing metabolic profiles. This systematic review and meta-analysis compared their glycaemic, cardiometabolic and safety outcomes when added to metformin.

METHODS

Following PRISMA guidelines, PubMed, Embase, Cochrane, Scopus and ClinicalTrials.gov were searched from inception to September 2025. Randomized trials and observational studies comparing empagliflozin + metformin versus sitagliptin + metformin in adults with T2DM were included. Primary outcomes were changes in HbA1c, body weight, fasting glucose, lipid profile and blood pressure. Safety outcomes included urinary tract infections, genital infections, gastrointestinal disturbances and rash. Risk of bias was assessed using RoB 2.0 and the Newcastle-Ottawa Scale. Random-effects models were used for meta-analyses, and meta-regression explored the impact of empagliflozin dose.

RESULTS

Eleven studies met eligibility criteria. Empagliflozin produced greater reductions in HbA1c, body weight, fasting glucose and systolic blood pressure compared with sitagliptin. Lipid changes were modest and inconsistent. Rates of urinary infections, gastrointestinal symptoms and rash were comparable between groups, whereas genital infections were significantly higher with empagliflozin. Rare but serious adverse events associated with SGLT2 inhibitors, including Fournier's gangrene and lower limb amputations, were not reported in the included trials. Meta-regression showed no meaningful dose-response relationship for glycaemic or weight outcomes.

CONCLUSIONS

In patients with T2DM on metformin, empagliflozin offers superior glycaemic and cardiometabolic benefits compared with sitagliptin, with an increase in genital infections. Both therapies are well tolerated, supporting empagliflozin as an effective metabolic add-on option.

TRIAL REGISTRATION: PROSPERO ID: CRD420251152360.