SGLT2 With Metformin Shows More Glycemic Reductions Compared With DPP-4

As the global prevalence of type 2 diabetes (T2D) continues to climb toward an estimated 629 million people by 2045, clinical focus is shifting beyond simple blood sugar management toward comprehensive cardiometabolic protection. Although metformin remains the undisputed first-line pharmacological treatment following lifestyle modifications, its effectiveness often wanes as pancreatic beta-cell function gradually declines, necessitating the addition of secondary agents.^1,2

A new systematic review and meta-analysis published in JOURNAL provides critical clarity for pharmacists navigating the 2 most common add-on choices of a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin, and a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin.

“Type 2 diabetes mellitus (T2DM) represents a profound global health challenge, characterized as a chronic metabolic disorder leading to significant morbidity and mortality,” the study authors wrote.¹ “The International Diabetes Federation (IDF) reports that one in every 11 adults aged 20–79 years is affected by diabetes, with a global prevalence of 8.8%.”

The Results of the Review

The findings, which consolidated data from 11 clinical trials and observational studies, suggest that empagliflozin offers superior clinical benefits when added to a metformin background. Patients on the empagliflozin-metformin combination experienced significantly greater reductions in glycated hemoglobin (HbA_1C), with an average additional drop of 0.51% compared to those on sitagliptin and metformin.

Beyond glycemic control, empagliflozin demonstrated a clear advantage in cardiometabolic markers, producing an average weight loss of 2 to 3 kilograms and a notable reduction in systolic blood pressure. These results align with the established pharmacology of SGLT2 inhibitors, which lower plasma glucose by decreasing renal glucose reabsorption and promoting its excretion through urine, a process that inherently causes caloric wasting and a mild diuretic effect.^1,3

Conversely, sitagliptin functions as a competitive inhibitor of the DPP-4 enzyme, which increases the activity of incretin hormones like glucagon-like peptide-1 to promote insulin secretion and inhibit glucagon release. Although highly effective at stabilizing blood sugar, sitagliptin is generally regarded as weight-neutral and has shown neutral effects on cardiovascular outcomes in landmark trials.

The meta-analysis confirmed that sitagliptin offers similar glycemic control to other agents but lacks the incremental metabolic gains seen with empagliflozin, such as the observed improvements in high-density lipoprotein cholesterol and reduced fasting blood glucose.

“Empagliflozin produced significantly greater glycemic reductions than sitagliptin across trials,” the study authors wrote. “In our meta-analysis, empagliflozin lowered HbA_1C more than sitagliptin. This finding is consistent with prior evidence: meta-analyses have shown that SGLT2 inhibitors yield meaningfully larger HbA_1C reductions than DPP-4 inhibitors in head-to-head comparisons.”

What Pharmacists Should Know

For pharmacists, the safety profiles of these adjunct therapies require careful patient counseling and monitoring. The meta-analysis highlighted a significantly higher risk of genital mycotic infections associated with empagliflozin—a direct consequence of the glycosuria induced by its mechanism of action.

Although these infections are typically mild and treatable, they represent a distinct drawback compared to the benign adverse effect profile of sitagliptin. Furthermore, pharmacists must remain vigilant regarding rare but serious risks associated with SGLT2 inhibitors, such as ketoacidosis and the rare necrotizing fasciitis of the perineum known as Fournier’s gangrene. Sitagliptin, although generally well-tolerated, has been associated with rare instances of pancreatitis, severe joint pain, and bullous pemphigoid.^3,4

Metformin itself, though the cornerstone of therapy, carries its own monitoring requirements that pharmacists must integrate into the dual-therapy plan. It is known to cause gastrointestinal disturbances in up to 30% of patients and is associated with a rare but severe black box warning for lactic acidosis. Long-term use can also lead to vitamin B12 deficiency, necessitating periodic screening for patients with anemia or peripheral neuropathy.²

The choice between these agents often hinges on a patient’s specific renal health and cardiovascular risk profile. Empagliflozin demonstrated significant reductions in cardiovascular death and hospitalizations for heart failure in high-risk populations, supporting its use in patients with established atherosclerotic disease. However, its efficacy is dependent on renal function. It is generally not recommended if the glomerular filtration rate falls below 45 mL/min/1.73 m² and is contraindicated once it drops below 30.³

Metformin shares this strict contraindication for patients with a glomerular filtration rate below 30 due to the heightened risk of lactic acidosis. Sitagliptin also requires dosage adjustments as kidney function declines, as slower removal of the drug from the body can increase the risk of adverse effects.^2,4

Although both drugs are effective adjuncts to metformin, empagliflozin provides a more robust package of metabolic and cardiovascular benefits. Pharmacists play a vital role in this interprofessional team by verifying dosages, conducting medication reconciliations to prevent interactions with diuretics or insulin, and counseling patients on the importance of hygiene to mitigate infection risks.^1-3

READ MORE: Diabetes Resource Center

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REFERENCES

1. Ashraf S, Burhan M, Sarwar S, et al. Glycaemic and Cardiometabolic Outcomes of Empagliflozin Versus Sitagliptin Added to Metformin in T2DM: Insights From a Systematic Review and Meta-Analysis. Endocrinol Diabetes Metab. 2026;9(3):e70238. doi:10.1002/edm2.70238

2. Corcoran C, Jacobs TF. Metformin. [Updated 2023 Aug 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK518983/

3. Sizar O, Podder V, Talati R. Empagliflozin. [Updated 2023 May 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532925/

4. Mayo Clinic. Sitagliptin (oral route). Updated February 1, 2026. Accessed May 13, 2026. https://www.mayoclinic.org/drugs-supplements/sitagliptin-oral-route/description/drg-20069730