Latest Triple Combination of Empagliflozin, Sitagliptin, and Metformin for Advanced Care in Indian T2DM Patients- When to Consider?

Diabetes mellitus affects nearly 90 million Indians (IDF 2025) [1], with the Indian phenotype conferring disproportionately higher cardiorenal risk compared to Western populations. Indian studies indicate that at diagnosis, more than one-third of T2DM patients are classified as "high risk" and more than half as "very high risk" for ASCVD, while about one-in-ten present with CKD stage 3b or higher [2] and 80% exhibit metabolic syndrome (MetS) [3], making early glycemic control as well as cardio-renal organ protection pivotal for the avoidance of long-term complications. Mounting evidence advocates earlier combination therapy to circumvent therapeutic inertia, preserve β-cell function, enhance glycemic durability, and improve long-term cardio-renal outcomes[4]. This article explores the clinical role of the triple combination of empagliflozin+sitagliptin+metformin therapy for supporting advanced care in T2DM management.

Empagliflozin + Sitagliptin + Metformin: Experienced Agents with Complementary Effects in T2D

T2DM involves multiple pathophysiologic defects of the ominous octet, necessitating multi-targeted therapy: [5]

• Empagliflozin (SGLT2i): Reverses the kidney's maladaptive glucose conservation by inhibiting proximal tubular glucose reabsorption, inducing glucosuria while conferring weight loss, BP reduction, and cardiorenal protection without hypoglycemia risk.
• Sitagliptin (DPP-4i): Enhances incretin-mediated insulin secretion and suppresses glucagon release, thereby reducing hepatic glucose output in a glucose-dependent manner with weight neutrality and established CV safety.
• Metformin: Reduces hepatic gluconeogenesis and enhances peripheral insulin sensitivity while promoting lipolysis in adipose tissue, establishing foundational glycemic control with wide clinical acceptibility.

Empagliflozin+Sitagliptin+Metformin in T2D: Clinical Evidence

Early Use of Empagliflozin+Sitagliptin+Metformin Triple FDC in T2D: A 24-month study in 170 drug-naïve T2DM patients (baseline HbA1c 11.0±1.8%) demonstrated that initial triple therapy with empagliflozin (10mg), sitagliptin (100mg), and metformin (1000mg) reduced HbA1c to 7.0±1.7%, with 72.5% and 61.7% achieving target (HbA1c <7.0%) at 12 and 24 months, respectively, without severe hypoglycemia. Fasting plasma glucose (FPG) decreased by 102.1 mg/dL (235.7±78.5 mg/dL to 133.6±48.1 mg/dL), and postprandial 2-hour glucose decreased by 197.9 mg/dL (394.8±114.1 mg/dL to 196.9±83.2 mg/dL). Beyond glycemic control, the regimen improved β-cell function, insulin resistance, body composition (−1.08% fat, +0.97% muscle), fatty liver indices, and albuminuria while normalizing elevated ketone bodies without ketoacidosis. This study supports triple combination of empagliflozin, sitagliptin, and metformin therapy as a safe, effective strategy for durable glycemic control in treatment-naïve T2DM patients. [6]

Figure 1: A, B, and C show HbA1c reduction, FBG reduction, and PPG reduction over 24 months.

Empagliflozin+Sitagliptin+Metformin-Long-term Safety: A 90-week extension trial evaluating empagliflozin+sitagliptin+metformin in T2DM patients demonstrated sustained efficacy. In the empagliflozin 10 mg + metformin group (n=166 ) and Sitagliptin 100 mg + metformin group (n=56). Over 90 weeks, empagliflozin–metformin and sitagliptin–metformin demonstrated sustained glycemic control with small improvements in weight and blood pressure and maintained a consistent safety profile. [7]

When to Consider Triple Combination in Clinical Practice

The use of empagliflozin + sitagliptin + metformin is guided by clinical scenarios where addressing multi-pathway pathophysiological interventions support aggressive and more durable glycemic control with cardio-renal-metabolic protective benefits (Table 1). [5,8,9,10]

Table 1: Triple Combination Therapy: Clinical Scenarios and Benefits

Guideline Insights

Major international and Indian guidelines increasingly support early combination therapy to accelerate glycemic control, mitigate glucotoxicity, and address cardio-renal risk from the outset (Table 2).

Table 2: Guidelines Insights on Combination Therapy

Key Takeaways

✔ Indian T2DM patients exhibit a disproportionately high cardiometabolic burden, indicating the need for early, multi-targeted therapy to overcome therapeutic inertia, preserve β-cell function, and improve long-term cardio-renal outcomes.

✔ Triple therapy with empagliflozin+sitagliptin+metformin provides comprehensive gluco-metabolic and cardio-renal benefits, without severe hypoglycemia.

✔ Guidelines endorse early combination therapy for patients with HbA1c ≥9%, persistent inadequate control, or high-risk phenotypes such as CKD, ASCVD, heart failure, or obesity.

Abbreviations: ADA – American Diabetes Association, AACE – American Association of Clinical Endocrinology, AGIs – Alpha-Glucosidase Inhibitors, ASCVD – Atherosclerotic Cardiovascular Disease, BP – Blood Pressure, CKD – Chronic Kidney Disease, CV – Cardiovascular, DBP – Diastolic Blood Pressure, DPP-4i – Dipeptidyl Peptidase-4 Inhibitor, eGFR – Estimated Glomerular Filtration Rate, FPG – Fasting Plasma Glucose, GLP-1 RA – Glucagon-Like Peptide-1 Receptor Agonist, GIP RA – Glucose-Dependent Insulinotropic Polypeptide Receptor Agonist, HF – Heart Failure, HDL – High-Density Lipoprotein, IDF – International Diabetes Federation, KDA – Korean Diabetes Association, MASLD – Metabolic Dysfunction–Associated Steatotic Liver Disease, MetS – Metabolic Syndrome, RAS – Renin–Angiotensin System, RSSDI – Research Society for the Study of Diabetes in India, SBP – Systolic Blood Pressure, SGLT2i – Sodium–Glucose Cotransporter-2 Inhibitor, T2DM – Type 2 Diabetes Mellitus