Introduction

Continuous glycemic control is a core component of diabetes management in individuals affected with type-2 diabetes mellitus (T2DM). Patients who do not achieve adequate glycemic control while on monotherapy are treated with a combination of antihyperglycemic agents. Empagliflozin, a selective sodium glucose cotransport-2 inhibitor (SGLT-2i) has demonstrated synergistic impact on glycemic control when combined with other antihyperglycemic agents. 

Aim

To determine the efficacy and safety of empagliflozin 10 and 25 mg compared to placebo as add-on treatment for patients with T2DM, uncontrolled after ≥8 weeks of treatment with metformin and sitagliptin.

Patient Profile

• Patients with T2DM and having glycosylated hemoglobin (HbA1c) levels 7%–10% and body mass index (BMI) of 18.5–40 kg/m² (age ≥19 years & ≤ 85 years; N=172). 
• The study subjects were receiving sitagliptin and metformin at the start of the trial.

Methods

Study Design

Treatment Strategy

• Patients receiving metformin at a dose of ≥1000 mg in combination with sitagliptin 100 mg without a change in dose for at least 8 weeks entered a 2-week single-blind run-in period. 
• After the run-in period, eligible patients were randomised 1:1:1 to empagliflozin 10 mg add-on group, empagliflozin 25 mg add-on group, or placebo add-on group.

Outcomes

Primary Outcome

Secondary & Exploratory Outcomes

• Change in HbA1c and fasting plasma glucose (FPG) from baseline to week 52.
• Proportion of patients achieving HbA1c <7% and 6.5% from baseline to week 24 and week 52.
• Change in body weight, waist circumference, and urine albumin to creatinine ratio (UACR) and the resolution rate of metabolic syndrome at week 24 and 52.

Safety Outcomes

Results

• A total of 162 patients completed the 24-week study period, the safety analysis set and the full analysis set (FAS) included 171 patients each. Of the 162, patients, 158 entered the extension phase of the trial. The extension period safety analysis set included 157 patients, and the FAS included 154 patients. 
• Mean age of the study subjects was 60.4 years, and 63.7% of them were men. The mean duration of diabetes was 134.3 months, the mean HbA1c was 7.8% and mean FPG was 152.1 mg/dL. The mean BMI for the study subjects was 25.5 kg/m² and waist circumference (WC) was 89.8 cm. The baseline characteristics, including presence of major chronic diseases (hypertension and dyslipidemia) were balanced in the study groups. 
• After 24 weeks of treatment, patients treated with empagliflozin 10 mg and 25 mg had significantly lower HbA1c levels as compared to those treated with placebo -0.7% and -0.8%, respectively (both p <.0001)). The decrease in HbA1c levels with empagliflozin 10 mg and 25 mg was maintained till 52 weeks (mean change from baseline to week 52: -0.7% each). Patients who switched from placebo to empagliflozin 10 mg during the extension period, showed a mean change -0.6% in HbA1c level. This was similar to the glycemic improvement observed in the empagliflozin 10 mg group during the treatment period.  
• The decrease in mean HbA1c levels was similar between the patients treated with empagliflozin 10 and 25 mg. Nevertheless, amongst the subgroup of patients with a baseline HbA1c ≥8.5%, empagliflozin 25 mg showed numerically greater reductions in HbA1c, as compared to empagliflozin 10 mg at both week 24 (empagliflozin 25 mg: -1.5%, empagliflozin 10 mg: -1.1%) and week 52 (empagliflozin 25 mg: -1.6%, empagliflozin 10 mg: -0.8%). The differences did not reach statistical significance. 
• Fasting plasma glucose levels decreased significantly in both empagliflozin groups, as compared to the placebo group (-32.2 mg/dL and -32.6 mg/dL; both p <.0001). 
• A greater proportion of patients treated with empagliflozin 10 mg and 25 mg reached HbA1c <7% or <6.5% after 24 weeks, as compared to those treated with placebo (both p <0.05) (Fig. 1). 

Fig. 1: Proportion of patients achieving the specified HbA1c thresholds

                 

• The findings from the per-protocol set (PPS) analysis were consistent with the FAS analysis, with statistically significant reductions in HbA1c and FPG. Moreover, a higher proportion of patients achieved the target HbA1c level in the empagliflozin 10 mg and 25 groups compared with the placebo group (all p <0.05). The improvements were sustained in the empagliflozin groups during the extension period.
• Patients treated with empagliflozin 10 mg and 25 mg showed significantly greater reductions in body weight and waist circumference at week 24 and 52 compared to baseline. Patients treated with empagliflozin 10 mg and 25 mg had significantly greater reductions in body weight at week 24, as compared to those treated with placebo (Table 1).
• As per a subgroup analysis, empagliflozin reduced body weight in patients with BMI ≥25 kg/m² and those with BMI <25 kg/m², with a greater reduction observed in patients with BMI ≥25 kg/m².
• Additionally, the urinary albumin to creatinine ratio (UACR) tended to increase in the placebo group, in contrast, the same decreased in the patients treated with empagliflozin (Table 1). 

Table 1: Mean change in body weight, waist circumference, & UACR during the study period

	Empagliflozin 10 mg		Empagliflozin 25 mg		Placebo to Empagliflozin 10 mg
	Δ Week 24	Δ Week 52	Δ Week 24	Δ Week 52	Δ Week 24	Δ Week 24
Body weight (kg)	-3.0 (2.1)b, d	-2.8 (1.5)b	-2.9 (2.4)b, d	-2.8 (2.5)b	-0.4 (1.8)	-2.6 (2.2)b
Waist circumference (cm)	-2.7 (2.9)b, c	-2.9 (3.0)b	-2.1 (2.7)b	-2.3 (2.3)b	-1.2 (3.2)a	-3.0 (3.3)b
UACR (mg/g)	-8.7 (62.0)	-16.9 (55.2)a	-19.9 (83.0)c	-30.6 (144.2)a	6.1 (24.5)	29.1 (181.9)

Significant change from baseline (^ap <.05, ^bp <.0001), significant change compared to placebo group (^cp <.05, ^dp <.0001).

Abbreviations: △, change from baseline; UACR, urine albumin-to-creatinine ratio.

Conclusions

• Addition of empagliflozin to sitagliptin and metformin was associated with improvement in glycemic parameters in Korean patients with T2DM inadequately controlled on dual therapy.
• Beyond glycemic control, empagliflozin therapy was associated with improvements in renal parameters, reduction in body weight, and favorable changes in metabolic syndrome indicators.
• The combination of metformin, sitagliptin, and empagliflozin represents a treatment approach addressing multiple metabolic parameters in the management of T2DM.

Diabetes Obes Metab. 2026;28:2027–2037.