Novel triple-drug FDC superior to dual combination in type 2 diabetes patients poorly controlled with metformin

"Our findings provide evidence for considering triple FDC of dapagliflozin + sitagliptin + metformin ER as an alternative option with minimal risk of weight gain and hypoglycemia while considering oral triple-combination therapy for patients to achieve their glycemic target," the researchers wrote in their study published in Advances in Therapy.

Type 2 diabetes is a progressive disease in which microvascular and macrovascular complications and mortality risks are strongly associated with hyperglycemia. Achieving glycemic control remains the treatment's primary goal to prevent these complications. Estimates in 2019 revealed that 77 million people had diabetes in India, which is expected to increase to over 134 million by 2045. Considering the disease's progressive nature, many guidelines recommend dual or triple drug therapy based on HbA1c (glycated haemoglobin) level.

Using FDC helps in improving therapy compliance and can provide optimum therapeutic benefits. Mechanisms of action of sodium–glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase 4 (DPP4) inhibitors are complementary to metformin with low hypoglycemia risk. Studies have shown the beneficial effects of adding both SGLT2 inhibitors and DPP4 inhibitors after metformin monotherapy.

Rakesh K. Sahay, Osmania General Hospital, Hyderabad, India, and colleagues aimed to compare the safety and efficacy of triple-drug FDC of sitagliptin (SITA) + dapagliflozin (DAPA) + metformin (MET) extended-release (ER) with DAPA + MET ER and h SITA + MET sustained release (SR) in type 2 diabetes patients poorly controlled with metformin in phase 3, randomized, open-label, active-controlled study.

The study included patients with HbA1c ≥ 8% (64 mmol/mol) and ≤ 11% (97 mmol/mol). They were randomized in the ratio of 1:1:1 to receive either once-daily FDC of DAPA + SITA + MET ER (10 mg + 100 mg + 1000 mg) tablets (n = 137) or co-administration of SITA + MET SR (100 mg + 1000 mg) tablets once daily (n = 139) or FDC of DAPA + MET ER (10 mg + 1000 mg) tablets once daily (n = 139). The primary endpoint was a mean change in HbA1c from baseline to week 16.

The authors reported the following findings:

• The mean baseline HbA1c was approximately 9% (75 mmol/mol) in each treatment group.
• At week 16, the adjusted mean reduction in HbA1c from baseline was significantly more significant with DAPA + SITA + MET ER (− 1.73%) compared to SITA + MET SR (− 1.28%) and DAPA + MET ER (− 1.33%; difference − 0.4%).
• At week 12, the reduction in HbA1c from baseline was significantly more significant with DAPA + SITA + MET ER compared to SITA + MET SR and DAPA + MET ER.
• At week 16, DAPA + SITA + MET ER showed a significant reduction in postprandial blood glucose compared to DAPA + MET ER and a significant decrease in fasting blood glucose with DAPA + SITA + MET ER compared to SITA + MET SR.
• The proportion of patients achieving HbA1c < 7.0% at week 16 was significantly higher with DAPA + SITA + MET ER (38.5%) versus SITA + MET SR (12.8%) and DAPA + MET ER (21.3%). All study medications were well tolerated.

"Triple FDC of once daily DAPA + SITA + MET ER tablets was significantly better in achieving glycemic control than dual combination once daily in type 2 diabetes patients poorly controlled with metformin without any significant safety concerns," the researchers concluded.

Reference:

Sahay, R.K., Giri, R., Shembalkar, J.V. et al. Fixed-Dose Combination of Dapagliflozin + Sitagliptin + Metformin in Patients with Type 2 Diabetes Poorly Controlled with Metformin: Phase 3, Randomized Comparison with Dual Combinations. Adv Ther (2023). https://doi.org/10.1007/s12325-023-02523-z