Study on Triple Fixed-Dose Combination for Type 2 Diabetes

An approach of using a once-daily triple fixed-dose combination of dapagliflozin, sitagliptin, and metformin ER (extended-release) in Indian type 2 diabetes patients poorly controlled with metformin alone showed greater reductions in glycated Hemoglobin (HbA1c) and a higher proportion of patients achieving glycemic control; without increased risk of hypoglycemia and weight gain compared to the conventional once-daily dual combinations of Sitagliptin and Metformin ER or Dapagliflozin and Metformin SR (sustained-release), a study published on Advances in Therapy has reported.

The study, designed in a 16-week, multicenter, randomized, three-arm, open-label, active-controlled, parallel-group, phase 3 clinical study, enrolled 415 Indian T2D patients poorly controlled on Metformin monotherapy with glycated hemoglobin (HbA1c) ≧8% and ≦11%, and was conducted across 15 sites in India. The primary objective of the study was to compare the reduction in HbA1c from baseline to week 16 with dapagliflozin, sitagliptin, and metformin ER compared to Sitagliptin and Metformin SR and Dapagliflozin and Metformin ER. The mean baseline HbA1c was approximately 9% in each treatment group.

Patients were randomized to receive either the FDC (fixed-dose combination) of Dapagliflozin (10mg), Sitagliptin (100mg), and Metformin (1000mg) ER tablets once daily (N=137), or co-administration of Sitagliptin (100mg) and Metformin (1000mg) tablets once daily (N=139) or Dapagliflozin (10mg) and Metformin (1000mg) tablets once daily (N=139). The key results of the study are as follows:

Effect on Glycated Hemoglobin (HbA1c) Levels

The adjusted mean reduction in HbA1c at week 16 was significantly greater with Dapagliflozin, Sitagliptin, and Metformin ER (-1.73% [-19.0 mmol/mol]) compared to sitagliptin and metformin SR (-1.28% [-14.1mmol/mol]; difference of -0.46% [-5.1 mmol/mol], p<0.001) and Dapagliflozin and Metformin ER (-1.33% [-14.6 mmol/mol]; difference -0.4% [4.4mmol/mol], p<0.001). (Refer Figure 1)

At week 12, the reduction in HbA1c from baseline was significantly greater with Dapagliflozin, Sitagliptin, and Metformin ER compared to Sitagliptin and Metformin SR (-1.15±0.87 vs -0.85±0.70, p=0.0006) and Dapagliflozin and Metformin ER (-1.15±0.87 vs -0.94±0.73, p=0.0276).

The triple combination of Dapagliflozin, Sitagliptin, and Metformin ER also significantly reduced HbA1c in the subgroup population (baseline HbA1c >9%) at 12 weeks compared to Sitagliptin and Metformin SR (-1.50±0.92 vs -1.03±0.61, p=0.0007) and Dapagliflozin and Metformin ER (-1.16±0.80, p=0.0169). Among this subgroup population, Dapagliflozin, Sitagliptin, and Metformin ER also reduced the HbA1c greater than Sitagliptin and Metformin SR (-2.18±0.97 vs -1.46±0.73, P<0.001) and Dapagliflozin and Metformin ER (-1.53±0.79, P<0.001) at 16 weeks. (Refer Figure 2)

CI=confidence interval, Dapa=dapagliflozin, ER=extended release, FDC=fixed dose combination, HbA1c=glycated hemoglobin, Met=Metformin, Sita=Sitagliptin, SR=sustained release. Mixed model for repeated measures included change in HbA1c as the dependent variable, treatment, visit, and treatment-by-visit interactions as fixed effects, and baseline HbA1c as a covariate.

The difference between treatment groups at the endpoints was estimated from least square (LS) means and the accompanying p-value and two-sided 95% CI.

Figure 1: Adjusted mean (95% CI) change in HbA1c (%) from baseline to week 16. Adapted from Sahay RK et al. Adv Ther. 2023 Jul;40(7):3227-3246

Dapa=dapagliflozin, ER=extended release, FDC=fixed dose combination, HbA1c=glycated hemoglobin, Met=Metformin, Sita=Sitagliptin, SR=sustained release.

Figure 2: Adjusted mean (95% CI) change in HbA1c (%) in the subgroup population (baseline HbA1c >9%) at week 12 and week 16. Adapted from Sahay RK et al. Adv Ther. 2023 Jul;40(7):3227-3246

Effect on Postprandial & Fasting Blood Glucose Levels

At week 16, Dapagliflozin, Sitagliptin, and Metformin ER showed a significant reduction in postprandial blood glucose compared to Sitagliptin and Metformin ER (-59.5±59.66 mg/dl vs -48±48.17 mg/dl, P=0.0696) and Dapagliflozin and Metformin ER (-44.5±40.73 mg/dl, P=0.0394).

Dapagliflozin, Sitagliptin, and Metformin ER also significantly reduced fasting blood glucose compared to Sitagliptin and Metformin SR at 16 weeks (-44.0±33.26 mg/dl vs -35.7±34.44 mg/dl, P=0.0226) and Dapagliflozin and Metformin ER (-36.4±30.76 mg/dl, P=0.0542).

Patients Achieving Target Glycemic Control

The proportion of patients achieving HbA1c <7.0% (53 mmol/mol) at week 16 was significantly higher with Dapagliflozin, Sitagliptin, and Metformin ER (38.5%) versus Sitagliptin and Metformin SR (12.8%) (p<0.001) and Dapagliflozin and Metformin ER (21.3%) (p=0.0023). (Refer Figure 3)

Dapa=Dapagliflozin, ER=extended release, FDC=fixed dose combination, HbA1c=glycated hemoglobin, Met=Metformin, Sita=Sitagliptin, SR=sustained release.

Figure 3: Proportion of patients achieving HbA1c <7% (53 mmol/mol) at week 16. Adapted from Sahay RK et al. Adv Ther. 2023 Jul;40(7):3227-3246

Effect on Weight

The mean reduction in body weight from baseline to week 16 was significantly greater in the Dapagliflozin, Sitagliptin, and Metformin ER group when compared with only Sitagliptin and Metformin SR (-0.69 ± 1.67 kgs versus -0.35 ± 1.56 kgs; p=0.0245).

Triple FDC of Dapagliflozin, Sitagliptin, and Metformin – Well-Tolerated Safety Profile

All drugs were well tolerated, and there were no clinically significant variations in systolic or diastolic blood pressure across treatment groups. During the study, no serious adverse events, fatalities, or severe or life-threatening treatment-emergent adverse events (TEAEs) were reported.

Guideline Recommendations on Triple Therapy for the Management of Type 2 Diabetes

The triple FDC treatment choice will be in accordance with various guidelines' recommendations. The ADA recommends that treatment intensification not be postponed for individuals who are not meeting treatment goals. The American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) and the American Association of Clinical Endocrinologists (AACE) recommendations also encourage the inclusion of a third non-insulin agent after weighing the benefits and risks of the new medicine. The ADA and the Research Society for the Study of Diabetes in India (RSSDI) guidelines recommend initiating combination therapy for patients with HbA1c [>1.5% above target]; whereas the AACE guidelines recommend dual or possibly triple-combination pharmacotherapy, usually including Metformin, for newly diagnosed people with T2D and an entry HbA1c [9.0% and/or >1.5% above target].

Reference

Sahay RK, Giri R, Shembalkar JV, Gupta SK, Mohan B, Kurmi P, Kumar SR, Sawardekar VM, Mishra A, Murthy LS, Arya VV, Sonawane AR, Soni PN, Gofne SK, Karnawat SR, Rajurkar MN, Patel PM, Lakhwani LK, Mehta SC, Joglekar SJ. 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 Jul;40(7):3227-3246. doi: 10.1007/s12325-023-02523-z. Epub 2023 May 31.