Efficacy and safety of dapagliflozin plus saxagliptin versus insulin glargine over 52 weeks as add-on to metformin with or without sulphonylurea in patients with type 2 diabetes: A randomized, parallel-design, open-label, Phase 3 trial

Abstract

Aim: Efficacy and safety of dapagliflozin plus saxagliptin (DAPA + SAXA) were compared with insulin glargine (INS) in patients with type 2 diabetes (T2D) in a 52-week extension study.

Materials and methods: This international Phase 3 study randomized adults with T2D on metformin with/without sulphonylurea. They received DAPA + SAXA or INS for 24 weeks (short-term) with a 28-week (long-term) extension. Week 52 exploratory endpoints included adjusted mean change from baseline in glycated haemoglobin A_1c (HbA1c) and body weight, and a proportion of patients achieving optimal glycaemic response without hypoglycaemia and without requiring rescue medication.

Results: Of the 1163 patients enrolled, 643 received treatment; 600 (DAPA + SAXA, 306; INS, 294) entered the long-term phase. At 52 weeks, HbA1c [adjusted least squares (LS) mean; 95% confidence interval (CI)] decreased more with DAPA + SAXA (-1.5% [-1.6%, -1.4%]) than with INS (-1.3% [-1.4%, -1.1%]); the LS mean difference (95% CI) was -0.25% (-0.4%, -0.1%; P = 0.009). Total body weight reduced with DAPA + SAXA [LS mean (95% CI): -1.8 kg (-2.4, -1.3)] and increased with INS [LS mean (95% CI): +2.8 kg (2.2, 3.3)]. More patients on DAPA + SAXA (17.6%) achieved HbA1c <7.0% without hypoglycaemia versus those on INS (9.1%). Rescue medication was required by 77 patients (23.8%) and 97 patients (30.4%) in the DAPA + SAXA and INS groups, respectively.

Conclusion: DAPA + SAXA treatment was non-inferior to INS in reducing HbA1c and body weight, and in achieving optimal glycaemic control without hypoglycaemia in patients with T2D 52 weeks after initiation.

Keywords: combination therapy; dapagliflozin; insulin glargine; saxagliptin; type 2 diabetes.

Figure 1

Study design. *Additional visits only for patients participating in the CGM substudy. ^#Increase in the daily dose of insulin (based on FPG and SMBG values) at weeks 8 and 12 was at the discretion of the investigator. The goal was to reach an acceptable and stable dose by week 12. After week 12, patients with confirmed central laboratory‐measured FPG values >200 mg/dL (11.1 mmol/L) were eligible for open‐label rescue medication (including further uptitration of daily dose of insulin). DAPA + SAXA, DAPA (10 mg/day) + SAXA (5 mg/day) + metformin ± SU; INS, INS (100 U/mL/day) + metformin ± SU. Abbreviations: CGM, continuous glucose monitoring; DAPA, dapagliflozin; FPG, fasting plasma glucose; INS, insulin glargine; SAXA, saxagliptin; SMBG, self‐monitored blood glucose; SU, sulphonylurea

Figure 2

Patient disposition. *Number of patients receiving metformin + SU = 166, number of patients receiving metformin – SU = 158. ^#Number of patients receiving metformin + SU = 165, number of patients receiving metformin – SU = 154. DAPA + SAXA, DAPA (10 mg/day) + SAXA (5 mg/day) + metformin ± SU. INS, INS (100 U/mL/day) + metformin ± SU. Abbreviations: DAPA, dapagliflozin; INS, insulin glargine; N, total number of patients in the group; n, number of patients analysed; SAXA, saxagliptin; SU, sulphonylurea

Figure 3

A, Percentage change from baseline in HbA1c over 52 weeks. Week 0 refers to the baseline value. Baseline is defined as patients in the randomized patient data set with non‐missing baseline assessment and at least one post‐baseline assessment. HbA1c assessments, collected after initiation of rescue treatment or collected more than 8 days after the last dose in the short‐term plus long‐term open‐label treatment period, were excluded from the analysis. n, number of patients. B, Change in BW from baseline over 52 weeks. Week 0 refers to the baseline value. Baseline is defined as patients in the randomized patient data set with non‐missing baseline assessment and at least one post‐baseline assessment. BW assessments, collected after initiation of rescue treatment or collected more than 8 days after the last dose in the short‐term plus long‐term open‐label treatment period, were excluded from the analysis. n, number of patients. C, Proportion of patients achieving adjusted optimal glycaemic response (HbA1c <7%) without hypoglycaemia at week 52. Percentages calculated on the randomized subject data set. *Patients with unknown status at week 52 and patients given rescue medication before week 52 were treated as non‐responders for the endpoint. ^#Based on the logistic regression method with adjustment for baseline HbA1c and randomization stratification factor (background medication of metformin ± SU). ^†Based on the logistic regression method with adjustment for baseline HbA1c (background medication of metformin ± SU and treatment by randomization stratification factor interaction). n, number of patients with an event of optimal glycaemic response at week 52. D, Proportion of patients requiring rescue or discontinuation due to lack of glycaemic control at week 52. Percentages calculated on the randomized subject data set. *Patients with unknown status at week 52 and patients given rescue medication before week 52 were treated as non‐responders for the endpoint. ^#Based on the logistic regression method with adjustment for baseline HbA1c and randomization stratification factor (background medication of metformin ± SU). n, number of patients needing rescue or discontinuation at week 52. DAPA + SAXA, DAPA (10 mg/day) + SAXA (5 mg/day) + metformin ± SU; INS, titrated INS (100 U/mL/day) + metformin ± SU. Abbreviations: BW, body weight; CI, confidence interval; DAPA, dapagliflozin; HbA1c, glycated haemoglobin; INS, insulin glargine; N, total number of patients in the treatment group; OR, odds ratio; SAXA, saxagliptin; SU, sulphonylurea