Sustained 52‐week efficacy and safety of triple therapy with dapagliflozin plus saxagliptin versus dual therapy with sitagliptin added to metformin in patients with uncontrolled type 2 diabetes

Abstract

Aims To compare the efficacy and safety of an intensification strategy of early triple combination therapy with dapagliflozin (DAPA) plus saxagliptin (SAXA) to a dual therapy strategy with sitagliptin (SITA) in patients with type 2 diabetes who are inadequately controlled with metformin (MET) monotherapy. Materials and methods This multinational, active‐controlled, parallel‐group phase 3b trial randomized 461 patients, at least 18 years of age, with glycated haemoglobin (HbA1c) of 8%–10.5% (64–91 mmol/mol), to either DAPA plus SAXA or SITA, added to MET, for a 26‐week double‐blind treatment period and an extension of a 26‐week blinded treatment period. Results Mean (± SD) baseline HbA1c was 8.8% ± 0.9% (73.0 ± 9.3 mmol/mol). DAPA plus SAXA (n = 232) provided a greater reduction from baseline in HbA1c at Weeks 26 and 52 compared with SITA (n = 229) (adjusted mean ± SE change, Week 26: −1.41 ± 0.07% vs −1.07 ± 0.07% [−15.4 ± 0.8 mmol/mol vs 11.7 ± 0.8 mmol/mol]; P = 0.0008; Week 52: −1.29 ± 0.08% vs −0.81 ± 0.09% [14.1 ± 0.9 mmol/mol vs 8.9 ± 1.0 mmol/mol]). The between‐group difference in adjusted mean (95% CI) change from baseline in HbA1c increased from −0.34 (−0.54, −0.14) at Week 26 to −0.48 (−0.71, −0.25) at Week 52. DAPA plus SAXA was generally well tolerated and the incidence of adverse events was similar in both treatment arms. Conclusions Early intensification to triple therapy with DAPA plus SAXA results in better, more durable glycaemic control than addition of SITA only (dual therapy) in patients with high HbA1c levels who are uncontrolled with MET monotherapy.

Efficacy of dapagliflozin versus sitagliptin on cardiometabolic risk factors in Japanese patients with type 2 diabetes: a prospective, randomized study (DIVERSITY-CVR)

“…Taken together, these data suggest that dapagliflozin might indeed be superior to sitagliptin for the cardiometabolic effects. In addition, previous studies reported the preferable cardiometabolic effects regarding SGLT2 inhibitors [36][37][38][39]. Dapagliflozin also showed stronger therapeutic effects on other indices that might contribute to the prevention of cardiovascular events.…”

DPP-4 Inhibition and the Path to Clinical Proof

“…This combination has been suggested as a potential early glucose-lowering treatment of type 2 diabetes due to their complementing mechanism of action (142). Clinical studies have also verified augmented glucose-lowering action of this combination in association with low risk for hypoglycemia (115, 143, 144).…”

Rationale for the Early Use of Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Type 2 Diabetes

“…A PubMed search conducted in July 2019 identified 15 studies in which SGLT-2 inhibitors were used early in the course of T2D [64, 85–97]. Ten studies evaluated dapagliflozin [64, 85–89, 91, 93, 94, 98], two studied canagliflozin [90, 97], two assessed empagliflozin [92, 96], and one evaluated ertugliflozin [95]. Seven studies investigated SGLT-2 inhibitors as monotherapy [85–90, 98], while, in eight studies, SGLT-2 inhibitors were given in combination with metformin (Table 2) [64, 91–97].…”

“…Two studies have also demonstrated that the magnitude of the change in HbA1c with an SGLT-2 inhibitor, with or without metformin, was similar in treatment-naive patients as in patients who had already received metformin [92] or insulin with metformin, pioglitazone, or rosiglitazone [86]. In a study of patients with T2D receiving stable metformin therapy, early addition of dapagliflozin plus saxagliptin was associated with a significantly greater reduction in HbA1c after 26 weeks compared with addition of sitagliptin ( p = 0.0008); the between-group difference in HbA1c reduction increased at 52 weeks [93]. Similarly, in the 52-week Evaluation of Ertugliflozin Efficacy and Safety Factorial (VERTIS FACTORIAL) study, significantly greater HbA1c reductions were observed with the combination of ertugliflozin plus sitagliptin as add-on therapy to metformin versus those with either agent individually after 26 weeks of treatment ( p < 0.001), with sustained HbA1c reductions at 52 weeks [95].…”