Dual Add-on Therapy in Type 2 Diabetes Poorly Controlled With Metformin Monotherapy: A Randomized Double-Blind Trial of Saxagliptin Plus Dapagliflozin Addition Versus Single Addition of Saxagliptin or Dapagliflozin to Metformin

Abstract

OBJECTIVEThis study compared the efficacy and safety of dual add-on of saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone in patients with type 2 diabetes poorly controlled with metformin. RESEARCH DESIGN AND METHODSThis was a double-blind trial in adults with HbA 1c ‡8.0% and £12.0% (64-108 mmol/mol), randomized to saxagliptin (SAXA) (5 mg/day) plus dapagliflozin (DAPA) (10 mg/day; n = 179), or SAXA (5 mg/day) and placebo (n = 176), or DAPA (10 mg/day) and placebo (n = 179) on background metformin extended release (MET) ‡1,500 mg/day. Primary objective compared changes from baseline in HbA 1c with SAXA+DAPA+MET versus SAXA+MET and DAPA+MET. RESULTSPatients had a mean baseline HbA 1c of 8.9% (74 mmol/mol), diabetes duration of 7.6 years, and a BMI of 32 kg/m 2 . At week 24, the adjusted mean change from the baseline HbA 1c was -1.5% (-16.1 mmol/mol) with SAXA+DAPA+MET versus -0.9% (-9.6 mmol/mol) with SAXA+MET (difference 20.59% [-6.4 mmol/mol], P < 0.0001) and -1.2% (-13.1 mmol/mol) with DAPA+MET (difference 20.27% [3.0 mmol/mol], P < 0.02). The proportion of patients achieving HbA 1c <7% (53 mmol/mol) was 41% with SAXA+DAPA+MET versus 18% with SAXA+MET and 22% with DAPA+MET. Urinary and genital infections occurred in £1% of patients receiving SAXA+DAPA+MET. Hypoglycemia was infrequent, with no episodes of major hypoglycemia. CONCLUSIONSIn this first report of adding a well-tolerated combination of saxagliptin plus dapagliflozin to background metformin therapy in patients poorly controlled with metformin, greater improvements in glycemic control were obtained with triple therapy by the dual addition of saxagliptin and dapagliflozin than dual therapy with the addition of saxagliptin or dapagliflozin alone.

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

“…The reduction in body weight was greater with the triple therapy than with metformin plus saxagliptin but not than the reduction seen with metformin plus dapagliflozin. Even if the objective was not to compare metformin plus saxagliptin versus metformin plus dapagliflozin, it appears that the difference in blood glucose control was greater when the triple therapy was compared with the dual therapy metformin + saxagliptin than when compared with the dual therapy metformin plus dapagliflozin [27].…”

“…A double-blind trial randomised adults with poorly controlled T2D on background metformin to saxagliptin 5 mg/day plus dapagliflozin 10 mg/day, or saxagliptin 5 mg/day and placebo, or dapagliflozin 10 mg/day and placebo [27]. As a primary objective, changes from baseline in HbA1c were compared with the triple therapy versus each dual therapy at week 24.…”

“…Pharmacokinetic interactions: [25,33] Clinical trials: [27,28,29,35,36] Article highlights box -Type 2 diabetes (T2D) often requires the combination of several medications with complementary actions to reach glucose control targets while limiting side effects -The combination of a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGLT2i) is an attractive approach for the management of T2D.…”

Empagliflozin/linagliptin single‐tablet combination: first‐in‐class treatment option

“…In patients on metformin, 24‐week treatment with the dapagliflozin 10 mg/saxagliptin 5 mg (D10/S5) combination significantly reduced HbA1c compared with the respective mono‐treatments (Table 3) 14. Adjusted mean (SE) change in HbA1c was −1.47% (0.08) [mean (SD) baseline, 8.93% (1.19)].…”

DPP‐4/SGLT2 inhibitor combined therapy for type 2 diabetes

“…8 Furthermore, a second comparison showed that adding saxagliptin/dapagliflozin to metformin improved beta-cell function more than adding saxagliptin alone. 9 A similar study comparing linagliptin/empagliflozin, empagliflozin, and linagliptin as add-on therapy to metformin found that the linagliptin/empagliflozin combination reduced fasting plasma glucose significantly more than its components; postprandial glucose was not reported.…”