SGLT2 and DPP-4 inhibitors have complementary mechanisms of action that can potentially improve glucose control with weight loss and low risk of hypoglycaemia. We compared the efficacy and safety of dual add-on of saxagliptin (SAXA) and dapagliflozin (DAPA) to SAXA and DAPA alone. In this 24-week, multicenter, randomized, double-blind, active-controlled trial, adults with type 2 diabetes (T2D) and A1C ≥8.0% and ≤12.0%, received SAXA 5 mg and DAPA 10 mg once daily compared to SAXA and placebo (PBO) or DAPA and PBO on background of metformin XR ≥1500 mg/d. Primary end point was the change in A1C from baseline to week 24. Safety and tolerability assessments included adverse events (AEs) and hypoglycaemia. 534 patients were randomized. Mean ± SD A1C at baseline in SAXA+DAPA, SAXA+PBO, and DAPA+PBO groups was 8.9 ± 1.2%, 9.0 ± 1.1%, and 8.9 ± 1.2%, respectively. Adjusted reduction from baseline in A1C was -1.47% in SAXA+DAPA compared to -0.88% in SAXA+PBO (difference −0.59%; 95% CI [-0.81, -0.37]; P<0.0001) and -1.20% in DAPA+PBO (difference −0.27%; 95% CI [-0.48, -0.05]; P<0.02). The adjusted proportion achieving A1C <7% was 41% in SAXA+DAPA compared to 18% in SAXA+PBO (difference of 23%; 95% CI [15, 32]) and 22% in DAPA+PBO (difference of 19%; 95% CI [10, 28]). AEs occurred in 48.6%, 52.8% and 48.6% in SAXA+DAPA, SAXA+PBO and DAPA+PBO, respectively. Urinary and genital infections occurred with the expected frequency previously reported. Incidence of hypoglycaemia was 1.1%, 0.6% and 1.1%, respectively with no episodes of major hypoglycaemia. In conclusion, this first report of triple therapy adding a well-tolerated combination of DPP-4 and SGLT2 inhibitors to poorly controlled metformin-treated T2D demonstrated that the combination of SAXA and DAPA had greater improvements in glucose control than each component alone, bringing >40% of poorly controlled T2D to goal, with weight loss as DAPA alone and very low hypoglycaemia risk.
Disclosure: J. Rosenstock: Advisory Panel; Author; Sanofi, Novo Nordisk, Inc., Eli Lilly and Company, GlaxoSmithKline, Takeda Pharmaceuticals U.S.A., Inc., Merck, Daiichi-Sankyo, Inc., Janssen Pharmaceuticals, Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., MannKind Corporation, Halozyme Therapeutics, Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc.. Research Support; Author; Merck, Pfizer, Inc., Sanofi, Novo Nordisk, Inc., Roche Pharmaceuticals, Bristol-Myers Squibb Company, Eli Lilly and Company, GlaxoSmithKline, Takeda Pharmaceuticals U.S.A., Inc., Novartis Pharmaceuticals Corporation, Amylin Pharmaceuticals, Inc., AstraZeneca Pharmaceuticals LP, Janssen Pharmaceuticals, Daiichi-Sankyo, Inc., MannKind Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc. L. Hansen: Employee; Author; Bristol-Myers Squibb Company. P. Zee: Employee; Author; Bristol-Myers Squibb Company. Y. Li: Employee; Author; Bristol-Myers Squibb Company. W. Cook: Employee; Author; AstraZeneca Pharmaceuticals LP. B. Hirshberg: Employee; Author; AstraZeneca Pharmaceuticals LP. N. Iqbal: Employee; Author; Bristol-Myers Squibb Company.