Randomized, Double-Blind Trial of Triple Therapy With Saxagliptin Add-on to Dapagliflozin Plus Metformin in Patients With Type 2 Diabetes

Abstract

OBJECTIVEThe objective of this study was to assess the efficacy and safety of triple therapy with saxagliptin add-on versus placebo add-on to dapagliflozin plus metformin in adults with type 2 diabetes. RESEARCH DESIGN AND METHODSPatients on stable metformin ( ‡1,500 mg/day) for ‡8 weeks with glycated hemoglobin (HbA 1c ) 8.0-11.5% (64-102 mmol/mol) at screening received open-label dapagliflozin (10 mg/day) plus metformin immediate release (IR) for 16 weeks. Patients with inadequate glycemic control (HbA 1c 7-10.5% [53-91 mmol/mol]) were then randomized to receive placebo (n = 153) or saxagliptin 5 mg/day (n = 162) in addition to background dapagliflozin plus metformin IR. The primary efficacy end point was change in HbA 1c from baseline to week 24. RESULTSThere was a significantly greater reduction in HbA 1c at 24 weeks with saxagliptin add-on (-0.51% [-5.6 mmol/mol]) versus placebo (-0.16% [-1.7 mmol/mol]) addon to dapagliflozin plus metformin (difference, -0.35% [95% CI -0.52% to -0.18%] and -3.8 [-5.7 to -2.0 mmol/mol], respectively; P < 0.0001). Reductions in fasting plasma glucose and 2-h postprandial glucose were similar between treatment arms. A larger proportion of patients achieved HbA 1c <7% (53 mmol/mol) with saxagliptin add-on (35.3%) versus placebo add-on (23.1%) to dapagliflozin plus metformin. Adverse events were similar between treatment groups. Episodes of hypoglycemia were infrequent in both treatment arms, and there were no episodes of major hypoglycemia. CONCLUSIONSTriple therapy with the addition of saxagliptin to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA 1c in patients with type 2 diabetes inadequately controlled with dapagliflozin plus metformin.

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

“…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.…”

Qtern: DPP-4 and SGLT2 inhibitor combination for type 2 diabetes

“…The proportion of patients with good glycaemic control (<53mmol/ mol; <7%) was significantly greater, and fasting and postprandial glucose were significantly reduced, with the addition of dapagliflozin (in the trial in which glycaemic control was worse overall) 4 but not when saxagliptin was added. 3 After a further 28 weeks' treatment, the differences in glycaemic control were maintained (see Figure 1). 5,6 The proportion of patients requiring additional treatment if HbA1c exceeded 64mmol/ mol (8%) or who discontinued treatment was lower with saxagliption or dapagliflozin add-on therapy than with placebo (19 vs 28% 5 and 21 vs 48% 6 ).…”

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

“…Adding a DPP-4 inhibitor to metformin/SGLT2 inhibitor was not associated with an increase in the frequency of adverse events in phase 3 trials. 10,13 Urinary tract infection was slightly but consistently more frequently reported with add-on linagliptin (8-10% vs 5-6% with placebo) or add-on saxagliptin (5% vs 4%); hypoglycaemia was rare.…”

“…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. 10 These data should be interpreted cautiously. This use of a DPP-4/SGLT2 inhibitor combination does not match the indication approved for therapeutic use (which would mean that patients were already established on treatment with one of the component drugs and metformin before receiving the combination).…”

“…11,12 Adding an SGLT2 inhibitor to metformin/DPP-4 inhibitor is also associated with a small reduction in blood pressure of about 1.0-2.5mmHg above the effect of placebo for systolic and diastolic pressures 11,12 but there is little impact when a DPP-4 inhibitor is the third drug added. 10,13 These trials did not report the effects on glycaemic control according to baseline HbA 1C but, according to regulatory reviews, adding empagliflozin to metformin/linagliptin was more effective in patients with higher pretreatment HbA 1C 14 whereas adding saxagliptin to metformin/dapagliflozin had limited effect in patients with high HbA 1C (defined as ≥75mmol/mol, ≥9%). 15 However, patients in the linagliptin/empagliflozin study had better baseline glycaemic control than those in the saxagliptin/ dapagliflozin study, suggesting that comparison between the trials is inappropriate.…”