Long-term effects of dapagliflozin plus saxagliptin versus glimepiride on a background of metformin in patients with type 2 diabetes: Results of a 104-week extension to a 52-week randomized, phase 3 study and liver fat MRI substudy

Diabetes Obes Metab. 2022 Jan;24(1):61-71. doi: 10.1111/dom.14548. Epub 2021 Sep 28.


Aim: To report the results of a 104-week extension to a 52-week study in which dapagliflozin plus saxagliptin (DAPA+SAXA) improved glycaemic control, liver fat and metabolic variables compared with glimepiride (GLIM) in participants with type 2 diabetes (T2D) receiving background metformin.

Materials and methods: This extension to a 52-week global, multicentre, parallel-group, active-controlled, double-blind study (NCT02419612) continued randomized participants (1:1) on DAPA+SAXA (10/5 mg) plus placebo, or GLIM (1-6 mg) plus placebo, once daily. Eligible participants were aged ≥18 years, had T2D (glycated haemoglobin [HbA1c] 58.5-91.3 mmol/mol [7.5%-10.5%]), and a body mass index of 20.0 to 45.0 kg/m2 , and were receiving metformin (MET; ≥1500 mg/d). Key outcomes were: requirement for treatment intensification, based on HbA1c ≥53 mmol/mol (7%); achieving therapeutic glycaemic response; and changes in adipose tissue and liver fat on magnetic resonance imaging in a substudy.

Results: Overall, 382 participants entered and 338 completed the 104-week extension period (MRI substudy, n = 82). The need for treatment intensification during the 156-week period was lower for DAPA+SAXA+MET (37.0%) than GLIM+MET (55.6%; hazard ratio 0.52, 95% confidence interval [CI] 0.39-0.68; P < 0.001). At week 156, 21.4% of DAPA+SAXA+MET versus 11.7% of GLIM+MET participants achieved therapeutic glycaemic response (HbA1c <53 mmol/mol; odds ratio 2.1, 95% CI 1.23-3.42; P = 0.006). DAPA+SAXA+MET led to greater adjusted mean reductions from baseline in liver fat and visceral and subcutaneous adipose tissue volumes versus GLIM+MET at week 122 (least-squares mean difference from GLIM+MET -4.89%, -0.41 L and -0.44 L, respectively; nominal P values ≤ 0.008). Safety was consistent with that of the monocomponents.

Conclusions: Overall, glycaemic control, metabolic benefits and efficacy were better maintained with DAPA+SAXA+MET than with GLIM+MET in T2D.

Keywords: DPP-4 inhibitor; dapagliflozin; liver; phase III study; sulphonylureas; type 2 diabetes.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives
  • Adipose Tissue / diagnostic imaging
  • Adolescent
  • Adult
  • Benzhydryl Compounds / therapeutic use
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Dipeptides
  • Double-Blind Method
  • Drug Therapy, Combination / adverse effects
  • Glucosides
  • Glycated Hemoglobin
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Liver / diagnostic imaging
  • Magnetic Resonance Imaging
  • Metformin* / therapeutic use
  • Sulfonylurea Compounds
  • Treatment Outcome


  • Benzhydryl Compounds
  • Dipeptides
  • Glucosides
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Sulfonylurea Compounds
  • dapagliflozin
  • glimepiride
  • Metformin
  • saxagliptin
  • Adamantane