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GLP-1RA as Add-on Therapy to SGLT-2 Inhibitor

Apr 13, 2019
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Dahlia Elimairi, Pharm D Student, UC Denver Skaggs School of Pharmacy

Combination treatment can help improve glucose levels in patients with elevated HbA1Cs.

Considering their mechanisms of action and efficacy and safety profiles, dual therapy with a GLP-1RA and an SGLT-2 inhibitor has many potential clinical benefits. Both classes of drugs directly or indirectly affect many of the organs and tissues involved in the pathogenesis of type 2 diabetes. Clinical trials have shown that the combination of GLP-1RAs and SGLT-2 inhibitors is more effective than monotherapy, with an acceptable safety profile.


In the Duration 8 trial, which was a 28-week multicenter double blind phase 3 randomized controlled trial, 695 patients were randomly assigned to receive exenatide plus dapagliflozin, exenatide alone, or dapagliflozin alone. Exenatide plus

dapagliflozin significantly reduced HbA1c from baseline to week 28 compared with exenatide alone or dapagliflozin alone. Exenatide plus dapagliflozin was significantly superior to either drug alone for all secondary efficacy endpoints, with greater reductions in fasting plasma and postprandial glucose, more patients with an HbA1c less than 7.0%, greater weight loss, a greater proportion of patients with weight loss of 5% or more, and greater reductions in systolic blood pressure. The most common adverse events were diarrhea, injection-site nodules, nausea, and urinary tract infections. No episodes of major hypoglycemia or minor hypoglycemia were reported.

The study concluded that co-initiation of exenatide and dapagliflozin improved various glycemic measures and cardiovascular risk factors in patients with type 2 diabetes inadequately controlled by metformin monotherapy. The dual treatment regimen was well-tolerated.

The elimination of glucose through the urine that is caused by SGLT-2 inhibitors may stimulate appetite, which could be offset by the appetite-suppressing effect of GLP1RAs, mitigating weight gain. In a randomized controlled trial by P. Lundkvist et al, using combination therapy (exenatide once weekly plus dapagliflozin), in adults who have obesity without diabetes, resulted in significant weight loss, as well as improvements in HbA1c and blood pressure. Adults with obesity also experienced improvements in fasting glucose.

A new study aimed to investigate the efficacy and safety of semaglutide when added to SGLT-2 inhibitor therapy in patients who have type 2 diabetes and elevated HbA1Cs.  

The SUSTAIN 9 double-blind, parallel-group trial was done at 61 centers in six countries. Adults with type 2 diabetes and HbA1c 7.0–10.0%, despite at least 90 days of treatment with an SGLT-2 inhibitor, were randomly assigned (1:1) to receive subcutaneous semaglutide 1.0 mg or volume-matched placebo once weekly for 30 weeks, after a dose-escalation schedule of 4 weeks of 0.25 mg semaglutide or placebo and 4 weeks of 0.5 mg semaglutide or placebo. Existing antidiabetic medications, including SGLT-2 inhibitor treatment, were continued for the duration of the trial.

The primary outcome was change in HbA1c from baseline at week 30, assessed in the full analysis set (all patients randomly allocated to treatment). The secondary outcome was change in body weight from baseline to week 30. Safety was also assessed in the safety analysis set.

Patients given semaglutide had greater reductions in HbA1c and bodyweight versus those randomized to placebo. Gastrointestinal adverse events were most common and were reported in 56 patients in the semaglutide group and 20 in the placebo group. Severe or blood glucose-confirmed hypoglycemic events were reported in four patients on semaglutide. There were no deaths during the trial.

The study concluded that adding semaglutide to SGLT-2 inhibitor therapy significantly improves HbA1c and reduces body weight in patients who have type 2 diabetes, and is generally well-tolerated.

Practice Pearls:

  • Combination therapy with an SGLT-2 inhibitor and GLP-1RA has shown to lead to greater improvements in HbA1c levels, weight, and the CV risk factors blood pressure and triglycerides, than when taken separately.
  • Combination therapy is usually well-tolerated with gastrointestinal adverse events being the most common.
  • Providers should be aware of the emerging data on combination therapy in suitable patients.


Zinman B, Bhosekar V, Busch R, Holst I, Ludvik B, Thielke D, Thrasher J, Woo, V, Philis-Tsimikas A. Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019 Mar.

Busch RS, Kane MP. Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: a complementary approach to the treatment of type 2 diabetes. Postgrad Med. 2017 Sep;129(7):686-697.

Frías JP, Guja C, Hardy E, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, doubleblind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4:1004–1016.

Lundkvist P, Sjöström CD, Amini A, et al. Dapagliflozin once-daily and exenatide once-weekly dual therapy: a 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes. Diab Obes Metab. 2017;19:49–60.

Dahlia Elimairi, Pharm D student UC Denver Skaggs School of Pharmacy