Original Research

Safety and Efficacy of GLP-1 Receptor Agonists and SGLT2 Inhibitors Among Veterans With Type 2 Diabetes

Fed Pract. 2022 November;39(5):1-5 | doi:10.12788/fp.0319

References

1. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2021. Diabetes Care. 2021;44(suppl 1):S111-S124. doi.10.2337/dc21-S009

2. DeFronzo RA. Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab. 2017;19(10):1353-1362. doi.10.1111/dom.12982

3. Jabbour S, Frias J, Guja C, Hardy E, Ahmed A, Ohman P. Effects of exenatide once weekly plus dapagliflozin, exenatide once weekly, or dapagliflozin, added to metformin monotherapy, on body weight, systolic blood pressure, and triglycerides in patients with type 2 diabetes in the DURATION-8 study. Diabetes Obes Metab. 2018;20(6):1515-1519. doi:10.1111/dom.13206

4. Ludvik B, Frias J, Tinahones F, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6(5):370-381. doi:10.1016/S2213-8587(18)30023-8

5. Blonde L, Belousova L, Fainberg U, et al. Liraglutide as add-on to sodium-glucose co-transporter-2 inhibitors in patients with inadequately controlled type 2 diabetes: LIRA-ADD2SGLT2i, a 26-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2020;22(6):929-937. doi:10.1111/dom.13978

6. Fulcher G, Matthews D, Perkovic V, et al; CANVAS trial collaborative group. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(1):82-91. doi:10.1111/dom.12589

7. Zinman B, Bhosekar V, Busch R, et al. 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;7(5):356-367. doi:10.1016/S2213-8587(19)30066-X

8. Mantsiou C, Karagiannis T, Kakotrichi P, et al. Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors as combination therapy for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2020;22(10):1857-1868. doi:10.1111/dom.14108

9. US Department of Veterans Affairs, Department of Defense. VA/DoD clinical practice guideline for the management of adult overweight and obesity. Version 3.0. Accessed August 18, 2022. www.healthquality.va.gov/guidelines/CD/obesity/VADoDObesityCPGFinal5087242020.pdf

10. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2015;387(10022):957-967. doi.10.1016/S0140-6736(15)01225-8

The primary objective was to determine the effect on HbA_1c levels at 12 weeks when using a GLP-1 RA and SGLT2i in combination vs separately. Secondary objectives were to determine change from baseline in mean body weight, BP, SCr, and eGFR at 12, 26, and 52 weeks; change in HbA_1c levels at 26 and 52 weeks; and incidence of prespecified adverse drug reactions during combination therapy vs separately.

Statistical Analysis

Assuming a SD of 1, 80% power, significance level of P < .05, 2-sided test, and a correlation between baseline and follow-up of 0.5, we determined that a sample size of 34 subjects was required to detect a 0.5% change in baseline HbA_1c level at 12 weeks. A t test (or Wilcoxon signed rank test if outcome not normally distributed) was conducted to examine whether the expected change from baseline was different from 0 for continuous outcomes. Median change from baseline was reported for SCr as a nonparametric t test (Wilcoxon signed rank test) was used.

Results

We identified 110 patients for possible study inclusion and 39 met eligibility criteria. After record review, 30 patients were excluded for receiving < 12 weeks of combination therapy or no 12 week HbA_1clevel; 26 patients were excluded for receiving < 12 weeks of monotherapy before starting combination therapy or no baseline HbA_1clevel; and 15 patients were excluded for lack of documentation in the VA EHR. Of the 39 patients included, 24 (62%) were prescribed empagliflozin first and then 8 started liraglutide and 16 started semaglutide.

Fourteen (36%) were prescribed liraglutide, and 1 (3%) was prescribed semaglutide first and then started empagliflozin (Table 1).

HbA_1c levels decreased by 1% after 12 weeks of combination therapy compared with baseline (P < .001), and this reduction was sustained through the duration of the study period (Table 2).

Similarly, body weight decreased by about 5 kg from baseline, equating to 5% total body weight loss, at 26 and 56 weeks of combination therapy, achieving both clinical and statistical significance (P < .001). SBP reduction reached both clinical and statistical significance after 26 and 52 weeks of combination therapy (P < .01 and P < .05, respectively). However, there was no significant change in diastolic BP (DBP). There were no significant findings regarding SCr or eGFR.

The most common AE during the trial was hypoglycemia, which was mostly mild (level 1) (Table 3).

Hypoglycemia occurred at similar frequency during the 6 months before and after starting the second agent and less frequently during the second 6 months of combined therapy. Only 1 patient in the study had a severe hypoglycemic event, causing mental status changes (a change to the insulin dosing may have contributed). Of the 2 patients with genital mycotic infections at baseline, 1 patient was prescribed empagliflozin, which was continued with no further AEs. The other patient was on liraglutide at baseline when the genital mycotic infection was first reported and had recurrence 3 months after starting empagliflozin, which was continued with no further AEs. Empagliflozin was discontinued in the patient who developed a genital mycotic infection after the 26- to 52-week period of combination therapy. There were no documented episodes of dehydration, diabetic ketoacidosis, pancreatitis, medullary thyroid cancer, or multiple endocrine neoplasia syndrome II.

Discussion

This study evaluated the safety and efficacy of combined use of semaglutide or liraglutide and empagliflozin in a veteran population with T2DM. The retrospective chart review captured real-world practice and outcomes. Combination therapy was associated with a significant reduction in HbA_1clevels, body weight, and SBP compared with either agent alone. No significant change was seen in DBP, SCr, or eGFR. Overall, the combination of GLP-1 RA and SGLT2i medications demonstrated a good safety profile with most patients reporting no AEs.

Several other studies have assessed the safety and efficacy of using GLP-1 RA and SGLT2i in combination. The DURATION 8 trial is the only double-blind trial to randomize subjects to receive either exenatide once weekly, dapagliflozin, or the combination of both for up to 52 weeks.³ Other controlled trials required stable background therapy with either SGLT2i or GLP-1 RA before randomization to receive the other class or placebo and had durations between 18 and 30 weeks.^4-7 The AWARD 10 trial studied the combination of canagliflozin and dulaglutide, which both have proven CVD benefit.⁴ Other studies did not restrict SGLT2i or GLP-1 RA background therapy to agents with proven CVD benefit.^5-7 The present study evaluated the combination of empagliflozin plus liraglutide or semaglutide, agents that all have proven CVD benefit.

References

1. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2021. Diabetes Care. 2021;44(suppl 1):S111-S124. doi.10.2337/dc21-S009

2. DeFronzo RA. Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab. 2017;19(10):1353-1362. doi.10.1111/dom.12982

3. Jabbour S, Frias J, Guja C, Hardy E, Ahmed A, Ohman P. Effects of exenatide once weekly plus dapagliflozin, exenatide once weekly, or dapagliflozin, added to metformin monotherapy, on body weight, systolic blood pressure, and triglycerides in patients with type 2 diabetes in the DURATION-8 study. Diabetes Obes Metab. 2018;20(6):1515-1519. doi:10.1111/dom.13206

4. Ludvik B, Frias J, Tinahones F, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6(5):370-381. doi:10.1016/S2213-8587(18)30023-8

5. Blonde L, Belousova L, Fainberg U, et al. Liraglutide as add-on to sodium-glucose co-transporter-2 inhibitors in patients with inadequately controlled type 2 diabetes: LIRA-ADD2SGLT2i, a 26-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2020;22(6):929-937. doi:10.1111/dom.13978

6. Fulcher G, Matthews D, Perkovic V, et al; CANVAS trial collaborative group. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(1):82-91. doi:10.1111/dom.12589

7. Zinman B, Bhosekar V, Busch R, et al. 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;7(5):356-367. doi:10.1016/S2213-8587(19)30066-X

8. Mantsiou C, Karagiannis T, Kakotrichi P, et al. Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors as combination therapy for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2020;22(10):1857-1868. doi:10.1111/dom.14108

9. US Department of Veterans Affairs, Department of Defense. VA/DoD clinical practice guideline for the management of adult overweight and obesity. Version 3.0. Accessed August 18, 2022. www.healthquality.va.gov/guidelines/CD/obesity/VADoDObesityCPGFinal5087242020.pdf

10. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2015;387(10022):957-967. doi.10.1016/S0140-6736(15)01225-8

Error message

Safety and Efficacy of GLP-1 Receptor Agonists and SGLT2 Inhibitors Among Veterans With Type 2 Diabetes

References

Recommended Reading

Safety and Efficacy of GLP-1 Receptor Agonists and SGLT2 Inhibitors Among Veterans With Type 2 Diabetes

References

Statistical Analysis

Results

Discussion

Pages

Recommended Reading