Selecting the best medication regimen for a patient with type 2 diabetes mellitus (T2DM) depends on many factors, such as glycemic control, adherence, adverse effect (AE) profile, and comorbid conditions.1 Selected agents from 2 newer medication classes, glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), have demonstrated cardiovascular and renal protective properties, creating a new paradigm in management.
The American Diabetes Association recommends medications with proven benefit in cardiovascular disease (CVD), such as the GLP-1 RAs liraglutide, injectable semaglutide, or dulaglutide, or the SGLT2i empagliflozin or canagliflozin, as second-line after metformin in patients with established atherosclerotic CVD or indicators of high risk to reduce the risk of major adverse cardiovascular events (MACE).1 SGLT2i are preferred in patients with diabetic kidney disease, and GLP-1 RAs are next in line for selection of agents with proven nephroprotection (liraglutide, injectable semaglutide, dulaglutide). The mechanisms of these benefits are not fully understood but may be due to their extraglycemic effects. The classes likely induce these benefits by different mechanisms: SGLT2i by hemodynamic effects and GLP-1 RAs by anti-inflammatory mechanisms.2 Although there is much interest, evidence is limited regarding the cardiovascular and renal protection benefits of these agents used in combination.
The combined use of GLP-1 RA and SGLT2i agents demonstrated greater benefit than separate use in trials with nonveteran populations.3-7 These studies evaluated effects on hemoglobin A1c (HbA1c) levels, weight loss, blood pressure (BP), and estimated glomerular filtration rate (eGFR). A meta-analysis of 7 trials found that the combination of GLP-1 RA and SGLT2i reduced HbA1c levels, body weight, and systolic blood pressure (SBP).8 All of the changes were statistically significant except for body weight with combination vs SGLT2i alone. Combination therapy was not associated with increased risk of severe hypoglycemia compared with either therapy separately.
The purpose of our study was to evaluate the safety and efficacy of the combined use of GLP-1 RA and SGLT2i in a real-world, US Department of Veterans Affairs (VA) population with T2DM.
This study was a pre-post, retrospective, single-center chart review. Subjects served as their own control. The project was reviewed and approved by the VA Ann Arbor Healthcare System Institutional Review Board. Subjects prescribed both a GLP-1 RA (semaglutide or liraglutide) and SGLT2i (empagliflozin) between January 1, 2014, and November 10, 2019, were extracted from the Corporate Data Warehouse (CDW) for possible inclusion in the study.
Patients were excluded if they received < 12 weeks of combination GLP-1 RA and SGLT2i therapy or did not have a corresponding 12-week HbA1c level. Patients also were excluded if they had < 12 weeks of monotherapy before starting combination therapy or did not have a baseline HbA1c level, or if the start date of combination therapy was not recorded in the VA electronic health record (EHR). We reviewed data for each patient from 6 months before to 1 year after the second agent was started. Start of the first agent (GLP-1 RA or SGLT2i) was recorded as the date the prescription was picked up in-person or 7 days after release date if mailed to the patient. Start of the second agent (GLP-1 RA or SGLT2i) was defined as baseline and was the date the prescription was picked up in person or 7 days after the release date if mailed.
Baseline measures were taken anytime from 8 weeks after the start of the first agent through 2 weeks after the start of the second agent. Data collected included age, sex, race, height, weight, BP, HbA1c levels, serum creatinine (SCr), eGFR, classes of medications for the treatment of T2DM, and the number of prescribed antihypertensive medications. HbA1c levels, SCr, eGFR, weight, and BP also were collected at 12 weeks (within 8-21 weeks); 26 weeks (within 22-35 weeks); and 52 weeks (within 36-57 weeks) of combination therapy. We reviewed progress notes and laboratory results to determine AEs within 26 weeks before initiating second agent (baseline) and 0 to 26 weeks and 26 to 52 weeks after initiating combination therapy.