ADA 81st Symposium: The Combination of SGLT-2 inhibitors and GLP-1 Receptor Agonists

Can a new potential combination treatment, using an SGLT-2 and a GLP-1 RA medication, mitigate cardiometabolic risk in people with diabetes?

Dr. Vanita R. Aroda presented at the 2021 Scientific Sessions of the American Diabetes Association regarding mitigating cardiometabolic risk by combining sodium-glucose cotransporter-2 inhibitors (SGLT-2) and glucagon-like peptide-1 (GLP-1) receptor agonists. A literature review of recent publications of the individual and combined SGLT-2 inhibitors and GLP-1 RA drug classes helps to indicate the cardiorenal benefits outweigh the risks. In addition, the AHA heart disease and stroke statistics released a 2021 update related to cardiovascular risk factors, health behaviors, and contributory health factors on associated outcomes. The leading global risk factor for years of life lost from 1990 to 2019 is ischemic heart disease. In addition, the top risk factors for years of life lived with disability or injury globally and in the United States from 1990 to 2019 are high fasting prandial glucose and body mass index, which increased from 44.1% to 60.2%. The newly released statistics depict a significant demand for cardiorenal risk reduction due to diabetes and obesity.

A randomized control trial published 2021 in the AHA Circulation by Dave CV et al. assesses the risk of cardiovascular outcomes in patients with type 2 diabetes after adding SGLT-2 inhibitors versus sulfonylureas to baseline GLP-1 RA therapy. The current study aims to establish if there are additional cardiovascular benefits from the combination therapy of SGLT-2 inhibitors and GLP-1 RA. The study included three datasets with 12,584 propensity score-matched pairs. The cardiovascular outcome of myocardial infarction and all-cause mortality was reduced by 24% in the SGLT-2 patients, and hospitalizations for heart failure were reduced by 35% compared to sulfonylureas patients. Thus, the addition of SGLT-2 to GLP-1 RA therapy resulted in more significant cardiovascular risk reduction. However, residual confounding among the therapeutic agents cannot be excluded. The EXSCEL trial by Clegg LE et al. studied the effects of exenatide and open-label SGLT-2 inhibitor treatment on mortality, cardiovascular, and renal outcomes in type 2 diabetes patients. The 2019 open-label parallel study evaluated 575 patients in the SLGT-2 arm and 572 patients in the placebo arm. There was a reduction in the risk of major adverse cardiovascular events and a significant improvement in eGFR in the SGLT-2 group compared to the placebo. Thus, post hoc analysis supports the combination of GLP-1 and SGLT-2 therapy for possible benefits on cardiovascular outcomes. However, additional investigatory trials are necessary to draw a more robust conclusion.

Aroda VR et al. published a study in 2019 that evaluated the efficacy, safety, and cardiovascular outcomes with subcutaneous semaglutide in treating type 2 diabetes. Data was review from SUSTAIN 1 to 7 phase 3 clinical trials with over 8,000 patients. Across all trials, semaglutide continuously demonstrated superior glycemic control, weight loss, and reduction in cardiovascular risk compared to placebo and the standard of care. In addition, the safety profile of semaglutide was similar to the comparator except for an increased occurrence of GI effects, malignant neoplasm, cholelithiasis, elevated lipase, pancreatitis, and diabetic retinopathy. The adverse events must be taken into consideration when identifying a patient-specific therapeutic plan. 

The 2021 ADA pharmacologic approaches to glycemic treatment pathway are initially divided into indicators of high-risk/established ASCVD, CKD, HF, and A1C above individualized target. Patients with heart failure LVEF less than 45% are recommended to initiate an SGLT-2 inhibitor.  High-risk ASCVD, CKD, promotion of weight loss, and minimized hypoglycemia indications can benefit from SGLT-2 inhibitors or GLP-1 RA for proven cardiorenal risk reduction, superior weight loss, and low incidence hypoglycemia in the clinical trials. Lastly, there is the monetary category where cost is a significant barrier to optimal care, where neither SGLT-2 nor GLP-1 RA is indicated. SGLT-2 and GLP-1 RA are among the more expensive anti-hyperglycemia medications. The 2020 JACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes discusses the lack of evidentiary studies regarding the concomitant use of SGLT-2 and GLP-1 RA with cardiovascular benefits. Regarding the personal benefits demonstrated in numerous trials, JACC 2020 determined that the use of both SGLT-2 and GLP-1 RA can be utilized if indicated.

Due to high cost, monotherapy or dual treatment is not viable for many individuals. According to the gaps in evidence, study-based therapy use in insured patients in the United States with type 2 diabetes and atherosclerotic cardiovascular disease evaluates the underutilization of evidence-based therapies in 155,958 patients. 24.7% of patients used high-intensity statins, 53.1% used ACE inhibitor or ARB, and 9.9% used either SGLT-2 inhibitor or GLP-1 RA. 2.7% of patients had insurance coverage for all three therapies. This study is a call to action for all involved parties to bridge the gap in care.

Practice Pearls:

• The EXSCEL trial concluded that SGLT-2 to GLP-1 RA therapy resulted in more significant cardiovascular risk reduction.
• JACC 2020 determined that the use of both SGLT-2 and GLP-1 RA can be utilized if indicated.
• Due to high cost, neither monotherapy or dual treatment is viable for many individuals.

Aroda VR. Combination Therapy with SGLT2i and GLP-1RA in Mitigating Cardiorenal Risk. American Diabetes Association mini-symposium. 2021 June 25 (Requires ADA Symposium login.)

Virani SS, Alonso AHeart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation. 2021 Feb 23

Jasmine Dumontier-Hiott, PharmD Candidate 2022, University of South Florida Taneja College of Pharmacy