A Resident's Perspective: SGLT2 Inhibitors for Primary Prevention

Type 2 diabetes mellitus (T2D) is a global pandemic affecting 30 million adults in the United States.1 Among the greatest risks associated with a diagnosis of T2D is the increased risk of developing heart failure (HF), which research suggests is doubled in men and quintupled in women.2 Not only is HF one of the most common cardiovascular complications of T2D, it is also the most disabling and deadly.3

Projections estimate T2D prevalence will increase by 55% in the next 2 decades.4 The combined healthcare burden of T2D and HF is already tremendous and I fear our healthcare system could be overwhelmed if we do not optimize cardiovascular disease (CVD) prevention for T2D patients now.

The most important way to prevent T2D and CVD is to promote a healthy lifestyle throughout life. As per the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease, adults should engage in at least 150 minutes per week of moderate-intensity or 75 minutes per week of vigorous-intensity physical activity. All adults should consume a healthy diet rich in vegetables, fruits, nuts, whole grains, lean vegetable or animal protein, and fish. Along with modifiable risk factor optimization, healthy lifestyle choices protect against the development and worsening of T2D and CVD, as well as the development of CVD among T2D patients.

A pharmacologic strategy for CVD protection of T2D patients involves an apple a day, sort of. Based on the chemical structure of phlorizin, a phytochemical discovered in apple tree bark in 1835, sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors) reduce the risk of incident heart failure for T2D patients. More recently, 4 large SGLT2 inhibitor cardiovascular outcome trials, EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS CV, of empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin, respectively, demonstrated a significant reduction in HF hospitalization among T2D patients with and without established CVD.

Although the prevalence of baseline CVD found within the patient populations of each trial varied, the reductions in HF hospitalization were significant and consistent across each of the aforementioned trials. Even in DIRECT-TIMI 58, the largest trial with the highest proportion of patients without CVD (10,186 of 17,160), investigators reported a significant reduction in HF hospitalization. These results suggest that dapagliflozin, and possibly the SGLT2 inhibitors class as a whole, might serve as a disease modifier for patients with pre-clinical CVD/HF. In October 2019, dapagliflozin (Farxiga) received FDA approval to reduce the risk of hospitalization for HF in primary prevention patients (with multiple CV risk factors) with T2D.

The exciting results of these trials, among others, set in motion a paradigm shift in the management of T2D beyond glucose control to include cardiovascular risk reduction. New societal guidelines reflect this movement.

The 2019 ESC Clinical Practice Guidelines on Diabetes, Pre-Diabetes and Cardiovascular Diseases recommend starting with an SGLT2 inhibitor or GLP-1RA before metformin in newly diagnosed T2D patients who are treatment naïve and either have established CVD or are at high CVD risk.

In contrast, the 2020 ADA Standards of Medical Care in Diabetes include SGLT2 inhibitors and GLP-1 RAs as second-line therapy after metformin for patients with established CVD or at high CVD risk. For patients with indicators of high ASCVD risk, established chronic kidney disease, or HF, the guidelines suggest an SGLT2 inhibitor may be used as part of the glucose-lowering regimen independent of a1c and in consideration of patient-specific factors.

Most recently, the 2020 JACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients with T2D recommends initiating a patient-clinician discussion about the use of SGLT2 inhibitors for patients with T2D who have or who are at very high risk for clinical ASCVD, HF, and/or diabetic kidney disease. Additionally, these recommendations suggest an SGLT2 inhibitor for patients with T2D who are at high risk of developing HF, diabetic kidney disease, clinically evident ASCVD, or any combination of these conditions.

The current guidelines provide strong recommendations for the use of SGLT2 inhibitors for the reduction of incident HF among T2D. Realistically, the widespread use of these medications for primary prevention may not be cost-effective for every patient, however, with projections suggesting the prevalence of HF will increase to more than 8 million by 2030, the burden of heart failure could grow to nearly $70 billion.5

Despite the mountain of clinical evidence, expanding FDA indications, and societal guideline recommendations for their use, SGLT2 inhibitors prescribing rates remain low. While the side effects of use must be accompanied by risk-benefit discussion with patients, as well as consideration of treatment burden and individual patient preferences, these agents have provided an opportunity to reshape the way we treat diabetes and other comorbidities early on with a more target-focused approach.