Flozins, The New Statins for Heart Failure?

Flozins, The New Statins for Heart Failure?
Sonal Divecha, PharmD, Community-University Health Care Center

Background: Ambulatory care providers are vital in screening and initiating appropriate therapy in patients who are at an increased risk of heart failure which is commonly seen in patients with diabetes. Evidence-based medicine guides initiation of medications for diabetes that are known to reduce progression of cardiovascular and renal disease. As such, sodium-glucose co-transporter-2 inhibitors (SGLT2i) have proven their place in therapy by reducing hemoglobin A1C and blood pressure, claiming their superiority if heart failure or chronic kidney disease is present in addition to diabetes. Heart failure, a progressive disease, accounts for the increased morbidity and mortality surrounding such patients and as with other chronic conditions, the novel use of current therapeutics extending beyond their primary indication is an emerging science. The American Diabetes Association  (ADA) guidelines denote SGLT2i to hold a significant role in the prevention and treatment of heart failure in patients with diabetes. Pharmacists in particular can play a vital role in implementing evidence-based medicine to individualize and optimize medication use.  

Evidence: Numerous trials evaluating the safety, efficacy, and place in therapy of each of the SGLT2i were conducted. The EMPA-REG and EMPA-REG OUTCOME trials demonstrated that empagliflozin treatment resulted in a significant reduction in hospitalization for heart failure or cardiovascular death in patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD). Similarly, the CANVAS trial showed that the use of canagliflozin in patients with heart failure was associated with a reduced risk of hospitalization for heart failure or cardiovascular death. This trial revealed a greater benefit in patients with established heart failure in comparison to those without. Thus, paving the way to prove canagliflozin's efficacy and place in therapy in preventing hospitalization for heart failure. The DECLARE-TIMI 58 and DAPA-HF trials evaluated the use of dapagliflozin in patients with non-type 2 diabetes, with or without ASCVD. These studies also revealed a significant reduction in hospitalization for heart failure or cardiovascular death supporting the Food and Drug Administration approval of dapagliflozin for heart failure. The development of more focused trials to seek a link between cardiovascular outcomes with the use of SGLT2i have provided sufficient evidence to support their role in risk reduction. As these effects are independent of blood glucose lowering, the underlying mechanism of cardiovascular risk reduction is yet to be identified but proves promising.

Discussion & Clinical Impact: Per an article from Chim et al. one possible mechanism of action of SGLT2i that could shed light on its use in ASCVD reduction is via the promotion of diuresis, resulting in reduced plasma volume, blood pressure, preload, afterload, cardiac stiffness, and remodeling. The key trials described above have provided the foundation for extending the indication of SGLT2i for this use. This new possible indication of ASCVD reduction for SGLT2i closely correlates with the historic use of HMG-CoA reductase inhibitors, more commonly referred to as statins, in the primary prevention of ASCVD. In this case, guideline driven therapy was based on risk-enhancing factors, and used related laboratory markers to direct its implementation. As with statins, more data is needed to individualize a risk-based systematic process to guide the use of SGLT2i to provide an array of safe and effective cardio-renal therapies. Similar to other novel therapeutic agents, the current market for SGLT2i is limited by brand patents preventing their widespread application. Despite large, multicenter population trials, there is limited evidence on the applicability of SGLT2i in patients without type 2 diabetes,with or without risk factors for heart failure. Yet, current data provides promising results to a potential indication of cardiovascular risk reduction based on the science and pleiotropic effects of the drug.

 

References:

  1. Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZ. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. American Heart Association Circulation. 2017;136:1643–1658. DOI: 10.1161/CIRCULATIONAHA.117.030012

  1. Chim C, Newaz S. SGLT2 inhibitors and heart failure outcomes. U.S. Pharmacist. 2020;45(2):18-22. https://www.uspharmacist.com/article/sglt2-inhibitors-and-heart-failure-outcomes. Accessed August 7, 2021. 

  1. Freaney P, Lloyd-Jones D, Khan, S. Could flozins be the statins for risk-based primary prevention of heart failure? JAMA Cardiol. 2021;6(7):741-742. doi:10.1001/jamacardio.2021.1133

  2. Shim CY, Seo J, ChoI, et al. Randomized, controlled trial to evaluate the effect of dapagliflozin on left ventricular diastolic function in patients with type 2 diabetes mellitus. Circulation. 2021;143(5):510-512. doi:10.1161/CIRCULATIONAHA.120.051992