Gliflozins in the Management of Cardiovascular Disease

Gliflozins

Despite the plethora of evidence-based medical and device therapies for heart failure, only several have enabled transformative patient outcomes.

Consider: the euphoria associated with the release of the SAVE and SOLVD results and the initiation of the ACE-inhibitor era; the standing ovations afforded to the disruptively positive beta-blocker trials; the awestruck faces when the landmark aldosterone antagonist trials reported positive results; and, for certain, the truly paradigm-changing results of PARADIGM HF and the entry of the ARNI compound as a treatment for heart failure. With each discovery, an iterative step towards better outcomes for patients laboring with heart failure emerged. There was a commentary RE: new hope and a new day.

Now the field is tectonically transformed by the “gliflozins." A sole drug class, sodium–glucose co-transporter inhibitors, with compelling disease modification data—32% reduction in new-onset heart failure in the setting of type II diabetes; 25% reduction in the combined endpoint of cardiovascular death or hospitalization for heart failure in HFrEF; 27% reduction in hospitalization for heart failure in HFpEF; and a 33% reduction in the progression of chronic renal disease in those with type II diabetes along with attenuation of the decline in renal function in the setting of HFrEF. These remarkably salutary benefits extend beyond the efficacy of already established GDMT. Ongoing research addressing hospitalized heart failure and protection from cardiotoxic chemotherapy may further extend this sterling spectrum of benefit juxtaposed against only a modest risk profile. The current 2022 AHA/ACC/HFSA clinical practice guidelines now firmly endorse quadruple therapy for HFrEF and, for the first time, offer a proven evidence-based treatment algorithm for HFpEF. The impetus for both new recommendations? The gliflozins work. The standard of care has changed in heart failure.

"Gliflozins in the Management of Cardiovascular Disease" is a sole-author NEJM review by E. Braunwald, MD. The commentary is expertly crafted, cogent in discussion, and remarkably clear in synthesis. Mechanisms of action are suggested but definitive proof remains under active investigation. Read the review as a reference document, but also read the review envisioning the lens of Dr. Braunwald. Who else has chaperoned the field from digitalis leaf to ACE-inhibitors, beta blockers, angiotensin receptor antagonist/sacubitril, and now the gliflozins? Who else established the metric of ejection fraction? And who was present and participatory for every important randomized trial in heart failure? The lens for Dr. Braunwald is both macro (spanning more than 7 decades) and micro (still homing in on molecular pathways of action). The review is prosaic (the story of discovery of the gliflozins) and precise (the insightful dissection of both cardiac and renal effects of this drug class).

Yet, this review is even more. It is a gift; offering the science of a potent new drug class and the unparalleled scholarship of a founding father of heart failure. In this moment of time, as we witness a generational change in the care of patients with cardiovascular disease, we are once again guided by the peerless wisdom of Dr. Braunwald. We and our patients are indeed grateful.