If there were ever any surprise stories in medicine, the incredible success of sodium glucose cotransporter 2 (SGLT-2) inhibitors is one. These drugs, which were initially intended as an adjunct therapy for type 2 diabetes, became a pillar of heart failure treatment in a few short years.

Intriguingly, this class transcended specialties and also helps with chronic kidney disease, irrespective of diabetes status.

DeSa T, Gong T. SGLT-2 inhibitors: A new pillar of the heart failure regimen. Reviews in Cardiovascular Medicine. Rev Cardiovasc Med. 2021;22(4):1253.

 

 

Inauspicious beginnings

The profound cardiovascular benefit of SGT2 inhibitors was discovered only after FDA and the European Medicine Agency mandated expanded evaluation for the safety for all antidiabetic treatments in 2008 and 2012, respectively. In 2007, researchers discovered a new safety signal for increased myocardial function risk with thiazolidinedione rosiglitazone, prompting increased scrutiny of other medications, including SGLT-2 inhibitors.

In 2013, canagliflozin was the first SGLT-2 inhibitor to be approved. To date, there are three other approved members of this class: empagliflozin, ertugliflozin, and dapagliflozin. Several large clinical trials have demonstrated that these drugs result in improvement in cardiovascular outcomes such as a decrease in major adverse cardiac events and hospitalizations due to heart failure.

 

The fourth pillar

The first three pillars of treating heart failure are ACE inhibitors:

• blockade of the renin-angiogtensin hormonal axis

• beta blockers

• mineralocorticoid antagonists

These treatments help decrease symptoms and mortality, and reduce the progression of heart failure to the need for heart transplant and left-ventricular assist devices. SGLT-2 inhibitors are now considered a crossover class that targets pathophysiology in the kidneys rather than the heart.

McGuire D. How 'diabetes drugs' became valuable tools in treating heart failure: Heart: UT southwestern medical center. UT Southwestern Medical Center. February 24, 2022.

 

A main hypothesis regarding how SGLT-2 inhibitors treat heart failure has to do with sodium regulation in the kidney. These drugs inhibit the uptake of glucose and sodium in the glomerulus.

Consequently, the kidney senses normal sodium and chloride levels in the urine. In response, there’s a decrease in blood flow and normalization of blood pressure at the level of the glomerulus.

Other hypotheses involve decreases in inflammation, renin-angiotensin-aldosterone system activation, sympathetic nervous activity, and intravascular volume. SGLT-2 inhibitors may also increase red blood cell production and boost production of ketone, an energy-efficient fuel for the heart that could decrease oxygen needs.

 

What about HFpEF?

The benefits of SGLT-2 inhibitors in the case of HFrEF in patients with or without diabetes are well-established in clinical trials. However, heart failure with preserved ejection fraction (HFpEF) impacts roughly half of the population.

Consequently, trials dedicated to examining the effects of SGLT-2 inhibitors in patients with HFpEF are emerging.

In August 2021, results of EMPEROR-PRESERVED (Empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction) indicated that empagliflozin decreased cumulative cardiovascular death and hospitalizations due to heart failure, although it did not decrease the chances of cardiovascular death.

These benefits were noted regardless of glycemic levels and across the gamut of ejection fraction (EF)—especially those patients with an EF of ≥ 60%. This trial also showed a decrease in major renal events, which were defined as sustained decreases in estimated glomerular filtration rate or the need for renal replacement therapy.

 

In the setting of CKD

“These agents prevent decline in kidney function through reduction in glomerular hypertension mediated through tubuloglomerular feedback independent of their effect on glycemic control,” stated the authors of a review published in Kidney International Reports.

Yau K, Dharia A, Alrowiyti I, et al. Prescribing SGLT-2 inhibitors in patients with CKD: expanding indications and practical considerations. Kidney Int Rep. 2022 May 5;7(7):1463-1476.

 

The proliferation of clinical trials on SGLT-2 inhibitors has rapidly expanded the approved clinical indications for these agents beyond patients with diabetes mellitus.

In addition to improving clinical outcomes in HFrEF and HFpEF regardless of diabetes status, SGLT-2 inhibitors can also help patients at different stages of chronic kidney disease (CKD) regardless of diabetes, as shown in the clinical trials.

On post-hoc analysis, they also decreased the chances of anemia or hyperkalemia in the setting of CKD; anemia and hyperkalemia are common complications of heart failure and CKD. These drugs did not increase the risk of hypoglycemia or acute kidney injury in patients with heart failure or CKD.

van der Aart-van der Beek AB, de Boer RA, Heerspink HJL. Kidney and heart failure outcomes associated with SGLT-2 inhibitor use. Nat Rev Nephrol. 2022 May;18(5):294-306.

 

Importantly, patients with CKD are at a higher risk of heart failure, with the converse also true. SGLT-2 inhibitors have been shown to decrease kidney disease progression and hospitalization for heart failure in those with CKD and heart failure.

Finally, SGT2 inhibitors are relatively safe drugs. Patients should be advised to watch out for certain adverse events such as infection due to glycosuria and diabetic ketoacidosis, which are rare.