Guidelines Recommend SGLT2 Inhibitors for Nearly All Patients With Heart Failure, Kidney Disease

The body of evidence supporting sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with cardiovascular and kidney disease is overwhelming, according to a panel of experts at the American College of Cardiology 2023 Scientific Session.

In the cardiovascular disease space, presenter Muthiah Vaduganathan, MD, MPH, said there is a strong body of evidence across the full range of ejection fraction, irrespective of care setting. Mechanistic data has also emerged showing that treatment with SGLT2 inhibitors improves exercise capacity, hemodynamic filling pressures, and remodeling endpoints to at least a modest extent.

Additionally, the SOLOIST-WHF trial found concordant benefits in the hospital setting and use of SGLT1/2 inhibitors resulted in reduced clinical events early after worsening heart failure. Other studies have shown significant improvements in patients’ health status as well as rapid stabilization of health status early after hospitalization.

“We really now see that these drugs are disease-modifying across the spectrum of ejection fraction,” Vaduganathan said.

Clinical trials have shown similar efficacy in kidney disease, according to presenter Mikhail Kosiborod, MD. Patients with chronic kidney disease (CKD) have a great disease burden, with higher risks of death, heart failure, atherosclerotic cardiovascular disease (ASCVD) events, and CKD progression. Key goals in this patient population are prolonging survival, reducing adverse cardiovascular events, and preventing progression of kidney disease.

Many trials have shown benefits toward these goals. For instance, the EMPAREG trial showed that acute decline in estimated glomerular filtration rate (eGFR) is not associated with a faster eGFR decline during chronic treatment, and there appears to be a correlation with eGFR decline and improved long-term kidney function. The DAPA-CKD trial furthered this work, showing both short- and long-term changes in eGFR and urine albumin-creatinine ratio (UACR) during treatment with dapagliflozin.

SGLT2 inhibitors have also demonstrated a class-wide effect in reducing the risk of composite kidney disease endpoints in patients with type 2 diabetes, based on findings from the EMPA-REG, DECLARE, CANVAS, and VERTIS trials. These effects were consistent regardless of the drug and patient population and saw results as dramatic as a 40% to 50% reduction in the risk of heart and kidney events.

Kidney outcome trials with SGLT2 inhibitors have now addressed the spectrum of CKD regardless of diabetes, and have shown improvements on kidney endpoints, eGFR, and albuminuria. Additionally, Kosiborod said there are other tangible benefits, such as reduced anemia in the OUTCOME trial, reduced hyperkalemia shown in multiple trials, and reduced all-cause hospitalization regardless of trigger in the DAPA-CKD and EMPA-KIDNEY trials.

With this massive body of data now well-established, the 2022 American Heart Association, American College of Cardiology, and Heart Failure Society of America guidelines recommend SGLT2 inhibitors for nearly all patients in cardiovascular practice, according to Prateeti Khazanie, MD, MPH, who was involved in writing the guidelines.

“The fact is there’s a huge body of evidence for all stages of heart failure,” Khazanie said. “We have one of the largest bodies of evidence in medicine for SGLT2 inhibitors.”

As of the 2022 guidelines, SGLT2 inhibitors are 1 of the 4 pillars of heart failure guideline-directed therapy, based on data from the DAPA-HF and EMPEROR-REDUCED trials showing a 15% reduction in death and 25% to 30% reduction in heart failure-related hospitalization. SGLT2 inhibition is included as step 1 for patients with stage C heart failure.

The guidelines advise continuation of guideline-directed medical therapy even for patients who have improved ejection fraction of greater than 40%. Importantly, Khazanie pointed out that the TRED-HF study showed that discontinuation of guideline-directed medical therapy in patients who had gone into “remission” with left ventricular ejection fraction (LVEF) resulted in recurrence of disease.

Value statements in the 2022 guidelines also address the costs of SGLT2 inhibitors, which are currently approximately $600 per month. Because of this higher cost, Khazanie said SGLT2 inhibitors received an intermediate value compared with other, older medications, although canagliflozin may be generic in 2025, offering a more affordable option.

Finally, expert Anastasia L. Armbruster, PharmD, FACC, BCCP, addressed how and when to initiate treatment with SGLT2 inhibitors. Although optimal timing has not been fully investigated, Armbruster said she advises clinicians to start this treatment early because there is known clinical benefit in the first 30 days.

SGLT2 inhibitors can also be combined with glucagon-like peptide-1 (GLP-1) receptor agonists, particularly in patients with type 2 diabetes and ASCVD, those on hemodialysis, those with CKD, or those at high risk for ASCVD. Additionally, renal function should be closely monitored and patients should be educated about signs of hypoglycemia or genital mycotic infections, which do have a higher incidence in patients with diabetes receiving SGLT2 inhibitors.

Armbruster also addressed the high costs of SGLT2 inhibitors, urging prescribers to select preferred formulary agents when possible. Patients should also be educated about the clinical benefits and why they are paying for these medications.

“Preventing sticker shock when they’re picking this up at the pharmacy can help them continue that therapy,” she concluded.

REFERENCE

Armbruster A, Khazanie P, Kosiborod M, Vaduganathan M. Pharmacology III: Keeping the Heart and Kidneys Happy with SGLT2 Inhibitors—Who, When, and How. Presented at: American College of Cardiology 2023 Scientific Session. March 5, 2023.