On Saturday, June 26, four experts reviewed recent trial results demonstrating the safety and efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors for both cardiovascular and renal treatment and discussed how those trial results will help improve care for people with diabetes.

Practice-Changing Trials in Heart Failure and Kidney Disease with SGLT2 Inhibitors can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.

Reviewing results from the DAPA-HF and EMPEROR-Reduced trials, Carolyn S.P. Lam, MBBS, PhD, FRCP, FAMS, FESC, FACC, Senior Consultant Cardiologist, National Heart Centre Singapore, said SGLT2 inhibitors deliver consistent, robust benefits for type 2 diabetes patients with heart failure with reduced ejection fraction (HFrEF). DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) compared dapagliflozin to placebo, while EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) compared empagliflozin to placebo.

EMPEROR-Reduced showed that empagliflozin led to a 30% reduction in heart failure hospitalizations, a 50% decrease in adverse renal events, and a 25% relative risk reduction (all P<0.001), Dr. Lam noted.

“We now have five pathways to modulate in our patients with HFrEF that have been proven to improve their heart outcomes: angiotensin II, norepinephrine, aldosterone, neprilysin, and SGLT,” she said. “These five pathways can be modulated by four drugs: ANRIs (angiotensin receptor neprilysin inhibitors), beta-blockers, MRAs (mineralocorticoid receptor antagonists), and SGLT2 inhibitors. The important concept is to try to get patients on these four drugs in combination as quickly and safely as possible.”

When compared with HFrEF, heart failure with preserved ejection fraction (HFpEF) has less established medical guidance and therapies, but Muthiah Vaduganathan, MD, MPH, said that SGLT2 inhibitors show promise mechanistically in targeting critical aspects of HFpEF pathogenesis and symptomatology.

A cardiologist at Brigham and Women’s Hospital Heart and Vascular Center, Dr. Vaduganathan discussed the largest trials of HFpEF conducted to date: DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) and EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction). Both trials will be reporting results soon and Dr. Vaduganathan said they are well-positioned to fill key evidence gaps.

“I believe it will be challenging to show true disease-modifying potential in reducing mortality because of lower overall mortality rates and high competing risks of non-cardiovascular events,” he said. “However, reductions in hospitalization burden and improvement in quality of life will certainly be clinically relevant to patients, clinicians, and regulators, and will certainly be welcomed to the community.”

Brendon Neuen, MBBS (Hons), MSc (Oxon), academic nephrology registrar and National Health and Medical Research Council Postgraduate Scholar, The George Institute for Global Health, University of New South Wales, Sydney, Australia, and David C. Wheeler, MD, FRCP, Professor of Kidney Medicine, University College London, United Kingdom, reviewed trial results from studies investigating the use of SGLT2 inhibitors in diabetic kidney disease.

CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) examined the effect of canagliflozin on major kidney outcomes, including a composite primary outcome, cardiorenal outcome, doubling of serum creatine, kidney failure, or renal death. After first enrolling patients in 2014, the trial was recommended to end at a planned interim analysis point in July 2018 based on demonstration of efficacy.

SGLT2 inhibition safely reduces the risk of kidney failure requiring dialysis or transplantation in people with type 2 diabetes and chronic kidney disease (CKD), Dr. Neuen said, and patients with more advanced CKD gain the greatest benefit.

“The average CREDENCE participant, who lost 4.5 mL per minute of eGFR (estimated glomerular filtration rate) per year if treated with placebo, with canagliflozin attenuated that loss of eGFR by 2.75 mL per minute per year,” Dr. Neuen said. “What this result projects beyond the lifespan of the trial is a substantially longer dialysis-free survival with important implications for patients, their caregivers, and health systems.”

In his overview of DAPA-CKD (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease), Dr. Wheeler said that for both patients with and without type 2 diabetes, dapagliflozin reduced the risk of kidney failure and reduced the risk of death from cardiovascular causes for heart failure while delivering prolonged survival. The effects of dapagliflozin were consistent across a range of patient subgroups, across CKD etiologies, including immunoglobulin A nephropathy and focal segmental glomerulosclerosis, and CKD stages. Patients with or without a prior cardiovascular event also saw benefit.