Sodium-glucose cotransporter 2 (SGLT2) inhibitors are multitaskers.
They have a profound renal effect, they lower blood glucose levels, and they work to prevent and treat heart failure, with beneficial results observed in a matter of days, according to Subodh Verma, MD, PhD, FRCSC, one of three presenters in the Scientific Sessions symposium SGLT2 Inhibitors—How Do They Reduce Cardiorenal Disease?
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SGLT2 inhibitors have been at the forefront of cardiovascular, metabolic, and renal regulation, said Dr. Verma, an internationally renowned cardiac surgeon-scientist at St. Michael’s Hospital and Professor of Surgery and Pharmacology & Toxicology at the University of Toronto, Ontario, Canada. But it can be difficult to determine which system receives the primary benefits of the drugs.
Dr. Verma and the session’s other presenters reviewed the benefits of SGLT2 inhibitors in metabolic mediation, in the heart, and in the kidney.
“The prime mover of SGLT2 inhibition is in the kidney because that’s where the SGLT2 isoforms of the cotransporter are expressed,” said Ele Ferrannini, MD. “As of today, we have very little evidence there is any significant expression of SGLT2 anywhere else but the kidney.”
Dr. Ferrannini, Senior Research Associate at the National Research Council Institute of Clinical Physiology and Professor of Medicine at the University of Pisa in Italy, was awarded with the ADA’s 2020 Banting Medal for Scientific Achievement during the Scientific Sessions. He also discussed the role of SGLT2 inhibitors in metabolic mediation during the virtual meeting. He said the overall effect of SGLT2 inhibition is an amplification of the dependency of energy products at the whole-body level on fatty substrates.
Evidence of nephroprotection from the use of the SGLT2 inhibitors empagliflozin, canagliflozin, and dapagliflozin has been consistent in multiple trials, which demonstrate a 40% to 45% reduction in relative risk of progression of kidney disease, Dr. Ferrannini said.
“The metabolic changes that start in the kidney are dependent on a sequence of events which is physiological because it’s the action of insulin on lipolysis, the excess delivery of fatty acids to all organs, ketogenesis and ketolysis in the heart, as well as the kidney,” he explained.
For the prevention and treatment of heart failure, Dr. Verma said the benefits of SGLT2 inhibitors do not compete with therapies already in use.
“We have several cardioprotective mechanisms that have been studied [in SGLT2 inhibitors],” Dr. Verma said. “The most compelling ones include inhibition of NHE1 (Na+/H+ exchanger isoform 1) and increase in EPO (erythropoietin), reduction in sympathetic activity, and reno-cardiac signaling. These effects, at least at the present time, appear to be independent of glucose-lowering, particularly in the context of patients with heart failure and reduced injection fraction.”
David Cherney, MD CM, PhD, FRCP(C), Associate Professor of Medicine at the University of Toronto and Director of the Renal Physiology Laboratory for University Health Network, discussed the effects of SGLT2 inhibitors in the kidney.
“A lot of the kidney protection leading to preservation of kidney function may preserve the body’s ability to maintain salt and water homeostasis, reduce cardiac preload, and thereby reduce heart failure and cardiovascular risk,” said Dr. Cherney, adding that, through kidney protection, SGLT2 inhibitors also reduce blood pressure and arterial stiffness, and ultimately, cardiac afterload. In turn, this may reduce some ventricular remodeling, which may also lead to cardiovascular protection.
The glucose-lowering benefits of SGLT2 inhibition plays little to no role in cardiorenal protection, he said.
“SGLT2 inhibitors appear to have much more pleiotropic effects beyond glucose, sort of similar to how RAAS (renin-angiotensin-aldosterone system) inhibitors work. I think that’s how we’re going to start to think about them more and more,” said Dr. Cherney, who anticipates further investigation into the use of SGLT2 inhibitors in non-hyperglycemic kidney disease.
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