Panelists Argue for SGLT2 Inhibitors Uptake Among Nephrologists

In a session focused on sodium-glucose cotransporter 2 (SGLT2) inhibitors presented at the American Society of Nephrology’s (ASN) Kidney Week, experts highlighted the benefits of using this drug class in patients with kidney disease and outlined future steps for integration of care.

SGLT2 inhibitors were originally indicated for patients with diabetes, but in recent years have been shown to reduce the risk of heart failure, renal failure, and myocardial infarction, among other cardiovascular complications.

Results from the DAPA-CKD trial presented at this year’s European Society of Cardiology conference found dapagliflozin, the SGLT2 inhibitor sold as Farxiga, brought a 39% decline in the risk of declining kidney function, the onset of end-stage kidney disease, or kidney failure death in patients. Notably, one third of patients enrolled in this trial did not have diabetes, raising the prospect of using the treatment to prevent kidney failure in a new group of patients.

“Now we have this very, very compelling data showing that there are clear, unambiguous renal protective effects of these therapies,” said David Cherney, MD, PhD, a nephrologist, professor in the Department of Medicine at the University of Toronto, and a clinician scientist at the University Health Network and Mount Sinai Hospitals.

During his presentation, Cherney laid out why those in the renal community should avoid clinical inertia when it comes to SGLT2 inhibitors and stressed the importance of becoming familiar with these therapies.

Nephrologists may be hesitant to integrate these therapies into care due to concerns regarding potential for kidney injury, volume effects and hypotension, and management of glucose and hypoglycemia, as these may not be the standard areas of focus for nephrologists. However, findings from previous trials of SGLT2 inhibitors largely quell these concerns.

For example, although initial dips in estimated glomerular filtration rate (eGFR) have been documented with SGLT2 inhibitor use, data show “there is a return to baseline and stability over time.” In particular, results from the CREDENCE trial (conducted on canagliflozin) show there is no difference in terms of subsequent decline in kidney function due to the dip. “In canagliflozin-treated patients, it didn’t matter if you had a big, a medium, or no dip at all, there was a lesser decline in GFR over time compared to the placebo,” Cherney said.

Additional data from DAPA-CDK and DIAMOND illustrate the effects of dapagliflozin in people with non-diabetic kidney disease. SLGT-2 inhibition still leads to a dip in this population but the decrease was similar in magnitude and pattern to those with diabetes. “We also know from DAPA-CKD…there was no increase in the risk of renal related adverse events in this cohort of patients with and without diabetes and no imbalance around serious adverse events following depletion.”

The class of drugs is also associated with a lower risk of acute kidney injury (AKI), which may be due to preservation of renal profusion with SGLT 2 inhibitors, among other mechanisms.

However, Cherney cautioned, no medication will work for every patient. Those with a history of type 2 diabetes and ketoacidosis should not receive SGLT2 inhibitors, in addition to those who are catheterized, or have a recent history of kidney injury.

“Glucose lowering plays little or no role in cardiorenal protection with the SGLT2 inhibitors,” Cherney concluded. “SGLT2 inhibitors clearly have pleiotropic effects that are beyond glucose…We now need to work on implementation of the clinical trial data to help our patients in an optimal and safe way.”

Following this presentation, Matthew Cavender, MD, MPH, a professor of medicine and an interventional cardiologist at the University of North Carolina School of Medicine, elaborated on the epidemiological dyad of kidney disease, diabetes, and heart failure.

Although CDC data show that since 1990 patients with diabetes have experienced marked reductions in cardiovascular events, rates of end stage renal disease in this population have not significantly changed. By 2030, it is projected the United States will experience significant increases in obesity and severe obesity rates, driven largely by rises in women, non-Hispanic Black individuals, and low-income individuals. “Overall, the incidence of diabetes is significantly increasing, hand in hand with the increase of the obesity epidemic,” Cavender said.

“Diabetes, heart failure and kidney disease also go hand in hand with about two-thirds of patients with heart failure and diabetes also having chronic kidney disease.” He continued, “These diseases work adversely together, and we know that one of the biggest predictors of adverse events in patients who have heart failure is actually the presence of chronic kidney disease, and as chronic kidney disease progresses, the risk associated with heart failure goes up accordingly.”

When analyzing renal outcomes in SGLT2 inhibitor studies, there is a consistency in effects across both cardiovascular outcomes trials and those conducted on kidney disease. To illustrate his point, Cavender cited data from the DAPA-HF trial which included patients who had heart failure but not diabetes. Results of this trial confirmed dapagliflozin is just as effective in preventing cardiovascular death and heart failure events in patients who do not have T2D as in those who do. “Any effects that are related to glucose are not going to be seen in those patients who do not have heart failure,” Cavender explained.

Elaborating on how to best to incorporate SGLT 2-inhibitors in management, Cavender offered the following recommendations for nephrologists and cardiologists:

• Accept that diabetes is a renal and cardiovascular disease
• Agree that risk reduction, with regard to renal disease, is important in improving outcomes
• Understand the benefits with regard to renal outcomes
• Collaborate with your primary care physicians or endocrinologists or cardiologists
• Gain experience with utilization

“There is always a real challenge when we as clinicians adopt new therapies that make us feel somewhat uncomfortable. It pushes us out of our comfort zone. It makes us worried whether or not we’re doing things appropriately,” Cavender said. “The only way to really overcome those barriers is to utilize these medications, to rely on people who have experience with them. Rely on a multidisciplinary approach and over time, you will gain familiarity with it and become comfortable using [SGLT2 inhibitors].”