SGLT2 Inhibitors, Combination Therapy Needed to Stem the Tide of CKD in Diabetes

Rising rates of type 2 diabetes (T2D) worldwide are driving up incidence of chronic kidney disease (CKD), but these patients can reduce their risk of early death if physicians make better use of available therapies, starting with sodium glucose cotransporter 2 (SGLT2) inhibitors.

Katherine R. Tuttle, MD, FASN, FACP, FNKF, clinical professor of medicine, Division of Nephrology at the University of Washington, and executive director for research, Providence Health Care, called for a more holistic approach to addressing glucose control while also protecting the heart and the kidney late last month, as she addressed the American Society for Preventive Cardiology, meeting in Louisville, Kentucky.

Despite all that is known about prevention, Tuttle said, “Today, 4 out of 10 people with type 1 (diabetes) and 3 out of 10 with type 2 will still develop kidney disease. This is half of all chronic kidney disease worldwide,” she said. With 537 million people having diabetes in 2021, that translates into 200 million developing CKD; and the numbers with diabetes are forecast to reach 783 million by 2040.

“So, for the foreseeable future, all of us will be seeing more and more people with chronic kidney disease,” she said.

Tuttle offered additional data highlighting the interconnected nature of diabetes, heart failure, and CKD, noting the majority of patients with end-stage renal disease have diabetes. Cardiologists treat many of these patients, and they may be the first clinicians in a position to prescribe newer therapies that can halt renal progression. These are the highest risk patients who have the most to gain from what you have to offer,” she said.

Not that it’s been easy to sort through conflicting advice. Guidelines from groups such as the American Diabetes Association (ADA) and nephrology professional society may not have been well “harmonized,” Tuttle explained, leading to confusion for treating physicians. To that end, she was part a joint effort by the American Diabetes Association and KDIGO (Kidney Disease: Improving Global Outcomes) that presented a consensus statement in June. The statement called for renin-angiotensin system inhibitors and statins to be used as first-line treatment for all CKD patients, including those with type 1 diabetes (T1D). But significantly, multiple other new therapies were included in first-line treatment, even ahead of metformin.

Over the past decade, she said, trials involving SGLT2 inhibitors, glucagon-like peptide-1 receptor agonists, have demonstrated significant benefits to the heart, kidney, and all-cause mortality in patients with diabetes.

Although SGLT2 inhibitors were developed to treat T2D, many other benefits have been discovered because of cardiovascular outcomes trials, which were required by the FDA to rule out any safety issues. When the drug class was shown to have benefits in heart failure and prevention of renal decline, manufacturers launched dedicated trials in these areas; some are still awaiting results.

Tuttle highlighted both a meta-analysis and 2 dedicated kidney studies that had been published this far (EMPA-KIDNEY for empagliflozin is due to report results). “Importantly, both the heart and kidney benefits are present, even in this very high risk group of patients with established kidney disease,” she said.

Kidney outcomes—measures of estimated glomerular filtration rate (eGFR) that track kidney decline, showing the need for dialysis or transplant—have shown 40% risk reduction, while composites for heart failure, hospitalization for heart failure, and cardiovascular outcomes have declined 25%. Both “are enormous,” Tuttle said. Remember, especially people with kidney disease, these are the two major risks in this population. “This is really a breakthrough moment for us.”

She made special note of the historic significance of the DAPA-CKD study, which led to dapagliflozin receiving fast track breakthrough therapy designations in 2020—firsts in nephrology. Results showed a 39% risk reduction for a composite measure of worsening renal function or risk of cardiovascular or renal death among CKD patients already receiving standard of care. Reductions in all-cause death or hospitalization for cardiovascular disease or heart failure were also impressive.

More recently, Tuttle said, trials involving the nonsteroidal mineralocorticoid antagonist (MRA) finerenone, have shown that the potent anti-inflammatory effects have produced positive renal outcomes. (Last year, results presented at the European Society of Cardiology showed finerenone cut hospitalization 29% in the highest-risk patients.)

“So, we’re beginning to build the concept of combination therapy, because these drugs work very differently,” she said.

It’s extremely important, Tuttle said, for cardiologists to not rely solely on eGFR but also to screen for albuminuria, because that can help catch CKD in its earliest stages, when it’s treatable. She highlighted trial results that showed how finerenone’s results are not adversely affected by SGLT2 use, and then presented a case study about their concurrent use. “So, the beautiful thing about this is, is not only may these drugs be providing complementary efficacy, but it may be that using and SGLT2 inhibitor mitigates hyperkalemia and allows us to deliver finerenone safely.”