SGLT2 Inhibitor Use Rising in Diabetic
Kidney Disease

Mitchel L. Zoler, PhD

August 24, 2021

U.S. prescribing data from 160,000 adults with type 2 diabetes and diabetic kidney disease showed a notable uptick in new prescriptions for sodium-glucose cotransporter 2 inhibitors and less dramatic gains for glucagonlike peptide–1 receptor agonists during 2019 and continuing into early 2020, compared with prior years, with usage levels of both classes during the first quarter of 2020 rivaling those of more traditional agents including metformin and insulin.

During the first 3 months of 2020, initiation of a SGLT2 inhibitor constituted 13% of all new starts of an antidiabetes drug among adults with type 2 diabetes and diabetic kidney disease (DKD). This compared with initiation rates during the same early 2020 period of 17% for GLP-1 receptor agonists, 19% for metformin, 16% for sulfonylureas, 15% for insulins, 14% for thiazolidinediones, and 6% for dipeptidyl peptidase–4 inhibitors, the seven drug classes examined in a study published in Diabetes Care.

Early 2020 was the first time that starts of a GLP-1 receptor agonist ranked second (behind only metformin) among these seven drug classes in the studied U.S. population, and early 2020 also marked an unprecedentedly high start rate for SGLT2 inhibitors that nearly tripled the roughly 5% rate in place as recently as 2018.

Rises Are "What We Expected"

The recent rise of SGLT2 inhibitors and GLP-1 receptor agonists in these patients "was what we expected," given the evidence for both classes in slowing progression of DKD, said Julie M. Paik, MD, senior author on the study and a nephrologist and pharmacoepidemiologist at Brigham and Women's Hospital in Boston.

"We've seen other beneficial drugs slow on the uptake, so it's not surprising to see it here, and I'm optimistic" about further increases going forward, she said in an interview.

Both drug classes "were originally marketed as diabetes drugs," and it is only since 2019, with the publication of trials showing dramatic renal benefits from canagliflozin (Invokana) in CREDENCE, and from dapagliflozin (Farxiga) in DAPA-CKD in 2020 that the evidence became truly compelling for SGLT2 inhibitors. This evidence also led to new renal-protection indications approved by the Food and Drug Administration for canagliflozin and for dapagliflozin, noted Paik.

Evidence for renal protection also emerged in 2017 for the GLP-1 receptor agonist liraglutide (Victoza) in the LEADER trial, and for dulaglutide (Trulicity) in the AWARD-7 trial, although neither drug has received a renal indication in its labeling.

By 2020, guidelines for managing patients with type 2 diabetes and chronic kidney disease from the influential Kidney Disease: Improving Global Outcomes organization had identified agents from the SGLT2 inhibitor class as top-tier options, along with metformin, for treating these patients, with agents from the GLP-1 receptor agonist class as the top third class to add in patients who require additional glycemic control.

Additional analyses Paik and associates ran showed how this played out in terms of which specialists prescribed these drugs during the full period studied beginning in 2013. Throughout this roughly 7-year span, about 70% of the prescriptions written for either SGLT2 inhibitors or for GLP-1 receptor agonists were from internal medicine physicians, followed by about 20% written by endocrinologists. Prescriptions from nephrologists, as well as from cardiologists, have hovered at about 5% each, but seem poised to start rising based on the recently added indications and newer treatment recommendations.

"It's good to see the recent uptick in use since 2019," Katherine R. Tuttle, MD, commented in an interview. It's a positive development for U.S. public health, "but we need to do more to disseminate and implement these life-, kidney-, and heart-saving therapies."

Future Use Could Approach 80% of DKD Patients

Tuttle estimated that "target" levels of use for SGLT2 inhibitors and for GLP-1 receptor agonists "could reasonably approach 80%" for patients with type 2 diabetes and diabetic kidney disease.

"We will likely move to combination therapy" with simultaneous use of agents from both classes in a targeted way using "precision phenotyping based on clinical characteristics, and eventually perhaps by biomarkers, kidney biopsies, or both." Combined treatment with both an SGLT2 inhibitor and a GLP-1 receptor agonist may be especially suited to patients with type 2 diabetes, atherosclerotic cardiovascular disease, low estimated glomerular filtration rate, and need for better glycemic control and weight loss, a profile that is "pretty typical" in real-world practice, said Tuttle, a nephrologist and endocrinologist and executive director for research at Providence Healthcare in Spokane, Wash.

Study Included Patients With Commercial or Medicare Advantage Coverage

The study used information in an Optum database that included patients enrolled in either commercial or in Medicare Advantage health insurance plans from 2013 to the first quarter of 2020. This included 160,489 adults with type 2 diabetes and DKD who started during that period at least one agent from any of the seven included drug classes.

This focus may have biased the findings because, overall, U.S. coverage of the relatively expensive agents from the SGLT2 inhibitor and GLP-1 receptor agonist classes has often been problematic.

"There are issues of cost, coverage, and access" using these medications, as well as limited data on cost-effectiveness, Paik acknowledged. Additional issues that have helped generate prescribing lags include concerns about possible adverse effects, low familiarity by providers with these drugs early on, and limited trial experience using them in older patients. The process of clinicians growing more comfortable prescribing these new agents has depended on their "working through the evidence," she explained.

The FDA's approval in July 2021 of finerenone (Kerendia) for treating patients with type 2 diabetes and chronic kidney disease threw yet another new variable into the prescribing mix for these patients.

"SGLT2 inhibitors are here to stay as a new standard of care for patients with diabetic kidney disease, but combination with finerenone might be especially useful for patients with diabetic kidney disease and heart failure," Tuttle suggested. A new generation of clinical trials will likely soon launch to test these combinations, she predicted.

Paik had no disclosures. Tuttle has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

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