New Agents, Clinical Research Promise More Personalized Treatment for Patients with Diabetic Kidney Disease, Type 2 Diabetes

New developments and clinical trials in SGLT-2 inhibitors and GLP-1 receptor agonists are showing promise for the treatment of patients with diabetic kidney disease as a result of type 2 diabetes. Continued developments in this space could lead to more personalized care, according to research published in BMC Medicine.

Diabetic kidney disease is the most common cause of kidney failure and end-stage kidney disease worldwide and will develop in nearly half of all patients with type 2 diabetes. Additionally, it is a leading cause of cardiovascular disease and overall mortality in individuals with diabetes. With the incidence of type 2 diabetes continuing to rise, early detection and management of diabetic kidney disease is essential.

In a new review, investigators aimed to provide a comprehensive clinical update for diabetic kidney disease in patients with type 2 diabetes, with a specific focus on new treatment modalities. Several strategies exist to help prevent the development of diabetic kidney disease and slow its progression, in addition to healthy lifestyle changes. Current goals for patients with type 2 diabetes include managing glycemic control, controlling blood pressure, managing cholesterol levels, and implementing lifestyle changes.

SGLT-2 inhibitors have shown particular promise. Two double-blind, randomized, placebo-controlled trials (CREDENCE and DAPA-CKD) have included kidney disease endpoints as the primary outcome, according to the study.

In the CREDENCE trial, participants assigned to receive canagliflozin had a 30% reduced risk of the primary kidney composite outcome, including end-stage kidney disease, doubling of serum creatinine from baseline sustained for at least 30 days, or death from kidney or cardiovascular disease causes. A similar effect was seen in the DAPA-CKD trial, with participants in the dapagliflozin arm having a 39% reduced risk of the primary kidney composite outcome (>50% decline in estimated glomerular filtration rate or kidney- or cardiovascular-related death).

Other clinical trials with SGLT-2 inhibitors have investigated kidney disease outcomes as a secondary outcome. Four trials (EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, and EMPEROR REDUCED) reported lower rates of kidney disease composite outcomes in patients assigned to the active drug than patients assigned to placebo. One study, eValuation of ERTugliflozin efficacy and safety—CardioVascular outcomes (VERTIS-CV), reported no significant difference in their secondary kidney disease outcome between those receiving ertugliflozin versus placebo.

Cardiovascular outcome trials have also investigated GLP-1 receptor agonists in patients with type 2 diabetes with kidney disease outcomes as secondary outcomes, although there are currently no published studies of GLP-1 receptor agonists with kidney outcomes as primary outcome. These trials included investigations of liraglutide; dulaglutide; albiglutide plus standard blood glucose-lowering therapies; semaglutide; lixisenatide; and efpeglenatide. All of these trials reported significantly lower rates of kidney disease outcomes in participants assigned to the active drug compared with those assigned to placebo, or active drug compared to insulin.

Other GLP-1 receptor agonist trials have reported on individual kidney disease measures. In the Harmony Outcomes trial, researchers found a between-group difference (albiglutide vs placebo) in change in eGFR at 8 months and at 16 months. Similarly, the SUSTAIN-6 trial reported a significantly lower risk of new or worsening nephropathy or persistent macroalbuminuria among those receiving semaglutide compared with placebo.

Two recent studies have reported on the effects of a non-steroidal mineralocorticoid receptor antagonist, finerenone, on kidney disease outcomes. Finerenone demonstrated positive results in the FIDELIO-DKD trial with kidney disease endpoints as primary outcomes. Specifically, participants assigned to finerenone had an 18% lower risk of the primary composite outcome compared with those assigned to placebo.

The FIGARO-DKD trial included kidney disease endpoints as secondary outcomes. Participants assigned to finerenone had a 23% lower risk of the composite kidney disease outcome of first occurrence of kidney failure, sustained decrease from baseline eGFR of 57% or greater for 4 or more weeks, or kidney disease death.

Both the FIDELIO-DKD and FIGARO-DKD trials included participants with type 2 diabetes and diabetic kidney disease who were on a maximally tolerated dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

Based on these findings, the investigators concluded that treatment with SGLT-2 inhibitors and GLP-1 receptor agonists has proven to reduce the risk for a combined major adverse cardiovascular event endpoint. Despite these new therapeutic opportunities, the risk of diabetic kidney disease progression remains. Evidence does suggest, however, that treatment with a mineralocorticoid receptor could play a role in controlling inflammation and fibrosis in this progression.

REFERENCE

Forst T, Mathieu C, Giorgino F, Wheeler D, Papanas N, Schmieder R, et al. New strategies to improve clinical outcomes for diabetic kidney disease. BMC Medicine. October 10, 2022. Accessed October 24, 2022. https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-022-02539-2