Treatment of Diabetic Kidney Disease: Current and Future

Abstract

Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease. However, only renin-angiotensin system inhibitor with multidisciplinary treatments is effective for DKD. In 2019, sodium-glucose cotransporter 2 (SGLT2) inhibitor showed efficacy against DKD in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, adding a new treatment option. However, the progression of DKD has not been completely controlled. The patients with transient exposure to hyperglycemia develop diabetic complications, including DKD, even after normalization of their blood glucose. Temporary hyperglycemia causes advanced glycation end product (AGE) accumulations and epigenetic changes as metabolic memory. The drugs that improve metabolic memory are awaited, and AGE inhibitors and histone modification inhibitors are the focus of clinical and basic research. In addition, incretin-related drugs showed a renoprotective ability in many clinical trials, and these trials with renal outcome as their primary endpoint are currently ongoing. Hypoxia-inducible factor prolyl hydroxylase inhibitors recently approved for renal anemia may be renoprotective since they improve tubulointerstitial hypoxia. Furthermore, NF-E2-related factor 2 activators improved the glomerular filtration rate of DKD patients in Bardoxolone Methyl Treatment: Renal Function in chronic kidney disease/Type 2 Diabetes (BEAM) trial and Phase II Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) trial. Thus, following SGLT2 inhibitor, numerous novel drugs could be utilized in treating DKD. Future studies are expected to provide new insights.

Keywords: Diabetic nephropathies; Epigenomics; Glycation end products, advanced; Hypoxia-inducible factor 1; NF-E2-related factor 2; Sodium-glucose transporter 2.

Fig. 1.

The concept of diabetic kidney disease and diabetic nephropathy. GFR, glomerular filtration rate.

Fig. 2.

The time course of current treatments. BENEDICT, Bergamo Nephrologic Diabetes Complications Trial; IRMA-2, Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study; MARVAL, Microalbuminuria reduction with valsartan; INNOVATION, Incident to overt: Angiotensin II receptor blocker, Telmisartan, Investigation On type II diabetic Nephropathy; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; IDNT, Irbesartan in Diabetic Nephropathy Trial; ROADMAP, Randomized Olmesartan and Diabetes Microalbuminuria Prevention; J-DOIT3, Japan Diabetes Optimal Integrated Treatment study for 3 major risk factors of cardiovascular disease; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; RAS, renin-angiotensin system; SGLT2, sodium-glucose cotransporter 2.

Fig. 3.

The time course of future treatments. LEADER, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SUSTAIN-6, the preapproval Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; AWARD-7, Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease; Nrf2, NF-E2–related factor 2; BEAM, 52-Week Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes; BEACON, the Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: the Occurrence of Renal Events; TSUBAKI, the Phase II Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes; AYAME, a Phase 3 Study of Bardoxolone Methyl in Patients with Diabetic Kidney Disease; HIF-PH, hypoxia inducible factor prolyl hydroxylase; AGE, advanced glycation end-product; ACTION, the Aminoguanidine Clinical Trial in Overt Nephropathy; PYR, pyridoxamine.