The Changing Trajectory of Diabetic Kidney Disease

Nupur Mistry; George L. Bakris


Curr Opin Nephrol Hypertens. 2023;32(1):98-102. 

In This Article

Abstract and Introduction


Purpose of Review: Progression of diabetic kidney disease has slowed over the past 40 years by as much as 70–75%, thanks to a diversity of drug classes that have less effect on glucose and more on reducing cardiorenal risk.

Recent Findings: With the advent of sodium-glucose co-transporter 2 (SGLT2) inhibitors and the novel nonsteroidal mineralocorticoid antagonist, finerenone, we now have three 'pillars of therapy' considering the renin–angiotensin system (RAS) inhibitors as already established treatment to slow diabetic kidney disease. Both renal and cardiovascular outcomes trials have provided solid evidence of the benefit by these agents to slow kidney disease progression and reduce heart failure hospitalizations. Using these agents together reduces the risk of hyperkalemia by finerenone and further reduces albuminuria in animal models. Trials are underway to also see if the glucagon-like peptide 1 receptor agonist, semaglutide, will also protect against diabetic kidney disease progression as seen in post hoc analyses of positive cardiovascular outcome trials. If positive, this would be the fourth pillar to support cardiorenal protection without fear of hypoglycemia.

Summary: Nephrologists now have three different agents neither of which has a major effect on blood pressure but both add to further reduce progression of diabetic nephropathy and hospitalization from heart failure.


After the discovery that angiotensin-converting enzyme (ACE) inhibitors could slow the progression of kidney disease in 1993, it was almost another decade before we had confirmation that another method of inhibiting the renin–angiotensin system (RAS) with angiotensin receptor blockers (ARBs) was also able to slow diabetic kidney disease (DKD) progression.[1] However, following this discovery, there was a failure for almost 20 years to develop novel therapies that would further slow kidney disease progression related to diabetes despite significant research, Figure 1. It was not until 2016 that we had evidence that inhibition of the sodium-glucose co-transport 2 (SGLT 2) receptor could slow the progression of DKD.[2] An additional 4 years later, we noted that a novel class of agents, nonsteroidal mineralocorticoid receptor antagonists (NSMRAs), specifically finerenone, could also slow kidney disease progression independent of glycemic or blood pressure control.[3] Moreover, SGLT2 inhibitors and finerenone could reduce the risk of heart failure development and hospitalization.[4] Thus, now we have two additional classes of agents to add to RAS blockers that could be used in a complementary fashion mechanistically to slow the progression of DKD and further reduce heart failure hospitalizations.

Figure 1.

Post RENAAL and IDNT, new therapeutic strategies for patients with type 2 diabetes mellitus and chronic kidney disease that failed. 1. Tuttle KR, et al. Clin J Am Soc Nephrol. 2007;2(4):631–636. 2. Mann JFE, et al. J Am Soc Nephrol. 2010;21(3):527–535. 3. Sharma K, et al. J Am Soc Nephrol. 2011;22(6):1144–1151. 4. Packham DK, et al. J Am Soc Nephrol. 2012;23(1);123–130. 5. Parving HH, et al. N Engl J Med. 2012;367(23):2204–2213. 6. Fried LF, et al. N Engl J Med. 2013;369(20):1892–1903. 7. de Zeeuw D, et al. N Engl J Med. 2013;369(26):2492–2503.

These three 'pillars of therapy' work in a complementary fashion to further slow DKD progression, and as a result, we have been able to slow renal functional decline from approximately 10–12 ml/min per year loss in the early 1980s with no specific therapy to now about 2–3 ml/min/year. Note that the average loss of kidney function in people without kidney disease or diabetes is about 0.7–0.9 ml/year (Figure 2). This article will present a brief overview of the data focused exclusively on the advanced DKD cohort of patients that have been evaluated with SGLT 2 inhibitors and finerenone, and how these agents can all work together as 'pillars of therapy' to further slow kidney disease progression more than any two agents.

Figure 2.

Historical perspective on slowing chronic kidney disease progression associated with diabetes. ACE inhibitors, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; NDCCB, nondihydropyridine calcium channel blockers (e.g. diltiazem); NS-MRA, nonsteroidal mineralocorticoid receptor antagonist (i.e. finerenone).

Lastly, we will discuss another novel therapy being developed to further slow kidney disease progression, the glucagon-like peptide receptor agonists (GLP1-RAs). Post hoc analyses of previous cardiovascular outcome trials demonstrate a benefit in slowing kidney disease progression by evaluating surrogate markers of disease progression.[5] Moreover, there is an ongoing clinical outcome trial on background RAS blocking therapy to assess the effect of semaglutide on kidney disease progression; the FLOW trial.[6]