Most Impactful Clinical Trials for Slowing CKD Progression

This is a highly subjective list, but these trials have been included as they have had a meaningful impact on guidelines, patients and clinicians at a global scale.

1. IDNT: Irbesartan Diabetic Nephropathy Trial

A randomized, blinded, placebo-controlled trial designed to assess whether irbesartan or amlodipine slow the progression of nephropathy in patients with type 2 diabetes, independent of effects on systemic blood pressure (BP) lowering.

The primary outcome, a composite of doubling of serum creatinine, onset of end-stage renal disease, serum creatinine ≥6.0 mg/dl, or death from any cause, was reduced by 23% compared to the amlodipine group (32.6% vs. 41.1%, p=0.006).

The authors found that the angiotensin-II–receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.

https://www.nejm.org/doi/full/10.1056/nejmoa011303

2. RENAAL: Reduction in End Points in NIDDM with the Angiotensin II Antagonist Losartan study

In this study, it was shown that losartan reduced the incidence of a doubling of the serum creatinine concentration and end-stage renal disease. The benefit exceeded that attributable to changes in blood pressure.

It was published at the same time as the IDNT study.

https://www.nejm.org/doi/full/10.1056/nejmoa011161

3. The Effect of Angiotensin-Converting-Enzyme Inhibition on Diabetic Nephropathy

This was a randomized, controlled trial comparing captopril with placebo in patients with type 1 diabetes mellitus who had protein in the urine of ≥ 500 mg per day.

This was an important study as it showed that captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death, dialysis, and transplantation. Notably, it was significantly more effective than blood-pressure control alone.

https://www.nejm.org/doi/full/10.1056/NEJM199311113292004

4. CREDENCE: Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

The first study to show that an SGLT2i can reduce kidney outcomes in patients with diabetes and kidney disease.

This study showed that in patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group.

https://www.nejm.org/doi/full/10.1056/nejmoa1811744

5. DAPA-CKD: Dapagliflozin in Patients with Chronic Kidney Disease

The first study to show that an SGLT2i can reduce kidney outcomes in both people with and people without diabetes.

Specifically, the authors found that among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo.

https://www.nejm.org/doi/full/10.1056/NEJMoa2024816

6. FIDELIO: Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes

While MRAs, including finerenone (a nonsteroidal, selective mineralocorticoid receptor antagonist) had been shown to reduce albuminuria in short-term trials involving patients with chronic kidney disease (CKD) and type 2 diabetes, long-term benefits on kidney and cardiovascular outcomes were unknown.

This was the first study that showed that in patients with CKD and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo.

https://www.nejm.org/doi/full/10.1056/NEJMoa2025845

7. EMPA-KIDNEY: Empagliflozin in Patients with Chronic Kidney Disease

The first study to show that an SGLT2i can reduce kidney and cardiovascular outcomes in both people with and people without diabetes, independent of whether albuminuria is present.

Specifically, the authors found that among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin led to a lower risk of progression of kidney disease or death from cardiovascular causes.

https://www.nejm.org/doi/full/10.1056/NEJMoa2204233