Kidney Failure–Free Survival Increased With ACE, SGLT2 Inhibitors


Treatment with an angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker and sodium-glucose cotransporter-2 (SGLT2) inhibitor combination demonstrated better outcomes in kidney failure.

Patients with albuminuric chronic kidney disease (CKD) had increased kidney failure–free survival when receiving a combination of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors, according to a study published in Clinical Journal of the American Society of Nephrology.

Although half of patients with CKD do not have diabetes, high rates of kidney failure and mortality are found in many. Risk of progressive kidney disease has been reduced through SGLT2 treatment in the past, which can also reduce the risk of heart failure and death. This study aimed to estimate the benefit of ACE inhibitor/ARB and SGLT2 inhibitor use vs no treatment in patients with albuminuric CKD and without diabetes.

The Ramipril Efficacy in Nephropathy (REIN) trial; the Guangzhou trial from Guangzhou, China; and the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial were used to obtain data for the present study.

The REIN trial included 352 patients aged 18 to 70 years who were enrolled from 1994 to 1995. The participants were split into 2 groups; 1 group received ramipril and the other received a placebo. The participants were followed for a median of 2.1 years. The Guangzhou trial enrolled 422 patients from 1999 to 2001 who were aged 18 to 70 years. Half of the participants received benazepril and the other half received a placebo. Participants were followed for a median of 3.0 years. DAPA-CKD enrolled 4304 patients between 2017 and 2020 who were 18 years and older and had diagnosed CKD with or without diabetes. Half of the patients received dapagliflozin once daily and the other half a placebo. The median follow-up was 2.4 years. The observational cohort were enrolled from the CRIC study, comprised a racially and ethnically diverse samples of patients with CKD.

The mean age of the participants in this study ranged from 45 to 62 years, the mean estimated glomerular filtration rate was 20 to 43 mlLmin/1.73 m2, and the median urinary albumin-creatinine ratio was 949 to 1499 mg/g.

The researchers found that the HR for combination ACE inhibitor/ARB and SGLT2 inhibitor vs no treatment for the incidence of doubling serum creatinine, kidney failure, or all-cause death was 0.35 (95% CI, 0.30-0.41). The HR for the incidence of doubling of serum creatinine or kidney failure was 0.33 (95% CI, 0.27-0.41).

In the 697 patients in the DAPA-CKD trial that were randomized to active treatment, 8% of patients experienced the primary end point of the current study and 6% experienced the secondary end point, which was a composite of sustained doubling of serum creatinine or kidney failure.

When treated with a combination of an ACE inhibitor/ARB and SGLT2 inhibitor, the estimated difference in risk was 17% to 29% in 3 years for the primary end point and 15% to 22% in 3 years for the secondary end point.

The estimated survival free from the primary end point in patients aged 50 to 75 years was 17.0 years (95% CI, 12.4-19.6) in patients with the combination therapy and 9.6 years (95% CI, 8.4-10.7) in those without treatment. Event-free survival also gained 8.0 years (95% CI, 6.3-9.6) for the secondary end point.

Event-free survival also saw gains in each age group, as for patients aged 55, 60, and 65 years it increased by 5.6 (95% CI, 4.8-6.6), 3.6 (95% CI, 3.0-4.2), and 2.8 (95% CI, 2.3-3.3) yers, respectively, when on the combination therapy.

There were some limitations to this study. There was no direct information for the combination therapy about the effect additivity, constancy, and adherence. Costs and adverse effects of combination therapy were not investigated in this study. In addition, it was unclear if SGLT2 inhibitors have a similar efficacy to dapagliflozin and if this effect is similar in patients with and without diabetes.

The researchers concluded that patients with albuminuric CKD without a diagnosis of diabetes may benefit from combination disease-modifying treatment with ACE inhibitors/ARBs and SGLT2 inhibitors, which could improve the number of years without kidney failure and mortality.


Vart P, Vaduganathan M, Jongs N, et al. Estimated lifetime benefit of combined RAAS and SGLT2 inhibitor therapy in patients with albuminuric CKD without diabetes. Clin J Am Soc Nephrol. 2022;17:1754-1762. doi:10.2215/CJN.08900722

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