Macrovascular Residual Risk Studies

COMMENT

CKD poses a major burden, already affecting up to 15% of the global population, with prevalence almost doubling over the last 30 years in some regions (2,3). Although diabetes is a major cause (4), CKD is also prevalent among individuals without diabetes (4). Avoiding progression of CKD to end-stage renal disease (ESRD), which substantially impacts patient morbidity and quality of life (4) and increases cardiovascular risk (5), is a priority.

Large prospective outcome trials showed that treatment with an SGLT-2 inhibitor (empagliflozin or canagliflozin) reduced cardiovascular risk among high-risk individuals with type 2 DM. Exploratory analyses also suggested potential benefit on kidney disease progression (6-8), warranting further study. The first major trial to evaluate the effects of SGLT-2 inhibition on diabetic kidney disease progression (CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy) was stopped early on the recommendation of the Independent Data Monitoring Committee due to benefit in the treatment arm. Among 4,401 patients with type 2 DM and macroalbuminuria, treatment with canagliflozin reduced the primary endpoint, a composite of end-stage kidney disease parameters by 30% (p=0.00001) and was also associated with a significantly lower risk of cardiovascular death, myocardial infarction, or stroke (by 20%, p=0.01) (9). Another trial with dapagliflozin (DAPA-CKD) in 2,152 patients with and without type 2 DM was also stopped early due to positive efficacy. Treatment with dapagliflozin reduced the primary composite endpoint (sustained decline in eGFR of at least 50%, ESRD, or death from renal or cardiovascular causes) by 42% (p<0.001) (10). Thus, DAPA-CKD showed that benefit from SGLT-2 inhibition irrespective of the presence of diabetes.

The third trial of SGLT-2 inhibition, EMPA-KIDNEY, aimed to evaluate the efficacy and safety of empagliflozin in a widely generalizable population of people with CKD at risk of kidney disease progression. EMPA-KIDNEY differed from CREDENCE and DAPA-CKD in terms of patient composition. In EMPA-KIDNEY less than half of the patients had type 2 DM. Additionally, mean eGFR in EMPA-KIDNEY was ~38 mL/min/1.73m2, and only those patients with eGFR ≥45 mL/min/1.73m2 were required to have albuminuria (1). In contrast, in DAPA-CKD mean eGFR was ~43 mL/min/1.73m2, and all patients had at least microalbuminuria. Additionally, in CREDENCE, the mean eGFR was ~56 mL/min/1.73m2 and all patients had macroalbuminuria (9,10). Publication of the findings of EMPA-KIDNEY are eagerly awaited. In the meantime, the collective findings from these trials have important impact for the management of patients with CKD, with and without type 2 DM.