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Macrovascular Residual Risk Studies

19 July 2022
EMPA-KIDNEY trial stopped early due to evidence of efficacy
EMPA-KIDNEY ( Identifier: NCT03594110) was testing whether empagliflozin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, prevents kidney disease progression or cardiovascular death in patients with chronic kidney disease (CKD). The trial was stopped on 16 March on the recommendation of the Independent Data Monitoring Committee due to evidence that empagliflozin is more effective than the placebo.
Objective: To investigate the effect of empagliflozin on kidney disease progression or cardiovascular death versus placebo on top of standard of care in patients with pre-existing CKD.
Study design: Multicentre, international, randomized, parallel-group, double-blind, placebo-controlled trial. Eligible patients with and without diabetes mellitus (DM) were randomized to treatment with empagliflozin 10 mg daily or matching placebo.
Study population: The trial randomized patients from eight countries in Europe, North America and East Asia. Eligible patients had evidence of CKD and were at risk of kidney disease progression, defined by at least 3 months before and at the time of Screening Visit as:
• estimated glomerular filtration rate (eGFR) ≥20 to <45 mL/min/1.73m² or
• eGFR ≥45 to <90 mL/min/1.73m² with urinary albumin:creatinine ratio ≥200 mg/g (or protein:creatinine ratio ≥300 mg/g).
Srudy outcomes: The composite primary outcome was time to first occurrence of:
(i) kidney disease progression (defined as End Stage Kidney Disease [ESKD], a sustained decline in eGFR to <10 mL/min/1.73m², renal death, or a sustained decline of ≥40% in eGFR from randomization). ESKD was defined as the initiation of maintenance dialysis or receipt of a kidney transplant or
(ii) Cardiovascular death.

According to published baseline data (1), EMPA-KIDNEY enrolled 6,609 patients (mean age 63.8 years, 33% female, 54% with no history of DM) between 15 May 2019 and 16 April 2021. Mean eGFR was 37.5 (14.8) mL/min/1.73m2; 5185 (78%) had an eGFR <45 mL/min/1.73m2. The causes of kidney disease included diabetic kidney disease (n=2057 [31%]), glomerular disease (n=1669 [25%]), hypertensive/renovascular disease (n=1445 [22%]), other (n=808 [12%]), and unknown causes (n=630 [10%]).

The trial was stopped early on the recommendation of the Independent Data Monitoring Committee due to evidence of significant efficacy versus placebo. Details relating to the efficacy results were not provided at this time.


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.

References 1. EMPA-KIDNEY Collaborative Group. Design, recruitment, and baseline characteristics of the EMPA-KIDNEY trial. Nephrol Dial Transplant 2022; doi: 10.1093/ndt/gfac040. Online ahead of print.
2. GBD 2015 Eastern Mediterranean Region Diabetes and Chronic Kidney Disease Collaborators. Diabetes mellitus and chronic kidney disease in the Eastern Mediterranean Region: findings from the Global Burden of Disease 2015 study. Int J Public Health 2018;63 (Suppl 1):S177–186.
3. Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease – a systematic review and meta-analysis. Plos One 2016;11(7):e0158765.
4. Jha V, Garcia-Garcia G, Iseki K. et al. Chronic kidney disease: global dimension and perspectives. Lancet 2013; 382: 260–272.
5. Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010;375:2073–2081.
6. Neal B, Perkovic V, Mahaffey KW. et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377: 644–657.
7. Zinman B, Wanner C, Lachin JM. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117–2128.
8. Wanner C, Inzucchi SE, Lachin JM. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323–334.
9. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-2306.
10. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-1446.
Key words SGLT-2 inhibitor; chronic kidney disease; empagliflozin; kidney disease progression; cardiovascular death