‘Clear’ reduction in CV, renal outcomes with SGLT2 inhibitors across all high-risk groups
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CHICAGO — A meta-analysis of 13 large SGLT2 inhibitor trials, including the recently published EMPA-KIDNEY trial, indicates that the drug class reduces CV and renal outcomes across all high-risk groups, with and without type 2 diabetes.
“There have been a number of studies of these drugs in different populations, and EMPA-KIDNEY is one of the most recent,” David Preiss, PhD, FRCPath, MRCP, associate professor and honorary consultant in metabolic medicine at the Medical Research Council Population Health Research Unit at the University of Oxford, U.K., said during a press conference at the American Heart Association Scientific Sessions. “However, these benefits may occur regardless of whether the patients have or do not have CVD, and, indeed, benefits may also accrue regardless of whether a patient has diabetes in high-risk individuals. The CV benefits of these treatments may be similar across high-risk groups in these trials, and that is what we wanted to explore.”
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As Healio previously reported, EMPA-KIDNEY showed that empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) safely reduced the composite primary outcome of chronic kidney disease (CKD) progression or CV death by 28%; relative benefits were consistent across the range of estimated glomerular filtration rate (eGFR) to at least 20 mL/min/1.73 m2. The findings were first presented at the American Society of Nephrology Kidney Week.
“With regard to CV outcomes ... the trial showed overwhelming renal disease benefit; so much so that the primary outcome was dominated by the kidney benefit of the trial, and we did not have enough events in terms of CV outcomes to show significant benefit, at least in this one trial,” Preiss said. “That is why it makes sense to look at the other trials as well.”
In a new systematic review and meta-analysis, Preiss and colleagues analyzed data from 13 randomized, double-blind, placebo-controlled trials with 90,409 participants that assessed efficacy and safety of SGLT2 inhibitor therapy. Participants were stratified into three groups: participants with type 2 diabetes at high CV risk; participants with HF; and participants with CKD. The main efficacy outcomes were kidney disease progression, defined as a sustained 50% or more decrease in eGFR from randomization, a sustained low eGFR, end-stage kidney disease or renal death; acute kidney injury; and a composite of CV death or HF hospitalization. Other outcomes were death from CV and non-CV causes considered separately. The main safety outcomes were ketoacidosis and lower limb amputation.
The meta-analysis findings were presented at the AHA Scientific Sessions and simultaneously published in The Lancet.
Across studies, 82.7% had type 2 diabetes and 17.3% did not. The trial-level mean baseline eGFR ranged from 37 mL/min per 1.73 m² to 85 mL/min per 1.73 m².
Compared with placebo, allocation to an SGLT2 inhibitor reduced risk for kidney disease progression by 37% (RR = 0.63; 95% CI, 0.58-0.69), with similar RRs in patients with and without diabetes.
In the four CKD trials, RRs were similar irrespective of primary kidney diagnosis. SGLT2 inhibitors reduced risk for acute kidney injury by 23% (RR = 0.77; 95% CI, 0.7-0.81) and risk for CV death or HF hospitalization by 23% (RR = 0.77; 95% CI, 0.74-0.81), also with similar effects in those with and without diabetes.
SGLT2 inhibitors also reduced risk for CV death (RR = 0.86; 95% CI, 0.81-0.92) but did not reduce risk for non-CV death (RR = 0.94; 95% CI, 0.88-1.02). Results did not change in analyses stratified by diabetes status.
“Overall, what you see is a very significant and consistent reduction in CV death across these high-risk populations, importantly, regardless of whether these patients had diabetes or not,” Preiss said during the press conference.
For all outcomes, results were broadly similar irrespective of trial mean baseline eGFR, Preiss said.
Based on estimates of absolute effects, the absolute benefits of SGLT2 inhibition outweighed any serious hazards of ketoacidosis or amputation.
“In the meta-analysis of 13 trials, including EMPA-KIDNEY, patients with diabetes derived significant benefit for both renal and CVD outcomes, regardless of whether or not they had CVD,” Preiss said. “For patients without diabetes, there were clear reductions and a benefit in patients with HF and in renal disease.”
Preiss said more information is still needed regarding any benefit with SGLT2 inhibition in adults with CKD without diabetes.
References:
- Diabetes medicine decreased cardiovascular risk in adults with chronic kidney disease. https://newsroom.heart.org/news/diabetes-medicine-decreased-cardiovascular-risk-in-adults-with-chronic-kidney-disease. Published Nov. 6, 2022. Accessed Nov. 6, 2022.
- The Nuffield Department of Population Health Renal Studies Group, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)02074-8.
Perspective
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Janani Rangaswami, MD, FACP, FCRS, FAHA
EMPA-KIDNEY builds on the signal we already have for kidney and heart protection from the DAPA-CKD and CREDENCE trials. Importantly, it broadens the population of risk. Particularly in CKD, there has been this one problematic area, which is the CKD patient who is not diabetic but has proteinuria. That is akin to the HF with preserved ejection fraction phenotype in cardiology. These data are also a win for people with CKD stage 4, who do not have many options for therapy.
EPMA-KIDNEY showed a 14% relative risk reduction for all-cause hospitalizations. We should all take note of this as cardiologists and nephrologists because this is a population at high risk for hospitalizations.
While the actual secondary composite endpoint for HF hospitalizations and CVD did not meet statistical significance, it definitely aligns with the totality of the messaging, as was reinforced with this nicely done meta-analysis.
The important message here is there is going to be heterogeneity in the populations we have studied, especially when trials are stopped early for efficacy. There are different rates of established CKD across trials, and importantly, the rate of albuminuria in EMPA-KIDNEY was one-third of what it was in other trials, and that is a big risk enhancer for CVD events. All those factors may contribute to the lower-than-expected CVD rate that was seen in EMPA-KIDNEY, but in no way does it diminish any of the findings. This is a very welcome addition to the already very strong body of evidence that we have. To paraphrase Eugene Braunwald, MD, the SGLT2 inhibitors are the statins of the 21st century.
Department of Nephrology
Einstein Medical Center
Clinical Associate Professor
Thomas Jefferson University, Philadelphia
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Preiss D, et al. LBS.05. Late Breaking Science: Changing how we prevent cardiovascular and renal disease. Presented at: American Heart Association Scientific Sessions; Nov. 5-7, 2022; Chicago (hybrid meeting).
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