Pooled results from 13 major trials of empagliflozin and similar medicines showed that they substantially reduce the risk of hospitalisation for heart failure and the risk of dying from cardiovascular disease in adults with chronic kidney disease (CKD) and other high risk conditions; the effects were similar in people with and without diabetes. The results were published today in The Lancet and presented at the American Heart Association Scientific Sessions 2022. Selected results were also presented at the American Society for Nephrology Conference, “Kidney Week”.
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors can help to lower blood glucose levels and were developed to treat diabetes. Previous studies of these medicines have shown that they reduce the risk of cardiovascular death or hospitalisation for heart failure in people with CKD and those with other high risk conditions. However, it was uncertain whether the treatments would work for patients without diabetes.
To answer this question, researchers from the Oxford Population Health Renal Studies Group and the SGLT2 Meta-analysis Cardio-Renal Trialists’ Consortium (SMART-C) combined the results from 13 comparable clinical trials of SGLT-2 inhibitors among 90,413 people with long-term kidney disease, heart failure, or Type 2 diabetes plus cardiovascular disease.
- SGLT-2 inhibitors reduced the risk of kidney disease progression by 37% overall (RR 0.63; 95% CI 0.58-0.69), with similar effects in those with and without diabetes.
- The risk of cardiovascular death or hospitalisation for heart failure was reduced by 23% (RR 0.77; CI 0.74-0.81), with similar effects in those with and without diabetes.
- The risk of acute kidney injury was reduced by 21% (RR 0.79; CI 0.72-0.86), with similar effects in those with and without diabetes.
- SGLT-2 inhibitors reduced the risk of cardiovascular death by 14% (RR 0.86; CI 0.81-0.92), again with similar effects in those with and without diabetes.
- Allocation to an SGLT-2 inhibitor did not significantly reduce the risk of non-cardiovascular death (RR 0.94; CI 0.88-1.02).
- The absolute benefits of SGLT-2 inhibition outweighed serious hazards. The absolute risk of ketoacidosis (a serious problem that can happen in people with diabetes if their body starts to run out of insulin) was low.
- An estimate of absolute rates, benefits and harms of SGLT2 inhibitors showed that, for every 1000 patients with CKD and type 2 diabetes treated for one year with an SGLT2 inhibitor, 11 fewer patients would develop kidney disease progression, four fewer patients would have acute kidney injury and there would be 11 fewer cardiovascular deaths or hospitalisations for heart failure; there would be one episode of ketoacidosis and one lower limb amputation.
- In patients with CKD without diabetes, there would be 15 fewer patients with kidney disease progression, five fewer with acute kidney injury, and two fewer cardiovascular deaths or hospitalisations for heart failure, with no excess risk of ketoacidosis or amputation.
Will Herrington, Associate Professor in the Medical Research Council Population Health Research Unit at the University of Oxford, and senior author of the study said ‘The majority of people with chronic kidney disease do not have diabetes and so it was important to find out whether these treatments would work for these patients. We now have very good evidence that they lower the chance of dying from cardiovascular disease or being hospitalised for heart failure in people at high risk of these outcomes.’
Natalie Staplin, Senior Statistician in the Medical Research Council Population Health Research Unit at the University of Oxford, and lead author of the study added ‘This new analysis included data from studies which included large numbers of people without diabetes, enabling us to assess the effects on a much broader population of patients than was previously possible. Our results suggest that SGLT-2 inhibitors such as empagliflozin should be offered to all adults who may benefit from the treatment, to reduce the risk of kidney disease progression and cardiovascular complications in people with chronic kidney disease or heart failure, regardless of whether they have diabetes or not.’
The authors acknowledge some limitations to this analysis: there were limited numbers of cardiovascular deaths and heart failure hospitalisations in patients with CKD without diabetes; summary data were used for the analyses since individual participant-level data from all of the trials is not yet available; the efficacy and safety of SGLT2 inhibitors in people with established kidney failure remains to be evaluated; there are insufficient data to assess the effects on kidney and cardiovascular clinical outcomes from the available trials in Type 1 diabetes; the absolute effect estimates are specific to the recruited trial populations.
The meta-analysis included results from the EMPA-KIDNEY trial, the largest study to assess the use of SGLT-2 inhibitors in people with CKD. Results from EMPA-KIDNEY were published on 4 November 2022 in the New England Journal of Medicine. The results showed that among the participants in the empagliflozin group, the risk of worsening kidney disease and death from cardiovascular disease decreased by 28%, with similar benefits for participants with and without diabetes.
This analysis was funded by core funding to the Medical Research Council Population Health Research Unit at the University of Oxford from the UK Medical Research Council. EMPA-KIDNEY was sponsored by Boehringer Ingelheim and funded by Boehringer Ingelheim and Eli Lilly and Company.