medwireNews: A meta-analysis published in The Lancet supports the use of sodium-glucose cotransporter (SGLT)2 inhibitors in people with chronic kidney disease, irrespective of whether they have type 2 diabetes.
The collaborative analysis from The Nuffield Department of Population Health Renal Studies Group and the SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium included 13 randomized placebo-controlled trials with 90,409 participants who were followed up for at least 6 months.
Writing in a linked commentary, Patrick Mark and Naveed Sattar, both from the University of Glasgow, UK, say: “This meta-analysis is expected to change chronic kidney disease guidelines with its robust findings on the benefits of SGLT2 inhibition in a wide range of patients with chronic kidney disease, including many without diabetes.”
Although the vast majority of participants had type 2 diabetes, four trials that focused on people with kidney disease included 4967 participants without diabetes. All included participants had high cardiorenal risk, in the form of a high risk for atherosclerotic disease, prevalent heart failure, or renal disease.
Across all the trials, taking an SGLT2 inhibitor rather than placebo was associated with a significant 37% reduction in the risk for the composite renal endpoint of a sustained decrease in estimated glomerular filtration rate (eGFR) of at least 50%, a sustained low eGFR, end-stage kidney disease, or death from renal failure.
In the trials focused on people with chronic kidney disease, SGLT2 inhibitor treatment was associated with a significant 40% reduction in the risk for progression among people with diabetic kidney disease or nephropathy, a significant 40% reduction among those with glomerular disease, and a 30% reduction among people with ischemic and hypertensive renal disease.
Taking an SGLT2 inhibitor also significantly reduced the risk for cardiovascular death or heart failure hospitalization, by 23%, and for cardiovascular death alone by a significant 14%, with these effects seen regardless of whether participants had diabetes. The size of the risk reductions was not influenced by baseline eGFR for any outcome.
In addition to these benefits on cardiorenal outcomes, Mark and Sattar stress that “[c]oncerns around acute kidney injury risk with SGLT2 inhibition based on theoretical risk of volume depletion have also been rebuffed.”
Indeed, across all trials in the meta-analysis, SGLT2 inhibition was associated with a significant 23% reduction in the risk for acute kidney injury, relative to placebo, with this effect seen both in participants with and without diabetes. And even for this outcome the team found “no strong evidence” for any differences according to baseline eGFR.
The risk for diabetic ketoacidosis was increased in people allocated to an SGLT2 inhibitor, by a significant 2.12-fold; however, the researchers note that the absolute risk for this outcome was low, with a rate of about 0.2 events per 1000 person–years in people with diabetes taking placebo.
The researchers therefore conclude that the benefits of SGLT2 inhibition “considerably outweighed any serious hazards,” and it should be regarded “as a foundational therapy” in people with chronic kidney disease “irrespective of diabetes status, primary kidney diagnosis, or level of kidney function.”
Mark and Sattar agree, but also highlight some remaining questions, such as the size of benefits in mild disease, the safety and benefits in end-stage disease, and the risk–benefit balance in people with type 1 diabetes who also have kidney disease.
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Lancet 2022; doi:10.1016/S0140-6736(22)02074-8
Lancet 2022; doi:10.1016/S0140-6736(22)02164-X