Meta-analysis of the effects of SGLT2i on kidney outcomes

Hello, I'm associate professor Natalie Staplin and I'll be talking on Sodium-glucose cotransporter 2, or SGLT2, inhibitors amongst patients with and without diabetes, and the results of a collaborative meta-analysis of large placebo-controlled trials. Here are my disclosures.

The aims of this meta-analysis were to do a meta-analysis of a common composite kidney disease progression outcome and also a meta-analysis of acute kidney injury across all of the large trials of SGLT2 inhibitors. We are going to compare those findings in patients with and without diabetes. A subsidiary aim was also to look at whether there's any effect modification by primary kidney diagnosis in the CKD trials. We used a common outcome definition for kidney disease progression across all of the trials, and that was a sustained 50% eGFR decline for randomization, start of maintenance dialysis, or kidney transplantation, a sustained low eGFR of less than 10 or less than 15 depending on the trial-specific definition used, and death from kidney failure. For acute kidney injury, we used a specific MedDRA Preferred Term.

Here are the characteristics of the 13 trials included in the meta-analysis. There are a total of just over 90,000 participants, and around 16,000 of these participants didn't have diabetes. For kidney disease progression, overall there was a 37% relative risk reduction. Then when looking at the results by diabetes status, we now have around 500 events in the group without diabetes and there's no evidence of heterogeneity by diabetes status.

For the CKD trials, we also were able to collect data on primary kidney diagnosis. For CREDENCE and SCORED, it was assumed that every participant had diabetic kidney disease, but in DAPA-CKD and EMPA-KIDNEY, more detailed information was collected. Additional diagnoses were available such as ischemic and hypertensive kidney disease and glomerular disease. When we split out the results by the different types of primary kidney diagnosis, there's no evidence of heterogeneity suggesting that SGLT2 inhibitors work equally effectively across all of the types of kidney diseases that have been studied in the trials. When looking at the subgroup of glomerulonephritis, we can split it out even further into IgA nephropathy and FSGS. Again, here, there was no evidence of heterogeneity across the subtypes of glomerular disease, albeit with the caveat that we do have relatively small numbers in these groups. For acute kidney injury, overall there was a 23% relative risk reduction. Again, when looking at this separately by diabetes and no diabetes, there was no heterogeneity by diabetes status.

Although the meta-analysis primarily focused on renal outcomes, we also collected information on cardiovascular death or hospitalization for heart failure. Here there, again, was a 23% risk reduction with no evidence of heterogeneity by diabetes status.

For the safety outcomes that we collected, which were ketoacidosis and amputation, for ketoacidosis, there was a doubling of risk in the subgroup with diabetes. In the subgroup without diabetes, there was only one event of this type, which means that it's not actually feasible to estimate the relative risks in this group.

For lower limb amputation, when looking across all of the trials that have been done, there's a small increased risk of lower limb amputation, but this appears to be primarily driven by the CANVAS trial where there was a doubling of the risk of amputation. If looking at only at the 12 trials that don't include CANVAS, then there is no evidence of an increased risk of lower limb amputation.

Now, this slide looks at the predicted absolute effects of SGLT2 inhibitors for every 1000 years that you treat participants. On the y-axis of this diagram, are the number of events avoided or caused per 1000 patient-years of treatment. In people with diabetes, there are 11 kidney disease progression events avoided versus 15 in those without diabetes. For acute kidney injury, the numbers of events avoided are relatively similar, about five in each of the groups. Then for the outcome of CV death or hospitalization for heart failure, there are lots more events avoided in the group with diabetes due to the higher absolute risk of cardiovascular disease in those with diabetes. Around 11 events avoided in those with diabetes versus two in those without diabetes. In people with diabetes, there were some small increases in the rates of ketoacidosis and lower limb amputation, about one additional event of each type for every 1000 patient-years of treatment with SGLT2 inhibitors. These very small increases in adverse events are very much outweighed by the benefits seen on the kidney and cardiovascular death and hospitalization for heart failure outcomes. In the group without diabetes, the rates of ketoacidosis and lower limb amputation were so small that we didn't see any increases in these particular events in people without diabetes.

To summarize, in the populations that have been studied, SGLT2 inhibitors safely reduce the risk of kidney disease progression and acute kidney injury, irrespective of diabetes status. These benefits also do not appear to be modified by primary kidney diagnosis, and the absolute benefits of SGLT2 inhibitors far exceed the harm in patients with chronic kidney disease.