Initiation of SGLT2i vs GLP1-RA and the Risk of Chronic Kidney Disease in Persons with Type 2 Diabetes Mellitus

Background: Chronic kidney disease (CKD) is a frequent and serious complication to type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have proven effective in preventing CKD development in placebo-controlled trials and have consequently redefined the prevention of CKD among individuals with T2DM. However, no trial has directly compared the kidney protective properties of SGLT2i and GLP-1RA.

Objectives: To compare the risk of CKD between SGLT2i and GLP1-RA in an emulated target trial design.

Methods: Using data from nationwide Danish population-based registries, we included all adults with T2DM initiating SGLT2i or GLP1-RA during 2015-2020. We excluded patients with prevalent CKD, defined as two or more estimated glomerular filtration rate (eGFR) measurements < 60 mL/min/1.73 m2 at least 90 days apart and patients initiating GLP1-RA marketed specifically for treatment of obesity.
We assessed demographic and diabetes-related baseline characteristics along with comorbidities and comedication. We used creatinine measurements from primary care and outpatient hospital settings to identify CKD during follow-up. To reduce confounding, we estimated propensity scores using logistic regression and computed stabilized inverse probability of treatment weights. Using an intention to treat approach, we followed patients from treatment initiation until development of CKD, death, emigration, or end of follow-up (31 December 2021). We estimated the 5-year risks of CKD and mortality using the Aalen-Johansen estimator, and reported 5-year risk differences comparing SGLT2i to GLP1-RA.

Results: We included 56,008 individuals of which 67% initiated SGLT2i. Initiators of SGLT2i were older (median age 61 vs 58 years) and more often male (64% vs 57%) than initiators of GLP1-RA, but with similar median diabetes duration (6 vs 6 years) and median eGFR (93 vs 95 mL/min/1.73 m2). Initiators of SGLT2i had a slightly higher prevalences of cardiovascular comorbidities and a correspondingly higher use of lipid lowering and antiplatelet drugs compared with initiators of GLP1-RA. Moreover, fewer initiators of SGLT2i used insulin (10% vs 25%) and more used metformin (92% vs 88%). After inverse probability of treatment weighting, each variable was well balanced.
The weighted absolute risk of CKD at 5 years was 11.4% for initiators of SGLT2i, and 13.6% for initiators of GLP1-RA, resulting in a risk difference of -2.2% (95% CI: -3.1% to -1.3%).

Conclusions: Individuals with T2DM who initiated SGLT2i had slightly a lower 5-year risk of CKD than those initiating GLP1-RA.