Kidney Outcomes with GLP-1 Receptor Agonists in Patients on SGLT2 Therapy

Key Takeaways

• GLP-1 receptor agonist initiation was linked to less frequent kidney disease progression than DPP-4 inhibitor or sulfonylurea initiation in this observational comparison.
• The primary kidney endpoint combined at least 40% eGFR decline, end-stage kidney disease, or death from kidney-related causes.
• No association was observed with acute pancreatitis or incident diabetic retinopathy.

Among adults with type 2 diabetes already using SGLT2 inhibitors, starting a GLP-1 receptor agonist was associated with less kidney disease progression than starting a DPP-4 inhibitor or sulfonylurea. In the UK primary care target trial emulation, the adjusted hazard ratio was 0.73 (95% CI 0.58-0.92).

The study emulated a pragmatic target trial with an active-comparator, new-user design in UK primary care records from March 31, 2013, to March 31, 2023. Investigators used the Clinical Practice Research Datalink with linkage to hospital inpatient, deprivation, and mortality data, and analyzed outcomes with intention-to-treat Cox models and double-robust overlap weighting. Eligible adults had type 2 diabetes, were already receiving SGLT2 inhibitors, and newly started either a GLP-1 receptor agonist or a DPP-4 inhibitor or sulfonylurea. The analysis excluded people with eGFR below 20 mL/min/1.73 m2 or end-stage kidney disease and included 33,659 treatment initiations among 31,650 individuals. There were 20,039 GLP-1 receptor agonist and 13,620 comparator initiations; median age was 60 years, 60% were male, and ethnicity makeup was 79% White, 13% South Asian, 4% Black, and 4% other.

The primary outcome was kidney disease progression, defined as at least 40% decline in eGFR, end-stage kidney disease, or death from kidney-related causes. Median follow-up was 1.4 years, with an interquartile range of 0.6 to 3.0 years, and follow-up was capped at 3 years. Kidney disease progression occurred in 187 of 20,039 GLP-1 receptor agonist initiations and 189 of 13,620 comparator initiations, or 0.9% versus 1.4%. After adjustment, the risk was lower with GLP-1 receptor agonist initiation than with DPP-4 inhibitor or sulfonylurea initiation. Events were uncommon in both groups.

Acute pancreatitis and incident diabetic retinopathy were prespecified safety outcomes among participants without a recorded history of either event at baseline. For acute pancreatitis, 32 events, or 0.2%, followed GLP-1 receptor agonist initiation versus 25 events, or 0.2%, after comparator initiation, with HR 0.94 (95% CI 0.52-1.70). For incident diabetic retinopathy, 1097 events, or 10.1%, followed GLP-1 receptor agonist initiation versus 936 events, or 10.7%, after comparator initiation, with HR 1.07 (95% CI 0.97-1.18). No association was observed for either prespecified safety outcome.