Kidney outcomes with GLP-1 receptor agonists in people with type 2 diabetes already receiving SGLT2 inhibitors: a target trial emulation study using UK primary care data

Background Type 2 diabetes is the leading cause of kidney failure and is predominantly managed in primary care. Large randomised trials have shown that GLP-1 receptor agonists and SGLT2 inhibitors each slow kidney disease progression, but their combined effect on kidney outcomes remains unclear. We aimed to evaluate the comparative effectiveness of GLP-1 receptor agonists versus DPP-4 inhibitors or sulfonylureas on kidney outcomes in individuals with type 2 diabetes already receiving SGLT2 inhibitor treatment. Methods In this observational study, we emulated a pragmatic target trial using an active-comparator, new-user cohort design with UK primary care electronic health record data (Clinical Practice Research Datalink, March 31, 2013–March 31, 2023) with linkage to hospital inpatient, deprivation, and mortality data. We included individuals with type 2 diabetes already receiving SGLT2 inhibitors who newly initiated either GLP-1 receptor agonists or comparator drugs DPP-4 inhibitors or sulfonylureas. We excluded those with estimated glomerular filtration rate (eGFR) of less than 20 mL/min per 1·73 m 2 or end-stage kidney disease. Individuals in the comparator group who initiated a GLP-1 receptor agonist during follow-up were censored at the date of GLP-1 receptor agonist initiation and subsequently re-entered into the GLP-1 receptor agonist group. We followed up all initiations regardless of subsequent treatment discontinuation (intention-to-treat analysis), with a maximum follow-up of 3 years. The primary outcome was kidney disease progression (defined as occurrence of ≥40% eGFR decline, end-stage kidney disease, or death from kidney-related causes). Safety outcomes were acute pancreatitis and incident retinopathy (among those without a recorded history at baseline). We estimated hazard ratios (HRs) using Cox proportional hazards models with double-robust overlap weighting. Findings We included 33 659 treatment initiations (20 039 GLP-1 receptor agonists and 13 620 DPP-4 inhibitors or sulfonylureas; among 31 650 unique individuals), of whom these initiations occurred among 20 239 (60%) male individuals and 13 420 (40%) female individuals; median age was 60 years (IQR 53–67), and 26 530 (79%) were White, 4492 (13%) south Asian, 1398 (4%) Black, and 1239 (4%) of other ethnicities. Over a median follow-up of 1·4 years (IQR 0·6–3·0), kidney disease progression occurred in 187 (0·9%) of 20 039 individuals who initiated a GLP-1 receptor agonist and 189 (1·4%) of 13 620 who initiated a DPP-4 inhibitor or sulfonylurea. GLP-1 receptor agonist initiation was associated with a lower risk of kidney disease progression compared with DPP-4 inhibitor or sulfonylurea initiation (HR 0·73 [95% CI 0·58–0·92]). GLP-1 receptor agonist initiation was not associated with occurrence of acute pancreatitis (32 [0·2%] of 19 727 individuals with no recorded history of pancreatitis who initiated a GLP-1 receptor agonist vs 25 [0·2%] of 13 305 who initiated a DPP-4 inhibitor or sulfonylurea; HR 0·94 [0·52–1·70]) or incident diabetic retinopathy (1097 [10·1%] of 10 844 individuals with no recorded history of diabetic retinopathy who initiated a GLP-1 receptor agonist vs 936 [10·7%] of 8719 who initiated a DPP-4 inhibitor or sulfonylurea; HR 1·07 [0·97–1·18]). Interpretation These real-world data suggest that the kidney-protective benefits of GLP-1 receptor agonists observed in randomised trials of individuals with type 2 diabetes might also extend to individuals already receiving SGLT2 inhibitors. This finding supports consideration of combination treatment for kidney protection in primary care, particularly in individuals at highest absolute risk. Further prospective data would be valuable to confirm these findings. Funding UK Medical Research Council.