Study Finds Sodium-Glucose Cotransporter 2 Inhibitors Associated With Reduced Risk of CKD

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were more effective in reducing chronic kidney disease (CKD) progression and death in adults with type 2 diabetes (T2D) compared with dipeptidyl-peptidase–4 (DPP4) inhibitors, a study published in Diabetes, Obesity and Metabolism found.

The study gleaned participant data from the Clinical Practice Research Datalink Aurum database, on primary care practices in England. Participants were excluded if they had started SGLT2 and DPP4 inhibitors on the same date or had a previous prescription of the same drug class 12 months before initiation.

All participants who received SGLT2 inhibitors were matched to a patient who received DPP4 inhibitors based on age, sex, presence of microvascular complications, frailty, and cardiovascular comorbidities. Only the first episode of inhibitor treatment was included in the study.

There were 131,824 participants with T2D identified, with 27,664 (21.0%) with a documented history of CKD; 117,089 (88.8%) with a history of using or taking metformin; 59,300 (45.0%) who had used sulphonylureas; and 16,964 (12.9%) who were using insulin. Participants on SGLT2 inhibitors were younger, less frail, had lower burden of CKD and heart failure, had a higher hemoglobin A_1C (HbA_1C) and estimated glomerular filtration rate (eGFR), and more frequently used glucose-lowering drugs.

The participants were women in 42.5% of the SGLT2 inhibitor group and 42.1% in the DPP4 inhibitor group; the mean ages were 56.8 and 56.4 years, respectively. The participants also had a mean HbA_1C of 77 mmol/mol (9.2%) and 76 mmol/mol (9.1%), respectively, and a mean eGFR of 79.7 and 80.4 mL/min/1.73m², respectively.

A median follow-up of 2.1 years was observed, during which SGLT2 inhibitors were associated with lower risk of progression to the primary outcome, which was risk of composite CKD end points of more than 40% decline in eGFR, kidney death, or end-stage kidney disease (ESKD). There were 359 primary composite kidney outcomes in participants taking SGLT2 inhibitors (7.48 events per 1000 patient-years) compared with 568 primary composite end point outcomes in participants taking DPP4 inhibitors (11.77 events per 1000 patient-years).

SGLT2 inhibitors were associated with reductions in the primary composite end point (HR, 0.64), with a reduction in both all-cause mortality (HR, 0.74; 95% CI, 0.64-0.86) and ESKD (HR, 0.37; 95% CI, 0.25-0.55) vs DPP4 inhibitors.

SGLT2 inhibitors were4 also associated with a reduction in eGFR decline (> 40% decline in eGFR: HR, 0.66; 95% CI, 0.57-0.76) and were associated with a lower rate of sustained low eGFR (HR, 0.33; 95% CI, 0.19-0.57). A reduction of diagnoses of ESKD was also observed in participants who took SGLT inhibitors (HR, 0.04; 95% CI, 0.01-0.18) compared with DPP4 inhibitors.

eGFR values also remained stable or rose in patients on SGLT2 inhibitors compared with the declining eGFR values in patients receiving DPP4 inhibitors.

Differences in mortality were more evident in patients with lower HbA_1C, and differences of renal outcomes were independent of glucose control. SGLT2 inhibitors significantly lowered all-cause mortality in patients with better glucose control (< 7%: HR, 0.47; 95% CI, 0.24-0.91; 7%-10%: HR, 0.67; 95% CI, 0.55-0.82; > 10%: HR, 0.93; 95% CI, 0.73-1.19) compared with DPP4 inhibitors.

Relative risk reduction in the primary composite renal end point was also independent of baseline HbA_1C (< 7%: HR, 0.49; 95% CI, 0.27-0.87; 7%-10%: HR, 0.61; 95% CI, 0.51-0.74; > 10%: HR, 0.59; 95% CI, 0.48-0.73).

There were some limitations to this study. Propensity matching meant that the study only used 61% of the full data set, and selection bias cannot be ruled out. Also, the proportion of patients with a history of using metformin was high, and residual confounding by covariates could not be excluded as a possibility in this study.

The researchers concluded that adults with T2D who started SGLT2 inihbitor therapy had a reduced risk of CKD progression and death compared with DPP4 inhibitors.

Reference

Idris I, Zhang R, Mamza JB, et al. Significant reduction in chronic kidney disease progression with sodium glucose co-transporter 2 inhibitors compared to dipeptidyl peptidase-4 inhibitors in adults with type 2 diabetes in UK clinical setting: an observational outcomes study based on international guidelines for kidney disease. Diabetes Obes Metab. Published online June 8, 2022. doi:10.1111/dom.14799