Effects of second-line antihyperglycemic drugs on the risk of chronic kidney disease: applying a target trial approach to a hospital-based cohort of Thai patients with type 2 diabetes

Abstract

Background The reno-protective effect of second-line treatments in type 2 diabetes has been assessed by clinical trials but generalizability to routine clinical practice is still uncertain. We aimed to assess the effectiveness of these treatments, when added to metformin, on the risk of chronic kidney disease (CKD). Methods A real-world, hospital-based, type 2 diabetes cohort was retrospectively assembled at Ramathibodi Hospital from 2010 to 2019. Patients who received sulfonylureas (SU), thiazolidinediones (TZD), dipeptidyl peptidase-4 inhibitors (DPP4i), or sodium-glucose cotransporter-2 inhibitors (SGLT2i), as second-line antihyperglycemic treatment were included. Treatment effect models with inverse probability weighting and regression adjustment were used to estimate CKD risk according to treatment. Results CKD was identified in 4,132 of the 24,777 patients with type 2 diabetes (16.7%). The CKD incidence (95% CI) was 4.1% (2.2%, 6.9%), 13.5% (12.5%, 14.6%), 14.8% (13.5%, 16.1%), and 18.0% (17.4%, 18.5%) for patients receiving SGLT2i, DPP4i, TZD, and SU treatment, respectively. The average treatment effects (i.e., the difference in CKD risk) for SGLT2i, DPP4i, and TZD compared to SU were − 0.142 (− 0.167, − 0.116), − 0.046 (− 0.059, − 0.034), and − 0.004 (− 0.023, 0.014), respectively, indicating a significant reduction in CKD risk of 14.2% and 4.6% in the SGLT2i and DPP4i groups, respectively, compared to the SU group. Furthermore, SGLT2i significantly reduced CKD risk by 13.7% (10.6%, 16.8%) and 9.5% (6.8%, 12.2%) when compared to TZD and DPP4i, respectively. Conclusions Our study identified 14.2%, 13.7%, and 9.5% reduced CKD risk in Thai patients with type 2 diabetes who were treated with SGLT2i compared to those treated with SU, TZD, and DPP4i, respectively, in real-world clinical data. Previous evidence of a reno-protective effect of SGLT2i reported in other populations is consistent with our observations in this Southeast Asian cohort.

Clinical effectiveness of second-line antihyperglycemic drugs on major adverse cardiovascular events: An emulation of a target trial

“…Moreover, SGLT2i can improve mitochondrial respiratory function and cardiac energy metabolism in the failing heart (31) when mitochondrial glucose oxidation and energy production is diminished. Extrapolating to the population level, we previously found that SGLT2i could directly lower CKD risk about 14% (32), and in this study, they could lower CVD risk of 2% relative to SUs with a number needed to treat of 140 and 20 per 1000 treated patients, i.e., for each 100 patients treated, we would prevent 14 CKD events and 2 CVD events over ~3.5 years of follow. Our current data also 3.…”