Effectiveness of gemigliptin on risk of major adverse kidney events in people with type 2 diabetes: A Korean cohort study

Managing diabetes in patients with renal impairment is challenging due to limited treatment options and the risk of drug accumulation. Gemigliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i), is excreted via hepatic and renal pathways with relatively low renal dependence, requiring no dose adjustment and suitable for use at all estimated glomerular filtration rate (eGFR) levels. Furthermore, gemigliptin has shown favourable outcomes in patients with moderate to severe renal impairment. In a randomized controlled trial (RCT), gemigliptin was well tolerated without dose adjustment over 12 weeks and was superior to placebo in glycaemic control. It also significantly reduced urinary albumin-to-creatinine ratio and urinary nephrin levels in patients with microalbuminuria and macroalbuminuria.1 However, the findings of this RCT may not be fully generalizable to real-world clinical settings, nor do they provide comprehensive insights into the protective effects of gemigliptin on renal disease progression. This study evaluates the effectiveness of gemigliptin compared to other active antihyperglycaemic medications in reducing the risk of major adverse kidney events (MAKE) in patients with type 2 diabetes and eGFR ≥60 mL/min/1.73 m2 in a real-world setting. Using the Korean National Health Insurance Service-National Sample Cohort data, we identified patients with type 2 diabetes who initiated gemigliptin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), or sulfonylurea (SU) between 1 January 2015 and 31 December 2017. These patients had no prior exposure to DPP-4i or the comparator drug classes (SGLT2i or SU). The primary outcome of MAKE was defined as the time to the first occurrence of any of the following: a decline in eGFR greater than 40% from baseline, more than a doubling of serum creatinine from baseline, end-stage kidney disease (ESKD) or all-cause mortality (Table S1). The follow-up period extended from the date of initiation of either gemigliptin, SGLT2i or SU (i.e., the index date) to the first occurrence of the outcome of interest, death or up to 2 years after the index date. Follow-up was limited to 2 years to minimize potential imbalances in eGFR changes due to varying treatment durations. Details of the study design and statistical methods are provided in the Supporting Information. The unweighted cohort comparing gemigliptin with SGLT2i (cohort 1) and SU (cohort 2) included 1651 and 1141 patients, respectively (Figure S1 and Table S2). A weighted cohort was generated based on the probability of gemigliptin initiation; the baseline characteristics are shown in Table S3. The distributions of specific SGLT2is and SUs are detailed in Table S4. In weighted cohort 1, there was no statistically significant difference in the risk of MAKE between gemigliptin and SGLT2i initiations (hazard ratio [HR], 0.87; 95% CI [confidence interval], 0.62–1.22; p = 0.414) (Figure 1A). Similarly, applying a 30-day washout or limiting to second-line therapy after metformin, there were no significant differences in MAKE risk between gemigliptin and SGLT2i (Figures S2A and S3A). In both the as-treated analysis and the unweighted cohort, ESKD risk was higher with gemigliptin but not statistically significant (Figures S4A and S5A). No significant interactions were observed in this association when subgroup was analysed according to sex, eGFR category, history of cardiovascular disease or renin-angiotensin-aldosterone system inhibitor use. However, among patients under 65 years of age, gemigliptin initiation was associated with a significantly lower risk of MAKE compared to SGLT2i. In contrast, among patients aged 65 and older, gemigliptin initiation showed a higher MAKE risk, although this was not statistically significant (p for interaction = 0.008) (Figure 2A). In weighted cohort 2, no significant difference in the risk of MAKE was observed between gemigliptin and SU initiations (HR, 0.86; 95% CI, 0.50–1.48; p = 0.576). However, for all-cause mortality, gemigliptin initiation was associated with a significantly lower risk compared to SU initiation (HR, 0.32; 95% CI, 0.12–0.89; p = 0.029) (Figure 1B). These patterns remained consistent after applying a 30-day washout or limiting to second-line therapy after metformin (Figures S2B and S3B). In the as-treated analysis and unweighted cohort, the lower risk of all-cause mortality with gemigliptin initiation was no longer significant (Figures S4B and S5B). Subgroup analysis according to confounding factors showed no differences in MAKE risk (all p for interaction >0.05) (Figure 2B). In this nationally representative cohort study of patients with type 2 diabetes and normal or mildly decreased kidney function, gemigliptin initiation did not significantly differ in MAKE events compared to the initiation of SGLT2i or SU over a 2-year follow-up period. Gemigliptin did not show an increased risk of MAKE compared to SGLT2i initiation. In real-world clinical settings, most studies have reported that SGLT2is are associated with a reduced risk of MAKE compared to DPP-4is.2-4 However, a study from both Canada and the United Kingdom found no statistically significant difference in the risk of MAKE between SGLT2is and DPP-4is (HR, 0.79; 95% CI, 0.58–1.08).5 Furthermore, in Korea, when stratified by eGFR category, while SGLT2is reduced the risk of ESKD in patients with eGFR below 90 mL/min/1.73 m2, there was no significant difference in ESKD risk for those with eGFR of 90 mL/min/1.73 m2 or higher (HR, 1.45; 95% CI, 0.67–3.11).6 Gemigliptin also did not show an increased risk of MAKE compared to SU initiation. Consistent with the findings of the current study, a previous study in Korea demonstrated that the risk of ESKD was not higher in the DPP-4i group than in the SU group.7 However, DPP-4i initiation was associated with a statistically significant reduction in all-cause mortality compared to SU initiation. Supporting evidence from meta-analyses shows that, while DPP-4is and SUs offer similar glycaemic control, DPP-4is have a more favourable weight profile and lower hypoglycaemia risk.8 The cardiovascular safety of SUs appears to be poorer than that of DPP-4is in both RCTs and cohort studies.9 Therefore, the reduced all-cause mortality with DPP-4is may be attributed to lower cardiovascular risk, reduced hypoglycaemia and weight neutrality. This study has several limitations. First, as an observational study, it is subject to inherent biases and confounding factors despite propensity score weighting. Second, eGFR changes were measured only once after initiation of the study drugs, which limited the ability to accurately assess sustained eGFR decline. Third, in SGLT2i renal outcome trials, eGFR trends typically show an initial dip, followed by a crossover point at approximately 18–24 months, where the rate of eGFR decline becomes slower than that in the placebo group.10-12 This suggests that the 2-year observation period in this study may be too short to fully assess the renal benefits. When the follow-up period was extended to 3 years, similar results were observed despite the reduced sample size (data not shown). Lastly, this study included only individuals with an eGFR ≥60 mL/min/1.73 m2. Prior to 2019 in Korea, the use of SGLT2is was recommended only for patients with an eGFR of 60 mL/min/1.73 m2 or higher. Given the limitations within the Korean reimbursement system, caution is warranted when interpreting comparisons between gemigliptin and SGLT2is in the eGFR <60 mL/min/1.73 m2 subgroup. In conclusion, in patients with type 2 diabetes and eGFR ≥60 mL/min/1.73 m2, gemigliptin initiation did not significantly differ from SGLT2is or SUs in the incidence of MAKE events in terms of decreasing in eGFR, doubling of serum creatinine level, ESKD or all-cause mortality over a 2-year follow-up. This study used National Health Insurance Service-National Sample Cohort (2002-2019) data (NHIS-2024-2-059) made by National Health Insurance Service (NHIS). The study was supported and funded by LG Chem, Ltd. LG Chem was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. K.H.H. has no relevant disclosures. Y.J. is an employee of LG Chem. D.J.K. has received grants or research support from Boehringer Ingelheim, LG Chem and Novo Nordisk. The authors declare no conflict of interest with NHIS. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.16230. This study utilized data from the Korean National Health Insurance Service (NHIS) Database. The data are owned by the Korean NHIS and are not available for public access due to legal and ethical restrictions. The authors are not permitted to share the data, except in an aggregated and anonymized form as presented in this study. For further inquiries, data access may be requested directly from the Korean NHIS. Data S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.