SGLT2 inhibitors easy on the kidneys of Asians with T2D

Among Asians with type 2 diabetes (T2D), users of sodium-glucose cotransporter-2 (SGLT2) inhibitors may have better kidney outcomes compared with those who use other glucose-lowering drugs.

In a retrospective study from Singapore, initiation of SGLT2 inhibitors was associated with >60-percent reduction in the risks of composite kidney outcome (hazard ratio [HR], 0.39, 95 percent confidence interval [CI], 0.31–0.48; p<0.001), kidney failure with replacement therapy (HR, 0.31, 95 percent CI, 0.17–0.59; p<0.001), and sustained ≥40-percent reduction in eGFR from baseline (HR, 0.38, 95 percent CI, 0.31–0.48; p<0.001) relative to other glucose-lowering medications. [Kidney Med 2024;7:100963]

“The association with composite kidney outcome was consistent across different ethnicities (Chinese, Malays, Indians) and subgroups of patients including young and older patients, men and women, various levels of glycaemic control, and different CKD stages,” the investigators noted.

Over a median follow-up of 26.5 months, eGFR declined at a slower rate among SGLT2 inhibitor users than among users of other glucose-lowering medications (−1.04 vs –3.71 mL/min/1.73m² per year), with a difference of 2.67 mL/min/1.73m² per year (p<0.001).

“SGLT2 inhibitors posed no safety risk for amputation and acute kidney injury (AKI),” the investigators said. Compared with users of other glucose-lowering medications, SGLT2 inhibitor users had similar risk of amputation (HR, 0.89, 95 percent CI, 0.51–1.55; p=0.68) but a significantly lower risk of AKI (HR, 0.23, 95 percent CI, 0.13–0.42; p<0.001).

The present data mirror those of earlier randomized trials and cohort studies on SGLT2 inhibitors’ effect on kidney outcomes in T2D. According to the investigators, this renoprotective effect may have been mediated by a number of both hemodynamic and nonhemodynamic mechanisms. [Cardiovasc Diabetol 2021;20:83; Diabetes Obes Metab 2023;25:2310-2330; Diabetes Care 2021; 44:2542-2551; Lancet Diabetes Endocrinol 2020;8:27-35]

Correction of glomerular hyperfiltration is the leading explanation, they said. Other benefits such as less inflammation, fewer reactive oxygen species, better endothelial function are also implicated. [J Am Coll Cardiol 2020;75:422-434; Circulation 2016;134:752-772; Cell Metab 2021;33:732-739]

The study included a propensity-score matched cohort of 4,254 T2D patients (mean age 63.4 years, 48.6 percent women) newly initiated on either SGLT-2 inhibitors or other glucose-lowering drugs (2,127 in each group). More than half of the patients (67.8 percent) were Chinese, 11.9 percent were Indian, 15.6 percent were Malay, and 4.7 percent were of other ethnicities.

Low uptake

Despite robust trial data and guideline inclusion, SGLT2 inhibitors remain underused. Uptake across various countries such as Australia, Canada, England, Scotland, Sweden, the United States, and Singapore had only reached up to 15 percent by 2021 since the drug’s introduction in 2013. [Br J Gen Pract 2021;71:e209-e218; Eur J Prev Cardiol 2023;30:634-643; J Diabetes Complications 2023;37: 108625; PLOS One 2021;16:e0259157]

Barriers to SGLT2 inhibitors use include inconsistent guideline recommendations, limited knowledge and experience among physicians, clinical inertia, concerns regarding serious side effects (eg, amputations, AKI, and diabetic ketoacidosis), and high costs. However, the drug has been shown to be cost-effective in several studies. [Nephrology 2023;28:415-424; JACC Heart Fail 2023;11:943-945; Diabetes Obes Metab 2022;24:1187-1196]

“Our findings of real-world effectiveness make a compelling case for enhancing the outreach and access to SGLT2 inhibitors to all individuals with T2D … for optimal protection from kidney disease,” the investigators said.

They emphasized that their work holds value for both patient care and public health, given the 2019 Global Burden of Disease Study report of an expected spike in T2D cases globally, from 530 million to 1.31 billion people by 2050. 

“Notably, the Asian region had the highest number of patients with T2D and are experiencing the most rapid increase in its prevalence,” the investigators said. “Consequently, addressing the mounting challenge of managing diabetes and its complications needs to be a critical health priority worldwide.”