Canagliflozin holds promise against MAFLD in T2D patients

Patients with type 2 diabetes (T2D) who received canagliflozin benefit from improved liver biochemistry and metabolism, a recent study has shown. In addition, treatment with canagliflozin appears to confer positive effects on liver fibrosis.

“Our data demonstrate that sodium-glucose cotransporter 2 (SGLT-2) inhibitors are not only highly beneficial in the treatment of diabetes, heart failure, and chronic kidney disease, but also highly promising in the treatment of metabolic dysfunction–associated fatty liver disease (MAFLD),” the investigators said.

“In addition to the known metabolic effects on glycaemia and body weight, treatment with canagliflozin vs placebo significantly improved liver biochemistry and reduced scores of noninvasive tests of fibrosis independent from improvements in glycaemic control or body weight,” they added.

This secondary post hoc analysis involved two large double-blind randomized controlled trials, CANVAS and CANVAS-R, which included patients with T2D and high cardiovascular risk who were randomized to receive either canagliflozin or placebo once daily.

A composite of improvement in alanine aminotransferase (ALT) levels >30 percent of normalization of ALT levels served as the primary endpoint. Secondary endpoints were change in noninvasive tests of fibrosis and weight reduction of >10 percent.

In total, 10,131 patients (mean age 62 years, mean duration of diabetes 13.5 years, 64.2 percent male) were analysed over a median follow-up of 2.4 years. Of these, 8,967 (88.5 percent) had MAFLD according to hepatic steatosis index and 2,599 (25.7 percent) presented with elevated liver biochemistry at baseline. [J Clin Endocrinol Metab 2023;108:2940-2949]

Improvements in the primary composite outcome were observed in 35.2 percent of patients treated with canagliflozin and in 26.4 percent on placebo (adjusted odds ratio [aOR], 1.51, 95 percent CI, 1.38‒1.64; p<0.001).

For the secondary outcomes, treatment with canagliflozin resulted in improvements in some noninvasive tests of fibrosis (ie, NFS, APRI, FNI) and in significant weight reduction >10 percent (within 6 years) in 12.7 percent of patients compared to 4.1 percent of those treated with placebo (aOR, 3.45, 95 percent CI, 2.91‒4.10; p<0.001).

“In line with previous small observational studies, we observed that treatment with canagliflozin vs placebo led to a rapid and sustained reduction of liver transaminases—even in patients with ‘normal’ ALT levels at baseline,” the investigators said. [Diabetes Obes Metab 2019;21:812‐821]

“Serum transaminases have been shown to correlate with the risk of fibrosis progression; therefore, sustained reduction or normalization can be considered a clinically meaningful endpoint,” they added. [J Hepatol 2018;68:353‐361]

Furthermore, earlier studies with paired biopsies found that ALT normalization, apart from improvements in HbA1c, was strongly associated with fibrosis improvement compared with other biomarkers. [Liver Int 2017;37:1887‐1896]

“Given the established cardiovascular and renal benefits in patients with T2D, SGLT-2 inhibitors could prove to be suitable and cost-effective pharmaceutical agents in the treatment of patients with MAFLD,” the investigators said.

“Future studies are needed to investigate the evolution of liver histology upon SGLT-2 inhibitor treatment in both diabetic and nondiabetic patients,” they added.