Real-world study: Combining SGLT2i and pioglitazone may ameliorate at-risk MASH in T2D patients

Combined use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and pioglitazone may be a potentially useful strategy to ameliorate metabolic dysfunction–associated steatohepatitis (MASH) in patients with type 2 diabetes (T2D), according to a real-world study conducted by researchers from the University of Hong Kong and Queen Mary Hospital (QMH).

Notably, among different combinations of SGLT2i, pioglitazone and/or glucagon-like peptide-1 receptor agonists (GLP-1 RA), combining SGLT2i and pioglitazone was associated with higher likelihood of maintaining low risk of fibrotic MASH and higher likelihood of fibrotic MASH risk regression compared with not using any of these medications. [Diabetes Obes Metab 2025;27:574-582]

The study included 888 Chinese patients with T2D aged 21–80 years who had undergone ≥1 reassessment vibration-controlled transient elastography (VCTE) by 30 June 2023. They were recruited from the Hong Kong West Diabetes NAFLD Cohort, a prospective cohort established in 2018 to identify risk factors of steatotic liver disease progression in T2D.

Longitudinal data were used to calculate serial FibroScan–aspartate aminotransferase (FAST) scores for classification of the patients’ risk of at-risk MASH (ie, MASH with stage ≥2 hepatic fibrosis), with FAST scores of ≥0.67, 0.36–0.66 and ≤0.35 indicating high, intermediate and low risk, respectively. Multivariable logistic regression analysis was performed to analyze associations between the use of pioglitazone, GLP-1 RA and/or SGLT2i (ie, continuous prescriptions of ≥180 days prior to the last reassessment VCTE) and changes in FAST scores.

At baseline, 21, 102 and 765 participants had FAST score of ≥0.67, 0.36–0.66 and ≤0.35, respectively. Over a median follow-up period of 3.9 years, a median of three VCTE reassessments were performed for the participants. Among those with baseline FAST score ≤0.35, 732 maintained FAST scores ≤0.35 during follow-up, while 33 had FAST score progression to >0.35 at reassessment. Among the 123 participants with baseline FAST score >0.35, 83 showed FAST score regression to ≤0.35 during follow-up, and 40 had no regression.

Within ≥180 days prior to reassessment VCTE, 453 participants were on SGLT2i, 281 were on pioglitazone (median dose, 15 mg daily), and 131 were on GLP-1 RA. On multivariable logistic regression analysis, use of dual or triple combinations of these medications was independently associated with higher likelihood of reassessment FAST scores ≤0.35 (OR, 2.20; 95 percent CI, 1.01–4.80; p=0.047) and FAST score regression to <0.35 (OR, 6.41; 95 percent CI, 1.78–23.0; p=0.004) vs not using any of these medications, after adjustment for baseline BMI, platelets, presence of coronary heart disease, triglycerides and FAST score as well as changes in HbA_1c and body weight during the study period.

Compared with monotherapy, use of dual therapy combinations was independently associated with higher likelihood of reassessment FAST scores ≤0.35 (OR, 2.84; 95 percent CI, 1.28–6.27; p=0.10) and FAST score regression to <0.35 (OR, 3.49; 95 percent CI, 1.05–11.59; p=0.041).

Among different drug combinations, using SGLT2i with pioglitazone, compared with not using any of the three types of medications, was associated with a higher likelihood of both reassessment FAST scores ≤0.35 (OR, 6.72; 95 percent CI, 1.65–27.39; p=0.008) and FAST score regression to <0.35 (OR, 12.52; 95 percent CI, 1.89–82.79; p=0.009).

“To our knowledge, our findings provided the first clinical evidence that the combination of SGLT2i and pioglitazone was associated with significant hepatic benefits in patients with T2D compared with either agent alone,” the investigators noted. “Combining SGLT2i and pioglitazone is a potentially useful strategy to ameliorate ‘at-risk’ MASH in patients with T2D.”