SGLT2 Inhibitors Improve Patient Outcomes in NAFLD, Type 2 Diabetes

Won Kim, MD, PhD

Credit: Seoul National University

Findings from a retrospective cohort study of patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) in Korea suggest sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an optimal oral antidiabetic drug for this patient population.¹

Published in JAMA Internal Medicine, study results highlighted a greater likelihood of NAFLD regression and lower incidence of adverse liver-related outcomes among patients taking SGLT2 inhibitors as compared to those taking thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas.¹

“Although patients with both NAFLD and T2D may benefit from oral antidiabetic drugs, large-scale data determining which drug class is favorable for NAFLD regression in a health care setting are sparse, hindering oral antidiabetic drug selection in clinical care,” wrote Won Kim, MD, PhD, associate professor of internal medicine at Seoul National University, and colleagues.¹

Along with its hand in T2D, insulin resistance also plays a key role in NAFLD pathogenesis. According to the American Diabetes Association, liver disease affects up to 70% of people with T2D, highlighting the bidirectional relationship between the diseases. The impact of oral antidiabetic drugs on health outcomes in patients with T2D and NAFLD relating to NAFLD regression and liver-related outcomes is not well understood but may aid treatment selection for this patient population with more research.^1,2

To examine patient outcomes in NAFLD and T2D based on oral antidiabetic drugs, investigators conducted a retrospective, nonrandomized, interventional cohort study leveraging data from the Korean National Health Information Database. For inclusion, patients were required to be ≥ 19 years of age, have hepatic steatosis (fatty liver index [FLI] score ≥ 60) at baseline, and be diagnosed with T2D.¹

Of note, oral semaglutide, a GLP-1 receptor agonist, was not included in the analysis. The study exposures included starting SGLT2 inhibitors, thiazolidinediones, DPP-4 inhibitors, or sulfonylureas as supplementary medications to metformin, consistently adhering to the prescribed regimen for ≥ 80% of 90 consecutive days spanning from October 1, 2014, to December 31, 2018.¹

The primary outcome was NAFLD regression, defined by investigators as a reduction in FLI score to < 30 at follow-up from a baseline of > 60. The secondary endpoint was a composite liver-related outcome incorporating incidences of liver-related hospitalization, liver-related mortality, liver transplant, and/or hepatocellular carcinoma (HCC) development.¹

In total, 80,178 patients who used an SGLT2 inhibitor (n = 9470), thiazolidinedione (n = 2191), DPP-4 inhibitor (n = 55,324), or sulfonylurea (n = 13,193) were followed up for 219,941 person-years. Among the cohort, the mean age was 58.5 (Standard deviation [SD], 11.9) years, the majority (53.6%) of patients were male, and 4102 experienced NAFLD regression.¹

Upon analysis, SGLT2 inhibitors (adjusted subdistribution hazard ratio [aSHR], 1.99; 95% CI, 1.75-2.27), thiazolidinediones (aSHR, 1.70; 95% CI, 1.41-2.05), and DPP-4 inhibitors (aSHR, 1.45; 95% CI, 1.31-1.59) were associated with NAFLD regression compared to sulfonylureas. Among the 4 oral antidiabetic drug classes, SGLT2 inhibitors produced the most favorable outcomes when compared with thiazolidinediones (aSHR, 1.40; 95% CI, 1.12-1.75) and DPP-4 inhibitors (aSHR, 1.45; 95% CI, 1.30-1.62).¹

Across the study population, 276 patients presented with adverse liver-related outcomes: 12 for SGLT2 inhibitors (52 events per 100,000 person-years), 8 for thiazolidinediones (118 events per 100,000 person-years), 191 for DPP-4 inhibitors (122 events per 100,000 person-years), and 65 for sulfonylureas (157 events per 100,000 person-years). Investigators noted only SGLT2 inhibitors (aSHR, 0.37; 95% CI, 0.17-0.82), not thiazolidinediones or DPP-4 inhibitors, were significantly associated with lower incidence rates of adverse liver-related outcomes when compared with sulfonylureas.¹

“The results of this cohort study demonstrated that SGLT2 inhibitors might have potential benefits for patients with both NAFLD and T2D, compared with other oral antidiabetic drug classes,” investigators concluded.¹

References:

1. ^{Jang H, Kim Y, Lee DH, et al. Outcomes of Various Classes of Oral Antidiabetic Drugs on Nonalcoholic Fatty Liver Disease. JAMA Intern Med. doi:10.1001/jamainternmed.2023.8029}
2. ^{American Diabetes Association. American Diabetes Association Releases a Guideline Update in NAFLD (Non-Alcoholic Fatty Liver Disease) and Diabetes. June 25, 2023. Accessed February 12, 2024. https://diabetes.org/newsroom/american-diabetes-association-releases-guideline-update-NAFLD-diabetes}