In adults with both type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), the use of SGLT2 inhibitors was linked to NAFLD regression and a lower incidence of poor liver-related outcomes, according to a retrospective cohort study.
Compared with sulfonylureas, SGLT2 inhibitors were associated with NAFLD regression (adjusted subdistribution HR 1.99, 95% CI 1.75-2.27), as were thiazolidinediones (adjusted subdistribution HR 1.70, 95% CI 1.41-2.05) and DPP-4 inhibitors (adjusted subdistribution HR 1.45, 95% CI 1.31-1.59), reported Won Kim, MD, PhD, of the Seoul National University College of Medicine and Seoul Metropolitan Government Boramae Medical Center, and colleagues.
Notably, SGLT2 inhibitors were associated with a higher likelihood of NAFLD regression compared with thiazolidinediones (adjusted subdistribution HR 1.40, 95% CI 1.12-1.75) and DPP-4 inhibitors (adjusted subdistribution HR 1.45, 95% CI 1.30-1.62), they noted in JAMA Internal Medicine.
Only SGLT2 inhibitors were significantly associated with lower incidence rates of adverse liver-related outcomes compared with sulfonylureas (adjusted subdistribution HR 0.37, 95% CI 0.17-0.82).
There are currently no medications approved by the FDA to treat NAFLD, also known as metabolic dysfunction-associated steatotic liver disease (MASLD). The researchers therefore sought to determine which types of antidiabetic drugs appeared most associated with better liver-related outcomes.
“The results of this cohort study demonstrated that SGLT2 inhibitors might have potential benefits for patients with both NAFLD and type 2 diabetes, compared with other oral antidiabetic drug classes,” the authors wrote, though they cautioned that the findings are based on observational analysis. They also noted that “thiazolidinediones are also beneficial in terms of improvements in nonalcoholic steatohepatitis (NASH) viewed on histologic examination, regardless of the presence of type 2 diabetes.”
Sammy Saab, MD, MPH, medical director of the Pfleger Liver Institute at the University of California Los Angeles, told MedPage Today that he was “thinking about how I’m going to use [antidiabetic drugs] in my own practice.” However, he also noted several limitations to the study, including lack of laboratory data on how well these drugs control diabetes and the use of the Fatty Liver Index as a surrogate endpoint.
“Most times with fatty liver, we’re using ultrasound or some type of imaging,” Saab said, adding that imaging would be expected in clinical trials assessing a drug for fatty liver disease. Similarly, “the most important thing is not the amount of fat to predict liver complications, it’s the amount of liver damage — fibrosis — and they did not estimate that.”
He also noted that heart attacks and stroke are important risks in this population, but the research did not assess cardiovascular disease, something the authors acknowledged as well. Still, the study remains helpful, he said, and a “fulcrum for additional research.”
Saab added that he would be interested in how GLP-1 receptor agonists, such as semaglutide (Ozempic, Wegovy), might compare to SGLT2 inhibitors given the recent evidence showing that GLP-1 agonists can reduce heart disease risk, and whether SGLT2 inhibitors might offer any fatty liver disease benefit in those without diabetes.
Lisa Ganjhu, DO, of the NYU Grossman School of Medicine in New York City, told MedPage Today that she was not surprised by the findings since a “cornerstone of therapy for NAFLD is controlling diabetes.”
She said she would like to have seen more data on longer-term diabetic control, but “since there is no one medication for NAFLD, this offers patients a therapeutic option if diabetes is present.”
Like Saab, Ganjhu noted the study’s reliance on the index endpoint instead of “imaging, FibroScan, or biopsy to stratify NAFLD.” The “aggressiveness of NAFLD leading to profound liver disease, such as cirrhosis, fibrosis, or hepatocellular carcinoma, needs to be assessed by some measure of quantity of fat or scarring,” she added.
For this study, Kim and colleagues analyzed 219,941 person-years of data from Korea’s National Health Information Database on 80,178 patients with both type 2 diabetes and NAFLD. Mean age was 58.5, and 53.6% were men. Patients were only included if they had hepatic steatosis at baseline, defined as a Fatty Liver Index score of 60 or more.
Participants had to start a new prescription of SGLT2 inhibitors, thiazolidinediones, DPP-4 inhibitors, or sulfonylureas to supplement metformin and have an adherence of at least 80% of 90 consecutive days from October 2014 through December 2018. The analysis excluded individuals who had taken oral antidiabetic drugs from January 2012 to September 2014.
A total of 4,102 patients experienced NAFLD regression, which the authors defined as a Fatty Liver Index score below 30 after a baseline of at least 60. The secondary outcome of a composite liver-related outcome involved incidence of liver-related hospitalization, mortality, or transplant, and/or development of hepatocellular carcinoma. The researchers also used several methods to statistically adjust for patients’ baseline differences.
Disclosures
The research was funded by the Korea National Institute of Health, the National Research Foundation of Korea, and the Seoul Metropolitan Government Seoul National University Boramae Medical Center.
Kim reported personal fees and/or grants from Celgene, Daewoong, Dicerna, Enyo, Ildong, GSK, Hanmi, Galmed, PharmaKing, KoBioLabs, Novartis, Novo Nordisk, OliX Pharma, Pfizer, Roche, Spring Bank Pharmaceuticals, Standigm, and TSD Life Sciences, as well as stock options from KoBioLabs and LepiDyne and founding RemedyGen. No other authors had disclosures.
Primary Source
JAMA Internal Medicine
Source Reference: Jang H, et al “Outcomes of various classes of oral antidiabetic drugs on nonalcoholic fatty liver disease” JAMA Intern Med 2024; DOI: 10.1001/jamainternmed.2023.8029.
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