Reference: JAMA Intern Med. 2024 Feb 12:e238029
Practice Point: SGLT2s may promote regression of NAFLD better than other oral antidiabetic agents, and this information is likely to affect diabetes medication selection.
EBM Pearl: Look for the absolute risk reduction where possible. It not only helps you have a better understanding of the current data, but can make it easier to compare data between studies.
Nonalcoholic fatty liver disease (NAFLD) is one of those conditions where diagnosis leads to a lot of testing and surveillance, but there’s not a lot to do about it. (Yet.) Weight loss is about the only available treatment, which of course proves to be hard for a majority of people. So like many things, a pill to fix it would be great. Enter: SGLT2s.
A recently published cohort study evaluated regression of NAFLD in patients living in South Korea taking various oral antidiabetic medications. In South Korea, public health insurance is provided for all citizens, inclusive of biennial checkups and “routine” testing. Investigators pulled information from this database for more than 80,000 adults who had hepatic steatosis, type 2 diabetes on metformin, and who had recently started an SGLT2 inhibitor, thiazolidinedione, DPP-4 inhibitor, or sulfonylurea. Notably, patients receiving GLP-1 agonists were excluded, with the only explanation offered being that they were injectables rather than oral agents. Hepatic steatosis was defined as a fatty liver index (FLI) score of ≥ 60, which is a complex algorithm based on triglycerides, GGT, BMI, and waist circumference. The FLI is a validated scoring system, but does not include any imaging, which we know to be a critical element of diagnosis for most patients where imaging is available. The primary outcome was 50% improvement in FLI score, to less than 30 at follow-up from a baseline of ≥ 60 at baseline.
Results showed an absolute risk reduction of 2,246 regression events per 100,000 person-lives for those taking SGLT2s, on the order of 2:1 better than sulfonylureas, and better to a lesser magnitude compared to thiazolidinediones or DPP-4s. By comparison, a randomized trial found that weight loss of about 20 lbs through lifestyle intervention had an NNT of 4 for regression of NAFLD, and a trial of semaglutide showed an NNT of 3 for regression of the most severe form of NAFLD, nonalcoholic steatohepatitis, at the highest dose of semaglutide, although the studies define regression slightly differently.
After a median follow-up of 2.6 years, a composite of liver-related hospitalization, liver-specific mortality, liver transplant, and development of hepatocellular carcinoma was slightly reduced with SGLT2s compared to sulfonylureas, but not compared to thiazolidinediones or DPP-4s. The authors also evaluated weight loss associated with each of the drug classes and found that SGLTs were associated with the most weight loss. Their statisticians assert that the degree of NAFLD regression was likely not solely explained by weight loss, however.
The bottom line for now is that SGLT2 inhibitors do seem to promote regression of NAFLD, moreso than other oral antidiabetic agents. It’s hard to know how much of that is attributable to weight loss, but to some extent, it doesn't even matter. GLP-1s are already being used off-label to treat NAFLD, so maybe SGLT2s can be too. In contrast to last week’s EBM Focus, where the authors concluded that antidiabetic medication selection should be influenced by the tiny reduction in nephrolithiasis that SGLT2s offer, this study gives us a real reason to preferentially choose SGLT2s over other oral agents for patients with diabetes and NAFLD.
For more information, see the topic Nonalcoholic Fatty Liver Disease (NAFLD) in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, MPH, FACP, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Associate Editor at DynaMed.