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Combination Therapy for NAFLD/NASH
Combination Therapy With T2D Drugs to Treat NAFLD and NASH: GLP-1 Receptor Agonists Plus SGLT2 Inhibitors

Released: February 02, 2023

Expiration: February 01, 2024

Manal F. Abdelmalek
Manal F. Abdelmalek, MD, MPH
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Key Takeaways
  • Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis are increasing in parallel with the obesity and type 2 diabetes epidemics.
  • The pleiotropic effects of GLP-1 receptor agonists are complementary to SGLT2 inhibitors.
  • SGLT2 inhibitors or GLP-1 receptor agonists should be used for metabolic dysfunction, especially when obesity, type 2 diabetes, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis coexist.  

Association Between T2D and Progressive Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) and its most progressive form, nonalcoholic steatohepatitis (NASH), are increasing in parallel with the obesity and type 2 diabetes (T2D) epidemics. Patients with T2D are at higher risk for the negative clinical outcomes of fibrosis progression, the development of cirrhosis, and even hepatocellular carcinoma. This integral association between T2D and progressive NAFLD creates a very promising and enticing therapeutic landscape for antimetabolic therapies that optimize glycemic control or improve the drivers of insulin resistance and T2D complications. T2D complications go hand in hand with the same types of comorbidities we also see in patients with NAFLD and NASH, specifically cardiovascular disease, chronic renal disease, and heart failure with preserved ejection fraction. Two therapies that show promise and are being used more extensively in T2D are sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. These 2 antidiabetic drugs have attracted scientific interest in the past decade because of their multiple pleiotropic effects, with emphasis on cardiac and renal protection in both classes. In addition, there is a new and emerging therapeutic strategy of combining these classes, each of which has independently demonstrated improvements in both NAFLD and NASH.

Retrospective data of SGLT2 inhibitors in patients with T2D and NASH have demonstrated significant improvement in hepatic steatosis without safety concerns. In fact, the glycosuric effects of SGLT2 inhibitors have led some investigators to speculate that this class, given its diuretic effects, may be valuable for patients with cirrhosis and ascites.

We have more data on the GLP-1 receptor agonists: Both retrospective and prospective clinical trials have demonstrated an improvement in biopsy-proven NASH and at least a suggestion of protection against fibrosis progression. The data initially emerged from a small pilot study of liraglutide at a dose of 1.8 mg SC daily. Patients who were receiving liraglutide demonstrated an improvement in biopsy-proven NASH without worsening of fibrosis. We subsequently have seen a much larger trial using semaglutide in 320 patients who were treated on varying doses of semaglutide vs placebo. Data show that all doses of semaglutide reached the primary endpoint of NASH resolution, with the highest efficacious dose of 0.4 mg achieving NASH resolution in 59% of patients.

Pleiotropic Effects of Combination Therapy

The pleiotropic effects of the GLP-1 receptor agonists are different and yet complementary to the SGLT2 inhibitors because GLP-1 receptor agonists work on satiety and cravings, and they improve pancreatic function and decrease lipogenesis in the liver. In the therapeutic landscape of T2D, there has been evidence that both these classes can be used together safely. Thus, it poses the question of whether combination therapies also can be effective in treatment of NASH, particularly as these drugs result in both glycemia reduction and weight loss.

Therapeutic Effects of Combination Therapy

When we couple these therapeutic effects of combination therapy, the greater reductions in glycemia—as well as weight loss—could translate into greater reductions in SC and visceral fat mass and intrahepatic fat content. For a patient with NASH or NAFLD, reductions in weight, glycemia, and intrahepatic fat content mean a higher probability of NASH resolution and even fibrosis improvement.

Based on safety data and data that are emerging on using SGLT2 inhibitors with GLP-1 receptor agonists, improvement in patients who have both T2D and NAFLD is plausible. If we receive supportive data from prospective clinical trials that the combination is better on NASH resolution and fibrosis regression than either class alone, then we certainly could tailor the treatment approach to using these drugs for their complementary mechanisms of decreasing insulin resistance and glycemia.

Likelihood of Future Labeled Indications for NASH or NAFLD

GLP-1 receptor agonists currently only have labeling for obesity and T2D. We know that the prevalence of NAFLD and NASH is quite high in patients with T2D—approaching 70%. Whether the labeling is necessary to effectively use this class of medication in patients who are at risk for NAFLD and NASH is debatable. However, labeling for NAFLD and NASH would lend more confirmation of efficacy and broader use independent of the indications of T2D or obesity alone, so I am hopeful that we will have labeled indications for NAFLD and NASH in the future.

Ultimately, I think we need to move away from the dogma of an “obesity drug” or a “T2D drug.” What we have is a continuum of metabolic dysfunction: Energy excess begets complications of T2D, obesity, NAFLD, and cardiovascular disease. We need to break down the silos in which we have practiced medicine in dealing with these as independent entities. I am hopeful that we can develop multidisciplinary teams to care for patients with metabolic and organ complications using drugs that target these metabolic dysfunctions.

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