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Studies Point to Empagliflozin as First Choice for Fatty Liver Disease in T2D

Mary Caffrey
The lead author of a study appearing this  month in Diabetes Care said other data support his findings, pointing to the potential for the SGLT2 inhibitor empagliflozin to replace metformin as first-line therapy.
Studies reported over the past 6 months increasingly point to empagliflozin, used to treat type 2 diabetes (T2D), as a treatment for nonalcoholic fatty liver disease (NAFLD), and one study author said it could lead to these patients being treated right away with the drug.

Mohammad Shafi Kuchay, MBBS, MD, was the first to present findings that show empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, reduces liver fat. Kuchay presented results from the E-LIFT trial in March at the Endocrine Society, and the full study was published this week in Diabetes Care.

In an email to The American Journal of Managed Care®, Kuchay said a new study published this week in Diabetologia is consistent with the E-LIFT results, bolstering the concept that patients with diagnosed with T2D who also have NAFLD should be treated first with empagliflozin (Jardiance from Eli Lilly and Boehringer-Ingelheim).

Kuchay noted that between 50% and 70% of those who have T2D also have NAFLD, which can lead to severe complications if it progresses to nonalcoholic steatohepatitis. Known as NASH, this condition occurs when fat in the liver causes liver cell damage, leading to scarring and cirrhosis. According to the National Institutes of Health (NIH), there are no approved therapies for NAFLD or NASH.

“Finding effective treatment for reducing liver fat and preventing or treating NAFLD is an urgent global public health need,” Kuchay wrote. “There is no medicine approved for NAFLD at present. Empagliflozin has a high potential of getting approval for NAFLD in patients who also have type 2 diabetes.”

If empagliflozin is able to reduce fat, Kuchay wrote, it would the “treatment of choice” for patients with T2D and NAFLD. “You can understand it by analogy from hypertension,” he wrote. “If a patient with type 2 diabetes has hypertension, the first drug of choice for hypertension" is angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers.

“Similarly, if a patient with type 2 diabetes has NAFLD, the first drug of choice can potentially be empagliflozin; at present it is metformin,” Kuchay wrote.

The E-LIFT trial. Kuchay and fellow investigators randomized 50 patients with T2D and NAFLD to either 10 mg of empagliflozin alongside standard of care, or a control group, which received standard care for T2D. Changes in liver fat were measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF), a noninvasive method.1

After 20 weeks of treatment, the group receiving empagliflozin showed a significant reduction in liver fat, while the reduction in the control group was not significant. The percentage of liver fat dropped in the treatment group from 16.2% to 11.3% (P <.0001), while the percentage in the control group dropped from 16.4% to 15.5% (P = 0.054).

Notably, this study did not find a correlation between body weight reduction and liver fat reduction, which is key because, until now, the best advice for NAFLD has been to lose weight, according to the NIH.

Diabetologia study. This week, a study led by Naveed Sattar appeared in Diabetologia,2 which examined data from 6 randomized trials involving empagliflozin, including the EMPA-REG OUTCOME trial that was the first to show cardiovascular benefits from a T2D therapy. Researchers evaluated measures of baseline measures of 2 key enzymes, and found changes for those taking empagliflozin that would indicate a reduction in liver fat.

Measures of alanine aminotransferase (ALT) and asparate aminotransferase (AST) by patients taking empagliflozin and other study drugs or placebo were evaluated.

“Transaminases, in particular ALT, are useful correlates of liver fat,” the authors wrote. The EMPA-REG OUTCOME analysis covered 7020 patients; a separate pooled analysis included 2477 patients in 4 placebo-controlled trials of 24 weeks, and a 104-week trial of 1545 patients that compared empagliflozin and glimepiride.

In the EMPA-REG OUTCOME trial, measures of ALT decreased from the baseline to week 28 and remained steady after that in the empagliflozin group. ALT declined steadily but to a lesser extent in the placebo group. The biggest reductions were seen in patients with the highest ALT levels when the study began. Similar reductions were seen in the pooled data.

The authors wrote, “in the EMPA-REG OUTCOME trial, treatment differences in ALT were largely independent of concomitant changes in [glycated hemoglobin] (A1C) or weight in the overall trial population.”

A similar pattern was seen in changes to AST between the empagliflozin and placebo groups in the EMPA-REG OUTCOME trial and in the pooled data, although these changes were of a lower magnitude than changes in ALT.

What’s next? Kuchay said there is now a need for “histological evidence that that examines effect of empagliflozin on inflammation and fibrosis of liver. The study is already going on in Malaysia.”

References
  1. Kuchay MS, Krishan S, Mishra SK, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT Trial). Diabetes Care. 2018;41(8):1801-1808. doi.org/10.2337/dc18-0165.
  2. Sattar N, Fitchett D, Hantel S, George JT, Zinman B. Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomised trials including the EMPA-REG OUTCOME trial [published online July 31, 2018]. Diabetologia. 2018; doi.org/10.1007/s00125-018-4702-3.


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