Closing in on Better Treatment for Non-Alcoholic Fatty Liver Disease

Combination therapy with SGLT2i and a potent omega-3 formula appears to reduce liver fat content; and dapagliflozin alone may be disease-modifying for NAFLD.

With Jan Eriksson, MD, PhD, and Arun Sanyal, MD

Facing the rapid rise in prevalence of non-alcoholic fatty liver disease (NAFLD) and an associated increase in type 2 diabetes and cardiovascular disease, in both adults and children, and with a significant risk of progression to advanced stage steatohepatitis (NASH) and fibrosis,1 there is an urgent need for an effective treatment.

A combination of dapagliflozin and omega 3 CA appear to clear liver fat reducing risk of NAFLD.

Combining the SGLT2 inhibitor, dapagliflozin (Farxiga) with omega-3 carboxylic acid (Epanova, a prescription level hypertriglyceridemia product) significantly reduced liver fat content in obese patients with type 2 diabetes (T2D) and NAFLD, according to results of the EFFECT-II study.2

Assessing liver content as measured by proton density fat fraction (PDFF) imaging has been demonstrated as an effective non-invasive tool to confirm NAFLD but not to distinguish between more advanced stages of the disease.3,4

Closing in on Treatment for Non-Alcoholic Fatty Liver Disease

Dapagliflozin alone reduced all measured hepatocyte injury biomarkers as well as fibroblast growth factor-21, which suggests a disease-modifying effect for NAFLD,2 according to the researchers.

Both findings are important, Jan W. Eriksson, MD, PhD, a study co-author, and professor of diabetes research at Uppsala University in Sweden, told EndocrineWeb.

At the present time, there are no approved drugs to manage NASH. Treatment recommendations for NAFLD have been limited to advising patients to make lifestyle changes consistent with management of type 2 diabetes and obesity, namely dietary improvements, weight loss, and increased exercise and medications suitable to manage concomitant conditions.

For example, dapagliflozin is indicated for T2D and has been shown to reduce hemoglobin A1c (HbA1c), body weight, body fat, and blood pressure.5 It can also reduce the risk of cardiovascular events and death when added to standard of care.6

"The incentive for doing this study was to look at the effectiveness of this combination for fatty liver disease," he said, particularly as that there are no completed placebo-controlled studies of the effects of SGLT2is on liver fat and hepatocyte injury biomarkers in those with type 2 diabetes and NAFLD.

The need for an effective therapy is clear given a prevalence of NAFLD in those with type 2 diabetes at about 75%, and patients with type 2 diabetes having a higher risk of developing NASH, a more aggressive form of the disease.

Trial Outcomes Favor Combination Therapy for NAFLD

Omega-3 carboxylic acids (OMCA) contain a non-esterified free fatty acid mixture, a new chemical entity with better bioavailability than the over-the-counter ethyl ester or triacylglycerol forms, making this an attractive consideration to potentiate therapeutic management of NAFLD and NASH.

The authors pointed to findings from a meta-analysis in which omega three fatty acid treatment of NAFLD showed a reduction in liver fat even without weight loss.7

In this phase 2a study,2 the investigators randomly assigned 84 people who were diagnosed with both type 2 diabetes and NAFLD to one of four treatment groups:

  • 10 milligrams of dapagliflozin
  • 4 grams of OM-3CA
  • Both the dapagliflozin and the OM-3CA
  • Placebo

The patients were on average 65.5 years with a BMI of 32.2, and liver PDFF of 18%.2

All four treatment protocols achieved a reduction in liver PDFF. The relative changes were: -13% for dapagliflozin, -15% for Om-3CA, and -21% for the combination. However, only the combination therapy —dapa plus OM-2CA—achieved a  significant reduction in liver PDFF (P = 0.046) and total liver fat volume (relative change, -24%, P =0.037) in comparison to placebo.2

Treatment of dapagliflozin alone but not in combined treatment showed a reduction in hepatocyte injury biomarkers. Solo therapy, as well as the combination of the SGLT2i plus OM-3CA, achieved improvements in glucose control, reduced body weight, and reduced abdominal fat volume.

However, treatments did not affect fatty acid oxidative stress biomarkers, and no new or unexpected adverse events occurred that differed from previous research.

Need to Take This Proof of Concept Study Further

Asked what is next for this EFFECT-ll study, Dr. Eriksson agreed that more research was needed. After all, more targeted treatments are sorely needed, he told EndocrineWeb, due to the sheer number of patients who have or will develop NAFLD and NASH. Already the prevalence of NAFLD in those with type 2 diabetes is about 75%, said Dr. Eriksson.

While the results of the EFFECT-ll trial are suggestive of benefit,2 he acknowledged that more robust research would be needed to confirm the efficacy of dual therapy with dapagliflozin and OMCA.

Asked if the combination therapy reduced liver fat enough that it would be considered clinically significant, Dr. Eriksson said: "likely, we are not quite there yet in proving that dapagliflozin alone or with omega-3 can reduce the risk of serious liver disease in these patients."

The study adds important information for this population, said Arun Sanyal, MD, a hepatologist and professor of medicine, psychology and molecular pathology at Virginia Commonwealth University in Richmond who was not involved in the study but agreed to review the findings.

"We know right off that SGLT2 inhibitors have been shown to improve MACE and all-cause mortality," he told EndocrineWeb. "Here, in this proof of concept study, they looked at the combination, and they showed that the combination had a greater effect on hepatic triglycerides, but it was a modest additive effect."

One novel finding was a demonstrated effect to achieve a reduction in liver fat even without a biopsy. "This sets the stage for further research," Dr. Sanyal said.

Combining treatments also holds the promise of reducing the pill burden for people with type 2 diabetes and liver problems, said Dr. Sanyal. As it is, "the average person with NASH is typically taking 10 drugs a day," he said, including medications for their diabetes, hyperlipidemia, hypertension, anxiety, and depression.

The study received funding from AstraZeneca, which products Farxiga. Dr. Eriksson received consultancy fees from Astra Zeneca. Dr. Sanyal has no conflicts as related to this research.

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