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Fatty liver disease and type 2 diabetes: Partners in crime

Non-alcoholic fatty liver is the accumulation of fat in liver cells (hepatocytes) in patients who do not consume significant amounts of alcohol. Commonly called fatty liver disease, this is the most common liver disease worldwide. In the United States, fatty liver disease is the second most common cause of liver transplantation, first being Hepatitis C – related liver disease. Although we have no formal data in India, but it is thought to be a significant contributor to end-stage liver disease and liver transplantation.
Fatty liver disease in patients with type 2 diabetes is a partner in crime. Type 2 diabetes accelerates the progression of fatty liver to more severe liver diseases like steatohepatitis (inflammation in liver), fibrosis and cirrhosis (scarring of liver) and hepatic cancer in some patients. These are the long-term hepatic consequences of fatty liver disease.
People who have fatty live disease and no diabetes, are more prone to develop diabetes. They are also more prone to develop cardiovascular disease (heart attack and stroke), rhythm disturbances of heart and chronic kidney disease. These are the long-term extra-hepatic consequences of fatty liver disease.
Fatty liver disease in patients with diabetes is a public health problem. Let’s see the burden of this disease in our society. In a population of 1000 people with diabetes at age 40, seventy percent (700 individuals) will have fatty liver disease. Out of these 700 individuals, 15 percent (105 individuals) will develop inflammation of liver over 15 years. Out of these 105 people, 15 percent (16 individuals) will develop cirrhosis over 10 years. Therefore, out of 1000 diabetes people of age 40 today, 16 patients would be struggling with liver failure at age 65.
Fatty liver disease, like type 2 diabetes, obesity and cholesterol problems, is a life-style disorder. It stems from long-term over-nutrition and under-activity. You will be surprised to know that there is not a single medicine approved for treating fatty liver disease. This is because we have no medicine that has been proven significantly beneficial for this disease. However, we have some strategies/medicines that help to some extent. Life-style modification (diet and exercise) has been shown to reduce liver fat to some extent in a number of studies. But same studies as well as studies in diabetes field showed that this strategy (diet and exercise) is not sustained for prolonged period of time. It is a common experience in diabetes management that although diet and exercise is advised for all the patients but only a small proportion of patients are actually able to adhere to the advice. The first line medicine for type 2 diabetes, metformin, has also been shown to help in fatty liver disease. But a number of other studies revealed only a modest or no effect on fatty liver disease. The prevalence of fatty liver disease in patients with type 2 diabetes is between 50-75 per cent. This is despite most of these patients having already been advised life-style modification and metformin therapy. This shows that these two strategies for improving fatty liver disease are not sufficient. We need other better strategies/medicines for reducing the incidence and complications of fatty liver disease.
Another diabetes medicine, pioglitazone, has been shown to improve fatty liver disease. However, in a famous PIVANS study, the improvement was not statistically significant and was inferior to vitamin E. Another reason for its lack of use in fatty liver disease is its undesirable adverse effects. Pioglitazone increases body weight that most patients do not like. It also causes fluid retention that is not desired in patients with type 2 diabetes who are already at risk for heart failure and cardiovascular disease. Pioglitazone also has an adverse effect on bone health, especially in post-menopausal women. Above all, although minimal, pioglitazone has been incriminated in bladder cancer. These are the reasons pioglitazone is not a favorite medicine among most experts as well as patients. For fatty liver disease, we need a medicine that has minimal side-effects because it has to be a long-term treatment.
Liraglutide is a daily injectable medicine that has been approved for type 2 diabetes. This medicine reduces body weight as well. In fatty liver studies, liraglutide failed to decrease liver fat in 3-month studies, but reduced liver fat in studies of 6-month duration. This shows that the treatment for fatty liver disease has to be a long-term treatment. Although liraglutide has a potential for being approved medicine for fatty liver disease (if further studies show similar favorable effect), but the patient acceptability of liraglutide is poor as this is an injectable therapy.
Vitamin E has been studied in patients with fatty liver disease and no diabetes. Vitamin E proved to be better than pioglitazone in this population. But it failed to be an approved medicine for fatty liver disease because of long term adverse effects of vitamin E supplementation. In the famous SELECT (the selenium and vitamin E cancer prevention trial) study, vitamin E actually increased the incidence of prostate cancer by 17 per cent.
Ursodeoxycholic acid was thought to improve liver function in fatty liver disease, based on open label single arm studies. But a long term (2 years) histological study showed that ursodeoxycholic acid is no better than a placebo in improving inflammation of liver in patients with fatty liver disease.
Sodium/glucose cotransporter 2 (SGLT-2) inhibitors, also called gliflozins, are a new class of anti-diabetes medicine. Empagliflozin, a member of this group, was first approved for type 2 diabetes in the USA in 2014. In India, it was launched in November 2015 for use in type 2 diabetes. As this medicine causes loss of glucose through urine, its long-term use leads to chronic calorie loss and thereby weight loss. Remember life-style diseases stem from chronic over-nutrition and under-activity. This class of medicine at least tends to correct one basic cause of lifestyle diseases, that is, over-nutrition.
In January 2016, a Japanese study on mice model of fatty liver disease was published that examined the effect of ipragliflozin (another gliflozin) on fatty liver disease. They found that ipragliflozin reduced not only liver fat, but also improved inflammation as well as fibrosis in mice. We had no data of this class of medicine on human liver fat. In February 2016, we registered a study, called empagliflozin on liver fat (E-LIFT trial) to see its effect on human liver fat. We randomized 50 patients with type 2 diabetes and fatty liver disease into empagliflozin group (empagliflozin 10 mg in addition to preexisting anti-diabetes medicine) and control group (standard anti-diabetes medicine without empagliflozin). Liver fat was measured by a robust technique of MRI called proton density fat fraction, which measures liver fat accurately in percentage. After 20-week of follow-up, liver fat decreased from 16.4 % to 15.5% in the control group and from 16.2% to 11.3% in the empagliflozin group. There was an absolute liver fat reduction of 4.9% and a relative liver fat reduction of 32% in this arm. This study also showed improvement in liver enzymes. The study got widespread acceptance first in the US endocrine society and then in global media. This is a first study that shows beneficial effect of gliflozins on human liver fat by using a robust method of liver fat quantification.
This medicine, and probably the other members of this class, has a potential of becoming approved medicine for fatty liver disease at least in patients with type 2 diabetes. For that we need similar and histopathological studies in other population groups. If the same effect of this medicine is reproduced on liver fat, this might be approved for fatty liver disease. As we know that this class of medicine has many other beneficial effects like weight loss, some reduction in blood pressure and prevention of death in patients with cardiovascular disease, its use has been on increase in the world. Although it is a costly medicine at present (which is hoped to decrease with time when competition increases), its patient acceptability is not a problem as this is available in tablet form and also causes weight loss.
(The author is a Kashmiri endocrinologist and researcher working in Medanta-The Medicity Hospital, Gurugram.)