Glucagon-like peptide-1 receptor agonists: A better option for treating and preventing steatohepatitis?

The pathogenesis of type 2 diabetes is underpinned by ectopic fat in key organs, with the liver being one of the most easily recognised in clinical terms, often via mildly raised transaminase levels or enhanced echogenicity on hepatic ultrasound. Indeed, the vast majority of people with type 2 diabetes have excessive liver fat sufficient to be categorised as non-alcoholic fatty liver disease (NAFLD; >5% fat). In most people, this excess liver fat is not a major concern other than the fact that it causes hepatic insulin resistance, as progression to more advanced liver disease will not occur (Sattar et al, 2014). However, in some people, NAFLD will progress to non-alcoholic steatohepatitis (NASH), and then the risk of cirrhosis and even hepatocellular carcinoma are meaningfully increased. Hence, we would like to know which of our patients will progress to NASH and how to identify them. The hepatologist, in turn, would like to offer treatments that can alleviate NASH or slow its progression, and do so in a safe manner.

In terms of identifying people at increased risk of NASH, several different and often complex algorithms have been put forward. Most, however, are unlikely to be widely used in primary care or in general outpatient clinics. Therefore, Sattar et al (2014) recently suggested that the simplest and most pragmatic clinical warning sign of impending NASH is the aspartate transaminase/alanine transaminase (AST/ALT) ratio, which is normally well below 0.8. In people with known NAFLD (and thus, by definition, most people with type 2 diabetes), when this AST/ALT ratio is rising towards 0.8, or certainly towards 1.0, referral to the hepatologist for more detailed assessment of NASH risk is warranted. In most people, however, mild elevations in ALT (and when ALT levels are higher than AST and the ratio is <0.8) should be dealt by reinforcement of dietary advice to alter weight trajectory (ideally weight loss), and to cut down on alcohol, irrespective of the current intake level.

In terms of treatments, other than lifestyle change, we have long been waiting for a “magic” drug to lessen or reverse features of NASH in people with and without diabetes. However, potential treatments to date have had side effects sufficient to make some cautious about their use. Certainly pioglitazone will lessen NAFLD and impede NASH development (Aithal et al, 2008), but its associated risks of weight gain and heart failure mean that its uptake has been limited. An arguably better treatment for NASH would be one that not only lowers liver fat levels but also lowers blood glucose and weight, as well as being safe. With this in mind, the results of the short-term randomised trial by Armstrong et al (summarised alongside), which demonstrated histological resolution of NASH by liraglutide with no significant safety issues, is to be welcomed, especially since glucagon-like peptide-1 receptor agonist treatment is now well established in diabetes management and is increasingly being used.

The authors correctly state that larger and longer-term NASH studies are needed to verify their findings and validate safety given the small size of the study. Nevertheless, the results are appealing and clinically impactful. The fact that liraglutide also appears to improve cardiovascular outcomes (see page 72) is a further benefit considering that, for reasons not yet clear, people with NASH have heightened cardiovascular risk.

Finally, future studies will also need to test whether other diabetes drugs that lower weight can be beneficial in NASH, especially since preliminary evidence shows that sodium–glucose cotransporter 2 inhibitor treatment improves liver enzyme levels (Katsuyama et al, 2016).

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