NASH in Diabetes: New Therapies on the Horizon

Much of the focus on diabetes complications centers on cardiovascular disease and chronic kidney disease, but a fast-emerging area of inquiry is the association of diabetes with liver disease—specifically nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH).

Although a number of promising therapies for NASH are in the pipeline, current treatment options are limited. What is the clinical burden of NASH, especially as it pertains to diabetes, and what can be done about it?

NASH and Diabetes

NAFLD is the most common chronic liver condition in the world, with a global and US prevalence of approximately 25% and at least 60%-70% among people with diabetes. Although NAFLD can be relatively benign, NASH can lead to cirrhosis and hepatocellular carcinoma and eventually require patients to undergo liver transplantation.

Only about 10% of the general population with NAFLD has NASH, but that proportion rises dramatically in the presence of diabetes or metabolic syndrome. In a recent study of 215 patients with metabolic syndrome and abnormal liver enzyme levels who underwent liver biopsy, 59% had NASH compared with 97% of the 136 patients with newly diagnosed diabetes.

The Burden of NASH

Up to 25% of patients with NASH develop cirrhosis or hepatocellular carcinoma, but that proportion would undoubtedly be higher were it not for the competing risk for mortality. Although liver-related mortality is greater in patients with NASH than in patients with NAFLD or the general population, the most common cause of death in both NASH and NAFLD is cardiovascular disease. This is not surprising given the strong association between NAFLD/NASH and cardiometabolic risk factors.

In addition to obesity, the high prevalence of metabolic syndrome and its components has long been known in patients with NASH. A meta-analysis found that 41% of patients with NASH had hypertriglyceridemia, 68% had hypertension, 72% had dyslipidemia, and 44% had diabetes, suggesting an even higher prevalence of hyperglycemia if patients with impaired fasting glucose or impaired glucose tolerance had been included in the category of diabetes.

The presence of type 2 diabetes influences the relationship between NAFLD/NASH and cardiovascular disease. One relatively small study demonstrated that NAFLD is independently associated with incident cardiovascular disease in patients with type 2 diabetes, and a population-based study suggested the impact of NAFLD on cardiovascular events was minimized after accounting for diabetes, hypertension, and dyslipidemia.

Another study found a stepped association between fibrosis level (determined by magnetic resonance elastography) and cardiovascular disease risk (determined by the Framingham risk score), as well as significantly greater coronary arterial calcification at high fibrosis levels among patients with type 2 diabetes. In addition, NASH has been linked to chronic kidney disease, which of course is of great concern for patients with diabetes.

Identifying NASH in Diabetes

Although one study suggested that virtually all patients with diabetes have NASH, other studies have found lower—albeit still high—rates in patients with diabetes. Liver biopsy is the gold standard for diagnosing NASH, but it has serious limitations in addition to being costly. Many clinicians rely on elevated liver enzyme levels as an initial indication of NASH, yet these test results are normal in up to 80% of patients and thus cannot be relied upon. However, liver enzyme levels are often included in the many fibrosis scores that can be estimated from varying sets of clinical parameters.

Ultrasonography is often used to identify NASH, and advances in imaging have given us the FibroScan, although the test results are less valid among patients with diabetes. The point is that there are noninvasive options for identifying suspected NASH that can help reduce the need for biopsy.

Treatments

NASH and NAFLD have long been overlooked, in part because they lack specific treatments. As with other obesity-related diseases, weight loss is highly recommended but difficult to achieve. NASH is strongly associated with insulin resistance, so a logical approach might be insulin sensitizers. This was the basis for the just-published randomized trial of pioglitazone with vitamin E, a three-arm investigation (vitamin E, vitamin E plus pioglitazone, or placebo) among patients with diabetes and biopsy-proven NASH.

After 18 months, 54% of the combination therapy group showed reductions in NAFLD activity (vs 19% in the placebo group) and significant improvements in steatosis, inflammation, and ballooning. However, there was no improvement in fibrosis, and the mean weight gain was 5.7 kg after 18 months. So, although pioglitazone may be better than no treatment at all, it is not the answer to the growing NASH problem.

On the Horizon

Pharmaceutical and biotechnology companies are working feverishly on therapies for NASH. Four drugs in phase 3 trials are expected to report out in 2019 or 2020, one of which had negative results. The expert consensus is that the complexity of NASH is likely to require combination therapy with more than one mechanism of action, so agents that are unsuccessful as monotherapies in phase 3 studies may still have a role.

A host of other products are in phase 2 trials. Within 10 years, 10 or more NASH therapies could be on the market. Meanwhile, diabetes-related NASH is reminiscent of chronic kidney disease. Neither has disease-specific treatments, but both contribute to disease-specific and cardiovascular morbidity and mortality. Even without available treatments, it is important to diagnose NASH and NAFLD and monitor progression while doing what we can to mitigate the associated excess risks.

Gregory A. Nichols, PhD, is a distinguished investigator at the Kaiser Permanente Center for Health Research, where he conducts real-world evidence studies on the epidemiology and burden of disease of diabetes, cardiovascular disease, and related complications. He has more than 130 publications and has been a Medscape contributor since 2006.

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