Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are well-recognized causes of progressive liver disease leading to cirrhosis and hepatocellular carcinoma. To date, no therapy provided evidence of significant efficacy in these conditions and no approved therapeutic options are available worldwide. As the renin-angiotensin system overexpression plays a central role in insulin resistance and subsequently in NAFLD/NASH as the hepatic expression of metabolic syndrome, an attempt to block its deleterious effects and thus to improve insulin sensitivity and to antagonize the local hepatic effects of a vicious cycle seems logically correct. In the light of this, angiotensin receptor blockers (ARBs) could act as an elegant tool for adequate correction of various imbalances that act in concert in NASH/NAFLD. Indeed, by inhibiting the renin-angiotensin system, the intracellular insulin signaling pathways can be improved, adipose tissue proliferation and adipokine production can be controlled better, and local and systemic levels of various cytokines can be adequately balanced. At the same time, by controlling this peptide system locally in the liver the evolution from steatosis to necroinflammation and consequent fibrosis can be slowed down, while by targeting the pancreatic effects of angiotensin it is possible to preserve an adequate insulin secretion and acquire a better metabolic balance.
A research team led by Prof. Eugen Georgescu from the Filantropia University Hospital of Craiova – Romania addressed this issue and their results will be published on February 28, 2009 in the World Journal of Gastroenterology.
They compared the efficacy of telmisartan vs valsartan in a randomized double blind pilot trial assessing insulin resistance, cytolysis and NASH activity score (NAS) in 54 patients with NASH and mild-to moderate hypertension. The primary endpoints of the study were to prove that ARBs can ameliorate insulin resistance in mild-to-moderate hypertensive patients with histologically confirmed NASH, showing that monotherapy with ARBs on a regularly base can ameliorate cytolysis and NAS, while the secondary endpoint was to prove certain superiority of telmisartan vs valsartan probably linked to its specific insulin sensitizing action releated to the peroxisome proliferator activated receptor (PPAR) gamma – modulatory effects. This is one of the first human blinded trials evaluating the effects of telmisartan and valsartan in steatohepatitis that uses paired liver biopsies with NAS evaluation, simultaneously with cytolysis, insulin resistance, and lipid profile assessment.
The group followed-up the patients for 20 months observing that although serum aminotransferases did not normalized in either group, telmisartan reduced cytolysis by 30.28% and improved insulin resistance by 42.63% consequently with a significant decrease of NAS and fibrosis scores and an amelioration of the lipid profile. Conversely, despite a significant reduction of cytolysis levels by 23.22% and of IR by 21.4%, valsartan did not improved liver histology (except steatosis) and had no effect on plasma lipids. By observing in clinical conditions significant reduction of insulin resistance by both ARBs, as well as a moderate decrease of cytolysis, the study confirms that ARBs not only can correct hypertension, but also can act by preventing and treating steatohepatitis as an end-organ effect of metabolic syndrome. On the other hand, ARBs can prevent collagen synthesis and further progression to cirrhosis. To date, as equally cheap, effective and well-supported antifibrotic therapies are hard to be found, the authors predict that this property will put ARBs in the pole position for treating at least the liver fibrosis.
There are two major advantages that make ARBs a first-class therapeutic option for treating NASH and metabolic syndrome: their specific antihypertensive effect and the impact on liver fibrosis. The potentially advantage for using ARBs in NASH/NAFLD resides in a more tailored action on the tissular targets, by interfering solely the AT1 receptors of angiotensin and thus providing a more clear-cut effect. However, not all ARBs have similar potencies in NASH/NAFLD, perhaps given to some different “second-level”pharmacologic effects such as the specific PPAR-gamma ligand effect of telmisartan and maybe some other some “concealed” mechanisms that further studies will undoubtedly unveil.