We read, with great interest, the article by Torres et al. about the efficacy of combination therapy with rosiglitazone and metformin or losartan on improving liver histology in patients with nonalcoholic fatty liver diseases; the investigators conclude that adjuvant therapies are ineffective.1 It is certainly a very interesting study to find out some prospect ideas about the therapeutic potential of “combination effects” or “combination therapy,” because we are still uncertain as to whether or not disregarding combination therapy is a good option for nonalcoholic steatohepatitis (NASH) patients. As discussed by the investigators, an interesting drug to consider is telmisartan, which also acts as a partial agonist of peroxisome proliferator-activated receptor gamma. In fact, in addition to the observed effects on fatty liver reversion, telmisartan is able to improve insulin resistance, but is less effective than losartan in preventing plasminogen-activator inhibitor-1 gene expression.2 Therefore, combining both actions in one molecule may improve some aspects of NASH, but not all of them.
At any rate, there are other reasons to think about the importance of the blockade of the renin-angiotensin system (RAS) in the liver of NASH patients. Perhaps, in the study of Torres et al., improvement in body weight was not as expected, because treatment with thiazolidinediones may prevent an interesting, poorly explored effect of angiotensin receptor blockers (ARBs) on the regulation of body weight.2 In addition, we recently observed a local upregulation of the angiotensin I–converting enzyme in the liver of patients with NASH, suggesting a putative role of the RAS in the progression of liver histology.3
Finally, the investigators speculated that both environmental and genetic influences are likely involved in the lack of universal improvement observed in the patients enrolled in this trial. Can we expect that all patients are equal responders to the therapy? Certainly, we cannot. We previously showed that a gene variant (A1166C) in the angiotensin II type 1 receptor predicts the therapeutic response to losartan; we found a higher response to losartan among AA homozygous.4 We wonder whether, before discharging ARBs, we might improve our ability to select patients who are able to respond better, tailoring the therapy, depending on their genetic background.