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• W2050587925 abstract "Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor -γ agonists widely used for the treatment of type 2 diabetes mellitus (T2DM). They improve glucose and lipid metabolism in insulin-resistant states primarily by restoring normal adipocyte biology with amelioration of obesity-induced lipotoxicity and systemic inflammation.1 The Food and Drug Administration approved in the past decade 3 TZDs for the treatment of T2DM: troglitazone (later discontinued owing to liver toxicity), rosiglitazone, and pioglitazone. They were not even remotely envisioned as a treatment for nonalcoholic steatohepatitis (NASH), but exclusively designed for the treatment of T2DM. Credit should be given to Caldwell et al2 who was the first to test troglitazone in an open-label pilot study in 10 patients with NASH. Seven demonstrated biochemical improvement, although histologic response was more variable. Still, the study was provocative and this was soon followed by pilot studies with the newer TZDs rosiglitazone3 and pioglitazone.4 Results were mixed, but overall promising. It was not until the randomized, controlled trial by Belfort et al5 that the safety and efficacy of a TZD (pioglitazone) was better established, with another recent study confirming these findings in patients with NASH.6 Still many questions remain: may TZDs change the natural history of NASH, as they have shown in patients with impaired glucose tolerance (IGT) (ie, “prediabetes”) by preventing the onset of T2DM?7–9 What is different among NASH patients who are responders versus nonresponders? Who are the best candidates for treatment? Is long-term treatment safe and effective? At the very core the issue we struggle with is whether TZD treatment for patients with NASH will have to be permanent (in the same way we treat diabetes, dyslipidemia, hypertension, and many other chronic metabolic conditions), or on the contrary, should we expect benefit to endure after treatment discontinuation? In this issue of the J Clin Gastroenterol, Argo et al10 attempt to answer some of these questions by reporting on the long-term follow-up of the original cohort of patients that participated in the landmark troglitazone trial by Caldwell et al.2 The median posttrial follow-up was 65±41-93 months. Patients were divided into 2 groups: (a) 4 that were engaged in behavioral modification after the trial with a mean weight loss of 8.1 kg (ranging from 1.7 to 17.2 kg/m2); fibrosis improvement was documented in the 2 undergoing a repeat liver biopsy with none developing diabetes and (b) 5 subjects that gained weight (mean 3.5 kg/m2) and all progressing to T2DM. Two of the 3 patients who underwent a repeat liver biopsy continued to have active steatohepatitis and fibrosis worsened. Of note, 2 were troglitazone nonresponders (patients 9 and 10) whereas the other patient already had stage 4 fibrosis that did not improve while on troglitazone (patient 7). An increase in body mass index and physical inactivity were the strongest predictors of disease progression in this group. This work is obviously limited by the small sample size, few subjects (n=3) with a liver biopsy before and after troglitazone treatment and at the end of the follow-up observation period, and lack of a systematic lifestyle intervention for all patients. Still the prospective nature of the report (the longest follow-up ever post-TZD therapy) is of considerable value and may be hypothesis generating for the long-term management of NASH. The most striking observation is that diabetes and nonalcoholic fatty liver disease seems much more closely linked than previously appreciated. Both share the “common soil” of obesity-induced lipotoxicity, that is, when insulin-resistant adipose tissue releases large amounts of fatty acids into the circulation and the high free fatty acid flux to tissues causes muscle, liver, and/or β cell dysfunction, and/or cellular apoptosis.11 Obesity-induced lipotoxicity and insulin resistance precede and promote disease progression from prediabetes to full blown T2DM and “bland” steatosis to NASH. In this regard, the liver in NASH may simply be the “metabolic sensor” of a “lipotoxic state.” It is quite telling that the 2 patients with biopsy-proven worsening fibrosis developed T2DM over time whereas the other one in this group already had cirrhosis and diabetes at the time of the original trial. Of note, in all 3 patients alanine aminotransferase (ALT) “improved” giving a false sense of security to the unaware clinician and confirming prior observations about the need of a liver biopsy in NASH trials.3–6 The close association between diabetes and NASH has also been our own experience. When systematically testing patients with biopsy-proven NASH for T2DM by means of an oral IGT, we observed that 2 out of 3 of patients who were believed to be free of diabetes have either impaired IGT (IGT or prediabetes) or frank T2DM.6 Moreover, in our hands 68% of patients with T2DM and normal plasma ALT levels have nonalcoholic fatty liver disease when the liver is studied by magnetic resonance imaging and spectroscopy.12 Taken together, both conditions seem linked to an extent not fully appreciated before. What does this mean for the treatment of NASH? It is becoming more and more clear that a treatment that may prevent the progression from prediabetes to T2DM (ie, lifestyle intervention like in the Diabetes Prevention Program7 or TZDs7–9) may likely also work to ameliorate progression of NASH. Unfortunately, dietary modification studies in NASH have been in general small, uncontrolled, and of short duration (none greater than 12 mo). Most have had limited success.11 Long-term treatment of NASH perhaps may hold a better chance of success if combined with pharmacologic therapy (ie, TZDs). This poses the question about what the duration of TZD therapy should be in patients with NASH. There is very limited information available. Only one prior study in NASH has reported so far on outcomes after TZD discontinuation and reported just on half of the original cohort of patients (9 out of 18).13 The results seem to be a crushing failure for TZD therapy: the metabolic and histologic benefits of pioglitazone treatment disappeared when examined 12 months after TZD withdrawal. However, a sustainable long-term benefit of TZD therapy may be an unreasonable expectation that clinicians do not have when treating other chronic metabolic conditions. Who would expect to prevent diabetic complications, coronary artery disease, or strokes by treating intermittently hyperglycemia, hypertension, or dyslipidemia? Why would steatohepatitis and/or fibrosis not return after TZD discontinuation if the same metabolic milieu of lipotoxicity that caused the disease to begin with persists over time? In this report by Argo et al10 talking of a “TZD (troglitazone) withdrawal effect” may be more difficult to assess as treatment in the initial report was short (3 to 6 mo). Moreover, despite a reduction in liver transaminases in 7 out of 10 patients (considered responders), a 1-grade necroinflammation improvement was observed only in 5 and 1-stage fibrosis in 1 out of these 7 responders. Also most with disease progression did not initially respond well to troglitazone. Indeed, the work by Argo et al10 speaks more about the long-term importance of diet and exercise than about troglitazone itself. This begs the question as to whether there are pharmacologic differences among the TZDs. Emerging evidence suggests that perhaps all TZDs may not be the same for the treatment of NASH. Although the full potential of troglitazone for the treatment of NASH will never be known, it was clearly a unique and different TZD in causing severe liver toxicity, an effect not observed with the newer TZDs. There are well-established differences between pioglitazone and rosiglitazone regarding lipoprotein metabolism and cardiovascular events, with a more favorable profile for pioglitazone.1 Rosiglitazone has been reported to reduce plasma ALT levels and steatosis, but has a more limited impact on necroinflammation and fibrosis in NASH.14 Moreover, the open-label 2-year follow-up of the trial study has been disappointing by showing no significant benefit of rosiglitazone in NASH.15 Pioglitazone has been the most effective in short-term 6 to 12-month studies,5,6 although we await ongoing longer-term trials in patients with NASH having T2DM (Cusi et al; unpublished) or without T2DM (PIVENS trial) to learn about its benefits and limitations. In summary, management of patients with NASH treatment will require a multidisciplinary approach in combining lifestyle intervention and pharmacologic therapy. Both have complementary mechanisms of action on insulin resistance and lipotoxicity that offer promise in NASH.1 Multiple metabolic and molecular pathways closely link NASH and T2DM, so lessons from large clinical trials on the prevention of T2DM with TZDs tell us what we may be realistic to expect (and not to expect) from them for the long-term management of NASH.7–9 This report by Argo et al10 proposes that the histologic improvement with TZDs therapy may be better sustained with long-term behavioral modification, or may have even have a long-term “priming effect.” Clinical trials will be needed to test this premise in the future, but a similar concept for a “TZD priming effect” is being tested with good preliminary results in clinical trials in hepatitis C.16 Clearly much more work lies ahead, but what appeared to be an unlikely and even odd couple at first (TZDs and NASH) may be seen more “hand-in-hand” in the near future." @default.
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• W2050587925 title "Thiazolidinediones in NASH An Odd Couple Meant To Be?" @default.
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