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Metformin Weight Loss Combo: Effect of Leucine plus Metformin and Sildenafil Combination
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<blockquote data-quote="Nelson Vergel" data-source="post: 132179" data-attributes="member: 3"><p>This is an editorial published on this paper:</p><p></p><p>"</p><p>We are reaching a tipping point in the treatment trials of patients with nonalcoholic steatohepatitis (NASH) with four investigational medications that are currently in phase 3 and more than 50 investigational drugs in the earlier phases of clinical trials.1 To date, several NASH treatments have shown efficacy but response rates in general are below 50% and therefore, there is an ongoing quest for better therapies to enhance treatment response.1 Combination therapy targeting multiple pathways involved in the pathogenesis of NASH has been suggested as a way to further boost efficacy.2 The concept of combining leucine, metformin and sildenafil (NS‐0200) is novel and aims at augmenting the effect on a particular pathway, the 5′ adenosine monophosphate‐activated protein kinase (AMPK)/Sirtuin 1 (Sirt1) pathway.</p><p></p><p>Metformin alone does not improve liver histology in NASH.3 In animal studies, when combined with leucine, hepatic steatosis improvements were noted,4 and further addition of sildenafil synergistically enhanced these effects by further stimulating Sirt1 and improving liver histology.5 On the basis of these preclinical studies, Chalasani and colleagues conducted a 16‐week multicentre randomised controlled trial in patients with nonalcoholic fatty liver disease (NAFLD) who were randomised to either low‐dose NS‐0200 (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) bid or high‐dose NS‐0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) bid or placebo.6 The trial population included patients with magnetic resonance imaging proton density fat fraction (MRIPDFF) ≥15%. Liver histology was not assessed. The primary outcome was reduction in MRIPDFF. Neither dose of the active treatment arm was better than placebo in reducing liver fat. A post hoc analysis showed that patients with baseline ALT above 50 U/L who received the high dose of NS‐0200 had 15.7% relative reduction in MRIPDFF. Body weight decreased in the high‐dose group (−2.4 ± 0.5 kg, P = 0.025).</p><p></p><p>This study has notable strengths. It included patients with MRIPDFF ≥15% which would have allowed us to see a significant difference relative to placebo thereby reducing the likelihood of type 2 error. Indeed, it was recently shown that patients with higher liver fat (MRIPDFF ≥15.7%) have higher fibrosis progression.7 Thus, these trial participants were more likely to have progressive NAFLD and were appropriate candidates for an early phase trial. The therapeutic effect seen with the higher dose also led to an appreciable weight loss. This weight loss is unlikely to be due to metformin alone as both the low‐dose and high‐dose treatment groups received the same metformin dose but the weight loss in the low‐dose group was not significant. Although NS‐0200 has a biologically plausible mechanism of action, the lack of appreciable potency at the 2 tested doses in the per‐protocol analyses is a notable finding. Utilising a higher dose or slight modifications in the individual doses of either leucine or metformin or sildenafil within the combination regimen may not be unreasonable to explore before undertaking further trials in patients with NASH. Each study within the landscape of treatment trials for NAFLD provide unique insights regarding treatment trial design and the study population, and this trial adds additional insights that help inform the future of NASH treatment trial design."</p></blockquote><p></p>
[QUOTE="Nelson Vergel, post: 132179, member: 3"] This is an editorial published on this paper: " We are reaching a tipping point in the treatment trials of patients with nonalcoholic steatohepatitis (NASH) with four investigational medications that are currently in phase 3 and more than 50 investigational drugs in the earlier phases of clinical trials.1 To date, several NASH treatments have shown efficacy but response rates in general are below 50% and therefore, there is an ongoing quest for better therapies to enhance treatment response.1 Combination therapy targeting multiple pathways involved in the pathogenesis of NASH has been suggested as a way to further boost efficacy.2 The concept of combining leucine, metformin and sildenafil (NS‐0200) is novel and aims at augmenting the effect on a particular pathway, the 5′ adenosine monophosphate‐activated protein kinase (AMPK)/Sirtuin 1 (Sirt1) pathway. Metformin alone does not improve liver histology in NASH.3 In animal studies, when combined with leucine, hepatic steatosis improvements were noted,4 and further addition of sildenafil synergistically enhanced these effects by further stimulating Sirt1 and improving liver histology.5 On the basis of these preclinical studies, Chalasani and colleagues conducted a 16‐week multicentre randomised controlled trial in patients with nonalcoholic fatty liver disease (NAFLD) who were randomised to either low‐dose NS‐0200 (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) bid or high‐dose NS‐0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) bid or placebo.6 The trial population included patients with magnetic resonance imaging proton density fat fraction (MRIPDFF) ≥15%. Liver histology was not assessed. The primary outcome was reduction in MRIPDFF. Neither dose of the active treatment arm was better than placebo in reducing liver fat. A post hoc analysis showed that patients with baseline ALT above 50 U/L who received the high dose of NS‐0200 had 15.7% relative reduction in MRIPDFF. Body weight decreased in the high‐dose group (−2.4 ± 0.5 kg, P = 0.025). This study has notable strengths. It included patients with MRIPDFF ≥15% which would have allowed us to see a significant difference relative to placebo thereby reducing the likelihood of type 2 error. Indeed, it was recently shown that patients with higher liver fat (MRIPDFF ≥15.7%) have higher fibrosis progression.7 Thus, these trial participants were more likely to have progressive NAFLD and were appropriate candidates for an early phase trial. The therapeutic effect seen with the higher dose also led to an appreciable weight loss. This weight loss is unlikely to be due to metformin alone as both the low‐dose and high‐dose treatment groups received the same metformin dose but the weight loss in the low‐dose group was not significant. Although NS‐0200 has a biologically plausible mechanism of action, the lack of appreciable potency at the 2 tested doses in the per‐protocol analyses is a notable finding. Utilising a higher dose or slight modifications in the individual doses of either leucine or metformin or sildenafil within the combination regimen may not be unreasonable to explore before undertaking further trials in patients with NASH. Each study within the landscape of treatment trials for NAFLD provide unique insights regarding treatment trial design and the study population, and this trial adds additional insights that help inform the future of NASH treatment trial design." [/QUOTE]
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Metformin Weight Loss Combo: Effect of Leucine plus Metformin and Sildenafil Combination
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