Metformin Weight Loss Combo: Effect of Leucine plus Metformin and Sildenafil Combination

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Objective: Leucine was previously demonstrated to allosterically activate mammalian sirtuin 1 and synergize with other sirtuin 1/AMP-activated protein kinase/nitric oxide pathway activators to modulate energy metabolism. The objective of this study was to evaluate the effects of a triple combination of leucine, metformin, and sildenafil (NS-0200) on body weight and obesity comorbidities in a phase 2 randomized trial.

Methods: A total of 91 subjects with obesity were randomized to placebo, low dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil), or high dose (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) twice daily for 16 weeks. Seventy subjects completed the trial and met all a priori compliance criteria. Hypertensive (n=35) and hypertriglyceridemic (n=22) sub cohorts were also analyzed.

Results: NS-0200 dose-responsively reduced weight; high dose reduced weight by 2.4 and 5.0 kg in the full and high-triglyceride cohorts, respectively (P<0.0001). High-dose NS-0200 treatment also decreased blood pressure (−5.5 mm Hg diastolic pressure; P=0.011), with greater effects among hypertensive subjects. NS-0200 also significantly reduced triglycerides and hemoglobin A1c. Significant improvement in ≥ 2 comorbidities was exhibited by 54% of subjects in the high-dose arm versus 5% of placebo subjects (P=0.0009). Treatment-emergent adverse events did not significantly differ among groups.

Conclusions: These data support further study of NS-0200 as a therapy for obesity and associated comorbidities.

Overall, data from the present study demonstrate that treatment with NS-0200 resulted in significant, dose-dependent reductions in body weight and concomitant improvements in multiple obesity comorbidities. These data support further development of NS-0200 as a therapy for obesity that exerts potential independent effects on obesity-associated comorbidities.


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Apparently, there’s some novel synergistic interactions between L-leucine and metformin I was not aware of. At first it seemed like an odd combination, but on reading this paper, it makes some sense. Interesting!

However, I'd like to see this combo compared to metformin alone as that has similar impacts on A1C, Trigs, etc and many do experience some weight loss with it. I dropped maybe 6-7lbs without doing anything but adding 1g of metformin daily.
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."
Vince, what dosing and combination/type medication are you taking? What did you notice when you were taking it? Side effects/benefits etc..

Vince, what dosing and combination/type medication are you taking? What did you notice when you were taking it? Side effects/benefits etc..

I've been taking that combination for years. No side effects, any benefits. I don't know if I get any benefits. I do have an awesome sex life and good workouts. I work a lot at my job, I'm an electrical worker. Also I'm 64.
Thanks Vince,

Are you taking the larger dose split 2 Xs a day? Did you experience any side effects (negative) when starting? Are you taking the Tadalafil (cialis) or the sildenafil (viagra) daily? I thought that viagra wasn’t a take daily drug? Only cialis? This is a very interesting doctor takes low dose cialis daily but did tell me there can be side effects from it..I do know a few people who take metformin for anti aging benefits but they didn’t notice any positive or negative sides from taking the metformin..
I take low-dose Tadalafil daily and 100 mg sildenafil daily before my work outs. My a1c is 5.2 and fasting glucose is 87. When I first started ED meds I did get severe back pain, it took months before it finally subsided.
100 mg Sildenafil is really a huge dose I would see everything in blue if I took 100 mg before my workouts, lol.
LOL, I agree it is a huge dose, for whatever reason I tolerate ED meds very well. Last year I stopped my ED meds for one week, just to get it out of my system. I still was able to perform in bed as if I was using them. Sometimes I think I should just stop using them.
Another study (placebo-controlled)

Randomised clinical trial: a leucine‐metformin‐sildenafil combination (NS‐0200) vs placebo in patients with non‐alcoholic fatty liver disease

To report the results from a Phase 2, randomized clinical trial of of NS‐0200 in 91 subjects with NAFLD (liver fat ≥15% by magnetic resonance imaging‐proton‐density fat fraction (MRI‐PDFF)).

Subjects were randomized to placebo, low‐dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) or high‐dose NS‐0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) b.d. for 16 weeks; change in hepatic fat was assessed via MRI‐PDFF, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50 U/L; n = 35).

In the full cohort, active treatments did not separate from placebo. High dose NS‐0200 reduced hepatic fat by 15.7% (relative change from baseline) in the high ALT group (P < 0.005) while low dose NS‐0200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose‐responsive treatment effects in both overall and high ALT cohorts, with significant decreases in metabolically active lipids and up‐regulation of fatty acid oxidation.

These data support further evaluation of high‐dose NS‐0200 for treating NASH, especially in those with elevated ALT (NCT 02546609).


  • leucine metformin sildenafil NASH.pdf
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Metabolism. 2015 Jul;64(7):845-56. doi: 10.1016/j.metabol.2015.03.007. Epub 2015 Mar 19

Leucine amplifies the effects of metformin on insulin sensitivity and glycemic control in diet-induced obese mice
Fu L1, Bruckbauer A2, Li F1, Cao Q1, Cui X1, Wu R1, Shi H1, Zemel MB2, Xue B3.

The Sirt1/AMPK signaling pathway is a key sensor of energy status and regulates glucose and lipid metabolism. Leucine (Leu) activates Sirt1 by lowering its Km for NAD(+) and potentiates other sirtuin/AMPK-activators, resulting in improvement of insulin sensitivity. Since metformin (Met) converges on this pathway, we hypothesized that leucine would amplify its gluco-regulatory effects.

The effects of Leu (24 g/kg diet)+Met (0.05-0.5 g/kg diet) combinations were compared to standard therapeutic Met (1.5 g/kg diet; ~300 mg/kg BW) on glycemic control in high fat diet induced insulin resistant mice for 6 weeks. The effects of Leu on Met stimulation of Sirt1 and AMPK activities were further evaluated in adipocytes.

Sub-therapeutic levels of Met combined with Leu resulted in increases in Sirt1 activity and in tissue P-AMPK/AMPK ratio and corresponding dose-responsive improvements in fasting and post-prandial glucose, in glucose response to an insulin tolerance test and in the area under the curve in glucose tolerance tests. Changes were evident within 7 days of treatment and sustained throughout the 6-week study duration. The Leu+Met (0.25 g/kg)-combinations produced a comparable effect to a standard therapeutic Met dose, while the Leu+Met (0.5 g/kg diet) resulted in greater improvements. Since resveratrol also synergizes with leucine to augment sirtuin signaling and insulin sensitivity, we tested the addition of resveratrol to Leu-Met and found no additional benefit.

These data demonstrate that adding Leu to Met enables a dose reduction of 66% with improved efficacy and of 83% with comparable efficacy to standard metformin in diet-induced obese mice, and addition of resveratrol does not provide further benefit.
We like all the anti-aging, anti-cancer, cardio-protective, gut-enhancing, cognitive, anti-diabetic, etc. benefits of a long-standing and safe drug as metformin, but hate the drawbacks of reduced mitochondrial function, testosterone, B12 and muscle mass.
What about this stack to counter these drawbacks?

TRT or enclomiphene

Combined with resistance training, of course.
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