Leucine and sildenafil combination therapy reduces body weight and metformin enhances the effect at low dose: a randomized controlled trial
Open accessAbstract
Background: This study evaluated the potential of activating the fuel-sensing enzymes Adenine monophosphate (AMP)-activated protein kinase and the deacetylase sirtuin1, to promote weight loss. We tested the efficacy of a fixed dose combination of the amino acid leucine and 2 well-characterized agents with established safety profiles to modulate energy metabolism and facilitate weight loss. Study Question: Will a combination of l-leucine with low-dose metformin and sildenafil produce a novel synergistic interaction that reduces body weight? Study Design: We conducted a 24-week randomized controlled trial evaluating the effect on weight loss of leucine 1.1 g and sildenafil 1.0 mg or 4.0 mg, with and without metformin 500 mg (Leu/Sil 1.0, Leu/Sil 4.0, Leu/Met/Sil 1.0, and Leu/Met/Sil 4.0 twice/day). We enrolled 267 participants who were 18–65 years of age without diabetes and with the body mass index (BMI) of 30–45 kg/m 2. Measures and Outcomes: The primary endpoint was percentage weight change after 24 weeks. Adverse events were evaluated. The primary analysis was performed using the perprotocol population analysis of covariance estimation. Subgroup analyses of patients residing above certain threshold limits at baseline and in populations at increased risk of obesity were assessed post-hoc as exploratory end points. Results: Placebo-adjusted mean bodyweight reductions in the Leu/Met/Sil 1.0, Leu/Met/Sil 4.0, and Leu/Sil 4.0 groups were −1.99%, −1.69%, and −1.67% (P = 0.015, 0.035, and 0.036, respectively). The most common adverse events were gastrointestinal-related and occurred in the metformin-treated groups consistent with metformin treatment. In African Americans, Leu/Met/Sil 1.0 produced 5.4% mean weight loss. In participants with BMI <40 kg/m 2 treated with Leu/Met/Sil 1.0, the weight loss increased to 2.84%, particularly in participants with baseline insulin ≥12mU/L (3.5%). Conclusions: Leu/Met/Sil 1.0 and 4.0 and Leu/Sil 4.0 reduced body weight, but Leu/Met/Sil 1.0 was associated with robust weight loss in African Americans, and individuals with BMI 30–39.9 kg/m 2, especially participants with hyperinsulinemia.
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The most common side effects with leucine/sildenafil/metformin were gastrointestinal, related to metformin (diarrhea 19% pooled effect in the treatment group).
“The most common side effects were gastrointestinal, related to metformin (diarrhea 19% pooled effect in the treatment group) (Appendix 3).”
From Emerging pharmacotherapies for obesity: A systematic review (2025) · cites this paper as Rebello et al, 2021
The Results and Discussion report that gastrointestinal adverse events, especially diarrhea, were the most common and occurred largely in the metformin-treated groups. The passages do not report a pooled 19% diarrhea rate; the “19” following the Results statement is a reference number, not a percentage. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAll combinations except 1.1 g leucine and 1 mg sildenafil achieved weight loss significantly greater than placebo.
“All the combinations except 1.1 g leucine and 1 mg sildenafil achieved weight loss that was significantly greater than placebo.”
From Emerging pharmacotherapies for obesity: A systematic review (2025) · cites this paper as Rebello et al, 2021
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- Authors
- Rebello, C. J., Zemel, M. B., Kolterman, O., Fleming, G. A., & Greenway, F. L.
- Affiliations
- Pennington Biomedical Research Center (US)
- NuSirt Biopharma, Nashville, TN; and
- Kinexium LLC, Harpers Ferry, WV.
- Corresponding author
- Greenway, Frank L.
- Venue
- American Journal of Therapeutics
- Published
- 2021-01
- Volume
- 28
- Issue
- 1
- Pages
- e1-e13
- ISSN
- 1075-2765 (ISSN-L)
- PMC
- PMC9035320
- OpenAlex
- W3116456925
- Cited by
- 8
- References
- 26
- Citations by year
- 2025: 1 · 2024: 4 · 2022: 2 · 2021: 1
- FWCI
- 0.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Civil War Book Review (submittedVersion)
- Funders
- National Institute on Aging (K99AG065419)
- National Institute of General Medical Sciences (U54GM104940)
- Topics
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- leucine, sildenafil, metformin, combination therapy, weight loss, obesity, AMPK, SIRT1, energy metabolism, insulin resistance, African Americans, body mass index, gastrointestinal adverse effects, drug synergy, low-dose metformin, weight regain after weight loss
- MeSH terms
- Sildenafil Citrate, Body Weight, Diabetes Mellitus, Type 2, Double-Blind Method, Drug Therapy, Combination, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Leucine, Metformin, Obesity
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