Combined Metabolic Activators Therapy Reduces Liver Fat by 10% In Nonalcoholic Fatty Liver Disease Patients
A recent phase 2 clinical trial published on Molecular Systems Biology found that a novel combined metabolic activators (CMAs) cocktail which included nicotinamide riboside (NR) significantly reduced hepatic fat in nonalcoholic fatty liver disease (NAFLD) patients by 10% [1].
Addressing a Growing, Silent Epidemic
NAFLD, the accumulation of excess fat in the liver, is the most prevalent liver disease in the world, with estimates indicating it affects nearly two billion people globally [2], yet it has no approved treatments. Management strategies such as increased exercise and dietary intervention, while effective, require a strong commitment from patients to lifestyle and behavioral changes [3, 4]. This can lead to slower than desired declines in prevalence trends of a growing epidemic. Recent evidence, however, demonstrates that targeting multiple pathways in the liver holds the greatest potential as an effective therapeutic strategy [5]. One of these pathways helps to boost levels of the coenzyme, nicotinamide adenine dinucleotide (NAD+).
Evidence suggesting NAD+ plays an important role in live health maintenance has been building over several years. Preclinical evidence in mice demonstrated that increasing NAD+ supports liver function, most notably when metabolically stressed by a high-fat diet [6, 7]. In a mouse model of NAFLD, mice fed a high-fat, high-sucrose (sugar) diet, had decreased liver NAD+ levels, as well as increased liver damage and declines in overall liver health. Supplementation with NR replenished liver NAD+ levels, improved liver function by reversing markers of liver damage, and reversed mitochondrial dysfunction. By replenishing NAD+ levels, NR supplementation prevented the onset of NAFLD, suggesting that NAD+ balance may be essential for maintaining liver health.
Could a Multimodal Approach Yield Better Results?
Dr. Adil Mardinoglu, professor at KTH—Royal Institute of Technology in Sweden & King’s College London, identified common molecular changes associated with NAFLD [8, 9], leading him to develop the concept of employing a multi-targeted treatment approach. In partnership with ScandiBio Therapeutics, he developed the combined metabolic cofactor supplement (CMCS) cocktail containing L-carnitine tartrate to increase transport of fat into the mitochondria, nicotinamide riboside (NR) to boost NAD+ levels and increase the metabolism of fat in the mitochondria, and L-serine and N acetyl-L-cysteine (NAC) to increase the availability of the well known antioxidant “reduced glutathione” (GSH), which helps scavenge damaging free radicals that are produced as a byproduct when fats are broken down to generate energy. This new science-based approach was designed to support mitochondrial function and energy metabolism in the liver by targeting these key pathways.
Through animal experiments, as well as a Phase 1 pilot clinical study [10], Dr. Mardinoglu and team found CMCS (now termed CMAs) promoted the oxidation of fat, reduced oxidative stress, and activated mitochondria—ultimately laying the groundwork for this phase 2 clinical trial.
The Phase 2 Human Trial Reports Promise
This latest 10-week trial was a randomized, single-blind, placebo-controlled phase 2 clinical study of overweight or obese men and women with NAFLD who were between 25-63 years of age. The patients received one dose of CMAs daily for the first 14 days and two doses daily for the remaining 56 days. Each dose consisted of: 3.73g L-carnitine tartrate, 1g NR, 12.35g serine, and 2.55g NAC.
Measurements taken upon completion of the trial revealed that CMAs supplementation significantly decreased liver fat by 10%, improved liver function, and significantly reduced liver inflammation. CMAs also significantly decreased systolic blood pressure by 5%.
Additionally, the CMAs significantly improved levels of metabolites associated with antioxidant metabolism. Fecal and salivatory sample analyses showed that supplementation also caused beneficial changes in the microbiome. These benefits elucidate additional ways in which the CMAs could be complementary in helping to improve common NAFLD comorbidities.
Results Warrant Continued Investigation
Overall, these results are consistent with the phase 1 pilot clinical findings [10] showing the CMAs supplementation was safe and well-tolerated in healthy subjects and reinforce the importance of targeting multiple pathways to address NAFLD.
This same set of metabolic cofactors was also used in a phase 2 clinical COVID-19 study [11] showing CMAs significantly reduced patients’ recovery time by 29% when combined with the in-country standard of care, hydroxychloroquine (HCQ). This research has progressed to phase 3 work whose results are yet unpublished.
Justification for use of this CMAs for COVID-19, as well as NAFLD, two seemingly mutually exclusive conditions, centers around the common metabolic abnormalities seen in both COVID-19 and NAFLD patients. Evidence suggests the most vulnerable subjects to COVID-19 infection are those with pre-existing conditions, including metabolic abnormalities [12]. As an example of a chronic metabolic pandemic, NAFLD’s disease progression is largely driven by oxidative stress and inflammatory responses [8]—common mechanisms also seen in the development of COVID-19. Because metabolism at the cellular level is largely NAD-dependent, the liver is one of many organs sensitive to declining levels of NAD+. Additionally, NAD+ depletion is a key metabolic abnormality observed in both conditions [13, 14], and contributes to an impaired mitochondrial, as well as antioxidant metabolism—both of which were improved by replenishing NAD+ in the abovementioned studies. These findings highlight the importance of NAD+ in the maintenance of metabolic health, as well as its essential role in supporting mitochondrial health.
In summary, this phase 2 work has demonstrated the CMAs to have direct implications for supporting liver health, through a multi-targeted approach focused on supporting mitochondrial function and energy metabolism in the liver, and thus, warrants further investigation as a potential therapeutic strategy for NAFLD.
References
Zeybel, M., et al., Combined Metabolic Cofactor Supplementation Reduces Liver Fat in Nonalcoholic Fatty Liver Disease. Available at Molecular Systems Biology: https://www.embopress.org/doi/full/10.15252/msb.202110459
Younossi, Z.M., et al., Global epidemiology of nonalcoholic fatty liver disease—meta‐analytic assessment of prevalence, incidence, and outcomes. Hepatology, 2016. 64(1): p. 73-84.
Romero-Gómez, M., S. Zelber-Sagi, and M. Trenell, Treatment of NAFLD with diet, physical activity and exercise. Journal of hepatology, 2017. 67(4): p. 829-846.
Sanyal, A.J., Past, present and future perspectives in nonalcoholic fatty liver disease. Nature reviews Gastroenterology & hepatology, 2019. 16(6): p. 377-386.
Li, X. and H. Wang, Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease. Cell & Bioscience, 2020. 10(1): p. 1-15.
Gariani, K., et al., Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology, 2016. 63(4): p. 1190-204.
Zhou, C.C., et al., Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing. Br J Pharmacol, 2016. 173(15): p. 2352-68.
Mardinoglu, A., et al., The Potential Use of Metabolic Cofactors in Treatment of NAFLD. Nutrients, 2019. 11(7).
Mardinoglu, A., et al., Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD. Mol Syst Biol, 2017. 13(3): p. 916.
Zhang, C., et al., The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alcoholic fatty liver disease. Mol Syst Biol, 2020. 16(4): p. e9495.
Altay, O., et al., Combined Metabolic Activators Accelerates Recovery In Mild-to-Moderate Covid-19. ADV SCI (WEINH), 2021: P.E2101222. DOI: HTTPS://DOI.ORG/10.1002/ADVS.202101222
Guarino, M. and Dufour, J.-F., Nicotinamide and NAFLD: Is There Nothing New Under the Sun? Metabolites, 2019. 9(9): p. 180.
Heer, C.D., et al., Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity. Journal of Biological Chemistry, 2020. 295(52): p. 17986-17996.