Therapeutics

kMCT-ONS

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Overview

Name: kMCT-ONS
Synonyms: medium chain triglyceride-based ketogenic oral nutritional supplement, kMCT
Therapy Type: Supplement, Dietary (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Not Regulated)
Company: Nestlé Health Science

Background

kMCT-ONS is a nutritional drink that raises blood ketone concentrations. The brain uses ketones as an energy source when glucose is limited, and inducing mild ketosis has emerged as a strategy to overcome the decline in glucose uptake that occurs in people with Alzheimer’s disease. In multiple small pilot studies, ketogenic diets such as the Atkins regimen, or ketogenic supplements, improve brain energy status and cognitive function in people with MCI and AD (reviewed in Cunnane et al., 2020).

The active components of kMCT-ONS are medium-chain triglycerides of caprylic acid and capric acid. Metabolism of these fats in the liver produces the ketones acetoacetate and β-hydroxybutyrate, which freely enter the brain. kMCT-ONS is produced by emulsifying a commercially available 60:40 mixture of the two fats derived from palm oil into lactose-free skim milk. kMCT’s composition is similar to the medicinal food Ketasyn or the experimental ketogenic drink Tricaprylin, both of which contain caprylic acid triglyceride as their main active ingredient.

kMCT has been shown to increase plasma ketone levels and brain ketone uptake in healthy adults and in people with AD (Croteau et al., 2018). Brain uptake of ketones does not appear to be diminished in people with AD compared to healthy people  (Castellano et al., 2015). A meta-analysis of trials testing medium-chain triglycerides for cognitive symptoms in older adults found a substantial increase in brain ketones and metabolic rates, but only occasional or domain-specific cognitive improvements (Meer and Fischer 2024). The authors noted heterogenous and poor study design, and conflicts of interest that weakened the evidence. A meta-analysis of trials in people with subjective cognitive decline, mild cognitive impairment, or AD likewise reported mixed outcomes for cognition (Castro et al., 2023). A third meta-analysis claimed some evidence for improvement in general cognition in people with AD, but only those lacking the ApoE4 allele (Sun et al., 2023). A pharmacokinetic study revealed high variability between people in blood ketone levels after an MCT dose, with major effects of meals and body fat (Juby et al., 2021).

In preclinical studies and one pilot clinical trial, inducing ketosis was reported to reduce amyloid load, ameliorate Aβ toxicity, and improve AD biomarkers (Kashiwaya et al., 2013; Zilberter et al., 2012; Neth et al., 2020).

A commercially available caprylic acid triglyceride supplement derived from coconut oil was claimed to stabilize or improve cognitive scores in most participants in a crossover study of 20 people with mild to moderate AD (Juby et al., 2022). Longer treatment of up to 11 months was reportedly associated with better scores on the MMSE and a Cogstate computerized battery in this study.

Findings

In June 2015, investigators at the University of Sherbrooke, Quebec, began the BENEFIC trial to test effects on brain metabolism of a six-month course of kMCT in 52 people with mild cognitive impairment. The active treatment was a twice-daily shake containing 15 g MCT, or a calorie-equivalent placebo of non-ketogenic high oleic sunflower oil. The primary outcome of the trial was brain glucose and ketone uptake, measured by FDG-PET and 11C-acetoacetate-PET, and tolerability. Secondary outcomes included performance on a neurocognitive battery, changes in global brain energy supply, and the relationship between ketone uptake and cognitive outcomes. According to published results, 19 and 20 people completed the treatment and placebo arms, respectively. Most participants reported gastrointestinal side effects, and one-quarter dropped out because of them. The kMCT group had a doubling of plasma ketones and brain ketone uptake compared to placebo; brain glucose uptake did not differ. The study was not powered to detect treatment effects on cognition, but improvements from baseline in the treated group were noted in several domains (Fortier et al., 2019). An increase ketone uptake into white-matter fascicles, and an associated increase in processing speed, was also reported (Roy et al., 2021).

Based on these results, a larger six-month trial enrolled 122 participants with MCI who were randomized to the same kMCT treatment or placebo. The primary outcome was scores on the neurocognitive battery. In this study, the dropout rate was 32 percent, mainly due to GI side effects. In all, 39 and 44 people completed the active and placebo treatments, respectively. Compared to the placebo group, the treated group improved on tests of memory, executive function, and language; their scores correlated with plasma ketone levels. A metabolic substudy found plasma ketones were elevated for one to two hours post-dosing, and this response was unchanged from the beginning to the end of the study. Results are published (Fortier et al., 2021).

In September 2018, University of British Columbia investigators began enrolling 40 people with a diagnosis of mild to moderate AD for an ascending-dose, safety, and pharmacokinetic study of the kMCT drink. Participants are to receive 10 to 50 g MCT or placebo per day for 10 days. Primary outcomes are serious adverse events and plasma ketone concentrations. Other outcomes include FDG-PET, cerebral blood flow, MR spectroscopy to assess brain chemistry, and daily physical activity.

In May 2024, Nestlé began a pivotal study of a new supplement that combines kMCT-ONS with B vitamins in aging adults with mild cognitive impairment. The rationale for adding B vitamins comes from studies suggesting they can help old adults maintain cognitive function (e.g., Li et al., 2021). The study plans to enroll 380 adults over age 60 with a diagnosis of MCI which is compatible with AD or vascular dementia. Treatment will entail one year of supplementation with 15 g kMCT plus a mix of B3, B6, B9/folic acid, and B12, or a matching placebo. There is an optional six month open-label extension. The primary outcome is change in the Preclinical Alzheimer’s Cognitive Composite score; secondary outcomes include individual components of the PACC, the Montreal Cognitive Assessment (MoCA) score, and the percent of participants who show faster than expected memory decline on the PACC, Wechsler memory scale, or MMSE, as well as adverse events.  The trial is running to the end of 2027 in approximately 30 sites in Italy, Spain, France, Germany, Switzerland, the U.K., and the U.S.

For details on these trials, see clinicaltrials.gov.

Last Updated: 19 Jul 2024

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References

Therapeutics Citations

  1. Ketasyn
  2. Tricaprilin

Paper Citations

  1. Fortier M, Castellano CA, Croteau E, Langlois F, Bocti C, St-Pierre V, Vandenberghe C, Bernier M, Roy M, Descoteaux M, Whittingstall K, Lepage M, Turcotte ÉE, Fulop T, Cunnane SC. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimers Dement. 2019 May;15(5):625-634. Epub 2019 Apr 23 PubMed.
  2. Roy M, Fortier M, Rheault F, Edde M, Croteau E, Castellano CA, Langlois F, St-Pierre V, Cuenoud B, Bocti C, Fulop T, Descoteaux M, Cunnane SC. A ketogenic supplement improves white matter energy supply and processing speed in mild cognitive impairment. Alzheimers Dement (N Y). 2021;7(1):e12217. Epub 2021 Nov 17 PubMed.
  3. Fortier M, Castellano CA, St-Pierre V, Myette-Côté É, Langlois F, Roy M, Morin MC, Bocti C, Fulop T, Godin JP, Delannoy C, Cuenoud B, Cunnane SC. A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT. Alzheimers Dement. 2021 Mar;17(3):543-552. Epub 2020 Oct 26 PubMed.
  4. Li S, Guo Y, Men J, Fu H, Xu T. The preventive efficacy of vitamin B supplements on the cognitive decline of elderly adults: a systematic review and meta-analysis. BMC Geriatr. 2021 Jun 16;21(1):367. PubMed.
  5. Cunnane SC, Trushina E, Morland C, Prigione A, Casadesus G, Andrews ZB, Beal MF, Bergersen LH, Brinton RD, de la Monte S, Eckert A, Harvey J, Jeggo R, Jhamandas JH, Kann O, la Cour CM, Martin WF, Mithieux G, Moreira PI, Murphy MP, Nave KA, Nuriel T, Oliet SH, Saudou F, Mattson MP, Swerdlow RH, Millan MJ. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat Rev Drug Discov. 2020 Sep;19(9):609-633. Epub 2020 Jul 24 PubMed.
  6. Croteau E, Castellano CA, Richard MA, Fortier M, Nugent S, Lepage M, Duchesne S, Whittingstall K, Turcotte ÉE, Bocti C, Fülöp T, Cunnane SC. Ketogenic Medium Chain Triglycerides Increase Brain Energy Metabolism in Alzheimer's Disease. J Alzheimers Dis. 2018;64(2):551-561. PubMed.
  7. Castellano CA, Nugent S, Paquet N, Tremblay S, Bocti C, Lacombe G, Imbeault H, Turcotte É, Fulop T, Cunnane SC. Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer's disease dementia. J Alzheimers Dis. 2015;43(4):1343-53. PubMed.
  8. Meer N, Fischer T. Medium-Chain Triglycerides (MCTs) for the Symptomatic Treatment of Dementia-Related Diseases: A Systematic Review. J Nutr Metab. 2024;2024:9672969. Epub 2024 Apr 12 PubMed.
  9. Castro CB, Dias CB, Hillebrandt H, Sohrabi HR, Chatterjee P, Shah TM, Fuller SJ, Garg ML, Martins RN. Medium-chain fatty acids for the prevention or treatment of Alzheimer's disease: a systematic review and meta-analysis. Nutr Rev. 2023 Jan 12; PubMed.
  10. Sun L, Ye KX, Wong HL, Wang L, Lim SL, Chao YX, Zhang C, Yap KZ, Feng L. The Effects of Medium Chain Triglyceride for Alzheimer's Disease Related Cognitive Impairment: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2023;94(2):441-456. PubMed.
  11. Juby AG, Brocks DR, Jay DA, Davis CM, Mager DR. Assessing the Impact of Factors that Influence the Ketogenic Response to Varying Doses of Medium Chain Triglyceride (MCT) Oil. J Prev Alzheimers Dis. 2021;8(1):19-28. PubMed.
  12. Kashiwaya Y, Bergman C, Lee JH, Wan R, King MT, Mughal MR, Okun E, Clarke K, Mattson MP, Veech RL. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease. Neurobiol Aging. 2013 Jun;34(6):1530-9. PubMed.
  13. Zilberter M, Ivanov A, Ziyatdinova S, Mukhtarov M, Malkov A, Alpár A, Tortoriello G, Botting CH, Fülöp L, Osypov AA, Pitkänen A, Tanila H, Harkany T, Zilberter Y. Dietary energy substrates reverse early neuronal hyperactivity in a mouse model of Alzheimer's disease. J Neurochem. 2012 Dec 14; PubMed.
  14. Neth BJ, Mintz A, Whitlow C, Jung Y, Solingapuram Sai K, Register TC, Kellar D, Lockhart SN, Hoscheidt S, Maldjian J, Heslegrave AJ, Blennow K, Cunnane SC, Castellano CA, Zetterberg H, Craft S. Modified ketogenic diet is associated with improved cerebrospinal fluid biomarker profile, cerebral perfusion, and cerebral ketone body uptake in older adults at risk for Alzheimer's disease: a pilot study. Neurobiol Aging. 2020 Feb;86:54-63. Epub 2019 Sep 26 PubMed.
  15. Juby AG, Blackburn TE, Mager DR. Use of medium chain triglyceride (MCT) oil in subjects with Alzheimer's disease: A randomized, double-blind, placebo-controlled, crossover study, with an open-label extension. Alzheimers Dement (N Y). 2022;8(1):e12259. Epub 2022 Mar 14 PubMed.

External Citations

  1. clinicaltrials.gov
  2. commercially available 60:40 mixture

Further Reading

Papers

  1. Cunnane SC, Plourde M, Pifferi F, Bégin M, Féart C, Barberger-Gateau P. Fish, docosahexaenoic acid and Alzheimer's disease. Prog Lipid Res. 2009 Sep;48(5):239-56. PubMed.
  2. Juby AG, Brocks DR, Jay DA, Davis CM, Mager DR. Assessing the Impact of Factors that Influence the Ketogenic Response to Varying Doses of Medium Chain Triglyceride (MCT) Oil. J Prev Alzheimers Dis. 2021;8(1):19-28. PubMed.