Skip to main content

Advertisement

SpringerLink
Log in

The Niche of n-of-1 Trials in Precision Medicine for Weight Loss and Obesity Treatment: Back to the Future

  • Diabetes and Obesity (M Dalamaga and F Magkos, Section Editors)
  • Published:
Current Nutrition Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The n-of-1 clinical trials are considered the epitome of individualized health care. They are employed to address differences in treatment response and adverse events between patients, in a comparative effectiveness manner, extending beyond the delivery of horizontal recommendations for all.

Recent Findings

The n-of-1 design has been applied to deliver precision exercise interventions, through eHealth and mHealth technologies. Regarding personalized and precision medical nutrition therapy, few trials have implemented dietary manipulations and one series of n-of-1 trials has applied comprehensive genetic data to improve body weight. With regard to anti-obesity medication, pharmacogenetic data could be applied using the n-of-1 trial design, although none have been implemented yet.

Summary

The n-of-1 clinical trials consist of the only tool for the delivery of evidence-based, personalized obesity treatment (lifestyle and pharmacotherapy), reducing non-responders, while tailoring the best intervention to each patient, through “trial and error”. Their application is expected to improve obesity treatment and mitigate the epidemic.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Khera AV, Chaffin M, Wade KH, et al. Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood. Cell. 2019;177:587–96. https://doi.org/10.1016/J.CELL.2019.03.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Malik VS, Willet WC, Hu FB. Nearly a decade on – trends risk factors and policy implications in global obesity. Nat Rev Endocrinol. 2020;16(11):615–6. https://doi.org/10.1038/s41574-020-00411-y.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bentham J, Di Cesare M, Bilano V, et al. Worldwide trends in body-mass index underweight overweight and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children adolescents and adults. Lancet. 2017;390:2627–42. https://doi.org/10.1016/S0140-6736(17)32129-3.

    Article  Google Scholar 

  4. Schulz KF, Altman DG, Moher D. coNSorT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:332. https://doi.org/10.1136/bmj.c332.

    Article  Google Scholar 

  5. Soldevila-Domenech N, Boronat A, Langohr K, de la Torre R. N-of-1 Clinical Trials in Nutritional Interventions Directed at Improving Cognitive Function. Front Nutr. 2019;6:110. https://doi.org/10.3389/FNUT.2019.00110.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Herrmann SD, Willis EA, Honas JJ, et al. Energy intake nonexercise physical activity, and weight loss in responders and nonresponders: The Midwest Exercise Trial 2. Obesity. 2015;23:1539–49. https://doi.org/10.1002/OBY.21073.

    Article  PubMed  Google Scholar 

  7. Kelly AS, Auerbach P, Barrientos-Perez M, et al. A Randomized Controlled Trial of Liraglutide for Adolescents with Obesity. N Engl J Med. 2020;382:2117–28. https://doi.org/10.1056/NEJMoa1916038.

    Article  CAS  PubMed  Google Scholar 

  8. Williamson PJ, Atkinson G, Batterham AM. Inter-individual differences in weight change following exercise interventions: a systematic review and meta-analysis of randomized controlled trials. Obes Rev. 2018;19:960–75. https://doi.org/10.1111/OBR.12682.

    Article  CAS  PubMed  Google Scholar 

  9. Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2021. https://doi.org/10.1038/s41573-021-00337-8.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Grammatikopoulou MG, Nigdelis MP, Theodoridis X, et al. How fragile are Mediterranean diet interventions? A research-on-research study of randomised controlled trials. BMJ Nutr Prev Heal. 2021;4:115–31. https://doi.org/10.1136/bmjnph-2020-000188.

    Article  Google Scholar 

  11. Zeilstra D, Younes JA, Brummer RJ, Kleerebezem M. Perspective: Fundamental Limitations of the Randomized Controlled Trial Method in Nutritional Research: The Example of Probiotics. Adv Nutr. 2018;9:561–71. https://doi.org/10.1093/advances/nmy046.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mirza RD, Punja S, Vohra S, Guyatt G. The history and development of N-of-1 trials. J R Soc Med. 2017;110:330–40. https://doi.org/10.1177/0141076817721131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wiseman R. Several chirurgical treatises. 2nd ed. London: Royston and Tonk; 1686.

    Google Scholar 

  14. Hogben L, Sim M. The self-controlled and self-recorded clinical trial for low-grade morbidity. Br J Prev Soc Med. 1953;7:163–79. https://doi.org/10.1136/jech.7.4.163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Glasziou PP. Commentary: The history and place of n-of-1 trials: a commentary on Hogben and Sim. Int J Epidemiol. 2011;40:1458–60. https://doi.org/10.1093/IJE/DYR031.

  16. Guyatt GH, Haynes RB, Jaeschke RZ, et al. Users’ Guides to the Medical Literature: XXV Evidence-based medicine: principles for applying the Users’ Guides to patient care Evidence-Based Medicine Working Group. JAMA. 2000;284:1290–6. https://doi.org/10.1001/JAMA.284.10.1290.

    Article  CAS  PubMed  Google Scholar 

  17. Lillie EO, Patay B, Diamant J, et al. The n-of-1 clinical trial: the ultimate strategy for individualizing medicine? Per Med. 2011;8:161. https://doi.org/10.2217/PME.11.7.

    Article  PubMed  PubMed Central  Google Scholar 

  18. •• Gkouskou KK, Grammatikopoulou MG, Lazou E, et al. Genetically-guided medical nutrition therapy in type 2 diabetes mellitus and prediabetes: a series of n-of-1 superiority trials. Front Nutr. 2022;9:772243. https://doi.org/10.3389/FNUT.2022.772243. This manuscript details a comprehensive nutrigenetics application in an n-of-1 clinical trial format.

  19. Kravitz RL, Duan N, Vohra S, et al. Introduction to N-of-1 Trials: Indications and Barriers. In: Kravitz RL, Duan N, DEcIDE Methods Center N-of-1 Guidance Panel, editors. Design and Implementation of N-of-1 Trials: A User’s Guide. Rockville, MD: Agency for Healthcare Research and Quality (US); 2014. p. 1–11. AHRQ Publication No. 13(14)-EHC122-EF.

    Google Scholar 

  20. Tsapas A, Matthews DR. N of 1 trials in diabetes: making individual therapeutic decisions. Diabetologia. 2008;51:921–5. https://doi.org/10.1007/S00125-008-0983-2.

    Article  CAS  PubMed  Google Scholar 

  21. Margolis A, Giuliano C. Making the switch: From case studies to N-of-1 trials. Epilepsy Behav Reports. 2019;12: 100336. https://doi.org/10.1016/J.EBR.2019.100336.

    Article  Google Scholar 

  22. Mirza RD, Guyatt GH. A Randomized Clinical Trial of n-of-1 Trials-Tribulations of a Trial. JAMA Intern Med. 2018;178:1378–9. https://doi.org/10.1001/JAMAINTERNMED.2018.3979.

    Article  PubMed  Google Scholar 

  23. Gray ID, Kross AR, Renfrew ME, Wood P. Precision Medicine in Lifestyle Medicine: The Way of the Future? Am J Lifestyle Med. 2020;14:169. https://doi.org/10.1177/1559827619834527.

    Article  PubMed  Google Scholar 

  24. Lanfranconi F, Zardo W, Moriggi T, et al. Precision-based exercise as a new therapeutic option for children and adolescents with haematological malignancies. Sci Rep. 2020;10(1):1–13. https://doi.org/10.1038/s41598-020-69393-1.

    Article  CAS  Google Scholar 

  25. Rask-Andersen M, Karlsson T, Ek WE, Johansson Å. Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity alcohol consumption and socioeconomic status. PLoS Genet. 2017;13: e1006977. https://doi.org/10.1371/JOURNAL.PGEN.1006977.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Moss RJ, Süle A, Kohl S. eHealth and mHealth. Eur J Hosp Pharm. 2019;26:57. https://doi.org/10.1136/EJHPHARM-2018-001819.

    Article  PubMed  Google Scholar 

  27. Wilson K. Mobile cell phone technology puts the future of health care in our hands. C Can Med Assoc J. 2018;190:E378. https://doi.org/10.1503/CMAJ.180269.

    Article  Google Scholar 

  28. Nasi G, Cucciniello M, Guerrazzi C. The Role of Mobile Technologies in Health Care Processes: The Case of Cancer Supportive Care. J Med Internet Res. 2015;17: e3757. https://doi.org/10.2196/JMIR.3757.

    Article  Google Scholar 

  29. Lin WY, Chan CC, Liu YL, et al. Performing different kinds of physical exercise differentially attenuates the genetic effects on obesity measures: Evidence from 18424 Taiwan Biobank participants. PLoS Genet. 2019;15: e1008277. https://doi.org/10.1371/JOURNAL.PGEN.1008277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rosenberg DE, Kadokura E, Morris ME, et al. Application of N-of-1 Experiments to Test the Efficacy of Inactivity Alert Features in Fitness Trackers to Increase Breaks from Sitting in Older Adults. Methods Inf Med. 2017;56:427–36. https://doi.org/10.3414/ME16-02-0043.

    Article  Google Scholar 

  31. Kwasnicka D, Dombrowski SU, White M, Sniehotta FF. N-of-1 study of weight loss maintenance assessing predictors of physical activity, adherence to weight loss plan and weight change. Psychol Health. 2017;32:686–708. https://doi.org/10.1080/08870446.2017.1293057.

    Article  PubMed  Google Scholar 

  32. Chevance G, Baretta D, Golaszewski N, et al. Goal Setting and Achievement for Walking: A Series of N-of-1 Digital Interventions. Health Psychol. 2021;40:30. https://doi.org/10.1037/HEA0001044.

    Article  PubMed  Google Scholar 

  33. Sniehotta FF, Presseau J, Hobbs N, Araújo-Soares V. Testing self-regulation interventions to increase walking using factorial randomized N-of-1 trials. Health Psychol. 2012;31:733–7. https://doi.org/10.1037/A0027337.

    Article  PubMed  Google Scholar 

  34. Hendriks MAL, van Wanroij JWM, Laros-van Gorkom BAP, et al. The SLIM study-Shared medical appointments to change lifestyles of overweight people with haemophilia: A randomized multiple baseline (n-of-1) design. Haemophilia. 2021;27:606–17. https://doi.org/10.1111/HAE.14306.

    Article  PubMed  PubMed Central  Google Scholar 

  35. •• Ordovás J, Ferguson L, Tai E, Mathers J. Personalised Nutrition and Health. BMJ. 2018;361:bmj.k2173. https://doi.org/10.1136/BMJ.K2173. In this manuscript, authors detail all possible applications of personalized and precision nutrition.

  36. Gameiro GR, Sinkunas V, Liguori GR, Auler-Júnior JOC. Precision Medicine: Changing the way we think about healthcare. Clinics. 2018;73: e723. https://doi.org/10.6061/CLINICS/2017/E723.

    Article  PubMed  PubMed Central  Google Scholar 

  37. San-Cristobal R, Navas-Carretero S, Martínez-González MÁ, et al. Contribution of macronutrients to obesity: implications for precision nutrition. Nat Rev Endocrinol. 2020;16:305–20. https://doi.org/10.1038/S41574-020-0346-8.

    Article  PubMed  Google Scholar 

  38. Tian Y, Ma Y, Fu Y, Zheng J-S. Application of n-of-1 Clinical Trials in Personalized Nutrition Research: A Trial Protocol for Westlake N-of-1 Trials for Macronutrient Intake (WE-MACNUTR). Curr Dev Nutr. 2020;4:nzaa143. https://doi.org/10.1093/cdn/nzaa143.

  39. •• Potter T, Vieira R, de Roos B. Perspective: Application of N-of-1 Methods in Personalized Nutrition Research. Adv Nutr. 2021;12:579–89. https://doi.org/10.1093/ADVANCES/NMAA173. This interesting review article suggests applications for the delivery of personalized nutrition through the use of the n-of-1 trial design.

  40. Feltham S, Westman EC. A case study of overfeeding 3 different diets. Curr Opin Endocrinol Diabetes Obes. 2021;28(5):446–52. https://doi.org/10.1097/MED.0000000000000668.

    Article  PubMed  Google Scholar 

  41. Ma Y, Fu Y, Tian Y, et al. Individual Postprandial Glycemic Responses to Diet in n-of-1 Trials: Westlake N-of-1 Trials for Macronutrient Intake (WE-MACNUTR). J Nutr. 2021;151:3158–67. https://doi.org/10.1093/JN/NXAB227.

    Article  PubMed  PubMed Central  Google Scholar 

  42. • Zheng J-S, Ordovás JM. Precision nutrition for gut microbiome and diabetes research: Application of nutritional n-of-1 clinical trials. J Diabetes. 2021. https://doi.org/10.1111/1753-0407.13220. This manuscript details the importance of applying the n-of-1 trial design for the delivery of precision nutrition, using gut microbiome data among patients with diabetes.

  43. • Pigsborg K, Magkos F. Metabotyping for Precision Nutrition and Weight Management: Hype or Hope? Curr Nutr Reports. 2022. https://doi.org/10.1007/S13668-021-00392-Y. In this interesting review the authors are stressing the importance of metablomics for precision nutrition and in particular, weight management.

  44. Cifuentes L, Daniela-Hurtado M, Eckel-Passow J, Acosta A. Precision Medicine for Obesity. Dig Dis Interv. 2021;5:239–48. https://doi.org/10.1055/s-0041-1729945.

    Article  Google Scholar 

  45. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129:S102–38. https://doi.org/10.1161/01.CIR.0000437739.71477.EE.

    Article  PubMed  Google Scholar 

  46. Tchang BG, Aras M, Kumar RB, Aronne LJ. Pharmacologic Treatment of Overweight and Obesity in Adults. South Dartmout (MA): MDText.com Inc; 2021.

    Google Scholar 

  47. Daneschvar HL, Aronson MD, Smetana GW. FDA-Approved Anti-Obesity Drugs in the United States. Am J Med. 2016;129:879. https://doi.org/10.1016/J.AMJMED.2016.02.009.

    Article  PubMed  Google Scholar 

  48. Kadric SI, Cesic AK, Dujic T. Pharmacogenetics of new classes of antidiabetic drugs. Bosn J Basic Med Sci. 2021;21:659–71. https://doi.org/10.17305/bjbms.2021.5646.

    Article  CAS  PubMed Central  Google Scholar 

  49. Spraggs CF, Pillai SG, Dow D, et al. Pharmacogenetics and obesity: common gene variants influence weight loss response of the norepinephrine/dopamine transporter inhibitor GW320659 in obese subjects. Pharmacogenet Genomics. 2005;15:883–9. https://doi.org/10.1097/01213011-200512000-00006.

    Article  CAS  PubMed  Google Scholar 

  50. Hwang IC, Kim KK, Ahn HY, et al. Effect of the G-protein β3 subunit 825T allele on the change of body adiposity in obese female. Diabetes Obes Metab. 2013;15:284–6. https://doi.org/10.1111/DOM.12023.

    Article  CAS  PubMed  Google Scholar 

  51. Hwang IC, Park JY, Ahn HY, et al. Effects of CYP3A5, CYP2C19, and CYP2B6 on the clinical efficacy and adverse outcomes of sibutramine therapy: a crucial role for the CYP2B6*6 allele. Clin Chim Acta. 2014;428:77–81. https://doi.org/10.1016/J.CCA.2013.11.007.

    Article  CAS  PubMed  Google Scholar 

  52. Hauner H, Meier M, Jöckel KH, et al. Prediction of successful weight reduction under sibutramine therapy through genotyping of the G-protein beta3 subunit gene (GNB3) C825T polymorphism. Pharmacogenetics. 2003;13:453–9. https://doi.org/10.1097/00008571-200308000-00003.

    Article  CAS  PubMed  Google Scholar 

  53. Hsiao DJ, Wu LSH, Huang SY, Lin E. Weight loss and body fat reduction under sibutramine therapy in obesity with the C825T polymorphism in the GNB3 gene. Pharmacogenet Genomics. 2009;19:730–3. https://doi.org/10.1097/FPC.0B013E3283307CF1.

    Article  CAS  PubMed  Google Scholar 

  54. Hsiao T-J, Wu LS-H, Hwang Y, et al. Effect of the common -866G/A polymorphism of the uncoupling protein 2 gene on weight loss and body composition under sibutramine therapy in an obese Taiwanese population. Mol Diagn Ther. 2010;14:101–6. https://doi.org/10.1007/BF03256359.

  55. Vazquez-Roque MI, Camilleri M, Clark MM, et al. Alteration of gastric functions and candidate genes associated with weight reduction in response to sibutramine. Clin Gastroenterol Hepatol. 2007;5:829–37. https://doi.org/10.1016/J.CGH.2007.02.037.

    Article  CAS  PubMed  Google Scholar 

  56. Grudell ABM, Sweetser S, Camilleri M, et al. A controlled pharmacogenetic trial of sibutramine on weight loss and body composition in obese or overweight adults. Gastroenterology. 2008;135:1142–54. https://doi.org/10.1053/J.GASTRO.2008.07.009.

    Article  CAS  PubMed  Google Scholar 

  57. Mullally JA, Chung WK, LeDuc CA, et al. Weight-loss response to naltrexone/bupropion is modulated by the Taq1A genetic variant near DRD2 (rs1800497): A pilot study. Diabetes Obes Metab. 2021;23:850–3. https://doi.org/10.1111/DOM.14267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Delahanty LM, Pan Q, Jablonski KA, et al. Genetic predictors of weight loss and weight regain after intensive lifestyle modification, metformin treatment, or standard care in the Diabetes Prevention Program. Diabetes Care. 2012;35:363–6. https://doi.org/10.2337/DC11-1328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Singh S, Ricardo-Silgado ML, Bielinski SJ, Acosta A. Pharmacogenomics of Medication-Induced Weight Gain and Antiobesity Medications. Obesity. 2021;29:265–73. https://doi.org/10.1002/OBY.23068.

    Article  PubMed  Google Scholar 

  60. Punja S, Bukutu C, Shamseer L, et al. N-of-1 trials are a tapestry of heterogeneity. J Clin Epidemiol. 2016;76:47–56. https://doi.org/10.1016/J.JCLINEPI.2016.03.023.

    Article  PubMed  Google Scholar 

  61. Li J, Gao W, Punja S, et al. Reporting quality of N-of-1 trials published between 1985 and 2013: a systematic review. J Clin Epidemiol. 2016;76:57–64. https://doi.org/10.1016/J.JCLINEPI.2015.11.016.

    Article  PubMed  Google Scholar 

  62. Schork NJ, Goetz LH. Single-Subject Studies in Translational Nutrition Research. Annu Rev Nutr. 2017;37:395–422. https://doi.org/10.1146/annurev-nutr-071816-064717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Shamseer L, Sampson M, Bukutu C, et al. CONSORT extension for reporting N-of-1 trials (CENT) 2015: Explanation and elaboration. BMJ. 2015;350: h1793. https://doi.org/10.1136/BMJ.H1793.

    Article  PubMed  Google Scholar 

  64. Duan N, Kravitz RL, Schmid CH. Single-patient (n-of-1) trials: a pragmatic clinical decision methodology for patient-centered comparative effectiveness research. J Clin Epidemiol. 2013;66:S21–8. https://doi.org/10.1016/J.JCLINEPI.2013.04.006.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Davidson KW, Cheung YK, McGinn T, Wang YC. Expanding the Role of N-of-1 Trials in the Precision Medicine Era: Action Priorities and Practical Considerations. NAM Perspect. 2018. https://doi.org/10.31478/201812D.

Download references

Author information

Authors and Affiliations

  1. Department of Nutritional Sciences and Dietetics, Faculty of Health Sciences, Alexander Campus, International Hellenic University, Sindos, PO Box 141, 57400, Thessaloniki, Greece

    Maria G. Grammatikopoulou

  2. Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Mikras Asias 75, 11527, Athens, Greece

    Kalliopi K. Gkouskou & Aristides G. Eliopoulos

  3. Embiodiagnostics Biology Research Company, 1 Melissinon and Damvergidon Street, Konstantinou Papadaki, 71305, Heraklion, Crete, Greece

    Kalliopi K. Gkouskou

  4. Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41334, Larissa, Greece

    Konstantinos Gkiouras & Dimitrios P. Bogdanos

  5. Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Street, 11527, Athens, Greece

    Aristides G. Eliopoulos

  6. Unit of Reproductive Endocrinology, 1St Department of Obstetrics and Gynecology, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Dimitrios G. Goulis

Authors
  1. Maria G. Grammatikopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kalliopi K. Gkouskou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Konstantinos Gkiouras
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dimitrios P. Bogdanos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aristides G. Eliopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dimitrios G. Goulis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria G. Grammatikopoulou.

Ethics declarations

Conflict of Interest

Maria G. Grammatikopoulou, Kalliopi K. Gkouskou, Konstantinos Gkiouras, Dimitrios P. Bogdanos, Aristides G. Eliopoulos and Dimitrios G. Goulis declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Diabetes and Obesity

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Grammatikopoulou, M.G., Gkouskou, K.K., Gkiouras, K. et al. The Niche of n-of-1 Trials in Precision Medicine for Weight Loss and Obesity Treatment: Back to the Future. Curr Nutr Rep 11, 133–145 (2022). https://doi.org/10.1007/s13668-022-00404-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13668-022-00404-5

Keywords

Search

Navigation