Continuous care intervention with carbohydrate restriction improves physical function of the knees among patients with type 2 diabetes: a non-randomized study

Kade S Lyman, Shaminie J Athinarayanan, Amy L McKenzie, Camy L Pearson, Rebecca N Adams, Sarah J Hallberg, James P McCarter, Jeff S Volek, Stephen D Phinney, John P Andrawis, Kade S Lyman, Shaminie J Athinarayanan, Amy L McKenzie, Camy L Pearson, Rebecca N Adams, Sarah J Hallberg, James P McCarter, Jeff S Volek, Stephen D Phinney, John P Andrawis

Abstract

Background: In a previous study, we assessed a novel, remotely monitored carbohydrate restricted diet regimen including nutritional ketosis in patients with type 2 diabetes and reported significant improvements in weight, glycemic control, abdominal fat and inflammation from baseline to 2 years. Knee outcome measures were collected as a secondary outcome in the trial. This study aims to assess the effect of this intervention on knee functional scores and to identify if changes in weight, central abdominal fat (CAF), glycemic status and high sensitivity C-reactive protein (hsCRP) were associated with its improvement.

Methods: This prospective analysis included continuous care intervention (CCI, n = 173) and usual care (UC, n = 69) trial participants with type 2 diabetes that reported knee pain at baseline. Knee outcome measures included the Knee injury and Osteoarthritis Outcome Score (KOOS) pain, symptoms, activities of daily living (ADL), sports and recreation function, and knee-related quality of life subscales, and total KOOS score were assessed from baseline to 2 years. Missing data at each time point were replaced with multiple imputation under the assumption of missing at random. To assess if the primary analysis of the knee scores changed under plausible missing not at random assumptions, sensitivity analysis was also performed using pattern mixture models. In CCI, we also assessed factors associated with the improvement of knee scores.

Results: In the primary analysis, CCI participants demonstrated a statistically significant improvement in total KOOS and all KOOS individual subscale scores at 1 year and maintained through 2 years as opposed to UC patients who showed no significant changes from baseline to 2 years. The significant improvement in total KOOS and its individual subscale scores from baseline to 2 years remained relatively stable in CCI in the sensitivity analysis under different missing not at random scenarios confirming the robustness of the findings from the primary analysis. Approximately 46% of the CCI participants met the 10 points minimal clinically important change at 2 years. A reduction in CAF was associated with improvement in total KOOS and KOOS ADL, while a decrease in hsCRP was associated with improvement in KOOS symptoms scores.

Conclusion: A very low carbohydrate intervention including nutritional ketosis resulted in significant improvements in knee pain and function among patients with T2D. The improvements in knee function were likely secondary to a reduction in central adiposity and inflammation. Future research on the applicability of this intervention in radiographically confirmed OA patients is important.

Trial registration: Clinical trial registration: NCT02519309 (10/08/2015).

Keywords: KOOS; Knee function; Osteoarthritis; Type 2 diabetes.

Conflict of interest statement

Athinarayanan, McKenzie, Adams, Pearson, Hallberg, and Phinney have been employed by Virta Health Corp and were offered stock options. McCarter holds stocks from Virta Health Corp. Phinney and Volek are founders of Virta Health Corp. Andrawis and Lyman declare no conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Percentage changes in the total and its individual subscale Knee Injury and Osteoarthritis Scores (KOOS) from baseline to 2 years in Continuous Care Intervention and Usual Care
Fig. 2
Fig. 2
Longitudinal change in total Knee Injury and Osteoarthritis Scores (KOOS) from baseline to 2 years under different MNAR scenarios. A. Continuous Care Intervention. 1: Primary imputed values under missing at random assumption. 0.95: Primary imputed values estimated 5% lower. 0.90: Primary imputed values estimated 10% lower. B. Usual Care. 1: Primary imputed values under missing at random assumption. 0.95: Primary imputed values estimated 5% lower. 0.90: Primary imputed values estimated 10% lower. 1.10: Primary imputed values estimated 10% higher

References

    1. Barbour KE, Helmick CG, Boring M, Brady TJ. Vital signs: prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation-United States, 2013-2015. MMWR Morb Mortal Wkly Rep. 2017;66:246–253. doi: 10.15585/mmwr.mm6609e1.
    1. Clynes MA, Jameson KA, Edwards MH, Cooper C, Dennison EM. Impact of osteoarthritis on activities of daily living: does joint site matter? Aging Clin Exp Res. 2019;31:1049–1056. doi: 10.1007/s40520-019-01163-0.
    1. Cheng YJ, Imperatore G, Caspersen CJ, Gregg EW, Albrright AL, Helmick CG. Prevalence of diagnosed arthritis and arthritis-attributable activity limitation among adults with and without diagnosed diabetes: United States 2008-2010. Diabetes Care. 2012;35:1686–1691. doi: 10.2337/dc12-0046.
    1. Eymard F, Parsons C, Edwards MH, Petit-Dop F, Reginster JY, Bruyere O, et al. Diabetes is a risk factor for knee osteoarthritis progression. Osteoarthr Cartil. 2015;23:851–859. doi: 10.1016/j.joca.2015.01.013.
    1. King KB, Rosenthal AK. The adverse effects of diabetes on osteoarthritis update on clinical evidence and molecular mechanisms. Osteoarthr Cartil. 2015;23:841–850. doi: 10.1016/j.joca.2015.03.031.
    1. Schett G, Kleyer A, Perricone C, Sahinbegovic E, Iagnocco A, Zwerina J, et al. Diabetes is an independent predictor for severe osteoarthritis: results from a longitudinal cohort study. Diabetes Care. 2013;36:403–409. doi: 10.2337/dc12-0924.
    1. Laiguillon MC, Courties A, Houard X, Auclair M, Sautet A, Capeau J, et al. Characterization of diabetic osteoarthritic cartilage and role of high glucose environment on chondrocyte activation: toward pathophysiological delineation of diabetes mellitus-related osteoarthritis. Osteoarthr Cartil. 2015;23:1513–1522. doi: 10.1016/j.joca.2015.04.026.
    1. Eitner A, Pester J, Vogel F, Marintschev I, Lehmann T, Hofmann GO, et al. Pain sensation in human osteoarthritic knee joints is strongly enhanced by diabetes mellitus. Pain. 2017;158:1743–1753. doi: 10.1097/j.pain.0000000000000972.
    1. Eitner A, Culvernor AG, Wirth W, Schaible HG, Eckstein F. Impact of diabetes mellitus on knee osteoarthritis pain and physical and mental status: data from the osteoarthritis initiative. Arthritis Care Res (Hoboken) 2021;73:540–548. doi: 10.1002/acr.24173.
    1. Alenazi AM, Alshehri MM, Alothman S, Alqahtani BA, Rucker J, Sharma N, et al. The association of diabetes with knee pain severity and distribution in people with knee osteoarthritis using data from the Osteoarthristis initiative. Sci Rep. 2020;10:3985. doi: 10.1038/s41598-020-60989-1.
    1. Charen DA, Solomon D, Zubizaretta N, Poeran J, Colvin AC. Examining the association of knee pain with modifiable cardiometabolic risk factors. Arthritis Care Res. 2020. 10.1002/acr.24423.
    1. Garessus ED, de Mutsert R, Visser AW, Rosandaal FR, Kloppenburg M. No association between impaired glucose metabolism and osteoarthritis. Osteoarthr Cartil. 2016;24:1541–1547. doi: 10.1016/j.joca.2016.04.007.
    1. American Academy of Orthopaedic Surgeons: Treatment of Osteoarthritis of the Knee-3rd Edition: Evidence-Based Guideline. . Published Aug 31, 2021.
    1. Taylor N. Nonsurgical Management of Osteoarthritis Knee Pain in the older adult. Clin Geriatr Med. 2017;33:41–51. doi: 10.1016/j.cger.2016.08.004.
    1. Alrushud AS, Rushton AB, Kanavaki AM, Greig CA. Effect of physical activity and dietary restriction interventions on weight loss and the musculoskeletal function of overweight and obese older adults with knee osteoarthritis: a systematic review and mixed method data synthesis. BMJ Open. 2017;7:e014537. doi: 10.1136/bmjopen-2016-014537.
    1. Messier SP, Mihalko SL, Legault C, Miller GD, Nicklas BJ, DeVita P, et al. Effects of intensive diet and exercise on knee joint loads, inflammation, and clinical outcomes among overweight and obese adults with knee osteoarthritis: the IDEA randomized clinical trial. JAMA. 2013;310:1263–1273. doi: 10.1001/jama.2013.277669.
    1. Messier SP, Beavers DP, Loeser RF, Carr JJ, Khajanchi S, Legault C, et al. Knee joint loading in knee osteoarthritis: influence of abdominal and thigh fat. Med Sci Sports Exerc. 2014;46(9):1677–1683. doi: 10.1249/MSS.0000000000000293.
    1. Gersing AS, Schwaiger BJ, Nevitt MC, Zarnowski J, Jospeh GB, Feuerriegel G, et al. Weight loss regimen in obese and overweight individuals is associated with reduced cartilage degeneration: 96-month data from the osteoarthritis initiative. Osteoarthr Cartil. 2019;27:863–870. doi: 10.1016/j.joca.2019.01.018.
    1. Foy CG, Lewis CE, Hairston KG, Miller GD, Lang W, Jakicic JM, et al. Intensive lifestyle intervention improves physical function among obese adults with knee pain: findings from the look AHEAD trial. Obesity (Silver Spring) 2011;19:83–93. doi: 10.1038/oby.2010.120.
    1. Loredo-Perez AA, Montalvo-Blanco CE, Hernandez-Gonzalez LI, Anaya-Reyes M, Fernandez Del Valle-Laisequilla C, Reyes-Garcia JG, et al. High-fat diet exacerbates pain-like behaviors and periarticular bone loss in mice with CFA-induced knee arthritis. Obesity (Silver Spring) 2016;24:1106–1115. doi: 10.1002/oby.21485.
    1. Forsythe CE, Phinney SD, Fernandez ML, Quann EE, Wood RJ, Bibus DM, et al. Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation. Lipids. 2008;43:65–77. doi: 10.1007/s11745-007-3132-7.
    1. Masino SA, Ruskin DN. Ketogenic diets and pain. J Child Neurol. 2013;28:993–1001. doi: 10.1177/0883073813487595.
    1. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;2:263–269. doi: 10.1038/nm.3804.
    1. Yamada Y, Uchida J, Izumi H, Tsukamoto Y, Inoue G, Watanabe Y, et al. A non-calorie-restricted low-carbohydrate diet is effective as an alternative therapy for patients with type 2 diabetes. Intern Med. 2014;53:13–19. doi: 10.2169/internalmedicine.53.0861.
    1. Saslow LR, Daubenmier JJ, Moskowitz JT, Kim S, Murphy EJ, Phinney SD, et al. Twelve-month outcomes of a randomized trial of a moderate-carbohydrate versus very low-carbohydrate diet in overweight adults with type 2 diabetes mellitus or prediabetes. Nutr Diabetes. 2017;7:304. doi: 10.1038/s41387-017-0006-9.
    1. Volek JS, Phinney SD, Forsythe CE, Quann EE, Wood RJ, Puglisi MJ, et al. Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet. Lipids. 2009;44:297–309. doi: 10.1007/s11745-008-3274-2.
    1. Hallberg SJ, McKenzie AL, Williams PT, Bhanpuri NH, Peters AL, Campbell WW, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. Diabetes Ther. 2018;9:583–612. doi: 10.1007/s13300-018-0373-9.
    1. Bhanpuri NH, Hallberg SJ, Williams PT, McKenzie AL, Ballard KD, Campbell WW, et al. Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study. Cardiovasc Diabetol. 2018;17:56. doi: 10.1186/s12933-018-0698-8.
    1. Athinarayanan SJ, Adams RN, Hallberg SJ, McKenzie AL, Bhanpuri NH, Campbell WW, et al. Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial. Front Endocrinol (Laussanne) 2019;10:348. doi: 10.3389/fendo.2019.00348.
    1. Poff A, Koutnik A, Egan B. Nutritional ketosis with ketogenic diets or exogenous ketones: features, convergence and divergence. Curr Sports Med Rep. 2020;19(7):251–259. doi: 10.1249/JSR.0000000000000732.
    1. Roos EM, Lohmander LS. The knee injury and osteoarthritis outcome score (KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes. 2003;1:64. doi: 10.1186/1477-7525-1-64.
    1. Rodriguez-Merchan EC. Knee instruments and rating scales designed to measure outcomes. J Orthop Traumatol. 2012;13:1–6. doi: 10.1007/s10195-011-0177-4.
    1. Collins NJ, Misra D, Felson DT, Crossley KM, Roos EM. Measures of knee function: international knee documentation committee (IKDC) subjective knee evaluation form, knee injury and osteoarthritis outcome score (KOOS), knee injury and osteoarthritis outcome score physical function short form (KOOS-PS), knee outcome survey activities of daily living scale (KOS-ADL), Lysholm knee scoring scale, Oxford knee score (OKS), Western Ontario and McMaster universities osteoarthritis index (WOMAC), activity rating scale (ARS), and Tegner activity score (TAS) Arthritis Care Res. 2011;63(Suppl 11):S208–S228. doi: 10.1002/acr.20632.
    1. Kline RB. Principles and practice of structural equation modeling. 3. New York: The Guilford Press; 2011.
    1. Permutt T. Sensitivity analysis for missing data in regulatory submissions. Stat Med. 2016;35:2876–2879. doi: 10.1002/sim.6753.
    1. Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to statistical analysis using pattern mixture models. Pharm Stat. 2013;12(6):337–347. doi: 10.1002/pst.1549.
    1. Gomes M, Gutacker N, Bojke C, Street A. Addressing missing data in patient-reported outcome measures (PROMS): implications for the use of PROMS for comparing provider performance. Health Econ. 2016;25(5):515–528. doi: 10.1002/hec.3173.
    1. Hagan TL, Belcher SM, Donovan HS. Mind the mode: differences in paper vs. web-based survey modes among women with Cancer. J Pain Symptom Manag. 2017;54(3):368–375. doi: 10.1016/j.jpainsymman.2017.07.005.
    1. Ebert JF, Huibers L, Christensen B, Christensen MB. Paper- or Web-Based Questionnaire Invitations as a Method for Data Collection: Cross-Sectional Comparative Study of Differences in Response Rate, Completeness of Data, and Financial Cost. J Med Internet Res. 2018;20(1):e24. doi: 10.2196/jmir.8353.
    1. Neumann J, Hofmann FC, Heilmeier U, Ashmeik W, Tang K, Gersing AS, et al. Type 2 diabetes patients have accelerated cartilage matrix degeneration compared to diabetes free controls: data from the osteoarthritis initiative. Osteoarthr Cartil. 2018;26:751–761. doi: 10.1016/j.joca.2018.03.010.
    1. Cro S, Morris T, Kenward M, Carpenter J. Sensitivity analysis for clinical trials with missing continuous outcome data using controlled multiple imputation: a practical guide. Stat Med. 2020;39. 10.1002/sim.8569.
    1. Strath LJ, Jones CD, George AP, Lukens SL, Morrison SA, Soleymani T, et al. The effect of low-carbohydrate and low-fat diets on pain in individuals with knee osteoarthritis. Pain Med. 2020;21(1):150–160. doi: 10.1093/pm/pnz022.
    1. Look AHEAD Research Group. Wadden TA, West DS, Delahanty L, Jakicic J, Rejeski J, Williamson D, et al. The look AHEAD study: a description of the lifestyle intervention and the evidence supporting it. Obesity (Silver Spring) 2006;14:737–752. doi: 10.1038/oby.2006.84.
    1. Belalcazar LM, Reboussin DM, Haffner SM, Hoogeveen RC, Kriska AM, Schwenke DC, et al. Look AHEAD research group. A 1-year lifestyle intervention for weight loss in individuals with type 2 diabetes reduces high C-reactive protein levels and identifies metabolic predictors of change: from the look AHEAD (action for health in diabetes) Diabetes Care. 2010;33:2297–2303. doi: 10.2337/dc10-0728.
    1. Kraus VB, Sprow K, Powell KE, Buchner D, Bloodgood B, Piercy K, et al. Effects of physical activity in knee and hip osteoarthritis: a systematic umbrella review. Med Sci Sports Exerc. 2019;51:1324–1339. doi: 10.1249/MSS.0000000000001944.
    1. Pan F, Tien K, Cicuttini F, Jones G. Metabolic syndrome and trajectory of knee pain in older adults. Osteoarthr Cartil. 2020;28:45–52. doi: 10.1016/j.joca.2019.05.030.
    1. Toda Y, Toda T, Takemura S, Wada T, Morimoto T, Ogawa R. Change in body fat, but not body weight or metabolic correlates of obesity, is related to symptomatic relief of obese patients with knee osteoarthritis after a weight control program. J Rheumatol. 1998;25:2181–2186.
    1. Narouze S, Souzdalnitski D. Obesity and chronic pain: systematic review of prevalence and implications for pain practice. Reg Anesth Pain Med. 2015;40:91–111. doi: 10.1097/AAP.0000000000000218.
    1. Urban H, Little CB. The role of fat and inflammation in the pathogenesis and management of osteoarthritis. Rheumatology (Oxford) 2018;57:iv10–iv21. doi: 10.1093/rheumatology/kex399.
    1. Azamar-Llamas D, Hernandez-Molina G, Ramos-Avalos B, Furuzawa-Carballeda J. Adipokine contribution to the pathogenesis of osteoarthritis. Mediat Inflamm. 2017;2017:5468023. doi: 10.1155/2017/5468023.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner