COMMETS- Combination MCI Metabolic Syndrome

Summary

The investigators propose a proof of concept RCT (randomized clinical trial), testing the efficacy of intranasal insulin (INI) with semaglutide, a combination therapy with strong biological plausibility to benefit impaired cognition through vascular mechanisms, in older adults with MetS (metabolic syndrome) and MCI (Mild Cognitive Impairment), who are enriched for cerebrovascular disease and at high dementia risk. The study will focus on cognitive and biological outcomes, allowing identification of relevant mechanisms.

Timeline

Start

2024-01-30

Primary completion

2027-12-01

Completion

2028-12-01

Publications

• Background Love S, Miners JS. Cerebrovascular disease in ageing and Alzheimer's disease. Acta Neuropathol. 2016 May;131(5):645-58. doi: 10.1007/s00401-015-1522-0. Epub 2015 Dec 28.
• Background Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease. J Neurosci Res. 2017 Apr;95(4):943-972. doi: 10.1002/jnr.23777. Epub 2016 Jun 27.
• Background Kim HW, Hong J, Jeon JC. Cerebral Small Vessel Disease and Alzheimer's Disease: A Review. Front Neurol. 2020 Aug 25;11:927. doi: 10.3389/fneur.2020.00927. eCollection 2020.
• Background Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Ryden L, Xavier D, Atisso CM, Dyal L, Hall S, Rao-Melacini P, Wong G, Avezum A, Basile J, Chung N, Conget I, Cushman WC, Franek E, Hancu N, Hanefeld M, Holt S, Jansky P, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Cardona Munoz EG, Pirags V, Pogosova N, Raubenheimer PJ, Shaw JE, Sheu WH, Temelkova-Kurktschiev T; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019 Jul 13;394(10193):121-130. doi: 10.1016/S0140-6736(19)31149-3. Epub 2019 Jun 9.
• Background Gerstein HC, Hart R, Colhoun HM, Diaz R, Lakshmanan M, Botros FT, Probstfield J, Riddle MC, Ryden L, Atisso CM, Dyal L, Hall S, Avezum A, Basile J, Conget I, Cushman WC, Hancu N, Hanefeld M, Jansky P, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Munoz EGC, Pogosova N, Raubenheimer PJ, Shaw JE, Sheu WH, Temelkova-Kurktschiev T. The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial. Lancet Diabetes Endocrinol. 2020 Feb;8(2):106-114. doi: 10.1016/S2213-8587(19)30423-1. Epub 2020 Jan 7.
• Background Cukierman-Yaffe T, Gerstein HC, Colhoun HM, Diaz R, Garcia-Perez LE, Lakshmanan M, Bethel A, Xavier D, Probstfield J, Riddle MC, Ryden L, Atisso CM, Hall S, Rao-Melacini P, Basile J, Cushman WC, Franek E, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Pirags V, Pogosova N, Raubenheimer PJ, Shaw JE, Sheu WH, Temelkova-Kurktschiev T. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurol. 2020 Jul;19(7):582-590. doi: 10.1016/S1474-4422(20)30173-3.
• Background Wu JH, Haan MN, Liang J, Ghosh D, Gonzalez HM, Herman WH. Impact of antidiabetic medications on physical and cognitive functioning of older Mexican Americans with diabetes mellitus: a population-based cohort study. Ann Epidemiol. 2003 May;13(5):369-76. doi: 10.1016/s1047-2797(02)00464-7.
• Background Chen Y, Zhou K, Wang R, Liu Y, Kwak YD, Ma T, Thompson RC, Zhao Y, Smith L, Gasparini L, Luo Z, Xu H, Liao FF. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3907-12. doi: 10.1073/pnas.0807991106. Epub 2009 Feb 23.
• Background Craft S, Raman R, Chow TW, Rafii MS, Sun CK, Rissman RA, Donohue MC, Brewer JB, Jenkins C, Harless K, Gessert D, Aisen PS. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol. 2020 Sep 1;77(9):1099-1109. doi: 10.1001/jamaneurol.2020.1840.
• Background Craft S, Claxton A, Baker LD, Hanson AJ, Cholerton B, Trittschuh EH, Dahl D, Caulder E, Neth B, Montine TJ, Jung Y, Maldjian J, Whitlow C, Friedman S. Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial. J Alzheimers Dis. 2017;57(4):1325-1334. doi: 10.3233/JAD-161256.
• Background Kellar D, Lockhart SN, Aisen P, Raman R, Rissman RA, Brewer J, Craft S. Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer's Disease. J Prev Alzheimers Dis. 2021;8(3):240-248. doi: 10.14283/jpad.2021.14.
• Background Yoo H, Kim H, Koh I, Lee K, Ok J. Effect of Metabolic Syndrome on the Incidence of Dementia Based on National Insurance Data in Korea. Metab Syndr Relat Disord. 2022 Feb;20(1):29-35. doi: 10.1089/met.2021.0046. Epub 2021 Nov 9.
• Background Zuin M, Roncon L, Passaro A, Cervellati C, Zuliani G. Metabolic syndrome and the risk of late onset Alzheimer's disease: An updated review and meta-analysis. Nutr Metab Cardiovasc Dis. 2021 Jul 22;31(8):2244-2252. doi: 10.1016/j.numecd.2021.03.020. Epub 2021 Apr 1.
• Background Atti AR, Valente S, Iodice A, Caramella I, Ferrari B, Albert U, Mandelli L, De Ronchi D. Metabolic Syndrome, Mild Cognitive Impairment, and Dementia: A Meta-Analysis of Longitudinal Studies. Am J Geriatr Psychiatry. 2019 Jun;27(6):625-637. doi: 10.1016/j.jagp.2019.01.214. Epub 2019 Feb 15.
• Background Pal K, Mukadam N, Petersen I, Cooper C. Mild cognitive impairment and progression to dementia in people with diabetes, prediabetes and metabolic syndrome: a systematic review and meta-analysis. Soc Psychiatry Psychiatr Epidemiol. 2018 Nov;53(11):1149-1160. doi: 10.1007/s00127-018-1581-3. Epub 2018 Sep 4.
• Background Shu MJ, Zhai FF, Zhang DD, Han F, Zhou L, Ni J, Yao M, Zhang SY, Cui LY, Jin ZY, Zhu HJ, Zhu YC. Metabolic syndrome, intracranial arterial stenosis and cerebral small vessel disease in community-dwelling populations. Stroke Vasc Neurol. 2021 Dec;6(4):589-594. doi: 10.1136/svn-2020-000813. Epub 2021 Apr 26.
• Background Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. doi: 10.1001/archneurol.2011.233. Epub 2011 Sep 12.
• Background Beeri MS, Schmeidler J, Silverman JM, Gandy S, Wysocki M, Hannigan CM, Purohit DP, Lesser G, Grossman HT, Haroutunian V. Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology. Neurology. 2008 Sep 2;71(10):750-7. doi: 10.1212/01.wnl.0000324925.95210.6d.
• Background Katsel P, Roussos P, Beeri MS, Gama-Sosa MA, Gandy S, Khan S, Haroutunian V. Parahippocampal gyrus expression of endothelial and insulin receptor signaling pathway genes is modulated by Alzheimer's disease and normalized by treatment with anti-diabetic agents. PLoS One. 2018 Nov 1;13(11):e0206547. doi: 10.1371/journal.pone.0206547. eCollection 2018.
• Background Doniger GM, Beeri MS, Bahar-Fuchs A, Gottlieb A, Tkachov A, Kenan H, Livny A, Bahat Y, Sharon H, Ben-Gal O, Cohen M, Zeilig G, Plotnik M. Virtual reality-based cognitive-motor training for middle-aged adults at high Alzheimer's disease risk: A randomized controlled trial. Alzheimers Dement (N Y). 2018 Mar 27;4:118-129. doi: 10.1016/j.trci.2018.02.005. eCollection 2018.
• Background Bahar-Fuchs A, Barendse MEA, Bloom R, Ravona-Springer R, Heymann A, Dabush H, Bar L, Slater-Barkan S, Rassovsky Y, Schnaider Beeri M. Computerized Cognitive Training for Older Adults at Higher Dementia Risk due to Diabetes: Findings From a Randomized Controlled Trial. J Gerontol A Biol Sci Med Sci. 2020 Mar 9;75(4):747-754. doi: 10.1093/gerona/glz073.
• Background Beeri MS, Ravona-Springer R, Moshier E, Schmeidler J, Godbold J, Karpati T, Leroith D, Koifman K, Kravitz E, Price R, Hoffman H, Silverman JM, Heymann A. The Israel Diabetes and Cognitive Decline (IDCD) study: Design and baseline characteristics. Alzheimers Dement. 2014 Nov;10(6):769-78. doi: 10.1016/j.jalz.2014.06.002. Epub 2014 Aug 20.
• Background Ravona-Springer R, Sharvit-Ginon I, Ganmore I, Greenbaum L, Bendlin BB, Sternberg SA, Livny A, Domachevsky L, Sandler I, Ben Haim S, Golan S, Ben-Ami L, Lesman-Segev O, Manzali S, Heymann A, Beeri MS. The Israel Registry for Alzheimer's Prevention (IRAP) Study: Design and Baseline Characteristics. J Alzheimers Dis. 2020;78(2):777-788. doi: 10.3233/JAD-200623.
• Background Hsu CL, Best JR, Davis JC, Nagamatsu LS, Wang S, Boyd LA, Hsiung GR, Voss MW, Eng JJ, Liu-Ambrose T. Aerobic exercise promotes executive functions and impacts functional neural activity among older adults with vascular cognitive impairment. Br J Sports Med. 2018 Feb;52(3):184-191. doi: 10.1136/bjsports-2016-096846. Epub 2017 Apr 21.
• Background Morris JC, Ernesto C, Schafer K, Coats M, Leon S, Sano M, Thal LJ, Woodbury P. Clinical dementia rating training and reliability in multicenter studies: the Alzheimer's Disease Cooperative Study experience. Neurology. 1997 Jun;48(6):1508-10. doi: 10.1212/wnl.48.6.1508.
• Background Shinar D, Gross CR, Bronstein KS, Licata-Gehr EE, Eden DT, Cabrera AR, Fishman IG, Roth AA, Barwick JA, Kunitz SC. Reliability of the activities of daily living scale and its use in telephone interview. Arch Phys Med Rehabil. 1987 Oct;68(10):723-8.
• Background Graf C. The Lawton instrumental activities of daily living scale. Am J Nurs. 2008 Apr;108(4):52-62; quiz 62-3. doi: 10.1097/01.NAJ.0000314810.46029.74.
• Background Birdsill AC, Carlsson CM, Willette AA, Okonkwo OC, Johnson SC, Xu G, Oh JM, Gallagher CL, Koscik RL, Jonaitis EM, Hermann BP, LaRue A, Rowley HA, Asthana S, Sager MA, Bendlin BB. Low cerebral blood flow is associated with lower memory function in metabolic syndrome. Obesity (Silver Spring). 2013 Jul;21(7):1313-20. doi: 10.1002/oby.20170. Epub 2013 May 19.
• Background Hoscheidt SM, Kellawan JM, Berman SE, Rivera-Rivera LA, Krause RA, Oh JM, Beeri MS, Rowley HA, Wieben O, Carlsson CM, Asthana S, Johnson SC, Schrage WG, Bendlin BB. Insulin resistance is associated with lower arterial blood flow and reduced cortical perfusion in cognitively asymptomatic middle-aged adults. J Cereb Blood Flow Metab. 2017 Jun;37(6):2249-2261. doi: 10.1177/0271678X16663214. Epub 2016 Jan 1.
• Background Merluzzi AP, Dean DC 3rd, Adluru N, Suryawanshi GS, Okonkwo OC, Oh JM, Hermann BP, Sager MA, Asthana S, Zhang H, Johnson SC, Alexander AL, Bendlin BB. Age-dependent differences in brain tissue microstructure assessed with neurite orientation dispersion and density imaging. Neurobiol Aging. 2016 Jul;43:79-88. doi: 10.1016/j.neurobiolaging.2016.03.026. Epub 2016 Apr 6.
• Background Eren E, Hunt JFV, Shardell M, Chawla S, Tran J, Gu J, Vogt NM, Johnson SC, Bendlin BB, Kapogiannis D. Extracellular vesicle biomarkers of Alzheimer's disease associated with sub-clinical cognitive decline in late middle age. Alzheimers Dement. 2020 Sep;16(9):1293-1304. doi: 10.1002/alz.12130. Epub 2020 Jun 26.
• Background Ashton NJ, Pascoal TA, Karikari TK, Benedet AL, Lantero-Rodriguez J, Brinkmalm G, Snellman A, Scholl M, Troakes C, Hye A, Gauthier S, Vanmechelen E, Zetterberg H, Rosa-Neto P, Blennow K. Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology. Acta Neuropathol. 2021 May;141(5):709-724. doi: 10.1007/s00401-021-02275-6. Epub 2021 Feb 14.
• Background Rozga M, Bittner T, Batrla R, Karl J. Preanalytical sample handling recommendations for Alzheimer's disease plasma biomarkers. Alzheimers Dement (Amst). 2019 Apr 2;11:291-300. doi: 10.1016/j.dadm.2019.02.002. eCollection 2019 Dec.
• Background Posti JP, Takala RSK, Lagerstedt L, Dickens AM, Hossain I, Mohammadian M, Ala-Seppala H, Frantzen J, van Gils M, Hutchinson PJ, Katila AJ, Maanpaa HR, Menon DK, Newcombe VF, Tallus J, Hrusovsky K, Wilson DH, Gill J, Sanchez JC, Tenovuo O, Zetterberg H, Blennow K. Correlation of Blood Biomarkers and Biomarker Panels with Traumatic Findings on Computed Tomography after Traumatic Brain Injury. J Neurotrauma. 2019 Jul 15;36(14):2178-2189. doi: 10.1089/neu.2018.6254. Epub 2019 Apr 5.
• Background Kellar D, Register T, Lockhart SN, Aisen P, Raman R, Rissman RA, Brewer J, Craft S. Intranasal insulin modulates cerebrospinal fluid markers of neuroinflammation in mild cognitive impairment and Alzheimer's disease: a randomized trial. Sci Rep. 2022 Jan 25;12(1):1346. doi: 10.1038/s41598-022-05165-3.
• Background Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey WH 2nd, Craft S. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis. 2008 Apr;13(3):323-31. doi: 10.3233/jad-2008-13309.
• Background Smits MM, Van Raalte DH. Safety of Semaglutide. Front Endocrinol (Lausanne). 2021 Jul 7;12:645563. doi: 10.3389/fendo.2021.645563. eCollection 2021.
• Background Li A, Su X, Hu S, Wang Y. Efficacy and safety of oral semaglutide in type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2023 Apr;198:110605. doi: 10.1016/j.diabres.2023.110605. Epub 2023 Mar 5.
• Background Warren M, Chaykin L, Trachtenbarg D, Nayak G, Wijayasinghe N, Cariou B. Semaglutide as a therapeutic option for elderly patients with type 2 diabetes: Pooled analysis of the SUSTAIN 1-5 trials. Diabetes Obes Metab. 2018 Sep;20(9):2291-2297. doi: 10.1111/dom.13331. Epub 2018 Jun 7.
• Background Lind M, Jendle J, Torffvit O, Lager I. Glucagon-like peptide 1 (GLP-1) analogue combined with insulin reduces HbA1c and weight with low risk of hypoglycemia and high treatment satisfaction. Prim Care Diabetes. 2012 Apr;6(1):41-6. doi: 10.1016/j.pcd.2011.09.002. Epub 2011 Oct 19.
• Background Novak V, Mantzoros CS, Novak P, McGlinchey R, Dai W, Lioutas V, Buss S, Fortier CB, Khan F, Aponte Becerra L, Ngo LH. MemAID: Memory advancement with intranasal insulin vs. placebo in type 2 diabetes and control participants: a randomized clinical trial. J Neurol. 2022 Sep;269(9):4817-4835. doi: 10.1007/s00415-022-11119-6. Epub 2022 Apr 28.
• Background Novak P, Pimentel Maldonado DA, Novak V. Safety and preliminary efficacy of intranasal insulin for cognitive impairment in Parkinson disease and multiple system atrophy: A double-blinded placebo-controlled pilot study. PLoS One. 2019 Apr 25;14(4):e0214364. doi: 10.1371/journal.pone.0214364. eCollection 2019.
• Background Hallschmid M, Benedict C, Schultes B, Born J, Kern W. Obese men respond to cognitive but not to catabolic brain insulin signaling. Int J Obes (Lond). 2008 Feb;32(2):275-82. doi: 10.1038/sj.ijo.0803722. Epub 2007 Sep 11.
• Background Chang YF, Zhang D, Hu WM, Liu DX, Li L. Semaglutide-mediated protection against Abeta correlated with enhancement of autophagy and inhibition of apotosis. J Clin Neurosci. 2020 Nov;81:234-239. doi: 10.1016/j.jocn.2020.09.054. Epub 2020 Oct 14.
• Background During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep;9(9):1173-9. doi: 10.1038/nm919. Epub 2003 Aug 17.
• Background Goke R, Larsen PJ, Mikkelsen JD, Sheikh SP. Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites. Eur J Neurosci. 1995 Nov 1;7(11):2294-300. doi: 10.1111/j.1460-9568.1995.tb00650.x.
• Background Femminella GD, Frangou E, Love SB, Busza G, Holmes C, Ritchie C, Lawrence R, McFarlane B, Tadros G, Ridha BH, Bannister C, Walker Z, Archer H, Coulthard E, Underwood BR, Prasanna A, Koranteng P, Karim S, Junaid K, McGuinness B, Nilforooshan R, Macharouthu A, Donaldson A, Thacker S, Russell G, Malik N, Mate V, Knight L, Kshemendran S, Harrison J, Holscher C, Brooks DJ, Passmore AP, Ballard C, Edison P. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study). Trials. 2019 Apr 3;20(1):191. doi: 10.1186/s13063-019-3259-x.
• Background Robinson A, Lubitz I, Atrakchi-Baranes D, Licht-Murava A, Katsel P, Leroith D, Liraz-Zaltsman S, Haroutunian V, Beeri MS. Combination of Insulin with a GLP1 Agonist Is Associated with Better Memory and Normal Expression of Insulin Receptor Pathway Genes in a Mouse Model of Alzheimer's Disease. J Mol Neurosci. 2019 Apr;67(4):504-510. doi: 10.1007/s12031-019-1257-9. Epub 2019 Jan 11.
• Background Avgerinos KI, Ferrucci L, Kapogiannis D. Effects of monoclonal antibodies against amyloid-beta on clinical and biomarker outcomes and adverse event risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer's disease. Ageing Res Rev. 2021 Jul;68:101339. doi: 10.1016/j.arr.2021.101339. Epub 2021 Apr 5.
• Background Cho Y, Han K, Kim DH, Park YM, Yoon KH, Kim MK, Lee SH. Cumulative Exposure to Metabolic Syndrome Components and the Risk of Dementia: A Nationwide Population-Based Study. Endocrinol Metab (Seoul). 2021 Apr;36(2):424-435. doi: 10.3803/EnM.2020.935. Epub 2021 Apr 14.
• Background Gaubert M, Lange C, Garnier-Crussard A, Kobe T, Bougacha S, Gonneaud J, de Flores R, Tomadesso C, Mezenge F, Landeau B, de la Sayette V, Chetelat G, Wirth M. Topographic patterns of white matter hyperintensities are associated with multimodal neuroimaging biomarkers of Alzheimer's disease. Alzheimers Res Ther. 2021 Jan 18;13(1):29. doi: 10.1186/s13195-020-00759-3.
• Background Heiss WD. The Additional Value of PET in the Assessment of Cerebral Small Vessel Disease. J Nucl Med. 2018 Nov;59(11):1660-1664. doi: 10.2967/jnumed.118.214270. Epub 2018 Jun 29.
• Background Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013 Feb;12(2):207-16. doi: 10.1016/S1474-4422(12)70291-0.
• Background Qiu M, Ding LL, Zhang M, Zhou HR. Safety of four SGLT2 inhibitors in three chronic diseases: A meta-analysis of large randomized trials of SGLT2 inhibitors. Diab Vasc Dis Res. 2021 Mar-Apr;18(2):14791641211011016. doi: 10.1177/14791641211011016.
• Background Douros A, Lix LM, Fralick M, Dell'Aniello S, Shah BR, Ronksley PE, Tremblay E, Hu N, Alessi-Severini S, Fisher A, Bugden SC, Ernst P, Filion KB; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis : A Multicenter Cohort Study. Ann Intern Med. 2020 Sep 15;173(6):417-425. doi: 10.7326/M20-0289. Epub 2020 Jul 28.
• Background Seidu S, Kunutsor SK, Topsever P, Khunti K. Benefits and harms of sodium-glucose co-transporter-2 inhibitors (SGLT2-I) and renin-angiotensin-aldosterone system inhibitors (RAAS-I) versus SGLT2-Is alone in patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Endocrinol Diabetes Metab. 2022 Jan;5(1):e00303. doi: 10.1002/edm2.303. Epub 2021 Oct 12.
• Background Heymann AD, Chodick G, Halkin H, Karasik A, Shalev V, Shemer J, Kokia E. The implementation of managed care for diabetes using medical informatics in a large Preferred Provider Organization. Diabetes Res Clin Pract. 2006 Mar;71(3):290-8. doi: 10.1016/j.diabres.2005.07.002. Epub 2005 Aug 19.
• Background BenAri O, Efrati S, Sano M, Bendlin BB, Lin H, Liu X, Sela I, Almog G, Livny A, Sandler I, Ben-Haim S, Sagi R, LeRoith D, Schnaider Beeri M, Ravona-Springer R. A double-blind placebo-controlled clinical trial testing the effect of hyperbaric oxygen therapy on brain and cognitive outcomes of mildly cognitively impaired elderly with type 2 diabetes: Study design. Alzheimers Dement (N Y). 2020 Apr 13;6(1):e12008. doi: 10.1002/trc2.12008. eCollection 2020.

Drugs

Indications