Subgroup-Specific Cardiovascular Effects of Intensive Lifestyle Intervention: A Causal Forest Analysis in Adults with Type 2 Diabetes and Overweight/obesity

Subgroup-Specific Cardiovascular Effects of Intensive Lifestyle Intervention: A Causal Forest Analysis in Adults with Type 2 Diabetes and Overweight/obesity | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Subgroup-Specific Cardiovascular Effects of Intensive Lifestyle Intervention: A Causal Forest Analysis in Adults with Type 2 Diabetes and Overweight/obesity lixiang he, Xingfeng Xu, Jiangjie Lei, Juntao Zheng, Peng Wang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6186612/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Objective: To evaluate the heterogeneity of treatment effects (HTEs) of intensive lifestyle intervention (ILI) in adults with type 2 diabetes and overweight/obesity, and identify a subgroup with greater cardiovascular benefits from ILI. Methods: In a post-hoc analysis of the Look AHEAD trial, causal forest modeling was used to identify HTEs of ILI. The study population was stratified into four subgroups, and the associations of ILI with cardiovascular outcomes were assessed using multivariable Cox modeling compared to diabetes support & education (DSE). Results: Among 4,710 participants (mean age 58.9 years, 58.5% women), 768 primary outcomes occurred over a median follow-up of 9.5 years. Key variables identified through causal forest modeling were SF-36 mental health, diabetes duration, and urine albumin-creatinine ratio (ACR). In Subgroup 4 (SF-36 mental health > 55.64 and ACR > 10 mg/g), which had more cardiovascular risk factors and comorbidities, ILI significantly reduced the primary outcome risk (HR: 0.87, 95% CI: 0.48-0.87, P = 0.004) and three secondary outcomes compared to DSE. No cardiovascular benefits were observed in participants with SF-36 mental health ≤ 55.64 or ACR < 10 mg/g. Conclusion: This post-hoc analysis of the Look AHEAD trial showed HTEs of ILI in adults with type 2 diabetes and overweight/obesity. Participants with better mental health, poorer renal function, and more cardiovascular risk factors were more likely to benefit from ILI. Health sciences/Risk factors Health sciences/Diseases/Cardiovascular diseases Heterogeneity of treatment effects Causal Forest analysis Intensive lifestyle intervention Cardiovascular outcomes Figures Figure 1 Figure 2 Figure 3 Full Text Additional Declarations There is NO conflict of interest to disclose Supplementary Files Supplementarymaterialonline.docx Supplementary material Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 20 Mar, 2026 Review # 2 received at journal 14 Feb, 2026 Reviewer # 2 agreed at journal 31 Jan, 2026 Review # 1 received at journal 09 May, 2025 Reviewer # 1 agreed at journal 08 May, 2025 Reviewers invited by journal 08 May, 2025 Submission checks completed at journal 10 Mar, 2025 Editor assigned by journal 08 Mar, 2025 First submitted to journal 08 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6186612","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":453819646,"identity":"907d48a4-3c81-46c6-bcaa-d54451f1b149","order_by":0,"name":"lixiang he","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDUlEQVRIie3RsUrEQBCA4RkCa7N4beBeYkVQjpPcg9hkCWi1NjZWMstCbHyAE0RfIb7BHgOmEa8NpDDXW2gjFudhOFGwSLhScP9qWeZbBhYgFPqDKYgIXlcHAFFkm+/buJ8g4VQctQSd2phEUnB7xPxnspfsb9k8lnJ+OLhAimHJE+WjWS0hOekio8uZU3FcmykjKcxZF15kYwnZaedilbaNUrWhlqRInCov94YSvKYu8rQgn6aP5rYl/muxwVs/qdA23ntTMFoCwVh4KfrJg3Y7ljJzx+hA58f6isXu6Fpl3aTk++EHJeZmzuX7y3I82S7dono+SzrJ71Jw7Z+un9poft355qOhUCj0b/oEN+BemKv9jW0AAAAASUVORK5CYII=","orcid":"","institution":"Sun Yat-sen University First Affiliated Hospital","correspondingAuthor":true,"prefix":"","firstName":"lixiang","middleName":"","lastName":"he","suffix":""},{"id":453819647,"identity":"336416f3-ab01-4679-81aa-326c9e1ab007","order_by":1,"name":"Xingfeng Xu","email":"","orcid":"","institution":"Sun Yat-sen University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xingfeng","middleName":"","lastName":"Xu","suffix":""},{"id":453819648,"identity":"1c38d571-a7d7-43f3-9f48-a83fa48e20a8","order_by":2,"name":"Jiangjie Lei","email":"","orcid":"","institution":"Sun Yat-sen University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jiangjie","middleName":"","lastName":"Lei","suffix":""},{"id":453819649,"identity":"9c69d34a-a3d2-4e5a-8e1e-52d6a7c564f0","order_by":3,"name":"Juntao Zheng","email":"","orcid":"","institution":"Sun Yat-sen University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Juntao","middleName":"","lastName":"Zheng","suffix":""},{"id":453819650,"identity":"9c45e7c1-c35a-49f5-83ac-289b8ca99a04","order_by":4,"name":"Peng Wang","email":"","orcid":"","institution":"Sun Yat-sen University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Wang","suffix":""},{"id":453819651,"identity":"6b9be751-4033-47bf-a7ea-0e2f77c96814","order_by":5,"name":"Yue Guo","email":"","orcid":"","institution":"Sun Yat-sen University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Guo","suffix":""},{"id":453819652,"identity":"80ee300f-276f-4725-9cb3-ec2613bab224","order_by":6,"name":"Menghui Liu","email":"","orcid":"","institution":"Sun Yat-sen University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Menghui","middleName":"","lastName":"Liu","suffix":""},{"id":453819653,"identity":"e89af127-793b-4aea-9f96-fdebf182a674","order_by":7,"name":"Xiaodong Zhuang","email":"","orcid":"","institution":"Sun Yat-sen University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaodong","middleName":"","lastName":"Zhuang","suffix":""},{"id":453819654,"identity":"36572121-ad85-462e-a85b-2b6b9844da01","order_by":8,"name":"Xinxue Liao","email":"","orcid":"","institution":"Sun Yat-sen University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xinxue","middleName":"","lastName":"Liao","suffix":""}],"badges":[],"createdAt":"2025-03-09 03:55:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6186612/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6186612/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82775855,"identity":"12ceff47-c889-4ccd-8b1a-9f31c72e0203","added_by":"auto","created_at":"2025-05-15 07:17:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":514831,"visible":true,"origin":"","legend":"\u003cp\u003eFour subgroups with HTEs identified by the causal forest model.\u003c/p\u003e\n\u003cp\u003eSF-36: short form (36) health survey; ACR: albumin-creatinine ratio; HTEs: heterogeneity of treatment effects.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6186612/v1/53b456ed09c91c16f6ad5946.png"},{"id":82775858,"identity":"41df82d1-000a-4772-93ce-885a76fdbfab","added_by":"auto","created_at":"2025-05-15 07:17:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3546501,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence curves with 95% CIs for primary outcomes between the ILI and DSE arms across the four subgroups identified by the causal forest model.\u003c/p\u003e\n\u003cp\u003eCI: confidence interval; ILI: intensive lifestyle intervention; DSE: diabetes support and education.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6186612/v1/c8e557888df4db671940e363.png"},{"id":82775856,"identity":"61ca0827-dd84-4c4d-9c5e-f72bb6bb4cd8","added_by":"auto","created_at":"2025-05-15 07:17:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3122045,"visible":true,"origin":"","legend":"\u003cp\u003eHeterogeneous cardiovascular effects of intensive lifestyle intervention in adults with type 2 diabetes and overweight/obesity identified by the causal forest model.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6186612/v1/e3afb8c4fa11758e0035d7ac.png"},{"id":82777295,"identity":"e9a992f6-d45e-4245-bf97-4aee0e72dd3a","added_by":"auto","created_at":"2025-05-15 07:33:44","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1940284,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6186612/v1_covered_8f55ec32-139a-449c-b9c9-31041790f958.pdf"},{"id":82776998,"identity":"319b0de0-d356-4fdd-8fa7-4855ef7c3fcb","added_by":"auto","created_at":"2025-05-15 07:25:36","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":156137,"visible":true,"origin":"","legend":"Supplementary material","description":"","filename":"Supplementarymaterialonline.docx","url":"https://assets-eu.researchsquare.com/files/rs-6186612/v1/e0f9781f17ab86e4ce84d554.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Subgroup-Specific Cardiovascular Effects of Intensive Lifestyle Intervention: A Causal Forest Analysis in Adults with Type 2 Diabetes and Overweight/obesity","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nutrition-and-diabetes","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nutd","sideBox":"Learn more about [Nutrition \u0026 Diabetes](http://www.nature.com/nutd/)","snPcode":"41387","submissionUrl":"https://mts-nutd.nature.com/cgi-bin/main.plex","title":"Nutrition \u0026 Diabetes","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Heterogeneity of treatment effects, Causal Forest analysis, Intensive lifestyle intervention, Cardiovascular outcomes","lastPublishedDoi":"10.21203/rs.3.rs-6186612/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6186612/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eTo evaluate the heterogeneity of treatment effects (HTEs) of intensive lifestyle intervention (ILI) in adults with type 2 diabetes and overweight/obesity, and identify a subgroup with greater cardiovascular benefits from ILI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eIn a post-hoc analysis of the Look AHEAD trial, causal forest modeling was used to identify HTEs of ILI. The study population was stratified into four subgroups, and the associations of ILI with cardiovascular outcomes were assessed using multivariable Cox modeling compared to diabetes support \u0026amp; education (DSE).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong 4,710 participants (mean age 58.9 years, 58.5% women), 768 primary outcomes occurred over a median follow-up of 9.5 years. Key variables identified through causal forest modeling were SF-36 mental health, diabetes duration, and urine albumin-creatinine ratio (ACR). In Subgroup 4 (SF-36 mental health \u0026gt; 55.64 and ACR \u0026gt; 10 mg/g), which had more cardiovascular risk factors and comorbidities, ILI significantly reduced the primary outcome risk (HR: 0.87, 95% CI: 0.48-0.87, P = 0.004) and three secondary outcomes compared to DSE. No cardiovascular benefits were observed in participants with SF-36 mental health ≤ 55.64 or ACR \u0026lt; 10 mg/g.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThis post-hoc analysis of the Look AHEAD trial showed HTEs of ILI in adults with type 2 diabetes and overweight/obesity. Participants with better mental health, poorer renal function, and more cardiovascular risk factors were more likely to benefit from ILI.\u003c/p\u003e","manuscriptTitle":"Subgroup-Specific Cardiovascular Effects of Intensive Lifestyle Intervention: A Causal Forest Analysis in Adults with Type 2 Diabetes and Overweight/obesity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-15 07:17:31","doi":"10.21203/rs.3.rs-6186612/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-03-20T19:10:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-02-15T02:03:32+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-01-31T13:02:36+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-05-09T04:03:23+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-05-09T02:50:43+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-05-08T13:13:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-10T14:29:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-09T03:53:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Nutrition \u0026 Diabetes","date":"2025-03-09T03:53:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nutrition-and-diabetes","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nutd","sideBox":"Learn more about [Nutrition \u0026 Diabetes](http://www.nature.com/nutd/)","snPcode":"41387","submissionUrl":"https://mts-nutd.nature.com/cgi-bin/main.plex","title":"Nutrition \u0026 Diabetes","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b3260a2b-84dc-4c2c-999a-aff9bcfdd2de","owner":[],"postedDate":"May 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":48259118,"name":"Health sciences/Risk factors"},{"id":48259119,"name":"Health sciences/Diseases/Cardiovascular diseases"}],"tags":[],"updatedAt":"2026-04-08T09:34:29+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-15 07:17:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6186612","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6186612","identity":"rs-6186612","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}