SummaryBackgroundMany subsistence-level and Indigenous societies around the world are rapidly experiencing urbanization, nutrition transition, and integration into market-economies, resulting in marked increases in cardiometabolic diseases. Determining the most potent and generalized drivers of changing health is essential for identifying vulnerable communities and creating effective policies to combat increased chronic disease risk across socio-environmental contexts. However, comparative tests of how different lifestyle features affect the health of populations undergoing lifestyle transitions remain rare, and require comparable, integrated anthropological and health data collected in diverse contexts.MethodsWe developed nine scales to quantify different facets of lifestyle (e.g., urban infrastructure, market-integration, acculturation) in two Indigenous, transitioning subsistence populations currently undergoing rapid change in very different ecological and sociopolitical contexts: Turkana pastoralists of northwest Kenya (n = 3,692) and Orang Asli mixed subsistence groups of Peninsular Malaysia (n = 688). We tested the extent to which these lifestyle scales predicted 16 measures of cardiometabolic health and compared the generalizability of each scale across the two populations. We used factor analysis to decompose comprehensive lifestyle data into salient axes without supervision, sensitivity analyses to understand which components of the multidimensional scales were most important, and sex-stratified analyses to understand how facets of lifestyle variation differentially impacted cardiometabolic health among males and females.FindingsCardiometabolic health was best predicted by measures that quantified urban infrastructure and market-derived material wealth compared to metrics encompassing diet, mobility, or acculturation, and these results were highly consistent across both populations and sexes. Factor analysis results were also highly consistent between the Turkana and Orang Asli and revealed that lifestyle variation decomposes into two distinct axes–the built environment and diet–which change at different paces and have different relationships with health.InterpretationOur analysis of comparable data from Indigenous peoples in East Africa and Southeast Asia revealed a surprising amount of generalizability: in both contexts, measures of local infrastructure and built environment are consistently more predictive of cardiometabolic health than other facets of lifestyle that are seemingly more proximate to health, such as diet. We hypothesize that this is because the built environment impacts unmeasured proximate drivers like physical activity, increased stress, and broader access to market goods, and serves as a proxy for the duration of time that communities have been market-integrated.