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A systematic primary literature review was conducted to evaluate the relationship of physical activity—as measured by daily step counts—with all-cause mortality, cardiovascular disease mortality, incident cardiovascular disease, and type 2 diabetes mellitus; to evaluate the shape of dose–response relationships; and to interpret findings in the context of development of the Physical Activity Guidelines for Americans, Second Edition.A primary literature search encompassing 2011 to March 2018 for existing literature reporting on these relationships was conducted.Eleven pertinent articles were identified. Seven longitudinal studies examined the relationship between daily step counts and mortality, disease incidence, or risk. Two studies examined objectively measured steps per day and all-cause mortality; one was restricted to a relatively small elderly population. One study examined cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The other four longitudinal studies addressed incident type 2 diabetes. All longitudinal studies reported an inverse relationship between steps per day and outcome risk. In one study, 531 cardiovascular events occurred during more than 45,000 person-years of follow-up. Before intervention, each increment of 2000 steps per day up to 10,000 steps was associated with a 10% lower cardiovascular event rate. Also, for every increase of 2000 steps per day over baseline, there was an 8% yearly reduction in cardiovascular event rate in individuals with impaired glucose tolerance.Daily step count is a readily accessible means by which to monitor and set physical activity goals. Recent evidence supports previously limited evidence of an inverse dose–response relationship of daily steps with important health outcomes, including all-cause mortality, cardiovascular events, and type 2 diabetes. However, more independent studies will be required before these observations can be translated into public health guidelines.