Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study

Lancet Diabetes Endocrinol. 2018 Sep;6(9):714-724. doi: 10.1016/S2213-8587(18)30137-2. Epub 2018 May 31.


Background: Cardiovascular disease risk among individuals across different categories of BMI might depend on their metabolic health. It remains unclear to what extent metabolic health status changes over time and whether this affects cardiovascular disease risk. In this study, we aimed to examine the association between metabolic health and its change over time and cardiovascular disease risk across BMI categories.

Methods: Between June and December, 1976, 121 701 female nurses were recruited to the Nurses' Health Study (NHS) of whom 103 298 returned a questionnaire in 1980 used as baseline in this study. After excluding women with a history of cardiovascular disease or cancer, with missing body weight and with underweight. 90 257 women were followed-up from 1980 to 2010 for incident cardiovascular disease. Participants were cross-classified by BMI categories, metabolic health (defined by absence of diabetes, hypertension and hypercholesterolaemia), and change in metabolic health status during follow-up. The cardiovascular component of the NHS is registered with, number NCT00005152.

Findings: During 2 127 391 person-years of follow-up with a median follow-up of 24 years, we documented 6306 cases of cardiovascular disease including 3304 myocardial infarction cases and 3080 strokes. Cardiovascular disease risk of women with metabolically healthy obesity was increased compared with women with metabolically healthy normal weight (HR 1·39, 95% CI 1·15-1·68), but risk was considerably higher in women with metabolically unhealthy normal weight (2·43, 2·19-2·68), overweight (2·61, 2·36-2·89) and obesity (3·15, 2·83-3·50). The majority of metabolically healthy women converted to unhealthy phenotypes (2555 [84%] of 3027 women with obesity, 22 215 [68%] of 32 882 women with normal-weight after 20 years). Women who maintained metabolically healthy obesity during follow-up were still at a higher cardiovascular disease risk compared with women with stable healthy normal weight (HR 1·57, 1·03-2·38), yet this risk was lower than for initially metabolically healthy women who converted to an unhealthy phenotype (normal-weight 1·90, 1·66-2·17 vs obesity 2·74, 2·30-3·27). Particularly incident diabetes and hypertension increased the risk among women with initial metabolic health.

Interpretation: Even when metabolic health is maintained during long periods of time, obesity remains a risk factor for cardiovascular disease. However, risks are highest for metabolically unhealthy women across all BMI categories. A large proportion of metabolically healthy women converted to an unhealthy phenotype over time across all BMI categories, which is associated with an increased cardiovascular disease risk.

Funding: US National Institutes of Health, German Federal Ministry of Education and Research.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Body Mass Index
  • Cardiovascular Diseases / complications*
  • Cardiovascular Diseases / epidemiology
  • Diabetes Complications / epidemiology
  • Female
  • Follow-Up Studies
  • Humans
  • Hypertension / complications
  • Metabolic Syndrome / complications
  • Metabolic Syndrome / epidemiology
  • Middle Aged
  • Obesity / complications*
  • Obesity / epidemiology
  • Obesity, Metabolically Benign / complications*
  • Obesity, Metabolically Benign / epidemiology
  • Phenotype
  • Prospective Studies
  • Risk Assessment*
  • Risk Factors

Associated data