Gammaglutamyltransferase is associated with incident vascular events independently of alcohol intake

1
Gamma-glutamyltransferase is associated with
incident vascular events independently of alcohol
intake. Analysis of the British Womens Heart and
Health Study and meta-analysis

• Fraser A, Harris R, Sattar N, Ebrahim S, Smith
  GD, Lawlor DA.

Arterioscler Thromb Vasc Biol. 2007 Oct 11 Epub
ahead of print
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Background

• Several population-based studies have found
  positive associations of gamma-glutamyltransferase
  (GGT) with incident cardiovascular events
• GGT has long been used as a marker of excessive
  alcohol intake
• However, additional mechanisms have been proposed
  as explanations of observed associations between
  GGT and cardiovascular and diabetes risk such as
  oxidative stress and non-alcoholic fatty liver
  disease (NAFLD)

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Objectives

• To study the associations of GGT with fatal and
  non-fatal coronary heart disease (CHD), stroke
  and a combined outcome of CHD or stroke in a
  random sample of older British women (60-79 years
  old at baseline)
• To pool existing relevant evidence in order to
  obtain a precise estimation of the associations
• To determine if the association is independent of
  alcohol intake by studying a sub-group of
  non-drinkers

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British Womens Heart Health Study (BWHHS)

• Prospective cohort.
• Includes 4286 women aged 60-79 years, randomly
  selected from general practitioner lists in 23
  British towns.
• Follow-up median of 4.6 years, to December 2004,
  by a detailed review of their medical records,
  conducted every two-years, to establish non-fatal
  cardiovascular disease events and by flagging
  with the NHS central register (NHSCR) for
  mortality data.

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Systematic review meta-analysis

• Medline and EMBASE (March 2007) were searched for
  prospective population based studies evaluating
  the association between ALT, GGT and CHD or
  stroke events.
• Studies conducted in populations restricted to
  patients with diagnosed CHD or previous stroke
  were excluded.
• When possible, data were extracted separately for
  men and women.

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Results

• BWHHS
• Of 3511 women free of CHD or stroke at baseline,
  complete data on exposures (GGT and ALT),
  outcomes (CHD and stroke) and potential
  confounders (childhood and adult social class,
  physical activity, smoking, alcohol consumption,
  diabetes, fasting insulin, BMI, triglycerides,
  HDL-c, and systolic blood pressure) were
  available for 2961 women (84).

• Systematic review Meta-analysis
• 11 prospective studies (including the BWHHS) were
  included in the systematic review.

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BWHHS Hazard ratios (95CI) of incident CHD,
stroke and combined CHD or stroke per 1 U/L
change in natural logged GGT
5 women had both an incident CHD and incident
stroke event. Model 1 adjusted for age. Model
2 model 1 plus potential confounder (childhood
and adult social class, physical activity,
smoking and alcohol consumption) Model 3 model
2 plus diabetes/insulin resistance, and other
components of the metabolic syndrome BMI,
triglycerides, HDL-c, SBP.
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Pooled fully-adjusted estimate of association of
GGT with CHD
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Pooled fully-adjusted estimate of association of
GGT with stroke
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Pooled fully-adjusted estimate of association of
GGT with CHD or stroke
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Sub-group analyses heterogeneity

• There was marked heterogeneity in all of the main
  meta-analyses of GGT presented above (I270),
  except for the association with ischemic stroke
  (I244).
• Heterogeneity was nearly eliminated when 2
  studies conducted in Asian populations were
  excluded
• When analyses were repeated in non-drinkers, the
  degree of heterogeneity among studies remained
  high and the point estimates were higher than
  those obtained in the main analyses

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Discussion

• GGT predicts incident cardiovascular events even
  in non-drinkers
• GGT may reflect NAFLD and/or oxidative stress
• It has been suggested that GGT should be used in
  risk stratification. Due to the modest
  associations (34 increase in risk of CHD per
  nearly tripling of GGT), this is debatable

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Conclusions

• GGT is positively associated with incident CHD
  and stroke in both women and men in European
  populations and among self-reported non-drinkers.
  
• Therefore, GGT levels probably also reflect
  other biological processes or indeed lifestyle or
  dietary behaviours that are linked to
  cardiovascular disease.
• Future studies, including more in Asians
  populations, will help provide insight into the
  nature of these processes.