Background The effect of body mass index (BMI) on coronary heart disease (CHD) risk is attenuated when mediators of this risk (such as diabetes, hypertension and hyperlipidaemia) are accounted for. However, there is now evidence of a differential effect of risk factors on fatal and non-fatal CHD events, with markers of inflammation more strongly associated with fatal than non-fatal events.
Objective To describe the association with BMI separately for both fatal and non-fatal CHD risk after accounting for classical risk factors and to assess any independent effects of obesity on CHD risk.
Methods and results In the West of Scotland Coronary Prevention Study BMI in 6082 men (mean age 55 years) with hypercholesterolaemia, but no history of diabetes or CVD, was related to the risk of fatal and non-fatal CHD events. After excluding participants with any event in the first 2 years, 1027 non-fatal and 214 fatal CHD events occurred during 14.7 years of follow-up. A minimally adjusted model (age, sex, statin treatment) and a maximally adjusted model (including known CVD risk factors and deprivation) were compared, with BMI 25–27.4 kg/m2 as referent. The risk of non-fatal events was similar across all BMI categories in both models. The risk of fatal CHD events was increased in men with BMI 30.0–39.9 kg/m2 in both the minimally adjusted model (HR=1.75 (95% CI 1.12 to 2.74)) and the maximally adjusted model (HR=1.60 (95% CI 1.02 to 2.53)).
Conclusions These hypothesis generating data suggest that obesity is associated with fatal, but not non-fatal, CHD after accounting for known cardiovascular risk factors and deprivation.
Clinical trial registration WOSCOPS was carried out and completed before the requirement for clinical trial registration.
- coronary disease
- coronary artery disease (CAD)
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The relationship between body mass and the risk of coronary heart disease (CHD) events is poorly understood. This is in part due to the complex relationship between weight and potential confounding factors such as smoking, medication, non-intentional weight loss due to prevalent disease and potential bias in the provision of primary preventive strategies. Several large prospective studies1 2 have investigated the associations between obesity and CHD death, with meta-analysis showing a 40% increase in mortality for every 5 kg/m2 increase in body mass index (BMI) above 25 kg/m2. However, the link to non-fatal CHD events has been studied to a lesser degree, with a graded relationship that attenuated with traditional risk factors seen in one cross-sectional study,3 with a similar result for composite events in a meta-analysis of four prospective studies.4 Prospective associations of the risk of non-fatal CHD events and obesity have been shown when the results are minimally adjusted.5
It is well known that an increasing BMI is associated with higher systolic and diastolic blood pressure (BP), higher non-HDL cholesterol, lower HDL cholesterol and a higher prevalence of diabetes; all are established cardiovascular risk factors.1 Previous studies have argued that these are the mediators by which BMI is thought to affect cardiovascular mortality.6 7 Examining the effects of obesity on CHD risk in a minimally adjusted model gives a good indication of the overall negative effects of obesity on cardiovascular health. However, adjusting for the known biological effects of obesity allows the further independent effects of obesity to be investigated. Manson et al have reported an attenuation of the association of BMI with risk after adjusting for classical cardiovascular risk factors,8 but this study had only a moderate number of events (n=418).
A possible additional biological effect of obesity, beyond its association with traditional cardiovascular risk factors, is the effect of inflammation; it is now well recognised that adipose tissue is an endocrine organ, can release proinflammatory cytokines,9 and as such obesity is a low-grade inflammatory state.10 11 Recent data have suggested that in cardiovascular disease (CVD) markers of inflammation—namely, C-reactive protein (CRP) and interleukin 6 (IL-6), are more strongly associated with fatal than non-fatal events.12 If inflammation is associated with greater risk of CHD mortality, the same might be hypothesised of adiposity, which is a major mediator of circulating inflammatory markers. Such an association may have implications for potential treatment targets.
To investigate whether there is an additional association between overweight and obesity and the risk of CHD, we related baseline BMI to the risk of incident events in the West of Scotland Coronary Prevention Study (WOSCOPS). Fatal and non-fatal CHD events were also examined separately in 15 years of follow-up data for this moderate-risk cohort.
The design of WOSCOPS has been reported elsewhere.13 14 Briefly, 6595 moderately hypercholesterolaemic men (serum low-density lipoprotein (LDL)-cholesterol 4.5–6.0 mmol/l and triglycerides <6.0 mmol/l) with no history of myocardial infarction (MI) were randomised to pravastatin 40 mg daily or placebo and followed up initially for an average of 4.9 years, with further follow-up completed to 15 years.14 All subjects provided written informed consent and ethical approval was obtained for the trial. Fasting blood samples were taken at the screening clinic before randomisation to pravastatin or placebo. Physical and biochemical CVD risk factors and other demographic variables were assessed at baseline.13
We related baseline BMI to future development of both fatal and non-fatal CHD events (data available to 15 years). All participants who were known to have diabetes before the study or had diabetes diagnosed at baseline screening were excluded from analyses; known baseline diabetes was defined by physician-reporting of diabetes, newly diagnosed baseline diabetes was defined as fasting plasma glucose ≥7.0 mmol/l. Participants with BMI<18.5 (n=16) and >39.9 kg/m2 (n=8) were excluded to limit the potential for small numbers of extreme BMIs to influence the central data. Participants who had any recorded event within the first 2 years (cardiovascular events and all-cause mortality) were excluded from analyses to avoid confounding from unintentional, disease-related weight loss leading to death; this was felt to be an appropriate exclusion timescale while not significantly affecting the statistical power of the analysis. Social deprivation was determined using the Carstairs Score, which applies a score to a postal code area based on social class, car ownership, overcrowding and male unemployment.15
Diagnoses of events
As previously detailed,14 follow-up of clinical CHD events and mortality was based on linkage of records held by the NHS Scotland. Of note, we have shown that using record-linked or adjudicated end points gives similar qualitative findings to the CVD relative risk reduction associated with statin use.16 Personal identifiers for study participants were electronically linked to hospital discharge records (Scottish Morbidity Record 01) and General Register Office death records (held by the Information and Statistical Division of NHS Scotland) by means of established record-linkage methods. Data on outcome events were extracted from the databases with the use of appropriate ‘International Classification of Diseases’ codes (versions 9 and 10). Approval for record linkage was given by the Privacy Advisory Committee at the Information and Statistics Division of NHS Scotland. CHD events were defined as:
CHD events: A composite of non-fatal CHD events and CHD death (ICD 10: I20–I25).
For the outcomes of MI and stroke, any record of MI or stroke, whether or not it was the primary reason for hospitalisation, was included as an event. For CHD events, any event that was the primary reason for hospitalisation and any non-fatal MI were recorded as events. For hospitalisations, the date of admission was used as the date of the event. The primary cause of death was used to identify the fatal outcomes of interest.
BMI was divided into five BMI categories of clinical interest (18.5–22.4, 22.5–24.9, 25–27.4, 27.5–29.9 and 30–39.9 kg/m2). Baseline characteristics were compared across BMI categories by one-way analysis of variance for continuous variables and χ2 test for categorical variables. The potential relationship between BMI and future non-fatal CHD events, CHD death, and composite CHD events was then examined by Cox proportional hazards models with 25–27.4 kg/m2 as the referent. We selected 25–27.4 kg/m2 as referent based on our analyses that suggested a J-shaped relationship between BMI and CHD mortality where 25–27.4 kg/m2 appeared to have the lowest risk of composite CHD events, and also as a continuous variable for each 1 unit increase in BMI. Where multiple events were recorded for a single individual, time to first event was used. The upper BMI category was further divided into 30–34.9 and 35–39.9 kg/m2 to allow more detailed analysis. The hazard ratios (HRs) were adjusted for randomised treatment and age in a minimally adjusted model (model 1) and additionally for the following baseline covariates: potential mediators of risk—cholesterol (HDL and LDL), triglycerides, BP (systolic and diastolic) and hypertension, and potential confounding factors—age, smoking status (current and ex), family history of CHD (first-degree relative CHD death in a woman aged <60 or man <55 years), angina, and social deprivation score (DEPCAT), statin treatment allocation, nitrates, specific drugs at baseline (aspirin, ACE inhibitors, β blockers, calcium channel blockers, diuretics, other antihypertensive agents), and family history of CHD (first-degree relative CHD death in a woman aged <55 or man <60 years) in a maximally adjusted model for the available data (model 2). CRP was further added to the fully adjusted model in order to examine any association independently of systemic inflammation.
Results are reported as number (percentage) of events and HR (95% CI). For differences in baseline characteristics p<0.05 was considered statistically significant. All analyses were carried out using the statistical software SAS (version 9.1, SAS Institute).
CRP was measured using a high-sensitivity, two-site enzyme linked immunoassay.17 The lower limit of the working range of the assay was 0.1 mg/l. The intra-assay and interassay coefficients of variation were 1.9% and 6.2%, respectively. Measurement of other parameters has been described previously.18
Data were available for 6571 participants with a baseline BMI of 18.5–39.9 kg/m2. After exclusion of 148 men with baseline diabetes, and 341 who had a CVD event or died in the first 2 years of the study, 6082 men were included in the analyses. Over 15 years of follow-up, there were 1241 CHD events, comprising 1027 non-fatal CHD events and 214 CHD deaths.
Baseline characteristics, split according to BMI category, are provided in table 1. As expected, systolic and diastolic BP increase with increasing BMI category, with a 7.9 mm Hg difference in systolic BP and a 7 mm Hg difference in diastolic BP between BMI 18.5–22.4 and 30–39.9 kg/m2. Total cholesterol increases slightly with increasing BMI along with an increase in triglyceride (0.56 mmol/l difference between BMI 18.5–22.4 and 30–39.9 kg/m2) and a decrease in HDL (0.16 mmol/l difference between BMI 18.5–22.4 and 30–39.9 kg/m2). There were lower proportions of current smokers and higher proportions of ex-smokers in higher than lower BMI categories.
Risk of CHD events and mortality in different BMI categories
The RR of all CHD events (ie, combined non-fatal and fatal CHD events), by BMI category relative to BMI 25–27.4 kg/m2 can be seen in table 2. In the minimally adjusted model, there was an increased risk of composite CHD events in BMI categories 27.5–29.9 kg/m2 (HR=1.18 (95% CI 1.00 to 1.39)) and 30.0–39.9 kg/m2 (HR=1.29 (95% CI 1.07 to 1.57)) relative to BMI 25–27.4 kg/m2. However, this increased risk was attenuated in the model adjusted for classical risk factors.
When examining non-fatal CHD events alone, there was no increase in risk across any of the BMI categories relative to BMI 25–27.4 kg/m2 in either model 1 or 2. The risk of fatal CHD events was increased in BMI category 30.0–39.9 kg/m2 relative to BMI 25–27.4 kg/m2 in both the minimally adjusted model, model 1 (HR=1.75 (95% CI 1.12 to 2.74)) and the maximally adjusted model, model 2 (HR=1.60 (95% CI 1.02 to 2.53)). Results of the analysis of BMI as a continuous variable supported these results, with the risk of composite CHD events increasing for each unit increase of BMI in the minimally adjusted model, although no longer significant in the maximally adjusted model: model 1 (HR=1.03 (95% CI 1.01 to 1.05)), model 2 (HR=1.01 (95% CI 0.99 to 1.03)). For fatal events the increased risk of CHD events with each unit increase in BMI remained apparent despite maximum adjustment for the available data: model 1 (HR=1.06 (95% CI 1.03 to 1.10)), model 2 (HR=1.05 (95% CI 1.01 to 1.09)).
Baseline CRP measurements were available for 5145 men. The addition of CRP to the fully adjusted model did not attenuate the risk of fatal CHD event in the 30.0–39.9 kg/m2 category (HR=1.66 (95% CI 1.03 to 2.69)).
Risk of CHD events and mortality in BMI 30.0–34.9 and 35.0–39.9 kg/m2
BMI category 30–39.9 kg/m2 was spilt into 30.0–34.9 kg/m2 and 35.0–39.9 kg/m2 to allow closer examination of the graded association of the risk of CHD events with increasing BMI. There were 532 men with a BMI of 30.0–34.9 kg/m2 and 49 with a BMI of 35.0–39.9 kg/m2. There was an increased risk of total CHD events in the minimally adjusted model, for 30.0–34.9 kg/m2 (HR=1.26 (95% CI 1.04 to 1.55)) relative to BMI 25–27.4 kg/m2 but, with a relatively low power, the evidence for a risk increase was very weak for the 35.0–39.9 kg/m2 category (HR=1.58 (95% CI 0.93 to 2.71)). In the model adjusted for classical risk factors there was no association of either category with risk of all CHD events. In addition, there was no increased risk of non-fatal events in the minimally adjusted model for either BMI subcategory. However, there was an increased risk of fatal CHD events in the minimally adjusted model, for both 30.0–34.9 kg/m2 (HR=1.63 (95% CI 1.02 to 2.61)) and 35.0–39.9 kg/m2 (HR=3.16 (95% CI 1.15 to 8.71)), relative to BMI 25–27.4 kg/m2. In the model adjusted for classical risk factors, this risk association was attenuated in the 30.0–34.9 kg/m2 category (HR=1.49 (95% CI 0.93 to 2.41)), but there remained evidence for an association in the 35.0–39.9 kg/m2 category (HR=3.01 (95% CI 1.08 to 8.39)) despite wide CIs.
We have shown that obesity is associated with an increased risk of fatal CHD events after adjusting for classical cardiovascular risk factors, deprivation and confounding factors such as drugs. This link was not seen for non-fatal CHD events and therefore, owing to large relative numbers of such events, also not seen for composite CHD events. In other words, our data suggest that obesity may give greater risk for fatal CHD events than non-fatal events, even after accounting for classical CHD risk factors.
Previous studies that have investigated the link between BMI and cardiovascular mortality in the general population have, in the main, only adjusted for a small number of potentially confounding factors, as hypertension, hyperlipidaemia and diabetes are the presumed mediators by which obesity increases cardiovascular risk.1 One study did adjust for a larger number of risk factors, including exercise and alcohol use, but did not include potential confounding factors such as prescribed drugs and family history. That study used BMI <25 kg/m2 as referent, and as such showed a decreased risk in the overweight category (BMI 25–30 kg/m2) and a slightly lower risk (HR=1.4 (95% CI 1.3 to 2.0)) for BMI >30 kg/m2, broadly in keeping with our results. Our analysis takes this a stage further by also examining non-fatal CHD events, suggesting that while men with an increased BMI may have an increased risk of fatal CHD events beyond that mediated by classical risk factors (such as cholesterol and BP, compared with men with a lower BMI, the same does not apply to non-fatal CHD events.
Recent work has shown that inflammatory markers—namely, IL-6, CRP and fibrinogen, are more strongly related to fatal than non-fatal cardiovascular events.12 As obesity is increasingly recognised as an inflammatory state, this is a potential aetiological pathway to account for the increased risk of fatal CHD events seen with obesity. The addition of CRP to our adjustment model did not attenuate the observed associations; however, as CRP was a weaker associate of fatal events than IL-612 the effects of adjusting for IL-6 and other novel inflammatory markers should be further explored in subsequent studies.
This study raises questions which may have clinical implications. Treating conventional risk factors alone may not be enough to neutralise the risk of CHD death in obese men. Obviously prevention of obesity is the key priority, but there is an established population of obese individuals and urgent work is required to examine cardiovascular outcomes with weight loss interventions.
A further outcome of this research is to re-assert the theme that researchers should consider investigation of fatal and non-fatal events separately rather than assuming a common aetiology. The question may be asked as to whether the nature of the event differs only in severity or whether there are subtle differences in underlying mechanisms that lead to fatal events versus non-fatal outcomes. While our work suggests a link between obesity and fatal CHD beyond known risk factors, these results are not conclusive, but they should be considered hypothesis generating. Future work is required to examine the relationship between BMI and CHD events, fatal and non-fatal, in a range of populations; more recent studies will have a higher prevalence of obesity in which to gain the power required to study these associations.
The strength of this work is the large cohort with a high number of events; this has allowed significant results to be generated while still allowing participants with events in the first 2 years to be excluded, along with those with known diabetes. A further strength of our study is having details of death; had we combined fatal and non-fatal CHD events we would have missed this important association. The number of participants who were obese is relatively small, reflecting the study population (a male population recruited two decades ago from a deprived area of the UK, with a high prevalence of smoking), and this somewhat limited the statistical power of this study. While this work is from an all-male moderate-risk hypercholesterolaemic cohort, associations of many baseline levels of risk factors (eg, lipids, glucose, CRP, liver function tests, etc19–22) in WOSCOPS with CHD and diabetes are broadly similar to data from other cohorts more representative of the general population23 24 and therefore we feel WOSCOPS data are applicable more widely. However, we accept that further work is required in women and in other ethnic groups, given that the physiological characteristics of adipose tissue in these groups differ from those of European men.
We used BMI rather than a direct measure of adiposity in this study. Although BMI has been criticised as a measure of risk as it reflects both lean and fat mass, recent studies have found no difference in risk of CHD events with either BMI or waist circumference, especially in men4 and it is far more practical test in clinical practice, and also more accurately assessed. However, if there were to be a bias through the use of BMI, this would be towards the null as men with increased muscle bulk would skew the body mass of our relatively lean sample. It may be that the association between fatal CHD events and waist circumference is stronger than that seen for BMI, and this should be investigated in cohorts where waist circumference data are available.
The choice of analysing in categories and the referent category might be questioned. However, the association between BMI and disease, disease severity and mortality is known to be non-linear, with a J-shaped relationship well described in many conditions including the general population.2 6 25–28 In order to extract the greatest information from our data for this hypothesis-generating analysis we used the lowest risk category as referent group. It was impossible to predict the lowest risk category as the WOSCOPS cohort is not the general population and no similar analysis existed; however, our results did match those of Mann et al,29 who found the lowest risk in the overweight category (BMI 25–30 kg/m2), and our continuous analysis for unit increase in BMI reinforced the results.
In summary, this study suggests that obesity is associated with an increased risk of fatal CHD events after adjustment for known cardiovascular risk factors and deprivation. This is in contrast to the work of other investigators, who have only examined composite CHD events, and raises questions as to the presumed common pathophysiology of fatal and non-fatal CHD events. Further work will be required to examine this risk in a range of populations, but these results further highlight the urgent need for obesity preventive strategies and evaluation of cardiovascular outcomes after effective interventions.
Funding Collection and analysis of data for the 15 year WOSCOPS follow-up was supported by a grant from the Chief Scientist Office of the Scottish Executive Health Department. The analyses of this study were funded by a grant from the Chest, Heart and Stroke Association in Scotland. The original WOSCOPS trial was funded by Bristol-Myers Squibb. The first 5 years of post-trial follow-up were funded by Bristol-Myers Squibb and Sankyo.
Competing interests None.
Ethics approval This study was conducted with the approval of the ethics committees of the University of Glasgow and all participating health boards.
Provenance and peer review Not commissioned; externally peer reviewed.
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