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1 Masters Paper: The Association between Waist-Hip Ratio and Coronary Heart Disease: A Systematic Review Michael J. Gillespie, MD June /?.5 f?f/1?.?/t!.5 ~~JI/0/fV'-'.S/J-fi/~U%-/55 bj ;11'( /ftji/jji"tt.'.5~ >~,y,i.j<"l.hj.bl-:;7 I T)fifrvl<-->; /f/1 tc.~4-z:t.- W -U:>f~e ~

2 Introduction: Coronary Heart Disease (CHD) is the number one cause of death in the United States (US). It is estimated that Americans will suffer 565,000 new heart attacks this year and 300,000 recurrent heart attacks. The prevalence of CHD is high, with a lifetime risk of developing CHD of 40 to 49% in men and 32% in women. The estimated direct and indirect cost ofchd in US in 2005 is $142.1 billion. 1 CHD is multifactorial in etiology and risk factors include age, gender, total cholesterol level, high-density cholesterol level, systolic blood pressure, cigarette smoking, glucose intolerance, cardiac enlargement and obesity? 3 Standard primary prevention strategies include calculating individual CHD risk based on presence and severity of these risk factors. Smoking cessation, blood pressure control and weight loss are generally recommended regardless of CHD risk. However, for those with intermediate and high risk, treatment with aspirin and/or statin medical therapy has been proven effective in reducing cardiovascular morbidity and mortality. 4 ' 5 Obesity can be defined as a high proportion of body fat mass to lean body mass and is most commonly defined as having a Body Mass Index (BMI) ::80 kg/m 2 Approximately 62% of the US population is overweight, defined as a BMI ~5 kg/m 2, and approximately 30% of the population is obese. 6 Over the last 40 years, obesity has doubled in prevalence, going from 12.8% in 1960 to 27% in the year 1994? Overweight and obesity exists in all populations groups, however, it is significantly higher among ethnic minority women. 8 Overweight and obesity is associated with adverse health outcomes and increased mortality and is responsible for an estimated 385,000 deaths annually, 9 a close second to cigarette smoking for the number one preventable cause for morbidity and mortality. As tobacco use declines, obesity is projected to be the number one preventable cause of morbidity and mortality in the near future. Obesity is associated with dysfunction and disease of several organ systems including, but not limited to, the gastrointestinal, endocrine, metabolic, cardiovascular, puhnonary, and musculoskeletal systems. Abdominal fat stores have been linked to excess plasma free fatty acid production, insulin resistance, dyslipidemia and glucose intolerance. 10 This may explain

3 the observation that measures of abdominal adiposity, for example, waist-to-hip ratio (WHR), are stronger predictors of cardiovascular disease than BMI. 11 Older patients tend to lose lean muscle mass and gain abdominal fat mass with age. This overall change leaves many older patients with abdominal obesity reflected by a high waist-to-hip ratio (WHR) and a normal body mass index (BMI). Several studies have found WHR to be an independent predictor of cardiovascular events and a more powerful predictor of cardiovascular events than BMI or waist circumference (WC). From their observations of the Framingham Heart Study, Wilson and colleagues found that CHD risk could be predicted for patients by measuring traditional risk factors of age, gender, total cholesterol, systolic blood pressure, diabetes and L VH and applying them to a multivariate predictive model, or risk assessment tool. 12 This risk assessment tool can accurately predict CHD risk over prospective 6 year intervals for patients and assist physicians in therapy options, including aspirin and statin. Although obesity was not included in the initial or subsequent revisions of Framingham Risk Assessment Tool, abdominal obesity's role in this CHD risk assessment tool has not been thoroughly examined. The National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP/ATP III) agree that obesity is strongly associated with risk for coronary heart disease; however, they have chosen not to include measures of obesity in a risk assessment tool because the incremental amount of risk has not been quantified and because of the unknown clinical and economical impact of prescribing lipid lowering statin medications to the large number of obese patients. 13 We preformed a systematic review of the literature to quantify the incremental CHD risk associated with having an elevated WHR ratio taking into account standard CHD risk factors. Methods: Inclusion and Exclusion Criteria:

4 To be included, studies had to be conducted in a developed country, be published from 1975 to 2004, written in English, use a prospective population-based cohort study design, have greater than 500 patients, measure the association between the exposure of WHR and an outcome of coronary heart disease (CHD) (as defined below) and report a corresponding independent relative risk. We defined eligible CHD outcomes to be: (1) myocardial infarction, (2) death from coronary heart disease, (3) all cause-mortality if included with an endpoint of myocardial infarction ( 4) revascularization, including coronary artery by-pass grafting (CABG) or percutaneous coronary intervention (PCI) if also included with an endpoint of myocardial infarction. Literature Search and Retrieval Process: We searched MEDLINE for articles to identify English-language articles that were published between 1975 and The key words used were: coronary heart disease AND: waist-hip ratio OR adipose tissue OR fat distribution OR abdominal obesity OR anthropometric OR population study. We limited our search to studies of humans. We also reviewed reference lists from articles meeting inclusion criteria for additional relevant publications. Article Selection Process: To determine whether an article met our selection criteria, we first examined the titles generated by our literature search. A single reviewer [MG] evaluated eligibility of titles by using a preliminary checklist of inclusion and exclusion criteria that included the following criteria: (1) use of an exposure of any measure of abdominal obesity; and the following exclusion criteria: (1) not a cohort study, (2) non-primary prevention populations (i.e. "among patients with coronary artery disease") (3) non-english language. Abstracts of articles that passed the preliminary inclusion and exclusion criteria were then pulled and scanned for the full inclusion and exclusion criteria. Articles that met these criteria were then entered into the full article review phase. For full article review, a single reviewer [MG] read each article to determine if it met inclusion criteria. Articles that did not meet inclusion criteria were assigned a reason for exclusion and entered into a table. [Table 1] Articles that did meet inclusion were then read and critically appraised by a single reviewer.!

5 Data Extraction: The first author [MG] entered all information of the 9 articles into an evidence table. [Table 2] Articles published from the same data sources were compared at this stage and duplicates were excluded based quality score and relevance of outcome measure. Rating the Quality oflndividual Studies: Each study that met inclusion and exclusion criteria was then given a rating from a 5 point scale adapted from a rating system for observational studies from West et. a! The articles were assigned a one or a zero for the following five criteria: followup, exposure measure, outcome measurement, statistical analysis, and funding/sponsorship. The average score for each article was calculated. Articles were labeled "good" for an average score of 1.0 to 0.8, "fair" for an average score of and "poor" for scores less than 0.6. [Table 3] Results: Literature Search: Our literature search generated 2409 abstracts from MEDLINE, of which 26 met inclusion and exclusion criteria and entered the full article review phase. Review ofthe references cited sections of these 26 articles generated another 13 articles for full article review. Of the 39 articles that were entered the full article review, 11 met inclusion and exclusion criteria and were entered into the critical appraisal phase. After critical appraisal, 2 studies were excluded because of duplicate data bases. Excluded studies and respective reasons for exclusion are listed in Table 1. Quality Rating: Nine articles met our inclusion criteria and were critically appraised and quality rated. [Table 2] Eight studies received average quality scores of 0.8 or higher and were therefore given quality rating values of "good". 11 ' 15 ' 22 One study received an average quality score of 0.6 and received a quality rating of "fair". 23 This study did not report percent follow-up at study completion and included episodes of prolonged chest pain in

6 their composite CHD outcome and therefore received scores of 0 for "follow-up" and for "outcome". Study Characteristics: Study size varied between 792 to 67,334 subjects and mean follow-up time varied between 2.5 years to 13 years. Two studies followed both men and women and reported relative risks for each individually Three studies included only women Four studies enrolled only men. 18 ' In total, women had approximately 962,634 person years of observation time, while men had approximately 288,638 years of observation time. For women, the mean ages for studies ranged from 46 years to 53 years, however, one study reported only an age range of 55 to 69 without reporting a mean. 15 For men, the mean ages for studies ranged from 46 to 61 years. One study that included both women and men did not report a mean age or an age range. 16 Six of the studies did not report the percentage of patients that were obese (defmed as a BMI? 30 kg/m2). 16 ' ' 23 Three studies reported baseline prevalence of obesity, which ranged from 10 to 20% ! I CHD Risk by WHR: All studies reported a relative risk for comparison between the highest and lowest division ofwhr. However, the number of population divisions for WHR varied between studies. For men, three studies compared quintiles ofwhr while three studies compared quartiles ofwhr. [Table 4] For women, one study compared sextiles of WHR, one group compared quintiles ofwhr, 2 groups compared quartiles ofwhr and one study compared tertiles of WHR. [Table 5] Effect size did not appear to be related to the number of divisions in the compared population, therefore, no attempt was made to standardize for this difference. Four of the six studies that included men reported unadjusted CHD relative risks for comparison of the highest to lowest WHR division. 16 ' Unadjusted RR for CHD for men with the highest WHR compared to the lowest WHR ranged from 1.58 (95% CI: 1.20, 2.08) to 2.62 (95% CI: 1.92, 3.57). [Table 4] [Figure 1]

7 Five studies reported RR for CHD in men with statistical adjustment for various CHD-risk factors ' 19 ' 21 ' 23 Adjusted RR for CHD for men with the highest WHR compared to the lowest WHR ranged from 1.5 (95% CI: 1.14, 1.98) to 2.91 (95% CI: ). [Table 4] [Figure 1] All studies adjusted for age and smoking. Four of the five studies also adjusted for family history of CHD. Only one study corrected for diabetes, total cholesterol, HDL and systolic blood pressure. 17 [Table 4] Four of the five studies that included women reported unadjusted CHD relative risks for comparison of the highest to lowest WHR division. 15 ' 17 ' 20 ' 22 Unadjusted RR for CHD for women with the highest WHR compared to the lowest WHR ranged from 1.5 (95% CI: 1.4, 1.8) to 5.04 (95% CI: 2.92, 8.71). [Table 5] [Figure 2] All five studies that included women reported RR for CHD with statistical adjustment for various CHD-risk factors Adjusted RR for CHD for wolnen with the highest WHR compared to the lowest WHR ranged from 1.01 (95% CI: 0.68, 1.48) to 2.5 (95% CI: ). [Table 5] [Figure 2] All five studies adjusted for age and smoking. Two studies adjusted for hypercholesterolemia Two studies corrected for family history of CHD. 16 ' 20 Three studies corrected for estrogen use Two studies for diabetes and hypertension? 0 22 [Table 5]! I Discussion: In the present study, we show that WHR is associated with an increased risk of CHD even after adjusting for other CHD-risk factors. For men, the independent relative risk for CHD ranged from 1.5 to 2.9. For women, the independent relative risk for CHD ranges from 1.0 to 2.5. However, only one study found no significant CHD risk associated with WHR in women. Hu and colleagues found a RR of 1.0 (95% CI; ) after adjustment for age, education, smoking, systolic BP, total cholesterol, HDL, diabetes, and physical activity. Although the reason why the four other studies that included women did find a statistical difference and Hu et. a! did not is unclear, we find several fundamental differences in the patient population and study protocol between this and the other studies.

8 The patient population in Hu's study had the youngest mean age at 46 years (range years). Since obesity is increasing with progressive generations, it is possible that the young women were disproportionately represented in the cohort with an elevated WHR and perhaps young age was a protective factor against CHD events in them. Another possibility is that the inclusion of stroke in their composite outcome had diluted the independent effect ofwhr on CHD risk. If we exclude Hu et al, we find an independent relative risk for CHD for women with an elevated WHR to lie between 2.1 and 2.5. After excluding Hu et. a!, we find that WHR confers a similar independent effect size as traditional CHD-risk factors. In a validation study of current traditional CHD risk factors, Wilson and colleagues found that cigarette use, diabetes, hypercholesterolemia and hypertension conferred similar independent CHD relative risk estimates ranging from 1.47 to However, what additional information in the form of increased accuracy or precision in risk assessment gained by the addition ofwhr to the current traditional CHD risk score is yet to be assessed. It is possible that WHR should be included in the risk assessment tool and possibly replace one or more traditional risk factors. Using the ARIC data base, an ongoing prospective population based cohort study, assessed the area under ROC (AUROC) curves using traditional risk factors and combinations of new risk factors? 4 The addition of WHR to the traditional risk factor assessment improved the AUROC only minimally across all racial and genders categories. However, the independent AUROC for WHR alone was not reported. In addition, AUROC for substituting WHR for traditional risk factors was not reported. The implications of our study are broad. If an elevated WHR confers about twice the relative risk of CHD events as other risk factors, it may enable physicians to identify patients at increased risk for CHD events despite normal or moderately elevated serum cholesterol. From the ASCOT-LLA trial, we saw that patients with controlled hypertension with average or less than average total serum cholesterol levels had significantly decreased CHD event rates with low dose, un-titrated (1 0 mg oral dose daily) atorvastatin therapy. 25 In subgroup analysis, obese patients had an absolute risk reduction of 4.4% in CHD events, translating to a Hazard Ratio of 0.59 (95%CI; ) for the atorvastatin group. These findings imply that obese patients with controlled

9 hypertension benefit from statin therapy regardless of their total serum cholesterol level. By measuring WHR and including this in the risk assessment tool, we may be able to identify patients that would benefit most from statin therapy. Alternately, WHR may help better define another syndrome that is associated with increased CHD risk, the metabolic syndrome. The metabolic syndrome includes a constellation of glucose intolerance, insulin resistance, central obesity, dyslipidemia and hypertension. 1 Currently, the International Diabetes Federation is attempting to define a uniform definition of the metabolic syndrome. Although it is generally accepted that central obesity is component of this syndrome, it is not universally accepted which measure of central obesity should be used. This study helps elucidate a more accurate estimate of the independent CHD risk associated with an elevated WHR. One limitation of our study is the heterogeneity of exposure measures between the included studies. Relative risks were calculated from comparisons between outcome rates from the highest and lowest categories of WHR for divisions ranging from tertiles to sextiles. In the majority of studies, however, quartiles and quintiles ofwhr were compared. We looked for a relationship between effect size and number of divisions of the population, however, none existed. Regardless, the cut-offvalues the highest division ofwhr similar among studies of men were similar, ranging between >0.98 to? The cut-offvalues for women, however, were more heterogeneous ranging from? 0.83 to? Included studies also differed in their measured composite endpoints. Outcomes ranged from nonfatal MI and revascularization to fatal CHD events. Methods for outcome measures were also different between studies, although all but one were judged to be of sound quality in this respect. In summary, it appears that an elevated WHR confers about twice the risk of CHD events for both women with a WHR? 0.89 and men with a WHR? 0.98 independent of age and tobacco use. How much additional information this adds to the traditional Framingham risk assessment, however, is still undetermined and should be evaluated in future studies

10 Table 1. Excluded Studies. Author Journal Year Reason Excluded Barakat lnt J Obese 1988 WHR compared to lipids (intermediate outcome) Bjorntorp Acta Med Scanda 1988 Unable to locate publication Brozhu Cor Art Dis 2000 Source population had CHD Chambless J Clin Epi 2003 Reported AU ROC. No Relative Risk reported for W HR. Ducimetiere lnt J Obese 1989 No measure ofwhr Fujimoto Diabetes Care 1999 No measure ofwhr Gillum J Clin Dis 1987 No measure ofwhr Gupta Indian Health J 1994 Intermediate outcomes (CHD risk factors) Kahn Am J of Card 1996 Case/Control, small population (n-116) Katzel Am J Card 1994 No measure ofwhr Lakka JAMA 2002 No measure ofwhr Larrson Am J ofepid 1992 Did not report risk by WHR. Morricone lnt J Obese Rei Met Dis 1999 Source population sip cardiac cath Nishtar Curr Med Res Pin 2004 Case Control study On at lnt J Obese 2004 Exposure is CT documented abdominal fat. Oshang lnt Arch Occup En vir 1995 Intermediate outcome (CHD risk factors) Health Son meg lnt J Obese Rei Met Dis 2003 Case-control, source population sip cardiac cath Terry In! J Obese 1992 Cohort too young Baik AmJ Epid 2000 No measure of WHR Dagenais Am Heart J 2005 No measure ofwhr Donahue Lancet 1987 No measure ofwhr Higgins NEJM 1990 No measure ofwhr Johnson Ann lnt Med 2002 No measure of WHR Kragelund lnt J Card 2005 Source population were sip Ml Lapidus BMJ 1984 Reported Kaplan-Meier curves for event free survival between WHR quintiles. No RR reported. Liese AEP 1997 No measure ofwhr Manson NEJM 1990 No measure of WHR Stevens Am J Epid 2002 No measure ofwhr Yusuf Lancet 2004 No measure ofwhr (uses vague term of "abdominal obesity" without defining) Folsom JAMA 1993 Duplicate data source as Folsom 2000, outcome of all-cause mortality less relevant. Prineas Ann Epidemiol 1993 Duplicate data source as Folsom 2000 '"; lower quality rating score.

11 cc ' Table 2. Characteristics of Studies Selected for Systematic Review Source Subjects Follow-up, No. of Events, Comparison Mean Types Category, Duration;% High Cut-off completed Larsson et al N -792; 13 y; 100% 233/ Quintiles of mean age (range): ischemic heart disease BMI, (91 ), stroke (33). all cause 50 y (NR) NR deaths (109) 100% Male %obese NR Rimm et al N ; 2.6y; 96% 420/ Quintiles of mean age (range): revascularization BMI procedures (220), nonfatal 54 y (40-75) > 0 g5 Ml (147), fatal Ml (53). 100% Male Folsom et al % obese N = 14040; 6.2 y; 86% 398/ Quartiles of mean age (range): all definite or probable BMI, CHDevent. NR (NR) Men:~ % Male Women:~ %obese NR 0.95 Rexrode et al N ; 8** y; NR 320/ Sextiles of mean age (range): nonfatal Ml (251), CHD BMI, deaths (69) 53 y (30-55) ~ % Female %obese NR Folsom et al N ; 10** y; 79% 438/ Quintiles of mean age (range): CHD (438) BMI, NR (55-69) > % Female 20% obese Rexrode et al N ; 3.9 y; 99% 552/ Quintiles of mean age (range): Ml (209), rest NR BMI, 61 y (40-84) ~ % Male %obese NR Lakka et al N- 1346; 10.6 y; NR 123/ Quartiles of mean age (range): definite Ml (71 ), probable BMI, Ml (37}, acute chest pain 52 y (42-61) > 0.98 episodes (15) 100% Male %obese NR Hu et al N ; 9.8* y; 92% 818/ Quartiles of mean age (range): CHD events (400), stroke BMI, (372), other CVD deaths 46 y (25-74); NR (46). 47% Men 18% obese Zhang et al N ; 2.5 y; 99.7% 70/ Tertiles of mean age (range): nonfatal Ml (49), fatal CHD BMI, events (21) 51 y (40-70) ~ % Female %obese NR *Median reported only. **Mean not reported. Presented is the reported study length... ~ ~

12 Table 3. Article Quality Rating Scores: Follow- Outcome Statistical Funding and Average up Exposure Measure Analysis Sponsorship Score Rating Larsson ** Good Rimm Good Folsom Good Rexrode *** Good Folsom * Good Rexrode Good Lakka *** 1 0**** Fair Hu Good Zhang Good *Outcomes collected from death certificates and mailed questionnaires. No mention of confirmation. **Did not correct possible confounders in statistical analysis. ***Follow-up percentage not reported. ****Outcome measure included probable myocardial infarctions and prolonged chest pain episodes.

13 Table 4. Reported Unadjusted and Adjusted CHD Relative Risk for Men (Highest vs Lowest Category ofwhr). Source Comparison Unadjusted Adjusted Adjusted For (cut-off)t Relative Risk Relative Risk (95% Cl) (95% Cl) Folsom Quartiles NR 1.80 age, ethnicity, smoking, (:?; 1.00) ( ) alcohol, family history of CHD Lakka Quartiles NR 2.91 age, smoking, family history of CHD, (>0.98) ( ) socioeconomic status, max oxygen uptake Hu Quartiles age, education, smoking, (NR) ( ) ( ) systolic BP, total chol, HDL, DM, ph;tsical activity Larsson Quintiles 2.5* NR NA (NR) Rimm Quintiles age, smoking, family (> 0.98) ( ) ( ) history of CHD, alcohol, calories, profession Rexrode Quintiles age, aspirin, smoking, (?o 0.99) ( ) ( ) family history of Ml, physical activity, alcohol, multivitamin use *95% CI not reported; p value reported as DM ~ diabetes; HTN ~hypertension; CHD ~ coronary heart disease; MI ~myocardial infarction. tcut-offvalue for the highest category ofwhr in each study. I Table 5. Female Reported Adjusted and Unadjusted CHD Relative Risk for Women (Highest vs Lowest Category ofwhr). Zhang Folsom Hu Folsom s Rexrode Comparison (cut-off)t Tertiles (:?; 0.83) Quartiles (:?; 0.95) Quartiles (NR) Quintiles (> 0.90) Sextiles (?o 0.88) Unadjusted Relative Risk (95% Cl} 3.0 ( ) NR 1.60 ( ) 1.5 ( ) 5.04 ( ) Adjusted Relative Risk (95% Cl) 2.4 ( ) 2.1 ( ) 1.01 ( ) 2.5 ( ) 2.43 ( ) Adjusted For age, age2, tobacco, alcohol, exercise, education, income, menopause, diet, estrogen, HTN, DM age, ethnicity, smoking, alcohol, family history of CHD age, education, smoking, systolic BP, total chat, HDL, DM, physical activity age, education, smoking, HTN, estrogen, physical activity, alcohol, vitamin use, diet age, age-squared, smoking, BMI, family history of Ml, alcohol, physical activity, fat intake, estrogen, DM, HTN, hyperchol, aspirin use DM- diabetes; HTN -hypertension; CHD -coronary heart disease; MI -myocardial infarction. tcut-off value for the highest category ofwhr in each study.

14 Figure 1. Reported Unadjusted and Adjusted CHD Relative Risk for highest category vs lowest category ofwhr for Men. A. Unadjusted Relative Risk Unadjusted Relative Risk Hu 2004 Larsson 1984 Rimm 1995 Rexrode 2001 B. Adjusted Relative Risk Adjusted Relative Risk Folsom 1998 Lakka 2002 Hu 2004 Rimm 1995 Rexrode 2001

15 Figure 2. Reported Unadjusted and Adjusted CHD Relative Risk for highest category vs lowest ofwhr for Females A. Unadjusted Relative Risk. Unadjusted Relative Risk 6 c J: 5 (.) ~ 0 4 -".. 0: 3 " > 2 "" " ~ 1 0 Zhang Hu Folsom Rexrode Publication B. Adjusted Relative Risk. Adjusted Relative Risk c J: (.) ~ 2 0 -".. 0: 1.5 -~ " - " ~ Zhang Folsom Hu Folsom Rexrode Publication L

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