Metabolic Syndrome Vs Framingham Risk Score for Prediction of Coronary Heart Disease, Stroke, and Type 2 Diabetes Mellitus

ORIGINAL INVESTIGATION Metabolic Syndrome vs Framingham Risk Score for Prediction of Coronary Heart Disease, Stroke, and Type 2 Diabetes Mellitus

S. Goya Wannamethee, PhD; A. Gerald Shaper, FRCP; Lucy Lennon, MSc; Richard W. Morris, PhD

Background: We sought to compare metabolic syn- ity of developing CVD or DM2 over 20 years increased drome (MetS) with the Framingham Risk Score (FRS) from 11.9% in those with no abnormalities to 31.2% in as predictors of coronary heart disease (CHD), stroke, those with 3 abnormalities to 40.8% in those with 4 or 5 and type 2 diabetes mellitus (DM2) in middle-aged men. abnormalities. The FRS was a better predictor of CHD and stroke than MetS but was less predictive of DM2. Areas Methods: A prospective study of 5128 men aged 40 to under the receiver-operating characteristic curves for FRS 59 years with no history of cardiovascular disease (CVD) vs the number of metabolic abnormalities were 0.68 vs (CHD or stroke) or DM2 drawn from general practices 0.59 for CHD, 0.60 vs 0.70 for DM2, and 0.66 vs 0.55 in 24 British towns and observed for 20 years. Metabolic for stroke (PϽ.001 for all). syndrome was defined as the presence of 3 or more metabolic abnormalities based on modified National Choles- Conclusions: Presence of MetS is a significant predic- terol Education Program criteria. tor of CVD and DM2 but is a stronger predictor of DM2 than of CHD. Although MetS does not predict CHD as Results: Men with MetS at baseline (26%) showed sig- well as the FRS, it serves well as a simple clinical tool for nificantly higher relative risk (RR) than men without MetS of developing CHD (RR, 1.64; 95% confidence interval identifying high-risk subjects predisposed to CVD or DM2. [CI], 1.41-1.90), stroke (RR, 1.61 95% CI, 1.26-2.06), and DM2 (RR, 3.57; 95% CI, 2.83-4.50). The probabil- Arch Intern Med. 2005;165:2644-2650

ETABOLIC SYNDROME disease (CHD) risk than other risk assess- (MetS), defined as a ments such as the Framingham Risk Score cluster of risk factors, (FRS), 3 recent US studies indicate that MetS including obesity, hy- isinferiortotheFRSinpredictingCHD.19,21,24 pertension,hyperglyce- Stern et al19 conclude that MetS is inferior to mia,M and dyslipidemia,1 is becoming increas- established rules for the prediction of either ingly common because of the increasing DM2 or CVD, and the use of MetS as a fo- prevalenceofobesity.2 TheWorldHealthOr- cus of screening for metabolic risk modifi- ganization(WHO)Consultationin1998pro- cation has become questionable. Nonethe- vided a provisional definition for MetS3 and less, MetS predicts both CVD and DM2, and revised it in 1999.4 The Third Report of the since previous studies have not shown National Cholesterol Education Program whethertheFRSisagoodpredictorofDM2,25 (NCEP) Expert Panel on Detection, Evalu- MetS may be a good all-purpose predictor ation, and Treatment of High Blood Choles- compared with the FRS. Furthermore, there terol in Adults (Adult Treatment Panel III)5 have been few prospective studies on the re- presented a simpler definition of MetS in- lationship between MetS and risk of stroke. tended for the identification of people with We have assessed the prospective relation- the syndrome in clinical practice.6 Whether ship between MetS and risk of CHD, stroke, defined on the basis of NCEP criteria7-21 or and DM2 using a modified NCEP definition WHO criteria,8-10,13,18,22,23 MetS is associated andhavecomparedMetSwiththeFRSinpre- with significantly increased risk of develop- dicting risk over 20 years follow-up. ing type 2 diabetes mellitus (DM2) and cardiovascular disease (CVD) and has been METHODS widely promoted as a means of identifying Author Affiliations: Department of Primary Care patients for lifestyle intervention to reduce The British Regional Heart Study26 is a large pro- and Population Sciences, Royal risk factors and incident disease, in particu- spective study of CVD comprising 7735 men 24,25 Free and University College lar CVD. aged 40 to 59 years drawn from general prac- Medical School, While it has not been established whether tices in each of 24 towns in England, Wales, London, England. MetS is a better predictor of coronary heart and Scotland. The criteria for selecting the

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 towns, the general practices, and the subjects as well as the meth- FOLLOW-UP ods of data collection have been reported.26 Research nurses administered a standard questionnaire that included ques- All men were evaluated on follow-up for all-cause mortality, tions on lifestyle and medical history. The men were asked to cardiovascular morbidity, and development of DM2 from the recall a physician’s diagnosis of CHD (angina or myocardial in- initial screening in January 1978–July 1980 to June 2000, a mean farction), stroke, and DM2. Physical measurements including period of 21.3 years; follow-up was achieved for 99% of the co- height and weight were made, and venous nonfasting blood hort.35 This analysis is based on a 20-year follow-up for each samples were obtained for measurement of biochemical and he- man. Criteria for accepting a diagnosis of nonfatal myocardial matologic characteristics. Triglyceride measurements were only infarction, stroke, and death have been reported, as has the available for men in the seventh to 24th towns visited (n=5663). method for ascertaining new cases of DM2.27,36 A combined end Details of smoking history, alcohol use, physical activity, so- point was also used, defined as the confirmed development of cial class, blood pressure (BP), and blood lipid measurements have a heart attack, stroke, or DM2. been reported.26-28 Heavy drinking was defined as 6 alcoholic drinks daily or on each of most days in the week (1 drink=10 g of alcohol). A physical activity (exercise) score was derived for each STATISTICAL ANALYSIS man, and the men were initially grouped into 6 broad categories based on their total score (none, occasional, light, moderate, mod- The Cox proportional hazards model was used to assess the ad- erately vigorous, or vigorous).27 Men who reported no or occa- justed relative risks (RRs). Receiver-operating characteristic sional physical activity were defined as “inactive.” Adjustments (ROC) curves and their respective areas under the curve (AUCs) were used to compare the ability of the FRS and the number of were made for the marked diurnal variation in serum triglycer- 37 ide concentration.29 Men with recall of a physician diagnosis of metabolic abnormalities to predict CHD and DM2. Tests for differences between the curves were performed using Stata soft- CHD or stroke, known diabetes at screening, and/or asymptom- 38 atic hyperglycemia (glucose level, Ն200 mg/dL [Ն11.1 mmol/L]) ware, version 9.0 (Stata Corp, College Station, Tex). were excluded (n=441). Data on MetS were not available in 94 men. After these exclusions, data were available for a group of RESULTS 5128 men, the subjects of this study. During the 20-year follow-up, there were 763 major CHD DEFINITION OF MetS events (fatal CHD and nonfatal myocardial infarction), Metabolic syndrome as defined by NCEP5 comprises 3 or more 291 major stroke events (fatal and nonfatal), and 299 cases of the following: (1) fasting plasma glucose level of at least 110 of DM2 in the 5128 men with no history of CHD, stroke, mg/dL (6.1 mmol/L); (2) serum triglyceride level of at least 150 or diabetes. Table 1 lists the baseline characteristics in mg/dL (1.7 mmol/l); (3) serum high-density lipoprotein cho- these men. Metabolic syndrome was present in over a lesterol level lower than 40 mg/dL (1.04 mmol/L); (4) BP of at quarter of the men (26.0%); 53.9% of men who devel- least 130/85 mm Hg or controlled with antihypertensive treat- oped DM2 had MetS at baseline compared with 35.5% ment; and/or (5) waist circumference of more than 102 cm.5 of the men developing CHD and 34.7% of the men who Waist circumference was not measured in the present study. developed stroke. Metabolic syndrome was associated with However, in a subset of 3000 of these men whose waist cir- a significant increase in CHD, stroke, and particularly DM2 cumference and body mass index (BMI) (calculated as weight after adjustment for age, social class, smoking status, in kilograms divided by the square of height in meters) were measured 20 years after initial screening, regression analysis physical activity level, and alcohol use (Table 2). Risk showed a BMI of 28.9 to be equivalent to a waist circumfer- of CHD and DM2 increased significantly with increas- ence of 102 cm, similar to analysis using data from a large US ing number of components of MetS (Table 3). The re- survey.30 We have therefore used a BMI of 28.8 or higher as a lationship with stroke was less consistent. proxy for abdominal adiposity in conformity with other stud- When the higher thresholds for nonfasting glucose were ies that have used BMI to replace waist circumference.7 used for the definition of high blood glucose level in MetS Sincetriglyceridelevelswerebasedonnonfastingmeasurements, (ie, Ն126 mg/dL (Ն7.0 mmol/L) and Ն140 mg/dL (Ն7.8 which are on average 20% to 30% higher than fasting levels,31 we mmol/L), this slightly attenuated the RR of CHD associ- have used a higher threshold and defined high triglyceride level Ն ated with MetS (RR, 1.57; 95% confidence interval [CI], as greater than or equal to 200 mg/dL ( 2.28 mmol/L). We retained 1.34-1.83 and RR, 1.54; 95% CI, 1.31-1.80, respectively), the cutoff level for blood glucose because this represents 20% of the men, and previous reports in this cohort have shown such lev- but absolute cumulative incidence rates in men with MetS els to be associated with significantly increased risk of CVD and remained unchanged. Similar attenuation was seen for the DM2.32 Thus, in this study, MetS includes any 3 of the following: DM2 RR, but risk was still over 3-fold (RR, 3.22; 95% CI, (1) hypertension (systolic BP Ն130 mm Hg, diastolic BP Ն85 2.55-4.06 using Ն126 mg/dL [Ն7.0 mmol/L] and RR, 3.05; mmHg,orBPcontrolledwithantihypertensivetreatment);(2)high 95% CI, 2.41-3.85 using Ն140 mg/dL [Ն7.8 mmol/L]), with blood glucose level (Ն110 mg/dL [Ն6.1 mmol/L]); (3) hypertri- little change in absolute cumulative incidence rates. glyceridemia (triglyceride level, Ն200 mg/dL [Ն2.28 mmol/L]); Ͻ (4) low level of high-density lipoprotein cholesterol ( 40 mg/dL COMPARISONS BETWEEN THE FRS AND MetS [Ͻ1.04 mmol/L]); and/or (5) elevated BMI (Ն28.8). However, in a subsidiary analysis, we used higher thresholds for the criteria of We compared the predictive power of number of high blood glucose level: greater than or equal to 126 mg/dL (Ͼ7.0 mmol/L) and greater than or equal to 140 mg/dL (Ն7.8 mmol/L). metabolic abnormalities with the FRS over 10 and 20 years. The subjects in the top quintile of the FRS showed a higher probability of developing CHD than FRAMINGHAM RISK SCORE even those with 4 or more abnormalities for both 10- The FRS for CHD over 10 years was calculated for each man,33,34 and 20-year follow-up (Table 4). The ROC curves for and the men were categorized according to quintiles of risk score. the FRS and the number of metabolic abnormalities in

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 1. Baseline Characteristics of 5128 Men With No History of CHD, Stroke, or Type 2 Diabetes Mellitus

Characteristic Value* Age, y 50.3 (5.7) Current cigarette smoker, % 42.1 Inactive, % 37.8 Manual social class, % 58.6 Nondrinkers,% 5.6 Heavy drinkers, % 11.3 BMI 25.4 (3.2) Systolic BP, mm Hg 145.7 (20.7) Diastolic BP, mm Hg 83.0 (13.2) Triglyceride, mg/dL (mmol/L) 152 (104-221) (1.72 [1.17-2.50]) HDL-C, mg/dL (mmol/L) 44.4 (10.4) (1.15 [0.27]) Cholesterol, mg/dL (mmol/L) 241.3 (39.8) (6.25 [1.03]) Glucose, mg/dL (mmol/L) 97.3 (90.1-106.3) (5.4 [5.0-5.9]) Indivdual components of metabolic syndrome† Hypertension, %‡ 78.5 High triglyceride (Ն200 mg/dL [Ն2.28 mmol/L], % 30.0 Low HDL-C (Ͻ40 mg/dL [Ͻ1.04 mmol/L]), % 37.1 High glucose (Ն110 mg/dL [Ն6.1 mmol]), % 20.2 Obesity (BMI Ն28.8), % 13.9 Metabolic syndrome, % 26.0

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); BP, blood pressure; CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol. *Values are given as mean, mean (SD), or median (interquartile range). †Based on modified National Cholesterol Education Program criteria.5 ‡Hypertension was defined as systolic BP Ն130 mm Hg or diastolic BP Ն85 mm Hg or BP controlled with antihypertensive treatment.

Table 2. Association of Metabolic Syndrome With Development of CHD, Stroke, and Type 2 Diabetes Mellitus

Metabolic Syndrome

Absent Present Characteristic (n = 3895) (n = 1333) Major CHD event (n = 763, 8.6/1000 person-years) Cumulative incidence, % 13.0 20.4 Adjusted RR* 1.00 1.64 (1.41-1.90) Major stroke event (n = 291, 3.2/1000 person-years) Cumulative incidence, % 5.0 7.6 Adjusted RR* 1.00 1.61 (1.26-2.06) Diabetes mellitus type 2 (n = 299, 3.3/1000 person-years) Cumulative incidence, % 3.7 12.1 Adjusted RR* 1.00 3.57 (2.83-4.50)

Abbreviations: CHD, coronary heart disease; RR, relative risk. *Adjusted for age, smoking status, social class, physical activity level, and alcohol intake; reported with 95% confidence interval.

predicting CHD and DM2 are shown in the Figure. fying CHD cases for both 10- and 20-year events but The FRS was a significantly better predictor of CHD less sensitive than MetS in identifying DM2. Further than was the number of metabolic abnormalities, as analysis indicated that if obesity and high glucose lev- indicated by the AUC of the ROC at both 10 and 20 els, which are not included in the FRS, were excluded years, but it was less predictive of DM2 (Table 4) from the syndrome score, the sensitivity for DM2 (PϽ.001 for all differences). Metabolic syndrome pro- would be reduced to 32.1%. vided no additional predictive value for CHD when The FRS was also a significantly better discrimina- the FRS was included in the multivariate model but tor of stroke than the number of metabolic abnormali- remained strongly associated with DM2 (adjusted RR, ties (AUC, 0.71; 95% CI, 0.65-0.77 vs AUC, 0.54; 95% 1.14; 95% CI, 0.96-1.35 for CHD and adjusted RR, CI, 0.48-0.60 for 10 years and AUC, 0.66; 95% CI, 2.98; 95% CI, 2.28-3.88 for DM2). Metabolic syn- 0.62-0.70 vs AUC, 0.55; 95% CI, 0.51-0.59 for 20 drome had a higher sensitivity for DM2 than for CHD years; PϽ.001 for all). at both 10 and 20 years’ follow-up (Table 4). For a We also repeated the ROC analysis using different given specificity (fixed at the specificity levels for thresholds for blood glucose level. The AUC hardly MetS) the FRS was more sensitive than MetS in identi- altered when we used glucose level thresholds of 126

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 3. Association of Number of Metabolic Abnormalities With Development of CHD, Stroke, and Type 2 Diabetes Mellitus (DM2)

Metabolic Abnormalities, No.

Characteristic 0 1 2 3 4or5 Men, No. (%) 557 (10.9) 1757 (34.3) 1481 (28.9) 902 (17.6) 431 (8.4) CHD Cases, No. 38 213 241 173 98 Rate† 3.7 6.9 9.5 11.3 13.9 Adjusted RR* 1.00 1.74 (1.22-2.39) 2.34 (1.65-3.32) 2.88 (2.02-4.11) 3.44 (2.35-5.03) Stroke Cases, No. 21 94 75 73 28 Rate† 2.0 3.0 2.9 4.7 3.8 Adjusted RR* 1.00 1.23 (0.76-1.57) 1.17 (0.72-1.90) 2.06 (1.27-3.36) 1.54 (0.87-2.73) DM2 Cases, No. 11 47 80 79 82 Rate† 1.1 1.5 3.1 5.1 11.7 Adjusted RR* 1.00 1.36 (0.70-2.62) 2.73 (1.45-5.14) 4.56 (2.48-8.78) 10.88 (5.77-20.50)

Abbreviations: CHD, coronary heart disease; RR, relative risk. *Adjusted for age, smoking status, social class, physical activity level, and alcohol intake; reported with 95% confidence interval. †Per 1000 person-years.

Table 4. Metabolic Syndrome and Framingham Risk Score and Measures of Probability (Percentage) for Occurrence of CHD Event and Type 2 Diabetes Mellitus (DM2)

CHD Event, % DM2, %

Characteristic Men, No. 10 Years 20 Years 10 Years 20 Years Metabolic Syndrome Metabolic abnormalities, No. 0 551 2.2 7.1 0.6 2.1 1 1759 4.8 12.8 0.8 2.9 2 1482 8.5 17.3 1.2 5.9 3 914 9.8 20.2 3.5 9.6 Ն4 422 13.4 24.5 6.5 21.0 AUC (95% CI) 0.63 (0.61-0.65) 0.59 (0.57-0.61) 0.72 (0.66-0.78) 0.70 (0.66-0.74) Sensitivity 39.5 35.5 62.6 53.9 Specificity 75.0 75.7 74.7 75.7 Framingham Risk Score Quintile 1 1024 1.0 4.8 1.0 3.4 2 1024 3.0 8.5 1.4 4.1 3 1024 5.9 15.4 1.6 6.8 4 1024 9.6 21.5 1.8 7.4 5 1024 16.6 29.8 3.5 10.8 AUC (95% CI) 0.73 (0.71-0.75) 0.68 (0.66-0.70) 0.61 (0.55-0.67) 0.60 (0.56-0.64) Sensitivity 56.5 47.2 40.7 35.6 Specificity* 75.0 75.7 74.7 75.7 Test for Differences Between AUCs P value Ͻ.001 Ͻ.001 Ͻ.001 Ͻ.001

Abbreviations: AUC, area under the receiver-operating characteristic curve; CHD, coronary heart disease; CI, confidence interval. *Fixed at levels for metabolic syndrome.

mg/dL (7.0 mmol/L) and 140 mg/dL (7.8 mmol/L) AUC, 0.61; 95% CI, 0.59-0.63; PϽ.001; sensitivity compared with 110 mg/dL (6.1 mmol/L) in our defini- 44.1% vs 37.3% for a fixed specificity of 77.6%), the tion of MetS (data not shown). probability of developing heart attacks, stroke, or DM2 over 20 years increased markedly with increasing CVD EVENTS AND DM2 COMBINED number of components from 11.9% in those with none to 19.0% in those with 1; 24.9% in those with 2; Although the FRS was a better discriminator of the 31.2% in those with 3; and 40.8% in those with 4 or combined cases (CHD, stroke, or diabetes) over 20 more abnormalities. The absolute probability was years than MetS (AUC, 0.67; 95% CI, 0.65-0.69 vs comparable to the probability associated with quintiles

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 Framingham Risk No. of Metabolic Reference Score Fifths Abnormalities

CHD Event Type 2 Diabetes Mellitus 1.0 10-Year Curves 1.0 10-Year Curves

0.8 0.8

0.6 0.6

Sensitivity 0.4 0.4

0.2 0.2

0 0.2 0.4 0.6 0.8 1.0 0 0.2 0.4 0.6 0.8 1.0

1.0 20-Year Curves1.0 20-Year Curves

0.8 0.8

0.6 0.6

Sensitivity 0.4 0.4

0.2 0.2

0 0.2 0.4 0.6 0.8 1.0 0 0.2 0.4 0.6 0.8 1.0 1–Specificity 1–Specificity

Figure. Receiver operating characteristic curves for the Framingham Risk Score (fifths) and number of metabolic abnormalities for prediction of coronary heart disease (CHD) events and type 2 diabetes mellitus over 10 and 20 years in men with no history of CHD, stroke, or diabetes.

of the FRS: 10.0%, 14.9%, 22.9%, 30.8%, and 40.8% ria and stroke. A recent report from the Atherosclerosis for the 5 FRS groups. Risk in Communities (ARIC) study21 showed a nonsig- nificant increased risk of stroke in men with MetS. How- COMMENT ever, in this study, MetS was shown to be associated with significant increased risk of stroke, consistent with the In this study of middle-aged British men with no history evidence that insulin resistance is associated with in- of CVD or diabetes, the risk of CHD and DM2 increased creased risk of stroke in subjects without diabetes.39,40 significantly and progressively with increasing number of metabolic abnormalities, as has been reported in other MetS AND THE FRS studies7,15,17,20; less consistent relationships were seen with stroke risk. Metabolic syndrome, as defined by the modi- Metabolic syndrome was less effective at predicting CHD fied NCEP criteria,5 was present in a quarter of the men than the FRS, which is consistent with the 2 recent US (26%) and was associated with significantly increased risk reports showing the syndrome to be less predictive of CHD of CHD, stroke, and DM2, in agreement with results from then the FRS.19,21 In the recent report of the National Heart, other studies.7-19 There have been few prospective stud- Lung, and Blood Institute and American Heart Associa- ies on the relationship between MetS using NCEP crite- tion conference proceedings, analysis of the Framing-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 ham data indicated that no advantage is gained in risk than CHD7,11 and with recent reports from US studies show- assessment by adding the components of MetS to ing the FRS to be a better predictor of CHD than MetS.19,21 the FRS.24 In conclusion, MetS (NCEP definition5) is associated It is not surprising that the FRS is a better predictor with a significant increase in risk of CHD, stroke, and of CHD. Prediction criteria based on MetS alone do not DM2 and is a far stronger predictor of DM2 than of CHD include several well-established risk factors for CHD such and stroke. Although it is inferior to the FRS in predict- as serum total cholesterol level and smoking status. How- ing CHD, MetS identifies people who are predisposed to ever, MetS was a far stronger predictor of DM2 than of either CVD or DM2 and may serve as a simple clinical CHD, as observed in previous studies,7,11 and was a bet- approach to identifying patients for clinical interven- ter predictor of DM2 than was FRS. This is likely due to tion to reduce CVD and DM2 risk. the inclusion of established risk factors for diabetes such as waist circumference (BMI) and high blood glucose lev- Accepted for Publication: August 19, 2005. els (short of diabetes), which are not included in the FRS. Correspondence: S. Goya Wannamethee, PhD, Depart- Exclusion of obesity and high glucose level from the syn- ment of Primary Care and Population Sciences, Royal Free drome score reduced the sensitivity of MetS for DM2 from and University College Medical School, Rowland Hill Street, over 50% to just over 30%. London NW3 2PF, England ([email protected]). Since CVD is more common than DM2, the FRS was Financial Disclosure: None. more sensitive in identifying overall events (CHD, stroke, Disclaimer: The British Regional Heart Study is a Brit- or diabetes), but absolute risk in those with 3 or more ish Heart Foundation Research Group and receives sup- metabolic abnormalities was very high (30%-40% chance port from the Department of Health (England). How- of developing CVD or DM2, comparable to the absolute ever, the views expressed in this publication are those incidence rates in the top 2 quintiles of the FRS distri- of the authors and not necessarily those of the Depart- bution). Thus, MetS is a simple tool that identifies sub- ment of Health (England). jects predisposed to either CVD or DM2.

LIMITATIONS REFERENCES

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