The short term effects of metabolic syndrome and its components on all-cause-cause mortality-the Taipei Elderly Health Examination Cohort Wen-Liang Liu Taipei City Hospital, Taipei, Taiwan

Background Kylin 1923, multiple risk factors related to DM and hypertension Syndrome X, Insulin resistance syndrome, Insulin resistance syndrome Risk factors such as hypertension, dyslipidemia, obesity, and insulin resistance have been extensively studied in young adults Reverse metabolic syndrome – The significance of these risk factors in the very old remains a subject of debate Survival benefit of metabolic syndrome MS: a time-dependent variable

Selective studies reported the assocaition between metabolic sybdrome and all- cause mortality Author Year PublishedCountryNMean age Follow-up PeriodHRRemark Pavaglia2006Italy (45-97)41.51(MI) Vischer2009France Reverse MetS Chiang2012Taiwan ( )Survival benefit Maralani2012Australia3, ( ≧ 49) ( ) 1.06( ) 1.23( ) Time-dependent association Bulter2006USA3, (N.S.) Thomas GN 2007Hong Kong 2, ( ) Tsai SP2008USA35,25 9 ≧ ( ) Wen CJ2008Taiwan10,54 7 > ( ) Sun DL2012China1, ( ) Luksiene2012Lithuania2, ( )

Implications from those studies Reverse metabolic syndrome – The significance of these risk factors in the very old remains unclear Survival benefit of MS in the elderly was observed in a short term period (<=4 years) Those studies involved a small sample size

Hypothesis The short term effect of MetS on all-cause mortality might be associated with a low risk of mortality The individual components of MetS might have different impacts on all-cause mortality and might modify the association

Purposes of the study To examine the impact of metabolic syndrome itself on all-cause mortality in the elderly population To explore the effects of individual components of MetS on all-cause mortality with a large sample size To evaluate the influence of individual components on the association between MetS and mortality

Methods Design: prospective study Study subjects: participants of the Taipei City Free Health Examination for the Elderly in ,686 elderly persons agreed to participate in the study and be followed up until December 31m2010 A structured questionnaire was designed to collect participants’ demographic, disease history, lifestyle factors Fasting blood sample were measured by an automated analyzer and to evaluate the blood biochemical indicators

Metabolic syndrome definition The National Cholesterol Education Program (NECP) Adult Treatment Panel III Guideline and modified by International Diabetes of Federation for Chinese Specially Metabolic syndrome: having any three of the following risk factors – Fasting glucose level >=100 mg/dL – Serum triglyceride level>=150 mg/dL – HDL-C level <40 mg/dL for male and <50 mg/dL for female – Systolic blood pressure >=130 mmHg or diastolic pressure>=85 mg/dL – Waist circumference >=90 for male and >=80 for female

Outcome variables All-cause mortality and CVD mortality Death records from National Mortality Registry – ICD9 for cause of death – Date of death – Basic information

Statistical analysis Continuous variable expressed as mean and standard deviation (Mean ±SD) Comparisons between continuous variables were performed by Student’s t-test Chi square test was used to evaluate the association between variables Cox proportional hazard model was used to evaluate the impact of MetS and its components on all-cause mortality All analysis were performed using SAS 9.3

Results 40,686 elderly persons participated in this study 15,775 (38.8%) persons were defined as having MetS 2,414 people died from all-cause within a mean follw-up period of 3.3 years Among those deceased, 526 (21.5%) were attributed to cardiovascular disease

Table 1: Baseline characteristic of study population Variables Overall cohort (N=40668) Age(yrs)74.91±6.34 Body mass index (Kg/M 2 )24.16±3.20 Height (cm)158.81±8.23 Weight (Kg)61.02±9.91 Waist circumference (cm)85.26±9.38 Systolic blood pressure (mmHg)135.67±18.80 Diastolic blood pressure (mmHg)75.41±11.10 Fasting blood sugar (mg/dL)104.63±22.67 Serum HDL-C (mg/dL)52.60±13.41 Serum total cholesterol (mg/dL)195.47±34.03 Serum triglyceride (mg/dL)121.54±62.50 Mean observation period (yrs)3.30±0.42

Table 1: Baseline characteristic of study population Variables% Gender (male %)53.62 Hypertension (5)42.24 Diabetes mellitus (%)11.80 Smoking (%)7.49 Alcohol drinking (%)19.28 Exercise (%)61.27 Medication use (%) Anti-hypertensive (%)42.66 Anti-diabetic agents (%)12.26 Lipid-lowering drugs (%)6.45 Metabolic syndrome (%)38.79 Central obesity (%)50.78 High plasma glucose (%)47.49 High blood pressure (%)63.13 High serum triglyceride (%)25.37 Low HDL-C (%)30.42 All-cause mortality (%)5.27 Cancer (%)0.58 Cardiovascular disease0.42

Table 2: Characteristics of the study cohort by metabolic syndrome status at baseline MetS(-) (N=24893) MetS(+) (N=15775) t-test p-value Age(yr)73.83± ± Body mass index(kg/m 2 )23.15± ±2.95< Height(cm)158.30± ±8.34< Weight(kg)58.84± ±9.68< Waist circumference(cm)82.28± ±8.12< Systolic blood pressure(mg/dl)131.50± ±17.17< Diastolic blood pressure(mg/dl)73.71± ±10.96< Fasting plasma glucose(mg/dl)98.18± ±27.01< Serum HDL-C(mg/dl)56.77± ±310.93< Serum total cholesterol(mg/dl)195.30± ±35.05< Serum Triglyceride(mg/dl)97.13± ±69.65<0.0001

Table 2: Characteristics of the study cohort by metabolic syndrome status at baseline Mortality(-) N=38524 Mortality(+) N=2144 x 2 -test p-value Sex (male %) < Hypertension (%) < Diabetes mellitus (%) < Smoking (%) < Alcohol drinking (%) < Exercise (%) < Medication use (%)< Anti-hypertensive (%) < Anti-diabetic agents (%) < Lipid-lowering drugs (%) < Metabolic syndrome (%)< Central obesity (%) < High blood pressure (%) < High plasma glucose (%) < High serum triglyceride (%) < Low HDL-C (%) < All-cause mortality (%) < Cancer (%) Cardiovascular disease (%)

Table 3. Comparisons of cardio-metabolic characteristics between study subjects who died or survived in the follow-up period ( ) Mortality (-) N=38524 Mortality (+) N=38524 t-test p-value Age (yrs)74.62± ±6.98< Body mass index24.22± ±3.53< Height (cm)158.80± ±8.40< Weight (Kg)61.14± ±10.58< Waist circumference (cm)85.28± ± Systolic blood pressure (mmHg)135.70± ± Diastolic blood pressure (mmHg)75.50± ±12.04< Fasting blood sugar (mg/dL)104.60± ± Serum HDL-C (mg/dL)52.75± ±13.64< Serum total cholesterol (mg/dL)196.10± ±35.89< Serum triglyceride (mg/dL)122.00± ±59.46<0.0001

Table 3. Comparisons of cardio-metabolic characteristics between study subjects who died or survived in the follow-up period ( ) Variables Mortality (-) N=38524 Mortality (+) N=38524 Chi suare p-value Gender (male %) < Hypertension (5) Diabetes mellitus (%) Smoking (%) < Alcohol drinking (%) < Exercise (%) < Medication use (%) Anti-hypertensive (%) Anti-diabetic agents (%) < Lipid-lowering drugs (%) Metabolic syndrome (%) Central obesity (%) < High plasma glucose (%) High blood pressure (%) High serum triglyceride (%) < Low HDL-C (%) <0.0001

Table 4: Association between and all-cause mortality- modified by single component of MetS HR95% CI of HR Unadjusted model MetS Central obesity Tryglyceride Low HDL Hypertension Fasting blood sugar Single components added into the model (HR for MetS) HR95% CI of HR Central obesity Tryglyceride Low HDL Hypertension Fasting blood sugar

Table 5: Risk factors for all-cause mortality-Cox regression model LevelHR 95% C.I. of HR P-value Metabolic syndromeYes vs No SexMale < Age(yr) < High serum triglyceride(mg/dL) ≧ High serum total cholesterol (mg/dL) ≧ < Diabetes Mellitus(mg/dL)> < Hypertension(mmHg)140/ Central obesity(cm)>80(female),>90(male) < SmokeYes vs. No < Alcohol drinking Often vs. none Occasionally vs none < Exercise Often vs non- /occasionally <0.0001

Table 6: Risk factors for CVD mortality -Cox regression model LevelHR95% C.I. of HRP-value Metabolic syndromeYes vs No SexMale Age(yr) < High serum triglyceride(mg/dL) ≧ High serum total cholesterol (mg/dL) ≧ Diabetes Mellitus (mg/dL)> Hypertension (mmHg)140/ Central obesity (cm) >80(female), >90(male) Low HDL-C (mg/dL) <50(female)/ <40(male) SmokeYes vs. No Alcohol drinking Often vs. none Occasionally vs none Exercise Often vs. non- /occasionally <0.0001

Conclusions MetS had a survival benefit in the elderly in this four year follow-up study Its survival effects mainly explained by higher triglyceride had larger waist circumference and strengthened by controlling for HDL-C High triglyceride level and a larger waist decreased mortality risk, and low-HDL-C had a greater mortality risk

Conclusions Weight loss may pose a high mortality risk in older people, and MetS was sensitive to weight change implying that non-MetS subjects might have experienced certain weight loss to a higher mortality The reverse metabolic syndrome proposed by Vischer, featured by low BMI. Low DBP, low total and HDL-C, might be associated with mortality in the elderly people Several epidemiologic studies had reported that lower serum cholesterol, triglyceride and DM increased all- cause mortality; suggesting the potential adverse impact of malnutrition