The Metabolic Syndrome: Is It A Valid Concept? YES Congress on Diabetes and Cardiometabolic Health Boston, MA April 23, 2013 Edward S Horton, MD Joslin Diabetes Center Harvard Medical School Boston, MA
Global Projections for the Diabetes Epidemic: 2011 2030 World 2011 = 366 M 2030 = 552 M >51% NAC 37.7 M 51.2 M 36% SACA 25.1 M 39.9 M 59% EUR 52.8 M WP 64.2 M MENA SEA 22% 112.8 M AFR 14.7 M 28.0 M 90% 32.6 M 59.7 M 83% 71.4 M 121 M 69% 187.9 M 60% 2011 2030 M = million, AFR = Africa, NAC = North America and Caribbean, EUR = Europe, SACA = South and Central America, MENA = Middle East and North Africa, SEA = South-East Asia, WP = Western Pacific Diabetes Atlas Committee. Diabetes Atlas 5th Edition: IDF 2011.
Obesity Is the Primary Risk Factor for Type 2 Diabetes 50 40 Age-adjusted relative risk of type 2 diabetes 42 100 Men 1 Women 2 75 93 30 50 40 20 12 25 10 2.2 8.1 1.0 1.0 0 0 <23 25 31 35 <22 25 31 35 BMI 1 Chan JM et al. Diabetes Care 1994;17:961-969; 2 Colditz G et al. Ann Intern Med 1995;122:481-486.
Age adjusted Percentage of U.S. Adults with Obesity or Diagnosed Diabetes Obesity (BMI 30 kg/m 2 ) O BE 1994 2000 2009 S I T Y Diabetes D IA No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0% 1994 2000 2009 B ET E S No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics
The Dual Epidemic: Obesity and Diabetes 65% of adult Americans are overweight (BMI >25) and 32% are obese (BMI >30). 34% have the Metabolic Syndrome (ATP III criteria). There are now an estimated 25.8 million people with DM in the USA (11.3% of adults) and 79 million with prediabetes (IFG/IGT). The lifetime risk of developing DM for people born in 2000 is 33% for men and 39% for women. In this population CVD is the major cause of mortality.
Mortality in People With Diabetes: 50 Causes of Death 40 % of deaths 30 20 10 0 Ischemic heart disease Other heart disease Diabetes Cancer Stroke Infection Other Geiss LS et al. In: Diabetes in America. 2nd ed. 1995; chap 11.
Diabetes and CVD Risk in Framingham Cohort Age 35 64 Years: 30-Year Follow-up 10 P<0.001 P<0.001 Risk Ratio 8 6 4 Men Women P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 2 P<0.001 P<0.05 0 CHD Stroke Intermittent. Claudication Cardiac Failure CVD Total Wilson. Am J Kidney Dis. 1998;32(5 Suppl 3):S89-100..
Factors Implicated in Macrovascular Disease in Type 2 Diabetes Dyslipidemia Hypertension Nephropathy Obesity/sedentary lifestyle Altered coagulation, platelet function, and fibrinolysis Hyperinsulinemia/hyperproinsulinemia/insulin resistance Cigarette smoking Hyperglycemia Inflammation Modified from Bierman EL. Arterioscler Thromb. 1992;12:647-656.
MRFIT: Cholesterol and CVD Mortality in Men With Type 2 Diabetes Age-Adjusted CVD deaths per 10,000 person-years 150 100 50 0 Controls Type 2 diabetes 92 85 62 29 20 14 <180 200-220 240-260 Plasma cholesterol (mg/dl) 46 130 280 Stamler et al. Diabetes Care. 1993;16:434-444.
Glycemia in Relation to Microvascular Disease and MI Incidence per 1,000 patient-years 80 60 40 20 MI Microvascular disease UKPDS 35. BMJ 2000;321:405 12 0 0 5 6 7 8 9 10 11 Updated mean HbA 1C (%)
DECODE: Mortality Rate Increases With Increasing 20 15 2-Hour Glucose (63/432) 15 (325/2766) 12 (146/909) 16 Mortality (%) 10 5 (1172/18,252) 6 0 Fasting glucose: <6.1 <7.0 (Not DM) <7.0 (Not DM) 7.0 (DM) 2-h glucose: <7.8 7.8 11.0 (IGT) 11.1 (DM) 11.1 (DM) (mmol/l) DECODE = Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe. Adapted from DECODE Study Group. Lancet. 1999;354:617-621.
What is a Syndrome? 1. A group of signs and symptoms that occur together and characterize a particular abnormality. 2. A set of concurrent things that usually form an identifiable pattern Ref. Merriam Webster s Collegiate Dictionary, 10 th Edition, 1997
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The Insulin Resistance Syndrome Physical Inactivity Obesity (esp. Abdominal Obesity) Insulin Resistance Aging Atherogenic Dyslipidemia Elevated Blood Pressure Modified from S. Grundy MD Genetic Variation In CVD Risk Factor Regulation Hyperglycemia Proinflammatory State Prothrombotic State
How do we identify people clinically who have insulin resistance and increased CVD risk?
Metabolic Syndrome ATP III (3 of 5) Atherogenic Dyslipidemia Obesity (esp. Abdominal Obesity) TG 150 mg/dl HDL-C < 40 mg/dl (M) < 50 mg/dl (F) Elevated BP BP 130/85 mm Hg Waist Circumference Men: 102 cm (40 in) Women: 88 cm (35 in) Genetic Variation in CVD Risk Factor Regulation Insulin Resistance Proinflammatory State Prothrombotic State Fasting Glucose 100 mg/dl *(modified)
IDF Criteria: Obesity + 2 Others Atherogenic Dyslipidemia Obesity Waist (esp. Abdominal Circumference Obesity) Men: > 94 cm (37 in) Women: > 80 cm (31.5 in) TG> 150 mg/dl HDL-C < 40 mg/dl (M) < 50 mg/dl (F) Elevated BP BP > 130/85 mmhg (Population Specific) Genetic Variation In CVD Risk Factor Regulation Insulin Resistance Fasting Glucose >100 mg/dl Proinflammatory State Prothrombotic State
Metabolic Syndrome as a Precursor of CVD and DM2: The Framingham Offspring Study 1163 men and 1386 women, age 22-81, with no CVD or DM2 at baseline exam (1989-1993),f/u @ 4 & 8 yrs. Age-adjusted Prevalence of Metabolic Syndrome (modified ATP III criteria: FBG 100-125mg/dl) Men: Baseline 21.4% 8 Yr f/u 33.9% 56% increase Women: 12.5% 23.6% 47% increase Compared to those without Met Synd, those with Met Synd also had higher total and LDL Cholesterol and women had a higher rate of cigarette smoking Wilson, PWF et al. Circulation 2005;112:3066-3072
Frequency of Risk Factors in Absence or Presence of Metabolic Syndrome Men Metabolic Syndrome Metabolic Syndrome Absent Present Waist >102 cm 14% 64% TG >150 mg/dl 15% 72% HDL-C <40 mg/dl 23% 78% BP >130/85 mmhg 43% 91% FBG 100-125 mg/dl 11% 43% Women Waist >88 cm 11% 78% TG >150 mg/dl 6% 65% HDL-C <50 mg/dl 27% 85% BP >130/85 mmhg 34% 89% FBG 100-125 mg/dl 5% 41% Wilson PWF et al. Circulation 2005; 112:3066-3072
Men RR Age-Adjusted Signif. CVD 2.88 (1.99 4.16) <0.0001 Hard CHD 2.56 (1.46 4.57) 0.0001 Total CHD 2.54 (1.62 3.98) <0.0001 DM2 6.93 (4.47 10.81) <0.0001 Women The Framingham Offspring Study Metabolic Syndrome and Age-Adjusted Risk for CVD and DM2 at 8 Years CVD 2.25 (1.31 3.88) 0.0034 Hard CHD 2.50 (0.80 7.79) 0.1151 Total CHD 1.54 (0.68 3.53) 0.3038 DM2 6.90 (4.35 10.94) <0.0001 Wilson, PWF et al. Circulation. 2005;112:3066-3072.
Metabolic Syndrome Increases Risk for CHD and Type 2 Diabetes High LDL-C Metabolic Syndrome Type 2 Diabetes Coronary Heart Disease Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
Prevalence of Metabolic Syndrome in IGT & Diabetes IGT: 53% at baseline in the Diabetes Prevention Program Type 2 Diabetes: 65-85% in various studies
Multifactorial Intervention and Treatment Goals in Type 2 Diabetes: Steno-2
Multifactorial Intervention and CV Events in Type 2 Diabetes: Steno-2 50% RR
What can we learn from the Diabetes Prevention Program? About the prevalence and prevention of the Metabolic Syndrome in people with IGT? About the effect of the DPP interventions on the reduction of CVD risk?
Prevalence of Metabolic Syndrome at Randomization 1711 (53%) of the 3234 participants had the syndrome at randomization Prevalence of the syndrome did not vary by gender or age group (<45, 45 64, 65+ years) Prevalence did vary by ethnicity, being lowest in Asians (41%) and highest in Caucasians (57%) Prevalence of the individual components did vary by ethnicity and by age group
Cumulative Incidence of Metabolic Syndrome by Treatment Group Cumulative Incidence of Metabolic Syndrome (%) 0.75 0.60 0.45 0.30 0.15 Risk reduction: 17%* by Metformin 41% # by Lifestyle Lifestyle vs Metformin 29% # Placebo Metformin Lifestyle 0.00 *p < 0.05; # p < 0.001 0 1 2 3 4 Year from Randomization
Other Key Findings HTN was present in 30% of subjects at baseline; over 3 years it increased in the placebo and metformin groups, but significantly decreased in the ILS group TG decreased in all groups, but fell significantly more in ILS group ILS significantly increased HDL-C and decreased LDL Phenotype B After 3 yrs the use of medications to achieve targets for HTN was 27 28% less and for dyslipidemia was 25% less in the ILS group
3-Year Incidence (%) of Components by Treatment Group Placebo Metformin Lifestyle Waist Circ. 33 15* 8* Low HDL-C 70 67 68 High Trig. 27 30 18* High FPG 40 29* 28* High BP 41 44 35* *p<0.001, comparison vs placebo
Effects of DPP Interventions on Reversal of the Metabolic Syndrome Placebo: reversal at 3.2 yrs 18% Metformin: " 23% Lifestyle: " 38% Overall prevalence of MS at 3.2 yrs Placebo: 61% +6% from baseline Metformin: 55% +2% " " Lifestyle: 42% -9% " "
Other Key Findings Mean baseline hscrp (5.9 mg/l) was increased in all groups and was higher in women than in men (median 4.9 vs 1.9 mg/l). Baseline hscrp correlated with BMI, waist circumference, FPG, and HOMA-IR. After 1 year the median change was: men: Placebo +5%, Met -7%, ILS -33% women: 0% -14% -29% The changes correlated mainly with weight loss and not with physical activity
Summary There is an epidemic of diabetes that is associated with lifestyle changes and obesity. The metabolic syndrome and IGT are more prevalent than diabetes. The metabolic syndrome and IGT are known risk factors for both type 2 diabetes and cardiovascular disease. Both lifestyle modification and medications are effective in preventing, delaying and treating type 2 DM and in reducing CVD risk factors.
My Conclusions YES-The Metabolic Syndrome is a useful clinical tool to identify people at high risk for type 2 diabetes and CVD The presence of one or more of the individual components of the Metabolic Syndrome should alert the clinician to check for and treat other related CVD risk factors A Global Approach to the treatment of diabetes must be the standard of care.
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