Date post: | 14-Jun-2015 |
Category: |
Health & Medicine |
Upload: | mohamed-badr |
View: | 345 times |
Download: | 2 times |
PBRC 2005
MACROVASCULAR COMPLICATION & DIABETES
PBRC 2005
What Are the Potential Benefits What Are the Potential Benefits of Personalized Medicine?of Personalized Medicine?
Earlier disease protection
Optimize therapeutic selection and dosing
Reduce adverse drug reactions
Increase patient compliance with therapy
Reduce the time, cost, and failure rate of clinical trials by
improving the selection of targets for drug discovery
“Save” therapeutics
Shift the emphasis in medicine from reaction to prevention
Reduce the overall cost of healthcare
PBRC 2005
Tools Needed for Prediction and Personalized Care
Dis
ease
Bur
den
Time
Cos
t
1/re
vers
ibili
ty
Typical Current
Intervention
Earliest Clinical
Detection
Earliest Molecular Detection
Initiating Events
Baseline Risk
Decision Support Tools:
Baseline Risk Preclinical Progression
Disease Initiation and Progression
Assess Risk Refine Assessment Predict/Diagnose Monitor Progression
Predict Events
Inform Therapeutics
Sources of New Biomarkers:
Stable Genomics: Single Nucleotide Polymorphisms (SNPs) Haplotype Mapping Gene Sequencing
Dynamic Genomics: Gene ExpressionProteomics Metabolomics Molecular Imaging
Therapeutic Decision Support
PBRC 2005
Macrovascular complications
PBRC 2005
MACROVASCULAR COMPLICATION
DIABETES
IHDCVD
PVD
Why accelerated
NO Definite Answers
Many factors
Risk factors
Is it preventable or at least delayed
yes
Atherosclerosis: An Inflammatory Disease
III.2© 2002 PPS®
C
PBRC 2005
1. Atherosclerotic lesions Fatty streaks.
Gelatinous plaques. Fibrous plaques.
Complicated plaques.2. Theories of atherogenesis
Lipid hypothesis. Thrombogenetic hypothesis.
Mesenchymal hypothesis. Monoclonal hypothesis.
Response to injury hypothesis.
PBRC 2005
C – Peptide and atherosclerosis
http://www.hindawi.com/journals/mi/2012/858692/
C-peptide protects endothelial cells from apoptosis and inflammation triggered by high glucose conditions [62]. The situation can be totally different in patients with insulin resistance and type 2 diabetes where high levels of C-peptide could have opposite effects.
PBRC 2005
Cardiometabolic Risk
Global Diabetes / CVD Risk
Overweight / Obesity
Inflammation Hypercoagulation
Elevated
Blood Pressure
Smoking
Age, Race, Sex,
Family History
GlucoseBP Lipids
Age Genetics
Insulin Resistance
Abnormal Lipid Metabolism.
LDL or ApoB HDL Triglycerides
PBRC 2005
Prevalence of MeS in different Countries
Country Year Sample Prevalence (%)
Arab Americans 2003 542 23
Oman 2001 1419 21
Jordan 2002 1121 36
Saudi Arabia 2004 2250 20.8
Palestine 1998 17*
Qatar 2007 817 27.6
Turkey 2004 1637 33.4*
Iran ? 10368 33.7
* Crude rates Mussallam et al. Int J Food Safety and PH 2008
PBRC 2005
PBRC 2005
PBRC 2005
What are the clinical outcomes of the metabolic syndrome?
Cardiovascular disease Relative risk = 2x
Type 2 diabetes Relative risk = 5x
Fatty liver Obstructive sleep apnea Cholesterol gallstone Polycystic ovarian disease
PBRC 2005
Definitions of the Metabolic Syndrome
We get a new definition about every 2 years
We now have 7 definitions
No definition has been accompanied by data on
its sensitivity, specificity and positive predictive
value
PBRC 2005
Metabolic Syndrome: Overview
Metabolic Syndrome is not a disease, but rather a cluster of disorders of your body’s metabolism, including:
o High blood pressureo High insulin levelso Excess body weighto Abnormal cholesterol levels
Each of these disorders is by itself a risk factor for other diseases.
In combination, however, these disorders dramatically boost the chances of developing potentially life-threatening illnesses, such as diabetes, heart disease or stroke.
PBRC 2005
What are unresolved questions about the MetS? (Kahn et al. 2005)
Metabolic syndrome name? Existence of metabolic syndrome? More than some of its parts? MetS vs. prediabetes & type 2 diabetes Diagnostic utility? Pathogenesis? Clinical utility?
PBRC 2005
Is the metabolic syndromea “syndrome”?
A collection of things Clustering of signs and symptoms Three or more related entities
PBRC 2005
Plurametabolic syndrome (Crepaldi) Syndrome X (Reaven) Deadly Quartet (Kaplan) Metabolic syndrome (WHO; NCEP: IDF) Insulin resistance syndrome (EGIR; AACE) Dysmetabolic syndrome Cardiometabolic syndrome CHAOS (Australia)
What should the metabolic syndrome be called?
PBRC 2005
What is the metabolic syndrome?
Clustering of
Metabolic Risk Factors (3+) Atherogenic dyslipidemia Elevated blood pressure Elevated plasma glucose Prothrombotic state Proinflammatory state
PBRC 2005
Diagnosing Metabolic Syndrome
Waist Circumference o Greater than 35 inches in women and 40 inches in men (abdominal obesity)
Triglycerideo Levels of 150 milligrams per deciliter (mg/dl) or higher
Blood Pressureo 130/85 millimeters of mercury or higher
Fasting blood glucoseo Level of 110 mg/dl or higher
High-density lipoprotein cholesterol (HDL)o Lower than 50 mg/dl in women and 40 mg/dl for men
According to the National Cholesterol Education Program (NCEP), the presence of three or more of the following traits indicates
metabolic syndrome:
PBRC 2005
ATP III Clinical Identification of the Metabolic Syndrome
Waist circumference: Men>102 cm (>40 in) Women>88 cm (>35 in)
Triglycerides >150 mg/dL HDL cholesterol:
Men<40 mg/dL Women<50 mg/dL
Blood pressure 130/ 85 mm Hg Fasting glucose >110 mg/dL*
* New ADA guidelines suggest >100mg/dl increases risk for Metabolic Syndrome
PBRC 2005
International Diabetes Federation (IDF) Definition
Modified ATPIII definition Fasting Glucose > 100mg/dl Adjusted waist circumference based on ethnicity
(i.e. asians with lower waist circumference threshold than pacific islanders)
PBRC 2005
Clinical Measure
WHO (1998) AACE (2003)AHA/NHLBI
(2005)IDF (2005)
Insulin resistance
IGT, IFG, T2DM, or ins. resist. And 2 of
the below
IGT or IFG. And any of the below. Clinical judgment
None.
3 of the belowNone
ObesityWHR >0.90 in men or >0.85 in women
and/or BMI >30BMI > 25
Waist ≥102 cm in men or ≥88 cm in
women
Waist (population specific).
And any 2 of the below
TG (mg/dl)TG >150 and/or
HDL-C <35 in men or < 39 in women
TG >150 and HDL-C <40 in men or <50 in
women
≥150 or Rx ≥150 or Rx
HDL (mg/dl)<40 in men, <50 in women or Rx
<40 in men, <50 in women or Rx
Blood pressure (mm Hg)
>140/90 > 130/85 mm Hg≥130 or ≥85 or
Rx ≥130 or ≥85 or
Rx
Glucose (mg/dl) IGT, IFG, or T2DMIGT or IFG (not
diabetes)> 100 or Rx > 100 or Rx
Other MicroalbuminuriaOther features of
insulin resistance
PBRC 2005
References
Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). (2)Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.
International Diabetes Federation Insulin-sensitising drugs, The Cochrane Database of
Systematic Reviews Date of last Substantial Update: December 31. 2002
Effects of Rimonabant on Metabolic Risk Factors in Overweight Patients with Dyslipidemia, NEJM. Nov 2005
PBRC 2005
Insulin-resistance and Insulin-resistance and ββ-cell function-cell function
Amiloyd storeAmiloyd store
GlucotoxicityGlucotoxicity(hyperglycemia(hyperglycemia))
Hyper-Hyper-insulinaemiainsulinaemia
ProteinProteinGlycosilationGlycosilation
LipotoxicityLipotoxicity((↑ ↑ FFA e TG)FFA e TG)
Insulin-Insulin-resistanceresistance
⇩⇩ ββ-cell-cell
functionfunction
PBRC 2005
The new IDF definition focusses on
abdominal obesity rather than insulin
resistance
International Diabetes Federation (IDF) Consensus Definition 2005
PBRC 2005
Fat Topography In Type 2 Diabetic Subjects
Intramuscular
Intrahepatic
Subcutaneous
Intra-abdominal
FFA*TNF-alpha*Leptin*IL-6 (CRP)*Tissue Factor*PAI-1*
Angiotensinogen*
PBRC 2005
NEFA
Cytokines(TNF &
IL-6)Adiponectin PAI-1
Leptin Resistin
Angioten-sinogen
Adipose Tissue
Adipose Tissue
MetabolicRisk Factors
ElevatedBlood Pressure
AtherogenicDyslipidemia
ElevatedGlucose
Pro-thrombotic
State
Pro-inflammatory
State
How does obesity contribute to MetS?
PBRC 2005
Diabetes Obesity
Dia Besity
DiabesityUp–regulation of adiponectin and its receptor, through the use of
thiazolidinediones, has been found to be partially related to insulin sensitization and thus antidiabetic effects.
PBRC 2005
Abdominal obesity and increased risk of cardiovascular events
Dagenais GR et al, 2005
Ad
just
ed r
elat
ive
risk
1 1 1
1.17 1.16 1.14
1.29 1.27
1.35
0.8
1
1.2
1.4
CVD death MI All-cause deaths
Tertile 1
Tertile 2Tertile 3
Men Women<95
95–103>103
<87
87–98>98
Waistcircumference (cm):
The HOPE study
Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-cholesterol, total-C; CVD: cardiovascular disease; MI: myocardial infarction; BMI: body mass index; DM: diabetes mellitus; HDL: high-density lipoprotein cholesterol
PBRC 2005
Abdominal obesity increases the risk of developing type 2 diabetes
<71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 >96.3
24
20
16
12
8
4
0
Rel
ativ
e ri
sk
Waist circumference (cm)
Carey VJ et al, 1997
PBRC 2005
Abdominal obesity is linked to an increased risk of coronary heart disease
Waist circumference has been shown to be independently associated with increased age-adjusted risk of CHD, even after
adjusting for BMI and other cardiovascular risk factors
0.0
0.5
1.0
1.5
2.0
2.5
3.0
<69.8 69.8<74.2 74.2<79.2 79.2<86.3 86.3<139.7
1.27
2.06 2.31
2.44p for trend = 0.007
Rel
ativ
e ri
sk
Quintiles of waist circumference (cm)
Rexrode KM et al, 1998
CHD: coronary heart disease; BMI: body mass index
PBRC 2005
QUALITY IMPROVEMENT & ASSURANCE
CONSENSUS GUIDELINES EVIDENCE BASED MEDICINE PERSONALIZED MEDICINE
PBRC 2005
MS Excel Program for Risk AssessmentFrom The Framingham Heart Study Enter Values HereCHD(MI and Coronary Death) Risk Prediction National Cholesterol Education Program Adult Treatment Panel III
Risk Factor Units
(Type Over Placeholder Values in
Each Cell) NotesGender male (m) or female (f) M Age years 52 Total Cholesterol mg/dL 220 HDL mg/dL 45 Systolic Blood Pressure mmHg 146 Treatment for Hypertension {Only if SBP>120} yes (y) or no (n) N Current Smoker yes (y) or no (n) Y
Time Frame for Risk Estimate 10 years 10
Your Risk (The risk score shown is derived on the basis of an equation. Other NCEP materials, such as ATP III print products, use a point-based system
to calculate a risk score that approximates the equation-based one.)0.17 17%
Tables for Graph
If value is < the minimum for the field, enter the minimum value. If value is > the maximum for the field, enter the maximum value.
These functions and programs were prepared by Ralph B. D'Agostino, Sr., Ph.D. and Lisa M. Sullivan, Ph.D., Boston University and The Framingham Heart Study and Daniel Levy, M.D., Framingham Heart Study, National Heart, Lung and Blood Institute.
0.17
0.04
0.02
0.00 0.05 0.10 0.15 0.20 0.25 0.30
Your Risk Estimate, Comparative Risks for Lowest = Total Chol<160, HDL>60, Optimal SBP (<120), No Trt for Htn, Non-Smoker Same Age and Gender Low = Total Chol 160-199, HDL 50-59, Normal SBP (<130), No Trt for Htn, Non-Smoker
PBRC 2005
TargetingTargeting
Cardiometabolic RiskCardiometabolic Risk
PBRC 2005
Six Aims for Improvement
Safe – avoiding injuries to patients from the care that is intended to help them.
Effective – providing services based on scientific knowledge to all who could benefit and refraining from providing services to those not likely to benefit (avoiding underuse and overuse)
Patient-centered – providing care that is respectful of and responsive to individual patient preferences, needs and values and ensuring that patients values guide all clinical decisions.
Timely – reducing waits and sometimes harmful delays for both those who receive and those who give care.
Efficient – avoiding waste, including waste of equipment, supplies, ideas and energy.
Equitable – providing care that does not vary in quality because of personal characteristics such as gender, ethnicity, geographic location, and socio-economic status.
PBRC 2005
Global cardiometabolic risk*
Gelfand EV et al, 2006; Vasudevan AR et al, 2005* working definition
PBRC 2005
Intensive therapyIntensive therapyAggressive Aggressive
TTOTTOMaximum TherapMaximum Therap
dosedose
PBRC 2005
Public Health Public Health ApprachApprach
PBRC 2005
Diabetes prevention
PBRC 2005
Public Education Screening for at risk individuals:
Blood Sugar/ HbA1cLipidsBlood pressureTobacco useBody habitusFamily history
Screening/Public Health ApproachScreening/Public Health Approach
PBRC 2005
Prevention of type 2 diabetesBefore people develop type 2 diabetes, they almost always have "pre-diabetes" -- blood glucose levels that are higher than normal but not yet high enough to be diagnosed as
diabetes
Take our diabetes risk test to see if you are at risk for developing diabetes. Diabetes is more common in African Americans, Latinos, Native Americans, Asian Americans and Pacific Islanders.
is a powerful new risk assessment tool. It can be used to explore the effects of a wide variety of health care interventions, including losing weight, stopping smoking, and taking certain medications.
Diabetes Prevention Program study conclusively showed that people with pre-diabetes can prevent the development of type 2 diabetes by making changes in their diet and increasing their
level of physical activity.
Keeping an eye on these risk factors -- keeping them "in check" -- can help you prevent diabetes and heart disease.Keeping an eye on these risk factors -- keeping them "in check" -- can help you prevent diabetes and heart disease.
PBRC 2005
PREVENTION AND MANAGEMENT OFDIABETES COMPLICATIONS
PBRC 2005
Lifestyle modification
Diet Exercise Weight loss Smoking
cessation
If a 1% reduction in HbA1c is achieved, you could expect a
reduction in risk of:• 21% for any diabetes-related
endpoint• 37% for microvascular
complications• 14% for myocardial infarction
However, compliance is poor and most patients will require oral pharmacotherapy within a few years of diagnosis
Stratton IM et al. BMJ 2000; 321: 405–412.
PBRC 2005
WEIGHT LOSSWEIGHT LOSS = =⇩⇩ INSULININSULIN--RESISTANCERESISTANCE
PBRC 2005
WEIGHT LOSS: HOW?WEIGHT LOSS: HOW?
PBRC 2005
Weight loss may be obtained Weight loss may be obtained through:through:
• Therapeutic lifestyle changeTherapeutic lifestyle change
• Drug therapyDrug therapy (if Therapeutic lifestyle change is not sufficient)(if Therapeutic lifestyle change is not sufficient)
• Bariatric surgery Bariatric surgery (in selected cases; to estimate the risk/benefit ratio)(in selected cases; to estimate the risk/benefit ratio)
PBRC 2005
glycemia ed insulinaemiaglycemia ed insulinaemia
HbAHbA1C1C
VLDL and triglycerides VLDL and triglycerides
HDL-cholesterolHDL-cholesterol
blood pressureblood pressure
microalbuminuriamicroalbuminuria..
EFFECTIVE LONG TERM WEIGHT LOSS:EFFECTIVE LONG TERM WEIGHT LOSS:ACHIEVABLE OBJECTIVES and HEALTH BENEFITS ACHIEVABLE OBJECTIVES and HEALTH BENEFITS
PBRC 2005
STANDARDS OF MEDICAL CARESTANDARDS OF MEDICAL CAREIN DIABETES ADAIN DIABETES ADA
PBRC 2005
ADA Evidence Grading System for Clinical ADA Evidence Grading System for Clinical RecommendationsRecommendations
Level of Level of EvidenceEvidence DescriptionDescription
A Clear or supportive evidence from adequately powered well-conducted, generalizable, randomized controlled trials
Compelling nonexperimental evidence
B Supportive evidence from well-conducted cohort studies or case-control study
C Supportive evidence from poorly controlled or uncontrolled studies
Conflicting evidence with the weight of evidence supporting the recommendation
E Expert consensus or clinical experience
ADA. Diabetes Care 2011;34(suppl 1):S12. Table 1.
PBRC 2005
Recommendations: Glycemic, Blood Pressure, Recommendations: Glycemic, Blood Pressure, Lipid Control in AdultsLipid Control in Adults
A1C <7.0%* 6.5
Blood pressure <130/80 mmHg†
LipidsLDL cholesterol <100 mg/dl (<2.6
mmol/l)‡
*More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on: duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations.
†Based on patient characteristics and response to therapy, higher or lower systolic blood pressure targets may be appropriate.
‡In individuals with overt CVD, a lower LDL cholesterol goal of <70 mg/dl (1.8 mmol/l), using a high dose of statin, is an option.
ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S31. Table 12.
PBRC 2005
J Am Coll Cardiol. 2012;60(14):1231-1238. doi:10.1016/j.jacc.2012.05.019
Clinical Research | October 2012 Statins, Risk of Diabetes, and Implications on Outcomes in
the General Population Kang-Ling Wang, MD; Chia-Je
Conclusions Risk of diabetes was increased after statins, but outcomes were favorable.
PBRC 2005
Diabetes. 2012 Feb;61(2):463-73.
Silence of TRIB3 suppresses atherosclerosis and stabilizes plaques in diabetic ApoE-/-/LDL receptor-/- mice.
Toll-like receptor (TLR)4TLR4 antagonist inhibited vascular inflammation and atherogenesis in diabetic apoE-/- mice and lowered serum cholesterol and triglyceride levels in non-diabetic apoE-/- mice.
PBRC 2005
A Critical Look at the A Critical Look at the Metabolic Syndrome Metabolic Syndrome
Is it a Syndrome?*Is it a Syndrome?* “…too much clinically important information is
missing to warrant its designations as a syndrome.”
Unclear pathogenesis, Insulin resistance is not a consistent finding in some definitions.
CVD risks has not shown to be greater than the sum of it’s individual components.
*ADA
PBRC 2005
A Critical Look at the A Critical Look at the Metabolic SyndromeMetabolic Syndrome
PBRC 2005