vascular protection in dm
DESCRIPTION
Vascular Protection in DM. Dr. R. V. S. N. Sarma., M.D., M.Sc., (Canada) Consultant Physician and Chest Specialist. www.drsarma.in. What types of lesions cause MI ?. Coronary stenosis severity prior to MI. 100. 100. 14%. 80. 80. 18%. 60. 60. 68%. Coronary stenosis (%). 40. 40. - PowerPoint PPT PresentationTRANSCRIPT
Dr. R. V. S. N. Sarma., Dr. R. V. S. N. Sarma., M.D., M.Sc., M.D., M.Sc., (Canada)(Canada)
Consultant Physician and Chest Consultant Physician and Chest SpecialistSpecialist
www.drsarmwww.drsarma.ina.in
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What types of lesions cause MI ?
Falk E, et al. Circulation. 1995;92:657-671.
100100
8080
6060
4040
2020
00
14%14%
18%18%
68%68%
All fourAll fourstudiesstudies
50%-70%<50% >70%
100100
6060
4040
2020
00AmbroseAmbrose
19881988LittleLittle19881988
NobuyoshiNobuyoshi19911991
GiroudGiroud19921992
Cor
onar
y st
enos
is (
%)
Cor
onar
y st
enos
is (
%)
Coronary stenosis severity prior to MICoronary stenosis severity prior to MI
8080
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What types of lesions cause MI ?
Falk E, et al. Circulation. 1995;92:657-671.
100100
8080
6060
4040
2020
00
14%14%
18%18%
68%68%
All fourAll fourstudiesstudies
50%-70%<50% >70%
100100
6060
4040
2020
00AmbroseAmbrose
19881988LittleLittle19881988
NobuyoshiNobuyoshi19911991
GiroudGiroud19921992
Cor
onar
y st
enos
is (
%)
Cor
onar
y st
enos
is (
%)
Coronary stenosis severity prior to MICoronary stenosis severity prior to MI
8080
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Eastman RC, Keen H. Lancet 1997;350 Suppl 1:29-32.
CV Risk Factors in Diabetes
3.2
2.3
6.5
10.0
0
2
4
6
8
10
12
Microalbuminuria Smoking Diastolic BP Cholesterol
Od d
s R
a tio
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Causes of death in Diabetes
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Why is it so ?Why is it so ?
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DM – Strongest RF for CVD
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Years after DM Diagnosis
≤ 2 3-5 6-9 10-14 15+
15%
21%24%
29%
48%
Harris, S et al.; Type 2 Diabetes and Associated Complications in Primary Care in Canada: The Impact of Duration of Disease on Morbidity Load. CDA 2003.
Duration of T2DM and CVD
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Duration of DM - CV Mortality
0
0.5
1
1.5
2
2.5
3
3.5
4
< 5 6 to 10 11 to 15 16 to 25 26 +
Duration of Diabetes (years)
p for trend <0.001
Cho, et al. J Am Coll Card 2002:40:954.
Rel
ativ
e R
isk
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Life Expectancy with Diabetes
Hux JE, et al. Diabetes in Ontario, an ICES Practice Atlas 2003.
0102030405060708090
Men Women
YearsDMNo DM
0200400600800
1000120014001600
Mortality rate/100,000
DiabetesNo Diabetes
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Cardiovascular Disease and T2DM
Hux JE, et al. Diabetes in Ontario, an ICES Practice Atlas 2003.
0%
5%
10%
15%
20%
Hypertension Heart Disease
Pre
vale
nce
of C
V D
isea
se
Diabetes
No Diabetes
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Clinical Outcome for Diabetes
4-year Follow-up
0
2
4
6
8
10
12
14
CV Death MI Stroke Dialysis
%
HOPE / MICRO-HOPE. Lancet 2000;355:253.
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ACS and Diabetes – Up to 1 Year
% o
f pa
tient
s
1.83.9
7.1
8.9 7.9
14.4 14.1
21.3
P<0.0001
P=0.035
P<0.0001
P<0.0001
0
5
10
15
20
25
In-Hospital
Mortality
Non-fatal MI 1-y All-Cause
Mortality
1-y
Mortality/MI
N = 3429
N = 1149
No Diabetes
Diabetes
Yan R, et al. Can J Cardiol 2003;19(suppl A):260A.
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OASIS Study: Total Mortality
3 6 9 12 15 18 21 24
0.25
0.20
0.15
0.10
0.05
0.0
Months
Eve
nt
rate
RR = 2.88 (2.37-3.49)
RR=1.99 (1.52-2.60)
RR=1.71 (1.44-2.04)
RR=1.00
Malmberg K, et al. Circulation 2000;102:1014–1019.
Diabetes/CVD +, (n = 1148)
No Diabetes/CVD +, (n = 3503)
Diabetes/CVD -, (n = 569)
No Diabetes/CVD -, (n = 2796)
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Predictors of CV Risk in DM
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DM = CAD - Because• CVD is responsible for 60 - 75% of mortality in T2DM
• CVD is 4 times more prevalent in diabetes; CADI is more
• CVD prevalence increases with age, so is T2DM
• CVD in DM is often severe, silent, poor prognosis and fatal
• Diabetes ↑ mortality, 50% pre adm / recurrent MI and ACS
• Diabetes erases the protection conferred to women
• At diagnosis of T2DM, most patients have evidence of CVD
• Abnormal Glucose tolerance is a strong CV Risk factor
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How to interpret ?How to interpret ?
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Lipoproteins
CTG
B 100 + E +C
CTG
B 100
CTG
A I, A II
HDL LDL
VLDL
TG
B 48+E+C
CM
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Apolipoprotein BApolipoprotein BNon-HDL-CNon-HDL-C
MeasurementsMeasurements
TG rich particlesTG rich particles
VLDLVLDL VLDLRVLDLR IDLIDL LDLLDL SDLSDL
Atherogenic Particles
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Cholesterol richCholesterol rich
The Good, Bad, Ugly and Deadly
• Total Cholesterol < 200 • ‘Good’ Cholesterols (HDL)
– HDL 1, HDL 2, HDL 3 > 50• ‘Bad’ Cholesterols (Non HDL) < 150
– LDL, IDL < 100– VLDL, VLDL-R < 30– Lp(a), Small LDL < 20
HDL 1 and HDL 2 are protective
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Various Sub Types
• LDL Sub types – (Seven subtypes as of now)– LDL 1– LDL 2a, 2b– LDL 3a, 3b– LDL 4a, 4b
• HDL Sub Types(Six sub types as of now)– HDL 1– HDL 2a, 2b– HDL 3a, 3b, 3c
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Today’s Safer ValuesTotal Cholesterol < 200
Triglycerides < 150
LDL Cholesterol < 100 preferably < 70
HDL Cholesterol > 50 (for women 55)
Bad Cholesterols the lower the better
Good Cholesterols the higher the better
Non HDL Cholesterol < 130
Lp(a) values < 20
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What are the What are the Mechanisms ?Mechanisms ?
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Atherosclerosis and Insulin Resistance
HypertensionHypertension
ObesityObesity
HyperinsulinemiaHyperinsulinemia
DiabetesDiabetes
Hyper triglyceridemiaHyper triglyceridemia
Small, dense LDLSmall, dense LDL
Low HDLLow HDL
Hyper coagulabilityHyper coagulability
InsulinInsulinResistanceResistance
InsulinInsulinResistanceResistance AtherosclerosisAtherosclerosisAtherosclerosisAtherosclerosis
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• Abdominal obesity
• ↑ TG + ↓ HDL-C
• Glucose intolerance
• Hypertension
• Atherosclerosis
• Ethnicity (Indians, Negroid races)
Insulin Resistance - Clinical Clues
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• Elevated total TG
• Reduced HDL
• Small, dense LDL
• ↑ HDL 3 and ↓ HDL1 and HDL
2
• LDL is not usually high
• Postprandial Hyper lipemia
• Lipemia Retinalis
Dyslipidemia in DM and IRS
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Increased
Decreased• Triglyceride
s
• VLDL
• LDL, sLDL
• Apo B
• HDL
• Apo A-I
Dyslipidemia in DM and IRS
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Dyslipidemia based on TG and LDL
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Dyslipidemia based on TG and Apo B
Mechanisms of DM Dyslipidemia
Fat CellsFat Cells LiverLiver
InsulinInsulin
IRIR XX
FFAFFA
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Fat CellsFat Cells LiverLiver
InsulinInsulin
IRIR XX
TGTG Apo BApo B VLDLVLDL
VLDLVLDL
FFAFFA
Mechanisms of DM Dyslipidemia
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(hepatic(hepaticlipase)lipase)
Fat CellsFat Cells LiverLiver
KidneyKidneyInsulinInsulin
IRIR XX
(CETP)(CETP)
CECE
TGTG Apo BApo B VLDLVLDL
HDLHDL
TGTGApo A-Apo A-
11
FFAFFA
VLDLVLDL
Mechanisms of DM Dyslipidemia
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(hepatic(hepaticlipase)lipase)
Fat CellsFat Cells LiverLiver
KidneyKidneyInsulinInsulin
IRIR XX
(CETP)(CETP)
CECE
TGTG Apo BApo B VLDLVLDL
(CETP)(CETP)
HDLHDL
(lipoprotein or hepatic lipase)(lipoprotein or hepatic lipase)
sLDLsLDLLDLLDL
TGTGApo A-1Apo A-1
TGTGCECE
FFAFFA
VLDLVLDL
Mechanisms of DM Dyslipidemia
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Fat CellsFat Cells LiverLiver
InsulinInsulin
IRIR XX
TGTG Apo BApo B VLDLVLDL
FFAFFA
VLDLVLDL
Mechanisms of DM Dyslipidemia
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VLDL -RVLDL -R AtherogeAtherogenicnic
↓ ↓ VLDL VLDL ClearancClearanc
ee
↓ ↓ LPLLPL Apo CApo C+
IR and TG Increase
Olefsky JM et al. Am J Med. 1974;57:551-560.
Insulin Response to Oral Glucose
625
500
400
300
200
100
100 200 300 400 500 600
Pla
sma T
G (
mg/d
L)
r = 0.73P < 0.0001
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DM, IRS and HDLH
DL-
C (
mg/d
L)
Reaven GM. In: Le Roith D et al., eds. Diabetes Mellitus.1996:509-519.
Non-obese
Hyperinsulinemic
Normoinsulinemic
Obese
P < 0.005
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P < 0.005
• Accumulation of chylomicron remnants
• Accumulation of VLDL remnants
• Generation of small, dense LDL
• Association with low HDL
• Increased coagulability
• PAI-1, and factor VIIc
• Activation of prothrombin to thrombin
Effects of TG on CV Risk
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• Increased susceptibility to oxidation
• Increased vascular permeability
• Increased binding to arterial wall proteoglycons
• Conformational change in Apo B
• ↓ Affinity for LDL receptor (↓ clearance)
• Association with insulin resistance syndrome
• Association with high TG and low HDL
Small Dense LDL and CHD Potential Atherogenic Mechanisms
Austin MA et al. Curr Opin Lipidol 1996;7:167-171.
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What the studies What the studies say ?say ?
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Clear Excess mortality in DM
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A New Paradigm !!!A New Paradigm !!!
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Vascular Protection in Diabetes Mellitus
Vascular Protection in Diabetes Mellitus
2004
This material has been reviewed and is supported by the Canadian Diabetes Association for its medical and scientific accuracy.
is hopelessly is hopelessly inadequate !!inadequate !!
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AA A1c (Hb A1c)A1c (Hb A1c)
BB Blood pressure Blood pressure (goal)(goal)
CC Cholesterol (all Cholesterol (all lipids)lipids) 51www.drsarma.in
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1. ACE inhibitors or ARBs2. ASA (Acetyl Salicylic Acid)3. Atorvastatin (Lipid management)4. A1c control (Glycemic control)5. Blood pressure goal (<130/80)6. Control of Nephropathy, Proteinuria
(MAU)7. Cigarette smoking cessation8. Weight and waist management9. Physical Activity – at least 2 km/d x
5 d
Ticking Clock of T2DM
1. Micro-vascular (DR, CKD, DPN, DAN) At the onset of hyperglycemia Control of hyperglycemia essential The A1c target of less than 7 must (A)
2. Macro-vascular (CAD, CVD, PVD) VP At the onset of insulin resistance Blood pressure goal of 130/80 (B) Control of lipid abnormalities (C)
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Goals inT2DM for VP
Risk FactorRisk Factor Goal or TargetGoal or Target
Glycemia Hb A1c < 6.5%
Blood Pressure < 130/80 mm Hg
LDL target < 100 mg%; better < 70
HDL target > 40 men, > 50 women
TG target < 150 mg%
BMI < 25 kg/m2
Physical activity At least 5 days - 2 km/day
ADA, CDA, IDF, WWD
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From Blood Sugar to Blood Vessel
ACEi (Ramipril) Vasoprotective, anti HT, ↓ ED
ASA (75 to 150 mg%)
Anti inflamm., Anti Platelet
Statin (Powerful, full)
↓ LDL, TG, Corrects ED, Inflam
BP Goal Vascular damage, LVH, CVA
Glycemic control ↓ Micro vascular ? Macrovascular
Physical activity ED, ↓ Inflammation, ↑ HDL
Diet and TLC ↓ TG, LDL, Glycemia, Weight
Smoking cessation ↓ ED and Inflammation56www.drsarma.in
ACEi in T2DM - VP• Antihypertensive, vasoprotective, antithrombotic,
and anti-inflammatory properties – Inevitable in DM
• Reduce CV events, Reduce atherosclerosis
• Reduce renal disease which is a strong CV risk
factor
• Metabolically ‘friendly’ drugs that prevent rises in
glucose & prevent diabetes
• Well-tolerated with few side effects
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RecommendationsRecommendations
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• Total CHO to be reduced < 50% of calories
• Saturated fat must reduced to< 7% of calories
• MUFA and PUFA up to 15% of calories
• Protein in take to be increased – 25% of cal.
• Dietary fiber > 20 g/day -Soy protein,
Fenugreek
• Vegetables, Nuts and fruits must every day
• Fish oils – Omega-3 fatty acids
MNT and Dyslipidemia
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If all lipid values are normal
1.Lifestyle interventions (TLC)
MNT, Physical Activity, Weight and Waist reduction
2.Statin in a minimum dose of 10 mg o.d
3.Follow up every one year by full lipid profile
4.All Indians must be tested for LP(a) and
If > 30 mg% - Niacin SR 350 to 500 mg started
Priorities for Treatment
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LDL cholesterol lowering – First priority
1.Lifestyle interventions (TLC)
2.Drugs - First choice – Statin with or without
3.Cholesterol absorption inhibitors (EZ)
4.Second choice – Niacin and Fibrate
5.Add on – BAR (Bile acid binding resins)
Priorities for Treatment
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Priorities for Treatment HDL cholesterol raising – Second
priority
1.Lifestyle interventions
2.First choice - Niacin (doses <2 g/day)
3.Preferably short acting Niacin
4.Concern about Dysglycemia
5.Fibrates are second choice
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Priorities for Treatment Triglyceride lowering – Third
priority
1.First choice: Lifestyle interventions - CHO
2.Glycemic control is the best Rx for ↓TG
3.Fibrates
4.Niacin
5.High dose statins (if LDL is also high )
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Priorities for Treatment Triglyceride Lowering
(continued)
• In case of severe hyper triglyceridemia
(> 1000 mg), severe fat restriction (<
10 % of calories ) in addition to
pharmacological therapy is necessary
to reduce the risk of pancreatitis and
lipemia effects
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Priorities for Treatment Combined Dyslipidemia
1.First choice: Glycemic control + Statin
2.Glycemic control+ Statin + Fibrate
3.Glycemic control+ Statin + Niacin
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This is no longer tenable LDLc Statin
Triglyceride Fibrate
HDL Niacin
• Statins should be given to all DM –• Except for T1DM and T2 DM < 30 yrs
• If TG > 400 – Fibrate must be combined
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Myopathy with Statins
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Drug Rx. – Effect on Lipoproteins
ADA. Diabetes Care 2003;26 (suppl 1):S 83-S 86
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Drugs for Dyslipidemia
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Anti Diabetic Drugs and Lipids
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Anti HT Drugs and Lipids
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Glycemic goal alone is not adequate at
all
CAD must be prevented at all costs
Vascular Protection in DM is the only key
Statins in full dose Fibrate or Niacin
All T2DM must receive drugs/advise on
ACEi/ARB, ASA, Statin, TLC, PA, ↓ Weight
To Reiterate
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