Vascular Protection in DM

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Vascular Protection in DM

• Dr. R. V. S. N. Sarma., M.D., M.Sc., (Canada)
• Consultant Physician and Chest Specialist

www.drsarma.in
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What types of lesions cause MI ?
Coronary stenosis severity prior to MI
100
100
14
80
80
18
60
68
60
Coronary stenosis ()
40
40
20
20
0
0
All fourstudies
Ambrose1988
Little1988
Nobuyoshi1991
Giroud1992
50-70
lt50
gt70
Falk E, et al. Circulation. 199592657-671.
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What types of lesions cause MI ?
Coronary stenosis severity prior to MI
100
100
14
80
80
18
60
68
60
Not the degree of stenosis
Coronary stenosis ()
40
40
20
20
0
0
All fourstudies
Ambrose1988
Little1988
Nobuyoshi1991
Giroud1992
50-70
lt50
gt70
Falk E, et al. Circulation. 199592657-671.
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CV Risk Factors in Diabetes
12
10.0
10
8
6.5
Odds Ratio
6
3.2
4
2.3
2
0
Microalbuminuria
Smoking
Diastolic BP
Cholesterol
Eastman RC, Keen H. Lancet 1997350 Suppl 129-32.
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Causes of death in Diabetes
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Diabetes Coronary A D

• Why is it so ?

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DM Strongest RF for CVD
DM CHD
10
Duration of T2DM and CVD
48
29
24
21
15
2
3-5
6-9
10-14
15
Years after DM Diagnosis
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.
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Duration of DM - CV Mortality
4
p for trend lt0.001
3.5
3
2.5
Relative Risk
2
1.5
1
0.5
0
lt 5
6 to 10
11 to 15
16 to 25
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Duration of Diabetes (years)
Cho, et al. J Am Coll Card 200240954.
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Life Expectancy with Diabetes
Years
DM
90
No DM
1600
80
1400
70
1200
60
Diabetes
1000
No Diabetes
50
800
40
600
30
400
20
200
10
0
0
Mortality rate/100,000
Men
Women
Hux JE, et al. Diabetes in Ontario, an ICES
Practice Atlas 2003.
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Cardiovascular Disease and T2DM
20
Diabetes
15
No Diabetes
10
Prevalence of CV Disease
5
0
Hypertension
Heart Disease
Hux JE, et al. Diabetes in Ontario, an ICES
Practice Atlas 2003.
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Clinical Outcome for Diabetes 4-year Follow-up
14
12
10
8

6
4
2
0
CV Death
MI
Stroke
Dialysis
HOPE / MICRO-HOPE. Lancet 2000355253.
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ACS and Diabetes Up to 1 Year
25
Plt0.0001
No Diabetes
20
21.3
N 3429
Plt0.0001
Diabetes
15
N 1149
of patients
14.4
14.1
P0.035
10
8.9
7.9
Plt0.0001
7.1
5
3.9
1.8
0
In-Hospital
Non-fatal MI
1-y All-Cause
1-y
Mortality
Mortality
Mortality/MI
Yan R, et al. Can J Cardiol 200319(suppl
A)260A.
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OASIS Study Total Mortality
0.25
Diabetes/CVD , (n 1148)
RR 2.88 (2.37-3.49)
Diabetes/CVD -, (n 569)
0.20
No Diabetes/CVD , (n 3503)
No Diabetes/CVD -, (n 2796)
RR1.99 (1.52-2.60)
0.15
Event rate
0.10
RR1.71 (1.44-2.04)
0.05
RR1.00
0.0
Months ?
3 6 9 12 15 18
21 24
Malmberg K, et al. Circulation 200010210141019.
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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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The Lipid Profile

• How to interpret ?

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Lipoproteins
LDL
VLDL
20
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Atherogenic Particles
Non-HDL-C
Measurements
Apolipoprotein B
VLDL
VLDLR
IDL
LDL
SDL
TG rich particles
Cholesterol rich
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The Good, Bad, Ugly and Deadly

• Total Cholesterol lt 200
• Good Cholesterols (HDL)
• HDL 1, HDL 2, HDL 3 gt 50
• Bad Cholesterols (Non HDL) lt 150
• LDL, IDL lt 100
• VLDL, VLDL-R lt 30
• Lp(a), Small LDL lt 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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Todays Safer Values

• Total Cholesterol lt 200
• Triglycerides lt 150
• LDL Cholesterol lt 100 preferably lt 70
• HDL Cholesterol gt 50 (for women 55)
• Bad Cholesterols the lower the better
• Good Cholesterols the higher the better
• Non HDL Cholesterol lt 130
• Lp(a) values lt 20

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Dyslipidemia in Diabetes

• What are the Mechanisms ?

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Atherosclerosis and Insulin Resistance
Hypertension Obesity Hyperinsulinemia Diabetes Hyp
er triglyceridemia Small, dense LDL Low HDL Hyper
coagulability
InsulinResistance
Atherosclerosis
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Insulin Resistance - Clinical Clues

• Abdominal obesity
• ? TG ? HDL-C
• Glucose intolerance
• Hypertension
• Atherosclerosis
• Ethnicity (Indians, Negroid races)

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Dyslipidemia in DM and IRS

• 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

LDL Level of 180 to 220 mg
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Dyslipidemia in DM and IRS
Increased
Decreased

• Triglycerides
• VLDL
• LDL, sLDL
• Apo B

• HDL
• Apo A-I

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Dyslipidemia based on TG and LDL
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Dyslipidemia based on TG and Apo B
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Mechanisms of DM Dyslipidemia
Fat Cells
Liver
?FFA
X
IR
Insulin
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Mechanisms of DM Dyslipidemia
Fat Cells
Liver
?FFA
? TG ? Apo B ? VLDL
VLDL
X
IR
Insulin
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Mechanisms of DM Dyslipidemia
Fat Cells
Liver
?FFA
CE
(hepaticlipase)
? TG ? Apo B ? VLDL
(CETP)
HDL
?VLDL
X
IR
TG
Apo A-1
Kidney
Insulin
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Mechanisms of DM Dyslipidemia
Fat Cells
Liver
?FFA
CE
(hepaticlipase)
? TG ? Apo B ? VLDL
(CETP)
HDL
?VLDL
X
IR
TG
Apo A-1
(CETP)
TG
CE
Kidney
Insulin
LDL
sLDL
(lipoprotein or hepatic lipase)
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Mechanisms of DM Dyslipidemia
Fat Cells
Liver
?FFA
? TG ? Apo B ? VLDL
?VLDL
?VLDL -R
Atherogenic
X
IR
? VLDL Clearance

? LPL
? Apo C
Insulin
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IR and TG Increase
Insulin Response to Oral Glucose
Olefsky JM et al. Am J Med. 197457551-560.
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DM, IRS and HDL
Hyperinsulinemic Normoinsulinemic
P lt 0.005
P lt 0.005
HDL-C (mg/dL)
Non-obese
Obese
Reaven GM. In Le Roith D et al., eds. Diabetes
Mellitus.1996509-519.
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Effects of ? TG on CV Risk

• 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

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Small Dense LDL and CHD Potential Atherogenic
Mechanisms

• 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

Austin MA et al. Curr Opin Lipidol 19967167-171.
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Research on DM Dyslipidemia

• What the studies say ?

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Multiplicative Effect
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• Clear Excess mortality in DM

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Vascular Protection in DM

• A New Paradigm !!!

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2004
Vascular Protection in Diabetes Mellitus
This material has been reviewed and is supported
by the Canadian Diabetes Association for its
medical and scientific accuracy.
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Glycemic control alone

• is hopelessly inadequate !!

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The A B C of Diabetes Management

• A A1c (Hb A1c)
• B Blood pressure (goal)
• C Cholesterol (all lipids)

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How to offer Vascular Protection ?

1. ACE inhibitors or ARBs
2. ASA (Acetyl Salicylic Acid)
3. Atorvastatin (Lipid management)
4. A1c control (Glycemic control)
5. Blood pressure goal (lt130/80)
6. Control of Nephropathy, Proteinuria (MAU)
7. Cigarette smoking cessation
8. Weight and waist management
9. Physical Activity at least 2 km/d x 5 d

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Ticking Clock of T2DM

• Micro-vascular (DR, CKD, DPN, DAN)
• At the onset of hyperglycemia
• Control of hyperglycemia essential
• The A1c target of less than 7 must (A)
• 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 Factor Goal or Target
Glycemia Hb A1c lt 6.5
Blood Pressure lt 130/80 mm Hg
LDL target lt 100 mg better lt 70
HDL target gt 40 men, gt 50 women
TG target lt 150 mg
BMI lt 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 Inflammation
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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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Treatment of DM Dyslipidemia

• Recommendations

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MNT and Dyslipidemia

• Total CHO to be reduced lt 50 of calories
• Saturated fat must reduced tolt 7 of calories
• MUFA and PUFA up to 15 of calories
• Protein in take to be increased 25 of cal.
• Dietary fiber gt 20 g/day -Soy protein, Fenugreek
• Vegetables, Nuts and fruits must every day
• Fish oils Omega-3 fatty acids

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Priorities for Treatment

• If all lipid values are normal
• Lifestyle interventions (TLC)
• MNT, Physical Activity, Weight and Waist
  reduction
• Statin in a minimum dose of 10 mg o.d
• Follow up every one year by full lipid profile
• All Indians must be tested for LP(a) and
• If gt 30 mg - Niacin SR 350 to 500 mg started

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Priorities for Treatment

• LDL cholesterol lowering First priority
• Lifestyle interventions (TLC)
• Drugs - First choice Statin with or without
• Cholesterol absorption inhibitors (EZ)
• Second choice Niacin and Fibrate
• Add on BAR (Bile acid binding resins)

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Priorities for Treatment

• HDL cholesterol raising Second priority
• Lifestyle interventions
• First choice - Niacin (doses lt2 g/day)
• Preferably short acting Niacin
• Concern about Dysglycemia
• Fibrates are second choice

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Priorities for Treatment

• Triglyceride lowering Third priority
• First choice Lifestyle interventions - CHO
• Glycemic control is the best Rx for ?TG
• Fibrates
• Niacin
• High dose statins (if LDL is also high )

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Priorities for Treatment

• Triglyceride Lowering (continued)
• In case of severe hyper triglyceridemia (gt 1000
  mg), severe fat restriction (lt 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
• First choice Glycemic control Statin
• Glycemic control Statin Fibrate
• 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 lt 30 yrs
• If TG gt 400 Fibrate must be combined
• This much more so in T2DM and IR

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Myopathy with Statins
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Drug Rx. Effect on Lipoproteins
Pharmacological Agents LDL HDL TG
Statins (HMG CoA Reductase In) ? ? ? ? ? ?
Fibrates (PPAR- ? Activators) ? ? ? ? ?
BAR (Bile Acid Sequestering Resins) ? ? ?
Niacin (Plain or SR) (Dysglycemia) ? ? ? ? ?
ADA. Diabetes Care 200326 (suppl 1)S 83-S 86
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Drugs for Dyslipidemia
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Treatment of ? LDL
High LDL
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice Statin
Add on drug - EZ , Niacin, BAR
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Treatment of ? HDL
Low HDL
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice Niacin
Add on drug - Finofibrate
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Treatment of ? TG
High TG
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice Fibrate
Add on drug Statin, Niacin
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Anti Diabetic Drugs and Lipids
Anti Diabetic Agents LDL HDL TG LDL Size
Metformin (Mildly favourable) ? ? ? ?
Pioglitazone (Very favourable) ? ? ? ? ? ?
Rosiglitazone (less favourable) ? ? ? ?
Sulfonylureas (Unfavourable) ? ? ? ?
Insulin (Not Atherogenic at all) ? ? ? ?
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Anti HT Drugs and Lipids
Anti hypertensive agents On Lipids
ACEi and ARBS (Excellent) ? ?
CCBs (Neutral on lipids) ?
Diuretics (Unfavourable) ?
? Blockers (Very unfavourable) ? ?
? Blockers (Mildly unfavourable) ?
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To Reiterate

• 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

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Thank you all