Transcript Diabetic Dyslipidemia – An Update

Dr. R. V. S. N. Sarma., M.D., M.Sc., (Canada)
Consultant Physician and Chest Specialist
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What types of lesions cause MI ?
Coronary stenosis (%)
Coronary stenosis severity prior to MI
100
100
80
80
18%
60
60
68%
40
40
20
20
0
0
Ambrose
1988
Little
1988
<50%
Nobuyoshi
1991
Giroud
1992
50%-70%
14%
All four
studies
>70%
Falk E, et al. Circulation. 1995;92:657-671.
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What types of lesions cause MI ?
Coronary stenosis (%)
Coronary stenosis severity prior to MI
100
100
80
80
18%
60
60
68%
40
40
20
20
0
0
Ambrose
1988
Little
1988
<50%
Nobuyoshi
1991
Giroud
1992
50%-70%
14%
All four
studies
>70%
Falk E, et al. Circulation. 1995;92:657-671.
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CV Risk Factors in Diabetes
12
10.0
10
8
6.5
6
3.2
4
2.3
2
0
Microalbuminuria
Smoking
Diastolic BP
Cholesterol
Eastman RC, Keen H. Lancet 1997;350 Suppl 1:29-32.
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Causes of death in Diabetes
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Why is it so ?
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DM – Strongest RF for CVD
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Duration of T2DM and CVD
48%
29%
21%
24%
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 <0.001
Relative Risk
3.5
3
2.5
2
1.5
1
0.5
0
<5
6 to 10
11 to 15
16 to 25
26 +
Duration of Diabetes (years)
Cho, et al. J Am Coll Card 2002:40:954.
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Life Expectancy with Diabetes
Years
DM
No DM
90
80
70
60
50
40
30
20
10
0
Men
1600
1400
1200
1000
800
600
400
200
0
Women
Diabetes
No Diabetes
Mortality rate/100,000
Hux JE, et al. Diabetes in Ontario, an ICES Practice Atlas 2003.
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Cardiovascular Disease and T2DM
Prevalence of CV Disease
20%
Diabetes
No Diabetes
15%
10%
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 2000;355:253.
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ACS and Diabetes – Up to 1 Year
% of patients
25
20
15
21.3
N = 3429
P<0.0001
Diabetes
N = 1149
14.4
P=0.035
10
5
P<0.0001
No Diabetes
P<0.0001
8.9
7.
1
14.1
7.9
3.9
0
1.8
In-Hospital
Mortality
Non-fatal MI
1-y All-Cause
Mortality
1-y
Mortality/MI
Yan R, et al. Can J Cardiol 2003;19(suppl A):260A.
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OASIS Study: Total Mortality
0.25
Diabetes/CVD +, (n = 1148)
Diabetes/CVD -, (n = 569)
Event rate
0.20
RR = 2.88 (2.37-3.49)
No Diabetes/CVD +, (n = 3503)
No Diabetes/CVD -, (n = 2796)
0.15
RR=1.99 (1.52-2.60)
0.10
RR=1.71 (1.44-2.04)
0.05
RR=1.00
0.0
Months  3
6
9
12
15
18
21
24
Malmberg K, et al. Circulation 2000;102:1014–1019.
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Predictors of CV Risk in DM
Age; But Gender looses its power
MAU (Microalbuminuria)
W/Ht Ratio (Abdominal Obesity)
LP(a) (Lipoprotein small ‘a’)
LDL Cholesterol
Not the Glycemic levels !!
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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 ?
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Lipoproteins
HDL
LDL
C
T
G
TG
A I, A II
C
B 100
VLDL
CM
TG
C
B 100 + E +C
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TG
B 48+E+C
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Atherogenic Particles
Non-HDL-C
Measurements
VLDL
VLDLR
TG rich particles
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Apolipoprotein B
IDL
LDL
SDL
Cholesterol rich
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The Good, Bad, Ugly and Deadly
• Total Cholesterol
• ‘Good’ Cholesterols (HDL)
– HDL 1, HDL 2, HDL 3
• ‘Bad’ Cholesterols (Non HDL)
– LDL, IDL
– VLDL, VLDL-R
– Lp(a), Small LDL
< 200
> 50
< 150
< 100
< 30
< 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 Values
 Total 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 Mechanisms ?
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Atherosclerosis and Insulin
Resistance
Hypertension
Obesity
Hyperinsulinemia
Insulin
Resistance
Diabetes
Atherosclerosis
Hyper triglyceridemia
Small, dense LDL
Low HDL
Hyper coagulability
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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
•
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Lipemia Retinalis
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Dyslipidemia in DM and IRS
Increased
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Decreased
•
Triglycerides
•
HDL
•
VLDL
•
Apo A-I
•
LDL, sLDL
•
Apo B
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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
IR X
Insulin
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Mechanisms of DM Dyslipidemia
Fat Cells
Liver
FFA
IR X
 TG
 Apo B
 VLDL
VLDL
Insulin
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Mechanisms of DM Dyslipidemia
Fat Cells
Liver
FFA
IR X
 TG
 Apo B
 VLDL
CE
VLDL
(CETP) HDL
(hepatic
lipase)
TG
Apo A-1
Kidney
Insulin
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Mechanisms of DM Dyslipidemia
Fat Cells
Liver
FFA
IR X
CE
 TG
 Apo B
 VLDL
VLDL
(CETP) HDL
(hepatic
lipase)
TG
Apo A-1
CE (CETP) TG
Kidney
Insulin
LDL
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sLDL
(lipoprotein or hepatic lipase)
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Mechanisms of DM Dyslipidemia
Fat Cells
Liver
FFA
IR X
 TG
 Apo B
 VLDL
↓ LPL
VLDL
+
 Apo
VLDL -R
Atherogenic
C
↓ VLDL
Clearance
Insulin
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IR and TG Increase
Plasma TG (mg/dL)
625
500
r = 0.73
P < 0.0001
400
300
200
100
100 200
300 400 500 600
Insulin Response to Oral Glucose
Olefsky JM et al. Am J Med. 1974;57:551-560.
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DM, IRS and HDL
Hyperinsulinemic
HDL-C (mg/dL)
P < 0.005
Normoinsulinemic
P < 0.005
Non-obese
Obese
Reaven GM. In: Le Roith D et al., eds. Diabetes Mellitus.1996:509-519.
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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 1996;7:167-171.
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What the studies say ?
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Clear Excess mortality in DM
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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.
is hopelessly inadequate !!
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A A1c (Hb A1c)
B Blood pressure (goal)
C Cholesterol (all
lipids)
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1.
2.
3.
4.
5.
6.
7.
8.
9.
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ACE inhibitors or ARBs
ASA (Acetyl Salicylic Acid)
Atorvastatin (Lipid management)
A1c control (Glycemic control)
Blood pressure goal (<130/80)
Control of Nephropathy, Proteinuria (MAU)
Cigarette smoking cessation
Weight and waist management
Physical Activity – at least 2 km/d x 5 d
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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 Factor
Goal 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 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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Recommendations
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MNT and Dyslipidemia
• 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
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Priorities for Treatment
 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
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Priorities for Treatment
 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)
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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
1.  LDLc
Statin
2.  Triglyceride
Fibrate
3.  HDL
Niacin
• Statins should be given to all DM –
•
Except for T1DM and T2 DM < 30 yrs
•
If TG > 400 – Fibrate must be combined
This much more so in T2DM and IR
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Myopathy with Statins
 CPK > 10 times UNL
Muscle weakness, Tenderness, pain
Amiodarone, Verapamil increase risk
0.02 with10, 0.07 with 20, 0.3 with 40 mg
Creatinine > 2, Elderly, BMI, Women
Statin1, Statin + Fibrate 10, BZP 100
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Drug Rx. – Effect on Lipoproteins
Pharmacological Agents
LDL
HDL
Statins (HMG CoA Reductase In)


Fibrates (PPAR- γ Activators)



BAR (Bile Acid Sequestering
Resins)



Niacin (Plain or SR) (Dysglycemia)




TG


ADA. Diabetes Care 2003;26 (suppl 1):S 83-S 86
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Drugs for Dyslipidemia
Statins
Fibric Acid
• Rosuvastati
n
• Atorvastati
n
• Simvastatin
• Lovastatin
• Pravastatin
• Cervistatin
• Fenofibrate
• Gemfibrozil
• Benzafibrat
e
• Clofibrate
• Ciprofibrat
e
• Clofibride
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Niacin
•
•
•
•
Neasyn SR
Neasyn
Nialip
Neaspan
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Anti Diabetic Drugs and Lipids
LDL
HDL
TG
LDL
Size
Metformin (Mildly favourable)




Pioglitazone (Very favourable)




Rosiglitazone (less favourable)




Sulfonylureas (Unfavourable)




Insulin (Not Atherogenic at all)




Anti Diabetic Agents
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Anti HT Drugs and Lipids
Anti hypertensive agents
ACEi and ARBS (Excellent)
On Lipids

CCBs (Neutral on lipids)

Diuretics (Unfavourable)

 Blockers (Very unfavourable)
 Blockers (Mildly unfavourable)
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

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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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