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Diabetic DyslipidemiaManagement
1
What types of lesions cause MI ?
Falk E, et al. Circulation. 1995;92:657-671.
100
80
60
40
20
0
14%
18%
68%
All fourstudies
50%-70%<50% >70%
100
60
40
20
0Ambrose
1988Little1988
Nobuyoshi1991
Giroud1992
Cor
onar
y st
enos
is (%
)
Coronary stenosis severity prior to MI
80
What types of lesions cause MI ?
Falk E, et al. Circulation. 1995;92:657-671.
100
80
60
40
20
0
14%
18%
68%
All fourstudies
50%-70%<50% >70%
100
60
40
20
0Ambrose
1988Little1988
Nobuyoshi1991
Giroud1992
Cor
onar
y st
enos
is (%
)
Coronary stenosis severity prior to MI
80
5
Not the degree of stenosis
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
Odd
s R
atio
6
7
Causes of death in Diabetes
Diabetes = Coronary A D
Why is it so ?
8
DM – Strongest RF for CVD
DM = CHD9
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
10
Duration of DM - CV Mortality
0
0.5
1
1.5
2
2.5
3
3.54
< 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
11
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
12
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
DiabetesNo Diabetes
13
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.
14
ACS and Diabetes – Up to 1 Year
% o
f pat
ient
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-HospitalMortality
Non-fatal MI 1-y All-CauseMortality
1-yMortality/MI
N = 3429
N = 1149
No Diabetes
Diabetes
Yan R, et al. Can J Cardiol 2003;19(suppl A):260A.
15
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 r
ate
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)
16
Predictors of CV Risk in DMAge; But Gender looses its power
MAU (Microalbuminuria)
W/H Ratio (Abdominal Obesity)LP(a) (Lipoprotein small ‘a’)
LDL Cholesterol
Not the Glycemic levels !!
17
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
18
AACE guidelines 2013
19
The Lipid Profile
How to interpret ?
20
Lipoproteins
CTG
B 100 + E +C
CTG
B 100
CTGA I, A II
HDL LDL
VLDL
TG
B 48+E+C
CM
21
Apolipoprotein BNon-HDL-C
Measurements
TG rich particles
VLDL VLDLR IDL LDL SDL
Atherogenic Particles
22
Cholesterol 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
23
Today’s Safer ValuesTotal Cholesterol < 200Triglycerides < 150LDL Cholesterol < 100
preferably < 70HDL Cholesterol > 50 (for
women 55)Bad Cholesterols the lower the
betterGood Cholesterols the higher
the betterNon HDL Cholesterol < 130Lp(a) values < 20
24
25
26
Dyslipidemia in Diabetes
What are the Mechanisms ?
27
Atherosclerosis and Insulin Resistance
HypertensionObesity
HyperinsulinemiaDiabetes
Hyper triglyceridemiaSmall, dense LDL
Low HDLHyper coagulability
InsulinResistance Atherosclerosis
28
• Abdominal obesity
• ↑ TG + ↓ HDL-C
• Glucose intolerance
• Hypertension
• Atherosclerosis
• Ethnicity (Indians, Negroid races)
Insulin Resistance - Clinical Clues
29
• Elevated total TG• Reduced HDL• Small, dense LDL
• ↑ HDL 3 and ↓ HDL1 and HDL
2
• LDL is not usually high• Postprandial Hyper lipemia
Dyslipidemia in DM and IRS
30
LDL Level of
180 to 220 mg
Increased
Decreased• Triglycerides
• VLDL• LDL, sLDL• Apo B
• HDL• Apo A-I
Dyslipidemia in DM and IRS
31
Dyslipidemia based on TG and LDL
32
33
Dyslipidemia based on TG and Apo B
Mechanisms of DM Dyslipidemia
Fat Cells Liver
Insulin
IR X
FFA
34
Fat Cells Liver
Insulin
IR X
TG Apo B VLDL
VLDL
FFA
Mechanisms of DM Dyslipidemia
35
(hepaticlipase)
Fat Cells Liver
KidneyInsulin
IR X(CETP)
CE TG Apo B VLDL
HDL
TGApo A-
1
FFA
VLDL
Mechanisms of DM Dyslipidemia
36
(hepaticlipase)
Fat Cells Liver
KidneyInsulin
IR X(CETP)
CE TG Apo B VLDL
(CETP)
HDL
(lipoprotein or hepatic lipase)
SDLDLLDL
TGApo A-1
TGCE
FFA
VLDL
Mechanisms of DM Dyslipidemia
37
IR and TG Increase
Olefsky JM et al. Am J Med. 1974;57:551-560.
Insulin Response to Oral Glucose
625500400300200100
100 200 300 400 500 600
Plas
ma
TG (m
g/dL
)r = 0.73P < 0.0001
38
DM, IRS and HDLHD
L-C
(mg/
dL)
Reaven GM. In: Le Roith D et al., eds. Diabetes Mellitus.1996:509-519.Non-obese
HyperinsulinemicNormoinsulinemic
Obese
P < 0.005
39
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
40
• Increased susceptibility to oxidation• Increased vascular permeability• 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.
41
Research on DM Dyslipidemia
What the studies say ?
42
43
44
45
46
47
Multiplicativ
e Effect
Clear Excess mortality in DM
48
Vascular Protection in DM
A New Paradigm !!!
49
Glycemic control alone
is hopelessly inadequate !!
50
The A B C of Diabetes Management
A A1c (Hb A1c)B Blood pressure (goal)C Cholesterol (all lipids) 51
Ticking Clock of T2DM1. Micro-vascular (DR, DKD, 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)
At the onset of insulin resistance Blood pressure goal of 130/80 (B) Control of lipid abnormalities (C)
52
53
Goals inT2DM for VPRisk Factor Goal or TargetGlycemia Hb A1c < 6.5%Blood Pressure < 130/80 mm HgLDL target < 100 mg%; better <
70HDL target > 40 men, > 50
womenTG target < 150 mg%BMI < 25 kg/m2
Physical activity At least 5 days - 2 km/day
ADA, CDA, IDF, WWD
54
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 Inflammation55
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 effects56
Treatment of DM Dyslipidemia
Recommendations
57
• 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
MNT and Dyslipidemia
58
If all lipid values are normal1.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
59
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
60
Priorities for Treatment HDL cholesterol raising – Second
priority1. Lifestyle interventions
2. First choice - Niacin ( doses <2 g/day)
3. Preferably short acting Niacin
4. Fibrates are second choice
61
Priorities for Treatment Triglyceride lowering – Third
priority1. First choice: Lifestyle interventions
2. Glycemic control is the best Rx for ↓TG
3. Fibrates
4. Niacin
5. High dose statins (if LDL is also high )
62
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
63
Priorities for Treatment Combined Dyslipidemia1. First choice: Glycemic control +
Statin2. Glycemic control+ Statin +
Fibrate3. Glycemic control+ Statin +
Niacin
64
Drug Rx. – Effect on Lipoproteins
Pharmacological Agents LDL HDL TGStatins (HMG CoA Reductase In) Fibrates (PPAR- γ Activators) BAR (Bile Acid Sequestering Resins)
Niacin (Plain or SR) ADA. Diabetes Care 2003;26 (suppl 1):S 83-S 86
65
Drugs for Dyslipidemia Statins
• Rosuvastatin
• Atorvastatin
• Simvastatin
• Lovastatin
• Pravastatin
• Cervistatin
Fibric Acid
• Fenofibrate
• Gemfibrozil
• Benzafibrate
• Clofibrate
• Ciprofibrate
• Clofibride
Niacin• Neasyn
SR• Neasyn • Nialip• Neaspan
66
Treatment of LDLHigh LDL
Therapeutic Lifestyle Change
Add on drug - EZ , Niacin, BAR
Therapy of Choice: Statin
Drug Therapy
67
Treatment of HDLLow HDL
Therapeutic Lifestyle Change
Add on drug - Finofibrate
Therapy of Choice : Niacin
Drug Therapy
68
Treatment of TGHigh TG
Therapeutic Lifestyle Change
Add on drug – Statin, Niacin
Therapy of Choice : Fibrate
Drug Therapy
69
AACE guidelines
70www.drsarma.in
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)
71
72
73
Studies
74ESC guidelines 2011
75ESC guidelines 2011
76ESC guidelines 2011
77
{Dyslipidemia Management
ScreeningIn adults, a screening lipid profile is reasonable at the time of first diagnosis, at the initial medical evaluation, and/or at age 40 years and periodically (e.g., every 1–2 years) thereafter.
Lipid profile testing
Cholesterol laboratory testing may be helpful in monitoring adherence to therapy, but may not be needed once the patient is stable on therapy.
Treatment recommendations
• Treatment not aimed towards achieving LDL-C target goals
• Rather, the type of treatment (high vs moderate intensity) should be based on risk profile of patient
• Do not agree with the use of ‘Risk calculator’ of ACC/AHA 2013 guidelines for DM patients since diabetes itself confers increased risk for CVD
Statin treatment recommendations
Combination Therapy
• Combination therapy (statin/ fibrate and statin/niacin) has not been shown to provide additional cardiovascular benefit above statin therapy alone and is not generally recommended.
• Combination therapy (statin and fibrate) may be efficacious for treatment for LDL cholesterol, HDL cholesterol, and triglycerides, but this combination is associated with an increased risk for abnormal transaminase levels, myositis, or rhabdomyolysis.
• The risk of rhabdomyolysis is more common with higher doses of statins and with renal insufficiency
Statins and diabetes• There is an increased risk of incident
diabetes with statin use which may be limited to those with diabetes risk factors. These patients may benefit from diabetes screening when on statin therapy.
• However, CV event rate reduction far outweighed the risk of DM, Even for patients with highest risk of diabetes
85
86
87Spratt • Managing Diabetic Dyslipidemia: Aggressive Approach JAOA • Supplement 1 • Vol 109 • No 5 • May 2009 • S7
88Spratt • Managing Diabetic Dyslipidemia: Aggressive Approach JAOA • Supplement 1 • Vol 109 • No 5 • May 2009 • S7
89
Anti HT Drugs and LipidsAnti hypertensive agents On Lipids
ACEi and ARBS (Excellent) CCBs (Neutral on lipids) Diuretics (Unfavourable) Blockers (Very unfavourable) Blockers (Mildly unfavourable)
90
Glycemic goal alone is not adequate at all
CAD must be prevented at all costs
The A, B, C of Diabetes must be addressed
Statins in full dose Fibrate or Niacin
All T2DM must receive drugs/advise on ACEi/ARB, ASA, Statin, TLC, PA, ↓
Weight
To Reiterate
91