Management of diabetic dyslipidemia

1. 1

4. 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 four
studies
50%-70%<50% >70%
100
60
40
20
0
Ambrose
1988
Little
1988
Nobuyoshi
1991
Giroud
1992
Coronarystenosis(%)
Coronary stenosis severity prior to MI
80

5. 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 four
studies
50%-70%<50% >70%
100
60
40
20
0
Ambrose
1988
Little
1988
Nobuyoshi
1991
Giroud
1992
Coronarystenosis(%)
Coronary stenosis severity prior to MI
80
5

6. 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
6

7. 7
Causes of death in Diabetes

8. Why is it so ?
8

9. DM – Strongest RF for CVD
9

10. 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

11. 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.
RelativeRisk
11

12. Life Expectancy with Diabetes
Hux JE, et al. Diabetes in Ontario, an ICES Practice Atlas 2003.
0
10
20
30
40
50
60
70
80
90
Men Women
Years
DM
No DM
0
200
400
600
800
1000
1200
1400
1600
Mortality rate/100,000
Diabetes
No Diabetes
12

13. Cardiovascular Disease and
T2DM
Hux JE, et al. Diabetes in Ontario, an ICES Practice Atlas 2003.
0%
5%
10%
15%
20%
Hypertension Heart Disease
PrevalenceofCVDisease
Diabetes
No Diabetes
13

14. 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

15. ACS and Diabetes – Up to 1
Year%ofpatients
1.8
3.9
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.
15

16. 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 
Eventrate
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

17. Predictors of CV Risk in DM
Age; But Gender looses its power
MAU (Microalbuminuria)
W/H Ratio (Abdominal Obesity)
LP(a) (Lipoprotein small ‘a’)
LDL Cholesterol
Not the Glycemic levels !!
17

18. 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

19. AACE guidelines 2013
19

20. How to interpret ?
20

21. Lipoproteins
CTG
B 100 + E +C
CTG
B 100
C
T
G
A I, A II
HDL LDL
VLDL
TG
B 48+E+C
CM
21

22. Apolipoprotein B
Non-HDL-C
Measurements
TG rich particles
VLDL VLDLR IDL LDL SDL
Atherogenic Particles
22
Cholesterol rich

23. 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

24. 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
24

25. 25

26. 26

27. What are the Mechanisms ?
27

28. Atherosclerosis and Insulin
Resistance
Hypertension
Obesity
Hyperinsulinemia
Diabetes
Hyper triglyceridemia
Small, dense LDL
Low HDL
Hyper coagulability
Insulin
Resistance
Atherosclerosis
28

29. • Abdominal obesity
• ↑ TG + ↓ HDL-C
• Glucose intolerance
• Hypertension
• Atherosclerosis
• Ethnicity (Indians, Negroid races)
Insulin Resistance - Clinical Clues
29

30. • 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

31. Increased Decreased
• Triglycerides
• VLDL
• LDL, sLDL
• Apo B
• HDL
• Apo A-I
Dyslipidemia in DM and IRS
31

32. Dyslipidemia based on TG and LDL
32

33. 33
Dyslipidemia based on TG and Apo
B

34. Mechanisms of DM Dyslipidemia
Fat Cells Liver
Insulin
IR X
FFA
34

35. Fat Cells Liver
Insulin
IR X
 TG
 Apo B
 VLDL
VLDL
FFA
Mechanisms of DM Dyslipidemia
35

36. (hepatic
lipase)
Fat Cells Liver
Kidney
Insulin
IR X
(CETP)
CE
 TG
 Apo B
 VLDL
HDL
TG
Apo A-1
FFA
VLDL
Mechanisms of DM Dyslipidemia
36

37. (hepatic
lipase)
Fat Cells Liver
Kidney
Insulin
IR X
(CETP)
CE
 TG
 Apo B
 VLDL
(CETP)
HDL
(lipoprotein or hepatic lipase)
SD
LDL
LDL
TG
Apo A-1
TGCE
FFA
VLDL
Mechanisms of DM Dyslipidemia
37

38. 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
PlasmaTG(mg/dL)
r = 0.73
P < 0.0001
38

39. DM, IRS and HDL
HDL-C(mg/dL)
Reaven GM. In: Le Roith D et al., eds. Diabetes Mellitus.1996:509-519.
Non-obese
Hyperinsulinemic
Normoinsulinemic
Obese
P < 0.005
39
P < 0.005

40. • 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

41. • 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

42. What the studies say ?
42

43. 43

44. 44

45. 45

46. 46

47. 47

48. Clear Excess mortality in DM
48

49. A New Paradigm !!!
49

50. is hopelessly inadequate !!
50

51. A A1c (Hb A1c)
B Blood pressure (goal)
C Cholesterol (all
lipids)
51

52. Ticking Clock of T2DM
1. 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. 53

54. 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
54

55. 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
55

56. 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
56

57. Recommendations
57

58. • 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

59.  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
59

60.  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

61. 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. Fibrates are second choice
61

62. Priorities for Treatment
 Triglyceride lowering – Third priority
1. 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

63. 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

64. Priorities for Treatment
 Combined Dyslipidemia
1. First choice: Glycemic control + Statin
2. Glycemic control+ Statin + Fibrate
3. Glycemic control+ Statin + Niacin
64

65. Drug Rx. – Effect on Lipoproteins
Pharmacological Agents LDL HDL TG
Statins (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

66. Drugs for Dyslipidemia
Statins
• Rosuvastati
n
• Atorvastati
n
• Simvastatin
• Lovastatin
• Pravastatin
• Cervistatin
Fibric Acid
• Fenofibrate
• Gemfibrozil
• Benzafibrat
e
• Clofibrate
• Ciprofibrat
e
• Clofibride
Niacin
• Neasyn SR
• Neasyn
• Nialip
• Neaspan
66

67. Treatment of  LDL
High LDL
Therapeutic Lifestyle Change
Add on drug - EZ , Niacin, BAR
Therapy of Choice: Statin
Drug Therapy
67

68. Treatment of  HDL
Low HDL
Therapeutic Lifestyle Change
Add on drug - Finofibrate
Therapy of Choice : Niacin
Drug Therapy
68

69. Treatment of  TG
High TG
Therapeutic Lifestyle Change
Add on drug – Statin, Niacin
Therapy of Choice : Fibrate
Drug Therapy
69

70. AACE guidelines
70www.drsarma.in

71. 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. 72

73. 73
Studies

74. 74ESC guidelines 2011

75. 75ESC guidelines 2011

76. 76ESC guidelines 2011

77. 77

78. {
Dyslipidemia Management

79. Screening
In 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.

80. 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.

81. 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

82. Statin treatment recommendations

83. 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

84. 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. 85

86. 86

87. 87Spratt • Managing Diabetic Dyslipidemia: Aggressive Approach
JAOA • Supplement 1 • Vol 109 • No 5 • May 2009 • S7

88. 88Spratt • Managing Diabetic Dyslipidemia: Aggressive Approach JAOA •
Supplement 1 • Vol 109 • No 5 • May 2009 • S7

89. 89

90. 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) 
90

91.  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