diabetic dyslipidemia

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

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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