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Diabetic Dyslipidemia. Dr. R. V. S. N. Sarma., M.D., M.Sc., (Canada) Consultant Physician and Chest Specialist. www.drsarma.in. What types of lesions cause MI ?. Coronary stenosis severity prior to MI. 100. 100. 14%. 80. 80. 18%. 60. 60. 68%. Coronary stenosis (%). 40. 40. 20.

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Diabetic Dyslipidemia

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Diabetic Dyslipidemia

Dr. R. V. S. N. Sarma., M.D., M.Sc., (Canada)

Consultant Physician and Chest Specialist

www.drsarma.in


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

60

68%

Coronary stenosis (%)

40

40

20

20

0

0

Ambrose1988

Little1988

Nobuyoshi1991

Giroud1992

All fourstudies

<50%

50%-70%

>70%

Falk E, et al. Circulation. 1995;92:657-671.

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What types of lesions cause MI ?

Coronary stenosis severity prior to MI

100

100

14%

80

80

18%

60

60

68%

Not the degree of stenosis

Coronary stenosis (%)

40

40

20

20

0

0

Ambrose1988

Little1988

Nobuyoshi1991

Giroud1992

All fourstudies

<50%

50%-70%

>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

Odds Ratio

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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Diabetes = Coronary A D

Why is it so ?

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DM – Strongest RF for CVD

DM = CHD

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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 <0.001

3.5

3

2.5

Relative Risk

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

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

Prevalence of CV Disease

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

25

P<0.0001

No Diabetes

20

21.3

N = 3429

P<0.0001

Diabetes

15

N = 1149

% of patients

14.4

14.1

P=0.035

10

8.9

7.9

P<0.0001

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 2003;19(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)

RR=1.99 (1.52-2.60)

0.15

Event rate

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

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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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HDL

A I, A II

B 100

TG

TG

C

TG

TG

C

C

B 48+E+C

CM

B 100 + E +C

Lipoproteins

LDL

VLDL

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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 < 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

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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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Dyslipidemia in Diabetes

What are the Mechanisms ?

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Atherosclerosis and Insulin Resistance

Hypertension

Obesity

Hyperinsulinemia

Diabetes

Hyper 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

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)

CE

TG

Kidney

Insulin

SDLDL

LDL

(lipoprotein or hepatic lipase)

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625

500

400

300

200

100

r = 0.73

P < 0.0001

Plasma TG (mg/dL)

100

200

300

400

500

600

IR and TG Increase

Insulin Response to Oral Glucose

Olefsky JM et al. AmJMed. 1974;57:551-560.

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DM, IRS and HDL

Hyperinsulinemic

Normoinsulinemic

P < 0.005

P < 0.005

HDL-C (mg/dL)

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

  • 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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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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Glycemic control alone

is hopelessly inadequate !!

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The A B C of Diabetes Management

AA1c (Hb A1c)

BBlood pressure (goal)

CCholesterol (all lipids)

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Ticking Clock of T2DM

  • Micro-vascular (DR, DKD, 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)

    • 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

ADA, CDA, IDF, WWD

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From Blood Sugar to Blood Vessel

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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 < 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

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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 > 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 <2 g/day)

  • Preferably short acting Niacin

  • Fibrates are second choice

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Priorities for Treatment

  • Triglyceride lowering – Third priority

  • First choice: Lifestyle interventions

  • 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 (> 1000 mg), severe fat restriction (< 10 % of calories ) in addition to pharmacological therapy is necessary to reduce the risk of pancreatitis and lipemiaeffects

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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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Drug Rx. – Effect on Lipoproteins

ADA. Diabetes Care 2003;26 (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

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Anti HT Drugs and Lipids

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To Reiterate

  • 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

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Thank you all


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