diabetic dyslipidemia2

7/27/2019 Diabetic Dyslipidemia2

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Dyslipidemia in diabetes

Dr. Shaival Chandalia

Consultant endocrinologistAsha Parekh , Jaslok and Bhatia

hospitals


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2

9.1

16.8

13.5

11.6

5

8.2

7.8

0 5 10 15 20

1984

1989

1995

2000

IGT

DM

%

Increasing Prevalence of Diabetes and IGT in

the Urban Population

Ramachandran et al DRCP 2002


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Does diabetes increase CV risk?


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Diabetes is a CV Risk Factor

Krolewski AS, et al. Evolving natural history of coronary disease in diabetes mellitus.Am J Med1991;90(Supp 2A):56S-

61S.

Diabetes

No Diabetes

60Men

0-3

Duration of Follow-up (Years)

50

40

30

20

10

0

Women

4-7 8-1112-1516-1920-23

60

0-3

Duration of Follow-up (Years)

50

40

30

20

10

04-7 8-1112-1516-1920-23

MortalityRatePer1000

MortalityRatePe

r1000

2x

4-5x


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THE FUNAGATA DIABETES STUDY

Impaired Glucose Tolerance is a

CV Risk Factor

Tominaga M, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose.

Diabetes Care 1999;22:920-4.

Normal

IGT (2 hr PG 140-200)

DM (2 hr PG >200)

1.00

Cumulative Cardiovascular Survival

0.99

0.98

0.97

0.96

0.95

0.94

0

1.00

0.98

0.96

0.94

0.92

0

Normal

IFG (FPG 110-126)

DM (FPG >126)

0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7

Year Year


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Is Diabetes a CV risk

equivalent?


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Is diabetes a CVD risk equivalent?


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Dyslipidemias in Adults with Diabetes

Framingham Heart Study

Increased chol

Increased LDL

Decreased HDL

Inc TG

Norml DM Norml DM

14

11

12

9

13

9

21

19

MEN WOMEN

21

16

10

8

24

15

25

17

Garg A et al. DiabetesCare 1990;13:153-169.


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MRFIT

Type 2 Diabetes is a CV Risk Factor

Additive Effects of Hypertension, Hypercholesterolemia, andSmoking

Stamler J, et al. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in

the Multiple Risk Factor Intervention Trial. Diabetes Care1993;16:434-44.

0

20

40

60

Number of Risk Factors

None One Two All Three

No Diabetes

Diabetes

Age

AdjustedCVDeathRate

P

er10,000PersonY

ears

80

100

120

140


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Atherogenic Dyslipidemia

(=Dyslipidemia of Diabetes Mellitus/Insulin Resistance)

Hypertriglyceridemia (HTG)

Low HDL-C

Small, dense LDL

(Increased VLDL-C)

(NonHDL-C)


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VLDL HDL

(CETP)

LDLSD

LDL

TG Apo B VLDL

Hepatic lipase

or lipoprotein lipase

(remove PL&TG)

TGCE

Fat Cells Liver

FFA

Kidney

Lipid-poor

Apo A-1

IR X

Insulin

(CETP)

CE

TG

CETP=cholesterol ester transfer protein.

CE on

TGRL HDL

SD LDL

The Atherogenic Dyslipidemia ofDM-2 (Insulin Resistance and HTG)

1

2

3

Ginsberg HN. J Clin Invest. 2000;106(4):453-457.


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onsensusStatement:

Treatment Goals in Patients With Cardiometabolic Risk

and Lipoprotein AbnormalitiesGoals

LDL-C NonHDL-C Apo B

Highest-Risk Patients

Known CVD

Diabetes plus 1 additional majorCVD risk factora


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What is the evidence for LDL

lowering?


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Should all patients with DM be

treated aggressively? positive log linear relation between LDL and

risk of CHD

This persists well below the range of typical

chol levels Large body of eveidence that chol lowering

improves outcomes

Reduction in absolute risk more important than

RR Parameters like QOL, life expectancy andconcomitant diseases need to be considered


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Are all diabetics alike?

Projected risk at age 65 , the risk will

be > 20%

At age 50, people with DM have thehighest risk

Prevalence of MS very high in diabetics

If no MS risk is only 8.7%

Increased case fatality rate

Overall prognosis poor after developing

CHD


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Should all diabetics be on

statin therapy? 18,686 people with DM

14 randomized trials

Metaanalysis

Mean followup of 4.3 years

Statin significantly reduced risk of all cause

and vascualr mortality Standard dose of statin that reduces LDL by

40% will help at least 1/3 rd of patientsKearney et al lancet 2008


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What about TG, HDL and non

HDL? Stars or second leads in diabetes?

Bitzer R etal Diabetes care Nov 2009


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Is TG an independent risk

factor? Metaanalysis of 17 population based

prospective studies . After adjustment

for HDL , there was increased risk inmen and women J cardiovascular risk

1996

Womens health study: No correlationwith fasting but correlated with non

fasting

Copenhagen heart study : correlated


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CHD Risk Prediction byHDL-C vs. LDL-C*

0.0

1.0

2.0

3.0

100 160 220 85

65

45

25

LDL-C (mg/dL)

HDL-C (mg/dL)

Adapted from and reprinted with permission from Castelli WP. Can JCardiol. 1988;4(suppl A):5A.

RR of CHD

After 4 yr

*Data in men age 5070 yr from the Framingham Study.

Patient 2:

LDL-C: 100 mg/dL

HDL-C: 25 mg/dL

Patient 1:

LDL-C: 220 mg/dL

HDL-C: 45 mg/dL


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Non-HDL IncludesAllAtherogenicLipoprotein Classes

Very low-density lipoprotein Made in the liver TG >> CE Carries lipids from the liver to peripheral tissues

HDL

LDL

IDL

VLDL

Ath

erogenic

Lipo

proteins

Non-HDL;ApoB100

-containing

Intermediate-density lipoprotein Formed from VLDL due to loss of TG Also known as a VLDL remnant

Low-density lipoprotein Formed from IDL due to loss of TG

CE>>TG

High-density lipoprotein Removes cholesterol from peripheral tissues

Lp(a)Lipoprotein (a)

Formed from LDL w/ addition of apo (a)?

Very atherogenic


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LDL-C Goal NonHDL-C GoalPatient Category (mg/dL) (mg/dL)

No CHD, 0-1 risk factors


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LDL-C vs. Non-HDL-C

Favoring LDL-C

Focus of mostresearch

Focus of currentguidelines

Always reportedinlipid profile

Favoring Non-HDL-C

Conceptually better(all pro-athero lipos)

Stronger CVDfactor

Valid in HTG

Valid non-fasting

Always measuredinlipid profile

Bo ttom l ine: Non-HDL-C is much better(no u nique advantages o f LDL-C)but w e are stuck w i th LDL-C for now !


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Non-HDL-C vs. Apo B

Favoring Apo B

Apo B may play

causalathero role

Stronger CVDfactor?

Complementary to

non-HDL-C?

Favoring Non-HDL-C

Already incorp

orated in guidelines

Cholesterolcontentconceptually better

Free with lipid profile(no extra testingneeded)

Well standardizedBo ttom l ine: Apo B sl ight ly better bu t harder.

Non-HDL-C good enough, bu t adding apo B m ay be usefu l


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Residual CVD Risk With Monotherapy

Versus Combination Therapy

14S Group. Lancet. 1994;344:1383-1389.2LIPID Study Group. N Engl J Med. 1998;339:1349-1357.

3HPS Collaborative Group. Lancet. 2002;360:7-22.4Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.

0

10

20

30

40

N 4444 20 5369014

PatientsExp

eriencing

MajorCHDE

vents,

%

4S1 LIPID2 HPS3 VA-HIT6 CDP7 FATS8 HATS9

6605

TNT5

10 001 2531 146 1606595

WOS4

5LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435.6Rubins HB, et al. N Engl J Med. 1999;341:410-418.

7CDP Research Group. JAMA. 1975;231:360-381.

8Brown BG, et al. N Engl J Med. 1990;323:1289-1298.9Brown BG, et al. N Engl J Med. 2001;345:1583-1592.

Statins

High-dose

statin

Fibrate

Niacin

Niacin +

BAS

Niacin +Statin

Ni i Fib t


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Niacin vs Fibrates:for Diabetic Dyslipidemia

Favoring Fibrates Better TG lowering

Reasonable LDL-C andHDL-C

Good Lp(a) (feno only) Ezetimibe combo data

Some CHD events (mono)

Microvasc. dis. (feno)

Better overall tolerability No flushing

Noglucose levels

Nogout/uric acid

NoPUD

Less Hcy

Favoring Niacin Better HDL-C raising

Reasonable LDL-C and TG

Better Lp(a) (esp vs. gemfib)

CHD events (mono & combo)

Total mortality

Statin combo compatibility

(better than gemfib only)

Statin combo tablet (ERNL)

Some tolerability advantages

Fewer GI Sx (N & V)

Nocreatinine

Nogallstones


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Fibrates and Renal Function

Modest in serum creatinine frequently

seen with fibrate use No evident in GFR

Mechanism unknown ( muscle

production vs renal secretion vs ?)

Clinical meaning unknown

Patients With CHD Risk Equivalentsa and


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Patients With CHD Risk Equivalentsa andLow HDL-C or High TG Taking Niacin or

Fibrates

Alsheikh-Ali AA, et al.Am J Cardiol. 2006;98:1231-1233.

Patients,%

4.7

8.2

4.9

9.5

0.91.9

0

5

10

15

20

a96% had diabetesbTG 200 mg/dL

Low HDL-Cn = 577

Elevated TGb

n = 158

NiacinFibrates

Niacin + Fibrates

Rhabdomyolysis Rate in Statins


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0.58

8.6

0

1

2

3

4

5

6

7

8

9

10

Fenofibrate Gemfibrozil

No.

CasesRep

orted

pe

rMillionPresc

riptions

15-Fold Increase

Jones PH, et al.Am J Cardiol. 2005;95:120-122.

*Excludes cases involving cerivastatin

Rhabdomyolysis Rate in Statins

Combo:

Gemfibrozil >> Fenofibrate


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Use ER-niacin instead of IR-niacin , dont cutorcrush tablet Take niacin at bedtime (alternates: supper or morning)

Start at 0.5g and uptitrate at 14 wk intervals to max dose 2g hs

Take with ASA 325mg

Naproxen 250-500 mg (notibuprofen, which may raise CVD risk)

Fish oil 1g/d Rx or 12g/d diet-supplement? Diphenhydramine?

Avoid interrupting niacin Rx whenever possible

Avoid spicy foods, hot beverages, alcohol and external heat near time

of niacin dose

Remind patient Flushing is notharmful and shows niacin is working*

Niacin is a vitamin

Dont take with high-dose antioxidant supplements

Consistent, long-term use may prevent CVD and save lives

After McKenney J.Arch Intern Med. 2004;164:697-705.

Rubenfire M.Am J Cardiol. 2004;94:306-311.*Flushing indicates best lipid and athero effects, see Taylor AJ and Staneck EJ, J Clin Lipidology2008:2:285-288

Instructions to Reduce Niacin-Induced

Flushing and Improve Patient Adherence


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STATINS and Elevated liver transaminases

Dose dependent elevations occur in 0.5-2% of

persons

Monitoring of ALT and AST should be obtained

initially, at 12 weeks and annually therafter

With hepatic disease, every 3-4 months

Minor elevations < 3 ULN recheck in 4 weeks

If > 3 times ULN repeat test. If elevated ,

discontinue statin


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COMMON PITFALLS

1 Failure to screen and treat dyslipidemia

2 Failure to identify dyslipidemia and other

risk factors in patients with CHD and

normal total cholesterol levels

3 Not searching for secondary causes and

screening family members of high riskpatients

4 Failure to initiate drug therapy

concurrently with lifestyle changes in high

risk groups


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5 Inadequate dosing of statins

6 Inadequate use of combination therapy

in higher risk patients who have not

achieved LDL cholesterol targets

7 Lack of follow up

8 Failure to educate patients about

benefits of lipid therapy beyond cholesterol

modification

9 Failure to initiate statins during

hospitalisation for acute coronary

syndromes

diabetic dyslipidemia2

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