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