Lipid disorders in diabetes

1
Lipid disorders in diabetes

• Dr. S.Martini
• MGSD, Padova, February 13, 2004

2
Lipid Metabolism
3
Lipoprotein Subclasses
4
LIPID M ETABOLISM IN DIABETES
Lancet 350, SI20, 1997
5
Dyslipidemia in Diabetes
Decreased
Increased

• Triglycerides
• VLDL
• LDL and small dense LDL
• Apo B

• HDL
• Apo A-I

6
LIPID DISORDERS IN DIABETES
7
Dyslipidemias in Adults with DiabetesFramingham
Heart Study
MEN
WOMEN
DM
DM
Normal
Normal
Increased cholesterol Increased LDL Decreased
HDL Increased triglycerides
14 11 12 9
13 9 21 19
21 16 10 8
24 15 25 17
Garg A et al. Diabetes Care 199013153-169.
8
Atherogenic Lipoprotein Profile
Small, dense LDL
TG
3 to 6 Increased CAD Risk
Metabolic Syndrome FCHL Type 2 Diabetes
HDL-C
(Austin et al. Circulation 1990)
9
LDL Atherogenicity
LDL Atherogenicity
LDL particle number
High
Risk of Premature CAD
Low
Hepatic Lipase
10
LDL Subclass Phenotypes in Diabetes Mellitus
LDL Subclass
Int
B
n
A
Men Diabetic Nondiabetic Women
Diabetic Nondiabetic
2987 54543
2847 3485
2129 309
5124 366
Percent
Feingold KR et al. Arterioscler Thromb 1992
121496-1502.
Selby JV et al. Circulation 1993 88381-387.
11
Diabetes and Atherosclerosis LDL Modifications
Small dense LDL
Normal LDL
Oxidized LDL
Glycated LDL
Monocytes -Macrophages
Foam Cells
12
Small Dense LDL and CHD Potential Atherogenic
Mechanisms

• Increased susceptibility to oxidation
• Increased vascular permeability
• Conformational changes in apo B
• Decreased affinity for LDL receptor
• Association with insulin resistance syndrome
• Association with high TG and low HDL

Austin MA et al. Curr Opin Lipidol 19967167-171.
13
Small dense LDL and Atherosclerotic Plaque
Vessel Lumen
Monocyte
Small-dense LDL
AdhesionMolecules
Endothelium
MCP-1
LDL
Intima
?ox-LDL
Cytokines
Growth FactorsMetalloproteinases
Cell ProliferationMatrix Degradation
Macrophage
Foam Cell
Unstable plaque
Ross R. N Engl J Med 1999340115-126.
14
HDL Antiatherogenic Lipoprotein
Vessel Lumen
Monocyte
LDL
Endothelium
LDL
Modified LDL
Foam Cell
Macrophage
Intima
Miyazaki A et al. Biochim Biophys Acta
1992112673-80.
15
Plasma Insulin and Triglycerides predict Ischemic
Heart Disease Quebec Cardiovascular Study
6.7
5.4
Plt0.001
P0.002
p0.001
Triglycerides
p0.005
Odds Ratio
5.3
1.5
4.6
gt150 mg/dl
1.0
lt150 mg/dl
lt12
12-15
gt15
F-Insulin (?U/ml)
Despres JP et al. N Engl J Med 1996334952-957.
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Plasma Insulin and Apolipoprotein B predict
Ischemic Heart Disease Quebec Cardiovascular
Study
11.0
9.7
plt0.001
Plt0.001
Odds Ratio
Apolipoprotein B
1.5
3.2
3.0
gt119 mg/dl
p0.04
p0.04
1.0
lt119 mg/dl
lt12
12-15
gt15
F-Insulin (?U/ml)
Despres JP et al. N Engl J Med 1996334952-957.
17
LDL particle size and Apolipoprotein B predict
Ischemic Heart Disease Quebec Cardiovascular
Study
6.2
(plt0.001)
2.0
Apo B
gt120 mg/dl
1.0
1.0
lt120 mg/dl
gt25.64
lt25.64
LDL Peak Particle Diameter (nm)
Lamarche B et al. Circulation 19979569-75.
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Frequency of different Forms of Dyslipidemia in
men with Coronary Artery Disease
Frequency ()
ALP ? TG ? HDL-C
Small, dense LDL
(Superko, Circulation, 1996)
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Mean Plasma Lipids at Diagnosis of Type 2
Diabetes - UKPDS
MEN
WOMEN
Type 2
Type 2
Control
Control
2139 213 139 39 159
52 205 132 43 103
1574 224 151 43 159
143 217 135 55 95
Number of Pts TC (mg/dl) LDL-C (mg/dl) HDL-C
(mg/dl) TG (mg/dl)
plt0.001, plt0.02 comparing type 2 vs.
control
UKPDS Group. Diabetes Care 1997201683-1687.
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Stepwise Selection of Risk Factors in 2693 White
Patients with Type 2 Diabetes with Dependent
Variable as Time to First Event UKPDS
Coronary Artery Disease (n280)
Position in Model First Second Third Fourth Fifth
Variable LDL Cholesterol HDL
Cholesterol Hemoglobin A1c Systolic Blood
Pressure Smoking
p Value lt0.0001 0.0001 0.0022 0.0065 0.056
Adjusted for age and sex. Turner RC et al. BMJ
1998316823-828.
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(No Transcript)
22
CVD PREDICTORS IN TYPE 2 DIABETES THE STRONG
HEART STUDY
Diabetes Care 26, 16, 2003
23
Insulin Resistance and Hyperinsulinemia
Clinical Clues

• Abdominal obesity
• ? TG ? HDL-C
• Glucose intolerance
• Hypertension
• Atherosclerosis

24
The metabolic syndrome (ATPIII)
Presence of ?3 of the following risk factors
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-2497.
25
Trials of CHD prevention with Statins in
Diabetics subgroup Analysis
Downs JR et al. JAMA 19982791615-1622. HPS
Investigators. Lancet 2002 Goldberg RB et al.
Circulation 1998982513-2519. Pyorala K et al.
Diabetes Care 199720614-620. Haffner SM et
al. Arch Intern Med 19991592661-2667. LIPID
Study Group. N Engl J Med 19983391349-1357.
26
Trials of CHD prevention with Statins in
Diabetics subgroup Analysis
Downs JR et al. JAMA 19982791615-1622. HPS
Investigators. Lancet 2002. Goldberg RB et al.
Circulation 1998982513-2519. Pyorala K et al.
Diabetes Care 199720614-620. LIPID Study
Group. N Engl J Med 19983391349-1357. Haffner
SM et al. Arch Intern Med 19991592661-2667.
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Major Coronary Events in 4S Patients with or
without Diabetes by History (n202)
1.0 0.9 0.8 0.7 0.6 0.5 0
Proportion without Major CHD Event
Diabetes by Hx, simvastatinDiabetes by Hx,
placebo No diabetes by Hx, simvastatinNo
diabetes by Hx, placebo
P0.002
P0.0001
0
1
2
3
4
5
6
Years Since Randomization
Pyörälä et al. Diabetes Care 199720614-620.
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EXPANDED 4S DIABETES ANALYSISMajor coronary
events
Haffner et al, Diabetes 199847 (Suppl 1)A54.
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4S Extended Diabetic Subgroup Analysis
Diabetes (n483 251 on Simvastatin) Fasting
Glucose gt126 mg/dl
0.72
CHD mortality (P0.26) Total mortality
(P0.34) Revascularizations (P0.005) Major
coronary events (P0.001)
0.79
0.52
0.58
0.8
0.0
1.4
0.6
1.0
1.2
0.2
0.4
Relative Risk
Adapted from Haffner SM et al. Arch Intern Med
19991592661-2667
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4S Extended Diabetic Subgroup
AnalysisImpaired Fasting Glucose (n678 343 on
Simvastatin) Fasting Glucose 110-125 mg/dl
0.45
CHD mortality (P0.007) Total mortality
(P0.02) Revascularizations (P0.01) Major
coronary events (P0.003)
0.57
0.57
0.62
0.4
0.0
1.4
0.6
1.0
1.2
0.8
0.2
Relative Risk
Adapted from Haffner SM et al. Arch Intern Med
19991592661-2667
31
Heart Protection Study Vascular Events by
Baseline Disease
Risk ratio and 95 CI
Statin better
Statin worse
? 24 2.6 (2P lt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
Collins R. Lancet 2002
32
HEART PROTECTION STUDY
Lancet 361, 2005, 2003
33
CARE Major Coronary Events in Diabetic
Subgroups
Diabetes by History
No Diabetes by History
45 40 35 30 25 20 15 10 5 0
45 40 35 30 25 20 15 10 5 0
Relative risk 0.75P0.05
Relative risk 0.77Plt0.001
Placebo
Placebo
Percent with Event
Percent with Event
Pravastatin
Pravastatin
Follow-up Time (years)
Follow-up Time (years)
Goldberg RB et al. Circulation 1998982513-2519.
34
Coronary heart disease in patients with low
LDL-cholesterol benefit of pravastatin in
diabetics and enhanced role for HDL-cholesterol
and triglycerides as risk factors Circulation
2002 Mar 26105(12)1424-8

• Combined analysis CARE and LIPID studies(PPP
  study)
• 13173 patients
• 2607 with LDL-C lt 125 mg/dl
• 270 diabetics with LDL-C lt 125 mg/dl

35
CHD Prevention Trials with Fibrates in Diabetic
Subjects Subgroup Analyses
Koskinen P et al. Diabetes Care 199215820-825.
Rubins HB et al. N Engl J Med 1999341410-418.
DAIS Investigators. Lancet 2001357905-910.
36
Primary CHD Prevention in Type 2 Diabetic
Patients The Helsinki Heart Study
P0.19
10.5
Plt0.02
7.4
5-Year Incidence of CHD ()
3.4
3.3
Type 2(n135)
Others(n3946)
Type 2 on Placebo(n76)
Type 2 onGemfibrozil(n59)
Myocardial infarction or cardiac death Adapted
from Koskinen P et al. Diabetes Care
199215820-825.
37
VA-HIT Incidence of Death from CHD and Nonfatal
MI
Placebo
Gemfibrozil
Cumulative Incidence ()
Year
Rubins HB et al. N Engl J Med 1999341410-418.
38
VA-HIT SUB-GROUP ANALYSIS
Arch Intern Med 162, 2597, 2002
39
CHD Risk Equivalent

• Patients with established CHD have a risk for
  recurrent MI and CHD death that exceeds 20 per
  10 years. Clinically evident noncoronary
  atherosclerosis, as well as type 2 diabetes
  mellitus, impose an approximately equal risk for
  developing CHD in patients without clinical CHD.
• CHD risk equivalents
• Multiple risk factors (gt20 10-year CHD risk)
• Type 2 diabetes mellitus
• Peripheral arterial disease
• Abdominal aortic aneurysm
• Carotid artery disease

Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-2497.
40
Diabetes as a CHD Risk Equivalent

• Implies that enhanced benefit will be achieved
  from aggressive LDL-lowering therapy
• Post-hoc analysis of all statin trials showed a
  trend for benefit of LDL lowering in persons with
  diabetes

41
LDL Cholesterol Goals and Cutpoints (mg/dl) for
Therapy in Different Risk Categories
42
Non-HDL-C Goals in Patients with TG ?200 mg/dL
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-2497.
43
ATP III Management of Diabetic Dyslipidemia

• Primary target of therapy LDL-C
• Diabetes CHD risk equivalent
• Therefore, goal for persons with diabetes lt100
  mg/dL
• Therapeutic options
• LDL-C 100129 mg/dL increase intensity of TLC
  add drug to modify atherogenic dyslipidemia
  (fibrate or nicotinic acid) intensify statin
  therapy
• LDL-C ?130 mg/dL simultaneously initiate TLC
  and LDL-Clowering drugs
• After LDL-C goal is met, if TG ?200 mg/dL
  nonHDL-C (lt130 mg/dl) becomes secondary target

ATP III. JAMA 20012852486-2497.
44
Clinical Management of Metabolic Syndrome

• Management of underlying causes
• Weight control enhances LDL lowering and
  reduces all risk factors
• Physical activity reduces VLDL and LDL and
  increases HDL
• Treat lipid and nonlipid risk factors
• Hypertension
• Aspirin in CHD patients
• Elevated triglycerides
• Low HDL

Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-2497.
45
Treatment Strategies for Diabetic Dyslipidemia

• Primary Strategy
• - Lower LDL cholesterol
• Secondary Strategy
• - Raise HDL cholesterol
• - Lower triglycerides
• Other Approaches
• - Non-HDL cholesterol
• - ApoB
• - Remnants

American Diabetes Association. Diabetes Care.
200023(suppl 1)S57-S60 Chait A, Brunzell JD.
Diabetes Mellitus. A Fundamental and Clinical
Text. Philadelphia Lippincott Raven,
1996772-779 European Diabetes Policy Group
1999. Diabet Med. 199916716-730.
46
Order of Priorities for Treatment of Diabetic
Dyslipidemia in Adults

• LDL cholesterol lowering
• - First choice HMG CoA reductase inhibitor
  (statin)
• - Second choice Bile acid binding resin or
  fenofibrate
• HDL cholesterol raising
• - Behavioral interventions such as weight
  loss, increased physical activity and smoking
  cessation
• - Glycemic control
• - Difficult except with nicotinic acid,
  which is relatively contraindicated, or fibrates
• Triglyceride lowering
• - Glycemic control first priority
• - Fibric acid derivatives (gemfibrozil,
  fenofibrate)
• - Statins are moderately effective at high
  dose in hypertriglyceridemic subjects who also
  have high LDL cholesterol
• Decision for treatment of high LDL before
  elevated triglyceride is based on clinical trial
  data indicating safety as well as efficacy of the
  available agents.

American Diabetes Association. Diabetes Care
200023(suppl 1)S57-S60.
47
Diabetes Care 26, suppl 1, 2003
48
Diabetes Care 26, suppl 1, 2003
49
European Task Force 2003 definition of high risk

• Subjects with established cardiovascular disease
  (CHD, PAD, CVD)
• Asymptomatic subjects who have
  a) multiple risk
  factors resulting in a 10 year risk of fatal
  cardiovascular events ? 5 (now or extrapolated
  to age 60)
  b) markedly raised levels
  of single risk factors CT ? 320 , LDL-C ? 240,
  blood pressure ?180/110
  c) diabetes type II and
  diabetes type I with microalbuminuria
  

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European Task Force 2003 goals of treatment in
type 2 diabetes

• HbA1c lt 6.1
• Fasting/pre-prandial venous plasma glucose lt 110
  mg/dl
• Self-monitored blood glucose Fasting/pre-prandia
  l 70-90 mg/dl post-prandial 70-135 mg/dl
• blood pressure lt 130/80
• total cholesterol lt 175 mg/dl
• LDL cholesterol lt 100 mg/dl