Diabetic Dyslipidemia

1
Diabetic Dyslipidemia
2
Interrelation Between Atherosclerosis and Insulin
Resistance
Insulin Resistance
Hyper- insulinemia
Hypertri- glyceridemia
Small, dense LDL
Hypercoagu-lability
Hypertension
Obesity
Low HDL
Diabetes
Atherosclerosis
3
SHEEP Risk Factors for Nonfatal MI in Men and
Women
Risk FactorDiabetes High TC (?6.5 mmol/L) High
TG (?6.3 mmol/L)HTN (?170/95 mm Hg)Overweight
(BMI ?30 kg/m²)WHR (?0.85)Physical
inactivitySmokingJob strain
Women
Odds Ratio
Men
SHEEPStockholm Heart Epidemiology
Program. Reuterwall C et al. J Intern Med.
1999246161-174.
4
Atherosclerosis in Diabetes

• 80 of all diabetic mortality
• 75 from coronary atherosclerosis
• 25 from cerebral or peripheral vascular disease
• gt75 of all hospitalizations for diabetic
  complications
• gt50 of patients with newly diagnosed type 2
  diabetes have CHD

National Diabetes Data Group. Diabetes in
America. 2nd ed. NIH1995.
5
Risk Similar in Patients With Type 2 Diabetes and
No Prior MI vs Nondiabetic Subjects With Prior MI
100
80
60
Survival()
40
Nondiabetic subjects without prior MI
(n1,304)Diabetic subjects without prior MI
(n890)Nondiabetic subjects with prior MI
(n69)Diabetic subjects with prior MI (n169)
20
0
0
1
2
3
4
5
6
7
8
Year
Haffner SM et al. N Engl J Med. 1998339229-234.
6
Women, Diabetes, and CHD

• Diabetic women are at high risk for CHD
• Diabetes eliminates relative cardioprotective
  effect of being premenopausal
• risk of recurrent MI in diabetic women is three
  times that of nondiabetic women
• Age-adjusted mean time to recurrent MI or fatal
  CHD event is 5.1 yr for diabetic women vs 8.1 yr
  for nondiabetic women

Kannel WB. Am Heart J. 19851101100-1107. Abbott
RD et al. JAMA. 19882603456-3460.
7
Framingham Heart Study 30-Year Follow-UpCVD
Events in Patients With Diabetes (Ages 35-64)
10
10
9
Men
Women
8
11
Risk ratio
6
30
19
4
9
6
38
20
3
2
0
Total CVD
CHD
Cardiac failure
Intermittent claudication
Stroke
Age-adjusted annual rate/1,000
Plt0.001 for all values except Plt0.05. Wilson
PWF, Kannel WB. In Hyperglycemia, Diabetes and
Vascular Disease. Ruderman N et al, eds. Oxford
1992.
8
Potential Mechanisms of Atherogenesis in Diabetes

• Abnormalities in apoprotein and lipoprotein
  particle distribution
• Glycosylation and advanced glycation of proteins
  in plasma and arterial wall
• Glycoxidation and oxidation
• Procoagulant state
• Insulin resistance and hyperinsulinemia
• Hormone-, growth-factor, and cytokine-enhanced
  SMC proliferation and foam cell formation

SMCsmooth muscle cell. Adapted from Bierman EL.
Arterioscler Thromb. 199212647-656.
9
Abnormal Lipid Levels in Men With Type 2 Diabetes
50
Men without diabetes
Men with diabetes
40
34
30
26
Prevalence()
21
19
20
14
13
12
11
9
9
10
0
TC ?260
TG ?235
VLDL-C ?40
LDL-C ?190
HDL-C ?31
Plt0.05. LRC approximate 90th percentile age- and
sex-matched values, except for HDL-C (10th
percentile). Adapted from Garg A, Grundy SM.
Diabetes Care. 199013153-169.
10
Abnormal Lipid Levels in Women With Type 2
Diabetes
50
Women without diabetes
Women with diabetes
38
40
31
30
25
24
Prevalence()
21
17
20
16
15
10
8
10
0
TC ?275
TG ?200
VLDL-C ?35
LDL-C ?190
HDL-C ?41
Plt0.05. LRC approximate 90th percentile age- and
sex-matched values, except for HDL-C (10th
percentile). Adapted from Garg A, Grundy SM.
Diabetes Care. 199013153-169.
11
The Strong Heart Study Differences in CVD Risk
Factors by Diabetic Status in Men and Women
HDL-C
LDL Size
(mg/dL)
(Å)
Difference
between
subjects
with and
without
diabetes
Adjusted for age and center.
Adapted from Howard BV et al.
Diabetes Care
. 1998211258-1265.
12
Association of Small, Dense LDL With Insulin
Resistance
Steady-state plasma glucose
n19
12
10
n17
8
n19
Glucose (mmol/L)
6
4
2
0
A
B
Intermediate pattern
Adapted from Reaven GM et al. J Clin Invest.
199392141-146.
13
CHD Mortality and HyperinsulinemiaParis
Prospective Study (n943)
3
Plt0.01
2
CHD mortality (per 1,000)
1
0
?29 30-50 51-72 73-114 ?115
Quintiles (pmol) of fasting plasma insulin
Fontbonne AM et al. Diabetes Care.
199114461-469.
14
Prevalence of Macrovascular Disease and CHD
According to Quintiles of Fasting C-Peptide
Nondiabetic controls(n178)
Noninsulin-treatedtype 2 diabetics (n154)
60
80
P
lt0.001
P
lt0.05
70
50
60
40
50
Macrovasculardisease
Macrovasculardisease
30
40
30
20
20
10
10
0
0
1
2
3
4
5
1
2
3
4
5
80
60
P
lt0.002
70
50
60
40
50
40
30
CHD
CHD
30
20
20
10
10
0
0
1
2
3
4
5
1
2
3
4
5
Fasting C-peptide quintiles (1-5)
Janka HU. Horm Metab Res. 198515(suppl)15-19.
15
Responses to a 75-g Oral Glucose Challenge in
Relation to LDL Particle Diameter
10
1000
Plasma glucose
Insulin
8
800
6
600
Glucose(mmol/L)
Insulin(pmol/L)
4
400
LDL diameter averagePattern A 2684
(n52)Intermediate 2613 (n29)Pattern B
2504(n19)
2
200
0
0
30
60
120
180
30
60
120
180
Time (min)
Time (min)
Reaven GM et al. J Clin Invest. 199392141-146.
16
Primary CHD Prevention in Patients With Type 2
Diabetes The Helsinki Heart Study
Type 2 (n135)
15
Others (n3,946)
Type 2 on placebo (n76)
PNS
10.5
Type 2 on gemfibrozil (n59)
10
Plt0.02
5-Yr incidenceof CHD ()
7.4
5
3.4
3.3
0
Myocardial infarction or cardiac death. NSnot
significant. Koskinen P et al. Diabetes Care.
199215820-825.
17
UKPDS Intensive Blood-Glucose vs Conventional
Treatment in Patients With Type 2 Diabetes
Favors
Favors
Log-rank
RR (95 CI)
intensive
conventional
P
value
0.1
1
10
Clinical End Point
Any diabetes-related end point
0.88 (0.790.99)
0.029
Diabetes-related deaths
0.90 (0.731.11)
0.34
All-cause mortality
0.94 (0.801.10)
0.44
MI
0.84 (0.711.00)
0.052
Stroke
1.11 (0.811.51)
0.52
Amputation or death from PVD
0.65 (0.361.18)
0.15
Microvascular disease
0.75 (0.600.93)
0.0099
RRrelative risk.
PVDperipheral vascular disease.
UKPDS Group.
Lancet
. 1998352837-853.
18
UKPDS Tight Blood Pressure Control vs Less
Tight Control in Patients With Type 2 Diabetes
RR for
Favors
Favors
tight control
tight
less tight

P

(95 CI)
control
control
value
1
0.1
10
Clinical End Point
Any diabetes-related end point
0.76 (0.620.92)
0.0046
Diabetes-related deaths
0.68 (0.490.94)
0.019
All-cause mortality
0.82 (0.631.08)
0.17
MI
0.79 (0.591.07)
0.13
Stroke
0.56 (0.350.89)
0.013
Peripheral vascular disease
0.51 (0.191.37)
0.17
Microvascular disease
0.63 (0.440.89)
0.0092
RRrelative risk.
UKPDS Group.
BMJ
. 1998317703-713.
19
Secondary Prevention CHD Risk Reduction in the
4S Subgroup of Patients With Diabetes
Pyörälä K et al. Diabetes Care. 199720614-620.
20
4S Total Mortality Reduction in a Subgroup of
Patients With Diabetes
1.00
29
0.90
Proportion alive
0.80
43
Diabetic, simvastatin
- P0.08
0.70
Diabetic, placebo
Nondiabetic, simvastatin
- P0.001
Nondiabetic, placebo
0.60
Yr since randomization
Pyörälä K et al. Diabetes Care. 199720614-620.
21
4S Major CHD Event Reduction in a Subgroup of
Patients With Diabetes
Proportionwithoutmajor CHD event
32
Diabetic, simvastatin
- P0.002
Diabetic, placebo
55
Nondiabetic, simvastatin
- P0.0001
Nondiabetic, placebo
Yr since randomization
Pyörälä K et al. Diabetes Care. 199720614-620.
22
4S Treatment Benefit in Subgroup With Impaired
Fasting Glucose (FG 110-125 mg/dL)
Majorcoronaryevents
Revas-culari-zations
Totalmortality
Coronarymortality
? inevents()
P0.001
P0.010
P0.005
Haffner SM et al. Diabetes. 1998(suppl 1)A54.
Abstract.
23
CARE Reduction of Coronary Events in Patients
With Diabetes
40
35
27
30
25
22
withevent
20
15
10
5
0
0
1
2
3
4
5
6
Yr
N4,159 males and females 976 diabetics. Goldberg
R et al. Circulation. 199694I-540. Abstract.
24
Post-CABG Effect of Aggressive Lipid Lowering on
a Subgroup of Patients With Diabetes
Diabetes No Diabetes
Therapy Therapy
RR RR Aggressive Moderate (99
CI) Aggressive Moderate (99 CI)
Substantial progressionPer patient of
grafts 27.0 43.3 0.49 27.8 39.0 0.60
(0.20-1.19) (0.46-0.79) Number of
grafts 122 104 1,238 1,214 OcclusionPer
patient of grafts 11.5 19.2 0.54 10.4 16.0 0.61
(0.15-2.02) (0.41-0.92) Number of
grafts 122 104 1,238 1,214
Hoogwerf BJ et al. Diabetes. 1999481289-1294.
25
DAIS Impact of Aggressive Therapy on
Atherosclerosis in Patients With Type 2 Diabetes

• Study population
• N418 (305 men, 113 women)
• Type 2 diabetes
• ?1 minimal lesion on angiography
• Mild elevations of LDL-C or TG TCHDL-C ?4
• Treatment
• 8 weeks on Step I diet
• Randomized, blinded to micronized fenofibrate
  (200 mg/d) and placebo
• Primary end point
• Progression or regression of CAD on quantitative
  angiography

DAISDiabetes Atherosclerosis Intervention
Study. Steiner G et al. Am J Cardiol.
1999841004-1010.
26
DAIS Mean Baseline Lipoprotein Levels
P0.0005
PNS
PNS
mg/dL
P0.0001
Significant difference between genders. Steiner
G et al. Am J Cardiol. 1999841004-1010.
27
DAIS Interim Lipid Results in Patients With Type
2 Diabetes
Mean D
P0.0001. Steiner G. Diabetes. 199948(suppl
1)A2. Abstract 0005.
28
DAIS Final Results in Patients With Type 2
Diabetes

• CAD
• Treatment with fenofibrate resulted in 40
  reduction in rate of progression of localized
  CAD versus placebo
• 23 reduction in combined coronary events
  following fenofibrate treatment (PNS)
• Lipids
• Average reductions with fenofibrate TC, 10
  LDL-C, 6 TG, 29 average increase in HDL-C,
  6
• Safety
• Very few serious adverse events no significant
  differences in tolerability between fenofibrate
  and placebo treatments 95 compliance

Researchers report that results suggest benefit
to patients. Steiner G. XIIth International
Symposium on Atherosclerosis June 27, 2000
Stockholm, Sweden.
29
ADA-Suggested Standards for Biochemical Indices
of Metabolic Control
Biochemical index Acceptable Borderline High
Fasting plasma glucose (mg/dL) lt115 126 gt200 Postp
randial (2 hr)plasma glucose (mg/dL) lt140 200 gt23
5 Hemoglobin A1c () (Goal lt7) lt6 gt7 gt10 Fasti
ng plasma TC (mg/dL) lt200 200-239 ?240 Fasting
plasma TG (mg/dL) lt200 200-399 ?400 Fasting
plasma LDL-C (mg/dL) lt100 100-129 ?130 (100 if
CAD) Fasting plasma HDL-C (mg/dL) gt45 35-45 lt35
Current ADA recommendations call for
therapeutic action for values above
borderline. Adjust for normal lab
values. Adapted from Garber AJ et al. Diabetes
Care. 1992151068-1074 ADA. Diabetes Care.
199316828-834 and ADA. Diabetes Care.
199821(suppl 1)S36-S39.
30
Glycemic Control for People With Diabetes
Diabetic ActionBiochemical index Nondiabetic go
al suggested
Preprandial glucose (mg/dL) lt115 80-120 lt80 gt12
6 Bedtime glucose (mg/dL) lt120 100-140 lt100 gt16
0 Hemoglobin A1c () lt6 lt7 gt8
These values are for nonpregnant individuals.
Action suggested depends on individual patient
circumstances. Hemoglobin A1c is referenced to a
nondiabetic range of 4.0-6.0 (mean 5.0,
standard deviation 0.5).
ADA. Diabetes Care. 199619(suppl 1)S8-S15.
31
1999 ADA Risk Stratification Based on Lipoprotein
Levels in Adults With Diabetes
Risk LDL-C HDL-C TG High ?130 lt35 ?400 Borderline
100-129 35-45 200-399 Low lt100 gt45 lt200
Values represent mg/dL. For women, HDL-C should
be increased by 10 mg/dL.
ADA. Diabetes Care. 199922S56-S59.
32
1999 ADA Recommendations Based on LDL-C Levels in
Adults With Diabetes
Medical nutrition tx Drug tx
Initiation LDL-C Initiation LDL-CStatus level go
al level goal With CHD, PVDor CVD gt100 ?100 gt100
?100 Without CHD,PVD, and CVD gt100 ?100 ?130 ?10
0
Values represent mg/dL. Some authorities
recommend drug initiation between 100 and 130
mg/dL.
ADA. Diabetes Care. 199922S56-S59.
33
Order of Priorities for Treatment of Diabetic
Dyslipidemia in Adults

• LDL-C lowering
• first choice HMG-CoA reductase inhibitors
  (statins)
• second choice bile acid binding resin or
  fenofibrate
• HDL-C raising
• behavioral interventions (weight loss, ? physical
  activity, smoking cessation)
• glycemic control
• difficult (except with niacin, which is
  relatively contraindicated, or fibrates)
• TG lowering
• glycemic control first priority
• fibric acid derivative (gemfibrozil, fenofibrate)
• statins (moderately effective at high dose in
  patients with ? TG and ? LDL-C)

ADA. Diabetes Care. 199922S56-S59.
34
Order of Priorities for Treatment of Diabetic
Dyslipidemia in Adults

• Combined hyperlipidemia
• first choice improved glycemic control plus
  high-dose statin
• second choice improved glycemic control plus
  statin plus fibric acid derivative (gemfibrozil
  or fenofibrate)
• third choice improved glycemic control plus
  resin plus fibric acid derivative
• or
• improved glycemic control plus statin plus
  niacin (glycemic control must be monitored
  carefully)

ADA. Diabetes Care. 199922S56-S59.
35
Approach to Patients With Diabetes and
Hyperlipidemia
Without vascular disease. With vascular
disease.
36
Continuum of Patients at Risk for a CHD Event
Post MI/Angina
Secondary Prevention
Other Atherosclerotic Manifestations
Subclinical Atherosclerosis
PrimaryPrevention
Multiple Risk Factors
Low Risk
Courtesy of CD Furberg.
37
The Solution? Its Our Choice
CHD 1 Killer
CV Health
Aggressive Tx
Discontinued Tx
Dead End
Progress Road
Drug Tx
Intolerance to Tx
NCEP ATP-II
Inappropriate Tx
No Tx
Diet/Exercise
Complacency Way
Awareness
Under-recognition