Diabetic Dyslipidemia
Jan 02, 2016
Hypertension Obesity Hyper-insulinemia
Diabetes Hypertri-glyceridemia
Small,dense LDL
Low HDL Hypercoagu-lability
Atherosclerosis
Insulin Resistance
Interrelation Between Atherosclerosis and Insulin Resistance
SHEEP: Risk Factors for Nonfatal MI in Men and Women
SHEEP=Stockholm Heart Epidemiology Program.
Reuterwall C et al. J Intern Med. 1999;246:161-174.
Risk Factor
Diabetes
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 inactivity
Smoking
Job strain
Men
Women 0 1 2 3 4 5 6 7 8
Odds RatioOdds Ratio
National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.
Atherosclerosis in Diabetes• ~80% of all diabetic mortality
– 75% from coronary atherosclerosis
– 25% from cerebral or peripheral vascular disease
• >75% of all hospitalizations for diabetic complications
• >50% of patients with newly diagnosed type 2 diabetes have CHD
Haffner SM et al. N Engl J Med. 1998;339:229-234.
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
Nondiabetic subjects without prior MI (n=1,304)Diabetic subjects without prior MI (n=890)Nondiabetic subjects with prior MI (n=69)Diabetic subjects with prior MI (n=169)
Survival(%)
Year
Risk Similar in Patients With Type 2 Diabetes and No Prior MI vs Nondiabetic Subjects With Prior MI
Kannel WB. Am Heart J. 1985;110:1100-1107.Abbott RD et al. JAMA. 1988;260:3456-3460.
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
Framingham Heart Study 30-Year Follow-Up:CVD Events in Patients With Diabetes (Ages 35-64)
109
20
11
9 63819
3*
30
0
2
4
6
8
10
Age-adjusted annual rate/1,000
Men Women
Total CVD CHD Cardiac failure
Intermittent claudication
Stroke
Riskratio
P<0.001 for all values except *P<0.05.
Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease.Ruderman N et al, eds. Oxford; 1992.
SMC=smooth muscle cell.
Adapted from Bierman EL. Arterioscler Thromb. 1992;12:647-656.
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
149
26
11 12139
21*
34*
19*
0
10
20
30
40
50 Men without diabetes
Men with diabetes
TC260
TG235
VLDL-C40
LDL-C190
HDL-C31
Prevalence(%)
*P<0.05.LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile).
Adapted from Garg A, Grundy SM. Diabetes Care. 1990;13:153-169.
Abnormal Lipid Levels in Men With Type 2 Diabetes
21
8
31
16
10
24
38
15
25*
17*
0
10
20
30
40
50 Women without diabetes
Women with diabetes
TC275
TG200
VLDL-C35
LDL-C190
HDL-C41
Prevalence(%)
*P<0.05.LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile).
Adapted from Garg A, Grundy SM. Diabetes Care. 1990;13:153-169.
Abnormal Lipid Levels in Women With Type 2 Diabetes
The Strong Heart Study: Differences in CVD RiskFactors by Diabetic Status in Men and Women*
*Adjusted for age and center.
Adapted from Howard BV et al. Diabetes Care. 1998;21:1258-1265.
-4.4
-3.7
-7.5
-5.3
-8
-7
-6
-5
-4
-3
-2
-1
0
Men
Women
HDL-C(mg/dL)
LDL Size(Å)
Differencebetweensubjectswith andwithoutdiabetes
A BIntermediatepattern
0
2
4
6
8
10
12
Glucose(mmol/L)
Adapted from Reaven GM et al. J Clin Invest. 1993;92:141-146.
Steady-state plasma glucose
n=19
n=17
n=19
Association of Small, Dense LDL With Insulin Resistance
0
1
2
3
CHD mortality
(per 1,000)
Fontbonne AM et al. Diabetes Care. 1991;14:461-469.
29 30-50 51-72 73-114 115
Quintiles (pmol) of fasting plasma insulin
P<0.01
CHD Mortality and Hyperinsulinemia:Paris Prospective Study (n=943)
0102030405060
1 2 3 4 5
% M
acro
vasc
ula
rd
isea
se
P<0.001
01020304050607080
1 2 3 4 5
% M
acro
vasc
ula
rd
isea
se
P<0.05
0102030405060
1 2 3 4 5
% C
HD
P<0.002
01020304050607080
1 2 3 4 5
% C
HD
Nondiabetic controls(n=178)
Noninsulin-treatedtype 2 diabetics (n=154)
Fasting C-peptide quintiles (1-5)
Janka HU. Horm Metab Res. 1985;15(suppl):15-19.
Prevalence of Macrovascular Disease and CHD According to Quintiles of Fasting C-Peptide
Glucose(mmol/L)
Time (min) Time (min)
Reaven GM et al. J Clin Invest. 1993;92:141-146.
Insulin(pmol/L)
0
2
4
6
8
10
30 60 120 180
Plasma glucose
LDL diameter averagePattern A: 268±4 (n=52)Intermediate: 261±3 (n=29)Pattern B: 250±4(n=19)
0
200
400
600
800
1000
30 60 120 180
Insulin
Responses to a 75-g Oral Glucose Challenge in Relation to LDL Particle Diameter
7.4
3.3
10.5
3.4
0
5
10
15Type 2 (n=135)
Others (n=3,946)
Type 2 on placebo (n=76)
Type 2 on gemfibrozil (n=59)
5-Yr incidenceof CHD (%)
*Myocardial infarction or cardiac death.NS=not significant.
Koskinen P et al. Diabetes Care. 1992;15:820-825.
P<0.02
P=NS
Primary CHD* Prevention in Patients With Type 2 Diabetes: The Helsinki Heart Study
UKPDS: Intensive Blood-Glucose vs ConventionalTreatment in Patients With Type 2 Diabetes
RR=relative risk.PVD=peripheral vascular disease.
UKPDS Group. Lancet. 1998;352:837-853.
Any diabetes-related end point 0.88 (0.79–0.99) 0.029
Diabetes-related deaths 0.90 (0.73–1.11) 0.34
All-cause mortality 0.94 (0.80–1.10) 0.44
MI 0.84 (0.71–1.00) 0.052
Stroke 1.11 (0.81–1.51) 0.52
Amputation or death from PVD 0.65 (0.36–1.18) 0.15
Microvascular disease 0.75 (0.60–0.93) 0.0099
Favors Favors Log-rank RR (95% CI) intensive conventional P value
Clinical End Point0.1 1 10
Any diabetes-related end point 0.76 (0.62–0.92) 0.0046
Diabetes-related deaths 0.68 (0.49–0.94) 0.019
All-cause mortality 0.82 (0.63–1.08) 0.17
MI 0.79 (0.59–1.07) 0.13
Stroke 0.56 (0.35–0.89) 0.013
Peripheral vascular disease 0.51 (0.19–1.37) 0.17
Microvascular disease 0.63 (0.44–0.89) 0.0092
UKPDS: Tight Blood Pressure Control vs LessTight Control in Patients With Type 2 Diabetes
RR=relative risk.
UKPDS Group. BMJ. 1998;317:703-713.
RR for Favors Favors tight control tight less tight P
(95% CI) control control value
Clinical End Point10.1 10
Secondary Prevention: CHD Risk Reduction in the 4S Subgroup of Patients With Diabetes
Pyörälä K et al. Diabetes Care. 1997;20:614-620.
Total mortality 232167
2415
CHD mortality 172991712
Major CHD event 578407
4424
Any CHD event 871667
5641
CABG or PTCA 363238
2015
Cerebrovascular event 907012
5
Any atherosclerotic event 961750
6146
NondiabeticDiabetic
P S
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
RR with 95% CIs
No. patients Simvastatin Placebowith events better better
0.60
0.70
0.80
0.90
1.00
4S: Total Mortality Reduction in a Subgroup of Patients With Diabetes
Pyörälä K et al. Diabetes Care. 1997;20:614-620.
Proportion alive
Yr since randomization
- P=0.08
- P=0.001
Diabetic, simvastatin
Diabetic, placebo
Nondiabetic, simvastatin
Nondiabetic, placebo
29%
43%
4S: Major CHD Event Reduction in a Subgroup of Patients With Diabetes
Pyörälä K et al. Diabetes Care. 1997;20:614-620.
0.50
0.60
0.70
0.80
0.90
1.00
Proportionwithout
major CHD event
Yr since randomization
- P=0.002
- P=0.0001
Diabetic, simvastatin
Diabetic, placebo
Nondiabetic, simvastatin
Nondiabetic, placebo
32%
55%
4S: Treatment Benefit in Subgroup With Impaired Fasting Glucose (FG 110-125 mg/dL)
Haffner SM et al. Diabetes. 1998;(suppl 1):A54. Abstract.
-46
-56
-40-43
-60
-50
-40
-30
-20
-10
0
Totalmortality
Coronarymortality
Majorcoronary
events
Revas-culari-zations
inevents
(%)
P=0.005
P=0.001P=0.010
CARE: Reduction of Coronary Events in Patients With Diabetes
N=4,159 males and females; 976 diabetics.
Goldberg R et al. Circulation. 1996;94:I-540. Abstract.
0
5
10
15
20
25
30
35
40
0 1 2 3 4 5
% withevent
Yr
27%
22%
- P=0.001Diabetic, pravastatin
Diabetic, placebo
Nondiabetic, pravastatin
Nondiabetic, placebo- P=0.012
6
Post-CABG: Effect of Aggressive Lipid Lowering on a Subgroup of Patients With Diabetes
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
Therapy Therapy
Diabetes No Diabetes
Hoogwerf BJ et al. Diabetes. 1999;48:1289-1294.
RR RRAggressive Moderate (99% CI) Aggressive Moderate (99%
CI)
DAIS: Impact of Aggressive Therapy on Atherosclerosis in Patients With Type 2 DiabetesStudy population• N=418 (305 men, 113 women)• Type 2 diabetes 1 minimal lesion on angiography• Mild elevations of LDL-C or TG + TC:HDL-C 4Treatment• 8 weeks on Step I diet• Randomized, blinded to micronized fenofibrate (200 mg/d)
and placeboPrimary end point• Progression or regression of CAD on quantitative angiography
DAIS=Diabetes Atherosclerosis Intervention Study.
Steiner G et al. Am J Cardiol. 1999;84:1004-1010.
mg/dL
* Significant difference between genders.
Steiner G et al. Am J Cardiol. 1999;84:1004-1010.
DAIS: Mean Baseline Lipoprotein Levels
215
40
133
214212
38
131
215223
44
137
212
0
50
100
150
200
250
TC HDL-C LDL-C TG
All Men Women
P=0.0005*
P=0.0001*
P=NS
P=NS
Mean%
*P=0.0001.
Steiner G. Diabetes. 1999;48(suppl 1):A2. Abstract 0005.
DAIS: Interim Lipid Results in Patients With Type 2 Diabetes
0.8 0.6 1.6 2.1
-9.0
6.7
-5.7
-27.2-30
-20
-10
0
10
20
30
TC* HDL-C* LDL-C* TG*
Placebo Fenofibrate
*Researchers report that results suggest benefit to patients.
Steiner G. XIIth International Symposium on Atherosclerosis; June 27, 2000; Stockholm, Sweden.
DAIS: Final Results in Patients With Type 2 DiabetesCAD• 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 (P=NS*)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
ADA-Suggested Standards for Biochemical Indices of Metabolic ControlBiochemical index Acceptable Borderline* High
Fasting plasma glucose (mg/dL) <115 126>200
Postprandial (2 hr)plasma glucose (mg/dL) <140 200
>235
Hemoglobin A1c (%)† (Goal: <7%) <6 >7>10
Fasting plasma TC (mg/dL) <200 200-239240
Fasting plasma TG (mg/dL) <200 200-399400
Fasting plasma LDL-C (mg/dL) <100 100-129130
(100 if CAD)
Fasting plasma HDL-C (mg/dL) >45 35-45<35
* Current ADA recommendations call for therapeutic action for values above “borderline.”† Adjust for normal lab values.Adapted from Garber AJ et al. Diabetes Care. 1992;15:1068-1074; ADA. Diabetes Care. 1993;16:828-834; and ADA. Diabetes Care. 1998;21(suppl 1):S36-S39.
Glycemic Control for People With Diabetes
Diabetic ActionBiochemical index Nondiabetic goal suggested
Preprandial glucose (mg/dL) <115 80-120 <80>126
Bedtime glucose (mg/dL) <120 100-140 <100>160
Hemoglobin A1c (%) <6 <7 >8These 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. 1996;19(suppl 1):S8-S15.
1999 ADA Risk Stratification Based on Lipoprotein Levels in Adults With Diabetes*
ADA. Diabetes Care. 1999;22:S56-S59.
Risk LDL-C HDL-C TG
High 130 <35 400
Borderline 100-129 35-45 200-399
Low <100 >45 <200
*Values represent mg/dL. For women, HDL-C should be increased by 10 mg/dL.
1999 ADA Recommendations Based on LDL-C Levels in Adults With Diabetes*
ADA. Diabetes Care. 1999;22:S56-S59.
Initiation LDL-C Initiation LDL-CStatus level goal levelgoal
With CHD, PVDor CVD >100 100 >100100
Without CHD,PVD, and CVD >100 100 130†
100
*Values represent mg/dL.†Some authorities recommend drug initiation between 100 and 130 mg/dL.
Medical nutrition txMedical nutrition tx Drug txDrug tx
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. 1999;22:S56-S59.
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. 1999;22:S56-S59.
* Without vascular disease.† With vascular disease.
Approach to Patients With Diabetes and Hyperlipidemia
AcceptableLDL-C <100
TG <200
Monitor annually
Improvement
Hypercholesterolemia Goal
LDL-C <130*LDL-C <100†
HMG-CoAResin
HypertriglyceridemiaGoal
TG <400* TG <200†
Fibrate HMG-CoA if LDL
Mixed DyslipidemiaGoal
TG <400 LDL-C <130*TG <200 LDL-C <100†
HDL-C >35
HMG-CoAFibrate + resin
HyperchylomicronemiaTG 1000
Fibrate and fat restriction
(<10% of calories)
Measure (fasting): TC, TG, HDL-C,LDL-C (calculated), glucose, HbA1c
Higher risk: LDL-C 130, TG 400, HDL-C <35Lower risk: LDL-C <100, TG <200, HDL-C >45
Regulate diabetes: weight loss, exercise,restrict dietary saturated fat and cholesterol
No improvement
Continuum of Patients at Risk for a CHD Event
Post MI/Angina
Other Atherosclerotic Manifestations
Subclinical Atherosclerosis
Multiple Risk Factors
Low Risk
SecondaryPrevention
PrimaryPrevention
Courtesy of CD Furberg.