4S: Total Mortality Reduction in a Subgroup of Patients With Diabetes
1.00
5.00
0.90 4.00
29%
Proportion alive
0.80
43%
2.00
3.00
0.70
1.00
0.60
0.00 0
Diabetic, simvastatin - P=0.08 Diabetic, placebo Nondiabetic, simvastatin - P=0.001 Nondiabetic, placebo
1 2 3 4 5 6
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Yr since randomization
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4S: Major CHD Event Reduction in a Subgroup of Patients With Diabetes
1.00 5.00 0.90 4.00
Proportion without major CHD event
0.80 3.00 0.70 2.00 0.60 1.00 0.50 0.00
0
Diabetic, simvastatin
32%
- P=0.002
Diabetic, placebo
Nondiabetic, placebo
55%
Nondiabetic, simvastatin
- P=0.0001
1
2
3
4
5
6
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Yr since randomization
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4S: Treatment Benefit in Subgroup With Impaired Fasting Glucose (FG 110-125 mg/dL)
0 -10
Total mortality Coronary mortality
Major coronary events Revascularizations
in events (%)
-20 -30 -40 -50 -60
-46 -56 -40 P=0.001
-43
P=0.010
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P=0.005
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CARE: Reduction of Coronary Events in Patients With Diabetes
40 35 30
27%
22%
% with event
25 20
15 10 5 0
0 1 2 Yr 3
Diabetic, pravastatin - P=0.001 Diabetic, placebo
Nondiabetic, pravastatin
Nondiabetic, placebo 4 5 6
- P=0.012
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N=4,159 males and females; 976 diabetics.
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CARE: Major Coronary Events in the Diabetic Subgroup
Number of patients Number (%) of patients with event
Risk reduction Pravastatin (95% CI)
Diabetes: Placebo Pravastatin Placebo Present
Absent
P value 0.05
304
1774
282
1799
112 (37)
437 (25)
81 (29)
349 (19)
25 (0 to 43)
23 (11 to 33) <0.001
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Sacks FM et al. N Engl J Med. 1996;335:1001-1009.
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Post-CABG: Effect of Aggressive Lipid Lowering on a Subgroup of Patients With Diabetes
Diabetes Therapy No Diabetes Therapy
RR RR Aggressive Moderate (99% CI) Aggressive Moderate (99% CI)
Substantial progression Per patient % of grafts
27.0
43.3
0.49 (0.20-1.19)
27.8
39.0
0.60 (0.46-0.79)
Number of grafts
Occlusion Per patient % of grafts
122
11.5
104
19.2 0.54 (0.15-2.02)
1,238
10.4
1,214
16.0 0.61 (0.41-0.92)
Number of grafts
122
104
1,238
1,214
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Hoogwerf BJ et al. Diabetes. 1999;48:1289-1294.
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Effects of Lipid-Lowering Therapy in Patients With Type 2 Diabetes
10 5 0 -5 Mean % from baseline -10 -15 at 4 wk -20 (N=17) -25 -30 -35 -40 -45 *P<0.01
8 TC LDL-C TG HDL-C 8
-18
-24 -30*
-42*
-30
-27
Atorvastatin 10 mg Simvastatin 10 mg
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WOSCOPS: Development of Type 2 Diabetes
6 5 4
Placebo Pravastatin 40 mg/d
% diabetic
3 2
1 0
0
0.5
1
1.5
2
2.5 3 3.5 Years in study
4
4.5
5
5.5
Kaplan-Meier plots of time to development of type 2 diabetes according to treatment assignment.
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© 1999 Professional Postgraduate Services ®
AHA Primary Prevention Guidelines for CVD in Patients with Diabetes
• Smoking: provide counseling to patient and family -- goal is complete cessation • Blood pressure control: Measure BP at each visit, consider medication above 130/85 (JNCVI), goal <130/80 (ADA) • Lipid management - Goal LDL-C <100 mg/dl (NCEP III), consider medication when LDL-C >130 mg/dl • Glucose control - weight reduction and exercise are first steps, further therapy involve oral hypoglycemic agents and insulin
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© 1999 Professional Postgraduate Services ®
AHA Primary Prevention Guidelines for Diabetics (continued)
• Antiplatelet agents - Aspirin 80-325 mg/day recommended in high risk pts (e.g., 1+ risk factors in addition to diabetes- ADA) • Physical activity - 30 minutes moderate intensity exercise 3-4 times/week in daily life habits • Weight management - Desirable BMI 21-25, desirable waist circumference <102cm in men and <88cm in women • Estrogen replacement therapy - no current recommendations given recent clinical trials
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Considerations for Prevention in Type I Diabetes
• Duration of disease is the predominant risk factor in Type I diabetics • Smoking, hypertension, renal disease (macroalbuminuria and renal insufficiency), and dyslipidemia remain important and should be treated as indicated for Type II diabetic patients
• Depending on age, use of certain lipid-lowering medications (e.g., statins) may be contraindicated, although goal LDL<100 mg/dl is still appropriate.
• Ongoing Epidemiology of Diabetes Interventions and Complications (EDIC) study will examine impact of intensive glucose control on future risk factor status and presence of subclinical disease (carotid atherosclerosis and coronary calcium)
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ADA-Suggested Standards for Biochemical Indices of Metabolic Control
Biochemical index Fasting plasma glucose (mg/dL) Postprandial (2 hr) plasma glucose (mg/dL) Hemoglobin A1c (%)† (Goal: <7%) Fasting plasma TC (mg/dL) Fasting plasma TG (mg/dL) Fasting plasma LDL-C (mg/dL) Fasting plasma HDL-C (mg/dL) Acceptable <115
<140 <6 <200 <200 <100 (100 if CAD) >45
Borderline* 126
200 >7 200-239 200-399 100-129
High >200
>235 >10 240 400 130
35-45
<35
* Current ADA recommendations call for therapeutic action for
values above “borderline.” † Adjust for normal lab values.
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Glycemic Control for People With Diabetes
Biochemical index Preprandial glucose (mg/dL)
Bedtime glucose (mg/dL)
Diabetic Action Nondiabetic goal suggested <115
<120
80-120
100-140
Hemoglobin A1c (%)
<6
<7
<80 >126 <100 >160 >8
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%).
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ADA. Diabetes Care. 1996;19(suppl 1):S8-S15.
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Weight Management and Physical Activity in Persons with Diabetes
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© 1999 Professional Postgraduate Services ®
1999 ADA Risk Stratification Based on Lipoprotein Levels in Adults With Diabetes*
Risk High LDL-C 130 HDL-C <35 35-45 >45 TG 400 200-399 <200
Borderline 100-129 Low <100
*Values represent mg/dL. For women, HDL-C should be increased by 10 mg/dL.
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ADA. Diabetes Care. 1999;22:S56-S59.
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1999 ADA Recommendations Based on LDL-C Levels in Adults With Diabetes*
Medical nutrition tx
Status Initiation level LDL-C goal
Drug tx
Initiation level LDL-C goal
With CHD, PVD or CVD Without CHD, PVD, and CVD
>100 >100
100 100
>100 130†
100 100
*Values represent mg/dL. †Some authorities recommend drug initiation between 100 and 130 mg/dL.
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ADA. Diabetes Care. 1999;22:S56-S59.
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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)
•
•
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ADA. Diabetes Care. 1999;22:S56-S59.
© 1999 Professional Postgraduate Services ®
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)
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ADA. Diabetes Care. 1999;22:S56-S59.
© 1999 Professional Postgraduate Services ®
Approach to Patients With Diabetes and Hyperlipidemia
Measure (fasting): TC, TG, HDL-C, LDL-C (calculated), glucose, HbA1c Acceptable LDL-C <100 TG <200
Higher risk: LDL-C 130, TG 400, HDL-C <35 Lower risk: LDL-C <100, TG <200, HDL-C >45 Regulate diabetes: weight loss, exercise, restrict dietary saturated fat and cholesterol
Monitor annually
No improvement Hypercholesterolemia Goal LDL-C <130* LDL-C <100† HMG-CoA Resin Mixed Dyslipidemia Goal TG <400 LDL-C <130* TG <200 LDL-C <100† HDL-C >35 HMG-CoA Fibrate + resin
Hypertriglyceridemia Goal TG <400* TG <200† Fibrate HMG-CoA if LDL
Hyperchylomicronemia TG 1000 Fibrate and fat restriction (<10% of calories)
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*Without vascular disease. † With vascular disease. Click
for larger picture
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Hypolipidemic Drug Therapy: HMG-CoA Reductase Inhibitors
Lipid effects (%)*
Drug at starting dose Lovastatin 20 mg Pravastatin 20 mg Simvastatin 20 mg TC 19 24 25 LDL-C 27 32 33 HDL-C 6 2 11 TG 9 11 9
Atorvastatin 10 mg Cerivastatin 0.3 mg
29 19
39 28
6 10
19 13
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* Values reported in Package Inserts.
© 1999 Professional Postgraduate Services ®
Hypolipidemic Drug Therapy
Range of lipid effects (%)
Drug Fibric acid derivatives TG 35-50 HDL-C LDL-C
10-25 10-15
Bile acid sequestrants Nicotinic acid
* 25-30
15-30
10-30 10-25
* May increase in patients with pre-existing hypertriglyceridemia.
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© 1999 Professional Postgraduate Services ®