1
Treatment of Dyslipidemia in Type 2 Diabetes:
New Targets, New Challenges
Keystone, Colorado
August 2005
Abhimanyu Garg, M.D.
Professor of Internal Medicine
Chief, Division of Nutrition and Metabolic Diseases
Endowed Chair in Human Nutrition Research
The University of Texas Southwestern Medical Center at Dallas
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Adult Treatment Panel (ATP) III
Diabetes as a CHD Risk Equivalent
• 10-year risk for CHD  20%
• High mortality with established CHD
– High mortality with acute MI
– High mortality post acute MI
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ATP III (Metabolic Syndrome)
• Abdominal obesity: Waist Men >40 in, F >35 in
• Impaired FPG ≥100 <126 mg/dL
• BP ≥ 130/80 mm Hg
• TG ≥ 150 mg/dL
• HDL-C: Men <40, F <50 mg/dL
Presence of ≥ 3 criteria
4
New Features of ATP III
• For patients with triglycerides 200 mg/dL
– LDL cholesterol: primary target of therapy
– Non-HDL cholesterol: secondary target of
therapy
Non HDL-C = total cholesterol – HDL cholesterol
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NonHDL Cholesterol
NTG
VLDL-C
HTG
VLDL-C
IDL-C
IDL-C
LDL-C
LDL-C
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Adult Treatment Panel III (2004 Update)
10 Y CHD RIsk
LDL-C
nonHDL-C
(mg/dL)
(mg/dL)
Very High Risk*
>20%
<70
<100 (optional)
High Risk*
>20%
<100
<130
Moderately High Risk
10-20%
<130
<160
Moderate Risk
<10%
<130
<160
Lower risk
<10%
<160
<190
* CHD or CHD risk equivalents
Grundy et al. Circulation 2004; 110; 227-39
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ATP III
Lipid and Lipoprotein Classification
HDL Cholesterol
Serum Triglycerides
<40
Low
• Normal
<150
60
High
• Borderline high
150–199
• High
200–499
• Very high
500
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Management of Dyslipidemia in T2DM
• Diet, Exercise, Weight loss
• Hypoglycemic Drugs
• Lipid Lowering Drugs
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Management of Dyslipidemia
Dietary Principle
Evidence Based Approach
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ADA Recommendations 2002
Level of
Evidence
10 – 20% of total energy
B
Saturated
< 10% of total energy
A
cis-monounsaturated
*
B
Polyunsaturated
Up to 10% of total energy
C
Carbohydrate
*
B
Cholesterol
 300 mg/day
A
Fiber
>25 g/day
B
Protein
Fat
*Divide 60 – 70% of daily energy between carbohydrates and cismonounsaturated fats
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Dietary Fats
• Saturated
– Short, Medium, Long chain
• Monounsaturated
– cis, trans
• Polyunsaturated
– -3, -6
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Saturated Fats
• Long chain saturates except stearic
acid [18:0] raise LDL cholesterol
• Main sources: Ghee, Butter, Palm Oil
• Medium chain saturates also raise
LDL cholesterol
• Main sources: Coconut oil
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Trans-Monounsaturated Fats
• Trans fatty acids like elaidic acid
(18:1 trans) raise LDL cholesterol
and lower HDL cholesterol
• Main sources: Hydrogenated fats
–Margarines, Shortenings, Frying
oils
• Butter, milk fat (traces)
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cis-Monounsaturated vs.
Polyunsaturated fats
• Both reduce LDL cholesterol equally
• High intakes of n-6 polyunsaturated
fats may reduce HDL cholesterol
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Plasma Lipids and Lipoproteins
Baseline
Carb
Mono
Total cholesterol (mg/dL)
225 ± 10**
205 ± 7
196 ± 9
Total triglyceride (mg/dL)
285 ± 62
218 ± 32
163 ± 26**
VLDL-cholesterol (mg/dL)
58 ± 12
43 ± 7
28 ± 5***
LDL-cholesterol (mg/dL)
134 ± 13
131 ± 8
HDL-cholesterol (mg/dL)
32 ± 3
30 ± 2
34 ± 2***
Total/HDL-cholesterol
7.4 ± 0.7
7.2 ± 6
6.0 ± 0.5*
134 ± 8
*p < 0.05 **p < 0.01 ***p < 0.005
Garg et al. N Engl J Med 1988;319; 829-34
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Metabolic Variables (Day 21 to 28)
Plasma glucose (mg/dL)
(03, 07, 11, 16, 20 hr q.d.)
Insulin requirements
(Units/d)
Carb
Mono
117 ± 5
101 ± 3*
81 ± 9
70 ± 9*
Energy intake (Kcal/d)
2410 ± 77
2420 ± 70
Weight (kg)
86.9 ± 3.7
86.8 ± 3.9
7.6 ± 0.8
8.1 ± 0.5
Glycosylated hemoglobin (%)
Mean ± SEM, *p < 0.05
Garg et al. N Engl J Med 1988;319; 829-34
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Sources of cis-monounsaturated Fats
Mustard oil
contains
erucic acid
(C20:1)
Canola Oil
contains oleic
acid (C18:1)
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N-3 polyunsaturated Fats
• N-3 Fatty acids (EPA (20:5)/DHA (22:6)
from fish oils) lower triglycerides
• May raise LDL cholesterol
• Can adversely affect glycemia
• Main sources: Fish
• Sources of -linolenic acid (18:3): Vegetables,
Flaxseed oil (No TG reduction)
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Alcohol
• Daily intake: <1 drink/d for women
and <2 drinks/d for men
• To avoid hypoglycemia consume
with food
• Raises TG and blood pressure
• Contributes to obesity
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Dietary Fiber Study
(Diet Composition)
Fiber (g)
Soluble (g)
Insoluble (g)
ADA
Diet
High
Fiber
24
8
16
50
25
25
Chandalia, Garg et al. NEJM 342; 1392-1398, 2000
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Metabolic Variables
ADA
Diet
P
High Fiber
Value
Diet
Mean plasma glucose
142  36
(mg/dL)
130  38
0.04
Urinary glucose
(g/d)
2.3  4.3
1.0  1.9
0.008
Hemoglobin A1c
(%)
7.2  1.3
6.9  1.2
0.09
Mean  SD values.
Chandalia, Garg et al. NEJM 342; 1392-1398, 2000
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Plasma Lipids and Lipoproteins
ADA
Diet
High
Fiber Diet
P
Value
(mg/dL)
Plasma Cholesterol
Plasma Triglycerides
VLDL-Cholesterol
LDL-Cholesterol
HDL-Cholesterol
Mean  SD.
210  33
205  95
40  19
142  29
29  7
196  31
184  76
35  16
133  29
28  4
0.02
0.02
0.01
0.11
0.80
Chandalia, Garg et al. NEJM 342; 1392-1398, 2000
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Dietary Fiber
Foods Rich in Soluble Fiber
Fruits:
Vegetables:
Beans:
Apricots
Cantaloupe
Cherries
Grapefruit
Orange
Papaya
Peaches
Plums
Prunes
Raisins
Green peas
Okra
Sweet potato
Winter squash
Zucchini
Chickpeas
Lima beans
Navy beans
Split peas
Cereal:
Granola
Oat Bran
Oatmeal
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Sources of Dietary Sterols
• Cholesterol
–Meats, sea food, eggs
• Phytosterols
–Oils from plants
–Sitostanol reduces LDL-C
by 15%
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Lipid Lowering Drugs
• Statins
• Fibrates
• Bile acid sequestrants
• Niacin
• Ezetimibe
• Combination Therapy
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HMG CoA Reductase
Inhibitors (Statins)
Statin
Lovastatin
Pravastatin
Simvastatin
Fluvastatin
Atorvastatin
Rosuvastatin
Dose Range
20–80 mg
20–40 mg
20–80 mg
20-80 mg
10–80 mg
10–40 mg
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Statins
• Reduce LDL-C 18–55% & TG 7–30%
• Raise HDL-C 5–15%
• Major side effects
– Myopathy
– Increased liver enzymes
• Contraindications
– Absolute: liver disease
– Relative: use with certain drugs
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HMG CoA Reductase
Inhibitors (Statins)
Demonstrated Therapeutic Benefits
• Reduce major coronary events
• Reduce CHD mortality
• Reduce coronary procedures (PTCA/CABG)
• Reduce stroke
• Reduce total mortality
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Statin Associated Myopathy
(Controlled Studies)
Myalgia
Placebo
Statin
Lovastatin
1.7
3.0
Pravastatin
1.0
2.7
Simvastatin
1.3
1.2
Fluvastatin
4.5
5.0
Atorvastatin
1.1
3.2
Cerivastatin
2.3
2.5
•Thompson PD, et al. JAMA 289;1681-90, 2003
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FDA Reports of Rhabdomyolysis
Drugs
No. of Reports
Cerivastatin
1899
Reports of
Rhabdomyolysis
Due to Drug
56.9%
Simvastatin
612
18.3%
Atorvastatin
383
11.5%
Pravastatin
243
7.3%
Lovastatin
147
4.4%
Fluvastatin
55
1.6%
Total
3339
100%
•Thompson PD, et al. JAMA 289;1681-90, 2003
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Concomitant Medications increasing Risk of
Statin-associated Myopathy
•
•
•
•
•
•
•
•
•
•
Fibric acid derivatives, especially gemfibrozil
Niacin
Cyclosporine
Azole antifungals
Macrolide antibiotics
HIV protease inhibitors
Nefazodone
Verapamil and diltiazem
Amiodarone
Grapefruit juice, >1 qt/d
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Cholesterol Biosynthetic Pathway
HMG-CoA
Statins
HMG-CoA
Reductase
Mevalonate
Isopentenyl
Pyrophosphate
Farnesyl
Pyrophosphate
Geranylgeranyl
Pyrophosphate
Squalene
Prenylation
Cholesterol
Isoprenylated
Proteins
Prenylation
Ubiquinone
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Fibric Acids
Drug
Dose
• Gemfibrozil
600 mg BID
• Fenofibrate
200 mg QD
• Clofibrate
1000 mg BID
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Fibric Acids
• Major actions
– Lower LDL-C 5–20% (with normal TG)
– May raise LDL-C (with high TG)
– Lower TG 20–50%
– Raise HDL-C 10–20%
• Side effects: dyspepsia, gallstones,
myopathy
• Contraindications: Severe renal or hepatic
disease
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Fibric acids
Demonstrated Therapeutic Benefits
• Reduce progression of coronary lesions
• Reduce major coronary events
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Bile Acid Sequestrants
• Major actions
– Reduce LDL-C 15–30%
– Raise HDL-C 3–5%
– May increase TG
• Side effects
– GI distress/constipation
– Decreased absorption of other drugs
• Contraindications
– Dysbetalipoproteinemia
– Raised TG (especially >400 mg/dL)
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Bile Acid Sequestrants
Drug
Dose Range
Cholestyramine
4–16 g
Colestipol
5–20 g
Colesevelam
2.6–3.8 g
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Bile Acid Sequestrants
Demonstrated Therapeutic Benefits
• Reduce major coronary events
• Reduce CHD mortality
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Nicotinic Acid
Drug Form
Dose Range
Immediate release
(crystalline)
1.5–3 g
Extended release
1–2 g
Sustained release
1–2 g
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Nicotinic Acid
• Major actions
– Lowers LDL-C 5–25%
– Lowers TG 20–50%
– Raises HDL-C 15–35%
• Side effects: flushing, hyperglycemia,
hyperuricemia, upper GI distress, hepatotoxicity
• Contraindications: Diabetes, liver disease, severe
gout, peptic ulcer
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Nicotinic Acid
Demonstrated Therapeutic Benefits
• Reduces major coronary events
• Possible reduction in total mortality
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Ezetimibe
•
Reduces cholesterol absorption by
inhibiting NPC1L1 receptors in small
intestine
•
10 mg per day can reduce LDL cholesterol
by 15-20%
•
More LDL reduction in combination with
statins
•
Negligible side effects
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Combination Therapy
For LDL reduction:
• Statins + Bile Acid Sequestrants
• Statins + Ezetimibe
For TG and LDL reduction:
Fibrates + Statins
Statins + Niacin
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Statin/Fibrate Combination Therapy
Advantages
Disadvantages
•
 LDL-C,  TG,  HDL-C
•
 nonHDL-C
•
 LDL particle size
•
 CHD protection (?)
•
 AEs (myopathy/
rhabdomyolysis)
•
 Cost
•
Lack of proven outcome
benefit
Modified from Jones PH.
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Myopathy with Fibrates
70
Adverse Events per One Million
Prescriptions
OR 10.8
60
50
40
Gemfibrozil
Fenofibrate
30
20
OR 1.8
10
0
Myopathy
Rhabdomyolysis
•Alsheikh-Ali et al. AM J Cardiol 2004; 94:935-8
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Reports of Rhabdomyolysis for
Fibrate/ Statin Therapies
No. Cases Reported
No. Prescriptions
Dispensed
No. Cases Reported
per Million
Prescriptions
With cerivastatin
14
100,000
140
With other statins
2
3,419,000
0.58
Fenofibrate total
16
3,519,000
4.5
With cerivastatin
533
116,000
4,600
With other statins
57
6,641,000
8.6
Gemfibrozil total
590
6,757,000
87
Medication
Fenofibrate
Gemfibrozil
•Jones & Davidson AM J Cardiol 2005; 95:120-2
•FDA Adverse Event Report Jan ’98 to Mar ’02
•IMS Health & Varispan LLC Report
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Management of Dyslipidemia in Diabetics
(Conclusions)
• Attempt intensive glycemic control with diet,
physical activity and anti-diabetic drugs
• For patients with NTG or borderline HTG- Statins
• For patients with HTG- Fibrates
• Consider statin + fibrate combination for HTG
patients unable to achieve goals
• Consider risk/benefit ratio for individual patient
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Acknowledgments
• Scott M. Grundy, M.D. Ph.D.
• Manisha Chandalia, M.D.
• Andrea Bonanome, M.D.
• Beverley Adams-Huet, M.S.
• Linda Brinkley, M.S.
• Meredith Millay, B.S.
• Patient volunteers