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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 DiseasesEndowed 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
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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
VLDL-CVLDL-C
IDL-C
IDL-C
LDL-CLDL-C
NTG HTG
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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
<40 Low
60 High
Serum Triglycerides
• Normal <150
• 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 PrincipleEvidence Based Approach
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ADA Recommendations 2002
Protein
Fat
Saturated
cis-monounsaturated
Polyunsaturated
Carbohydrate
Cholesterol
Fiber
10 – 20% of total energy
< 10% of total energy
*
Up to 10% of total energy
*
300 mg/day
>25 g/day
*Divide 60 – 70% of daily energy between carbohydrates and cis-monounsaturated fats
B
A
B
C
B
A
B
Level of Evidence
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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
Total cholesterol (mg/dL)
Total triglyceride (mg/dL)
VLDL-cholesterol (mg/dL)
LDL-cholesterol (mg/dL)
HDL-cholesterol (mg/dL)
Total/HDL-cholesterol
Baseline Carb
225 ± 10**
285 ± 62
58 ± 12
134 ± 13
32 ± 3
7.4 ± 0.7
205 ± 7
218 ± 32
43 ± 7
131 ± 8
30 ± 2
7.2 ± 6
196 ± 9
163 ± 26**
28 ± 5***
134 ± 8
34 ± 2***
6.0 ± 0.5*
Mono
*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)
Energy intake (Kcal/d)
Weight (kg)
Glycosylated hemoglobin (%)
Carb
117 ± 5
81 ± 9
2410 ± 77
86.9 ± 3.7
7.6 ± 0.8
Mono
Mean ± SEM, *p < 0.05
101 ± 3*
70 ± 9*
2420 ± 70
86.8 ± 3.9
8.1 ± 0.5
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)
ADADiet
HighFiber
Fiber (g)
Soluble (g)
Insoluble (g)
24
8
16
50
25
25
Chandalia, Garg et al. NEJM 342; 1392-1398, 2000
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Metabolic VariablesADADiet
High FiberDiet
PValue
Mean SD values.
Mean plasma glucose (mg/dL) 142 36
2.3 4.3
7.2 1.3
130 38
1.0 1.9
6.9 1.2
0.04
0.008
0.09
Urinary glucose(g/d)
Hemoglobin A1c
(%)
Chandalia, Garg et al. NEJM 342; 1392-1398, 2000
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Plasma Lipids and LipoproteinsADADiet
HighFiber Diet
Plasma Cholesterol
Plasma Triglycerides
VLDL-Cholesterol
LDL-Cholesterol
HDL-Cholesterol
210 33
205 95
40 19
142 29
29 7
0.02
0.02
0.01
0.11
0.80
PValue
196 31
184 76
35 16
133 29
28 4
(mg/dL)
Mean SD.Chandalia, Garg et al. NEJM 342; 1392-1398, 2000
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Dietary FiberFoods Rich in Soluble Fiber
Fruits:
ApricotsCantaloupeCherriesGrapefruitOrangePapayaPeachesPlumsPrunesRaisins
Vegetables:
Green peasOkraSweet potatoWinter squashZucchini
Cereal:
GranolaOat BranOatmeal
Beans:
ChickpeasLima beansNavy beansSplit peas
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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 Dose Range
Lovastatin 20–80 mgPravastatin 20–40 mgSimvastatin 20–80 mgFluvastatin 20-80 mgAtorvastatin 10–80 mgRosuvastatin 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
Reports of Rhabdomyolysis
Due to Drug
Cerivastatin 1899 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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HMG-CoA
HMG-CoAReductase
Mevalonate
IsopentenylPyrophosphate
FarnesylPyrophosphate
Cholesterol Ubiquinone
Squalene GeranylgeranylPyrophosphate
IsoprenylatedProteins
PrenylationPrenylation
Statins
Cholesterol Biosynthetic Pathway
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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 1.5–3 g(crystalline)
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 TherapyAdvantages 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
0
10
20
30
40
50
60
70A
dve
rse
Eve
nts
per
On
e M
illio
n
Pre
scri
pti
on
s
Gemfibrozil
Fenofibrate
•Alsheikh-Ali et al. AM J Cardiol 2004; 94:935-8
Myopathy Rhabdomyolysis
OR 1.8
OR 10.8
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46Reports of Rhabdomyolysis for Fibrate/ Statin Therapies
Medication No. Cases Reported No. Prescriptions Dispensed
No. Cases Reported per Million
Prescriptions
Fenofibrate
With cerivastatin 14 100,000 140
With other statins 2 3,419,000 0.58
Fenofibrate total 16 3,519,000 4.5
Gemfibrozil
With cerivastatin 533 116,000 4,600
With other statins 57 6,641,000 8.6
Gemfibrozil total 590 6,757,000 87
•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