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Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Ad

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Diet, Exercise, Weight loss. Hypoglycemic Drugs. Lipid Lowering Drugs. 9 ... intensive glycemic control with diet, physical activity and anti-diabetic drugs ... – PowerPoint PPT presentation

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Title: Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Ad


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
2
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

3
ATP III (Metabolic Syndrome)
  • Abdominal obesity Waist Men gt40 in, F gt35 in
  • Impaired FPG 100 lt126 mg/dL
  • BP 130/80 mm Hg
  • TG 150 mg/dL
  • HDL-C Men lt40, F lt50 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

5
NonHDL Cholesterol
NTG
HTG
VLDL-C
VLDL-C
IDL-C
LDL-C
IDL-C
LDL-C
6
Adult Treatment Panel III (2004 Update)
  • 10 Y CHD RIsk LDL-C nonHDL-C
  • (mg/dL) (mg/dL)
  • Very High Risk gt20 lt70 lt100 (optional)
  • High Risk gt20 lt100 lt130
  • Moderately High Risk 10-20 lt130 lt160
  • Moderate Risk lt10 lt130 lt160
  • Lower risk lt10 lt160 lt190

CHD or CHD risk equivalents
Grundy et al. Circulation 2004 110 227-39
7
ATP III Lipid and Lipoprotein Classification
  • HDL Cholesterol
  • lt40 Low
  • ?60 High
  • Serum Triglycerides
  • Normal lt150
  • Borderline high 150199
  • High 200499
  • Very high ?500

8
Management of Dyslipidemia in T2DM
  • Diet, Exercise, Weight loss
  • Hypoglycemic Drugs
  • Lipid Lowering Drugs

9
Management of Dyslipidemia
Dietary Principle Evidence Based Approach
10
ADA Recommendations 2002
Level of Evidence
Protein Fat Saturated
cis-monounsaturated Polyunsaturated Carbohydr
ate Cholesterol Fiber
10 20 of total energy lt 10 of total
energy Up to 10 of total energy 300
mg/day gt25 g/day
B A B C B A B
Divide 60 70 of daily energy between
carbohydrates and cis-monounsaturated fats
11
Dietary Fats
  • Saturated
  • Short, Medium, Long chain
  • Monounsaturated
  • cis, trans
  • Polyunsaturated
  • ?-3, ?-6

12
Saturated Fats
  • Long chain saturates except stearic acid 180
    raise LDL cholesterol
  • Main sources Ghee, Butter, Palm Oil
  • Medium chain saturates also raise LDL cholesterol
  • Main sources Coconut oil

13
Trans-Monounsaturated Fats
  • Trans fatty acids like elaidic acid (181 trans)
    raise LDL cholesterol and lower HDL cholesterol
  • Main sources Hydrogenated fats
  • Margarines, Shortenings, Frying oils
  • Butter, milk fat (traces)

14
cis-Monounsaturated vs. Polyunsaturated fats
  • Both reduce LDL cholesterol equally
  • High intakes of n-6 polyunsaturated fats may
    reduce HDL cholesterol

15
Plasma Lipids and Lipoproteins
Mono
Baseline
Carb
Total cholesterol (mg/dL) Total triglyceride
(mg/dL) VLDL-cholesterol (mg/dL) LDL-cholesterol
(mg/dL) HDL-cholesterol (mg/dL) Total/HDL-choleste
rol
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
p lt 0.05 p lt 0.01 p lt 0.005
Garg et al. N Engl J Med 1988319 829-34
16
Metabolic Variables (Day 21 to 28)
Mono
Carb
Plasma glucose (mg/dL) (03, 07, 11, 16, 20 hr
q.d.) Insulin requirements (Units/d) Energy
intake (Kcal/d) Weight (kg) Glycosylated
hemoglobin ()
117 5 81 9 2410 77 86.9 3.7
7.6 0.8
101 3 70 9 2420 70 86.8
3.9 8.1 0.5
Mean SEM, p lt 0.05
Garg et al. N Engl J Med 1988319 829-34
17
Sources of cis-monounsaturated Fats
Mustard oil contains erucic acid (C201) Canola
Oil contains oleic acid (C181)
18
N-3 polyunsaturated Fats
  • N-3 Fatty acids (EPA (205)/DHA (226) from fish
    oils) lower triglycerides
  • May raise LDL cholesterol
  • Can adversely affect glycemia
  • Main sources Fish
  • Sources of ?-linolenic acid (183) Vegetables,
    Flaxseed oil (No TG reduction)

19
Alcohol
  • Daily intake lt1 drink/d for women and lt2
    drinks/d for men
  • To avoid hypoglycemia consume with food
  • Raises TG and blood pressure
  • Contributes to obesity

20
Dietary Fiber Study (Diet Composition)
ADA Diet
High Fiber
Fiber (g) Soluble (g) Insoluble (g)
24 8 16
50 25 25
Chandalia, Garg et al. NEJM 342 1392-1398, 2000
21
Metabolic Variables
Mean plasma glucose (mg/dL)
142 ? 36
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
22
Plasma Lipids and Lipoproteins
ADA Diet
High Fiber Diet
P Value
(mg/dL)
Plasma Cholesterol Plasma Triglycerides VLDL-Chole
sterol LDL-Cholesterol HDL-Cholesterol
210 ? 33 205 ? 95 40 ? 19 142 ? 29 29 ? 7
0.02 0.02 0.01 0.11 0.80
196 ? 31 184 ? 76 35 ? 16 133 ? 29 28 ? 4
Mean ? SD.
Chandalia, Garg et al. NEJM 342 1392-1398, 2000
23
Dietary Fiber Foods Rich in Soluble Fiber
Fruits Apricots Cantaloupe Cherries Grapefruit O
range Papaya Peaches Plums Prunes Raisins
Beans Chickpeas Lima beans Navy beans Split peas
Vegetables Green peas Okra Sweet potato Winter
squash Zucchini Cereal Granola Oat Bran Oatmeal
24
Sources of Dietary Sterols
  • Cholesterol
  • Meats, sea food, eggs
  • Phytosterols
  • Oils from plants
  • Sitostanol reduces LDL-C by 15

25
Lipid Lowering Drugs
  • Statins
  • Fibrates
  • Bile acid sequestrants
  • Niacin
  • Ezetimibe
  • Combination Therapy

26
HMG CoA Reductase Inhibitors (Statins)
  • Statin Dose Range
  • Lovastatin 2080 mg
  • Pravastatin 2040 mg
  • Simvastatin 2080 mg
  • Fluvastatin 20-80 mg
  • Atorvastatin 1080 mg
  • Rosuvastatin 1040 mg

27
Statins
  • Reduce LDL-C 1855 TG 730
  • Raise HDL-C 515
  • Major side effects
  • Myopathy
  • Increased liver enzymes
  • Contraindications
  • Absolute liver disease
  • Relative use with certain drugs

28
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

29
Statin Associated Myopathy (Controlled Studies)
Thompson PD, et al. JAMA 2891681-90, 2003
30
FDA Reports of Rhabdomyolysis
Thompson PD, et al. JAMA 2891681-90, 2003
31
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, gt1 qt/d

32
Cholesterol Biosynthetic Pathway
33
Fibric Acids
  • Drug Dose
  • Gemfibrozil 600 mg BID
  • Fenofibrate 200 mg QD
  • Clofibrate 1000 mg BID

34
Fibric Acids
  • Major actions
  • Lower LDL-C 520 (with normal TG)
  • May raise LDL-C (with high TG)
  • Lower TG 2050
  • Raise HDL-C 1020
  • Side effects dyspepsia, gallstones, myopathy
  • Contraindications Severe renal or hepatic disease

35
Fibric acids
  • Demonstrated Therapeutic Benefits
  • Reduce progression of coronary lesions
  • Reduce major coronary events

36
Bile Acid Sequestrants
  • Major actions
  • Reduce LDL-C 1530
  • Raise HDL-C 35
  • May increase TG
  • Side effects
  • GI distress/constipation
  • Decreased absorption of other drugs
  • Contraindications
  • Dysbetalipoproteinemia
  • Raised TG (especially gt400 mg/dL)

37
Bile Acid Sequestrants
  • Drug Dose Range
  • Cholestyramine 416 g
  • Colestipol 520 g
  • Colesevelam 2.63.8 g

38
Bile Acid Sequestrants
  • Demonstrated Therapeutic Benefits
  • Reduce major coronary events
  • Reduce CHD mortality

39
Nicotinic Acid
  • Drug Form Dose Range
  • Immediate release 1.53 g (crystalline)
  • Extended release 12 g
  • Sustained release 12 g

40
Nicotinic Acid
  • Major actions
  • Lowers LDL-C 525
  • Lowers TG 2050
  • Raises HDL-C 1535
  • Side effects flushing, hyperglycemia,
    hyperuricemia, upper GI distress, hepatotoxicity
  • Contraindications Diabetes, liver disease,
    severe gout, peptic ulcer

41
Nicotinic Acid
  • Demonstrated Therapeutic Benefits
  • Reduces major coronary events
  • Possible reduction in total mortality

42
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

43
Combination Therapy
  • For LDL reduction
  • Statins Bile Acid Sequestrants
  • Statins Ezetimibe
  • For TG and LDL reduction
  • Fibrates Statins
  • Statins Niacin

44
Statin/Fibrate Combination Therapy Advantages
Disadvantages
  • ? AEs (myopathy/ rhabdomyolysis)
  • ? Cost
  • Lack of proven outcome benefit
  • ? LDL-C, ? TG, ? HDL-C
  • ? nonHDL-C
  • ? LDL particle size
  • ? CHD protection (?)

Modified from Jones PH.
45
Myopathy with Fibrates
OR 10.8
OR 1.8
Myopathy
Rhabdomyolysis
Alsheikh-Ali et al. AM J Cardiol 2004 94935-8
46
Reports of Rhabdomyolysis for Fibrate/ Statin
Therapies
Jones Davidson AM J Cardiol 2005
95120-2 FDA Adverse Event Report Jan 98 to Mar
02 IMS Health Varispan LLC Report
47
Management of Dyslipidemia in Diabetics (Conclusi
ons)
  • 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

48
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
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