treatment of dyslipidemia in type 2 diabetes: new targets, new challenges

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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)

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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


• Reduce progression of coronary lesions


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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



• 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


• 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

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

treatment of dyslipidemia in type 2 diabetes: new targets, new challenges

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