Hyperlipidemiafor the primary care physician

Charles E. Henley, D.O. , M.S., M.P.H.Professor, Family Medicine

What is Atherosclerosis?• More than just an accumulation of excess lipid.• Think of it as an inflammatory process• Inflammatory cells and mediators participate at every stage of

atherogenesis• Elevated glucose, increased blood pressure, and inhaled cigarette

by products can trigger inflammation. • One of the key features is oxidized LDL• When LDL is taken up by macrophages it triggers the release of

mediators. • These mediators lead to formation and thickening of endothelial

plaque• Lipid lowering is therefore anti inflammatory and plaque

stabilizing.

When Does Arthrosclerosis Start?

• Evidence from pathology specimens show fatty streaks in children as young as two.

• long term studies show that atherosclerosis is largely a predictable process that begins in childhood and progresses at a rate determined by coronary risk factors.

• The carotid intima medial thickness of adults is used as a surrogate for systemic atherosclerosis. It can be predicted by childhood measures of LDL and BMI.

Case #1

• 55 y/o WM with a five year history of type ll AODM and hypertension. There is a strong family history of heart disease and his younger brother has died from an MI just two months earlier. He has known elevated cholesterol but has previously refuse treatment. He is obese, has GERD and IBS and takes lisinopril, metformin, and omeprazole. He works as a realtor and has erratic eating habits. V/S are: Wt. 268lbs, Ht. 69 ‘’ BP 130/80, pulse 74

• His lipid profile is:• TC= 235 mg/dl• TG= 185 mg/dl• HDL=28 mg/dl• LDL= 170 mg/dl

Case #1• Risk assessment: diabetes is a coronary artery disease

equivalent.• TG, TC, LDL are all elevated and HDL is low• These are lipid values commonly seen in insulin resistance and type

ll diabetes mellitus.• Goals of treatment: reduce LDL to < 100 mg/dl ( < 70 optimal),

reduce TG to < 150 mg/dl, and to increase his HDL to > 40 mg/dl .• Life style modification with exercise and weight loss to a BMI of 25

Kg/Msq. • The British Heart protection study (BHP) showed that simvastin

helped diabetic patients regardless of the numerical effect on lipid values.

Case #1 Case Outcomes

• TSH was normal• HBgA1c was 7.8 mg%• Fasting bld. glucose averaged 140 mg%• Pioglitazone was added to his metformin.• A dietician placed him on a diet• Started on 81 mg ASA per day.• Started on a walking program increased daily

Case #1 outcomes cont.

• Started on 40 mg a day of Simvastin• Rechecked liver enzymes, HBA1c, and lipid profile

at 12 wks: HBA1C had decreased to 7.0 TC= 178 mg/dl, TG= 174 mg/dl, HDL = 31,

LDL=112 mg/dl As his lifestyle modifications begin to take hold he

will experience further improvements in his glucose control. However, it is unlikely he will reach goals for lipids without further intervention.

Case #1 Next Step• A fibrate could be added, the statin could be changed, or

niacin could be added. • In this case a decision was made to add a combination

medicine, Advicor, a combination of lovastatin and niacin.

• After 12 wks his lipid profile was :• TG= 155 mg/dl• TC= 156 mg/dl• LDL= 82 mg/dl• HDL= 44 mg/dl

Pre-Statin trials• The lipid Research Clinics Coronary Primary

Prevention Cholestyramine Trial showed that lowering cholesterol by 9% resulted in a 19% reduction in CHD morbidity and mortality.

• The Helsinki Heart Study tested fibrate agents such as gemfibrozil and showed a reduction is all- cause mortality.

Statin Trials

• Against this backdrop the HMG-CoA reductase drugs were introduced.

• They inhibit the enzyme that catalyzes the conversion of HMG-CoA to Mevalonate an early step in the biosynthesis of cholesterol.

• More potent , with fewer side effects• 1990’s clinical trials studied them in primary

prevention and secondary prevention.

Primary Prevention Trials 0f the 90’s

• West of Scotland Coronary Prevention Study (WPSCOPS-1995)

• Treated 6596 men with elevated cholesterol but no heart disease with pravastatin. Reduced coronary events by 31% over five years.

• United States Air Force and U. of Texas Coronary Atherosclerosis Prevention Trial

• Treated 6605 patients with average cholesterol with Lovastatin. Showed a 25% risk reduction in coronary events after five years, (40% in fatal MI’s).

Secondary Prevention Statin Trials of the 90’s

• Scandinavian Simvastin Survival Study-1994• Studied 4444 high risk patients with pre-existing disease

and high cholesterol treated with Simvastin. CAD deaths were reduced by 34% , Infarcts were reduced by 42%

• The Long term Intervention with Pravastatin in Ischemic Disease Study Group (LIPID-1998) followed 9014 patients with CHD for 6.1 yrs. All treated with Pravastatin. A marked reduction in nonfatal and fatal infarcts was observed.

Trials Since 1999• Veterans Administration Study (VA-HIT) evaluated Fibrinates as

secondary prevention, showed a 22% reduction in CHD events after five years.

• HPS, Heart Protection Study, Largest statin trial ever. Showed that the largest risk reduction occurred with the largest reduction in LDL. The lower the LDL , the lower the risk.

• Prove IT-TIMI (Pravastatin or Artorvastatin Evaluation and Infection Thrombolysis in Myocardial Infarction Trial). Compared standard dosages with intensive therapy (80mg of Artorvastatin) All cause mortality was reduced by 28%.

• The Reversal Trial used US to show a reduction in atherosclerotic plaque with intensive treatment.

Results of trials of intensive Statin treatment: How low do you go?

REVERSAL PROVE-IT TNT IDEAL ASTEROID

Clinical situation

Stable CHD Acute coronary syndrome

Stable CHD Prior myocardial infarction

Stable CHD

Outcomes Ultrasound measure of plaque

Clinical events Clinical events Clinical events Ultrasound measure of plaque

Pretreatment mean LDL (mg/dl)

150 106 152 __ 130.4

Posttreatment mean LDL (mg/dl)

110 95 101 104 None

Posttreatment mean LDL (mg/dl), intensive therapy

79 62 77 81 60.8

Key results Reduced plaque burden

28% RR reduction in mortality

22% RR reduction and 2.2% AR reduction in cardiovascular events

Nonfatal myocardial infarction reduced by 12%

Reduced plaque burden

NCEP and ATP lll Guidelines

• ATP lll published in 2002 and updated in 2004 provides guidelines for cholesterol measurement and management.

• ATP l provided a framework for primary prevention for patients with elevated LDL or borderline high LDL, plus two major risk factors

• ATP ll confirmed this and added the intensive management of LDL in patients with CHD.

• ATP lll called for a more rigorous LDL lowering in CHD patients and CHD equivalents.

ATP lll Normal Lipid Values

LDL cholesterol Values Less than 100 Optimal100-129 Near optimal/above optimal130-159 Borderline high160-189 HighMore than 190 Very high

Total cholesterolLess than 200 Desirable200-239 Borderline highMore than 240 High

HDL cholesterolLess than 40 LowMore than 40 High

Case #2 High Triglycerides, low HDL and metabolic syndrome

• 43 y/o man presents for a check up. His father had died a few months before from sudden cardiac death at age 62. His PMH is significant for reflux and hypertension for three yrs. He takes Lisinopril 20 mg/day and lansoprazole. He works as an attorney. He is a nonsmoker but drinks a martini 3-4 nights a week. He does not exercise. Besides his father, he has an uncle who underwent a coronary bypass operation at age 53. His labs are as follows:

TC= 233 mg/dl• TG= 735 mg/dl• LDL= *** mg/dl unable to calculate due to high TG• HDL= 28 mg/dl

Case #2 Case Analysis

Physical exam: waist circumference=36 in., 71 ‘‘ 210lbs. P 74, BP 138/78

• The patient’s 10 year risk of having a coronary event is 3 % based on Framingham criteria, and he has two risk factors.

• Based on his risk, his LDL goal is < 130mg/dl, and his LDL cannot be determined. The NCEP/ATP lll guidelines remind us to review HDL and TG levels for possible metabolic syndrome. The patient has three of the five criteria (TG> 150mg/dl, BP > 130mmhg, HDL < 40, which is diagnostic for metabolic syndrome.

NCEP/ATP lll Criteria for metabolic syndrome (any 3 out of 5 risk factors)

Risk factor Criteria Waist circumference

Men > 40 in.Women > 35 in.

Triglycerides 150 mg/dl or more HDL

Men <40 mg/dlWomen < 50 mg/dl

Blood Pressure 130/85mmhg or higher Fasting glucose 110 mg/dl or higher

• NCEP/ATP lll guidelines NIH publication 02-3305, May 2001

Outcomes of the Case• Weight watchers + exercise up 10, 000 steps/day• Antihypertensive therapy was augmented with a low dose diuretic

to control his BP to a mean of 124/74 mmhg• Started on Fenofibrinate at 148 mg /day to reduce his triglycerides,

and niacin 500mg BID to increase his HDL.• After 12 wks: his weight was less, and his lipid profile was:• TG = 100 mg/dl• TC = 186 mg/dl• LDL = 128 mg/dl• HDL = 38 mg/dl • Once he turns 45 his 5 yr. risk will be > 5% and he will add ASA qd

Case #3 High LDL but unable to tolerate Statins

• A 54 y/o wf recently diagnosed with type ll AODM. Her PMH is positive for dysthymic mood and depression, obesity, hypertension, and a 40 pack year history of smoking. Current meds include; fluoxetine, glipizide, metformin, fosinopril, and HCTZ. There is a positive family history for diabetes and her screening HGBA1c is 6.8 mg% and a FBS of 110 mg%

• PE: wt. 238 lbs, 65” tall p 80, BP 126/72mmHg Lipid profile:• TC =230 mg/dl• TG 155 mg/dl• HDL = 36 mg/dl• LDL = 163 mg/dl

Case Analysis

• High risk patient because of her diabetes, her smoking history, family history, hypertension, obesity and abnormal lipids.

• Her goal LDL should be < 100mg/dl, and possibly < 70 mg/dl

• Critical factors include weight loss and smoking cessation.

• Reduce LDL by 60% and increase her HDL by 40% (to get 50 mg/dl). Daily ASA to reduce risk of stroke

Case Outcome

• Patient was prescribed a 1600 Cal diet and a walking program (progressive up to 30 min a day five days a week).

• ‘Started on 81 mg ASA a day and 40 mg a day of simvastin. • Patient reported severe calf muscle cramps and refused to

take the statin.• Given the alternative pathway for metabolism with

pravastatin it was chosen as an alternative.• She had the same complaint with Pravastatin.• Statin effects are agent and not class specific, so the patient

was switched to artovastin. She had calf pain with this as well.• Patient refused to consider any other statin medications.

Case Outcome• Niacin was started and slowly titrated up. The patient complained

of flushing, stomach upset, and a worsening of her moods. • The patient decided to try “natural herbal remedies”. She chose to

start on garlic and guggulipid… with no effect on her lipid levels.• One year later she returned to her physician frustrated. But

because of her weight loss, her LDL had decreased to 144 mg/dl and HDL had increased to 41mg/dl.

• After reviewing options it was decided to prescribe Ezetimibe 10mg qd. and use a diet rich in soluble fiber. Her LDL decreased to 110 mg/dl and her HDL stayed at 41. Her program of lifestyle changes and drug treatment reduced her risks substantially.

Summary of the 2006 American Heart Association Recommendations for secondary prevention of atherosclerotic vascular disease

INTERVENTION RECOMMENDATIONS LEVEL OF EVIDENCE

Smoking cessation Assist with a plan for quitting I (B)

Blood pressure control Goal less than 140/90 mm Hg or less than 130/80 mm Hg for those with diabetes or chronic kidney disease

I (A)

Lipid management For all, LDL less than 100 mg/dl and reduction to an LDL level less than 70 mg/dl is reasonable

I (A)II (A)

Physical activity 30 to 60 min/day for 5 to 7 days per week I (B)

Weight management Maintain BMI 18.5 to 24.9 kg/m[2] and waist less than 40 in. in men and less than 35 in. in women

I (B)

Diabetes management Maintain hemoglobin A1c less than 7.0% I (B)

Antiplatelet therapy Start aspirin 75-162 mg/day unless contraindicated I (A)

Renin-angiotensin system blocker

Start and continue ACE inhibitors or ARBs in patients with LV ejection fraction less than 40%

I (A)

Beta-blockers Start and continue for any patients who have had an acute coronary syndrome or LV dysfunction

I (A)

Influenza vaccination Annual vaccination I (B)

LDL Cholesterol goals based on risk categories

• Risk Category LDL Goal (mg/dl)

• CHD and CHD risk equivalents <100• 2+ risk factors <130• 0-1 risk factors <160

Statins

Medication dose LDL TG HDL side effects Reduction Reduction Reduction Increase

Atarastatin 10-80 mg 35-65% 15-40% 5-10% myalgias( Lipitor)Fluvastatin 20-80mg 15-35% 10-20% 3-7% same(Lescol)Lovastatin 20-40mg 20-35% 5-10% 5% same(Mevacor)Pravastatin 10-40mg 20-40% 10-25% 3-10% same(Pravacol)

Statins

Medications dose LDL TG HDL side effects reduction reduction increase

Rosuvastatin 5-40mg 40-70% 20-30% 5-15% same(Crestor)

Simvastatin 10-60mg 25-50% 10-25% 5-10% same(Zocor)

Fibrates and Niacin

Medication dose LDL TG HDL Side effects

FibratesGemfobrozil 600mg BID minimal 20-50% 10-20% nausea,

(Lopid) rare hep.

Fenofibrate 48-148mg minimal 20-50% 10-20% myositis

(Tricor)

Niacin Short acting 500-1500mg 10-25% 20-50%15-30% flushing, nausea

(Niacor) BID pruritis,

Extended release 500-2000mg

(Niaspan) @HS dose dependent

Resins and absorption inhibition

medication dosage LDL TG HDL side effectsResinsColestipol 4-8 g bid 10-20% may increase minimal bloating

(Colestid ) nausea, constipation

Cholestyramine 5-10 g BID flatulent (Questran) Colesvelum 6 capsules(Welchol) BIDAbsorption InhibitorsEzitimibe 10mg/d 15-20% 5-10 % 1-3% occ. G.i upset.

(Zetia)

Dyslipidemia and Diabetes• The metabolic syndrome and type 2 diabetes mellitus both

increase the risk of cardiovascular disease• There is an inverse relationship between serum levels of HDL

and triglycerides in diabetic patients, with low serum HDL levels possibly representing an independent risk factor for cardiovascular disease.

• Small, dense, LDL-C particles are also highly atherogenic as they are more likely to form oxidized LDL

• Insulin resistance, which is central to the metabolic syndrome and type 2 diabetes mellitus, leads to high levels of very low-density lipoprotein (VLDL), which contain a high concentration of triglycerides, resulting in high serum triglyceride levels and low serum HDL-C levels.

Atherogenic lipid triad

• High serum triglyceride levels, low serum high-density lipoprotein cholesterol (HDL-C) levels, and a preponderance of small, low-density lipoprotein cholesterol (LDL-C) particles. All of the processes involved in atherogenesis can be exacerbated by insulin resistance and/or the metabolic syndrome.

Dyslipidemia and diabetes

• modification of the atherogenic lipid triad is probably one of the most effective methods of reducing cardiovascular risk,

• therapy for diabetic dyslipidemia is often directed to first lowering serum LDL-C levels with a HMG-CoA reductase inhibitor.

• However, Fibric acid derivatives, such as fenofibrate, bezafibrate and gemfibrozil, are potentially well suited to the treatment of dyslipidemia ( triglyceridemia) that is generally associated with type 2 diabetes mellitus and the metabolic syndrome. They are usually more effective than Statins for normalizing serum levels of HDL-C and triglycerides.

Lipid Lowering Foods and supplements

Supplement effect recommendation Plant sterols * 4-8% red. of TC 2-3 g/d 10-15% LDL Omega3 FA Improved morbidity 2-4 g/d & mortality S/P MI Soluble fiber * 4% TC reduction 3-10 g/d 7-12% reduction LDL Chocolate * 10-12% mortality red. 50-100 g/d 4-13% LDL red. HDL increase Alcohol * HDL increase 5 oz/d LDL oxidation inhibition

Lipid Lowering foods and Supplements

Supplement effect recommendation Soy Protein * 5-6% reduction LDL 25g/d Artichoke leaf * 18.5% reduction TC 1800mg/d 23% reduction LDL Garlic evidence is mixed No recommendation Folic Acid reduces homo-cys . No recommendation no beneficial effect on cardiac mortality or lipids Vitamin E High dose ( 400IU/d) No recommendation assoc. With increased mortality

Primary Care take home points

• Lifestyle modification can reduce insulin resistance and can help with lowering both triglycerides and LDL cholesterol

• Stains have a significant role to play in reducing Total Cholesterol and LDL , thereby reducing cardiovascular risk in some patients.

• Statins may not be enough in type ll diabetics, and Fibrinates and Niacin may be needed reduce triglycerides and raise HDL in order to lower over all cardiovascular risk.

The End