Hyperlipidemia
for 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
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
Less than 100
100-129
130-159
160-189
More than 190
Values
Optimal
Near optimal/above optimal
Borderline high
High
Very high
Total cholesterol
Less than 200
200-239
More than 240
Desirable
Borderline high
High
HDL cholesterol
Less than 40
More than 40
Low
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
Waist circumference
Men
Women
Triglycerides
HDL
Men
Women
Blood Pressure
Fasting glucose
•
Criteria
> 40 in.
> 35 in.
150 mg/dl or more
<40 mg/dl
< 50 mg/dl
130/85mmhg or higher
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
• 2+ risk factors
• 0-1 risk factors
<100
<130
<160
Statins
Medication
dose
LDL
TG
HDL
side effects
Reduction Reduction Reduction Increase
Atarastatin
( Lipitor)
Fluvastatin
(Lescol)
Lovastatin
(Mevacor)
Pravastatin
(Pravacol)
10-80 mg 35-65% 15-40% 5-10% myalgias
20-80mg 15-35% 10-20% 3-7%
same
20-40mg 20-35% 5-10%
same
5%
10-40mg 20-40% 10-25% 3-10% same
Statins
Medications dose LDL TG
HDL
side effects
reduction reduction increase
Rosuvastatin
(Crestor)
5-40mg 40-70% 20-30% 5-15% same
Simvastatin
(Zocor)
10-60mg 25-50% 10-25% 5-10% same
Fibrates and Niacin
Medication dose
LDL
TG
HDL
Side effects
Fibrates
Gemfobrozil
(Lopid)
Fenofibrate
(Tricor)
600mg BID minimal 20-50% 10-20% nausea,
rare hep.
48-148mg minimal 20-50% 10-20% myositis
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 effects
Resins
Colestipol
4-8 g bid 10-20% may increase minimal bloating
(Colestid )
nausea, constipation
Cholestyramine 5-10 g BID
flatulent
(Questran)
Colesvelum
6 capsules
(Welchol)
BID
Absorption Inhibitors
Ezitimibe
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 lowdensity 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 highdensity 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
Plant sterols * 4-8% red. of TC
10-15% LDL
Omega3 FA
Improved morbidity
& mortality S/P MI
Soluble fiber * 4% TC reduction
7-12% reduction LDL
Chocolate *
10-12% mortality red.
4-13% LDL red.
HDL increase
Alcohol *
HDL increase
LDL oxidation inhibition
recommendation
2-3 g/d
2-4 g/d
3-10 g/d
50-100 g/d
5 oz/d
Lipid Lowering foods and Supplements
Supplement
Soy Protein *
Artichoke leaf *
Garlic
Folic Acid
Vitamin E
effect
recommendation
5-6% reduction LDL 25g/d
18.5% reduction TC 1800mg/d
23% reduction LDL
evidence is mixed No recommendation
reduces homo-cys . No recommendation
no beneficial effect
on cardiac mortality or lipids
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