Primary Care Approach to Dyslipidemia David Thom, MD, PhD Associate Professor Family

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Primary Care Approach to Dyslipidemia David
Thom, MD, PhDAssociate ProfessorFamily
Community Medicine
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Overview

• Introduction
• Epidemiology
• Definitions
• Pathophysiology
• Screening
• Treatment

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Introduction Goals of screening and Treatment

• Primary and secondary prevention of
  cardiovascular events
• CHD (MI, SCD, revascularization, angina)
• Stroke
• PVD
• Renal disease
• Maintain/improve quality of life
• Avoid harm

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Introduction Principals of Risk Factor Reduction

• Risk factors (RFs) tend to be additive
• RFs similar across different types of CVD
• RFs weaker in older age groups
• RF reduction has less impact in older age groups

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Epidemiology of CHD

• Cross-sectional association between total
  cholesterol and CHD risk is well established

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Risk of CHD Events Increases with Increasing
Total Cholesterol
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Epidemiology of CHD Fixed Risk Factors

• Older Age
• Male Sex
• Family history of early CVD

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Epidemiology of CHD Modifiable, Established Risk
Factors

• Hypertension
• Diabetes
• Smoking
• Obesity
• Sedentary lifestyle
• Metabolic syndrome/insulin resistance

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Epidemiology of CHD Modifiable, Possible Risk
Factors

• C-reactive protein (CRP)
• Renal insufficiency
• Homocysteine
• Plasma fibrinogen
• Hyperuricemia

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Cumulative Incidence of Recurrent Myocardial
Infarction or Death from Coronary Causes, by
Achieved LDL Cholesterol or CRP Level
Ridker, P. M et al. N Engl J Med 200535220-28
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Cumulative Incidence of Recurrent Myocardial
Infarction or Death from Coronary Causes, by
LDL-C and CRP Levels
Ridker, P. M et al. N Engl J Med 200535220-28
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Change in CRP and Change in Atheroma
Ridker, P. M et al. N Engl J Med 200535220-28
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Epidemiology of CHD Established Lipid Risk
Factors

• High LDL
• Low HDL
• High LDL/HDL or
• High TC/HDL or
• High non-HDL

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Epidemiology Possible Lipid Risk Factors

• High Lp(a)
• High Triglycerides
• High apolipoprotein B
• Low apolipoprotein A-1
• Apolipoprotein e subtypes

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Measurement of Lipid Types

• TC can be measured non-fasting
• HDL can be measured non-fasting
• Non-HDL-C TC-HDL (LDLIDLVLDL)
• TG must be measured fasting
• LDL rarely measured directly. Instead,
  estimated as LDL TC - TG/5 HDL (only valid
  if TG lt 400).

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Pathophysiology Medical Conditions Associated
with Dyslipidemia

• Diabetes
• Cholestatic liver disease
• Nephrotic syndrome
• Hypothyroidism
• Chronic renal insufficiency (raises TGs)
• Medications (thiazides, beta-blockers, atypical
  anti-psychotics)

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Pathophysiology Role of Oxidized LDL in
Atherosclerosis

• Oxidative injury to epithelium
• Alteration in vascular tone
• Promotion of recruitment of monocytes to foam
  cells
• Induction of growth factors
• Increased platelet aggregation

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Screening

• USTFPS and ACP men age 35 to 65 and women age
  45 to 65
• AAFP men starting at age 35 and women starting
  at age 45
• NCEP men and women starting at age 20
• All 3 recommend screening men and women with
  family history of early CHD or multiple CHD risk
  factors starting at age 20

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Screening

• USTFPS and AAFP do not specify interval. NCEP
  recommends q 5 yrs
• While obtaining fasting TC, HDL and TG is
  preferred, a non-fasting TC and HDL is acceptable

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Treatment General Principals

• Meta-analysis estimate that 10 drop in TC
  predicts 15 drop in CHD event rate and 11 drop
  in total mortality rate1
• Numerous national organizations have treatment
  guidelines (e.g., ATP III, ACC, AHA, NHLBI, NKF,
  NCEP)
• Need mean of 2 measurements to be within 10 of
  true value

1. Circulation 199897946
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Treatment Has Similar Effects by Subgroups
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Treatment has Similar Effects on CVD Events
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Treatment Rules to Remember

• Target LDL and HDL levels based on
  stratification by risk factors
• Major CHD risk factors
• smoking
• hypertension (even if controlled),
• age (gt44 for men, gt54 for women)
• FHx of CHD in 1st degree relative (lt55 if
  male, lt65 if female)

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Treatment Rules to Remember

• CHD equivalent risk factors
• diabetes
• known ASCVD (CHD, symptomatic Carotid Dz, PVD,
  aortic aneurysm)
• risk of CHD event gt20 in 10 years (based on
  Framingham data)
• CRI (Cr gt 1.5 or GFRlt60)

NKF, ACC and AHA only
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Treatment Target levels1

• First target LDL levels based on risk strata
• Low risk 0 or 1 major RF (LDL lt160)
• Medium risk 2 major RFs (LDL lt130)
• High risk gt 2 major RFs but no CHD
• equivalent RF (LDL lt100)
• Very high risk CHD equivalent risk (LDL lt70)
• If TG gt200, use non-HDL-C with target being
  above levels of LDL 30

1. Grundy SM et al Circulation 2004110227
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Treatment Target levels (see figure)

• Next target HDL, if needed, with a goal of HDL
  gt 40 mg/dL for all risk levels (less evidence
  then for LDL)
• Next can target TG with goal of lt 200 mg/dL for
  all risk levels (benefit of doing this is not
  established)

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Treatment Diet and Exercise

• Should be recommended as part of any treatment
  regimen
• Usually need to combine with medication if LDL
  is over 30 mg/dL from target
• While potential impact of diet and exercise is
  significant, effect on lipid levels is modest
  in practice due in part to poor adherence

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Treatment Diet and Exercise

• Recent study found equivalent, modest
  improvement in lipids with 4 major diets
  (Atkins, Ornish, Zone and W Watchers)
• Evidence that trans- and saturated fats raise
  lipids compared to poly and mono- and un-
  saturated fats (see figure)
• Exercise of 60 minutes/week raises HDL

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Treatment Statins

• Potential mechanisms of action
• reduction in LDL, increase in HDL
• reduction in oxidative stress
• reduction in inflammation
• decreased thrombogenicity
• reversal of endothelial dysfunction
• plaque stabilization
• reduction in monocyte adherence

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Treatment Statins

• First line treatment for dyslipidemia
• Only class shown to reduce mortality in primary
  prevention
• Similar reduction in risk across multiple
  subgroups (see figure)
• Reduction in events beginning within the first
  few months of use (see figure)

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Treatment Statins - Choosing

• May choose based on specific lipid profile, but
  no evidence that this helps
• Statins have relatively modest effects on HDL
  and TG, so usually compared on LDL
• Comparison of efficacy and costs (see table)
• Formulary coverage (see table)

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Comparison of Statins1

1. Medical Letter 20034581 and 20044693
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Treatment Side Effects of Statins

• Muscle toxicity (markedly increased with
  concurrent use of cyclosporine and fibrates)
• Hepatic dysfunction
• Incidence of persistently elevated
  transaminases is 0.5-3.0
• Check LFTs prior to Tx and at 12 weeks
• Probably OK in patients with isolated
  preexisting, mild transaminase elevation
• Use in chronic, progressive liver disease not
  clear

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Treatment Side Effects of Statins

• Potential, not established side effects
• cognitive dysfunction
• peripheral neuropathy
• cancer

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Treatment Fibrates

• Gemfibrozil and Fenofibrate (micronized)
• Lowers TG 20-50 (better than statins)
• Also raises HDL 10-20
• Lowers LDL 5-20 (modest effect)
• Dyspepsia a common side effect. Also risk of
  gallstones
• Synergistic risk of myopathy if used with
  statins (may be less with fluvastatin or
  pravastatin)

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Treatment Nicotinic Acid (Niacin)

• Lowers LDL
• Raises HDL more than statins
• Little effect on TGs
• Flushing most common side effect
• Can raise liver enzymes
• Slow release is better tolerated

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Treatment Other Medications

• Bile acid sequestrants (resins)
• cholestyramine, colestipol, and colesevelam
• can be combined with statins
• limited use due to high rate of side effects
  (constipation, bloating, nausea)
• Absorption inhibitors
• ezetimibe only one in this class
• can be combined with statins
• well tolerated

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Comparison of Other Lipid-Lowering Drugs1

1. Medical Letter 20034581 and 20044693
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Treatment Other 3-omega acids

• Includes docosahexaenoic acide (DHA)
  eicosapentaenoic acid (EPA) and
  alpha- linolenic acid (ALA)
• DHA and EPA, found in fish and fish oil, are
  most studied with over 40 RCTs rated as good
  quality (4/5)
• 2-4 g/d DHAEPA decrease TG 20-40 (LOE A)
• Risk of bleeding increases with gt 3 g/d
• Risk of mercury poisoning from fish

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Treatment Other Red Yeast Rice

• Red yeast rice (a yeast grown on rice) extract
  contains lovastatin, and has been shown to
  reduce LDL and TG levels in RCTs (LOE A)
• Current formulations of the extract sold in the
  US do not contain lovastatin due to FDA
  regulations. Their effectiveness is not clear.

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Treatment Other Soy

• 30-50 grams soy protein/day moderately
  decreases LDL, with small decreases in TG and
  no apparent effect on HDL (LOE A)
• Effects of isolated components of soy
  (genistein, daidzein) not clear
• No study of effect on CVD endpoints

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Effects of Soy Protein on Serum LDL-C in 31
Clinical Trials1
1. Anderson, J. W. et al. N Engl J Med
1995333276-282
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Treatment Other Garlic

• There have been over 20 published RCTs, rated
  as good or better, of garlic in treating
  hyperlipidemia1
• Several meta-analyses have found a significant,
  though modest, benefit on lipids, lowering LDL lt
  10 mg/dL and TG lt 20 mg/dL over 3 months (LOE
  B)2,3
• Typical amounts are 600-1200 mg/day garlic
  powder or about 2 cloves/day
• Possible inhibition of clotting

1. www.naturalstandard.com. 2. Ackerman RT Arch
intern Med 20011612505. 3. Stevinson C. Ann
Intern Med 200013565
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Treatment Other Barley Bran and Oil

• 2 RCTs rated as good (3/5) found small decrease
  in LDL (6-10) over 4 weeks with 3 ml of barley
  oil or 30 g barley bran per day compared to
  cellulose or wheat bran (LOE B)1,2

1. McIntosh et al Am J Clin Nutr 1991531205.
2. Lupton JR, et al. J Am Diet Assoc 19949465
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Treatment Special Groups

• Patients over age 65
• Good evidence to treat for secondary prevention
• Also recommended to treat if have 1 or more
  additional major RFs or one or more CHD
  equivalent RFs
• Insufficient evidence to recommend treatment of
  primary prevention if no additional RFs

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Treatment Special Groups

• Patients with high LDL and high HDL
• recommended to subtract 1 major risk factor if
  HDL gt60
• Patients with isolated low HDL (lt 40)
• treat to target HDL of gt 40

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Treatment Special Groups

• Patients with isolated high TGs (gt200)
• treat any patient with TG gt500
• treat to target levels of non-HDL-C target
  LDL levels 30
• treat to target TG lt200 if has CHD

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Treatment Adherence

• Discontinuation rates at 1 year1
• Diet and exercise probably gt 90
• Lovastatin 15
• Gemfibrozal 37
• Cholestyromine 41
• Nicotinic acid 46

1. Andrade SE at al. NEJM 19853321125
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Treatment Improving adherence

• Patient education
• Treatment goals
• Preferred treatment method(s)
• Plan to monitor and adjust treatment
• Discussion of possible side effects
• Enlist support of family members

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Treatment Cultural aspects

• Poverty, less than a high school education,
  being uninsured, and having to regular source
  of care all associated with lower rates of
  screening1
• One national household survey found lower rates
  of cholesterol screening among Mexican Americans
  and Asians, but no difference after adjustment
  for differences in above variables2

• Shi L, Stevens GD. Med Care 200543193.
• Stewart SH, Silverstein MD. J Gen Intern Med
  200212405

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Treatment Cultural aspects

• Little is known about perceptions of screening
  and treatment of hyperlipidemia among another
  cultures.
• While the actual pathophysiologic model of
  dyslipidemia may not fit with non-Western
  belief systems, concepts of excess, balance,
  diet, exercise and even medication to restore
  balance in the body exist in most cultures.

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Treatment Monitoring

• Follow-up visits to reinforce behavioral
  changes
• Trial of diet and exercise X 3 months
• Check lipids and LFTs 6 weeks after each change
  in medication and every 6 to 12 months when
  stable
• Discuss risk of myopathy

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Summary

• Screening recommended for all men age 45 to 65
  and all women over age 55 to 65
• Screen high risk patients starting at age 20
• Identify major and CHD-equivalent RFs
• Treatment based on risk stratification
• Emphasize life-long commitment to treatment
  with follow-up and monitoring

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References

• Andrade SE, Walker AM, Gottlieg LK.
  Discontinuation of antihyperlipidemic drugs do
  rates reported in trials reflect rates in primary
  care settings? New Engl J Med 19853321125-32.
• Grundy SM, Cleeman JI, Bairey CN et al.
  Implications of recent clinical trials for the
  National Cholesterol Education Program Adult
  Treatment Panel III guidelines. J Am Coll
  Cardiol 200444720-32.
• Heart Protection Study Collaborative Group.
  MRC/BHF Heart Protection Study of cholesterol
  lowering with simvastatin in 20,536 high risk
  individuals a randomized, placebo-controlled
  trial. Lancet 20023607-22.
• Lupton JR, Robinson MC, Morin JL.
  Cholesterol-lowering effect of barley bran flout
  and oil. J Am Diet Assoc 19949465-70.
• The Medical Letter October 13, 200345(1167)81-3
  November 22, 200446(1196)93-5.
• McIntosh JH, Whyte J, McArthur R, Nestel PJ.
  Barley and wheat foods influence on cholesterol
  concentrations in hypercholesterolemic men. Am J
  Clin Nutr 1991531205-9.
• Nissen SE, Tuzcu EM, Shoenhagen P. Statin
  therapy, LDL cholesterol, C-reactive protein, and
  coronary artery disease. N Eng J Med 200535229
• Ridker PM, Cannon CC, Morrow D. C-reactive
  protein levels and outcomes after statin
  therapy. N Eng J Med 200535220.
• Shi L, Stevens GD. Vulnerability and the receipt
  of recommended medical services the influence
  of multiple risk factors. Med Care 200543193-8.
  
• Stewart SH, Silverstein MD. Racial and ethnic
  disparity in blood pressure and cholesterol
  measurement. J Gen Intern Med 200212405-11.
• United States Preventive Services Task Force,
  Guide to Clinical Preventive Services, 3rd
  edition, 20-01. Available online at
  www.ahrq.gov/clinic/prevnew.htm