Approach to Dyslipidemia

1
Approach to Dyslipidemia

• Dr Zuhair M Shawagfeh
• FRCPI

2
Covered Topics

• Physiology of Lipid Metabolism
• Role of lipoproteins in atherosclerosis
• Hypolipidemic Agents ,indications, and side
  effects
• Screening and Risk Assessment
• Treatment Paradigms
• Treatment of Special Population

3
Exogenous Pathway of Lipid Metabolism
Cholest AA FA P, glycerol

Vessel wall
4
Endogenous Pathway of Lipid Metabolism
5
Key Enzymes and Cofactors in Lipid Metabolism

• HMG-CoA reductase-reduces HMG-CoA to mevalonic
  acid in the rate-limiting step of cholesterol
  biosynthesis (mainly liver and intestine)
• Lipoprotein Lipase- digests TG core of CMC and
  VLDL

6
LDL Oxidation and Atherosclerosis
7
Increased Atherogenicity of Small Dense LDL

• Direct Association
• Longer residence time in plasma than normal sized
  LDL due to decreased recognition by receptors in
  liver
• Enhanced interaction with scavenger receptor
  promoting foam cell formation
• More susceptible to oxidation due to decreased
  antioxidants in the core
• Enter and attach more easily to arterial wall
• Endothelial cell dysfunction

• Indirect Association
• Inverse relationship with HDL
• Marker for atherogenic TG remnant accumulation
• Insulin resistance

8
High Density Lipoprotein and Atherosclerosis

• Reverse cholesterol transport
• Maintenance of endothelial function
• Protection against thrombosis
• With Apo A-I inhibits generation of
  calcium-induced procoagulant activity on
  erythrocytes by stabilizing cell membrane
• Low blood viscosity via permitting red cell
  deformability
• Anti-oxidant properties-may be related to enzymes
  called paraoxonase

9
Lipoprotein (a)

• Specialized form of LDL (apolipoprotein (a)
  covalently bound to apo B by disulfide bridge)
• Structural similarity to plasminogen, thus
  interfering with fibrinolysis
• Macrophage binding and cholesterol deposition
• Measured by ELISA
• Cross-sectional and retrospective epidemiologic
  studies have shown association between excess Lp
  (a) and CHD while prospective results are
  conflicting
• Associated with unstable angina and presence of
  complex coronary lesions
• Commonly detected in premature CHD
• Possible role in target organ damage in presence
  of HTN

• Indications for screening
• CHD and no other identifiable dyslipidemia
• Strong CHD family history and no other
  dyslipidemia
• HTN and early premature target organ damage
• Hypercholesterolemia refractory to statins and
  bile acid sequestrants
• Treatment guidelines
• Primary goal is to lower LDL to target and
  lowering to lt80 may reduce risk
• If LDL cannot become optimized, then Lpa loweing
  with nicotinic acid (38) shoud be tried
• Goal lt20 in whites

10
Primary Disorders of LDL-Cholesterol Metabolism

• Familial hypercholesterolemia- defect in gene
  coding for apo B/E LDL receptor thus reduced
  clearance of LDL from circulation
• Homozygotes with higher LDL-C levels
• Excess LDL deposited in arteries as atheroma and
  in tendons and skin as xanthomata and xanthelasma
• Hypercholesterolemia, normal TG, genetic or
  cellular confirmation of LDL receptor defect
• Usually serum cholesterol levels AND premature
  CHD in first-degree or 2 second-degree relatives
• Usually requires multiple drugs for treatment
• Familial combined hyperlipidemia
• Usually associated with metabolic syndrome
• 1-2 general population
• 1/3-1/2 familial causes of CHD and 10 of
  premature cases
• Overproduction of hepatically derived apo-B 100
  associated with VLDL /- decreased LDL receptor
  activity
• LDL phenotype B, increased TG, decreased HDL
  (atherogenic dyslipidemia)
• Phenotypic heterogeneity depends on problems with
  VLDL or LDL metabolism
• Elevated TG and cholesterol
• Elevated LDL
• Isolated hypertriglyderidemia (rise in VLDL)

11
(No Transcript)
12
(No Transcript)
13
(No Transcript)
14
(No Transcript)
15
(No Transcript)
16
(No Transcript)
17
Statins

• Competitive inhibitors of HMG CoA reductase,
  rate-limiting step in cholesterol biosynthesis
• Reduction in intrahepatic cholesterol leading to
  increased LDL receptor turnover
• Most powerful for lowering LDL cholesterol
• Modest effect on raising HDL
• Reduction in TG due to decreased VLDL synthesis
  and clearance of VLDL remnants by apo B/E (LDL)
  receptors
• Reduction in oxidized and small dense LDL
  subfractions and reduce remnant lipoprotein
  cholesterol levels (reduction of CE transfer from
  LDL to VLDL)

18
Comparable Efficacy of Statins
Special considerations No renal dosing
Atorvastatin and Fluvastatin Use in chronic liver
disease pravastatin or rosuvastatin Less drug
interactions pravastatin, fluvastatin,
rosuvastatin (not metabolized via CYP3A4) Less
muscle toxicity Pravastatin and
Fluvastatin Cost-effectiveness Rosuvastatin,
atorvastatin, fluvastatin
19
Evidence in Primary Prevention
Name of Study Design Outcome
West of Scotland Coronary Prevention Study (WOSCOPS) 6595 men Mean TC 272 LDLgt155 diet placebo Diet pravastatin 31 risk reduction in coronary deaths and nonfatal MI Benefit gttreating mild HTN but 3 x less than that in 4S study
Air Force/Texas Coronary Atherosclerosis Prevention Study 5614 Men 991 women 45-73 y.o.mean TC 221 LDL 150 (130-190) Diet placebo Diet lovastatin 37 risk reduction in coronary events
20
Evidence in Secondary Prevention
Name of Study Design Outcome
Scandinavian Simvastatin Survival Study (4S) 4444 patients (angina or h/o MI) TC 212-309 5 year f/u Placebo v. simvastatin 20-40 qd Goal TC lt200 Total mortality (8 v.12) Major events (19 v. 28) CHD deaths 42 lower Revascularization 37 CVA (2.7 vs 4.3) 1 LDL decrease1.7 RR
CARE 4159 h/o MI 2 yrs prior Borderline Average TC 209 LDL 139 HDL 39 Pravastatin 40 qhs x 5 yrs Coronary death/MI 10.2 v. 13.2 Revascularization 14.1 v. 18.8 Stroke frequency 2.6 v. 3.8 LDL reduction unrelated to events
LIPID 9014 men and women with recent MI or unstable angina TC 155-270 Pravastatin or placebo CHD deaths 6.4 v. 8.3 Total mortality 11 v. 14 Stroke 20 decrease Bypass 8.9 v. 11.3
Heart Protection Study 20,536 simvastatin 40 qd 33 LDLlt11625 116-135 42 LDLgt135 h/o CVD, DM, or treated HTN 5.5 yrs All cause mortality RRR 13 CHD death RRR 17 Major events RRR 24 Similar in 3 tertiles of LDL and in those with LDLlt100
21
Mechanism of Benefit of Statins in Secondary
Prevention

• Regression of atherosclerosis
• Plaque stabilization
• Reduced inflammation
• Decreased thrombogenicity
• Reversal of endothelial dysfunction
• Others
• Reduced monocyte adhesion to endothelium
• Reduced oxidative modification of LDL
• Increased mobilization and differentiation of
  endothelial progenitor cells leading to new
  vessel formation

22
Adverse Effects of Statins

• In general, less than with other agents. Fairly
  tolerable and safe
• Myopathy
• Ranges from myalgias (2-11), myositis(0.5) to
  rhabdomyolysis (lt0.1) (possibly ARF)
• Few weeks-4 months onset
• Symptoms and CK should normalize over days to one
  month after d/c
• Pravastatin and Fluvastatin less risk
• Increased risk in
• ARF/CRF
• Obstructive liver disease
• Hypothyroidism
• Concomittant use of drugs interfering with
  CYP3A4??
• Gemfibrozil combined therapy
• Hepatic
• 0.5 to 3 persistent elevations in
  amino-transferases in first 3 months and
  dose-dependent
• Several randomized trials have found no
  difference compared with placebo
• FDA recommends LFTs before and 12 weeks after
  starting and with any dose elevation and
  periodically
• CNS
• Case reports of memory loss associated with
  statins (mainly lipophilic)
• If memory loss and recent initiation of statin,
  then d/c and use a hydrophilic statin such as
  pravastatin or rosuvastatin

23
Fibric Acid Derivatives

• Decrease Triglycerides (35-50)
• Reduced hepatic secretion of VLDL through
  activation of PPAR-alpha receptors in liver
• Stimulate lipoprotein lipase and thus clearance
  of TG-rich lipoproteins
• Raise HDL (15-25)
• Direct stimulation of HDL apolipoprotein
  synthesis A-I,II
• Increased transfer of apo A-I with diminished
  cholesterol transfer from HDL to VLDL
• Increases LDL buoyancy
• May also improve endothelial function and
  favorable effect on macrophage responses
  (possible reduction in CHD risk independent of
  effect on lipoproteins)
• Agents
• Gemfibrozil- 600 mg po BID (11 raise in HDL).
  Modest LDL reduction but little effect in
  combined hyperlipidemia. Can increase LDL in pure
  hypertriglyderidemia
• Fenofibrate 200 mg capsules or iii caps 67 mg qd
  (renal dosing and can decrease Cyclosporin
  levels). Better for LDL lowering
• Side effects
• Gallstone formation
• Dyspepsia, diarrhea, nausea, vomiting, abdominal
  pain, eczema, rash, vertigo and myalgias
• Adverse drug interaction
• Gemfibrozil- inhibits glucuronidation of
  lipophilic statins and increases levels thus
  increasde risk of myopathy. Also decreases
  warfarin by 30

24
Bile Acid Sequestrants

• Lower LDL (10-15)
• BINDING BILE ACIDS IN INTESTINE CAUSING A DECLINE
  IN HEPATIC CHOLESTEROL POOL THUS SYNTHESIS OF
  apo B/E (LDL) RECEPTORS
• Max doses cause 30 reduction
• Raise HDL
• Intestinal formation of nascent HDL
• Available agents
• Cholestyramine 8 grams/day. 24-30 grams/day can
  lower LDL up to 24
• Colestipol 10 grams/day
• Colesevelam 1.5-4.5 grams/d
• Adverse effects
• Usually limit use
• Mainly GI (nausea, bloating, cramping)- least
  problematic with colesevelam
• Increased liver enzymes
• Also drug interactions (impair absorption)
• Digoxin, warfarin, and fat soluble vitamins (give
  one hour before or 4 hours after bile acid
  sequestrant)
• Contraindications pts with elevated TG

25
Nicotinic Acid

• Mechanism of Action
• Inhibits hepatic VLDL production and its
  metabolite LDL
• Raises HDL by reducing lipid transfer of
  cholesterol from HDL to VLDL and by delaying HDL
  clearance
• Increase in LDL size
• Reduction in plasma fibrinogen levels
• Formulations and dosing
• Immediate release (crystalline) 100 TID and
  titrated to tolerance
• Sustained release
• Niacor
• Niaspan 500 mg qhs x one month and then titrated
  to 1000 mg usually given daily after evenng meal
• 1-1.5 grams/day for HDL raising
• 3 grams/day for VLDL and LDL lowering and
  possibly lowering lipoprotein a levels
• OTC IR preps are cheaper and effective
• OTC preps labeles NO FLUSH usually not
  efficacious
• Side effects
• Flushing (less common with controlled release)
  minimized with ASA 30 minutes before and limited
  in 7-10 days

26
Ezetimibe(Zettia)

• Mechanism
• impairs dietary and biliary cholesterol
  absorption at the brush border of the intestines
  without affecting TG or fat-soluble vitamins
• possible Niemann-Pick C1 like protein involved in
  cholesterol transport
• LDL decrease 15-20
• Trivial effects on HDL and TG
• Also adjunctive therapy to statins but same
  effect with higher dose of statin as in one study
  10 zettia and 10 atorvastatin same effect as 80
  atorvastatin
• Indications
• Avoiding high doses of statins
• Very high LDL (FCH) not sufficiently controlled
  on statins
• Adverse effects
• Only 20 absorption so lower side-effect profile
• Higher incidence of myopathy and elevated
  transaminases when coadministered with a statin
• Should not be used as the first-line agent in
  lowering LDL
• Check LFTs prior to starting in combo with
  statins
• No definite clinical outcome studies available

27
Effect of Lifestyle Modification

• Diet
• Decreased saturated fat (decrease LDL)
• Replacing saturated and trans unsaturated fats
  with unhydrogenated monounsaturated or
  polyunsaturated fats
• Recommended diet
• Dietary cholesterol lt200 mg/d total fat lt30
  saturated fat lt7
• CHO (whole grains, fruits,veggies) 50-60 total
  calories
• Dietary fiber 20-30 g/d
• Protein 10-25 g/day
• Plant stanols/sterols 2 grams/day
• Effect of LDL lowering should be evident in 6-12
  months
• Elevated BMI associated with decreased dietary
  response
• Referral to dietitian helpful
• Exercise
• In a prospective study of 111 sedentary men and
  women with dyslipidemia randomized to different
  levels of exercise, decrease in VLDL TG and
  increase in LDL size observed. Increase in HDL
  and size and largest effect on LDL seen with high
  amount high intensity exercise
• Mechanisms of benefit reduction in CETP,
  elevation in LCAT, reduced hepatic lipase and
  elevated LPL activity
• Possible effect on LDL particle size
• Moderate intensity exercise (3-4 mi/hr) for 30
  minutes on most days of the week

28
Diet Supplements

• Fish Oil (source of omega-3 polyunsaturated fatty
  acids)
• Salmon, flaxseed, canola oil, soybean oil and
  nuts
• At high doses gt 6 grams/day reduces TG by
  inhibition of VLDL-TG synthesis and
  apolipoprotein B
• Possibly decreases small LDL (by inhibiting CETP)
• Several studies have shown lower risk of coronary
  events
• 2 servings of fish/week recommended??
• Pharmacologic use restricted to refractory
  hypertriglyceridemia
• Number of undesirable side effects (mainly GI)
• Soy
• Source of phytoestrogens inhibiting LDL oxidation
• 25-50 grams/day reduce LDL by 4-8
• Effectiveness in postmenopausal women is
  questionable
• Garlic
• Mixed results of clinical trials
• In combination with fish oil and large doses
  (900-7.2 grams/d), decreases in LDL observed
• Cholesterol-lowering Margarines
• Benecol and Take Control containing plant sterols
  and stanols
• Inhibit cholesterol absorption but also promote
  hepatic cholesterol synthesis
• 10-20 reduction in LDL and TC however no outcome
  studies

29
Measurement of Lipoproteins

• Lipoprotein analysis 12-14 hours fasting
• TC and HDL-C can be measured fasting or
  non-fasting
• LDL-Cholesterol Total cholesterol VLDL (1/5
  TG)-HDL
• Validity depends on TG lt400 mg/dL
• Measured directly if patients have profound
  hypertrig
• Errors in TC, HDL, and TG can affect values
• Non-HDL cholesterol TC HDL-C
• All cholesterol in atherogenic lipoproteins incl
  LDL, Lipoprotein a, IDL, VLDL
• Acute phase response (i.e. MI, surgical trauma or
  infection)
• Can reduce levels of TC, HDL, LDL, apo AB
  through impairment of hepatic lipoprotein
  production and metabolism
• Raise Lpa and TG
• Lipoprotein analysis should be done as outpatient
  one month after event

30
Risk Assessment

• CHD equivalents
• Symptomatic carotid artery disease
• Peripheral arterial disease
• AAA
• DM
• Multiple risk factors that confer a 10-year risk
  of CHD gt 20
• Identify major risk factors other than LDL
• Smoking
• HTN BP gt140/90 or on anti-hypertensive medication
• Low HDL lt40 mg/dL
• Family history premature CHD (CHD in men 1st
  degree relative lt55 women lt65 y.o.)
• Age (men gt or 45 women gtor 55)
• Other potential risk factors
• Chronic renal insufficiency (Cr gt 1.5 mg/dL OR
  GFR lt60 cc/min) per Up-To-Date
• Obesity, physical inactivity, impaired fasting
  glucose, markers for inflammation
• HDL gt 60 mg/dL is a negative risk factor
• If patient without CHD or equivalent has 2 or
  more major risk factors, then calculate the
  Framingham risk (age,TC,HDL,smoking,SBP)

31
Validation study found Framingham CHD predictor
worked well in white and black population but
overestimated risk in Japanese American, Hispanic
men and native American women and other studies
have shown possible overestimation in European
and Asian populations
32
New Guidelines for LDL Goal
Risk category Goal LDL (mg/Dl)
CHD (CHD risk equivalent) lt100 lt70 optional
2 or more major risk factors 10 yr gt20 lt100 lt70 optional
2 or more major risk factors 10 yr 10-20 lt130 lt100 optional
2 or more major risk factors 10 yr risk lt10 0-1 major risk lt130 lt160
33
Elevated LDL

• Statins are first choice and selection is based
  on extent of LDL reduction, cost and reduction in
  clinical CHD events as well as presence of renal
  impairment
• 30-35 decrease in LDL-C with equivalent doses
• Titrate statin dose at 3-4 week intervals
• Doubling statin dose reduced LDL an additional 6
• Consider adding second agent instead of dose
  increase
• Variable drug response depending on endogenous v.
  exogenous hypercholesterolemia
• Second agents may include bile acid resins (15),
  ezetimibe (20), or plant stenol/sterol margarine
  (10)
• Niacin may be added as a third agent if needed

34
Mixed (Combined Hyperlipidemia)

• Elevated LDL and/ or triglycerides
• Objective is to achieve LDL goals
• With very high TGgt 400, start with fibrate or
  niacin
• Then treat LDL with statin
• If LDL-C goal achieved, but TGgt200, non-HDL-C
  should be targeted
• Non-HDL goal 30 above LDL goal
• Statin titration dose OR Statin-fibrate OR
  Statin-Niacin combinations more effective in this
  type of dyslipidemia but adverse reactions more
  common with combined treatment so benefit/risk
  ratio considered
• Titration for mild TG elevations
• Combination TX for moderate to severe TG
  elevations

35
Isolated Low HDL

• Treatment Indications of Isolated low HDL
• CHD OR CHD equivalent
• if first-degree relative early onset CHD and
  similar lipid profile
• Weight management, exercise, and smoking
  cessation
• Niacin /- gemfibrozil
• CETP inhibitors (NEW and investigational)

36
Treatment Guidelines

• Always Consider secondary causes of dyslipidemia
  (DM, hypothyroidism, obstructive liver disease,
  CRF or nephrotic syndrome or drugs)
• All patients with LDL above goal start with
  adequate trial of lifestyle modification only but
  concomitant drug therapy may be appropriate if
• LDL gt220 or gt 190 if gt 2 risk factors
• Pre-existing CHD or CHD equivalent
• If CHD or risk equivalent and? significantly
  above goal, then start pharmacotherapy
  (preferably statin) immediately
• If CHD or equivalent and LDL goal lt100 not
  achieved on maximal statin (atorvastatin 80 or
  rosuvastatin 40), then additional agent should be
  added based on abnormalities in other
  lipoproteins
• In no CHD or CHD equivalent, consider drug
  therapy with statin if after adequate lifestyle
  trial
• LDL gt190 if 0 or 1 risk factor
• LDL gt160 if 2 or more risk factors if 10 yr risk
  lt10 130 if risk 10-20
• If persistent elevation in LDL purely, then add
  bile acid sequestrant or zettia
• In patients with ACS, atorvastatin 80 mg/day
  should be started soon after hospitalization
• PROVE-IT TIMI 22 Trial, MIRACLE, A to Z trial
• When LDL goal reached but TG gt200, then consider
  non-HDL cholesterol and treat to goal 30 above
  LDL
• In patients with ACS, atorvastatin 80 mg/day
  should be started soon after hospitalization
  (event reduction and LDL lowering effect)
• PROVE-IT TIMI 22 Trial, MIRACLE, A to Z trial

37
Elderly

• Should be individualized based on chronologic and
  physiologic age
• Secondary prevention studies support treatment
• CARE 50 patients gt60 derived similar benefits
  as in younger patients
• HPS reduction in events similar in lt or gt 65
  y.o.
• Cardiovascular Health Study showed benefit in
  primary prevention in gt65 y.o.
• All major statin trials and VA-HIT trial have
  shown reduction of atherothrombotic stroke with
  lipid-lowering
• ATP III recommends diet as first line of primary
  intervention but drugs can be considered if
  multiple risk factors possibly with LDL gt160
• Underutilization of lipid-lowering drugs in
  elderly due to
• Concern for safety (hapatic/renal impairment)
• Time course to benefit

38
Adults With DM

• Both primary and secondary intervention trials
  have shown benefit and reduction of CVD in
  diabetic subgroups treated with lipid-lowering
  agents (HPS and CARE trial showed significant
  outcome improvement with statins even at LDL
  lt116)
• Despite their often elevated TG and low HDL due
  to insulin resistance, etc. LDL should be primary
  goal
• Niacin-Statin combination can be particularly
  effective
• LDL goal lt100 and threshold for drug tx is 130
  and optional 100-129 if diet effective
• ADA 2004 guidelines adults gt40 y.o. and TC gt135,
  statin to lower LDL by 30
• Based on HPS, drug therapy should not be
  postponed if LDL goal unlikely achieved by
  nonpharmacologic means
• TZDs are insulin sensitizers and affect adipose
  tissue distribution by decrease in intraabdominal
  fat shown to increase HDL and peak LDL buoyancy
  rosiglitazone/atorvastatin led to reduction in
  TG/LDL and elevation in HDL (Promising but more
  studies required)

39
Hyperlipidemia in Nephrotic Syndrome

• Marked hypercholesterolemia
• Increased apo B lipoprotein synthesis by liver
  due to decreased oncotic pressure
• Decreased catabolism
• Hypertriglyceridemia
• Slow conversion of VLDL to IDL then LDL
• Decreased LDL-receptor clearance of LDL and IDL
• Associated Risks
• Small study showed RR 5.5 for MI and 2.8 for
  coronary death
• Possible progression of glomerular disease
• Treatment rationale
• Tx of underlying disease (i.e. steroids in
  minimal change disease)
• Little benefit in diet therapy (vegetable soy
  diet rich in MUFA/PUFA) and low protein with
  20-30 reduction in lipids
• Best drug tx is statins
• ACE-Inhibitor or ARB by decreasing protein
  excretion cause 10-20 reduction in TC and LDL

40

• Thank you