Dyslipidemia approach

1. Dyslipidemia
PATHOGENESIS, ROLE IN
ATHEROSCLEROSIS,
SCREENING AND TREATMENT

2. Definition
• Dyslipidemia or hyperlipidemia in a clinical scenario is an
abnormally increased level of lipids in blood.
• It could be due to
• Increased Triglycerides,
• Increased Cholesterol and/or
• Increased fat phospholipids rich in either of them.

3. Facts and Stats: US vs Global
• In the United States, roughly 53% of adults, have elevated LDL-C levels.
Less than 50% of patients with high LDL-C receive treatment to reduce
their levels, and among those receiving treatment, fewer than 35%
achieve adequate control.
(CDC: MMWR Morb Mortal Wkly Rep. 2011;60(4):109-114.)
• Approximately 17% of adults had low high-density lipoprotein (HDL)
cholesterol (Carroll et al, 2013; Smith et al., 2006)
• Globally World Health Organization (WHO) estimates in 2008, the
prevalence of dyslipidemia in the Southeast Asia (30.3%) and the Western
Pacific (36.7%) were much lower than that in the Europe (53.7%) and the
Americas (47.7%), with average global estimate of ~ 41 %.
http://apps.who.int/gho/data/view.main.2570?lang=en

4. Atherosclerosis sites
Hyperlipidemia is a
common Risk Factor
of atherosclerosis

5. Leading Causes of Death: USA
• Number of deaths for leading causes of death
1. Heart disease: 647,457
2. Cancer: 599,108
3. Accidents (unintentional injuries): 169,936
4. Chronic lower respiratory diseases: 160,201
5. Stroke (cerebrovascular diseases):
146,383
6. Alzheimer’s disease: 121,404
7. Diabetes: 83,564
8. Influenza and pneumonia: 55,672
9. Nephritis, nephrotic syndrome, and nephrosis:
50,633
10. Intentional self-harm (suicide): 47,173
Deaths: Leading Causes for 2017, table 1 pdf icon[PDF- 2 MB]: CDC

6. Most relevant Lipids in the blood: Composition

7. Summary of lipid metabolism

8. HDL Metabolism

9. LDL Oxidation and Atherosclerosis

10. Mechanism of Atherogenic Dyslipidemia
Insulin resistance
increased free Fatty
Acids and glucose
flux to liver
Insulin resistance
and decreased
apo-B
degradation
Insulin
resistance
and
decreased
LPL
Increased
VLDL

11. HDL vs LDL and Atherosclerosis
 HDL is main part of 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

12. High LDL cholesterol = Atherogenesis
High Triglycerides ≠ Atherogenesis

13. Enzymes defect in hyperlipidemia

15. Statins
• Competitive inhibitors of HMG CoA reductase, rate-limiting step in
cholesterol biosynthesis
• Reduction in intrahepatic cholesterol leading to increased LDL receptor
turnover
Pleotropic effect in ASCVD risk reduction
•Regression of atherosclerosis
•Plaque stabilization
•Reduced inflammation
•Decreased thrombogenicity
•Reversal of endothelial dysfunction

16. 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 (<0.1%) (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
◦ No significant difference with placebo in trials

17. 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
• Agents
• Gemfibrozil- 600 mg po BID (11% raise in HDL). Modest LDL reduction but little
effect in combined hyperlipidemia. Can increase LDL in pure
hypertriglyceridemia
• 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 increased risk of myopathy. Also decreases warfarin by 30%

18. 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
◦ 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/day
 Adverse effects
◦ Mainly GI (nausea, bloating, cramping)- least problematic with
colesevelam
◦ Also drug interactions due to impaired absorption)
 Digoxin, warfarin, and fat soluble vitamins (give one hour before
or 4 hours after bile acid sequestrant)
 Contraindications: pts with elevated TG

19. Nicotinic Acid
 Mechanism of Action
◦ Inhibits hepatic VLDL production
◦ Raises HDL by reducing lipid transfer of cholesterol from HDL to VLDL and by delaying HDL
clearance
 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
evening 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
◦ Nausea, paresthesia's, pruritis (20% each)
◦ Elevation of hepatocellular enzymes and possible hepatotoxicity, jaundice and fulminant
hepatitis (generally less common with Niaspan and crystalline niacin)
◦ Insulin resistance and worsening hyperglycemia (less with crystalline Niaspan)
◦ Hyperuricemia (AVOID IF H/O GOUT)
◦ Hypotension in combination with other vasodilators (can increase unstable angina)

20. Ezetimibe (Zettia)
• Mechanism:
• impairs dietary and biliary cholesterol absorption at the brush border of the intestines
without affecting TG or fat-soluble vitamins
• LDL decrease 15-20%
• Also adjunctive therapy to statins
• 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 statin

21. Effect of Lifestyle Modification

22. Diet Supplements
• Fish Oil (source of omega-3 polyunsaturated fatty acids)
• Salmon, flaxseed, canola oil, soybean oil and nuts
• Used in hypertriglyceridemia
• At high doses > 6 grams/day reduces TG by inhibition of VLDL-TG
synthesis and apolipoprotein B
• 2 servings of fish/week recommended??
• Soy , Garlic and Cholesterol-lowering Margarines have no
outcome studies.
• Other agents include soluble fiber, nuts (esp. walnuts), green
tea
• Overall a combination diet with multiple cholesterol-lowering
agents causes much more significant LDL reductions

23. Measurement of Lipoproteins: Screening Recommendations
• Lipoprotein analysis is usually done in 12-14 hours fasting
• Adult Treatment Panel III (NCEP) : Fasting lipid profile at least once q 5
years for all persons 20 y.o. or older

24. Treatment approach for Elevated LDL or mixed
Treatment approach for Elevated LDL or mixed

25. Hypertriglyceridemia
1. Start with Statin
2. Add Fibrates if not
controlled.

26. Isolated Low HDL
 Framingham Heart Study: MI risk
increases by 25% per 5 mg/Dl decrease
below mean HDL for men and women
 LIPID and CARE trials: 10 increase in HDL,
29% decrease in event rate in LDL <125
vs 10% decrease in LDL>125
 Familial h/o premature CHD helpful in
differentiating high from low risk pts with
low HDL
 Causes:
◦ Familial forms
◦ Elevated CETP
◦ LPL deficiency
◦ Elevated hepatic TG lipase
◦ LCAT deficiency
◦ Insulin deficiency
◦ Drugs
 Beta blockers
 BDZ
 Anabolic steroids
• Evidence in Treatment
• VA-HIT trial: strong correlation of
reduction in MI and CHD death with
serum HDL achieved with gemfibrozil
• Simvastatin plus Niacin: higher
reduction in events achieved than
statin-only trial
HPS: vascular event rate in baseline HDL
<35 was 29.9% vs 20.9% for HDL >42
• HDL < 40 mg/Dl; if metabolic syndrome <40
men and <50 women
• 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)

27. Treatment Guidelines
 Consider secondary causes (DM, hypothyroidism, CRF or nephrotic syndrome or
drugs)
 start with adequate trial of lifestyle modification:
 Start meds if
◦ LDL >220 or > 190 if >= 2 risk factors
◦ Pre-existing CHD or CHD equivalent
 If CHD or equivalent and LDL goal <100 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 >190 if 0 or 1 risk factor
◦ LDL >160 if 2 or more risk factors if 10 yr risk <10%; 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 >200, then consider non-HDL cholesterol and treat to
goal 30 above LDL

28. Risk Assessment
 CHD equivalents:
◦ Symptomatic carotid artery disease
◦ Peripheral arterial disease
◦ AAA
◦ DM
◦ Multiple risk factors that confer a 10-year risk of CHD > 20%
 Identify major risk factors other than LDL:
◦ Smoking
◦ HTN BP >140/90 or on anti-hypertensive medication
◦ Low HDL <40 mg/dL
◦ Family history premature CHD (CHD in men 1st degree relative <55; women
<65 y.o.)
◦ Age (men > or =45; women >or =55)
 Other potential risk factors
◦ Chronic renal insufficiency (Cr > 1.5 mg/dL OR GFR <60 cc/min) per Up-To-
Date
◦ Obesity, physical inactivity, impaired fasting glucose, markers for
inflammation
 HDL > 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)

29. Adults With DM
• Both primary and secondary intervention trials have shown benefit and
reduction of CVD in diabetic
• LDL goal <100 and threshold for drug tx is 130 and optional 100-129 if diet
effective
• 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)

30. Metabolic Syndrome : > 3/5 ATP criteria
Treatment
Weight reduction and exercise
◦LDL goal is same as in patient w/o MS
◦If LDL goal reached, then focus on TG if
>200?
◦Calculate non-HDL and goal is 30
above LDL goal
◦Fibrates and nicotinic acid are good
choices for elevated TG

31. Hyperlipidemia : in Nephrotic Syndrome
and CKD
• Increased apo B lipoprotein synthesis leading to
Hypertriglyceridemia ( nephrotic syndrome)
• Diminished clearance due to apo C-III and reduction in
lipoprotein lipase and hepatic triglyceride lipase (CKD)
 Treatment
• Best drug tx is statins for both of them
Statins should be used to lower LDL <100 or better yet <80 as CKD
considered CHD risk equivalent. Atorvastatin and fluvastatin better
choices. Hydrophilic statins safer and dose adjustment needed with CrCl
<30

32. Evolving Methods of Risk Assessment
1. Total/HDL cholesterol ratio
• Ratio <4.0 advocated by the Canadian guidelines
• Better epidemiologic predictor of CV events than LDL (Lipid Research Clinics
and Framingham Heart Study) however no trials based on this ratio
2. Non-HDL cholesterol (Total-HDL)
• Lipid Research clinics program showed slightly stronger predictor of CVD than
LDL
• Goal 30 above LDL goal
3. Apo B/ Apo A-I found to be a better predictor of events than LDL and
total/HDL in AMORIS study; best predictor of events on statins in
AFCAPS/TexCAPS study
◦ <0.7 considered target in Canadian guidelines
4. Hs-CRP
◦ Intensity of atherosclerotic process
◦ Recommendation of AHA, should be measured in the patient with intermediate
Framingham risk (10-20%)

33. Lipoprotein (a): form of LDL, As/w Increased risk of ASCVD

34. When to use lipoprotein- A
 CHD and no other identifiable dyslipidemia
◦ Strong CHD family history and no other dyslipidemia
 Treatment guidelines
◦ Primary goal is to lower LDL to target and lowering
to <80 may reduce risk
◦ If LDL cannot become optimized, then Lpa lowering
with nicotinic acid (38%) should be tried
◦ Goal <20

36. Questions??
Thank you