Dyslipidemia approach
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Dyslipidemia, or abnormal lipid levels in the blood, increases the risk of atherosclerosis and cardiovascular disease. The document discusses the definition and causes of dyslipidemia as well as screening recommendations. It also summarizes the roles of different lipids like LDL, HDL, and triglycerides in atherosclerosis. The treatment approaches for different lipid abnormalities are outlined, including lifestyle modifications and medications like statins, fibrates, bile acid sequestrants, nicotinic acid, and ezetimibe.
![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](https://image.slidesharecdn.com/dyslipidemiaapproach-201213235238/85/Dyslipidemia-approach-5-320.jpg)
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
- 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
Editor's Notes
- #9: 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 Hepatic Lipase-conversion of IDL to LDL CETP-transfers cholesteryl esters from HDL to other lipoproteins in exchange for TG LCAT(lecithin cholesterol acyl transferase) conversion of cholesterol to cholesterol esters Apo A-major protein of HDL activating many reactions Apo-B-major protein of VLDL, IDL, and LDL Apo-CII and Apo E obtained from HDL by CMC and VLDL for activation of LPL and receptor recognition respectively
- #16: 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
- #22: Decreased saturated fat (decrease LDL) Replacing saturated and trans unsaturated fats with unhydrogenated monounsaturated or polyunsaturated fats Recommended diet Dietary cholesterol <200 mg/d; total fat <30%; saturated fat <7% Carbs: 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 exercise : Increase in HDL and size and largest effect on LDL seen with high amount high intensity exercise Mechanisms via CETP, elevation in LCAT, reduced hepatic lipase and elevated LPL activity Moderate intensity exercise (3-4 mi/hr) for 30 minutes on most days of the week
- #24: TC and HDL-C can be measured fasting or non-fasting LDL-Cholesterol = Total cholesterol –VLDL (1/5 TG)-HDL 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 alter the levels of different Lipoproteins so analysis should be done as outpatient one month after event