High density lipoprotein medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Treatment

When To Treat

National Cholesterol Education Program (NCEP) has not set a formal goal for HDL levels as a therapeutic target because of lack of evidence for decrease in primary CHD risk reduction with pharmacotherapy. Drug therapy for HDL can be considered in patients in presence of other risk factors for CHD such as hypertension, smoking, family history of premature coronary heart disease. The following are the ATP III guidelines for low HDL management (i.e., HDL-C≤40 mg/dl):

  • First LDL goal should be achieved
  • Weight reduction and physical exercise
  • If triglycerides 200-499 mg/dL, achieve non-HDL goal
  • If triglycerides <200 mg/dL (isolated low HDL) in CHD or CHD equivalent, consider nicotinic acid or fibrate

Treatment Options

Non-pharmacologic Therapies

Weight Loss

In a metanalysis of 70 studies,12% increase in HDL level was observed in subjects with stable reduced weight.[1]

Smoking Cessation

Smoking increases activity of CETP enzyme and lowers activity of LCAT, which results in reduced amount of HDL. In a study done by Gepner et al, smoking cessation increased HDL level by 5.2%.[2]

Alcohol Consumption

Moderate amount of alcohol consumption can result in increased HDL. However, alcohol can also lead to increased triglyceride levels.

Exercise

Physical activity increases HDL level. One of the suggested mechanisms is increased amount of LPL enzyme.[3]

Dietary Measures

DIET EFFECT ON HDL
Multivitamins 31% increase in HDL
DASH diet 21% increase in HDL[4]
Low carbohydrate diets 4.5mg/dl increase in HDL[5]
Soy protein with isoflavones 3% increase in HDL[6]
Fish oil (omega-3 fatty acid) Significant increase in HDL2 fraction[7]
Fish oil with exercise 8% increase in HDL[8]
Low fat diet 5-14% increase in HDL when combined with exercise[9]

Significant increase in HDL was observed when a calorie restricted version of DASH diet was used. Liese et al found a lower level of HDL with DASH diet in diabetic patients.[10]

Pharmacologic Therapies

Medications

Drugs MECHANISM OF ACTION AVERAGE OBSERVED INCREASE ON HDL-C IN TRIALS SIDE EFFECTS
Nicotinic acid (Niacin) Decreases VLDL synthesis 21% increase in HDL[11] Cutaneous flushing, hyperglycemia, hyperuricemia, hepatotoxicity
Fibric acid derivatives Increased synthesis of Apo-A1 6% increase in HDL in one year[12] Increased risk of myopathy with statins
HMG CoA reductase inhibitors They increase HDL by increasing level of Apo-A1 13% increase in HDL [13] Myopathy, rhabdomyolyisis
Ezetimibe Inhibits cholesterol absorption at intestine level 3% increase in HDL along with statins[14] Headache, diarrhea, hypersensitivity
Thiazolidinediones Increase in adiponectin which increases insulin resistance 14% increase in HDL[15] Fluid retention
Hormone replacement therapy Increased Apo-A1 and decreased activity of hepatic lipase 5 to 20% increase in HDL Increased risk of stroke and thromboembolic diseases

Algorithm

 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low HDL
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rule out secondary causes
Hypothyroidism
Diabetes mellitus
Uremia
Liver disease
Medications - diuretics, progestin, androgens, beta blockers
Acute illness - MI, burns, surgery
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lifestyle modification
Diet
Physical exercise
Smoking cessation
Weight loss
Intake of unhydrogenated monounsaturated fat e.g., olive oil, canola oil
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CHD
 
 
 
 
 
 
 
 
 
 
 
 
No CHD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid profile
 
 
 
 
 
 
 
 
 
 
 
 
Assess risk
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low density lipoprotein
 
 
 
 
 
 
 
Triglyceride
 
 
 
 
 
High risk

HDL<40 mg/dl

HDL<40 mg/dl in patients with metabolic syndrome
 
 
 
 
Low risk
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low LDL
 
High LDL
 
 
TG<200 mg/dl
 
 
 
 
TG>200
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consider fibrates/niacin or statins
 
Statins
 
 
 
 
 
 
 
 
 
 
Assess non-HDL goals
 
Statins or Niacin
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess LDL
 
 
Isolated low HDL-C
 
 
Achieved?
 
Not achieved
 
 
Positive family history of premature CHD
 
 
 
 
 
Negative family history of premature CHD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Target reached
 
 
 
 
 
 
 
 
 
 
 
 
Find out
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HDL<40
 
HDL>40
 
Considar niacin or fibrates
 
 
 
 
 
 
 
 
 
 
 
Considar statins or niacin
 
 
 
 
 
Continue non-pharmacological approach
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Add niacin or gemfibrozil
 
Continue statins
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

References

  1. Dattilo AM, Kris-Etherton PM (1992). "Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis". Am J Clin Nutr. 56 (2): 320–8. PMID 1386186.
  2. Gepner AD, Piper ME, Johnson HM, Fiore MC, Baker TB, Stein JH (2011). "Effects of smoking and smoking cessation on lipids and lipoproteins: outcomes from a randomized clinical trial". Am Heart J. 161 (1): 145–51. doi:10.1016/j.ahj.2010.09.023. PMC 3110741. PMID 21167347.
  3. Thompson PD (1990). "What do muscles have to do with lipoproteins?". Circulation. 81 (4): 1428–30. PMID 2317921.
  4. Azadbakht, L.; Mirmiran, P.; Esmaillzadeh, A.; Azizi, T.; Azizi, F. (2005). "Beneficial effects of a Dietary Approaches to Stop Hypertension eating plan on features of the metabolic syndrome". Diabetes Care. 28 (12): 2823–31. PMID 16306540. Unknown parameter |month= ignored (help)
  5. Nordmann, AJ.; Nordmann, A.; Briel, M.; Keller, U.; Yancy, WS.; Brehm, BJ.; Bucher, HC. (2006). "Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials". Arch Intern Med. 166 (3): 285–93. doi:10.1001/archinte.166.3.285. PMID 16476868. Unknown parameter |month= ignored (help)
  6. Zhan, S.; Ho, SC. (2005). "Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile". Am J Clin Nutr. 81 (2): 397–408. PMID 15699227. Unknown parameter |month= ignored (help)
  7. Sacks FM, Hebert P, Appel LJ, Borhani NO, Applegate WB, Cohen JD; et al. (1994). "The effect of fish oil on blood pressure and high-density lipoprotein-cholesterol levels in phase I of the Trials of Hypertension Prevention. Trials of Hypertension Prevention Collaborative Research Group". J Hypertens Suppl. 12 (7): S23–31. PMID 7769501.
  8. Herrmann W, Biermann J, Kostner GM (1995). "Comparison of effects of N-3 to N-6 fatty acids on serum level of lipoprotein(a) in patients with coronary artery disease". Am J Cardiol. 76 (7): 459–62. PMID 7653444.
  9. Varady KA, Jones PJ (2005). "Combination diet and exercise interventions for the treatment of dyslipidemia: an effective preliminary strategy to lower cholesterol levels?". J Nutr. 135 (8): 1829–35. PMID 16046704.
  10. Liese, AD.; Bortsov, A.; Günther, AL.; Dabelea, D.; Reynolds, K.; Standiford, DA.; Liu, L.; Williams, DE.; Mayer-Davis, EJ. (2011). "Association of DASH diet with cardiovascular risk factors in youth with diabetes mellitus: the SEARCH for Diabetes in Youth study". Circulation. 123 (13): 1410–7. doi:10.1161/CIRCULATIONAHA.110.955922. PMID 21422385. Unknown parameter |month= ignored (help)
  11. Taylor, AJ.; Sullenberger, LE.; Lee, HJ.; Lee, JK.; Grace, KA. (2004). "Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins". Circulation. 110 (23): 3512–7. doi:10.1161/01.CIR.0000148955.19792.8D. PMID 15537681. Unknown parameter |month= ignored (help)
  12. Rubins, HB.; Robins, SJ.; Collins, D.; Fye, CL.; Anderson, JW.; Elam, MB.; Faas, FH.; Linares, E.; Schaefer, EJ. (1999). "Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group". N Engl J Med. 341 (6): 410–8. doi:10.1056/NEJM199908053410604. PMID 10438259. Unknown parameter |month= ignored (help)
  13. Schaefer, JR.; Schweer, H.; Ikewaki, K.; Stracke, H.; Seyberth, HJ.; Kaffarnik, H.; Maisch, B.; Steinmetz, A. (1999). "Metabolic basis of high density lipoproteins and apolipoprotein A-I increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease". Atherosclerosis. 144 (1): 177–84. PMID 10381291. Unknown parameter |month= ignored (help)
  14. Ballantyne, CM.; Houri, J.; Notarbartolo, A.; Melani, L.; Lipka, LJ.; Suresh, R.; Sun, S.; LeBeaut, AP.; Sager, PT. (2003). "Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial". Circulation. 107 (19): 2409–15. doi:10.1161/01.CIR.0000068312.21969.C8. PMID 12719279. Unknown parameter |month= ignored (help)
  15. Szapary, PO.; Bloedon, LT.; Samaha, FF.; Duffy, D.; Wolfe, ML.; Soffer, D.; Reilly, MP.; Chittams, J.; Rader, DJ. (2006). "Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome". Arterioscler Thromb Vasc Biol. 26 (1): 182–8. doi:10.1161/01.ATV.0000195790.24531.4f. PMID 16284192. Unknown parameter |month= ignored (help)


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