High density lipoprotein medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Since low HDL is associated with an increased risk of cardiovascular disease events, elevation of HDL concentration among subjects with low HDL is advised. The treatment of a patient with low HDL cholesterol should be individualized. Before the initiation of any medical treatment to elevate the HDL concentration, the initial treatment should aim to reduce the LDL and non-HDL lipoprotein concentrations if they are elevated. The management of low HDL should also begin with life style modification targeting diet, exercise, and smoking cessation. If HDL concentration remains high despite optimal LDL and non-HDL concentrations and life style modifications, then medical therapy with fibrates or niacin might be considered among patients with risk factors of coronary artery disease or its equivalent.
Treatment
Who To Treat
The question on who to treat should be answered on a patient-by-patient basis. According to the ATP III guidelines, the treatment of low HDL cholesterol has become a tertiary target in the management of patients with low HDL, with the primary and secondary goals targeting LDL and non-HDL cholesterol, respectively.[1] There are several variables to be considered in a patient with low HDL such as serum triglyceride levels and metabolic abnormalities (diabetes mellitus, metabolic syndrome).
When To Treat
The 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 the 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):[2]
- Among patients with high LDL, achieve the LDL goal first
- Among patients with elevated HDL, rule out secondary causes:
- Recommend weight reduction, physical exercise, and smoking cessation to elevate HDL
- If serum triglyceride concentration is between 200 and 499 mg/dL, achieve non-HDL goal before the initiation a treatment for HDL
- If triglycerides <200 mg/dL (isolated low HDL) in CHD or CHD equivalent, consider nicotinic acid or fibrate
Among patients with low HDL, attempts towards a reduction in LDL and non-HDL concentration should be performed before the administration of medical therapy to raise HDL. Non-HDL-C represents the cholesterol content present in all the atherogenic lipoproteins i.e., a combination of LDL-C, VLDL-C, IDL-C, and lipoprotein(a) cholesterol.[2] Non-HDL-C is the difference between the total cholesterol and HDL cholesterol (Non-HDL-C = Total cholesterol minus HDL-C). Some studies have demonstrated that non-HDL cholesterol fraction may be a better predictor of future cardiovascular risk than LDL cholesterol.[3][4] The treatment goal for non-HDL-C is 30 mg/dL above the LDL-C treatment target.
Below is a table showing the non-HDL and LDL cholesterol goals to be achieved in the management of patients with a low HDL cholesterol according to the ATP III guidelines:
| RISK CATEGORY | NON-HDL-GOAL mg/dl | LDL GOAL mg/dl |
| 0 to 1 CHD risk factor | <190 | <160 |
| Two or more CHD risk factors (10-year risk for CHD≤20%) | <160 | <130 |
| Coronary heart disease (CHD) and CHD risk equivalent (10-year risk for CHD>20% ) | <130 | <100 |
Non-pharmacologic Therapies
| LIFESTYLE MEASURE | EFFECT ON HDL |
| Physical exercise[5] | 5-30% increase |
| Weight reduction | 5-20% increase[6] |
| Smoking cessation | 5% increase[7] |
| Multivitamins | 31% increase in HDL |
| DASH diet | 21% increase in HDL[8] |
| Low carbohydrate diet | 4.5mg/dl increase in HDL[9] |
| Soy protein with isoflavones | 3% increase in HDL[10] |
| Fish oil (omega-3 fatty acid) | Significant increase in HDL2 fraction[11] |
| Fish oil with exercise | 8% increase in HDL[12] |
| Low fat diet | 5-14% increase in HDL when combined with exercise[13] |
| Monounsaturated fat | Increase in HDL |
| Moderate alcohol consumption | 5-10% increase in HDL[14] |
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.[15]
Pharmacologic Therapy
| DRUGS | MECHANISM OF ACTION | EFFECT ON HDL | SIDE EFFECTS |
| Nicotinic acid (Niacin) | Decreases VLDL synthesis in the liver through diaglycerol acyl transferase-2 (DGAT-2),[16] decreases HDL-apo A-I catabolism[17] | 15-30% increase | Cutaneous flushing, hyperglycemia, hyperuricemia, hepatotoxicity |
| Fibrates | Direct stimulation of apo-A1 and apo-AII synthesis via peroxisome proliferator-activated receptors,[18] | 5-15% increase | Increased risk of myopathy when combined with statins, gallstones, dyspepsia |
| HMG-CoA reductase inhibitor | Increases synthesis of apo-A1 and HDL in the liver,[19] increases ABCA1 mRNA in hepG2 cells,[20] inhibits CETP mass and activities[21] | 5-10% increase | Myopathy, rhabdomyolysis |
| Ezetimibe | Inhibits cholesterol absorption at intestine level | 3% increase in HDL along with statins[22] | Headache, diarrhea, hypersensitivity |
| Thiazolidinediones | Increase in adiponectin which increases insulin resistance | 14% increase in HDL[23] | Fluid retention |
| Hormone replacement therapy | Increases Apo-A1 and decreases activity of hepatic lipase | 5 to 20% increase | Increases risk of stroke and thromboembolic diseases |
| Bile acid sequestrants | Increases apo A-1 production[24] | 3-5% increase | GI discomfort, constipation, reduces absorption of other medications |
References
- ↑ "Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)". JAMA. 285 (19): 2486–97. 2001. PMID 11368702. Unknown parameter
|month=ignored (help) - ↑ Ballantyne, CM.; Grundy, SM.; Oberman, A.; Kreisberg, RA.; Havel, RJ.; Frost, PH.; Haffner, SM. (2000). "Hyperlipidemia: diagnostic and therapeutic perspectives". J Clin Endocrinol Metab. 85 (6): 2089–112. PMID 10852435. Unknown parameter
|month=ignored (help) - ↑ Ridker, PM.; Rifai, N.; Cook, NR.; Bradwin, G.; Buring, JE. (2005). "Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women". JAMA. 294 (3): 326–33. doi:10.1001/jama.294.3.326. PMID 16030277. Unknown parameter
|month=ignored (help) - ↑ Di Angelantonio, E.; Sarwar, N.; Perry, P.; Kaptoge, S.; Ray, KK.; Thompson, A.; Wood, AM.; Lewington, S.; Sattar, N. (2009). "Major lipids, apolipoproteins, and risk of vascular disease". JAMA. 302 (18): 1993–2000. doi:10.1001/jama.2009.1619. PMID 19903920. Unknown parameter
|month=ignored (help) - ↑ Thompson PD (1990). "What do muscles have to do with lipoproteins?". Circulation. 81 (4): 1428–30. PMID 2317921.
- ↑ 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.
- ↑ 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.
- ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Rimm, EB.; Williams, P.; Fosher, K.; Criqui, M.; Stampfer, MJ. (1999). "Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors". BMJ. 319 (7224): 1523–8. PMID 10591709. Unknown parameter
|month=ignored (help) - ↑ 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) - ↑ Wierzbicki, AS. (2011). "Niacin: the only vitamin that reduces cardiovascular events". Int J Clin Pract. 65 (4): 379–85. doi:10.1111/j.1742-1241.2011.02630.x. PMID 21401825. Unknown parameter
|month=ignored (help) - ↑ Kamanna, VS.; Kashyap, ML. (2008). "Mechanism of action of niacin". Am J Cardiol. 101 (8A): 20B–26B. doi:10.1016/j.amjcard.2008.02.029. PMID 18375237. Unknown parameter
|month=ignored (help) - ↑ Vu-Dac, N.; Schoonjans, K.; Kosykh, V.; Dallongeville, J.; Fruchart, JC.; Staels, B.; Auwerx, J. (1995). "Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor". J Clin Invest. 96 (2): 741–50. doi:10.1172/JCI118118. PMID 7635967. Unknown parameter
|month=ignored (help) - ↑ Yamashita, S.; Tsubakio-Yamamoto, K.; Ohama, T.; Nakagawa-Toyama, Y.; Nishida, M. (2010). "Molecular mechanisms of HDL-cholesterol elevation by statins and its effects on HDL functions". J Atheroscler Thromb. 17 (5): 436–51. PMID 20513953. Unknown parameter
|month=ignored (help) - ↑ Maejima, T.; Sugano, T.; Yamazaki, H.; Yoshinaka, Y.; Doi, T.; Tanabe, S.; Nishimaki-Mogami, T. (2011). "Pitavastatin increases ABCA1 expression by dual mechanisms: SREBP2-driven transcriptional activation and PPARα-dependent protein stabilization but without activating LXR in rat hepatoma McARH7777 cells". J Pharmacol Sci. 116 (1): 107–15. PMID 21521932.
- ↑ van Venrooij, FV.; Stolk, RP.; Banga, JD.; Sijmonsma, TP.; van Tol, A.; Erkelens, DW.; Dallinga-Thie, GM. (2003). "Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes". Diabetes Care. 26 (4): 1216–23. PMID 12663600. Unknown parameter
|month=ignored (help) - ↑ 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) - ↑ 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) - ↑ Shepherd, J. (1989). "Mechanism of action of bile acid sequestrants and other lipid-lowering drugs". Cardiology. 76 Suppl 1: 65–71, discussion 71-4. PMID 2713876.