Which HDL-raising therapies are used in the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

Updated: May 21, 2021
  • Author: Vibhuti N Singh, MD, MPH, FACC, FSCAI; Chief Editor: George T Griffing, MD  more...
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Answer

Low HDL levels often reflect a genetic abnormality, although they can also be pushed downward by a high blood level of TGs or by cigarette smoking, inactivity, or hypertension, as well as by a diet very high in carbohydrates or polyunsaturated fats.

Another pharmacologic approach geared towards raising HDL levels involves inhibiting cholesteryl ester transfer protein (CETP). CETP helps to exchange cholesterol between lipoproteins and can transfer it from HDL to LDL and VLDL. Individuals with a genetic mutation that causes the loss of all CETP activity have very high levels of HDL cholesterol. These individuals appear to be at lower risk of coronary disease. [30, 31]

A small study in 2004 involving the CETP inhibitor torcetrapib showed that the drug markedly increased HDL levels and decreased LDL levels when taken alone and also when taken in combination with a statin. The increases in HDL levels were much higher than can be achieved with existing lipid drugs. Although this points researchers in a promising direction, therapy with torcetrapib needs to be tested in a larger population; it must be shown through outcome studies that the drug not only to increases HDL levels, but that it also prevents heart problems. [32]

HDL infusion therapy studied in a group of 40 Italian villagers led to the discovery of a rare type of HDL that seemed to protect against heart disease even when the levels of HDL were not very high. People in the study had a protein in their HDL, the aforementioned apo A-I Milano, that seemed to be better at stimulating the removal of cholesterol from plaques than was HDL containing the normal protein, called apo A-I.

Nissen and colleagues tested whether a synthetic version of apo A-I Milano (recombinant apo A-1 Milano/phospholipid complexes, ETC-216) infused into the blood of people who did not naturally have this protein would have the same effect. [33] The small trial randomly assigned 47 people who had recently had a heart attack to receive either a placebo or a low or high dose of the synthetic protein.

Studying ultrasonograms of the arteries, the researchers found that from the beginning to the end of the 5-week trial, the plaque in the treatment groups shrank by 4%, while that of the placebo group increased by a small amount. Although these were exciting results, a larger trial employing synthetic HDL infusion therapy is needed.

Estrogen replacement or hormone replacement therapy (HRT) raises HDL by about 8% in postmenopausal women, but its use is controversial; such treatment is not recommended for CAD prevention due to a demonstrated lack of benefit and the possible risk of increased thrombosis.

The Heart and Estrogen/progestin Replacement Study (HERS) found no net decrease in secondary prevention of CHD events over 4 years. [34] Events increased 50% with HRT during year 1 but then progressively decreased to 33% lower by the study's end. The early increase may have resulted from prothrombotic and/or pro-inflammatory effects of HRT, while the later decrease may have reflected the 8% increase in HDL cholesterol and/or other antiatherosclerotic mechanisms. [35] Results of HRT in primary prevention await completion of the Women's Health Initiative in 2007.

Because an increase in the consumption of cold-water fish (eg, salmon) rich in polyunsaturated fats may help to raise HDL, fish oil capsules (capsules containing omega-3 fatty acids, ie, 1.48 grams of docosahexaenoic acid and 1.88 grams of eicosapentaenoic acid) have been studied in small trials. In a study in patients with familial combined hyperlipidemia, treatment with this formulation for 8 weeks increased HDL by 8%, particularly the more buoyant HDL-2 subfraction. levels of paraoxonase, an HDL-associated, antioxidant enzyme, were also increased by 10%. [36]

None of these HDL-raising therapies have been studied in Asian Indians. Therefore, no particular treatment recommendations can be made at this juncture. Nonetheless, the treatment strategies appear to be well suited for this subpopulation, which has a high prevalence of HA.


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