Article

High-density lipoprotein as a therapeutic target: clinical evidence and treatment strategies

Sterling Rock Falls Clinic, Sterling, Illinois 61081-1252, USA.
The American Journal of Cardiology (Impact Factor: 3.43). 11/2005; 96(9A):50K-58K; discussion 34K-35K. DOI: 10.1016/j.amjcard.2005.08.008
Source: PubMed

ABSTRACT The clinical importance of low serum levels of high-density lipoprotein (HDL) cholesterol is often under-recognized and underappreciated as a risk factor for premature atherosclerosis as well as for cardiovascular morbidity and mortality. Low serum levels of HDL are frequently encountered, especially in patients who are obese or have the metabolic syndrome. In prospective epidemiologic studies, every 1-mg/dL increase in HDL is associated with a 2% to 3% decrease in coronary artery disease risk, independent of low-density lipoprotein (LDL) cholesterol and triglyceride (TG) levels. The primary mechanism for this protective effect is believed to be reverse cholesterol transport, but several other anti-inflammatory, antithrombotic, and antiproliferative functions for HDL have also been identified. In recognition of these antiatherogenic effects, recent guidelines have increased the threshold for defining low levels of HDL for both men and women. The first step in achieving these revised targets is therapeutic lifestyle changes. When these measures are inadequate, pharmacotherapy specific to the patient's lipid profile should be instituted. Niacin therapy, currently the most effective means for raising HDL levels, should be initiated in patients with isolated low HDL (HDL <40 mg/dL, LDL and non-HDL at or below National Cholesterol Education Program (NCEP) targets based on global cardiovascular risk evaluation). Patients who have both low HDL and elevated LDL should receive a statin or statin-niacin combination therapy, and patients with concomitant low HDL and elevated TGs should receive a fibrate initially, with a statin, niacin, or ezetimibe added thereafter as needed to help attain NCEP lipoprotein targets.

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    ABSTRACT: Background. Hyperlipidemia is a common concern in patients with heterozygous familial hypercholesterolemia (HeFH) and in cardiac transplant recipients. In both groups, an elevated serum LDL cholesterol level accelerates the development of atherosclerotic vascular disease and increases the rates of cardiovascular morbidity and mortality. The purpose of this study is to assess the pharmacokinetics, efficacy, and safety of cholesterol-lowering pravastatin in children with HeFH and in pediatric cardiac transplant recipients receiving immunosuppressive medication. Patients and Methods. The pharmacokinetics of pravastatin was studied in 20 HeFH children and in 19 pediatric cardiac transplant recipients receiving triple immunosuppression. The patients ingested a single 10-mg dose of pravastatin, and plasma pravastatin concentrations were measured up to 10/24 hours. The efficacy and safety of pravastatin (maximum dose 10 to 60 mg/day and 10 mg/day) up to one to two years were studied in 30 patients with HeFH and in 19 cardiac transplant recipients, respectively. In a subgroup of 16 HeFH children, serum non-cholesterol sterol ratios (102 x mmol/mol of cholesterol), surrogate estimates of cholesterol absorption (cholestanol, campesterol, sitosterol), and synthesis (desmosterol and lathosterol) were studied at study baseline (on plant stanol esters) and during combination with pravastatin and plant stanol esters. In the transplant recipients, the lipoprotein levels and their mass compositions were analyzed before and after one year of pravastatin use, and then compared to values measured from 21 healthy pediatric controls. The transplant recipients were grouped into patients with transplant coronary artery disease (TxCAD) and patients without TxCAD, based on annual angiography evaluations before pravastatin. Results. In the cardiac transplant recipients, the mean area under the plasma concentration-time curve of pravastatin [AUC(0-10)], 264.1 * 192.4 ng.h/mL, was nearly ten-fold higher than in the HeFH children (26.6 * 17.0 ng.h/mL). By 2, 4, 6, 12 and 24 months of treatment, the LDL cholesterol levels in the HeFH children had respectively decreased by 25%, 26%, 29%, 33%, and 32%. In the HeFH group, pravastatin treatment increased the markers of cholesterol absorption and decreased those of synthesis. High ratios of cholestanol to cholesterol were associated with the poor cholesterol-lowering efficacy of pravastatin. In cardiac transplant recipients, pravastatin 10 mg/day lowered the LDL cholesterol by approximately 19%. Compared with the patients without TxCAD, patients with TxCAD had significantly lower HDL cholesterol concentrations and higher apoB-100/apoA-I ratios at baseline (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.031; and 0.7 ± 0.2 vs. 0.5 ± 0.1, P = 0.034) and after one year of pravastatin use (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.013; and 0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). Compared with healthy controls, the transplant recipients exhibited elevated serum triglycerides at baseline (median 1.3 [range 0.6-3.2] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P=0.0002), which negatively correlated with their HDL cholesterol concentration (r = -0.523, P = 0.022). Recipients also exhibited higher apoB-100/apoA1 ratios (0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). In addition, elevated triglyceride levels were still observed after one year of pravastatin use (1.3 [0.5-3.5] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P = 0.0004). Clinically significant elevations in alanine aminotransferase, creatine kinase, or creatinine ocurred in neither group. Conclusions. Immunosuppressive medication considerably increased the plasma pravastatin concentrations. In both patient groups, pravastatin treatment was moderately effective, safe, and well tolerated. In the HeFH group, high baseline cholesterol absorption seemed to predispose patients to insufficient cholesterol-lowering efficacy of pravastatin. In the cardiac transplant recipients, low HDL cholesterol and a high apoB-100/apoA-I ratio were associated with development of TxCAD. Even though pravastatin in the transplant recipients effectively lowered serum total and LDL cholesterol concentrations, it failed to normalize their elevated triglyceride levels and, in some patients, to prevent the progression of TxCAD. Hyperlipidemia (korkea kolesteroli- ja/tai korkea triglyseridipitoisuus) on yleinen ongelma heterozygoottista familiaalista hyperkolesterolemiaa (HeFH) sairastavilla potilailla ja sydämensiirron saaneilla potilailla. Molemmissa potilasryhmissä plasman korkea LDL-kolesterolipitoisuus kiihdyttää sepelvaltimotaudin kehittymistä ja lisää sydän- ja verisuonitauteihin sairastuvuutta ja kuolleisuutta. Noin 15 % sydämensiirron saaneista lapsipotilaista kehittää sydänsiirteen vaikean sepelvaltimotaudin siirron jälkeen. FH-taudissa valtimomuutokset alkavat jo lapsuusiällä mutta potilaan kliiniset oireet ilmaantuvat vasta keski-iässä. Aikuisilla kolesterolia alentavien statiini-lääkkeiden on osoitettu vähentävän verisuonitauteihin sairastuvuutta ja kuolleisuutta molemmissa potilasryhmissä. Tähän saakka lasten hyperkolesterolemian tehokasta lääkehoitoa statiineilla on rajoittanut tutkimustiedon puute. Työmme tarkoituksena on tutkia pravastatiinin farmakokinetiikkaa, tehoa ja turvallisuutta HeFH sairastavilla lapsilla ja sydämensiirron saaneilla lapsipotilailla, joilla on käytössä siirron jälkeinen hylintälääkitys. Tässä väitöskirjatutkimuksessa osoitettiin, että molemmissa potilasryhmissä yksilölliset erot pravastatiinin farmakokinetiikassa olivat huomattavia. Eroista huolimatta pravastatiinilääkitys todettiin molemmissa ryhmissä turvalliseksi lääkkeeksi. Sydämensiirron saaneilla lapsilla siirron jälkeinen hyljintälääkitys nostaa plasman pravastatiinipitoisuudet noin kymmenkertaisiksi verrattuna HeFH sairastaviin lapsiin, joilla ei pravastatiinin lisäksi ollut käytössä muita lääkkeitä. Pravastatiinin farmakokineettiset havainnot vastaavat hyvin aikuisilla saatuja tutkimustuloksia. HeFH sairastavilla lapsilla todettiin plasman kokonais- ja LDL kolesterolitasot huomattavani korkeiksi, omassa aineistossamme keskimääräiset arvot olivat 8.1 mmol/L ja 6.3 mmol/L. Näillä lapsilla pravastatiini laski plasman kolesterolipitoisuuksia enimmillään noin 30 %. Lievässä ja keskivaikeassa hyperkolesterolemiassa, joissa lähtökolesterolitaso oli 6-7.5 mmol/L, pravastatiinin kolesterolia laskeva teho oli usein riittävä saavuttamaan tutkimuksemme tavoitekolesterolitason 5 mmol/L, mutta vaikeassa hyperkolesterolemiassa teho oli pääsääntöisesti riittämätön. Niinpä vain noin 30 % potilaistamme saavutti tavoitellun kolesterolitason. Havaitsimme, että korkean lähtökolesterolitason lisäksi runsas kolesterolin imeytyminen johti riittämättömään lääkeainevasteeseen. Terveisiin lapsiverrokkeihin verrattuna sydämensirron saneilla lapsilla oli korkeammat seerumin triglyseriidipitoisuudet ja korkeampi apoB-100/apoA1 suhde, mutta heidän kokonais- ja LDL_kolesteroliarvonsa olivat vain lievästi koholla. Korkeista plasman pravastatiinipitoisuuksista huolimatta sydämensiirtopotilailla pravastatiini (10 mg vuorokaudessa) laski plasman kolesterolipitoisuuksia keskimäärin 19 %, joka vastasi hyvin saman annoksen tehoa HeFH sairastavilla lapsilla. Noin 90 %:lla sydämensiirron saaneista potilaista pravastatiinin kolesterolia laskeva teho oli riittävä saavuttamaan tai ylläpitämään tavoitekolesterolitason (≤ 5 mmol/L). Pravastatiinin plasman triglyseridi-pitoisuutta alentava ja HDL kolesterolipitoisuutta lisäävä teho oli kuitenkin sydämensiirron saaneilla potilailla pääsääntöisesti riittämätön. Väitöskirjatutkimus osoitti, että ne sydämensiirron saaneet lapsipotilaat, joilla on matala HDL-kolesterolipitoisuus tai korkea apoB-100/apoA-I suhde olivat suuremassa riskissä sairastua siirron jälkeiseen sydämensiirteen sepelvaltimotautiin. Molemmissa potilasryhmissä 1-2 vuoden seurantajakson aikana pravastatiinihoito oli turvallista, eikä aiheuttanut vakavia haittavaikutuksia kuten rabdomyolyysia. HeFH sairastavilla lapsilla lievät haittavaikutukset, kuten päänsärky ja vatsavaivat olivat tavallisia (13% ja 37% potilailla) hoidon alkuvaiheessa, mutta sivuvaikutukset jäivät useimmiten pois ensimmäisten hoitokuukausien jälkeen. Kummassakaan potilasryhmässä ei seurantajakson aikana esiintynyt kliinisesti merkittäviä maksan tai munuaisten toimintahäiriöitä eikä lihasentsyymien nousua. HeFH sairastavilla lapsilla pravastatiinihoito ei seurantajakson aikana häirinnyt lasten normaalia kasva tai murrosiän kehitystä.
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