Ezetimibe Combined with a Statin Is Effective in Lowering LDL Cholesterol and Triglycerides in Patients Treated with Protease Inhibitors

By Ronald Baker, PhD

Elevated low-density lipoprotein (LDL) cholesterol and triglycerides are commonly seen in patients taking antiretroviral therapy (in particular, protease inhibitors [PIs]), which may put them at higher risk for the development of cardiovascular disease. Statin drugs are frequently used to help normalize these metabolic parameters.

However, study results suggest that statins often are only partially effective at correcting metabolic abnormalities in patients with HIV. In addition, some HIV patients on statins develop abnormally high levels of creatinine phosphokinase (CPK), which may be symptomatic of muscle toxicity, heart attack, myocarditis (heart muscle inflammation), or stroke. For these individuals, lowering the statin dose may allow them to better tolerate the drug.

Zetia (ezetimibe) 10 mg

Ezetimibe (Zetia) lowers cholesterol by blocking cholesterol absorption in the intestine. Data regarding its use are limited in HIV-infected patients. In 2 posters presented at the recent 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in Sydney, Australia (July 22-25, 2007), investigators evaluated whether using ezetimibe plus a statin could safely and effectively reduce cholesterol and triglyceride levels in patients on anti-HIV therapy who had persistently elevated cholesterol despite statin therapy.

Ezetimibe Plus Low-Dose Pravastatin or Atorvastatin

In the first study [1], researchers at Temple University in Philadelphia, PA, and Abbott Laboratories in Abbott Park, IL, assessed LDL reduction 18 weeks after addition of low-dose ezetimibe (10 mg/day) in statin-treated patients on PI-based antiretroviral therapy.

HIV-infected adults on stable PI-based antiretroviral regimens were enrolled in this prospective pilot study if their LDL was not at goal (per the National Cholesterol Education Program III guidelines) despite therapy with pravastatin (Pravachol) 20 mg or atorvastatin (Lipitor) 10 mg.

A total of 20 patients were enrolled: 12 (60%) men, 18 (90%) African American, 2 (10%) Latino; mean age was 49.1 years. With regard to statins, 19 were on pravastatin and 1 was on atorvastatin. With regard to antiretroviral therapy, 17 patients (85%) were on ritonavir-boosted PIs and 3 (15%) were on nelfinavir.

In a subgroup of patients taking lopinavir/ritonavir, trough lopinavir and ritonavir concentrations were obtained before and after addition of ezetimibe.

Results

• Cholesterol changes are described in table below.

• Among the 13 patients taking lopinavir/ritonavir, lopinavir and ritonavir trough concentrations did not change after addition of ezetimibe.

• 1 patient experienced elevated CPK possibly related to study medications.

• No other laboratory abnormalities or adverse effects were seen.

TC = total cholesterol
LDL = low-density lipoprotein cholesterol
HDL = high-density lipoprotein cholesterol
TG = triglycerides

Based on these findings, the investigators concluded that the addition of ezetimibe to a low-dose statin "effectively lowers LDL and total cholesterol and appears to be safe and well-tolerated."

Ezetimibe Plus High-dose Lipid-Lowering Therapy

In a second poster presentation at the Sydney conference [2], Canadian investigators sought to determine the efficacy and safety of adding ezetimibe to maximally-tolerated lipid-lowering therapy in patients with HIV.

The Canadian researchers analyzed changes in serum concentrations of total cholesterol, LDL, HDL high-density lipoprotein (HDL) cholesterol, triglycerides, and apolipoprotein B100 in 33 HIV positive patients who had been prescribed ezetimibe 10 mg per day.

These patients were seen in the HIV Metabolic Clinic, a tertiary referral clinic, and had been prescribed ezetimibe because they had not achieved target lipid levels despite taking maximally tolerated doses of other lipid-lowering therapies. At baseline, 24 were on statins (2 on pravastatin, 15 on rosuvastatin [Crestor] and 7 on atorvastatin), 17 were on fibrates (all fenofibrate [Tricor]), 2 were taking niacin, and 4 were taking salmon oil.

With regard to antiretroviral therapy, 24 were taking PIs, 25 were taking NNRTIs, 29 were taking NRTIs, 1 was taking enfuvirtide (Fuzeon, T-20), and 1 was on no antiretroviral therapy.

Adverse events -- defined as an elevation in the liver enzymes AST or ALT more than 5 times the upper limit of normal (ULN) or CPK more than 10 times ULN, or any symptom requiring discontinuation -- were documented.

Results

• Mean total cholesterol was reduced from 6.95 to 5.51 mmol/L (21% reduction; P<0.001).

• Mean LDL was reduced from 4.05 to 2.63 mmol/L (35% reduction; P<0.001).

• Mean HDL increased from 1.07 to 1.16 mmol/L (8% increase; P=0.038).

• Mean triglyceride level was reduced from 6.22 to 3.85 mmol/L (34% reduction; P=0.006).

• Mean apolipoprotein B100 was reduced from 1.45 to 1.09 g/L (33% reduction; P=0.043).

• No adverse events were observed.

In the absence of consensus guidelines for the treatment of abnormal blood lipid levels in patients with HIV, the Canadian clinicians currently use moderate risk lipid profile targets.

Following the addition of ezetimibe, total cholesterol was reduced to less than or equal to 5.0 mmol/L in 13 of 33 patients (39%), vs none at baseline. LDL was reduced to less than or equal to 3.5 mmol/L in 15 of 25 patients (60%), vs 6 at baseline. The ratio of total cholesterol to HDL was reduced to less than or equal to 5.0 in 15 of 33 patients (45%), vs 4 at baseline.

In conclusion, the study investigators noted, "Ezetimibe appears safe and effective when added to maximally-tolerated lipid-lowering therapy in patients with HIV."

University of British Columbia, Medicine, Vancouver, Canada; Immunodeficiency Clinic-HIV Metabolic Clinic, St. Paul's Hospital, University of British Columbia, Medicine, Vancouver, Canada.

08/07/07

References

1. O M Klibanov, J P Gaughan, E M Tedaldi, and others. Ezetimibe combined with low dose statin effectively lowers LDL in protease inhibitor treated patients. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2007), July 22-25, 2007. Sydney, Australia. Abstract (poster) TUPEB076.

2. M Bennett, K Johns, G Bondy, and others. Ezetimibe is effective when added to maximally tolerated lipid lowering therapy in patients with HIV. IAS 2007. Abstract (poster) TUPEB075.