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Fluvastatin (Lescol) Reduces Angiotensin II Sensitivity in Patients With Familial Hypercholesterolaemia: Presented at EMH

By Chris Berrie

MILAN, ITALY -- June 21, 2005 -- In patients with familial hypercholesterolaemia, fluvastatin (Lescol) induces reduced sensitivity to angiotensin II, a potent vasoconstrictor that also has atherogenic properties, according to results of a randomised, double-blind, placebo-controlled, cross-over study.

Nicole van der Linde, PhD, Coordinator and Research Fellow in Vascular Medicine, Department of Internal Medicine, Vascular Research Laboratory, Erasmus Medical Centre, Rotterdam, the Netherlands, presented the findings here June 19^th at the 15^th European Meeting on Hypertension (EMH).

Researchers have theorised that atherosclerosis and plaque instability are the result of changes in the combination of low-density lipoprotein (LDL) cholesterol-induced upregulation of angiotensin II type 1 (AT₁) receptors in vascular tissue and angiotensin II activation of the AT₁ receptor, Dr. van der Linde explained.

It has also been shown that while hypercholesterolaemia does not itself cause changes in blood pressure, it does result in increased sensitivity to angiotensin II infusion. It is this mechanism that Dr. van der Linde and colleagues sought to inhibit through the use of a statin agent.

They designed their study to determine the angiotensin II sensitivity of subjects with FH during placebo and statin therapy, and compared their response to that of control subjects with normal cholesterol levels. The researchers also monitored each subject's lipid status and haemodynamic parameters at baseline and throughout the treatment period. All subjects were non-smokers.

The cohort of 30 patients with FH, a mean age of 30 years (male, 57%) underwent a 4-week washout period before being randomised to placebo (n = 15) or 80 mg fluvastatin (n = 15) once daily. The two treatment groups showed no significant differences in demographic characteristics or lipid profiles.

At week 4, patients underwent treatment crossover, for the final 4 weeks of the study. At four weeks of fluvastatin treatment, significant differences (P <.001) were seen in levels of total cholesterol (6.1 vs. 7.9 mmol/L for placebo), LDL cholesterol (4.6 vs. 6.3 mmol/L) and triglycerides (1.15 vs. 1.38). No significant differences were seen between placebo and fluvastatin in levels of high-density lipoprotein (HDL) cholesterol (1.17 vs. 1.19 mmol/L), blood pressure and heart rate.

At weeks 4 and 8, the researchers determined each patient's sensitivity to incremental infusions of angiotensin II and noradrenaline by blood pressure monitoring. Before the start of infusions, blood samples were taken to determine fasting serum lipid levels, and samples were taken after the infusions to determine plasma angiotensin II and noradrenaline concentrations.

The infusions were also given to 10 age- and sex-matched healthy control subjects with normal cholesterol levels (mean age, 31 years; male, 80%).

Baseline characteristics between the subjects with familial hypercholesterolaemia and controls (respectively) showed significant differences (P <.001) for body mass index (24.6 vs. 23.4) as well as levels of total cholesterol (7.93 vs. 3.90 mmol/L); LDL (6.33 vs. 2.20 mmol/L); HDL (1.19 vs. 1.30 mmol/L); triglycerides (1.38 vs. 0.90 mmol/L).

There were no significant differences between controls and subjects in terms of glucose levels (4.1 vs. 3.8 mmol/L) and blood pressure (122/72 vs. 124/75 mm Hg).

The researchers calculated for each subject the angiotensin II and noradrenaline infusion rates that were required to achieve a 20-mm Hg increase in systolic blood pressure (Pd-20).

While there were no significant changes in the noradrenaline Pd-20 values between placebo and fluvastatin, those for angiotensin II were significantly increased with fluvastatin treatment (placebo, 4.8 ng/kg/min; fluvastatin, 6.1 ng/kg/min; P =.0022). This effect on sensitivity to angiotensin II of fluvastatin did not reach the Pd-20 seen n subjects with normal cholesterol levels (8.1 ng/kg/min; P =.0002 vs. placebo subjects with familial hypercholesterolaemia).

In summarising, Dr van der Linde indicated that when compared to the placebo, this 4-week fluvastatin treatment for subjects with familial hypercholesterolaemia decreased the serum total (24%) and LDL (27%) cholesterol and reduced the pressor response to angiotensin II.

Although fluvastatin resulted in a 24% increase in the Pd-20 for angiotensin II, this reduced sensitivity of the fluvastatin-treated subjects did not reach that of the subjects with normal cholesterol levels.

"This fluvastatin-induced decrease in angiotensin II sensitivity potentially contributes to the beneficial effects of the statins in cardiovascular disease," Dr van der Linde concluded.

Novartis supplied the salary for Dr. Nicole van der Linde and the drug used in the study.


[Study title: Increased Angiotensin II Sensitivity in Familial Hypercholesterolaemia. Abstract 4D.1]

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