Obstructive sleep apnea (OSA) syndrome represents a serious health hazard and is recognized as an independent risk factor for adverse cardiovascular outcomes such as hypertension, arrhythmias, stroke, and coronary heart disease [
In OSA patients, reversing early disorders in the cardiovascular system before the occurrence of major clinical events, such as myocardial infarction or stroke, may be a means of reducing cardiovascular risk.
Continuous positive airway pressure (CPAP) the first line therapy for OSA has been suggested in small size randomized controlled trials (RCTs) as being able to reverse some of these subclinical alterations [
Statins were initially introduced for the prevention of cardiovascular risk because of their lowering lipid effects. During the last decade, numerous in vivo and in vitro studies have described pleiotropic effects of statins, independent of their lipid-lowering properties. Some of the reported pleiotropic effects of statins may impact intermediate mechanisms underlying cardiovascular risk in OSA patients. Simvastatin treatment is able to reduce sympathetic tone and normalize autonomic function in chronic heart failure (CHF) rabbits by inhibiting central Ang II mechanisms and therefore the superoxide pathway [
Statins through their pleiotropic properties that impact intermediary mechanisms might modify cardiovascular outcomes in OSA. The aim of this study was thus to determine the effect of 3 months of atorvastatin treatment on endothelial function, blood pressure, and early signs of atherosclerosis in OSA patients, through a randomized double-blind placebo-controlled trial.
The study was conducted in accordance with applicable good clinical practice requirements in Europe, French law, ICH E6 recommendations, and ethical principles of the Helsinki Declaration (South Africa 1996 and Edinburgh 2000). The study was approved by an independent ethics committee (Comité de Protection des Personnes, Grenoble, France, IRB0005578) and registered on the ClinicalTrials.gov site (
This multicenter, randomized, double-blind, parallel group study compared atorvastatin 40 mg/day versus placebo over 12 weeks. The primary endpoint was change in endothelial function from baseline to 12 weeks, measured by PAT. Other endpoints included office blood pressure (BP), early carotid atherosclerosis (intima-media thickness (IMT) and carotid diameters), arterial stiffness measured by pulse wave velocity (PWV), and metabolic and inflammatory parameters.
Patients were recruited from sleep laboratories of 3 university hospitals (Grenoble and Angers, France and Geneva, Switzerland). Only subjects diagnosed with OSA (apnea-hypopnea index (AHI) > 30/h) aged over 18 years and who gave written informed consent were eligible. The study was conducted following the CONSORT recommendations [
Patients presenting any of the following criteria were not included: history of stroke, coronary heart disease, chronic respiratory failure, hypothyroidism, already on statin treatment, multiple antihypertensive medications, pregnant or lactating women, alcohol consumption > 3 units/day, treatment by itraconazole, ketoconazole, protease inhibitor, fibrates, antivitamin K, diltiazem, verapamil, erythromycin, clarithromycin, or cyclosporine.
The determination of the sample size was based on published data on the beneficial effect of an oral appliance using the same endpoint [
Patients underwent an overnight polysomnography. After waking up and while still in a fasting state, a peripheral blood sample was drawn. Then, endothelial function was assessed by PAT and arterial stiffness measured by PWV. A carotid ultrasonography was performed to assess IMT and carotid diameters. The Epworth sleepiness scale was completed and arterial blood gases analysis was performed in order to exclude obesity hypoventilation syndrome. Patients were then randomized to receive statin or placebo treatment. The randomization was made by an independent statistician. Investigators, patients, and the study team were blinded to treatment allocation. Patients randomly allocated to the statin group received 40 mg/day atorvastatin (Tahor, Pfizer Laboratories, France) during 12 weeks. Patients randomly allocated to the control group received placebo (lactose, LC2 Laboratories, France) similarly administered. In order to maintain the double blind status, atorvastatin tablets were encapsulated in capsules identical to the lactose placebo capsules (by LC2 Laboratories, France).
Twelve weeks after the baseline visit, the same parameters were measured to compare the effect of the statin treatment with placebo.
The primary endpoint was the effect of atorvastatin treatment on endothelial function between baseline and 12 weeks, as measured by PAT. The secondary objectives of the study were to determine the effect of atorvastatin treatment on BP, IMT and carotid diameters, arterial stiffness (PWV evaluation), and metabolic parameters. The primary analysis was in intention to treat.
Overnight sleep studies were scored manually according to standard criteria [
Clinical BP was measured using a mercury sphygmomanometer on three occasions, in line with European Society of Hypertension-European Society of Cardiology guidelines [
After BP measurements, endothelial function was assessed by reactive hyperaemia using the finger plethysmographic methodology (PAT) with the EndoPAT device (Itamar Medical Ltd, Caesarea, Israel) as previously described [
B-mode ultrasonography was performed using an HP Sonos 2500 (Hewlett Packard) machine with a sectorial 7.5 MHz probe. The method used to determine the mean common carotid IMT and luminal diameter has been previously described [
After peripheral blood sampling, plasma glucose and serum triglyceride levels were measured automatically (Modular 700, Roche, Meylan, France). Serum insulin was measured using a radio-immunometric sandwich assay (CIS bio international, Gif-Sur-Yvette, France).
The high-sensitivity C-reactive protein (hs-CRP) level was measured using automated immunonephelometry (Behring Nephelometer II Analyzer, Dade Behring, Germany). Urinary leukotriene E4 (LTE4, a validated marker of proinflammatory cysteinyl leukotriene production) and 11-dehydro-thromboxane B2 (11-DHTXB2) were quantified using liquid chromatography-tandem mass spectrometry [
Statistical analysis was performed by using NCSS 97 software (Kaysville, Utah, USA). The data were analyzed in intention to treat, which includes all patients who signed the informed consent form. Missing baseline data were replaced by the median of each group and missing data at 12 weeks were replaced by the median of the opposite group (maximum bias method). Baseline data were compared by a Student or a Mann-Whitney test for continuous data (depending on the validity of the normality of distributions) and by a Chi-Square test for categorical data. For the analysis of data evolution between baseline and 12 weeks, a repeated measure two-way analysis of variance (ANOVA) was performed, followed by a Bonferroni post hoc test when necessary. When normality was not respected, a transformation of variables was used. All
Fifty-one patients were included and randomized (
Key demographics for the study population included age
Baseline characteristics of placebo and statin patients.
Placebo | Statin |
|
|
---|---|---|---|
|
26 | 25 | |
Age (years) | 56 ± 9 | 51 ± 12 | NS |
Male gender (%) | 73 | 84 | NS |
BMI (kg/m²) | 28.70 ± 3.94 | 28.28 ± 5.12 | NS |
History | |||
Smoking (%) | 50.0 | 60.0 | NS |
Alcohol (%) | 38.5 | 56.0 | NS |
Diabetes (%) | 0.0 | 4.0 | NS |
Dyslipidemia (%) | 3.9 | 12.0 | NS |
Respiratory characteristics | |||
AHI (n/h) | 45.47 ± 13.10 | 43.26 ± 19.19 | NS |
Mean SaO2 (%) | 92.57 ± 1.44 | 92.70 ± 2.40 | NS |
SaO2 < 90% (%) | 10.33 ± 13.20 | 11.66 ± 18.11 | NS |
Clinical BP | |||
SBP (mmHg) | 127.67 ± 15.27 | 127.78 ± 15.07 | NS |
DBP (mmHg) | 79.02 ± 11.61 | 79.16 ± 11.60 | NS |
MAP (mmHg) | 95.22 ± 11.93 | 95.37 ± 12.21 | NS |
HR (bpm) | 63 ± 8 | 64 ± 10 | NS |
Biological parameters | |||
Total cholesterol (g/L) | 2.25 ± 0.64 | 2.46 ± 0.94 | NS |
LDL cholesterol (g/L) | 1.41 ± 0.45 | 1.60 ± 0.67 | NS |
HDL cholesterol (g/L) | 0.54 ± 0.23 | 0.74 ± 0.52* |
|
Triglycerides (g/L) | 1.55 ± 1.10 | 1.16 ± 0.59 | NS |
Data are mean ± SD or percentage. BMI, body mass index; SaO2, oxygen saturation; SaO2 < 90%, percentage of recording time spent at a SaO2 < 90%; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HR, heart rate.
After 12 weeks of treatment, adherence was not significantly different between the two groups (
After 12 weeks, there was no improvement in endothelial function when the statin intervention group was compared with the placebo group. The mean difference in PAT measurements between the groups was 0.008 (−0.29; 0.28),
Cardiovascular parameters at baseline (J0) and after 12 weeks (M3) of placebo or statin treatment.
J0 | M3 | Change M3 − J0 | Difference in change (95% CI) | |
---|---|---|---|---|
PAT | ||||
Placebo ( |
|
|
|
0.008 (−0.29; 0.28) |
Statin ( |
|
|
|
|
Carotid-to-femoral PWV (m/s) | ||||
Placebo ( |
|
|
|
0.54 (−0.45; 1.52) |
Statin ( |
|
|
|
|
Right carotid IMT ( |
||||
Placebo ( |
|
|
|
0.02 (−70.38; 70.35) |
Statin ( |
|
|
|
|
Left carotid IMT ( |
||||
Placebo ( |
|
|
|
17.42 (−45.98; 80.81) |
Statin ( |
|
|
|
|
Mean carotid IMT ( |
||||
Placebo ( |
|
|
|
5.34 (−51.34; 62.02) |
Statin ( |
|
|
|
|
Right carotid luminal diameter ( |
||||
Placebo ( |
|
|
|
83 (−305; 472) |
Statin ( |
|
|
|
|
Left carotid luminal diameter ( |
||||
Placebo ( |
|
|
|
−73 (−360; 215) |
Statin ( |
|
|
|
Data are mean ± SD or percentage. PAT, peripheral arterial tone; PWV, pulse wave velocity; IMT, intima-media thickness. Analysis of data by repeated measure two-way ANOVA, followed by a Bonferroni post hoc test when necessary.
$
SBP significantly decreased after 12 weeks of atorvastatin treatment with a mean difference between groups of −6.34 mmHg (−12.68; −0.01),
Blood pressure at baseline (J0) and after 12 weeks (M3) of placebo or statin treatment.
J0 | M3 | Change M3 − J0 | Difference in change (95% CI) | |
---|---|---|---|---|
SBP (mmHg) | ||||
Placebo ( |
|
|
|
−6.34 (−12.68; −0.01) |
Statin ( |
|
|
|
|
DBP (mmHg) | ||||
Placebo ( |
|
|
|
−3.98 (−9.98; 2.03) |
Statin ( |
|
|
|
|
MAP (mmHg) | ||||
Placebo ( |
|
|
|
−4.74 (−10.15; 0.67) |
Statin ( |
|
|
|
Data are mean ± SD. SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure.
After 12 weeks, there was no effect of statin treatment in reducing arterial stiffness compared with the placebo group. The mean difference in PWV measurements between the groups was 0.54 m/s (−0.45; 1.52),
After 12 weeks of treatment both carotid IMT and left and right luminal carotid diameters remained unchanged in both groups (Table
Total and LDL cholesterol levels significantly improved after 12 weeks of atorvastatin treatment (
Metabolic parameters at baseline (J0) and after 12 weeks (M3) of placebo or statin treatment.
J0 | M3 | Change M3 − J0 | Difference in change (95% CI) | |
---|---|---|---|---|
Total cholesterol (g/L) | ||||
Placebo ( |
|
|
|
−0.89 (−1.50; −0.27) |
Statin ( |
|
|
|
|
LDL cholesterol (g/L) | ||||
Placebo ( |
|
|
|
−0.65 (−0.96; −0.34) |
Statin ( |
|
|
|
|
HDL cholesterol (g/L) | ||||
Placebo ( |
|
|
|
−0.31 (−0.78; 0.17) |
Statin ( |
|
|
|
|
Triglycerides (g/L) | ||||
Placebo ( |
|
|
|
0.09 (−0.27; 0.46) |
Statin ( |
|
|
|
|
Glycemia (mmol/L) | ||||
Placebo ( |
|
|
|
0.06 (−0.34; 0.46) |
Statin ( |
|
|
|
|
Insulinemia (mUI/L) | ||||
Placebo ( |
|
|
|
−2.27 (−8.96; 4.42) |
Statin ( |
|
|
|
|
HOMA | ||||
Placebo ( |
|
|
|
−0.66 (−2.83; 1.51) |
Statin ( |
|
|
|
|
Hemoglobin A1c (%) | ||||
Placebo ( |
|
|
|
0.04 (−0.12; 0.19) |
Statin ( |
|
|
|
Data are mean ± SD. LDL, low-density lipoprotein; HDL, high-density lipoprotein; HOMA, homeostasis model assessment of insulin resistance.
$
Inflammatory parameters at baseline (J0) and after 12 weeks (M3) of placebo or statin treatment.
J0 | M3 | Change M3 − J0 | Difference in change (95% CI) | |
---|---|---|---|---|
hs-CRP (mg/L) | ||||
Placebo ( |
|
|
|
2.5 (−3.8; 8.8) |
Statin ( |
|
|
|
|
Urinary LTE4 (pg/mg creatinine) | ||||
Placebo ( |
|
|
|
14.1 (−10.4; 38.6) |
Statin ( |
|
|
|
|
Urinary 11-DHTXB2 (pg/mg creatinine) | ||||
Placebo ( |
|
|
|
41.0 (−156.9; 238.9) |
Statin ( |
|
|
|
Data are mean ± SD. hs-CRP, high-sensitivity C-reactive protein; LTE4, leukotriene E4; 11-DHTXB2, 11-dehydro- thromboxane B2; TXB2, thromboxane B2.
This multicenter, randomized, double-blind, and parallel group study in OSA patients was the first to investigate the effect of statin treatment on OSA-related cardiovascular outcomes.
OSA impairs macro- and microvascular endothelial function compared to healthy controls. PAT reflects changes in digital microvessel dilatation which is only partly dependent on nitric oxide [
However and importantly, we showed that this statin dosage is able to lower systolic office blood pressure in OSA patients. This observation is in accordance with previous results from our group showing that in rodents statin treatment reduces IH-induced blood pressure elevation [
In vascular smooth muscle cells statins are known to inhibit hypoxia-induced endothelin-1 via accelerated degradation of HIF-1
In this study, the impact of statin in reducing blood pressure (around 6 mmHg mean difference) is clinically relevant. This is particularly true in view of the limited impact of CPAP treatment in reducing BP [
Finally, we also showed that statin treatment improved the lipid profile in normolipidemic OSA patients, in accordance with previous studies on normolipidemic hypertensive patients [
Recent large RCTs demonstrate that CPAP alone is not sufficient to address cardiometabolic risk in OSA patients [
Finally, combined statin and CPAP therapy should be put in a realistic perspective compared to the undisputed effects of weight loss and/or exercise not only on blood pressure but also on the cardiometabolic consequences of sleep apnea [
The authors declare that they have no conflict of interests regarding the publication of this paper.
Marie Joyeux-Faure and Renaud Tamisier contributed equally to this work and should be considered as co-first authors. Frédéric Gagnadoux and Jean-Louis Pepin (principal investigator) equally managed this work and should be considered as co-last authors.
The authors thank Dr. Alison Foote (Grenoble Clinical Research Center) for English editing. This study was supported by grants from the “Conseil scientifique AGIR à Dom,” the “Conseil scientifique ANTADIR,” and Grenoble University Hospital (research in pneumology for therapeutic innovation grant).