Comparison of amlodipine and enalapril in the treatment of isolated systolic hypertension in the elderly: an open-label, randomized, parallel-group study

Background: The benefits of treating isolated systolic hypertension (ISH) are well established, but the most appropriate drug choice is still uncertain.Objective: The purpose of this study was to compare amlodipine, a calcium channel blocker, with enalapril, an angiotensin-converting enzyme inhibitor, in the treatment of ISH in a cohort of elderly patients (≥60 years of age).Methods: Ambulatory patients with ISH (seated systolic blood pressure [SBP] >160 mm Hg and <220 mm Hg; diastolic blood pressure [DBP] <95 mm Hg) who had not been treated previously or who had stopped their medication at least 4 weeks before the study were enrolled. Patients were randomized to receive amlodipine 5 mg/d or enalapril 10 mg/d. After 4 weeks of treatment, the dose was doubled for those patients whose sitting SBP had not decreased to <150 mm Hg or by >20 mm Hg, and treatment was continued for an additional 4 weeks.Results: A total of 89 patients were randomized to treatment, 46 to amlodipine and 43 to enalapril; 1 patient in the enalapril group died due to ischemic stroke despite adequate blood pressure control. The absolute reductions in seated and standing SBP/DBP were similar with both drugs after 8 weeks: 27 mm Hg/4.6 mm Hg with amlodipine and 23.9 mm Hg/3.9 mm Hg with enalapril (sitting) and 25.1 mm Hg/4.1 mm Hg and 21.3 mm Hg/4.2 mm Hg (standing) with amlodipine and enalapril, respectively (P = NS). At 4 weeks, 24 patients (52.2%) in the amlodipine group and 33 patients (76.7%) in the enalapril group had their medication dose doubled because their SBP was not adequately controlled with the initial dose (P < 0.01). At the end of the study, 24 patients were taking 10 mg amlodipine and 22 patients were taking 5 mg (mean dose 7.6 ± 2.5 mg); 33 patients were taking 20 mg enalapril and 10 patients were taking 10 mg (mean dose 17.8 ± 4.1 mg). Side effects occurred significantly more frequently in the amlodipine group (P = 0.01).Conclusion: The results of this study suggest that amlodipine and enalapril are similarly effective in treating ISH in elderly patients, with few side effects.     

Antihypertensive effect of barnidipine 10 mg or amlodipine 5 to 10 mg once daily in treatment-naive patients with essential hypertension: A 24-week, randomized, open-label, pilot study

Background: Dihydropyridine calcium antagonists are largely employed for the treatment of hypertension, coronary heart disease, and heart failure.Objective: The aim of our study was to compare the antihypertensive effect of the dihydropyridine calcium antagonists barnidipine and amlodipine.Methods: This was a 24-week, randomized, open-label, pilot study. Consecutive treatment-naive patients with grade I or II essential hypertension (office sitting systolic blood pressure [BP] of 140-179 mm Hg and diastolic BP of 90-109 mm Hg) were enrolled. The primary end points were the effect of treatment with either barnidipine 10 mg or amlodipine 5 mg once daily on office and ambulatory BP, left ventricular mass index (LVMI), and markers of cardiac damage, serum procollagen type I C-terminal propeptide, and plasma amino-terminal pro-B-type natriuretic peptide concentrations. Patients were assessed at enrollment, and 12 and 24 weeks. During each visit, the prevalence of adverse events (AEs) was also monitored using spontaneous reporting, patient interview, and physical examination, the relationship to study drug being determined by the investigators. Compliance with treatment was assessed at each study visit by counting returned tablets.Results: Thirty eligible patients (20 men, 10 women; mean [SD] age, 47 [12] years) were included in the study; all patients completed the 24 weeks of study treatment. Twelve weeks after randomization, 6 patients in the amlodipine group had their dose doubled to 10 mg due to inadequate BP control. Mean BP reductions at study end were not significantly different between the barnidipine and amlodipine groups (office BP, −10.3/−9.4 vs −16.6/−9.1 mm Hg; ambulatory BP, 9.4/6.4 vs 8.1/5.1 mm Hg). Reductions in LVMI and markers of cardiac damage were not significantly different between the 2 groups. Significantly more patients in the amlodipine group reported drug-related AEs compared with those in the barnidipine group (9 [60%] vs 2 [13%]; P < 0.05).Conclusion: In this small sample of treatment-naive hypertensive patients, the antihypertensive effect of barnidipine 10 mg once daily was not significantly different from that of amlodipine 5 to 10 mg once daily.     

Effects of Dividing Amlodipine Daily Doses on Trough Drug Concentrations and Blood Pressure Control Over a 24-Hour Period

Background

In the treatment of hypertension, once-daily administration of long-acting antihypertensive drugs has been recommended for the improvement of treatment adherence; however, it is unclear whether dividing daily doses has the additional benefit of more ideal blood pressure (BP) control over a 24-hour period.

Objective

The aim of the study was to investigate whether dividing a 10-mg daily dose of amlodipine, a long-acting calcium channel blocker, is associated with increased trough plasma amlodipine concentrations, reduced arterial stiffness, and improved BP control over a 24-hour period.

Methods

Outpatients with essential hypertension were included this open-label, 2-period crossover study. The patients were administered amlodipine 10 mg/d in 2 divided doses for 8 weeks. At week 4, blood was collected just before amlodipine administration for the evaluation of trough plasma amlodipine concentrations. At week 8, 24-hour, daytime, nighttime, and early morning BP, as well as arterial stiffness, were measured using ambulatory BP monitoring (ABPM) and cardio-ankle vascular index (CAVI), respectively. In the subsequent study period, amlodipine 10 mg/d was administered once daily, and the same tests were performed at the same timings as in period 1.

Results

Ten patients were enrolled (7 men, 3 women; mean age, 61.0 [15.3] years). Mean 24-hour BP with twice-daily administration was not significantly lower than that with once-daily administration (129.7 [7.3]/80.1 [7.9] mm Hg vs 130.5 [11.8]/80.1 [7.9] mm Hg, respectively). Similarly, there were no significant differences in daytime, nighttime, or early morning BP between twice- and once-daily administration. In addition, the differences in trough plasma amlodipine concentrations (22.37 [7.66] ng/mL vs 20.57 [8.22] ng/mL) and CAVI values (8.2 [1.8] vs 8.5 [1.0]) were not significantly different between twice- and once-daily administration.

Conclusions

Administering amlodipine in 2 divided doses was not associated with increased trough plasma amlodipine concentrations, reduced arterial stiffness, or improved BP control over a 24-hour period in patients with essential hypertension. UMIN Clinical Trials Registry no. UMIN000003914.     

Comparison of candesartan and felodipine alone and combined in the treatment of hypertension: a single-center, double-blind, randomized, crossover trial

Background: In the past decade, many studies have indicated that the combination of low doses of different classes of antihypertensive agents may be more efficacious than monotherapy while minimizing the likelihood of dose-dependent adverse effects (AEs).Objective: The aim of this study was to determine whether combination therapy with lower doses of candesartan and a calcium antagonist, felodipine, would be more effective and tolerable in controlling mild to moderate hypertension compared with either drug used alone.Methods: In this 18-week, single-center, double-blind, crossover study, patients with mild to moderate essential hypertension were randomized to 1 of 2 treatment groups after a 2-week placebo washout period. Patients in group 1 received candesartan 16 mg once daily and patients in group 2 received felodipine 5 mg once daily, for 6 weeks. All patients then received half-dose combination therapy (candesartan 8 mg plus felodipine 2.5 mg, once daily) for 6 weeks. Finally, patients received 6 weeks of monotherapy with the alternate medication (group 1 received felodipine 5 mg once daily and group 2 received candesartan 16 mg once daily).Results: Thirty patients (18 men, 12 women; mean [SD] age, 54.0 [4.9] years; range, 39-62 years) were included in the study. During both monotherapy periods, candesartan and felodipine significantly reduced blood pressure (BP) (both P<0.001). BP further decreased with combination therapy (P<0.001 in both groups). Overall, 90.0% (27/30) of the patients achieved the target BP at the end of combination therapy. The incidence of AEs was similar with combination therapy compared with either monotherapy.Conclusions: In this study population, candesartan and felodipine had additive effects when used in combination, even at low doses, in the treatment of hypertension. Therefore, the combination of candesartan and felodipine is an effective alternative to that of candesartan and hydrochlorothiazide.     

Antihypertensive effect of zofenopril plus hydrochlorothiazide versus zofenopril monotherapy in patients with essential hypertension according to their cardiovascular risk level: A post hoc analysis

Background: International guidelines recommend the use of angiotensin-converting enzyme inhibitors, possibly in combination with other antihypertensive drugs, to treat hypertension with associated risk factors.Objective: The aim of this study was to compare the antihypertensive effect of the combination of zofenopril plus hydrochlorothiazide versus zofenopril monotherapy in patients with essential hypertension, according to their cardiovascular risk level.Methods: This was a post hoc analysis of a previously published efficacy and tolerability study. After a 4-week placebo washout, patients with mild to moderate essential hypertension (diastolic blood pressure [DBP] 95-115 mm Hg), aged 18 to 75 years, were randomized at a ratio of 2:1:1 to treatment with zofenopril 30 mg plus hydrochlorothiazide 12.5 mg or monotherapy with zofenopril 30 mg or hydrochlorothiazide 12.5 mg for 12 weeks in an international, multicenter, double-blind study. This period was followed by 24 weeks of open-label treatment. Systolic BP [SBP] and DBP were measured by mercury sphygmomanometry, and changes associated with treatment were calculated. Patients' cardiovascular risk was computed using the Heart Score algorithm. Patients were classified in quartiles according to distribution of cardiovascular risk level, and comparisons were limited to the zofenopril plus hydrochlorothiazide and zofenopril monotherapy treatment groups. The primary end point was change in office DBP.Results: Two hundred forty-six patients (139 men, 107 women; mean [SD] age, 54 [11] years) were included in the analysis. Mean baseline cardiovascular risk was similar in the zofenopril plus hydrochlorothiazide group and the zofenopril monotherapy group (7% vs 9%). DBP and SBP reductions with treatment were significantly greater (both, P < 0.01) with combination treatment than with monotherapy for each quartile of cardiovascular risk. Cardiovascular risk reduction at the end of the 12 weeks of double-blind treatment was greater in the zofenopril plus hydrochlorothiazide group than in the zofenopril monotherapy group (1.9% vs 0.2%; P < 0.01), particularly in the group of patients with the highest cardiovascular risk at baseline (5.2% vs 2.0%). At the end of the 24-week open-label treatment period, the mean reduction in cardiovascular risk was also significantly greater in the combination treatment group than in the monotherapy group (1.4% vs 0.5%; P < 0.01).Conclusions: In these hypertensive patients, combination treatment with zofenopril plus hydrochlorothiazide was associated with a significantly greater decrease in BP compared with zofenopril monotherapy, regardless of the patient's cardiovascular risk. The difference between combination treatment and monotherapy was particularly evident for the group of patients at highest risk.     

Effects of low-dose treatment with felodipine versus fosinopril in Chinese patients with nonischemic heart failure and normal blood pressure: A double-blind, randomized, crossover study

Background: Two second-generation calcium channel blockers, felodipine and amlodipine besylate, have been associated with similar high mortality rates in patients with ischemic heart failure (HF) but not in patients with nonischemic causes of HF. In patients with nonischemic HF, amlodipine might have a beneficial effect on survival. However, no difference in mortality rates was found between felodipine and placebo in a nonischemic HF group. Felodipine 10 mg/d was used in 1 large study, a dose considered high for nonischemic HF usually associated with normal blood pressure (BP).Objective: The aim of this study was to compare the effects of 12-week, low-dose treatment with felodipine versus those of an angiotensin-converting enzyme inhibitor, fosinopril sodium, in patients with nonischemic HF and normal BP.Methods: This double-blind, randomized, crossover trial was conducted at Taipei Medical University Hospital (Taipei, Taiwan). Patients aged ≥ 18 years with angiographically proved, nonischemic HF and normal BP who were being treated with an optimal regimen of digitalis and diuretics were enrolled. After a 2-week run-in period, patients were randomized to first receive 12 weeks of treatment with felodipine tablets (2.5 mg/d) or fosinopril tablets (7.5 mg/d) and, after a 2-week washout period, were crossed over to the opposite treatment. Efficacy analysis was performed before (baseline) and after treatment and included symptomatic assessment using a 7-grade clinical scale; 2-dimensional echocardiography (2-D echo); exercise tests; and neurohumoral data, including plasma renin activity, plasma aldosterone, and 24-hour urinary epinephrine (E) and norepinephrine (NE) measurements. The primary end point was death due to HF, and the secondary end point was hospital admission due to worsening HF. Compliance was measured using a pill count at the end of each treatment period.Results: We enrolled 33 patients. One developed worsening HF during the run-in period and was admitted. A total of 32 patients entered the study (18 men, 14 women; mean [SD] age, 48.2 [6.3] years [range, 34-56 years]; mean [SD] systolic BP, 117.2 [9.8] mm Hg [range, 100-138 mm Hg]; mean [SD] diastolic BP, 59.4 [5.7] mm Hg [range, 50-72 mm Hg]). No hospital admission or cardiac death due to HF occurred during 12 weeks of treatment. Twenty-seven patients were included in the felodipine assessment, and 30 patients were included in the fosinopril assessment. Significant improvement in clinical score was noted in both treatment groups (both P < 0.01). The clinical scores did not differ significantly between the 2 treatments. No significant differences were found in 2-D echo parameters between treatments or within groups after treatment versus baseline. Significant improvement in exercise duration was noted with both study drugs after treatment versus baseline (both P < 0.01). No significant difference in exercise duration was found between the 2 treatments. Urinary E and NE were not significantly different between treatments or after treatment with either study drug compared with baseline.Conclusion: The present findings suggest that, in Chinese patients with moderate to severe HF who have normal BP and insignificant coronary artery disease and were being treated with diuretics and digitalis, a 12-week, low-dose course of felodipine (2.5 mg/d) as a vasodilator was associated with as satisfactory an outcome as standard treatment with fosinopril (7.5 mg/d).     

Effects of replacing metformin with pioglitazone on glycemic control in japanese patients with poorly controlled type 2 diabetes mellitus: A 12-week, open-label, prospective study

Background: Insulin resistance is a critical aspect of the pathophysiology of type 2 diabetes mellitus and is also associated with other risk factors for cardiovascular disease (eg, dyslipidemia and hypertension). Accordingly, insulin resistance is a possible target for lowering plasma glucose concentration and preventing diabetic macroangiopathy. Biguanides, such as metformin, and thiazolidinediones (TZDs), such as pioglitazone, improve insulin resistance.Objectives: The aims of this study were to assess the effects of replacing a biguanide with a TZD on glycemic control in patients with poorly controlled type 2 diabetes mellitus, and also to identify the factors affecting interpatient variation in the effects of treatment change.Methods: This was a 12-week, open-label, prospective study in which previously prescribed metformin (500 or 750 mg/d) was replaced with pioglitazone (15 or 30 mg/d) in patients with poorly controlled type 2 diabetes mellitus. Patients with a glycosylated hemoglobin (HbA_1c) concentration >7% despite treatment with diet, exercise, and hypoglycemic agents other than TZDs were eligible for the study. Patients who never received TZDs were also eligible for inclusion. Vital signs, metabolic parameters, and arterial stiffness were assessed at baseline and after 12 weeks of treatment with pioglitazone. The primary end point was change in HbA_1c concentration after replacing metformin with pioglitazone. Tolerability was assessed by medical history, physical examination, and laboratory tests (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase).Results: Twenty-one Japanese patients (15 women, 6 men; mean [SD] age, 61.8 [8.4] years; body mass index, 25.5 [3.0] kg/m²) were included in the study. HbA_1c concentration was not significantly changed from baseline after 12 weeks of pioglitazone treatment (8.0% [0.7%] vs 8.2% [0.7%]). Fasting plasma glucose (FPG) concentration also was not significantly changed after the replacement of treatment (156 [27] vs 144 [30] mg/dL). In addition, the resistin concentration did not change significantly from baseline after 12 weeks of pioglitazone treatment (6.6 [3.8] vs 6.4 [3.6] ng/mL). In contrast, significant improvement from baseline was observed in triglyceride (TG) concentrations (157 [109] vs 117 [68] mg/dL; P = 0.003), high-density lipoprotein cholesterol (HDL-C) (55 [12] vs 61 [16] mg/dL; P = 0.016), remnant-like particle cholesterol (6.6 [6.0] vs 5.3 [3.5] mg/dL; P = 0.048), and serum adiponectin (8.8 [4.3] vs 23.3 [11.7] μg/mL; P < 0.001). Pulse wave velocity was also significantly improved (1730 [361] vs 1622 [339] m/sec; P = 0.009). Changes in HbA_1c were significantly correlated with serum fasting insulin concentration at baseline in the patients not receiving insulin preparations (r = -0.635, P = 0.013). The percentage change in serum adiponectin concentration was correlated with the percentage changes in HbA_1c and FPG concentrations (HbA_1c, r = -0.518, P = 0.019; FPG, r = -0.594, P = 0.006). Body weight was significantly increased after treatment (62.6 [11.9] vs 65.5 [12.2] kg; P < 0.001). Mild edema was reported in 5 patients. One patient discontinued treatment due to an increase in serum creatine kinase activity to ~6.6 times the upper limit of normal.Conclusions: Replacement of metformin with pioglitazone did not produce significant differences in HbA_1c and FPG concentrations from baseline after 12 weeks of treatment in these patients with poorly controlled type 2 diabetes mellitus. However, the replacement was effective in a subset of patients whose serum insulin concentrations were high or whose serum adiponectin concentrations were sensitive to TZDs. In addition, the replacement was associated with significant improvements in TG, HDL-C, serum adiponectin concentration, pulse wave velocity, and body weight increase from baseline.     

Effects of the fixed combination of manidipine plus delapril in the treatment of hypertension inadequately controlled by monotherapy with either component: a phase III, multicenter, open-label, clinical trial

Background: Failure to achieve good blood pressure (BP) control is probably the most important reason for high rates of morbidity and mortality in patients with hypertension. Combination therapy has been shown to increase the percentage of patients in whom BP control is achieved. One combination is a calcium channel blocker (CCB) and an angiotensin-converting enzyme inhibitor (ACE-I).Objective: The aim of this study was to assess the effects of the fixed combination of the CCB manidipine and the ACE-I delapril in the treatment of hypertensive patients already given monotherapy with either component but with poor results (ie, insufficient BP control or adverse events [AEs]).Methods: In this Phase III, multicenter, open-label, clinical trial, patients with mild to moderate hypertension were assigned to 1 of 2 groups. Group 1 comprised patients whose diastolic BP (DBP) was >90 mm Hg or who experienced AEs with manidipine 20 mg once daily. Group 2 comprised patients who had a DBP >90 mm Hg or who experienced AEs with delapril 30 mg BID. In both groups, patients aged <65 years were to be treated with a fixed combination of manidipine 10 mg plus delapril 30 mg once daily for 12 weeks, whereas patients aged ≥65 years were to be treated with manidipine 5 mg plus delapril 15 mg once daily for 2 weeks and then manidipine 10 mg plus delapril 30 mg once daily for 10 weeks. Patients were assessed at baseline and at 2, 4, 8, and 12 weeks of treatment. At each visit, systolic blood pressure (SBP), DBP, and heart rate were measured 24 hours after dosing, and AEs were recorded.Results: Group 1 included 154 patients (80 men, 74 women; mean [SD] age, 55 [6] years); group 2 included 158 patients (79 men, 79 women; mean [SD] age, 56 [5] years). Mean BP decreased significantly in both groups (P<0.01). Compared with baseline values, mean SBP/DBP decreased 16.2 (3.8)/10.1 (1.9) mm Hg in group 1 and 15.8 (3.1)/11.0 (1.5) mm Hg in group 2 at the last visit. The success rate—rate of normalized DBP (≤90 mm Hg) and responder rate (DBP reduction ≥10 mm Hg)—was 79% in group 1 and 82% in group 2. The rates of treatment-related AEs were 11% in group 1 and 8% in group 2. In group 1, heart rate significantly increased from baseline only at 2 weeks (P<0.05); in group 2, at each visit (P<0.05) except at week 12. However, none of these differences were clinically significant.Conclusion: In this study population of patients whose BP was not adequately controlled by monotherapy, the fixed combination of manidipine 10 mg plus delapril 30 mg, once daily, was effective and well tolerated.     

Efficacy and Tolerability of Nilvadipine in Combination with an Angiotensin II Receptor Antagonist in Patients with Essential Hypertension: A Multicenter, Open-Label, Uncontrolled Study

Background: Combination therapy with different classes of antihypertensive drugs often is needed to achieve controlled blood pressure (BP). The combination of an angiotensin II receptor antagonist (AIIA) and a calcium antagonist is a preferred option for reducing uncontrolled BP.Objective: The aim of this study was to assess the clinical efficacy and tolerability of nilvadipine, a dihydropyridine calcium antagonist, in combination with an AIIA.Methods: Patients with essential hypertension whose BP was not controlled by an AIIA alone were eligible for this multicenter, open-label, uncontrolled study. One of 3 AIIAs (candesartan cilexetil, losartan potassium, or valsartan) was given for at least 10 weeks before the addition of nilvadipine (daily dose, 4 or 8 mg orally). This combination therapy was given for 8 weeks. BP and heart rate were measured between 2 and 4 weeks before and 0, 4, and 8 weeks after the start of combination therapy. Adverse events were monitored at each visit.Results: Thirty-one patients (18 women [58.1%], 13 men [41.9%]; mean [SD] age, 58.5 [10.5] years) were enrolled. At weeks 4 and 8 of combination therapy, mean systolic BP (SBP) and diastolic BP (DBP) were significantly decreased (P<0.01) (at week 8, by 22.0 mm Hg and 12.5 mm Hg, respectively). The mean BP-lowering effect did not differ significantly between the 3 AIIAs tested. Pulse pressure also decreased significantly at week 8, by 9.6 mm Hg (P<0.01). The responder rate (ie, the percentage of patients with DBP <90 mm Hg or a decrease in DBP ≥10 mm Hg) was 72.0% at week 8. Three patients experienced a total of 4 adverse events: mild or severe flushing, mild headache, and mild palpitation. All of these symptoms resolved after nilvadipine treatment was discontinued.Conclusions: Nilvadipine in combination with an AIIA showed good antihypertensive efficacy and was well tolerated in the hypertensive patients in this study. This combination also significantly decreased pulse pressure, suggesting that this combination therapy also may have a beneficial effect in elderly patients with isolated systolic hypertension.     

Effects of valsartan treatment on indicators of cardiovascular damage in newly diagnosed hypertensive patients: A prospective, twelve-month, open-label, pilot study

Background: Myocardial fibrosis and dysfunction can be detected in the early phases of organ damage associated with hypertension. Valsartan, an angiotensin-II receptor blocker, is efficacious in lowering blood pressure (BP) and reducing left ventricular mass in patients with hypertension. Levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and procollagen type I carboxy-terminal propeptide (PICP) are correlated with organ damage in patients with overt congestive heart failure; however, few data are available in patients with hypertension.Objective: The aim of this study was to assess the effects of 12 months of valsartan treatment on echocardiographic measures and indices of organ damage (NT-proBNP and PICP) in newly diagnosed patients with hypertension.Methods: This was a prospective, open-label, single-center, exploratory study. Patients with newly diagnosed, previously untreated hypertension were treated for 12 months with valsartan 160 mg/d and compared with an equal number of healthy, untreated control subjects. Baseline and follow-up visits at 3, 6, and 12 months included physical examination, systolic BP (SBP) and diastolic BP (DBP) measurements, ECG, echocardiography, and NT-proBNP and PICP determination.Results: A total of 20 patients (mean [SD] age, 48.05 [7.29] years) were enrolled and compared with 20 healthy controls (age, 49-6 [6.95] years). Compared with baseline, valsartan was associated with reduced BP in the group with hypertension after 12 months of treatment (mean SBP, 150.05 [11.15] vs 120.00 [8.43] mm Hg, P < 0.001; DBP, 97.80 [8.36] vs 79-50 [4.26] mm Hg, P < 0.001). Compared with the control group, at baseline, the group with hypertension had significantly higher mean left ventricular mass index (LVMI) (119.88 [22.86] vs 87.31 [15.77] g/m²; P < 0.001), relative wall thickness (thickness/radius [h/r] ratio: 0.45 [0.08] vs 0.35 [0.07]; P = 0.001), and NT-proBNP (50.00 [32.01] vs 25.47 [9.69] pg/dL; P = 0.002). PICP was higher, but the difference was not statistically significant (46.10 [15.69] vs 37.50 [7.20] μg/L). After 12 months, treatment with valsartan was associated with significant reductions in all measured parameters compared with baseline (LVMI, 106.51 [17.12] g/m², P = 0.004; h/r, 0.41 [0.07], P = 0.026; NT-proBNP, 22.55 [13.52] pg/dL, P = 0.001; PICP, 35.20 [9-19] μg/L, P < 0.008). At 12 months, patients with hypertension treated with valsartan achieved NT-proBNP and PICP levels not statistically different from those of the healthy controls (NT-proBNP, 22.55 [13-52] vs 25.24 [8.43] pg/dL; PICP, 35.20 [9.19] vs 36.90 [6.41] μg/L).Conclusion: Patients treated with valsartan for 12 months had significant reductions in BP, LVMI, and indices of subclinical organ damage (NT-proBNP and PICP) compared with baseline.     

Arterial wave reflection during antihypertensive therapy with barnidipine: A 6-month,open-label study using an integrated cardiovascular ultrasound approach in patients with newly diagnosed hypertension

Background: Increased central aortic pressure resulting from large artery stiffening and increased wave reflection is associated with higher hypertension-related morbidity.Objective: The goal of this study was to evaluate the effects of a vasodilator-based therapy with the calcium channel blocker barnidipine on arterial stiffness, wave reflection, and left ventricular (LV) performance using an integrated cardiovascular ultrasound approach (including wave intensity analysis).Methods: Newly diagnosed, previously untreated patients with grade 1 or 2 essential hypertension (systolic blood pressure [BP] ≥140 and <180 mm Hg, and/or diastolic BP ≥90 and <110 mm Hg), and with no signs of clinical cardiovascular disease, were eligible for study. Carotid artery mechanics were investigated at baseline and after 3 and 6 months of barnidipine therapy (10–20 mg once daily, according to an open-label design) using a double-beam carotid ultrasound technique. This provided a simultaneous recording of diameter-derived pressure and flow velocity signals and allowed analysis of wave intensity. Indices of local arterial stiffness and wave reflection, as well as separated forward and backward pressure waves, were estimated. LV geometry, mass, and systolic and diastolic performance were also assessed using Doppler echocardiography. All ultrasound examinations and readings were performed by investigators blinded to patient demographics and treatment phase. Normotensive control subjects (office BP <140/90 mm Hg) were included as a reference group.Results: Twenty-one white, treatment-naive patients with hypertension (mean [SD] age, 58 [8] years; 14 males; mean body mass index, 27 [5] kg/m²; mean BP, 159 [14]/96 [5] mm Hg) were enrolled. Twenty normotensive subjects comprised the control group. Compared with the control subjects, patients with hypertension had a higher mean augmentation index ([AIx] 22.0% [7.0%] vs 13.1% [5.2%]; P < 0.01), Peterson's pressure-strain elastic modulus (175 [49] vs 126 [41] kPa; P < 0.01), and forward and backward pressure waves (137 [17] vs 108 [7] mm Hg [P < 0.001] and 21 [6] vs 17 [5] mm Hg [P < 0.05], respectively) at baseline. After 6 months of barnidipine treatment, mean office BP in the patients with hypertension decreased from 159 (14)/96 (5) mm Hg at baseline to 138 (16)/81 (9) mm Hg (P < 0.001) due to a significant reduction in forward and backward pressure waves, and AIx decreased to 17.0% (8.0%) (P < 0.01); there were no significant changes in indices of intrinsic arterial stiffness. A significant direct relationship between AIx and pulse pressure (r = 0.45 [P < 0.05]) was observed at baseline in hypertensive patients but not after therapy (r = 0.26 [P = NS]). Mean stress-adjusted LV midwall shortening increased from 110% (17%) at baseline to 118% (13%) at 6 months (P < 0.05), which was comparable to baseline values in the control subjects (119% [10%]).Conclusion: In these middle-aged patients with newly diagnosed mild to moderate hypertension, vasodilator therapy with barnidipine reduced central BP by a parallel reduction of forward and backward pressure waves, together with a later arrival of the reflected waves, with no significant changes in intrinsic arterial stiffness.     

Effectiveness and tolerability of rosiglitazone on insulin resistance and body composition in nondiabetic Thai patients undergoing continuous ambulatory peritoneal dialysis: A 12-week pilot study

Background: Patients with chronic renal insufficiency, especially those undergoing continuous ambulatory peritoneal dialysis (CAPD), normally have insulin resistance due to deficiencies in insulin secretion and degradation, as well as tissue resistance to insulin at both receptor and postreceptor levels.Objective: The aim of this study was to investigate the effectiveness and tolerability of rosiglitazone on insulin resistance and body composition in patients without diabetes mellitus (DM) undergoing CAPD.Methods: This pilot study included a pretest and posttest with a repeated-measure design in a small number of patients. CAPD patients without DM received rosiglitazone 2-mg tablets BID for 12 weeks. Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR) and bioelectrical impedance analysis (BIA) were used to assess insulin resistance and body composition, respectively. Tolerability was assessed using laboratory analyses as well as physical examination findings to evaluate peripheral edema. Peripheral edema was assessed by the study investigators.Results: Thirteen Thai patients (mean [SD] age, 54.17 [11.42] years [range, 35-85 years]; body mass index [BMI], >20 to <30 kg/m²; fasting blood glucose [FBG] concentration, <5.39 mmol/L) were included in the study. One patient was withdrawn due to illness unrelated to the study. No significant difference was found in FBG concentration between baseline and posttreatment (after 12 weeks of treatment) (5.45 [0.59] vs 5.24 [0.51] mmol/L), but fasting plasma insulin concentrations (28.50 [23.70] vs 10.15 [4.22] μIU/mL; P = 0.005) and HOMA-IR score (6.70 [5.23] vs 2.40 [1.15]; P = 0.011) were significantly lower. There were no significant changes in weight or BMI from baseline to posttreatment. Seven subjects (58.3%) experienced weight gain at week 4, while 2 patients (16.7%) still had weight gain after 12 weeks of treatment. A significant increase was found between baseline and posttreatment in total body water (38.03 [4.55] vs 42.44 [5.99] L; P = 0.018), extracellular fluid (20.24 [3.75] vs 26.22 [8.69] L; P = 0.005), plasma fluid (4.29 [0.80] vs 5.20 [0.93] L; P = 0.005), and interstitial fluid (14.99 [2.78] vs 17.68 [3.07] L; P = 0.040). Using BIA, no significant changes were observed in intracellular fluid, fat mass, or liver function. After 12 weeks of rosiglitazone administration, 2 patients (16.7%) had mild edema.Conclusions: Rosiglitazone 2 mg BID for 12 weeks was associated with significantly improved insulin resistance in this small group of nondiabetic Thai patients undergoing CAPD. There was a significant increase in total body water and extracellular fluid after administration of rosiglitazone for 12 weeks. There were no significant changes in FBG, weight, or BMI.     

Comparative assessment of the effectiveness and tolerability of lornoxicam 8 mg BID and diclofenac 50 mg TID in adult indian patients with osteoarthritis of the hip or knee: A 4-week, double-blind, randomized, comparative, multicenter study

Background: Reports of cardiovascular adverse events (AEs) associated with the use of cyclooxygenase-2 inhibitors for the treatment of osteoarthritis (OA) have prompted the quest for a better-tolerated NSAID.Objective: The aim of this study was to compare the effectiveness and tolerability of lornoxicam 8 mg BID and diclofenac 50 mg TID in adult Indian patients with OA of the hip or knee.Methods: This 4-week, double-blind, randomized, comparative, multicenter study was undertaken to compare oral lornoxicam and diclofenac in patients with OA. Patients who met the selection criteria were enrolled consecutively from the outpatient clinics of each of the participating hospitals in India. Participants completed the Western Ontario and McMasters Individual Osteoarthritis Index (WOMAC-OA), WOMAC Composite Index (WOMAC-CI) (for pain, stiffness, and physical function), and a 10-cm visual analog scale (VAS) (0-10 where 0 = no pain and 10 = worst possible pain or severe or excruciating pain) at each study visit (weeks 0 [baseline], 2, and 4 [or at early termination]). Patients' and physicians' global assessments of arthritis control were measured at each study visit when laboratory and clinical AEs were also monitored. The primary end points were the WOMAC-OA, the WOMAC-CI, and VAS scores for pain among the patients who completed the study.Results: Of the 273 patients (159 men, 114 women; mean [SD] age, 44.73 [10.72] years; range, 28-68 years) enrolled in the study, 13 (7 in the lornoxicam group and 6 in the diclofenac group) were lost to follow-up and their effectiveness and tolerability results were not included in the study analysis. Over the 4-week study period, both drugs provided significant (P < 0.05) sustained relief of OA symptoms compared with baseline. Compared with baseline, the mean pain score (WOMAC-CI) decreased 90.6% (13.88 [4.47] vs 1.30 [1.49]; P < 0.05) in the lornoxicam group and 88.9% (14.15 [4.56] vs 1.57 [1.49]; P < 0.05) in the diclofenac group after 4 weeks of treatment. After 4 weeks of treatment, the VAS pain score decreased from baseline 83.1% (8.04 [2.70] vs 1.36 [1.43]; P < 0.05) in the lornoxicam group and 79.3% (7.98 [2.98] vs 1.65 [1.47]; P < 0.05) in the diclofenac group. Compared with baseline, the improvement rated at 2 weeks was not significantly different between the 2 groups. Lornoxicam and diclofenac were well tolerated. The rate of mild to moderate adverse gastrointestinal events was not significantly different in the lornoxicam group compared with the diclofenac group (14.6% vs 18.4%). Similarly, overall tolerability between the 2 groups was not significantly different. None of the patients experienced cardiovascular AEs (eg, edema or increased blood pressure).Conclusion: The results of the present study suggest that lornoxicam was comparable to diclofenac in effectiveness and tolerability after 4 weeks of treatment in these adult Indian patients with OA of the hip or knee who completed the study.     

Effects of a weight-reduction program with orlistat on serum leptin levels in obese women: A 12-week, randomized, placebo-controlled study

Background: Leptin, which has been identified as an antiobesity hormone, regulates body weight by controlling food intake and energy expenditure via the hypothalamic-pituitary-gonadal axis. It appears that leptin may be an important factor in obesity management. Orlistat, a pancreatic lipase inhibitor, could reduce fat absorption and promote weight loss due to leptin metabolism.Objective: The purpose of this study was to investigate the effects of orlistat therapy on serum leptin levels.Methods: Obese women (body mass index [BMI], 30 kg/m²) aged 18 to 50 years were randomly assigned to receive 12 weeks of oral treatment with diet-orlistat (120 mg TID) (DO group) or diet-placebo (DP group). During the treatment period, patients were asked to eat a balanced diet of -1200 to 1600 kcal/d. Body composition was determined by bioelectrical impedance. Serum leptin levels were measured using radioimmunoassay at baseline and at study end.Results: A total of 24 patients entered the study; 14 patients (mean [SE] BMI, 37.7 [1.1] kg/m²) received orlistat and 10 patients (mean [SE] BMI, 39.4 [1.3] kg/m²) received placebo. Compared with baseline, mean percentages of loss of body weight and fat mass after 12 weeks of treatment were significant in the DO group (9.1% and 14.8%, respectively; both P = 0.001) and in the DP group (9.5% and 17.6%; both P = 0.005). The between-group differences were not statistically significant. Mean (SE) serum leptin levels also decreased significantly after treatment in the DO group (16.2 [1.2] vs 9.0 [1.0] ng/mL; P = 0.001) and in the DP group (19.3 [2.1] vs 9.7 [1.4] ng/mL; P = 0.005). The between-group difference was not statistically significant.Conclusions: In this study of obese women, orlistat treatment was associated with a similar decrease in body weight, fat mass, and serum leptin levels as placebo over a 12-week period. In this regard, short-term orlistat therapy may not provide an additional effect on serum leptin levels, and reduction in leptin levels were closely related to the decrease in fat mass.     

Efficacy and Tolerability of Delapril Plus Indapamide Versus Lisinopril Plus Hydrochlorothiazide Combination Treatments in Mild to Moderate Hypertension: A Multicenter, Randomized Clinical Study

Background: Several studies have shown that antihypertensive monotherapy is commonly insufficient to control blood pressure (BP) in hypertensive patients and that concomitant use of ≥2 drugs is necessary in ∼50% of these patients. The combination of an angiotensin-converting enzyme (ACE) inhibitor and a diuretic, delapril plus indapamide (D + I), has been shown to be effective and tolerable, with no interaction between the 2 components. Another widely used combination of ACE inhibitor and diuretic is lisinopril plus hydrochlorothiazide (L + H).Objectives: The aims of this study were to confirm the antihypertensive efficacy and tolerability of the fixed combination of D + I in mild to moderate hypertension, and to compare its therapeutic efficacy and tolerability with that of L + H.Methods: The antihypertensive efficacy and tolerability of a fixed combination of D + I (30-mg + 2.5-mg tablets once daily) or L + H (20-mg + 12.5-mg tablets once daily) in patients with mild to moderate hypertension were compared in a multinational, multicenter, randomized, 2-armed, parallel-group study. Eligible patients were aged 18 to 75 years and had a diastolic blood pressure (DBP) 95 to 115 mm Hg and a systolic blood pressure (SBP) ≤180 mm Hg, both measured in the sitting position. After a single-blind, placebo run-in period of 2 weeks, patients were randomized to receive 1 of the 2 treatments for a 12-week period. The primary efficacy end point was the BP normalization rate (ie, the percentage of patients with a sitting DBP ≤90 mm Hg) after 12 weeks of treatment. Secondary end points were as follows: (1) the responder rate (ie, the percentage of patients whose sitting DBP was reduced by ≥10 mm Hg from baseline or had a DBP ≤90 mm Hg after 12 weeks of treatment), (2) the percentage of patients with a DBP ≤85 mm Hg, and (3) changes in sitting SBP and DBP after 4, 8, and 12 weeks of treatment.Results: A total of 159 hypertensive patients (88 women, 71 men) were randomized to receive D + I (44 women, 36 men; mean [SD] age, 53 [¹¹] years) or L + H (44 women, 35 men; mean [SD] age, 55 [¹⁰] years). No significant between-group differences were found in any of the primary or secondary end points of the study. Both combinations induced a significant reduction in sitting DBP and SBP from baseline (P<0.001 for both groups at week 12), without significant differences between the groups. Five mild to moderate adverse drug reactions (ADRs) occurred in each treatment group. No patient dropped out of the study because of an ADR.Conclusion: This study showed no difference between D + I and L + H interms of antihypertensive efficacy or tolerability in patients with mild to moderate hypertension.     

Effects of dibutyryl cyclic adenosine monophosphate on hypercapnic depression of diaphragmatic contractility in pentobarbital-anesthetized dogs

Background: Hypercapnia is associated with diaphragm muscle dysfunction that causes a reduction of diaphragmatic force generated for a constant elective myographic activity. No published data are available concerning hypercapnic depression of diaphragmatic contractility during dibutyryl cyclic adenosine monophospate (DBcAMP) administration.Objective: The aim of this study was to assess the effects of DBcAMP on hypercapnic depression of diaphragmatic contractility in pentobarbital-anesthetized dogs.Methods: This experimental study was conducted from July to December 2008 at the Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan. Adult (aged >5 years) mongrel dogs weighing 10 to 15 kg were randomly divided into 3 equal groups. Hypercapnia (80-90 mm Hg) was induced with 10% carbon dioxide added to the inspired gas. When hypercapnia was established, group 1 was infused with low-dose DBcAMP (0.05 mg/kg/min); group 2 was infused with high-dose DBcAMP (0.2 mg/kg/min); and group 3 received placebo (saline). Study drug was administered intravenously for 60 minutes. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi) at baseline, induction of hypercapnia, and study drug administration.Results: Twenty-one dogs were divided into 3 groups of 7. There were no significant differences observed at baseline. In the presence of hypercapnia, Pdi (mean [SD], cm H₂O) at low- (20-Hz) and high-frequency (100-Hz) stimulation was significantly decreased from baseline in each group (all, P = 0.001). In groups 1 and 2, Pdi at both stimuli was significantly increased during DBcAMP administration compared with hypercapnia-induced values (group 1: 20-Hz, 13.5 [2.2] vs 15.0 [2.4], respectively, P = 0.001, 100-Hz, 21.2 [1.6] vs 22.5 [1.6], P = 0.001; group 2: 20-Hz, 13.7 [1.4] vs 19.2 [1.7], P = 0.001, 100-Hz, 21.0 [2.4] vs 27.2 [2.5], P = 0.001). The Pdi at both stimuli during DBcAMP administration was significantly higher in group 2 than in group 1 (20-Hz, 19.2 [1.7] vs 15.0 [2.4], P = 0.001, 100-Hz, 27.2 [2.5] vs 22.5 [1.6], P = 0.003). In group 3, Pdi did not significantly change in regard to either stimulus from hypercapnia-induced values.Conclusion: DBcAMP, in a dose-dependent manner, was associated with improved hypercapnic depression of diaphragmatic contractility in these pentobarbital-anesthetized dogs.     

Effects of fosinopril on blood pressure, lipid profile, and lipoprotein(a) levels in normotensive patients with type 2 diabetes and microalbuminuria: An open-label, uncontrolled study

Background: Patients with type 2 diabetes mellitus often have other cardiovascular risk factors, and alterations in lipid profile play an important role. The angiotensin-converting enzyme inhibitors are often used in these patients, particularly those with type 2 diabetes and proteinuria.Objective: This study evaluated the effects of fosinopril therapy on fasting plasma glucose (FPG), lipid profile, and lipoprotein(a), or Lp(a), levels in normotensive patients with type 2 diabetes mellitus and microalbuminuria.Methods: Normotensive (systolic blood pressure [SBP] <130 mm Hg and diastolic blood pressure [DBP] <85 mm Hg) patients with type 2 diabetes and microalbuminuria and a normal lipid profile were enrolled. Patients had their diabetes controlled by diet alone or diet plus oral hypoglycemic agents. Fosinopril 10 mg/d was administered for 6 months and then interrupted for 1 month. FPG, glycosylated hemoglobin, SBP, DBP, lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), Lp(a), albumin excretion rate (AER), and creatinine levels were evaluated at baseline; 1, 3, and 6 months after initiation of treatment; and 1 month after interruption of treatment.Results: A total of 120 patients were enrolled (63 men, 57 women; mean age ± SD, 54 ± 10 years; duration of diabetes, 7 ± 2 years). Significant decreases versus baseline were observed in the following parameters at month 6: SBP (122 ± 7 vs 117 ± 9.1 mm Hg, P < 0.01), DBP (80 ± 4.8 vs 74 ± 4.5 mm Hg, P < 0.05), TC (186 ± 11 vs 176 ± 10 mg/dL, P < 0.05), LDL-C (124 ± 10 vs 114 ± 11 mg/dL, P < 0.05), Lp(a) (24 ± 10 vs 19 ± 7.5 mg/dL, P < 0.05), and AER (103 ± 45 vs 48 ± 21 mg/24 hours, P < 0.01). When fosinopril therapy was interrupted for 1 month, the values for all these parameters tended to return to baseline values; SBP, TC, and Lp(a) values were significantly different from month 6 values, whereas DBP, LDL-C, and AER did not change significantly during the washout period.Conclusions: Fosinopril therapy for 6 months resulted in a reduction of microalbuminuria and an improvement in lipid profile and Lp(a) levels in patients with type 2 diabetes. This suggests that fosinopril may improve lipid profile and reduce Lp(a) levels by lowering proteinuria or by other more direct actions on lipid and Lp(a) metabolism. Additional controlled studies are needed to confirm these results.     

Irbesartan monotherapy in systemic hypertension: An open-label, uncontrolled trial

Background: Irbesartan is an orally active, specific blocker of the AT₁ receptor of angiotensin II that produces insurmountable antagonism. Irbesartan's plasma half-life of 11 to 15 hours and higher affinity for the AT₁ receptor versus other angiotensin II receptor subtypes may make it a suitable choice for once-daily treatment of hypertension. Few studies have examined the efficacy of this agent in Asian patients.Objective: The purpose of this open-label, uncontrolled study was to assess the 24-hour efficacy of irbesartan once-daily monotherapy in Chinese outpatients with mild to moderate hypertension.Methods: Patients with stage I or stage II hypertension (as defined by the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) were treated with irbesartan once daily for 6 to 8 weeks. The dose of irbesartan was titrated from an initial dose of 150 mg to 275 mg or 300 mg if adequate blood pressure (BP) control was not achieved by week 3 or 4; doses were taken once daily between 8 am and 9 am. For each patient, 24-hour ambulatory BP monitoring was performed twice, once before and once after 6 to 8 weeks of treatment.Results: A total of 25 patients (mean age, 54 years) were enrolled; 24 completed the study. Mean 24-hour systolic/diastolic BP after irbesartan treatment was significantly decreased compared with baseline values (128 ± 14 mm Hg/82 ± 8 mm Hg vs 143 ± 12 mm Hg/91 ± 7 mm Hg, P < 0.05 for both). The mean final dose of irbesartan was 243.8 ± 63.5 mg daily after a 7-week titration period. Mean daytime (6 am to 6 pm) BP decreased from 146 ± 11 mm Hg/94 ± 7 mm Hg to 130 ± 14 mm Hg/84 ± 8 mm Hg (P < 0.05), and nighttime (6 pm to 6 am) BP decreased from 139 ± 14 mm Hg/88 ± 7 mm Hg to 127 ± 15 mm Hg/81 ± 9 mm Hg (P < 0.05). The BP decrease was more pronounced during the day. Before treatment, the circadian variation showed a peak BP at 11 am and a nadir at 4 am. After treatment, significant BP reductions versus baseline (P < 0.05 for both diastolic and systolic BP) were observed for 23 of the 24 hourly mean points. The circadian rhythm of BP cycles was preserved. Mean heart rate did not change after treatment. Two patients reported dizziness and 1 reported heartburn.Conclusions: Irbesartan administered as once-daily monotherapy provided effective BP control during 23 of the 24 hourly mean points while preserving the circadian rhythm of BP cycles, and was well tolerated.     

Olmesartan compared with other angiotensin II receptor antagonists: Head-to-head trials

Background: Drugs that block the renin-angiotensin system represent one of the most significant therapeutic interventions available for the treatment of hypertension. The angiotensin II receptor antagonists (AIIRAs), also known as sartans, are one such class of drugs that block the effects of angiotensin II by antagonizing the angiotensin II type 1 receptor. Olmesartan is the newest member of this class.Objective: The present article reviews 3 head-to-head trials directly comparing the antihypertensive efficacy of olmesartan with that of 4 other AURAS, at recommended maintenance doses, already in clinical use for the treatment of hypertension.Results: In the first study, olmesartan 10 mg/d was compared with losartan 50 mg/d in 316 patients with mild to moderate hypertension (mean baseline diastolic blood pressure [DBP], 95–114 mm Hg). Dosage was doubled at week 4 and hydrochlorothiazide was added at week 12 if blood pressure response was inadequate. Olmesartan was significantly more effective than losartan with respect to the reduction in blood pressure at weeks 2, 4, and 12, and to the responder rate at weeks 2 and 4 (with the starting dose of the respective drug). In a second study, olmesartan 20 mg/d was shown to be significantly more effective than losartan 50 mg/d, valsartan 80 mg/d, and irbesartan 150 mg/d in 588 patients with mild to moderate hypertension (mean sitting baseline DBP, 100–115 mm Hg) (P ⩽ 0.05). At week 2, the reduction in blood pressure observed with olmesartan was significantly greater than that of the comparator treatments (P ⩽ 0.05). The superiority of olmesartan was maintained at week 8. The third study involved 643 evaluable patients with moderate to severe hypertension (mean DBP, 100–120 mm Hg; mean systolic blood pressure, >150 mm Hg). Olmesartan 20 mg/d was more effective than candesartan 8 mg/d in lowering 24-hour blood pressure at week 8 (P ⩽ 0.05). Most of this treatment effect was evident after only 1 or 2 weeks, with greater reductions in blood pressure compared with candesartan.Conclusions: These data indicate that, at the doses studied, olmesartan is more effective than other AIIRAs tested at their recommended doses, in terms of reduction of cuff or 24-hour ambulatory blood pressure, in patients with essential hypertension. These differences in blood pressure reduction between these agents may be clinically relevant and have important long-term implications. Additional studies will further define the role of olmesartan in the management of cardiovascular diseases, such as atherosclerosis.     

Effects of Fluvastatin on Plasma Levels of Low-Density Lipoprotein Subfractions, Oxidized Low-Density Lipoprotein, and Soluble Adhesion Molecules: A Twenty-Four-Week, Open-Label, Dose-Increasing Study

Background: Statins not only lower low-density lipoprotein (LDL) levels, but also have several antiarteriosclerotic effects (eg, decreasing arterial inflammation and arterial smooth muscle cell proliferation, as well as antioxidant effects). The relationship between the dose of statin and its effects on plasma LDL levels and other arteriosclerosis-related effects remains to be clarified.Objective: We investigated the effect of a statin, fluvastatin, on plasma levels of lipoprotein subfractions, oxidized LDL (Ox-LDL), Ox-LDL immunoglobulin G (IgG), soluble adhesion molecules, reverse cholesterol transport (ie, transport of esterified high-density lipoprotein cholesterol [HDL-C] to triglyceride [TG]-rich lipoproteins by cholesteryl ester transfer protein [CETP] and reduction of plasma HDL-C levels), and on the intima-medial thickness (IMT) of the common carotid arteries.Methods: Patients with nonfamilial type 2 hyperlipoproteinemia were eligible for this open-label, dose-increasing study. Fluvastatin 20 mg/d was administered for the first 12 weeks, and the daily dose was increased to 40 mg for the subsequent 12 weeks. Patients were examined at baseline and after 12 and 24 weeks of treatment. Plasma lipoprotein subfractions were determined using sequential ultracentrifugation at 100,000g. The plasma levels of Ox-LDL, Ox-LDL-IgG, CETP, and soluble adhesion molecules were measured using sandwich enzyme-linked immunosorbent assay. The maximum IMT of the common carotid arteries was measured using sonography.Results: The plasma levels of LDL cholesterol (LDL-C) and apolipoprotein (apo) B were reduced by 25% and 17%, respectively (P<0.001 for both), after 12 weeks of treatment with fluvastatin 20 mg/d; no further significant reductions in LDL were observed after increasing the daily dose to 40 mg. Fluvastatin 20 mg/d for 12 weeks decreased plasma levels of intermediate-density lipoprotein cholesterol, LDL-I-C, LDL-II-C, and LDL-III-C by 25% (P<0.01), 30% (P<0.001), 23% (P<0.01), and 20% (P = 0.02), respectively. No further significant reductions in these levels were observed after increasing the daily dose to 40 mg. The plasma levels of Ox-LDL decreased in a similar fashion to the plasma levels of LDL-C (P<0.001). However, plasma levels of Ox-LDL-IgG and soluble P-selectin did not decrease after 12 weeks of fluvastatin 20 mg/d, but did decrease significantly (both 22%) after the next 12 weeks of treatment with fluvastatin 40 mg/d (P<0.05). Plasma levels of intercellular adhesion molecule 1and vascular cell adhesion molecule 1 and CETP mass were not altered by fluvastatin treatment. Significant changes in maximum IMT of the common carotid arteries were not seen throughout 24 weeks of fluvastatin treatment.Conclusions: In this patient population, fluvastatin 20 mg/d was sufficient to significantly reduce plasma levels of LDL, the 3 LDL subfractions, and Ox-LDL, but was not sufficient to reduce plasma levels of Ox-LDL-IgG and soluble P-selectin. It is important to check not only plasma lipoprotein levels but also other factors relating to arteriosclerosis during treatment with statins for the prevention and treatment of arteriosclerosis.