Combination pravastatin and valsartan treatment has additive beneficial effects to simultaneously improve both metabolic and cardiovascular phenotypes beyond that of monotherapy with either drug in patients with primary hypercholesterolemia.

Statin and angiotensin II type 1 receptor blocker therapy improves endothelial dysfunction using distinct mechanisms. We evaluated simultaneous vascular and metabolic responses to pravastatin and valsartan therapy, alone or in combination, in hypercholesterolemic patients. Forty-eight hypercholesterolemic patients (23 had metabolic syndrome) were given pravastatin 40 mg and placebo, pravastatin 40 mg and valsartan 160 mg, or valsartan 160 mg and placebo daily during each 2-month treatment period in a randomized, single-blind, placebo-controlled, crossover trial with three treatment arms and two washout periods (each 2 months). Brachial artery flow-mediated dilation and C-reactive protein improved to a greater extent with combined therapy compared with either monotherapy. Importantly, we also observed simultaneous improvement in metabolic phenotypes, with all three treatments causing increased plasma adiponectin levels, reduced fasting insulin levels, and increased insulin sensitivity relative to baseline measurements. For the first time in a statin combination trial, pravastatin combined with valsartan therapy increased plasma adiponectin, lowered fasting insulin levels, and improved insulin sensitivity in an additive manner when compared with monotherapy alone. In contrast to other statins, hydrophilic pavastatin may be combined with other drugs to safely reach lipid target levels while simultaneously improving the metabolic and cardiovascular phenotype of patients at high risk.

RCT Entities:   Population Interventions Outcomes

Hypercholesterolemia and hypertension are major public health problems that are frequently treated with statins and angiotensin II type 1 receptor blockers, respectively. Although the mechanisms of action for these two classes of drugs differ, both classes have beneficial effects on the vasculature by reducing LDL cholesterol and blood pressure, respectively (1,2).

Hypercholesterolemia and hypertension are frequently associated with insulin resistance and disorders of metabolic homeostasis such as obesity and type 2 diabetes mellitus. The endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance and the pathophysiology of diabetes and its vascular complications (3). However, it has recently been recognized that statin therapy, one of the mainstays of treatment for hypercholesterolemia that reduces coronary heart disease and atherosclerosis, may have adverse consequences for glucose homeostasis, such as increased risk for diabetes and insulin resistance (4). This is particularly problematic from a therapeutic standpoint, since the presence of diabetes and insulin resistance increases the risk for cardiovascular diseases including coronary heart disease (5) and cancer mortality (6). Indeed, simvastatin and atorvastatin worsened insulin sensitivity by decreasing adiponectin levels despite improvement in endothelial function (7,8). Therefore, we did not observe additive metabolic improvement with combination therapy in hypercholesterolemic patients. Since pravastatin may differ from other statins in that it is nonlipophilic and has beneficial effects on metabolic phenotypes (4,9,10), we reasoned that a combination trial of pravastatin plus valsartan may cause simultaneous additive benefit to both endothelial function and metabolic phenotypes that are greater than those observed with either pravastatin or valsartan therapy alone in hypercholesterolemic patients.

RESEARCH DESIGN AND METHODS

Study population and design.

Fifty-one hypercholesterolemic patients (LDL cholesterol levels ≥130 mg/dL) participated in this study. We excluded patients with overt liver disease, chronic renal failure, uncontrolled diabetes (HbA1c >9% or 75 mmol/mol), severe hypertension, or alcohol abuse. A research nurse counted pills at the end of treatment to monitor compliance. In order to minimize acute side effects to valsartan, study medication was titrated from 80 to 160 mg upwards over a 2-week period. Two patients were hypotensive, and the other one suffered from dry cough. Thus, data from a total of 48 patients were analyzed. Patients were randomly assigned to one of the three treatments: pravastatin 40 mg and placebo, pravastatin 40 mg and valsartan 160 mg, or valsartan 160 mg and placebo daily during 2 months. This study design was randomized, single-blind, placebo-controlled, with three treatment arms (each 2 months), and crossover with two washout periods (each 2 months). Allocation concealment was achieved by using envelopes with the collaboration of a statistician. Twenty-three patients among 48 had metabolic syndrome (11). The study was approved by the Gil Hospital Institute Review Board, and all participants gave written, informed consent.

Laboratory assays.

Blood samples for laboratory assays were obtained at ∼8:00 a.m. following overnight fasting before and at the end of each 2-month treatment period. Assays for lipids, glucose, and plasma adiponectin were performed in duplicate by ELISA (R&D Systems, Minneapolis, MN), assays for high-sensitivity C-reactive protein (hsCRP) levels by latex agglutination [CRP-Latex(II); Denka-Seiken, Tokyo, Japan] and assays for plasma insulin levels by immunoradiometric assay (Insulin Riabead II; SRL, Inc, Tokyo, Japan) and assays for HbA1c by high performance liquid chromatography assay (VARIANT II TURBO; Bio-Rad, Hercules, CA) as previously described (7–9,12–14). The interassay and intra-assay coefficients of variation were <6%. Quantitative Insulin-Sensitivity Check Index (QUICKI) was calculated (15,16). Imaging studies of the right brachial artery were performed using an ATL HDI 3000 ultrasound machine (ATL Philips, Bothell, WA) equipped with a 10-MHz linear-array transducer, based on a previously published technique (7–9,12–14). The intraobserver variability for repeated measurement of maximum diameter was 0.01 ± 0.06 mm. The intraobserver variability for repeated measurement of percent flow-mediated dilation (FMD) was 0.13 ± 1.33%.

Statistical analysis.

Data are expressed as mean ± SEM or median (range 25–75%). After testing data for normality, we used the Student paired t or Wilcoxon signed-rank test to compare values before and after each treatment and the relative changes in values in response to treatment, as reported in Tables 1 and 2. The effects of the three therapies were analyzed by one-way repeated-measures ANOVA or Friedman repeated ANOVA on ranks. Post hoc comparisons, Pearson, or Spearman correlation coefficient analysis was used. We calculated that 40 subjects would provide 80% power for detecting an absolute increase of ≥1.7% in FMD between baseline and pravastatin, with α = 0.05 based on our previous studies (9). The comparison of endothelium-dependent dilation among the three treatment schemes was prospectively designated as the primary end point of the study. All other comparisons were considered secondary. A value of P < 0.05 was considered to be statistically significant.

TABLE 1

Effects of pravastatin, combination, and valsartan in 48 hypercholesterolemic patients

TABLE 2

Effects of pravastatin, combination, and valsartan in 23 hypercholesterolemic patients with metabolic syndrome

RESULTS

No significant differences among baseline values were noted in any of the parameters measured (Tables 1 and 2). There was no carryover effect from one treatment period to the next treatment period.

Effects of therapies on blood pressure and lipids.

Valsartan alone or combined therapy significantly reduced systolic and diastolic blood pressure after 2 months' administration when compared with baseline. These reductions were significantly greater than those observed with pravastatin alone (P < 0.05 by ANOVA). However, there were no significant differences between valsartan alone and combined therapy for these parameters (Table 1). Pravastatin alone or combined therapy significantly lowered total cholesterol (both P < 0.001), triglycerides (both P < 0.05), LDL cholesterol (both P < 0.001), and apolipoprotein B levels (both P < 0.001) when compared with baseline. These reductions were significantly greater than those observed with valsartan alone (P < 0.05 by ANOVA). However, there were no significant differences between pravastatin alone and combined therapy for these parameters (Table 1).

Effects of therapies on vasomotor function and marker of inflammation.

Pravastatin, combined therapy, or valsartan significantly improved the percent FMD relative to baseline measurements by 37 ± 2, 47 ± 3, and 32 ± 2%, respectively (all P < 0.001); however, combined therapy significantly improved this response more than pravastatin or valsartan alone (P < 0.001 by ANOVA; Fig. 1 and Table 1). Pravastatin, combined therapy, or valsartan lowered plasma hsCRP levels relative to baseline measurements from 0.85 to 0.60 (P < 0.001), 1.00 to 0.65 (P < 0.001), and 1.10 to 0.80 mg/L (P = 0.158), respectively; however, combined therapy significantly lowered plasma hsCRP levels more than pravastatin or valsartan alone (P = 0.019 by ANOVA on ranks; Fig. 1 and Table 1).

FIG. 1.

Percent change in flow-mediated dilation (left) and percent change in hsCRP levels (right) from respective pretreatment values after treatment with pravastatin alone, combined therapy, and valsartan alone (the median was zero for valsartan). Mean with SEM (left) or median (right) values are provided.

Effects of therapies on adiponectin and insulin resistance.

Pravastatin, combined therapy, or valsartan significantly increased the plasma adiponectin levels relative to baseline measurements from 2.97 to 3.38 (P = 0.007), 2.81 to 3.73 (P < 0.001), and 2.96 to 3.45 μg/mL (P = 0.002), respectively. Of note, combined therapy significantly increased the plasma adiponectin levels more than pravastatin or valsartan alone in an additive fashion (P = 0.003 by ANOVA on ranks; Fig. 2 and Table 1). Pravastatin, combined therapy, or valsartan lowered plasma insulin levels relative to baseline measurements from 10.90 to 9.35 (P = 0.012), 10.16 to 7.78 (P < 0.001), and 9.62 to 8.67 μU/mL (P = 0.103), respectively; however, combined therapy significantly lowered plasma insulin levels more than pravastatin or valsartan alone (P = 0.049 by ANOVA on ranks; Fig. 2 and Table 1). Pravastatin, combined therapy, or valsartan significantly increased QUICKI relative to baseline measurements by 3 ± 1 (P = 0.020), 6 ± 1 (P < 0.001), and 2 ± 1% (P = 0.053), respectively. Of note, combined therapy significantly increased QUICKI more than pravastatin or valsartan alone (P = 0.049 by ANOVA; Fig. 2 and Table 1). The three therapies did not significantly change fasting glucose or HbA1c levels relative to baseline measurements.

FIG. 2.

Percent change in adiponectin levels (A), percent change in insulin levels (B), and percent change in QUICKI (C) from respective pretreatment values after treatment with pravastatin alone, combined therapy, and valsartan alone. Median values (A and B) or mean with SEM (C) are provided.

There were correlations between percent changes in adiponectin levels and percent changes in QUICKI (r = 0.521, P < 0.001 after pravastatin; r = 0.437, P = 0.002 after combined therapy; and r = 0.297, P = 0.040 after valsartan). There were inverse correlations between percent changes in adiponectin levels and percent changes in insulin levels (r = −0.284, P = 0.050 after pravastatin; r = −0.373, P = 0.009 after combined therapy; and r = −0.258, P = 0.077 after valsartan).

We investigated whether pravastatin- or valsartan-induced changes in the percent FMD, serological markers of inflammation, and insulin resistance were mediated by changes of lipoprotein or blood pressure levels. There were no significant correlations. Of note, following combined therapy, improvement in FMD correlated with changes in QUICKI (r = 0.397; P = 0.005) and insulin levels (r = −0.292; P = 0.040).

Effects of therapies in patients with metabolic syndrome.

We analyzed 23 patients with metabolic syndrome, as reported in Table 2. Overall, compared with the effects of each therapy in 48 hypercholesterolemic patients, we observed similar results in 23 patients with metabolic syndrome. When compared with baseline, all three treatment arms improved endothelial dysfunction as assessed by FMD. Of note, FMD improved to a greater extent with combined therapy versus either monotherapy (P = 0.008 by ANOVA). Combined therapy reduced hsCRP levels compared with valsartan therapy (P = 0.003 by ANOVA). We also observed simultaneous improvement in metabolic phenotypes, with combined therapy causing increased plasma adiponectin levels, reduced fasting plasma insulin levels, and increased insulin sensitivity in an additive manner when compared with either monotherapy alone (P = 0.009, P = 0.065, and P = 0.070 by ANOVA on ranks, respectively). Following combined therapy, improvement in FMD correlated with changes in QUICKI (r = 0.499; P = 0.015) and insulin levels (r = −0.480; P = 0.021).

DISCUSSION

In our hypercholesterolemic cohort, pravastatin therapy alone significantly improved the lipid profile, while valsartan therapy alone significantly lowered blood pressure. Comparable beneficial effects on both lipids and blood pressure were observed with combination therapy. We reasoned that distinct biological actions of pravastatin and valsartan therapies on lipoproteins and the angiotensin system may improve endothelium-dependent vascular function by different mechanisms. Indeed, while monotherapy with pravastatin or valsartan improved endothelial function and inflammatory markers (assessed by FMD and hsCRP levels), combined therapy had additional significant beneficial effects on these parameters over those seen with monotherapy for either drug.

In all of our previous intervention studies combining simvastatin or atorvastatin with losartan, ramipril or fenofibrate, we observed beneficial additive effects on endothelial function but not on metabolic parameters (12–14). We reasoned that these results may be explained by direct adverse metabolic consequences of these statins that masked the beneficial metabolic effects expected from improved endothelial function (2–4). Indeed, in head-to-head comparisons of simvastatin or rosuvastatin with pravastatin at equal lipid-lowering doses, we observed effects of simvastatin and rosuvastatin to worsen insulin resistance and related metabolic parameters, while pravastatin had beneficial metabolic actions to lower fasting insulin levels, increase adiponectin levels, and improve insulin sensitivity (9,17). Moreover, therapy with high-dose atorvastatin causes glucose intolerance (8). Our small clinical intervention studies are consistent with larger multicenter outcome studies that suggest most statins, except for pravastatin, cause an increase in the incidence of new onset diabetes (10,18,19). This has recently led to the Food and Drug Administration requiring a label warning for statins regarding the increased risk of diabetes. Thus, we reasoned that combination therapy of pravastatin with valsartan would result in simultaneous additive beneficial effects on both cardiovascular and metabolic parameters that was lacking in our previous statin combination intervention studies.

Recent large-scale clinical studies and meta-analyses have demonstrated that some statins, particularly at high dose, increase the rate of new-onset diabetes (10,20–22). Pravastatin would not suffer from this potential downside. Pravastatin retarded the progression of glucose intolerance in diabetes model (23). Pravastatin enhances adiponectin secretion from 3T3-L1 adipocytes and causes an increase in adiponectin mRNA and plasma adiponectin levels with enhanced insulin sensitivity (24). Indeed, pravastatin significantly increases plasma adiponectin levels and insulin sensitivity in hypercholesterolemic patients (9,17).

In the current study, we observed correlations between percent changes in adiponectin levels and percent changes in QUICKI and inverse correlations between percent changes in adiponectin levels and percent changes in insulin levels following each therapy. We also observed significant correlations between improvement in FMD and changes in QUICKI and insulin levels following combined therapy. We observed similar results in a subgroup of 23 patients with the metabolic syndrome. Thus, our study may have the same implication for the treatment of patients with the metabolic syndrome.

One caveat in the use of pravastatin for lipid treatment is that it has weaker lipid-lowering effects than other lipophilic statins. Thus, other statins tend to save lives even in diabetic populations. However, one wonders whether even more lives might be saved if lipid targets could be reached without causing diabetes or even diminishing diabetes (2,4,25).

In summary, our study demonstrates for the first time that a combination trial with a statin (pravastatin) and valsartan simultaneously improved endothelial function and insulin sensitivity to a greater extent than monotherapy in hypercholesterolemic patients. This may be due to combined effects of the respective monotherapy to improve lipid profile, blood pressure, endothelial function, adiponectin levels, and insulin sensitivity.