Eak Kyun Shin

Additive Beneficial Effects of Losartan Combined With Simvastatin in the Treatment of Hypercholesterolemic, Hypertensive Patients

Background—Biological mechanisms underlying statin and angiotensin II type 1 receptor blocker therapies differ. Therefore, we compared vascular and metabolic responses to these therapies either alone or in combination in hypercholesterolemic, hypertensive patients. Methods and Results—This was a randomized, double-blind, placebo-controlled crossover trial with 3 treatment arms (each 2 months) and 2 washout periods (each 2 months). Forty-seven hypertensive, hypercholesterolemic patients were given simvastatin 20 mg and placebo, simvastatin 20 mg and losartan 100 mg, or losartan 100 mg and placebo daily during each 2-month treatment period. Losartan alone or combined therapy significantly reduced blood pressure compared with simvastatin alone. Compared with losartan alone, simvastatin alone or combined therapy significantly changed lipoproteins. All 3 treatment arms significantly improved flow-mediated dilator response to hyperemia and decreased plasma malondialdehyde and monocyte chemoattractant protein-1 levels relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy compared with simvastatin or losartan alone (both P<0.001 and P=0.030 for monocyte chemoattractant protein-1 by ANOVA). Combined therapy or losartan alone significantly increased plasma adiponectin levels and insulin sensitivity (determined by QUICKI) relative to baseline measurements. These changes were significantly greater than in the group treated with simvastatin alone (P<0.001 for adiponectin, P=0.029 for QUICKI by ANOVA). Conclusions—Simvastatin combined with losartan improves endothelial function and reduces inflammatory markers to a greater extent than monotherapy with either drug in hypercholesterolemic, hypertensive patients.

Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients.

OBJECTIVES We investigated the vascular effects of candesartan in hypertensive patients. BACKGROUND The renin-angiotensin system may contribute to atherogenesis through the promotion of endothelial dysfunction. The plausible mechanisms are that angiotensin II promotes superoxide anion generation, endothelial dysfunction, inflammation, and impaired fibrinolysis. The effects of candesartan on these conditions have not been clearly observed. METHODS We administered placebo or candesartan 16 mg daily during two months to 45 patients with mild-to-moderate hypertension. This was a randomized, double-blind, placebo-controlled, crossover study in design. RESULTS Candesartan did not significantly change lipoprotein levels. However, compared with placebo, candesartan significantly reduced plasma levels of malondialdehyde from 1.50 +/- 0.07 to 1.29 +/- 0.09 microM (p = 0.009); improved the percent flow-mediated dilator response to hyperemia from 5.17 +/- 0.24 to 6.22 +/- 0.26% (p < 0.001); and, furthermore, reduced plasma levels of monocyte chemoattractant protein (MCP-1) from 213 +/- 8 to 190 +/- 7 pg/ml (p = 0.003), tumor necrosis factor-alpha from 2.93 to 2.22 pg/ml (p = 0.026), and plasminogen activator inhibitor type 1 from 74 +/- 4 to 53 +/- 4 ng/ml (p < 0.001) but not C-reactive protein (CRP), matrix metalloproteinase protein, and fibrinogen. There were no significant correlations between these changes and reduction of systolic blood pressure (BP) (-0.247 < or = r < or = 0.195) and between these changes and reduction of diastolic BP (-0.262 < or = r < or = 0.197). There were no significant correlations between markers of inflammation and flow-mediated dilation percent or reduction of oxidant stress (-0.119 < or = r < or = 0.127). Furthermore, we observed no significant correlations between CRP and MCP-1 levels (r = -0.162). CONCLUSIONS Inhibition of the angiotensin II type 1 (AT1) receptor in hypertensive patients reverses endothelial dysfunction, measured as an improvement in flow-mediated dilation and fibrinolysis and reduction of oxidant stress and inflammatory cytokines, suggesting that AT1 receptor blocker therapy has antiatherogenic effects.

Atorvastatin Causes Insulin Resistance and Increases Ambient Glycemia in Hypercholesterolemic Patients

OBJECTIVES We investigated whether atorvastatin might decrease insulin sensitivity and increase ambient glycemia in hypercholesterolemic patients. BACKGROUND Clinical trials suggest that some statin treatments might increase the incidence of diabetes despite reductions in low-density lipoprotein (LDL) cholesterol and improvement in endothelial dysfunction. METHODS A randomized, single-blind, placebo-controlled parallel study was conducted in 44 patients taking placebo and in 42, 44, 43, and 40 patients given daily atorvastatin 10, 20, 40, and 80 mg, respectively, during a 2-month treatment period. RESULTS Atorvastatin 10, 20, 40, and 80 mg significantly reduced LDL cholesterol (39%, 47%, 52%, and 56%, respectively) and apolipoprotein B levels (33%, 37%, 42%, and 46%, respectively) after 2 months of therapy when compared with either baseline (all p < 0.001 by paired t test) or placebo (p < 0.001 by analysis of variance [ANOVA]). Atorvastatin 10, 20, 40, and 80 mg significantly increased fasting plasma insulin (mean changes: 25%, 42%, 31%, and 45%, respectively) and glycated hemoglobin levels (2%, 5%, 5%, and 5%, respectively) when compared with either baseline (all p < 0.05 by paired t test) or placebo (p = 0.009 for insulin and p = 0.008 for glycated hemoglobin by ANOVA). Atorvastatin 10, 20, 40, and 80 mg decreased insulin sensitivity (1%, 3%, 3%, and 4%, respectively) when compared with either baseline (p = 0.312, p = 0.008, p < 0.001, and p = 0.008, respectively, by paired t test) or placebo (p = 0.033 by ANOVA). CONCLUSIONS Despite beneficial reductions in LDL cholesterol and apolipoprotein B, atorvastatin treatment resulted in significant increases in fasting insulin and glycated hemoglobin levels consistent with insulin resistance and increased ambient glycemia in hypercholesterolemic patients. (Effects of Atorvastatin on Adiponectin Levels and Insulin Sensitivity In Hypercholesterolemic Patients; NCT00745836).

Vascular Effects of Synthetic or Natural Progestagen Combined With Conjugated Equine Estrogen in Healthy Postmenopausal Women

BackgroundSynthetic, not natural, progestagen may negate the favorable effects of estrogen. Nonetheless, observational studies report no differences in risk for clinical cardiovascular events between users of unopposed estrogen and users of estrogen combined with synthetic progestin. Methods and ResultsIn a double-blind study, we randomly assigned 20 healthy postmenopausal women to micronized progesterone (MP) 200 mg or medroxyprogesterone acetate (MPA) 10 mg for 10 days with conjugated equine estrogen (CEE) 0.625 mg for 25 days and the remaining 5 days off cyclically during 2 months, followed by crossover to the alternate therapy. CEE+MP and CEE+MPA significantly improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements (P =0.004 by ANOVA) by a similar degree (P =0.863). Both therapies significantly decreased E-selectin, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 levels from baseline values (P <0.001, P =0.048, and P =0.016 by ANOVA, respectively) by a similar degree (P =0.977 for ICAM-1 and P =0.541 for VCAM-1, respectively). CEE+MPA decreased E-selectin levels more than CEE+MP did (P =0.040). Both therapies significantly decreased monocyte chemoattractant protein-1 levels from baseline values (P <0.005 by ANOVA) by a similar degree (P =0.194). Both therapies significantly decreased tissue factor antigen and increased tissue factor activity levels from baseline values (P =0.003 and P <0.001 by ANOVA, respectively) by a similar degree (P =0.652 for antigen and P =0.173 for activity). Both therapies significantly lowered plasma plasminogen activator inhibitor-1 levels from baseline values (P <0.001 by ANOVA) by a similar degree (P =0.533). ConclusionsCEE+MP and CEE+MPA provide similar improvement in endothelium-dependent vasodilator responsiveness and effects on markers of inflammation, hemostasis, and fibrinolysis inhibition in healthy postmenopausal women.

Vascular and Metabolic Effects of Combined Therapy With Ramipril and Simvastatin in Patients With Type 2 Diabetes

Mechanisms underlying biological effects of statin and angiotensin-converting enzyme inhibitor therapies differ. Therefore, we compared vascular and metabolic responses to these therapies either alone or in combination in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled crossover trial with 3 treatment arms (each 2 months) and 2 washout periods (each 2 months). Fifty patients with type 2 diabetes were given simvastatin 20 mg and placebo, simvastatin 20 mg and ramipril 10 mg, or ramipril 10 mg and placebo daily during each 2-month treatment period. Ramipril alone or combined therapy significantly reduced blood pressure when compared with simvastatin alone. When compared with ramipril alone, simvastatin alone or combined therapy significantly improved the lipoprotein profile. All 3 treatment arms significantly improved flow-mediated dilator response to hyperemia and reduced plasma levels of malondialdehyde relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy when compared with simvastatin or ramipril alone (P<0.001 by ANOVA). When compared with simvastatin or ramipril alone, combined therapy significantly reduced high-sensitivity C-reactive protein levels (P=0.004 by ANOVA). Interestingly, combined therapy or ramipril alone significantly increased plasma adiponectin levels and insulin sensitivity relative to baseline measurements. These changes were significantly greater than in the group treated with simvastatin alone (P<0.015 by ANOVA). Ramipril combined with simvastatin had beneficial vascular and metabolic effects when compared with monotherapy in patients with type 2 diabetes.

Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients.

BACKGROUND Lipophilic and hydrophilic statins have different effects on adiponectin and insulin resistance in experimental studies and different effects on the rate of onset of new diabetes in large scale clinical studies. Therefore, we hypothesized that simvastatin and pravastatin may have differential metabolic effects in hypercholesterolemic patients. METHODS This was a randomized, single-blind, placebo-controlled, parallel study. Age, gender, and body mass index were matched. Forty-three patients were given placebo, simvastatin 20mg, or pravastatin 40 mg, respectively once daily for 2 months. RESULTS Simvastatin and pravastatin therapy significantly changed lipoprotein levels and improved flow-mediated dilation after 2 months when compared with baseline (P<0.001) or placebo treatment (P<0.001 by ANOVA). Simvastatin therapy significantly increased insulin levels (mean % changes; 127%, P=0.014) and decreased plasma adiponectin levels (10%, P=0.012) and insulin sensitivity as assessed by QUICKI (6%, P=0.007) when compared with baseline. By contrast, pravastatin therapy did not significantly change insulin levels (-3%, P=0.437) but significantly increased plasma adiponectin levels (9%, P=0.011) and insulin sensitivity (6%, P=0.008) when compared with baseline. In addition, these effects of simvastatin were significant when compared with pravastatin (P<0.001 for insulin levels by ANOVA on Ranks, P<0.001 for adiponectin and P=0.001 for QUICKI by ANOVA). When compared with baseline, simvastatin significantly increased plasma leptin levels (35%, P=0.028), but pravastatin did not (1%, P=0.822). CONCLUSIONS Despite causing comparable changes in lipoprotein and endothelium-dependent dilation, simvastatin and pravastatin therapy had differential metabolic effects in hypercholesterolemic patients that may be clinically relevant.

Antiatherosclerotic and Anti-Insulin Resistance Effects of Adiponectin: Basic and Clinical Studies

Adiponectin is a protein secreted by adipose cells that may couple regulation of insulin sensitivity with energy metabolism and serve to link obesity with insulin resistance. Obesity-related disorders characterized by insulin resistance including the metabolic syndrome, diabetes, atherosclerosis, hypertension, and coronary artery disease are associated with both decreased adiponectin levels and endothelial dysfunction. Recent studies demonstrate that adiponectin has insulin-sensitizing effects as well as antiatherogenic properties. Lifestyle modifications and some drug therapies to treat atherosclerosis, hypertension, diabetes, and coronary heart disease have important effects in increasing adiponectin levels, decreasing insulin resistance, and improving endothelial dysfunction. In this review, we discuss insights into the relationships between adiponectin levels, insulin resistance, and endothelial dysfunction that are derived from various therapeutic interventions. The effects of lifestyle modifications and cardiovascular drugs on adiponectin levels and insulin resistance suggest plausible mechanisms that may be important for understanding and treating atherosclerosis and coronary heart disease.

Distinct vascular and metabolic effects of different classes of anti-hypertensive drugs

BACKGROUND ASCOT-BPLA study demonstrates that in hypertensive subjects, atenolol+bendroflumethiazide therapy is associated with higher incidence of adverse cardiovascular outcomes and developing diabetes than an amlodipine+perindopril regimen. This is not explained by changes in blood pressure alone. We hypothesized that distinct vascular and metabolic effects of anti-hypertensive drugs may explain these differential effects. METHODS Either placebo or one class of anti-hypertensive drug (atenolol 100 mg, amlodipine 10 mg, hydrochlorothiazide 50 mg, ramipril 10 mg, or candesartan 16 mg) was given daily during 8 weeks to 31 patients in each of 6 arms of a randomized, single-blind, placebo-controlled, parallel study. RESULTS Atenolol, amlodipine, and candesartan therapies significantly reduced systolic blood pressure when compared with ramipril (P<0.05 by ANOVA). Atenolol and thiazide therapies increased triglycerides levels greater than ramipril or candesartan (P=0.005 by ANOVA). Amlodipine significantly increased HDL cholesterol levels greater than atenolol (P=0.011 by ANOVA). Ramipril and candesartan therapies improved FMD and increased adiponectin levels and insulin sensitivity to a greater extent than atenolol or thiazide therapies (P<0.001 and P<0.015 by ANOVA). Amlodipine therapy increased adiponectin levels greater than atenolol therapy (P<0.05 by ANOVA). Ramipril, candesartan, and amlodipine therapies significantly decreased leptin levels to a greater extent when compared with atenolol or thiazide therapies (P<0.001 by ANOVA). Amlodipine therapies significantly decreased resistin levels greater than ramipril or candesartan therapies (P=0.001 by ANOVA). CONCLUSIONS We observed differential effects of anti-hypertensive drugs on endothelial dysfunction and plasma adipocytokines.

Effects of Conventional or Lower Doses of Hormone Replacement Therapy in Postmenopausal Women

Objective—The effects of hormone replacement therapy (HRT) can affect many aspects relevant to cardiovascular disease, including vasomotor function, inflammation, and hemostasis. Recent studies have demonstrated that current doses of HRT exert a mixture of both protective and adverse effects. In the current study, we compared the effects of lower doses of HRT (L-HRT) and conventional doses of HRT (C-HRT) on a variety of relevant cardiovascular parameters. Methods and Results—This randomized, double-blind, crossover study included 57 women who received micronized progesterone 100 mg with either conjugated equine estrogen 0.625 mg (C-HRT) or 0.3 mg (L-HRT) daily for 2 months. L-HRT showed comparable effects to C-HRT on high-density lipoprotein cholesterol and triglyceride levels, but not on low-density lipoprotein cholesterol levels. C-HRT and L-HRT significantly improved the percent flow-mediated dilator response to hyperemia from baseline values (both P <0.001) by a similar degree (P =0.719). C-HRT significantly increased high-sensitivity C-reactive protein (hsCRP) levels from baseline values (P <0.001); however, L-HRT did not significantly change hsCRP (P =0.874). C-HRT and L-HRT significantly decreased antithrombin III from baseline values (P <0.001 and P =0.042, respectively). C-HRT significantly increased prothrombin fragment 1+2 (F1+2) from baseline values (P <0.001); however, L-HRT did not significantly change F1+2 (P =0.558). Of interest, the effects of C-HRT and L-HRT on hsCRP, antithrombin III, and F1+2 were significantly different (all P <0.001). C-HRT and L-HRT significantly reduced plasma PAI-1 antigen levels from baseline values (P =0.002 and P =0.038, respectively) to a similar degree (P =0.184). Conclusions—Compared with C-HRT, L-HRT has comparable effects on lipoproteins, flow-mediated dilation, and PAI-1 antigen levels. However, L-HRT did not increase hsCRP or F1+2 levels, and it decreased antithrombin III less than C-HRT.

Effects of statin on plaque stability and thrombogenicity in hypercholesterolemic patients with coronary artery disease

OBJECTIVE Plaque stability and thrombogenicity contribute to development and clinical expression of atherosclerosis. Experimental studies have shown that lipoproteins or mevalonate regulate matrix metalloproteinase (MMP)-9, tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1) expression, providing nonlipid mechanism. METHODS We administered simvastatin 20 mg daily during 14 weeks to 32 hypercholesterolemic patients with coronary artery disease. RESULTS Compared with pretreatment values, simvastatin significantly lowered lipoprotein levels (all P<0.01). Compared with pretreatment values, simvastatin significantly lowered plasma levels of MMP-9, TF, and PAI-1 (P=0.009, P=0.032, and P=0.007, respectively). There were significant inverse correlations between pretreatment MMP-9, TF activity or PAI-1 antigen and the degree of change in those levels after simvastatin (r=-0.793, P<0.001; r=-0.482, P=0.005 and r=-0.590, P<0.001, respectively). Of interest, there were significant correlation between pretreatment or percent changes in MMP-9 levels and pretreatment or percent changes in PAI-1 antigen (r=0.293, P=0.019 and r=0.375, P=0.034, respectively). However, no significant correlations between lipoprotein levels and levels of plaque stability or thrombogenicity markers were determined. CONCLUSIONS Reduction of plaque stability and thrombogenicity markers with statin may contribute to the cardiovascular event reduction and explain the early clinical benefit in clinical trials, independent of lipoprotein changes.