Statins: Another Class of Antihypertensive Agents?

Home , Enzyme inhibitor

HJ Milionis1, EN Liberopoulos2, A Achimastos3, MS Elisaf1 and DP Mikhailidis2 1Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece; 2Department of Clinical Biochemistry (Vascular Disease Prevention clinics), Royal Free Hospital, London, UK and 3Department of Internal Medicine, Medical School, University of Athens, Athens, Greece

The assessment of global cardiovascular risk is an statins have blood pressure (BP)-lowering effects. In essential step in the management of atherosclerotic this review, we discuss the beneficial effects of statins disease prevention. Among the risk factors to be on BP, and provide an overview of the underlying addressed are hypertension and hyperlipidaemia; these pathophysiology. We also consider the evidence justify- commonly coexist. A neutral or lipid-friendly antihyper- ing the use of statins in the management of hypertensive tensive agent is probably useful in the presence of lipid patients. abnormalities. Similarly, statins have been shown to Journal of Human Hypertension (2006) 20, 320–335. decrease cardiovascular risk in hypertensive patients. doi:10.1038/sj.jhh.1002001; published online 2 March 2006 There is also experimental and clinical evidence that

Keywords: blood pressure; dyslipidaemia; pleiotropic effects; statins; vascular disease

Introduction lipid-friendly antihypertensive and a lipid-lowering agent. However, clinical experience shows that the The first step in evaluating a patient with dyslipo- implementation of global risk-oriented prevention proteinaemia is calculating the global vascular risk strategies in hypertensive patients is unsatisfactory, as multiple risk factors are often present. When risk and low-density lipoprotein cholesterol (LDL-C) factors coexist their combined effect is much greater levels are commonly not on target.7 than the sum of their individual effects. Multiple In this review, we consider the relationships relatively mild risk factors can greatly increase the 1 between hypertension and lipid abnormalities and risk of developing coronary heart disease (CHD). discuss the clinical and experimental data regarding Thus, a patient with severe hypercholesterolaemia the effects 3-hydroxy-3-methylglutatyl co-enzyme A may be at lower risk than a smoker with moderate (HMG CoA) reductase inhibitors (statins) on blood hypertension and moderately elevated lipid levels. pressure (BP). The risk for cardiovascular events increases con- siderably when hypertension and dyslipidaemia coexist, but the underlying common pathophysiolo- Search strategy gical mechanisms remain undefined. Dyslipidaemia is commonly diagnosed in patients with hyperten- Sources included MEDLINE and EMBASE (last sion,2 but owing to the high prevalence of both search update performed on 2 January 2006). The conditions in the general population, this associa- search strategy was based on the combination of tion should not be regarded as merely coinciden- ‘statin’, ‘HMG-CoA enzyme inhibitor’, ‘atorvastatin’, tal.3,4 Lipid abnormalities and hypertension are ‘simvastatin’, ‘lovastatin’, ‘fluvastatin’, ‘cerivasta- principal constituents of the metabolic syndrome.5 tin’, ‘rosuvastatin’ and ‘pitavastatin’ with either Moreover, in cases of secondary hypertension ‘BP’ or ‘hypertension’. References of retrieved associated with renal dysfunction (renal insuffi- articles were also screened. ciency, nephrotic syndrome), hyperlipidaemia is a frequent comorbidity.6 Therefore, it seems appro- priate to treat both conditions by using a Do lipid abnormalities predict the risk for hypertension? In a new analysis from the Physicians’ Health Correspondence: Dr DP Mikhailidis, Department of Clinical Study,8 elevated levels of total cholesterol (TC) were Biochemistry (Vascular Disease Prevention Clinics), Royal Free associated with an increased risk of hypertension in Hospital, Pond Street, London NW3 2QG, UK. E-mail: [email protected] middle-aged and older men. Also, higher levels of Received 8 October 2005; revised 16 January 2006; accepted 17 high-density lipoprotein cholesterol (HDL-C) were January 2006; published online 2 March 2006 associated with a lower risk of hypertension.8 Statins and hypertension HJ Milionis et al 321 Elevated lipid levels seemed to predate the onset of Thus, the metabolic abnormalities associated with hypertension by years. Specifically, Halperin et al. a positive family history (FH þ ) of hypertension prospectively examined data from 3110 participants suggest a genetic predisposition to the ‘metabolic who were free of hypertension, cardiovascular hypertensive syndrome’.13,18 In a study of 23 lean disease and cancer at baseline. Participants re- normal volunteers with a negative (FHÀ, n ¼ 11) or sponded to follow-up questionnaires at 6 months positive family history (FH þ , n ¼ 12) of hyperten- and then annually reported the incidence of hyper- sion, Lopes et al.19 evaluated the metabolic and tension, other conditions and health habits. Over an haemodynamic responses of acute hyperlipidaemia average of 14 years of follow-up, approximately one- provoked by 4 h infusion of intralipid and heparin. third of participants developed hypertension. The Lean normotensive FH þ subjects had higher authors reported that higher levels of TC, non-HDL- baseline TGs and very-low-density lipoprotein C and the TC/HDL-C ratio were independently cholesterol levels than FHÀ volunteers (Po0.05). associated with a 23% (P ¼ 0.0067), 39% However, non-esterified fatty acids (NEFA) in- (P ¼ 0.0001) and 54% (Po0.0001) increased risk of creased similarly in both groups during the infusion incidence hypertension, respectively.8 In addition, of intralipid and heparin. Blood pressure and heart those in the highest quintile of HDL-C had a 32% rate significantly increased with acute hyperlipidae- (P ¼ 0.0002) lower risk of developing hypertension mia in all subjects combined (Po0.05).19 Despite the compared with those in the lowest quintile.8 similar increase in NEFA, mean BP, pulse pressure Hypertension is one of the constituents of the and pressure-rate product increased significantly in metabolic syndrome together with abdominal obe- FH þ subjects but not in FHÀ volunteers. The rise of sity, hypertriglyceridaemia, low HDL-C and hyper- systolic BP in particular was significantly greater in glycaemia.9,10 The common denominator in this FH þ than in FHÀ volunteers during the acute syndrome is probably insulin resistance.9,11,12 Free hyperlipidaemia (1472vs1072 mm Hg, Po0.05),19 fatty acids are related to insulin resistance and may indicating that dyslipidaemia characteristic of the have a direct effect on hypertension. In the Paris metabolic syndrome might cause an increase in BP, Prospective Study,13 lipid abnormalities (TC, trigly- especially in subjects with a positive family history cerides (TG) and free fatty acids) were studied as of hypertension. possible predictors of hypertension in 2968 middle- There is evidence that normotensive subjects with aged non-hypertensive and non-diabetic men fol- hypercholesterolaemia have excessive BP responses lowed for 3 years. Confounding factors, including to stress tests.20 In a study involving 15 hypercho- obesity, abdominal fat distribution, serum insulin lesterolaemic (HC) patients and 24 normocholester- and glucose levels, were taken into account. The olaemic controls, Minami et al.21 showed that weight increase, a high body mass index (BMI), cholesterol-lowering therapy can improve excessive waist circumference, baseline BP levels, glucose, BP responses to stress tests, thus confirming that insulin, TC, TGs and free fatty acids were all hypercholesterolaemia plays a role in the regulation univariate predictors of hypertension. After control- of BP. All participants carried out mental arithmetic ling for BMI, waist circumference and weight stress and handgrip tests. Blood pressure was increase, TC and TGs were not significant risk measured during these tests. In HC patients, the factors for hypertension. Nevertheless, fasting and tests were repeated at the end of a 12-week treatment 2 h free fatty acid levels were highly significant risk with pravastatin 10 mg/day. In HC patients, BP factors for hypertension, when controlled for age, responses to both tests were greater than those of family history of hypertension, alcohol consump- controls. Serum TC, LDL-C and lipid peroxides were tion, BMI, iliac circumference and weight change significantly decreased in association with the (hazard rate ratio (RR) ¼ 1.73, 95% confidence pravastatin treatment. Systolic BP to mental arith- interval (CI): 1.44–2.08).13 Further controlling for metic tests and systolic BP/diastolic BP to handgrip systolic BP, heart rate and fasting insulin and tests decreased (Po0.01, Po0.01/Po0.02, respec- glucose did not decrease their predictive power tively) after pravastatin treatment.21 (RR ¼ 1.58, 95% CI: 1.30–1.91 comparing the 90th with the 10th percentiles at fasting; RR ¼ 1.54, 95% CI: 1.33–1.79 at 2 h). These independent effects of Hypertension and dyslipidaemia: a genetic link? free fatty acids on hypertension are suggestive of Patients with a high BP often have an abnormal underlying metabolic and haemodynamic derange- serum lipid profile. Up to 40% of untreated patients ments related to the metabolic syndrome that lead to with essential hypertension and many patients with an increased pressor response.13 Fatty acids might borderline hypertension already have lipid abnorm- contribute to elevated BP in part by actions that alities, such as elevated LDL-C and a decrease in enhance a1-adrenoceptor-mediated vascular and HDL-C levels.22 In a study from 13 English general pressor reactivity and impair endothelium-depen- practices,23 over 85% of the hypertensive patients dent dilation.13–16 had TC levels 45.2 mmol/l (200 mg/dl). Moreover, It has been shown that the pre-hypertensive about 65% had levels 46.0 mmol/l (232 mg/dl) metabolic abnormalities may manifest early in life (which doubles the risk of a CHD event), the mean in normotensive offspring of hypertensive parents.17 level was approximately 6.5 mmol/l (251 mg/dl).

Journal of Human Hypertension Statins and hypertension HJ Milionis et al 322 There is also evidence that a significant proportion oxide (NO) synthase (eNOS) Glu298Asp gene of hypertensive patients have other lipid abnormal- variant and TC (P ¼ 0.02), log-transformed TGs ities associated with the metabolic syndrome, such (P ¼ 0.004) or non-HDL-C (P ¼ 0.003) in the determi- as low HDL-C and high TG concentrations.5,24 nation of systolic BP.31 The authors suggest that Similarly, in a Japanese study,25 a review of the these results provide evidence supporting the role of profiles of 830 hypertensive patients revealed a the eNOS Glu298Asp gene variant in modulating BP diagnosis of hyperlipidaemia in more than 45%. Of through a relationship with lipid levels.31 these, less than 65% were on any lipid-lowering treatment and less than 40% reached lipid target levels.25 Statins and blood pressure: data from experimental Genetic studies in humans and animal models studies suggest that a predisposition for the development of The importance of lowering plasma cholesterol to both hypertension and dyslipidaemia may result reduce the incidence of vascular events is well from the inheritance of shared genetic risk fac- established. The key role of statins in the manage- tors.18,26 In spontaneously hypertensive mice, Bott- ment of patients with increased risk of cardiovas- ger et al.26 showed that the genes responsible for cular disease is widely accepted. Although, control BP regulation and those linked to an increased pro- of hypertension has been unanimously considered pensity for dyslipidaemia were located in the of principal importance in the prevention of stroke, same three general areas of chromosomes 8, 19 there is also evidence that lipid-lowering therapy and 20. (namely statins) significantly decreases stroke Among population-based sibships in Utah (USA) risk.32–34 Among lipid-regulating agents, statins are with essential hypertension diagnosed before the the most widely studied drugs. In addition to their age of 60 years, the prevalence of familial combined lipid-lowering effects, other beneficial properties dyslipidaemia was 10 times that of the general (referred to as ‘pleiotropic effects’) have been population.18,27 This subgroup of patients with recognised.35 hypertension and associated lipid abnormalities There are scarce experimental data regarding the was termed familial dyslipidaemic hypertension. direct effect of statins on BP. Lovastatin has been Studies in subjects with familial combined hypercho- shown to reduce BP in spontaneous hypertensive lesterolaemia showed that hypertension is present in rats (SHR, an experimental model widely used for as much as 30–40% of patients, thus suggesting a the study of essential hypertension). Jiang et al.36 lower penetrance for hypertension compared to evaluated the effects of lovastatin on renal function dyslipidaemia in this group.28,29 However, although and the development of hypertension in SHR. Four- lipid-lowering (statins or fibrates) treatment is week-old SHR were given lovastatin (10 mg/kg) commonly introduced in patients with familial or vehicle twice daily by gavage. After 4 weeks of combined hypercholesterolaemia, the effect of these treatment, mean arterial BP was significantly lower drugs on BP in these patients is not documented. in the lovastatin-treated SHR (n ¼ 5) compared with In genetic mapping studies of hypertension the control (n ¼ 12) animals (13174 vs 16074mmHg, involving kindreds with familial combined hyper- Po0.05). The decrease in arterial BP in the lovasta- cholesterolaemia, a quantitative trait linkage of tin-treated rats was accompanied by changes in sodium–lithium countertransport (SLC, a membrane renal function. The slope of the relationship transport marker associated with hypertension and between arterial BP and sodium excretion was insulin resistance) activity to human chromosome threefold greater in lovastatin-treated SHR than in 4p in the region containing a fatty acid hydrolase control rats, and this was associated with significant (CD36) and a-adducin has been shown.28,29 Further- elevations in renal medullary blood flow and renal more, secondary loci for SLC have been identified in interstitial hydrostatic pressure. Glomerular filtra- chromosome 8p close to the lipoprotein lipase gene tion rate was 17% higher in the lovastatin-treated and for diastolic BP in chromosome 19 close to the SHR than in controls (0.9470.05 vs 0.8170.07 ml/ apolipoprotein B locus.28 min per g of kidney weight, Po0.05). The wall-to- Ferrari et al.30 showed that young normotensives lumen area ratio of renal arterioles was significantly in apparently good health, but with one essential reduced in lovastatin-treated SHR compared with hypertensive parent, tend to have an impairment of vehicle-treated rats (0.8670.05 vs 1.0870.04 for insulin-mediated glucose disposal, hyperinsulinae- vessels with inner diameters o50 mmand mia and dyslipidaemia. The investigators suggested 0.6270.02 vs 0.7570.04 for vessels with inner that a familial trait for essential hypertension seems diameters of 50–100 mm, Po0.05). These results to coexist with defects in carbohydrate and lipo- indicate that chronic treatment with lovastatin shifts protein metabolism. These defects can be detected the relations between renal medullary blood flow, at an early age and before or at least at a very early renal interstitial pressure, sodium excretion and stage of the development of high BP.17,30 renal perfusion pressure to lower levels of arterial In a study of 1577 individuals randomly selected pressure and attenuate the development of hyper- from the general population, Pereira et al. recently tension and hypertension-induced renal vascular reported significant interactions between the nitric hypertrophy in SHR.36

Journal of Human Hypertension Statins and hypertension HJ Milionis et al 323 In a model of cerebral blood flow (CBF) auto- These effects were independent of changes in regulation, Regriny et al.37 assessed the structure plasma lipids.43 and mechanics of cerebral arterioles and the lower Statin treatment may favourably affect vascular limit of CBF autoregulation in SHR untreated or endothelium in the hypertensive state. Ge et al.44 treated with lovastatin (20 mg/kg per day) for 1 showed that atorvastatin can improve vascular month. Lovastatin significantly reduced mean arter- remodelling of the thoracic aorta in SHR. Indeed, ial BP (15373 mm Hg in treated vs 17175mmHgin treatment with atorvastatin produced a significant untreated, Po0.05) and normalised the cross-sec- reduction of systolic BP of caudal artery (Po0.01) tional area of the vessel wall in maximally dilated combined with significant reductions in serum cerebral arterioles (treated: 826752 vs untreated: concentrations of TC, TGs and HDL-C compared 1099716 mm,2 Po0.05). Lovastatin also attenuated with the non-atorvastatin-treated group. Wall thick- the increase in passive distensibility, but had no ness media thickness and medial cross-sectional effect on the external diameter of cerebral arterioles area to lumen ratio were significantly lower in the or the lower limit of CBF autoregulation.37 atorvastatin-treated group (Po0.05). In an experimental model involving Dahl salt- sensitive rats (Dahl S, a model of salt-sensitive hypertension), pravastatin treatment reduced the Statins and blood pressure: data from clinical trials severity of hypertension and renal damage (protei- The effect of statin treatment on BP was studied in a nuria and glomerular injury).38 Moreover, in a wide range of patients, including normotensive mouse model of salt-dependent hypertension subjects, hypertensive, normolipidaemic, hyper- chronic treatment with lovastatin (40 mg/kg body lipidaemic and diabetic patients, as well as com- weight) and bezafibrate (50 mg/kg body weight) binations of these groups.45–48 Both neutral and diminished deoxycorticosterone acetate (DOCA)- favourable effects on BP levels have been reported salt-induced reductions in total renal blood flow. with all HMG-reductase inhibitors (Table 1). Lovastatin improved medullary blood flow (130% Sung et al.20 evaluated the systemic effects of increase of baseline values) reactions to increased elevated cholesterol on BP and BP reactivity. The BP perfusion pressure or to volume expansion and response to provoked stress (induced by a standard resulted in a significant decrease of systemic BP in mental arithmetic test (MAT)) was examined in 37 DOCA-salt mice.39 healthy, normotensive HC subjects and 33 normoli- Chronic treatment with cerivastatin (2 mg/kg per pidaemic controls. HCs had slightly higher systolic day by gavage) prevented or retarded hypertension- BP at baseline (122 vs 118 mm Hg, Po0.05) and induced renal injury via inhibition of renal fibrosis systolic BP response during MAT (1878vs and proteinuria in stroke-prone SHR and inhibited 1075 mm Hg, Po0.05) than controls. Maximal the expression of transforming growth factor-b1in changes in systolic BP were significantly correlated the kidneys.40 Cerivastatin has also been shown to with cholesterol (r ¼ 0.41, Po0.001), whereas heart protect against hypertension-based stroke and ame- rate and diastolic BP changes were unrelated to liorate the disease severity. Kawashima et al.41 serum cholesterol. To confirm that BP reactivity was showed that chronic treatment of stroke-prone SHR dependent on cholesterol, the MAT was repeated resulted in a significant decrease in the incidence after treatment with using a crossover design in 26 and size of stroke and early mortality. These effects HC subjects. Lovastatin (20 mg/day for 6 weeks) were independent of BP and lipid levels. Statin significantly improved lipid profiles (À26% TC, treatment significantly reduced superoxide produc- þ 8% HDL-C, À34% LDL-C) and resulted in a small tion from non-stroke parenchyma of the brain and nonsignificant decrease in systolic BP at baseline infiltration of inflammatory cells to the stroke (À3 mm Hg) and a significantly lower systolic BP lesions.41 In another experimental model of stroke- (À8 mm Hg, Po0.05) during the MAT.20 prone SHR,42 atorvastatin decreased the BP, at least In two open-label clinical studies49,50 involving 49 in part via the reduction of sympathetic nervous and 23 hypertensive HC patients, respectively, system activity. This so-called ‘sympatho-inhibitory a significant fall in systolic (mean arterial systolic effect’ may be mediated by an increase in NO BP was reduced from 147716 to 142715, and production, with the upregulation of eNOS expres- from 145714 to 139718 mm Hg, respectively) and sion in the brain.42 diastolic BP (mean arterial diastolic BP was reduced In another study, Susic et al.43 evaluated the from 9579to8878, and from 9779to92711 mm effects of rosuvastatin on systemic and regional Hg, respectively) was observed after 12 weeks of haemodynamics in two hypertensive rat models treatment with fluvastatin.49,50 (one genetically determined, and the other hyper- In another study,51 30 subjects with moderate tensive-induced via inhibition of NO synthesis). hypercholesterolaemia and untreated hypertension Rosuvastatin reduced arterial BP in SHR rats and (systolic and diastolic BP 14976and9772 mm Hg, decreased total peripheral resistance. Regional respectively) were randomised in a double-blind haemodynamics improved with rosuvastatin in both manner to placebo or pravastatin (20–40 mg/day) hypertensive models, as evidenced by increased in a crossover design. In the 25 participants blood flows and decreased vascular resistance. who completed the 32-week trial, pravastatin

Journal of Human Hypertension Statins and hypertension HJ Milionis et al 324 Table 1 Clinical trials showing a beneficial or neutral effect of statins on blood pressure (BP) levels

Author N Statin Patients Duration of Tx Effect on BP D (mm Hg)

Morgan et al. (1990)52 49 SMV H 3 months À5.2/3.5 Jarai et al. (1996)49 49 FLV H 12 weeks À5.0/2.0 Abetel et al. (1998)50 23 FLV H 12 weeks À4.0/2.0 Glorioso et al. (1999)51 30 PRV H 32 weeks À8.0/5.0 Tonolo et al. (2000)53 26 SMV H 10 months À4.0/6.0 Ferrier et al. (2002)54 22 ATV H 3 months À6.0/2.0 Prasad et al. (2003)55 113 Statin H 12 months À7.0/3.0 Ikeda et al. (2004)119 52 PRV H 6 months À4.7/0.7 Terzoli et al. (2005)56 51 SMV, PRV or ATV H, N 2 months À5.7/3.5 Kanbay et al. (2005)57 32 ATV H 3 months À5.1/5.2 Magen et al. (2005)58 48 ATV H 2 months À13.7/7.8 Borghi et al. (2004)59 1356 SMV H, N 5 years À13.0/13.0a Sartor et al. (1995)60 25 SMV N 16 weeks No change Antonicelli et al. (1990)61 20 SMV N 12 months No change Kool et al. (1995)62 19 PRV N 8 weeks No change D’ Agostino et al. (1993)63 213 LOV H 6 months No change Ichihara et al. (2005)64 85 FLV, PRV or SMV H 12 months No change

Abbreviations: D ¼ mean change in systolic/diastolic BP; ATV ¼atorvastatin; FLV ¼ fluvastatin; H ¼ hypertensives; LOV ¼ lovastatin; N ¼ normotensives; PRV ¼ pravastatin; SMV ¼ simvastatin; Tx ¼ treatment. aMean percentage change at the highest quartile of BP.

significantly decreased TC and LDL-C (P ¼ 0.001), treatment) and 3 months of placebo treatment. systolic and diastolic BP (À8 and À5 mm Hg, both Besides a 48% decrease in LDL-C levels, atorvastatin P ¼ 0.001), and pulse pressure (À3 mm Hg, reduced brachial systolic BP (14872 vs 15473mm P ¼ 0.011), and blunted the BP increase caused by Hg in the placebo group, P ¼ 0.03), mean BP the cold pressor test (À4 mm Hg, P ¼ 0.005) com- (10772 mm Hg vs 11172, P ¼ 0.04) and diastolic pared with placebo. A significant reduction in BP (8172vs8371 mm Hg, P ¼ 0.04).54 circulating endothelin-1 levels was also seen in the In addition to their beneficial effects on lipid pravastatin-treated patients.51 abnormalities in kidney transplant patients, statins Simvastatin improved lipid abnormalities in have proved efficient antihypertensives by reducing patients treated for hypertension, and produced an systolic, diastolic and mean arterial BP by 7 mm Hg additional nonsignificant fall (À5.2 mm Hg) in (P ¼ 0.005), 3 mm Hg (P ¼ 0.05) and 4 mm Hg systolic BP levels.52 The potential effects of simvas- (P ¼ 0.007), respectively, after 12 months of treat- tatin on BP and urinary albumin excretion beyond ment. In a study involving 113 stable kidney graft its capacity to lower serum cholesterol were eval- recipients, patients on statins had lower systolic, uated in 26 microalbuminuric hypertensive type II diastolic and mean BP measurements (P ¼ 0.05, 0.03 diabetic patients (diastolic BP consistently 490 and 0.02, respectively) at 12 months compared with ando100 mm Hg; plasma LDL-C43.9 and o6.5 non-statin-treated controls. These findings were mmol/l (4151 and o251 mg/dl)).53 In random order, independent of lipid-lowering associated with statin these patients received simvastatin (20 mg/day) or treatment.55 cholestyramine (6 g three times a day) for a period of In another study,56 hypertensive and normoten- 10 months, and after 3 months of wash-out (cross- sive subjects with hypercholesterolaemia were over), the sequence was reversed for an additional randomised to receive a statin (n ¼ 51, simvastatin 10 months. Simvastatin and cholestyramine were 10–20 mg/day, pravastatin 10–20 mg/day or atorvas- equally effective in reducing TC and LDL-C. How- tatin 5–10 mg/day) or placebo (n ¼ 23) for 2 months. ever, only during simvastatin treatment, a signifi- Statin-treated hypertensive subjects showed lower cant reduction in diastolic BP (from 9773to systolic and diastolic ambulatory BP (À5.775.8 9173 mm Hg, Po0.01) and both 24 h urinary and À3.573.9 mm Hg, respectively, both Po0.001).56 albumin and glycosaminoglycan (a marker of renal This effect was unrelated to the concomitant injury) excretion rates were observed, whereas no cholesterol reduction.56 In contrast, no effect was significant changes were seen with cholestyramine observed in normotensive subjects.56 treatment. These findings are indicative of an Hypertensive and dyslipidaemic subjects (n ¼ 32) antihypertensive effect of simvastatin indepen- were treated with atorvastatin (20 mg/day) in one dently of its cholesterol-lowering capacity.53 study.57 After 2 months, significant reductions in In a randomised, double-blinded, cross-over ambulatory systolic (total average systolic BP from study,54 22 patients with isolated systolic hyperten- 124.0712.2 to 118.979.9 mm Hg, Po0.05) and sion (ISH) received 3 months of atorvastatin therapy diastolic BP (total average diastolic BP from (80 mg/day, that is, intensive hypolipidaemic 73.979.4 to 68.777.9, Po0.05) were observed.57

Journal of Human Hypertension Statins and hypertension HJ Milionis et al 325 Furthermore, 2-month atorvastatin treatment effect owing to higher baseline values or a specific (20 mg/day) resulted in significant reductions in pathophysiological mechanism remains to be systolic (À13.775.6 mm Hg, P ¼ 0.001) and diastolic answered. BP (À7.875.7 mm Hg, P ¼ 0.01) in 48 hyperlipidae- It is of interest to overview the findings of large mic patients with resistant hypertension.58 landmark statin trials where statins were prescribed In the Brisighella Heart Study,59 a total of 1356 HC for long periods to diverse subgroups in primary and subjects were randomly treated for 5 years with secondary prevention (Table 2). It appears that the either low-fat diet, cholestyramine, gemfibrozil or overall benefit in cardiovascular risk reduction was simvastatin. Participants were divided at baseline similar among subjects/patients with or without into four quartiles according to systolic BP. A hypertension; in a recent meta-analysis of data from significant decrease in BP was observed in the two 90 056 participants in 14 randomised statin trials, upper quartiles of systolic BP and was greater in major vascular event reduction per mmol/l of LDL-C subjects treated with cholesterol-lowering drugs.59 decrease was not different between patients with In particular, the BP reduction was greater in treated hypertension (RR 0.81) or not (RR 0.77), patients treated with a statin despite comparative as well as between participants with diastolic reductions in LDL-C (reduction by 13% in both BPp90 mm Hg (RR 0.79) and those with diastolic systolic and diastolic BP at the highest quartiles BP490 mm Hg (RR 0.77).65 Although a sizable after 5 years of treatment with a statin vs 10% after number of hypertensive subjects were included in treatment with non-statin drugs, Po0.005).59 these studies, there is no report as to whether statin The BP-lowering effect of statins is not a consis- treatment produced any significant BP reductions. tent finding in all studies. Thus, 16-week simvasta- The most probable explanations for the absence tin treatment in HC normotensive patients with of an antihypertensive effect associated with statin insulin-dependent diabetes mellitus did not affect therapy in the landmark statin trials could be body weight, BP or glycaemic control.60 Similarly, summarised as follows: simvastatin had no effect on BP, heart rate or body The influence of statin treatment on BP was not weight in HC normotensive elderly patients.61 included in the study design. Pravastatin (40 mg daily for 8 weeks) in normotensive patients with primary hypercholesterolaemia A beneficial effect on BP in hypertensive patients could have been attenuated by a large numbers of had no effect on BP, heart rate, cardiac function normotensive participants, in whom no effect and systemic vascular resistance.62 In a study of occurred. 213 hypertensive HC patients, BP levels were Antihypertensive drugs may have masked any not influenced by chronic lovastatin treatment beneficial effect of statins. (10–80 mg daily for 6 months).63 Moreover, in a recent study,64 85 hyperlipidaemic hypertensive subjects whose BP was insufficiently controlled Reduction in blood pressure owing to statin therapy: by antihypertensive treatment were randomised to pathophysiological mechanisms receive pravastatin, fluvastatin, simvastatin or a In the statin studies demonstrating a beneficial non-statin hypolipidaemic drug for 12 months. No effect on BP, there was no correlation between the effect on BP was observed in either of these decrease of BP and the changes in plasma TC and groups.64 This is the only single-blind randomised LDL-C levels. This observation is in favour of a non- prospective study designed to compare the long- lipid-lowering mechanism being responsible for the term effects of different statins (a head-to-head antihypertensive action of these agents (Table 3). On comparison between one hydrophilic (pravastatin) the other hand, there are only scarce data showing and two lipophilic drugs (simvastatin and fluvasta- reductions in BP levels achieved by other classes of tin)) on BP control in hypertensive patients with hypolipidaemic agents. These statin-specific actions high cholesterol levels.64 are probably part of the so-called ‘pleiotropic effects’ Although a beneficial effect of statins on BP was of this class of drugs and may account for the CVD seen in the majority of studies, the question whether protection related to statin treatment.35 However, these reductions in systolic and diastolic BP are there is a paucity of randomised, placebo-controlled clinically relevant remains to be answered. Gener- studies with reference to the BP-lowering effect of ally, statin treatment is associated with a decrease of statins in relation with their anticipated LDL-C 5–8 mm Hg in systolic BP and a 3–5 mm Hg decrease lowering effect. in diastolic BP. These reductions are comparable with those achieved in some long-term studies using Effects on endothelial dysfunction and nitric oxide antihypertensive agents. Therefore, we can presume synthesis. The vascular endothelium is a dynamic that the statin-induced BP changes are clinically endocrine organ that regulates contractile, secretory relevant. Nevertheless, long-term, large-scale studies and mitogenic activities in the vessel wall and are necessary in order to evaluate this phenomenon. haemostatic processes within the vascular lumen.66 Moreover, it appears that hypertensive subjects Endothelial dysfunction is present in patients with are more responsive to LDL-C reduction compared hypertension, diabetes mellitus, insulin resistance with normotensives; whether this is a nonspecific and dyslipidaemia. Lipid-lowering treatment

Journal of Human Hypertension Statins and hypertension HJ Milionis et al 326 Table 2 Use of statins in hypertensive patients: data from the landmark statin trials

Trial Primary events N (%) RR (%)

Placebo Active Tx

Primary prevention WOSCOPS Hypertensives NR/506 NR/531 NR Normotensive NR/2787 NR/2771 NR AFCAPS/TexCAPS Hypertensives 62/729 (8.5) 38/719 (5.3) 38 Normotensives 121/2572 (4.7) 78/2585 (3.0) 36

Secondary prevention 4S Hypertensives 186/584 (32) 119/570 (21) 37 Normotensives 426/1639 (26) 313/1651 (19) 32 CARE Hypertensives 263/899 (29) 200/875 (23) 23 Normotensives 286/1179 (24) 230/1206 (19) 24 LIPID Hypertensives 314/1891 (17) 266/1867 (14) 15 Normotensives 400/2609 (15) 291/2644 (11) 30 TNT Hypertensives NR/2721a NR/2692 NR Normotensives NR/2285a NR/2303 NR IDEAL Hypertensives NR/1469b NR/1461 NR Normotensives NR/2980b NR/2978 NR

High-risk individuals PROSPER Hypertensives 283/1793 (15.8) 246/1799 (13.7) 16 Normotensives 190/1120 (17) 162/1092 (14.8) 15 HPS Hypertensives 1195/4246 (28.1) 942/4211 (22.4) 24 Normotensives 1390/6021 (23.1) 1091/6058 (18) 24 ASCOT-LLA Hypertensives 154/5135 (3.0) 100/5168 (1.9) 36 Normotensives — — — CARDS Hypertensives NR/1184 NR/1193 NR Normotensives NR/226 NR/235 NR

Abbreviations: AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study142; ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm34; CARDS: Collaborative Atorvastatin Diabetes Study108; CARE: Coronary and Recurrent Events144; HPS: Heart Protection Study32; IDEAL: Incremental Decrease in End points through Aggressive Lipid lowering109; LIPID: Long-term Intervention with Pravastatin Ischemic Disease145; NR: not reported; PROSPER: PROspecive Study of Pravastatin in the Elderly at Risk146; RR: risk reduction; 4S: Scandinavian Simvastatin Survival Study143; TNT: Treating to New Targets106; Tx: treatment; WOSCOPS: West of Scotland COronary Prevention Study.141 Pravastatin was used in WOSCOPS, CARE, LIPID and PROSPER trials; lovastatin was used in AFCAPS/TexCAPS; simvastatin was used in 4S, HPS and IDEAL; and atorvastatin was used in ASCOT-LLA, CARDS, TNT and IDEAL. aNot placebo, but treatment with atorvastatin 10 mg/day. bNot placebo, but treatment with simvastatin 20 mg/day.

improves endothelial function. The endothelium- dependent manner, the inhibitory effect of oxidised derived relaxing factor, NO, is thought to be the key LDL on L-NG-monomethyl arginine (L-NMMA) mediator of these beneficial effects. Statins appear to inhibitable nitrite production (L-NMMA is a specific restore or improve endothelial function by increas- inhibitor of endothelium-derived NO). At high ing the bioavailability of NO, promoting re-endothe- statin concentrations, nitrite production exceeded lialisation, reducing oxidative stress and inhibiting levels observed in the absence of oxidised LDL. The inflammatory responses.66,67 authors further demonstrated that this effect was Laufs et al.68 demonstrated a direct effect of caused by an increased stability of eNOS mRNA lovastatin and simvastatin on constitutive eNOS induced by the statin.68 These findings are in protein mass and messenger RNA levels in endothe- agreement with experimental studies showing im- lial cells of the human saphenous vein exposed to provement of focal cerebral ischaemia following oxidised LDL. Simvastatin reversed, in a dose- statin treatment.69

Journal of Human Hypertension Statins and hypertension HJ Milionis et al 327 Table 3 Non lipid-lowering effects of statins that may be endothelin-1 mRNA (60–70% maximum inhibition) associated with blood pressure reduction and endothelin-1 synthesis in bovine aortic endothelial cells in vitro. Pravastatin reduced the K Restoration of endothelial dysfunction K Increased nitric oxide synthesis circulating levels of endothelin-1 in patients with K Decreased synthesis of endothelin-1 essential hypertension and primary hypercholester- K Decreased synthesis of aldosterone olaemia.51 However, in the Reduction of Cholesterol K Decreased expression of type 1 angiotensin II receptors in Ischemia and Function of Endothelium (RECIFE) K Other potential mechanisms (increased urinary sodium 84 excretion, inhibition of calcium influx in vascular smooth trial, pravastatin had no effect on plasma endothe- muscle cells) lin-1 after 6 weeks of treatment, and this was also true with fluvastatin given over a period of 6 months.85

Data from the Framingham study have implicated Effect on the renin–angiotensin system. Experi- pulse pressure as major cardiovascular risk factor, mental data underline the role of vascular renin– especially in the elderly.70 Pulse pressure is raised angiotensin systems in mediating the early stages of as a result of rapid pulse wave reflection in stiffer vascular endothelial dysfunction and inflammation arteries leading to the development of ISH, which as prerequisites for unleashing the cascade of affects about 25% of the population older than 55 cellular and molecular events that lead to the years of age.29,71 The association between pulse deposition of foam cells and their eventual progres- wave velocity, hypertension and cardiovascular sion to the atherosclerotic plaque.86 Statins may disease risk has been repeatedly demonstrated in cause vasodilation by correcting endothelial dys- several studies.29,72,73 In addition to antihyperten- function, which frequently accompanies hyper- sive agents, lipid-lowering drugs (especially statins) tension and hypercholesterolaemia. In this respect, favourably affect pulse wave velocity. In a study pravastatin has been shown to decrease endothelial involving 22 normolipidaemic patients with ISH, reactivity responses (assessed by BP measurement) atorvastatin (80 mg/day for 3 months) had a bene- to incremental infusions of angiotensin II or nor- ficial effect on large artery stiffness and BP.54 epinephrine.87 Similarly, aortic stiffness was reduced in men after The role of aldosterone as part of the renin– treatment with atorvastatin.74 In addition to the angiotensin aldosterone system in the development reduction of LDL-C levels and brachial systolic, and maintenance of hypertension is well documen- mean and diastolic BP, atorvastatin caused an ted. Although plasma aldosterone is an erratic increase in systemic arterial compliance (atorvasta- parameter to determine, there is some evidence that tin vs placebo: 0.4370.05 vs 0.3670.03 ml/mm Hg, statins may lower circulating aldosterone levels.88 P ¼ 0.03).54 Atorvastatin has also been shown to Hypercholesterolaemia is associated with an over- increase aortic pulse wave velocity in hypertensive expression of angiotensin II type 1 (AT1) receptors HC patients.75 in experimental models and in humans, leading to There is evidence that statins exert their favour- a significant increase of angiotensin-II-induced BP able effects on the endothelium within 24 h.76,77 For elevation. There is evidence that statins down- example, in a short-term study in CHD patients, regulate AT1 receptor expression.67,89 Nickenig pravastatin 40 mg improved endothelium-depen- et al.89 showed that AT1 receptor expression is dent coronary vasomotion within 24 h in the significantly enhanced in HC compared with nor- absence of any significant reduction of cholesterol mocholesterolaemic individuals, whereas statin or C-reactive protein levels.76 treatment attenuated the elevated BP response to angiotensin II infusion and downregulated AT1 Effect on endothelin. Endothelial vasoreactivity is receptor density. a complex process and involves many molecules besides NO. Another way to improve blood flow Other potential mechanisms of action. The experi- would be to inhibit the production of a potent mental model of rat genetic hypertension has been endothelial-derived vasoconstrictor, endothelin-1. considered as a valuable tool to investigate the Animal studies suggest that endothelin plays a role pathophysiological interactions between hypercho- in certain models of hypertension.78,79 The applic- lesterolaemia and hypertension, as it is free from the ability of these findings to hypertension in humans confounding effects of other risk factors or athero- is uncertain, but an increasing number of studies sclerosis and does not exhibit the extreme hetero- suggest that endothelin antagonists will be clinically geneity of the human disease. It has been shown that useful.80,81 Plasma endothelin levels are usually dietary lipids may affect sodium handling and the normal in hypertensive subjects78; however, there development of hypertension.90 Cholesterol enrich- may be an increase in sensitivity to endothelin in ment in renal cellular membranes may decrease essential hypertension.82 sodium efflux along the nephron, consequently Hernandez-Perera et al.83 showed that both ator- reducing the fractional clearance rate of sodium vastatin and simvastatin reduced in a dose- and and favouring its retention. There is also evidence time- dependent manner, the pre–pro expression of that hypercholesterolaemia exerts a significant

Journal of Human Hypertension Statins and hypertension HJ Milionis et al 328 influence on adrenal steroid metabolism in SHR. tin þ angiotensin-converting enzyme (ACE) inhibi- In particular, in an experimental study, a three-fold tors produced significantly better results than either increase in plasma cholesterol was associated in drugs alone or none of these drugs. these animals with a notable increase in aldosterone The benefit of lowering both BP and cholesterol and a reduction of corticosterone that resulted in a was evaluated in two large-scale trials, ALLHAT103 marked rise of the mineralocorticoid/glucorticoid and ASCOT-LLA.34 Part of the ALLHAT (Antihyper- ratio.91 In addition, the urinary sodium excretion tensive and Lipid-Lowering Treatment to Prevent ratio was reduced.91 The effects of hypercholester- Heart Attack Trial) study was designed to determine olaemia on adrenal steroids as well as water and salt whether pravastatin compared with usual care metabolism were reversible following withdrawal of reduces all-cause mortality in hypertensive, moder- the high cholesterol diet, implying a potential role ately HC patients with at least one additional CHD for cholesterol-lowering treatment. In line with this risk factor. A total of 10 355 ambulatory patients, concept, in patients with primary hyperlipidaemia, aged X55 years, with an LDL-C of 3.1–4.9 mmol/l atorvastatin 40 mg daily was reported to increase the (120–189 mg/dl) or 2.6–3.3 mmol/l (100–129 mg/dl) urinary excretion of sodium in conjunction with an for CHD patients and TGs o3.95 mmol/l (350 mg/ increase in renal excretion of uric acid.92 dl), were randomised to pravastatin (40 mg/day; Another interesting issue involves voltage-gated n ¼ 5170), or usual care (n ¼ 5185). Mean age was calcium influx through L-type Ca2 þ channels, 66 years; 49% were women; 14% had a history of which regulate the diameters of small arteries and CHD and 35% type II diabetes. At 4 years, TC was arterioles, and maintains the myogenic tone of reduced by 17.2% with pravastatin vs 7.6% with resistance vessels and contribute to the pathogenesis usual care. All-cause mortality was similar in the of hypertension.93 Diet-induced hypercholesterolae- two groups (RR ¼ 0.99; 95% CI: 0.89–1.11; P ¼ 0.88), mia has been reported to alter the activity of several with 6-year mortality rates of 14.9% in the pravas- smooth muscle membrane channels and pumps, tatin-treated group and 15.3% in the group receiving including voltage-gated calcium channels and so- usual care. CHD event rates were not different dium/potassium ATPase,94 an effect that has been between the two groups (RR ¼ 0.91; 95% CI: 0.79– attributed to changes in membrane-free cholesterol 1.04; P ¼ 0.16); 6-year CHD event rates were 9.3% content.95 Indeed, animal studies have showed an (pravastatin) and 10.4% (usual care), respectively. inverse relationship between membrane free choles- These results could be attributed to the small terol content and L-type Ca2 þ channel–pump activ- difference in TC (9.6%) and LDL-C (16.7%) between ity.96 Thus, statin treatment may inhibit calcium pravastatin and usual care compared with other influx leading to vascular smooth muscle relaxation statin trials. The need for aggressive lowering of and subsequent lowering of BP.97 LDL-C levels was clearly demonstrated in recent clinical trials.104–109 In the Anglo-Scandinavian Cardiac Outcomes Effects of managing serum lipids and hypertension Trial-Blood Pressure Lowering Arm (ASCOT- on cardiovascular risk BPLA),110 19 342 men and women with hyperten- There is convincing evidence that treating hyper- sion and at least three other cardiovascular risk tension is associated with a reduction in stroke factors were randomised to amlodipine (5–10 mg/ and a less prominent decline in the incidence of day)7perindopril (4–8 mg/day) or to atenolol (50– CHD-related events.98,99 It is also well known that 100 mg/day)7bendroflumethiazide (1.25–2.5 mg/ elevated serum cholesterol levels significantly in- day). A total of 10 305 of these patients with normal crease CHD risk. Therefore, it seems logical that or slightly elevated TC were randomised to atorvas- coexisting cardiovascular risk factors including tatin 10 mg/day or placebo (Lipid-Lowering Arm).34 abnormal lipid profiles should be an integral part The atorvastatin arm was prematurely stopped at of hypertension management. 3.3 years owing to a significant 36% reduction Support for correcting both hyperlipidaemia and (P ¼ 0.0005) in the primary end point. Benefits were hypertension comes from the Gothenburg Primary apparent within the first year of treatment. Fatal/ Prevention Study,100 which showed that coronary non-fatal stroke (89 atorvastatin vs 121 placebo, risk is not greatly reduced when BP is lowered, RR ¼ 0.73, 95% CI: 0.56–0.96, P ¼ 0.024) and total whereas serum cholesterol rises. However, patients cardiovascular/coronary events (178 vs 247, in whom both BP and serum cholesterol were RR ¼ 0.71, 95% CI: 0.59–0.86, P ¼ 0.0005) were also reduced benefited the most in terms of CHD risk reduced with atorvastatin. At 1 year, atorvastatin reduction. The Helsinki Heart Study also demon- reduced TC and LDL-C by 24 and 35%, respectively. strated that effectively treating hypertension in It is particularly relevant that there was a significant hypertensive, dyslipidaemic men (primarily with reduction in stroke despite very good BP control.34 diuretics and beta-blockers) reduced the risk of CHD events by more than 50% when compared to those with persistent hypertension.101 Similarly, Treating the hypertensive hyperlipidaemic patient in the Greek Atorvastatin and Coronary heart An essential component of the management of the disease Evaluation (GREACE) trial102 atorvasta- hyperlipidaemic hypertensive patient is dietary and

Journal of Human Hypertension Statins and hypertension HJ Milionis et al 329 lifestyle advice. In addition to the standard non- (À1872%, Po0.01) and 10477 mm Hg in the pharmacological interventions (reduction in salt enalapril monotherapy group (À1271%, Po0.01).121 and alcohol intake), these patients require advice Statin plus antihypertensive drugs combination to reduce saturated fat, cholesterol and total caloric treatment has a favourable additive effect on intake and increase exercise. Lifestyle modification inflammation, arterial compliance and vascular should be recommended in the management of smooth muscle cell proliferation mediated by AT1 both hypertension and dyslipidaemia.111–114 Lipid- receptors.122–124 friendly (e.g. alpha-blockers) or lipid neutral (cal- The addition of a statin has also been shown to cium antagonists, ACE inhibitors, angiotensin II have an additional effect on reducing left ventricular receptor antagonists115) may be considered in the mass (a powerful predictor of cardiovascular events) context of hypertension and dyslipidaemia. In in patients with systemic hypertension and hyperli- addition, an extra BP-lowering effect may be pidaemia on antihypertensive agents and diet.125 In anticipated by lipid-lowering interventions. It is this context, the Hypertension High Risk Manage- also of interest that lipid-friendly and lipid neutral ment (HYRIM)126 trial investigated the effects of antihypertensives may also exert beneficial haemo- fluvastatin and lifestyle intervention in drug-treated static effects when compared with lipid hostile hypertensive patients with the primary end point BP-lowering drugs.116,117 being carotid intima-media thickness (IMT) progres- Combination therapy is of major interest in the sion over 4 years. Hypertension High Risk Manage- management of high-risk patients with dyslipidae- ment also investigated the effect of fluvastatin on the mia. Statins (pravastatin) plus ACE inhibitors development of left ventricular hypertrophy (LVH). (captopril) were shown to have additive effects Hypertension High Risk Management was a rando- on atherosclerosis reduction in hyperlipidaemic mised, placebo-controlled 2 Â 2 factorial trial. Dysli- hamsters.118 In another study, pravastatin, but not pidaemic middle-aged men (n ¼ 568) on treatment probucol, had an additional BP-lowering effect for hypertension were randomly assigned to receive in patients receiving antihypertensive therapy.119 either fluvastatin 40 mg/day or placebo and either In fact, systolic BP was significantly decreased intensive lifestyle intervention or usual care. Flu- after pravastatin treatment (from 141.274.7 to vastatin significantly reduced common carotid IMT 136.575.3 mm Hg, Po0.001), whereas no signifi- progression compared with placebo and usual care, cant changes were noted in diastolic BP levels (from whereas lifestyle intervention alone had no signifi- 81.374.9 to 80.675.1 mm Hg).119 cant effect on carotid IMT progression in patients In a 14-week, open, three-phase design study, receiving either fluvastatin or placebo treatment. carried out on 30 HC, hypertensive subjects, Naz- Fluvastatin treatment significantly (P ¼ 0.0144) re- zaro et al.120 found that simvastatin (10 mg daily) tarded the development of LVH compared with and enalapril (20 mg daily) had similar, distinct and placebo.126 On the other hand, in an experimental combined vascular effects. Stress-induced and post- model of NO-deficient hypertension, simvastatin ischaemic forearm blood flow and HDL-C levels monotherapy improved NO production and par- were significantly increased and vascular resistance tially prevented the development of hypertension lowered by both drugs. A significant additive effect via attenuation of the inhibition of eNOS, but had no was also observed on levels of LDL-C, HDL-C and significant effect on left ventricular mass or aorta BP, as well as on vascular damage (as reflected by a remodelling.127 decrease in minimal vascular resistance). Further- more, simvastatin monotherapy lowered diastolic BP modestly but significantly (À5% compared with Renal function, hypertension, lipids and statins À10% with enalapril).120 The association between renal function and hyper- In another study, Sposito et al.121 aimed at tension is well established.6,36,38–40,53 This associa- lowering diastolic BP at levels o95 mm Hg with tion may also be influenced by lipid changes enalapril and lisinopril in 70 HC hypertensive occurring in patients with renal disease and who patients, half of whom were treated with either also have a raised BP, as discussed above.6,36,38–40,53 pravastatin or lovastatin in order to achieve similar The contribution of lipids to the renal function– target concentrations of plasma TC (o5.2 mmol/l hypertension association may at least in part explain (200 mg/dl)). After 16 weeks, but not after 4 weeks of why statins exert beneficial effects on both renal treatment, the statin þ ACE inhibitor-treated group function and hypertension.6,36,38–40,53,128 It is also had a greater reduction in diastolic BP compared relevant that recent trials have shown that aggres- with the group receiving ACE inhibitor monother- sive treatment with statins improves serum creati- apy. The diastolic BP reduction correlated with nine and urate levels.129–137 These findings probably changes in TC (r ¼ 0.87, P ¼ 0.013). Reductions in reflect an improved creatinine clearance. In turn, systolic BP were greater on combination therapy this effect is probably another consequence of from the second week, but did not correlate with TC improved blood flow following treatment with reduction. From baseline levels averaging 118 mm statins. Serum creatinine and urate levels may also Hg, the mean BP was reduced to 9774 mm Hg after be considered as predictors of vascular risk.129,138 16 weeks of treatment in the combination group Thus, the beneficial effects of statins in hypertensive

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