Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 15, Number 5, 2009


Contents


Are the Pleiotropic Effects of Drugs Used for the Prevention of Cardiovascular Disease Clinically Relevant?
Executive Editors: M. Elisaf and E.N. Liberopoulos



Editorial Pp. 463-466


Statins and Cardiovascular Diseases: From Cholesterol Lowering to Pleiotropy Pp. 467-478
Q. Zhou and J.K. Liao
[Abstract] [Purchase Article] [PMID: 19199975 PubMed - indexed for MEDLINE]


Pleiotropic Effects of Statins - Clinical Evidence Pp. 479-489
V.G. Athyros, A.I. Kakafika, K. Tziomalos, A. Karagiannis and D.P. Mikhailidis
[Abstract] [Purchase Article] [PMID: 19199976 PubMed - indexed for MEDLINE]


Lipid-Lowering Drugs Acting at the Level of the Gastrointestinal Tract Pp. 490-516
T.D. Filippatos and D.P. Mikhailidis
[Abstract] [Purchase Article] [PMID: 19199977 PubMed - indexed for MEDLINE]


Pleiotropic Effects of Fenofibrate Pp. 517-528
V. Tsimihodimos, E. Liberopoulos and M. Elisaf
[Abstract] [Purchase Article] [PMID: 19199978 PubMed - indexed for MEDLINE]


Effects of Thiazolidinediones Beyond Glycaemic Control Pp. 529-536
R.G. Kalaitzidis, P.A. Sarafidis and G.L. Bakris
[Abstract] [Purchase Article] [PMID: 19199979 PubMed - indexed for MEDLINE]


Fibrates and Microvascular Complications in Diabetes - Insight from the Field Study Pp. 537-552
J.C. Ansquer, C. Foucher, P. Aubonnet and K.L. Malicot
[Abstract] [Purchase Article] [PMID: 19199980 PubMed - indexed for MEDLINE]


Pleiotropic Effects of Rimonabant: Clinical Implications Pp. 553-570
J.-P. Després
[Abstract] [Purchase Article] [PMID: 19199981 PubMed - indexed for MEDLINE]


Pleiotropic Effects of Drugs Inhibiting the Renin-Angiotensin-Aldosterone System Pp. 571-584
P. Jankowski, M.E. Safar and A. Benetos
[Abstract] [Purchase Article] [PMID: 19199982 PubMed - indexed for MEDLINE]




Abstracts


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Editorial: Are the Pleiotropic Effects of Drugs Used for the Prevention of Cardiovascular Disease Clinically Relevant?

Cardiovascular disease (CVD) is the leading cause of death worldwide. Many drugs are currently used for CVD prevention. Some of these drugs seem to exhibit effects beyond their main indication that they are administered for. These so called ‘pleiotropic’ effects are believed to contribute to the clinical benefits these drugs offer. Furthermore, they may differentiate drugs within the same category.

The aim of the present issue of Current Pharmaceutical Design is to comprehensively review the pleiotropic actions associated with drugs commonly used for CVD prevention. Authors are leading experts in their field and they also present their own research contribution.

Statins are the mainstay of lipid-lowering therapy [1]. Statin treatment is associated with less CVD evens and deaths both in primary and secondary prevention [2]. It has been suggested that the main mechanism by which statins reduce CVD events is lowering of low-density lipoprotein cholesterol (LDL-C) [3]. Indeed, lowering of LDL-C by other means also leads to reduced CVD events [4,5]. However, the lag time for these CVD benefits to become apparent is approximately 5 years when LDL-C is lowered by non-statin means, but much lower (i.e. <1 year) when statins are used, for the same degree of LDL-C lowering [6,7]. Newer statins (such as atorvastatin) may require only 15 days to differentiate from older statins (such as pravastatin) in terms of CVD protection in very high-risk patients [8]. Moreover, statin pretreatment for only 12 hours before a percutaneous coronary intervention may be associated with a large reduction of CVD events as compared with placebo [9]. It is clear that LDL-C lowering itself cannot fully explain these immediate vascular statin effects. It should be remembered that mevalonic acid, the product of 3-hydroxyl-3-methylgloutaryl coenzyme A (HMG-CoA) reductase, is the precursor not only of cholesterol but also of non-steroidal isoprenoid compounds. These compounds serve as important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42 and mediate a number of adverse vascular and metabolic reactions. Thus, inhibition of HMG-CoA reductase by statins leads not only to reduced cholesterol synthesis, but also to a decrease in these intracellular signaling molecules. It has been suggested that LDL-C decrease is responsible for the long-term beneficial effects of statins, while the elimination of isoprenoid compounds is associated with the immediate vasculoprotective actions seen with statin treatment. In this issue, Zhou and Liao extensively review the underlying molecular mechanisms responsible for the cholesterol-independent statin effects [10]. These mainly include improvement of endothelial function, antiiflammatory and antioxidant effects as well as normalization of coagulation-fibrinolysis system [10]. Statins may also decrease blood pressure [11], have antiarrhythmic properties [12], as well as reduce serum uric acid levels and improve renal function [13]. In this issue, Athyros et al. comprehensively review current evidence from clinical trials regarding the contribution of these pleiotropic effects to improved clinical outcomes [14]. They conclude that these effects do indeed contribute to the clinical benefit afforded by statins. The very recently published Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) may be relevant in this context [15]. In JUPITER 17,802 primary prevention subjects with LDL-C <130 mg/dL but elevated levels of high sensitivity C-reactive protein (hsCRP) (>2 mg/L) were randomly assigned to either placebo or rosuvastatin 20 mg/day. LDL-C and hsCRP levels were reduced by 50% and 37%, respectively, in the active treatment group. The trial was prematurely stopped after only 1.9 years due to impressive reductions in CVD events (by 44%, p<0.00001) and all-cause death (20%, p=0.02). Which is the relative contribution of LDL-C and hsCRP reduction to this clinical benefit remains to be determined.

A common strategy for augmenting LDL-C lowering is the addition of a drug that blocks intestinal cholesterol absorption to current statin treatment. The most commonly used drug in this setting is ezetimibe, the addition of which offers incremental LDL-C lowering [16]. Other options include bile acid sequestrants (BAS), phytosterols and orlistat. Do these agents (especially ezetimibe) have additional properties except for LDL-C lowering? Fillipatos and Mikhailidis extensively review current literature and conclude that these drugs do have cholesterol-independent effects [17]. Whether these additional actions contribute to improved clinical outcome remains unknown and is a matter of controversy. The same holds true for the question whether similar LDL-C lowering either by high-dose of a statin or by low-dose of a statin plus ezetimibe leads to the same clinical benefit [18,19]. Also, is further LDL-C reduction with ezetimibe clinically meaningful? A recent study, the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE), was the first to assess the additional clinical benefits of ezetimibe/simvastatin combination over simvastatin alone in terms of carotid intima media thickness (CIMT) reduction in patients with familial hypercholesterolemia [20]. No further benefit in terms of CIMT reduction by the addition of ezetimibe to high dose simvastatin treatment was seen, despite the incremental decrease of LDL-C and hsCRP. However, ENHANCE was only an imaging study and we have to wait the results of the Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (IMPROVE-IT) study which evaluates the clinical efficacy of ezetimibe/simvastatin 10/40 mg/day compared with simvastatin 40 mg/day monotherapy in patients (n=18,000) with acute coronary syndrome [21]. Until the results of ongoing studies with clinical endpoints are available, the whole dose range of powerful statins should be used and if treatment goals are not met, then one should consider the addition of ezetimibe [22] or a BAS [23].

Fibrates are widely used for the treatment of high triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C). Fibrates have been associated with CVD reduction, especially when used in individuals with atherogenic dyslipidaemia. The most commonly used fibrate is fenofibrate. Tsimihodimos et al. review current evidence for the existence of pleiotropic effects of fenofibrate [24]. They show that fenofibrate may improve endothelial function, exhibit antioxidant and antiinflammatory properties, attenuate thrombotic process, ameliorate insulin resistance, and, unique among all fibrates, decrease serum uric acid levels [24]. Are these effects of fenofibrate clinically useful? In the Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) study fenofibrate treatment, although not successful in reducing the primary end-point of CVD death or non-fatal myocardial infarction, demonstrated a significant 30% reduction in the need for laser therapy in patients with and without known diabetic retinopathy [25]. In addition, fenofibrate treatment was associated with less albuminuria progression and reduced risk of non traumatic amputations [26]. An indepth insight into these effects is provided by Ansquer et al. in this issue [27]. It is possible that the pleiotropic effects of fenofibrate are useful in reducing the microvascular complications of diabetes.

A drug class used for diabetes treatment is the glitazones, which serve as ligands for the gamma peroxisome proliferator-activated receptors (PPAR γ). Glitazones (pioglitazone and rosiglitazone) improve insulin resistance and reduce blood glucose levels. Data from human studies supports the concept that thiazolidinediones exert several other beneficial metabolic and vascular effects, in addition to glycaemic control, including improvement in lipid profile, blood pressure lowering, redistribution of body fat away from the central compartment, improvement in endothelial function as well as anti-inflammatory effects, such as reduction in hsCRP, decrease in microalbuminuria and amelioration of subclinical vascular inflammation [28]. Conversely, thiazolidinediones have well-established side effects, most important of which are fluid retention leading to weight gain and development of heart failure as well as an increased incidence of bone fractures [29]. In this issue, Kalaitzidis et al. shed light into the pleiotropic effects of glitazones [30]. Do these effects play any role in terms of CVD prevention in diabetics? The answer to this question remains obscure and may depend on the specific glitazone. Differences in the pleiotropic effects between the 2 glitazones (especially on lipid profile) may translate into differences in clinical benefit. Indeed, there is some evidence that pioglitazone may reduce CVD events [31], while the effects of rosiglitazone are either neutral or negative [32]. This is the reason why rosiglitazone is no longer recommended by the recent consensus algorithm for diabetes treatment [33].

An underlying feature of type 2 diabetes and the metabolic syndrome is abdominal obesity, which is strongly associated with CVD and mortality [34]. Recent research has highlighted the role of chronic overactivation of the endogenous endocannabinoid system, acting through its CB1 receptor, as a key factor involved in the development of abdominal obesity and related cardiometabolic risk abnormalities such as insulin resistance, low HDL-C, hypertriglyceridemia, inflammation and low adiponectin. Antagonism of the endocannabinoid system provides a novel strategy to target several unaddressed cardio-metabolic risk markers/factors. Randomized trials of rimonabant (an inhibitor of CB1 receptors) in patients with overweight or obesity and/or type 2 diabetes have demonstrated marked and significant improvements in body weight, waist circumference, glycemic control (in patients with type 2 diabetes), features of atherogenic dyslipidemia, insulin resistance, adipose tissue-derived cytokines (leptin and adiponectin) and hsCRP. Further analyses suggested that about half of the improvement of several cardiometabolic markers were independent from concomitant weight loss. Després critically analyzes these pleiotropic effects of rimonabant and their importance in clinical practice in this issue [35]. Unfortunately, an excess in psychiatric side effects (especially depression) associated with rimonabant use led to the recent decision of European Medicines Agency (EMEA) to suspend this drug [36].

Drugs inhibiting the renin-angiotensin-aldosterone system (RAAS) are widely used for hypertension treatment. In addition, these drugs may offer CVD protection in high-risk patients independently of the presence of hypertension [37]. Several pleiotropic effects of these agents have been elucidated. These include reduction of inflammation, oxidative stress and vascular remodeling in hypertension beyond blood pressure reduction. Also, these drugs may prevent onset of new type 2 diabetes [38]. Telmisartan is unique among the other angiotensin 2 receptor blockers in that it partially activates PPAR γ, thus being associated with further improvements of metabolic parameters [39]. In the recently published Ongoing Telmisartan Alone and in Combination with Ramipril Global End-point Trial (ONTARGET) telmisartan was as good as ramipril in reducing CVD events in high-risk patients [40]. However, their combination was not associated with any further improvement in CVD risk, while it was accompanied by an excess of side effects [40]. In this issue, Jankowski et al. review the pleiotropic effects of RAAS inhibitors and note that some of them may not be blood pressure-independent [41]. Instead, they state that there is growing agreement that the relatively greater influence of agents blocking RAAS on central blood pressure may at least partly explain their advantages over other antihypertensives in many clinical situations. Aliskiren is a novel renin inhibitor which promises to offer improved organ protection by inhibiting RAAS at its initial step of activation [42]. We have to wait results of ongoing studies to see whether aliskiren will hold its promise.

Drugs used for CVD prevention do have pleiotropic effects that contribute to their clinical benefit. Combination of these drugs together with intensive lifestyle changes is expected to substantially decrease the burden of CVD.

References

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[2] Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. for the Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267-78.

[3] Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005; 46: 1855-62.

[4] The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984; 251: 351-64.

[5] Buchwald H, Varco RL, Matts JP, Long JM, Fitch LL, Campbell GS, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med 1990; 323: 946-55.

[6] Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001-9.

[7] Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22.

[8] Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, et al. for the PROVE IT-TIMI 22 Investigators. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005; 46: 1405-10.

[9] Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G, et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007; 49: 1272-8.

[10] Zhou Q, Liao JK. Statins and cardiovascular diseases: from cholesterol lowering to pleiotropy. Curr Pharm Des 2009; 15(5): 467-78.

[11] Milionis HJ, Liberopoulos EN, Achimastos A, Elisaf MS, Mikhailidis DP. Statins: another class of antihypertensive agents? J Hum Hypertens 2006; 20: 320-35.

[12] Kostapanos MS, Liberopoulos EN, Goudevenos JA, Mikhailidis DP, Elisaf MS. Do statins have an antiarrhythmic activity? Cardiovasc Res 2007; 75: 10-20.

[13] Athyros VG, Mikhailidis DP, Liberopoulos EN, Kakafika AI, Karagiannis A, Papageorgiou AA, et al. Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Nephrol Dial Transplant 2007; 22: 118-27.

[14] Athyros VG, Kakafika AI, Tziomalos K, Karagiannis A, Mikhailidis DP. Pleiotropic effects of statins-clinical evidence. Curr Pharm Des 2009; 15(5): 479-89.

[15] Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. for the the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195-207.

[16] Mikhailidis DP, Sibbring GC, Ballantyne CM, Davies GM, Catapano AL. Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy. Curr Med Res Opin 2007; 23: 2009-26.

[17] Filippatos TD, Mikhalidis DP. Lipid-lowering drugs acting at the level of gastrointestinal tract. Curr Pharm Des 2009; 15(5): 490-516.

[18] Landmesser U, Bahlmann F, Mueller M, Spiekermann S, Kirchhoff N, Schulz S, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005; 111: 2356-63.

[19] Settergren M, Böhm F, Rydén L, Pernow J. Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease. Eur Heart J 2008; 29: 1711-3.

[20] Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, et al. for the ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358: 1431-43.

[21] Cannon CP, Giugliano RP, Blazing MA, Harrington RA, Peterson JL, McCrary Sisk C, et al. for the IMPROVE-IT Investigators. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): Comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J 2008; 156: 826-32.

[22] Liberopoulos EN, Rizos CV, Elisaf MS. Should we abandon ezetimibe? CML-Cardiology 2008; 27: 77-89.

[23] Florentin M, Liberopoulos EN, Mikhailidis DP, Elisaf MS. Colesevelam hydrochloride in clinical practice: a new approach in the treatment of hypercholesterolaemia. Curr Med Res Opin 2008; 24: 995-1009.

[24] Tsimihodimos V, Liberopoulos E, Elisaf M. Pleiotropic effects of fenofibrate. Curr Pharm Des 2009; 15(5): 517-28.

[25] Keech AC, Mitchell P, Summanen PA, O’Day JO, Davis TME, Moffitt MS et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007; 370: 1687-97.

[26] The FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (The FIELD study): randomised controlled trial. Lancet 2005; 366: 1849-61.

[27] Ansquer JC, Foucher C, Aubonnet P, Le Malicot K. Fibrates and microvascular complications in diabetes-insight from the FIELD study. Curr Pharm Des 2009; 15(5): 537-52.

[28] Rizos CV, Liberopoulos EN, Mikhailidis DP, Elisaf MS. Pleiotropic effects of thiazolidinediones. Expert Opin Pharmacother 2008; 9: 1087-108.

[29] Rizos CV, Elisaf MS, Mikhailidis DP, Liberopoulos EN. How safe is the use of thiazolidinediones in clinical practice? Expert Opin Drug Saf 2009; in press.

[30] Kalaitzidis RG, Sarafidis PA, Bakris GL. Effects of thiazolidinediones beyond glycaemic control. Curr Pharm Des 2009; 15(5): 529-36.

[31] Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. for the PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279-89.

[32] Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2457-71.

[33] Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2008; 31: 1-11.

[34] Pischon T, Boeing H, Hoffmann K, Bergmann M, Schulze MB, Overvad K, et al. General and abdominal adiposity and risk of death in Europe. N Engl J Med 2008; 359: 2105-20.

[35] Després J-P. Pleiotropic effects of rimonabant: clinical implications. Curr Pharm Des 2009; 15(5): 553-70.

[36] Press Release - The European Medicines Agency recommends suspension of the marketing authorisation of Acomplia. Available at http://www.emea.europa.eu/ [Last assessed October 29, 2008].

[37] Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G for the Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145-53.

[38] Liberopoulos EN, Tsouli S, Mikhailidis DP, Elisaf MS. Preventing type 2 diabetes in high risk patients: An overview of lifestyle and pharmacological measures. Curr Drug Targets 2006; 7: 211-28.

[39] Karagiannis A, Mikhailidis DP, Athyros VG, Kakafika AI, Tziomalos K, Liberopoulos EN, et al. The role of renin-angiotensin system inhibition in the treatment of hypertension in metabolic syndrome: are all the angiotensin receptor blockers equal? Expert Opin Ther Targets 2007; 11: 191-205.

[40] Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. for the ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547-59.

[41] Jankowski P, Safar ME, Benetos A. Pleiotropic effects of drugs inhibiting the renin-angiotensin-aldosterone system. Curr Pharm Des 2009; 15(5): 571-84.

[42] Brown MJ. Aliskiren. Circulation 2008; 118: 773-784.


Moses Elisaf
Evangelos N. Liberopoulos
Department of Internal Medicine
Medical School, University of Ioannina
451 10 Ioannina
Greece
Tel: +302651097509
Fax: +302651097016
E-mail: egepi@cc.uoi.gr; vaglimp@yahoo.com


[Back to top] [Purchase Article] [PMID: 19199975 PubMed - indexed for MEDLINE]
Statins and Cardiovascular Diseases: From Cholesterol Lowering to Pleiotropy
Q. Zhou and J.K. Liao

Statins are 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are prescribed extensively for cholesterol lowering in the primary and secondary prevention of cardiovascular disease. Recent compelling evidence suggests that the beneficial effects of statins may not only be due to their cholesterol lowering effects, but also, to their cholesterol-independent or pleiotropic effects. Through these so-called pleiotropic effects, statins are directly involved in restoring or improving endothelial function, attenuating vascular remodeling, inhibiting vascular inflammatory response, and perhaps, stabilizing atherosclerotic plaques. These cholesterol-independent effects of statins are predominantly due to their ability to inhibit isoprenoid synthesis, the products of which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil containing protein kinase (ROCK), has emerged as the principle mechanisms underlying the pleiotropic effects of statins. This review provides an update of statin-mediated vascular effects beyond cholesterol lowering and highlights recent findings from bench to bedside to support the concept of statin pleiotropy.


[Back to top] [Purchase Article] [PMID: 19199976 PubMed - indexed for MEDLINE]
Pleiotropic Effects of Statins - Clinical Evidence
V.G. Athyros, A.I. Kakafika, K. Tziomalos, A. Karagiannis and D.P. Mikhailidis

The present review considers the potential pleiotropic effects of statins and the evidence indicative of the “real world” benefit from these effects in patients with cardiovascular disease (CVD). Some of these cholesterol-independent effects of statins involve improved endothelial function, stability of atherosclerotic plaques, attenuation of oxidative stress and inflammation, as well as inhibition of the thrombogenic response. Clinical evidence from early statin administration in acute coronary syndromes and in revascularisation procedures is reported. Moreover, the “metabolic” effects of statin treatment, such as renal function improvement and reduction in serum uric acid levels, in patients with stable coronary heart disease are discussed.

Evidence suggests that in high CVD risk patient groups pleiotropic effects of statins may play a role in the reduction of morbidity and mortality. However, this concept requires proof in appropriately designed trials that will include clinically relevant end points in order to set specific targets in new CVD-related biomarkers, in addition to lipid levels, that should be used to fully assess the statin contribution to CVD treatment.


[Back to top] [Purchase Article] [PMID: 19199977 PubMed - indexed for MEDLINE]
Lipid-Lowering Drugs Acting at the Level of the Gastrointestinal Tract
T.D. Filippatos and D.P. Mikhailidis

This review considers the hypolipidaemic drugs that act on the gastrointestinal (GI) tract. We searched PubMed up to April 2008 and included randomized controlled trials, original papers, review articles and case reports. Bile acid sequestrants (BAS) have a well-established low density lipoprotein cholesterol (LDL-C) lowering effect, but may increase triglyceride (TG) levels. BAS have no systematic adverse effects, but are associated with increased GI adverse effects and interactions with the absorption of other drugs. Ezetimibe improves LDL-C, high density lipoprotein cholesterol and TG levels, as monotherapy or especially when given with a statin. Ezetimibe has not been associated with serious adverse ef-fects. Ezetimibe has not been evaluated in large clinical trials with cardiovascular disease (CVD) endpoints. Phytosterols are not licensed drugs; they have a well-established LDL-C lowering effect, but there are no large long-term randomized clinical trials investigating their effects on CVD events. Orlistat is an antiobesity drug with a small additional LDL-C lowering effect independent of weight loss. Orlistat-assisted weight loss improves the overall lipid profile, carbohydrate metabolism and transaminase activities. However, its use should be limited to weight reduction. This drug is associated with increased GI adverse effects.


[Back to top] [Purchase Article] [PMID: 19199978 PubMed - indexed for MEDLINE]
Pleiotropic Effects of Fenofibrate
V. Tsimihodimos, E. Liberopoulos and M. Elisaf

Fenofibrate represents the most commonly used fibric acid derivative. The drug exerts its metabolic effects by modulating the expression of several genes involved in lipoprotein metabolism. In addition, numerous studies suggest that fenofibrate may also affect the progression of the atherosclerotic process by several lipid-independent mechanisms. This review considers the clinical pharmacology of fenofibrate and the current evidence on the pleiotropic effects of this fibric acid derivative.


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Effects of Thiazolidinediones Beyond Glycaemic Control
R.G. Kalaitzidis, P.A. Sarafidis and G.L. Bakris

The incidence of type 2 diabetes continues to increase in the western world over the past decade. Consequently, complications of this disease have reached crisis proportions. In addition to the classical oral hypoglycaemic agents, i.e. sulfonylureas, newer classes have emerged that work by different mechanisms such as insulin sensitizers. One such class are the thiazolidinediones (rosiglitazone and pioglitazone). These agents act as ligands for the gamma peroxisome prolif-erator-activated receptors (PPARs) and result in a lower glucose. Data from animal and human studies supports the concept that thiazolidinediones exert several other beneficial metabolic and vascular effects, in addition to glycaemic control, including improvement in lipid profile, blood pressure lowering, redistribution of body fat away from the central compartment, anti-inflammatory effects such as reduction in hs-CRP and microalbuminuria as well as subclinical vascular inflammation, improvement in endothelial function. Conversely, thiazolidinediones have well-established side effects, most important of which are fluid retention leading to weight gain and development of heart failure as well as an increased incidence of bone fractures. Moreover, evidence from clinical trials suggests that these agents do not reduce cardiovascular risk. This article discusses the pleiotropic effects of thiazolidinediones focusing on clinical cardiovascular outcomes as well as other potential therapeutic uses in the context of their side-effect profile.


[Back to top] [Purchase Article] [PMID: 19199980 PubMed - indexed for MEDLINE]
Fibrates and Microvascular Complications in Diabetes - Insight from the Field Study
J.C. Ansquer, C. Foucher, P. Aubonnet and K.L. Malicot

Fibrates are widely prescribed lipid-lowering drug in the treatment of dyslipidemia. Their main clinical effects, mediated by peroxisome proliferative activated receptor (PPAR) alpha activation, are a moderate reduction in total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, a marked reduction in triglycerides (TG) and an increase in high-density lipoprotein cholesterol (HDL-C), usually dependent of their baseline levels and dyslipidemia type. A beneficial effect on cardiovascular outcomes but also on inflammatory and thrombogenesis pathways as well as antioxidant properties have been evidenced conferring other pleiotropic effects to fibrates. Diabetic retinopathy, nephropathy and neu-ropathy are the major microvascular complications of Type 2 diabetes mellitus (T2DM) and their presence can accentuate the risk of cardiovascular disease. Hyperglycemia, hypertension, genetic susceptibility among other risk factors play a significant role in the development and progression of these complications. Plasma lipid abnormalities are also involved in the pathogenesis of microvascular diseases suggesting a potential benefit of lipid lowering drugs in their prevention. Clofibrate was the first fibrate in the 60’s to show an improvement in the retinal hard exudation in subjects with diabetic retinopathy. Recently, in the Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) study fenofibrate treatment demonstrated a significant 30% reduction in the need for laser therapy in patients with and without known diabetic reti-nopathy, and more particularly in the first course of laser treatment for both macular edema and proliferative retinopathy. In addition, fenofibrate treatment was associated with less albuminuria progression and reduced risk of non traumatic dis-tal amputations. These results, along with previous evidence of positive effects on microvascular complications, suggest that fibrates, and particularly fenofibrate, offer good opportunity to prevent the most serious complications of diabetes.


[Back to top] [Purchase Article] [PMID: 19199981 PubMed - indexed for MEDLINE]
Pleiotropic Effects of Rimonabant: Clinical Implications
J.-P. Després

Abdominal obesity (high waist circumference) is more strongly associated with cardiovascular disease and type 2 diabetes than generalized adiposity (high body mass index). Recent research has highlighted the role of chronic overactivation of the endogenous endocannabinoid system, acting through its CB^₁ receptor, as a key factor involved in the development of abdominal obesity and related cardiometabolic risk abnormalities such as insulin resistance, low HDL-cholesterol, hypertriglyceridemia, inflammation and low adiponectin. Evidence suggests that these cardiometabolic risk factors/markers are not optimally managed by current treatments. Improving the nutrition and physical activity/exercise habits of patients remains the cornerstone of management of elevated global cardiometabolic risk. Antagonism of the endocannabinoid system provides a novel strategy to target several unaddressed cardiometabolic risk markers/factors. Ran-domized trials of rimonabant in patients with overweight or obesity and/or type 2 diabetes have demonstrated marked and significant improvements in body weight, waist circumference, glycemic control (in patients with type 2 diabetes), features of atherogenic dyslipidemia, insulin resistance, adipose tissue-derived cytokines (leptin and adiponectin) and C-reactive protein (a marker of systemic inflammation). Further analyses suggested that about half of the improvements of several cardiometabolic risk markers were independent from concomitant weight loss. Blood pressure also improved with rimonabant treatment, this effect being consistent with the blood pressure lowering effect of weight loss. The tolerability and safety of rimonabant have been extensively studied and most transient side effects include some gastrointestinal side effects, anxiety, mood changes and incidence of depressive disorders, particularly in patients with previous history of depression. Rimonabant is a useful option for patients with abdominal obesity and with related cardiometabolic risk abnormalities such as an atherogenic dyslipidemia and/or type 2 diabetes.


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Pleiotropic Effects of Drugs Inhibiting the Renin-Angiotensin-Aldosterone System
P. Jankowski, M.E. Safar and A. Benetos

The renin-angiotensin-aldosterone system blockade is a key component in the modern management of cardiovascular diseases. Agents that interfere with the different components of this system such as angiotensin converting enzyme inhibitors, sartans and mineralocorticoid receptor antagonists represent valuable therapeutic tools to reduce cardiovascular risk in brachial blood pressure independent mechanisms. Indeed, antagonists of the renin-angiotensin-aldosterone system reduce inflammation, oxidative stress and vascular remodeling in hypertension beyond blood pressure reduction and have demonstrated better cardiovascular protection compared with some of the other antihypertensive agents, especially in selected populations such as patients with diabetes and renal failure. These advantages were confirmed recently in several large-scale randomized trials. Latest evidence suggests that the effect of some antihypertensive drugs on central blood pressure is greater when compared with the effect on peripheral pressure. Nowadays, there is growing agreement that relatively greater influence of agents blocking reninangiotensin system on central blood pressure may at least partly explain their advantages over other antihypertensives in many clinical situations. Clinical consequences of overestimation of the antihypertensive effect of some drug classes and underestimation blood pressure changes in patients treated with angiotensin converting enzyme inhibitors when analyzing brachial instead of central blood pressure is being increasingly recognized recently.