Which drugs should be combined with antihypertensive agents to ensure synergistic vascular protection?






Stefano TADDEI, MD
Department of Clinical and Experimental Medicine
University of Pisa
Pisa, ITALY

Rosa Maria BRUNO, MD, PhD
Institute of Clinical Physiology
CNR, Pisa, ITALY

Which drugs should be combined with antihypertensive agents to ensure synergistic vascular protectionh


by S. Taddei and R. M. Bruno, Italy



Cardiovascular risk stratification in hypertensive patients plays a key role in deciding what therapeutic strategy to take. Current European Society of Cardiology (ESC)/European Society of Hypertension (ESH) Guidelines recommend taking into consideration not only blood pressure values and target organ damage, but also the presence of other risk factors beyond hypertension. This approach is justified by the fact that associated risk factors critically influence morbidity and mortality in hypertensive patients, determining the so-called residual risk. For example, the cardiovascular event rate, though perhaps reduced by blood pressure control may remain unacceptably high in some patients. Thus, the possibility of using drug classes that exert additional vasculoprotective benefits beyond their main action is appealing. This article aims to review recommended therapeutic options for risk factors associated with arterial hypertension, focusing on the most effective options for vascular protection. In particular, the effects on hard end points as well as on vascular function and structure of old and new lipid-lowering drugs (including statins, fibrates, omega 3 polyunsaturated fatty acids, ezetimibe, and highdensity lipoprotein–raising drugs), glucose-lowering drugs (including insulin providers, insulin sensitizers, and glucose absorption inhibitors), and antiplatelet drugs will be discussed.

Medicographia. 2015;37:412-420 (see French abstract on page 420)



In hypertension, cardiovascular (CV) risk stratification of patients is very important for choosing a therapeutic strategy. For estimating CV risk, the current European Society of Cardiology (ESC)/European Society of Hypertension (ESH) Guidelines recommend considering not only blood pressure (BP) values and target organ damage, but the presence of other CV risk factors beyond hypertension as well.1 Indeed, associated risk factors heavily influence CV morbidity and mortality in hypertensive patients.

Here we review recommended therapeutic options for risk factors associated with arterial hypertension, with a focus on those demonstrating the most effective vascular protection. The effects of lipid-lowering, glucose-lowering, and antiplatelet drugs on hard end points, as well as vascular function and structure, will be reviewed. Table I provides a brief summary of the known effects of such drugs on vasculoprotection in patients with CV risk factors.


Table I
Table I. Summary of known effects of lipid-lowering,
glucose-lowering, and antiplatelet drugs on vasculoprotection
in patients with cardiovascular risk factors.

“+,” “++,” and “+++” indicate a positive effect; “-” indicates a negative
effect; “=” indicates a neutral effect; NA, data not available.
Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like
peptide-1; HDL, high-density lipoprotein; n-3 PUFA, omega-3
polyunsaturated fatty acid.


Lipid-lowering drugs

Statins
Several randomized controlled trials (RCTs) have demonstrated the benefit of statin therapy either in primary or in secondary prevention for myocardial infarction and stroke, regardless of the presence of hypertension. For example, in the Heart Protection Study—the largest RCT testing a lipid-lowering drug ever conducted—simvastatin reduced the incidence of CV events in patients with established CV disease. This effect was evident even in the hypertensive subgroup (41% of the overall population), regardless of the antihypertensive drug class used.2 When overt coronary heart disease is present, there is clear evidence that statins should be administered to achieve low-density lipoprotein (LDL) cholesterol levels below 70 mg/dL.3

The ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) and ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) studies specifically recruited hypertensive patients in primary prevention, and obtained conflicting results. In the ALLHAT study, pravastatin administration (40 mg/day) significantly reduced total and LDL cholesterol levels without influencing CV morbidity and mortality.4 Conversely, in the ASCOT study, atorvastatin administration (10 mg/ day) caused a greater reduction in cholesterol levels than that seen in the ALLHAT study (20% reduction vs 11%), accompanied by a significant reduction in CV events (reduced by 36%) and in stroke (reduced by 27%).5 On the basis of the ASCOT results, current ESC/ESH Guidelines recommend the use of statins in patients with a 10-year CV risk greater than 20%, with a target level for LDL cholesterol of 115 mg/dL and for total cholesterol of 190 mg/dL.1


Figure 1
Figure 1. The effects of atorvastatin or placebo in the amlodipine/perindopril-based and atenolol/thiazide-based arms on the cumulative
incidence of myocardial infarction and fatal coronary artery disease in the ASCOT study.

Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; CI, confidence interval; HR, hazard ratio.
After reference 10: Sever et al. Eur Heart J. 2006;27:2982-2988. © 2006, European Society of Cardiology. All rights reserved.



Among additional benefits, statins might have a BP-lowering effect per se,6 though this finding was not confirmed in all studies.5 Other studies highlighted an effect on central, but not peripheral, BP values7,8; however, a degree of uncertainty exists due to scarce, conflicting data. In the ASCOT-LLA study (ASCOT – Lipid-Lowering Arm), the carotid augmentation index and carotid systolic BP levels were significantly lower after 18 months of atorvastatin treatment than in the place group.7 Conversely, in the CAFE-LLA study (Conduit Artery Function Evaluation – Lipid Lowering Arm), another ASCOT substudy, atorvastatin lowered LDL cholesterol by 32.4 mg/ dL in comparison with placebo, but had no impact on augmentation index and central aortic BP.9 Interestingly, CV prevention induced by statins was greater in hypertensive patients enrolled in the amlodipine/perindopril arm, with a significant 53% reduction in the primary outcome, as compared with those enrolled in the atenolol/thiazide arm, according to a subanalysis of the ASCOT study, suggesting a synergistic effect between certain antihypertensive drug classes and statins (Figure 1, page 413).10 Experimental and clinical studies have also shown beneficial actions of statins for the vasculature that may extend beyond their lipid-lowering properties, such as improvement of endothelial function, inhibition of vascular smooth muscle cell proliferation, and reduction in vascular inflammation.11 However, it is interesting to note that in hypertensive patients with normal cholesterol levels, a 2-week treatment with fluvastatin did not modify BP, endothelial function, and oxidative stress.12

Conversely, studies investigating the effect of statins on arterial stiffness have given contradictory results, especially those recruiting hypertensive hypercholesterolemic patients.13 However, this finding could, in some cases, result from methodological limitations (eg, small sample sizes, short duration of the intervention, and nonrandomized clinical design) rather than represent the absence of a true treatment effect. With regards to mechanistic background, the possible “destiffening” effect of statins is not related as much to changes in serum lipid profile as to improvement in endothelial function and reduction in oxidative stress.8,14

Fibrates
Fibrates are lipid-lowering drugs, acting as peroxisome proliferator- activated receptor (PPAR)-ϒ agonists and are prescribed mainly for their beneficial effects on triglyceride and high-density lipoprotein (HDL) cholesterol levels, accompanied by total and LDL cholesterol reduction. Their beneficial effect on CV outcome was demonstrated in high-risk patients when administered as an alternative to statins; however, in the ACCORD study (Action to Control Cardiovascular Risk in Diabetes), combination therapy between fenofibrate and statin did not reduce the incidence of CV events in type 2 diabetic patients, despite significant amelioration of the lipid profile.15 Interestingly, a small RCT enrolling hypertriglyceridemic hypertensive patients compared fenofibrate, candesartan, and combination therapy: whereas an improved flow-mediated dilation (FMD) was found in all three treatment arms, combination therapy was superior in terms of reduction in plasma malondialdehyde, high-sensitivity C-reactive protein, and soluble CD40L levels.16 Furthermore, a BP-lowering effect of fenofibrate was demonstrated, at least in salt-sensitive hypertensive patients.17 The authors hypothesized a counteracting effect on the kidney, reducing renal vasoconstriction mediated by the renin- angiotensin and sympathetic nervous system. Currently, since fibrates have not been specifically tested in hypertensive patients for CV-event reduction, the strongest evidence of benefit is for their addition to statin treatment in high-risk patients with type 2 diabetes and dyslipidemia.





Omega-3 polyunsaturated fatty acids
Omega-3 polyunsaturated fatty acids (n-3 PUFA), and in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential components of the phospholipidic membrane that should be introduced mainly by fish consumption or commercially available supplements. Among RCTs, the JELIS study (Japan EPA Lipid Intervention Study) enrolled 18 000 hypercholesterolemic patients randomized to statin alone or in combination with EPA (600 mg three times a day).18 This study demonstrated a significant reduction in coronary events after a 4.6-year follow-up only in patients with established CV disease. Though this result might be due to known antiarrhythmic effects of n-3 PUFA, a vasculoprotective effect is also suggested. Experimental studies have demonstrated that n-3 PUFA can reduce the production of vasoconstrictor, proinflammatory, and prothrombotic molecules and can modulate the expression of proinflammatory and proatherogenic genes.19 Thus, it has been hypothesized that n-3 PUFA might exert a particular vasculoprotective action that goes beyond the triglyceride-lowering effect. Furthermore, a BP-lowering effect was demonstrated in hypertriglyceridemic patients with high-normal BP.20 In conclusion, supplementation with n-3 PUFA is indicated in hypertriglyceridemic hypertensive patients; additive benefits are suggested by some studies, but do not justify widespread treatment.

Ezetimibe
Ezetimibe is an inhibitor of intestinal absorption of cholesterol. The use of ezetimibe is of interest in clinical practice because it allows achievement of LDL targets with statins used at low doses and thus might be used in statin-intolerant patients. Its clinical efficacy has been questioned since publication of the ENHANCE study (Ezetimibe and simvastatiN in Hypercholesterolemia enhANces atherosClerosis rEgression), which demonstrated a smaller reduction in intima-media thickness and a higher incidence of CV events, despite a greater LDL reduction, with statin plus ezetimibe than with statin plus niacin in patients with established CV disease or risk-equivalent.21 That study suggested a lack of vascular protection from ezetimibe, despite the lipid-lowering efficacy, which translates into a lack of effect on hard end points. Interestingly, a post hoc analysis on 159 patients randomized to ezetimibe within the ARBITER 6-HALTS study (ARterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol 6-HDL And LDL Treatment Strategies in atherosclerosis) demonstrated a paradoxical increase in carotid intima-media thickness (CIMT) associated with LDL-cholesterol reduction: the greater the exposure to ezetimibe, the greater the CIMT increase. The authors hypothesized off-target mechanisms and/ or counterregulatory mechanisms that may interfere with the positive effects from the lowering of LDL.22 Accordingly, an RCT enrolling 234 coronary artery disease patients with LDL cholesterol levels below 70 mg/dL after treatment with atorvastatin 10 mg randomized the patients to doubling of the atorvastatin dose or adding ezetimibe 10 mg to the treatment regimen. In the group randomized to doubling of the atorvastatin dose, LDL reduction was less marked than in the ezetimibe– add-on group, but endothelial function showed greater improvement, as measured by peripheral arterial tonometry.23 Conversely, in a different study, ezetimibe 10 mg plus simvastatin 10 mg had an effect similar to simvastatin 80 mg on endothelial function in obese patients with metabolic syndrome.24 As the SHARP study (Study of Heart And Renal Protection) enrolling 9438 patients with chronic kidney disease demonstrated a significant reduction in CV events—proportional to LDL reduction—in patients randomized to ezetimibe 10 mg plus simvastatin 20 mg as compared with placebo,25 it seems reasonable to recommend this association in hypertensive patients with chronic kidney disease. To our knowledge, vascular protection with ezetimibe in the hypertensive population has yet to be studied.

High-density lipoprotein–raising drugs
Up to now, drugs designed to raise the level of HDL cholesterol have had disappointing results for reduction in CV events. For example, extended-release niacin, which was effective in reducing CIMT,21 failed to reduce CV events and increased adverse events in 25 673 high-risk patients enrolled in the HPS2-THRIVE study (Heart Protection Study 2 – Treatment of HDL to Reduce the Incidence of Vascular Events).26 The dalcetrapib story tells us a lot about the importance of vascular protection for effective CV reduction in high-risk patients. In the dal-VESSEL RCT (a study showing the safety, tolerability, and effect on endothelial function of dalcetrapib in patients with or at risk of coronary heart disease), 466 patients received either dalcetrapib (a cholesteryl ester transfer protein inhibitor) at 600 mg/day or placebo for 36 weeks on top of standard therapy (including statins).27 The primary outcome measure was the change from baseline in FMD of the right brachial artery. After 36 weeks, no change in FMD despite increased HDL levels was demonstrated.27 Accordingly, no benefit on CV events in the dal-OUTCOME study (a study showing the effect of dalcetrapib on CV mortality and morbidity in clinically stable patients with a recent acute coronary syndrome) was observed, suggesting that short-term RCTs using vascular biomarkers as surrogate end points might be useful in CV research as they may speed up selection of the most promising drugs without setting up long-term, expensive RCTs for hard end points.

Glucose-lowering drugs

Hypertensive patients with diabetes mellitus are automatically classified as having a very high CV risk by ESC/ESH Guidelines1; thus, glucose control is a crucial issue for achieving CV protection in hypertensive diabetic patients. In past decades, a number of large RCTs were designed to address this issue. The effects on macrovascular complications—on CV events in particular—and the glycated hemoglobin A1c (HbA1c) threshold to reach in order to obtain benefits in that regard, was then investigated in the ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation) and ACCORD studies.28,29 In the ADVANCE study, intensive glycemic control (HbA1c approximately 6.5%) led to a significant reduction in the primary composite end point (microand macrovascular complications), whereas CV events were not significantly reduced and severe hypoglycemic episodes were increased in comparison with standard treatment.28 The ACCORD study was prematurely stopped due to increased mortality in the intensive treatment arm.29 Later meta-analyses have documented that more intensive glycemic control is likely to reduce nonfatal coronary events and myocardial infarction, as well as nephropathy, but not stroke or all-cause or CV mortality.30 Thus, international scientific societies recommend, even in hypertensive diabetic individuals, a target HbA1c of 7%. Caution should be used in patients with a positive history of severe hypoglycemia, long diabetes duration, and multiple comorbidities, for whom higher (less stringent) HbA1c targets are acceptable.1

Arterial hypertension and type 2 diabetes mellitus often coexist and are both characterized by increased arterial stiffness and endothelial dysfunction.31 Endothelial dysfunction is a determinant of aortic stiffness in hypertensive diabetic patients, but not in hypertensive patients without diabetes, suggesting a mechanistic role for endothelium-related mechanisms.31 For this reason, a number of studies investigated possible differences in vasculoprotection exerted by different glucose-lowering therapeutic agents.

Insulin providers
This group includes insulin, sulfonylureas, meglitinides and incretin mimetics, including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors; these drug classes all act by stimulating endogenous insulin secretion by the pancreatic βcell. The GLP-1 receptor agonists also favor weight loss, by modulation of the sense of satiety: this beneficial effect is associated with a significant reduction in BP values in comparison with insulin, as demonstrated by a retrospective analysis of a large cohort database (Figure 2).32 Furthermore, a retrospective analysis performed on the LifeLink database demonstrated that exenatide treatment was associated with a lower risk of CV events and CV related and all-cause hospitalizations in comparison with other glucose-lowering therapies.33 However, there are no RCTs available that specifically address this point.


Figure 2
Figure 2. Adjusted association between BP-lowering effect of exenatide and weight loss in a retrospective analysis of the General
Electric Centricity research database.

*, P<0.05; **, P<0.0001; compared with patients who did not lose weight. Orange indicates exenatide; green, sitagliptin; and red, insulin. Abbreviations:CI, confidence interval; DBP, diastolic blood pressure; SBP, systolic blood pressure.
After reference 32: Horton et al. Diabetes care. 2010;33:1759-1765. © 2010, American Diabetes Association.



In contrast, sulfonylureas may lead to body weight gain, thus promoting the development of hypertension: this adverse effect might explain the neutral effect on arterial stiffness despite the glucose-lowering effect.34 A 10-year post-trial follow up of UKPDS (UK Prospective Diabetes Study) revealed that the patient group treated with either sulfonylurea or insulin(sulfonylurea-insulin) had a significantly reduced risk of myocardial infarction and all-cause death; however, metformin outperformed sulfonylurea-insulin as far as CV protection was concerned.35,36 In a meta-analysis of clinical trials, combination therapy with metformin and sulfonylureas was associated with reduced survival.37 Scarce data are available on the CV safety of mitiglinides; however, nateglinide was neutral on CV outcomes in individuals with impaired glucose tolerance.38

The effect of the DPP-4 inhibitor saxagliptin on CV outcomes in patients with type 2 diabetes was investigated by the SAVOR- TIMI 53 trial (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus – Thrombolysis In Myocardial Infarction 53). Despite improvement in glycemic control, results of that trial, enrolling 16 492 patients followed-up for 2.1 years, were neutral in terms of ischemic events rate, with a significantly increased rate of hospitalization for heart failure in the treatment arm compared with placebo.39 Also, in the EXAMINE trial (EXamination of cArdiovascular outcoMes with alogliptIN versus standard care in patients with type 2 diabetes mellitus and acute coronary syndrome), the rates of major adverse CV events were not increased by alogliptin treatment in diabetic patients who had had a recent acute coronary syndrome.40 From the pathophysiological point of view, DPP-4 inhibitor use is associated with improved endothelial function, antioxidant and anti-inflammatory actions, and renal effects.41 For example, in type 2 diabetic subjects, vildagliptin caused an increase in vasodilation in response to acetylcholine, a measure of endothelial function.42 Furthermore, DPP-4 inhibitors might have a direct BP-lowering effect, by modulation of the cross-talk between the sympathetic nervous system and angiotensin II at the renal vascular level.41 Indeed, a small reduction in BP was observed in nondiabetic hypertensive patients treated with the DPP-4 inhibitor sitagliptin.43

Insulin sensitizers
This group of therapeutic agents includes metformin and glitazones. Glitazones are PPAR-ϒ agonists with partial α effects, which lower glucose by ameliorating insulin resistance, while metformin is a biguanide that exerts similar effects through adenosine monophosphate (AMP) kinase activation.

In addition to its hepatic-mediated hypoglycemic actions in human subjects, the CV benefits of metformin were demonstrated early on by the UKPDS study in patients with type 2 diabetes mellitus, particularly in overweight diabetic patients.35,36 A meta-analysis of 35 clinical trials suggested a beneficial effect on CV morbidity and mortality that was more evident for younger patients and longer treatment duration.37 Metformin improved endothelial function in patients with type 2 diabetes mellitus via an action that seems to be unrelated to its hypoglycemic actions, but rather to insulin resistance and oxidative stress amelioration; a direct vascular effect is also possible.44 Metformin was also shown to reduce arterial stiffness in several studies, including in patients with type 2 diabetes mellitus.45


Figure 3
Figure 3. Potential mechanisms leading to arterial stiffness reduction after treatment
with SGLT2 inhibitors.

Abbreviations: AS, arterial stiffness; BP, blood pressure; SGLT2, sodium-glucose cotransporter-2.
After reference 52: Cherney et al. Cardiovasc Diabetol. 2014;13:28. © 2014, Cherney et al; license
BioMed Central Ltd.



CV safety of glucose-lowering drugs was a neglected issue for many years, until publication of a 42-trial meta-analysis highlighted an excess rate of myocardial infarction in patients treated with rosiglitazone, a PPAR-ϒ agonist.46 Conversely, pioglitazone in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events) achieved a significant reduction in a secondary composite outcome of all-cause mortality, fatal myocardial infarction, and stroke.47 Treatment with pioglitazone was shown not only to improve insulin resistance and glycemic control, but also to decrease arterial stiffness and improve endothelial function in obese glucosetolerant men.48

Glucose absorption inhibitors
This group includes α-glucosidase inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors. The &lapha;-glucosidase inhibitor acarbose reduces glucose absorption from the gastrointestinal tract, and the SGLT2 inhibitors act on the proximal renal tubule to reduce glucose absorption.

In the STOP-NIDDM trial (Study to Prevent Non–Insulin-Dependent Diabetes Mellitus), acarbose reduced CV morbidity and mortality in individuals with impaired glucose tolerance.49 Beyond the known reduction mainly of postprandial glucose levels, acarbose provides additional benefits in terms of weight loss, BP reduction, and lowering of triglycerides.50

The SGLT2 inhibitors represent a promising treatment option for diabetes and hypertension. Emerging data suggests that the SGLT2 inhibitors provide a significant reduction in BP, possibly due to a combination of diuresis, nephron remodeling, reduction in arterial stiffness, and weight loss.51 Interestingly, in 40 normotensive type 1 diabetes mellitus patients, empagliflozin determined a decline in arterial stiffness. The underlying mechanisms may relate to pleiotropic actions of SGLT2 inhibition, including glucose-lowering, antihypertensive, and weight reduction effects (Figure 3, page 417).52

Antiplatelet drugs

Based on current evidence, antiplatelet therapy is indicated in hypertensive patients with previous CV events and should be considered in patients with reduced renal function, provided that BP is well controlled.1 A large meta-analysis analyzed CV and hemorrhagic events in 6 primary prevention trials (95 000 individuals) and 16 secondary prevention trials (17 000 individuals), demonstrating that absolute CV benefit is greater than harm for antiplatelet therapy only in the latter group.53 A subanalysis of the HOT study (Hypertension Optimal Treatment), which was especially designed to evaluate risks and benefits of antiplatelet therapy in hypertensive patients, demonstrated that in patients with a glomerular filtration rate below 45 mL/min/1.73m2, the risk of bleeding was negligible in comparison with CV benefit.54 Additional benefits of aspirin might be due to a BP-lowering effect, as suggested by Hermida and coauthors, who highlighted a reduction in systolic BP of about 7 mm Hg and in diastolic BP of 5 mm Hg by 24-hour BP monitoring, when aspirin is administered at bedtime, but not when administered on awakening.55 The bedtime timing of aspirin intake seems to enable it to better influence renin-angiotensin activity and levels of cortisol and catecholamine, all of which increase in the early morning hours according to a circadian pattern.56

Conclusions

Residual CV risk is a crucial issue in the management of hypertensive patients, whose CV-event rate is reduced, but not normalized, by effective BP control. In high-risk patients with multiple comorbidities, the CV-event rate at 10 years remains unacceptably high despite extensive use of lipid-lowering, glucose-lowering, and antiplatelet drugs.57 From this point of view, choosing a drug class able to provide an additional vasculoprotective benefit is a promising strategy. This aspect should be considered as a key factor for the development of new CV drugs. Finally, it is highly important that vasculoprotective effects of new and old drugs be tested specifically in the hypertensive population.


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Keywords: antihypertensive; antiplatelet; cardiovascular; glucose-lowering; lipid-lowering; vasculoprotection