It is well known that hypertension is a strong independent risk factor for coronary and cerebrovascular diseases, as well as for heart failure, atrial fibrillation and chronic renal failure, in both industrialised and developing countries,1 thus substantially contributing to the global burden of disease. Moreover, it is well known that reducing blood pressure (BP) in hypertensive patients is associated with a significant reduction in the rate of cardiovascular complications and decline in renal function.2,3 The association between blood pressure and cardiovascular risk is continuous, without apparent lower threshold, up to the value of 70mmHg, which epidemiologically supports the assumption that the lower the blood pressure, the better the cardiovascular prognosis.2
Today, a remarkable number of antihypertensive drug classes with robust scientific evidence of long-term efficacy and safety are available on the market. The therapeutic arsenal includes many different compounds, such as diuretics, beta-adrenergic receptor blockers, alpha-adrenergic receptor blockers, angiotensinogen-converting enzyme inhibitors, angiotensin receptor blockers and calcium antagonists.2,4 Other drug classes, such as nitrates and imidazoline II receptor agonists, could also provide an additional antihypertensive effect and contribute to improving blood pressure control.
At present, several new antihypertensive drugs are under clinical development. Among them, the renin inhibitors seem to have an interesting therapeutic profile and one representative of this class, aliskiren, is in an advanced phase of clinical research.5 In addition, some ‘older’ antihypertensive drug classes are still under development. These include: a) nebivolol, a third-generation, cardioselective beta-blocker that produces vasodilation and improves endothelial function via the l-arginine/nitric oxide pathway; b) clevidipine, an ultra-short-acting, vascular-selective, dihydropyridine calcium antagonist that is being developed for intravenous use in acute hospitalised patients and c) darusentan, an endothelin (A) selective endothelin receptor antagonist that is effective in improving BP control in patients whose blood pressure values are uncontrolled despite treatment with three or more antihypertensive drugs.6
However, despite the availability of several effective and safe antihypertensive drugs and the many efforts of the national and international scientific societies,4,7 hypertension is still untreated in many subjects,8 while the persistence of antihypertensive treatment and the achievement of blood pressure targets is incredibly low,9,10 even in patients with very high cardiovascular risk profile (e.g. post-myocardial infarction, diabetes).11
Thus, the real challenge for any expert in the field of cardiovascular disease is to increase the percentage of currently untreated hypertensive patients who are effectively treated to achieve their specific blood pressure goal. This is particularly relevant for those hypertensive patients bearing multiple cardiovascular risk factors whose risk of fatal and non-fatal disease increases exponentially with the number and level of associated risk factors. Among this high-risk population, most of the attention should be paid to the management of those patients in whom hypertension is combined with dyslipidemia and/or type 2 diabetes, who are largely prevalent in the general population and responsible for a considerable amount of the overall cardiovascular risk attributable to hypertension. Accordingly, the management of the global risk of hypertensive disease is a mandatory strategy to prevent cardiovascular complications in the near future.12
To achieve this comprehensive goal, the following important aspects of the drug treatment of hypertension have to be carefully considered: some antihypertensive drugs may worsen/improve the metabolic profile of the patient; some antihypertensive treatments may increase/reduce the incidence of type 2 diabetes; and some lipid-lowering and antidiabetic drugs may also slightly reduce blood pressure control. The choice of the best available treatment to be used in patients with hypertension has to take into account the global characteristics of the patients and the need to achieve the best metabolic control in addition to decreasing blood pressure.13
Large-scale epidemiological and clinical evidence has clearly documented an association between hypertension and resistance to insulin-stimulated glucose uptake into skeletal muscle cells in over 60% of the hypertensive population. The combined presence of both risk factors in the same patient is associated with a significant increase in the rate of cardiovascular events that exceeds the separate contribution of each risk factor.14 In addition, insulin-resistant individuals are characterised by an increase in plasma levels of triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-C), while the levels of high-density cholesterol (HDL-C) are significantly reduced.15 This constellation of haemodynamic and metabolic disturbances, which is typical of patients with hypertension complicated by diabetes or metabolic syndrome16 and negatively affects their clinical prognosis, must be considered among the new targets of the treatment of hypertension. In patients with hypertension complicated by metabolic abnormalities, treatment with drugs that inhibit the renin-angiotensin system and improve insulin sensitivity is currently considered the most suitable strategy in the overall approach to cardiovascular risk.17
On the other hand, it has been shown that some classes of antidiabetic drugs with insulin-sensitising properties, e.g. thiazolidinediones, can positively modulate blood pressure control,18 and this dual activity may be very useful for the treatment of those patients where hypertension complicates diabetes.
Hypertension and dyslipidaemia are also often associated in non-diabetic subjects and approximately 40% of hypertensive patients have hypercholesterolaemia.19 As with insulin resistance, the combined presence of both risk factors in the same patient is associated with a significantly increased rate of cardiovascular events that exceeds the contribution of each of them separately.20 Accordingly, the treatment of hyperlipidaemia is a crucial step in hypertensive patients and must be considered one of the future objectives of the treatment of hypertension, in order to reduce the overall cardiovascular risk. Statins are the lipid-lowering agents with the strongest preventative effect in patients at a high risk of cardiovascular disease,21 and their properties also apply to hypertensive subjects.20 The preventative effect of statins has been ascribed to effects beyond the cholesterol-lowering action, such as their capacity to increase endothelial nitric oxide synthase (eNOS) activity and inhibit the expression of vasoconstrictive substances such as endothelin-1 (ET-1) with a significant improvement in endothelium-dependent vasodilatation. Statins may also have some effect on blood pressure control.22 In the epidemiological setting of the Brisighella Heart Study, the impact of a five-year antihypertensive treatment was enhanced in the hypertensive and hyperlipidaemic patients undergoing statin treatment.23 The BP-lowering effect of statins seems to be enhanced in patients treated with selected classes of antihypertensive drugs. A study carried out in our department demonstrated that combining statins with an ACE inhibitor or calcium channel blocker results in more effective blood pressure control independent of lipid-lowering activity.24 A very recent meta-analysis carried out by Strazzullo et al. and including 20 randomised clinical trials (828 patients) has tested the effect of statins on blood pressure.25 The use of statin is associated with a statistically significant decrease of systolic blood pressure (-1.9mmHg; 95% CI: -3.8 to -0.1) that appears to be more relevant in subjects with higher pre-treatment blood pressure irrespective of age, changes in serum cholesterol, or duration of the trial.25
Probably, the calculated BP-lowering effect of statins reported by the meta-analysis was less than can be achieved in clinical practice, since most of the results of trials were unadjusted for important confounding factors such as concomitant antihypertensive therapy, gender, age,26 baseline blood pressure24 and serum cholesterol levels.27
A further improvement of the therapeutic approach to hypertension would reside in the individualisation of the antihypertensive therapy through the use of pharmacogenetic tests that will a priori screen subjects potentially responsive or resistant to different drugs.28 However, even if the literature is rapidly increasing, no clear indication is yet available for a wide use of these tests, which are relatively expensive (especially when applied to inexpensive drugs, such as diuretics) and not widely available.
In conclusion, beyond the search for new drugs able to adequately and safely treat hypertension in every single patient (regardless of gender, age, race, co-morbidites, etc), we suggest that the ‘new way’ for the management of hypertensive patients must be based on a more extensive identification of patients, as well as on the overall management of the many determinants of the individual risk profile. This has been clearly indicated by the most recent national and international guidelines, even if their practical implementation is still far from being satisfactory. A comprehensive approach to hypertension implies an effective strategy of detection of additional risk factors beyond blood pressure, and choosing those treatment strategies that reduce the risk of cardiovascular disease by simultaneously controlling blood pressure and additional risk factors, including metabolic profile and the presence of target organ damage.