Introduction
Arterial hypertension affects around 1.28 billion of people worldwide, and this number is expected to grow to 1.5 billion by 2025, especially in low-income and medium-income countries, where two-thirds of hypertensive patients reside (1,2). The prevalence is highest in Africa, reaching 46%, while in Europe it is approximately 37.5%, and in Croatia, one in three adults has high blood pressure (BP) (2,3).
This condition accounts for 10.8 million deaths annually and remains the leading cause of cardiovascular (CV) diseases, including acute myocardial infarction (AMI) and stroke (3). The global burden of hypertension is associated with urbanization, unhealthy lifestyle and aging population (3).
One of the main challenges in managing hypertension is poor therapeutic adherence. Research shows that up to 53% of patients with resistant hypertension are non-adherent to treatment, and 30% of patients never take the prescribed medications (4). This data highlights the value of simple therapeutic approaches, such as fixed combinations, which increase compliance and BP control (4).
Mechanism of action and effects of the valsartan
Valsartan is a drug belonging to the class of angiotensin II receptor blockers that selectively inhibits the action of angiotensin II on AT1 receptors. As a non-peptide antagonist, valsartan prevents the vasoconstrictive and aldosterone effects of angiotensin II, resulting in decreased systemic vascular resistance, lower BP, and target organ protection, including the heart, kidneys, and blood vessels. This molecule enables better hypertension control without inhibiting the angiotensin-converting enzyme (ACE), thereby avoiding adverse effects such as cough and angioedema, which are frequently associated with ACE inhibitors (5).
The pharmacological profile of valsartan has a distinctively high selectivity for AT1 receptors, while enabling angiotensin II to maintain its effect on AT2 receptors, which potentially provides additional benefits, such as vasodilation and tissue regeneration (5). Its prolonged activity enables efficient 24-hour BP control with once-daily administration. The effect of valsartan on the morning BP surge is particularly important, since it is associated with an increased risk of AMI and stroke. A study conducted by Hermida et al. demonstrated that taking valsartan in the evening not only effectively controls BP during the day but also significantly increases the ratio of day-to-night BP dipping, further reducing CV risk (6).
Besides lowering BP, valsartan also demonstrates unique properties of decreasing vascular inflammation. The Val-MARC study found a significant decrease in the levels of high-sensitivity C-reactive protein in patients treated with high doses of valsartan, regardless of its effect on BP, demonstrating the potential of valsartan in inhibiting vascular inflammation, thereby further contributing to CV risk reduction (7).
In addition to CV protection, valsartan has proven effects on kidney function, especially in decreasing microalbuminuria. A study published in 2002 in Circulation showed that valsartan significantly reduces the urinary excretion of albumin in hypertensive patients with diabetes, thereby contributing to slowing kidney disease progression (8). A similar randomized study published in 2007 highlighted the superiority of valsartan over amlodipine in decreasing microalbuminuria in patients with diabetic nephropathy, while maintaining similar levels of BP control (9).
Moreover, research also shows valsartan’s beneficial effects on neurocognitive functions. A randomized study from 2004 conducted by Fogari et al. showed that valsartan improves neurocognitive abilities in hypertensive patients, including attention, memory and the speed of information processing. This is an additional advantage compared to antihypertensive agents such as beta-blockers, that may have unfavorable effects on cognitive functions (10).
Valsartan also has a very favorable safety profile. Studies such as the meta-analysis by Bangalore et al. from 2016, which included 254,301 patients, show that angiotensin II receptor blockers are equally effective as ACE inhibitors in controlling BP but have a significantly lower incidence of adverse effects. (11) Furthermore, the conclusions of the analysis by Messerli et al. from 2018 state that, considering the equal effectiveness and lower frequency of adverse effects with angiotensin II receptor blockers, there are currently few, if any, reasons to use ACE inhibitors in hypertension treatment (12).
In addition to hypertension treatment, valsartan is also used for heart failure treatment, kidney damage prevention and in post-myocardial infarction conditions. Its versatility and proven effectiveness have been confirmed in over 60 large-scale clinical trials with over 100,000 patients, such as VALIANT, MARVAL, and VALUE (13). These comprehensive research studies make valsartan one of the most well-researched drugs in the class of angiotensin II receptor blockers on the market, with robust scientific evidence supporting its use in everyday clinical practice.
Indapamide – far more than just another thiazide diuretic
Indapamide is a thiazide-like diuretic distinguished by its strong antihypertensive activity and additional benefits that go beyond the effects of the traditional diuretics such as hydrochlorothiazide (HCTZ). This drug is used primarily to treat hypertension, but its metabolic neutrality and its effects on vascular function make it particularly suitable for long-term therapy, especially in patients under increased risk of metabolic disorders (13).
Indapamide works by inhibiting sodium and chloride reabsorption in the distal part of nephrons, encouraging diuresis and reducing plasma volume, which then leads to BP decrease. However, the effects of indapamide are not limited to diuresis. Its effect on the vascular system includes the relaxation of smooth muscles in blood vessels through increased availability of nitrogen oxide (NO) and reduction of oxidative stress, which in turn improves vascular function and reduces arterial stiffness. These effects are crucial for the long-term control of hypertension and CV risk reduction (14,15).
Pharmacological studies have indicated the importance of the slow-release (SR) formulation of indapamide, which provides stable 24-hour plasma levels of the drug. This prolonged release contributes to steady BP lowering during both daytime and nighttime, with reduced occurrence of adverse effects such as sudden drops in BP or dehydration. In their literature overview from 2005, Sassard et al. emphasize that the SR formulation of indapamide not only prolongs its action but also additionally increases the tolerability of the drug, making it suitable for daily use in hypertensive patients (15).
In addition, evidence suggests that the timing of drug administration can have an additional impact on its effectiveness. A research study by Huangfu et al. from 2015 indicated that evening dosing of antihypertensive drugs, including combination therapy with indapamide, results in a significant decrease in nocturnal BP, with better control over day-to-night BP dipping. This dosing strategy can additionally reduce CV risk, especially in patients with inadequately controlled BP at night (16).
Clinical trials confirm indapamide’s superiority versus HCTZ. According to a meta-analysis conducted by Roush et al., indapamide demonstrated significantly better efficacy in reducing systolic pressure compared to HCTZ, with a 54% higher average reduction. This difference highlights the superiority of indapamide in achieving optimal BP control, making it a preferred choice in antihypertensive therapy (17).
Indapamide has a proven favorable effect on myocardial remodeling. The LIVE study (Left Ventricular Hypertrophy Indapamide Versus Enalapril) demonstrated that indapamide was more effective than the ACE inhibitor enalapril in reducing left ventricular hypertrophy in hypertensive patients. This is particularly significant because ACE inhibitors are known for their beneficial effects on myocardial remodeling. These results further confirm the unique role of indapamide in CV protection, especially in patients with left ventricular hypertrophy (18).
Unlike HCTZ, indapamide has a proven favorable impact on CV outcomes. The HYVET study (Hypertension in the Very Elderly Trial) demonstrated a significant reduction in CV mortality and stroke incidence in elderly patients with hypertension treated with indapamide. These results additionally confirm the role of indapamide as s drug that not only lowers BP but also provides broader CV protection (19). Considering all of the above, both expert analyses of the published literature and professional guidelines, including the European hypertension treatment guidelines, clearly prefer indapamide over HCTZ (20,21).
Conclusion
The combination of valsartan and indapamide represents an exceptionally potent and rational option in arterial hypertension treatment, encompassing key mechanisms of BP regulation and providing additional benefits for CV and renal health.
Valsartan is a proven effective antihypertensive drug that offers all the advantages of renin-angiotensin system inhibition comparable to ACE inhibitors, but with better tolerability and significantly lower risk of adverse effects such as cough and angioedema. In practice, there is no clear reason to continue giving preference to ACE inhibitors in hypertension treatment, especially considering the larger presence of sartans in European markets compared to Croatia. In patients prone to cough, including smokers, people with asthma, allergies or gastroesophageal reflux disease, valsartan could be the drug of choice.
Indapamide, as a thiazide-like diuretic, surpasses HCTZ in its antihypertensive effectiveness, safety profile, and pharmacokinetic properties. In addition to lowering BP, indapamide has a favorable effect on left ventricular remodeling, which is especially significant in hypertensive patients with left ventricular hypertrophy. The formulation of indapamide with gradual release enables long-lasting stable plasma concentrations of the drug with once-daily dosage, further improving patient compliance.
The combination of valsartan and indapamide administered in the evening is particularly useful in patients with impaired day-to-night variability BP (non-dippers), because it can help establish a normal curve of nocturnal BP drop and reduce CV risk.
The European guidelines emphasize the importance of starting antihypertensive treatment with a dual combination, with s special focus on patient compliance. Considering that adherence is the main challenge in BP control, it is recommended to use fixed combinations of drugs with a lower risk of adverse effects, such as valsartan and indapamide. This combination provides optimal BP control with minimal risk, increasing the probability of achieving treatment goals and long-lasting patient protection, while also being ideally aligned with the modern requirements of personalized medicine, with a focus on effectiveness, safety, and patient acceptance of therapy.