Hypertension is a major risk factor for cardiovascular disease (CVD) and death worldwide [1]. The global burden of hypertension was approximately 1.4 billion in 2021 and may exceed 1.6 billion by 2025 [2]. The age-standardized prevalence of hypertension in adults aged 30–79 years was 33% in the global population [3]. At present, the number of CVD cases exceeds 500 million worldwide [4]. Additionally, the increasing incidence of hypertension and clinical complications (e.g., heart, cerebrovascular and kidney injury) has a serious impact on people’s health and quality of life. However, according to different studies, hypertension treatment and control rates are less than 50% and 20%, respectively [5, 6, 7]. The initial treatment recommended in recent research is antihypertensive treatment with combination therapy and the recommendation of single-pill combinations [8]. The use of drug combinations significantly decreases blood pressure (BP). In particular, combination therapy could improve clinical complications [9]. Numerous studies have indicated that renin-angiotensin system (RAS)-inhibiting drugs are the cornerstone of combination treatment for hypertension and are recommended for combination treatment [10]. The widely used fixed combination is based the addition of angiotensin II (Ang II) receptor blockers (ARBs), such as valsartan, to calcium channel blockers (CCBs) or thiazide diuretics [9]. In addition, the rate of adverse effects associated with the above combination treatment may be reduced because the effects of each agent are reciprocally counterbalanced [11]. Currently, although it is widely known that a relatively large dose of valsartan (320 mg) could treat clinical complications with relatively sufficient blocking of Ang II type 1 receptor (AT${}_1$R), there is no clinical consensus regarding the influence of different dosages of valsartan combined with different types and dosages of other drugs on BP and clinical complications. Moreover, a single randomized controlled trial (RCT) and traditional meta-analysis could not provide strong evidence-based support. The purpose of the current network meta-analysis was to assess which drug could be combined with a relatively large dose of valsartan to more control BP more effectively. Combination therapy with valsartan could increase the dose of valsartan to a relatively large dose without causing an excessive reduction in BP.

According to the latest statistics, the number of people with hypertension in China has reached 245 million. Residents over the age of 18 suffering from hypertension accounted for 27.9%, which means that 3 out of every 10 adults in China suffer from hypertension [6]. ARBs are the guideline-recommended first-line treatment for hypertension [12]. ARB binding to AT${}_1$R restrains the effects of Ang II, a member of the RAS.

Valsartan, similar to all ARBs, acts by inhibiting the binding of Ang II to AT${}_1$R to lower BP. Valsartan is the most commonly used ARB in China and many other countries [13]. Valsartan can effectively control BP to meet the requirements, but will not cause hypotension due to excessive BP reduction [14]. The initial dose of valsartan, 80 mg, shows comparable efficacy to some other ARBs (e.g., candesartan (8–16 mg), losartan (50–100 mg), irbesartan (150 mg), olmesartan (10 mg), and telmisartan (40 mg)) in patients with essential hypertension [13]. Moreover, valsartan administered at 160 or 320 mg is more effective at lowering BP than losartan 100 mg, irbesartan 150 mg and candesartan 16 mg [15]. Valsartan has good tolerability with a side-effect profile indistinguishable from placebo and superior to some other ARBs (e.g., olmesartan and losartan), which improved patient compliance, resulting in increased drug efficacy [16, 17, 18, 19]. One study showed total discontinuations in olmesartan, losartan and valsartan during treatment of 16.9%, 13.5% and 10.3%, respectively [20]. Additionally, there were more indications observed outside of hypertension of valsartan than some other ARBs, such as CVD, heart failure, kidney damage, etc. [14, 21, 22]. These advantages, in addition to the comparative cost-effectiveness of valsartan, indicate that valsartan remains a favorable option for ARB and combined treatment of hypertension [23, 24].

According to the results of the network meta-analysis, among many combination therapies, the combination of valsartan 320 mg with amlodipine 10 mg could better reduce BP without further adverse effects. Amlodipine, similar to other CCBs, acts primarily by inhibiting extracellular calcium influx through cardiac and vascular smooth muscle cell membranes [25]. Its main site of action is the peripheral vasculature, which is related to its direct relaxant effect on vascular smooth muscle, leading to dilation of both arteries and arterioles [25, 26]. A relatively large dose of valsartan could block AT${}_1$R more sufficiently, which combined with CCB with a complementary mechanism could better reduce BP [27]. In addition, for SBP, hydrochlorothiazide 12.5 mg or 25 mg is also equally recommended when the uric acid level is not high.

Additionally, the results of the network meta-analysis showed that when valsartan was combined with hydrochlorothiazide 25 mg, the increase in valsartan from 80 mg to 320 mg did not induce a further reduction in BP. With a single dose of valsartan blocking AT${}_1$R to relatively sufficient blocking AT${}_1$R, the above combined treatment would not affect BP but downregulate the expression of the angiotensin converting enzyme (ACE)-Ang II-AT${}_1$ axis and upregulate the expression of the ACE2-angiotensin 1-7 (Ang (1-7))-MAS axis simultaneously [28, 29]. On the one hand, circulating Ang II levels tend to further increase and will be more combined with angiotensin type 2 receptor (AT${}_2$R) [30, 31], which plays a role in anti-inflammation, antioxidation, reducing cardiomyocyte hypertrophy, anti-fibroblast proliferation and other related protective effects [31, 32]. On the other hand, the level of ACE2 is upregulated through feedback, which could convert Ang II to Ang (1-7) and then bind to the MAS receptor [33]. It can also improve oxidative stress, cell proliferation, inflammation, etc. [34]. The above mechanism could highlight the fact that a relatively large dose of valsartan combined with other treatments induces improvements in clinical complications [35, 36, 37, 38, 39].

The network meta-analysis results also showed that combined treatment with a relatively large dose of valsartan did not increase the incidence of permanent discontinuations related to treatment. The occurrence of other adverse effects was not higher than that of low-dose valsartan. The reduction in adverse effects of the combination of valsartan with hydrochlorothiazide or amlodipine may be attributed to the complementary mode of action by acting through different pathophysiologic pathways to offset each drug’s side effects [11].

The first limitation of this study is that the classification of the included population is not detailed enough. The included studies did not compare patients of different sexes. Therefore, the study could further analyze whether there were differences in changes in BP in patients of different sexes after treatment. Second, some of the articles we included did not mention detailed quantitative data on adverse effects. We can only rely on the statements in the article as evidence. Third, some patient baseline disease and hypertension course time information was incomplete, so no analysis was conducted. Fourth, valsartan 320 mg combined with amlodipine 5 mg could not further reduce BP as well. However, due to the limited number of included studies and samples on this combined treatment, it may lead to deviation of the results. Studies with large sample sizes or randomized controlled clinical trials should be conducted in real-world settings to further validate these results. Fifth, for the combination of two drugs, it was not discussed whether it was a single drug combination or compound preparation.

In conclusion, combination therapy with a relatively large dose of valsartan could control BP and improve clinical complications effectively. However, for hypertensive patients with different treatment requirements, we should make specific choices about whether to control BP, improve clinical complications, or both.

The datasets used or analysed during the study are available from the corresponding author on reasonable request.

All authors have contributed to the development of the research question and study design. ZRW, SXW, JXW, RW and HYW developed the literature search. ZRW, SXW, LQZ, RW and LYW performed the study selection. QLS, SDC and RW analysed the data. ZRW, LQZ, JXW, RW, SDC, QLS, HYW and LYW interpret the results and wrote the manuscript. NYL and SXW provided guidance on interpretation of results, critically advising important intellectual content and involved in editing the final manuscript. All authors reviewed and approved the manuscript, and are accountable to all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Not applicable.

Not applicable.

This study was supported by the Youth Science and Technology Fund of Gansu Province (21JR1RA164), Innovation Fund for Higher Education of Gansu Province (2020B-037) and Cuiying Scientific Training Program for Undergraduates of Lanzhou University Second Hosptial (CYXZ2021-41).

The authors declare no conflict of interest.