Efficacy Of Omesartan Amlodipine In The Treatment Of Essential Hypertension And Effect On Target Organ Injury

BackgroundHypertension is a public health issue of global concern and an independent risk factor for cardiovascular and cerebrovascular diseases and kidney diseases.The overall prevalence of hypertension in China is increasing,and a survey on hypertension in China points out that the weighted prevalence of hypertension among Chinese adults is about 27.5%.If hypertension is not effectively controlled for a long time,patients may experience functional damage to target organs,which can be life-threatening in severe cases.Therefore,how to effectively control blood pressure and reduce target organ damage is the focus of current research,and the search for new mechanisms of action and appropriate therapeutic drugs is urgent.There is a wide range of antihypertensive drugs available,but monotherapy often fails to achieve satisfactory antihypertensive efficacy.Both domestic and international guidelines currently recommend combination antihypertensive drug therapy as the ideal regimen for hypertensive patients,including free combination or single-pill combination(SPC).SPC is recommended as an initial drug regimen for newly diagnosed hypertensive patients with blood pressure levels of grade 2 and above,and initial low-dose combination antihypertensive drug therapy can also be considered for patients with grade 1 hypertension.The combination regimen not only facilitates faster achievement of blood pressure targets but also helps to reduce drugrelated adverse effects.Combination regimens should use drugs with different antihypertensive mechanisms.Currently,the recommended combination regimens include:ACEI/ARB+thiazide diuretics;ACEI/ARB+dihydropyridine CCB;dihydropyridine CCB+β-receptor antagonists,etc.Due to the reliable efficacy and good safety of the combination of ARB and CCB,several guidelines recommend their combination as the initial treatment for patients with essential hypertension,but the combination of antihypertensive drugs often reduces patient compliance.Compared with free combination regimens,SPC can enhance the blood pressure attainment rate of hypertensive patients and achieve the target value of blood pressure control earlier,therefore,SPC is increasingly used in clinical practice.Olmesartan/amlodipine,as the representative of SPC,which can not only smoothly and effectively lower patients’ blood pressure,but also reduce adverse drug reactions.A previous systematic review demonstrated the efficacy of olmesartan/amlodipine in the treatment of patients with essential hypertension but only compared the efficacy between olmesartan/amlodipine and olmesartan/hydrochlorothiazide,and no further analysis of drug-related adverse effects was performed.In addition,there are two commonly used doses of olmesartan/amlodipine for clinical application,including 20/5 mg once daily and 40/10 mg once daily,but there is no metaanalysis comparing the efficacy and safety of these two commonly used doses of olmesartan/amlodipine.Therefore,the efficacy of olmesartan/amlodipine treatment in essential hypertension and its effect on target organ damage still requires further clinical evaluation and meta-analysis.The mechanism of hypertension and its target organ damage has not been fully elucidated.G protein-coupled receptor is the largest superfamily of drug targets and plays an important role in cell signaling.As an important member of the GPCR family,the APJ receptor is closely related to cardiac development,cardiovascular homeostasis,and cardiac contraction,and is one of the most interesting new drug targets for cardiovascular diseases in recent years.And activation of this signaling pathway can alleviate or treat heart failure,hypertension,and other diseases.Apelin and Elabela,as endogenous ligands of APJ,have received much attention in recent years due to their effects on the cardiovascular system.It has been shown that the Apelin/Elabela-APJ axis can balance the activation of RASS in various forms to improve cardiovascular damage and dysfunction in essential hypertension.The APJ receptor has significant sequence homology and similar tissue expression patterns to the ARB drug blockade target angiotensin Ⅱ type 1 receptor,which plays an important role in the regulation of cardiovascular homeostasis.A study in rats with renal vascular hypertension found that puerarin regulated blood pressure and protected target organs through the apelin/APJ pathway and that cerebroside had synergistic effects with CCB.This suggests that both ARB and CCB may exhibit additional cardiovascular benefits by modulating the APJ receptor signaling pathway,so further clinical studies to assess the effect of ARB/CCB on the Apelin/Elabela-APJ axis and whether this signaling axis is associated with improved target organ damage in hypertension are urgently needed.In conclusion,it is urgent to investigate whether olmesartan/amlodipine can modulate the expression levels of Apelin and Elabela and improve target organ damage in patients with essential hypertension.In this study,the efficacy and safety of olmesartan/amlodipine in the treatment of essential hypertension and its effects on the expression levels of Apelin and Elabela and target organ damage in patients will be evaluated through clinical trial and meta-analysis.Dissertation I:Effects of olmesartan/amlodipine on Apelin and Elabela levels and target organ damage in patients with essential hypertensionObjectives(1)To clarify the expression of Apelin and Elabela in patients with essential hypertension;(2)To investigate the correlation between the expression levels of Apelin and Elabela and target organ damage in patients with essential hypertension;(3)To investigate whether olmesartan/amlodipine improves target organ damage in patients with essential hypertension by modulating the expression levels of Apelin and Elabela.MethodsPatients who attended Qilu Hospital of Shandong University,Dezhou People’s Hospital,Zaozhuang Municipal Hospital and Qingdao Fuwai Cardiovascular Hospital from June 2021 to November 2022 were selected,and 106 patients with confirmed essential hypertension were included in the essential hypertension group.Thirty-nine of these patients were included in the medication group at Qilu Hospital of Shandong University and given olmesartan/amlodipine for 12 weeks;in addition,people who had not been diagnosed with cardiovascular diseases were included as a control group.Clinical data were collected,blood and urine specimens were routinely sent for examination before and after drug administration,and plasma Apelin and Elabela concentrations were determined by ELISA,and pulse wave velocity of extremities were completed.All data were subjected to the Kolmogorov-Smirnov normality test,and the t-test was used for comparison between two groups for normally distributed measures;the MannWhitney U test was used for comparison for measures that did not conform to the normal distribution.Correlation analysis was performed by Person and Spearman correlation analysis.Results(1)Plasma Apelin and Elabela expression levels were reduced in the essential hypertension group compared with the control group;(2)After treatment with olmesartan/amlodipine,systolic and diastolic blood pressure decreased significantly,Apelin and Elabela expression levels increased significantly in patients in the medication group compared with those before medication;(3)After treatment with olmesartan/amlodipine,the brachial-ankle pulse wave velocity and ankle-brachial index were significantly reduced in the drug-using group.Conclusions(1)Apelin and Elabela expression levels are reduced in patients with essential hypertension;(2)Olmesartan/amlodipine is effective in lowering blood pressure,increasing Apelin and Elabela expression levels and improving target organ damage,and part of the mechanism may be related to the upregulation of Apelin and Elabela expression levels.Dissertation Ⅱ:Efficacy and safety of olmesartan/amlodipine in essential hypertension:A network meta-analysisObjectives(1)To evaluate the antihypertensive effect and safety of different doses of olmesartan/amlodipine in patients with essential hypertension;(2)To compare the antihypertensive effect and safety of olmesartan/amlodipine with olmesartan or amlodipine monotherapy;(3)To compare the antihypertensive effect and safety of olmesartan/amlodipine with twodrug combination and single-pill combination.MethodsPubmed,Embase,Medline,Cochrane Library,CNKI and Wanfang databases were searched for randomized controlled trials that met the inclusion criteria through December 2022.A total of 9 eligible randomized controlled trials with a total of 3296 subjects were included after the screening.Two researchers independently extracted data and assessed the risk of bias for included articles.We used the "network" command in Stata 16.0 to perform statistical analyses.Data from each study were analyzed using a random effects model.Potential heterogeneity between studies was assessed by global consistency tests and local consistency tests.The effectiveness of the treatment modalities was ranked according to the surface area under the preferred probability curve(SUCRA).Finally,funnel plots were generated to detect potential publication bias.Results(1)Compared with 20/5 mg olmesartan amlodipine once daily,40/10 mg olmesartan amlodipine once daily was more effective in reducing systolic and diastolic blood pressure;(2)Compared with two-drug combination and single-pill combination,40/10 mg olmesartan amlodipine once daily showed better efficacy;(3)Compared with 100/25 mg of losartan hydrochlorothiazide once daily,40/10 mg of olmesartan amlodipine once daily was more effective in reducing nighttime ambulatory systolic blood pressure;(4)Compared with 10/25 mg amlodipine hydrochlorothiazide once daily,40/10 mg olmesartan amlodipine once daily was more effective in increasing the number of patients with normalized blood pressure and had fewer drug-related adverse effects.ConclusionsOlmesartan/amlodipine was more effective in lowering blood pressure in patients with essential hypertension compared with monotherapy,two-drug combination,or single-pill combination in a dose-dependent manner.In terms of safety evaluation,olmesartan/amlodipine had fewer adverse reactions than amlodipine/hydrochlorothiazide.