Abstract
Background: Angiotensin II type I Receptor Blockers (ARB) are a frequently used class of antihypertensive drugs. The ARB losartan is known to decrease the serum uric acid (SUA) level. However, there are very few clinical data comparing the effects of other ARBs on SUA level under the conditions of clinical practice. This study evaluated and compared the long-term effects of monotherapy with five ARBs on SUA level in hypertensive patients in Mosul city.
Methods: We identified hypertensive patients who had been treated with monotherapy with losartan (n = 30), valsartan (n = 32), telmisartan (n = 29), candesartan (n = 31), or irbemesartan (n = 28), in whom laboratory data of SUA between December 1 2019 and February 1 2021 were available and compared the SUA level. The mean exposure of losartan was 245 days, valsartan 240 days, telmisartan 238 days, candesartan 242 days, and irbesartan 239 days.
Results: In losartan users, mean SUA level was significantly decreased from baseline, while it was conversely increased in users of other ARBs; valsartan, telmisartan, candesartan, and irbemesartan. The mean reduction of SUA level from baseline was significantly greater in losartan users compared with that in other ARB users. Comparison of ARBs other than losartan showed no significant difference in mean change in SUA level from baseline.
Conclusions: Our study showed that losartan had the most beneficial effect on SUA level among five ARBs, and that there was no significant difference in the unfavorable effects on SUA level among four ARBs other than losartan, at least during one year. These findings provide evidence of an effect of ARBs on SUA level.
Keywords: ARB monotherapy; Losartan; Valsartan; Telmisartan; Candesartan; Irbesartan; Serum Uric Acid; Hypertension
Abbreviations
ARB: Angiotensin type II Receptor Blocker; CCB: Calcium Channel Blockers; NSAID: Non-Steroidal Anti- Inflammatory Drug; SUA: Serum Uric Acid; URAT1: Urate Transporter 1
Introduction
The main cause of gout is high concentration of serum uric acid (SUA), and is also associated with the metabolic syndrome, including hypertension [1-4]. In the report of the US National Health and Nutrition Examination Survey, among patients with gout, 74% had hypertension [5]. Many patients with hyperuricemia are using antihypertensive agents because hypertension and hyperuricemia are conditions that frequently coexist. Antihypertensive drugs have different effects on uric acid. Beta blockers and thiazide diuretics increase the SUA level whereas alpha-blockers and Calcium-Channel Blockers (CCB) decrease the SUA level [6-8]. The effect of Angiotensin II type I Receptor Blockers (ARBs) on the SUA level differs among drugs. Of ARBs, losartan decreases the SUA level [9-17] via its influence on Urate Transporter 1 (URAT1) [18-20]. Differing from losartan, valsartan and candesartan have been reported to increase the SUA level in patients with hypertension [21,22]. Several studies have compared the effect of losartan on SUA with that of another drug or placebo. Few studies have performed a multiple comparison of the effects on SUA level among various ARBs in clinical practice. The aim of this study was to evaluate and compare the long-term effect of five ARB monotherapies; losartan, valsartan, candesartan, telmisartan, and irbesartan, on SUA in hypertensive patients in Mosul city.
Study Populations
We identified patients with mild to moderate hypertension aged over 20 years, who had been newly treated with ARB monotherapy for at least two months between December 1, 2019 and February 1, 2021. The five ARBs used in this study were losartan potassium, valsartan, telmisartan, candesartan cilexetil, and irbesartan (Table 1). The numbers of monotherapy patients in this study were; losartan (n = 30), valsartan (n = 32), telmisartan (n = 29), candesartan (n = 31), and irbesartan (n = 28) (Table 2). The experimental protocol was approved by the Ethical Committee of Al-Quds health center and was conducted in compliance with the ethical guidelines for epidemiological research of the Ministry of Health Iraq.
Generic name
Trade name
Number of cases of monotherapy
Losartan
Losartess
30
Valsartan
Diovan
32
Candesartan
Atacand
31
Telmisartan
Micardis
29
Irbisartan
Aprovel
28
Table 1: Angiotensin II type I receptor blockers.
Characteristics
Number of patients
Losartan
Valsartan
Candesartan
Telmisartan
Irbesartan
Total No of Patients
30
32
31
29
28
Men
17
16
19
13
15
Medical History
4
3
8
3
2
Cerebrovascular disease
5
4
3
2
1
Ischemic heart disease
1
0
2
3
3
Other heart disease
6
5
4
2
3
Thyroid disease
4
1
0
2
3
Rheumatoid disease
5
9
9
8
9
Hyperlipidemia
4
1
0
2
3
Current medication
5
9
9
8
9
Immunosuppressive drugs
2
0
3
2
2
Lipid lowering drugs
6
9
9
9
11
Statins
5
8
9
6
8
Fibrate
1
3
8
6
7
Other
drugs lipid lowering0
5
3
4
7
Thyroid drugs
6
5
4
2
2
Antithrombotic drugs
19
17
20
23
19
Steroids
2
3
2
0
1
NSAIDs
11
15
17
19
20
Proton pump inhibitors
6
12
13
17
10
H2 receptor blockers
4
5
6
8
4
Table 2: Baseline characteristics.
Exposure and Measurements
The baseline measurement period (non-exposure period) was defined as within 12 months before the start of ARB monotherapy. The exposure period (outcome measurement period) was defined as between 2 and 12 months after the start of ARB monotherapy. Laboratory data of the level of SUA for each subject were collected at the date nearest the start of ARB monotherapy in the baseline period, and at the date nearest 12 months after the start of ARB monotherapy in the exposure period. The mean exposure of losartan was 245 days, valsartan 240 days, telmisartan 238 days, candesartan 242 days, and irbesartan 239 days.
Data Elements
For each patient, we collected information of patient demographics (age and sex), medical history, use of medication, and laboratory results as baseline covariates. Medical history included cerebrovascular disease, ischemic heart disease, other heart disease, thyroid gland disorder, rheumatoid disease and hyperlipidemia. Drugs used during the 60 days before the start of ARB monotherapy included, lipid- lowering drugs (including statins, fibrates, and other lipid-lowering drugs), thyroids drugs, antipsychotics, antithrombotic drugs, drugs, steroids, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), proton pump inhibitors, and histamine H2 receptor blockers.
Statistical Analysis
All statistical analyses were performed with Microsoft Office Excel 2013 software. This is a retrospective observational study. We compared the mean change from the baseline value to the exposure value among ARB users. A result was considered statistically significant if the p value was less than 0.05.
Results
Tables 2 shows the characteristics of the patients who had been treated with ARB monotherapy. Table 3 shows the results of laboratory tests at baseline and during the exposure period. In losartan users, the mean level of SUA was significantly decreased in the exposure period compared with the baseline level. In users of other ARBs, valsartan, telmisartan candesartan, and irbesartan, the mean levels of SUA were significantly increased in the exposure period compared with those in the baseline. There was no significant difference in the increase of SUA level among the users of ARBs other than losartan; valsartan, telmisartan, candesartan, and irbesartan.
ARB
Baseline
Exposure
P value
Mean
95% CL
Mean
95% CL
Losartan
5.18
(5.03, 5.32)
5.04
(4.90, 5.19)
0.0194
Valsartan
5.30
(5.15, 5.45)
5.49
(5.34, 5.63)
0.0012
Candesartan
5.54
(5.43, 5.65)
5.68
(5.57, 5.79)
0.0011
Telmisartan
5.35
(5.18, 5.49)
5.47
(5.32, 5.63)
0.0253
Irbesartan
5.39
(5.22, 5.56)
5.58
(5.41, 5.75)
0.0013
Table 3: Adjusted mean level of SUA at baseline and during exposure period.
Discussion
In this study, we evaluated and compared the effect of longterm monotherapy, up to one year, among five ARBs on SUA in hypertensive patients. The mean level of SUA after treatment with losartan significantly decreased compared with the baseline. The mean level of SUA after treatment with other ARBs (valsartan, telmisartan, candesartan, and irbesartan) significantly increased compared with baseline. The reduction of SUA level from baseline in losartan users was significantly greater than that in other ARB users. This study suggests that, among the five ARBs, losartan had the most beneficial effect on SUA in hypertensive patients. It is known that losartan decreases the level of SUA in clinical practice and in animals. In clinical practice, some studies have reported a lowering effect of losartan on SUA level. It was reported that losartan significantly lowered SUA compared to placebo in patients with type 2 diabetes and nephropathy [16]. In patients with hypertension, 12-week treatment with losartan decreased the mean level of SUA compared with baseline [21]. In patients with mild to moderate hypertension, the mean level of SUA was significantly decreased from baseline after 12 weeks of treatment with losartan [26]. A study using xenopus oocytes, an in vitro study, and administration in hypertensive patients have revealed that losartan decreases SUA level via inhibition of URAT 1, which is the transporter of uric acid reabsorption in the proximal renal tubule [18-20]. Supporting these previous reports, our study indicated that long-term monotherapy with losartan has a beneficial effect on SUA level in mildly to moderately hypertensive patients. Because hypertension and hyperuricemia often coexist, therapy with losartan is suitable for hypertensive patients. In a comparison of ARBs, it has been shown that the reduction of SUA level by losartan is stronger than that by other ARBs. In patients with hypertension and serum uric acid ≥ 7 mg/dL, the mean level of SUA was significantly decreased after 24 weeks of losartan treatment compared with candesartan treatment [22]. In one study, losartan but not irbesartan significantly lowered SUA level compared to placebo in patients with type 2 diabetes and nephropathy [14]. The risk of onset of gout, which is strongly related to SUA level, has been reported to be lower in losartan users than in other ARB or CCB users [26,27]. In this multiple comparison study, we showed that losartan had the most beneficial effect on SUA level among five ARBs in hypertensive patients. Based on these clinical findings, losartan should be preferentially used in patients with hypertension, especially in those with comorbid disease of hyperuricemia or gout, over other ARBs. Some in vitro studies have investigated the different effects of ARBs on URAT1, which may explain the variable effects of ARBs on SUA level. Candesartan, irbesartan and valsartan did not show a cis-inhibitory effect but showed a trans-stimulatory effect on URAT1, potentially leading to an increase of SUA level [19]. Corresponding with these in vitro studies, several clinical studies have reported that some ARBs increased SUA level. In patients with hypertension, 12-week treatment with valsartan increased the mean level of SUA compared with baseline [22]. In patients with coronary artery disease, the mean SUA level in valsartan users was increased compared with the baseline [28]. In patients with mild to moderate hypertension, the mean level of SUA was significantly increased after 12 weeks of treatment with candesartan [26]. In this study, the mean SUA level in candesartan, irbesartan and valsartan users was increased in comparison with baseline, and there was no significant difference in the mean change of SUA level in the exposure period from baseline among these ARBs. On the other hand, in the study using xenopus oocytes, losartan and telmisartan exhibited a cisinhibitory effect on uric acid transport via URTA1, which means a reduction of reabsorption of uric acid [19]. To our knowledge, however, there is no clinical report that telmisartan may decrease SUA level, whereas some clinical studies have shown a lowering effect of losartan on SUA level. In patients with hypertension, high- dose treatment with telmisartan for three months significantly increased SUA level [29]. In this study, we showed that long-term monotherapy with telmisartan increased SUA level. The reason for this discrepancy between in vitro and clinical study outcomes is unclear. The contribution of other mechanisms, e.g., disturbance of urinary excretion, which may be predominant over the inhibitory effect on URTA1 in telmisartan users, cannot be excluded. Concerning ARBs other than losartan, our findings suggest that regular checks of SUA level are recommended in patients treated with candesartan, irbesartan, valsartan or telmisartan. Our study has several limitations. First, the retrospective and non-randomized nature of the design entailed inherent issues of selection bias and confounding. Other potential confounding factors that could not be considered in this database study are alcohol intake, smoking, Body Mass Index (BMI) and Muscle Mass Index (MMI). Furthermore, the possibility that the findings of comparison of the baseline and exposure period in each treatment group may be confounded by other variables should be considered when interpreting the results. Therefore, the findings of our study, based on a nonrandomized design, call for further studies, such as similar analyses of larger databases, prospective population-based studies, and randomized clinical trials, for confirmation. Second, we did not fix the daily dosage of ARBs, because the achievement of BP goal requires various doses of an agent across different individuals or even in the same individual in clinical practice. This study was not designed to assess the effects of ARBs at each dosage, because it is difficult to determine whether or not pharmaco dynamics are dose-dependent in clinical settings. However, we consider that the findings of our study, in a real-world setting, are reliable and will be informative for clinicians.
Conclusion
The results of the present study suggested that losartan had the most beneficial effect on SUA level among five ARBs; losartan, valsartan, candesartan, telmisartan, and irbesartan, at least up to one year. Our study provides evidence of the long-term effect of various ARBs on SUA level in hypertensive patients.
Competing Interests
The authors declare that they have no competing interests.
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