Efficacy and safety of Azelnidipine-Telmisartan vs. Amlodipine-Telmisartan: a prospective randomized trial in Indian hypertensive patients

Abstract

Objective: The present study aimed to assess the efficacy and safety of a fixed-dose combination (FDC) of Azelnidipine 16 mg and Telmisartan 40 mg compared to FDC of Amlodipine 5 mg and Telmisartan 40 mg in Indian essential hypertensive patients with a special focus on the impact on micro-albuminuria. Methods: This prospective, randomized, open-label 12-week study enrolled 225 patients with treatment-naive stage II hypertensive patients or hypertensive patients not controlled on Telmisartan 40 mg monotherapy. The eligible participants were randomized to receive either FDC of Azelnidipine-Telmisartan (Test group; n=115) or FDC of Amlodipine-Telmisartan (Reference group; n=110). Efficacy was assessed via changes in systolic and diastolic blood pressure (SBP/DBP), pulse rate (PR), and urinary albumin-to-creatinine ratio (UACR), a marker of microalbuminuria. Safety parameters were evaluated by documenting the adverse effects. Results: Both groups showed significant reductions in SBP and DBP from baseline, with no statistical difference among the groups. However, the test group expressed a more favorable effect on pulse rate, displaying a significant reduction compared to the reference group. Additionally, the occurrence of pedal edema was significantly lower in the test group vs. the reference group (1.7% vs. 9.1%). Changes in UACR were nominal and comparable in both groups, indicating limited renoprotective effects. Conclusion: Collectively, the study confirms that FDC of Azelnidipine-Telmisartan is as effective as the commonly used FDC of Amlodipine-Telmisartan combination for management of hypertension, with additional safety benefits related to heart rate and edema. These findings support the clinical utility of Azelnidipine in hypertensive patients with concerns associated with tachycardia or pedal edema.

Introduction

Hypertension (HTN) is a clinical condition that occurs when blood pressure increases to an abnormal level, with systolic blood pressure (SBP) measuring ≥140 and/or diastolic blood pressure (DBP) measuring/≥90 mmHg. It is the leading risk factor for half of cardiovascular disease (CVD) and stroke-related mortality, affecting nearly 1.3 billion people worldwide [1]. Over 46% of adults aged between 39 and 70 years with hypertension are unaware of their condition, accounting for the increasing incidence rate, especially in low and middle-income countries [1,2]. HTN is mostly common in older people or caused by several factors such as lack of exercise, obesity, genetics, high alcohol intake, and a low potassium and high sodium diet [2,3]. The diagnosis and management of this disease are easy, however, lack of awareness, self-medication practices, and inconsistent HTN management guidelines or non-adherence to treatment regimens lead to its suboptimal control [1,2].

The seventh report of the Joint National Committee on Prevention, detection, evaluation, and Treatment of High Blood Pressure (JNC-7) recommends that prehypertension or stage 1 HTN (SBP: 130-139 mmHg and/DBP: 80-89 mmHg) can be easily managed with a combination of lifestyle modifications and cost-effective antihypertensive drugs (such as Thiazide-type diuretics) [4]. However, people with Stage 2 HTN (SBP: ≥140 and/DBP: ≥90 mmHg) is difficult to treat and will require a combination of two or more antihypertensive drug classes such as a thiazide diuretic, angiotensin-converting-enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), or a direct renin inhibitor and calcium channel blocker (CCB) [4].

In this context, the combination of an ARB and a CCB has been widely recognized as a preferable prescription owing to their complementary pharmacological effect. ARB inhibits the renin-angiotensin system (RAS), while CCBs induce vasodilation by blocking Ca 2⁺ channels, leading to a greater reduction in BP than either drug alone [5]. This combination is also preferred due to the safety profile and anti-proteinuric effect of ARBs and the high potency of CCBs [6-9]. Therefore, the ARB-CCB combination might avoid potential adverse effects, including increased serum potassium concentrations and worsening of renal anemia, especially in patients with mild to moderately impaired kidneys [9].

There are a variety of efficacious ARBs such as candesartan cilexetil (8-32 mg, once daily), losartan (25-100 mg, once daily), olmesartan (10-40 mg, once daily), and Telmisartan (20-80 mg, once daily) that are available in the market. However, unlike other ARBs, Telmisartan is not a pro-drug and possesses higher bioavailability and metabolic stability with excellent BP-lowering effect and reduced risk of stroke and heart failure [10,11]. New-generation dihydropyridine (DHP) CCBs have considerably higher vascular selectivity, a slower onset of action, and sustained hypotensive action compared to earlier DHPs [5]. Third-generation DHPs, amlodipine, and Azelnidipine, exhibit highly stable pharmacokinetics, are less cardio-selective, induce lesser side effects, and are consequently, well tolerated in patients, especially with cardiovascular and chronic kidney diseases [12,13]. Amlodipine has a high bioavailability and shows a slower rate of impaired elimination without any accumulation. If amlodipine is withdrawn, BP usually returns to baseline over 1 week without any dangerous rebound elevations in BP [14]. On the other hand, Azelnidipine, significantly reduces BP, heart rate, and proteinuria in hypertensive patients and retains its hypotensive effect even after clearance [13,15]. This DHP is highly effective and safe with confirmed cardio-protective, cerebro-protective, and anti-atherosclerotic effects [6,16].

Numerous clinical trials have investigated the effectiveness of combinations of either Amlodipine or Azelnidipine with an ARB, to support their usage in clinical practice. Studies suggest that a single-pill Fixed Dose Combination (FDC) combination of Telmisartan and amlodipine offers a substantial 24-hour BP-lowering effect that is superior to that of either drug administered alone [17]. This combination is particularly beneficial in patients with moderate-to-severe hypertension, diabetes mellitus, and obesity or those who are intolerant to amlodipine monotherapy/ACE inhibitors [18,19]. However, its rapid vasodilatory effect might lead to reflex tachycardia and is more frequently associated with dose-dependent peripheral edema, influencing patient adherence [20]. Furthermore, the combination of an ARB, along with Azelnidipine, proved to be more effective in controlling BP and metabolic outcomes than the combination of olmesartan with low-dose trichlormethiazide in hypertensive patients [8]. Studies suggest that the combination of Azelnidipine and Telmisartan might be useful because Azelnidipine is characterized by a slow onset of action, which might help in reducing the risk of reflex tachycardia offering a better control of morning BP surges. It also possesses antioxidant and anti-inflammatory properties, which may confer additional vascular protection. Moreover, Azelnidipine is associated with a lower incidence of peripheral edema compared to Amlodipine, making it more tolerable in patients sensitive to fluid retention. However, the combination is less explored in large cohorts, and its slow onset might be less suitable for patients who require rapid BP control [21]. Moreover, these combinational studies are conducted in hypertensive patients belonging to international origin; however, limited data are available on Indian essential hypertensive patients. In 2020 the Drugs Controller General of India (DCGI) recently approved Azelnidipine 8 and 16 mg tablets for hypertensive patients. Thereafter, recently, the office of DCGI approved FDC of Azelnidipine 16 mg with Telmisartan 40 mg for manufacturing and marketing in India. Although these formulations have been approved for manufacturing and marketing, limited real-world evidence is available. The current clinical study aims to evaluate the efficacy and safety of FDC of Azelnidipine 16 mg and Telmisartan 40 mg as compared to FDC of Amlodipine 5 mg and Telmisartan 40 mg in Indian essential hypertensive patients with a special focus on the impact on micro-albuminuria.

Methodology

Study design

The current investigator-initiated clinical study was designed as a prospective, randomized, open-label, parallel, and active-controlled study aimed to evaluate the efficacy and safety of FDC of Azelnidipine and Telmisartan as compared to FDC of Amlodipine and Telmisartan in Indian essential hypertensive patients. Both these FDCs were already approved by the Office of the DCGI for manufacturing and marketing in India. Moreover, as this is an investigator-initiated study involving an approved product in an approved indication, no permission was required from the central licensing authority following Rule 28 of the New Drugs and Clinical Trial Rules, 2019, to generate more data on the Indian Population. However, the Ethics Committee’s permission was taken before the conduct of the study. This study was registered with the Clinical Trial Registry India (CTRI/2023/07/055818).

Patient population

The present study enrolled a total of 240 Indian hypertensive patients. Treatment Naïve stage II HT patients or Stage I or II HT patients not controlled on Telmisartan monotherapy (40 mg) of either sex aged between 18-75 years with no significant abnormalities were included in the trial. Patients were excluded for any of the following reasons: severe HT, suspected secondary hypertension, heart failure & diagnosed CVD or new cerebrovascular diseases, current usage of other concomitant medications known to affect BP or medication prohibited as per protocol, hypersensitive or allergic to CCBs and ARBs, history of other clinically significant comorbidities, renal insufficiencies, uncontrolled systemic disorders or malignancy, pregnant or lactating females, smoke >1 pack of cigarettes/day, continuing history of substance abuse and participation in another clinical trial within 3 months before screening.

Study flow, screening, and randomization

In the present study, treatment-naive stage-II HT patients or HT patients not controlled on Telmisartan 40 mg monotherapy were screened on visit 1. On the same visit, the eligible participants were then randomly allocated into the following 2 study groups, according to the centralized computer-generated randomization plan in an approximately 1:1 (Test: Reference) ratio. Test group: FDC of Azelnidipine 16 mg and Telmisartan 40 mg and Reference group: FDC of Amlodipine 5 mg and Telmisartan 40 mg. After randomization, all the patients in the test and the reference study groups were instructed to take one tablet of FDCs once daily, as per the recommended dosage. As FDCs were already approved in India, the marketed pack was used for both drugs. Thereafter, patients were followed up on an outpatient basis with scheduled visits at week 4 (visit 2) and week 12 (visit 3). All the enrolled patients were instructed to take the allocated study medications for a treatment period of 12 weeks. The patients were followed up in a parallel manner till the completion of the study. All the patients underwent a thorough clinical evaluation, including recording of vital signs, BP, pulse rate, respiratory rate, oxygen saturation, and systemic examination at each visit throughout the study (Figure 1). The urine pregnancy test was performed in females of childbearing potential on visit 1. In cases where BP control was inadequate at Visit 2, an additional Telmisartan 40 mg tablet was prescribed at the investigator’s discretion.

Figure 1.

Study Flow.

Study assessment

All the enrolled subjects who completed the study as per the protocol including the subjects with minor protocol deviations were considered in the per protocol (PP) analysis. Further, all the enrolled subjects who completed the visit (visit 2/3) irrespective of major protocol deviation was considered in the modified intention to treat (mITT) analysis. The mITT population for efficacy analysis was considered in visit wise manner for better patient outcome.

Assessment of efficacy

Change in blood pressure

In each visit, the seated office SBP and DBP of patients in both the Test and the Reference groups were measured with a regularly calibrated and validated BP device. The same device was used throughout the study. On each visit, BP was measured 3 times, and an average of 3 readings were recorded and used for analysis. The time interval between successive measurements was 30-60 seconds. The resting period before measurement was at least 5 min in the supine or seated position and awake. Pulse rate was measured at rest between the 2nd and 3rd BP readings. The mean SBP, DBP, and PR of patients and the change in the same of the two study groups from baseline to visits 2 and 3 were calculated and statistically analysed.

Assessment of urinary albumin creatinine ratio

Urine Albumin to Creatinine Ratio (UACR) was measured from spot urine samples at baseline (visit 1) and visit 3 (end of 12 weeks of treatment). Change in UACR from baseline to end of 12 weeks in the two groups was calculated and statistically analyzed.

Assessment of safety

The safety of the study drugs was assessed by recording the adverse events occurring during the study. All irregularities found in the physical examination (including vitals) and laboratory investigations were dealt with as adverse events. The safety indicators primarily assessed included the incidence of pedal edema, headache, dizziness, and nausea, which were documented throughout the study.

Statistical analysis

The sample size calculation ensured 90% power to detect a significant difference in BP reduction with a two-sided 5% significance level. Descriptive statistics were used to summarize demographic and baseline data. The primary endpoint was the change in seated SBP and DBP at Weeks 4 and 12, while secondary endpoints included PR changes, UACR, and safety outcomes. Statistical analysis was performed between the two Test and Reference groups, and P<0.05 was defined as statistically significant.

Ethical considerations

The study protocol was approved by the Institutional Ethics Committee (IEC). Written informed consent was obtained from all participants before screening, and the confidentiality of patient data was maintained throughout the study. The trial adhered to the principles outlined in the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines.

Results

Baseline demographics

Between August and October 2023, a total of 240 hypertensive patients were enrolled in the study and assessed for their eligibility for randomization. The treatment-naive stage II hypertensive patients or hypertensive patients not controlled on Telmisartan 40 mg monotherapy were screened. According to the inclusion and exclusion criteria of the study, 15 participants were excluded, resulting in 225 participants being randomized into two study groups. Of 225 eligible patients (n=115) were allocated to the Test group (FDC of Azelnidipine 16 mg and Telmisartan 40 mg) and (n=110) to the Reference group (FDC of Amlodipine 5 mg and Telmisartan 40 mg). All the randomized patients received the allocated treatment for a treatment duration of 12 weeks. The flow of the patients in the study is shown in Figure 2.

Figure 2.

The flow of the patients during the conduct of the study.

During the follow-up, (n=15) patients in the Test group discontinued after visit 2 (10 were lost to follow-up (LTFU) and 5 withdrew consent), while 9 patients in the Reference group discontinued after visit 2 (8 were LTFU and 1 withdrew consent). The mITT population for both efficacy and safety analysis included 115 patients in the Test group and 110 patients in the Reference group. The demographic characteristics and mean baseline anthropometric data are shown in Table 1. The mean age of the patient population in the test and reference groups was 53.5±12.2 and 54.7±11.2 years, respectively. The proportion of men was slightly higher than that of women between the two groups, >50%. The basal metabolic index (BMI) values were comparable in both groups (Table 1). The baseline mean SBP, mean DBP, respiratory rate, and pulse rate were also comparable between the Test and Reference groups (Table 1).

Table 1.

Baseline demographic details mean baseline anthropometric of the study participants

Parameter		Test Group (N=115)	Reference Group (N=110)	P value
Age (years)*		53.5±12.2	54.7±11.2	0.4637
Gender#	Male	63 (54.8)	59 (53.6)	0.7304
	Female	52 (45.2)	51 (46.4)
Height (cm)*		158.9±10.34	157.5±9.15	0.3169
Weight (kg)*		70.9±15.89	68.5±11.72	0.2140
Body Mass Index (kg/m2)*		27.9±4.40	27.6±3.88	0.5885
SBP (mmHg)*		151.5±8.7	152.3±7.6	0.4425
DBP (mmHg)*		92.7±3.3	92.9±3.3	0.7254
Respiratory Rate (/min)*		19.7±1.3	19.7±1.5	0.7979
Pulse Rate (/min)*		79.7±4.2	79.5±5.5	0.7618

SBP - Systolic blood pressure, DBP - Diastolic blood pressure.

^*Data presented as mean ± SD.

^#Data presented as n (%).

P value by unpaired T-test.

Effects of study drugs on hemodynamics

The SBP and DBP of all the patients in the study were recorded at every visit. The mean SBP, DBP, PR, and change in SBP, DBP, and PR of the mITT patient population in the Test and Reference group are shown in Figure 3. The mean SBP values were analyzed from baseline (visit 1) to end of 4 (visit 2) and 12 weeks (visit 3) in both study groups (Figure 3A). As shown in Figure 3A. The mean SBP of patients at baseline (visit 1) was 151.5±8.7 mmHg in the Test group and 152.3±7.6 mmHg in the Reference group. This difference was not statistically significant (P=0.4425). The findings from the study demonstrate that the mean SBP in the test group was reduced from baseline to 130.0±13.9 mmHg and 127.0±14.0 at visit 2 and 3 respectively. The mean SBP in the Reference group was reduced from baseline to 132.3±15.6 mmHg and 130.2±16.9 mmHg at visits 2 and 3 respectively. No significant differences were observed in the mean SBP of patients between the Test and Reference group at visit 2 (P=0.2557) and at visit 3 (P=0.1277). Further, the change in SBP (ΔSBP) of the patients from baseline to visits 2 and 3 was calculated. The ΔSBP of patients in the Test and Reference group was (-21.4±15.7 vs. -20.0±16.3 mmHg) at visit 2 and (-24.5±16.1 vs. -22.1±17.7 mmHg) at visit 3. The difference observed in the ΔSBP of patients between the Test and the Reference group after visit 2 (P=0.5120) and visit 3 (P=0.3056) was not significant.

Figure 3.

Mean SBP, DBP and PR and change in SBP, DBP and PR (mITT). A and B. The mean SBP and DBP of all the patients in the Test group (N=115) and Reference group (N=110) at all the visits with a change from baseline ΔSBP and ΔDBP after visits 2 and 3. C. The mean PR of all the patients in the Test group (N=115) and Reference Group (N=110) at all the visits with a change from baseline ΔPR after visits 2 and 3. *Data presented as Mean ± SD, P value by unpaired T-test.

Similar trends were observed when the mean DBP values were analyzed from baseline to the end of visit 2 and visit 3 in both study groups (Figure 3B). The mean DBP of patients between the Test and Reference group at visit 1 was 92.7±3.3 vs. 92.9±3.3, P=0.7254 mmHg. This difference was comparable with no statistical significance. Further, as shown in Figure 3B, the mean DBP of patients in the test group was reduced from baseline to 82.5±7.0 and 81.1±7.6 mmHg at visits 2 and 3, respectively. Whereas in the Reference group, the mean DBP of patients reduced from baseline to 83.8±7.4 mmHg and 82.3±8.3 mmHg at visits 2 and 3, respectively. No significant differences were observed in the mean DBP of patients between the Test and Reference group at visit 2 (P=0.1930) and at visit 3 (P=0.2376). We observed that the ΔDBP of patients in the Test and Reference group was -10.2±7.5 vs. -9.1±8.1 mmHg at visit 2 and (-11.7±8.1.1 vs. -10.5±9.3 mmHg) at visit 3. The difference observed in the ΔDBP of patients between the Test and the Reference group after visit 2 (P=0.2932) and visit 3 (P=0.3433) was not significant. The results revealed that the decrease in the mean BP (SBP and DBP) of patients in the Test group from baseline to visits 2 and 3 was comparable to that observed in the Reference group.

Further, when the PR of the patients of both groups was analyzed, it was observed that the mean PR of patients at visit 1 was comparable between the Test group (79.7±4.2/min.) and the Reference group (79.5±5.5) with no statistical significance (P=0.7618) (Figure 3C). Further, a significant difference was observed in the mean PR of patients at visit 2 (77.7±7.0 vs. 80.4±5.9/min, P=0.0020). This difference between the Test and Reference groups became significantly higher at visit 3 (77.1±8.5 vs. 80.9±5.6/min, P=0.00015), respectively. Further, ΔPR of the patients from baseline to subsequent visits was also estimated. The ΔPR of patients in the Test and Reference group was -2.0±7.4 vs. 0.9±6.3/min at visit 2 and -2.5±8.9 vs. 1.4±6.6/min at visit 3. The difference observed in ΔPR of patients between the Test and the Reference group after visit 2 (P=0.0017) and visit 3 (P=0.00024) was highly significant. The overall results indicate that there was a slight decrease in the mean PR of patients in the Test group from baseline to subsequent visit, while a slight increase in the mean PR was observed in the Reference group over the same duration of treatment.

Effects of study drugs on UACR

The mean UACR values were analyzed from visit 1 to the end of study (visit 3) in both study groups (Figure 4). The mean UACR of patients at visit 1 was 13.8±3.6 mg/g in the Test group and 13.6±3.7 mg/g in the Reference group and the difference between two group was not statistically significant (P=0.7563). As demonstrated in Figure 4, the mean UACR in the Test and Reference group was slightly reduced from baseline to 12.9±3.1 mg/g and 12.9±3.3, respectively at visit 3. However, no significant differences were observed in the mean UACR of patients between the Test and Reference group at visit 3 (P=0.9649). Further, data from the ΔUACR of the patients from baseline to visits 3 revealed that the ΔUACR values in the Test and Reference group (-0.9±3.2 vs. -0.7±2.4 mg/g) was comparable with no significant difference (P=0.7259).

Figure 4.

Effect of drug treatment on UACR. The mean UACR of all the patients in the Test group (N=115) and Reference group (N=110) at visit 1 and 3 with a change from baseline ΔUACR after visits 3. Data presented as Mean ± SD. P value by unpaired T test.

Adverse side effects

The safety of the study medication was assessed by recording the adverse events that occurred during the study. Four major adverse events were recorded, which are pedal edema, headache, dizziness, and nausea in both the Test and Reference groups. The data indicates that of 115 patients in the Test group and 110 patients in the Reference group, patients experiencing pedal edema was [2 (1.7%) vs. 10 (9.1%), P=0.0170], headache was [4 (3.5%) vs. 4 (3.6%), P=0.9490], dizziness was [3 (2.6%) vs. 2 (1.8%), P=0.6876], and nausea was [1 (0.9%) vs. 1 (0.9%), P=0.9748] (Table 2). Overall, the results suggest that, except for the number of patients experiencing pedal edema, which was higher in the Reference group, the number of patients experiencing all the other adverse effects was comparable, and the difference between the groups was not significant.

Table 2.

Adverse events were recorded after the treatment of study drugs during the study

Adverse Events	Test Group (N=115)	Reference Group (N=110)	P value
Pedal edema	2 (1.7%)	10 (9.1%)	0.0170
Headache	4 (3.5%)	4 (3.6%)	0.9490
Dizziness	3 (2.6%)	2 (1.8%)	0.6876
Nausea	1 (0.9%)	1 (0.9%)	0.9748

N: Number of subjects evaluated in the study. n: Number of patients who experienced adverse drug reactions (ADRs) following the administration of study drugs. P-value calculated by chi-square test.

Escalation of Telmisartan

The doses of the Azelnidipine and Amlodipine were fixed throughout the study, however, a total of 7 patients required an escalation of Telmisartan from visit 2. Among the 7 patients, who required an escalation of Telmisartan after visit 2, 5 patients belonged to the Test group and 2 patients belonged to the Reference group (Figure 5).

Figure 5.

Escalation of Telmisartan is required from visit 2.

Discussion

The current prospective study aimed to evaluate the efficacy and safety of the Test group; FDC of Azelnidipine 16 mg and Telmisartan 40 mg compared to the Reference Group; FDC of Amlodipine 5 mg and Telmisartan 40 mg in Indian essential hypertensive patients, focusing on the impact on micro-albuminuria (measured as UACR). The goal of any anti-hypertensive therapy is to achieve BP with SBP <140/90 mmHg. Results from the current trial demonstrated that drugs from both the Test and Reference groups substantially reduced blood pressure (<140/90 mmHg) over the 12 weeks of the study, with comparable gradual lowering in SBP and DBP. However, despite these hypotensive effects, the differences between the outcomes of the 2 groups were not statistically significant. These findings suggested that the FDC of Azelnidipine and Telmisartan was as effective as the FDC of Amlodipine and Telmisartan in reducing hypertension. Our findings were consistent with prior evidence from the hypotensive effect of the ARB-CCB combination owing to the ARB’s renin-angiotensin system (RAS) blockade and CCB’s improved vasodilator effect [8]. Moreover, since here the Telmisartan’s dose was the same in both groups, the BP-lowering effect in both groups can be attributed to the potencies of the CCBs present in the combination. These findings were in accordance with a previously performed randomized clinical trial reporting that mean reductions of BP in the Azelnidipine and amlodipine groups were similar [13].

Intriguingly, Azelnidipine revealed added benefits concerning heart rate control. The FDC of Azelnidipine and Telmisartan exhibited a mild reduction in heart rate, whereas the FDC of Amlodipine and Telmisartan increased heart rate by the end of the study. The difference between the two groups was statistically significant. This clinical outcome aligns with Azelnidipine’s unique pharmacological profile, including the sympatholytic effect that Amlodipine does not possess. Further, it also aligns with the previous studies that suggest a significant decrease in pulse rate in the Azelnidipine group, whereas it is a modest to significant increase in the amlodipine group [13,22-24]. From a clinical standpoint, this indicates that Azelnidipine might be a better option for HTN patients with concomitant tachycardia or for patients who are susceptible to cardiac stimulation. Our interpretation is that heart rate modulation might be an underappreciated advantage of newer-generation Azelnidipine and must be kept in mind while prescribing therapy, especially in older adults or those with borderline sinus tachycardia.

Elevated blood pressure creates more pressure on the glomeruli, which causes albumin, a protein that is normally retained in the blood, to “leak” into the urine. Many studies have affirmed the strong relationship between higher blood pressure and the amount of albumin found in urine [15,25,26]. Based on this background, the study focused on evaluating the impact of the FDC of Azelnidipine and Telmisartan on microalbuminuria as measured by UACR and comparing it with the effect of the FDC of Amlodipine and Telmisartan. Both groups displayed a mild reduction in UACR from baseline to the end of the 12-week study. Data regarding the change in UACR revealed that there were no significant differences between the two groups, suggesting that while both combinations are effective in controlling hypertension, their effect on microalbuminuria is inadequate. This moderate renal improvement, particularly in the Test group, sustains the role of Telmisartan’s RAS blockade; however, it does not establish a significant renoprotective advantage for Azelnidipine over Amlodipine. However, a plethora of evidence supports the anti-proteinuria effect of Azelnidipine [15,27]. A plausible explanation of this might be the relatively short 12-week follow-up. Moreover, the absence of baseline microalbuminuria in the majority of participants might have masked any additive renoprotective benefit of Azelnidipine. Future studies with longer follow-ups or enrolling patients with diabetic nephropathy might offer an explicit understanding of these subtle renoprotective effects.

Further, both groups were evaluated for their safety profile, and it was observed that both treatment regimens were well-tolerated. However, the incidence of pedal edema was significantly lower in the patients administered the FDC of Azelnidipine and Telmisartan compared to the FDC of Amlodipine and Telmisartan. This difference in the safety outcome between the groups signifies Azelnidipine’s vasoselective action and lower affinity to augment capillary hydrostatic pressure, a common side effect of Amlodipine [28]. This tolerability benefit could translate into improved long-term adherence, especially for women and older patients who are inordinately impacted by CCB-induced edema. Occurrences of other adverse events, including headache, dizziness, and nausea, were similar between the groups. Notably, a higher percentage of patients administered with FDC of Azelnidipine and Telmisartan required an escalation of Telmisartan dosage compared to the patients administered with FDC of Amlodipine and Telmisartan, suggesting that Azelnidipine may not provide sufficient BP control for certain patients and may require additional therapeutic adjustments due to its slower onset of hypotensive action. Thus, this warrants further studies with real-world cohorts with resistant HTN and higher baseline BP.

It is noteworthy that this real-world evidence (RWE) substantiates the clinical benefits of Azelnidipine, especially in lowering HR-associated impediments and reducing edema risks. Unlike randomized controlled trials (RCTs), which are operated in controlled settings, RWE studies deliver an understanding of the drug efficacy in routine clinical practice, strengthening the safety and tolerability of Azelnidipine in HTN patients.

The findings of the current trial should be interpreted with caution due to certain limitations. The trial mainly included treatment-naive or incompetently controlled hypertensive patients and the outcomes might not be generalizable to individuals with advanced renal disease or those requiring thorough BP treatment. Additionally, the mild reduction in UACR, while suggestive of renal benefits, warrants further evaluation in a larger population with longer follow-up durations to comprehensively elucidate the renoprotective capacity of the Azelnidipine and Telmisartan combination.

Conclusion

The present study revealed that the FDC of Azelnidipine and Temisartan is as effective as the FDC of Amlodipine and Telmisartan in controlling blood pressure in Indian hypertensive patients. Azelnidipine demonstrated an advantage in lowering pulse rate and incidence of pedal edema, making it a safer alternative for patients vulnerable to such adverse effects. However, its effect on UACR was comparable to Amlodipine, suggesting no significant nephroprotective advantage. Additionally, the need for Telmisartan dose escalation in patients emphasizes the significance of personalized treatments. Further, studies with a larger number of patients and longer follow-ups are required to estimate Azelnidipine’s long-term effects on microalbuminuria and renal function.

Disclosure of conflict of interest

None.