Efficacy and Safety of Telmisartan 20 mg/S-Amlodipine 2.5 mg versus Telmisartan 40 mg in Patients with Hypertension, Inadequately Controlled on Telmisartan 20 mg Monotherapy: A Randomized, Double-Blind, Multicenter, Phase 3 Trial

Abstract

Purpose

This 8-week, randomized, double-blind study evaluated the efficacy and safety of low-dose combination of telmisartan 20 mg/S-amlodipine 2.5 mg (T20/SA2.5) versus telmisartan 40 mg (T40) monotherapy in patients with essential hypertension inadequately controlled on T20.

Patients and Methods

After a 4-week run-in period with T20 (baseline), patients with uncontrolled blood pressure (BP) were randomized (1:1) to T20/SA2.5 or T40 for 8 weeks. The primary endpoint was the change in mean sitting systolic blood pressure (MSSBP) from baseline to week 8. Secondary endpoints included changes in MSSBP and mean sitting diastolic blood pressure (MSDBP) at weeks 4 and 8, BP control rate, response rate (≥20 mmHg reduction in MSSBP and ≥10 mmHg in MSDBP), and treatment-emergent adverse events (TEAEs).

Results

Overall, 108 patients were randomized. At week 8, least squares (LS) mean (standard error [SE]) reduction in MSSBP from baseline was greater with T20/SA2.5 than with T40 (−16.97 [2.06] mmHg vs. −7.42 [2.04] mmHg; P<0.001). LS mean (SE) reductions in MSDBP at week 8 were also greater with T20/SA2.5 than with T40 (−7.98 [1.17] mmHg vs. −4.01 [1.15] mmHg; P=0.006). The BP control rate was significantly higher with T20/SA2.5 than with T40 (53.70% vs. 29.63%; P=0.010); the response rate was numerically higher with T20/SA2.5 (12.96% vs. 5.56%; P=0.182). The incidence of TEAEs was lower with T20/SA2.5 than with T40 (9.26% vs. 20.37%, P=0.104); most events were mild.

Conclusion

T20/SA2.5 demonstrated superior BP-lowering efficacy and favorable tolerability compared with T40 in patients inadequately controlled on T20, supporting the value of early low-dose combination therapy.

Graphical Abstract

Introduction

Many patients require two or more antihypertensive agents to achieve adequate blood pressure (BP) control. Combining drugs from different classes provides additive or synergistic BP-lowering effects compared to dose escalation of a single agent.1,2 Furthermore, combination therapy allows for lower doses of each drug, thereby reducing adverse effects and improving adherence and treatment persistence, as supported by randomized controlled trials and real-world data.3,4 As a result, early initiation of low-dose combination therapy is increasingly recognized as beneficial for minimizing side effects, achieving faster BP control, and improving long-term adherence in patients with hypertension.5–7 The superiority of combination therapy over monotherapy has been demonstrated consistently in meta-analyses,2 and the combination of renin–angiotensin system (RAS) inhibitors with calcium channel blockers (CCBs) is among the most widely recommended approaches, as highlighted in the 2024 ESC Guidelines and reflected in national prescription trends in Korea.8,9

Specifically, the combination of telmisartan and amlodipine is supported by substantial clinical evidence demonstrating its robust antihypertensive efficacy, attributed to the long half-life of both drugs.10,11 S-amlodipine, the more active isomer of amlodipine besylate, demonstrates a hypotensive effect comparable to at least half the dose of conventional amlodipine besylate, with the reduced dosage also contributing to a lower incidence of adverse events (AEs), such as edema. In addition, it not only exerts vasodilatory effects but also promotes natriuresis, making it effective against hypertension caused by renin-independent fluid retention.12 Telmisartan exhibits very high affinity for the AT1 receptor, effectively blocking the vasoconstrictive effects of angiotensin II and providing a prolonged antihypertensive effect. Additionally, it has minimal impact on renal function and a lower risk of bradykinin-related adverse effects, contributing to its favorable safety profile.13–15

This study was designed to establish the foundation for the development of a fixed-dose combination (FDC) of telmisartan/S-amlodipine 20/2.5 mg (T20/SA2.5). The objective was to demonstrate the superiority of the combination therapy with T20/SA2.5 compared to telmisartan 40 mg monotherapy (T40) in patients with hypertension inadequately controlled by initial telmisartan 20 mg (T20) monotherapy.

Patients and Methods

Study Design and Ethics

This study was a multicenter, double-blind, active-controlled, phase 3 randomized clinical trial designed to evaluate the efficacy and safety of combination therapy with T20/SA2.5 compared to T40 monotherapy in patients with essential hypertension inadequately controlled on T20 monotherapy.

During the 4-week run-in period, participants discontinued their prior antihypertensive medications and received T20 once daily. Patients whose BP remained inadequately controlled after the run-in period (baseline) were randomized (1:1) to receive either T20/SA2.5 or T40 once daily for 8 weeks.

To ensure balanced group allocation, a restricted block randomization method was applied, stratified by baseline mean sitting systolic blood pressure (MSSBP): (1) MSSBP <140 mmHg, (2) 140 mmHg ≤ MSSBP <160 mmHg, or (3) MSSBP ≥160 mmHg (Figure 1).

Figure 1.

Study design.

The study was approved by the Institutional Review Board at each study site. Patients provided written informed consent prior to any study-related procedures. The study was registered prospectively at ClinicalTrials.gov (NCT05526703; registration date: 31 August 2022). The trial was conducted in accordance with the Declaration of Helsinki principles and adhered to Standards of Good Clinical Practice. Ethical approval was obtained from all participating institutions (Box S1).

Study Population

Adults aged ≥19 years with essential hypertension were eligible. At the screening visit (Visit 1), patients who had not received antihypertensive treatment within the past 4 weeks were required to have an MSSBP ≥140 mmHg, whereas those currently on antihypertensive therapy were required to have an MSSBP ≥130 mmHg. Only patients who exhibited an inadequate response (MSSBP ≥140 mmHg) after 4 weeks of telmisartan 20 mg monotherapy during the run-in period were eligible for randomization. For patients with cardiovascular disease (eg coronary artery disease, peripheral vascular disease, aortic disease, heart failure, or left ventricular hypertrophy in patients aged ≥50 years) or chronic kidney disease (evidenced by significant albuminuria or proteinuria), an MSSBP threshold of ≥130 mmHg was applied.16,17

Exclusion criteria included the following: (1) MSSBP ≥180 mmHg or MSDBP ≥110 mmHg; (2) Variability of ≥20 mmHg in SBP or ≥10 mmHg in DBP across three measurements; (3) Secondary hypertension; (4) Symptomatic orthostatic hypotension; (5) Type 1 diabetes or uncontrolled diabetes (HbA1c >9%); (6) NYHA class 3–4 heart failure, clinically significant arrhythmias, hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, aortic stenosis, valvular heart disease requiring intervention or causing hemodynamic instability, or a history of severe aortic valve stenosis; (7) Unstable angina, myocardial infarction, or cerebrovascular disease within the past 6 months; (8) Current use of three or more antihypertensive drugs from different classes at screening; (9) Severe hepatic or renal dysfunction; (10) Abnormal laboratory findings (AST or ALT >3×ULN, eGFR [CKD-EPI] <30 mL/min/1.73 m², serum potassium >5.5 mmol/L); (11) Pregnancy, potential pregnancy, or breastfeeding.

Study Outcomes

The primary endpoint was the change in MSSBP from baseline to week 8. Secondary endpoints included changes in MSSBP at week 4 and changes in MSDBP at weeks 4 and 8. BP control rates and response rates at weeks 4 and 8 were also evaluated. BP control was defined as MSSBP/MSDBP <140/90 mmHg, or <130/80 mmHg for patients with cardiovascular disease (eg coronary artery disease, peripheral vascular disease, aortic disease, heart failure, or left ventricular hypertrophy in patients aged ≥50 years) or chronic kidney disease (evidenced by significant albuminuria or proteinuria). A treatment response was defined as an MSSBP reduction ≥20 mmHg and an MSDBP reduction ≥10 mmHg.

Safety endpoints were assessed using data on AEs, physical examinations, and laboratory test results for all patients who received at least one dose of the study drug. All AEs occurring during the study were recorded, and their severity and relationship to the investigational drug were evaluated. The incidence of AEs was analyzed by organ system to assess the overall safety profile. The 8-week treatment duration was selected based on previous clinical trials of telmisartan and amlodipine, which demonstrated that the full blood pressure-lowering effect is typically stabilized within 4 to 8 weeks. This timeframe allows for an adequate assessment of both efficacy and steady-state safety profiles.11,12

Office BP Measurements

Office BP was measured using an electronic BP monitor of the same model provided by the sponsor. Measurements were taken in a seated position after approximately 5 minutes of rest, with three readings recorded at intervals of at least 2 minutes. The average of the three measurements was used for analysis. At the screening visit (Visit 1), BP was measured in both arms, and the arm with the higher MSSBP was selected. For subsequent visits, all BP measurements were consistently taken from the same arm.

Statistical Analysis

The sample size was calculated based on previous studies,18,19 and data on file (unpublished), assuming a mean difference of −8.24 mmHg in MSSBP change between treatment groups, a standard deviation of 12.41, a significance level of 5%, and a power of 90%. The required number of participants per treatment group was 48, and accounting for a 10% dropout rate, the total sample size was set at 108 patients (54 per group). The Full Analysis Set (FAS), based on the intention-to-treat principle, was used for the primary analysis, while the Per Protocol Set was used for additional analysis. For missing data in the efficacy analysis, the last-observation-carried-forward approach was applied to the FAS population only.

Continuous variables were compared using the Independent Samples t-test or Wilcoxon Rank Sum Test, while categorical variables were compared using Pearson’s chi-square test or Fisher’s Exact Test. The treatment effects on the primary and secondary efficacy endpoints were analyzed using Analysis of Covariance (ANCOVA), adjusting for the stratification variable of baseline MSSBP [(1) MSSBP <140 mmHg, (2) 140 mmHg ≤ MSSBP <160 mmHg, or (3) MSSBP ≥160 mmHg] as a covariate.20 For MSDBP analysis, baseline MSDBP was also included as a covariate. BP control rates and response rates at weeks 4 and 8 were compared between groups using the Cochran-Mantel-Haenszel test, adjusted for the baseline MSSBP as a stratification variable.21

Pearson’s chi-square test or Fisher’s exact test was used to compare the frequency of AEs potentially associated with the study drug. A two-sided P-value of <0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc).

Results

Patient Disposition and Baseline Characteristics

Among 167 patients screened across 17 centers, 108 patients who met the eligibility criteria were randomized into two treatment groups and received at least one dose of the study medication. Eight patients discontinued the study for the following reasons: mean BP during the study exceeding MSSBP 180 mmHg or MSDBP 110 mmHg (n=4), violation of inclusion/exclusion criteria identified during the study (n=2), AEs (n=1), and protocol violations (n=1). A total of 100 patients completed the study (Figure 2).

Figure 2.

Patient disposition. Flow diagram illustrating the study population from screening and randomization, including those who discontinued with specific reasons, through to the analysis populations: Safety set, Full Analysis Set, and Per-Protocol Set T20/SA2.5, telmisartan 20 mg/S-amlodipine 2.5 mg; T40, telmisartan 40 mg.

Mean (standard deviation [SD]) age was 62.18 (10.78) years, and 69 patients (63.89%) were male. Baseline MSSBP and MSDBP were 147.70 (10.01) mmHg and 88.80 (8.28) mmHg, respectively, with a mean (SD) heart rate of 72.59 (11.32) beats/min. The mean (SD) duration of hypertension was 8.69 (8.19) years, and 89 patients (82.41%) had a history of antihypertensive medication use. Among the patients, 52 (48.15%) had cardiovascular disease, defined as coronary artery disease, peripheral artery disease, aortic disease, heart failure, or left ventricular hypertrophy, and 1 (0.93%) had chronic kidney disease, defined as clinically significant albuminuria or proteinuria. Except for the duration of hypertension, there were no significant differences in baseline characteristics between the groups (Table 1).

Table 1.

Demographic and Baseline Characteristics

Variable	T20/SA2.5 (n=54)	T40 (n=54)	Total (n=108)	P-value
Age, mean (SD), y	63.30 (10.50)	61.06 (11.03)	62.18 (10.78)	0.369†
Sex, n (%)
Male	35 (64.81)	34 (62.96)	69 (63.89)	0.841‡
Female	19 (35.19)	20 (37.04)	39 (36.11)
Smoking, n (%)
Never	28 (51.85)	32 (59.26)	60 (55.56)	0.693‡
Current	12 (22.22)	9 (16.67)	21 (19.44)
Former	14 (25.93)	13 (24.07)	27 (25.00)
Alcohol drinking, n (%)
Never	17 (31.48)	15 (27.78)	32 (29.63)	0.765‡
Current	27 (50.00)	26 (48.15)	53 (49.07)
Former	10 (18.52)	13 (24.07)	23 (21.30)
Vital signs, mean (SD),
Baseline MSSBP, mmHg	147.37 (9.51)	148.03 (10.56)	147.70 (10.01)	0.985†
Baseline MSDBP, mmHg	88.08 (7.30)	89.52 (9.18)	88.80 (8.28)	0.366†
Pulse rate, beats/min	71.81 (11.14)	73.37 (11.55)	72.59 (11.32)	0.685†
Duration of hypertension, mean (SD), y	10.47 (8.79)	6.91 (7.18)	8.69 (8.19)	0.043†
Use of antihypertensive agent, n (%)
Yes	47 (87.04)	42 (77.78)	89 (82.41)	0.206‡
No (drug-naive)	7 (12.96)	12 (22.22)	19 (17.59)
Current comorbidity, n (%)
Cardiovascular disease*	27 (50.00)	25 (46.30)	52 (48.15)	0.700‡
Chronic kidney disease*	-	1 (1.85)	1 (0.93)	1.000‡

Notes: ^† Wilcoxon Rank Sum test or Independent samples T-test.^‡ Chi-square test or Fisher’s exact test.* Cardiovascular disease was defined as the presence of coronary artery disease, peripheral vascular disease, aortic disease, heart failure, or left ventricular hypertrophy in patients aged ≥50 years. Chronic kidney disease was defined as a history of clinically significant albuminuria or proteinuria.

Abbreviations: T20/SA2.5, telmisartan 20 mg/S-amlodipine 2.5 mg; T40, telmisartan 40 mg; MSSBP, mean sitting systolic blood pressure; MSDBP, mean sitting diastolic blood pressure.

Efficacy results

At weeks 4 and 8, the T20/SA2.5 group demonstrated a significantly greater least squares (LS) mean reduction in MSSBP and MSDBP compared to the T40 group (Figure 3 and Table S1).

Figure 3.

LS-mean changes in sitting systolic (MSSBP) and diastolic blood pressure (MSDBP) from baseline to Weeks 4 and 8 with telmisartan 20 mg/S-amlodipine 2.5 mg (T20/SA2.5) or telmisartan 40 mg (T40).*P < 0.05 vs. baseline; †P < 0.05 vs. telmisartan 40 mg.

At week 8, the LS mean (standard error [SE]) reductions in MSSBP were −16.97 mmHg (SE 2.06) in the T20/SA2.5 group versus −7.42 mmHg (SE 2.04) in the T40 group, resulting in a between-group difference of −9.56 mmHg (SE 2.49; 95% confidence interval [CI]: −14.50 to −4.61; P<0.001). A similar trend was observed for MSDBP, with reductions of −7.98 mmHg (SE 1.17) and −4.01 mmHg (SE 1.15), respectively, yielding a between-group difference of −3.96 mmHg (SE 1.41; 95% CI: −6.76 to −1.16; P=0.006).

These significant effects were evident as early as week 4. The reduction in MSSBP was −15.91 mmHg (SE 1.87) in the T20/SA2.5 group and −6.21 mmHg (SE 1.85) in the T40 group, with a between-group difference of −9.69 mmHg (SE 2.26; 95% CI: −14.18 to −5.20; P<0.001). For MSDBP, the corresponding reductions were −7.65 mmHg (SE 1.09) and −2.54 mmHg (SE 1.07), with a between-group difference of −5.11 mmHg (SE 1.32; 95% CI: −7.72 to −2.50; P<0.001). Changes in both MSSBP and MSDBP from baseline to week 8 are illustrated in Figure 4.

Figure 4.

Mean change from baseline in (A) sitting systolic blood pressure (SBP) and (B) sitting diastolic blood pressure (DBP) at weeks 4 and 8. *P < 0.05 vs. baseline (paired t-test or Wilcoxon signed rank test); †P < 0.05 vs. telmisartan 40 mg (ANCOVA adjusted for baseline MSSBP strata: <140, 140–159, ≥160 mmHg).

The T20/SA2.5 group also achieved significantly higher BP control rates compared to the T40 group: 48.15% versus 27.78% at week 4 (P = 0.026), and 53.70% versus 29.63% at week 8 (P=0.010). Similarly, response rates, defined as an MSSBP reduction ≥20 mmHg and an MSDBP reduction ≥10 mmHg, were significantly higher in the T20/SA2.5 group at week 4 (22.22% vs. 7.41%; P=0.033), although the difference was not statistically significant at week 8 (12.96% vs. 5.56%; P=0.182) (Figure 5).

Figure 5.

(A) Control and (B) Response rate of Telmisartan 20 mg/S-amlodipine 2.5 mg compared with telmisartan 40 mg at Weeks 4 and 8 from baseline.

The favorable BP-lowering effect of T20/SA2.5 compared to T40 was generally consistent across subgroups stratified by sex, age, body mass index (BMI), smoking status, alcohol consumption, diabetes mellitus, dyslipidemia, and baseline systolic BP, thereby supporting the robustness and consistency of the treatment effect (Figure 6).

Figure 6.

Forest plot of between-group differences in the change from baseline to Week 8 in mean sitting systolic blood pressure (MSSBP) across subgroups. Squares represent LS-mean differences; horizontal bars indicate 95% confidence intervals. Negative values favor T20/SA2.5 (greater reduction in MSSBP).

Safety Results

Treatment-emergent adverse events (TEAEs) were reported in 5 patients (9.26%) in the T20/SA2.5 group and 11 patients (20.37%) in the T40 group, indicating that the incidence of AEs in the T20/SA2.5 group was less than half that observed in the T40 group. However, this difference did not reach statistical significance (P=0.104). The most frequently reported AEs were nasopharyngitis, headache, and eye edema, each occurring in 1.85% of patients. Peripheral edema, a characteristic AE associated with CCBs, was not observed in either group during the study period.

No significant differences in the overall incidence of AEs were observed between the two groups, and the majority of events were classified as mild in severity. Additionally, there were no statistically significant differences between the groups in terms of drug-related AEs, serious AEs, serious drug-related AEs, or AEs leading to treatment discontinuation (Table 2).

Table 2.

Summary of Adverse Events (Safety Analysis Set). Data are Given as Number of Patients (%) [Events]

Variable	T20/SA2.5 (n=54)	T40 (n=54)	Total (n=108)	P-value†
TEAEs	5 (9.26) [6]	11 (20.37) [17]	16 (14.81) [23]	0.104
Nasopharyngitis	-	2 (3.70) [2]	2 (1.85) [2]	0.495
Headache	-	2 (3.70) [2]	2 (1.85) [2]	0.495
Eye oedema	1 (1.85) [1]	1 (1.85) [1]	2 (1.85) [2]	1.000
Acute myocardial infarction*	1 (1.85) [1]	-	1 (0.93) [1]	1.000
Anxiety disorder	1 (1.85) [1]	-	1 (0.93) [1]	1.000
Insomnia	1 (1.85) [1]	-	1 (0.93) [1]	1.000
Gastric mucosal lesion	1 (1.85) [1]	-	1 (0.93) [1]	1.000
Ureterolithiasis	1 (1.85) [1]	-	1 (0.93) [1]	1.000
Atrial fibrillation	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Coronary artery disease	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Cystitis	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Alanine aminotransferase increased	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Aspartate aminotransferase increased	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Blood alkaline phosphatase increased	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Gamma-glutamyltransferase increased	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Dyslipidaemia	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Type 2 diabetes mellitus	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Joint dislocation	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Dermatitis	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Hypertension**	-	1 (1.85) [1]	1 (0.93) [1]	1.000
Severity
Mild	5 (9.26) [6]	9 (16.67) [15]	14 (12.96) [21]	-
Moderate		1 (1.85) [1]	1 (0.93) [1]	-
Severe		1 (1.85) [1]	1 (0.93) [1]	-
ADRs	1 (1.85) [1]a	1 (1.85) [2]b	2 (1.85) [3]	1.000
SAEs	1 (1.85) [1]a	1 (1.85) [1]c	2 (1.85) [2]	1.000
Serious ADRs	1 (1.85) [1]a	-	1 (0.93) [1]	1.000
TEAEs leading to drug discontinuation	1 (1.85) [1]a	1 (1.85) [2]b	2 (1.85) [3]	1.000

Notes: ^† Chi-square test or Fisher’s exact test.* Reported adverse event: aggravation of Non-STEMI.** Reported adverse event: Aggravation of hypertension.(a) A case of acute myocardial infarction (reported adverse event: aggravation of Non-STEMI) was documented in one patient. The patient had a medical history of “Non-STEMI” and “heart failure,” and the reported adverse event was assessed as “possible” in its causality with the investigational product. However, the patient fully recovered during the clinical trial period.(b)Two TEAEs (headache and hypertension) were reported in one patient, with each event occurring once.(c) A case of cystitis was reported in one patient. This adverse event occurred in a subject with a prior history of bladder inflammation (cystitis) and was attributed to the subject’s pathological condition rather than the investigational product. The causality with the investigational drug was therefore assessed as “not related.”.

Abbreviations: ADRs, adverse drug reactions; SAEs, serious adverse events; TEAEs, treatment-emergent adverse events.

Discussion

Hypertension treatment has long relied on monotherapy as a standard approach. However, increasing the dosage of a single antihypertensive drug has limitations, including an increased risk of AEs and delayed achievement of target BP. In contrast, low-dose combination therapy enables more rapid and sustained BP control through complementary mechanisms of action, while reducing AEs. This strategy has increasingly become an established approach endorsed by major guidelines.22–25

The recently updated European guidelines recommend upfront low-dose combination therapy that targets multiple mechanisms of action as the initial treatment for hypertension.8 This approach is designed to reduce variability in BP responses and provide a steeper dose-response curve compared to dose escalation with monotherapy. However, monotherapy is still recommended for select patient groups, such as those with BP in the range of 120/70–139/89 mmHg, moderate-to-severe frailty, symptomatic orthostatic hypotension, or those aged 85 years or older. For most patients, however, treatment initiation with a combination of two low-dose antihypertensive agents is advised. In contrast, the current Korean hypertension guidelines recommend initiating pharmacological treatment for Stage 1 hypertension without cardiovascular disease or target organ damage only if BP remains above the target level after several months of lifestyle modifications. For these patients, monotherapy is initially recommended; if the target BP is not achieved within 2–3 months, dose escalation or combination therapy may be considered.15 This approach is considered less aggressive than European and American guidelines in terms of recommending early combination therapy.8,25

In this study, we compared two treatment strategies in Korean patients with hypertension whose BP remained uncontrolled with low-dose telmisartan (T20) monotherapy: traditional dose escalation to T40 versus low-dose combination therapy with T20/SA2.5. The results showed that the T20/SA2.5 group achieved significantly greater BP reduction. Although the difference in AE incidence between groups was not statistically significant, the T20/SA2.5 group had less than half the incidence observed with T40 monotherapy, and no cases of peripheral edema, a common AE associated with CCBs, were reported in either group. These findings support the effectiveness of early low-dose combination therapy. They also align with the current trend that emphasizes its use as initial treatment.8 Moreover, the BP-lowering effect of T20/SA2.5 over T40 was consistently observed across various subgroups, such as sex, age, BMI, smoking status, alcohol consumption, diabetes mellitus, dyslipidemia, and baseline SBP, reinforcing the robustness of the treatment effect.

Substantial clinical evidence from previous studies has supported the antihypertensive efficacy of telmisartan and S-amlodipine combination therapy, leading to the development of FDC of these agents.26–28 A notable feature of our study is that it is the first to evaluate the efficacy and safety of the low-dose T20/SA2.5 combination. Our findings provide a rationale for the development of the T20/SA2.5 mg FDC. In terms of BP control and AE profile, the FDC of T20/SA2.5 mg may offer a more effective treatment option than traditional dose escalation to T40 in patients who fail to respond adequately to initial T20 monotherapy.

Our findings are consistent with the established synergistic benefits of telmisartan and amlodipine combinations demonstrated in major trials, such as the TEAMSTA-5 study. While TEAMSTA-5 utilized standard doses (eg., telmisartan 40–80 mg/amlodipine 5–10 mg), our study uniquely highlights the efficacy of a lower-dose regimen (T20/SA2.5). Despite the lower dosage, the significant blood pressure (BP) reduction observed in the T20/SA2.5 group confirms that targeting complementary pathways remains effective even at reduced concentrations. Furthermore, our results align with previous studies in Korean populations, including the TENUVA-BP study and the work by Ihm et al, which demonstrated the favorable efficacy and safety profile of S-amlodipine-based combinations. By corroborating these findings, our study reinforces the reliability of T20/SA2.5 as a potent therapeutic option specifically within this demographic.11,27,28

In the present study, the T20/SA2.5 group achieved a control rate of 53.7% at Week 8. While this may seem moderate compared to high-dose combinations, it represents a significant improvement over the 29.6% observed in the T40 group (P=0.010). Compared to previous trials where standard doses were utilized, our results demonstrate that even a sub-maximal, low-dose FDC can successfully bring more than half of the non-responders to target levels. This provides a valuable “middle-ground” treatment option for clinicians before resorting to higher dosages or additional agents.

A critical aspect of these findings is the distinction between statistical significance and clinical relevance. The 9.56 mmHg difference in SBP reduction between the groups (P<0.001) is not merely a statistical figure; according to cardiovascular meta-analyses, a reduction of this magnitude in clinical practice is associated with a substantial decrease in the risk of stroke and major coronary events. This reinforces the practical utility of T20/SA2.5 in reducing long-term cardiovascular burden.

Furthermore, a key clinical implication lies in the comparison between low-dose combination and dose escalation. The limitations of doubling a monotherapy dose, such as diminishing returns in efficacy and a linear increase in adverse effects, are well-documented. In our study, the T20/SA2.5 group achieved superior BP control compared to the T40 group, with a better safety profile. The incidence of TEAEs in the combination group was less than half that of the T40 group (9.26% vs. 20.37%), likely because the use of minimal effective doses mitigates dose-dependent side effects. Since adverse events are a primary driver of non-adherence, the T20/SA2.5 combination may improve long-term adherence by maximizing efficacy while minimizing side effects.4

These findings strongly support the paradigm shift advocated by the current guidelines, which recommend upfront low-dose combination therapy as the initial treatment strategy for most patients with hypertension. Unlike the traditional stepped-care approach that often leads to therapeutic inertia, early initiation of T20/SA2.5 aligns with current recommendations to achieve faster and more sustained BP control. Our data provides specific evidence that this low-dose FDC is an optimal entry point, particularly for patients who require more than monotherapy but are sensitive to the adverse effects of full-dose combinations.8

While these initial results are promising, they must be interpreted within the context of the study’s 8-week duration. Further longitudinal research with larger cohorts is warranted to determine whether this initial efficacy and tolerability translate into sustained long-term blood pressure control and improved hard cardiovascular outcomes over several years.

This study has some limitations. First, the sample size was relatively small, and the follow-up duration was short, limiting our ability to assess long-term outcomes. Second, the study population was restricted to Korean patients, which may limit generalizability to other populations.

Conclusion

In patients with essential hypertension inadequately controlled by T20 monotherapy, T20/SA2.5 combination therapy resulted in a statistically significant reduction in MSSBP and MSDBP compared to T40 monotherapy, alongside a favorable tolerability profile. From a clinical perspective, the magnitude of blood pressure reduction observed suggests that this low-dose combination could serve as an effective alternative to monotherapy dose escalation, potentially optimizing both blood pressure control and patient adherence. To build upon these findings, further longitudinal studies with larger patient populations and longer follow-up periods are warranted to fully confirm the long-term clinical benefits and comparability of T20/SA2.5 with other established combination therapies.

Funding Statement

This study was initiated and financially supported by Chong Kun Dang Pharmaceutical Co., Ltd.

Data Sharing Statement

The datasets generated and analyzed during the present study are not publicly available due to patient privacy restrictions but are available from the corresponding author on reasonable request.

Disclosure

The author(s) report no conflicts of interest in this work.