Introduction

Hypertension control guidelines recommend early intensification of the antihypertensive treatment with combination therapy in patients with uncontrolled blood pressure (BP). A single-pill combination (SPC) is preferred to improve the patient adherence to the treatment. Cur­rently, a combination of 3 antihypertensive drug; an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), a calcium channel blocker, and a thiazide or thiazide-like diuretic is the pre­ferred first-line option for low-dose SPCs. Low-dose triple SPC has demonstrated good efficacy and safety in BP control. Nevertheless, there are limited studies comparing this SPC to standard-dose monotherapies. 

Aim

To determine the efficacy and safety of a low-dose SPC of telmisartan, amlodipine, and chlorthalidone vs. standard-dose telmisartan monotherapy in patients with essential hypertension.

Patient Profile

• Adult patients (age ≥ 19 years) with BP as follows:
  1. Reference arm: mean sitting systolic BP (MSSBP) ≥ 140 and <180 mmHg.
  2. Treatment naïve arm: < 180 mmHg for those receiving antihypertensive medication within 4 weeks.

Methods

Study Design

Treatment Strategy

• After the screening, the study participants had a 4-week run-in period, during which they received once daily placebo.
• Participants eligible at baseline after the run-in period (n=314), were randomized 1:1 to receive either the telmisartan/amlodipine/chlorthalidone 20/2.5/6.25 mg (combination therapy) or telmisartan 40 mg (monotherapy). 
• At randomization, all participants were required to have MSSBP between ≥140 and <180 mmHg and mean diastolic BP (MSDBP) <110 mmHg. 
• All the participants had a drug adherence of ≥70% during the 4-week placebo run-in period. 
• The study participants were followed up at weeks 4 and 8. 

Outcomes

Primary Outcome

Secondary Outcomes

• Changes from baseline to week 4 and week 8 in MSSBP (only week 4), MSDBP, and pulse pressure (MSSBP−MSDBP).
• Proportion of patients achieving target BP (<140/90 mm Hg) and BP response (defined as a reduction of ≥20 mm Hg in MSSBP or reduction of ≥10 mm Hg in MSDBP from baseline).

Safety Outcomes

Results

• The FAS included 151 and 155 participants and 136 and 142 sub­jects and the per-protocol set (PPS) included 136 and 142 participants from the combination and monotherapy groups, respectively.
• As per the PPS analysis, the combination therapy was non-inferior to monotherapy in reduction in MSSBP from baseline to 8 weeks (LS mean difference: −3.8 mmHg, P=0.01). this was below the predefined noninferiority margin of 3 mm Hg (Table 2).

Fig. 1: Change in BP during the study period

• At week 8, the combination therapy group demonstrated significant MSDPB reduction compared with monotherapy in the PPS analysis (least squares mean difference, −3.8 mmHg; P= 0.01), establishing its noninferiority. The FAS confirmed the superiority of the combination therapy over monotherapy (LS mean difference, −4.0 mm Hg, P<0.01). 
• With regards to the secondary outcomes, patients in the combination group had significantly greater reduction in MSSBP at week 4, as compared to those in the monotherapy group (LS mean changes: −21.0 vs. −15.2 mmHg, LS mean diff: -5.9 mmHg, p < 0.01). 
• With regards to MSDBP, the LS mean differences between combination and monotherapy group at week 4 and week 8 were −3.4 mmHg (P<0.01) and −2.8 mmHg (P<0.01), respectively. 
• At week 4, patients in the combination group had a significantly greater reduction in pulse pressure, as compared to those in the monotherapy group (LS mean difference: −2.6 mmHg; P=0.01). The difference at week 8 (−1.2 mmHg; P = 0.25) was not statistically significant, but numerically in favor of the combination therapy.
• BP control rate was higher in the combination therapy group at both week 4 [74% versus 57%; odds ratio (OR), 2.20; P <0.01] and week 8 (70% versus 55%; OR, 1.99; P <0.01), as compared to the monotherapy group. 
• The BP response rate was higher in patients treated with the combination vs. monotherapy at week 4 (71% vs. 50%, OR: 2.52; P<0.01) and at week 8 (63% vs. 47%, OR: 1.92, p <0.01).
• The incidence of adverse events was comparable between groups. No serious TEAEs were reported during the study period.

Conclusions

• Low-dose triple SPC of telmisartan/amlodipine/chlorthalidone demonstrated superior BP-lowering efficacy, was well tolerated and safe, as compared to standard-dose telmisartan monotherapy.
• The efficacy of the low-dose triple SPC was consistent across age groups and irrespec­tive of prior antihypertensive treatment history. The use of low-dose triple SPC therapy was clinically effective and well-tolerated option, both as an initial and add-on strategy, particularly in populations including older adults.

Hypertension. 2026 Apr;83(4):e25810.  doi: 10.1161/HYPERTENSIONAHA.125.25810.