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Efficacy and Safety of a Novel Low-Dose Triple Single-Pill Combination for Initial Hypertension Treatment
TAKE-HOME MESSAGE
- This randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of a new single-pill combination comprising low doses of telmisartan, amlodipine, and indapamide for treating hypertension in 295 adults with mild to moderate hypertension. Both quarter- and half-dose combinations significantly reduced home and clinic systolic blood pressure (BP) measurements compared with placebo. The reductions in home systolic BP were 7.3 mm Hg and 8.2 mm Hg for quarter- and half-dose combinations, respectively. The treatment was well-tolerated, with few discontinuations owing to adverse events.
- These findings suggest that this novel triple single-pill combination is effective and safe for early hypertension management, offering a promising option for improved BP control.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Single-pill combinations of 3 or more low-dose blood pressure (BP)-lowering drugs hold promise for initial or early treatment of hypertension.
OBJECTIVES
We conducted a placebo-controlled trial of a new single-pill combination containing low doses of telmisartan, amlodipine, and indapamide in 2 dose options to assess efficacy and safety.
METHODS
This international, randomized, double-blind, placebo-controlled, parallel-group trial enrolled adults with hypertension receiving 0 to 1 BP-lowering drugs. After a 2-week placebo run-in during which any BP-lowering medication was stopped, participants were eligible if home systolic BP (SBP) was 130 to 154 mm Hg. Participants were randomized in a 2:2:1 ratio to GMRx2 ¼ dose (telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg), GMRx2 ½ dose (telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg), or placebo. The primary efficacy outcome was difference in change in home SBP from randomization to week 4, and primary safety outcome was treatment discontinuation due to an adverse event.
RESULTS
From June 14, 2021 to October 18, 2023, a total of 295 participants (mean age: 51 years; 56% female) were randomized and 96% completed the trial. Baseline mean home BP was 139/86 mm Hg and clinic BP was 138/86 mm Hg after placebo run-in. The placebo-corrected least square mean differences in home SBP at Week 4 were -7.3 mm Hg (95% CI: -4.5 to -10.2) for GMRx2 ¼ dose and -8.2 mm Hg (95% CI: -5.2 to -11.3) for GMRx2 ½ dose; reductions for clinic BP were 8.0/4.0 and 9.5/4.9 mm Hg. At Week 4, clinic BP control (<140/90 mm Hg) was 37%, 65%, and 70% for placebo, GMRx2 ¼ dose, and GMRx2 ½ dose, respectively (both doses P < 0.001 vs placebo). Placebo, GMRx2-triple ¼, and GMRx2 ½ treatment discontinuation due to an adverse event occurred in 1 (1.6%), 0, and 6 (5.1%), respectively; out of normal range serum sodium or potassium was observed in 4 (6.3%), 12 (10.6%), and 12 (10.1%), respectively, but no participant had a serum sodium <130/>150 mmol/L or potassium <3.0/>6.0 mmol/L. Serious adverse events were reported by 2 participants in the placebo and GMRx2 ½ groups and none in the GMRx2 ¼ group.
CONCLUSIONS
In a population with mild-to-moderate BP elevation, both dose versions of the novel low-dose triple single-pill combination showed good tolerability and clinically relevant BP reductions compared with placebo. (Efficacy and Safety of GRMx2 Compared to Placebo for the Treatment of Hypertension: NCT04518306).
Additional Info
Efficacy and Safety of a Novel Low-Dose Triple Single-Pill Combination Compared With Placebo for Initial Treatment of Hypertension
J Am Coll Cardiol 2024 Aug 30;[EPub Ahead of Print], A Rodgers, A Salam, AE Schutte, WC Cushman, HA de Silva, GL Di Tanna, D Grobbee, K Narkiewicz, DB Ojji, NR Poulter, MP Schlaich, S Oparil, W Spiering, B Williams, JT Wright, A Gutierez, A Sanni, P Lakshman, D McMullen, G Ranasinghe, C Gianacas, M Shanthakumar, X Liu, N Wang, P WheltonFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
We have known for decades that low-dose combinations of antihypertensive drugs are more effective in lowering blood pressure (BP) measurements than maximum doses of any one single antihypertensive drug. There have been numerous trials and meta-analyses on this topic, including a summary by Volpe et al.1
The seminal work of Irish pharmacologist John Feely is an important early example.2 In Feely's study, an approach that combined four medications, each at a quarter of the standard dose was more effective than an approach that applied any of those four medications alone at the full standard dose. In other words, when it comes to low-dose combinations, the total BP-lowering effect may be greater than the sum of its parts.
In this context, we can consider a recent report by Rodgers et al on their triple combination of telmisartan/amlodipine/indapamide in the Journal of the American College of Cardiology.3 This report is part of a series of reports on this specific combination, known as “GMRx2” (which I believe stands for George Medicines Treatment #2).4
In the report, Rodgers et al enrolled patients who were taking at least one antihypertensive agent or none before trial entry, had a baseline systolic BP of 130 to 154 mm Hg during a placebo run-in, and had a low estimated 10-year risk for cardiovascular disease (<10%). The patients were randomized in a double-blind manner into three different arms: GMRx2 at a quarter dose, GMRx2 at a half dose, or placebo. After 4 weeks, the authors reported a placebo-corrected reduction in clinic BP measurements of 8.0/4.0 mm Hg in the GMRx2 quarter-dose arm and 9.5/4.9 mm Hg in the GMRx2 half-dose arm. Overall, the low-dose combination treatment was well-tolerated.
This trial adds to a growing body of evidence supporting the effectiveness of a low-dose triple combination treatment as an initial strategy for BP control. This aligns with the recently published 2024 European Society of Cardiology guidelines for the management of elevated BP and hypertension, which I co-chaired, recommending initial low-dose triple combination therapy for most hypertensive adults.5
Where the trial by Rodgers et al may contribute new insights is in its focus on adults with hypertension, a relatively low pre-randomization BP measurement (systolic BP, 130–154 mm Hg), and a low cardiovascular disease risk. These data are consequently important as we increasingly test the lower boundaries of treatment thresholds and targets in the management of elevated BP and hypertension.
References