Key Points:
- A single pill containing low doses of three different medicines induced significant and rapid reductions in blood pressure (BP) vs. dual therapy or placebo, with around 70% of patients with hypertension achieving BP control.
- The triple single-pill combination had good tolerability with no increase in treatment withdrawals.
- A low-dose triple single-pill combination could help to reverse current therapeutic inertia and transform hypertension management.
Hypertension control remains an elusive target at the global level, both in low- and middle-income countries (where over 75% of deaths related to cardiovascular disease are concentrated) and in high-income countries, where widespread access to and affordability of hypertension drugs remains a challenge.
During the 2024 European Society of Cardiology (ESC) Conference in London, this important topic took center stage with the release of the updated 2024 ESC Guidelines for the Management of Elevated Blood Pressure and Hypertension. Among the main take-home messages, the updated guidelines recommend single-pill combination in preference to separate pills, in order to improve therapeutic adherence and patient outcomes. While the traditional consensus has been to consider multi-pronged therapies later in the disease process, there is increasing evidence on the safety and effectiveness of low-dose combination therapy as early as possible after the diagnosis of hypertension.
As part of the Late-Breaking Science Programme, Prof. Anthony Rodgers (The George Institute, Australia) presented the results of the GMRx2 randomized clinical trial programme, which was comprised of two separate international trials (placebo controlled and active control arm, respectively) to study the safety and efficacy of a novel combination of telmisartan, amlodipine and indapamide, including at ultra-low novel combination, which may still achieve the desired efficacy compared to traditional doses, while minimizing the risk of side effects.
The goal of the first trial (placebo-controlled) was to demonstrate the first key principle of this novel combination, namely that the therapeutic effect can be achieved despite the use of low- and ultra-low doses of each medication. To do so, 295 patients were randomized to GMR-2 in ultra-low dose (10 telmisartan /1.25 amlodipine /0.625 indapamide, n=113) vs low-dose (20 telmisartan /2.5 amlodipine /1.25 indapamide, n=119) vs placebo (n=63). The primary efficacy endpoint was home systolic BP (SBP) after 4 weeks of treatment. Of note, eligible patients were considered if likely to have a diagnosis of HTN (based on BP values collected in clinic or at home) and with overall low cardiovascular risk. This suspected diagnosis was then confirmed after a 2-week run-in phase on placebo, after which eligible participants had to have SBP of at least 130-154 mm Hg to formally enroll in the randomized portion of the trial. The final study cohort had a mean age of 50 years, 55-60% female, roughly 50% on 0 and 50% on 1 BP medication at baseline. Notably, their average baseline SBP was lower compared to traditional pivotal trials of prior BP meds (138/85 mm Hg). After 4 weeks of treatment, there was a significant mean reduction of both home and clinic SBP by about 8-10 mm Hg in both the ultra-low and low dose treatment arms, compared to placebo (p<0.001, with no notable subgroup effects). In terms of safety, both combinations were well tolerated with non-serious adverse events such as 4-5% dizziness/hypotension in the two treatment arms.
The goal of the second trial (with active control arms) was to demonstrate that each individual component of this triple regimen is contributing to the reduction in SBP. To do so, 1,385 patients were randomized in a 2:1:1:1 fashion to low dose GMR-2 (20 telmisartan /2.5 amlodipine /1.25 indapamide, n=551) vs low dose of two of the three drugs (i.e. telmisartan/indapamide, n=276 vs telmisartan/amlodipine, n=282 vs amlodipine/indapamide, n=276). In this case, study participants were eligible to participate as long as they had elevated BP readings (in a proportional manner according to baseline therapy with 0, 1, 2 or 3 agents), after which they were enrolled in a 4-week run-in period on low-dose GMR-2. If their SBP was within 110-154 mm Hg by the end of this period, they were then eligible to be randomized in one of the four aforementioned groups. Similarly to the first trial, the final study cohort was middle-aged (mean age 60) with 50% females and baseline SBP (at the end of the run-in period) on the lower range with mean 128/78 mm Hg. After 12 weeks of treatment, there was a significant decline in SBP in the GMR-2 group compared to any of the two-drug arms, with mean SBP reduction in the 2.5-5.4 mm Hg range (point estimates, p<0.001 with no notable subgroup effects) Once again, the safety profile of GMR-2 was overall reassuring.
In summary, the two GMRx2 trials demonstrated that a low and ultra-low dose combination therapy of telmisartan, amlodipine and indapamide can achieve the desired efficacy in terms of blood pressure reduction, due to the synergistic contribution of each individual drug component.
“GMRx2 reduced BP quickly in mild-to-moderate hypertension and more effectively than dual therapy in a broad, large hypertensive population, without safety concerns. The availability of a single-pill combination could help to reduce current therapeutic inertia, helping patients achieve BP control quickly in a small number of steps, with potential benefits for improved adherence,” concluded Professor Rodgers.