Time course of onset and offset of blood pressure reduction with a novel low-dose triple single pill combination

Background Understanding how blood pressure (BP)-lowering effects of antihypertensive drugs evolve over time is important for effective treatment of hypertension. GMRx2 is a novel low-dose triple single-pill combination approved by the USFDA for the treatment of hypertension, including as initial therapy. Home BP measurements conducted in GMRx2 clinical trials provide an opportunity to assess onset and offset of effects. Objective To characterize the time course of systolic BP (SBP) reduction with GMRx2 in adults with hypertension, including time to maximal effect, and the time course of SBP increase when down-titrating to dual therapy. Methods We analyzed home BP data from two double-blind randomized controlled international trials of GMRx2 (telmisartan/amlodipine/indapamide at a ¼, ½, standard dose [Std.]: 10/1.25/0.625, 20/2.5/1.25, 40/5/2.5 mg/d, respectively). The first placebo-controlled trial (PCT) compared GMRx2 ¼ and ½ dose with placebo over 4 weeks, after a 2-week placebo run-in. The second active-controlled trial (ACT) provided data on effects of down titration, since after a 4-week active run-in during which all existing BP medications were switched to GMRx2 ½ dose, participants were randomized to continue the GMRx2 ½ dose or switched to respective dual ½ combinations (amlodipine + indapamide [AI], telmisartan + amlodipine [TA], telmisartan + indapamide [TI] at the same dose as in GMRx2 (½ dose) over 6 weeks. Following this, all doses were doubled (GMRx2 std. vs dual std. combinations) for use over another 6 weeks. Home BP data were averaged per day, and non-linear smoothing models were fitted. The time to maximal effect was defined as the time point of most BP reduction from baseline. Results A total of 3299 participants were included in the analysis. In PCT, after starting either the GMRx2 ¼ or GMRx2 ½ dose, SBP was reduced rapidly, with the maximum decrement occurring within 1 week after randomization and no apparent additional reduction thereafter. During the ACT randomized period, the withdrawal of one component increased SBP in all arms by week 6, with all the increase being observed during the first 2 weeks following the withdrawal of telmisartan or indapamide, whereas the increase in SBP after withdrawal of amlodipine was more gradual throughout the 6 weeks. When all doses were doubled, most of the additional BP reduction was achieved within 1 week and reached a maximum by 2 weeks. The ACT run-in on GMRx2 (½ dose) was non-comparative, with BP changes due to both treatment effects and regression to the mean, with most SBP reduction occurring during the first 2 weeks. Conclusion GMRx2 achieved virtually all of its reductions in SBP within 2 weeks, and a switch from triple to dual therapy typically led to an increase in BP within 2 weeks, although this took somewhat longer when amlodipine was withdrawn. This information helps inform triple and dual therapy treatment decisions and scheduling of patient follow-up.