Effects of a New Low Dose Triple Single Pill Antihypertensive Combination on Electrolytes and Creatinine Compared to Placebo and Dual Therapies

Objective: Single-pill combinations (SPCs) containing three or more low-dose blood pressure (BP)–lowering agents represent a promising hypertension management strategy. A new triple SPC, GMRx2, comprising telmisartan (T), amlodipine (A), and indapamide (I), was recently approved by the US Food and Drug Administration (WIDAPLIKTM). We assessed its effects on serum potassium, sodium, calcium, and creatinine compared with placebo and dual-combination comparators. Design and method: In a placebo-controlled trial (PCT), 295 participants were randomised to GMRx2 dose_1 (T10 mg/A1.25 mg/I0.625 mg), GMRx2 dose_2 (T20 mg/A2.5 mg/I1.25 mg), or placebo for 4 weeks. In an active-controlled trial (ACT), 1385 participants were randomised following active run-in on GMRx2 dose_2 to continue GMRx2 dose_2 or switch to dual combinations of TI 20/1.25, TA 20/2.5, or AI 2.5/1.25 for 6 weeks, followed by up-titration to double doses for 6 weeks. Results: In the PCT, there were no differences in serum sodium, calcium, or creatinine between placebo and either GMRx2 dose. Potassium was unchanged with dose_1 (–0.01 mmol/L, p=0.86) and showed a small, borderline significant decrease with dose_2 (–0.1 mmol/L, p=0.053). Hypokalaemia (<3.5mmol/l) occurred in 1.7%, 3.5%, and 5.0% of participants receiving placebo, GMRx2 dose_1, and GMRx2 dose_2, respectively. In the ACT, mean serum potassium at week 12 was 4.1 mmol/L with GMRx2; levels were higher with TA (+0.2 mmol/L P<0.05), lower with AI (–0.2 mmol/L P<0.05), and similar with TI. Hypokalaemia occurred in 7% with GMRx2, 5% with TI, 13% with AI, and 0% with TA. At week 12, mean serum sodium was 139.2 mmol/L with GMRx2 and was 1.0 mmol/l higher with TA, 0.6 mmol/l higher with AI and unchanged with TI. A small increase in creatinine was observed with GMRx2 compared with TA and AI (2.2 versus 1.8 umol/L, respectively), with no difference compared with TI. Serum calcium remained unchanged across groups Conclusions: There were minimal effects on electrolytes and creatinine with lowest doses of GMRx2 versus placebo. At higher doses, modest hypokalaemia was observed but less pronounced than with AI likely due to telmisartan's counterbalancing effect. These findings support the safety of this low-dose triple SPC strategy for hypertension.