Single-pill combination therapy for blood-pressure lowering: clinical and implementation differences between the United States and Nigeria

More than two decades ago, Law and colleagues synthesized 354 randomized trials and established the principles that still anchor combination antihypertensive therapy: each of the major drug classes lowers blood pressure by a broadly similar amount; most of that effect is achieved at low doses while adverse effects rise steeply with dose increases; and the effects of different classes are additive [ 1 ]. The practical corollary was that combining several drugs at low doses optimizes the balance between efficacy and tolerability for most patients and more efficiently than uptitrating one drug toward its ceiling. In 2025, the Double-blind, Randomised trials of Effects of Antihypertensive Medicines (DREAM) database, assembled by Wang and colleagues from 484 placebo-controlled trials including more than 104,000 participants, updated and extended these foundational estimates [ 2 ]. One standard-dose monotherapy lowered systolic blood pressure by roughly 9 mmHg, each dose doubling added only about 1.5 mmHg, whereas adding a second class was several-fold more efficient. Notably, several combinations were as well tolerated as, if not better than, placebo based on a lower incidence of headache among individuals randomized to some blood pressure lowering combinations. This observation serves as a reminder for patients and clinicians alike that hypertension is not always asymptomatic, and that well-chosen low-dose combinations need not trade tolerability for efficacy [ 3 ]. Over the same period the global burden of raised blood pressure has continued to grow steeply. High systolic blood pressure is the leading modifiable risk factor for premature cardiovascular death worldwide, implicated in approximately 10.8 million cardiovascular deaths annually [ 4 ]. Yet mean population blood pressure has risen only modestly and has fallen in some high-income settings [ 5 ]. The apparent paradox dissolves on inspection: even as age-standardized rates and mean pressures stabilize or decline, the absolute burden climbs, driven by population growth, ageing, and secular increases in mean body-mass index, unhealthy diets, and physical inactivity. Our central argument follows from this divergence. The principal barriers to single-pill combination (SPC) therapy are no longer pharmacological but contextual. The high-income setting, despite its resources, may be a less hospitable environment for initiating three- and four-drug combinations than health systems addressing hypertension care at scale for the first time. In this Perspective, we use the United States and Nigeria to illustrate the two examples along this continuum (Table 1 ). Table 1 Contrasting contexts for single-pill combination (SPC) therapy: the United States and Nigeria as illustrative of high-income and many low- and middle-income settings. Full size table