A 46-year-old man with a history of class 1 obesity (body mass index 31.0 kg/m2) and prediabetes (hemoglobin A1c 5.9%) returns to the office 4 weeks after an annual wellness visit for follow-up of an elevated blood pressure (BP) reading. At his last visit, his BP was 154/86 mm Hg. Since then, he has checked his BP at home, with readings in a similar range. He has no known history of coronary artery disease (personal or family), hyperlipidemia, or tobacco use and takes only a multivitamin. He works from home, prepares his own meals, and has been told for years that he snores at night. His repeat average BP today is 151/82 mm Hg. Is single-pill combination (SPC) therapy appropriate to treat his hypertension?
Yes. In addition to lifestyle changes and testing for sleep apnea, our patient will likely require 2 antihypertensive medications for BP control. We would consider SPC therapy for him.
See related article page 471
The 2017 American College of Cardiology/American Heart Association guidelines1 recommend starting 2 antihypertensive medications with complementary mechanisms of action for adults with stage 2 hypertension (BP > 140/90 mm Hg) whose BP levels average 20/10 mm Hg above their target, as seen in our patient.1 The medications may be administered either as single agents or in a fixed-dose combination. Evidence supporting this recommendation comes mostly from studies using SPC therapy.1 The updated 2024 European Society of Cardiology guidelines2 now recommend starting SPC for most patients with hypertension (BP > 140/90 mm Hg).
Hypertension is the most common comorbidity in the United States, where it affects approximately 47.7% of adults age 18 and older.3 Only 20.7% of individuals achieve their target BP, and 70% or more require at least 2 antihypertensives for control.3,4
WHAT IS SPC THERAPY?
Traditionally, antihypertensive treatment has followed a “start low and go slow” approach, starting treatment with a single antihypertensive medication and gradually increasing the dose. A second medication is added only if the target BP is not achieved—typically weeks to months after the initial diagnosis.
SPC therapy uses 2 or more antihypertensive drugs with complementary mechanisms of action combined at fixed doses into a single-pill formulation. Available formulations combine first-line antihypertensive drugs: renin-angiotensin-aldosterone system inhibitors (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARB], and mineralocorticoid receptor antagonists), calcium channel blockers, and thiazide-type diuretics. Table 1 provides a noncomprehensive list of titratable SPC therapy options.
Cost of single-pill combination therapya
WHY CONSIDER SPC THERAPY?
Efficacy
SPC therapy is associated with increased likelihood of achieving targeted BP control in a shorter duration of time. The STRATHE (Strategies of Treatment in Hypertension: Evaluation) trial5 was among the first to show that low-dose SPC was associated with higher success at achieving BP goal (62%) after 3, 6, and 9 months compared with sequential monotherapy (49%, P = .02) and stepped-care regimens (47%, P = .005). A retrospective analysis compared more than 100,000 patients newly diagnosed with hypertension who started treatment with SPC or monotherapy.6 SPC was associated with a 53% greater likelihood of achieving targeted BP goals (P < .001). Further, patients started on SPC had significantly decreased times to achieving their target BP (195 days vs 280 days, P < .001).
SPC therapy is also associated with prolonged BP-lowering duration, leading to improved 24-hour efficacy compared with both monotherapy alone and multi-pill regimens.7,8 This effect was observed even with SPCs that contain shorter-acting antihypertensives such as losartan (P < .001).8
Adherence
Poor adherence to treatment remains a barrier for BP control, with nonadherence rates between 24% and 51% in the United States.9 SPC improves adherence through reduced pill burden.6,10 In a large meta-analysis (44 studies), SPC use was associated with significant improvements in adherence (18 of 23 studies) and persistence (14 of 16 studies) and lower levels of medication discontinuation.11
Adverse events
For most patients, adverse event rates associated with starting multiple antihypertensives are comparable to rates when starting 1 medication.12 Exceptions include patients who are elderly (older than 80) or frail, and patients with elevated BP (systolic BP of 120–129 mm Hg).1,2,12 A large meta-analysis including 13,095 patients started on combination therapy (SPC or free single agents) found no significant difference in adverse events that prompted cessation of treatment in antihypertensive combinations compared with monotherapy.12 The use of combination therapy was associated with a higher incidence of patient-reported dizziness that did not result in drug withdrawal; this affected approximately 1 in 50 patients.12
In patients who develop an allergic reaction or adverse effect to an SPC, determining which anti-hypertensive component is responsible may be a challenge. However, the nature of the adverse effect may provide clues; for example, the development of a cough, a bradykinin-mediated side effect, in a patient receiving lisinopril-hydrochlorothiazide suggests ACE inhibitor intolerance.
Conversely, some combinations of drugs can offset the adverse effects of each other.7 Combining thiazide diuretics with renin-angiotensin system inhibitors less frequently results in hypokalemia compared with thiazide diuretics alone.7 The combination of calcium channel blockers with ACE inhibitors is associated with a 58% reduced incidence of peripheral edema compared with calcium channel blockers used alone (P < .0001).13
Affordability
Despite historical issues of increased cost, SPC therapy is affordable due to the availability of generic SPCs and growing use of non–insurance-based discount programs. Combinations of all first-line antihypertensive classes are available as generic SPC formulations1,2,10 (Table 1). Many of these are available through online direct-to-consumer pharmacies and in-store discount vouchers, which reduce costs and increase accessibility.
Interestingly, patients on SPC therapy have been shown to have lower hypertension-related annual healthcare costs ($709 in favor of SPC) and total annual healthcare costs ($1,357 in favor of SPC) than those on multi-pill regimens of the same antihypertensive agents.9 This cost reduction is attributed to reduced cardiovascular events secondary to improved BP control and adherence.
LIMITATIONS OF SPC THERAPY
SPC therapy is associated with improved BP control and adherence, but research is needed to fully assess its cardiovascular benefits. A 2020 Cochrane review highlighted the need for studies evaluating its impact on cardiovascular events and mortality.14 However, in more recent studies, SPC therapy was associated with lower rates of stroke, myocardial infarction, hospitalization, and mortality compared with both monotherapy and multi-pill regimens.15,16
The evidence supporting SPC therapy in patients with stage 1 hypertension (systolic BP 130–140 mm Hg) is less robust than in those with higher-stages of hypertension.2 Similarly, the benefits and tolerability of SPC therapy in the elderly, particularly those older than 75, are not well established. While BP control in this population is associated with reduced morbidity and mortality, the risk of side effects must be considered, especially in frail individuals.
Finally, the fixed-dose nature of SPC therapy may limit flexibility in titrating individual antihypertensive agents. However, this is a theoretical risk, as most physicians do not appropriately increase drug doses (so-called therapeutic inertia), leading to suboptimal hypertension control.6,12,16 The theoretical concern can be negated by starting with moderate doses of both agents in the SPC (eg, amlodipine 5 mg and benazepril 20 mg, as was shown to be effective in the ACCOMPLISH [Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension] trial17) and instructing patients to increase the dose to 2 pills if home BP is not controlled in 3 to 4 weeks. If the increased dose is tolerated, then that dose should be prescribed prior to the medication being refilled, and the patient would take the amlodipine-benazepril 10/40 mg pill once daily.
WHICH SPC THERAPY TO START?
SPC therapy should be individualized to the patient with consideration given to comorbidities. These include albuminuria or proteinuria in type 2 diabetes and chronic kidney disease; guideline-directed medical therapy in heart failure; and beta-blockers and ACE inhibitors or ARBs for select patients with coronary artery disease.2 If none of these compelling indications are present, the ACCOMPLISH trial demonstrated improved cardiovascular outcomes with an SPC that combined a calcium channel blocker and ACE inhibitor, compared with an ACE inhibitor-diuretic SPC.17 The authors often extrapolate these data to support use of calcium channel blocker and ARB combination SPC as first-line therapy.17
Regardless of the SPC, both in-office reassessment 4 weeks after starting and home monitoring are recommended to assess BP control.
THE BOTTOM LINE
Most patients with hypertension will require 2 or more antihypertensives to achieve their BP target. SPC therapy provides a well-tolerated, effective approach with superior efficacy and adherence compared with both monotherapy and free-pill combinations, while also minimizing therapeutic inertia. For many patients, starting treatment with an SPC should be considered for the initial management of hypertension.
DISCLOSURES
Dr Laffin has disclosed serving as a research principal investigator for Arrowhead and Crisper Therapeutics; consulting for Astrazeneca Pharmaceuticals, Idorsia Pharmaceuticals Ltd, Medtronic, and ReCor Medical; serving as an advisor or review panel participant for Gordy Health and LucidAct Health; teaching and speaking for Cardiometabolic Health Congress and ReCor Medical; serving as an Executive Committee member of SURMOUNT MMO trial and Executive Committee Chair of the ATTAIN-HTN trial for Eli Lilly; serving as an Executive Committee member in phase 2 trials for Mineralys Therapeutics. The other authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
- Copyright © 2025 The Cleveland Clinic Foundation. All Rights Reserved.
REFERENCES
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