Some combinations are better tolerated than single drugs
In short-term trials, treatment stopping due to side effects differed by drug type, and some two-drug combinations were tolerated as well as or better than placebo.
*Systematic review and network meta-analysis of randomized trials; Level 1a.

Citation

Wang N, Van Der Hoorn S, Pant R, et al. Adverse effects and treatment discontinuation of blood pressure–lowering drugs and combinations: A network meta-analysis. JAMA. 2026;335(24):2135-2145. doi:10.1001/jama.2026.6214

Background

Concerns about side effects from blood pressure–lowering medicines can delay starting treatment and lead to early stopping. This study compared short-term side effects and stopping rates across major drug classes and combinations.

Patients

Adults in double-blind randomized trials (mostly hypertension; mean age 54.6 years; 44% women). Excluded: trials longer than 26 weeks and trials with an active “run-in” period.

Intervention

Blood pressure–lowering drugs from 5 major classes and their combinations.

Control

Placebo or another active drug regimen.

Outcome

Stopping assigned treatment due to side effects (primary); dizziness, headache, swelling of legs/ankles, cough (secondary).

Follow-up Period

4–26 weeks (mean 8.6 weeks).

Results

716 trials (159,362 participants). Compared with placebo, the following differences were significant:
Outcome Regimen vs placebo Effect Absolute change Number needed to treat (or harm)
Stopped treatment due to side effects (primary) Calcium channel blockers Odds ratio 1.43 (1.23–1.67) +1.2% Harm: 84
Stopped treatment due to side effects (primary) Angiotensin-converting enzyme inhibitor + calcium channel blocker Odds ratio 1.46 (1.13–1.87) +1.1% Harm: 91
Stopped treatment due to side effects (primary) Beta-blocker + thiazide diuretic Odds ratio 1.58 (1.04–2.47) +1.7% Harm: 59
Stopped treatment due to side effects (primary) Angiotensin II receptor blocker Odds ratio 0.73 (0.61–0.86) −0.8% Treat: 125
Stopped treatment due to side effects (primary) Angiotensin II receptor blocker + calcium channel blocker Odds ratio 0.61 (0.47–0.79) −1.2% Treat: 84

Limitations

Short follow-up (weeks), so later side effects and long-term stopping were not assessed. Results rely on network meta-analysis assumptions and trial-level (not individual) data. Absolute differences in stopping were small (about 1–2%).

Funding

Australia’s National Health and Medical Research Council; no role in study conduct.

Clinical Application

When choosing initial therapy, consider an angiotensin II receptor blocker (often with a calcium channel blocker) to reduce early stopping; counsel about dizziness and monitor for swelling.