In a network meta-analysis of discontinuation of blood-pressure (BP)-lowering medications due to adverse effects (AEs), the best-tolerated treatment was a combination of an angiotensin receptor blocker (ARB) and a calcium channel blocker (CCB), with four of the top five best-tolerated regimens containing ARBs.
Researchers reviewed 716 short-term, double-blind, randomized clinical trials from the Cochrane Central Register of Controlled Trials, MEDLINE, and Epistemonikos databases to compare short-term AEs and the risk of treatment discontinuation across BP-lowering drug classes and combinations.
The studies included 159,362 participants who received either a placebo or antihypertensive medications from five major classes: ACE inhibitors, ARBs, beta-blockers, CCBs, and diuretics (thiazides, thiazide-like agents, and mineralocorticoid receptor agonists), alone or in combination, for four to 26 weeks. [JAMA2026;doi: 10.1001/jama.2026.6214]
The participants’ mean age was 55 years, and 44 per cent were women. Mean baseline BP was 158/100 mm Hg. The primary outcome was the discontinuation of treatment due to AEs, defined as any unfavourable medical occurrence that may not have been causally related to the treatment.
Results showed that the likelihood of patients with hypertension discontinuing their prescribed BP-lowering medications varies by drug regimen. “Overall, five combination and two monotherapy regimens had higher surface under the cumulative ranking curve values than placebo, suggesting overall symptomatic improvement,” said study investigator Dr Nelson Wang from The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
ARBs better tolerated overall
Ranked by tolerance, the five best-tolerated BP drug classes and combinations were: ARB + CCB, ARB + beta-blocker, ARB monotherapy, CCB + thiazide diuretic, and ARB + thiazide diuretic. All ARB-containing regimens were associated with a lower rate of treatment discontinuation.
Combination therapies, particularly ARBs paired with CCBs, were generally better tolerated than monotherapies.
Antihypertensives vs placebo
Some antihypertensive medications had lower discontinuation rates than placebo. Over an average follow-up of 8.6 weeks, ARB + CCB (odds ratio [OR], 0.61) and ARB monotherapy (OR, 0.73) were associated with a lower risk of treatment discontinuation due to AEs than placebo, with risk differences (RDs) of –1.2 percent and –0.8 percent, respectively.
By contrast, three treatment regimens were associated with a higher risk of AE-related treatment discontinuation than placebo: CCB monotherapy (OR, 1.43; RD, 1.2 percent), ACE + CCB (OR, 1.46; RD, 1.1 percent) and beta-blocker + thiazide diuretics (OR, 1.58; RD, 1.7 percent). “
The researchers said these findings support consideration of ARBs as initial therapy for patients without comorbidities requiring alternative medications.
Reason for undertreatment
“Fear of AEs remains a major reason for undertreatment of high BP, the leading modifiable risk factor for death and cardiovascular disease worldwide. AEs are often falsely attributed to BP-lowering drugs, leaving patients undertreated,” said Wang.
“For years, we have assumed that more BP-lowering treatment equates to worse tolerability,” he continued. “Hence, most patients are started and remain on single drug monotherapy.”
AEs are commonly reported with antihypertensive use in clinical practice, “but it is difficult and sometimes impossible to know whether these are due to treatment or not,” Wang pointed out.
Unusually surprising results
“For the first time, we have shown that certain [types of] combination therapy has lower rates of treatment discontinuation due to adverse events than monotherapy, or even placebo,” he emphasized. “This was highly surprising because very few treatments in medicine have been shown to be better tolerated than placebo.”
He said the improved adherence with combination therapies might be due to compensatory mechanisms across different drug classes. “For instance, inhibition of the renin-angiotensin-aldosterone system can offset oedema related to CCBs.”
Practice-changing implications
“These results provide definitive evidence that combination therapy should be the first-line treatment for patients with high BP,” Wang emphasized. “We knew for a fact that combination therapy was more effective at lowering BP. Now, we know that certain drug-class combinations are also better tolerated.”
In a related editorial, Dr Mary McDermott, Deputy Editor of JAMA, and Dr Stephen Persell from the Northwestern University Feinberg School of Medicine in Chicago, Illinois, US, however, advised caution against overinterpreting the findings. [JAMA 2026; doi:10.1001/jama.2026.7685]
“Potential differences in tolerability of these drug classes overall should not prompt changes in antihypertensive medications for patients for whom the benefits are well established, such as ARBs or ACE inhibitors for patients with diabetes and albuminuria or heart failure with reduced ejection fraction,” the editorialists warned.
A delicate balance
The results could help inform the selection of antihypertensive therapies for patients initiating medications for hypertension. However, both experts emphasized that “clinicians should consider both the likelihood of adverse effects and potential benefits,” noting that the meta-analysis did not evaluate how discontinuation affects cardiovascular and other outcomes.
Still, Wang said the results should encourage upfront use of combination therapies for patients with hypertension. “Our findings also challenge the long-standing belief that BP-lowering therapies cannot lead to short-term symptomatic improvements.”
Finally, he asserted that not all adverse events experienced while taking a medication are treatment-related.