Lowering Blood Pressure, Raising Cancer Risk?

Corresponding Author

As cancer survivorship improves and the global burden of hypertension continues to rise, clinicians are increasingly confronted with questions regarding the long-term safety of antihypertensive therapies and the potential risk of cancer. A central question, therefore, is whether reducing blood pressure (BP) may impact the likelihood of developing cancer. Although a prior meta-analysis has largely refuted concerns about harmful effects of antihypertensive drug classes on overall cancer risk, as well as on the occurrence of site-specific cancer types,¹ the direct effect of BP reduction itself was not assessed. The study by Nazarzadeh et al² in this issue of JACC: CardioOncology integrated largescale individual participant data (IPD) from randomized controlled trials (RCTs) with Mendelian randomization (MR) to examine the potential causal relationship between BP lowering and cancer risk.

Leveraging IPD from major BP-lowering RCTs within the BPLTTC (Blood Pressure Lowering Treatment Trialists’ Collaboration), the investigators analyzed outcomes from 314,016 participants across 42 trials that reported cancer incidence. Over a median follow-up of 4 years, nearly 18,000 incident cancers and 4,878 deaths from cancers were recorded. Pharmacologically induced reductions in systolic (by 5 mm Hg) or diastolic (by 3 mm Hg) BP were not associated with an increased risk of overall cancer or cancer-related mortality. Further subgroup analysis revealed no observed differences between age, sex, body mass index, smoking status, baseline BP, or prior antihypertensive therapy. Site-specific analyses did not reveal any significant associations, except for a modest 17% increase in lung cancer risk with systolic BP lowering (HR: 1.17 [99.5% CI: 1.02-1.32]). The observed signal for lung cancer, although consistent with prior concerns about angiotensin receptor blockers,³ was not supported by MR analyses⁴ and by earlier BPLTTC IPD meta-analyses,¹ aligning with a lack of association of angiotensin receptor blockers and other antihypertensive classes. However, given the latency of cancer occurrence, and the relatively short duration of included clinical trials, it is conceivable that some new cancer cases may not have occurred during the follow-up period. Thus, to strengthen causal inference, the investigators implemented a 2-sample MR approach using genetic variants as proxies for lifelong BP exposure.⁵ These findings confirmed those of the IPD meta-analyses, demonstrating an absence of significant genetic associations between lower systolic or diastolic BP and the risk of six common cancers, including breast, colorectal, kidney, lung, prostate, and skin.

These conclusions are particularly meaningful considering earlier observational studies, which had reported associations between hypertension and breast, colorectal, and kidney cancers; although these studies might have been affected by confounding and reverse causality.^6,7 Notably, MR studies have generally found no relationship between genetically determined BP and cancer, except for renal cell carcinoma, where elevated diastolic BP may confer a modest increased risk.⁸ Another MR study using genetically proxied therapeutic inhibition of 3 antihypertensive drug targets (angiotensin-converting enzyme [ACE], β-1 adrenergic receptor [ADRB1], and sodium-chloride symporter [NCC]) and risk of 4 common cancers (breast, colorectal, lung, and prostate) suggested an association with long-term ACE inhibition and an increased risk of colorectal cancer.⁹

The biological explanation of a link between hypertension and cancer may rely on mechanisms such as increased oxidative stress and lipid peroxidation,¹⁰ renin-angiotensin-aldosterone system activation,¹¹ and endothelin-mediated endothelial dysfunction.¹² Yet the absence of a causal relationship in this study suggests that these pathways may be more reflective of shared risk factors, such as age, unhealthy lifestyle, smoking, body mass index and immune system dysfunction, than a direct carcinogenic effect of BP.

While not all eligible RCTs contributed to the IPD, and analyses of rarer cancers (eg, kidney) were underpowered due to low event counts (n = 195), MR, based on larger datasets, could overcome these limitations, and provided narrower confidence intervals. Moreover, cancer was not a primary or secondary endpoint in the included clinical trials, which may have led to under-ascertainment or misclassification, although such biases are likely nondifferential.

From a clinical standpoint, these findings offer reassurance for patients and clinicians alike: blood pressure reduction remains a fundamental strategy in cardiovascular disease prevention without added cancer risk. As concerns about cancer frequently arise in practice, this evidence strengthens clinician confidence in promoting adherence to established hypertension guidelines. This study also reflects the emerging trend toward integrating complementary methodologies such as IPD meta-analyses and MR in precision medicine. Although such triangulation strategies enhance causal inference, they are not without limitations. Both approaches demand significant resources—infrastructure for harmonizing participant-level trial data and genetic analysis—which may not be feasible in resource-limited settings where the burden of hypertension and cancer is growing most rapidly. Furthermore, MR studies remain constrained by the ancestry of available genome-wide association studies, which are predominantly derived from European populations. The 2-sample MR approach employed here leverages summary statistics from major transethnic genome-wide association studies consortia, offering one way forward in enhancing inclusivity and robustness in diverse settings.

Further research should focus on extended follow-up of clinical trial populations, improved cancer phenotyping, and evaluation of treatment effects in sub-groups at high-risk. Additionally, the question for class-specific drug effects remains, and deserves to be explored in future hypothesis-driven analyses. Integration of pharmacogenomic data could also help investigate whether certain antihypertensive classes influence cancer pathways in susceptible individuals.

In summary, this largescale analysis offers robust evidence that pharmacological BP lowering does not increase cancer incidence or mortality, moving beyond prior research that focused solely on the safety of specific antihypertensive drug classes without evaluating the effect of BP reduction per se. Clinically, this study affirms the use of antihypertensive therapy as a foundational strategy in cardiovascular prevention, without oncologic concern. The combined use of trial and genetic data here underscores the power of triangulation approaches in modern epidemiology.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.