Does Lisinopril Cause Cancer? What Recent Studies Show

Lisinopril, a widely prescribed ACE inhibitor, is used to manage high blood pressure and heart failure. While its benefits are well-documented, concerns have emerged about whether long-term use could be linked to cancer. Researchers have examined potential biological mechanisms and epidemiological data to determine if such a risk exists.

Recent studies have explored possible associations, but findings remain inconclusive. Some suggest a theoretical link based on cellular changes, while others find no significant correlation in patient populations. Understanding the latest research is essential for patients and healthcare providers when weighing treatment risks and benefits.

Mechanism of Action in the Renin-Angiotensin System

Lisinopril targets the renin-angiotensin system (RAS), a hormonal network that regulates blood pressure, fluid balance, and vascular resistance. It works by inhibiting angiotensin-converting enzyme (ACE), which prevents the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor. This leads to vasodilation, reduced sodium retention, and lower blood pressure.

Beyond circulation, lisinopril influences cellular signaling pathways. Angiotensin II interacts with angiotensin type 1 (AT1) receptors, which are implicated in inflammation, oxidative stress, and fibrosis. By reducing angiotensin II levels, lisinopril modulates these pathways, impacting endothelial function and tissue remodeling.

The suppression of angiotensin II also alters the balance of other bioactive peptides, including angiotensin-(1-7), which has vasodilatory and anti-inflammatory properties. This shift may contribute to the protective effects of ACE inhibitors in conditions such as heart failure and chronic kidney disease. However, the long-term consequences of these biochemical changes remain under investigation, particularly in relation to cellular proliferation and apoptosis.

Theories Linking ACE Inhibitors and Cellular Changes

The potential link between ACE inhibitors like lisinopril and cellular changes has drawn interest due to the drug’s impact on biochemical pathways regulating growth, differentiation, and apoptosis. Since disruptions in these processes are hallmarks of oncogenesis, researchers have investigated whether long-term lisinopril use could contribute to tumorigenesis.

A central focus of this inquiry is the reduced availability of angiotensin II. While primarily recognized for its vasoconstrictive properties, angiotensin II also influences mitogenic pathways, including those mediated by extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB). These pathways are involved in cell survival and inflammatory responses, which can contribute to pathological tissue remodeling. Some studies suggest that by suppressing angiotensin II, ACE inhibitors may decrease cellular proliferation in certain tissues, potentially lowering malignancy risk. Conversely, this suppression might also disrupt normal apoptotic mechanisms, which could, under specific conditions, allow for the survival of aberrant cells.

Another line of investigation considers bradykinin, a peptide that accumulates when ACE activity is inhibited. Bradykinin exerts vasodilatory and anti-inflammatory effects through its interaction with B2 receptors but also activates signaling cascades associated with nitric oxide production and vascular permeability. Some researchers propose that increased bradykinin levels may influence angiogenesis—the formation of new blood vessels. While controlled angiogenesis is necessary for wound healing, excessive or dysregulated angiogenic activity is a known factor in tumor development. This raises questions about whether chronic ACE inhibition could create an environment that supports neoplastic growth in certain contexts.

Observational Data in Different Patient Groups

Large-scale epidemiological studies have attempted to determine whether lisinopril use is associated with an increased cancer risk, but findings remain inconsistent. Some retrospective analyses have examined electronic health records from millions of patients, comparing cancer incidence among those using ACE inhibitors versus other antihypertensive medications. These studies have produced conflicting results, with some suggesting a modest association with specific cancers, while others find no significant difference in overall cancer rates. Differences in study design, patient demographics, and follow-up duration contribute to the variability in findings.

One area of focus has been the potential link between long-term ACE inhibitor use and cancers of epithelial origin, such as lung, breast, and gastrointestinal malignancies. A meta-analysis published in The BMJ examined pooled data from multiple cohort studies and found a slight increase in lung cancer risk among patients on ACE inhibitors for more than five years. Researchers hypothesized that this association could stem from the accumulation of bradykinin and substance P in lung tissue, which may promote local inflammation and oxidative stress. However, other studies, including one from JAMA, found no meaningful correlation between ACE inhibitor use and lung cancer when adjusting for confounding factors like smoking history and preexisting respiratory conditions.

The relationship between lisinopril and gastrointestinal cancers has also been explored, with mixed findings. Some observational studies have reported a lower incidence of colorectal cancer among ACE inhibitor users, possibly due to the drug’s role in reducing chronic inflammation and improving vascular function in the intestinal lining. Conversely, a few reports have suggested a potential increase in esophageal cancer risk, particularly in patients with gastroesophageal reflux disease (GERD), though causality remains unproven. These discrepancies highlight the complexity of interpreting epidemiological data, as underlying health conditions, lifestyle factors, and concurrent medication use can all influence cancer risk independently of lisinopril.

Factors Studied in Cancer Risk Assessments

Evaluating whether lisinopril contributes to cancer risk requires a multifaceted approach that accounts for patient demographics, dosage, duration of use, and potential interactions with other medications. Researchers rely on cohort studies, randomized controlled trials, and meta-analyses to assess patterns in cancer incidence among ACE inhibitor users. These investigations often involve extensive follow-up periods to capture long-term trends and distinguish between correlation and causation.

One primary consideration is cumulative exposure. Some studies have explored whether prolonged use—typically exceeding five to ten years—correlates with a measurable increase in cancer cases. However, separating medication effects from age-related cancer risks presents a challenge, as older populations inherently face a higher likelihood of malignancies. Researchers employ statistical adjustments to control for confounding factors such as smoking history, obesity, and genetic predispositions, ensuring observed associations are not merely reflective of underlying health conditions.