ACE Inhibitors are group of commonly used drugs for hypertension and heart failure. In this article we discuss the link between ACE inhibitors and lung cancer.
Introduction
Millions of people take ACE inhibitors (ACEIs) every day to manage high blood pressure and heart disease. These medications help relax blood vessels, making it easier for the heart to pump blood. But several studies have raised an important question:
Could long-term use of ACE inhibitors increase the risk of lung cancer?
Several studies have investigated this potential link, with some suggesting a small but noticeable increase in lung cancer risk among long-term ACEI users. While the overall risk remains low, the findings have sparked concern among doctors and patients alike.
Understanding the connection between blood pressure medications and lung health is essential. This is crucial, especially for those who have been taking ACEIs for years.
This article breaks down the research, explains what we know so far, and helps you make informed decisions about your health.
What Are ACE Inhibitors and How Do They Work?
ACE inhibitors (ACEIs) are a common type of medication used to treat high blood pressure (hypertension) and heart disease. They work by relaxing and widening blood vessels, making it easier for blood to flow. This helps lower blood pressure and reduces the strain on the heart.
How Do They Work?
ACE inhibitors block the action of an enzyme called angiotensin-converting enzyme (ACE). Normally, this enzyme helps produce angiotensin II, a substance that makes blood vessels tighten and raises blood pressure. By blocking ACE, these medications prevent the formation of angiotensin II, leading to:
- Lower blood pressure
- Less strain on the heart
- Improved blood flow to organs like the kidneys
ACE inhibitors are widely prescribed for conditions such as:
- High blood pressure (hypertension) – To reduce the risk of heart attacks, strokes, and kidney damage.
- Heart failure – To improve heart function and prevent worsening symptoms.
- Diabetes-related kidney disease – To protect kidney function and prevent complications.
Commonly Used ACE Inhibitors
Several ACE inhibitors are available, with some being more widely used than others.
Most commonly used in the U.S.:
- Lisinopril (Prinivil, Zestril) – One of the most prescribed blood pressure medications.
- Enalapril (Vasotec) – Used for both high blood pressure and heart failure.
- Ramipril (Altace) – Often prescribed after heart attacks to improve survival.
- Benazepril (Lotensin) – Used for lowering blood pressure.
Most commonly used globally:
- Lisinopril – Popular due to its effectiveness and affordability.
- Enalapril – Widely used for hypertension and heart disease.
- Ramipril – Prescribed in many countries for cardiovascular protection.
- Perindopril – Commonly used in Europe and Asia for heart health benefits.
- Captopril – One of the oldest ACE inhibitors, still used in some regions.
ACE inhibitors are generally safe and effective, but like all medications, they have potential side effects. Some people experience a persistent dry cough, dizziness, or increased potassium levels. More serious but rare side effects include kidney problems and swelling of the face or throat (angioedema).
While ACE inhibitors provide many benefits, recent studies suggest they may be linked to a slightly higher risk of lung cancer with long-term use.
Once we go to the studies, we will read about ARBs. Let’s take a moment to know the difference between ARBs and ACE inhibitors.
What Are Angiotensin Receptor Blockers (ARBs), and How Do They Compare to ACE Inhibitors?
Another class of medications, angiotensin receptor blockers (ARBs), is often prescribed as a substitute.
What Are ARBs and How Do They Work?
Like ACE inhibitors, ARBs help lower blood pressure. They also reduce strain on the heart. However, they work in a slightly different way.
Instead of blocking the enzyme that produces angiotensin II (like ACEIs do), ARBs directly block the receptors that angiotensin II binds to. This prevents angiotensin II from tightening blood vessels, leading to:
- Lower blood pressure
- Less strain on the heart
- Improved blood flow to organs, including the kidneys
Similarities Between ACE Inhibitors and ARBs
- Both relax blood vessels, lowering blood pressure.
- Both are used for high blood pressure, heart failure, and kidney protection in diabetes.
- Both have been shown to reduce the risk of heart attacks and strokes.
Differences Between ACE Inhibitors and ARBs
| Feature | ACE Inhibitors (ACEIs) | Angiotensin Receptor Blockers (ARBs) |
|---|---|---|
| How They Work | Block ACE, reducing angiotensin II production | Block angiotensin II from attaching to its receptor |
| Common Side Effects | Can cause a persistent dry cough, higher risk of angioedema (swelling of the face and throat) | Less likely to cause cough or angioedema |
| Lung Cancer Risk (Based on Studies) | Some studies suggest a higher long-term lung cancer risk | ARBs are often used as a comparison group in studies and show a lower lung cancer risk |
Why ARBs Are Mentioned in the Studies
Many studies exploring the possible link between ACE inhibitors and lung cancer compare ACEI users to ARB users. This is because ARBs treat the same conditions as ACEIs but work differently, making them a useful comparison group. If ACE inhibitors show a higher lung cancer risk than ARBs, it indicates that the risk could be specifically related to ACEIs. This risk is not necessarily related to high blood pressure itself.
Commonly Used ARBs (Generic & Brand Names)
- Losartan (Cozaar) – One of the most widely prescribed ARBs.
- Valsartan (Diovan) – Commonly used for high blood pressure and heart failure.
- Olmesartan (Benicar) – Often used for hypertension.
- Irbesartan (Avapro) – Used for both blood pressure control and kidney protection in diabetes.
- Candesartan (Atacand) – Another option for heart failure and high blood pressure.
- Telmisartan (Micardis) – Used for cardiovascular risk reduction.
ARBs work differently and do not seem to have the same bradykinin-related effects as ACE inhibitors. Therefore, they are often considered an alternative for patients who experience side effects like cough or angioedema with ACEIs.
Additionally, research suggests that ARB users have a lower lung cancer risk than ACEI users. This makes them a key comparison group in studies on this topic.
In the next sections, we’ll explore what the research says about ACE inhibitors and lung cancer. We will also examine what this means for people taking these medications.
The Possible Link Between ACE Inhibitors and Lung Cancer
ACE inhibitors (ACEIs) have been widely used for decades to manage high blood pressure and heart disease, but recent research suggests a potential concern: Could these medications increase the risk of lung cancer, especially with long-term use?
Why Would ACE Inhibitors Affect the Lungs?
Scientists believe that ACE inhibitors might contribute to lung cancer development. They affect certain substances in the body, particularly bradykinin and substance P. Both of these can accumulate in lung tissue.
- Bradykinin – ACE inhibitors prevent its breakdown, leading to higher levels in the lungs. Some researchers suggest that bradykinin might promote inflammation and cell growth, which could contribute to cancer development over time.
- Substance P – This compound is also broken down by ACE and has been linked to tumor growth. When ACEIs block its breakdown, levels may increase, potentially influencing cancer risk.
What Do the Studies Say?
Understanding Odds Ratios (OR) and Hazard Ratios (HR)
When reading studies about health risks, we will come across terms like odds ratio (OR) and hazard ratio (HR). These statistical measures help researchers compare the likelihood of an event happening in one group versus another.
- Odds Ratio (OR) – This compares the odds of an event (like lung cancer) occurring in one group (ACEI users) versus another group (non-users or ARB users).
- An OR of 1.0 means no difference in risk.
- An OR above 1.0 suggests increased risk.
- An OR below 1.0 suggests decreased risk.
- Example: An OR of 1.19 means ACEI users had 19% higher odds of developing lung cancer compared to non-users.
- Hazard Ratio (HR) – This measures the rate at which an event occurs over time in different groups. Unlike OR, which looks at total odds, HR considers timing—how quickly an event (like cancer) develops in one group compared to another.
Both OR and HR help researchers understand whether a treatment or exposure increases or decreases the likelihood of an outcome. However, they do not prove cause and effect—other factors may be involved. With that, let us go to the studies.
1. Large-Scale Meta-Analysis Finds Increased Lung Cancer Risk (British Journal of Cancer, January 2023)
This is one of the most comprehensive studies to date, combining data from seven cohort studies and four case-control studies.[1]
A large systematic review and meta-analysis was published in the British Journal of Cancer. It analyzed data from over 13 million patients. The aim was to assess whether ACE inhibitors are linked to lung cancer.
Key Findings:
- ACE inhibitor use was linked with a 19% increased risk of lung cancer than those who did not take these medications. (OR 1.19, 95% CI 1.05–1.36; P = 0.008).
- The study included adults 18 years and older, with at least one year of follow-up.
- The analysis found higher lung cancer risk in ACEI users compared to ARB users. This suggests the effect might be specific to ACE inhibitors.
- Asian patients appeared to be at greater risk, though the study included diverse populations.
- Despite the strong association, high heterogeneity (I² = 98%) indicates variability between studies, meaning results should be interpreted with caution.
What This Means:
This large-scale analysis provides strong evidence that ACE inhibitors may be linked to lung cancer. However, it does not prove a direct cause-and-effect relationship. While the increased risk is relatively small, the study highlights the need for more randomized controlled trials to confirm whether ACEIs directly contribute to lung cancer development.
2. Higher Doses of ACE Inhibitors Linked to Increased Lung Cancer Risk (Circulation, January 2021)
A nationwide nested case-control study was published in Circulation. It examined whether ACE inhibitors were linked to lung cancer in a Danish population.[2]
This study sought to replicate previous findings from a UK-based study, using a large national health database.
Key Findings:
- The study included 9,652 lung cancer cases. These cases were matched with 190,055 controls. This makes it one of the largest case-control studies on this topic.
- High cumulative doses of ACE inhibitors (more than 3,650 defined daily doses) were linked with a 33% increased risk of lung cancer. (adjusted OR 1.33, 95% CI 1.08–1.62).
- Lower cumulative doses (≤1,800 defined daily doses) showed no significant increase in lung cancer risk (OR 1.01, 95% CI 0.94–1.09).
- The association was not strongly linked to any specific type of lung cancer. This means different lung cancer subtypes were affected similarly.
- ACE inhibitors showed a higher risk of lung cancer than thiazide diuretics (another type of blood pressure medication). (OR 1.34, 95% CI 0.96–1.88), The confidence interval suggests some uncertainty.
What This Means:
This study supports the idea that long-term and high-dose use of ACE inhibitors may increase lung cancer risk. It also suggests that lower doses do not show the same risk.
The absolute risk remains low. However, these findings highlight the need for careful consideration of cumulative ACEI exposure. This is especially true for long-term users.
3. Long-Term ACE Inhibitor Use Shows Small Increased Lung Cancer Risk (Journal of Cardiovascular Pharmacology and Therapeutics, January 2021)
An observational study was published in the Journal of Cardiovascular Pharmacology and Therapeutics. It examined whether ACE inhibitors (ACEIs) increase the risk of lung cancer. The comparison was made with angiotensin receptor blockers (ARBs). [3]
This study used a large U.S.-based health database spanning 22 years and followed patients for an average of 7.1 years, with some reaching 20 years of follow-up.
Key Findings:
- Study size: 187,060 patients, with a near-equal split between men and women (51% women).
- Lung cancer cases: 3,039 cases of lung cancer and 43,505 deaths were recorded.
- Lung cancer rates:
- 2.16 cases per 1,000 patient-years in the ARB group.
- 2.31 cases per 1,000 patient-years in the ACEI group.
- Hazard ratios (HR):
- Unadjusted HR: 1.11 (95% CI 1.02–1.22, P = .014).
- Adjusted HR: 1.18 (95% CI 1.06–1.31, P = .002), meaning an 18% increased risk of lung cancer with ACEIs compared to ARBs.
- Long-term risk pattern:
- The difference in lung cancer rates between ACEI and ARB users only became noticeable after 10-12 years of continuous use.
- The number needed to harm (NNH) was 6,667, meaning for every 6,667 patients treated with an ACEI instead of an ARB, one additional lung cancer case might occur over time.
The graph below shows that the longer ACE inhibitors are used, the higher the risk of lung cancer.
What This Means:
This study suggests that long-term ACE inhibitor use (10+ years) is linked to a slightly increased lung cancer risk. However, the absolute risk remains low.
The gradual separation of lung cancer rates over time suggests a cumulative effect. This means the risk may increase the longer ACEIs are used.
These findings align with previous studies showing a small but statistically significant increased risk compared to ARBs.
4. Long-Term ACE Inhibitor Use Linked to Higher Lung Cancer Risk (BMJ, October 2018)
A large population-based cohort study was published in British Medical Journal. It analyzed nearly 1 million patients from the UK Clinical Practice Research Datalink. [4]
The study aimed to assess whether ACE inhibitors increase lung cancer risk compared to angiotensin receptor blockers (ARBs).
Key Findings:
- Study size: 992,061 patients newly treated with blood pressure medications between 1995 and 2015.
- Follow-up period: 6.4 years on average, with some patients followed for over 20 years.
- Lung cancer cases: 7,952 incidents of lung cancer were recorded.
- Risk comparison (ACEI vs. ARB users):
- Overall hazard ratio (HR) = 1.14 (95% CI 1.01–1.29), indicating a 14% increased risk of lung cancer with ACEIs.
- Risk increased with longer use:
- 5+ years: HR = 1.22 (95% CI 1.06–1.40).
- 10+ years: HR = 1.31 (95% CI 1.08–1.59), meaning a 31% increased risk after a decade of use.
- Lung cancer incidence rates:
- ACEI users: 1.6 cases per 1,000 person-years.
- ARB users: 1.2 cases per 1,000 person-years.
What Does “Person-Years” Mean?
In medical studies, person-years is a way to measure risk over time. It accounts for both the number of people in a study and how long they were followed.
For example, if a study follows 1,000 people for 10 years, that would be 10,000 person-years (1,000 × 10). If another study follows 5,000 people for 2 years, that would be 10,000 person-years as well.
By using person-years, researchers can compare how often a disease like lung cancer occurs in different groups. This is possible even if the groups have different numbers of people or follow-up times.
This makes the results more accurate when studying long-term health risks.
What This Means:
This large-scale study reinforces the idea that long-term ACE inhibitor use may increase lung cancer risk. This is especially true for usage over 10+ years. There is a progressive rise in risk over time.
The study suggests that patients on ARBs had a lower lung cancer incidence. This finding makes them a potential alternative for long-term blood pressure management.
While the absolute risk remains low, the study highlights the importance of careful long-term monitoring of ACEI users. This is crucial for those with additional lung cancer risk factors like smoking and family history.
Let us now summarize the four studies.
Summary of Key Findings from the Four Studies on ACE Inhibitors and Lung Cancer
| Study | Type & Population | Key Findings | Main Conclusion |
|---|---|---|---|
| British Journal of Cancer (Jan 2023) | Meta-analysis of 13 million patients (7 cohort & 4 case-control studies) | ACE inhibitors were linked to a 19% increased lung cancer risk (OR 1.19, 95% CI 1.05–1.36). Risk was higher in Asian patients. | Large-scale analysis suggests ACEI use is linked with increased lung cancer risk, but further trials are needed for confirmation. |
| Circulation (Jan 2021) | Nationwide Danish case-control study of 9,652 lung cancer cases & 190,055 controls | High-dose ACEI users (3,650+ daily doses) had a 33% increased lung cancer risk (OR 1.33, 95% CI 1.08–1.62). Lower doses showed no significant risk increase. | Long-term, high-dose ACEI use may contribute to lung cancer, but more research is needed to confirm causation. |
| Journal of Cardiovascular Pharmacology and Therapeutics (Jan 2021) | Observational study of 187,060 patients, followed for an average of 7.1 years (max 20 years) | ACEI use was linked with an 18% increased lung cancer risk compared to ARBs (HR 1.18, 95% CI 1.06–1.31). The risk difference became noticeable after 10–12 years of use. | Long-term ACEI use may have a small but meaningful increase in lung cancer risk, with ARBs showing a lower risk. |
| British Medical Journal (Oct 2018) | Cohort study of 992,061 UK patients, followed for 6.4 years on average | ACEI users had a 14% higher lung cancer risk compared to ARB users (HR 1.14, 95% CI 1.01–1.29). Risk increased over time, reaching 31% higher risk after 10+ years (HR 1.31, 95% CI 1.08–1.59). | Lung cancer risk increases with longer ACEI use, particularly beyond 5–10 years. Additional long-term studies are needed. |
Key Takeaways:
- All four studies found a small but consistent increase in lung cancer risk with ACE inhibitors.
- Risk increases with higher doses and longer duration (especially beyond 5–10 years).
- ARBs were used as a comparison group in multiple studies and did not show the same increased lung cancer risk.
- The absolute risk remains low. However, these findings suggest a need for further investigation. Careful consideration of long-term ACEI use is also necessary.
Are There Any Studies Showing No Link Between ACE Inhibitors and Lung Cancer?
Multiple studies suggest a small but increased risk of lung cancer with long-term ACE inhibitor use. However, not all research supports this connection. We found one study that found no significant association between ACEIs and lung cancer.
The research was published in Medicine (April 2021). It conducted a meta-analysis of observational studies. The analysis found no evidence that ACE inhibitors increase lung cancer risk. Let’s take a closer look at its findings.
Why Did This Study Find Different Results?
Several factors could explain why this 2021 Medicine meta-analysis found no increased lung cancer risk, while others did:
1. Differences in Study Selection and Sample Size
- This meta-analysis included 13 observational studies with 458,686 ACEI users. This number is smaller than the 13 million patients analyzed in the British Journal of Cancer (2023) meta-analysis.
- The BMJ (2018) and Circulation (2021) studies used national health databases. These databases include millions of patients. This method potentially captures more cases of long-term ACEI use.
2. Study Inclusion Criteria and Exposure Duration
- This study pooled data from different observational studies, some of which may have had shorter follow-up periods.
- Long-term exposure seems to be key. The BMJ (2018) and Circulation (2021) studies found that lung cancer risk increased after 5–10 years of ACEI use.
- This study specifically states that 5+ years of ACEI exposure did not show a significant risk increase (RR 0.95, 95% CI 0.75–1.20; P = .70)—which contradicts other studies that reported a higher risk after prolonged use.
3. High Heterogeneity Between Studies (Inconsistent Data Sources)
- The meta-analysis reported significant heterogeneity (I² = 86.07%), meaning the studies included were very different from each other in terms of:
- Populations studied (ethnic variations, underlying health conditions).
- Comparator drugs (some compared ACEIs to ARBs, others to placebo or different medications).
- Study designs (case-control, cohort studies, or randomized trials).
- When studies vary widely, it can be hard to draw strong conclusions. Results may not be consistent across different populations.
4. Publication Date and Data Cutoff
- The Medicine (2021) meta-analysis included studies published before June 1, 2019. This means it did not include more recent research such as the British Journal of Cancer (2023) study.
- The most recent studies with larger datasets found a small but significant risk increase. This increase may not have been captured in this older meta-analysis.
Takeaways: What You Need to Know
Most studies suggest a small but significant increase in lung cancer risk with long-term ACE inhibitor use, especially beyond 5–10 years. The increase ranges from 14% to 33% depending on dose and duration.
The absolute risk remains low, meaning most people taking ACE inhibitors will not develop lung cancer. However, ARBs (angiotensin receptor blockers), which treat the same conditions, have not shown the same increased risk in multiple studies.
One meta-analysis found no link between ACEIs and lung cancer, highlighting that research is not unanimous. Differences in study design, patient populations, and follow-up time may explain these conflicting findings.
People with other lung cancer risk factors—like smoking, family history, or lung disease—should discuss these findings with their doctor. While the increased risk is small, it is relevant for those already at higher risk.
Do not stop taking your ACE inhibitor without consulting your doctor. These medications have proven benefits in preventing heart attacks, strokes, and kidney disease. If concerned, ask your healthcare provider whether switching to an ARB might be an option for you.
Final Thoughts
The question of whether ACE inhibitors increase lung cancer risk remains under investigation. Several large studies suggest a small but gradual increase in risk with long-term use. Conversely, at least one meta-analysis found no significant association.
The key takeaway is that the overall risk is relatively low. However, the possibility of increased lung cancer cases with ACE inhibitors can’t be ignored.
That said, because lung cancer is one of the deadliest cancers worldwide, even a small increase in risk is significant. This risk is worth considering. This is especially true for people who have other risk factors, like smoking or a history of lung disease.
At this stage, more long-term studies are needed. These studies will determine if this link is causal. They will also evaluate whether certain populations are at greater risk than others.
In the meantime, patients should be aware of the research and discuss any concerns with their doctor. For those at higher risk, ARBs may be a reasonable option to consider.
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References:
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- Anderson JL, Knowlton KU, Muhlestein JB, Bair TL, Le VT, Horne BD. Evaluation of TReatment With Angiotensin Converting Enzyme Inhibitors and the Risk of Lung Cancer: ERACER-An Observational Cohort Study. J Cardiovasc Pharmacol Ther. 2021 Jul;26(4):321-327. doi: 10.1177/1074248420987054. Epub 2021 Jan 29. PMID: 33514290.
- Kristensen KB, Hicks B, Azoulay L, Pottegård A. Use of ACE (Angiotensin-Converting Enzyme) Inhibitors and Risk of Lung Cancer: A Nationwide Nested Case-Control Study. Circ Cardiovasc Qual Outcomes. 2021 Jan;14(1):e006687. doi: 10.1161/CIRCOUTCOMES.120.006687. Epub 2021 Jan 13. PMID: 33435729.
- Hicks BM, Filion KB, Yin H, Sakr L, Udell JA, Azoulay L. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ. 2018 Oct 24;363:k4209. doi: 10.1136/bmj.k4209. PMID: 30355745; PMCID: PMC6199558.
- Batais M, Almigbal T, Alotaibi K, Alodhayani A, Alkhushail A, Altheaby A, Alhantoushi M, Alsaad S, Dalbhi SA, Alghamdi Y. Angiotensin converting enzyme inhibitors and risk of lung cancer: A systematic review and meta-analysis. Medicine (Baltimore). 2021 Apr 30;100(17):e25714. doi: 10.1097/MD.0000000000025714. PMID: 33907158; PMCID: PMC8084080.
Image credits:
- Lung cancer – James Heilman, MD • CC BY-SA 3.0
- Lung cancer incidence – Source: U.K. Office for National Statistics licensed under the Open Government Licence v.1.0.
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