A new preliminary study published on bioRxiv claims that long-term use of certain antihypertensive medications increases the risk for colorectal cancer. Previous clinical trials suggested that antihypertensive drugs had no severe side effects, but these studies only lasted four years on average. Patients take these medications for decades, and they are widely prescribed, so identifying potential long-term side effects is critical.
The connection between hypertension medications and cancer risk has been debated for some time. James Yarmolinsky, a senior research associate (CRUK Fellowship) at the Bristol Medical School and the first author of this paper, thinks that the disagreement stems from how the previous clinical trials were done. His fascination with quantitative epidemiology inspired him to design a better study.
“I like the fusion of human biology and disease biology and applying sophisticated quantitative methods to try and understand human biology and disease biology,” said Yamolinksy. “[I like] the clinical dimension to it as well — trying to improve our understanding of how disease develops and how...to better prevent it and treat it.”
Previous studies compared the number of people who developed cancer in groups who were or were not taking an antihypertensive medication. There was no way to factor in the effect of other prescriptions on either group. Yarmolinsky aimed to avoid this and other common biases by grouping people based on single nucleotide polymorphisms (SNPs) within specific genes associated with blood pressure, a strategy called Mendelian randomization.
In an ideal world, epidemiologists design a study where they randomly assign 100,000 people to take a drug (and no other drugs) and another 100,000 not to take the drug. However, this perfect design is incompatible with real patients’ needs. Yarmolinsky used SNPs as a genetic proxy for the effect of drugs. Genetic sequences pass from generation to generation, and outside factors such as drug use don’t affect SNPs.
One type of antihypertensive medication inhibits angiotensin converting enzyme (ACE), an enzyme that controls blood pressure by regulating hormone levels. Yarmolinsky and his colleagues analyzed SNPs in ACE associated with systolic blood pressure, which mimic the effect of the medication. They analyzed sequencing data obtained from breast, prostate, and colorectal cancer, and found that ACE mutations were enriched in patients with colorectal cancer.
These results suggested to Yarmolinsky that long-term inhibition of ACE may increase the risk for colorectal cancer, leading them to call for clinical trials to test the safety of long-term treatment with ACE inhibitors. One expert thinks that conclusion is premature.
“I think this is a good paper, but I [would] not be calling to develop a clinical trial based on this paper. This is an observational study,” said Sanjay Shete, professor of biostatistics and epidemiology at The University of Texas, M.D. Anderson Cancer Center.
Shete recommended that the authors tone down the language in their conclusions and further discuss the limitations of their study. He questioned if the study truly employed Mendelian randomization. The ACE SNPs the researchers analyzed affect systolic blood pressure, but they do not necessarily inhibit ACE function in the same way an ACE inhibitor does. The SNPs may not serve as a true genetic proxy for ACE inhibitors, making the study subject to the same biases as classical epidemiological studies.
Shete also raised concerns about the genomic data that the group analyzed, which they acquired through the International Lung Cancer, the PRACTICAL, and the FinnGen consortiums.
“By [using] consortia, they don’t get the granular individual level data. They really get the summary level data, so they don’t have the BMI or any other medications that the people are taking,” said Shete.
Despite the critics, Yarmolinsky keeps on trucking. He wants to do other large-scale -omics studies to reveal the connection between long-term ACE inhibition and colorectal cancer.
“The next steps are to try to unravel molecular mediating pathways that might underpin the effective ACE inhibition of colorectal cancer, and this includes a host of different tiers of biological data, including circulating proteins, metabolites, and gene expression methylation data,” said Yarmolinksy.
Yarmolinsky, J. et al. Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers. bioRxiv. (2021).