In the winter of 1957, physicians working at the NCI conducted a clinical trial that would forever change oncology. At the time, there were only a handful of chemotherapeutic drugs. Individually, these drugs could only achieve fleeting remissions measured in weeks. The physicians at the NCI wanted the answer to a question: Would outcomes improve when chemotherapeutic drugs were combined? To test this, they designed a trial with three arms. One arm with methotrexate, one with 6-Mercaptopurine (6-MP) and one with methotrexate and 6-MP combined. The arms with the individual chemotherapies produced response rates of about 15%, but when the two drugs were combined, the response rate rose to 45%. More exotic combinations became possible as more chemotherapeutic drugs were discovered in the 1960s. Oncologists at the NCI ran a trial with a four-drug combination called VAMP on childhood leukemia that was able to cure most of the children. A four-drug combination called MOPP soon followed and was discovered to treat Hodgkin's disease effectively. These early trials established the power of drug synergy in oncology, a lesson that has guided chemotherapy strategy ever since.
Repurposing drugs for cancer: The synergistic effect between metformin and statins in aggressive gliomas
Over the years, two commonly used medications, metformin, and statins, have received headlines when retrospective studies suggested that users of the medications appeared to have significantly reduced cancer rates. When users did get cancer, their outcomes were better than nonusers. These drugs are interesting because they have a long clinical history of safety, are affordable, and do not interfere with most standard-of-care therapies – making them ideal candidates for adjunctive treatments. While many studies looked at the effect of the drugs individually, few looked at the two in combination.
However, a recent study extensively examined the combined anti-cancer synergy of metformin and statins.(1) The study, published last April in the Lancet, was designed to examine the overall survival benefit of each drug individually and in combination in a cohort of 85 patients with confirmed pathologically aggressive glioma. The survival rates were measured in months survived post-surgery and were as follows:
Patients not taking metformin or simvastatin/atorvastatin: 12.2 months
Patients taking metformin: 13 months
Patients taking simvastatin or atorvastatin: 13.8 months
Patients taking metformin and simvastatin or atorvastatin: 15.5 months
The study also looked at the effect of the drugs individually and in combination on tumor volume in a mouse model of glioma. The result again demonstrated a potent synergistic effect.
The authors then did extensive in vitro studies to assess the mechanisms behind the observed metformin/statin synergy by measuring the inhibition of critical cancer-promoting cellular pathways.
“Remarkably, while treatment with metformin or simvastatin alone did not significantly alter the activity of many of the elements belonging to these signaling pathways, the combination of both drugs significantly altered the activity of these elements…”
Metformin/statin synergy in chemoprevention
The chemopreventive properties of metformin and statins have intrigued researchers for decades. One of the advantages of commonly prescribed medications is that researchers can retrospectively look through medical records and analyze the incidence of different diseases in cohorts of people taking the drugs compared to those not. The first study looking at cancer rates of both metformin and statins users was done in Tawain and published in 2015. (2)
The study suggested that metformin and statins individually reduced cancer rates, but the reduction was more pronounced in combination. The study groups comprised individuals with the hepatitis B virus because the virus is known to increase the rate of liver and other cancers. The authors identified 71,847 individuals with HBV and recorded the number of cancers diagnosed between 2000 and 2008. They then determined the hazard ratio for the patients taking metformin, statins, or both metformin and statins.
The hazard ratio quantifies the effect of treatment compared to a control group not receiving the treatment. For example, suppose the hazard ratio for a treatment group is .5. In that case, the group is 50% less likely to have a cancer diagnosis during the study period than the group not receiving the treatment. If the hazard ratio is .3, the patients were 70% less likely to have a cancer diagnosis. And if the hazard ratio is 1, the treatment had no effect.
You can see that the hazard ratio for most cancer types is lowest in the metformin + statin group. As with the Lancet study, the authors attribute the chemopreventive effect to pathway synergy:
“Given the possible synergistic effects of deregulated AMPK, RAS, and cholesterol biosynthesis pathways on cancer risk, the use of the combination may reduce cancer risk. Few studies have formally examined the interactive and potentially synergistic effects of the combination treatment with both drugs. This is the first article suggesting a synergistic protective effect of using both statin and metformin in patients with HBV infection. Because glucose metabolism is interrelated with lipid synthesis, the synergistic effect of metformin and statins on reduced cancer risk may be partly mediated by their joint lipid-lowering effect.”
At Meakin metabolic clinic, we are interested in adjunctive therapies that may enhance the outcomes of standard-of-care treatments. We additionally offer combinations for non-cancer patients to reduce risk while monitoring established metrics that predict mortality threats. All care is delivered virtually from the comfort of your home, using local Quest labs, and is available in 45 states. While researchers found the synergistic effect of combinational chemotherapy in the mid-20th century, the lessons learned apply today when evaluating combinations of adjunctive cancer therapies to treat cancer or chemo prevention.
Article Summary
Metformin and statins are commonly used medications that have been shown to have anti-cancer properties.
A recent study found that the combination of metformin and statins synergizes in treating aggressive gliomas.
Patients who took metformin and statins after surgery for glioma had a median survival time of 15.5 months, compared to 12.2 months for patients who did not take the drugs.
The study also found that the combination of metformin and statins inhibited the activity of critical cancer-promoting cellular pathways.
Metformin and statins have also been shown to have chemopreventive properties, meaning they can help to reduce the risk of developing cancer.
MeakinMetabolicCare.com offers these synergistic combinations and more to the standard of care therapies and for prevention through a low-cost virtual platform
Stay Strong and Curious,
Charles Meakin MD, MS, MHA
Travis Christofferson MS
Meakin Metabolic Care Website
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Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.
Fuentes-Fayos AC, G-García ME, Pérez-Gómez JM, Montero-Hidalgo AJ, Martín-Colom J, Doval-Rosa C, Blanco-Acevedo C, Torres E, Toledano-Delgado Á, Sánchez-Sánchez R, Peralbo-Santaella E, Ortega-Salas RM, Jiménez-Vacas JM, Tena-Sempere M, López M, Castaño JP, Gahete MD, Solivera J, Luque RM. Metformin and simvastatin exert additive antitumour effects in glioblastoma via senescence-state: clinical and translational evidence. EBioMedicine. 2023 Apr;90:104484. doi: 10.1016/j.ebiom.2023.104484. Epub 2023 Mar 10. PMID: 36907105; PMCID: PMC10024193.
Chen CI, Kuan CF, Fang YA, Liu SH, Liu JC, Wu LL, Chang CJ, Yang HC, Hwang J, Miser JS, Wu SY. Cancer risk in HBV patients with statin and metformin use: a population-based cohort study. Medicine (Baltimore). 2015 Feb;94(6):e462. doi: 10.1097/MD.0000000000000462. PMID: 25674734; PMCID: PMC4602747
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