METFORMIN AND LUNG CANCER RISK

Use of metformin in patients with type 2 diabetes is not associated with subsequent lung-cancer risk, a new study indicates.

However, never-smokers in the study did show a 43% lower risk of lung cancer with metformin use, and that apparent protection increased further with longer use of the drug, although these reductions were not statistically significant.

In contrast, current smokers demonstrated associations in the opposite direction (ie, metformin use was associated with increased lung-cancer risk), but again this was not statistically significant.

"Evidence from our study and others largely suggests no association between metformin use and risk of lung cancer in patients with diabetes," remarked Dr Lori Sakoda (Kaiser Permanente Division of Research, Oakland, California), who led the study.

"But when we examined whether this association might differ in patient subgroups, we found that it might by smoking history. While this finding is intriguing, it must be confirmed or refuted by other large, well-conducted studies," she told Medscape Medical News.

Therefore, she added, no implications with regard to current clinical practice can be drawn from this large retrospective cohort study, which is published in the February issue of  Cancer Prevention Research, a journal of the American Association for Cancer Research.

Conflicting Results From Previous Studies

Metformin, the drug most commonly used as first-line therapy in type 2 diabetes, is thought to offer some protection against cancer, although results from studies looking into this have varied depending on the type of tumor in question.

With regard to lung cancer specifically, prior research has been inconsistent, say Dr Sakoda and colleagues.

They drew their data from a total of 47,351 diabetic patients of 40 years or older (the vast majority of whom had type 2 diabetes) who completed a health-related survey between 1994 and 1996.

Information on their diabetes medications was collected from electronic pharmacy records. About 46% of patients were "ever-users" of metformin, defined as those who filled two or more prescriptions within a 6-month period.

The researchers estimated lung-cancer risk associated with use of metformin, along with total duration, recency, and cumulative dose, adjusting for potential confounding factors including body mass index (BMI), smoking status, and pack-years smoked.

They also examined metformin use and relation to risk of lung cancer in certain subgroups of patients, specifically by gender, smoking history, tumor histology and stage.

To account for potential time-related biases — for example, when unexposed time is misclassified as exposed — patients were defined as users of metformin only once they actually started taking the drug, and the researchers also controlled for possible effects due to diabetes duration and severity.

Metformin Reduces Adenocarcinoma, Ups Small-Cell Carcinoma 

During 15 years of follow-up, 747 patients were diagnosed with lung cancer. Of them, 80 were never smokers, 203 were current smokers, and the remainder were former smokers.

Considering all patients, no association was found between metformin use and lung-cancer risk. Nor was there any association with duration, dose, or recency of metformin use and overall lung-cancer risk.

However, "we noted suggestive but intriguing differences in risk associated with metformin use between subgroups defined by smoking history and tumor histology," the authors observe.

They found that, among approximately 18,400 never-smokers, ever use of metformin was associated with a 43% decrease in lung-cancer risk (hazard ratio [HR], 0.57; P = .11 for interaction between metformin use and smoking status), declining further to a 52% reduction in risk with metformin use of 5 years or longer (HR, 0.48; P = .35).

But among the approximately 4400 current smokers, the opposite association was identified, with risk estimates greater than 1.0, although these weren't statistically significant, either.

With respect to tumor histology, Dr Sakoda said: "Consistent with this variation in risk by smoking history, we found that longer use of metformin was associated with a lower risk of adenocarcinoma [31% decrease in risk], a common histologic subtype of lung cancer diagnosed in nonsmokers, but a higher risk of small-cell carcinoma [82% increase in risk], a histology subtype of lung cancer diagnosed often in smokers.

"However, these associations by tumor histology also did not reach statistical significance," she told Medscape Medical News.

Asked to comment, Dr Laurent Azoulay, from the department of oncology, McGill University, Montreal, Quebec, commended the authors on their work.

"With the use of a proper study design and method of analysis, they have effectively avoided time-related biases, the latter being the most significant methodological shortcoming in some of the previous studies," he observed.

"The decreased risk of lung cancer with metformin among never-smokers is intriguing. Although, as carefully stated by the authors, this may have been a chance finding, since it was based on only 29 metformin-exposed events," he added.

He concluded with a note of caution. "Certainly, additional studies using the same rigorous methods are needed to replicate these findings."

Is Anti-Inflammatory Effect of Metformin Protective in Never-Smokers? 

Adding another expert perspective, Dr Phillip Dennis, from the department of oncology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, and an employee of AstraZeneca, noted that "other confounding factors, such as BMI and HbA1c, were only measured at baseline and not during the study. Therefore, it is possible that these factors could have muddied the data over the long-term follow-up."

However, putting that concern aside, Dr Dennis also commended the authors and said there remains an important question: why does metformin appear to reduce the risk of lung cancer in never-smokers vs ever/current smokers?

Metformin reduces inflammation, he observed. "It is therefore possible that the ability of metformin to decrease lung-cancer risk in never-smokers is related to…less inflammation and less mutational burden.

"Smoking may simplistically lead to a burden of inflammation and mutations in key genes that metformin cannot counteract," he suggested.

"Future clinical trials could test whether metformin prospectively inhibits lung cancer in never-smokers and whether changes in inflammatory biomarkers are associated with this decreased risk."

Dr Sakoda and Dr Azoulay report no relevant financial relationships. Disclosures for the coauthors are listed in the article. Dr Dennis is retained as an adjunct professor at John Hopkins but is now a full-time employee of AstraZeneca.

Cancer Prev Res. 2015;8:174-179. Abstract