The study was published online November 20 in the Oncologist.

Compared with other therapies, there was a relative survival benefit for both cancer-specific (hazard ratio [HR], 0.62) and overall (HR, 0.66) survival with metformin. These results were also observed across subgroups and geographic locations, report Ming Yin, MD, from Geisinger Medical Center in Danville, Pennsylvania, and colleagues.

When analyzed by cancer subtype, the reduction in risk for death was significant in patients with pancreatic, colorectal, breast, prostate, and other cancers, but not for lung cancer.

Even when the largest study was excluded from the analysis, which accounted for nearly 40% of all participants, the results were not significantly different. In addition, a sensitivity analysis, which involved excluding one study at a time from the analysis, showed that no single study influenced the overall conclusion.

”While there is little doubt that type 2 diabetes increases the incidence of various solid tumors, the added contribution of specific insulin medications now seems unlikely,” said Bruce Chabner, MD, editor-in-chief of the Oncologist, in a statement. This meta-analysis ”addresses a more relevant and informative topic — the growing evidence for an antitumor effect of metformin, which is a common oral medication for control of type 2 diabetes.”

However, the researchers caution that it is not clear whether metformin can modulate clinical outcomes in cancer patients with diabetes; this meta-analysis only provided evidence that metformin improved survival compared with other glucose-lowering medications. But the results suggest that metformin ”is the drug of choice in the treatment of patients with cancer and concurrent type 2 diabetes,” they write.

Interpreting the Data

There are also at least ”2 major difficulties” in interpreting these data, according to an accompanying editorial by Carlo La Vecchia, MD, and Cristina Bosetti, PhD, both from the Istituto di Ricerche Farmacologiche ”Mario Negri,” in Milan, Italy.

First, these data come from observational studies because antidiabetic therapy is individualized and cannot be randomized, they note.

Second, the caseline clinical characteristics of diabetic patients who are using metformin ”are largely different” from those being treated with other agents. Thus, ”any interference or comparison on their subsequent cancer risk is difficult,” the editorialists point out. ”Confounding is therefore complex and difficult to allow for, despite the use of multivariate late methods of analysis.”

However, they acknowledge that the nearly 40% reduced risk for cancer that has been observed in diabetics using metformin and the ”appreciably reduced risk of colorectal or pancreatic cancer appear to be too large to be totally accounted for by different baseline characteristics of the 2 groups of diabetic patients,” Drs. La Vecchia and Bosetti write. ”Hence, a real favorable effect of metformin — of potential clinical and public health relevance — is possible.”

Benefit in Certain Cancers

For the meta-analysis, Dr. Yin and colleagues evaluated 20 studies with 13,008 patients who had cancer and concurrent diabetes. The 20 studies reported survival data according to metformin treatment, and data were adjusted for confounding variables, heterogeneity between studies, and publication bias.

Roughly half the cohort received metformin, either alone or in combination with other glucose-lowering therapies; the remaining patients received other treatments, including insulin.

In a subgroup analysis that looked at Asian and Western countries, metformin was associated with a reduced mortality risk in Asian countries (HR, 0.49 by fixed effect; P = .150 for heterogeneity). In Western countries, the relative survival benefit remained (HR, 0.73 by random effect; P < .001 for heterogeneity). Stratified analysis did not detect any publication bias.

The reduction in cancer-related mortality with metformin by cancer type in the 9 studies that reported cancer-specific survival was similar to that seen in the overall meta-analysis. Stratification by ethnicity was not done because there were insufficient data from Asian countries.

The authors have disclosed no relevant financial relationships.

Oncologist. Published online November 20, 2013. Abstract

Metformin Is Associated With Survival Benefit in Cancer Patients With Concurrent Type 2 Diabetes: A Systematic Review and Meta-Analysis