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Meta-analysis: TZD use neutral on breast cancer risk in women

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November 15, 2017

Women with type 2 diabetes prescribed thiazolidinediones did not see an increased risk or benefit with respect to incident breast cancer, according to a meta-analysis published in Diabetes Metabolism Research and Reviews.

“Previous studies demonstrated that diabetes could contribute to an increased risk of breast cancer-specific mortality,” Jieli Lu, MD, PhD, of the Key Laboratory for Endocrine and Metabolic Diseases at Ruijin Hospital in Shanghai, and colleagues wrote in the study background. “Interestingly, increasing evidence suggests that anti-diabetic therapies, such as metformin, insulin glargine and TZDs, might also affect the risk of breast cancer incidence and mortality.” Results across studies, however, have been inconsistent, the researchers noted.

Lu and colleagues analyzed data from 14 studies examining any association between TZD treatment and risk for breast cancer in women with diabetes published before January 2016, including five randomized controlled trials, seven cohort studies and two case-control studies (n = 1,089,039 with 12,233 breast cancer cases). Exposure to TZDs was defined as TZD monotherapy or ever use of TZDs. Researchers used random-effects models to assess the association between TZD use and risk for incident breast cancer, using RR as the common effect size for cohort studies and randomized controlled trials and ORs for case-control studies.

Researchers found that the strength of any association between TZD use and breast cancer risk depended on the type of study, event number and effect size. In the five randomized controlled trials, women prescribed TZDs did not experience a decrease in breast cancer risk vs. TZD nonusers, which included reference groups assigned placebo, metformin or glyburide, metformin or sulfonylurea, insulin plus sulfonylurea or metformin, or sitagliptin plus metformin (pooled RR = 0.77; 95% CI, 0.39-1.53). Across the seven cohort studies, however, researchers observed that TZD use had a mild, protective effect on breast cancer risk (pooled RR = 0.81; 95% CI, 0.66-0.99). Comparison groups in those studies were described as never pioglitazone users, non-TZD users, other antidiabetic drug users, or metformin or sulfonylurea users, or were assigned to placebo. In the two case-controlled studies, where reference groups were described as other antidiabetic drug users or never TZD users, respectively, the result did not rise to significance (pooled OR = 0.99; 95% CI, 0.76-1.28), according to researchers.

In separate analyses for rosiglitazone and pioglitazone, researchers found no association between the individual therapies and breast cancer risk. Additionally, when removing one cohort study from analysis with the smallest event number and greatest effect size compared with the other included studies, heterogeneity decreased and the association among cohort studies became nonsignificant, according to researchers.

They noted that the randomized controlled trials included in the current study were not designed for breast cancer prevention — breast cancer was considered an adverse event in these trials, and the event numbers were small. In the observational studies, the protective effect was observed primarily in studies with small sample sizes, whereas four of the studies did not adjust for any confounders.

“Our study attests [to] the challenges in epidemiological investigations of this issue,” the researchers wrote. – by Regina Schaffer

Disclosures: The authors report no relevant financial disclosures.

itj+ Perspective

Derek LeRoith

Soon after the antidiabetic agents TZDs were discovered, trials in cancer patients were initiated. However, very soon, it was noted that, despite early results that showed promise, as the trials progressed, the results were less favorable. TZDs are no longer considered as therapeutic options in cancer patients.

More recently, use of the TZD pioglitazone was shown to be associated with bladder cancer. While not all studies have conformed this association, there remain serious concerns.

In the recent meta-analysis by Du and colleagues from Shanghai, China, no association was found between TZD use and breast cancer risk in diabetic women. They analyzed 14 independent studies that included five randomized controlled clinical trials, seven cohort studies and two case-control studies, with a relative risk ratio that was actually below 1, but not significant.

While there has not been any obvious concern between TZD use and breast risk or prognosis, these results are always reassuring for physicians around the world who are still prescribing TZDs in the treatment of diabetic patients.

Derek LeRoith, MD, PhD

Director of Research
Department of Medicine, Division of Endocrinology, Diabetes and Bone Disease
Icahn School of Medicine at Mt Sinai

Disclosure: LeRoith reports he has received consultant honoraria from AstraZeneca/Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck & Co. and Sanofi-Aventis US.