Does Insulin Glargine Increase Cancer Risk in Children?
Do children using insulin glargine have a higher risk of developing cancer?
Insulin glargine is a human insulin analogue with a modified amino acid sequence. This results in altered pharmacokinetic properties such that it is released in small amounts over a 24-hour period, allowing for insulin glargine to be dosed and marketed as a once-daily formulation. Insulin glargine contains a modified domain that is responsible for potential and prolonged interaction with the insulin-like growth factor-I receptor (IGF-IR) compared with endogenous human insulin. IGF-IR mediates growth and differentiation activities and is often overexpressed in many types of cancer, thus resulting in the hypothesis that insulin glargine may be mitogenic.
Eleven in vitro studies examined the possible mitogenic effect of insulin glargine in human and murine cell cultures. Insulin glargine was found to stimulate mitosis in 5 malignant cell lines and in 1 nonmalignant primary culture. The mitogenic potency of insulin glargine in cell cultures is increased by 10%-60% compared with that with human insulin.
Due to the controversial nature of the in vitro findings, in vivo studies were conducted in rats and mice. These studies did not find that insulin glargine had a carcinogenic potential.
Five additional studies investigated the risk of developing cancer with insulin glargine treatment in humans. A study by Hemkens and colleagues found that treatment with insulin glargine alone led to a slightly increased cancer risk in patients with type 2 diabetes in a dose-dependent fashion. However, when the age- and sex-adjusted analysis was conducted, a protective effect for insulin glargine was actually found. Thus, the results of this study remain controversial and the subject of much debate. Three additional studies (including a randomized controlled trial) did not find any increased cancer risk following treatment with insulin glargine.
The fifth study did, however, find an increase in breast cancer risk in female patients treated with insulin glargine alone compared with those treated with insulin glargine and an additional human insulin. However, other known risk factors for the development of breast cancer were not considered by the authors of this study and, therefore, the resultant increased risk for breast cancer may be due to random frequency fluctuation. The authors concluded that the data could not demonstrate a causal relationship between the use of insulin glargine and any subsequent occurrence of malignancies.
In summary, there were several methodologic limitations of these 5 studies, which question the validity of their findings. In fact, the authors of the 4 observational studies also agree that their findings are not conclusive given that these were not clinical trials. Moreover, the authors also state that they cannot exclude the possibility that the varied observed rates of cancer were not due to inherent genetic and environmental differences between groups of patients studied. Finally, due to the short duration of the in vivo studies, the development of cancers secondary to insulin glargine exposure seems less plausible.
Given the limitations and controversy associated with the previous studies, a meta-analysis was conducted. This meta-analysis analyzed the manufacturer's pharmacovigilance database for all 31 randomized clinical trials (phases 2-4) comparing insulin glargine with any comparator in type 1 or type 2 diabetes and identified all serious adverse events considered to be treatment-emergent malignant neoplasms. (Of note, this analysis included 3 trials with a total of 285 children who were treated with insulin glargine and, as such, is the only study to date to include pediatric patients.)
Insulin glargine was not associated with an increased incidence of malignancies in short-term exposure. In fact, the relative risk for malignant cancer in the insulin glargine group was 10% lower than that in the comparator groups. However, the findings of this study have also been challenged by some, leaving the safety of insulin glargine still open for debate.
Some researchers have suggested that if there is, in fact, a higher risk of developing cancer with insulin glargine treatment, there may be pharmacogenetic subpopulations that are at a higher risk than others. It has been hypothesized in the literature that this might be secondary to a slower metabolism of insulin glargine via enzymatic biotransformation. One study in adults found that the metabolism of insulin glargine varied by 46%-98% between the individuals studied.
Given that the functioning of metabolic enzymes present in children varies depending on age and stage of development, it may be reasonable to assume that this variation in insulin glargine metabolism may be even more pronounced within a pediatric population. The subsequent clinical impact that this might have on the risk of developing cancer with insulin glargine treatment in children, especially given the hypothesis that the risk may be dose-dependent, however, remains unknown.
Due to the methodologic limitations of the studies available to date, the current evidence in the literature does not conclusively suggest a causal relationship between treatment with insulin glargine and increased risk for cancer compared with other insulin-based therapies in an adult population.
In January 2011, the US Food and Drug Administration (FDA) released an updated safety announcement regarding their review of insulin glargine and risk for cancer. The FDA reviewed the 4 observational studies and determined that the evidence presented is inconclusive due to study design and methodology limitations. However, the FDA also stated that they are continuing to work with the manufacturer and the US Department of Veterans Affairs in order to continue to assess the potential risk of developing cancer with insulin glargine. The FDA will provide ongoing public updates as further information becomes available.
In addition to the above FDA statements, the American Diabetes Association, European Association for the Study of Diabetes, American Association of Clinical Endocrinologists, and European Medicines Agency state that changes in treatment protocols at this time are not warranted for most patients.
Question:
Do children using insulin glargine have a higher risk of developing cancer?
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Response from Jessica Stovel, RPh Adjunct Assistant Professor, Department of Psychiatry, Schulich School of Medicine and Dentistry, University of Western Ontario; Pediatric Clinical Pharmacist, London Health Sciences Center, London, Ontario, Canada |
What Is Insulin Glargine? How Might It Be Mitogenic?
Insulin glargine is a human insulin analogue with a modified amino acid sequence. This results in altered pharmacokinetic properties such that it is released in small amounts over a 24-hour period, allowing for insulin glargine to be dosed and marketed as a once-daily formulation. Insulin glargine contains a modified domain that is responsible for potential and prolonged interaction with the insulin-like growth factor-I receptor (IGF-IR) compared with endogenous human insulin. IGF-IR mediates growth and differentiation activities and is often overexpressed in many types of cancer, thus resulting in the hypothesis that insulin glargine may be mitogenic.
Is There Evidence to Suggest That Treatment With Insulin Glargine Is Associated With an Increased Risk for Cancer?
Eleven in vitro studies examined the possible mitogenic effect of insulin glargine in human and murine cell cultures. Insulin glargine was found to stimulate mitosis in 5 malignant cell lines and in 1 nonmalignant primary culture. The mitogenic potency of insulin glargine in cell cultures is increased by 10%-60% compared with that with human insulin.
Due to the controversial nature of the in vitro findings, in vivo studies were conducted in rats and mice. These studies did not find that insulin glargine had a carcinogenic potential.
Five additional studies investigated the risk of developing cancer with insulin glargine treatment in humans. A study by Hemkens and colleagues found that treatment with insulin glargine alone led to a slightly increased cancer risk in patients with type 2 diabetes in a dose-dependent fashion. However, when the age- and sex-adjusted analysis was conducted, a protective effect for insulin glargine was actually found. Thus, the results of this study remain controversial and the subject of much debate. Three additional studies (including a randomized controlled trial) did not find any increased cancer risk following treatment with insulin glargine.
The fifth study did, however, find an increase in breast cancer risk in female patients treated with insulin glargine alone compared with those treated with insulin glargine and an additional human insulin. However, other known risk factors for the development of breast cancer were not considered by the authors of this study and, therefore, the resultant increased risk for breast cancer may be due to random frequency fluctuation. The authors concluded that the data could not demonstrate a causal relationship between the use of insulin glargine and any subsequent occurrence of malignancies.
In summary, there were several methodologic limitations of these 5 studies, which question the validity of their findings. In fact, the authors of the 4 observational studies also agree that their findings are not conclusive given that these were not clinical trials. Moreover, the authors also state that they cannot exclude the possibility that the varied observed rates of cancer were not due to inherent genetic and environmental differences between groups of patients studied. Finally, due to the short duration of the in vivo studies, the development of cancers secondary to insulin glargine exposure seems less plausible.
Given the limitations and controversy associated with the previous studies, a meta-analysis was conducted. This meta-analysis analyzed the manufacturer's pharmacovigilance database for all 31 randomized clinical trials (phases 2-4) comparing insulin glargine with any comparator in type 1 or type 2 diabetes and identified all serious adverse events considered to be treatment-emergent malignant neoplasms. (Of note, this analysis included 3 trials with a total of 285 children who were treated with insulin glargine and, as such, is the only study to date to include pediatric patients.)
Insulin glargine was not associated with an increased incidence of malignancies in short-term exposure. In fact, the relative risk for malignant cancer in the insulin glargine group was 10% lower than that in the comparator groups. However, the findings of this study have also been challenged by some, leaving the safety of insulin glargine still open for debate.
Can Other Factors Place a Pediatric Patient at Increased Risk for Cancer When Taking Insulin Glargine?
Some researchers have suggested that if there is, in fact, a higher risk of developing cancer with insulin glargine treatment, there may be pharmacogenetic subpopulations that are at a higher risk than others. It has been hypothesized in the literature that this might be secondary to a slower metabolism of insulin glargine via enzymatic biotransformation. One study in adults found that the metabolism of insulin glargine varied by 46%-98% between the individuals studied.
Given that the functioning of metabolic enzymes present in children varies depending on age and stage of development, it may be reasonable to assume that this variation in insulin glargine metabolism may be even more pronounced within a pediatric population. The subsequent clinical impact that this might have on the risk of developing cancer with insulin glargine treatment in children, especially given the hypothesis that the risk may be dose-dependent, however, remains unknown.
What Conclusions Can Be Drawn From the Current Evidence?
Due to the methodologic limitations of the studies available to date, the current evidence in the literature does not conclusively suggest a causal relationship between treatment with insulin glargine and increased risk for cancer compared with other insulin-based therapies in an adult population.
In January 2011, the US Food and Drug Administration (FDA) released an updated safety announcement regarding their review of insulin glargine and risk for cancer. The FDA reviewed the 4 observational studies and determined that the evidence presented is inconclusive due to study design and methodology limitations. However, the FDA also stated that they are continuing to work with the manufacturer and the US Department of Veterans Affairs in order to continue to assess the potential risk of developing cancer with insulin glargine. The FDA will provide ongoing public updates as further information becomes available.
In addition to the above FDA statements, the American Diabetes Association, European Association for the Study of Diabetes, American Association of Clinical Endocrinologists, and European Medicines Agency state that changes in treatment protocols at this time are not warranted for most patients.