Glargine (Lantus) and Cancer: Is There a Relationship to Type 1 Diabetes?
(Please note that this is a comprehensive blog - if you wish to see the conclusions and my recommendations only, feel free to skip to the end. Otherwise, it might be a good idea to read everything to understand recent developments.)
A recent publication in the journal Diabetologia suggested a possible link between the development of cancer and Glargine (Lantus) administration. Concerns were so high that the pharmaceutical company, Sanofi-Aventis, took a hit in the stock market. There have been several blogs discussing these findings on this site, mostly by bloggers discussing type 2 diabetes. What do these research findings mean to the children, teens, and adults who have type 1 diabetes? Due to the serious nature of these potentially scary findings, I evaluated all related articles to find out the details. I also met with a representative from Sanofi-Aventis to find out what is going on internally and if there is any concern for my pediatric patient population.
What prompted scientists to study the link between insulin and cancer? It has been known for quite some time that type 2 diabetes is associated with an increased risk of cancer and that treatment, which increases circulating levels of insulin, might possibly contribute to this risk. According to many authors, there is a concern that high insulin levels and associated changes in the insulin growth factor-1 (IGF-1) axis may increase the progression of preexisting cancer cells. These concerns grew when a large observational study suggested that insulin glargine was, after dose adjustment, associated with a possible increase in tumor risk in humans. I reviewed four studies that looked at this association. Please note that all of the studies involved patients with type 2 Diabetes.
- The German Insurance study looked at 127,031 patients who started insulin therapy in 2000 and were treated with either human insulin (NPH) or one of the three analogs (Lantus, humalog, or novolog). Almost all of the patients had type 2 diabetes, as the median age was 67 in all groups. The major finding was a strong correlation between insulin dose and cancer risk regardless of insulin type. However, dose for dose, insulin glargine appeared to carry a higher risk of cancer than for NPH. The greatest risk was an insulin glargine dose of 50 units. Because of this finding and concern for the millions of patients on Glargine, additional studies were conducted.
- The observational Swedish study identified 114,841 patients who were on insulin and divided them into three groups: glargine only, glargine plus other insulins, and insulin users not on glargine. Classification was based on age at diagnosis and those diagnosed after age 30 were considered to have type 2 diabetes. The analysis found no statistically significant difference in cancer incidence between those on insulins other than glargine and those on glargine plus other insulins. However, those on insulin glargine alone did appear to have a higher risk of breast cancer. The number of breast cancers was relatively low and the authors stated that these findings must be interpreted with caution. No definitive conclusions regarding a causal relationship between insulin glargine use and the occurrence of malignancies could be drawn from the results of this study.
- The Scottish analysis included 49,197 patients and divided the patients into the same groups as the Swedish study. This analysis considered overall cancer incidence. One important observation was that those on glargine alone were older and more likely to be overweight, more hypertensive, and more likely to be on oral medications than those on glargine plus other insulins and glargine. 97 percent of these patients had type 2 diabetes versus 37 percent of those who were on glargine plus other insulins (type 1 or type 2 diabetes). In addition, those on insulin glargine with rapid acting insulin (novolog, etc.) actually had a slightly lower rate of cancer progression than did those patients on NPH insulin (human insulin). Those on glargine alone had a higher overall rate. This study found that more cancers were diagnosed in those on insulin glargine alone. However, due the limited sample size the authors concluded that their findings were more likely to have arisen from allocation bias than from a biological effect of glargine. Overall, insulin glargine use was not associated with an increased risk of all cancers in Scotland during a four-year time frame.
- The United Kingdom GP database enabled cancer risk to be determined in patients on oral medication (sulfonylureas or metformin), on combination therapy, or on insulin (subdivided into insulin glargine only, NPH only, human biphasic, and analog biphasic insulin only). Once again, these were type 2 patients. The most striking finding was that metformin was protective in terms of the development of cancer. In addition, the study was negative after comparing all 4 insulin treated groups, including all types of cancers.
Another major consideration to note is that these patients had only a relatively short period of exposure to insulin (studies looked at smaller time intervals than are typical in cancer studies looking at different drugs). It was therefore felt that the studies should be interpreted such that glargine or other insulins do not cause cancer, but rather may accelerate the progression of early cancer cells. All of the studies demonstrate that short acting analogs (humalog, etc.) do not appear to be a problem.
A letter from Dr. Rosenstock discussed his study looking at the safety of NPH (human insulin) and glargine in patients with type 2 diabetes. In his study, the longest controlled treatment comparison of glargine and NPH in type 2 patients, no new safety issues emerged for either insulin studied. Additional data also confirmed that there was no evidence of any difference in the rate of benign or malignant tumor development with glargine compared to NPH.
Summary of the Studies and Comments:
- The authors of the Diabetologia study state "the evidence presented in all of these studies (above) is sufficient to establish that there is a case to answer, but is entirely insufficient to bring in a verdict. There is no evidence that insulin (in all forms) causes cancer. There also is no evidence of an overall increase in the rate of cancer development in patients on insulin glargine, and some suggestion that the risk may actually be reduced... There is no evidence of harm in type 1 diabetes."
- American Diabetes Association stated "findings from these research papers are conflicting and inconclusive, and the ADA cautions against over-reaction until more information is available."
- American Association of Clinical Endocrinologists (AACE) states "the authors themselves, and the accompanying editorial, cautioned against over-interpretation of their limited data and analyses, which precluded them from drawing any firm conclusions. There were contradictory findings among the studies, patient populations were not always comparable, and the duration of observation was short."
- Federal Drug Administration said "the duration of patient follow-up in all four studies was shorter than what is generally considered necessary to evaluate for cancer risk and drug exposure. Further, inconsistencies in findings within and across individual studies raise concerns as to whether an association between the use of insulin glargine truly exists. Additionally, differences in patient characteristics across the treatment groups may have contributed to a finding of increased cancer risk."
- None of these studies were conducted on patients with type 1 diabetes.
- All studies were observational and NOT prospective, randomized controlled studies, thus results must be interpreted with caution.
- All patients with type 1 diabetes are on a combination of basal insulin (NPH, Lantus, or Levemir) and short (regular) or rapid acting insulin (novolog, humalog, or apidra). The purported association with cancer risk was with glargine use alone.
- The type 2 diabetes population consists of generally older individuals with co-existing medical conditions and a greater risk for cancer.
- There is a known association between type 2 diabetes and cancer risk.
- Levemir or Detemir insulin (another basal insulin analog) has only been recently developed and adopted in clinical practice. As such, there have been no studies regarding any association with cancer.
- Finally, based on the above studies, organizational recommendations, communications with other physicians, and pharmaceutical representatives, I am of the opinion that all type 1 patients should remain on their current insulin therapy. This includes basal /bolus therapy with Lantus/Levemir and rapid acting insulin.
I will remain "on alert" for further evidence-based research studies.