The insulin glargine story
In June 2009, four observational, database studies were published in Diabetologia investigating the relationship between insulin analogues, such as insulin glargine, and the risk of cancer. These publications had generated debate and concern over the safety of such insulin treatments. However, the findings of the four studies had been inconclusive with respect to a potential link between the use of insulin glargine by diabetic patients and an increased risk of developing cancer; furthermore, critical methodological limitations of the studies precluded a clear and conclusive interpretation of their findings. Key diabetes medical associations and regulatory authorities had considered that the results were inconclusive and called for more research, but did not recommend that patients change their treatment. The debate generated by the Diabetologia papers prompted Sanofi to take an active approach, and, in September 2009, the company announced the initiation of a basic science and epidemiological programme, in collaboration with external experts, that was aimed at generating methodologically robust information on the potential association between insulin treatment options and the risk of cancer. The epidemiological programme is now complete, and, together with available other clinical and basic-science evidence, further supports the safety profile of insulin glargine as suggested earlier by its pharmacovigilance record.
The possibility that a widely used drug could be associated with a severe safety signal poses multiple problems to various stakeholders: firstly, to the patients and their health care providers, who need to be informed accurately on the safety and efficacy profile of their treatment choices; to the medical associations and the regulatory authorities, who will need to evaluate the merit of the allegations, the available evidence, and the actions necessary to address any concerns; and finally, to the drug maker, who will need to ensure that the benefit/risk of its market products is positive and that the use of the treatment called into question is supported by demonstration of its medical value.
The risk for a crisis of confidence in a product’s safety must be addressed in the most rigorous manner: it has to be done fast, and needs to be driven by a scientifically systematic approach. Hierarchically, the very first question that needs to be addressed is the one that concerns the existing knowledge on the product’s safety, as derived from its pharmacovigilance dossier. There is no doubt that full transparency of a product’s safety history is a prerequisite for rigorous evaluation. Next, the biological plausibility that a specific product could be associated with a safety signal needs to be investigated, while, at the same time, an ad hoc clinical investigation needs to be initiated.
Hereafter, the various components of just such an action programme will be presented, and the results of the component activities will be described.
The Insulin Glargine Record: Is there any historical evidence of an increased risk for cancer in users of insulin glargine?
In December 2009, an analysis by Home and Lagarenne was published in Diabetologia assessing if there was a possible relationship between treatment with insulin glargine and increased incidence of cancer/breast cancer using data from Sanofi’s pharmacovigilance database. The database included 31 randomised controlled trials, and captured data from 5,657 patients on insulin glargine and 5,223 on a comparator. The analysis concluded that insulin glargine was not associated with an increased incidence of cancer (RR 0.90, 95% CI 0.60–1.36), or breast cancer specifically (RR 0.62, 95% CI 0.17–2.18), versus the comparator group.
The Plausibility Theory: Are the molecular characteristic of insulin glargine compatible with an increased risk for cancer
Figure 1: Schematic diagram showing the metabolism of insulin glargine In vivo studies have consistently shown that almost all insulin glargine is rapidly metabolised to M1 (Figure 1), in rats, dogs, diabetic pigs and also humans with Type 1 or Type 2 diabetes, and that M1 is the driver of the pharmacodynamic effects in all species investigated.
In vitro, insulin glargine metabolites have been shown to have similar metabolic activity to insulin glargine and modestly reduced mitogenic activity compared with human insulin. Further evidence have shown that IR-A, IR-B and IGF-1 bioactivity in serum from patients with Type 2 diabetes receiving insulin glargine is comparable to that of NPH insulin. Mechanistic studies have demonstrated that in rats, the pharmacodynamic effects of human insulin and insulin glargine on IR signalling are comparable and distinctively different from AspB10, and that insulin analogues do not cause significant IGF-R phosphorylation in tissue even at high dose. No increases in tumour growth and metastases were observed in a study of MKR mice (exhibit endogenous hyperinsulinaemia) treated with insulin glargine.In addition, a re-evaluation of data from previous 2-year carcinogenicity rodent studies confirmed that there was no significant effect of insulin glargine on mammary gland neoplastic lesions, and regulatory agencies agreed on the interpretation of these study results as negative.
The Clinical Proof: Can state-of-the-art methodological clinical investigation show an increased risk of cancer?
The now-completed epidemiological programme sponsored by Sanofi evaluated cancer risk in diabetes and generated comprehensive insulin glargine exposure data from large databases. It comprised four studies and is the largest observational programme designed for this purpose to date. The epidemiology studies were designed independently of Sanofi by the lead investigators, were endorsed by the European Medicines Agency and were shared with the Food and Drug Administration.
The Northern European Observational Study
The Northern European Study analyzed over 1.5 million person years of exposure to insulin in 447,821 patients using insulin from national cause-of-death registries and effective population-based cancer and diabetes registries from five countries: Denmark, Finland, Sweden, Norway and Scotland. The study reported no increased risk of breast cancer in women, prostate cancer in men, and colorectal cancer in men and women in users of insulin glargine versus other insulins, among all users of insulin, and similarly among users of human insulin.
US Databases: The Kaiser Permanente Observational study
The US databases study, conducted using the Northern and Southern California Kaiser Permanente diabetes registries, was designed to compare cancer risk in insulin glargine users with cancer risk in NPH insulin users.The study comprised 115,514 patients with median duration of 1.2 years for insulin glargine use and 1.4 years for NPH insulin use. In the main analysis among all insulin users (insulin glargine and NPH insulin [reference group]) there was no association between use of insulin glargine and increased risk of breast cancer in women (HR 1.0, 95% CI 0.9–1.3), prostate cancer in men (HR 0.7, 95% CI 0.6–0.9) or colorectal cancer in men and women (HR 1.0, 95% CI 0.8–1.2). The study also reported that among new users of insulin, there was no association between insulin glargine use, or duration of insulin use, and risks for prostate, colorectal or all cancers combined. A modest increase in the risk of breast cancer with ≥2 years of insulin glargine use was suggested in new users of insulin, although this should be viewed cautiously, as there were only a small number of breast cancer cases in this group so the estimates are imprecise. These results are not supported by findings from the full cohort or from an analysis of prevalent users of NPH insulin at baseline, and the study authors believe it to be “…implausible that duration of glargine use would be associated with risk of breast cancer among new users but not prevalent users of insulin…”.
US Databases: The UNC New User Study
As individuals with diabetes often change insulin type during the course of their disease management, an ad hoc study was designed to investigate the risk for cancer in patients exposed to only one specific type of insulin, i.e. who were never switched from one insulin to another.
In this study, researchers at the University of North Carolina compared the effects of insulin glargine versus NPH insulin on the risk of cancer among patients newly initiating insulin treatment who were covered by the Inovalon MORE2 Registry (43,306 initiated insulin glargine and 9,147 initiated NPH insulin [reference group]).In this new user cohort study, there was no evidence of an increased risk for any cancer (HR 1.12, 95% CI 0.95–1.32) or breast cancer (HR 1.07, 95% CI 0.65–1.75) with use of insulin glargine; in particular, there was no evidence for increased breast cancer risk with insulin glargine use over 24 months (HR 0.67, 95% CI 0.18–2.54; based on 3,415 person-years and 14 incident cases).
ISICA Breast cancer & Diabetes Case-control Study
The International Study on Insulin and Cancer (ISICA) specifically investigated breast cancer risk associated with the use of individual insulins and was conducted in France, the UK and Canada.This case-control cohort study included 775 cases (breast cancer and diabetes) and 3,050 matched controls (diabetes without cancer). ISICA reported no difference in the risk of developing breast cancer among the different insulins with short- to mid-term duration of use. Results from ISICA confirmed that insulin glargine use, after a mean exposure of 3.2 years, was not associated with an increased risk of breast cancer in patients with diabetes (OR 1.04, 95% CI 0.76–1.44). Two-by-two comparisons between insulin glargine and other insulins showed no significant differences in the risk of breast cancer, and additional analyses on insulin glargine found no evidence that either dose or duration of use affected the risk of breast cancer.
ORIGIN was a landmark, 7-year, randomized trial that assessed the effects of insulin glargine versus standard care on cardiovascular outcomes in participants with pre-diabetes or early type 2 diabetes and high cardiovascular risk.  Of the more than 12,500 participants enrolled worldwide, 6,264 were randomised to receive insulin glargine titrated to achieve fasting normoglycemia. Cancer-related findings from ORIGIN showed that there was no increase in risk for all-cancer-combined (HR 1.00, 95% CI 0.88–1.13; P=0.97) or breast cancer (HR 1.01, 95% CI 0.60–1.71; P=0.95), and that there was no increase in cancer mortality (HR 0.94, 95% CI 0.77–1.15; P=0.52).
The basic science programme did not provide supportive evidence for an interaction between insulin glargine and its active metabolites with the IGF-1 receptor. The clinical epidemiology programme concluded that the use of insulin glargine was not associated with an increased risk of breast cancer in women, prostate cancer in man, and colorectal cancer in men and women. Finally, in ORIGIN, which was a randomized controlled trial, insulin glargine users did not have an increased risk for cancer in general or for any organ-specific cancer being investigated, or an increase in cancer mortality. When taken together, these data further reinforce the product’s safety profile. The pro-active approach that Sanofi has undertaken in response to a safety concern has addressed that question in a rigorous and transparent manner and has reassured patients and health care professionals
[a]Financial & competing interest disclosure
^ Home PD, Lagarenne P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia 2009;52:2499-506.
^ Tennagels N et al. The metabolic and mitogenic properties of basal insulin analogues. Arch Physiol Biochem 2013;119:1-14.
^ Sommerfeld MR et al. In vitro metabolic and mitogenic signaling of insulin glargine and its metabolites. PloS ONE 2010;5:e9540.
^ Varewijck AJ et al. Concentrations of insulin glargine and its metabolites during long-term insulin therapy in type 2 diabetic patients and comparison of effects of insulin glargine, its metabolites, IGF-I, and human insulin on insulin and IGF-I receptor signaling. Diabetes 2013;62:2539-44.
^ Tennagels N et al. Differences in metabolic and mitogenic signalling of insulin glargine and AspB10 in rats. Diabetologia 2013;56:1826-34.
^ Gallagher EJ et al. Insulin glargine does not increase breast cancer growth in an animal model. Diabetologia 2013;56 (Suppl 1):S320 [Abstract 798]
^ Stammberger I et al. Insulin glargine: a reevaluation of rodent carcinogenicity findings. Int J Toxicol 2012;31:137-42.
^ Sanofi Press Release, June 11, 2012: New Epidemiological Data Provide Additional Safety Evidence for Lantus®. Available at: http://en.sanofi.com/Images/30539_20120611_LANTUSEPI_en.pdf (last accessed: January 23, 2014)
^ Boyle P. Northern European Database Study of Insulin and Cancer Risk. Oral presentation at ADA 2012, Philadelphia, PA, USA. Symposium CT-SY13: Cancer Link with Insulin–Data from the U.S. and Northern Europe, June 11, 2012.
^ Habel LA et al. Cohort study of insulin glargine and risk of breast, prostate, and colorectal cancer among patients with diabetes. Diabetes Care 2013;36:3953-60
^ Stürmer T et al. Cancer incidence among those initiating insulin therapy with glargine versus human NPH insulin. Diabetes Care 2013;36:3517-25.
^ Grimaldi-Bensouda L et al. Risk of breast cancer by individual insulin use - an international multicenter study. Diabetes Care 2014;37:134-43.
^ ORIGIN Trial Investigators et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012; 367: 319-28.
^ R Perfetti is employed by Sanofi. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this article apart from those disclosed.