 | July 14, 2009
On June 26, 2009, four retrospective epidemiologic studies were posted on the Web site of the European Association for the Study of Diabetes (EASD) examining the association of cancer with use of insulins, including Lantus® (insulin glargine [rDNA origin] injection), in patients with diabetes. The EASD had initially received a single study indicating a potential link between Lantus and cancer risk (Hemkens, 2009) but then commissioned three additional studies by other groups to determine the reproducibility of the original observations (Currie, 2009; Jonasson, 2009; SDRN Epidemiology Group, 2009).
Rather than providing clear and convincing support for the original study, the four studies taken together provided inconsistent and conflicting information, including analyses refuting a general association of Lantus with excess risk of malignancies.
In contrast with controlled clinical trials, which establish and compare well-matched populations given clearly defined treatment regimens, retrospective observational studies (the four studies referenced above) reconstruct cohorts from data extracted from registries not intended for this application, often lacking information critical to establishing matched, clinically relevant comparisons, directly affecting interpretation of results.
Sanofi-aventis has monitored the safety of Lantus in preclinical studies and clinical trials prior to market introduction and continues to actively assess risk in the post-marketing setting via active safety surveillance. Extensive experience with Lantus in the 9 years since global market introduction and prior to that in clinical studies has not produced an indication of excess cancer risk:
| | • | | In preclinical studies, there was no evidence that physiologic concentrations of insulin glargine may have a tumor-promoting or even carcinogenic potential (Stammberger, 2002)
| | | • | | Controlled clinical trials:
| - | | In studies of up to 1-year duration comprising more than 10,000 patients with type 1 and type 2 diabetes, no significant difference has been observed in the risk of malignancies, including breast cancer, versus other insulin treatments, primarily NPH insulin (Sanofi-aventis, 2009)
| | - | | In a 5-year trial in 1017 subjects with type 2 diabetes comparing Lantus and NPH insulin, the occurrence of malignancies, including breast cancer, was similar between groups (Rosenstock, 2009)
| | | | • | | In uncontrolled studies of more than 60,000 patients with type 1 and type 2 diabetes, the rate of malignancies, including breast cancer, was similar to that reported in the literature (Sanofi-aventis, 2009)
| | | • | | In post-marketing safety surveillance, with an estimated global exposure of nearly 24 million patient-years, no specific pattern of malignancies or risk factors has emerged to suggest a newly identified risk with Lantus use (Sanofi-aventis, 2009)
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A statement from the U.S. Food and Drug Administration (FDA) is consistent with the position and views of other organizations, including the American Diabetes Association and the European Medicines Agency (EMEA), that there are inconsistencies in the findings of these recent registry analyses. The FDA recommends that patients should not stop taking their insulin therapy without consulting a physician, since uncontrolled blood sugar levels can have both immediate and long-term serious adverse effects. The full statement is attached for your reference.
A statement from the American Diabetes Association (ADA) notes that the findings from the four retrospective studies are inconclusive, conflicting, and confusing, and cautions against overreaction to the information (ADA, 2009). The statement also makes specific recommendations:
| Diabetologia, the journal of the European Association for the Study of Diabetes (EASD), published a series of research papers today examining a possible link between insulin glargine (brand name, Lantus) and cancer. Findings from these research papers are conflicting and inconclusive, and the American Diabetes Association cautions against over-reaction until more information is available.
| | | Four different population based studies were reported and published in Diabetologia and the data within these studies and between these studies are conflicting and confusing. Until more information is available, the American Diabetes Association advises patients using insulin not to stop taking it.
| | | For patients using glargine and considering switching to another form of insulin, the data in these studies make it unclear as to whether any one type of insulin increases the risk of cancer more than other types of insulin.
| | | Patients concerned about these studies or their insulin regimen should talk to their doctor and should not stop taking their insulin on the basis of the findings reported here.
| | | Insulin is a hormone normally produced by the pancreas that helps the body use glucose for energy. All people with type 1 diabetes need to take insulin to survive; many patients with type 2 diabetes also need to take insulin to control their blood glucose.
| | | Glargine insulin, which has been widely used since 2000, is an artificial form of insulin that is typically administered once a day.
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The American Association of Clinical Endocrinologists (AACE) issued a similar statement (AACE, 2009):
| On June 26, 2009 several articles published online in Diabetologia by the European Association for the Study of Diabetes investigated the possible relationship between use of insulin glargine (Lantus, sanofi-aventis) and the development of certain malignancies. 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. For example, there were contradictory findings among the studies, patient populations were not always comparable, and the duration of observation was short. Nonetheless, since the relationship of type 2 diabetes to cancer is of critical importance, further study is warranted.
| | | The American Association of Clinical Endocrinologists (AACE) does not recommend that the use of any insulin be changed. AACE supports further research into the effectiveness and safety of all diabetes therapies and will continue to update recommendations as further data becomes available. Individual patient concerns should be discussed with their physicians.
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For further information, please contact Medical Information Services at 1-800-633-1610 or go to www.factsaboutlantus.com.
Sincerely,
Michelle A. Baron, MD, F.A.C.E.
Vice President, Metabolism Medical Unit
U.S. Medical Affairs
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References: | | 1. | | American Diabetes Association. Statement from the American Diabetes Association related to studies published in 'Diabetologia.' http://www.diabetes.org/for-media/pr-glargine-0602609.jsp. Accessed June 29, 2009.
| | | 2. | | American Association of Clinical Endocrinologists. AACE response to insulin glargine articles in Diabetologia. http://www.aace.com/newsroom/alerts/index.php. Accessed June 29, 2009.
| | | 3. | | Currie CJ, Poole CD, Gale EAM. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009. Epub ahead of print.
| | | 4. | | Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009. Epub ahead of print.
| | | 5. | | Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of malignancies—a population-based follow-up study in Sweden. Diabetologia. 2009. Epub ahead of print.
| | | 6. | | Rosenstock J, Fonseca V, McGill JB, et al. Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study. Diabetologia. 2009. Epub ahead of print.
| | | 7. | | Sanofi-aventis. Sanofi-aventis stands behind the safety of Lantus® [press release]. Paris, France: June 26, 2009.
| | | 8. | | SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009. Epub ahead of print.
| | | 9. | | Stammberger I, Bube A, Durchfeld-Meyer B, Donaubauer H, Troschau G. Evaluation of the carcinogenic potential of insulin glargine (LANTUS) in rats and mice. Int J Toxicol. 2002;21(3):171-179.
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Early Communication About Safety of Lantus (insulin glargine)
7/1/2009
FDA is aware of four recently-published observational studies that looked at the use of Lantus (insulin glargine) and possible risk for cancer in patients with diabetes. Three of the four studies suggest an increased risk for cancer associated with use of Lantus. See http://www.diabetologia-journal.org/cancer.html.
Based on the currently available data, the FDA recommends that patients should not stop taking their insulin therapy without consulting a physician, since uncontrolled blood sugar levels can have both immediate and long-term serious adverse effects. Patients should also contact their healthcare professional if they have concerns about the medicines they are taking.
Similar to human insulin, insulin glargine is used to control blood sugar in people with Type 1 and Type 2 diabetes. Insulin glargine, however, is a modified version of human insulin (an insulin analogue) that allows for the control of blood sugar for extended periods of time (a long-acting insulin). Insulin glargine is approved for once-a-day dosage by subcutaneous injection (injection under the skin).
The four observational studies evaluated large patient databases and all reported some level of association between the use of insulin glargine, and other insulin products, and various types of cancer. The duration of patient follow-up in all four studies was shorter than what is generally considered necessary to evaluate for cancer risk from drug exposure. Further, inconsistencies in findings within and across individual studies raise concerns as to whether an association between the use of insulin glargine and cancer truly exists. Additionally, differences in patient characteristics across the treatment groups may have contributed to a finding of increased cancer risk.
FDA is currently reviewing many sources of safety data for Lantus, including these newly published observational studies, data from all completed controlled clinical trials, and information about ongoing controlled clinical trials, to better understand the risk, if any, for cancer associated with use of Lantus.
Discussions are also ongoing between FDA and the manufacturer of Lantus as to whether any additional studies evaluating the safety and efficacy of this drug will need to be performed.
FDA will communicate the results on its ongoing review to the public, as appropriate, as our review continues.
The FDA encourages both healthcare professionals and patients to report side effects from the use of insulin glargine to the FDA's MedWatch Adverse Event Reporting Program using the information at the bottom of the page.
This early communication is in keeping with FDA's commitment to informing the public about its ongoing safety reviews of drugs. FDA will communicate its findings with the public as soon as its review of insulin glargine is complete.
This information reflects FDA's current analysis of available data concerning this drug. Posting this information does not mean that FDA has concluded there is a causal relationship between the drug product and the emerging safety issue. Nor does it mean that FDA is advising health care professionals to discontinue prescribing this product. FDA is considering, but has not reached a conclusion about whether this information warrants any regulatory action. FDA intends to update this document when additional information or analyses become available.
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