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New Data Shows Lantus® Activation of Insulin Receptor Comparable to Human Insulin
Paris (ots/PRNewswire) - - Human and in vivo Studies Indicate Lantus(R) Metabolites do not ConferCarcinogenic Potential via IGF-1 Receptor Activation
Sanofi announced at the 71st American Diabetes Association Scientific Sessions 2011 the results of four studies[1,2,3,4] indicating that the effect of Lantus(R) (insulin glargine) metabolites on the IGF-1 receptor is distinctly different from AspB10, the only insulin analog shown to have a carcinogenic effect.
Insulin receptor signalling pattern of AspB10 distinctly different from glargine
The goal of the first study by Tennagels et al was to investigate the metabolic and mitogenic signalling of [AspB10] insulin (AspB10 or also called X10) and insulin glargine in vitro and in vivo. AspB10 is the only insulin analog shown so far to have a tumorogenic effect (breast cancer in rats).The study showed that following subcutaneous injection of 1.0 or 12.5 U/kg in rats, neither human insulin nor insulin glargine nor AspB10 induced IGF-1 receptor activation in responsive tissues, whereas IGF-1 injection produced a robust activation.
In the study, AspB10 induced an increased and prolonged activation of insulin receptor (IR) signalling molecules in several tissues. The IR signalling pattern found for AspB10 is distinctly different from that of human insulin and insulin glargine, confirming earlier in vitro findings.
In vitro, AspB10 displays a higher affinity toward both IR and IGF-1 receptors, a prolonged occupancy time at the IR and a higher proliferation rate in mammalian cell lines. This is the basis for the contention that insulin analogs with increased IGF-1 receptor affinity in vitro also have increased growth promoting activity in vivo. The study shows, however, that the IGF-1 receptor is not involved in the mode of action of AspB10, the only insulin analog shown to have a carcinogenic effect.
Furthermore, the study underlines the distinct differences between insulin receptor signalling patterns of AspB10 is distinctly different from human insulin and insulin glargine, suggesting that insulin glargine does not confer carcinogenic potential through IGF-1 receptor activation.
The goal of the second study by Tennagels et al was to further elucidate the characteristics of insulin glargine signalling in rats. It investigated the time action profile of insulin glargine in different rat tissues with respect to pharmacological and signalling parameters and compared it to human insulin, insulin detemir and AspB10.
Male Wistar rats were injected subcutaneously with 1 U/kg of either human insulin or each of the insulin analogs, and the effects on blood glucose and activation status of IR, IGF-1 receptor and additional pathways in tissue samples derived from muscle, fat, liver, heart and kidney investigated over time. The time course of IR signalling by human insulin and insulin glargine clearly correlated with the time course of their pharmacodynamic effects, whereas the time course of IR signalling by insulin glargine was found to be distinctively different from that of AspB10.
Insulin glargine treatment resulted in activation levels of IR that were comparable to human insulin although delayed in some tissues. In contrast, AspB10 treatment resulted in at least two- to threefold higher activation and significantly longer duration in most tissues ex vivo, confirming the in vitro observations of increased affinity and occupancy time of the IR.
Importantly, neither human insulin nor insulin glargine nor AspB10 treatment resulted in any detectable IGF-1 receptor activation in muscle and heart tissue, whereas injection of IGF-1 increased activation of this receptor.
Glargine metabolized to products with lower affinity for IGF-1 vs human insulin
The goal of the third study, involving 12 patients with type 1 diabetes, was to investigate the plasma exposure to insulin glargine and its metabolites. The study showed following subcutaneous injection, insulin glargine was almost completely transformed into two metabolites (M1 and M2), with M1 accounting almost totally for the pharmacodynamic effect of injected glargine.
Insulin glargine and M2 were only detectable in approximately one-third of patients and at a few time points only. When detectable, insulin glargine and M2 exposure did not increase with increasing dose, and concentrations were far below endogenous interprandial plasma insulin concentrations of people without diabetes.
After injection of a therapeutic dose, glargine is minimally detectable in blood
Finally, the goal of the fourth study was to examine the metabolism of insulin glargine in patients with type 2 diabetes. This study confirmed that, after injection of a therapeutic dose in patients with type 2 diabetes, insulin glargine is minimally detectable in blood. Its metabolite M1 accounts for most (~90%) of the plasma insulin concentration.
Notes to editors
About the studies
Study 1 and study 2: Animal studies.
Study 3: Plasma concentrations for insulin glargine, M1 and M2 were determined from samples taken in a single-center, randomized, euglycemic glucose clamp study, where the 12 male persons (BMI 25 kg/m2; A1C < 8.0%) per group received single doses of 0.3, 0.6, or 1.2 U/kg insulin glargine.
Study 4: Insulin glargine, M1, and M2 plasma concentrations were determined from samples obtained from a single-center, 32 hour euglycemic glucose clamp study, where 18 type 2 diabetes patients received a single dose of 0.4 U/kg insulin glargine after one week of daily administration. Data from 9 subjects and 31 hour glucose clamp are here.
Lantus(R) (insulin glargine) is the first 24-hour once-daily basal insulin analogue. Lantus(R) is as effective as NPH insulin with similar reductions in HbA1c, but is associated with lower fasting blood glucose concentrations. People with type 2 diabetes experience a consistent and significant reduction in the incidence of nocturnal hypoglycemia with Lantus(R).
Lantus(R) is one of the most widely-studied insulins for the treatment of type 1 and type 2 diabetes. It has been tested in over 100 clinical studies, many of which are completed and published. These studies include detailed safety evaluations and constitute in-depth evidence for the absence of effects related to growth promoting or tumor promoting activity.
With the estimated experience of nearly 34 million patient-years worldwide, Lantus(R) has been used safely and effectively by adults and children (6 years and older) in the treatment of type 1 diabetes and in adult patients with type 2 diabetes since it received marketing authorization in 2000.
About the Sanofi Diabetes Division
Sanofi strives to help people manage the complex challenges of diabetes by delivering innovative, integrated and personalized solutions. Driven by valuable insight that comes from listening to and engaging with people living with diabetes, the Company is forming partnerships to offer diagnostics, therapies, services, and devices. Sanofi markets both injectable and oral medications for people with type 1 or type 2 diabetes. Investigational compounds in the pipeline include an injectable GLP-1 agonist being studied as a single agent, in combination with basal insulins, and/or in combination with oral antidiabetic agents.
Sanofi, a global and diversified healthcare leader, discovers, develops and distributes therapeutic solutions focused on patients' needs. Sanofi has core strengths in the field of healthcare with seven growth platforms: diabetes solutions, human vaccines, innovative drugs, rare diseases, consumer healthcare, emerging markets and animal health. Sanofi is listed in Paris and in New York .
1. Tennagels N., Sommerfeld M., Müller G., Tschank G., Habermann P., Seipke G., et al. Metabolic and mitogenic signaling of AspB10 and insulin Glargine in vitro and in vivo (0076-OR) ADA 2011
2. Tennagels N., Welte S., Jordan H., Hoffmann M., Werner U. Characteristics of insulin glargine signalling in rats (1562-P) ADA 2011
3. Bolli G.B., Frick A., Schmidt R., Eisenblaetter T., Becker R. Plasma exposure to insulin glargine and its metabolites in patients with type 1 diabetes (0071-OR) ADA 2011
4. Lucidi P., Porcellati F., Rossetti P., Candeloro P., Marinelli Andreoli A., Frick A., et al. Metabolism of insulin glargine after SC injection of therapeutic dose in type 2 diabetes mellitus (1092-P) ADA 2011
5. Wang F [http://www.ncbi.nlm.nih.gov/pubmed?term=%22Wang%20F%22%5BAuthor%5D]. et al. Insulin glargine: a systematic review of a long-acting insulin analogue. Clin. Ther. 2003 25:1541-77
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Contacts: Global Diabetes Division Communications, Yanyan Chang,Tel.:
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