[Safety of insulin analogues: what to evaluate, how to do it, and how to interpret the results].
The widespread use of insulin analogues is based not only on the pharmacokinetics of these preparations, which is much closer to the physiology of insulin secretion under normal conditions, but also on their safety and effectiveness. The publication of a possible association between the use of a long-acting insulin analogue (glargine) and breast cancer has caused uneasiness among the medical community regarding the safety of these analogues. The mechanism of increased tumor activity of insulin analogues is explained by the fact that they act through insulin receptors (IR) and insulin-like growth factor-1 (IGF-1R), stimulating cell growth and inhibiting apoptosis. There are two major mechanisms: an increase in the binding time of insulin to IR and increased activation of IGF-1R. Therefore, to evaluate the safety of an analogue, the slower dissociation rate from its insulin receptor must be excluded, as well as the increased affinity for the IGF-1 receptor. This is equivalent to an index of mitogenic/metabolic activity of less than 1. These aspects can only be evaluated through study of cell lines and animal testing, which are reductionist models that cannot always be extrapolated to humans. To date, there are no data to question the safety of insulin analogues in general. However, the results of observational studies and some in vitro studies, suggesting a potential risk of mitogenicity with the administration of glargine, have caused some alarm among the medical community. Until now, there are no data to refute or confirm this risk and, therefore, evaluation of the existing data is crucial to obtain objective information.
Hernández Mijares
Antonio
A
Servicio de Endocrinología y Nutrición, Hospital Universitario Dr. Peset, Valencia, España. hernandez_antmij@gva.es
Solá Izquierdo
Eva
E
García Malpartida
Katherinne
K
Verge
Danilo
D
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use; D007328:Insulin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced; D008938:Mitosis / Q000187:drug effects; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000819:agonists / Q000502:physiology; D011972:Receptor, Insulin / Q000502:physiology
D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D000069036:Insulin Glargine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin