Seguridad de los análogos de insulina: qué evaluar, cómo hacerlo y cómo interpretar los resultados / Safety of insulin analogues: What to evaluate, how to do it, and how to interpret the results

La utilización casi generalizada de análogos de insulina está basada no solo en la farmacocinética de estos preparados, mucho más cercana a la fisiología de la secreción de insulina en condiciones normales, sino, además, en su eficacia y seguridad. Se ha publicado una posible asociación entre el uso de un análogo lento de insulina (glargina) y la aparición de cáncer de mama, lo que ha condicionado una inquietud en la comunidad médica sobre la seguridad de estos análogos. Resumen Para explicar el mecanismo del aumento de la actividad tumoral de los análogos de insulina es que actúan a través de los receptores de insulina (IR) y del factor de crecimiento insulínico–1 (IGF-1R) estimulando el crecimiento celular e inhibiendo la apoptosis. En este sentido, existen dos mecanismos principales: el aumento del tiempo de unión de la insulina al IR y la activación aumentada del IGF-1R. Por tanto, para evaluar la seguridad de un análogo hay que descartar su disociación más lenta al IR así como un aumento de su afinidad por el IGF-1. Esto equivale a un índice de actividad mitogénica/metabólica menor a 1. Evaluar estos aspectos sólo es posible mediante el estudio de líneas celulares y la experimentación animal, modelos reduccionistas que no siempre son extrapolables al ser humano. Hasta el momento no existen datos para poner en duda la seguridad de los análogos de insulina en general, si bien la observación de un potencial riesgo de mitogenicidad con la administración de glargina basada en estudios observacionales y en algunos estudios in vitro ha causado cierta alarma en la comunidad médica. A la espera de datos que descarten o confirmen este riesgo, es fundamental poder evaluar los datos existentes de forma crítica con el objeto de proporcionar información objetiva (AU)

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 (AU)

[Safety of insulin analogues: what to evaluate, how to do it, and how to interpret the results]. / Seguridad de los análogos de insulina: qué evaluar, cómo hacerlo y cómo interpretar los resultados.

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.

Impact of GLP-1 and GLP-1 receptor agonists on cardiovascular risk factors in type 2 diabetes.

Type 2 diabetes (T2D) is associated with increased cardiovascular disease and mortality. Most diabetes treatments have not proven to reduce this risk and may be associated with worsening of specific cardiovascular risk factors. GLP-1 receptor agonists (GLP-1R agonists) are new incretin-based therapies for the treatment of T2D. They improve glucose control by stimulating insulin secretion and suppressing glucagon release, both in a glucose-dependent manner. There are two GLP-1R agonists approved for the treatment of T2D: once daily liraglutide and twice daily exenatide, both administered by sc injection. Based on recent clinical trials, GLP-1R agonists suggest having a protective role in cardiovascular risk factors besides improving glycemic control, compared to placebo and to standard diabetes therapies. Both liraglutide and exenatide have demonstrated to induce clinically significant weight loss and to reduce systolic blood pressure. Liraglutide also has a positive effect on the lipid profile and cardiovascular risk biomakers. Furthermore, recent data shows a direct effect of GLP-1 and its metabolites in the vascular endothelium and the myocardium, leading to vasodilator effects and improved cardiac function in humans with acute myocardial infarction or congestive heart failure. GLP-1R agonists have a positive impact on cardiovascular risk factors otherwise not addressed by most standard diabetes therapies. Whether these new compounds actually decrease cardiovascular disease and mortality remains to be demonstrated in outcome studies.

[Biotechnological and administration innovations in insulin therapy]. / Insulinothérapie: nouvelles molécules et voies d'administration.

The importance of the intensive control of blood glucose in patients with diabetes has been well documented in several large scale studies. Attempts to attain strict glucose control when managing diabetes have traditionally utilized daily subcutaneous injections of human insulin. This strategy has offered improvements in glycaemic control but is unable to replicate fully the normal diurnal plasma profile of endogenous human insulin. Advances in protein engineering techniques have, however, resulted in the formulation of a number of insulin analogues that offer more desirable properties of absorption from the subcutaneous depot and hence improved insulin profiles in patients with diabetes. Concurrent to the development of insulin analogues, devices to deliver insulin either subcutaneously or by other routes have also advanced. These novel delivery strategies are also likely to contribute to improved glycaemic control for patients with diabetes in the future.

Insulin aspart: promising early results borne out in clinical practice.

The novel, rapid-acting insulin analogue insulin aspart (IAsp; Novo Nordisk) has been shown in preclinical studies to be more rapidly absorbed than human insulin (HI) when administered subcutaneously. IAsp reaches higher peak serum concentrations in a shorter time than HI, whilst maintaining a similar receptor binding and safety profile. The physiological pharmacokinetic profile of IAsp compared to that of HI has been demonstrated in both adult and paediatric populations and was accompanied by small but statistically significant reductions in HbA(1c), lower postprandial glucose excursions and a reduced risk of late postprandial and major nocturnal hypoglycaemia. Benefits may be maximised by dose optimisation, using bolus doses that result in effective postprandial glucose reduction, as well as higher and multiple basal insulin doses. The safety profile, including cardiovascular risk, is equivalent to HI.