Insulin Detemir Therapy in Pediatric and Pregnant Population

PICHON RIVIERE, A.; AUGUSTOVSKI, F. A.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; BARDACH, A.; CIAPPONI, A; MEZA, V

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2012 p. 1 - 30

1668-2793

The incidence of insulin-dependent diabetes mellitus in children is approximately 3-5% according to different sources. Its treatment is intended to improve short and long-term glycemic control by keeping the glycemia levels within normal ranges and avoiding hypoglycemic episodes. The main indicators of control are the levels of glycosilated hemoglobin (HBA1c), fasting glycemia and the frequency of major episodes of hypoglycemia.The use of insulin is one of the main therapeutic features in children with type 1 diabetes and in some patients with Type 2 diabetes. The most commonly used insulins are short-acting and long-acting insulins (baseline insulin, generally referred to as NPH). Patients usually require the administration of several daily injections, specially when on an intensive regimen.As regards pregnant diabetic patients, insulin analogues allow a more consistent action during the day when compared with NPH, thus mimicking natural release of baseline insulin. Some years ago, two long-acting insulin analogues (Detemir and Glargine) became commercially available and they show advantages in the above mentioned indicators when compared with NPH insulin.TechnologyInsulin Detemir is a long-acting insulin analog manufactured using genetic engineering. The action starts one hour after its administration and, depending on the dose and frequency of the injection, steady-state levels are reached 2-3 days after treatment is initiated. Response and duration are dose-dependent. Compared to NPH insulin, action onset is slower and it takes longer to achieve maximum concentrations. This drug was approved by the US Food and Drug Administration (FDA) and by ANMAT in Argentina, in 2005.PurposeThe purpose of this report is to evaluate the evidence available on the efficacy, safety and coverage related policies aspects for the use of Insulin Detemir for the treatment of Diabetes Mellitus in children, adolescents and pregnant women.MethodsA bibliographic search was carried out on the main databases (MEDLINE, Cochrane, DARE, NHS EED), on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to including systematic reviews, meta-analysis, randomized controlled clinical trials, clinical practice guidelines, health technology assessments, financial assessments, and coverage policies from other health systems.ResultsThe following documents have been identified in this search a) Indication for children and adolescents: Two systematic reviews, one meta-analysis, four randomized clinical trials (RCTs), two observational studies, one health technology assessment (HTA) and three recommendations from international societies b) Indication for pregnant women: One systematic review, one RCT, one recommendation from an international society and one observational study.Children and AdolescentsOne meta-analysis published in 2009 on the efficacy and safety of insulin analogues for the management of diabetes identified only one RCT that assessed Insulin Detemir (IDet) in children and adolescents with Type 1 DM. Another systematic review from 2011 did not find any new studies on the pediatric population. The principal findings are summarized below.The 2007 open-label RCT included in the above mentioned systematic review compared the effect of IDet on glycemic control with HbA1c and fasting plasma glucose versus NPH insulin and the safety of these therapies. The follow-up extended for 26 weeks. Three hundred and forty-seven children and adolescents participated (140 pre-adolescents and 207 adolescents). They received IDet (n=232) or NPH insulin (n=115), in addition to insulin aspart before meals in both arms. The intervention extended for 6 months. After 26 weeks, there were no significant differences in the HbA1c values (8.0% for IDet and 7.9% for NPH). The relative risk of nocturnal hypoglycemia was lower with insulin detemir (0.85; 0.77-0.94 95%CI) and the risk of severe hypoglycemias and 24-hour hypoglycemias was similar in both treatments. The body mass index (BMI) was lower with IDet (BMI IDet 19.3 vs. NPH 19.8; p<0.001).Another multinational RCT published in 2011 compared IDet with NPH in combination with insulin aspart. Of the 348 randomized children, 82 (23.6%) were 2-5 years old. Fasting plasma glucose decreased during the study year (-18 vs. -8 mg/dL). A lower rate of hypoglycemias was observed with IDet when compared with NPH (50.6 vs. 78.3 episodes per patient-year) and of nocturnal hypoglycemia (8.0 vs. 17.4 episodes per patient-year), with no reports of statistically significant tests.One Canadian HTA published in 2008 did not find studies different from the ones already described.The British Institute of Health and the Scottish Medicines Consortium recommend that children and adolescents with Type 1 diabetes are administered the type of insulin most suitable for them based on their individual needs to attain a HbA1c level below 7.5% without losing quality of life in terms of frequency of hypoglycemia. In 2010, the Scottish Intercollegiate Guidelines Network (SIGN) determined that in children and adolescents none of the baseline insulin analogues were associated with a significant difference in HbA1c, being the baseline-action insulin analogues a therapeutic alternative.PregnancyOne non-inferiority RCT conducted in 2012 compared the efficacy and safety of IDet vs. NPH. The included patients started treatment 12 months prior to pregnancy and up to 12 weeks after delivery. Three hundred and ten patients were randomized. The decrease in HBA1c at 36 weeks of pregnancy was similar in both arms. Fasting plasma glucose was significantly lower with IDet than with NPH. Mild and severe rates of hypoglucemia during pregnancy were similar in the two groups.Unlike insulin glargine, in 2012, Insulin Detemir was approved by the US FDA to be reclassified from Category C to Category B in pregnant women. In 2010, the Scottish Intercollegiate Guidelines Network (SIGN) expressed that there is lack of high-quality evidence in pregnant women using insulin analogues, and recommend NPH insulin as the baseline regimen of choice in pregnancy, except with the clinical benefit of the analogue is individually demonstrated for the patient.CostsThe cost of insulin Detemir (5 3-mL cartridges) is AR$937.5 (Argentine Pesos, September 2012), approximately U$S 200.ConclusionsEvidence of high methodological quality was identified. The efficacy of Insulin Detemir in children and adolescents with Type 1 DM is similar to that of NPH in terms of HBA1c decrease. Based on the information reported by two RCTs and several observational studies, the evidence shows that Insulin Detemir might have only a slightly better profile in relation to risks of hypoglycemia. For these reasons and because the insulin analogues are very expensive, they are not considered standard therapies; they are used in special situations such as lack of metabolic control or frequent occurrence of nocturnal or severe episodes of hypoglycemia, where a lower number of administrations might be required.Several European health systems recommend the use of NPH insulin during pregnancy because it helps to better adjust the response to a variable calorie intake and the insulin-sensitivity in pregnant women. The available information on insulin detemir is not enough to recommend its routine use as substitute of NPH during pregnancy.