Evaluación de Sitagliptina para el tratamiento de pacientes adultos con diabetes mellitus tipo 2: revisión sistemática de costo-efectividad / Evaluation of Sitagliptin for the treatment of adult patients with type 2 diabetes mellitus: a systematic review of cost-effectiveness

Introducción: La diabetes mellitus tipo 2 es un problema de salud pública mundial y es una de las principales causas de mortalidad en Ecuador. La Sitagliptina fue el primer fármaco potenciador del sistema de las incretinas comercializado localmente. Los países no tienen recursos ilimitados para atender las necesidades de salud de su población, por lo que deben adoptar las intervenciones sanitarias más adecuadas, considerando los costos que un país pueda asumir y sostener. Objetivo: Sintetizar los resultados de estudios de costo-efectividad de la sitagliptina para el tratamiento oral combinado de pacientes adultos con diabetes tipo 2 en comparación con sulfonilureas. Metodología: Se realizó una revisión sistemática sin metaanálisis basado en las recomendaciones PRISMA. Los términos de búsqueda se estructuraron en base a la estrategia PICO y la pesquisa se realizó en las bases de datos: Pubmed, Tripdatabase y Pubmed Central para artículos de evaluaciones de tecnologías sanitarias, evaluaciones económicas y guías de práctica clínica, y para las políticas de cobertura se utilizó HTAiVortal y Google avanzado. Resultados: Se seleccionaron 3 ensayos clínicos y 8 revisiones sistemáticas-metaanálisis, 2 estudios de cohorte, 3 políticas de cobertura y 1 estudio de costo-efectividad. Tres revisiones sistemáticas establecieron pocos efectos modestos en cuanto a los efectos hipoglicemiantes de sitagliptina en adultos y adultos mayores; con un bajo riesgo de hipoglicemia. Un metaanálisis de 25 ensayos clínicos reportó mayor riesgo cardiovascular en los pacientes tratados con sitagliptina. Una revisión sistemática con evaluación económica mostró que la sitagliptina con metformina fue una alternativa costo-efectiva versus añadir una sulfonilurea o roziglitazona. Conclusiones: Por el perfil de costo-efectividad podría considerarse a la sitagliptina como segundo fármaco para pacientes que no consiguen control glicémico con dosis máximas de metformina, o en donde su asociación a una sulfonilurea no sea factible (por riesgos de hipoglicemia o adultos mayores).

Introduction: Type 2 diabetes mellitus is a global public health problem, being one of the main causes of mortality in Ecuador. Sitagliptin was the first locally marketed incretin-enhancing drug. Countries do not have unlimited resources to meet the health needs of their population, so they must adopt the most appropriate health interventions, considering the costs that a country can assume and sustain. Objective: To synthesize the results of cost-effectiveness studies of sitagliptin for combined oral treatment of adult patients with type 2 diabetes, compared with sulfonylureas.Methodology: This is a systematic review study without meta-analysis, conducted on PRISMA recommendations. The in-formation search was structured under the PICO strategy and the searches were conducted in Pubmed, Tripdatabase and Pubmed Central for articles on health technology evaluations, economic evaluations and clinical practice guides and for coverage policies HTAiVortal and advanced Google were used.Results: 3 clinical trials and 8 systematic reviews-meta-analysis, 2 cohort studies, 3 coverage policies and 1 cost-effectiveness study were selected. Three systematic reviews establish few effects regarding the hypoglycemic effects of sitagliptin in adults and elderly, with a low risk of hypoglycemia. A meta-analysis of 25 clinical trials reported an increased cardiovascular risk in patients treated with sitagliptin. A systematic review with economic evaluation showed that sitagliptin with metformin was a cost-effective alternative, versus adding a sulfonylurea or roziglitazone.Conclusions: Due to its cost-effectiveness profile, sitagliptin could be considered as a second drug for patients who do not achieve glycemic control with maximum doses of metformin, or where its association with a sulfonylurea is not feasible (due to risks of hypoglycemia or elderly).

Loss of Eyebrows and Eyelashes During Concomitant Treatment with Sitagliptin and Metformin.

The fixed dose combination of sitagliptin 50 mg and metformin 850 mg (Janumet ®), is indicated for the treatment of type 2 diabetes mellitus in addition to diet and exercise to improve glycemic control in patients treated with metformin alone. METHODS: We report a 69-year-old man with type 2 diabetes that developed sudden loss of eyebrows and eyelashes about 4 months after the beginning of Janumet®. Clinical and laboratory findings excluded the presence of systemic or skin diseases able to induce these manifestations, while the Naranjo probability scale documented a possible association between the drug and the adverse drug reaction.

Los inhibidores de la dipeptidil peptidasa 4 y el riesgo de enfermedad cardiovascular: el caso de la sitagliptina / Dipeptidyl peptidase 4 inhibitors and the risk of cardiovascular disease: the case of sitagliptin

Fundamento: Existe una carencia de datos a largo plazo sobre los efectos cardiovasculares de la utilización de la sitagliptina, un antidiabético oral de la familia de los inhibidores de la dipeptidil peptidasa 4 (inh DPP-4) en pacientes afectos con diabetes tipo 2 (DM2) y enfermedad cardiovascular (ECV). Método: Se trata de un ensayo clínico aleatorizado a doble ciego (ECA) en el que se aleatorizaron a 14.671 pacientes a ser tratados mediante sitagliptina o placebo añadidos a su tratamiento habitual. El propósito fue determinar si la sitagliptina no era inferior al placebo utilizando un riesgo relativo (RR) de 1,3 como margen superior de estos objetivos. El objetivo primario cardiovascular estuvo compuesto por muerte cardiovascular (MCV), infarto agudo de miocardio no fatal (IAM), accidente cerebrovascular no fatal (AVC) u hospitalización por angina inestable. Resultados: Durante un seguimiento medio de 3,0 años hubo una pequeña diferencia en los niveles de HbA1c entre ambos grupos de -0,29% (IC 95%: -032 a -0,27). Globalmente el objetivo primario se cumplió en 839 pacientes que utilizaban sitagliptina (11,4% o en 4,06 por 100 personas/año) y en 851 en el grupo placebo (11,6% o en 4,17 por 100 personas/año). Según este, la sitagliptina no fue inferior al placebo en el objetivo primario compuesto cardiovascular, hazard ratio (HR): 0,98 (IC 95%: 0,88-1,09; p<0,001). Las tasas de hospitalización por insuficiencia cardíaca (IC) no difirieron entre los 2 grupos HR: 1,00 (IC 95%: 0,83-1,20; p=0,98). No hubo diferencias significativas en las tasas de pancreatitis agudas (p=0,07) ni en el cáncer de páncreas (p=0,32) entre los 2 grupos. Conclusiones: Se concluye que entre los pacientes con DM2 y ECV, establecida la prescripción de sitagliptina al tratamiento habitual, no parece incrementar el riesgo de ECV mayores, la hospitalización por IC u otros efectos adversos (AU)

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An open-label, multiple-dose study to assess the pharmacokinetics and tolerability of sitagliptin/metformin fixed-dose combination (FDC) tablet in healthy Chinese adult subjects.

AIM: This study investigated the pharmacokinetics of sitagliptin and metformin after multiple oral doses of the sitagliptin/metformin fixed-dose combination (MK0431A) tablet in healthy Chinese volunteers. METHODS: This was a singlecenter, randomized study in 24 healthy adults. Subjects received twice-daily doses of MK0431A 50-mg/500-mg tablet and 50-mg/850-mg tablet for 7 days. Serial blood and urine samples were collected at predefined time points for bioassay of sitagliptin and metformin. Safety was assessed throughout the study. RESULTS: Based on consecutive trough concentrations, the steady states of sitagliptin and metformin were reached after twice-daily administration of MK0431A tablets for 5 days. After the last dose, the mean ± SD (standard deviation) peak sitagliptin concentration of 167.3 - 22.52 and 174.1 ± 22.16 ng/mL was reached in a median tmax of 2.25 - 3 hours. The mean ± SD Cmax of metformin appeared in a median tmax of 1.75 - 2.25 hours at 888.3 ± 195.19 and 1,337 ± 269.19 ng/mL with MK0431A 50 mg/500 mg and 50 mg/850 mg, respectively Mean ± SD AUC012h of sitagliptin was between 1,404 ± 147.48 and 1,374 ± 179.12 h×ng/mL, while mean ± SD AUC0-12h of metformin were 6,015 ± 854.98 and 8,587 ± 1,715.93 h×ng/mL with MK0431A 50 mg/500 mg and 50 mg/850 mg, respectively. Approximately 75% sitagliptin and 40% metformin were excreted unchanged in the urine, corresponding to a renal clearance of 17.84 - 18.27 L/h for sitagliptin and 27.11 - 27.94 L/h for metformin. CONCLUSION: No clinically-significant pharmacokinetic difference was identified between Chinese and foreign healthy volunteers regarding sitagliptin and metformin with multiple doses of MK0431A tablets. The treatments were well tolerated.

[Sitagliptin in the treatment of type 2 diabetes: insights five years after commercialisation]. / La sitagliptine dans le traitement du diabète de type 2: le point, cinq ans après sa commercialisation.

Sitagliptin (Januvia) was the first selective inhibitor of dipeptidyl peptidase-4 commercialized for the management of type 2 diabetes. It is also available as a fixed-dose combination with meformin (Janumet). Almost 5 years after its launch in Belgium, the present review summarizes the most recent data regarding the clinical efficacy of this antidiabetic agent, the controversy about its safety profile, its use at lower dosage in case of moderate to severe renal insufficiency, the various indications that have been successively accepted and reimbursed, and, finally, the perspectives offered by a large ongoing cardiovascular outcome trial (TECOS).

Avaliação da eficácia e tolerabilidade da sitagliptina quando adicionada à terapia combinada de metformina e sulfoniluréia no tratamento ddo diabetes mellitus tipo 2 / Evaluation of the efficacy and tolerability of sitagliptin when added to metformin and sulfonylurea combination therapy in the treatment of type 2 diabetes

O Diabetes Mellitus é uma condição crescente em todo o mundo. Em pacientes com Diabetes Mellitus tipo 2 (DM2), um ótimo controle bglicêmico é dificilmente alcançado ou mantido por longo-prazo com monoterapia ou até mesmo com terapia dupla. A Sitagliptina é um inibidor da DPP-4 seletivo, potente, reversível e ativo por via oral. Sua adição a outros hipoglicemiantes orais mostrou redução significativa dos níveis séricos de hemoglobina glicada (HbA1c). Objetivos: Avaliar a eficácia e a tolerabilidade da adição da sitagliptina na dose de 100 mg/dia, dividida em 2 tomadas, ao tratamento de pacientes com DM2 já em uso de metformina e sulfoniluréia em doses plenas Métodos: Nosso estudo envolveu pacientes com DM2 não controlados com metformina e sulfoniluréia. Esses pacientes receberam sitagliptina por 12 semanas. A eficácia foi avaliada através da redução da HbA1c e da glicemia de jejum e a tolerabilidade através dos efeitos colaterais reportados e avaliação de hepato e nefrotoxicidade. Resultados: A média da HbA1c basal foi de 8,7%. Após 12 semanas de estudo houve importante redução da HbA1c (-1,17%) e da glicemia de jejum (-18,75%). 50% dos pacientes atingiram o algo de HbA1c de 7% ou menos e 75% apresentaram redução de mais de 1% na HbA1c. O peso, pressão arterial, perfil lipídico, função renal, transaminases, enzimas canaliculares e leucócitos não apresentaram grandes alterações entre o início e o fim do estudo. A sitagliptina foi bem tolerada no geral. 36,84% apresentaram efeitos colaterais e 15,78% interromperam o tratamento por esses efeitos. A taxa de aderência foi de 75%. Conclusão: Nesse estudo de 12 semanas, a adição de sitagliptina foi efetiva e bem tolerada por pacientes com DM2 inadequadamente controlados com metformina associada à sulfoniluréia.

[Medication of the month. Sitagliptin-metformin fixed combination (Janumet)]. / Le médicament du mois. Combinaison fixe sitagliptine-metformine (Janumet).

Type 2 diabetes is a complex disease with the coexistence of several pathophysiological abnormalities such as a defect of insulin secretion, a relative hyperglucagonaemia, an increased hepatic glucose production and a muscular insulin resistance. In order to tackle all these abnormalities, the coadministration of several drugs with complementary actions is frequently required. Janumet is a fixed-dose combination of sitagliptin, a specific inhibitor of dipeptidylpeptidase-4 that blocks the rapid degradation of so-called incretin hormones (resulting in a potentiation of insulin secretion and reduction of glucagon secretion in a glucose-dependent manner), and of metformin, a biguanide compound that reduces glucose hepatic production and slightly improves insulin sensitivity. This pharmacological combination improves glucose control without inducing hypoglycaemia or weight gain. The tolerance profile is rather good, with (digestive) side effects and contraindications (risk of lactic acidosis in case of renal insufficiency) attributable to metformin. Janumet (50/850 mg or 50/1.000 mg), twice daily, is indicated in the treatment of type 2 diabetes and is currently reimbursed in Belgium after failure of metformin monotherapy or the prior demonstration of the efficacy of adding sitaglitptin (Januvia) to metformin.

Bioequivalence of sitagliptin/metformin fixed-dose combination tablets and concomitant administration of sitagliptin and metformin in healthy adult subjects: a randomized, open-label, crossover study.

BACKGROUND: Treatment with an oral antihyperglycaemic agent administered as monotherapy is often unsuccessful at achieving or maintaining glycaemic control in patients with type 2 diabetes mellitus. The combined use of sitagliptin and metformin is an effective treatment for type 2 diabetes mellitus, consistent with the complementary mechanisms of action by which these two agents improve glucose control. OBJECTIVES: To establish bioequivalence between sitagliptin/metformin fixed-dose combination (FDC) tablets (Janumet®) and co-administration of corresponding doses of sitagliptin and metformin as individual tablets. METHODS: This was an randomized, open-label, two-part, two-period crossover study, which included a total of 48 healthy subjects, 24 subjects per part (parts I and II). Within each part, subjects were assigned to receive treatments in random order; treatment periods were separated by a washout interval of at least 7 days. Eligible study participants included healthy, non-smoking (within previous 6 months), male and female subjects aged between 18 and 45 years with a body mass index ≤32 kg/m². Part I consisted of treatments A (co-administration of sitagliptin 50 mg and metformin 500 mg) and B (sitagliptin/metformin 50 mg/500 mg FDC tablet); part II consisted of treatments C (co-administration of sitagliptin 50 mg and metformin 1000 mg) and D (sitagliptin 50 mg/metformin 1000 mg FDC tablet). Blood samples were collected pre-dose and up to 72 hours post-dose in each treatment period for determination of plasma sitagliptin and metformin concentrations and calculation of the respective pharmacokinetic parameters. The area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) and the maximum plasma concentration (C(max)) for both sitagliptin and metformin were designated as the primary and secondary study endpoints, respectively, and analysed using an ANOVA model after logarithmic transformation of the data. Bioequivalence was established if the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs; FDC tablet/co-administration) of the AUC(∞) and C(max) for both sitagliptin and metformin fell within pre-specified bounds of (0.80, 1.25). RESULTS: The GMRs (90% CI) for the AUC(∞) of sitagliptin 50 mg and metformin 500 mg were 0.98 (0.96, 1.00) and 1.0 (0.95, 1.04), respectively, and for C(max) of sitagliptin and metformin were 1.00 (0.94, 1.06) and 1.00 (0.94, 1.06), respectively. The GMRs (90% CI) for the AUC(∞) of sitagliptin 50 mg and metformin 1000 mg (part II) were 0.97 (0.95, 0.99) and 1.00 (0.94, 1.07), respectively, and for the C(max) of sitagliptin and metformin were 0.94 (0.88, 1.01) and 1.01 (0.93, 1.10), respectively. In both part I and part II, the 90% CIs of the GMRs of the AUC(∞) and C(max) for both sitagliptin and metformin all fell within the pre-specified bioequivalence bounds of (0.80, 1.25). Administration of single doses of sitagliptin/metformin 50 mg/500 mg (part I) and 50 mg/1000 mg FDC tablets (part II) and co-administration of corresponding doses of sitagliptin and metformin as individual tablets were generally well tolerated. CONCLUSION: The sitagliptin/metformin 50 mg/500 mg and 50 mg/1000 mg FDC tablets are bioequivalent to co-administration of corresponding doses of sitagliptin and metformin as individual tablets and support bioequivalence to the sitagliptin/metformin 50 mg/850 mg tablet strength. These results indicate that the safety and efficacy profile of co-administration of sitagliptin and metformin can be extended to the sitagliptin/metformin FDC tablets.

Janumet: a combination product suitable for use in patients with Type 2 diabetes.

Inhibition of the enzyme dipeptidyl peptidase-4 represents the latest pharmacologic intervention to become available to assist patients with Type 2 diabetes to achieve glycemic control. A combination tablet of sitagliptin (Januvia) and metformin HCl (Glucophage) is now available from Merck (Janumet). The FDA has approved this drug for use in patients who are not adequately controlled by taking either sitagliptin or metformin HCl alone or for patients who are at present taking both simultaneously. Sitagliptin has been shown to be safe and effective at 100 mg daily doses. When given in combination with metformin the effect on glycemic control is thought to be complementary and possibly additive.