Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616.

BACKGROUND: MK-0616 is an oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) in development for the treatment of hypercholesterolemia. OBJECTIVES: This Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial aimed to evaluate the efficacy and safety of MK-0616 in participants with hypercholesterolemia. METHODS: This trial was planned to include 375 adult participants with a wide range of atherosclerotic cardiovascular disease risk. Participants were assigned randomly (1:1:1:1:1 ratio) to MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo. The primary endpoints included percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) at Week 8 and the proportion of participants with adverse events (AEs) and study intervention discontinuations due to AEs; participants were monitored for AEs for an additional 8 weeks after the 8-week treatment period. RESULTS: Of the 381 participants randomized, 49% were female, and the median age was 62 years. Among 380 treated participants, all doses of MK-0616 demonstrated statistically significant (P < 0.001) differences in least squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). AEs occurred in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group. CONCLUSIONS: MK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 of up to 60.9% from baseline and was well tolerated during 8 weeks of treatment and an additional 8 weeks of follow-up. (A Study of the Efficacy and Safety of MK-0616 [Oral PCSK9 Inhibitor] in Adults With Hypercholesterolemia [MK-0616-008]; NCT05261126).

Corifollitropin Alfa Combined With Human Chorionic Gonadotropin in Adolescent Boys With Hypogonadotropic Hypogonadism.

CONTEXT: Adolescent males with hypogonadotropic hypogonadism (HH) have traditionally been treated with exogenous testosterone (T) or human chorionic gonadotropin (hCG) to produce virilization; however, those modalities do not result in growth of the testes and may promote premature maturation and terminal differentiation of Sertoli cells prior to their proliferation, which may impact future fertility. Another option is to use gonadotropins in those individuals to induce testicular growth, proliferation and maturation of Sertoli cells, and production of endogenous T with consequent virilization. OBJECTIVE: We examined the efficacy and safety of corifollitropin alfa (CFA) combined with hCG for the induction of testicular growth and pubertal development in adolescent boys with HH. METHODS: This was a 64-week, multicenter, open-label, single-group study of CFA in adolescent boys, aged 14 to younger than 18 years, with HH. Seventeen participants initiated a 12-week priming period with CFA (100 µg if weight ≤ 60 kg, or 150 µg if weight > 60 kg) given subcutaneously once every 2 weeks, after which they entered a 52-week combined treatment period with CFA, once every 2 weeks, and subcutaneous hCG, twice-weekly (hCG dose adjusted between 500 IU and 5000 IU to keep total T and estradiol levels within protocol-specified ranges). The primary efficacy end point was change from baseline in testicular volume (TV), measured as the sum of volumes of left and right testes by ultrasound. RESULTS: After 64 weeks of therapy with CFA/CFA combined with hCG, geometric mean fold increase from baseline in TV was 9.43 (95% CI, 7.44-11.97) (arithmetic mean of change from baseline at week 64, 13.0 mL). Hormonal, Tanner stage, and growth velocity changes were consistent with initiation and progression of puberty. Treatment was generally well tolerated. No participant developed anti-CFA antibodies. CONCLUSION: Treatment of adolescent boys with HH with CFA alone for 12 weeks followed by CFA combined with hCG for 52 weeks induced testicular growth accompanied by pubertal progression, increased T, and a pubertal growth spurt (EudraCT: 2015-001878-18).

A randomised, double-blind, trial of the safety and efficacy of omarigliptin (a once-weekly DPP-4 inhibitor) in subjects with type 2 diabetes and renal impairment.

AIMS: To assess the safety and efficacy of omarigliptin in subjects with type 2 diabetes mellitus (T2DM) and chronic renal impairment (RI). METHODS: Patients with T2DM with moderate RI (estimated glomerular filtration rate [eGFR] ≥30 to <60 mL/min/1.73 m2 ) (N=114), severe RI (eGFR <30 mL/min/1.73 m2 ) (N=55) or end-stage renal disease on dialysis (N=44), who were either not on an antihyperglycaemic agent therapy for at least 12 weeks at screening, washed-off of oral antihyperglycaemic agent monotherapy or low-dose dual combination therapy, or on insulin monotherapy, with baseline glycated haemoglobin (HbA1c) of 6.5%-10.0% were randomised to omarigliptin or to placebo for 24 weeks (primary end-point) followed by a 30-week period with subjects on placebo switched to blinded glipizide (if not on insulin). RESULTS: After 24 weeks, from a mean baseline HbA1c of 8.4% in the omarigliptin group and 8.3% in the placebo group, the least squares mean (95% CI) change from baseline in HbA1c in the overall population (all renal strata combined) was -0.77% (-1.00 to -0.54) in the omarigliptin group and -0.44% (-0.67 to -0.21) in the placebo group; between-group difference of -0.33% (-0.63 to -0.02); P=0.035. After 24 weeks, the incidences of subjects with symptomatic hypoglycaemia, one or more adverse event (AE), drug-related AE, serious AE and discontinuation due to an AE were similar in the omarigliptin and placebo groups. CONCLUSIONS: In this study in subjects with T2DM and RI, relative to placebo, omarigliptin provided clinically meaningful reductions in HbA1c, had a similar incidence of symptomatic hypoglycaemia and was generally well tolerated.

Enoxaparina como alternativa antitrombótica para la cirugía en pacientes de alto riesgo tromboembólico crónicamente anticoagulados con dicumarínicos / Enoxaparinas an alternative to antocoagulant therapy in hight risk patients under chronic treatment with vitamin K antagonists

En la actualidad no existe un criterio uniforme para el manejo anticoagulante perioperatorio de los pacientes con alto riesgo tromboembólico y crónicamente anticoagulados con dicumarínicos. Se ha propuesto el uso de las HBPM en reemplazo de la heparina no fraccionada pero la experiencia publicada es escasa y no hay un consenso sobre la dosis y el momento adecuado para reiniciar la anticoagulación en el período post quirúrgico, especialmente en cirugía mayor. Nuestro objetivo fue evaluar la efectividad y seguridad de la enoxaparina 1 mg/kg SC cada 12 horas en el manejo perioperatorio de pacientes con alto riesgo tromboembólico. Resultados: 48 pacientes (edad promedio: 70 años, 32 hombres) anticoagulados por RVM 64,5 porciento y FA con antecedente de embolia o trombo auricular en 35,5 porciento. El 45 porciento requirió suspender los AO por una cirugía programada, 33 porciento por cirugía odontológica, 16 porciento cateterismo cardíaco y 6 porciento por una biopsia. Los pacientes suspendían la AO 3 a 5 días previos al procedimiento y lo reemplazaban por enoxaparina. la dosis promedio de enoxaparina fue de 80 mg cada 12 horas. El 92 porciento de los pacientes reinició AO en las primeras 24 horas de la cirugía. No se detectaron eventos trombóticos hasta 1 mes de la cirugía. Cuatro pacientes presentaron hemorragias, 3 sangrados menores y 1 sangrado mayor que requirió múltiples transfusiones. Conclusión: La enoxaparina puede ser una alternativa antitrombótica eficaz en pacientes con alto riesgo tromboembólico y permitirá mediante 1 o 2 dosis diarias (ajustadas al peso) el manejo ambulatorio con un bajo índice de sangrado