RESUMO
11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) may be involved in several abnormalities associated with the metabolic syndrome. This study evaluated the antihypertensive efficacy and safety of two 11ß-HSD1 inhibitors, MK-0736 and MK-0916, in overweight-to-obese hypertensive patients. Patients aged 18-75 years with sitting diastolic blood pressure (SiDBP) 90-104 mm Hg, systolic BP <160 mm Hg (after washout of prior antihypertensive medications), and BMI ≥27 to <41 kg/m(2) were randomized to receive 2 or 7 mg/d MK-0736, 6 mg/d MK-0916, or placebo for 12 weeks (n = 51-54/group). Patients with BMI ≥20 to <27 kg/m(2) received 6 mg/d MK-0916 or placebo for 24 weeks (n = 19/group). The primary endpoint was placebo-adjusted change from baseline in trough SiDBP in patients treated for 12 weeks with 7 mg/d MK-0736. The primary endpoint was not met (placebo-adjusted reduction = 2.2 mm Hg; P = .157). With 7 mg/d MK-0736, placebo-adjusted LDL-C decreased by 12.3%, high-density lipoprotein cholesterol by 6.3%, and body weight by 1.4 kg. Both 11ß-HSD1 inhibitors were generally well tolerated. In overweight-to-obese patients with hypertension, reduction in SiDBP with MK-0736 was not statistically significant. Nonetheless, MK-0736 was well tolerated and did appear to modestly improve other BP endpoints, LDL-C, and body weight.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1 , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Drogas em Investigação , Hipertensão/tratamento farmacológico , Obesidade/tratamento farmacológico , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/administração & dosagem , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/efeitos adversos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adolescente , Adulto , Idoso , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/metabolismo , Índice de Massa Corporal , Método Duplo-Cego , Monitoramento de Medicamentos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/metabolismo , Feminino , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The safety and efficacy of combination ezetimibe/simvastatin (E/S) plus extended-release niacin was assessed in 942 patients with type IIa/IIb hyperlipidemia for 64 weeks in a randomized, double-blind study. Patients received E/S (10/20 mg) plus niacin (to 2 g) or E/S (10/20 mg) for 64 weeks, or niacin (to 2 g) for 24 weeks and then E/S (10/20 mg) plus niacin (2 g) or E/S (10/20 mg) for an additional 40 weeks. The primary end point, the safety of E/S plus niacin, included prespecified adverse events (ie, liver, muscle, discontinuations due to flushing, gallbladder-related, cholecystectomy, fasting glucose changes, new-onset diabetes). The secondary end points included the percentage of change from baseline in high-density lipoprotein (HDL) cholesterol, triglycerides, non-HDL cholesterol, and low-density lipoprotein cholesterol, other lipids, lipoprotein ratios and high-sensitivity C-reactive protein. The anticipated niacin-associated flushing led to a greater rate of study discontinuations with the E/S plus niacin regimen than with E/S alone (0.7%, p <0.001). The rate of liver and muscle adverse events was low (<1%) in both groups. Four patients had gallbladder-related adverse events; 1 patient in the E/S and 1 in the E/S plus niacin group underwent cholecystectomy. The occurrence of new-onset diabetes was 3.1% for the E/S and 4.9% for the E/S plus niacin group. The fasting glucose levels increased to greater than baseline during the first 12 weeks (E/S, 3.2 mg/dl; E/S plus niacin, 7.7 mg/dl) and gradually decreased to pretreatment levels by 64 weeks in both groups. E/S plus niacin significantly improved HDL cholesterol, triglycerides, non-HDL cholesterol, low-density lipoprotein cholesterol, apolipoprotein B and A-I, and lipoprotein ratios compared with E/S (p Assuntos
Azetidinas/uso terapêutico
, Hiperlipidemias/tratamento farmacológico
, Hipolipemiantes/uso terapêutico
, Niacina/uso terapêutico
, Sinvastatina/uso terapêutico
, Complexo Vitamínico B/uso terapêutico
, Adolescente
, Adulto
, Idoso
, Azetidinas/administração & dosagem
, Azetidinas/efeitos adversos
, Biomarcadores/sangue
, Proteína C-Reativa/metabolismo
, HDL-Colesterol/sangue
, LDL-Colesterol/sangue
, Preparações de Ação Retardada
, Método Duplo-Cego
, Quimioterapia Combinada
, Ezetimiba
, Feminino
, Seguimentos
, Humanos
, Hiperlipidemias/sangue
, Hiperlipidemias/diagnóstico
, Hipolipemiantes/administração & dosagem
, Hipolipemiantes/efeitos adversos
, Lipoproteínas/sangue
, Masculino
, Pessoa de Meia-Idade
, Niacina/administração & dosagem
, Niacina/efeitos adversos
, Índice de Gravidade de Doença
, Sinvastatina/administração & dosagem
, Sinvastatina/efeitos adversos
, Tennessee
, Fatores de Tempo
, Resultado do Tratamento
, Complexo Vitamínico B/administração & dosagem
, Complexo Vitamínico B/efeitos adversos