title: Efficacy and safety of the selective 11β-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension.
abstract: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be involved in several abnormalities associated with the metabolic syndrome. This study evaluated the antihypertensive efficacy and safety of two 11β-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 11β-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.
authors.affiliation: Merck Sharp & Dohme Corp., Rahway, New Jersey 07065-0900, USA. sukrut_shah@merck.com
authors.forename: Sukrut
authors.initials: S
authors.lastname: Shah
authors.forename: Anne
authors.initials: A
authors.lastname: Hermanowski-Vosatka
authors.forename: Kendra
authors.initials: K
authors.lastname: Gibson
authors.forename: Rae Ann
authors.initials: RA
authors.lastname: Ruck
authors.forename: Gang
authors.initials: G
authors.lastname: Jia
authors.forename: John
authors.initials: J
authors.lastname: Zhang
authors.forename: Peggy M T
authors.initials: PM
authors.lastname: Hwang
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Ryan
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Langdon
authors.forename: Peter U
authors.initials: PU
authors.lastname: Feig
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D015992:Body Mass Index; D001835:Body Weight / Q000187:drug effects*; D004311:Double-Blind Method; D016903:Drug Monitoring; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D015507:Drugs, Investigational; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1