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Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Under Re-organization)


ISSN (Print): 1871-5222
ISSN (Online): 1875-6115

The Effect of Modified-Release Ketoconazole on Insulin Resistance in Patients with Severe Metabolic Syndrome

Author(s): Per Marin, Robert R. Henry, Sunder R. Mudaliar, Willa Hsueh, Grethe Stoa Birketvedt

Volume 12 , Issue 1 , 2012

Page: [64 - 72] Pages: 9

DOI: 10.2174/187152212799857600

Price: $65


Introduction: The association between metabolic syndrome and cortisol levels has previously been discussed and recent studies have also shown that down-regulation of cortisol improves metabolic and circulatory risk factors in obese patients with the metabolic syndrome.

Aim: The primary objectives were to establish the effect of modified-release formulation of ketoconazole, a substance known to inhibit cortisol secretion, on insulin resistance and to establish a suitable dose for further investigation. The secondary objectives were to confirm improvement in other parameters related to metabolic syndrome such as HbA1c, blood pressure, liver enzymes, serum lipids, fasting blood glucose, and 24-hour urinary microalbuminuria.

Method: Seventy-two overweight and viscerally obese male and female patients aged 18 to 75 year were included in a randomized, double-blind, placebo-controlled, 3-month study, with a 4 weeks safety follow-up period. They were randomized to receive 200 mg and 400 mg of the modified-release formulation of ketoconazole and placebo with 24 patients in each group. Entry criteria included a diagnosis of type 2 diabetes for at least one year prior to study entry, HbA1c levels ≥ 6.7%, fasting plasma insulin ≥ 15mU/L (ref: ≤ 10mU/L), visceral obesity withwaist to hip ratio of ≥ 0.93 for males and ≥ 0.88 for females, and the presence or history of two or more of the following: hypertension, dyslipidemia and microalbuminuria.

Results: Administration of 400mg of the modified-release formulation of ketoconazole improved HbA1c levels, fasting blood glucose and total cholesterol compared to placebo with less consistent effects at 200mg of the modified-release formulation of ketoconazole. Additionally, reductions in systolic and diastolic blood pressure were found, and the study showed reductions in urinary microalbuminuria. Urinary cortisol decreased without signs of cortisol deficiency as measured with the standardized ACTH test. We found small mean increases from baseline in glucose disposal rate (GDR).

Conclusion: This study with modified-release ketoconazole, showed improvements in several parameters of the metabolic syndrome, but did not meet the primary efficacy endpoint of improvement in insulin resistance most likely due to the short study period.

Keywords: Blood lipids, cortisol regulation, fasting blood glucose, HbA1c, insulin resistance, liver enzymes, metabolic syndrome, microalbuminuria, modified-release ketoconazole, obesity, type 2 diabetes type, waist to hip ratio

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