Effect of Ursolic Acid Administration on Insulin Sensitivity and Metabolic Syndrome

A randomized, double-blind, placebo-controlled clinical trial in 24 patients of both sexes aged between 30 and 60 years, with a diagnosis of metabolic syndrome according to the modified International Diabetes Federation (IDF) criteria, without treatment.

They will be assigned randomly two groups of 12 patients, each to receive 150 mg of ursolic acid or placebo before breakfast for 12 weeks.

Insulin sensitivity will be calculated by Matsuda Index with dates from glucose and insulin levels from Oral Glucose Tolerance Test; Waist circumference will be measured; triglycerides and High density lipoprotein (HDL-C) and blood pressure will be evaluated before and after intervention in both groups.

Statistical analysis will be presented through measures of central tendency and dispersion, average and deviation standard for quantitative variables; frequencies and percentages for variable qualitative. Qualitative variables will be analyzed by X2, will be used for differences inter-group Mann-Whitney U Test and Wilcoxon Test for the within-groups differences. Will be considered statistical significance p ≤0.05.

This protocol was approved by a local ethics committee (CEI/075/2014) and written informed consent will be obtained from all volunteers.

• Ursolic acid (Drug), also known as Urson, Prunol, Micromerol, Malol: Ursolic acid capsules of 150 mg extracted from rosemary, once a day before breakfast
• Placebo (Drug), also known as Calcined magnesia: Calcined magnesia capsules of 150 mg, once a day before breakfast

Primary outcomes

• Total Insulin Sensitivity [Week 12]: The insulin sensitivity was calculated at baseline and at week 12. The value reported corresponds at week 12 with Matsuda index. Matsuda Index value is used to indicate insulin resistance on diabetes. Insulin sensitivity was calculated with Matsuda index \[10,000 / √glucose 0' x insulin 0') (mean glucose oral glucose tolerance test (OGTT) x mean insulin OGTT)\]. The entered values reflect the insulin sensitivity
• Waist Circumference [Week 12]: Waist circumference was evaluated at baseline and at week 12 with a flexible tape and the entered values reflect the waist circumference measure at week 12
• Fasting Glucose [Week 12]: The fasting glucose levels were evaluated at baseline and week 12 with enzymatic/colorimetric techniques and the entered values reflect the fasting glucose level at week 12
• Triglycerides [Week 12]: The triglycerides were evaluated at baseline and week 12 with enzymatic-colorimetric techniques and the entered values reflect the triglycerides level at week 12
• High Density Lipoprotein Cholesterol (HDL-c) [Week 12]: The HDL-c levels were evaluated at baseline and week 12 with enzymatic/colorimetric techniques and the entered values reflect the c-HDL level at week 12
• Systolic Blood Pressure [Week 12]: The systolic blood pressure was evaluated at baseline and week 12 with a digital sphygmomanometer and the entered values reflect the systolic blood pressure at week 12
• Diastolic Blood Pressure [Week 12]: The diastolic blood pressure was evaluated at baseline and week 12 with a digital sphygmomanometer and the entered values reflect the diastolic blood pressure at week 12

Secondary outcomes

• Body Weight [Week 12]: The body weight was measured at baseline and week 12 with a bioimpedance balance and the entered values reflect the weight at week 12
• Body Mass Index [Week 12]: The Body Mass index was calculated at baseline and at week 12 with the Quetelet index and the entered values reflect the body mass index at week 12
• Total Cholesterol [Week 12]: The total cholesterol was estimated by standardized techniques at baseline and week 12 and the entered values reflect the total cholesterol level at week 12
• Low Density Lipoproteins Cholesterol (LDL-c) [Week 12]: The LDL-c levels were measured at baseline and at week 12 with standardized techniques and the entered values reflect the c-LDL levels at week 12
• Creatinine [Week 12]: The creatinine levels were measured at baseline and at week 12 with standardized techniques and the entered values reflect the creatinine levels at week 12
• Uric Acid [Week 12]: The uric acid levels were measured at baseline and at week 12 with standardized techniques and the entered values reflect the uric acid levels at week 12

Sex: All, ages: 30 Years to 60 Years

Inclusion Criteria:

* Informed consent signed
* Patients both sexes
* Age between 30 and 60 years
* Metabolic Syndrome according to the IDF criteria:
* Waist circumference Man ≥90 cm, Woman ≥80 cm; and two of the following criteria:
* High density lipoprotein Man ≤40 mg/dL, Woman ≤50 mg/dL;
* Fasting glucose ≥100 mg/dL;
* Triglycerides ≥150 mg/dL;
* Blood pressure ≥130/85 mmHg

Exclusion Criteria:

* Women with confirmed or suspected pregnancy
* Women under lactation and/or puerperium
* Hypersensibility to ursolic acid o calcined magnesia
* Physical impossibility for taking pills
* Known uncontrolled renal, hepatic, heart or thyroid diseased
* Previous treatment for the metabolic syndrome components
* Body Mass Index ≥39.9 kg/m2
* Fasting glucose ≥126 mg/dL
* Triglycerides ≥500 mg/dL
* Total cholesterol ≥240 mg/dL
* Low density lipoprotein (c-LDL) ≥190 mg/dL
* Blood Pressure ≥140/90 mmHg

Participant flow

Outcome results

• Total Insulin Sensitivity (Primary), Mean, index: Ursolic Acid 4.2 +/- 1.2; Placebo 2.6 +/- 1.4 (p 0.003)
• Waist Circumference (Primary), Mean, cm: Ursolic Acid 83 +/- 9; Placebo 96 +/- 8 (p 0.008)
• Fasting Glucose (Primary), Mean, mmol/L: Ursolic Acid 4.7 +/- 0.4; Placebo 5.7 +/- 0.7 (p 0.002)
• Triglycerides (Primary), Mean, mmol/L: Ursolic Acid 1.8 +/- 0.8; Placebo 2.5 +/- 1.3 (p 0.308)
• High Density Lipoprotein Cholesterol (HDL-c) (Primary), Mean, mmol/L: Ursolic Acid 1.8 +/- 0.9; Placebo 1.8 +/- 0.7 (p 0.575)
• Systolic Blood Pressure (Primary), Mean, mmHg: Ursolic Acid 120 +/- 8; Placebo 124 +/- 15 (p 0.169)
• Diastolic Blood Pressure (Primary), Mean, mmHg: Ursolic Acid 76 +/- 6; Placebo 76 +/- 7 (p 0.373)
• Body Weight (Secondary), Mean, kg: Ursolic Acid 71 +/- 11; Placebo 81 +/- 15 (p 0.002)
• Body Mass Index (Secondary), Mean, kg/m^2: Ursolic Acid 24.9 +/- 1.2; Placebo 32.1 +/- 3.9 (p 0.049)
• Total Cholesterol (Secondary), Mean, mmol/L: Ursolic Acid 5.2 +/- 1.2; Placebo 6.4 +/- 1.9 (p 0.224)
• Low Density Lipoproteins Cholesterol (LDL-c) (Secondary), Mean, mmol/L: Ursolic Acid 2.8 +/- 1.2; Placebo 4.3 +/- 2.3 (p 0.116)
• Creatinine (Secondary), Mean, mmol/L: Ursolic Acid 0.06 +/- 0.02; Placebo 0.06 +/- 0.02 (p 0.953)
• Uric Acid (Secondary), Mean, µmol/L: Ursolic Acid 249.8 +/- 53.5; Placebo 422.3 +/- 124.9 (p 0.999)

Adverse events

Time frame: Throughout the study (12 weeks)

Other adverse events by term

• Manuel González-Ortíz, PhD, Principal investigator, University of Guadalajara