Clinical trial NCT02113241: Effect of Dapagliflozin Administration on Metabolic Syndrome, Insulin Sensitivity, and Insulin Secretion
Official title: Effect of Dapagliflozin Administration on Metabolic Syndrome, Insulin Sensitivity, and Insulin Secretion
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Metabolic Syndrome X
Keywords: metabolic syndrome
forxiga
dapagliflozin
insulin secretion
insulin sensitivity
Lead sponsor: University of Guadalajara
Sponsor class: OTHER
First posted: 2014-04-14
Enrollment: 24
Sex: ALL
Minimum age (years): 30
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The Metabolic Syndrome is a high prevalence disease worldwide. About a quarter of the adult population suffers the disease.

Dapagliflozin is an inhibitor of the sodium-glucose co-transporter SGLT2 in the kidney and is a novel treatment for diabetes type 2. Some studies indicate that SGLT2 inhibitors have benefits on blood pressure, triglycerides levels and help to raise the levels of high density lipoproteins cholesterol (c-HDL).

The aim of this study is to evaluate the effect of dapagliflozin on metabolic syndrome, insulin sensitivity and insulin secretion.

The investigators hypothesis is that the administration of dapagliflozin modifies the metabolic syndrome, insulin sensitivity and insulin secretion.

Detailed description: A randomized, double-blind, placebo-controlled clinical trial its going to carry out in 24 patients with a diagnosis of metabolic syndrome in accordance with the International Diabetes Federation (IDF). Waist circumference, glucose, insulin levels, lipid profile, creatinine and acid uric are going to be load after a 75 g of dextrose load.

12 patients will receive Forxiga (dapagliflozin), 10 mg, one per day before breakfast during 3 months.

The remaining 12 patients will receive placebo at the same dose.

There will be calculated Area Under the Curve of glucose and insulin, total insulin secretion (insulinogenic index), first-phase of insulin secretion (Stumvoll index) and insulin sensitivity (Matsuda index).

This protocol it's already approved by the local ethics committee and written informed consent it's going to be obtained from all volunteers.

Results will be presented as mean and standard deviation. Intra and inter group differences are going to be tested using the Wilcoxon signed-rank and Mann-Whitney U-test respectively; p≤0.05 it's going to be considered significant.

Eligibility criteria: Inclusion Criteria:

* 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
* Informed consent signed

Exclusion Criteria:

* Women with confirmed or suspected pregnancy
* Women under lactation and/or puerperium
* Hypersensibility to SGLT2 inhibitors
* 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

Primary outcomes:
measure: Waist Circumference at Week 12.
timeFrame: Week 12
measure: Triglycerides Levels at Week 12.
timeFrame: Week 12
measure: High Density Lipoprotein (c-HDL) Levels at Week 12.
timeFrame: Week 12
measure: Glucose Levels at Minute 0 at Week 12.
timeFrame: Week 12
measure: Systolic Blood Pressure at Week 12.
timeFrame: Week 12
measure: Diastolic Blood Pressure at Week 12.
timeFrame: Week 12
measure: Insulinogenic Index (Total Insulin Secretion) at Week 12.
timeFrame: Week 12
measure: Stumvoll Index (First Phase of Insulin Secretion) at Week 12.
timeFrame: Week 12
measure: Matsuda Index (Total Insulin Sensitivity) at Week 12.
timeFrame: Week 12
Secondary outcomes:
measure: Body Weight at Week 12.
timeFrame: Week 12
measure: Body Mass Index at Week 12
timeFrame: Week 12
measure: Fat Mass at Week 12.
timeFrame: Week 12
measure: Total Cholesterol at Week 12
timeFrame: Week 12
measure: Low Density Lipoproteins (c-LDL) at Week 12
timeFrame: Week 12
measure: Alanine Aminotransferase (ALT) at Week 12.
timeFrame: Week 12.
measure: Aspartate Aminotransferase (AST) at Week 12.
timeFrame: Week 12
measure: Creatinine at Week 12.
timeFrame: Week 12.
measure: Uric Acid at Week 12.
timeFrame: Week 12.
measure: AUC of Glucose at Week 12.
timeFrame: Week 12
measure: AUC of Insulin at Week 12.
timeFrame: Week 12
measure: Glucose at Minute 30 at Week 12.
timeFrame: Week 12
measure: Glucose at Minute 60 at Week 12.
timeFrame: Week 12
measure: Glucose at Minute 90 at Week 12.
timeFrame: Week 12
measure: Glucose at Minute 120 at Week 12.
timeFrame: Week 12
Other outcomes:
Locations:
city: Guadalajara
country: Mexico
facility: Instituto de Terapeútica Experimental y Clínica. Centro Universitario de Ciencias de la Salud. Universidad de Guadalajara
state: Jalisco
Study officials:
affiliation: University of Guadalajara
name: MANUEL GONZALEZ, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bolinder J, Ljunggren O, Kullberg J, Johansson L, Wilding J, Langkilde AM, Sugg J, Parikh S. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012 Mar;97(3):1020-31. doi: 10.1210/jc.2011-2260. Epub 2012 Jan 11.
citation: Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012 Jul;35(7):1473-8. doi: 10.2337/dc11-1693. Epub 2012 Mar 23.
citation: Chao EC. Dapagliflozin: an evidence-based review of its potential in the treatment of type-2 diabetes. Core Evid. 2012;7:21-8. doi: 10.2147/CE.S16359. Epub 2012 Jun 1.
citation: Kasichayanula S, Liu X, Lacreta F, Griffen SC, Boulton DW. Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet. 2014 Jan;53(1):17-27. doi: 10.1007/s40262-013-0104-3.
citation: Yang L, Li H, Li H, Bui A, Chang M, Liu X, Kasichayanula S, Griffen SC, Lacreta FP, Boulton DW. Pharmacokinetic and pharmacodynamic properties of single- and multiple-dose of dapagliflozin, a selective inhibitor of SGLT2, in healthy Chinese subjects. Clin Ther. 2013 Aug;35(8):1211-1222.e2. doi: 10.1016/j.clinthera.2013.06.017. Epub 2013 Aug 2.
citation: Obermeier M, Yao M, Khanna A, Koplowitz B, Zhu M, Li W, Komoroski B, Kasichayanula S, Discenza L, Washburn W, Meng W, Ellsworth BA, Whaley JM, Humphreys WG. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Drug Metab Dispos. 2010 Mar;38(3):405-14. doi: 10.1124/dmd.109.029165. Epub 2009 Dec 8.
citation: Kasichayanula S, Liu X, Pe Benito M, Yao M, Pfister M, LaCreta FP, Humphreys WG, Boulton DW. The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus. Br J Clin Pharmacol. 2013 Sep;76(3):432-44. doi: 10.1111/bcp.12056.
citation: Kilov G, Leow S, Thomas M. SGLT2 inhibition with dapagliflozin -- a novel approach for the management of type 2 diabetes. Aust Fam Physician. 2013 Oct;42(10):706-10.
citation: Kaku K, Inoue S, Matsuoka O, Kiyosue A, Azuma H, Hayashi N, Tokudome T, Langkilde AM, Parikh S. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2013 May;15(5):432-40. doi: 10.1111/dom.12047. Epub 2013 Jan 25.
citation: Zhang L, Feng Y, List J, Kasichayanula S, Pfister M. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes Obes Metab. 2010 Jun;12(6):510-6. doi: 10.1111/j.1463-1326.2010.01216.x.
citation: Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013 Sep;15(9):853-62. doi: 10.1111/dom.12127. Epub 2013 Jun 5.
citation: Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010 Oct;33(10):2217-24. doi: 10.2337/dc10-0612. Epub 2010 Jun 21.
citation: Bolinder J, Ljunggren O, Johansson L, Wilding J, Langkilde AM, Sjostrom CD, Sugg J, Parikh S. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014 Feb;16(2):159-69. doi: 10.1111/dom.12189. Epub 2013 Aug 29.
citation: Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, Xiong J, Perez Z, Norton L, Abdul-Ghani MA, DeFronzo RA. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014 Feb;124(2):509-14. doi: 10.1172/JCI70704. Epub 2014 Jan 27.