Correlation Between Plasma- and Endothelial DPP-4 Activity

Type 2 Diabetes Mellitus Clinical Trial

Official title:

Plasma and Endothelial Activity of Dipeptidyl Peptidase 4 During Different Doses of Sitagliptin

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02192853
• Other study ID #: H-2-2012-149
• Status: Completed
• Phase: Phase 4
• First received: January 4, 2014
• Last updated: September 7, 2017
• Start date: May 2013
• Est. completion date: March 2014

Study information

• Verified date: September 2017
• Source: University Hospital, Gentofte, Copenhagen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The investigators want to estimate both the endothelial and the plasma activity of dipeptidyl peptidase 4 during different doses of sitagliptin in healthy subjects and patients with type 2 diabetes. Furthermore, the investigators want to investigate whether the current clinical dose of 100 mg of sitagliptin is sufficient to inhibit both the plasma and the endothelial activity of the enzyme dipeptidyl peptidase 4.

Description:

The two incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the intestinal L- and K- cells, respectively in response to ingestion of nutrients. The two hormones are able to lower blood glucose levels during high glucose levels - by the so called incretin effect. GIP and GLP-1 are both rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4). The remaining metabolites are without insulinotropic effects. The effect of DPP-4 inhibitors used in treatment of type 2 diabetes relies on their impact on DPP-4 activity.

DPP-4 exists in a soluble form in plasma ad as a membrane-bound form in blood vessels and other tissues. The impact of DPP-4 inhibitors on DPP-4 activity has only been evaluated in plasma. We aim to investigate plasma and endothelial DPP-4 activity (i.e. whole-body DPP-4 activity) in patients with type 2 diabetes during different doses of the DPP-4 inhibitor sitagliptin.

Both healthy control subjects and patients with type 2 diabetes are subjected to 4 experimental days (in a randomized order) with continuous infusion of GLP-1 and pre-treatment with 25 mg sitagliptin, 100 mg sitagliptin, 200 mg sitagliptin and placebo, respectively. Afterwards, we are going to measure the whole-body DPP-4 activity by comparing plasma levels of active (intact) GLP-1 and total GLP-1, and relate to plasma DPP-4 activity.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: March 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 35 Years to 80 Years

Eligibility

Inclusion Criteria:

• Caucasians with diet and/or metformin treated patients with type 2 diabetes (diagnosed according to the criterias of the World Health Organization)

• Normal Hemoglobin

• Prior Informed Consent

Exclusion Criteria:

• Nephropathy

• Liver disease

• Inflammatory bowel disease

• Pregnancy

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• sitagliptin
In randomized order: Day 1: tablet of 25 mg of sitagliptin + i.v. GLP-1 infusion Day 2: tablet of 100 mg of sitagliptin + i.v. GLP-1 infusion Day 3: tablet of 200 mg of sitagliptin + i.v. GLP-1 infusion
• Placebo
Day 4: placebo tablet

Locations

Country	Name	City	State
Denmark	Diabetes Research Division, Department of Endocrinology, Gentofte Hospital	Hellerup

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Gentofte, Copenhagen

Country where clinical trial is conducted

Denmark, 

References & Publications (9)

Deacon CF, Hughes TE, Holst JJ. Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig. Diabetes. 1998 May;47(5):764-9. — View Citation

Deacon CF. Circulation and degradation of GIP and GLP-1. Horm Metab Res. 2004 Nov-Dec;36(11-12):761-5. Review. — View Citation

Gutzwiller JP, Drewe J, Göke B, Schmidt H, Rohrer B, Lareida J, Beglinger C. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol. 1999 May;276(5 Pt 2):R1541-4. — View Citation

Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005 Dec;78(6):675-88. — View Citation

Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009 Jan 15;297(1-2):127-36. doi: 10.1016/j.mce.2008.08.012. Epub 2008 Aug 20. Review. — View Citation

Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. Review. — View Citation

Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, Hüfner M, Schmiegel WH. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002 Mar;87(3):1239-46. — View Citation

Orskov C, Wettergren A, Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes. 1993 May;42(5):658-61. — View Citation

Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003 Jul 15;114(2-3):115-21. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Correlation between the total and intact GLP-1 hormone during different doses of sitagliptin measured as total area under the curve (tAUC)		GLP.1 total and GLP-1 intact will be calculated based on blood samples at time points: -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days
Secondary	Differences in serum-/plasma concentrations of GLP-1 measured as total Area under the curve (tAUC)		GLP-1 will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days
Secondary	Differences in glucose measured as total Area under the curve (tAUC)		Glucose will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days
Secondary	Differences in Insulin measured as total Area under the curve (tAUC)		Insulin will be measured at time points(minutes): -40,-30,-20,-10,0,10,20,30,40,50,60,75,90,105,120,150,180,240,300,360 on all days