The Incretin Effect in Patients With Kidney Impairment

Renal Insufficiency, Chronic Clinical Trial

— UREMINC  

Official title:

The Incretin Effect in Non-diabetic Patients With Severe Renal Impairment Depending on Chronic Dialysis Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01327378
• Other study ID #: H-C-2009-007
• Status: Completed
• Phase: N/A
• First received: March 29, 2011
• Last updated: March 31, 2011
• Start date: March 2009
• Est. completion date: October 2010

Study information

• Verified date: June 2010
• Source: University Hospital, Gentofte, Copenhagen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Ethics CommitteeDenmark: Danish Dataprotection Agency
• Study type: Observational

Clinical Trial Summary

The current study explores the incretin effect; a central mechanism of sugar metabolism. People with type 2 diabetes have a markedly reduced incretin effect, while the incretin effect never has been studied in patients with severe chronic renal failure. Non-diabetic patients with severe kidney failure and patients with diabetes and normal kidney function share several pathophysiological traits, including decreased sensitivity to insulin, fasting hyperinsulinaemia and impaired beta cell function. The investigators expect the incretin effect to be affected in patients with chronic renal failure without diabetes, which in time can result in therapeutic changes in this group of patients.

Description:

The novel and original aspect of this investigator initiated study is the focus on incretin (patho)physiology in an uraemic milieu. In this first of 5 substudies (separate notification and registration) the investigators explore the incretin effect. Our hypothesis is that it is impaired in non-diabetic patients in chronic dialysis treatment.

The prevalence of type 2 diabetes mellitus (T2DM) is rapidly increasing worldwide. In addition to reduced insulin sensitivity and beta cell dysfunction, T2DM is characterized by a severely impaired incretin effect. The incretin effect refers to the insulinotropic action of the nutrient-released incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Both hormones are secreted from intestinal endocrine mucosal cells. The incretin effect is defined as the difference in insulin secretory responses between oral and isoglycaemic intravenous (iv) glucose challenges. In healthy individuals it accounts for as much as 70% of insulin secreted in response to oral glucose, whereas patients with T2DM exhibit an incretin effect in the range of 0 to 30%. The incretin hormone GLP-1 has a potent blood glucose-lowering effect in patients with T2DM. However, following secretion of GLP-1, the ubiquitous enzyme dipeptidyl peptidase-4 (DPP-4) rapidly cleaves the hormone, by which it is completely inactivated. This has formed the basis for new pharmacological agents blocking DPP-4 (DPP-4 inhibitors) or DPP-4 resistant GLP-1 receptor agonists. Long-term treatment has showed positive effect on glycaemic control and risk factors of cardiovascular diseases in patients with T2DM.

These effects may be applicable also in patients with end-stage renal disease (ESRD) because patients with T2DM and normal kidney function and non-diabetic patients with ESRD show several identical characteristics. These include decreased insulin sensitivity, hyperinsulinaemia and impaired beta cell function. The incretin effect has only to a small extent been investigated in patients with ESRD.

The single most frequent cause of ESRD and need of chronic maintenance dialysis is diabetic nephropathy. In the U.S. more than 50% of patients in dialysis have diabetes compared with about 23% in Denmark. The life expectancy of dialysis patients with T2DM is severely reduced with a median survival of 2 to 4 years and there is no treatment documented to significantly improve this poor prognosis. The most common cause of death in this group of patients is related to cardiovascular disease that seems to result from death of causes different from classical atherosclerosis. So far intervention directed towards hypertension, dyslipidaemia and other classical risk factors have showed divergent and primarily negative results.

There is therefore an unmet medical need to find new treatments to protect these patients from cardiovascular disease and premature death.

Improving the glycaemic control using incretin-based therapies has the potential to meet this medical need. The incretin hormones and their metabolites are however to a large extent excreted by the kidneys and this may lead to problems (or benefits!) when administered to patients without kidney function or with severely reduced kidney function. The present knowledge about the incretin effect and incretin hormone physiology as well as pharmacokinetics, clinical effects and side effects of GLP-1 analogues in patients with reduced kidney function is limited and the few studies available are predominantly confined to patients with only mild or moderately reduced kidney function. The investigators will explorer basic and pharmacologic aspects in patients with severe reduced kidney function depending on chronic maintenance dialysis treatment. Before any potential treatment can be initiated, the investigators need basic information on how the incretin system is affected by an uraemic milieu. Current and succeeding substudies will provide us with that information.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: October 2010
• Est. primary completion date: October 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

• Male or female; age: 18 - 90 years

• CKD stage 5 (CrCL < 15 ml/min) in chronic haemodialysis (minimum 3 months)

• NGT or IGT (diagnosed according to WHO criteria)

• Body mass index 18.5 - 28 kg/m2

Exclusion Criteria:

• Type 1 or 2 diabetes mellitus

• Pancreatitis

• Medication with influence on insulin secretion and/or glucose metabolism

• Previous or actual malignancy

• Inflammatory bowel disease

• Congestive heart failure (NYHA III-IV)

• Previous bowel resection

• Severe hypertension

• Impaired liver function

• Haemoglobin < 6.5 mmol/L

Study Design

Observational Model: Case Control, Time Perspective: Cross-Sectional

Related Conditions & MeSH terms

• Renal Insufficiency
• Renal Insufficiency, Chronic

Locations

Country	Name	City	State
Denmark	Department of Nephrology P 2131, Rigshospitalet	Copenhagen Ø

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital, Gentofte, Copenhagen	Rigshospitalet, Denmark, University of Copenhagen

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incretin effect	IE= 100%*(iAUC,OGTT - iAUC,IIGI)/iAUC,OGTT Assessed at two separate examination days. Day 1: Oral glucose tolerance test (OGTT), Day 2: Intravenous isoglycaemic glucose infusion (IIGI).; Data will be presented when all analyses have been performed. Estimated in May 2011.	Minimum 3 days and maximum 3 weeks between the two examination days. Cross-sectional design. No follow up.	No
Secondary	Gastric-induced glucose disposal (GIGD)	GIGD=100%*(glucose,OGTT-glucose,IIGI)/glucose,OGTT) Assessed at two separate examination days. Day 1: Oral glucose tolerance test (OGTT), Day 2: Intravenous isoglycaemic glucose infusion (IIGI).; Data will be presented when all analyses have been performed. Estimated in May 2011.	Minimum 3 days and maximum 3 weeks between the two examination days. Cross-sectional design. No follow up.	No