DPP4inhibitors in Type 1 Diabetes

A Dipeptidyl Peptidase 4 (DPP-4) Inhibitor in Type 1 Diabetes

A small, pilot, randomised, cross over trial that investigates the potential for DPPIVi therapy to reduce insulin requirements in type 1 diabetes was studied. We investigated whether this drug reduces daily insulin doses, leads to weight reduction, reduces blood glucose fluctuation and improves glucose control. Through reduction of blood glucose variability, we want investigated, whether it has the capability of improving the magnitude of epinephrine responses at 2.5mmol/L by performing a hyperinsulinaemic, hypoglycaemia clamp study after each arm. A successful outcome would then lead to an application for funds for a larger, multicentre intervention study. The benefits of this therapeutic advance are clear and this has the potential to make a dramatic improvement to the lives of people with type 1 diabetes in our community.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes; Hypoglycaemia
• Intervention / Treatment: Drug: Saxagliptin

Detailed Description

Ninety years ago the discovery of insulin and its development as a drug revolutionized the management of type 1 diabetes, which until that point had almost inevitably proven fatal. However, very rapidly it was recognized that like all "wonder" drugs there were problems with insulin. Elliot Joslin, one of the pioneers of diabetes therapy described insulin as "…a potent preparation alike for evil and for good"(1922). There are two major reasons for this. Firstly, in non-diabetic individuals insulin produced by the pancreas acts directly on the liver, the major organ for regulating blood glucose levels. In contrast, people with type 1 diabetes inject insulin under the skin, and this is then absorbed into the circulation and much of it is degraded (~50%) before it gets to the liver. This means that in order to act effectively in the liver a type 1 diabetic needs to inject at least double the amount of insulin. Many studies have now shown that high insulin levels lead to weight gain, accelerated blood vessel disease (atherosclerosis) and a higher risk of suffering low blood glucose (hypoglycaemia). A second major problem is that individuals with type 1 show high levels of the hormone, glucagon. Glucagon is also produced in the pancreas and is normally regulated by pancreatic insulin, so the loss of this effect in people with type 1 diabetes means they run high glucagon levels. This has been shown to increase blood glucose, particularly after a meal. It is because of this that the diabetes community has called for novel therapies that can reduce high insulin levels and high glucagon levels. A new class of drugs called dipeptidylpeptidase IV inhibitors (DPPIVi) are currently used to treat people with type 2 diabetes. DPPIV inhibition increases endogenous levels of glucagon like peptide-1 (GLP-1). These drugs have a number of actions but the most relevant to this application is that they directly suppress glucagon, induce satiety (i.e. reduce hunger and leads to a reduction in body weight) and indirectly reduce the need for high dose insulin injections. This makes them an ideal candidate drug as an insulin sparing or adjunct therapy in type 1 diabetes, but there is very limited data to date for this use.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Dundee, United Kingdom, DD1 9SY
    • Clinical research centre, Ninewells Hospital and Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria;

• Type 1 diabetes over 5 years duration
• HbA1c less than 10%
• Age 18 and over
• Current use of intensive insulin therapy (injections or pump)
• BMI 19-35
• Ability to give written informed consent to participate in the study

Exclusion criteria;

• Previous history of pancreatic disease/cancer
• Significant renal disease estimated glomerular filtration rate (eGFR) less than 50
• Significant microvascular disease
• Personal/family history of Medullary thyroid cancer
• Personal/family history of multiple endocrine neoplasia (MEN) Type 2
• Moderate/Severe hepatic impairment
• Pregnancy or breast feeding
• History of epilepsy/hypoglycaemia induced seizure
• Those on any other hypoglycaemia drug apart from insulin for their diabetes.
• Currently on CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampicin
• Currently on CYP3A4 inhibitors like ketoconazole, diltiazem
• Less than 30 days since participation in another drug trial or longer depending on the drug half life.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Saxagliptin; 5mg once daily in addition to insulin therapy	Drug: Saxagliptin; 5mg saxagliptin
Placebo Comparator: Placebo; Crossover Placebo once daily	Drug: Saxagliptin; 5mg saxagliptin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Magnitude of epinephrine release at 2.5mmol/L	During hyperinsulinaemic hypoglycaemia clamp

Collaborators and Investigators

• Sponsor: University of Dundee

Publications and helpful links

General Publications

• George PS, McCrimmon RJ. Saxagliptin co-therapy in C-peptide negative Type 1 diabetes does not improve counter-regulatory responses to hypoglycaemia. Diabet Med. 2016 Sep;33(9):1283-90. doi: 10.1111/dme.13046. Epub 2015 Dec 28.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: August 6, 2013
• First Submitted That Met QC Criteria: August 12, 2013
• First Posted (Estimate): August 14, 2013

Study Record Updates

• Last Update Posted (Actual): October 15, 2019
• Last Update Submitted That Met QC Criteria: October 11, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Saxagliptin
• Other Study ID Numbers: 2012DM07