NCT03881995: Lixibrain01

Effects of Insulin Glargine and Lixisenatide on the Brain

Terminated Phase 4 Last updated 10 July 2020

What this trial tests

Phase 4 trial testing IGlarLixi in Diabetes Mellitus, Type 2 in 1 participant. Terminated before completion.

Timeline

18 March 2019

Primary endpoint
29 June 2020

29 June 2020

Quick facts

Lead sponsor	University Hospital Tuebingen
Phase	Phase 4
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	basic science
Enrollment	1
Start date	18 March 2019
Primary completion	29 June 2020
Estimated completion	29 June 2020
Sites	1 location across Germany

Drugs / interventions tested

• IGlarLixi — full drug profile →
• Insulin Glargine 100 UNT/ML — full drug profile →

Conditions studied

• Diabetes Mellitus, Type 2 — all drugs for Diabetes Mellitus, Type 2 →

Sponsor

University Hospital Tuebingen

Who can join

Adults 18 to 65, any sex, with Diabetes Mellitus, Type 2. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

1. Background During the last years, the brain has been identified as a major insulin-sensitive organ . The investigators and also other scientists identified hypothalamus, fusiform gyrus and prefrontal cortex as major insulin-sensitivity brain areas in humans . Brain insulin action regulates important physiological functions in humans such as food intake, body weight regulation, and cognition. Furthermore, animal studies suggest that insulin action specifically in the brain is involved in the control of peripheral glucose metabolism via regulation of the sensitivity to insulin in the rest of the body. Recently, the investigators were able to replicate these findings in humans: The investigators measured whole-body insulin sensitivity in combination with the well-established experimental delivery of human insulin to the brain via an intranasal approach. Peripheral insulin sensitivity was profoundly improved by brain insulin action in lean but not in obese healthy volunteers. What determines the effectiveness of this brain-derived pathway is still unknown. Furthermore, insulin resistance of the brain is linked to neurodegenerative diseases possibly explaining the elevated risk for such diseases in patients with type 2 diabetes.

GLP-1 receptor agonists have been shown to acutely modulate appetite- and reward-related brain areas in humans. Research in animals suggest a close interaction between insulin and GLP-1 action especially in homeostatic centers of the hypothalamus. In this context, it is important that GLP-1 sensitivity of the brain is still present in the insulin resistant human brain.

The investigators therefore hypothesized that GLP-1 agonists are able to improve insulin sensitivity of the brain; this might be one mechanism how GLP-1 agonists lead to weight loss and improved glucose metabolism. This might also have beneficial implications for cognitive function.

However, at present, there are no human studies examining the effect of a GLP-1 agonist on brain activity and especially insulin action in the brain in patients with type 2 diabetes mellitus (T2D).

Furthermore, there is no study in humans examining the effect of newly initiated insulin therapy on brain activity and especially insulin action in the brain in patients with T2D.
2. Rationale Based on the close interplay between hypothalamic insulin and GLP-1 signalling, the investigators hypothesize that the antidiabetic therapy with insulin glargine/lixisenatide combination (iGlarLixi) induces improved hypothalamic and prefrontal insulin sensitivity compared to a therapy with insulin glargine alone. This could underlay iGlarLixi's beneficial effects on body weight and whole-body glucose homeostasis.
3. Objective To assess whether treatment with iGlarLixi versus insulin glargine changes brain regional insulin sensitivity and thereby glucose metabolism, eating behaviour, and cognition in patients with type 2 diabetes insufficiently controlled with oral antidiabetic drugs (OAD).

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression.
   van Sloten TT, Sedaghat S, Carnethon MR, Launer LJ, et al · · 2020 · cited 501× · PMID 32135131 · DOI 10.1016/s2213-8587(19)30405-x