Off target benefits of GLP-1 agonist therapy in type 2 diabetes

Abstract

Type 2 Diabetes (T2D) is a chronic, progressive condition associated with hyperglycaemia and numerous secondary complications are linked with sub-optimal management, including mental health problems and risk of dementia. There are numerous drugs available for the treatment of T2D, each with different mechanism of action to lower blood glucose. Non-response to therapy is a significant problem in T2D as patients will not derive benefit, may come to harm, and will be exposed to persistent elevations in blood glucose which can increase risk of secondary complications. Some T2D drugs are associated with off-target benefits, beyond glucose lowering, including glucagon-like peptide-1 (GLP-1) agonists which are associated with weight loss, reduced cardiovascular complications and potential neuroprotective benefits. GLP-1 agonists are expensive and presently indicated as 3rd or 4th line therapy when other less expensive T2D drugs have failed. Earlier identification of response to GLP-1 therapy and improved understanding of off-target benefits (i.e. improved quality of life via a reduction in mental health complications and cognitive decline) may support changes in prescribing guidance for this drug class.

In Chapter 3, we identified three novel proteomic biomarker signatures associated with patient responsiveness to GLP-1 agonist therapy utilizing different measures of response to therapy, including HbA1c thresholds of 53 and 58mmol/mol and current National Institute of Health and Excellence (NICE) guidelines. Three common biomarkers across the different measures of response were identified, indicative of a need for a clearer definition of response. Chapter 4 reports a verification of biomarkers of response to GLP-1 in a secondary cohort, identifying eight reproducible biomarkers that will be validated in prospective studies. In Chapter 5, we report an interim analysis of the effect of GLP-1 agonist therapy on anxiety, depression and cognition in a locally recruited cohort. Here we evidence significantly increased levels of depression and anxiety in those with T2D, and an increased proportion of GLP-1 agonist non-responders experiencing high levels of anxiety whilst GLP-1 agonist responders are comparable to controls without T2D. Furthermore, in cognitive tests, particularly the quick Mild Cognitive Impairment (qMCI) instrument, GLP-1 agonist responders perform similarly to controls without T2D, whilst GLP-1 agonist non-responders and T2D controls perform significantly worse than controls without T2D, indicative of a protective effect associated with response to GLP-1 agonist therapy. Well-designed prospective studies measuring change from baseline in anxiety, depression and cognitive function will confirm the potential of GLP-1 agonists to reduce mental health complications of T2D. In Chapter 6 we evaluated the prescribing trends of diabetes drugs across Northern Ireland and their co-prescription with anxiolytics, antidepressants and Alzheimer’s disease drugs. Of those exposed to diabetes drugs, 13.8% were co-prescribed an anxiolytic, 41.8% were co-prescribed an antidepressant and 2.6% were co-prescribed an Alzheimer’s disease drug. Different diabetes drug classes were associated with differential risk of co-prescription of anxiolytics, antidepressants and Alzheimer’s disease drugs. These findings warrant further investigation in prospective studies, given the importance of improving mental health and preventing cognitive decline in an at-risk population.

Overall, the work presented within this thesis indicates that responsiveness to GLP-1 agonist therapy reduces anxiety and cognitive decline and that proteomic biomarkers hold promise in identifying responsiveness to therapy. With additional prospective effectiveness and cost-effectiveness studies this may inform changes to prescribing guidelines for this drug class.

Date of Award	Jan 2023
Original language	English
Sponsors	Department for the Economy
Supervisor	Paula McClean (Supervisor) & Catriona Kelly (Supervisor)