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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 4  |  Page : 126-127

Heart and mind: The story of glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus

Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Center of Vojvodina; Department of Internal Medicine, Medical Faculty, University of Novi Sad, Novi Sad, Serbia

Date of Submission27-Apr-2020
Date of Acceptance06-Jul-2020
Date of Web Publication07-Oct-2020

Correspondence Address:
Dr. Djordje S Popovic
Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Center of Vojvodina, Hajduk Veljkova 1, 21000 Novi Sad
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/hm.hm_11_20

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How to cite this article:
Popovic DS. Heart and mind: The story of glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus. Heart Mind 2020;4:126-7

How to cite this URL:
Popovic DS. Heart and mind: The story of glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus. Heart Mind [serial online] 2020 [cited 2022 Dec 4];4:126-7. Available from: http://www.heartmindjournal.org/text.asp?2020/4/4/126/297743

Dear Editor,

Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced by the L-cells of distal ileum and colon, where it is generated by the posttranslational processing of the proglucagon gene, but is also derived as a neurotransmitter by preproglucagon-expressing neurons in the nucleus tractus solitarius of the brain stem.[1],[2] GLP-1 is released in response to food intake. Its receptors have been identified in several tissues, including the pancreatic islets, heart, kidney, lung, nervous system, and gastrointestinal tract.[1] Some of the major actions of GLP-1 are enhancement of glucose-stimulated insulin secretion, inhibition of glucagon secretion, as well as enlargement of the beta-cell mass through both stimulation of replication and inhibition of apoptosis of pancreatic beta-cells.[1] GLP-1 also affects gut motility and induces satiety in the central nervous system.[1] It is important to underline that impaired incretin effect is recognized as one of the most important pathogenetic mechanisms in the natural history of Type 2 diabetes mellitus (T2DM) development.

Taking into account the favorable properties of this hormone, synthesized GLP-1 receptor agonists (GLP-1 RAs) have been established as important pharmacologic agents in the treatment of T2DM patients.[3] Several large randomized controlled cardiovascular outcome trials reported statistically significant reductions in cardiovascular events, as well as beneficial effects on the indices of chronic kidney disease in T2DM patients treated with different GLP-1 RAs (liraglutide, semaglutide, and dulaglutide).[3] The practical implication of these observations is that these GLP-1 RAs are now recommended not only for the treatment of T2DM patients with established atherosclerotic cardiovascular disease, or with indicators of high atherosclerotic cardiovascular disease risk, but also for those patients with predominance of heart failure or chronic kidney disease in the case of intolerance or existence of contraindications for the sodium-glucose co-transporter 2 inhibitor (SGLT-2i) therapy.[3]

T2DM is an important risk factor not only for cognitive dysfunction[4] but also for the development of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, where insulin desensitization in the brain is the major underlying mechanism.[5] Chronic hyperglycemia causes brain impairment through various pathophysiological mechanisms including mitochondrial dysfunction, neuroinflammation, alteration of neurotransmitters, and vascular disease.[4] All these lead to the cognitive impairment, neurodegeneration, synaptic plasticity loss, brain aging, and dementia.[4] GLP-1 exhibits effects on various neuronal functions including thermogenesis, blood pressure control, neurogenesis, neurodegeneration, retinal repair, and energy homeostasis, while GLP-1 activity modulation can influence both amyloid beta-peptide aggregation in Alzheimer's disease and dopamine levels in Parkinson's disease.[2],[4] Because GLP-1 RAs have demonstrated protective effects in animal models of both Alzheimer's and Parkinson's diseases, several pilot clinical trials have been carried out which have shown encouraging favorable effects of GLP-1 RAs in patients with these neurodegenerative diseases.[5]

A nested case–control study of 170,417 people with T2DM revealed that the use of GLP-1 analogs was associated with a lower odds of dementia (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.50–0.67), and that this tendency for GLP-1 analogs used alone remained after adjusting for other antidiabetic medications (OR, 0.59; 95% CI, 0.45–0.77).[6] One small randomized controlled trial (RCT), including fifty previously metformin-treated T2DM patients, found no significant impact of 12-month treatment with incretins (GLP-1 RAs or dipeptidyl peptidase-4 inhibitors) or SGLT-2i on cognitive function among 39 patients which completed the study.[7] Finally, Vadini et al. conducted another small RCT, which included forty metformin-treated obese patients with prediabetes or newly diagnosed T2DM, and assigned them to receive either liraglutide or lifestyle counseling until achieving a modest and comparable weight loss.[8] Both before and after a weight loss, a detailed neuropsychological assessment was performed among 32 patients which completed the study.[8] After comparable weight loss and superimposable glycemic control and insulin sensitivity, a significant increase in memory function was observed in patients treated with liraglutide in comparison to those which received lifestyle counseling.[8]

In addition to the firmly established positive effects on the heart of T2DM patients, there is some evidence that GLP1-RAs might have beneficial effects on their mind as well, but this notion needs further investigation through large RCTs.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Drucker DJ, Nauck MA. The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696-705.  Back to cited text no. 1
Katsurada K, Yada T. Neural effects of gut- and brain-derived glucagon-like peptide-1 and its receptor agonist. J Diabetes Investig 2016;7(Suppl 1):64-9.  Back to cited text no. 2
American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020;43(Suppl 1):S98-110.  Back to cited text no. 3
Grieco M, Giorgi A, Gentile MC, d'Erme M, Morano S, Maras B, et al. Glucagon-like peptide-1: A focus on neurodegenerative diseases. Front Neurosci 2019;13:1112.  Back to cited text no. 4
Hölscher C. Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models. Neuropharmacology 2018;136:251-9.  Back to cited text no. 5
Wium-Andersen IK, Osler M, Jørgensen MB, Rungby J, Wium-Andersen MK. Antidiabetic medication and risk of dementia in patients with type 2 diabetes: A nested case-control study. Eur J Endocrinol 2019;181:499-507.  Back to cited text no. 6
Perna S, Mainardi M, Astrone P, Gozzer C, Biava A, Bacchio R, et al. 12-month effects of incretins versus SGLT2-inhibitors on cognitive performance and metabolic profile. A randomized clinical trial in the elderly with Type-2 diabetes mellitus. Clin Pharmacol 2018;10:141-51.  Back to cited text no. 7
Vadini F, Simeone PG, Boccatonda A, Guagnano MT, Liani R, Tripaldi R, et al. Liraglutide improves memory in obese patients with prediabetes or early type 2 diabetes: A randomized, controlled study. Int J Obes (Lond) 2020;44:1254-63.  Back to cited text no. 8


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