GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art

Michael A Nauck, Daniel R Quast, Jakob Wefers, Juris J Meier, Michael A Nauck, Daniel R Quast, Jakob Wefers, Juris J Meier

Abstract

Background: GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.).

Scope of review: To summarize current knowledge about GLP-1 receptor agonist.

Major conclusions: At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.

Keywords: Albiglutide; Body weight; Cardiovascular disease; Dulaglutide; Exenatide; Glucagon-like peptide-1 receptor agonists; Liraglutide; Lixisenatide; Semaglutide; Type 2 diabetes.

Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.

Figures

Figure 1
Figure 1
Arrows indicate the time from injection (or oral administration in the case of oral semaglutide) to peak plasma concentrations (Cmax) for GLP-1 RAs (Tmax). For references, please see [20]. Peak plasma concentrations may determine the time when nausea and vomiting are observed with GLP-1 RA treatment. The extremely slow absorption of once-weekly exenatide does not allow identification of a peak.
Figure 2
Figure 2
Recommendations issued in official package inserts regarding the necessity for slow up-titration of approved GLP-1 receptor agonists.
Figure 3
Figure 3
Optical appearance and properties of pen injection devices for approved GLP-1 receptor agonists (as mono substances or fixed-dose combinations with basal insulin). Modified from Nauck and Meier 2019 [20]. ∗Thorough shaking was necessary to evenly resuspend the active ingredient. The ease of use was estimated semi-quantitatively based on informal feedback from patients using these pen injection devices.
Figure 4
Figure 4
Comparison of approved GLP-1 RAs with respect to their effectiveness in reducing HbA1C (A), fasting plasma glucose (B), and body weight (C). A linear regression analysis relating reductions in fasting plasma glucose to reductions in HbA1c is shown in panel D. A comparison of the reported coefficients of variation for reducing HbA1c and body weight is displayed in panel E. All data are from clinical trials reporting head-to-head comparisons between various GLP-1 RAs (exenatide b.i.d. vs lixisenatide [36], exenatide b.i.d. vs liraglutide [37], lixisenatide vs liraglutide [38], exenatide once-weekly vs liraglutide [39], albiglutide vs liraglutide [40], dulaglutide vs liraglutide [41], subcutaneous semaglutide vs dulaglutide [42], and oral semaglutide vs liraglutide [43]) on a background of oral glucose-lowering agents. Data concerning the same GLP-1 RA were pooled using conventional equations to calculate common means and their standard deviations.
Figure 5
Figure 5
Meta-analysis comparing effects of short- and long-acting GLP-1 receptor agonists added to basal insulin in HbA1c (A), HbA1c target (≤7.0%) achievement (B), fasting plasma glucose (C), and body weight (D). For each variable, the results were significantly better for long-acting compounds (liraglutide, once-weekly exenatide, dulaglutide, and semaglutide based on 6 studies) compared to short-acting compounds (exenatide b.i.d. and lixisenatide based on 8 studies). Both studies with free and fixed-dose combinations were analyzed. Modified from [50].
Figure 6
Figure 6
Schematic diagram demonstrating how various methods of GLP-1 or GLP-1 RA administration into the general circulation can reach and influence brain areas involved in the regulation of energy intake and expenditure [72,73]. (A) Evidence also suggests that GLP-1 receptors in the hepatoportal region [75] (B) and on afferent parasympathetic nerve endings in the intestinal mucosa (C) [76] may generate central nervous system signals influencing insulin secretion and metabolism. Stimulatory signals (+) are shown in green, inhibitory (−) signals are depicted in red, and afferent parasympathetic (vagal) signals are denoted in blue. See the text for a more detailed explanation of the mechanisms.
Figure 7
Figure 7
Results of cardiovascular outcome studies comparing GLP-1 RAs with placebo on a background of standard of care. (A) Reduction in major adverse cardiovascular events (MACE: time to first event) in published individual clinical trials. (B) Results of a published meta-analysis [108] analyzing various cardiovascular endpoints across all of the clinical trials shown in panel A. MACE (a combination of either cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) was the primary endpoint in all studies. Meta-analysis results are supplemented with I2 and related p values indicating the heterogeneity of the analysis of individual endpoints (column of panels to the far right) as reported in [108].
Figure 8
Figure 8
Regression analysis of differences achieved in HbA1c concentrations between patients treated with placebo and active drug vs hazard ratios for major adverse cardiovascular outcomes (MACE; A), cardiovascular death (B), non-fatal stroke (C), non-fatal myocardial infarction (D), and hospitalization for heart failure (E) reported from cardiovascular outcome studies with GLP-1 receptor agonists (red), SGLT-2 inhibitors (blue), and DPP-4 inhibitors (green). Significant associations are shown for MACE (A) and non-fatal stroke (C) with similar slopes of the regression lines, while for cardiovascular death (B) and non-fatal myocardial infarction (D), a less prominent, non-significant correlation resulted from the analysis. Regarding hospitalization for heart failure (E), hazard ratios did not vary with HbA1c reduction. Analyzing GLP-1 receptor agonists only resulted in significant correlations for MACE and stroke as well as previously reported by Caruso et al. [119] but not for the other endpoints. Numbers in symbols identify the clinical trials: 1: SUSTAIN-6 (subcutaneous semaglutide) [100], 2: PIONEER-6 (oral semaglutide) [101], 3: REWIND (dulaglutide) [98], 4: LEADER (liraglutide) [96], 5: EXCSEL (once-weekly exenatide) [97], 6: ELIXA (lixisenatide) [95], 7: EMPA-REG Outcomes (empagliflozin) [120], 8: DECLARE-TIMI-58 (dapagliflozin) [121], 9: CANVAS program (canagliflozin) [122]; 10: VERTIS-CV (ertugliflozin, presented at the 80th scientific session of the American Diabetes Association); 11: EXAMINE (alogliptin) [123], 12 CARMELINA (linagliptin) [124], 13: SAVOR-TIMI-53 (saxagliptin) [125], and 14: TECOS (sitagliptin) [126].
Figure 9
Figure 9
Mechanisms driving the development of atherosclerotic lesions in patients with type 2 diabetes (A) and effects of GLP-1 RAs on the progression of atherogenesis and the development of its complications (B). See the text for further details on the mechanisms involved and references to the supporting literature. EC: endothelial cell, eNOS: endothelial nitrous oxide synthase, ICAM-1: intercellular adhesion molecule-1, IL: interleukin, KLF-2: Krüppel-like factor-2, LDL: low-density lipoprotein, MCP-1: monocyte chemoattractant protein-1, NO: nitrous oxide, oxLDL: oxidized low-density lipoprotein, ROS: reactive oxygen species, TNF-α: tumor necrosis factor, VCAM-1: vascular cell adhesion protein 1, VSMC: vascular smooth muscle cell.

References

    1. Holst J.J., Ørskov C., Vagn-Nielsen O., Schwartz T.W. Truncated glucagon-like peptide 1, an insulin-releasing hormone from the distal gut. FEBS Letters. 1987;211:169–174.
    1. Mojsov S., Weir G.C., Habener J.F. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. Journal of Clinical Investigation. 1987;79:616–619.
    1. Bell G.I., Sanchez-Pescador R., Laybourn P.J., Najarian R.C. Exon duplication and divergence in the human preproglucagon gene. Nature. 1983;304:368–371.
    1. Suzuki S., Kawai K., Ohashi S., Mukai H., Murayama Y., Yamashita K. Reduced insulinotropic effects of glucagonlike peptide 1-(7-36)-amide and gastric inhibitory polypeptide in isolated perfused diabetic rat pancreas. Diabetes. 1990;39:1320–1325.
    1. Nauck M.A., Heimesaat M.M., Ørskov C., Holst J.J., Ebert R., Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. Journal of Clinical Investigation. 1993;91:301–307.
    1. Nauck M.A., Weber I., Bach I., Richter S., Ørskov C., J.J. H. Normalization of fasting glycaemia by intravenous GLP-1 ([7-36 amide] or [7-37]) in Type 2-diabetic patients. Diabetic Medicine. 1998;15:937–945.
    1. Nauck M.A., Kleine N., Ørskov C., Holst J.J., Willms B., Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744.
    1. Deacon C.F., Nauck M.A., Toft-Nielsen M., Pridal L., Willms B., Host J.J. Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in type 2-diabetic patients and in healthy subjects. Diabetes. 1995;44:1126–1131.
    1. Deacon C.F., Pridal L., Klarskov L., Olesen M., Holst J.J. Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig. American Journal of Physiology. 1996;271:E 458–E 464.
    1. Nauck M.A., Heimesaat M.M., Behle K., Holst J.J., Nauck M.S., Ritzel R. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. Journal of Clinical Endocrinology & Metabolism. 2002;87:1239–1246.
    1. Wettergren A., Schjoldager B., Mortensen P.E., Myhre J., Christiansen J., Holst J.J. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Digestive Diseases and Sciences. 1993;38:665–673.
    1. Flint A., Raben A., Astrup A., Holst J.J. Glucagon-like peptide-1 promotes satiety and suppresses energy intake in humans. Journal of Clinical Investigation. 1998;101:515–520.
    1. Eng J., Kleinman W.A., Singh L., Singh G., Raufman J.P. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from Guinea pig pancreas. Journal of Biological Chemistry. 1992;267:7402–7405.
    1. Göke R., Fehmann H.C., Linn T., Schmidt H., Krause M., Eng J. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. Journal of Biological Chemistry. 1993;268:19650–19655.
    1. Nauck M.A., Meier J.J. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinology. 2016;4:525–536.
    1. Nauck M.A. The rollercoaster history of using physiological and pharmacological properties of incretin hormones to develop diabetes medications with a convincing benefit-risk relationship. Metabolism. 2020;103:154031.
    1. Kim D., MacConell L., Zhuang D., Kothare P.A., Trautmann M., Fineman M. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care. 2007;30:1487–1493.
    1. Drucker D.J., Buse J.B., Taylor K., Kendall D.M., Trautmann M., Zhuang D. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372:1240–1250.
    1. Davies M., Pieber T.R., Hartoft-Nielsen M.L., Hansen O.K.H., Jabbour S., Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. Journal of the American Medical Association. 2017;318:1460–1470.
    1. Nauck M.A., Meier J.J. Management of endocrine disease: are all GLP-1 agonists equal in the treatment of type 2 diabetes? European Journal of Endocrinology. 2019;181:R 211–R 234.
    1. Kolterman O.G., Kim D.D., Shen L., Ruggles J.A., Nielsen L.L., Fineman M.S. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. American Journal of Health-System Pharmacy. 2005;62:173–181.
    1. Becker R.H., Stechl J., Steinstraesser A., Golor G., Pellissier F. Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects. Diabetes Metabolism Research Reviews. 2015;31:610–618.
    1. Damholt B., Golor G., Wierich W., Pedersen P., Ekblom M., Zdravkovic M. An open-label, parallel group study investigating the effects of age and gender on the pharmacokinetics of the once-daily glucagon-like peptide-1 analogue liraglutide. The Journal of Clinical Pharmacology. 2006;46:635–641.
    1. Geiser J.S., Heathman M.A., Cui X., Martin J., Loghin C., Chien J.Y. Clinical pharmacokinetics of dulaglutide in patients with type 2 diabetes: analyses of data from clinical trials. Clinical Pharmacokinetics. 2016;55:625–634.
    1. Matthews J.E., Stewart M.W., De Boever E.H., Dobbins R.L., Hodge R.J., Walker S.E. Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. Journal of Clinical Endocrinology & Metabolism. 2008;93:4810–4817.
    1. Marbury T.C., Flint A., Jacobsen J.B., Derving Karsbol J., Lasseter K. Pharmacokinetics and tolerability of a single dose of semaglutide, a human glucagon-like peptide-1 analog, in subjects with and without renal impairment. Clinical Pharmacokinetics. 2017;56:1381–1390.
    1. Granhall C., Donsmark M., Blicher T.M., Golor G., Sondergaard F.L., Thomsen M. Safety and pharmacokinetics of single and multiple ascending doses of the novel oral human GLP-1 analogue, oral semaglutide, in healthy subjects and subjects with type 2 diabetes. Clinical Pharmacokinetics. 2019;58:781–791.
    1. Gough S.C., Jain R., Woo V.C. Insulin degludec/liraglutide (IDegLira) for the treatment of type 2 diabetes. Expert Review of Endocrinology and Metabolism. 2016;11:7–19.
    1. Davies M.J., Leiter L.A., Guerci B., Grunberger G., Ampudia-Blasco F.J., Yu C. Impact of baseline glycated haemoglobin, diabetes duration and body mass index on clinical outcomes in the LixiLan-O trial testing a titratable fixed-ratio combination of insulin glargine/lixisenatide (iGlarLixi) vs insulin glargine and lixisenatide monocomponents. Diabetes, Obesity and Metabolism. 2017;19:1798–1804.
    1. Overgaard R.V., Lindberg S.O., Thielke D. Impact on HbA1c and body weight of switching from other GLP-1 receptor agonists to semaglutide: a model-based approach. Diabetes, Obesity and Metabolism. 2019;21:43–51.
    1. Meier J.J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nature Reviews Endocrinology. 2012;8:728–742.
    1. Umapathysivam M.M., Lee M.Y., Jones K.L., Annink C.E., Cousins C.E., Trahair L.G. Comparative effects of prolonged and intermittent stimulation of the glucagon-like peptide 1 receptor on gastric emptying and glycemia. Diabetes. 2014;63:785–790.
    1. Meier J.J., Menge B.A., Schenker N., Erdmann S., Kahle-Stephan M., Schliess F. Effects of sequential treatment with lixisenatide, insulin glargine, or their combination on meal-related glycemic excursions, insulin and glucagon secretion, and gastric emptying in patients with type 2 diabetes. Diabetes, Obesity and Metabolism. 2020;22:599–611.
    1. Meier J.J., Rosenstock J., Hincelin-Mery A., Roy-Duval C., Delfolie A., Coester H.V. Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial. Diabetes Care. 2015;38:1263–1273.
    1. Huthmacher J.A., Meier J.J., Nauck M.A. Efficacy and safety of short- and long-acting glucagon-like peptide 1 receptor agonists on a background of basal insulin in type 2 diabetes: a meta-analysis. Diabetes Care. 2020;43:2303–2312.
    1. Rosenstock J., Raccah D., Koranyi L., Maffei L., Boka G., Miossec P. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X) Diabetes Care. 2013;36:2945–2951.
    1. Buse J.B., Rosenstock J., Sesti G., Schmidt W.E., Montanya E., Brett J.H. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6) Lancet. 2009;374:39–47.
    1. Nauck M., Rizzo M., Johnson A., Bosch-Traberg H., Madsen J., Cariou B. Once-daily liraglutide versus lixisenatide as add-on to metformin in type 2 diabetes: a 26-week randomized controlled clinical trial. Diabetes Care. 2016;39:1501–1509.
    1. Buse J.B., Nauck M., Forst T., Sheu W.H., Shenouda S.K., Heilmann C.R. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013;381:117–124.
    1. Pratley R.E., Nauck M.A., Barnett A.H., Feinglos M.N., Ovalle F., Harman-Boehm I. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinology. 2014;2:289–297.
    1. Dungan K.M., Povedano S.T., Forst T., Gonzalez J.G., Atisso C., Sealls W. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384:1349–1357.
    1. Pratley R.E., Aroda V.R., Lingvay I., Lüdemann J., Andreassen C., Navarria A. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinology. 2018;6:275–286.
    1. Pratley R., Amod A., Hoff S.T., Kadowaki T., Lingvay I., Nauck M. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019;394:39–50.
    1. Abd El Aziz M.S., Kahle M., Meier J.J., Nauck M.A. A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients. Diabetes, Obesity and Metabolism. 2017;19:216–227.
    1. Singh S., Wright E.E., Jr., Kwan A.Y., Thompson J.C., Syed I.A., Korol E.E. Glucagon-like peptide-1 receptor agonists compared with basal insulins for the treatment of type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes, Obesity and Metabolism. 2017;19:228–238.
    1. Buse J.B., Peters A., Russell-Jones D., Furber S., Donsmark M., Han J. Is insulin the most effective injectable antihyperglycemic therapy? Diabetes, Obesity and Metabolism. 2015;17:145–151.
    1. Davies M.J., D'Alessio D.A., Fradkin J., Kernan W.N., Mathieu C., Mingrone G. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American diabetes association (ADA) and the European association for the study of diabetes (EASD) Diabetologia. 2018;61:2461–2498.
    1. Aroda V.R., Bain S.C., Cariou B., Piletic M., Rose L., Axelsen M. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinology. 2017;5:355–366.
    1. Bettge K., Kahle M., Abd El Aziz M.S., Meier J.J., Nauck M.A. Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: a systematic analysis of published clinical trials. Diabetes, Obesity and Metabolism. 2017;19:336–347.
    1. Huthmacher J.A., Meier J.J., M.A. N. Efficacy and safety of short- and long-acting GLP-1 receptor agonists on a background of basal insulin in type 2 diabetes: a meta-analysis. Diabetes Care. 2020;43:2303–2312.
    1. Nauck M.A., Meier J.J. Pharmacotherapy: GLP-1 analogues and insulin: sound the wedding bells? Nature Reviews Endocrinology. 2011;7:193–195.
    1. Buse J.B., Bergenstal R.M., Glass L.C., Heilmann C.R., Lewis M.S., Kwan A.Y. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Annals of Internal Medicine. 2011;154:103–112.
    1. Ahmann A., Rodbard H.W., Rosenstock J., Lahtela J.T., de Loredo L., Tornoe K. Efficacy and safety of liraglutide versus placebo added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes: a randomized, placebo-controlled trial. Diabetes, Obesity and Metabolism. 2015;17:1056–1064.
    1. Pozzilli P., Norwood P., Jodar E., Davies M.J., Ivanyi T., Jiang H. Placebo-controlled, randomized trial of the addition of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide to titrated daily insulin glargine in patients with type 2 diabetes (AWARD-9) Diabetes, Obesity and Metabolism. 2017;19:1024–1031.
    1. Leiter L.A., Gross J.L., Chow F., Miller D., Johnson S., Ahren B. Once weekly glucagon-like peptide-1 receptor agonist albiglutide vs. prandial insulin added to basal insulin in patients with type 2 diabetes mellitus: results over 52 weeks. Journal of Diabetic Complications. 2017;31:1283–1285.
    1. Rodbard H.W., Lingvay I., Reed J., de la Rosa R., Rose L., Sugimoto D. Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomized, controlled trial. Journal of Clinical Endocrinology & Metabolism. 2018;103:2291–2301.
    1. Zinman B., Aroda V.R., Buse J.B., Cariou B., Harris S.B., Hoff S.T. Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial. Diabetes Care. 2019;42:2262–2271.
    1. Diamant M., Nauck M.A., Shaginian R., Malone J.K., Cleall S., Reaney M. Glucagon-like Peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care. 2014;37:2763–2773.
    1. Gough S.C., Bode B., Woo V., Rodbard H.W., Linjawi S., Poulsen P. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinology. 2014;2:885–893.
    1. Frias J., Puig Domingo M., Meneghini L., Napoli R., Liu M., Soltes Rak E. More patients reach glycemic control with a fixed-ratio combination of insulin glargine and lixisenatide (iGlarLixi) than with basal insulin at 12 weeks of treatment: a post hoc time-to-control analysis of LixiLan-O and LixiLan-L. Diabetes, Obesity and Metabolism. 2018;20:2314–2318.
    1. Tabak A.G., Anderson J., Aschner P., Liu M., Saremi A., Stella P. Efficacy and safety of iGlarLixi, fixed-ratio combination of insulin glargine and lixisenatide, compared with basal-bolus regimen in patients with type 2 diabetes: propensity score matched analysis. Diabetes Therapeutics. 2020;11:305–318.
    1. Turton M.D., D O.S., Gunn I., Beak S.A., Edwards C.M., Meeran K. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996;379:69–72.
    1. Drucker D.J., Nauck M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–1705.
    1. Astrup A., Rossner S., Van Gaal L., Rissanen A., Niskanen L., Al Hakim M. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606–1616.
    1. Pi-Sunyer X., Astrup A., Fujioka K., Greenway F., Halpern A., Krempf M. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine. 2015;373:11–22.
    1. Blundell J., Finlayson G., Axelsen M., Flint A., Gibbons C., Kvist T. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes, Obesity and Metabolism. 2017;19:1242–1251.
    1. Kushner R.F., Calanna S., Davies M., Dicker D., Garvey W.T., Goldman B. Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP Trials 1 to 5. Obesity (Silver Spring) 2020;28:1050–1061.
    1. O'Neil P.M., Birkenfeld A.L., McGowan B., Mosenzon O., Pedersen S.D., Wharton S. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018;392:637–649.
    1. Nauck M., Marre M. Adding liraglutide to oral antidiabetic drug monotherapy: efficacy and weight benefits. Postgraduate Medical Journal. 2009;121:5–15.
    1. Davies M.J., Bergenstal R., Bode B., Kushner R.F., Lewin A., Skjoth T.V. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. Journal of the American Medical Association. 2015;314:687–699.
    1. Frias J.P., Bonora E., Nevarez Ruiz L.A., Li G., You Z., Milicevic Z. Efficacy and safety of dulaglutide 3 mg and 4.5 mg vs. dulaglutide 1.5 mg: 52-week results from AWARD-11 (abstract 357-OR) Diabetes. 2020;69(Suppl. 1)
    1. Secher A., Jelsing J., Baquero A.F., Hecksher-Sorensen J., Cowley M.A., Dalboge L.S. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. Journal of Clinical Investigation. 2014;124:4473–4488.
    1. Gabery S., Salinas C.G., Paulsen S.J., Ahnfelt-Ronne J., Alanentalo T., Baquero A.F. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight. 2020;5 epub Mar 26, 2020.
    1. Campos C.A., Bowen A.J., Schwartz M.W., Palmiter R.D. Parabrachial CGRP neurons control meal termination. Cell Metabolism. 2016;23:811–820.
    1. Nishizawa M., Nakabayashi H., Uehara K., Nakagawa A., Uchida K., Koya D. Intraportal GLP-1 stimulates insulin secretion predominantly through the hepatoportal-pancreatic vagal reflex pathways. American Journal of Physiology. 2013;305:E 376–E 387.
    1. Hansen L., Deacon C.F., Ørskov C., Holst J.J. Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology. 1999;140:5356–5363.
    1. Di Marzo V., Ligresti A., Cristino L. The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation. International Journal of Obesity (Lond) 2009;33(Suppl 2):S18–S24.
    1. Kadouh H., Chedid V., Halawi H., Burton D.D., Clark M.M., Khemani D. GLP-1 analog modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity. Journal of Clinical Endocrinology & Metabolism. 2020;105
    1. Leibel R.L., Rosenbaum M., Hirsch J. Changes in energy expenditure resulting from altered body weight. New England Journal of Medicine. 1995;332:621–628.
    1. van Bloemendaal L., Veltman D.J., Ten Kulve J.S., Groot P.F., Ruhe H.G., Barkhof F. Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans. Diabetes, Obesity and Metabolism. 2015;17:878–886.
    1. Daniele G., Iozzo P., Molina-Carrion M., Lancaster J., Ciociaro D., Cersosimo E. Exenatide regulates cerebral glucose metabolism in brain areas associated with glucose homeostasis and reward system. Diabetes. 2015;64:3406–3412.
    1. Dickson S.L., Shirazi R.H., Hansson C., Bergquist F., Nissbrandt H., Skibicka K.P. The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors. Journal of Neuroscience. 2012;32:4812–4820.
    1. Richard J.E., Anderberg R.H., Goteson A., Gribble F.M., Reimann F., Skibicka K.P. Activation of the GLP-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system. PloS One. 2015;10
    1. van Bloemendaal L., Rg I.J., Ten Kulve J.S., Barkhof F., Konrad R.J., Drent M.L. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes. 2014;63:4186–4196.
    1. Frias J.P., Wynne A.G., Matyjaszek-Matuszek B., Bartaskova D., Cox D.A., Woodward B. Efficacy and safety of an expanded dulaglutide dose range: a phase 2, placebo-controlled trial in patients with type 2 diabetes using metformin. Diabetes, Obesity and Metabolism. 2019;21:2048–2057.
    1. le Roux C.W., Astrup A., Fujioka K., Greenway F., Lau D.C.W., Van Gaal L. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017;389:1399–1409.
    1. Kelly A.S., Auerbach P., Barrientos-Perez M., Gies I., Hale P.M., Marcus C. A randomized, controlled trial of liraglutide for adolescents with obesity. New England Journal of Medicine. 2020;382:2117–2128.
    1. Diamant M., Van Gaal L., Stranks S., Northrup J., Cao D., Taylor K. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet. 2010;375:2234–2243.
    1. Schlogl H., Kabisch S., Horstmann A., Lohmann G., Muller K., Lepsien J. Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity. Diabetes Care. 2013;36:1933–1940.
    1. de Boer S.A., Lefrandt J.D., Petersen J.F., Boersma H.H., Mulder D.J., Hoogenberg K. The effects of GLP-1 analogues in obese, insulin-using type 2 diabetes in relation to eating behaviour. International Journal of Clinical Pharmacy. 2016;38:144–151.
    1. Jorgensen P.G., Jensen M.T., Mensberg P., Storgaard H., Nyby S., Jensen J.S. Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: a randomized double-blind placebo-controlled clinical trial. Diabetes, Obesity and Metabolism. 2017;19:1040–1044.
    1. Wadden T.A., Tronieri J.S., Sugimoto D., Lund M.T., Auerbach P., Jensen C. Liraglutide 3.0 mg and intensive behavioral therapy (IBT) for obesity in primary care: the SCALE IBT randomized controlled trial. Obesity (Silver Spring) 2020;28:529–536.
    1. Pieber T.R., Bode B., Mertens A., Cho Y.M., Christiansen E., Hertz C.L. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinology. 2019;7:528–539.
    1. Miyagawa J., Odawara M., Takamura T., Iwamoto N., Takita Y., Imaoka T. Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide is non-inferior to once-daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26-week randomized phase III study. Diabetes, Obesity and Metabolism. 2015;17:974–983.
    1. Pfeffer M.A., Claggett B., Diaz R., Dickstein K., Gerstein H.C., Kober L.V. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. New England Journal of Medicine. 2015;373:2247–2257.
    1. Marso S.P., Daniels G.H., Brown-Frandsen K., Kristensen P., Mann J.F., Nauck M.A. Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2016;375:311–322.
    1. Holman R.R., Bethel M.A., Mentz R.J., Thompson V.P., Lokhnygina Y., Buse J.B. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2017;377:1228–1239.
    1. Gerstein H.C., Colhoun H.M., Dagenais G.R., Diaz R., Lakshmanan M., Pais P. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394:121–130.
    1. Hernandez A.F., Green J.B., Janmohamed S., D'Agostino R.B., Sr., Granger C.B., Jones N.P. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392:1519–1529.
    1. Marso S.P., Bain S.C., Consoli A., Eliaschewitz F.G., Jodar E., Leiter L.A. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine. 2016;375:1834–1844.
    1. Husain M., Birkenfeld A.L., Donsmark M., Dungan K., Eliaschewitz F.G., Franco D.R. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine. 2019;381:841–851.
    1. Butler P.C., Elashoff M., Elashoff R., Gale E.A. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care. 2013;36:2118–2125.
    1. Nauck M.A., Friedrich N. Do GLP-1-based therapies increase cancer risk? Diabetes Care. 2013;36(Suppl. 2):S 245–S 252.
    1. Abd El Aziz M., Cahyadi O., Meier J.J., Schmidt W.E., Nauck M.A. Incretin-based glucose-lowering medications and the risk of acute pancreatitis and malignancies: a meta-analysis based on cardiovascular outcomes trials. Diabetes, Obesity and Metabolism. 2019;22:699–704.
    1. Steinberg W.M., Buse J.B., Ghorbani M.L.M., Orsted D.D., Nauck M.A., Committee L.S. Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treated with liraglutide: results from the LEADER randomized trial. Diabetes Care. 2017;40:966–972.
    1. Nauck M.A., Frossard J.L., Barkin J.S., Anglin G., Hensley I.E., Harper K.D. Assessment of pancreas safety in the development program of once-weekly GLP-1 receptor agonist dulaglutide. Diabetes Care. 2017;40:647–654.
    1. Bjerre Knudsen L., Madsen L.W., Andersen S., Almholt K., de Boer A.S., Drucker D.J. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151:1473–1486.
    1. Kristensen S.L., Rorth R., Jhund P.S., Docherty K.F., Sattar N., Preiss D. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinology. 2019;7(10):776–785.
    1. Caruso I., Cignarelli A., Giorgino F. Heterogeneity and similarities in GLP-1 receptor agonist cardiovascular outcomes trials. Trends in Endocrinology and Metabolism. 2019;30:578–589.
    1. Zelniker T.A., Wiviott S.D., Raz I., Im K., Goodrich E.L., Bonaca M.P. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393:31–39.
    1. Zelniker T.A., Wiviott S.D., Raz I., Im K., Goodrich E.L., Furtado R.H.M. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019;139:2022–2031.
    1. Jorsal A., Kistorp C., Holmager P., Tougaard R.S., Nielsen R., Hanselmann A. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a multicentre, double-blind, randomised, placebo-controlled trial. European Journal of Heart Failure. 2017;19:69–77.
    1. Margulies K.B., Hernandez A.F., Redfield M.M., Givertz M.M., Oliveira G.H., Cole R. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. Journal of the American Medical Association. 2016;316:500–508.
    1. Marsico F., Paolillo S., Gargiulo P., Bruzzese D., Dell'Aversana S., Esposito I. Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials. European Heart Journal. 2020
    1. Nauck M.A., Meier J.J., Cavender M.A., Abd El Aziz M., Drucker D.J. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation. 2017;136:849–870.
    1. Buse J.B., Bain S.C., Mann J.F.E., Nauck M.A., Nissen S.E., Pocock S. Cardiovascular risk reduction with liraglutide: an exploratory mediation analysis of the LEADER trial. Diabetes Care. 2020;43:1546–1552.
    1. Colhoun H.M., Hasnour C., Riddle M.C., Brancj K., M K., Atisso C. Exploring potential mediators of the cardiovascular benefit of dulaglutide in REWIND (abstract 924-P) Diabetes. 2020;69(Suppl. 1)
    1. Ray K.K., Seshasai S.R., Wijesuriya S., Sivakumaran R., Nethercott S., Preiss D. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009;373:1765–1772.
    1. Caruso I., Cignarelli A., Natalicchio A., Perrini S., Laviola L., Giorgino F. Commentary: glucose control: not just a bystander in GLP-1RA-mediated cardiovascular protection. Metabolism. 2020;109:154272.
    1. Zinman B., Wanner C., Lachin J.M., Fitchett D., Bluhmki E., Hantel S. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine. 2015;373:2117–2128.
    1. Wiviott S.D., Raz I., Bonaca M.P., Mosenzon O., Kato E.T., Cahn A. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2019;380:347–357.
    1. Neal B., Perkovic V., Mahaffey K.W., de Zeeuw D., Fulcher G., Erondu N. Canagliflozin and cardiovascular and renal events in type 2 diabetes. New England Journal of Medicine. 2017;377:644–657.
    1. White W.B., Cannon C.P., Heller S.R., Nissen S.E., Bergenstal R.M., Bakris G.L. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. New England Journal of Medicine. 2013;369:1327–1335.
    1. Rosenstock J., Perkovic V., Johansen O.E., Cooper M.E., Kahn S.E., Marx N. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. Journal of the American Medical Association. 2019;321:69–79.
    1. Scirica B.M., Bhatt D.L., Braunwald E., Steg P.G., Davidson J., Hirshberg B. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. New England Journal of Medicine. 2013;369:1317–1326.
    1. Green J.B., Bethel M.A., Armstrong P.W., Buse J.B., Engel S.S., Garg J. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2015;373:232–242.
    1. Spartalis M., Spartalis E., Athanasiou A., Paschou S.A., Kontogiannis C., Georgiopoulos G. The role of the endothelium in premature atherosclerosis: molecular mechanisms. Current Medicinal Chemistry. 2020;27:1041–1051.
    1. Ku H.C., Chen W.P., Su M.J. DPP4 deficiency exerts protective effect against H2O2 induced oxidative stress in isolated cardiomyocytes. PloS One. 2013;8
    1. Alharby H., Abdelati T., Rizk M., Youssef E., Gaber N., Moghazy K. Association of fasting glucagon-like peptide-1 with oxidative stress and subclinical atherosclerosis in type 2 diabetes. Diabetes, Metabolic Syndrome. 2019;13:1077–1080.
    1. Barale C., Buracco S., Cavalot F., Frascaroli C., Guerrasio A., Russo I. Glucagon-like peptide 1-related peptides increase nitric oxide effects to reduce platelet activation. Thrombosis & Haemostasis. 2017;117:1115–1128.
    1. Tang S.T., Zhang Q., Tang H.Q., Wang C.J., Su H., Zhou Q. Effects of glucagon-like peptide-1 on advanced glycation endproduct-induced aortic endothelial dysfunction in streptozotocin-induced diabetic rats: possible roles of Rho kinase- and AMP kinase-mediated nuclear factor kappaB signaling pathways. Endocrine. 2016;53:107–116.
    1. Wu Y.C., Wang W.T., Lee S.S., Kuo Y.R., Wang Y.C., Yen S.J. Glucagon-like peptide-1 receptor agonist attenuates autophagy to ameliorate pulmonary arterial hypertension through Drp1/NOX- and Atg-5/Atg-7/Beclin-1/LC3beta pathways. International Journal of Molecular Sciences. 2019;20 epub 25 July 2019.
    1. Helmstädter J., Frenis K., Filippou K., Grill A., Dib M., Kalinovic S. Endothelial GLP-1 (glucagon-like peptide-1) receptor mediates cardiovascular protection by liraglutide in mice with experimental arterial hypertension. Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:145–158.
    1. Dai Y., Mercanti F., Dai D., Wang X., Ding Z., Pothineni N.V. LOX-1, a bridge between GLP-1R and mitochondrial ROS generation in human vascular smooth muscle cells. Biochemical and Biophysical Research Communications. 2013;437:62–66.
    1. Shiraki A., Oyama J., Komoda H., Asaka M., Komatsu A., Sakuma M. The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis. 2012;221:375–382.
    1. Cai X., She M., Xu M., Chen H., Li J., Chen X. GLP-1 treatment protects endothelial cells from oxidative stress-induced autophagy and endothelial dysfunction. International Journal of Biological Sciences. 2018;14:1696–1708.
    1. Li Q., Tuo X., Li B., Deng Z., Qiu Y., Xie H. Semaglutide attenuates excessive exercise-induced myocardial injury through inhibiting oxidative stress and inflammation in rats. Life Sciences. 2020;250:117531.
    1. Dorecka M., Siemianowicz K., Francuz T., Garczorz W., Chyra A., Klych A. Exendin-4 and GLP-1 decreases induced expression of ICAM-1, VCAM-1 and RAGE in human retinal pigment epithelial cells. Pharmacological Reports. 2013;65:884–890.
    1. Erdogdu Ö., Nathanson D., Sjöholm Å., Nyström T., Zhang Q. Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Molecular and Cellular Endocrinology. 2010;325:26–35.
    1. Wei R., Ma S., Wang C., Ke K., Yang J., Li W. Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner. American Journal of Physiology. 2016;310:E 947–E 957.
    1. Chang W., Zhu F., Zheng H., Zhou Z., Miao P., Zhao L. Glucagon-like peptide-1 receptor agonist dulaglutide prevents ox-LDL-induced adhesion of monocytes to human endothelial cells: an implication in the treatment of atherosclerosis. Molecular Immunology. 2019;116:73–79.
    1. Dai Y., Mehta J.L., Chen M. Glucagon-like peptide-1 receptor agonist liraglutide inhibits endothelin-1 in endothelial cell by repressing nuclear Factor-kappa B activation. Cardiovascular Drugs and Therapy. 2013;27:371–380.
    1. Arakawa M., Mita T., Azuma K., Ebato C., Goto H., Nomiyama T. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010;59:1030–1037.
    1. Ding L., Zhang J. Glucagon-like peptide-1 activates endothelial nitric oxide synthase in human umbilical vein endothelial cells. Acta Pharmacologica Sinica. 2012;33:75–81.
    1. Dai Y., Mehta J.L., Chen M. Glucagon-like peptide-1 receptor agonist liraglutide inhibits endothelin-1 in endothelial cell by repressing nuclear factor-kappa B activation. Cardiovascular Drugs and Therapy. 2013;27(5):371–380.
    1. Vinué Á., Navarro J., Herrero-Cervera A., García-Cubas M., Andrés-Blasco I., Martínez-Hervás S. The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype. Diabetologia. 2017;60:1801–1812.
    1. Bruen R., Curley S., Kajani S., Lynch G., O'Reilly M.E., Dillon E.T. Liraglutide attenuates preestablished atherosclerosis in apolipoprotein E-deficient mice via regulation of immune cell phenotypes and proinflammatory mediators. Journal of Pharmacology and Experimental Therapeutics. 2019;370:447–458.
    1. Hirano T., Mori Y. Anti-atherogenic and anti-inflammatory properties of glucagon-like peptide-1, glucose-dependent insulinotropic polypepide, and dipeptidyl peptidase-4 inhibitors in experimental animals. Journal of Diabetes Investigations. 2016;7(Suppl. 1):80–86.
    1. Nagashima M., Watanabe T., Terasaki M., Tomoyasu M., Nohtomi K., Kim-Kaneyama J. Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice. Diabetologia. 2011;54:2649–2659.
    1. Tashiro Y., Sato K., Watanabe T., Nohtomi K., Terasaki M., Nagashima M. A glucagon-like peptide-1 analog liraglutide suppresses macrophage foam cell formation and atherosclerosis. Peptides. 2014;54:19–26.
    1. Zhan Y., Sun H.L., Chen H., Zhang H., Sun J., Zhang Z. Glucagon-like peptide-1 (GLP-1) protects vascular endothelial cells against advanced glycation end products (AGEs)-induced apoptosis. Medical Science Monitor. 2012;18:BR 286–BR 291.
    1. Yang X., Feng P., Zhang X., Li D., Wang R., Ji C. The diabetes drug semaglutide reduces infarct size, inflammation, and apoptosis, and normalizes neurogenesis in a rat model of stroke. Neuropharmacology. 2019;158:107748.
    1. Burgmaier M., Liberman A., Möllmann J., Kahles F., Reith S., Lebherz C. Glucagon-like peptide-1 (GLP-1) and its split products GLP-1(9-37) and GLP-1(28-37) stabilize atherosclerotic lesions in apoe⁻/⁻ mice. Atherosclerosis. 2013;231:427–435.
    1. Sudo M., Li Y., Hiro T., Takayama T., Mitsumata M., Shiomi M. Inhibition of plaque progression and promotion of plaque stability by glucagon-like peptide-1 receptor agonist: serial in vivo findings from iMap-IVUS in Watanabe heritable hyperlipidemic rabbits. Atherosclerosis. 2017;265:283–291.
    1. Hirata Y., Kurobe H., Nishio C., Tanaka K., Fukuda D., Uematsu E. Exendin-4, a glucagon-like peptide-1 receptor agonist, attenuates neointimal hyperplasia after vascular injury. European Journal of Pharmacology. 2013;699:106–111.
    1. Jojima T., Uchida K., Akimoto K., Tomotsune T., Yanagi K., Iijima T. Liraglutide, a GLP-1 receptor agonist, inhibits vascular smooth muscle cell proliferation by enhancing AMP-activated protein kinase and cell cycle regulation, and delays atherosclerosis in ApoE deficient mice. Atherosclerosis. 2017;261:44–51.
    1. Rizzo M., Rizvi A.A., Patti A.M., Nikolic D., Giglio R.V., Castellino G. Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study. Cardiovascular Diabetology. 2016;15:162.
    1. Tang S.T., Tang H.Q., Su H., Wang Y., Zhou Q., Zhang Q. Glucagon-like peptide-1 attenuates endothelial barrier injury in diabetes via cAMP/PKA mediated down-regulation of MLC phosphorylation. Biomedicine & Pharmacotherapy. 2019;113:108667.
    1. Krasner N.M., Ido Y., Ruderman N.B., Cacicedo J.M. Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PloS One. 2014;9
    1. Rakipovski G., Rolin B., Nohr J., Klewe I., Frederiksen K.S., Augustin R. The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE(-/-) and LDLr(-/-) mice by a mechanism that includes inflammatory pathways. JACC Basic Translational Science. 2018;3:844–857.
    1. Garczorz W., Gallego-Colon E., Kosowska A., Kłych-Ratuszny A., Woźniak M., Marcol W. Exenatide exhibits anti-inflammatory properties and modulates endothelial response to tumor necrosis factor α-mediated activation. Cardiovascular Therapeutics. 2018;36(2)
    1. Anholm C., Kumarathurai P., Pedersen L.R., Samkani A., Walzem R.L., Nielsen O.W. Liraglutide in combination with metformin may improve the atherogenic lipid profile and decrease C-reactive protein level in statin treated obese patients with coronary artery disease and newly diagnosed type 2 diabetes: a randomized trial. Atherosclerosis. 2019;288:60–66.
    1. Balestrieri M.L., Rizzo M.R., Barbieri M., Paolisso P., D'Onofrio N., Giovane A. Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of incretin treatment. Diabetes. 2015;64:1395–1406.
    1. Mann J.F.E., Orsted D.D., Brown-Frandsen K., Marso S.P., Poulter N.R., Rasmussen S. Liraglutide and renal outcomes in type 2 diabetes. New England Journal of Medicine. 2017;377:839–848.
    1. Gerstein H.C., Colhoun H.M., Dagenais G.R., Diaz R., Lakshmanan M., Pais P. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 2019;394:131–138.
    1. Tuttle K.R., Lakshmanan M.C., Rayner B., Busch R.S., Zimmermann A.G., Woodward D.B. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinology. 2018;6:605–617.
    1. Perkovic V., Jardine M.J., Neal B., Bompoint S., Heerspink H.J.L., Charytan D.M. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. New England Journal of Medicine. 2019;380:2295–2306.
    1. Giorgino F., Penfornis A., Pechtner V., Gentilella R., Corcos A. Adherence to antihyperglycemic medications and glucagon-like peptide 1-receptor agonists in type 2 diabetes: clinical consequences and strategies for improvement. Patient Preference and Adherence. 2018;12:707–719.
    1. Carls G.S., Tuttle E., Tan R.D., Huynh J., Yee J., Edelman S.V. Understanding the gap between efficacy in randomized controlled trials and effectiveness in real-world use of GLP-1 RA and DPP-4 therapies in patients with type 2 diabetes. Diabetes Care. 2017;40:1469–1478.
    1. Alatorre C., Fernandez Lando L., Yu M., Brown K., Montejano L., Juneau P. Treatment patterns in patients with type 2 diabetes mellitus treated with glucagon-like peptide-1 receptor agonists: higher adherence and persistence with dulaglutide compared with once-weekly exenatide and liraglutide. Diabetes, Obesity and Metabolism. 2017;19:953–961.
    1. Qiao Q., Ouwens M.J., Grandy S., Johnsson K., Kostev K. Adherence to GLP-1 receptor agonist therapy administered by once-daily or once-weekly injection in patients with type 2 diabetes in Germany. Diabetes Metabolism Syndrome Obesity. 2016;9:201–205.
    1. Nguyen H., Dufour R., Caldwell-Tarr A. Glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy adherence for patients with type 2 diabetes in a Medicare population. Advances in Therapy. 2017;34:658–673.
    1. Mody R., Yu M., Nepal B., Konig M., Grabner M. Adherence and persistence among patients with type 2 diabetes initiating dulaglutide compared with semaglutide and exenatide BCise: 6-month follow-up from US real-world data. Diabetes, Obesity and Metabolism. 2020
    1. McGovern A., Tippu Z., Hinton W., Munro N., Whyte M., de Lusignan S. Comparison of medication adherence and persistence in type 2 diabetes: a systematic review and meta-analysis. Diabetes, Obesity and Metabolism. 2018;20:1040–1043.
    1. Jones S.C., Ryan D.L., Pratt V.S., Niak A., Brinker A.D. Injection-site nodules associated with the use of exenatide extended-release reported to the U.S. Food and drug administration adverse event reporting system. Diabetes Spectrum. 2015;28:283–288.
    1. Turner R.C., Cull C.A., Frighi V., Holman R.R. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) group. Journal of the American Medical Association. 1999;281:2005–2012.
    1. Brubaker P.L., Drucker D.J. Minireview: glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology. 2004;145:2653–2659.
    1. Tschen S.I., Dhawan S., Gurlo T., Bhushan A. Age-dependent decline in beta-cell proliferation restricts the capacity of beta-cell regeneration in mice. Diabetes. 2009;58:1312–1320.
    1. Meier J.J., Butler A.E., Saisho Y., Monchamp T., Galasso R., Bhushan A. Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes. 2008;57:1584–1594.
    1. Buse J.B., Wexler D.J., Tsapas A., Rossing P., Mingrone G., Mathieu C. 2019 update to: management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American diabetes association (ADA) and the European association for the study of diabetes (EASD) Diabetes Care. 2020;43:487–493.
    1. Cosentino F., Grant P.J., Aboyans V., Bailey C.J., Ceriello A., Delgado V. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. European Heart Journal. 2020;41:255–323.
    1. Laux G., Berger S., Szecsenyi J., Kaufmann-Kolle P., Leutgeb R. Prescribing differences in family practice for diabetic patients in Germany according to statutory or private health insurance: the case of DPP-4-inhibitors and GLP-1-agonists. BMC Family Practice. 2016;17:146.
    1. Hong D., Si L., Jiang M., Shao H., Ming W.K., Zhao Y. Cost effectiveness of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors: a systematic review. PharmacoEconomics. 2019;37:777–818.
    1. Kruger D.F., LaRue S., Estepa P. Recognition of and steps to mitigate anxiety and fear of pain in injectable diabetes treatment. Diabetes Metabolism Syndrome Obesity. 2015;8:49–56.
    1. Aroda V.R., Ratner R. The safety and tolerability of GLP-1 receptor agonists in the treatment of type 2 diabetes: a review. Diabetes Metabolism Research Reviews. 2011;27:528–542.
    1. Tibaduiza E.C., Chen C., Beinborn M. A small molecule ligand of the glucagon-like peptide 1 receptor targets its amino-terminal hormone binding domain. Journal of Biological Chemistry. 2001;276:37787–37793.
    1. Teng M., Johnson M.D., Thomas C., Kiel D., Lakis J.N., Kercher T. Small molecule ago-allosteric modulators of the human glucagon-like peptide-1 (hGLP-1) receptor. Bioorganic & Medicinal Chemistry Letters. 2007;17:5472–5478.
    1. Sloop K.W., Willard F.S., Brenner M.B., Ficorilli J., Valasek K., Showalter A.D. Novel small molecule glucagon-like peptide-1 receptor agonist stimulates insulin secretion in rodents and from human islets. Diabetes. 2010;59:3099–3107.
    1. Fan H., Gong N., Li T.F., Ma A.N., Wu X.Y., Wang M.W. The non-peptide GLP-1 receptor agonist WB4-24 blocks inflammatory nociception by stimulating beta-endorphin release from spinal microglia. British Journal of Pharmacology. 2015;172:64–79.
    1. Kielgast U., Holst J.J., Madsbad S. Antidiabetic actions of endogenous and exogenous GLP-1 in type 1 diabetic patients with and without residual beta-cell function. Diabetes. 2011;60:1599–1607.
    1. Creutzfeldt W.O., Kleine N., Willms B., Ørskov C., Holst J.J., Nauck M.A. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients. Diabetes Care. 1996;19:580–586.
    1. Dupré J., Behme M.T., Hramiak M., McFarlane P., Williamson M.P., Zabel P. Glucagon-like peptide 1 reduces postprandial glycemic excursions in IDDM. Diabetes. 1995;44:626–630.
    1. Dupré J., Behme M.T., McDonald T.J. Exendin-4 normalized postcibal glycemic excursions in type 1 diabetes. Journal of Clinical Endocrinology & Metabolism. 2004;89:3469–3473.
    1. Dejgaard T.F., Knop F.K., Tarnow L., Frandsen C.S., Hansen T.S., Almdal T. Efficacy and safety of the glucagon-like peptide-1 receptor agonist liraglutide added to insulin therapy in poorly regulated patients with type 1 diabetes-a protocol for a randomised, double-blind, placebo-controlled study: the Lira-1 study. BMJ Open. 2015;5
    1. Dejgaard T.F., Frandsen C.S., Hansen T.S., Almdal T., Urhammer S., Pedersen-Bjergaard U. Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycemic control (Lira-1): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinology. 2016;4:221–232.
    1. Dejgaard T.F., Schmidt S., Frandsen C.S., Vistisen D., Madsbad S., Andersen H.U. Liraglutide reduces hyperglycaemia and body weight in overweight, dysregulated insulin-pump-treated patients with type 1 diabetes: the Lira Pump trial-a randomized, double-blinded, placebo-controlled trial. Diabetes, Obesity and Metabolism. 2020;22:492–500.
    1. Johansen N.J., Dejgaard T.F., Lund A., Schluntz C., Frandsen C.S., Forman J.L. Efficacy and safety of meal-time administration of short-acting exenatide for glycemic control in type 1 diabetes (MAG1C): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinology. 2020;8:313–324.
    1. Ahlqvist E., Storm P., Karajamaki A., Martinell M., Dorkhan M., Carlsson A. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinology. 2018;6:361–369.
    1. Dennis J.M., Shields B.M., Henley W.E., Jones A.G., Hattersley A.T. Disease progression and treatment response in data-driven subgroups of type 2 diabetes compared with models based on simple clinical features: an analysis using clinical trial data. Lancet Diabetes Endocrinology. 2019;7:442–451.
    1. Zaharia O.P., Strassburger K., Strom A., Bonhof G.J., Karusheva Y., Antoniou S. Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study. Lancet Diabetes Endocrinology. 2019;7:684–694.
    1. Giorgino F., Caruso I., Moellmann J., Lehrke M. Differential indication for SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with established atherosclerotic heart disease or at risk for congestive heart failure. Metabolism. 2020;104:154045.
    1. Frias J., Guja C., hardy E., Ahmed A., Dong F., Öhmann P. Combination of exenatide once weekly and dapagliflozin once daily versus exenatide and dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a phase 3, 28-week, double-blind, randomised controlled study. Lancet Diabetes Endocrinology. 2016
    1. Jabbour S.A., Frias J.P., Hardy E., Ahmed A., Wang H., Ohman P. Safety and efficacy of exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy: 52-week results of the DURATION-8 randomized controlled trial. Diabetes Care. 2018;41:2136–2146.
    1. Terauchi Y., Utsunomiya K., Yasui A., Seki T., Cheng G., Shiki K. Safety and efficacy of empagliflozin as add-on therapy to GLP-1 receptor agonist (liraglutide) in Japanese patients with type 2 diabetes mellitus: a randomised, double-blind, parallel-group phase 4 study. Diabetes Therapeutics. 2019;10:951–963.
    1. Ali A.M., Martinez R., Al-Jobori H., Adams J., Triplitt C., DeFronzo R. Combination therapy with canagliflozin plus liraglutide exerts additive effect on weight loss, but not on HbA1c, in patients with type 2 diabetes. Diabetes Care. 2020;43:1234–1241.
    1. Ludvik B., Frias J.P., Tinahones F.J., Wainstein J., Jiang H., Robertson K.E. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinology. 2018;6:370–381.
    1. Frias J.P., Guja C., Hardy E., Ahmed A., Dong F., Ohman P. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinology. 2016;4:1004–1016.
    1. Jabbour S.A., Frias J.P., Guja C., Hardy E., Ahmed A., Ohman P. Effects of exenatide once weekly plus dapagliflozin, exenatide once weekly, or dapagliflozin, added to metformin monotherapy, on body weight, systolic blood pressure, and triglycerides in patients with type 2 diabetes in the DURATION-8 study. Diabetes, Obesity and Metabolism. 2018;20(6):1515–1519.
    1. Castellana M., Cignarelli A., Brescia F., Perrini S., Natalicchio A., Laviola L. Efficacy and safety of GLP-1 receptor agonists as add-on to SGLT2 inhibitors in type 2 diabetes mellitus: a meta-analysis. Scientific Reports. 2019;9:19351.
    1. Frias J.P., Nauck M.A., Van J., Kutner M.E., Cui X., Benson C. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet. 2018;392:2180–2193.
    1. Baggio L.L., Drucker D.J. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Molecular Metabolism. 2020 doi: 10.1016/j.molmet.2020.101090.
    1. Sathananthan A., Man C.D., Micheletto F., Zinsmeister A.R., Camilleri M., Giesler P.D. Common genetic variation in GLP1R and insulin secretion in response to exogenous GLP-1 in nondiabetic subjects: a pilot study. Diabetes Care. 2010;33:2074–2076.
    1. Li W., Li P., Li R., Yu Z., Sun X., Ji G. GLP1R single-nucleotide polymorphisms rs3765467 and rs10305492 affect beta cell insulin secretory capacity and apoptosis through GLP-1. DNA and Cell Biology. 2020 epub 27 Jul 2020.
    1. Yau A.M.W., McLaughlin J., Maughan R.J., Gilmore W., Ashworth J.J., Evans G.H. A pilot study investigating the influence of glucagon-like peptide-1 receptor single nucleotide polymorphisms on gastric emptying rate in caucasian men. Frontiers in Physiology. 2018;9:1331.
    1. Chedid V., Vijayvargiya P., Carlson P., Van Malderen K., Acosta A., Zinsmeister A. Allelic variant in the glucagon-like peptide 1 receptor gene associated with greater effect of liraglutide and exenatide on gastric emptying: a pilot pharmacogenetics study. Neuro-Gastroenterology and Motility. 2018;30
    1. Schäfer S.A., Tschritter O., Machicao F., Thamer C., Stefan N., Gallwitz B. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia. 2007;50:2443–2450.
    1. Beinborn M., Worrall C.I., McBride E.W., Kopin A.S. A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness. Regulatory Peptides. 2005;130:1–6.
    1. Lin C.H., Lee Y.S., Huang Y.Y., Hsieh S.H., Chen Z.S., Tsai C.N. Polymorphisms of GLP-1 receptor gene and response to GLP-1 analogue in patients with poorly controlled type 2 diabetes. Journal of Diabetes Research. 2015;2015:176949.
    1. Karras S.N., Rapti E., Koufakis T., Kyriazou A., Goulis D.G., Kotsa K. Pharmacogenetics of glucagon-like peptide-1 agonists for the treatment of type 2 diabetes mellitus. Current Clinical Pharmacology. 2017;12:202–209.
    1. During M.J., Cao L., Zuzga D.S., Francis J.S., Fitzsimons H.L., Jiao X. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nature Medicine. 2003;9:1173–1179.
    1. Holst J.J., Burcelin R., Nathanson E. Neuroprotective properties of GLP-1: theoretical and practical applications. Current Medical Research and Opinion. 2011;27:547–558.
    1. Batista A.F., Forny-Germano L., Clarke J.R., Lyra E.S.N.M., Brito-Moreira J., Boehnke S.E. The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease. The Journal of Pathology. 2018;245:85–100.
    1. Grieco M., Giorgi A., Gentile M.C., d'Erme M., Morano S., Maras B. Glucagon-like peptide-1: a focus on neurodegenerative diseases. Frontiers in Neuroscience. 2019;13:1112.
    1. Vadini F., Simeone P.G., Boccatonda A., Guagnano M.T., Liani R., Tripaldi R. Liraglutide improves memory in obese patients with prediabetes or early type 2 diabetes: a randomized, controlled study. International Journal of Obesity (Lond) 2020;44:1254–1263.
    1. Watson K.T., Wroolie T.E., Tong G., Foland-Ross L.C., Frangou S., Singh M. Neural correlates of liraglutide effects in persons at risk for Alzheimer's disease. Behavioural Brain Research. 2019;356:271–278.
    1. Nordberg A., Rinne J.O., Kadir A., Langstrom B. The use of PET in Alzheimer disease. Nature Reviews Neurology. 2010;6(2):78–87.
    1. Femminella G.D., Frangou E., Love S.B., Busza G., Holmes C., Ritchie C. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study) Trials. 2019;20:191.
    1. Foltynie T., Athauda D. Repurposing anti-diabetic drugs for the treatment of Parkinson's disease: rationale and clinical experience. Progress in Brain Research. 2020;252:493–523.
    1. Yun S.P., Kam T.I., Panicker N., Kim S., Oh Y., Park J.S. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nature Medicine. 2018;24:931–938.
    1. Aviles-Olmos I., Dickson J., Kefalopoulou Z., Djamshidian A., Ell P., Soderlund T. Exenatide and the treatment of patients with Parkinson's disease. Journal of Clinical Investigation. 2013;123:2730–2736.
    1. Athauda D., Maclagan K., Skene S.S., Bajwa-Joseph M., Letchford D., Chowdhury K. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:1664–1675.
    1. Mulvaney C.A., Duarte G.S., Handley J., Evans D.J., Menon S., Wyse R. GLP-1 receptor agonists for Parkinson's disease. Cochrane Database of Systematic Reviews. 2020;7:Cd 012990.
    1. Martin B., Golden E., Carlson O.D., Pistell P., Zhou J., Kim W. Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington's disease. Diabetes. 2009;58:318–328.
    1. Yeung H., Takeshita J., Mehta N.N., Kimmel S.E., Ogdie A., Margolis D.J. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatology. 2013;149:1173–1179.
    1. Hogan A.E., Tobin A.M., Ahern T., Corrigan M.A., Gaoatswe G., Jackson R. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis. Diabetologia. 2011;54:2745–2754.
    1. Buysschaert M., Tennstedt D., Preumont V. Improvement of psoriasis during exenatide treatment in a patient with diabetes. Diabetes & Metabolism. 2012;38:86–88.
    1. Ahern T., Tobin A.M., Corrigan M., Hogan A., Sweeney C., Kirby B. Glucagon-like peptide-1 analogue therapy for psoriasis patients with obesity and type 2 diabetes: a prospective cohort study. Journal of the European Academy of Dermatology and Venereology. 2013;27:1440–1443.
    1. Buysschaert M., Baeck M., Preumont V., Marot L., Hendrickx E., Van Belle A. Improvement of psoriasis during glucagon-like peptide-1 analogue therapy in type 2 diabetes is associated with decreasing dermal γδ T-cell number: a prospective case-series study. British Journal of Dermatology. 2014;171:155–161.
    1. Faurschou A., Gyldenløve M., Rohde U., Thyssen J.P., Zachariae C., Skov L. Lack of effect of the glucagon-like peptide-1 receptor agonist liraglutide on psoriasis in glucose-tolerant patients-a randomized placebo-controlled trial. Journal of the European Academy of Dermatology and Venereology. 2015;29:555–559.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться