Mechanistic Pathways and Clinical Implications of GLP-1 Receptor Agonists in Type 1 Diabetes Management
Abstract
:1. Introduction
2. Mechanistic Pathways of GLP-1 Receptor Agonists in Type 1 Diabetes
2.1. Pancreatic Effects
2.2. Extrapancreatic Effects
3. GLP-1 Receptor Agonists in Glycemic Control
3.1. Liraglutide
3.1.1. Initial Studies on Liraglutide in Type 1 Diabetes
3.1.2. Large-Scale Trials: ADJUNCT ONE and ADJUNCT TWO
3.1.3. Additional Studies
3.1.4. Liraglutide in Combination Therapies
3.2. Exenatide
3.3. Dulaglutide
3.4. Albiglutide
3.5. Semaglutide
3.6. Tirzepatide
4. Potential Benefits beyond Glycemic Control
4.1. Cardiovascular Disease
4.2. Overweight
4.3. Neuroprotection
4.4. Bone Metabolism
5. Future Directions and Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Kobayati, A.; Haidar, A.; Tsoukas, M.A. GLUCAGON-LIKE PEPTIDE-1 Receptor Agonists as Adjunctive Treatment for Type 1 Diabetes: Renewed Opportunities through Tailored Approaches? Diabetes Obes. Metab. 2022, 24, 769–787. [Google Scholar] [CrossRef] [PubMed]
- Jones, B. The Therapeutic Potential of GLP-1 Receptor Biased Agonism. Br. J. Pharmacol. 2022, 179, 492–510. [Google Scholar] [CrossRef] [PubMed]
- Trapp, S.; Stanford, S.C. New Developments in the Prospects for GLP-1 Therapy. Br. J. Pharmacol. 2022, 179, 489–491. [Google Scholar] [CrossRef]
- Brunton, S.A.; Wysham, C.H. GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes: Role and Clinical Experience to Date. Postgrad. Med. 2020, 132, 3–14. [Google Scholar] [CrossRef] [PubMed]
- Sachinidis, A.; Nikolic, D.; Stoian, A.P.; Papanas, N.; Tarar, O.; Rizvi, A.A.; Rizzo, M. Cardiovascular Outcomes Trials with Incretin-Based Medications: A Critical Review of Data Available on GLP-1 Receptor Agonists and DPP-4 Inhibitors. Metabolism 2020, 111, 154343. [Google Scholar] [CrossRef]
- Nauck, M.A.; Quast, D.R.; Wefers, J.; Meier, J.J. GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes—State-of-the-Art. Mol. Metab. 2021, 46, 101102. [Google Scholar] [CrossRef]
- Wan, W.; Qin, Q.; Xie, L.; Zhang, H.; Wu, F.; Stevens, R.C.; Liu, Y. GLP-1R Signaling and Functional Molecules in Incretin Therapy. Molecules 2023, 28, 751. [Google Scholar] [CrossRef]
- Yu, J.H.; Park, S.Y.; Lee, D.Y.; Kim, N.H.; Seo, J.A. GLP-1 Receptor Agonists in Diabetic Kidney Disease: Current Evidence and Future Directions. Kidney Res. Clin. Pract. 2022, 41, 136–149. [Google Scholar] [CrossRef]
- Ackeifi, C.; Wang, P.; Karakose, E.; Manning Fox, J.E.; González, B.J.; Liu, H.; Wilson, J.; Swartz, E.; Berrouet, C.; Li, Y.; et al. GLP-1 Receptor Agonists Synergize with DYRK1A Inhibitors to Potentiate Functional Human β Cell Regeneration. Sci. Transl. Med. 2020, 12, eaaw9996. [Google Scholar] [CrossRef]
- Schuit, F.C.; Drucker, D.J. β-Cell Replication by Loosening the Brakes of Glucagon-Like Peptide-1 Receptor Signaling. Diabetes 2008, 57, 529–531. [Google Scholar] [CrossRef]
- Quoyer, J.; Longuet, C.; Broca, C.; Linck, N.; Costes, S.; Varin, E.; Bockaert, J.; Bertrand, G.; Dalle, S. GLP-1 Mediates Antiapoptotic Effect by Phosphorylating Bad through a β-Arrestin 1-Mediated ERK1/2 Activation in Pancreatic β-Cells. J. Biol. Chem. 2010, 285, 1989–2002. [Google Scholar] [CrossRef] [PubMed]
- Cunha, D.A.; Ladrière, L.; Ortis, F.; Igoillo-Esteve, M.; Gurzov, E.N.; Lupi, R.; Marchetti, P.; Eizirik, D.L.; Cnop, M. Glucagon-Like Peptide-1 Agonists Protect Pancreatic β-Cells From Lipotoxic Endoplasmic Reticulum Stress Through Upregulation of BiP and JunB. Diabetes 2009, 58, 2851–2862. [Google Scholar] [CrossRef]
- Holst, J.J. From the Incretin Concept and the Discovery of GLP-1 to Today’s Diabetes Therapy. Front. Endocrinol. 2019, 10, 260. [Google Scholar] [CrossRef]
- Almandoz, J.P.; Lingvay, I.; Morales, J.; Campos, C. Switching Between Glucagon-Like Peptide-1 Receptor Agonists: Rationale and Practical Guidance. Clin. Diabetes 2020, 38, 390–402. [Google Scholar] [CrossRef]
- Tashiro, Y.; Sato, K.; Watanabe, T.; Nohtomi, K.; Terasaki, M.; Nagashima, M.; Hirano, T. A Glucagon-like Peptide-1 Analog Liraglutide Suppresses Macrophage Foam Cell Formation and Atherosclerosis. Peptides 2014, 54, 19–26. [Google Scholar] [CrossRef]
- Mazidi, M.; Karimi, E.; Rezaie, P.; Ferns, G.A. Treatment with GLP1 Receptor Agonists Reduce Serum CRP Concentrations in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J. Diabetes Its Complicat. 2017, 31, 1237–1242. [Google Scholar] [CrossRef] [PubMed]
- Lin, C.-H.; Lin, C.-C. Sitagliptin Attenuates Inflammatory Responses in Lipopolysaccharide-Stimulated Cardiomyocytes via Nuclear Factor-κB Pathway Inhibition. Exp. Ther. Med. 2016, 11, 2609–2615. [Google Scholar] [CrossRef] [PubMed]
- Huang, J.; Yi, H.; Zhao, C.; Zhang, Y.; Zhu, L.; Liu, B.; He, P.; Zhou, M. Glucagon-like Peptide-1 Receptor (GLP-1R) Signaling Ameliorates Dysfunctional Immunity in COPD Patients. COPD 2018, 13, 3191–3202. [Google Scholar] [CrossRef]
- Zhao, X.; Wang, M.; Wen, Z.; Lu, Z.; Cui, L.; Fu, C.; Xue, H.; Liu, Y.; Zhang, Y. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front. Endocrinol. 2021, 12, 721135. [Google Scholar] [CrossRef]
- Mathieu, C.; Zinman, B.; Hemmingsson, J.U.; Woo, V.; Colman, P.; Christiansen, E.; Linder, M.; Bode, B. for the ADJUNCT ONE Investigators Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial. Diabetes Care 2016, 39, 1702–1710. [Google Scholar] [CrossRef]
- Kielgast, U.; Krarup, T.; Holst, J.J.; Madsbad, S. Four Weeks of Treatment with Liraglutide Reduces Insulin Dose Without Loss of Glycemic Control in Type 1 Diabetic Patients With and Without Residual β-Cell Function. Diabetes Care 2011, 34, 1463–1468. [Google Scholar] [CrossRef]
- Ahrén, B.; Hirsch, I.B.; Pieber, T.R.; Mathieu, C.; Gómez-Peralta, F.; Hansen, T.K.; Philotheou, A.; Birch, S.; Christiansen, E.; Jensen, T.J.; et al. Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects with Type 1 Diabetes: The ADJUNCT TWO Randomized Trial. Diabetes Care 2016, 39, 1693–1701. [Google Scholar] [CrossRef] [PubMed]
- Johansen, N.J.; Dejgaard, T.F.; Lund, A.; Schlüntz, C.; Frandsen, C.S.; Forman, J.L.; Wewer Albrechtsen, N.J.; Holst, J.J.; Pedersen-Bjergaard, U.; Madsbad, S.; et al. Efficacy and Safety of Meal-Time Administration of Short-Acting Exenatide for Glycaemic Control in Type 1 Diabetes (MAG1C): A Randomised, Double-Blind, Placebo-Controlled Trial. Lancet Diabetes Endocrinol. 2020, 8, 313–324. [Google Scholar] [CrossRef] [PubMed]
- Thivolet, C.; Larger, E.; Cariou, B.; Renard, E.; Hanaire, H.; Benhamou, P.-Y.; Guerci, B.; Mathiotte, É.; Chikh, K. Dulaglutide and Insulin Microsecretion in People with Type 1 Diabetes (DIAMOND-GLP-1): A Randomized Double-Blind Placebo-Controlled Trial. Diabetes Metab. 2023, 49, 101433. [Google Scholar] [CrossRef]
- Frandsen, C.S.; Dejgaard, T.F.; Andersen, H.U.; Holst, J.J.; Hartmann, B.; Thorsteinsson, B.; Madsbad, S. Liraglutide as Adjunct to Insulin Treatment in Type 1 Diabetes Does Not Interfere with Glycaemic Recovery or Gastric Emptying Rate during Hypoglycaemia: A Randomized, Placebo-controlled, Double-blind, Parallel-group Study. Diabetes Obes. Metab. 2017, 19, 773–782. [Google Scholar] [CrossRef]
- Pozzilli, P.; Bosi, E.; Cirkel, D.; Harris, J.; Leech, N.; Tinahones, F.J.; Vantyghem, M.-C.; Vlasakakis, G.; Ziegler, A.-G.; Janmohamed, S. Randomized 52-Week Phase 2 Trial of Albiglutide Versus Placebo in Adult Patients With Newly Diagnosed Type 1 Diabetes. J. Clin. Endocrinol. Metab. 2020, 105, e2192–e2206. [Google Scholar] [CrossRef]
- Herold, K.C.; Reynolds, J.; Dziura, J.; Baidal, D.; Gaglia, J.; Gitelman, S.E.; Gottlieb, P.A.; Marks, J.; Philipson, L.H.; Pop-Busui, R.; et al. Exenatide Extended Release in Patients with Type 1 Diabetes with and without Residual Insulin Production. Diabetes Obes. Metab. 2020, 22, 2045–2054. [Google Scholar] [CrossRef]
- Karakus, K.E.; Klein, M.P.; Akturk, H.K.; Shah, V.N. Changes in Basal and Bolus Insulin Requirements with Tirzepatide as an Adjunctive Therapy in Adults with Type 1 Diabetes Using Tandem Control-IQ. Diabetes Ther. 2024, 15, 1647–1655. [Google Scholar] [CrossRef] [PubMed]
- Pieber, T.R.; Deller, S.; Korsatko, S.; Jensen, L.; Christiansen, E.; Madsen, J.; Heller, S.R. Counter-regulatory Hormone Responses to Hypoglycaemia in People with Type 1 Diabetes after 4 Weeks of Treatment with Liraglutide Adjunct to Insulin: A Randomized, Placebo-controlled, Double-blind, Crossover Trial. Diabetes Obes. Metab. 2015, 17, 742–750. [Google Scholar] [CrossRef]
- Zenz, S.; Regittnig, W.; Boulgaropoulos, B.; Augustin, T.; Brunner, M.; Korsatko, S.; Münzker, J.; Narath, S.H.; Raml, R.; Magnes, C.; et al. Effect of Liraglutide Treatment on Whole-Body Glucose Fluxes in C-Peptide–Positive Type 1 Diabetes During Hypoglycemia. J. Clin. Endocrinol. Metab. 2022, 107, e3583–e3593. [Google Scholar] [CrossRef]
- Dejgaard, T.F.; Von Scholten, B.J.; Christiansen, E.; Kreiner, F.F.; Bardtrum, L.; Von Herrath, M.; Mathieu, C.; Madsbad, S. ADJUNCT ONE and ADJUNCT TWO Investigators Efficacy and Safety of Liraglutide in Type 1 Diabetes by Baseline Characteristics in the ADJUNCT ONE and ADJUNCT TWO Randomized Controlled Trials. Diabetes Obes. Metab. 2021, 23, 2752–2762. [Google Scholar] [CrossRef] [PubMed]
- Kuhadiya, N.D.; Dhindsa, S.; Ghanim, H.; Mehta, A.; Makdissi, A.; Batra, M.; Sandhu, S.; Hejna, J.; Green, K.; Bellini, N.; et al. Addition of Liraglutide to Insulin in Patients with Type 1 Diabetes: A Randomized Placebo-Controlled Clinical Trial of 12 Weeks. Diabetes Care 2016, 39, 1027–1035. [Google Scholar] [CrossRef] [PubMed]
- Schmidt, S.; Frandsen, C.S.; Dejgaard, T.F.; Vistisen, D.; Halldórsson, T.; Olsen, S.F.; Jensen, J.B.; Madsbad, S.; Andersen, H.U.; Nørgaard, K. Liraglutide Changes Body Composition and Lowers Added Sugar Intake in Overweight Persons with Insulin Pump-treated Type 1 Diabetes. Diabetes Obes. Metab. 2022, 24, 212–220. [Google Scholar] [CrossRef] [PubMed]
- Von Herrath, M.; Bain, S.C.; Bode, B.; Clausen, J.O.; Coppieters, K.; Gaysina, L.; Gumprecht, J.; Hansen, T.K.; Mathieu, C.; Morales, C.; et al. Anti-Interleukin-21 Antibody and Liraglutide for the Preservation of β-Cell Function in Adults with Recent-Onset Type 1 Diabetes: A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial. Lancet Diabetes Endocrinol. 2021, 9, 212–224. [Google Scholar] [CrossRef]
- Ilkowitz, J.T.; Katikaneni, R.; Cantwell, M.; Ramchandani, N.; Heptulla, R.A. Adjuvant Liraglutide and Insulin Versus Insulin Monotherapy in the Closed-Loop System in Type 1 Diabetes: A Randomized Open-Labeled Crossover Design Trial. J. Diabetes Sci. Technol. 2016, 10, 1108–1114. [Google Scholar] [CrossRef]
- Park, J.; Ntelis, S.; Yunasan, E.; Downton, K.D.; Yip, T.C.-F.; Munir, K.M.; Haq, N. Glucagon-Like Peptide 1 Analogues as Adjunctive Therapy for Patients With Type 1 Diabetes: An Updated Systematic Review and Meta-Analysis. J. Clin. Endocrinol. Metab. 2023, 109, 279–292. [Google Scholar] [CrossRef]
- Dimitrios, P.; Michael, D.; Vasilios, K.; Konstantinos, S.; Konstantinos, I.; Ioanna, Z.; Konstantinos, P.; Spyridon, B.; Asterios, K. Liraglutide as Adjunct to Insulin Treatment in Patients with Type 1 Diabetes: A Systematic Review and Meta-Analysis. Curr. Diabetes Rev. 2020, 16, 313–326. [Google Scholar] [CrossRef]
- Avgerinos, I.; Manolopoulos, A.; Michailidis, T.; Kitsios, K.; Liakos, A.; Karagiannis, T.; Dimitrakopoulos, K.; Matthews, D.R.; Tsapas, A.; Bekiari, E. Comparative Efficacy and Safety of Glucose-lowering Drugs as Adjunctive Therapy for Adults with Type 1 Diabetes: A Systematic Review and Network Meta-analysis. Diabetes Obes. Metab. 2021, 23, 822–831. [Google Scholar] [CrossRef]
- Sarkar, G.; Alattar, M.; Brown, R.J.; Quon, M.J.; Harlan, D.M.; Rother, K.I. Exenatide Treatment for 6 Months Improves Insulin Sensitivity in Adults with Type 1 Diabetes. Diabetes Care 2014, 37, 666–670. [Google Scholar] [CrossRef]
- Kim, Y.J.; Hwang, S.D.; Lim, S. Effects of Sodium-Glucose Cotransporter Inhibitor/Glucagon-Like Peptide-1 Receptor Agonist Add-On to Insulin Therapy on Glucose Homeostasis and Body Weight in Patients with Type 1 Diabetes: A Network Meta-Analysis. Front. Endocrinol. 2020, 11, 553. [Google Scholar] [CrossRef]
- Raman, V.S.; Mason, K.J.; Rodriguez, L.M.; Hassan, K.; Yu, X.; Bomgaars, L.; Heptulla, R.A. The Role of Adjunctive Exenatide Therapy in Pediatric Type 1 Diabetes. Diabetes Care 2010, 33, 1294–1296. [Google Scholar] [CrossRef] [PubMed]
- Jiang, L.-L.; Wang, S.-Q.; Ding, B.; Zhu, J.; Jing, T.; Ye, L.; Lee, K.-O.; Wu, J.-D.; Ma, J.-H. The Effects of Add-on Exenatide to Insulin on Glycemic Variability and Hypoglycemia in Patients with Type 1 Diabetes Mellitus. J. Endocrinol. Investig. 2018, 41, 539–547. [Google Scholar] [CrossRef] [PubMed]
- Mertens, J.; De Winter, H.T.; Mazlom, H.; Peiffer, F.W.; Dirinck, E.L.; Bochanen, N.; Van Gaal, L.F.; De Block, C. 751-P: Effect Of Once-Weekly Semaglutide on Weight Change and Metabolic Control in People with Type 1 Diabetes—Six-Months Results from the Real-World STEMT Trial. Diabetes 2022, 71, 751-P. [Google Scholar] [CrossRef]
- Perkovic, V.; Tuttle, K.R.; Rossing, P.; Mahaffey, K.W.; Mann, J.F.E.; Bakris, G.; Baeres, F.M.M.; Idorn, T.; Bosch-Traberg, H.; Lausvig, N.L.; et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N. Engl. J. Med. 2024, 391, 109–121. [Google Scholar] [CrossRef]
- Akturk, H.K.; Dong, F.; Snell-Bergeon, J.K.; Karakus, K.E.; Shah, V.N. Efficacy and Safety of Tirzepatide in Adults With Type 1 Diabetes: A Proof of Concept Observational Study. J. Diabetes Sci. Technol. 2024, 19322968231223991. [Google Scholar] [CrossRef]
- Garg, S.K.; Akturk, H.K.; Kaur, G.; Beatson, C.; Snell-Bergeon, J. Efficacy and Safety of Tirzepatide in Overweight and Obese Adult Patients with Type 1 Diabetes. Diabetes Technol. Ther. 2024, 26, 367–374. [Google Scholar] [CrossRef]
- Ma, X.; Liu, Z.; Ilyas, I.; Little, P.J.; Kamato, D.; Sahebka, A.; Chen, Z.; Luo, S.; Zheng, X.; Weng, J.; et al. GLP-1 Receptor Agonists (GLP-1RAs): Cardiovascular Actions and Therapeutic Potential. Int. J. Biol. Sci. 2021, 17, 2050–2068. [Google Scholar] [CrossRef]
- Helmstädter, J.; Keppeler, K.; Küster, L.; Münzel, T.; Daiber, A.; Steven, S. Glucagon-like Peptide-1 (GLP-1) Receptor Agonists and Their Cardiovascular Benefits—The Role of the GLP-1 Receptor. Br. J. Pharmacol. 2022, 179, 659–676. [Google Scholar] [CrossRef]
- Ferhatbegović, L.; Mršić, D.; Macić-Džanković, A. The Benefits of GLP1 Receptors in Cardiovascular Diseases. Front. Clin. Diabetes Healthc. 2023, 4, 1293926. [Google Scholar] [CrossRef]
- Dalsgaard, N.B.; Brønden, A.; Vilsbøll, T.; Knop, F.K. Cardiovascular Safety and Benefits of GLP-1 Receptor Agonists. Expert. Opin. Drug Saf. 2017, 16, 351–363. [Google Scholar] [CrossRef]
- Lorber, D. GLP-1 Receptor Agonists: Effects on Cardiovascular Risk Reduction. Cardiovasc. Ther. 2013, 31, 238–249. [Google Scholar] [CrossRef]
- Cariou, B. Harnessing the Incretin System beyond Glucose Control: Potential Cardiovascular Benefits of GLP-1 Receptor Agonists in Type 2 Diabetes. Diabetes Metab. 2012, 38, 298–308. [Google Scholar] [CrossRef]
- Johansen, N.J.; Dejgaard, T.F.; Lund, A.; Schlüntz, C.; Larsen, E.L.; Poulsen, H.E.; Goetze, J.P.; Møller, H.J.; Vilsbøll, T.; Andersen, H.U.; et al. Effect of Short-acting Exenatide Administered Three Times Daily on Markers of Cardiovascular Disease in Type 1 Diabetes: A Randomized Double-blind Placebo-controlled Trial. Diabetes Obes. Metab. 2020, 22, 1639–1647. [Google Scholar] [CrossRef]
- Dejgaard, T.F.; Johansen, N.B.; Frandsen, C.S.; Asmar, A.; Tarnow, L.; Knop, F.K.; Madsbad, S.; Andersen, H.U. Effects of Liraglutide on Cardiovascular Risk Factors in Patients with Type 1 Diabetes. Diabetes Obes. Metab. 2017, 19, 734–738. [Google Scholar] [CrossRef]
- Brown, E.; Heerspink, H.J.L.; Cuthbertson, D.J.; Wilding, J.P.H. SGLT2 Inhibitors and GLP-1 Receptor Agonists: Established and Emerging Indications. Lancet 2021, 398, 262–276. [Google Scholar] [CrossRef]
- Nachawi, N.; Rao, P.P.; Makin, V. The Role of GLP-1 Receptor Agonists in Managing Type 2 Diabetes. Clevel. Clin. J. Med. 2022, 89, 457–464. [Google Scholar] [CrossRef]
- Pondel, K.; Kawałko, K.; Bielewicz, K.; Chmura, A.; Karaś, A. Effect of Glucagon-like Peptide-1 (GLP-1) Agonists on the Example of Semaglutide on the Cardiovascular System and Their Role in the Treatment of Obesity. J. Educ. Health Sport. 2022, 12, 55–60. [Google Scholar] [CrossRef]
- Dejgaard, T.F.; Schmidt, S.; Frandsen, C.S.; Vistisen, D.; Madsbad, S.; Andersen, H.U.; Nørgaard, K. 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 Obes. Metab. 2020, 22, 492–500. [Google Scholar] [CrossRef]
- Dejgaard, T.F.; Frandsen, C.S.; Hansen, T.S.; Almdal, T.; Urhammer, S.; Pedersen-Bjergaard, U.; Jensen, T.; Jensen, A.K.; Holst, J.J.; Tarnow, L.; et al. Efficacy and Safety of Liraglutide for Overweight Adult Patients with Type 1 Diabetes and Insufficient Glycaemic Control (Lira-1): A Randomised, Double-Blind, Placebo-Controlled Trial. Lancet Diabetes Endocrinol. 2016, 4, 221–232. [Google Scholar] [CrossRef]
- Wegeberg, A.; Meldgaard, T.; Bæk, A.; Drewes, A.M.; Vyberg, M.; Jessen, N.; Brock, B.; Brock, C. Subcutaneous Adipose Tissue Composition and Function Are Unaffected by Liraglutide-induced Weight Loss in Adults with Type 1 Diabetes. Basic. Clin. Pharma Tox 2021, 128, 773–782. [Google Scholar] [CrossRef]
- Ghanim, H.; Batra, M.; Green, K.; Abuaysheh, S.; Hejna, J.; Makdissi, A.; Borowski, R.; Kuhadiya, N.D.; Chaudhuri, A.; Dandona, P. Liraglutide Treatment in Overweight and Obese Patients with Type 1 Diabetes: A 26-week Randomized Controlled Trial; Mechanisms of Weight Loss. Diabetes Obes. Metab. 2020, 22, 1742–1752. [Google Scholar] [CrossRef]
- Dubé, M.; D’Amours, M.; Weisnagel, S.J. Effect of Liraglutide on Food Consumption, Appetite Sensations and Eating Behaviours in Overweight People with Type 1 Diabetes. Diabetes Obes. Metab. 2020, 22, 1417–1424. [Google Scholar] [CrossRef] [PubMed]
- Dubé, M.; D’Amours, M.; Weisnagel, S.J. Beyond Glycaemic Control: A Cross-over, Double-blinded, 24-week Intervention with Liraglutide in Type 1 Diabetes. Diabetes Obes. Metab. 2018, 20, 178–184. [Google Scholar] [CrossRef]
- Sivakumar, P.M.; Premkumar, B.; Prabhawathi, V.; Prabhakar, P.K. Role of GLP-1 Analogs in the Management of Diabetes and Its SecondaryComplication. Mini Rev. Med. Chem. 2021, 21, 3166–3182. [Google Scholar] [CrossRef]
- Johansen, N.J.; Dejgaard, T.F.; Lund, A.; Schlüntz, C.; Hartmann, B.; Holst, J.J.; Vilsbøll, T.; Andersen, H.U.; Knop, F.K. Effects of Short-acting Exenatide Added Three Times Daily to Insulin Therapy on Bone Metabolism in Type 1 Diabetes. Diabetes Obes. Metab. 2022, 24, 221–227. [Google Scholar] [CrossRef]
- Unger, J. Rationale Use of GLP-1 Receptor Agonists in Patients with Type 1 Diabetes. Curr. Diab Rep. 2013, 13, 663–668. [Google Scholar] [CrossRef]
GLP-1 Agonist | Participants | Duration | Primary Outcome | Results | Ref. |
---|---|---|---|---|---|
Liraglutide | 1398 T1D patients on insulin. | 52 weeks | Change in HbA1c | Significant reduction in HbA1c, weight loss, and lower insulin dose requirements compared to placebo. | [20] |
Liraglutide | 835 T1D patients with capped insulin | 52 weeks | Change in HbA1c | Improved glycemic control with reduced insulin requirements, no increase in hypoglycemia. | [22] |
Exenatide | 106 T1D patients | 24 weeks | Glycemic control, postprandial glucose levels | Significant reduction in postprandial glucose excursions and weight loss; modest reductions in HbA1c. | [23] |
Dulaglutide | 23 T1D patients with residual function | 24 weeks | Insulin microsecretion, weight loss | Significant weight loss without significant changes in insulin microsecretion or HbA1c. | [24] |
Semaglutide | 20 adults with T1D | 6 months | Weight change, metabolic control | Significant weight loss and reduction in daily insulin dose, with a slight decrease in HbA1c. | [25] |
Albiglutide | 68 adults newly diagnosed with T1D | 52 weeks | Preservation of C-peptide levels | Modest preservation of β-cell function and improved glycemic control without increasing hypoglycemia. | [26] |
Exenatide ER | 142 T1D patients with/without C-peptide | 24 weeks | Glycemic control, weight loss | Significant HbA1c reduction in C-peptide positive group and weight loss without increased hypoglycemia. | [27] |
Tirzepatide | Adults with T1D using Tandem Control-IQ | 24 weeks | Insulin requirements, glycemic control | Significant reduction in both basal and bolus insulin doses and improved glycemic control; notable weight loss observed. | [28] |
Mechanism/Outcome | Description | Clinical Significance |
---|---|---|
β-cell function preservation | GLP-1 receptor agonists showed potential in preserving β-cell function in some trials, particularly with albiglutide and liraglutide. | Preserving β-cell function can help maintain endogenous insulin secretion, potentially reducing the need for exogenous insulin and improving long-term glycemic control. |
Glycemic variability reduction | Trials indicated that GLP-1 receptor agonists reduce glycemic excursions, particularly postprandial spikes, and overall glycemic variability. | Reducing glycemic variability is crucial for minimizing complications and improving quality of life in T1D patients. |
Insulin dose reduction | Several studies found a reduction in insulin requirements with the use of GLP-1 receptor agonists, without increasing the risk of hypoglycemia. | Lower insulin doses can reduce the risk of weight gain and hypoglycemia, making insulin therapy more manageable for patients. |
Weight management | All GLP-1 receptor agonists demonstrated weight loss benefits, with significant reductions noted in liraglutide, semaglutide, and dulaglutide trials. | Weight loss is beneficial for T1D patients, who often struggle with weight gain due to intensive insulin therapy. This can improve metabolic outcomes and reduce cardiovascular risks. |
Cardiovascular and metabolic benefits | GLP-1 receptor agonists provided additional benefits beyond glycemic control, including improved lipid profiles and reduced cardiovascular risks. | These benefits make GLP-1 receptor agonists attractive adjuncts to insulin therapy for comprehensive diabetes management. |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Delrue, C.; Speeckaert, M.M. Mechanistic Pathways and Clinical Implications of GLP-1 Receptor Agonists in Type 1 Diabetes Management. Int. J. Mol. Sci. 2024, 25, 9351. https://doi.org/10.3390/ijms25179351
Delrue C, Speeckaert MM. Mechanistic Pathways and Clinical Implications of GLP-1 Receptor Agonists in Type 1 Diabetes Management. International Journal of Molecular Sciences. 2024; 25(17):9351. https://doi.org/10.3390/ijms25179351
Chicago/Turabian StyleDelrue, Charlotte, and Marijn M. Speeckaert. 2024. "Mechanistic Pathways and Clinical Implications of GLP-1 Receptor Agonists in Type 1 Diabetes Management" International Journal of Molecular Sciences 25, no. 17: 9351. https://doi.org/10.3390/ijms25179351