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In this video, Associate Prof. Sam Hocking discusses the potential benefits of GLP-1 RAs beyond glucose lowering, including benefits on weight reduction, blood lipids and blood pressure that could make the drug class an important option to consider in people living with type 2 diabetes.1–3

 

GLP-1 RAs can vary in their molecular size and structure, which may impact on the individual efficacy and safety profile of the different agents.3–6 

 

For agent-specific recommendations, please refer to the manufacturers’ prescribing information.

 

For more videos and other educational materials, visit the Resources page →

 

GLP-1 RA: Glucagon-like peptide-1 receptor agonist

What is GLP-1 and why does it matter?

What is GLP-1 and why does it matter?
How do GLP-1 RAs work

How do GLP-1 RAs work and why could they be an important option for some patients?
What type of patients could benefit from a GLP-1 RA?

What type of patients could benefit from a
GLP-1 RA?

Reference not found
Reference not found

 

 

 

Download this simple guide to explain the benefits of GLP-1 RAs to your patients.

  • DPP-4is inhibit the breakdown of endogenous GLP-1 in the body by inhibiting DPP-4. This helps to maintain circulating physiological levels of GLP-1, which reduces blood glucose levels when they are high. While DPP-4is and GLP-1 RAs act on the same incretin system, GLP-1-RAs increase circulating levels of GLP-1 to much higher, therapeutic levels.39–41
 
  • The mode of action of SGLT2is and GLP-1 RAs is different; SGLT2is primarily work to lower blood glucose by inhibiting the reabsorption of glucose in the kidney and facilitate its excretion in urine (glycosurea).42,43
  • DPP-4is are considered to have a neutral effect on weight44, whereas GLP-1 RA are known to have a direct effect on central and peripheral receptors in the stomach and the brain, slowing gastric emptying and increasing satiety to promote weight loss.29-31,33
 
  • Though weight loss is often observed in individuals taking SGLT2is, the resulting weight loss is less than expected from the energy excreted via glycosuria and the associated energy expenditure. This may be because the mode of action of SGLT2is does not have an independent effect on weight loss like GLP-1 RAs do, and glycosuria triggers counter-regulatory mechanisms that actually cause an increase (~10-15%) in food intake, striving to maintain body weight.45,46
  • Cardiovascular outcomes trials have demonstrated cardiovascular safety but no cardiovascular benefit of DPP-4is 1, whereas all
    GLP-1 RAs have been shown to reduce CV risk factors4,29,31,33,35,36 and some have been proven to reduce the risk of CV events.34

 

  • SGLT2is have proven CV benefits but the actual mechanism(s) responsible for these cardioprotective effects have yet to be determined.47
  • Similar to GLP-1 RAs, DPP-4-is can be used second-line, as monotherapy or in combination with metformin. DPP-4is act on the same incretin system as GLP-1 RAs so use of these two drug classes simultaneously is not recommended as it may have limited additive clinical benefit.40

 

  • Similar to GLP-1 RAs, SGLT2is can be used second-line, as monotherapy or in combination with metformin. For patients requiring triple therapy, GLP-1 RAs can be combined with metformin and a SGLT2i in patients with persistent hyperglycaemia.48

*For agent-specific recommendations, please refer to the manufacturers’ prescribing information.

CV: Cardiovascular; DPP-4i: Dipeptidyl peptidase 4 inhibitor; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; SGLT2i: Sodium-glucose cotransporter 2 inhibitor.

 

 

Shift in type 2 diabetes

Early intensive treatment is important for glycaemic control and to avoid future complications.

Explore our range of resources and educational materials on GLP-1 RAs and the management of type 2 diabetes.
ADA/EASD consensus report for early treatment

Explore this simple guide to early treatment recommendations for type 2 diabetes as stated in the EASD/ADA consensus report.

1.

Davies MJ, Aroda VR, Collins BS, et al. Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022 Nov 1;45(11):2753-2786.

2.

Garber AJ Abrahamson MJ, Barzilay JI et al. AACE/ACE comprehensive diabetes management algorithm 2015. Endocr Pract. 2016 Jan;22(1):84-113.

3.

Dalsgaard N, Vilsbøll T, Knop FK. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk factors: A narrative review of head-to-head comparisons. Diabetes Obes Metab. 2018;20:508–19.

4.

Nauck MA Quast DR, Wefers J et al. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab 2021;46:101102.

5.

Lovshin JA. Glucagon-like Peptide-1 Receptor Agonists: A Class Update for Treating Type 2 Diabetes. Can J Diabetes. 2017;41:523–35.

6.

Goldenberg RM & Steen O. Semaglutide: Review and Place in Therapy for Adults With Type 2 Diabetes. Can J Diabetes 2019;43:136–45.

7.

Aronoff S, Berkowitz K, Shreiner B et al. Glucose Metabolism and Regulation: Beyond Insulin and Glucagon. Diabetes Spectr 2004;17(3):183–190.

8.

Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27:740-756.

9.

Højberg PV, Vilsbøll T, Rabøl R et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia. 2009;52:199-207.

10.

Kjems LL, Holst JJ, Vølund A et al. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes. 2003;52:380-386.

11.

Calanna S, Christensen M, Holst JJ et al. Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia. 2013;56:965-972.

12.

Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 2013;17:819-837.

13.

Nauck MA & Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab 2018;20:5–21.

14.

Leahy JL. Pathogenesis of type 2 diabetes. Arch Med Res. 2005;36:197-209.

15.

DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-795.

16.

Holst JJ, Knop FK, Vilsbøll T et al. Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care. 2011;34(suppl 2):S251-S257.

17.

Herzberg-Schäfer S, Heni M, Stefan N et al. Impairment of GLP1-induced insulin secretion: role of genetic background, insulin resistance and hyperglycaemia. Diabetes Obes Metab. 2012;14(suppl 3):85-90.

18.

Nauck MA & Meier JJ. GIP and GLP-1: stepsiblings rather than monozygotic twins within the incretin family. Diabetes. 2019;68:897-900.

19.

Simonson G, Cuddihy R, Reader D et al. International diabetes center treatment of type 2 diabetes glucose algorithm. Diabetes Manage. 2011:1:175-189.

20.

Reed J, Bain S, Kanamarlapudi K et al. Recent advances in understanding the role of glucagon-like peptide 1. F1000Res. 2020 Apr 6;9:F1000 Faculty Rev-239.

21.

Muskiet MHA, Tonneijck L, Smits MM et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol. 2017;13(10):605–628.

22.

Vilsbøll T, Krarup T, Madsbad S et al. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia 2002;45:1111–9.

23.

Wajchenberg BL. beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007;28:187–218.

24.

Baggio LL & Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007;132:2131–57.

25.

Sharma D, Verma S, Vaidya S et al. Recent updates on GLP-1 agonists: Current advancements & challenges. Biomed Pharmacother. 2018;108:952–962.

26.

Holst JJ, Vilsbøll T, Deacon CF et al. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297(1-2):127–136.

27.

Nauck MA & Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2016;4(6):525–536.

28.

Hinnen D. Glucagon-like peptide 1 receptor agonists for type 2 diabetes. Diabetes Spectr. 2017;30(3):202-210.

29.

Andreasen CR, Andersen A, Knop FK et al. How glucagon-like peptide 1 receptor agonists work. Endocr Connect. 2021;10(7):R200–R212.

30.

Shaefer Jr CF, Kushner P, Aguilar R. User's guide to mechanism of action and clinical use of GLP-1 receptor agonists. Postgrad Med. 2015;127(8):818–826.

31.

Cornell SJ. A review of GLP-1 receptor agonists in type 2 diabetes: A focus on the mechanism of action of once-weekly agents. Clin Pharm Ther. 2020;45(Suppl 1):17–27.

32.

Rasalam R, Barlow J, Kennedy M et al. GLP-1 Receptor Agonists for Type 2 Diabetes and Their Role in Primary Care: An Australian Perspective. Diabetes Ther. 2019;10(4):1205–1217.

33.

Kalra S, Das AK, Sahay RK et al. Consensus Recommendations on GLP-1 RA Use in the Management of Type 2 Diabetes Mellitus: South Asian Task Force. Diabetes Ther. 2019;10(5):1645–1717.

34.

Kristensen SL, Rørth R, Jhund PS et al. 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 Endocrinol. 2019;7(10):776–785.

35.

Andrikou E, Tsioufis C, Andrikou I et al. GLP-1 receptor agonists and cardiovascular outcome trials: An update. Hellenic J Cardiol.2019;60(6):347–351.

36.

Sposito A, Berwanger O, de Carvalho LSF et al. GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data. Cardiovasc Diabetol. 2018;17(1):157.

37.

David, Nathan M, et al. “Results of the Glycemia Reduction Approaches in Diabetes—A Comparative Effectiveness (GRADE) Study.” American Diabetes Association 81st Scientific Sessions.

38.

Unger J, Allison D´C, Kaltoft M et al. Maintenance of glycaemic control with liraglutide versus oral antidiabetic drugs as add-on therapies in patients with type 2 diabetes uncontrolled with metformin alone: A randomized clinical trial in primary care (LIRA-PRIME). Diabetes Obes Metab. 2022 Feb;24(2):204-11.

39.

Herman GA, Bergman A, Stevens C et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 2006;91:4612–9.

40.

Nauck M A, Kahle M, Baranov O et al. Addition of a dipeptidyl peptidase-4 inhibitor, sitagliptin, to ongoing therapy with the glucagon-like peptide-1 receptor agonist liraglutide: A randomized controlled trial in patients with type 2 diabetes. Diabetes Obes Metab. 2017 Feb;19(2):200-207.

41.

Marbury TC, Flint A, Jacobsen JB et al. Pharmacokinetics and Tolerability of a Single Dose of Semaglutide, a Human Glucagon-Like Peptide-1 Analog, in Subjects With and Without Renal Impairment. Clin Pharmacokinet 2017;56:1381–90.

42.

Garber AJ, Handelsman Y, Grunberger G et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2020 executive summary. Endocr Pract 2020;26:107–39.

43.

Kalra S. Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of Their Basic and Clinical Pharmacology. Diabetes Ther 2014;5:355-66.

44.

American Diabetes Association. Standards of Medical Care in Diabetes—2020. Diabetes Care. 2020;43(suppl 1):S1–S212.

45.

Ferrannini G, Hach T, Crowe S, et al. Energy Balance After Sodium–Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015;38(9):1730-1735.

46.

Pereira MJ, Eriksson JW. Emerging Role of SGLT-2 Inhibitors for the Treatment of Obesity. Drugs. 2019;79(3):219-230.

47.

Lopaschuk G & Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors. JACC Basic Transl Sci. 2020;5(6):632–644.

48.

Padhi S, Kumar Nayak A, Behera A. Type II diabetes mellitus: a review on recent drug based therapeutics. Biomed Pharmacother. 2020;131:110708.

49.

Nauck M, El-Ouaghlidi A, Hompesch M et al. No impairment of hypoglycaemia counter-regulation via glucagon with NN2211, a GLP-1 derivative, in subjects with type 2 diabetes. Diabetes. 2003;52(Suppl.1):A128.

50.

Buse JB, Wexler D, Tsapas A et al. 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(2):487-493

51.

American Diabetes Association. 1. Improving Care and Promoting Health in Populations: Standards of Medical Care in Diabetes-2021. Diabetes Care 2021;44:S7–S14.

52.

Cosentino F, Grant PJ, Aboyans V et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323.

53.

Data on file. IQVIA Midas December 2020, IQVIA Disease Analyser Germany December 2020, LAAD USA November 2020.