GLP-1 RA education

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of medication used to treat type 2 diabetes in patients uncontrolled on metformin.

As well as effectively lowering HbA_1c, GLP-1 RAs have the potential to address multiple risk factors in your type 2 diabetes patients.^1–3

Below you will find the latest information about developments in GLP-1 science and GLP-1 RA therapy to keep you up to date.

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.

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

What is GLP-1 and why does it matter?

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?

Help patients control their blood sugar level

By stimulating insulin secretion in the pancreas and suppressing glucagon secretion in the liver.^28–30 GLP-1 RAs only work in response to high blood sugar level, which is why there is a low risk of hypoglycaemia for patients.^31,32

Help patients lose weight by slowing gastric emptying

GLP-1 RAs slow food absorption by slowing emptying of food from the stomach, preventing blood sugar from spiking after a meal.^30,33

GLP-1 RAs also act on the central nervous system to reduce patients’ appetite and make them feel full sooner, so that they eat less.³⁰

Help protect patients’ heart and blood vessels

GLP-1 RAs can reduce patients’ blood pressure and blood triglyceride levels, so that there is less burden on the heart and blood vessels.^{*4,29,31,33,35,36}

These effects can also help protect the kidneys.^4,33

With a GLP-1 RA, you can address multiple risk factors in type 2 diabetes, where other agents, such as metformin, mainly target one.³⁰

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

When people living with type 2 diabetes are uncontrolled on metformin, it is important to consider which treatment will enable your patients to maintain glycaemic control.³⁷

Improvement in blood glucose levels is associated with greater adherence to therapy and further maintaining adequate glycaemic control which, in turn, reduces the long-term risk of type 2 diabetes complications.³⁷

In studies comparing a GLP-1 RA with other glucose-lowering therapies, all in combination with metformin, GLP-1 RA had a longer time to inadequate HbA_1c control (HbA_1c >7.0%) demonstrating a durability of treatment effect that could help patients adhere to therapy, delay further intensification and reduce the risk of future complications.^37,38

When intensifying type 2 diabetes therapy in a primary care setting, a GLP-1 RA may help your patients stay controlled on therapy for longer.^37,38

GLP-1 RAs have shown durability of effect

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-4is¹, whereas all GLP-1 RAs have been shown to reduce CV risk factors^{4,29,31,33,35,36} 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.

The most reported side effects with GLP-1 RAs are nausea (typically reported in up to 25% of patients), vomiting, and diarrhoea (each reported in up to 10% of patients). These symptoms are often summarised as gastrointestinal adverse events. They are typically most prominent when initiating treatment with any GLP-1 RA or after increasing the dose.⁴

For most patients, these symptoms are short, self-limited episodes that cease spontaneously, even with continued treatment.⁴

An often-used recommendation to avoid these adverse events is a standardised, slowly increased exposure through increase in dose, which has been shown to mitigate gastrointestinal side effects.⁴

Additional ways you can help your patients manage gastrointestinal adverse events

● Educate and set the expectations for patients

● Decrease food intake and avoid fatty meals

● Keep a food diary to identify foods that worsen nausea

GLP-1 RAs are well suited for early use in type 2 diabetes, since they stimulate release of insulin and suppress glucagon secretion only when blood glucose levels are elevated keeping the risk of hypoglycemia low.^48,49

As glucose levels decrease, so does the effect of GLP-1 RA on insulin secretion.⁴⁹

The glucose-dependent action of GLP-1 RAs

Hypoglycaemic episodes have been reported in patients taking GLP-1 RAs but mostly when combined with therapies such as sulfonylureas or insulin.⁴

Acute pancreatitis has been observed with the use of GLP-1 RAs. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, treatment should be discontinued. Caution should be exercised when using GLP-1 RAs in patients with diabetic retinopathy. These patients should be monitored closely and treated according to clinical guidelines.

For further important safety information on GLP-1 RAs please refer to the manufacturers’ prescribing information for each individual agent.

Injectable GLP-1 RAs are delivered from pre-filled, dedicated pen injection devices developed for each particular product. Each formulation has its own standardised dosage recommendations from once daily, to once weekly.⁴

Oral GLP-1 RA tablets are taken once daily.⁴

● GLP-1 RAs are also available in both short-acting and long acting formulations.¹

● 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

The current ADA/EASD consensus algorithm suggests that GLP-1 RAs should be preferentially used early and possibly in combination with SGLT2i. Guidelines also recommend that GLP-1 RAs can also be used to prevent weight gain and hypoglycemia.^1,4,50

The ADA/EASD consensus report recommends GLP-1 RAs (or SGLT2is) therapy in patients with established atherosclerotic cardiovascular disease or in those at high or very high risk. According to these international recommendations, 30–60% of patients with type 2 diabetes could qualify for a GLP-1 RA.⁴

Can be initiated early in the continuum of care, to manage CV risk^1,51,52

Can be started directly after lifestyle modifications or after/in combination with metformin,^51,52

May be prescribed independent  of baseline HbA_1c^1,51

When treating type 2 diabetes, two main goals are to prevent or delay complications and maintain quality of life.¹

It is important to ensure treatment decisions are timely, rely on evidence-based guidelines, and are made collaboratively with patients.⁵¹

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.

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

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.

Garber AJ Abrahamson MJ, Barzilay JI et al. AACE/ACE comprehensive diabetes management algorithm 2015. Endocr Pract 2015 Apr;21(4):438–47.

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.

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.

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

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

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

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

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.

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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.

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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.

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

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

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

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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.

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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.

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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.

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

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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.

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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.

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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.

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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.

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

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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.

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

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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.

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

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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.

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