GLP-1 receptor agonists in the treatment of type 2 diabetes: role and clinical experience to date

Figures & data

Figure 1. Impact of various classes of antihyperglycemic medications on the ‘ominous octet’ of pathophysiological defects contributing to hyperglycemia in patients with T2D [14].American Diabetes Association [Novel Agents for the Treatment of Type 2 Diabetes, American Diabetes Association, 2014]. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.*Reduced satiety and appetite suppression.DPP-4i, dipeptidyl peptidase-4 inhibitor; GI, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist; HGP, hepatic glucose production; MET, metformin; SGLT2i, sodium-glucose co-transporter-2 inhibitor; T2D, type 2 diabetes; TZD, thiazolidinedione

Table 1. Overview of the key characteristics of GLP-1RAs currently available for treating adults with T2D in the USA [11–13,23,25,27–30,33–35]

Agent	FDA approval	Dosing frequency	Recommended dosage	Timing of administration	Administration method
Short-acting agents*
Exenatide	2005	Twice daily	5 μg s.c. twice daily After 1 month, may increase to 10 μg s.c. twice daily based on clinical response	Take within 60 minutes before morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart)	Multi-use pens (each containing 60 doses of either 5 µg or 10 µg)
Lixisenatide^†	2016	Once daily	10 μg s.c. once daily for the first 14 days On day 15, increase to 20 μg once daily	Take within 1 hour before the first meal of the day	Multi-use pens (each containing 14 doses of either 10 µg or 20 µg)
Long-acting agents*
Liraglutide^‡	2010	Once daily	0.6 mg s.c. once daily for 1 week, then increase to 1.2 mg once daily If glycemic control is unacceptable after a further week, can increase dose to 1.8 mg s.c. once daily	Take at any time of day	Multi-use pen (6 mg/mL pen that delivers doses of 0.6 mg, 1.2 mg or 1.8 mg)
Exenatide extended- release	2012	Once weekly	2 mg s.c. once weekly	Take at any time of day	Single-use pen (2 mg), single-dose vial (2 mg), or single-use autoinjector (2 mg)
Dulaglutide	2014	Once weekly	0.75 mg s.c. once weekly May increase to 1.5 mg s.c. once weekly for inadequate glycemic control	Take at any time of day	Single-use pen (0.75 mg or 1.5 mg)
Subcutaneous semaglutide	2017	Once weekly	0.25 mg s.c. once weekly for 4 weeks, then increase to 0.5 mg s.c. once weekly If glycemic control is unacceptable after a further 4 weeks, can increase dose to 1 mg s.c. once weekly	Take at any time of day	Multi-use pens (one delivering doses of 0.25 mg or 0.5 mg, and the other 1 mg)
Oral semaglutide	2019	Once daily	3 mg orally once daily for 30 days, then increase to 7 mg orally once daily If glycemic control is unacceptable after a further 30 days, increase to 14 mg orally once daily	Take at least 30 minutes before first food, drink or other medication of the day	Oral tablet (3 mg, 7 mg, or 14 mg)

*Short acting: drug concentrations decline to low levels a few hours after administration; long-acting: drug concentrations are sustained at effective concentrations for the dosing period [25]; ^†also available as a fixed-dose combination with insulin glargine 100 U [32]; ^‡also available as a fixed-dose combination with insulin degludec 100 U [31].

FDA, US Food and Drug Administration; GLP-1RA, glucagon-like peptide-1 receptor agonist; s.c., subcutaneous; T2D, type 2 diabetes.

Figure 2. Current ADA recommendations for pharmacological treatment of adults with T2D [3].American Diabetes Association [9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes–2020, American Diabetes Association, 2020]. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.A1C, glycated hemoglobin; ADA, American Diabetes Association; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1RA, glucagon-like peptide-1 receptor agonist; HF, heart failure; HFrEF, heart failure reduced ejection fraction; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, sulfonylurea; T2D, type 2 diabetes; TZD, thiazolidinedione; UACR, urine albumin-to-creatinine ratio

Table 2. Overview of key clinical outcomes with GLP-1RAs [11–13,25,27,28,30]

Agent	Relative efficacy (based on authors’ clinical judgment and data from RCTs)*		Composite MACE outcome^†
	HbA1c reduction*	Body weight reduction (kg)*
Exenatide twice daily	+	+(+)	No CVOT performed
Lixisenatide once daily	+	+	Noninferior to placebo when added to standard of care
Liraglutide once daily	++	++	Superior to placebo when added to standard of care^‡
Exenatide once weekly	+	+	Noninferior to placebo when added to standard of care
Dulaglutide once weekly	++	++	Superior to placebo when added to standard of care^#
Subcutaneous semaglutide once weekly	+++	+++	Superior to placebo when added to standard of care^‡
Oral semaglutide once daily	++(+)	++(+)	Noninferior to placebo when added to standard of care^§

*These estimates are based on clinical judgment and data from RCTs evaluating GLP-1RAs as monotherapy or as a single addition to oral antihyperglycemic agents reported in the prescribing information; ^†based on results from CVOTs with a primary outcome of MACE (first events of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) – a prospective CVOT for exenatide twice daily has not been performed; ^‡FDA-approved for reducing risk of MACE in adults with T2D who have established CVD; ^#FDA-approved for reducing risk of MACE events in adults with T2D who have established CVD or multiple cardiovascular risk factors; ^§a phase 3 clinical study (SOUL; NCT03914326) is ongoing to determine whether oral semaglutide is superior to placebo for reducing the risk of MACE in patients with T2D [36].

CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; FDA, US Food and Drug Administration; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA_1c, glycated hemoglobin; MACE, major adverse cardiovascular events; RCT, randomized controlled trial; T2D, type 2 diabetes.

Figure 3. Overview of the global PIONEER clinical trial program for oral semaglutide [117–124].Text in italics indicates allowed background medications.*In PIONEER 8, patients could receive basal, basal bolus, or premixed insulin regimens.CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase 4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; met, metformin; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione; vs, versus

DeFronzo RA, Triplitt CL, Abdul-Ghani M, et al. Novel agents for the treatment of type 2 diabetes. Diabetes Spectr. 2014;27(2):100–112.

 PubMedGoogle Scholar

Gentilella R, Pechtner V, Corcos A, et al. Glucagon-like peptide-1 receptor agonists in type 2 diabetes treatment: are they all the same? Diabetes Metab Res Rev. 2019;35(1):e3070.

 PubMed Web of Science ®Google Scholar

Nauck MA, Meier JJ. Are all GLP-1 agonists equal in the treatment of type 2 diabetes? Eur J Endocrinol. 2019;181:R211–R234.

 PubMed Web of Science ®Google Scholar

Soliqua^® (lixisenatide + insulin glargine) prescribing information [updated Nov 2019; cited 2020 May 25]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208673s008s009lbl.pdf

 Google Scholar

Xultophy^® (liraglutide + insulin degludec) prescribing information [updated Nov 2019; cited 2020 May 25]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208583s014s015lbl.pdf

 Google Scholar

American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S98–S110.

 PubMed Web of Science ®Google Scholar

Byetta^® (exenatide) prescribing information [updated Feb 2020; cited 2020 May 25]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021773s043lbl.pdf

 Google Scholar

Bydureon^® (exenatide extended-release) prescribing information [updated Feb 2020; cited 2020 May 25]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022200s030lbl.pdf

 Google Scholar

Adlyxin^® (lixisenatide) prescribing information [updated Jan 2019; cited 2020 May 25]. Available from: http://products.sanofi.us/Adlyxin/Adlyxin.pdf

 Google Scholar

Clinicaltrials.gov. A heart disease study of semaglutide in patients with type 2 diabetes (SOUL). ClinicalTrials.gov Identifier: NCT03914326 [cited 2020 May 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT03914326

 Google Scholar