A Review of Practical Issues on the Use of Glucagon-Like Peptide-1 Receptor Agonists for the Management of Type 2 Diabetes

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well established as effective treatments for patients with type 2 diabetes. GLP-1 RAs augment insulin secretion and suppress glucagon release via the stimulation of GLP-1 receptors. Although all GLP-1 RAs share the same underlying mechanism of action, they differ in terms of formulations, administration, injection devices and dosages. With six GLP-1 RAs currently available in Europe (namely, immediate-release exenatide, lixisenatide, liraglutide; prolonged-release exenatide, dulaglutide and semaglutide), each with its own characteristics and administration requirements, physicians caring for patients in their routine practice face the challenge of being cognizant of all this information so they are able to select the agent that is most suitable for their patient and use it in an efficient and optimal way. The objective of this review is to bring together practical information on the use of these GLP-1 RAs that reflects their approved use.Funding: Eli Lilly and Company.Plain Language Summary: Plain language summary available for this article.

Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes: Their Use and Differential Features

“…Overall, GLP-1RAs are well tolerated, with gastrointestinal effects being the most common adverse drug reactions (ADRs; Table 5) [19,[49][50][51]. Of note, as the effects of GLP-1RAs are glucose-dependent, they do not have an intrinsic risk of hypoglycaemia.…”

“…The relative incidences of injection-site reactions with GLP-1RAs are difficult to determine as their frequency and characteristics in RCTs are inconsistently reported and lack statistical analysis [19,51]. In head-to-head RCTs, exenatide ER recipients had a higher rate of injectionsite reactions than exenatide IR recipients [12][13][14] and semaglutide recipients had a lower rate of injection-site reactions than exenatide ER recipients [31].…”

“…Most common type of ADR; most frequent at the beginning of treatment, then ↓ gradually [19,[50][51][52] Use is not recommended in pts with inflammatory bowel disease or diabetic gastroparesis [4][5][6][7][8][9][10][11][12][13][14][15][16] Nausea: very common a (reported in up to 50% of pts); generally mild to moderate in severity and dose-dependent [49] Short-acting GLP-1RAs b : ↑ risk due to substantial delays in gastric emptying; ↓ slowly over several months; may lead to treatment discontinuation (long-acting GLP-1RAs do not delay gastric emptying; nausea rapidly resolves) [19,49,52] Other common a events: dyspepsia, constipation, abdominal pain [52]; vomiting is more common with dulaglutide than with exenatide IR [53] Cardiovascular-related effects No significant ↑ in the risk of cardiovascular effects (Sect. 5) [44,48,[54][55][56] May cause small ↑ in heart rate (2.1-3.3 beats/min) and moderate ↓ in systolic blood pressure (1.8-4.6 mmHg) vs PL [56] No significant ↑ in rates of hypertension [56], atrial fibrillation [55] or heart failure [54]; no effect on QT interval [49] Microvascular effects Diabetic retinopathy: ↑ risk of early worsening with semaglutide (consistent with early worsening that occurs with insulin; associated with rapid and sizeable improvements in glycaemic control) [57], but not other GLP-1RAs [58,59] Nephropathy: ↓ risk [58,…”

“…vomiting and diarrhoea) or are receiving drugs (i.e. renin-angiotensin system inhibitors) that predispose them for volume depletion [20,49] Pancreatitis and pancreatic cancer Current data do not support a link between these conditions and incretin-based drugs [62,63] As a precautionary measure, do not use GLP-1RAs in pts with pancreatic cancer or acute pancreatitis [20,49,51] Thyroid C-cell tumours GLP-1RAs caused thyroid C-cell tumours at clinically relevant exposures in rodent, but not primate, studies; unknown whether GLP-1RAs cause thyroid C-cell tumours, including medullary thyroid carcinoma, in humans (relevance of rodent studies in humans is likely to be low, but cannot be excluded) [4][5][6][7][8][9][10][11][12][13][14][15][16] USA: use is contraindicated (black-box warning) in pts with a personal or family history of medullary thyroid carcinoma or in pts with multiple endocrine neoplasia syndrome type 2 [5,7,9,11,13,14,16] Others Infections and headache: frequently reported in RCTs, but no causal association with GLP-1RA treatment [49] ↑ risk of bone fractures: linked to exenatide but not liraglutide [64]; causality is controversial [49] EU: ↑ risk of thyroid ADRs (e.g. goitre); reported in RCTs, particularly in pts with pre-existing thyroid disease; use with caution in such pts [4,6,8,10,12,15] ADR adverse drug reaction, IR immediate release, PL placebo, pts patients, RCT randomized, controlled trial, ↑ increase(s), ↓ de...…”

Pharmacologically relevant drug interactions of Glucagon-like peptide-1 receptor agonists

“…The drugs such as Exenatide, Liraglutide, Lixisenatide, Albiglutide, Dulaglutide and Semaglutide are approved as GLP-1 agonists and administered subcutaneously to manage fasting and postprandial blood glucose. 1 The antidiabetic effect of GLP-1 agonists occurs through many mechanisms including increased glucose-dependent insulin secretion, suppressed glucagon levels, delayed gastric emptying and reduced food intake. 2 Diabetes affects millions of people around the world and it is one of the leading causes of cardiovascular diseases, blindness, kidney failure, amputations, and others.…”