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

Abstract

Glucagon-like peptide-1 (GLP-1) is a hormone of the incretin system responsible for a variety of glucoregulatory effects, including glucose-dependent secretion of insulin and inhibition of glucagon release, the effects of which are impaired in people with type 2 diabetes (T2D). Targeting this deficiency using GLP-1 receptor agonists (GLP-1RAs) is a well-established approach in T2D, with over a decade of clinical experience now accrued. This article reviews the evidence for subcutaneous GLP-1RAs and their role in T2D treatment, and explores the rationale for an oral GLP-1RA from a primary care perspective. Clinical trials and real-world studies with subcutaneous GLP-1RAs indicate that these agents have good glycated hemoglobin (HbA 1c)-lowering efficacy, an inherently low potential for hypoglycemia, and reduce body weight. Cardiovascular outcomes trials have established cardiovascular safety, and three GLP-1RAs have been proven to reduce the risk of major adverse cardiovascular events (MACE) in patients with established cardiovascular disease or at high cardiovascular risk. The most common adverse events associated with GLP-1RAs are gastrointestinal effects, which tend to occur soon after initiation and decline over time. T2D treatment guidelines recommend GLP-1RAs as a therapeutic option in various settings, including in those patients: i) not achieving HbA 1c targets after first-line metformin and lifestyle modifications; ii) at high risk of/with established atherosclerotic cardiovascular disease (regardless of HbA 1c ; GLP-1RAs of proven benefit); iii) not achieving HbA 1c targets on basal insulin if not already receiving a GLP-1RA. Despite the known benefits of GLP-1RAs, adherence and persistence rates are suboptimal, potentially due in part to injection-related concerns. With some patients having a preference for oral medications, the development of an oral GLP-1RA is a logical approach to improving treatment options for patients with T2D. Co-formulation of semaglutide with an absorption enhancer has enabled the development and recent approval of the first oral GLP-1RA, oral semaglutide, which has the potential to expand use of GLP-1RAs in clinical practice.

Intestinal HIF-2α Regulates GLP-1 Secretion via Lipid Sensing in L-Cells

“…Compelling evidence shows that GLP-1–based therapies are superior in restoring normoglycemia in type 2 diabetic patients. 52 , 53 , 54 However, no current treatments leverage the endogenous GLP-1 owing to an incomplete understanding of the GLP-1 secretory mechanisms. Our data provide a strong mechanistic insight into the role of HIF-2α in regulating GLP-1 secretion through lipid sensing.…”

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

“…However, selecting the right drug for the treatment of diabetic patients with malignancies is a difficult clinical decision. As mentioned, GLP-1RAs are increasingly used in the treatment of T2MD owing to their following advantages: lowering of the levels of blood glucose, reducing body weight, improving the function of islet, and exerting potential cardiovascular benefits ( 206 ). Whether GLP-1RAs could also affect the occurrence and development of tumors has been the focus of attention only in recent years.…”

Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective

“…Since 2008, FDA requires all new diabetes therapies to demonstrate cardiovascular safety; therefore, cardiovascular outcomes trials have been carried out to establish the cardiovascular safety of incretin-based therapies [ 244 ]. To date, four GLP-1RAs have been proven to reduce the risk of major adverse cardiovascular events (MACE) in patients at high cardiovascular risk or with established cardiovascular disease.…”