What is the role of Incretin-Based Therapy in the management of Type 2 Diabetes Mellitus (T2DM)?

From the Guidelines

Incretin-based therapies, particularly GLP-1 receptor agonists, are a crucial component in the management of Type 2 Diabetes Mellitus (T2DM), offering significant glucose lowering, weight loss, and cardiovascular benefits, and should be considered as second-line agents after metformin or as first-line therapy when metformin is contraindicated. The evidence from recent studies, including a series of seven published CVOTs 1, demonstrates that GLP-1 receptor agonists, such as semaglutide, dulaglutide, and liraglutide, have shown statistically significant reductions in major adverse cardiovascular events (MACE) and all-cause mortality.

The mechanism of action of incretin therapies involves enhancing glucose-dependent insulin secretion, suppressing glucagon release, slowing gastric emptying, and promoting satiety 1. GLP-1 agonists, in particular, have been shown to offer additional cardiovascular and renal benefits, with meta-analyses demonstrating a 12% reduction in 3-point MACE, 12% reduction in CV death, 11% reduction in all-cause mortality, and 17% reduction in a broad kidney composite outcome 1.

Key considerations for the use of incretin-based therapies include:

• Patient characteristics, such as the presence of cardiovascular disease or chronic kidney disease
• Patient preferences and priorities, including the need for weight loss or the presence of needle aversion
• The potential for common side effects, such as nausea and vomiting with GLP-1 agonists, which typically improve over time
• The importance of avoiding these medications in patients with a history of pancreatitis or medullary thyroid cancer

Recent guideline recommendations and consensus statements, including those from the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the European Society of Cardiology (ESC) 1, emphasize the importance of individualized care and the need to consider the latest evidence when making therapeutic decisions. The use of GLP-1 receptor agonists, such as semaglutide, dulaglutide, and liraglutide, should be prioritized in patients with T2DM who require significant glucose lowering and weight loss, and who are at high risk of cardiovascular events.

From the FDA Drug Label

VICTOZA is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated: • as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus (1) • to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (1).

The role of Incretin-Based Therapy, such as liraglutide, in the management of Type 2 Diabetes Mellitus (T2DM) is:

• Improving glycemic control: as an adjunct to diet and exercise in adults and pediatric patients aged 10 years and older with T2DM.
• Reducing cardiovascular risk: to reduce the risk of major adverse cardiovascular events in adults with T2DM and established cardiovascular disease. 2 2

From the Research

Role of Incretin-Based Therapy in T2DM Management

• Incretin-based therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, have been shown to be effective in improving glycemic control in patients with type 2 diabetes mellitus (T2DM) 3, 4.
• DPP-4 inhibitors, such as sitagliptin, have been found to reduce HbA1c levels by 0.5-1.1% without increasing the risk of hypoglycemia or weight gain 4.
• GLP-1 analogues, such as exenatide and liraglutide, have been shown to reduce HbA1c levels by 0.8-1.7% and promote weight loss, although they may be associated with gastrointestinal side effects 4.
• The combination of SGLT2 inhibitors and DPP-4 inhibitors has been found to be effective in reducing HbA1c levels and promoting weight loss, with a low risk of hypoglycemia 5.

Advantages of Incretin-Based Therapy

• Incretin-based therapies have been found to have a favorable safety profile, with a low risk of hypoglycemia and weight gain 3, 4.
• DPP-4 inhibitors, such as sitagliptin, have been found to be effective in improving glycemic control in patients with T2DM, including those with renal impairment or cardiovascular disease 3.
• The combination of SGLT2 inhibitors and DPP-4 inhibitors has been found to be effective in reducing HbA1c levels and promoting weight loss, with a low risk of hypoglycemia 5.

Long-Term Efficacy of Incretin-Based Therapy

• Sitagliptin has been found to be effective in improving glycemic control over 2 years of treatment, both as monotherapy and as add-on therapy to metformin 6.
• The long-term efficacy of incretin-based therapies has been found to be associated with improvements in measures of beta-cell function, such as HOMA-β and proinsulin/insulin ratio 6.
• Further studies are needed to determine the long-term effects of incretin-based therapies on glycemic control and cardiovascular outcomes in patients with T2DM 7.