What is the relationship between Dipeptidyl Peptidase-4 (DPP-4) inhibitors and Glucagon-Like Peptide-1 (GLP-1)?

From the Guidelines

DPP-4 inhibitors should not be added to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control to reduce morbidity and all-cause mortality, instead, a GLP-1 agonist or SGLT-2 inhibitor should be considered. This recommendation is based on the most recent and highest quality study, which prioritized outcomes such as all-cause mortality, major adverse cardiovascular events, and progression of chronic kidney disease 1. The study found that GLP-1 agonists and SGLT-2 inhibitors have a stronger evidence base for reducing these outcomes compared to DPP-4 inhibitors.

Key Points

• DPP-4 inhibitors, such as sitagliptin, saxagliptin, and linagliptin, work by preventing the breakdown of naturally occurring GLP-1, leading to modest improvements in blood glucose with minimal side effects and no weight changes 1.
• GLP-1 receptor agonists, such as semaglutide, dulaglutide, and liraglutide, directly activate GLP-1 receptors, providing stronger glucose-lowering effects while promoting weight loss and offering cardiovascular benefits 1.
• The American College of Physicians recommends adding a GLP-1 agonist or SGLT-2 inhibitor to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control, rather than a DPP-4 inhibitor 1.

Considerations

• When choosing a medication, consider the patient's individual needs and characteristics, such as the presence of cardiovascular disease or the desire for weight loss.
• GLP-1 agonists and SGLT-2 inhibitors may have a higher cost and may require more frequent monitoring compared to DPP-4 inhibitors.
• The potential benefits of GLP-1 agonists and SGLT-2 inhibitors, including reduced risk of major adverse cardiovascular events and progression of chronic kidney disease, should be weighed against the potential risks and costs.

From the FDA Drug Label

In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved Saxagliptin is a competitive DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells

The DPP-4 inhibitors, such as saxagliptin, work by slowing the inactivation of incretin hormones like GLP-1. This results in:

• Increased bloodstream concentrations of GLP-1
• Reduced fasting and postprandial glucose concentrations in patients with type 2 diabetes mellitus
• Increased glucose-dependent insulin secretion from pancreatic beta cells 2

From the Research

DPP-4 Inhibitors and GLP-1

• DPP-4 inhibitors, such as sitagliptin, vildagliptin, and saxagliptin, are a novel oral treatment for type 2 diabetes 3, 4, 5, 6
• They work by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which prevents the inactivation of glucagon-like peptide-1 (GLP-1) 3, 4, 7
• The increased levels of active GLP-1 stimulate insulin secretion and inhibit glucagon secretion, resulting in lowered glucose levels and improved glycemic control in patients with type 2 diabetes 3, 4, 7

Mechanism of Action

• DPP-4 inhibitors have no intrinsic glucose-lowering activity, and their efficacy is related directly to their ability to inhibit DPP-4 activity and protect its substrates, including GLP-1 7
• The effects of GLP-1 are glucose-dependent, which means that the risk of hypoglycemia with DPP-4 inhibitors is low 7

Clinical Efficacy

• DPP-4 inhibitors have been shown to improve metabolic control in type 2 diabetes, both as monotherapy and in combination with other treatments such as metformin, sulfonylurea, and thiazolidinediones 3, 4, 5, 6
• The reduction in HbA(1c) levels with DPP-4 inhibitors is approximately 0.6-1.1% in studies up to 52 weeks 3, 4
• DPP-4 inhibitors are safe and tolerable, with a low risk of hypoglycemia and no significant weight gain 3, 4, 6

Safety Profile

• DPP-4 inhibitors have a favorable safety profile, with a low risk of adverse events compared to placebo 4, 7, 6
• However, there is a potential increased risk of acute pancreatitis associated with DPP-4 inhibitors 7