From the Guidelines
The interaction between GLP-1 and DPP-4 is a crucial aspect of glucose regulation, and manipulating this interaction with medications such as GLP-1 receptor agonists is a more effective approach than using DPP-4 inhibitors in reducing morbidity and mortality in patients with type 2 diabetes, as evidenced by the most recent and highest quality study 1. The GLP-1 hormone, produced in the intestines, stimulates insulin secretion, inhibits glucagon release, slows gastric emptying, and promotes satiety, but its short half-life due to rapid degradation by DPP-4 limits its therapeutic potential.
- DPP-4 inhibitors, such as sitagliptin, saxagliptin, and linagliptin, work by blocking the DPP-4 enzyme, thereby prolonging the activity of endogenous GLP-1, as described in the 2019 standards of medical care for type 2 diabetes in China 1.
- Alternatively, GLP-1 receptor agonists, such as semaglutide, dulaglutide, and liraglutide, are modified versions of GLP-1 that resist DPP-4 degradation, allowing them to remain active much longer than natural GLP-1. The American College of Physicians recommends adding a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) agonist to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control, as stated in the 2024 clinical guideline 1.
- The use of GLP-1 receptor agonists has been shown to reduce the risk of all-cause mortality, major adverse cardiovascular events, and stroke, making them a preferred treatment option over DPP-4 inhibitors, which do not have the same level of evidence for reducing morbidity and mortality, as noted in the 2024 systematic review and network meta-analysis 1. In clinical practice, the choice between GLP-1 receptor agonists and DPP-4 inhibitors should be guided by the most recent and highest quality evidence, with a strong recommendation for the use of GLP-1 receptor agonists in patients with type 2 diabetes and inadequate glycemic control, as recommended by the American College of Physicians 1.
From the FDA Drug Label
Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. 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 interaction between GLP-1 and DPP-4 is that DPP-4 inactivates GLP-1 within minutes. Saxagliptin, a DPP-4 inhibitor, slows the inactivation of GLP-1, increasing its bloodstream concentrations and enhancing its effects, including:
- Increasing glucose-dependent insulin secretion
- Lowering glucagon secretion
- Reducing hepatic glucose production 2
From the Research
GLP1 and DPP4 Interaction
- GLP-1 is an incretin hormone that stimulates insulin secretion, increases beta cell neogenesis, inhibits beta cell apoptosis, inhibits glucagon secretion, delays gastric emptying, and induces satiety 3.
- GLP-1 is rapidly inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme, resulting in a short circulating half-life of the active form of GLP-1 (< 2 min) 3.
- Two strategies have been employed to overcome this obstacle: using GLP-1 receptor agonists with a prolonged half-life due to reduced degradation by DPP-4, and inhibiting the enzyme DPP-4 to prolong the half-life of endogenously released active GLP-1 3, 4.
DPP4 Inhibition and GLP1 Levels
- DPP-4 inhibition increases levels of active GLP-1, which enhances insulin secretion and diminishes glucagon secretion, reducing glucose concentrations in blood 4.
- GLP-1 analogues, such as exenatide and liraglutide, have been shown to reduce HbA1c levels and weight in type 2 diabetic patients when combined with insulin 5.
- DPP-4 inhibitors, such as sitagliptin, saxagliptin, and vildagliptin, have also been shown to reduce HbA1c levels and have no significant effect on weight 5.
Association between GLP1 and DPP4
- Studies have found a significant positive correlation between GLP-1 and DPP-4 levels in newly diagnosed type 2 diabetic patients and controls 6.
- GLP-1 levels were found to be significantly higher in controls than in impaired glucose tolerant and newly diagnosed type 2 diabetic patients, while DPP-4 concentrations were significantly lower in newly diagnosed type 2 diabetic patients compared to controls and impaired glucose tolerant patients 6.