Utilizing incretins in type 2 diabetes

Learn about the benefits of using incretin therapies (GLP-1 agonists and DPP-4 inhibitors) in the treatment of type 2 diabetes.

Tracy Tylee, MD
Tracy Tylee, MD
20th Oct 2018 • 4m read

Incretin mimetics have changed the face of type 2 diabetes management. In this video, from our Diabetes Mellitus Masterclass course, you'll learn about the incretin effect and how incretin therapies (GLP-1 agonists and DPP-4 inhibitors) can be used in the treatment of type 2 diabetes. You'll learn about their mechanisms of action, administration routes, typical effects on HbA1c, and possible complications.

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Video Transcript

[00:00:00] One of the newer classes of diabetes medications is the incretins. Normally, when glucose is given orally, it triggers a greater insulin release than when the same amount of glucose is given IV. This is known as the incretin effect, and this effect is blunted in type 2 diabetes. The incretin effect suggests there are glucose responsive receptors in the GI tract that

[00:00:30] trigger the release of a hormone that results in increased insulin release, in response to food. One of these hormones is called glucagon-like peptide-1 or GLP-1. GLP-1 is released by the L cells of the small intestine in response to a meal. GLP-1 then travels to the pancreas where it enhances insulin release. Medications that target this pathway provide a unique method for lowering blood sugars, for patients with type 2 diabetes, by

[00:01:00] increasing insulin release, in response to food. These medications are known as incretins and several have been developed for clinical use. One of the group of medications in this class is known as the dipeptidyl peptidase-4 inhibitors or DPP-4. Normally, GLP-1 is rapidly degraded by a DPP-4, which limits its activity. When we have increasing GLP-1 levels, in patients with type 2 diabetes, is to inhibit the activity of DPP-4

[00:01:30] and prolong the activity of endogenous GLP-1. The other medications that have been developed to target this pathway are synthetic GLP-1 receptor agonists. These bind and trigger, signaling via the GLP-1 receptor but are resistant to DPP-4 degradation so can increase GLP-1 signaling to supraphysiologic levels. The GLP-1 agonists have other actions outside their effect on the beta cell. They also delay gastric

[00:02:00] emptying, which slows the post-meal rise in glucose and increases satiety. They may also act to increase peripheral glucose uptake at the adipose tissue, liver, and muscle. In general, the GLP-1 receptor agonists are more effective than the DPP-4 inhibitors at lowering blood sugars, as they increase GLP-1 levels to supraphysiologic levels, while DPP-4 inhibitors simply prolong the action of endogenous GLP-1.

[00:02:30] You will typically get half to 1% A1c lowering with the DPP-4 inhibitors and 1 to 1.5% lowering with the GLP-1 receptor agonists. The GLP-1 receptor agonists are only available as injections, while the DPP-4 inhibitors are oral. This can be an important factor in deciding between the medications, as some patients may feel uncomfortable with injections. All DPP-4 inhibitors are taken once daily. The dose

[00:03:00] varies depending on the medication used. With the GLP-1 receptor agonists, there are options for short-acting daily or twice daily or long-acting once weekly formulations. The long-acting formulations tend to be more effective at lowering fasting blood sugar, while the short-acting have a greater effect on gastric emptying, and thus, on lowering post-meal blood sugars. The slowing of gastric emptying is responsible for the primary side effect

[00:03:30] of the GLP-1 receptor agonists, nausea. This is not seen with the DPP-4 inhibitors due to the fact that they do not have a significant impact on gastric emptying. In fact, the DPP-4 inhibitors produce very few side effects and are well tolerated. Pancreatitis has been noted with the use of incretins but it's unclear if this is actually related to incretin use. Pancreatitis is more common in diabetic patients and there's a lack of data

[00:04:00] and mechanism linking incretins to pancreatitis, thus, the cause of this complication remains unclear. There's also concern for increased risk for medullary thyroid cancer, based on preclinical studies in rodents, after treatment with certain GLP-1 receptor agonists. However, humans have much lower levels of GLP-1 receptors in their thyroid than do rodents, so it's believed that the risk for humans is actually quite low. Another possibly beneficial side effect of the incretins is their

[00:04:30] effect on weight. The DPP-4 inhibitors do not have a significant effect on gastric emptying or satiety and are considered weight neutral. However, the GLP-1 receptor agonists are associated with weight loss and have actually been developed as a weight loss medication for individuals who do not have type 2 diabetes. There have been several studies looking at cardiovascular effects of the incretins and to date, none have shown an increased risk of cardiovascular disease. There may be a small

[00:05:00] benefit with some GLP-1 receptor agonists. The incretins are a good option for patients who need additional glucose lowering but want to avoid weight gain. They are also good for patients who want to avoid hypoglycemia and may also be a good option for patients at high risk of cardiovascular disease. However, the nausea associated with the GLP-1 receptor agonists is limiting for many patients and while the DPP-4 inhibitors avoid this nausea, they're not as effective as other medications.

[00:05:30] Cost of these medications is often a concern as well. We'll discuss options that can result in effect of A1c lowering with weight loss but without nausea, in the next lesson.