Incretin therapies in type 2 diabetes: clinical considerations for prescribing GLP-1 agonists

Incretin therapies target a key physiologic response involved in post-meal glucose control. Normally, when glucose is given orally, it triggers a greater insulin release than when the same amount of glucose is given by IV. This response, called the incretin effect, is reduced in type 2 diabetes. By mimicking the action of natural GLP-1, these therapies enhance insulin release in response to food and help lower blood sugar levels effectively.

In this lesson from our Advanced Management Strategies in Type 2 Diabetes course, you’ll learn how incretin therapies:

• Enhance insulin release in response to food
• Slow gastric emptying
• Improve overall blood sugar control
• Support weight loss
• Provide very high efficacy in lowering blood sugars, with a low risk of hypoglycemia

Whether you’re starting therapy or revisiting treatment decisions, this lesson provides a clear, clinically grounded view of how incretin therapies are used in the advanced management of type 2 diabetes.

The incretin effect in type 2 diabetes

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GLP-1 receptor agonists are a category of medications known as 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 phenomenon, called the incretin effect, highlights the role of glucose-sensitive receptors in the gastrointestinal tract. These receptors stimulate the release of hormones such as glucagon-like peptide, also known as GLP-1. 

How incretin-based therapies work

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Unfortunately, in type 2 diabetes, the incretin effect is diminished. By mimicking the action of natural GLP-1, the GLP-1 agonists enhance insulin release in response to food, helping lower blood sugar levels effectively. GLP-1 is released by cells in the small intestine after a meal. Once in circulation, it travels to the pancreas and stimulates insulin secretion while also suppressing glucagon release. It slows gastric emptying, which increases satiety and helps patients feel full sooner and eat less. This delay in digestion also slows the post-meal rise in blood sugar. Together, these effects improve blood sugar control and support weight loss. For patients with type 2 diabetes, where the natural GLP-1 response is reduced, GLP-1 receptor agonists provide a valuable way to restore these benefits.

Dual incretin therapy: GLP-1 and GIP combinations

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A newer addition to this class combines GLP-1 receptor agonists with another hormone called gastric inhibitory polypeptide, or GIP. GIP works similarly to GLP-1 by enhancing insulin release in response to food. This combination, found in the medication tirzepatide, offers impressive efficacy for lowering blood sugar, enhancing satiety, and promoting weight loss. Unlike traditional GLP-1 receptor agonists, GIP does not slow gastric emptying, which may help reduce some of the gastrointestinal side effects commonly associated with this class of medications.

Additional benefits of incretin therapies

Cardiovascular effects of incretin therapies

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Beyond their role in lowering blood sugars, several GLP-1 receptor agonists have cardiovascular benefits and should be the initial treatment options for patients with type 2 diabetes and established cardiovascular disease. While the combination GLP-1 / GIP receptor agonists haven’t yet demonstrated similar benefits, they are considered safe from a cardiovascular outcomes perspective. 

Renal outcomes with incretin therapies

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Several GLP-1 receptor agonists have shown potential to slow the progression of diabetic kidney disease in patients with chronic kidney disease, offering an additional layer of protection. While they may help reduce the risk of worsening kidney function, they do not reverse existing damage. Emerging evidence also suggests that combination therapies like tirzepatide may help preserve kidney function compared to glargine, though long-term studies are still ongoing to confirm these benefits.

Glycemic control with incretin-based therapies

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The GLP-1 receptor agonists have very high efficacy in lowering blood sugars and are also a reasonable option for patients with type 2 diabetes without other complications to help lower A1c and achieve glucose control. On average, they can reduce A1c by about 1%, and the combination therapies can achieve reductions of up to 2%. Most of these medications are injectables, but they are convenient to use, with many available as once-weekly injections. This dosing schedule can help improve adherence, especially for patients who find daily medications challenging.

Safety considerations with incretin therapies

Common side effects of incretin therapies

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Like any treatment, GLP-1 receptor agonists have potential side effects. The most common is nausea, which occurs due to the slowing of gastric emptying. The severity of nausea varies widely. Some patients tolerate these medications well, while others may struggle, even at low doses. Gradual dose titration can help minimize this side effect. These medications are contraindicated in gastroparesis, as their effects on gastric emptying could worsen symptoms.

Additional considerations: pancreatitis

[04:20]

There are other considerations as well. Pancreatitis has been reported in some patients using GLP-1 receptor agonists, though it’s unclear if the medications are the direct cause. If pancreatitis develops, it’s appropriate to stop the medication. 

C-cell hyperplasia in preclinical studies

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Preclinical animal studies showed an increase in C-cell hyperplasia, which could increase the risk of medullary thyroid cancer, a cancer of the C cells in the thyroid. It is unclear if this is relevant for humans. As a precaution, these medications are not recommended for individuals with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia types 1 or 2. However, there is no increased risk for other types of thyroid cancer.

Low hypoglycemia risk and weight benefits of incretin therapy

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One major advantage of GLP-1 and GIP receptor agonists is their low risk of hypoglycemia. Since they only enhance insulin release when blood sugar levels are elevated, such as after a meal, they are a safe option for patients at risk of low blood sugar. Additionally, their weight loss benefits have led to their approval as a weight loss treatment, even for individuals without diabetes. For patients with type 2 diabetes who are also working on weight management, these medications can be particularly helpful.