Type 2 Diabetes

GLP-1 Receptor Agonists

What Are GLP-1 Agonists and How Do They Work?

Non-insulin injectables are a type of medicine that is injected subcutaneously into fatty tissue via syringe or pen device. They are not meant to be used as a first line treatment agent, but most types can be used in combination with oral diabetes medicines as well as with insulin therapy.

GLP-1 agonists affect multiple organs inside your body to help improve blood glucose control.

Specifically, GLP-1 receptor agonists are a type of non-insulin injectable medication that is becoming increasingly popular and prominent, making its way into the forefront of diabetes care and research.

Studies have shown that these types of medicines, when used in combination with diet and exercise, both short acting and long acting, may help patients with type 2 diabetes lose weight, reduce their hemoglobin A1C (3 month average of their blood sugar), as well as potentially reduce the rate of cardiovascular death.

Current research suggests that these medicines are superior in reducing blood sugars compared to many different types of oral medicines and are not inferior to combination regimens such as basal insulin (long acting insulin), plus GLP-1 agonist versus basal insulin, plus rapid acting insulin.

How Do They Work?

These types of medications work because people with type 2 diabetes have a decrease in incretin affect, meaning that they have less incretin hormones. One incretin hormone specifically, known as glucagon-like peptide (GLP-1), is lower in people with diabetes. GLP-1 is normally released from your small intestine when you eat, and works to slow down the process by which food leaves your stomach, controlling your blood sugar after meals.

The benefit of GLP-1 agonists is that they mimic GLP-1 hormone by binding to GLP-1 receptors and stimulating insulin release, which reduces blood sugar.

GLP-1 agonists also act on the stomach, brain, pancreas, and liver to increase feelings of fullness and reduce after meal blood sugars, which promotes weight loss and improves blood sugar control.

Typically, they do not promote hypoglycemia because they only work when there is glucose in your system. This is a benefit for those people who are prone to hypoglycemia, however, when used in combination with insulin or sulfonylurea the risk for hypoglycemia increases. If you're looking for a different option for your diabetes management, talk to your doctor to better understand if this option is right for you and can help you better control your diabetes.

Effects on the Body

Brain: GLP-1 sends a signal to the brain, specifically the hypothalamus, telling it to decrease water and food intake. As a result, the person taking the GLP-1 agonist gets full more quickly. As you feel full more quickly, you are likely to consume less food and, as a result, lose weight. Because your sensation to drink can decline, it is also important to remember to hydrate to prevent dehydration.

Muscle: GLP-1 increases gluconeogensis in the muscle. This helps to lower blood sugars by stimulating glucose uptake by the cells and increasing insulin sensitivity (how well your body uses insulin).

Pancreas: GLP-1 increases insulin secretion when in contact with glucose. This helps to lower after meal blood sugars. In addition, GLP-1 decreases glucagon secretion and increases somostatin secretion. Glucagon’s job is to prevent blood sugars from going too low. In people with type 2 diabetes, glucagon can raise blood glucose levels too high because there is either not enough insulin present to lower blood sugar or the body is less able to respond to insulin. Therefore, by lowering glucagon output, blood sugars are reduced.

Liver: GLP-1 lowers hepatic (liver) glucose output, which helps to lower blood sugars. GLP-1 increases gluconeogensis, which is the metabolic pathway that generates glucose from non-carbohydrate substances, such as protein and fat. As gluconeogensis increases, glucagon (the hormone that helps to increase blood sugars) receptors are reduced in liver, inhibiting glucose formation and stimulating glucose uptake by cells which helps to lower sugar.

Stomach: GLP-1 decreases acid secretion and decreases gastric emptying, which slows down how quickly food leaves your stomach, increasing fullness, reducing how fast blood sugars rise, and often causing nausea. The reduced rate at which food leaves the stomach results in a decrease in food intake, which typically yields weight loss. Weight loss decreases insulin resistance, hence lowering blood sugars.

What Are the Different Types of GLP-1 Agonists?

GLP-1 agonists can be broken into two different categories: short acting formulas, which are typically dosed once or twice a day, or long-acting formulas, which are given once weekly. The type of GLP-1 you receive will depend on your medical history, insurance, personal preference and blood sugar control. Some GLP-1 agonists can be expensive; therefore it may make sense to call your insurance prior to receiving a prescription to make sure you can afford the medicine.

Short Acting GLP-1 Agonists – Once or Twice Daily Injectable

Drug: Exenatide

Brand Name: Byetta

Dose: Start with 5mcg twice daily 60 minutes before meals and increase to 10mcg after one month.

Positives: One of the least expensive types of GLP-1 agonists, probably because it’s been around the longest.

Negative: Must be given 60 minutes before a meal which can be inconvenient.

Other Considerations: Byetta is excreted through the kidneys and is not recommended for people with GFR’s of 30 or less.

Drug: Liraglutide

Brand Name: Victoza

Dose: 0.6mcg for one week and increase dose to 1.2mcg. If blood sugars are at goal, you can keep this dose, or increase to 1.8mcg as tolerated. Your doctor should advise you on how to increase the dose.

Positive: Has been proven to provide the most weight loss.

Negative: Must be given once daily. Patients report a high incidence of nausea, which is probably why there is so much weight loss.

Drug: Lixisenatide

Brand Name: Adlyxin

Dose: 10 mcg daily for two weeks and then increase to 20 mcg daily.

Positives: Has relatively the same efficacy as Byetta.

Negatives: Must be dosed daily 60 minutes before the first meal of the day

Other considerations: Is excreted via the kidneys and should be avoided with GFR’s

Long Acting GLP-1 Agonist – Once Weekly Injectable

Drug: Exenatide long acting form of Byetta

Brand Name: Bydureon (prescribed as a vial with a kit or pen)

Dose: 2mg weekly, given once per week.

A1C reduction: About 1.3 percent.

Positives: Given once weekly; can be prescribed via pen.

Negatives: Is renally excreted and should be avoided with GFR’s 30 or less. In addition, the gauge of the needle is thick (23G).

Other Considerations: Studies have shown that it is inferior to Victoza with regards to A1C reduction and can be laborious when dosing (must be mixed). In addition, many people complain of site reactions where the medicine is injected.

Drug: Dulaglitide

Brand Name: Trulicity (pen)

Dose: Start with 0.75mg weekly and increase to 1.5mg in 6 to 8 weeks.

A1C reduction: About 1.4 percent.

Positives: Does not need to be manually mixed. You do not have to attach needle and can throw away the entire pen in a sharps container after you’ve delivered the dose. It is dosed once per week and has a higher A1C reduction than Victoza.

Negatives: Is not covered by all insurances and can be expensive.

What Are the Side Effects?

  • The most common side effect of the GLP-1 agonists is nausea, vomiting and diarrhea. This occurs in about 10 to 40 percent (depending on the specific medication) of people and is more common in short acting agents. However, these side effects tend to lessen as a person is on the medication for a longer period of time. In addition, if you are taking a short acting GLP-1, such as Victoza, taking it before bed may help to reduce nausea.
  • Studies that have been conducted on rodents show that certain GLP-1 agonists, particularly liraglutide and dulaglutide, can promote thyroid cell tumors. Although these studies have not been conducted on humans, it is recommended that those people with a history or family history of medullary thyroid cancer and Multiple Endocrine Neoplasia type 2 do not use GLP-1 agonsists.
  • With certain GLP-1 agonists there is a possible small increased risk of pancreatitis (inflammation of the pancreas).
  • People can experience injection site reactions where the medication is inserted.

Who Should Avoid These Types of Medicines?

This medication is not recommended if:

Also, people with diabetes who have decreased kidney function, with a GFR (glomerular filtration rate) or 30 or less should not use bydureon and byetta. Discuss renal dosing with your physician if you are taking other GLP-1 agonists.

There is not enough evidence to support the safety in patients who are on dialysis, therefore avoiding GLP-1 use in this population is prudent.

What Is Next?

As diabetes medicines continue to emerge and research is rapidly underway for safer, more convenient, and more effective types of GLP-1 agonists, we are sure to see more medicines come our way in the future. In fact, another GLP-1 agonist that is currently applying for FDA approval, semaglutide, is said to reduce heart risks by 26 percent. And as a bonus, oral semaglutide is in phase II trials, which means one day, GLP-1 agonists may not need to be injected.

Sources:

Dungan, K, DeSantis, A. Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus. UptoDate.

Vishal, Gupta. Glucagon-like peptide-1 analogues: An overview. Indian J Endocrinol Metab. 2013 May-June, 17 (3): 413-421.

Smilowitz, N, Donnino, Robert, Schwartzbard, Arthur. Glucagon-like peptide receptor agonists for diabetes: A role in cardiovascular disease. Circulation.

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