GLP-1s and GLP-1 Agonist

GLP-1 agonists are a group of medications that mimic the actions of glucagon-like peptide or GLP-1. GLP-1 is one of several naturally occurring incretin compounds that affect the body after they are released from the gut during digestion. Because of its name, GLP-1 might seem to act like glucagon that increases glucose production by the liver and raises glucose levels. Instead, GLP-1 lowers both glucose and glucagon levels. Despite their different actions, GLP-1 and glucagon are both derived from the same parent compound called proglucagon, hence the similarity in names.

We all know that insulin, either naturally from beta-cell or injected from outside, affects the level of glucose in the blood. Other compounds from the gut, called Incretins, also lower the glucose level, as well as affects other biologic areas. In 1902, researchers first proposed that the gut might directly signal the pancreas. The term incretin was first used in 1930 to describe the enhanced glucose-lowering effect that was seen when a gut extract was fed to dogs. In the 1960s, researchers discovered that almost twice as much insulin was released when they infused glucose directly into the gut rather than into the blood as an IV solution. This renewed the search for compounds produced by the gut that might contribute to lowering the glucose.

Following food intake, these compounds, called incretins, are released into the blood from the intestine. GLP-1 or glucagon-like peptide-1 is one incretin that lowers glucose levels especially after meals as well as fasting levels through its natural effects on several organs.

  1. GLP-1 delays food absorption from the intestines, allowing injected insulin’s slow response time to better match digestion and lower postmeal readings. (Type 1and Type 2)
  2. In the pancreas, GLP-1 stimulates the release of insulin from the beta cells by increasing the size and number of beta cells. This often restores first phase insulin secretion and the amount of insulin produced to keep the glucose from rising after meals.1,2(Type 2)
  3. Also in the pancreas, GLP-1 reduces the inappropriate and excessive release of glucagon after meals. This also lowers postmeal glucose levels.2 (Type 1 and Type 2)
  4. In the brain, GLP-1 suppresses an appetite receptor in the hypothalamus. This reduces hunger and improves satiety in many people.30,31(Type 1 and Type 2)

Because of its name, glucagon-like peptide-1 might seem to act like glucagon that increases glucose production by the liver and raises glucose levels. Instead, GLP-1 lowers both glucose and glucagon levels. GLP-1 and glucagon are both derived from the same parent compound called proglucagon but have very different actions.

GLP-1 itself could not be used as a drug because it is broken down in less than 2 minutes by an enzyme called DPP-4 found throughout the body. To overcome this problem, GLP-1 agonists have been developed to act like GLP-1 but not be broken down as quickly.

The first incretin released by the FDA was Byetta, approved in May of 2005. This GLP-1agonist was found to work longer in the body but has the same effects as natural GLP-1. Its origin was rather unusual, being derived from a compound found in the saliva of the Gila monster, a large lizard native to the southwestern US. Gila monsters eat just 5 to 10 times a year, so researchers suspected correctly that they could provide interesting incretins to study. One incretin modified from Gila monster saliva turned into Byetta. Besides lower glucose levels, research showed that people on Byetta eat about 20% less and often lose weight.

Since then, several GLP-1 agonists, injected at the following schedules, have been approved by the FDA:

  • exenatide (Byetta/Bydureon), 2005/2012, twice a day/once a week
  • liraglutide (Victoza, Saxenda), 2010/2017, both once a day/Saxenda for weight loss
  • lixisenatide (Lyxumia), 2016, once a day
  • albiglutide (Tanzeum), 2014, once a week
  • dulaglutide (Trulicity), 2014, once a week
  • semaglutide (Ozempic), 2017, once a week

The GLP-1s above are currently available by prescription for people with Type 2 diabetes.

GLP-1 Agonist

GLP-1 agonists lower glucose levels and improve control for those on insulin, and can often substantially delay the need to start insulin in those with Type 2 diabetes. They carry a low risk of hypoglycemia, promote weight loss, and show improvements in beta-cell function, lipid levels, and blood pressure. Used by themselves or with insulin, they greatly improve post-meal glucose levels for most users. However, like other diabetes medications, they are not as effective as insulin at lowering glucose levels.

For Type 2 diabetes, starting early on a GLP-1 appears to be important. GLP-1s protect the beta cells that make insulin, extend beta-cell function, and help maintain glucose control, often for years. A 2017 report in the Lancet found that when people with pre-diabetes and obesity were treated with Victoza for 3 years, only one-third of them progressed to Type 2 diabetes compared to controls.3 GLP-1s can significantly slow the progression of Type 2 diabetes if used early when enough beta-cell mass and function allows these cells to be preserved or restored. However, GLP-1 agonists are unlikely to protect beta cells in Type 1 diabetes, even though its additional actions can be quite helpful.

Insulin production in the pancreas with Type 2 diabetes is greatly reduced by the time diabetes is diagnosed, so any medication that improves insulin production and lowers glucose levels is very helpful. Unlike a glitazone medication like Actos that reduces insulin resistance, GLP-1 agonists do not affect insulin resistance. Because of their distinct protective actions, these two classes of drugs may have additive effects that protect the beta cells.

Both GLP-1 agonists and glitazones like Actos slow down the loss of insulin production that is a primary cause for rising glucose levels over time and forces many with Type 2 diabetes to start on insulin. In his 2008 Banting Lecture to the American Diabetes Association, Dr. Ralph DeFronzo, a diabetes specialist and researcher at the University of Texas Health and Science Center in San Antonio, recommended that these two medication classes be considered first when treating Type 2 diabetes because they preserve beta-cell function and that they might be considered in those who have pre-diabetes due to their capacity to protect beta cells. This makes it easier to control glucose levels and delays or reduces the need for insulin.

Unfortunately, GLP-1 agonists do not maintain insulin production in Type 1 or Type 1.5 diabetes. Here, diabetes is caused by an antibody attack by the immune system that gradually destroys the beta cells that make insulin. GLP-1 agonists cannot stop this process.

Not yet approved for Type 1 diabetes, GLP-1 agonists have been used in 9 trials of people with Type 1 diabetes.4 The researchers found a non-significant A1c reduction of 0.6% versus 0.2% for controls and a weight loss of 14.1 lbs (6.4 kg). Nausea was the most common side effect. The authors concluded: “The use of GLP-1 agonists should be considered in T1DM patients who are overweight or obese and not at glycemic goals despite aggressive insulin therapy.”

Following its clinical trials with a GLP-1 agonist, Novo-Nordisk decided not to seek FDA approval for Type 1 diabetes. They were disappointed with a non-significant reduction of 0.5% in A1c for those on the drug compared to 0.3% in the placebo group in poorly controlled patients with an A1c above 8% with no reduction in hypoglycemia, but an average weight loss of 10 lbs.

GLP-1 agonists come in pens that allow doses to be gradually increased. Correct dosing is critical. An ideal dose is easy to spot: you feel either mild nausea or a decrease in hunger. Do not increase any dose if it worsens nausea. Another good marker for the right dose is to check several pre and 2-hour post glucose levels or use a CGM for breakfast and dinner over at least 3 days before you start. Then repeat this once you appear to have reached an ideal dose. Glucose readings, especially the postmeal ones, should be considerably improved.

Clinicians usually start GLP-1s at a low dose to avoid side effects and then gradually increase it. For example, the Victoza pen that is injected daily can be started at the 0.6 mcg mark on the first day and then gradually increased by one click a day. It has 10 clicks between 0.6 and the next mark at 1.2 and anther 10 clicks up to 1.8 mcg. If mild nausea occurs at one of these steps, wait 3 days and you can usually increase another click. If worse nausea or vomiting does occur, skip a day, and restart at a slightly lower dose the next day.

GLP-1 agonists that are taken once a week generally have fewer symptoms, but no one wants to start with a week of nausea or vomiting! Again with these, start at the lowest marked dose, usually about 1/3 of the max dose. Then increase by 3 clicks each week until mild nausea or a noticeable decrease in hunger occurs.

Side Effects

Rarely and for unknown reasons, a person may not tolerate even a minimal dose of a GLP-1 agonist, so another approach will be needed. The most common side effects of GLP-1 agonists are a feeling of fullness, nausea, and diarrhea. Nausea does not appear to be related to dose size and usually disappears after a couple of weeks. Side effects usually decrease in most people and less than one in ten users stops a GLP-1 agonist due to side effects. Users may experience a decreased appetite, acid reflux, headaches, or increased sweating. Immune system reactions occasionally occur with skin hives being the most common.

Your doctor should be called and the medication stopped immediately if unusual abdominal pain or intestinal problems occur. Although there was initial concern that GLP-1 medications might cause acute pancreatitis, no evidence for this has been forthcoming. A 2017 review of 3 studies longer than 2 years with over 9,000 people in both the treated and placebo arms actually found a non-significant reduction in risk for those on a GLP-1 agonist.5 Initially, there was also some concern about pancreatic cancer, but subsequent large clinical studies have found no reliable link between GLP-1 agonists and pancreatic cancer.6

Benefits:

  • Less glucose variability with fewer highs and lows
  • Lower post-meal glucose levels with some lowering of the fasting glucose
  • Often helps weight loss
  • Does not cause hypoglycemia directly unless insulin or sulfonylurea doses are excessive
  • May improve and preserve the health of the beta cell, and delay or lessen the need for injected insulin in Type 2 diabetes
  • OK with liver or heart problems

Drawbacks

  • Must be taken by injection.
  • Not FDA approved for Type 1 diabetes, although research studies suggest some benefits.
  • Nausea or vomiting may occur at first but usually resolves
  • People with gastrointestinal problems or moderate to severe kidney disease are not good candidates.
  • Responses to GLP-1 agonists vary widely from person to person.

References

  1. Fehse, F., Trautmann, M., Holst, J.J., et al. (2005) Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab, 90, 5991-5997.
  2. Kolterman, O.G., Kim, D.D., Shen, L., et al. (2005) Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Sys Pharmacy, 62, 173-181.
  3. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30069-7/fulltextThree years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: A randomized, double-blind trial.
  4. Janzen KM, Steuber TD, and Nisly SA. GLP-1 Agonists in Type 1 Diabetes Mellitus. Annals of Pharmacotherapy. Vol 50, Issue 8, pp. 656 – 665.
  5. Storgaard H, Cold F, Gluud LL, Vilsbøll T, Knop FK. Glucagon-like peptide-1 receptor agonists and risk of acute pancreatitis in patients with type 2 diabetes. Diabetes Obes Metab. 2017 Jun;19(6):906-908.
  6. Nauck MA, Friedrich N. Do GLP-1–Based Therapies Increase Cancer Risk? Diabetes Care 2013 Aug; 36(Supplement 2): S245-S252.
  7. Klonoff, D.C., Buse, J.B., Nielsen, L.L., et al. (2008) Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin, 24, 275-286.