The Incretins: GLP-1 Agonists and DPP-4 Inhibitors

We all know that insulin, either naturally from beta cells 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. In the intestines, GLP-1 delays food absorption, allowing injected insulin’s rather slow response to catch up for lower postmeal readings.
  2. In the pancreas in Type 2 diabetes, GLP-1 stimulates the release of insulin from the beta cells by increasing the size and number of beta cells and restoring first phase insulin secretion that gets in quicker and keeps the glucose from rising after meals.1,2
  3. At the same time, GLP-1 inhibits the inappropriate and excessive release of glucagon following meals that occurs in both Type 1 and Type 2 diabetes. This also lowers postmeal glucose levels.2 Even though it structure is similar to glucagon that raises the glucose, GLP-1 lowers it.
  4. In the brain, a GLP-1 receptor in the hypothalamus reduces hunger and improves satiety in many people.30,31

Unfortunately, injecting natural GLP-1 provides no benefit because it is broken down by an enzyme called DPP-4 (dipeptidyl peptidose IV) about 5 minutes after it is given. This problem leads to a search for modified GLP-1 molecules that would not break down as quickly. The first incretin released by the FDA was Byetta, approved in May of 2005. Byetta is a GLP-1agonist, which means it increases the GLP-1 effect. It is a drug that works longer in the body but has the same effects as natural GLP-1. Its origin was rather unusual in that it is 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 would provide some 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

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

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, 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.

For people with Type 2 diabetes, side effects like nausea or vomiting are more likely to occur in some individuals for reasons that are unclear. 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. Your glucose readings, especially the postmeal ones, should be considerably improved.

Clinicians usually start with a low dose 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 do 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.

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. Although there was an 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

Other new GLP-1 agonists are currently in clinical trials.

  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. 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.