Diabetes Drugs: GLP-1 Agonists

Editor’s Note: This is the sixth post in our miniseries about diabetes drugs. Tune in on September 18 for the next installment.


A curious fact that has been known almost since the discovery of insulin is that glucose taken by mouth stimulates insulin secretion to a greater degree than glucose that is injected straight into the bloodstream. Researchers theorized that a hormone might be released by the gastrointestinal tract in response to glucose that could stimulate insulin secretion above and beyond that stimulated by glucose alone. This then-undiscovered hormone was called “incretin.”

The search for “incretin” was not fruitful until the DNA sequence of gastrin (an important hormone that helps regulate stomach acid secretion) was found to contain the DNA of a hormone called GLP-1, for glucagon-like peptide-1. The incretin GLP-1 was found to have a profound effect on stimulating the release of insulin from the pancreas. Unfortunately for researchers interested in diabetes treatments, GLP-1 was also found to be active for only a very short time because it was broken down by an enzyme called dipeptidyl peptidase-4, or DPP-4.

A solution to the issue of GLP-1’s short action time came from an unusual source. Scientists working on toxins in the saliva of the lizard Heloderma suspectum, otherwise known as the Gila monster, found a protein that activated GLP-1 receptors. This protein, named exendin-4, originates in the salivary glands but has endocrine effects.

Exendin-4 is a protein composed of 39 amino acids that mimics many of the actions of GLP-1 but that, unlike GLP-1, has a prolonged half-life in the bloodstream (meaning it remains in the blood for longer). Exendin-4 has several properties that mimic those of GLP-1. These include the stimulation of insulin secretion, the suppression of glucagon (a hormone that signals the liver to release glucose when blood glucose levels drop) secretion, and the slowing of stomach emptying.

In a study involving people with Type 2 diabetes and a synthetic form of exendin-4 known as exenatide (brand name Byetta), those taking the exenatide showed significantly reduced blood glucose, insulin, and glucagon levels after meals compared to people taking placebo (an inactive treatment). These results highlight some of the differences between exendin-4 and insulin: With insulin therapy, a person obtains lower blood glucose levels with high insulin levels, while exenatide therapy decreases blood glucose levels with a much lower level of insulin. This is most likely due to exenatide’s slowing of stomach emptying after a meal, which delays the introduction of glucose into the bloodstream, thus reducing a major source of stimulation for insulin secretion. Exenatide also inhibits glucagon secretion and stimulates insulin secretion, which additionally helps to drive blood glucose levels down.

Exenatide, which is administered via injection, is approved for use in people with Type 2 diabetes as an addition to the oral medicines metformin (brand name Glucophage and others) and sulfonylureas (Diabinese, Diabeta, Glynase, Micronase, Glucotrol, Glucotrol XL, Amaryl). It is not approved for people with Type 1 diabetes, because pancreatic function is required for exenatide’s insulin-stimulating effects to work. Nonetheless, the delayed stomach emptying and suppression of glucagon caused by this medicine may prove to be useful in people with Type 1 diabetes, and it is currently being studied in this population.

In clinical trials lasting six months, average reductions in HbA1c (an indicator of blood glucose control over the previous 2–3 months) in people with Type 2 diabetes have been between roughly 0.4% and 0.8% when exenatide is used along with metformin, a sulfonylurea, or both. Additionally, a small group of people taking exenatide who had an HbA1c reduction of 1.1% sustained the HbA1c reduction with continued use of the medicine over a year. Studies have shown that exenatide therapy also results in reductions in fasting blood glucose levels and reductions in weight (the greatest weight loss, of roughly 5 pounds, has been shown to occur when exenatide is taken with metformin), and that between a quarter and a third of people using this medicine achieve an HbA1c level of less than 7%.

Exenatide is injected under the skin twice daily, within one hour before the morning and evening meals, respectively. (This medicine should not be administered after a meal.) The typical starting dose is 5 micrograms taken twice a day, which can be increased up to 10 micrograms twice a day after four weeks on the 5-microgram dose. When exenatide is added to metformin, no change in the metformin dose is recommended, but when it is given with a sulfonylurea, the dose of the sulfonylurea may sometimes need to be changed to reduce the risk of hypoglycemia (low blood glucose).

Exenatide is associated with some side effects. The most frequent are gastrointestinal and include nausea, vomiting, and diarrhea, with nausea occurring most frequently. These side effects are reduced with the continued use of the drug, however, and in trials, only 3% of people stopped taking exenatide due to nausea. Hypoglycemia can occur when exenatide is taken with a sulfonylurea. Pancreatitis, inflammation of the pancreas, is a rare but serious condition that can occur with use of this medicine. Pancreatitis often requires hospitalization, and it may sometimes necessitate surgery and treatment in an intensive care setting.

Liraglitude, another type of GLP-1 agonist, is approved in Europe and is currently awaiting a ruling by the U.S. Food and Drug Administration. A longer-acting version of exenatide and several other new GLP-1 agonists are also under development.

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  • CalgaryDiabetic

    Reductions of a fraction or 1% in the HA1c seem to be very modest and you wonder if in fact caused by the drug or just more control. However if it helps with weight loss then they may be some justification.

  • Marcie

    About 2 years ago, I was bitten by a pit bull and had to be on a strong antibiotic. Taking it caused me to have a yeast infection that was hard to get rid of, despite medication. During this time, my A1c — which for years was always less than 6.5 — shot up to 9.1. I started on Byetta 5mcg to go along with the 500mg dose of metformin I was already on. My next a1c was 5.8. Now it’s usually right around 5.5.

    I lost some weight, but I’d been working at that already, so I can’t give Byetta the credit. However, I will attribute the fall in my liver enzymes levels to it, since that’s a known benefit of Byetta. I notice, too, that it diminishes my appeptite.

    While the statistical average A1c reduction with Byetta might seem not too impressive, I wouldn’t consider a 5-pound weight loss over 6 months to be statistically impressive, either — though it’s certainly better than the weight gain that comes with the use of some other diabetes meds or no weight loss at all. All I know is, Byetta did wonders for my A1c. So,even without the possibility of it causing me to lose weight, it seems that “then they [sic] may be some justification” for me to be using it.

    I’m watching the drug company’s press releases for when it comes out in a once-weekly dose so that I can get it. I’ll have even better coverage from it than I have now.

  • Valerie

    I have been taking Byetta for about 3 years. I started on 5 mg for a month and then went to 10mg. I lost 25 lbs. without even trying in the first 2 months at the 10mg dosage. You must take Byetta from 1 minute to 1hr. before the first meal and last meal of the day. It lasts about 10 hours. I found that the longer I waited to eat within that 1 hour window helped keep me from eating as much as I usually did. It also makes you feel full longer since it causes the stomach to empty more slowly. Sometimes I would just look at my food and think “Do I really have to eat this?” because I wasn’t hungry any more. I also take 1000 mg of Metformin twice daily and 5 mg. of glipizide. For overweight people this regimen may help you lose weight. I’ve had trouble all of my life with my weight and I am thrilled with this result. Doesn’t work as well if you inject the Byetta and wait one minute to eat. If you stick with the waiting as close to an hour as possible, you will find that you can’t eat as much. I love Byetta for this reason and it has helped my BS come down, especially after meals. Oh, it does cause me to have a very slight feeling of nausea for the first couple of hours which also helps keep you from eating much! Overweight people, talk to your doctor about using Byetta.

  • Everett Henson

    I use Byetta 10 two times a day. I called the company and asked about the 1 hour wait and they told me (Just so you take it before you start eating. I am told by my Dr and others That I should take it 1 hour before I eat. Valerie thanks for explaining this in a way I can understand it. I will try my best to follow your advise:

  • carolyn

    I took Byetta and got along well for a year or so, and then I began to throw up after the evening meal. I also had to consume more and more
    carbs to avoid going low. The vomiting became
    fairly regular and extremely annoying. I finally
    quit taking Byetta for that reason. I also was told to adjust my glimipiride which I did while taking the Byetta, but that didn’t make any difference. I am now controlling my blood sugar with oral medication, but I wonder if anyone else has had such problems
    with Byetta. I would gladly use it again if it
    didn’t cause such problems. How will I react to the once a week shotif it ever becomes available?

  • Dan Kashefska

    I took Byetta for 9 months starting w/ the 5 and increased to 10 mg. I was sick all the time and lost 45 lbs because I didn’t want to eat! I felt like I always had the flu and my skin turned a shade of mustard. If I would over eat I became very sick! My A1c dropped from 7.5 to 5.5 though but for some reason I was one of the few who’s body would not tolerate it. I now uae Lantus and am getting a1c’s of between 6 and 6.5

    Sadly I had to give Byetta up. It was more than serving it’s purpose!!!! I reccomend it highly if your body will tolerate it!! Both for weight loss and type 2 D. Dan

  • Tina

    Byetta caused me so much trouble. I started on the 5 mcg’s then went to the 10. I lost 40 pounds in a year by throwing up every day. I had a really hard time staying on the medicine. It gave me severe stomache pains and caused migraines, too, but my BG’s were really good. My stomache pains were because the food was not moving. I was miserable all the time. The last straw came when I spent 2 hours waiting and hoping that my dinner would start digesting and it laid in my belly like a brick. My husband and I were walking the waterfront in Seattle and I had to come to a stop or I would have thrown up on the sidewalk. My food still was not moving and my BG had dropped seriously low. Scared me pretty badly.

    I called my doctor the next day and told her I was not taking it anymore and why. In order to get a great BG, I had to suffer from throwing up daily, 2-4 migraines every week, severe stomache pains, and short term memory problems. Not an acceptable trade off.

    I’ve been off of it for about a year now and I still have stomache problems and I can’t eat very much at all. Every meal out is a take home bag.

  • Rogerio Luz Coelho – MD

    A reduction of 1% on the A1c levels can diminish by 37% the cardiovascular risc of Diabetes. And remember, this is a MEDIAN, Metformin has a MEDIAN reduction of something in the 1% ballpark.

    Same to weight reduction.

    The GOOD thing about GLP-1 is that is reduces the Beta Cell overload (which can have great implications in the future). That is to say if someone finds a cure for Diabetes that depends on your pancreas being able to produce even a small amount of endogenous insulin your bet is to keep to GLP-1.

    Besides it lowers Triglycerides, rises HDL, and lowers the vascular inflammation of your veins.

    The pancreatites is a very rare condition, and new studies show it to be non significant.

    The greatest issue with these drugs is the injections (twice daily 30-45 min before meals) and the current cost.

    Cheers from Brasil ūüėČ

  • jim snell

    I must take umbridge of the 1 percent number on metformin.

    Given the general use and prescription of it – yes 1 % may be a number.

    Research and data and my own use shows a drop on the a1c fro 13.3 to 6.9 by using the feature of metformin up to strength in blood stream shutting off liver excess glucose production. Remaining met in body has little impact. Up to strength in blood is very powerful.

    This has been documented by numerous reserach groups.

    It is possible to shut doem dawn effect and extra un warranted glucose release by liver by round the clock ingestion of metformin.

  • FlaGuy954

    I took Byetta for several months (along with metformin) and it did significantly lower fasting blood sugar levels and A1c levels. However, I also lost a considerable amount of weight and I began to look anorexic. I also lost my appetite and had to force myself to eat. I felt low-level nausea all the time which contributed to having no appetite. Eventually I stopped Byetta and began taking Januvia along with metformin. I regained my appetite, gained some weight, and still maintained good blood sugar levels and A1cs.

  • JB lewis

    I took Byetta for a year and I was diagnosed with Pancreatitis and kidney failure due to the pancreatitis. I had not stopped making urine so had not idea I was in kidney failure. Just knew I was throwing up several times a day and also had diarrhea just as often. I eventually lost my abilty to stand. As soon as I got to the hospital I was put on daily dialysis for the 21 days I was there. I was so toxic I was very near death. After d/c I was on dialysis 3Xwk for 4 hours which means you are at the clinic for at least 6 hrs. This lasted 3 months. Thanks be to God that my kidney function returned. So even though this pharmaceutical company says that pancreatitis is rare, it does happen. I would never in a million years take another med in this class. By the way, my Hb-A1C runs 5.6-5.8 without the use of Byetta and I’ve been Type 2 since 1989.