Glucagon-like peptide-1 (GLP-1) receptor agonists can control diabetes by inducing weight loss and are actually synthetic analogues of naturally occurring GLP-1. GLP-1 and gastric inhibitory polypeptide (GIP), incretin hormones that are released by small intestinal cells in response to a meal, have four primary functions: They stimulate insulin release by the beta cells in response to a glucose load; they inhibit glucagon released by the alpha cells, and therefore they reduce hepatic glucose production; they slow down gastric emptying; and they act on receptors on the hypothalamus and induce early satiety. Therefore, people feel full quicker after eating less. That's primarily how these drugs work. Naturally occurring GLP-1 is degraded by the dipeptidyl peptidase-4 (DPP-4) enzyme, which is produced by the body, and the synthetic analogues are variably resistant to this degradation.
In this class, we have the older drugs that first came out in 2005, for example, Byetta or exenatide, which is short acting and dosed via injection twice daily. Then there are the daily injections, like liraglutide, which was branded as Victoza. Then the weekly GLP-1 agonists were developed. These include Bydureon BCise, which is long-acting exenatide; semaglutide, which is branded as Ozempic for diabetes and is used at a higher dose to treat obesity; and dulaglutide, branded as Trulicity. The latest drug on the market, tirzepatide or Mounjaro, is a dual GLP-1 and GIP agonist. In addition, there's one oral GLP-1 receptor agonist, oral semaglutide marketed as Rybelsus.
With this drug class, you have the FDA approval for diabetes, which was the original intent. Then you have the FDA approval for obesity, which is just for two of the drugs: semaglutide marketed as Wegovy and liraglutide marketed as Saxenda.
All of the type 2 diabetes drugs had to undergo rigorous cardiovascular outcomes trials to demonstrate safety, and three GLP-1 agonists—liraglutide, semaglutide, and dulaglutide—were found to reduce major adverse cardiovascular events (MACE) and received FDA approval for the same. These drugs don't really reduce the risk of heart failure, unlike the sodium-glucose cotransporter-2 inhibitor class, but they do reduce MACE, primarily nonfatal strokes, particularly semaglutide.
Semaglutide marketed as Ozempic has pretty good HbA1c reduction, between 1.5% to 2%. One important point to keep in mind is that this drug can cause an average weight loss of around 15%. A third of the patients in clinical trials reached a weight loss of 20%, which is equivalent to the kind of weight loss that you see after gastric sleeve surgery. Tirzepatide, which was just approved in May 2022, has the largest effect on HbA1c, around -2.5% or so. In clinical trials, tirzepatide led to an average weight loss of around 20% with the 15-mg dose, and a third of the patients had weight loss over 25%, making it the most efficacious drug [for weight loss] that we have on the market. However, tirzepatide has not yet been approved for treatment of obesity and the impact on MACE is still being studied.
GLP-1 receptor agonists are not without side effects. The most common are GI-related issues, such as nausea, vomiting, and a feeling of fullness. These are mitigated by starting at a low dose and titrating upwards. For example, with Ozempic, you start at 0.25 mg weekly for one month. If the patient tolerates it, then you go up to 0.5 mg and stay on that for a month, and if they still tolerate it, then you can go up to 1 mg and then 2 mg to reach weight loss and glycemic goals. If the patient is not able to tolerate the dose escalation, then they can stay on the lower dose for as long as they want.
These drugs are rarely associated with risk of pancreatitis and biliary tract disease, so if the patient develops pancreatitis or has a history of pancreatitis, they're contraindicated. The newer drugs really don't require renal dose adjustment, but some of the older ones, like Byetta, do. If someone has chronic kidney disease and is having nausea, vomiting, and GI disturbances and are at risk of acute kidney injury, you need to monitor the creatinine, especially with some of the older drugs.
GLP-1 receptor agonists are contraindicated in anyone with a history of multiple endocrine neoplasia syndrome or medullary thyroid cancer. I always tell my residents, we have to do a good thyroid exam on all these patients, and if you were to feel a nodule, then you have to work it up appropriately and get thyroid ultrasounds. There's no routine recommendation to monitor for high calcitonin levels, which is a marker for medullary thyroid cancer, but that could be considered.
Two additional points. First, GLP-1 receptor agonists can decrease absorption of orally administered medications. Tirzepatide or Mounjaro can reduce the impact of oral contraceptive pills, for example, so young women should be warned about this and advised to use alternate kinds of contraception.
Second, in the SUSTAIN-6 trial, published in the New England Journal of Medicine in November 2016, they found an increased risk of worsening retinopathy with semaglutide. This is not a class effect; this was only seen with semaglutide. The thought is that rapid glycemic lowering could have contributed to this. One clinically important aspect to remember is if you have a patient on semaglutide who already has retinopathy, you have to have a good baseline retinal exam, you have to monitor their retinas while they are on the drug, and if they have any worsening, then you may have to withdraw the drug or reduce the dose and refer the patient to an ophthalmologist for appropriate management.