It is always interesting when you two legends in diabetes care sit down and have a conversation about the use of medications in patient care. Usually these thought leaders are early adopters when it comes to using medication combinations for diabetes. I had the opportunity to review a conversation that John E. Anderson, MD, and Vivian Fonseca, MD, had about the use of incretin mimetics with insulin.
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Dr. Fonseca: The GLP-1 receptor agonists offer a nice alternative to prandial insulin and they have the advantage of being additive as well as complementary to insulin. For example, basal insulin, as I said earlier, controls FPG whereas the GLP-1 receptor agonist controls PPG. Insulin causes hypoglycemia and weight gain; GLP-1 receptor agonists can result in weight loss.
There may not always be weight loss in combination with insulin but certainly GLP-1 receptor agonists limit the weight gain. As monotherapy, there is no increased risk of hypoglycemia. They have different mechanisms of action so you end up with better HbA1c control without hypoglycemia and weight gain, which is a big advantage.
Dr. Anderson: Let us talk about the three currently approved GLP-1 receptor agonists in the United States. Can you walk us though the similarities and the differences?…
Dr. Fonseca: Sure. The first that came on the market was exenatide, an exendin-based drug that has to be injected twice a day. You start with a small dose (5 µg), and then increase to 10 µg twice a day. It has been studied well in combination with insulin and has been effective without causing too much weight gain and hypoglycemia. Then you have liraglutide, which is a human GLP-1 analog and it is injected once a day.
There may be differences in PPG control but overall, liraglutide works very well. It also lowers FPG, so you need to watch out for that, but once a day can be an advantage for some people. You have exenatide extended release (ER), which is a once-weekly preparation.
Dr. Anderson: You have the patient sitting in front of you. You know you need to do something for prandial control. How do you make the decision between prandial insulin and a GLP-1 agonist? Do you have any tricks or tools that you can provide?
Dr. Fonseca: As we advance therapy, we have to have a discussion with the patient. You talk to them about the pros and cons of each. The GLP-1 receptor agonists are more costly but they require less monitoring. You do not have to monitor PPG or care so much about hypoglycemia during the day. A discussion with the patient as to what their priorities are, what is covered by their insurance, and what they would like to take, helps in the decision-making process.
Dr. Anderson: Or you might have the option of losing weight and for some patients that is a big decision.
Dr. Fonseca: That is true. We also need to have a discussion about the side effects of GLP-1 receptor agonists, such as nausea, vomiting, and how to minimize them, as well as contraindications, such as renal failure. You weigh all those things, have a discussion with the patient, and then choose the therapy. Both therapies work.
Dr. Anderson: Vivian, is there is a difference between these three GLP-1 receptor agonists in terms of nausea rates? Anything one needs to know as a clinician when making a decision about which drug to choose?
Dr. Fonseca: Yes. With the longer-acting GLP-1 receptor agonists, it seems there is less nausea and vomiting. The rapid-acting ones have a very potent effect on gastric emptying and that, in addition to their central effect, leads to higher rates of nausea. The rapid-acting class has better PPG control. It is a trade-off between these various agents. The once-weekly preparation (exenatide ER) is not designed to deliver PPG control, whereas exenatide (twice daily) has been shown to do that very well.
There is also a difference in HbA1c lowering among these agents. Liraglutide did very well in head-to-head comparative trials vs exenatide twice daily and exenatide ER. Perhaps it relates to its effects on prandial control as well as FPG. You also have to consider side effects. For example if you get nausea and vomiting in a renal patient, you need to keep your eyes open for dehydration. It seems to me that the other long-term concerns about side effects appear to be the same although there are some differences in the label. Exenatide ER and liraglutide have some wording about medullary thyroid cancer, while exenatide twice daily does not. We really do not know what is going to happen over the next 20 years.
Dr. Anderson: I also like what you said about some of the longer-acting agents (liraglutide), especially if somebody is already maximized on basal insulin with low FPG. The fact that these longer-acting GLP-1 receptor agonists can further lower FPG might make a decision about your nighttime basal insulin dose.
Dr. Fonseca: That is true. You may need to lower it. In many of the trials the dose was lowered and then titrated back up depending on need.
Dr. Anderson: Let us talk about safety because you know that has been a current topic in the literature. Can you talk to us about the GLP-1 receptor agonists and the pancreas?
Dr. Fonseca: Regarding side effects and tolerability, nausea, vomiting, and abdominal pain can be quite common. One needs to be careful to differentiate these from the side effect that everyone is concerned about, which is pancreatitis. There have been reports and a lot of discussion about pancreatitis but the rate has not been excessive in randomized trials. Many also speculate if pancreatitis can eventually lead to a diagnosis of pancreatic cancer. There have been a lot of scares about that; however, the FDA and the European Medicines Agency (EMA) have looked into this very carefully and concluded that there simply aren’t enough data. Over the past 5 years GLP-1 receptor agonists have been used regularly. Reports of pancreatitis have been few and signs of associated pancreatic cancer have also been absent.
Dr. Anderson: There are some major, large, long-term cardiovascular outcomes trials that may help inform us about safety as well.
Dr. Fonseca: I think those are going to be extremely informative, particularly if we pool data across these trials and look at what this class of drugs is doing in relation to side effects long-term. These studies are designed as cardiovascular outcome trials and may not address some of these issues.
Dr. Anderson: Before we close, any key take-home messages you would like to sum up with?
Dr. Fonseca: I am excited about the synergies between these 2 classes of drugs, and look forward to using the newer long acting products as well.