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GLP-1 RAs in T2D: FAQ
Expert Answers to FAQ About GLP-1 RAs in Patients With Type 2 Diabetes

Released: November 23, 2022

Expiration: November 23, 2023

Kristi Kelley
Kristi Kelley, PharmD, FCCP, BCPS, BCACP, CDCES, BC-ADM
Christie Schumacher
Christie Schumacher, PharmD, BCPS, BCACP, BCCP, BC-ADM, CDCES, FCCP
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Key Takeaways
  • For patients with ASCVD or indicators of high risk for ASCVD or those who need assistance with weight or glycemic management, GLP-1 receptor agonists can be used first and prior to metformin.
  • Nausea and vomiting due to GLP-1 receptor agonists can be reduced by using a slower dose titration and by dietary modifications such as eating smaller, more frequent, and lower-fat meals.
  • Patients should be counseled on the missed-dose window specific for the GLP-1 receptor agonists that they are receiving. 

In this commentary, Kristi W. Kelley, PharmD, FCCP, BCPS, BCACP, CDCES, BC-ADM, and Christie Schumacher, PharmD, BCPS, BCACP, BCCP, BC-ADM, CDCES, FCCP, answer learner questions about glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) from the webcast “Enhancing Use of GLP-1 RAs in Patients With Type 2 Diabetes to Improve Individualized Patient-Centered Care.”

Among the GLP-1 RAs with cardiovascular (CV) indications, (ie, dulaglutide, liraglutide, and semaglutide), are any of these better tolerated than the others? Are the weekly injectables semaglutide and dulaglutide better tolerated over other agents? 

Dr. Kelley:
There are short-acting and long-acting options for GLP-1 RAs. Short-acting GLP-1 RAs are taken daily and long-acting agonists are taken weekly. I think it depends on patients’ preferences on which option they would prefer, but we should also think about whether weekly agents are better tolerated than daily agents. 

In my experience, if we start patients on a GLP-1 RA and titrate up, then usually patients tolerate the medication well. 

Dr. Schumacher:
Among the 3 agents with CV risk-reducing benefit—liraglutide, dulaglutide and semaglutide—we had many patients in our clinic receive liraglutide because it was approved first. However, once patients switched to the once-weekly agents, we found that we had a lot better efficacy. I do not know if that speaks to the efficacy of the medication, whether it is better tolerated, or if people have a difficult time to adhering to daily injections. 

We have not seen much of a difference in terms of tolerability between semaglutide and dulaglutide. Each one can have unique effects in individual patients. Not every patient will tolerate every drug, and we have had patients who did not tolerate dulaglutide but did tolerate semaglutide. I think if a person cannot tolerate one GLP-1 RA, switching to another GLP-1 RA would be a good option, unless the intolerability is pancreatitis or something serious. With just general gastrointestinal upset, I would consider switching to the lowest dose of the other GLP-1 RA option and see if the person can tolerate that. In general, I think we have seen much better tolerability and adherence with the once-weekly agents, and the notion of only injecting once weekly makes it more appealing to our patient population.

Can sodium-glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 RAs be used together in patients without CV disease? 

Dr. Schumacher:
We think of GLP-1 RAs as CV risk–reducing agents and that they help with obesity and lowering body weight. The 2022 American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) consensus update now recommends using GLP-1 RAs first, especially those with a high efficacy for weight loss. However, GLP-1 RAs can be beneficial for people with diabetes without atherosclerotic CV disease (ASCVD) or who are not at a high risk for ASCVD, because GLP-1 RAs will prevent future weight gain, help the patient live a healthier lifestyle, and may even prevent ASCVD in the future, even if a person is not at high risk now. 

In addition, some clinical trials of SGLT2 inhibitors in people with heart failure (HF) without diabetes showed that SGLT2 inhibitors prevent HF from happening. I think SGLT2 inhibitors are great drugs to start patients on even if they currently do not have ASCVD, chronic kidney disease (CKD), or HF because it might slow their progression to one of those complications. So we will definitely use metformin, GLP-1 RAs, and SGLT2 inhibitors together.

Can GLP-1 RAs and dipeptidyl peptidase-4 (DPP-4) inhibitors be used together? 

Dr. Kelley:
The recommendations do not support the use of DPP-4 inhibitors and GLP-1 RAs together as they are not complementary and are considered duplicative therapy.

Dr. Schumacher:
DPP-4 inhibitors prevent the breakdown of endogenous GLP-1. When you inject in a GLP-1 RA, because of their mechanism of action, you are getting 3-5 times the amount of GLP-1 compared with a DPP-4 inhibitor, preventing the breakdown of that endogenous GLP-1. DPP-4 inhibitors do not prevent the breakdown of the GLP-1 RA, so these drugs do not work synergistically. There is no reason to use them together because the GLP-1 RA is going to completely overpower the DPP-4 inhibitor. The patient would have to pay 2 brand copays and not get much extra efficacy from the DPP-4 inhibitor since the GLP-1 RA is more potent and is working on all those different mechanisms. I consider it duplicate therapy. You want to pick something to go with your GLP-1 RA such as an SGLT2 inhibitor that has a different mechanism of action and is more complementary. 

How should missed doses be handled?

Dr. Kelley:
There are different recommendations for when a patient misses a dose, when therapy is interrupted for an extended period of time, and whether retitration is needed based on the individual agent. Ultimately, you should refer back to the prescribing information for details on each agent. 

Dr. Schumacher:
I think one of the most important things we counsel patients on is the missed dosing window. We all know we are not perfect, so inevitably our patients are going to miss doses, and the GLP-1 RAs, especially the weekly ones, have a nice, missed dose interval due to their long half-life. With subcutaneous semaglutide, if patients miss a dose, they have 5 days to take it. For example, if patients take semaglutide every Monday and forgets about it until Saturday, they can still take it on that Saturday and then take it again 2 days later on Monday, and then resume their every Monday dosing schedule. 

For the long-acting agents, for patients who miss the dosing window and it has been 2 weeks, I would tell them to continue with their regularly scheduled dose. However, if it has been 1 or 2 months, or even 3 months or longer, we will titrate our patients back down and then restart the titration. 

Dr. Kelley:
I agree. When we see those longer interruptions, patients are more likely to have adverse events if they go immediately back to the preinterruption dose. I think reminding patients and providers that this is a possibility is helpful and should be considered when writing those prescriptions so that patients can get what they need to be able to retitrate if necessary.

How do you choose between SGLT2 inhibitors vs GLP-1 RAs for patients with HF?

Dr. Schumacher:
We must think about SGLT2 inhibitors as a CV medication that also lowers blood sugar. I think we need to ensure that people with HF and reduced ejection fraction are on an angiotensin receptor neprilysin inhibitor if they can tolerate it or an angiotensin-converting enzyme, angiotensin II receptor blocker, β-blocker, mineralocorticoid receptor antagonist, or aldosterone antagonist, and then an SGLT2 inhibitor, since those are the 4 drug classes that are considered guideline-directed medical therapy in HF. Adding an SGLT2 inhibitor is now the standard of care for people with HF. Any A1C lowering achieved with the SGLT2 inhibitor is great, but the patient would probably benefit also from a GLP-1 RA to help with weight loss and A1C lowering. Therefore, I would start the SGLT2 inhibitor first, knowing that it is going to reduce the risk of a HF hospitalization, and it is guideline-recommended therapy now for HF even in people without diabetes, and then consider something else for the management of diabetes in that person.

Dr. Kelley:
In our practice with a patient population that has issues with medication accessibility, we see that providers recognize the benefits of SGLT2 inhibitors. We are now figuring out how to get people with HF and also those with diabetes on the guideline-directed therapy that has such positive benefits.

Dr. Schumacher:
We have also started doing a lot more patient assistance programs and different access programs because we know it is a challenge when all of these drugs are brand name medications. Since companies have streamlined the process and reduced some of the restrictions, we have had a lot more success getting many of the brand name medications through patient assistance programs. I recommend looking at those programs, especially if you are worried about the costs that may accumulate for your patients on multiple medications.

What is the role of metformin with GLP-1 RAs?

Dr. Schumacher:
As pharmacists, we know that clinical trial participants were on background metformin therapy if they could tolerate it. If patients with diabetes start a GLP-1 RA and lose 50 pounds, their A1C lowers from 10% to 5% because they lost weight, and they started exercising and are eating less—the GLP-1 RA has jumpstarted healthy lifestyle modifications for these patients with diabetes. I do not want to tell the patients to stop the GLP-1 RA because their A1C is 5%. In our practice, we have been backing off on the metformin and leaving the GLP-1 RA on, even in people with clinical ASCVD or those at high risk. The guidelines now state that people do not need to be on metformin, so if they have ASCVD or indicators of high risk such as CKD, HF, or if they just need help with weight management, GLP-1 RA and SGLT2 inhibitors can be used first and prior to metformin.

Therefore, if you notice that patients receiving GLP-1 RA are doing very well, their A1C is below goal, and they have lost weight, do not back down on the GLP-1 RA and consider having the patients stop metformin first. We know that metformin does have a lot of benefits, but if you are worried about hypoglycemia or gastrointestinal adverse events, titrate down on the metformin first. 

Updated guidelines for management of type 2 diabetes

Dr. Schumacher:
The new ADA and EASD algorithm for the management of type 2 diabetes has transitioned to the consideration of comorbidities, weight management, and glycemic efficacy when selecting different medications.

The left side of the algorithm focuses on cardiorenal and cardiometabolic diseases that we have for patients with clinical ASCVD or those at high risk. The new guidelines recommend using a GLP-1 RA with proven CV disease benefit such as semaglutide, dulaglutide, and liraglutide or an SGLT2 inhibitor with proven CV benefit before metformin. For patients with a high risk of ASCVD or clinical ASCVD, only canagliflozin and empagliflozin showed a statistically significant decrease in superiority for the 3 point major adverse cardiac events in the EMPA-REG and CANVAS trials. Dapagliflozin did not achieve significance in the DECLARE-TIMI 58 trial, which is why preference is given to empagliflozin and canagliflozin for just those at high risk for ASCVD or those with clinical ASCVD.

For people with HF, an SGLT2 inhibitor is preferred before any other medication class due to the reductions in hospitalization and potentially CV death in people with HF with or without diabetes. Based on the CREDENCE, DAPA-CKD, and EMPA-KIDNEY trial results, an SGLT2 inhibitor is preferred for patients with CKD. SGLT2 inhibitors have also slowed the progression of CKD, possibly prevented patients from going on dialysis, and have several other kidney benefits.

Dr. Kelley:
The new algorithm now highlights the importance of both glycemic management and weight management. With many GLP-1 RAs, we see an A1C decrease of ≥2%, depending on the particular agent and the dose (with higher-dose agents, we see greater A1C reductions). The consensus recommendations provide an efficacy ranking based on the amount of efficacy we expect to see with the various agents. At the top of the list with the highest efficacy are dulaglutide (high dose), semaglutide, and tirzepatide and then insulin in combination with a GLP-1 RA (oral or injectable). Other GLP-1 RAs come into play with high A1C reduction and are considered comparable with metformin and SGLT2 inhibitor as well as some of the other agents.

We can also focus on weight management and not just on A1C and glycemic control. Although we want to think about an individualized approach, we should also consider the role of medications such as GLP-1 RAs with both strong A1C lowering and good efficacy for weight loss, as mentioned in the ADA/EASD consensus algorithm. These agents include the GLP-1 RA semaglutide and the glucose-dependent insulinotropic polypeptide/GLP-1 RA tirzepatide. Dulaglutide and liraglutide are next in the ranking with high efficacy for weight loss, followed by intermediate efficacy with other GLP-1 RAs and SGLT2 inhibitors. The new algorithm gives us some additional considerations or a tool kit for use when we are thinking about how to approach various patients regarding an individualized approach while trying to balance cardiorenal, A1C lowering, and weight loss benefits.

Dr. Schumacher:
When considering the benefits of GLP-1 RAs, it is really important that we counsel our patients correctly and make sure they can tolerate the medication. Do not forget to counsel the patients that when they start a GLP-1 RA, they should eat smaller, more frequent meals to prevent nausea and vomiting and to stop eating as soon as they start to feel full. This will help the person to successfully get this agent on board. If they are still having some nausea, low-fat foods should be considered. In addition, if patients are not feeling well on the dose increase, take it back down and do a slower titration. Typically, the adverse events (ie, nausea and vomiting) will resolve within a few weeks, so if patients can change their lifestyle, they should be able to tolerate the medication well. 

Your Thoughts?
How often do you prescribe GLP-1 RA for your patients with type 2 diabetes and CV risk factors or excess weight? Join the conversation by adding a comment in the discussion section.