Two experts in endocrinology, diabetes, and primary care discuss the current evidence and rationale for integrating incretin-based therapies into diabetes management in the primary care setting. Learn strategies that will allow you to move beyond a glucose-centric approach in diabetes care and help patients improve their overall cardiometabolic health.
In this podcast, Jennifer Green, MD, and Jay H. Shubrook, DO, FAAFP, FACOFP, share strategies for integrating incretin-based therapies in type 2 diabetes (T2D) management in the primary care setting, including:
Presenters:
Jennifer Green, MD
Professor of Medicine
Division of Endocrinology
Duke Clinical Research Institute
Duke University School of Medicine
Durham, North Carolina
Jay H. Shubrook, DO, FAAFP, FACOFP
Professor, Diabetologist
Department of Clinical Sciences and Community Medicine
Touro University California, College of Osteopathic Medicine
Vallejo, California
Full program link:
https://bit.ly/4uSKCqv
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Enhancing Cardiometabolic Health in Diabetes Care With Incretin-Based Therapies
Dr. Jay Shubrook (Touro University California): Hi. I am Dr. JayShubrook.
Dr. Jennifer Green (Duke University School of Medicine): Hi. I am Jennifer Green. It is great to be here.
Core podcast premise
Dr. Shubrook: Today's podcast is really going to be focusing on a practical and conversational discussion between a primary care clinician and an endocrinologist about how to move beyond a glucose-centric approach to type 2 diabetes, and really start looking at integrating the benefits that GLP-1-based therapies and emerging therapies into real-world cases and really say, “How can we provide comprehensive care?”
Why this topic matters
Dr. Shubrook: So why does this topic matter? We know that most people with diabetes receive their diabetes management in primary care, and we want people to live a long and healthy life. An A1C tells you only about glucose, and we really need to start thinking about how do we take a more comprehensive approach, addressing obesity, hypertension, chronic kidney disease, cardio-kidney-metabolic disease and cardiovascular risk.
And because of that, we want to make sure that we are providing the tools to equip primary care clinicians so that they can provide the best care for patients.
Case setup
Dr. Green: We will start with a case. This person is a 58-year-old with type 2 diabetes who is coming in for a routine follow-up appointment. The hemoglobin A1C is stable, let us say, 7.1%. The patient also has hypertension, obesity, and early chronic kidney disease.
The primary care physician is deciding whether the treatment should change, even though the hemoglobin A1C is not dramatically elevated. The key question for us to discuss is whether or not the treatment should change, even if the hemoglobin A1C is not dramatically.
Beyond glucose control
Dr. Shubrook: Yes, this is really tricky, right? Because first of all, patients may feel pretty happy that they got the 7.1%. We do not know where they came from. I do love that you framed this in a way that this person has more than just diabetes. Certainly, we have learned from the ADA guidelines that when someone has a compelling indication, and this person had chronic kidney disease, obesity and hypertension, we could be choosing agents that have proven benefits for some of these complications and that we need to make room for those treatments when they have those conditions.
What are your thoughts here?
Dr. Green: Yes, I absolutely agree. One thing that I want to make sure to mention though, is that although we are talking about beyond glucose control, that does not mean that glucose control is unimportant.
What we are really talking about now are opportunities to intervene to reduce the risk of a wide array of both microvascular and macrovascular, and additional metabolic risks that each person, for example, with diabetes, might be faced with during their lifetime.
We should not completely disregard A1C and A1C targets, but we definitely need to think bigger than that. It is actually attractive to be able to think about and recommend a regimen that can reduce a wide array of risks with perhaps one or two different therapeutic interventions.
In fact, I would think of this more as opportunities to make informed choices rather than additional burdens that we need to bear. For each person, we have to think about whether or not they have or they are at high-risk for things like atherosclerotic disease, kidney disease. Again, we need to be thinking about both their EGFR and their degree of albuminuria. We are pretty good at checking EGFRs or creatinine at least once a year in people with diabetes in the US, but not very good at checking the UACR.
You really have to know both of those values to understand whether or not, A, the person has chronic kidney disease, and if they do, what their degree of risk for cardiovascular events and progressive kidney disease might be.
Of course, like our old friends, hypertension, hyperlipidemia, these are foundational approaches to care that can allow us to really effectively chip away what we know is a residual risk of adverse outcomes that is borne by people with diabetes.
Dr. Shubrook: I love some of the things you said there. It is so important that when we see patients in the primary care setting, we are managing so many different things that it would be very easy to say, “Hey, you are doing a good job, 7.1. We will see you in three months.”
It might be nine months before we actually take another action. I loved what you mentioned about the idea of trying to combine treatments, becoming a lumper saying, “Hey, by the way, if you choose an agent like a GLP-1, you might actually be able to treat not only the diabetes, but also improve your kidney function or albuminuria or lower your weight.”
And you are right, that is very attractive to patients when they can get more bang out of their buck for the medications that they have to take because most have to take a lot of medicines.
Dr. Green: Yes. It has been really attractive to me too, because we are talking about incretin-based therapies, and endocrinologists always use a lot of incretin-based therapies for glucose management, weight management, etc..
Let us say the most recent trial, FLOW, that demonstrated a reduction in cardiovascular and kidney risk in patients with type 2 diabetes and chronic kidney disease treated with semaglutide, basically I would just have the opportunity to pat myself on the back because although I might have been giving the person that medication for a different reason, I was doing good things for their kidneys all along.
This is actually a really exciting time to help people live, as you had mentioned, longer and healthier lives.
Role of incretin-based therapies
Dr. Green: I have already put my toe in the water a little bit talking about how the incretin-based therapies can address. I am just going to start with cardiometabolic risk.
We know that there are a number of different agents now that have been shown to reduce the risk of adverse outcomes in people with type 2 diabetes and atherosclerotic cardiovascular disease. Really the people enrolled in those studies had disease affecting one or more of the different vascular beds. It was not only coronary disease, it was coronary disease, cerebrovascular disease or peripheral vascular disease, so again we need to think broadly there as well.
We know that some of the incretin-based therapies have been shown to improve outcomes in people with those established complications, or in people who have multiple risk factors for atherosclerotic disease.
There is a trial, as I had mentioned earlier, the FLOW study that showed improved outcomes with semaglutide treatment in people with type 2 diabetes and chronic kidney disease. That was relatively advanced.
There are also trials showing that there can be improvement in outcomes in people with heart failure with preserved ejection fraction, really with or without type 2 diabetes. The trials have shown that certain incretin-based therapies, in addition to lowering weight can, in some cases, reduce the risk of, for example, heart failure hospitalizations, but also in some trials were shown specifically to improve symptoms and functional status.
Again, we are learning more and more about these therapies as we go along in addition to what we have known about their effects as glucose-lowering agents and as anti-obesity medications. There is so much more. There is even more, for example, the drugs appear to hold great promise in the treatment of patients with obesity and obstructive sleep apnea, and also have improved outcomes in people with obesity and atherosclerotic disease who did not have diabetes.
We are really just starting to understand the array of patients who might benefit from these therapies. So we are all going to need to know about them and get comfortable with them.
What are your thoughts or how much do you think about efficacy, safety, how the drug is administered, how it is dosed when you are thinking about starting someone on an incretin-based therapy in clinic?
Dr. Shubrook: Yes. Having a wide array of incretin-based therapies actually can make a nice opportunity for us to do some shared decision-making with our patients because they might have an opinion, whether they want to take something once a day or once a week, or by mouth or by injection.
I also think that in the real setting of primary care, probably use what is covered. First of all, it is whatever drug they can afford is the one they are going to take. If I know which ones are covered, and one of these medicines have compelling indications, it is a whole lot easier to get them covered even in primary care, it is nice to give the person an opportunity. This medication is available once a day as an oral agent or once a week as an injection.
I do think that is the first and most important. I do think there are times where I consider efficacy if that obesity or the A1C are the main factors. Often these agents in primary care are being added to other agents. So it might be that the compelling indication might be the reason that I add it and I am getting the gravy of reduced weight loss, or improved kidney function, or improved liver function or sleep apnea.
I do think it is an important thing, but knowing that there is so much to think about in the primary care space. Coverage is first. Patient's willingness to administer the medicine a second, and then really giving a patient an opportunity to know the most common side effects and being proactive about what those side effects are, and then saying, “This is how we can handle it.”
Because so often if we do not give them the common GI side effects that they might experience, they can be very frustrated. If you tell them up front, “Hey, you might experience some nauseousness, you are definitely going to feel a change in appetite if you can moderate your eating,” then they usually come back and say, “You gave me these warnings, but actually I feel pretty good. I actually feel better.” So it is an opportunity for us to have a win.
Dr. Green: That is a really important point.
Practical primary care decisions
Dr. Green: For clinicians who are just getting comfortable with use of the incretin-based therapies, GLP-1 receptor agonists, etc., who would you recommend they prioritize for starting these medications? What do you think might be the best idea? Or if someone is really trying to address risk in their clinic patient population, what do you think the best approach might be?
Dr. Shubrook: Again, in the primary care space, coverage is important. You would want to pick someone where they have access to the medicine, and you are going to know that they are going to have regular access.
Then there are good wins, right? There are some nonglycemic wins. If someone needs to or wants to lose a fair amount of weight, this is going to be one of the best classes when someone has diabetes and gives you those additional benefits, or if someone has been maximized on their risk reduction from other agents, this would be a great time to add it. Let us say that they have been on the maximum dose of the RAS agent, and they still have residual albuminuria or CKD, what a great time to add this. Or if they have cardiovascular risk.
That is where I would start, hit ones where you know they are going to have a home run.
Dr. Green: Yes, I think that is a great approach. I do think that we need to make sure that we are focusing on starting these beneficial medications in the highest risk patients. However, that does not mean that people without those established complications will not benefit. In fact, many of the guidelines are now emphasizing earlier use of these agents that are known to reduce the risk of cardiovascular and kidney complications, although a little bit harder to demonstrate in clinical trials, it is very likely that patients at lower risk will benefit as well.
It just might take a longer period of treatment for that to be realized. At the same time, for people with diabetes, the metabolic benefits will clearly occur in real time.
I would agree with the approach of addressing those at highest risk first, get comfortable and then expand who you are prescribing to. To a certain extent, for better or for worse, there is so much in the lay press about this, and there is so much that people have already heard about before they come to see us. Nine times out of 10, in my experience, people have already heard about these medications, and often they are bringing them up themselves if they are not already treated with them.
The conversation has often been started before they show up for their clinic appointments. So do not hesitate to discuss.
The access issues are not trivial. You know that even if people have one that is covered, it can be difficult to figure out which one it is and it might change the following year. That is a chronic problem. Do not forget that there are, in fact, some formulations that are generic now, that does not necessarily mean it is always going to be a lot less expensive, particularly at first, but there should be more and more availability of generic formulations moving forward.
Hopefully, we will have much greater access in the relatively near future.
Dr. Shubrook: I have found that in the primary care space, if you are writing these agents, be real mindful about what the FDA indications are and actually put that as part of your sig, either in the sig or link that diagnosis to it, because it can reduce the rejections and actually reduce the PAs in some extents as well, and that is going to be more value to your time. Really be thoughtful about that because that step will save you a lot of time downstream.
Dr. Green: I was just going to say that I completely agree with that. I would strongly encourage primary care providers and clinicians to be starting these therapies themselves to get the ball rolling. In the US, I believe that endocrinologists manage between 15% and 17% of people with diabetes. That is a pretty small number. If we were to wait to treat people with these medications until they could see an endocrinologist, it could be a really long time before they were ever treated with these beneficial medications.
Honestly, even for the treatment of type 2 diabetes, these are vastly better choices than what we have used in the past, for example, sulfonylureas. To be honest, I am always pleased and shared with the patient that I am pleased when they come to see me and they are already on one of these indicated medications.
You will impress the endocrinologist that maybe they would not need to see for a longer time if they have already started it.
Supporting adherence
Dr. Shubrook: I was going to say that that is a great shout out that primary care should be comfortable using it. When do you think it is a good time to refer to endocrinology and diabetology to make sure this is the right match?
Dr. Green: That is a really good question. What I would say is the patients with diabetes who tend to be referred by their clinician to endocrinologists are probably people who are on GLP-1 as part of a more complex regimen. They might be on a GLP-1 in addition to several other medications and possibly insulin as well.
For whatever reason, they have not achieved adequate control and/or they are having a lot of hypoglycemia. I would say that is more common now.
There are also people who have had trouble tolerating one or two of the incretin-based therapies and then the primary care clinician wants to call in some help and see if we can strategize all together to figure out what the next best step might be. That is extra important again in these higher risk individuals.
Honestly, if it is just not going smoothly, you can refer to an endocrinologist at any time. I have a feeling that that these agents are going to allow a lot of people to be successful in management of their diabetes and management of their cardiorenal risk, and maybe they would not need to come see us at all, which is really the ultimate goal, is not it?
PCP-endocrinologist collaboration
Dr. Shubrook: Yes. Trying to keep care as compact as possible is really a great opportunity, but we know it takes a team-based approach. Really want to shout out to the primary care clinicians that feel comfortable, but also say that do not go it alone. This is a complex progressive condition. It is going to keep moving forward. If we can stay ahead of it, that is going to be good for us and it is good for the patient.
Dr. Green: Yes, definitely. In our system, we have set up an electronic consult for people to send relatively concise questions to me about specific patient situations. Sometimes they are related to safety or prior intolerance of certain agents. Much of the time I can answer and provide a little bit of guidance and allow that person to be successful remaining under primary care.
Think about ways to enhance that interface between primary and specialty care without having to have the person make a trip in-person. Often a lot can be accomplished without asking the person to do that.
Should we talk a little bit about side effect management and counselling? We touched on that a little.
Dr. Shubrook: Well of course, because these agents do have a fair amount of side effects and that is in studies and in real life. Most patients that I have seen will tolerate these side effects because they are transient. If they are understood, they can work around them. It is important for us to let the patients know what is realistic and maybe that separates what they see online. What are ways that they can manage them, and eating smaller meals, making sure that they are mindful to eat slowly to make sure that they do dose titration slowly.
If they have problems, reach out, right? I mean, we can help them with that.
Dr. Green: Definitely.
Dr. Shubrook: What are some strategies you like?
Dr. Green: I always make sure that they know that it is a possibility. That is forewarned is forearmed. If you send somebody home with a prescription for one of these medicines and they start feeling sick, they are going to stop it and you would not know about it, probably until their next appointment. This is just the way that medicine works.
If you tell the person, “I am going to start you on this medicine, and I want you to know that somewhere between about 25% and 30% of people who start these medicines, or either when they first started or when they go up on the dose, can have some,” and you can describe the GI side effects in any way you like.
Make sure they understand that usually they are not severe, that they often will resolve with continued use. You can talk through, as you had mentioned, some strategies to reduce the risk that it will happen, but that they should also know that if the side effects are very troublesome or severe, that they should contact the office so that they can get some guidance.
I really think that goes a long way towards establishing trust and really making sure that the person is fully informed and not caught off guard by a side effect that is really unpleasant for them. It is a team-based approach. We are, for the most part, going to want these patients to be on the medications indefinitely. This successful ramp up is really key.
Dr. Shubrook: We should always give the red light or the red flag warnings as well. If someone has intractable vomiting, they are unable to eat at all, or they have severe belly pain that radiates to their back. Of course, we sometimes worry about pancreatitis. Those are hard stops, call right away, and go to the emergency room.
I do think it is worthwhile to share that while there is no statistical or FDA indication that there is higher risk of pancreatitis, it can occur, but letting patients know and letting them know it is uncommon and that is when they need to get help right away is an important sign.
Dr. Green: Right. Fortunately, I prescribe these medicines very often. I have seen very little of that. There is an increase in risk of biliary tract disease associated with these medications, probably because in some cases, of course, they can result in a very significant and rapid weight loss. You can actually see that with similar weight loss that is induced through other mechanisms. That is a known potential side effect of sudden and profound weight loss. That is another reason maybe to take it easy.
I do not know that that is necessarily going to completely eliminate the risk of biliary disease, but it cannot hurt for a lot of different reasons to make sure that if the person is losing a really dramatic amount of weight quickly, that we moderate the approach a little bit and maybe do not uptitrate unless it is clear that they actually need a higher dose.
Dr. Shubrook: Today, we have talked about a lot of important things. One of the things that we want to make sure that primary care knows is that these are great agents that give you both glycemic and extra-glycemic benefit, but we can only know to do that if we are actually looking for this. So please make sure that we document in our patients, if they have chronic kidney disease with both an EGFR and albuminuria, make sure that you are documenting their current weight and BMI and what the weight goals are, if they have cardiovascular or other risks, and certainly if there is medication burdens or patient preferences.
Putting all those things into context really builds the case of why you are using an agent, such as an incretin-based therapy.
We have heard pretty clearly from both of us that we do not need to wait. This is a medicine that is safe and can be used in primary care, and do not let inertia get in your way. Make sure you make room for these medications when they have additional opportunities to improve care.
When we look at referring to endocrinology, that is going to be an individual-based decision, right? Where is your comfort end and when do you need help? Jennifer, I would love to hear from you, how do you introduce the concept of cardiometabolic care? Because that might be foreign to some of our audience and that could be very beneficial when they are talking to their patients.
Dr. Green: It may be a concept that is difficult to explain to patients in the way that we think about it. What often can be really useful is to tell someone this is a medicine that I am recommending you start to help improve your diabetes management. However, this is a medicine that also, in people like you, can reduce the risk of stroke, for example, or heart attack and even the risk of dying from a cardiovascular event.
That is easy. That kind of language, that discussion is less scary than just clarifying. That is the conversation that people can understand fairly readily. Maybe if it is not persuasive to them, it can be convincing to the significant other who is sitting next to them. It is always nice to have the other important family members or partners or friends in the room when you are having that conversation, and it seems there might be a little bit of hesitancy.
Do not forget to engage other key people if you think that that person might either be a supporter or they might have a whole lot of questions if the patient comes home with a new prescription and they have not had the opportunity to talk about it.
Getting back to your point about referring to endocrinology, I want everybody to know, you can refer patients to endocrinology at any time. Actually one of our main source of referrals is patient requests. So do not hesitate and feel like you need to gatekeep if a person really wants to come see an endocrinologist.
What I love being able to do is to see a patient who has come to me and they are really already on all the right things. They are on guideline-directed medical therapy to the fullest that it can be implemented by the time they come to see me in endocrinology and I have the opportunity to say, “You know what? Your primary care doc is doing a fantastic job. You do not really need me to do anything right now, but we have met, and if anything should change in the future, you can come right back.”
I feel like that is a really nice opportunity for me to reinforce what has already been recommended. Of course, if there is any problem or difficulty or real question about whether or not a therapy is appropriate, endocrinology is always available.
Rapid-Fire “Curbside Consult” Questions
Dr. Green: Before we close, we have some rapid fire questions. I will kick it off.
If a patient's A1C is 7.4% and they also have kidney disease and obesity, should you intensify? Should you change treatment?
Dr. Shubrook: Of course, the important thing here is to, one, make sure you have an agreed upon A1C goal and see if you have already optimized those things. In this case, the use of incretin-based agent with kidney benefit would be a great option because they not only get the CKD benefit, but the obesity benefit, which also helps CKD and A1C.
Dr. Green: If the patient is worried about injections and how would you discuss either that in and of itself or options that might not include injections.
Dr. Shubrook: The good news is that we have oral and injectable therapy, so the patient has a choice. Many of them have shown benefit in both formulations. I do think it is important, though, that we find out why someone is worried about injections, because often injections are going to be a great option because most people at some point will probably need insulin. I do think getting past that injection would be great.
Dr. Green: Yes, I agree. Sometimes if you can get your nurse to show them how tiny the needles are, because they might be remembering when their grandmother used insulin. It is a whole new world when it comes to injectable medications. Sometimes if you can just show them how very tiny these needles are, and maybe they could even do like a little test run in clinic. Sometimes that can help overcome the injection concerns, in addition to the fact that the injection, even if they do not like it, might only need to be taken once a week. So not multiple times a day or even once a day.
What if a patient has nausea after the first dose of a GLP-1? What are the options they are considering stopping therapy and what can we do to try to prevent that?
Dr. Shubrook: First of all, sometimes I might say, “Well, the medicine is working if you have nauseousness as long as it is not too bad.” Absolutely if we have told them ahead of time, “Hey, let us be real mindful about how we are eating as we started this therapy, that is when the side effects are most frequent.” We can certainly help slow down the titration.
If they are in the middle of a titration therapy, I might down-titrate shortly, but let the patient know they can be in charge and we will help them be comfortable.
Dr. Green: Yes, that is true. Now I do not automatically prescribe antiemetic agents. I know that there are some clinicians who do that. I suppose if they are really feeling terrible and they need some help right away, that is a reasonable thing to do. Personally, I would prefer not to have them be on a dose of a medication or a type of medication that requires them to take an antiemetic on a regular basis. That to me would be a sign to, as you mentioned, down-titrate.
Maybe take a break for a little while, and if they are not successful on retrial to maybe go a different direction and try an entirely different GLP-1-based therapy. That often is successful.
I wish I knew what was going to work best for each person in advance, but you generally do not.
We talked a little bit already about how to explain cardiovascular benefit in patient-friendly language. Kidney benefit almost is a little tougher to describe. We did not talk much about the KDIGO heat map, but I do actually have a copy of that in my clinic room because I can use the patient's EGFR and UACR value to figure out which of those squares they are in.
The version that I use has a color. It is like stoplight colors, green, yellow, orange and red. I can show them where they are kidney health-wise and what that color means as far as their risk for associated cardiovascular events or progressive kidney disease.
Sometimes that can be a useful tool because kidney disease is not very well understood even by people who have it. So use those tools.
What do you think is one thing that primary care providers can do tomorrow to significantly improve care for people with type 2 diabetes? That is a big question.
Dr. Shubrook: Well, involve the patient in their care, ask them what they want and know that you have multiple tools that can give you multiple benefits and do not go it alone. That was a lot of ones, but those are things I would recommend. What advice do you have?
Dr. Green: I would encourage primary care providers to think big. I want primary care to be empowered, to take steps to improve the health of organs that they might have thought were somebody else's area of focus.
It is okay. You can be concerned about heart health, about kidney health and liver health. Go for it. What I really want to be able to say each time someone is referred to me is, “Wow, your doctor did all the right things, but I am glad that you are here.”
Take steps, do what you think is right. If you are not sure what the next best step might be, that is definitely the time to refer or reach out for help.
Dr. Shubrook: I love that. That is important.
Closing takeaways
Dr. Shubrook: Alright, so today, we talked about a lot of different things. What we hope that you have taken from this is that for your patients with diabetes, do not rely on the hemoglobin A1C alone. Look at overall cardio-kidney-metabolic risk. We can certainly match treatments that have multiple benefits to their multiple conditions, and that is going to make the care more efficient and often even safer.
Let us remember that starting therapy is the beginning. Let us get off to a good foot, but let us make sure that we engage the patients in titration, making sure they get to the dose that gives them the benefit and that they can tolerate. Let us help them stay on therapy because these therapies have big benefits when it looks at length of life and quality of life.
As you have mentioned, the goal is patient-centered care, but also not just treating diabetes, but sustainable cardiometabolic risk reduction as well.