This transcript has been edited for clarity.
Silvio Inzucchi, MD: Welcome to Medscape InDiscussion. I'm your host, Dr Silvio Inzucchi, professor of medicine at Yale School of Medicine. Today, we're talking about guideline updates in type 2 diabetes, and we're really fortunate to have Dr Rita Kalyani, who's a perfect person for this discussion.
Let me tell you a little bit about Dr Kalyani. She is associate professor of medicine in the Division of Endocrinology, Diabetes, and Metabolism at the Johns Hopkins University School of Medicine. Dr Kalyani is an active clinician and sees patients regularly at the Hopkins Comprehensive Diabetes Center. She is also co-founder and editor-in-chief of the Johns Hopkins Diabetes Point of Care IT Guide for Health Care Professionals. Dr Kalyani has served on the editorial boards of several diabetes journals, and her research focuses on diabetes and aging. She is also past chair of the American Diabetes Association's (ADA's) Professional Practice Committee, which is responsible for the annual clinical guidelines position statement known as the ADA Standards of Care. She is also a member of the Endocrine Society's Clinical Guidelines Committee. Welcome to our discussion today, Rita.
Rita Kalyani, MD: Thanks so much, Silvio, for having me.
Inzucchi: I know you're juggling a lot in your career at Johns Hopkins, working in so many different arenas. But before we get to the diabetes questions, I wanted to ask you, can you tell me something that you've learned during your career that you wish you had been taught during your training?
Kalyani: I think that what would have been most helpful to learn earlier in my training is the ability to critically review the literature — to question why things are done the way they're done. And just because something's been done before, it doesn't mean that it needs to be done the same way. I think we'll see that in the way that the guidelines have evolved over time that as new knowledge accumulates, it behooves us to keep up with the knowledge and know how to critically evaluate it. That's something I wish that I had been taught earlier in my training, because I think it's a useful skill, no matter what you do as a clinician, researcher, or educator.
Inzucchi: I totally, totally agree. Let's get to a discussion about diabetes guidelines. Those of us that have been working in this field have seen the evolution of these guidelines, particularly over the past 4-5 years, where we're seeing more of a focus on complications of diabetes and less on the so-called glucose-centricity of previous guidelines. We are discussing today, the so-called ADA Standards of Care. And this is a document that is published annually. It comes out in January from the American Diabetes Association. So, Rita, these really have changed over the past 3-4 years in particular. Can you focus on two or three high-impact changes that pertain to the primary care physician and how we approach the care of diabetes nowadays as opposed to, you know, the prehistoric era, which was maybe 2015?
Kalyani: So much has changed in the past 5-6 years. It does seem prehistoric when we look back even a decade ago, not only because we didn't have all the therapies that we currently have available to us today but also we're learning so much more from the trials that have been done.
What I would say to the primary care physicians, who really manage the bulk of diabetes that's out there, is that the guidelines have changed so much over the past 5-10 years; this has not only been because we have so many more classes of medications, but because we're now understanding that in addition to glucose lowering or A1c lowering, we have medications that can reduce the onset or progression of comorbidities.
The highest-impact change I would zero in on is first, the focus on patient-centered or individualized care. I know this is something that you also, in your involvement in guidelines, have had a very active role in. That's really on focusing on, what are the individual characteristics of the patients that help us determine the optimal targets? What are the patient preferences, and what are the support systems they have available? It's no longer a one-size-fits-all for A1c target. In general, for most nonpregnant adults, an A1c target of 7% is a good starting point. But our recent guidelines have supported the notion that for some adults, a more aggressive target, such as less than 6.5% might be appropriate, particularly for those who are young with short duration of disease. And conversely, less aggressive targets might be more appropriate for those with longer disease duration, older adults, or those with complex comorbidities who might be at higher risk for hypoglycemia.
The first high-impact change is to focus on patient-centered and individualized care. The second is that for years, our gold-standard regimen was the basal bolus regimen. The idea was that if a patient had natural progression of type 2 diabetes and eventually needed insulin therapy, the gold-standard replacement would be a basal insulin, usually once-a-day bolus insulin injections at mealtime — so up to four injections a day. But I think we could debate that that's perhaps no longer the gold standard — that now, it's not a clear path to insulin or a clear path back from insulin. You could add oral agents, even for someone who's on insulin therapy, to reduce the insulin requirement. You could add a noninsulin injectable, such as a glucagon-like peptide 1 (GLP-1) receptor agonist, to reduce the comorbidities associated with diabetes as well.
It's no longer a linear path toward how we sequence therapy. It's really keeping in mind the comorbidities that the patient has. And then also, what are the goals of care? The biggest question I think that we probably will be focusing on today is the shift in the past few years away from just A1c lowering. We now have really two goals in diabetes care. A1c lowering clearly is still the foundation for reduction of microvascular complications, particularly, but for cardiovascular risk reduction and perhaps even reduction in chronic kidney disease (CKD) progression, we now have glucose-lowering agents that reduce the risk for and progression of these complications, seemingly apart from their A1c-lowering effects. So even in someone who is at their glycemic target, we might still consider adding another diabetes medication, which requires some explanation in conversation with patients. Why are we adding another medicine when I'm always at my A1c target? It's very important that we keep that in mind to best reduce the risk for complications for our patients.
Inzucchi: I'm going to dissect a few of the things that you just said, and we're going to go in reverse. We're focusing now on this critically important issue that has been almost a revolution in our management of patients with type 2 diabetes. It is this notion of using medications that have been demonstrated to reduce cardiovascular or renal risk on top of the baseline therapy, usually metformin, even if the A1c is controlled. I totally agree that this is really difficult to explain to patients. They're thinking, hey, my A1c is 6.8%; I'm expecting congratulations, and now you want to add another medication. And sometimes the medication may be quite expensive. Now we're obviously talking about the GLP-1 receptor agonists — mostly injectables, although there's one oral version available — and the sodium-glucose cotransporter 2 (SGLT2) inhibitors. Do you want to review very quickly the evidence base for prescribing these medications, particularly in patients who are already under good glycemic control?
Kalyani: Since 2008, the US Food and Drug Administration has required that approved medications for diabetes need to have a postmarketing cardiovascular outcome trial; this is to demonstrate safety of the agents. What we have seen is not only that almost all of the agents have been safe, but that a few have actually been superior to placebo in their ability to reduce the risk for cardiovascular events. The first one that came out was the EMPA-REG trial looking at empagliflozin, an SGLT2 inhibitor. It found that there was a significant reduction in major adverse cardiovascular events, nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular mortality as a composite endpoint, and then also cardiovascular mortality as a secondary endpoint alone. This was one of the first trials in 2015 that demonstrated that these agents may have a role beyond that of A1c lowering — that they can actually reduce cardiovascular disease and mortality.
This was a tremendous finding because for decades, as endocrinologists, diabetes specialists, we struggled to find ways to optimally reduce cardiovascular risk apart from cardiovascular risk modification, which is important. But the role of A1c lowering and the therapies we use for diabetes has always been debatable. This was a tremendous finding when it came out, and perhaps there were some who were skeptical at first. How could this be? What are the mechanisms? It's fair to say we're still trying to better understand the mechanisms.
Then came the LEADER trial for liraglutide, the first GLP-1 receptor agonist, which showed a similar finding. It also found superiority compared with placebo in the reduction of major adverse cardiovascular events, that composite outcome, and cardiovascular mortality.
Since then, we've seen subsequent trials for the SGLT inhibitor canagliflozin as well. And then also for other GLP-1 receptor agonists, which include dulaglutide and semaglutide, as well — the injectable versions that have also shown cardiovascular benefits. Now we have findings from thousands and thousands of participants that have shown to us that these agents — specific agents in the SGLT2 inhibitor class, empagliflozin and canagliflozin in particular, and specific agents in the GLP-1 receptor agonist class, liraglutide, dulaglutide, and semaglutide — all have benefits in cardiovascular risk reduction in those with a history of cardiovascular disease, for the most part. Across these trials, the majority of, if not all, patients had cardiovascular disease.
That being said, the REWIND trial with dulaglutide was in a largely primary prevention cohort — patients who had cardiovascular disease risk factors but did not necessarily have a cardiovascular disease history — and the benefit was still seen for dulaglutide.
We now have, in our armamentarium, other agents that can be used to reduce cardiovascular risk. The cardiologists are excited if they see this, almost like a statin, in that it can reduce cardiovascular risk. But we have to be careful that these agents really are glucose-lowering agents. We do have to keep that in mind, especially when we prescribe these to patients who are already at their glycemic target.
Inzucchi: Let's get back to the guidelines and boil it down to some patient scenarios. According to the most recent iteration of the Standards of Care from the ADA, if you have a patient on metformin and the A1c target is not achieved — let's say they're at 7.4% and you want to get them to 7% or lower — and the person is a 62-year-old man with atherosclerotic cardiovascular disease (ASCVD) who just had cardiac bypass surgery, then what do the guidelines tell us? What would be the next step after metformin?
Kalyani: The ADA guidelines would tell us that after metformin, the branch point to ask yourself as a healthcare provider is, does the patient have ASCVD? If they do, it takes you down a different path than if they don't. If they have ASCVD, the choices among those agents that I mentioned are those that have demonstrated cardiovascular benefit, within the SGLT2 inhibitor and the GLP-1 receptor agonist class. Which one you choose may be informed by, does a patient prefer an oral vs an injectable? Are you looking for weight loss? Many GLP-1 receptor agonists can lead to significant weight loss, although the SGLT2 inhibitors can as well.
Both classes of agents have their own profile for side effects, and if there is any contraindication to their use, that might also be a consideration. But really, once you're in that path where the patient has a history of cardiovascular disease, the choice should be using an agent with demonstrated cardiovascular benefit, specifically the SGLT2 inhibitor class vs the GLP-1 receptor agonist class.
Inzucchi: Let's talk about another scenario. This might be a 78-year-old man who has an A1c of, let's say, 8.1%, who is already taking metformin and perhaps a dipeptidyl peptidase 4 (DPP-4) inhibitor. This individual has heart failure, so let's say it's heart failure with reduced ejection fraction (HFrEF). What would the guidelines tell us now?
Kalyani: In addition to the trials that were done in patients with cardiovascular disease or at high risk for cardiovascular disease, we also have trials that were done in patients with heart failure with reduced ejection fraction. What the guidelines would tell us based on those trials is that the SGLT2 inhibitor class would be the preferable class for a patient with a history of heart failure with reduced ejection fraction specifically, although we now have newer trials that also look at patients with heart failure with preserved ejection fraction, too. The evidence has been largely consistent that the use of the SGLT2 inhibitor class — almost all those agents — would be preferred for that patient [with HFrEF], as primary or secondary outcomes have had heart failure benefit.
Inzucchi: A third scenario might be a 68-year-old woman who has no evidence of coronary artery disease and no evidence of heart failure but has a reduced glomerular filtration rate (GFR), say 58. And, as is typical in people with diabetes, she has microalbuminuria. What would the guidelines tell us now?
Kalyani: Again, the SGLT2 inhibitors would be largely favored in that case — although the GLP-1 receptor agonists, for secondary outcomes, some of them have had benefit, particularly in those who have albuminuria. But we to date only have trials that have studied the use of SGLT2 inhibitors in a CKD population, although there is one under way looking at semaglutide in those with CKD as well, and hopefully we'll have those results soon.
Inzucchi: To emphasize the change that we alluded to from the 2018 to the 2019 guidelines, when we were asked not to consider necessarily solely A1c in each of those three patient scenarios, if the A1c was already at target, according to the guidelines, we'd still at least need to consider the addition of these agents — not as glucose-lowering drugs, because these patients would not need any further glucose lowering, but simply to impact their complication risk. Because when A1c was looked at in these trials, it didn't seem to be an effect modifier of the treatment benefit, and I think that's a real departure from the earlier guidelines.
I wanted to go back to this notion of combination therapy with a basal insulin and a GLP-1 agonist in our patients with type 2 diabetes who need more than just basal insulin. You mentioned that the old approach had been to add mealtime insulin. It was totally logical. It mimicked what we did in type 1 diabetes. But type 2 diabetes is a real different disease, and the studies that I recall when those two strategies were compared seemed to give a benefit or an advantage to the GLP-1 when added to basal insulin, right?
Kalyani: You're right, Silvio. For many years, when a patient was being considered for injectable therapy and they'd been on multiple oral agents, the first one to go to was insulin. Now, as we see more GLP-1 receptor agonists on the market and we have more data over the past few years, the guidelines have actually bumped insulin out. For one year in the guidelines, it was you could choose insulin or GLP-1 receptor agonist; they were equal branch points. And now the GLP-1 receptor agonist is actually the preferred initial injectable to consider. It's from these studies showing that patients do well with them. You have less hypoglycemia. Although you do have to keep in mind the gastrointestinal side effects, for the most part, they're well tolerated. I think the main consideration, though, is still cost for many patients, and that is something that is a consideration, no matter which of these newer agents we think about. But in the guidelines, GLP-1 receptor agonists are now the preferred and initial injectable before insulin, and it can be used in combination with insulin, too.
That being said, if someone has end-stage, long-standing diabetes, and they no longer have endogenous insulin production left, the GLP-1 receptor agonist won't work. They really depend on having some endogenous production. Sometimes in my practice, I'll see patients referred to me who've been on GLP-1 receptor agonists but clearly have no endogenous production left. We do have to keep in mind that they benefit a lot of people, but really near the end of beta cell production, they may not be the best therapy to use.
Inzucchi: These patients are more like a patient with type 1 diabetes. They may not be ketosis-prone, but they have such anemic insulin production that you really need to give them mealtime insulin, which is an enormous imposition on our patients (particularly as they're aging) because of the four injections per day, and the four finger-sticks per day, or continuous glucose monitoring.
If you can get by with the basal insulin and GLP-1 combination, patients tend to be happier. They lose weight; they don't have as much hypoglycemia. And the studies have shown that the A1c control surprisingly is almost identical. In fact, some studies suggest that the GLP-1 receptor agonists may even do better.
Let's talk now about this notion of the optimal provider for the patient with type 2 diabetes. Obviously, there must be 30 million people with type 2 diabetes in the US now. There are very few endocrinologists comparatively. I think there's some 7000 of us, and we certainly don't manage the bulk of patients with diabetes. This is really a primary care disease, isn't it?
Kalyani: Very much so, and our primary care colleagues really do so much for our patients with diabetes. It very much is a primary care disease.
Inzucchi: When do you think a patient should be referred to an endocrinologist for management of their diabetes?
Kalyani: You know, in my practice (and I'm sure it's similar in your practice), I often see patients who come to me who have seen their primary care physician for years, and I'll ask them, "Why are you here to see me?" And insulin initiation is often a very common indication. This is not necessarily due in any part to lack of trying. But I think that coming to see a specialist might denote an extra level of care that we can provide in our clinic. Certainly if there is a patient who's difficult to manage, who is ready for the next step, which would be an injectable therapy, that would be a patient that could be referred to our clinic for comprehensive care with a diabetes educator and dietitian and then the endocrinologist.
Another reason for a referral would be the use of these newer agents. These guidelines, which really apply to every individual with diabetes, can be hard to implement in practice if you're not as familiar with the newer medications. That's where perhaps the implementation really needs to be a focus — being familiar with these therapies, feeling comfortable with titration of the therapies. If a primary care physician is interested in having their patients be on one of these newer agents and would like to have that person have a discussion with the endocrinologist about the benefits vs not being on these therapies, might be another reason to refer to us. We're now seeing these agents prescribed by cardiologists also, and nephrologists, although that's emerging even more so. It's not just a primary care physician that is referring to us anymore. It's also the specialists, and the primary care physician really may be in the best position to coordinate this care among all the different specialists. That might be another opportunity for them to work with the endocrinologists.
Inzucchi: Very good. Well, Rita, we are out of time. I want to thank you so much for joining me today on Medscape InDiscussion.
Kalyani: Thank you. It's been great.
Inzucchi: So to summarize, we think that the ADA Standards of Care are an extraordinarily detailed, excellent document to review, particularly for primary care clinicians interested in the management of patients with diabetes. There have been enormous changes in our approach to managing type 2 diabetes in particular over the past 4 or 5 years, and we've talked about some of these today. Thanks for joining us. I'm Silvio Inzucchi, signing off for Medscape InDiscussion.
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022
Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes
Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups Results From the Randomized CREDENCE Trial
Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND): A Double-Blind, Randomised Placebo-Controlled Trial
Semaglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes
SGLT2 Inhibitors in Patients With Heart Failure With Reduced Ejection Fraction: A Meta-analysis of the EMPEROR-Reduced and DAPA-HF Trials
The SGLT2 Inhibitor Dapagliflozin in Heart Failure With Preserved Ejection Fraction: A Multicenter Randomized Trial
A Research Study to Find Out How Semaglutide Works in the Kidneys Compared to Placebo, in People With Type 2 Diabetes and Chronic Kidney Disease (the REMODEL Trial) (REMODEL)
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Cite this: High-Impact Type 2 Diabetes Treatment Guidelines - Medscape - Mar 22, 2022.