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Carol Wysham, MD: Hello. I’m Dr Carol Wysham. Welcome to the second season of Medscape’s InDiscussion series on type 2 diabetes. Today I’m welcoming Dr Silvio Inzucchi, host of the first season of the InDiscussion series on type 2 diabetes. He is a professor of medicine at Yale University School of Medicine in New Haven, where he serves as the clinical chief of the section of endocrinology, medical director of the Yale Diabetes Center, and program director of the Endocrinology and Metabolism Fellowship. Welcome to InDiscussion, Silvio.
Silvio Inzucchi, MD: Thanks very much, Carol. It’s good to be here with you.
Wysham: You are on the other side of the microphone this time, Silvio. I like to start by asking all my guests an icebreaker question to get the discussion started. What has fundamentally changed about our field from when you started until now?
Inzucchi: I think there have been two major changes in diabetes management. The first is this movement away from being solely focused on glucose. When I started out, we had sulfonylureas and insulin as the sole treatment strategies for certain for our patients with diabetes. When I started, metformin had just come out, and since then, there have been probably 10 or maybe even 11 new classes, new categories of medications. What we have learned about the non-glucose effects of these medications, their benefits on cardiovascular risk and renal risk, and trying to fashion together a designer portfolio for each patient to not only lower the glucose but also have a beneficial effect on their risk of future complications, has really been a sea change in our field. Second is the focus on technology. True, it’s mostly become inculcated in the care of patients with type 1 diabetes, for obvious reasons. But we’re now seeing more and more of our patients using the technology, particularly continuous glucose monitoring, in type 2 diabetes. And that’s been a huge change, a huge benefit, for our patients with any type of diabetes.
Wysham: Silvio, you’re about 10 years behind me in my entry into the field. At that time, we didn’t even have fingerstick A1c and we didn’t know about blood pressure control. We had nothing to control lipids. You talk about a sea change in events in your career; it’s been overwhelmingly exciting in my career as well. This is the final episode of the season, and we’re going to talk about where things have been, where they are now, and where things are going. I’d like to start out by pointing out that you and I chose a lot of the same subjects for our discussions last year and this year. I think that really speaks to how much is going on in diabetes and how we are moving away from just thinking about glucose and looking more holistically at our patients. What would you say is the most impactful change that you’ve seen in the management of patients with type 2 diabetes in the past year or two?
Inzucchi: It probably goes back a few more years than that, this focus on the cardiovascular complications of diabetes, and also to some degree the renal complications, the kidney complications, of type 2 diabetes. The more widespread use of two categories of medications — the GLP-1 receptor agonists and the SGLT2 inhibitors — has been great to see because we found, back in 2015, that one of the SGLT2 inhibitors, empagliflozin, had this very surprising impact on not only cardiovascular outcomes but also the risk for kidney disease. Since reporting that, there have been series of other trials, both with other SGLT2 inhibitors and also several of the GLP-1 agonists, that have definitively demonstrated a beneficial cardiovascular effect — and in the case of the SGLT2s, a beneficial kidney effect. This has certainly impacted the guidelines. We’ll talk about guidelines, I suspect, in just a few minutes. But the professional organizations that put out the recommendations for which drug to use in which setting, in which patients, have clearly altered their approach to the management of glucose in diabetes insofar as we’re choosing drugs not for their glucose-lowering effect alone, but for their beneficial effects on the heart and on the kidney. I think that’s been the biggest change in the approach of diabetes, and it’s pretty recent. It’s really only in the past 5 or 6 years that we’re starting to think in this light.
Wysham: A lot has happened to make us understand the impact of obesity in the presence of diabetes for some of the other nontraditional complications of diabetes, such as fatty liver disease and nonalcoholic steatohepatitis (NASH). Heart failure is an example, which we all know is extraordinarily common in patients with type 2 diabetes, particularly if they’re lucky to live long enough. It is just something we haven’t really paid as much attention to. I find that exciting, to find out how we can use our medications and lifestyle recommendations to help improve the treatments of those more nontraditional complications.
Inzucchi: We always knew that heart disease was important in diabetes. We knew that as endocrinologists. Certainly, our cardiology colleagues knew that from their perspective. The nephrologists knew that from their perspective as well. But it’s really been the trials that have underscored the linkages between these three disciplines: cardiology, endocrinology, and nephrology. When we impact glucose control with certain agents, we see these very surprising — at least to me — beneficial effects on cardiovascular events, on the progression of chronic kidney disease. Remember, we had previous trials that lowered hemoglobin A1c to an even larger degree than we’re seeing, certainly with the SGLT2 inhibitors if not the GLP-1 agonists. Despite that robust reduction in A1c, we could not demonstrate a beneficial effect on the heart or on the kidney. It’s clearly related to the mechanisms by which we lower glucose with these newer strategies that have opened up new doors for our understanding of the associations between diabetes, cardiovascular complications, and chronic kidney disease. The other thing I would add is that we’ve also always known that obesity is not a good thing for diabetes. Patients with diabetes are almost always at least overweight, if not obese. We’ve all seen patients who have gone on very strict diets, lost weight, and totally resolved their diabetes. We always knew it was important, but the tools in our shed to lower glucose, perhaps except for metformin, had added to body weight: insulin, sulfonylureas, thiazolidinediones. While we knew that weight loss was important, we couldn’t achieve substantive weight loss in our patients other than through very rigid diets which often could not be sustained for a long period of time, or with bariatric surgery, which was never a popular recommendation to our patients. The advent of the GLP-1 agonists, particularly the higher doses that we’re using now, and now the co-agonists, the GLP-1 and GIP-1 co-agonist tirzepatide, has really given us new opportunities to get substantial weight off of our patients. We’re talking, in some circumstances 15, 20, even 30 or 40 or more pounds, which is really gratifying to see.
Wysham: I agree. It’s exciting to see how quickly these agents are being taken up for this purpose. Hopefully, we’re going to be seeing more and more coverage for the agents for that purpose. That really leads us into the next topic quite well. As you recall, I think we first met while we both sat on — and you were chairing — the Professional Practice Committee for the American Diabetes Association (ADA). And then while I was chairing, you were very, very heavily involved in the very first recommendations for treatment of hyperglycemia and diabetes. We have updates every year, and we have new updates for this year. I would love to know what you think are the key takeaways from the most recent ADA standards of care.
Inzucchi: From a glucose perspective, there were some changes. I don’t think they’re as dramatic as the ones that occurred in 2018 and 2019, where the writing committee set forth its new strategy, which is, “Hey, look at your patient. If they’re at risk for cardiovascular disease (CVD) or progression of chronic kidney disease, you really need to use these drugs preferentially initially after metformin.” But by 2019, even that recommendation had become attenuated so that it gave us the opportunity to use these drugs even as initial therapies — monotherapy in specific circumstances. So that has been refined over the years. In the past couple of years, we’re no longer compelled to begin with metformin. That’s no longer foundational therapy, although many of us still start with metformin because we realize that, very often, metformin is a reasonable add-on drug to lower glucose in addition to GLP-1s or SGLT2s. Sometimes we’re starting now with GLP-1s and SGLT2s in selected patients.
Then there’s the focus on weight loss, again because of the availability of potent drugs that can get our patients to lose weight — like the incretin-based therapies that we alluded to before — as a specific strategy, almost as important as reducing the glucose. Obviously, those things go hand in hand in most circumstances; when you’re inducing weight loss, you will improve glycemic control. Those recommendations have been in the guidelines for the past 4 or 5 years, but I think we’re chiseled even more in the 2023 guidelines, particularly with the emphasis on weight reduction.
Another important change is a little more rigor, shall we say, in lowering blood pressure. Typically, the ADA guidelines had been a bit more conservative than the cardiovascular guidelines from groups like the American College of Cardiology, the American Heart Association, insofar as that we had been targeting a blood pressure of 140/90 mm Hg. Over time, because of some new data and also an attempt to harmonize the guidelines with the cardiovascular organizations, the new target is 130/80 mm Hg. That is an important one for us in clinical practice because many of our patients are in the 130s. And in the past, we would say you’re doing a good job. Now, according to at least the ADA, the ideal target should be under 130/80 mm Hg. I think we do have to individualize not only for glycemic control but also for blood pressure control because polypharmacy is a problem. There are adverse effects from medication. We have to take these recommendations and apply them to the individual patient level, always.
The third tweak to the guidelines was a little more rigor in terms of lipid control. Nowadays, according to the 2023 ADA guidelines, everyone over age 40 should be on at least a moderate-intensity statin. So that would be atorvastatin 20 mg or equivalent drugs. If there are multiple cardiovascular risk factors — and I think most of our patients with diabetes have at least one other risk factor, such as dyslipidemia, hypertension, or family history — then the new target for LDL-C should be at least a 50% reduction and an achievement of an LDL-C under 70 mg/dL. If there is established CVD, then the target is even tighter — now under 55 mg/dL. I think this really also harmonizes with some of the other more rigorous guidelines, such as those from American Association of Clinical Endocrinology, as well as the European Society of Cardiology, targeting less than 55 mg/dL for those patients with established CVD. So almost all of our patients, at least over age 40, should be on a statin. And the new target is no longer under 100 mg/dL but under 70 mg/dL — and even tighter if there is established CVD.
Wysham: I agree with all the points that you made, and I think that it is important for that information to get out to the practicing clinician. I spent a lot of time working with our residents on those newer guidelines and was quite impressed with the discussion they had on managing diabetes in the elderly, which is getting to be an increasing part of my practice as I age with my patients. So, I appreciate their discussions about understanding frailty and helping to set appropriate targets for all of these issues in our elderly patients. The other thing that I really am excited about, and it’s changing my practice, is to apply the recommendations for screening for heart failure routinely in our patients with type 2 diabetes with a brain natriuretic peptide (BNP).
Inzucchi: Those are the major changes. I want to loop back to the elderly population and diabetes care in the elderly. I think that de-escalation of care in certain circumstances is important. When patients are too tightly controlled — we see that all the time in our diabetes center, patients who are in their late seventies or early eighties and have hemoglobin A1cs that are just too tight. There’s really no benefit to controlling patients, particularly elderly patients, to a super-controlled A1c of less than 6%, 6.5%. We can easily de-escalate care, back off (particularly if they’re on insulin injections), reduce the rates of hypoglycemia, and there’s no penalty. Sure, the hemoglobin A1c may increase, but it’s still within the targeted range — in the low 7% range, shall we say. I think that’s a really important aspect to diabetes care. Practice safe diabetes management.
Wysham: The other side of the coin, though, is that if a patient is just on metformin, then you don’t have to back them off if their A1c is low. That’s a question I frequently get, at least in CME-type talks. I like to emphasize that point.
Inzucchi: There’s nothing wrong with the low A1c; it’s only when it’s a low A1c because patients are on too much insulin or even sulfonylureas.
Wysham: The other exciting aspect in that field is the use of GLP-1s in place of prandial insulin, either before prandial insulin or frequently I’ll see patients already on them and I will substitute a GLP-1. Yes, the A1c sometimes goes up a bit, but I’m actually surprised at how well people do. Most people can maintain a very satisfactory A1c without having to use prandial insulin.
Inzucchi: Yes, that’s one of the surprises in my practice, If you asked me 10 years ago: Could I ever see a day where you’re taking patients with basal bolus insulin therapy, multiple daily injections, and switch them to basal alone with a GLP-1 agonist? In other words, getting rid of the three additional mealtime injections. I would say that that would be an unsuccessful strategy because I always thought of these patients with requirements for multiple daily injections as being type 1-ish, meaning that their insulin secretion capacity had waned to the degree that they were very insulin deficient and couldn’t muster enough insulin around mealtimes to control their postprandial glucose levels. Boy, was I wrong. The trials are very convincing. You’re taking people on basal insulin that is not successfully controlling their diabetes. You’ll randomize them to three additional injections of rapid-acting analog, like lispro or aspart, vs just keeping them on the basal and adding a GLP-1. And guess what? They do the same in terms of glycemic control, but the benefits with the GLP-1 randomized group would be less weight gain; certainly some with no weight gain; and, in fact, some weight loss vs weight gain with the multiple daily injections, and also less hypoglycemia. That’s kind of a win-win for patients: good glucose control, less hypoglycemia and weight loss vs weight gain. I was shocked when I began to read those studies and am happy when I see that in my practice. I’m able to take patients off these complicated regimens, many of which they’re not adhering to anyway because they’re too complicated. I now give them a weekly GLP-1 and they do really well.
Wysham: Yes, the number of injections — that’s the key. The ability to adhere to the regimen is so much easier for the patients. Well, let’s look forward to 2023 and beyond. What excites you about what’s out there, and what do you expect that you might be focusing on in the clinic and in your education efforts in the upcoming year or two?
Inzucchi: The trials that are coming out over the next 2-3 years excite me. Number one is SELECT, which is a semaglutide study. This is injectable semaglutide, but this time in an obese population that has prevalent CVD. Here the trial question is whether GLP-1 agonist therapy not only leads to weight loss but also whether it reduces cardiovascular complications, as it does in type 2 diabetes. If SELECT is positive, I think that’s going to radically change our approach to obesity because it won’t be seen as simply a cosmetic issue. We’re using a drug that reduces body weight, but it also has this beneficial effect on reducing morbid and costly downstream complications of this disease. The study is powered to look at major adverse cardiovascular events. I think that’s probably going to be the most interesting study over the next couple of years. I’m involved with SOUL, which is a study of cardiovascular complications and diabetes, this time using oral semaglutide to see if oral semaglutide has the same benefits as injectable semaglutide. And there are also a couple of other GLP-1 trials that are underway looking at the effects on renal complications of diabetes, and also this nagging concern about the potential deleterious effect on the retinas; there has been a signal about advancing retinopathy in some of the semaglutide studies from early on. The group is looking at that specifically and hopefully will have some safety data on this category of drugs as well. What about you, Carol? Any trials coming up that you see as being of great interest over the next couple of years?
Wysham: Well, I expect that we’re going to see a positive outcome from the SURPASS-6 study, which is looking at tirzepatide in patients with CVD and diabetes. The interesting thing about that study is that the comparator is dulaglutide, so that they have an active comparator, and their goal is to show that tirzepatide is at least going to be as good as dulaglutide. But as you know, the studies suggest that you’d probably need 10% weight loss or more to see additional cardiovascular outcomes. And we’re seeing that with our patients who are being treated with tirzepatide. We’re seeing 10%-20% weight loss. There’s a very good chance that it may be superior to just the GLP-1 alone. Of course, that’s why the trials are being done.
Inzucchi: Those are hard studies to power because you’re presumably reducing events in both arms. So, you can get a noninferiority claim, but then there are some issues in terms of, what does the label say? Do you have a cardiovascular indication if all you’ve shown is that you’re noninferior to another drug that had shown the cardiovascular indication?
Wysham: They have those conversations with the FDA ahead of time, and assuming that the FDA advisory panel doesn’t change dramatically, presumably they will be given that, if they’re at least noninferior. The other thing that I’m really excited about is the issue of nonalcoholic fatty liver disease and the studies that are being done with both the GLP-1s as well as the dual and triple agonists for that. I’m actually screening all of my type 2 patients just by doing a FIB4 when I get their routine annual labs. We just calculate the FIB4 for them. That’s identifying a significant number of people who have fibrosis and should be treated more aggressively. I am surprised at how easy it is to get approval for GLP-1s, even if the patients are in good glycemic control. That’s something else to keep in mind as well.
Inzucchi: The preliminary studies look encouraging. I have not seen that any long-term large studies are looking at actual progression of cirrhosis and reversal of fibrosis; those are hard studies to do. Then there are the other drugs that are not even glucose-lowering agents that are being looked at in the hepatology field. I think the NASH issue is going to become the fifth complication of diabetes. We know about the heart, the brain, the kidneys, the nerves, and now certainly the liver is apt to be damaged in patients with NASH who have type 2 diabetes. It is very, very prevalent in that group of patients.
Wysham: Yes, about 70% of them. We’ve come to the end of our time. I really want to thank you, Silvio, for participating in this conversation today. We’ve talked a lot about the newer guidelines, the importance of medications, and the complication-focused selection of medications as opposed to just glycemic control, as well as the importance of weight loss and the tools we have for weight loss in our patients with diabetes. I want to thank the audience for joining us. This is Dr Carol Wysham for InDiscussion.
Listen to additional seasons of this podcast.
Resources
Continuous Glucose Monitoring in Persons With Type 2 Diabetes Not Using Insulin
Macrovascular Complications of Type 2 Diabetes Mellitus
Rate of Decline in Kidney Function and Known Age-of-Onset or Duration of Type 2 Diabetes
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
Tirzepatide Prescribing Information
Glycemic Targets: Standards of Care in Diabetes-2023
2018 ESC/ESH Guidelines for the Management of Arterial Hypertension
The Role of BNP Testing in Heart Failure
A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL)
GLP-1 Receptor Agonists and Kidney Protection
The Emerging Role of Glucagon-like Peptide-1 Receptor Agonists for the Management of NAFLD
Comparison of Noninvasive Markers of Fibrosis in Patients With Nonalcoholic Fatty Liver Disease
Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus
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