Jennifer B. Green, MD

 We can’t forget about insulin therapy. Insulin is a very effective tool. I talk about insulin as though it’s 1 thing, but there are many types of insulin being developed. One area that has seen a tremendous amount of evolution in recent years is the development of artificial pancreas systems. We have devices available that include both an insulin delivery component and a glucose sensor, or CGM [continuous glucose monitoring], component that are at least partially linked. The insulin delivery in at least some respect is directly affected by the ambient glucose level that the sensor detects.

We have a couple of devices that alter basal insulin delivery based on what the glucose level is, and that represents an exciting step forward. A true artificial pancreas—there are many such systems in development—would be completely hands-free or at least come very close. There are also a number of systems in development that include an algorithm or very sophisticated algorithms that alter insulin adjustment—not just for basal insulin delivery but for correction insulin or, to some extent, mealtime insulin in response to the individual’s activity and blood glucose level that will come a little closer. None of those hands-free systems are in development, but they’re getting closer.

We’ve seen published data, particularly in the pediatrics population, that look incredibly promising. Consistently, almost all the trials I’ve reviewed suggest that these kinds of systems reduce the risk of hypoglycemia compared with the traditionally available semi-integrated systems. The challenges we’ll see moving forward will be how these systems can be designed to account for meal intake, how to customize or appropriately deliver insulin in response to what the person is eating, and how the system reacts to hypoglycemia, should it occur.

Some of these systems are dual-hormonal systems that infuse not just insulin but also glucagon. Although none of these appear extremely close to becoming available, within the next 5 years, we’ll probably have multiple systems on the market that I hope will make life much easier for individuals who require these sophisticated insulin delivery systems. They’re not just for people with type 1 diabetes. These systems hold great potential for people with type 2 diabetes who need this intensive and complex treatment as well.

 Technology has certainly taken off. We have penny-size sensors for continuous glucose monitoring. We have subcutaneously implanted sensors. We get a lot of questions from patients who might not necessarily benefit from sensors. They may be cardiovascular patients or any patient with diabetes who says, “I’m on 2 medications. I’m on metformin, and my hemoglobin A1C [glycated hemoglobin] is 6.8%. Should I wear a sensor?” That’s probably not helpful. These are meant more for patients on complex insulin regimens or multiple daily injections, combined with insulin pumps and an algorithm used to semiautomate—at least for now—the basal rates.

If you look at the requirements from the FDA for diabetes medications, they’re very stringent on outcome trials. For durable medical equipment, we’ve never had an outcome trial, other than looking at time in euglycemia or hemoglobin A1C. We don’t know well whether using a pump vs multiple daily injections would reduce microvascular or macrovascular complications. I alway s thought that would be a very interesting area to explore. But much of this has to do with quality of life in addition to quality of care. More time spent in euglycemia, safer insulin use, shut-off algorithms—basal insulin in the middle of the night—etc. These are the main advantages of pumps and continuous glucose monitoring. It’s available with phone data, so it becomes much more user friendly. If you look at pictures of how the first pump, the backpack pump, was developed to now automated algorithms, it’s really taken off. Diabetes care will become much easier, much safer, and outcomes will become much better in the future.

Some of the most encouraging data for us endocrinologists and cardiologists have been from a large Swedish cohort that looked at mortality data in patients with diabetes, emphasizing the comprehensive care model. I keep citing the Steno-2 trial in every presentation because it sends the message of comprehensive care, where if patients are treated with their hemoglobin A1C and albuminuria protected, and smoking, LDL cholesterol, and blood pressure all under control—all 5 of those factors were under control in this large Swedish cohort—there was no significant excess mortality across every age group. This is really encouraging. We have all the tools available to do that. The challenge will be to bring this to the wider population and to fill a lot of the gaps that we’re dealing with.

 I completely agree. I briefly mentioned the GRADE study. We have just a few moments left, but some of the information that trial will ultimately provide will be a bit of insight into personal phenotypes and drug choices that may be particularly effective and tolerable for individual patients. I’m interested to hear more from that study about personal phenotypes, individual predictors of accomplishment of good glycemic control, and even benefits from a microvascular or macrovascular perspective within the various classes of drugs that were studied in that trial.

Thank you, Dr Bruemmer. I’d like to thank everyone for watching this 

®. If you enjoyed the content, please subscribe to the e-newsletters to receive upcoming 

® and other great content right in your in-box. Thank you very much.

Videos

Expert clinicians discuss insulin therapy for treating type 2 diabetes and comment on what to look forward to in the future of diabetes care.

Insulin Therapy and the Future of Type 2 Diabetes Care

 We should shift to what we see in the future as options to treat and improve the lives of patients with type 2 diabetes. One of the exciting topics at the last ADA [American Diabetes Association] meeting was related to data presented from the tirzepatide trial, which is a novel but not available combination GIP and GLP1 receptor agonist. This has been an interesting concept. There have been a number of agents in development that have had varying effects on GLP1 receptors, GIP receptors, and glucagon receptors, because we know that various degrees of stimulation or inhibition of those receptors can be associated with a wide and complementary way of metabolic benefits.

This agent, tirzepatide, appears to be closest to becoming available for treatment for our patients. The trial data were very exciting to see that use of this combination agent provided outcomes benefits, particularly with respect to weight loss and glycemic control, that appeared to reproduce and exceed those provided by the comparator GLP1 receptor agonist. We’re seeing an option for patients who either need more than effective and available GLP1 receptor agonism, or patients who might already be maxed out on the dose of a GLP1 receptor agonist that they can tolerate, or that’s FDA approved for glycemic control. Perhaps this represents a next step for such patients. We all have patients who are on as many classes as we feel are effective choices for them, but still struggle with glycemic control, weight management, or both. It’s very exciting to have at least 1 such agent on the near horizon. Did you have any other thoughts about the data that were presented?

 It’s fair to say that the data were quite powerful if not stunning. If you look at the SURPASS-3 trial data, the hemoglobin A1C [glycated hemoglobin] drop was 2.3% with 1 injection per week compared with degludec. More than 80% of patients achieved hemoglobin A1C of less than 7% in that study. That’s the most powerful drug that will become available. The maximum body-weight reduction was 12.9 kg compared with degludec, which raised the weight by 2 kg. It’s a very powerful medication, with less hypoglycemia, not just because of the comparison with basal insulin but also through the increased glucagon secretion that occurs with the GIP component of the dual incretin molecules. It’s a promising and powerful drug that will expand our tools that we have available.

One of the main challenges that we’re faced with is: how do we apply all these new medications to the broad population? How do we make this available? You mentioned that we need to be proactive in our care. That will be the main challenge: going from socioeconomics to formulary restrictions to access to patients to physicians and nurses. There’s a lot to be discussed and to be done, but it’s certainly a powerful medication.

 What we may see over time is a shake-up in the traditional stepwise approach to diabetes care, where you add 1 drug and essentially wait for it to fail before another is added. Perhaps we’ll be able to treat diabetes a little differently if we can choose very effective agents from the outset. Certainly, the GRADE trial results weren’t encouraging regarding long-term effectiveness of available agents, but we can talk about that further. That trial probably has much more interesting information to come.

Drs Dennis Bruemmer and Jennifer Green review recent trial data on a novel combination of GIP and GLP1 receptor agonists to treat type 2 diabetes.

Novel Dual Agonists for Type 2 Diabetes

 We talked a little about ways to reduce the risk of specific complications. We should take a moment to talk about some of the advances in the care of patients with diabetes and chronic kidney disease. Would you mind taking a moment to talk about how the care of such patients has expanded dramatically in recent years, particularly with the wrap-up of the key finerenone trials? We’re entering a new space for the care of such patients that will hopefully change their traditional trajectory of kidney failure.

 One of the main problems with microvascular complications in patients with diabetes is that for a long time there was no treatment other than ACE inhibitors and ARBs [angiotensin-receptor blockers], which are well established in patients with microalbuminuria in type 1 and type 2 diabetes. We’ve entered an era where we have medications to prevent kidney complications very effectively in patients with diabetes. Obviously, we have the SGLT2 inhibitors, which are well established through the CREDENCE and DAPA-CKD trials. DAPA-CKD extended this benefit from patients with diabetes to patients without diabetes. Then we have newer agents, like finerenone, which falls into the mineralocorticoid antagonist group. The idea came out of early spironolactone data, which had shown less progression in albuminuria in patients with type 2 diabetes. We went on to finerenone, and now the FIDELIO-DKD trial had been completed, which included about 5000 patients with type 2 diabetes and an increased albumin-to-creatinine ratio and retinopathy, whereas the second arm in the study had higher levels of the albumin-to-creatinine ratio.

In this study, the primary outcome was a composite of kidney failure decrease in the GFR [glomerular filtration rate] to less than 40 mL/min from baseline over a period. It also included death from renal causes. There was a significant reduction in the primary end point, 17.8% primary end point occurrence in the group with finerenone vs 21% with placebo. That’s a protective effect. This extends our armamentarium of all the data we’re looking at with SGLT2 inhibitors or mineralocorticoid receptor antagonists on top of the ACE and ARBs. We extended the armamentarium from ACE and ARBs to SGLT2 inhibitors and now to mineralocorticoid receptor antagonists. One important question is, what happens when we combine these optimal ACEs and ARBs plus an SGLT2 inhibitor plus a mineralocorticoid receptor antagonist, such as finerenone? What will we see? How much of morbidity and renal-related mortality can we reduce with these novel agents? But these are very promising new approaches, and it’s a very exciting area to be in the care for diabetes with all the all the new developments.

 It’s an exciting time. Before we move on, I want to mention that there are nonpharmacological options that convey outcome benefits as well. I’m guilty of probably not referring my patients to at least consider the option of bariatric surgery as often or as early as I should in the course of their disease. When we think about the outcomes data that we’ve seen in the bariatric surgery studies, they often aren’t randomized trials, but they’re very well conducted and complete studies—many of which were conducted in Sweden, which has very robust health care data for all its citizens. It’s very clear that the earlier patients with diabetes and obesity undergo bariatric surgery as clinically appropriate, the more likely they are to experience a remission in diabetes, at least in the short term after surgery, and the greater the reduction in their risk of both microvascular and macrovascular complications. It doesn’t always have to be something we achieve through use of medications.

Of course, weight loss is a very important intervention. The type of weight loss we see with bariatric surgery has very meaningful benefits in our patient population. But if we wait too long, those benefits are minimized to some extent, so I’m personally trying to not wait until all other options to improve a person’s health are exhausted before I consider the option of bariatric surgery. That has perhaps been the traditional way that bariatric surgery is considered—as a last resort—when we need to be thinking about it very early on in the course of disease.

Thank you, Dr Bruemmer. And I’d like to thank everyone for watching this 

Thought leaders discuss recent advances in treatments for patients with type 2 diabetes with chronic kidney disease.

Controlling Chronic Kidney Disease in Type 2 Diabetes

 There’s a role for all these medications. As you know, most people with diabetes will progress over time and need additional glucose-lowering therapy. We’re fortunate that we have a large number of tools to use. Where it can become tricky is figuring out not so much how to design care for the person with newly diagnosed diabetes—that’s still reasonably straightforward—but how we incorporate these drugs into an already complex diabetes treatment regimen. This is where the diabetes care specialist can be helpful.

SGLT2 inhibitors and GLP1 receptor agonists are intrinsically classes that don’t cause hypoglycemia on their own, but any time you add an additional class of drug to the regimen of somebody who’s on a sulfonylurea or insulin or both, the risk of hypoglycemia will be increased. It’s important to make some room for the newer agent that will provide the outcomes benefit and reduce the doses, or even discontinue the sulfonylurea that the person might be taking or decrease their insulin dose. I’ve had a lot of success in substituting these classes of drugs effectively for medicines that the patients might already be taking. I always try to look for an opportunity to make a substitution for a drug that they might be taking already that they don’t tolerate very well or is expensive and doesn’t provide an outcomes benefit. In that case, the change in their regimen is relatively cost neutral. There are always nice opportunities to look for that.

Don’t forget to ask your patient if they’re taking any medicines that seem to be causing them any problems. That’s a great way to incorporate a new drug in a way that will make the patient hopefully feel a little better or more satisfied with their care regimen. Being very proactive like that, I’ve had very little trouble with unexpected hypoglycemia while incorporating these newer agents. Are there any other tips or tricks that you think we need to keep in mind when we use GLP1s or SGLT2 inhibitors for the first time?

 Typically, the majority of patients we see for diabetes treatment are uncontrolled. I agree with you that hypoglycemia is usually not a problem. It occurs infrequently, particularly when we replace other medications with an SGLT2 inhibitor, for example. We see quite a few patients on metformin and basal insulin in whom we want to add a GLP1 receptor agonist, particularly after CABG [coronary artery bypass graft] surgery. They’re being very actively treated by endocrinology in the hospital, and then we see them in the preventive clinic for follow-up. A large portion of these patients are newly diagnosed, and then there’s the intention to be very aggressive and protect them from surgical complications.

Patients come to our program on insulin, or maybe basal insulin, correction factor insulin, or perennial insulin. In our preventive cardiology clinic, we want to add an SGLT2 or, more commonly, GLP1 receptor agonists because obesity is a major comorbidity. And then the patient would enter cardiac rehab at the same day and start to get more exercise. These patients need frequent access and need to provide their glucose data, but we try to reduce their insulin doses, which we do much more frequently with GLP1 receptor agonists than with SGLT2 inhibitors.

As you know, there’s a large tendency for overbasalization in care. Those patients then may be at a little higher risk for hypoglycemia, so we dial back the basal insulins in someone who’s better controlled at that time, because the GLP1 receptor agonists are quite powerful at lowering the hemoglobin A1C [glycated hemoglobin] and their weight. Then you add the cardiac rehab, and hypoglycemia can become a bit of a problem. There are studies to support all this—adding GLP1 receptor agonists or SGLT2 inhibitors to basal insulin—and the risk for hypoglycemia is rather low.

 I agree. And it’s important to keep an eye on patients over time who are on the GLP1 receptor agonists, particularly as their dose is uptitrated. If they lose a lot of weight, there may be an opportunity to further cut back on their insulin doses that they may be taking. I don’t necessarily wait for hypoglycemia to occur, but I tend to be fairly proactive to see how much I can cut back and still maintain good control. Sometimes I can cut back a surprising amount on the doses of insulin that an individual is taking.

There are obviously some safety concerns with all drugs. I‘ll just throw a couple of quick tips out there to help smooth the path for making sure the patients are able to stay on the drugs we want them on. I’ve noticed that with the GLP1 receptor agonists, if I give my patient the heads-up that they may have some GI [gastrointestinal] upset, and that it’s to be expected and usually goes away over time, they’re much less likely to stop the drug when any of those adverse effects occurs. I also ask people to avoid eating very large amounts of food at any 1 time. I have some patients who are in the habit of eating 1 very large meal a day, and I encourage them to eat more frequent small meals, particularly as they’re starting the drug, and that helps with tolerability.

The other thing I’ve noticed is that if you add the GLP1 receptor agonists to max-dose metformin, some people can have some problems with loose stools. If that’s a persistent problem, I’ve been pretty successful at improving that by asking them to cut down a bit on the dose of metformin. There are all kinds of strategies for keeping people on the medicines that we know will benefit them most from an outcomes perspective. But it’s important to follow up with patients closely when they start these new medicines and make sure that we’re responsive to any concerns they might have. It goes a long way. I’m fortunate to have a clinical pharmacist in my clinic who helps a lot with that touch point between clinic visits, which can be so important in effectively keeping people on their medication regimen.

Dennis Bruemmer, MD, PhD, and Jennifer B. Green, MD, have a conversation about the use of SGLT2 inhibitors and GLP1 receptor agonists in treating type 2 diabetes.

Jennifer B. Green, MD

Articles