What's the Goal in Treating Type 2 Diabetes?

This transcript has been edited for clarity. 

I'm going to talk about the new guidelines from the American College of Physicians regarding the treatment of adults with type 2 diabetes. They published three basic articles around this topic. First was the clinical guideline, which I'm going to speak most about. Second was a systematic review and network meta-analysis, which is basically the background from which the guidelines came. The third was a cost-effectiveness analysis, which also had something to do with the final guidelines as well but isn't my particular strength when it comes to reviewing. 

In terms of their meta-analysis, they basically included randomized controlled trials (RCTs) of a year or more, with 500 or more adult patients, which came to 130 publications. They looked at sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, insulin, and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agent tirzepatide. They came out with results that seemed to be results we already knew. 

We basically know that SGLT2 inhibitors and GLP-1 receptor agonists reduce all-cause mortality and major adverse cardiovascular events compared with usual care. They also note that SGLT2 inhibitors reduce chronic kidney disease (CKD) progression and heart failure hospitalization, and GLP-1 receptor agonists reduce stroke. They noted that hypoglycemia was less common with these newer agents compared with insulin and sulfonylurea agents. 

Now, interestingly, even though these are guidelines for the management of type 2 diabetes, in this meta-analysis, they do not look at glycemic control. They say — and I think this is true — that you can't really tell much about glycemic control in the papers they analyzed for this meta-analysis because of the heterogeneity of the study design and because in many cases, there was post-randomization treatment allowed with add-on medications that differed depending on the trial. 

They suggest that we look at older reviews as better data sources for assessing the short-term impact of medications on glucose levels. The problem, of course, with many of those older publications is they don't include the newer agents. Be that as it may, keep in mind we're going to be thinking mostly on our own about glucose lowering. 

They don't actually think that these newer agents should be used as first-line therapy. They still believe that metformin should be used as first-line therapy in everybody with type 2 diabetes. They basically say we don't have information as to where these drugs fit in these newly diagnosed or drug-naive patients. Start with metformin and then add something new. 

Their first recommendation reiterates what I just said, which is basically that adding an SGLT2 inhibitor or GLP-1 receptor agonist to metformin and lifestyle in adults with type 2 diabetes and inadequate control is a good idea. They say to use an SGLT2 inhibitor to reduce the risk for all-cause mortality, major cardiovascular events, CKD progression, and hospitalization due to heart failure. They say to use a GLP-1 receptor agonist to reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke. That's recommendation one. 

Recommendation two is that the American College of Physicians recommends against adding a DPP-4 inhibitor to metformin in adults with type 2 diabetes to reduce morbidity and all-cause mortality. I buy that there aren't data for that. 

Then they go on to suggest that the target A1c in most adults should be 7%-8%. Here, I disagree, and I know there has been many a debate as to what the target A1c should be and in whom. I am sorry, but I'm a firm believer that if a person can, without undue side effects or complexity, get to an A1c < 7%, particularly if they have a longer life expectancy, that that's preferable to a higher A1c. 

I adjust my A1c targets as patients get older, as they perhaps need to use insulin or drugs that can cause hypoglycemia. I really do feel I'm fairly fluid with regards to my A1c targets and my patients because they are something we work on together. 

They also say — and this bugs me — that we should de-intensify therapy if the A1c is < 6.5%. To support this contention, they reference the 2018 American College of Physician guideline on A1c targets. That's well and good if you have a drug that causes hypoglycemia or other side effects. Let's just say you have a patient on an SGLT2 inhibitor because they have CKD or they have heart failure and their A1c happens to be 6%. Does that mean you should reduce or stop the SGLT2 inhibitor? I don't think so. I think you should keep them on that. 

Lately, I've had patients ask me if I can reduce the drugs for their diabetes because their A1c is too low. I'm not using drugs for their glucose. I'm using these agents for their cardiovascular and renal benefits. Why should I use an A1c target to tell me whether or not I should have these patients on these drugs that I'm using for another reason? 

I don't like that de-intensification part. I think it needs to be better described because I know what they mean. Trust me, I don't like complexity. I try to make regimens as simple as I can for patients, but I don't blatantly say, "If their A1c is less than 6.5%, start de-intensifying medications," because that's not correct. 

They also say that self-monitoring of blood glucose (SMBG) isn't necessary in patients who are on agents that don't cause hypoglycemia. That's probably true, except that it's hard to look at that actual statement and understand it. SMBG has shown to be useful in settings where there's feedback based on the data, where there's education around it, and where it's part of a program. More importantly, we don't really use SMBG that much anymore. We use continuous glucose monitoring (CGM), and they don't talk about CGM at all.

They may have a whole additional guideline coming out, I don't know, but CGM, at least to me, is a very important tool and not just for patients on insulin. I use it in many people with type 2 diabetes who aren't on insulin, and I can show that providers do a better job in intensifying therapy, that patients learn about lifestyle from looking at CGM, and there are increasing amounts of data coming out to show that CGM is helpful in patients who aren't on insulin therapy. We need to think about what monitoring is and how we are going to use it in these patients as we look at targets and trying to get patients to where they should be. 

In terms of the cost-effectiveness analysis, they again reiterate that GLP-1 receptor agonists and SGLT2 inhibitors are of low value as first-line therapy, but may be of intermediate value when added to metformin. Again, I'm not a genius when it comes to cost-effectiveness analysis, but I see some amazing weight loss in my patients who are on GLP-1 receptor agonists. 

I do not see this in everybody, but I've had patients lose 100 lb and not have to have bariatric surgery. I've had patients lose 10% or more of their body weight and keep it off. From Look AHEAD, we actually know that losing 10% or more of your body weight actually can reduce cardiovascular events and help people do better. I think that, if you start looking at obesity as a key end point here, we're going to find all sorts of benefits that need to be included in this cost-effectiveness analysis. 

These guidelines don't stress the treatment of obesity at all. I really applaud the American Diabetes Association guidelines for looking at obesity as something we need to concurrently consider and treat, and that if we can do that, we're going to lower many things — not only the risk for hypoglycemia but also the risk for all the comorbidities associated with obesity. 

I think this is a different world from the one it used to be when it comes to looking at things like cost effectiveness. Again, I don't claim to be an expert, but I know clinically there's a variety of benefits. Even just making sleep apnea better for a human being is huge, and you get to reduce the cost of all that machinery. 

They do say that there are no data — and there aren't — to support the use of combination therapy with SGLT2 inhibitors and GLP-1 receptor agonists, but we do use these commonly together. I do, and in part it's because of glucose lowering. It makes me ask the question, what's the goal of treating diabetes? Well, it's to reduce the risk of micro- and macrovascular complications. This guideline does seem to lose the thought that lowering glucose levels is a good thing, or at least it's kind of like, that's just a given. It isn't just a given. 

When I work in underresourced communities, I see all sorts of microvascular complications that are due to poor glycemic control, and I even see it in more affluent communities. We really do need to never forget the need for lowering glucose levels to reduce the risk for microvascular complications. It's just something that happens. It would be great if we could treat everybody early and prevent all of the complications, but we're not in that utopian world yet. 

For macrovascular complications, we do seem to be doing better with some of these agents. I think that we need to remember that that's always a part of what we're doing. 

Finally, they talk about the fact that we basically don't need to use sulfonylurea agents and insulin much anymore for glycemic control. I would argue that perhaps we don't need to use sulfonylurea agents all that much, although they do lower glucose. 

What we really do need to still use is insulin. As an endocrinologist, what I see the most are patients whose primary care provider put them on basal insulin, but then can't really make a change. They can't effectively add prandial insulin. 

I see all sorts of patients who still need to be on insulin. I would love to think that we're not going to need to put patients on insulin in the future, but we sure aren't there. There are many patients who need to be on insulin, who need to be on intensive insulin regimens who have type 2 diabetes.

Maybe there's not just one kind of type 2 diabetes. We know this now. There was a recent article published in Diabetes Care beginning to define all these different subtypes. There may well be subtypes that are more insulin deficient, in people who have what we call type 2 diabetes, compared with other subtypes where people are more insulin resistant. We can't believe that there's just one type of type 2 diabetes that's going to respond in one way and not require insulin. 

I think it's very important that providers understand how to use insulin — basal insulin and prandial insulin — and use it effectively in patients where it's needed. Again, I see all the time patients who are on every possible noninsulin therapy and their A1c is 10% or 11%. These are not people who don't need insulin. These are people who do need insulin. In the absence of insulin, they have exceedingly high glucose levels and end up with terrible complications. Insulin isn't gone. 

Again, I would love to see it such that diabetes becomes really simple; we don't need complicated regimens, we don't need insulin, it's cost-effective, and everybody's happy. I think that's still a ways off in the future. 

For now, I think these guidelines state pretty much what we know. I don't think that metformin should be first-line therapy in patients with known cardiovascular disease, heart failure, or CKD or those at high risk for cardiovascular disease. I think that they do better if given an SGLT2 inhibitor or GLP-1 receptor agonist, despite what these cost-analyses say. What can I say? I am not the world's expert on this, and I do applaud the American College of Physicians for doing this and trying to do this as thoughtfully as possible. 

We can all agree to disagree, in particular, in terms of how we treat all these patients. I think that we all need to clinically remember what our goals are, and that we're not just doing one thing. We're not just lowering glucose, but we're not just lowering macrovascular risk either. 

We're lowering glucose, weight, and risk for macrovascular disease; we're slowing progression for existing complications; and most of all, we're trying to give people a longer and better quality of life. Thank you. 

Anne L. Peters, MD, is a professor of medicine at the University of Southern California (USC) Keck School of Medicine and director of the USC clinical diabetes programs. She has published more than 200 articles, reviews, and abstracts, and three books, on diabetes, and has been an investigator for more than 40 research studies. She has spoken internationally at over 400 programs and serves on many committees of several professional organizations.