Diabetes Treatment Updates

Featured panelist Craig D. Williams, PharmD, FNLA, BCPS, Clinical Professor of Pharmacy Practice at the Oregon Health and Science University joins us to talk about diabetes treatment updates.

Listen in as we discuss management of type 2 diabetes, including overcoming hurdles with metformin, GLP-1 agonists, and SGLT2 inhibitors.

You’ll also hear practical advice from a panelist on TRC’s Editorial Advisory Board:

• Andrea Darby Stewart, MD, Associate Director, Honor Health Family Medicine Residency Program and Clinical Professor of Family, Community & Occupational Medicine at the University of Arizona College of Medicine - Phoenix

None of the speakers have anything to disclose. 

TRC Healthcare offers CE credit for this podcast. Log in to your Pharmacist’s Letter or Prescriber Insights account and look for the title of this podcast in the list of available CE courses.

Claim Credit

The clinical resources mentioned during the podcast are part of a subscription to Pharmacist’s Letter and Prescriber Insights: 

• Chart: Drugs for Type 2 Diabetes
• Algorithm: Improving Tolerability to Metformin
• FAQ: Hyperglycemia in the Hospital

Email us: ContactUs@trchealthcare.com.

The content of this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment.

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Transcript

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[Intro Music]

Welcome to Medication Talk, the official podcast of TRC Healthcare, home of Pharmacist’s Letter, Prescriber Insights, RxAdvanced, and the most trusted clinical resources.

On today’s episode, we’ll discuss management of type 2 diabetes, including overcoming hurdles with metformin, GLP-1 agonists, and SGLT2 inhibitors.

Our featured panelist today is Dr. Craig Williams from the Oregon Health and Science University. 

You’ll also hear practical advice from another panelist on TRC’s Editorial Advisory Board:

Dr. Andrea Darby Stewart from The University of Arizona College of Medicine - Phoenix

This podcast is an extract from one of TRC’s monthly live CE webinars. Each month, experts and frontline providers discuss and debate evidence-based practice recommendations.

The full webinar originally aired on February 20th, 2024.

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And now, the CE Information.

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This podcast offers Continuing Education credit for pharmacists, physicians, and nurses. Please log in to your Pharmacist’s Letter or Prescriber Insights account and look for the title of this podcast in the list of available CE courses.

None of the speakers have anything to disclose. 

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Now, let’s join TRC Editor, Dr. Jeff Langford, and start our discussion!

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JEFF LANGFORD:
We're talking about diabetes treatment updates. As we navigate this discussion today I'd really like to start by pulling the lens back a bit and and look broadly at type two diabetes management, including a treatment overview, thinking about choosing first line medications, And then we'll dive into some of those problem solving tips including for Metformin, as well as overcoming some common hurdles that are arising in practice with GLP one agonist. And we're gonna dig into managing and reducing the risk of ketoacidosis with SGLT2 inhibitors. This is kind of popping up against a background evolving guidelines. So early in the year annually we get new new guidance from American Diabetes Association and we have that for 2024. But we also have a recent guidance last year from American College of Clinical Endocrinologist. The recent guidance from the VA department of defense…and older guidance, 2018 from American College of Physicians So when as these guidelines emerge from different bodies that always creates questions about which to follow and sometimes discrepancies across practice. In one area that that does align nicely across these recommendations that we continue to emphasize for our patients is a lifestyle change. And so we do wanna continue to emphasize as the foundation for management of type two diabetes weight loss where it's needed for our patients, healthy eating, managing sleep and mood smoking cessation if appropriate getting healthy movement in, and limiting alcohol. And kind of the next area that is also consistent across guidance is individualization of a1c goals. And Andrea I'd like to pull you in here to talk to us a little bit about this and perhaps how you do this in your practice…

ANDREA DARBY STEWART:
Sure That's a great question. One of the first things that we talk about is whether or not the patient, has experienced any comorbidities…already related to diabetes We talk about diabetes as really a long game, against, kidney disease…a cardiovascular…disease, and ensuring that the patients can, live a very long and healthy life patient's age and life expectancy certainly play into that So I'm much likely more likely to be…to negotiate a stricter a1c uh in my younger patients who have not experienced any comorbidities…and can follow directions well are at less risk for hypoglycemia…than I am in some of my elderly patients who may have already had some of the significant um adverse event events associated with diabetes. and I'm really trying to mitigate their risk of the adverse effect of the medications I'm using to help keep them relatively euglycemic and, prevent just some of the symptoms that are related to significant hyper vicenia…

JEFF LANGFORD:
Well I love that theme of individualization throughout all of those conversations. Craig I'd like to move to thinking about medications, specifically wondering if you can step us through the medications that are now considered first line, for management. 

CRAIG WILLIAMS:
It's almost easier in this area think about like what is not definitely a first line So I think unless you have a type one diabetes patient, we're rarely reaching for insulin first line but that's certainly a it's a wonderful medication when we need it and we get almost anybody…really close to their goal optimize the insulin but that can be challenging and carries the biggest risk of hypoglycemia so and sofonurias have definitely kind of fallen down the list But lots of things have come up So…as you see illustrated here historically and not that long ago was kinda metformin metformin metformin first line but…as we are now getting into maybe the sixth or seventh year of getting outcomes trials. For the newer classes of medications where the FDA decided it's no longer sufficient…to just show that you provide glycemic control You need to show other benefits as well So we're can't have many trials now where we're looking at outcomes besides just glysemic control And and those trials have kind of been elevating some of these newer classes of medications so yes very much in a way besides metformin, which still can certainly remain a first line drug for a lot of patients with certain comorbidities it really is now the GLP ones and the SGLT2s sort of kinda floating…to the surface. 

JEFF LANGFORD:
With that in mind let's turn to Metformin. And I in our content we have talked about Metformin and and often said that it still remains a first line option for many patients. And can you describe for us kind of some of the advantages or reasons it would still have that kind of gold standard label so many patients Craig? 

CRAIG WILLIAMS:
Yeah I mean it has been around for a long time So in fact it's you know it's kinda late to the game here in the US The Europeans were using it for a couple decades before we were using it So, you know they're we're not gonna find some new skeletons in the closet for metformin…And it got kind of unfortunately tagged with the lactic acidosis risk uh the risk there is much lower than we kind of thought and much much lower than FENform and it's kinda chemical precursor so it it has a safety profile that really is pretty hard to beat So, been around for a long time It's as a consequence it's been around for a long time It is generically…available Has been generically available for a long time So it's an inexpensive way to get a safe drug and it again does not cause, I'd say significant and certainly severe hypoglycemia, by the way it works. You know it was really kind of the first major oral drug besides the sulfonylureas that where we could get you know pretty good a1c effects and and we didn't have this hypo based senior risk that kind of came in here with all the Safani areas So it's inexpensive it's safe It doesn't cause for hypoglycemia and maybe one strike against it is I think it it does not necessarily improve vascular outcomes like these newer medicines are proving to do, so.

JEFF LANGFORD:
Alright. And of course we do have to uh as always as we think through meds we're gonna consider the limitations or downsides with with drugs as well. And and we know that metformin does commonly cause GI upset It carries the warnings as you mentioned Craig for rare lactic acidosis and we do have to be mindful about using it appropriately in kidney disease which will unpack in a bit But I wanna focus on that GI uh upset first Andrea and and some of our content in the past We've said that about one in three patients with type two diabetes who start metformin, stop it within three months. So against that backdrop I'm kind of wondering how you set expectations for your patients about…starting metformin What should they expect How can we make it a success for them. 

ANDREA DARBY STEWART:
That's a great question I actually set them up to, um tell them you're going to experience GI side effects you might feel bloated You might get some diarrhea. If you can go if we can start uh start at a low dose same thing as simple as five hundred milligrams once a day. And when she was tolerating that for four to five days maybe even slower we'll increase that slowly to a maximum dose of a thousand twice daily. and if that doesn't work or if you start to get symptoms at any point we'll just back off to the dose that didn't cause you those symptoms. I basically lay a plan out for them ahead of time so that they don't initially feel after a couple of days of taking the medication lousy and just write it off as ineffective and something that they're quote allergic, to or intolerant of. 

JEFF LANGFORD:
Okay Great. And Craig and as Andrea painted out that picture of the starting low going slow stepping them up carefully with that I'd like also your thoughts on the product that you choose for that initiation do you…we recommended in the past to use an extended release product to help improve tolerability wonder if you align with that…

CRAIG WILLIAMS:
Yeah But only by a little bit So you know the benefit of metformin is one of the big benefits is inexpensive and generic and available almost everybody that's a little less true for extended released version but it is generally still pretty expensive and pretty well covered. So it is a bit better. and if it's available to patients it's certainly…as effective and would not be a wrong strategy to try But Andrea's comments are well taken of, some warning, um to patients Although as we talk about with our you know pharmacy students and pharmacy residents the more you set someone up that something's gonna happen the more you kind of plant that seed that's going to happen So we have good discussions around it How much do you warn about the muscle side effects with statins to you know scare people off and this maybe falls in that category but it is common enough I think it is fair. To warn about so not caught off guard But then kinda my second sentence besides you're gonna get some GI upset is gonna be mild and you're gonna be fine with it you know kinda set them up with that It's just like that But um but yeah starting low there's no rush to this Diabetes is a long term…condition We're managing long term comorbidities and if it takes you a few months to start ramping up the dose of metformin that's okay. 

JEFF LANGFORD:
Well Craig you already noted that lactic acidosis is rare with metformin…And we mentioned that we can use it appropriately in kidney disease but we do need to be mindful of that appropriate use so that we're keeping that risk very low And I wondered if you could talk about kind of your…approach for dosing metformin or using metformin in patients with kidney disease. 

CRAIG WILLIAMS:
Yeah I think…let me see What you have here on the slide is certainly fair So I was kinda…glad to help in the effort a bunch years ago to get the labeling for a change from certain serum creatinine cutoffs for use to the GFR SMA GFR cutoff for use And Yep You know below thirty is still the fair number to keep in mind Now that doesn't mean that you know, estimated GFR of thirty one you're all good in estimated GFR of twenty ninth problem So these are all kind of rough guesstimate…equations as we use them in practice., but yeah if you're gonna kinda keep one number in mind with it is thirty. 

JEFF LANGFORD:
Well let's dive in now We we've talked about solving some some common problems with metformin but let's turn to the GLP one agonist class. We have duloglutide a couple of different formulations of eczemaitide, liraglutide semaglutide and for purposes of conversation today we've launched tirzepatide in this conversation It's a a dual agonist of course a GLP one and GIP agonist but we're gonna include it here today So round out our discussion since it is partially a GLP one agonist. And Craig I wonder if as we turn to this class if you can walk us through the Again you like that pharmacology hat so I'm gonna use it tonight and ask you to walk us through mechanism of action here and talk a little bit about that. 

CRAIG WILLIAMS:
As we have kind of said alluded to It's complicated but the parts we well understand and what they were developed from was a hormone that really kind of slows…gatheric emptying and helps improve early satiety in patients so, like the bottom line is they help patients consume fewer calories for a couple reasons one of which we understand well which is delayed gastric emptying and the other which we don't understand too well which is this complex…communication between the gut and the brain that determine when we feel hungry and when we feel sated so those two together account for just less… caloric consumption among our patients and discussions early on or how much was it the GI upset from these medications that made patients eat less And but then we figured out now it's not GI upset Patients said that don't get GI upset still get the weight loss benefits. 

JEFF LANGFORD:
Okay So brain gut and pancreas kind of working together getting that blood glucose lowered and getting some weight loss in there as you mentioned as well. But our as we already have nodded to the the potential benefits the GLP one agonists don't really stop with just this glycemic management or even the weight loss piece. We do have other considerations and other potential benefits with them. And wondered if you would talk to us a little bit about those benefits Craig We've suggested them already but let's just recap again what goes beyond the a1c lowering with this class…

CRAIG WILLIAMS:
And so you're getting into like vascular effects that we still are kinda working I mean we know quantitatively…they happen We're still trying to think figure out kind of qualitatively exactly how and why they happen So remember to kind of put our complications still into the kind of macrovascular and microvascular…kind of camps and these drugs have effects on both And for that chronic kidney disease in particular, Yeah There's benefits there that I'd say we certainly do not understand with this drug class like we do with the SGLT2s twos but it is persistent…across trials Where you define it as acute kidney injury or progression of serum creatinine during the trials there is benefit there So it's really the one big what I would kinda call microvascular benefit at the GLPs. And then the macrovascular is still just atherosclerosis and the consequence MI stroke and heart failure risks And so yeah across the board. 

JEFF LANGFORD:
What we have seen with these drugs is that a1c lowering is kind of varies across the class I think it starts around one percent perhaps for shorter acting drugs like Xenatide, goes up to maybe two plus percent for our more potent and longer acting agents semiclutide and tirzepatide, and then kind of encapsulated here on this slide Craig or some of the benefits you've been highlighting that we've seen that in those outcome studies in particular uh duloglutide, semaglutide and larynglutide have also known as reduction cardiovascular events with those three agents as well as renal benefits. And we do have the three agents in this class that are approved specifically for weight loss The lira gluotide, tirzepatide and semaglutide so we can uh I think based on the information you've shared with us it's reasonable for us to keep these drugs in mind for patients with cardiovascular disease or high risk, certainly for the…as an option uh for chronic kidney disease patients and certainly for diabetes when when weight loss is important. Well I think one of the issues with these drugs so we're talking about benefits and and reasons we would like to use them Of course shortages have plagued our pharmacists prescribers and patients in terms of trying to get these GLP one agonist and we've said in our content that we can expect these shortages to continue due to high demand, for for the foreseeable future and a couple of different approaches that we might can investigate or consider for any given patient…One would be to temporarily lower the dose, perhaps change GLP one agonist or even switch to a different class altogether even if temporarily to kind of navigate through that shortage. And I think out of that list the one that would probably raise the most questions for many…of our listeners would be how to change GLP one agonist. And I wonder if if you'll help us with that Craig in thinking through perhaps a practical approach if we need switch agents. Um in particularly if we're thinking about this context of shortage is it…our decision making might be different for somebody that isn't tolerating it or has other reasons change But if it's simply that we can't get it what would be some practical things to hit on here? 

CRAIG WILLIAMS:
We can look at average typical…dosing and say you know this is a kind of a typical mid range dose. I do think that, you know for the most part we're coalescing around kind of a weekly…injection most commonly And so yeah I'd be pretty unexcited as someone on a weekly agent to go to something that's that's you know daily more frequent So, But yeah sticking with the weekly injection Those are on a weekly. And then if it is a matter of converting back for I know we have a slide coming up where we kinda give what we think are equivalent doses. I do think for if a patient is tolerating a mid range dose of an agent's general they will probably tolerate mid range dose of the other agents So I don't think you have to go back to a beginning titrating dose of that agents. but if an abundance of precaution is your approach you don't know for sure that their GI experience will be the same with agent number two as it was with agent number one So not never a bad advice to go back to a starting dose if you do have to switch agents But our experience has been if again if you're tolerating kind of a good mid range dose you highlighted there you can probably jump to that dose with a newer agent And as Andrea said it's this is individualization and history tends to predict history here So if you had that patient that had a started off great and had a smooth titration you're probably gonna be fine So don't feel like you have to start the whole titration over again with drug number two would be my take home. 

JEFF LANGFORD:
Okay Well let's turn and think about some side effects that go with this class and some limitations again that we need to have top of mind if we're going to consider using them and and we've noted GI upset typically modest and temporary but certainly can be a limiting factor injection site reactions, severe reactions are possible uncommon but things like pancreasitis or gallbladder disease are rarely associated with this class. And we do in fairness have things we're continuing to learn about For example FDA recently released an analysis that looked at reports of suicidal faults and actions in patients with GLP one agonist. They didn't confirm a link there but there is ongoing monitoring So there are things that we need to stay tuned and…be be abreast of as as data emerges. But I want to talk a little bit about the GI side effects first and Andrea and Craig I'd love your thoughts here, perhaps some practical tips that we could share with patients for mitigating those GI side effects when we start and we've mentioned starting low and going slow But do you have other things Andrea that that you suggest with patients…

ANDREA DARBY STEWART:
That's a great question So we often talk a little bit about how these medications work and how patients might just need to adjust their normal dietary habits As we said earlier in the webinar managing diabetes is not just about which medication we give to patients but how we help them manage all of the other things that impact their disease process so things like are you eating…smaller meals, perhaps, listening to your hunger cues a little bit more closely. Particularly if you've noted some GI upset, with any medications that you've been taking. and we will occasionally, utilize things like on dansetron, to help relieve that mild nausea I'm curious if Craig has noticed that his patients tend to complain of these symptoms more frequently on the day of dosing rather than later in the week that's what I've noticed with most of my patients So if they do need to use something like an undansetrom, It typically is just for that day of injection and then they seem to improve over the course of the following five to six days. 

CRAIG WILLIAMS:
Yeah It knows that it is definitely a benefit of the weekly injections that it is not a for the whole week you kinda feel the same So it is definitely worse And And that that does kinda fit, you know this is not something that kinda…slowly leaks in the system over the first three or four days You kinda get some peaks And then most of them have half life measured in the in days which is why we can dose them once per week And, But yeah you know those first couple days and your weekly dosing cycle of it are gonna be a bit worse So and yeah we are not opposed certainly to using some symptomatic management medications if it helps patients. 

JEFF LANGFORD:
Let's move along now to the SGLT2 inhibitors. We have six agents within this class. Five of these are approved for management of type two diabetes in addition to other indications around reducing some of them have additional indications for reducing cardiovascular risk The kind of the outlier here is the type of fluzen It is not approved for managing type two diabetes but it's approved solely for reduction of CV risk So but the other five agents the plexaglaflazin…tpaglaflazin impaglaflazin and artiglaflazin…are all approved for type two diabetes with potentially other indications folded in there And Craig, thinking again mechanistically, if we're talking about…the mechanism…of blood glucose lowering for management of type two diabetes Could you step us through that briefly? 

CRAIG WILLIAMS:
Yeah No In this one we can kinda sum up We we still debate if there's anything else these might do but you know the ninety nine percent of what they do is just inhibit reabsorption of glucose…in the glomerulus So we're helping the kidney kind of flush out that excess glucose And whether you first got this training in pharmacy school or medical school or nursing school we all learned at one point that the kidney basically reabsorbs…most all of the glucose that is filtered. So glucose is freely filtered at the glomerulus If your blood sugar is one twenty, concentration Ultra filtrate is one twenty milligrams per deciliter but you very avidly reabsorb that And it makes sense We wanna basically hang on to our glucose from an evolutionary standpoint, we are built to conserve glucose But when it gets high enough now you overwhelm those receptors and it starts spilling out So But there was among the receptors you used to reabsorb that is this receptor And so by inhibiting this we basically help that excess glucose just flush out of the system. 

JEFF LANGFORD:
Okay That's a very nice picture and I think that helps us kind of wrap our heads around how these drugs are are working for type two diabetes. We do have as you noted earlier lots of cardiovascular outcomes data with this drug class as well., so I wondered if you would talk to us about that. 

CRAIG WILLIAMS:
So in fact you know if asked me to pick what is the most impressive kind of outcome from these drugs in the now almost decade we have in the market It's the kidney benefits. It really does somewhat stand out with heart failure benefit kind of close behind And then the vascular benefit besides heart failure So that MI reduction in macro infarction and stroke risk, not quite as impressive from a magnitude standpoint. 

JEFF LANGFORD:
Okay. Well Andrea I want to ask you as we think about these drugs we're faced with lots of great benefits that Craig has summarized for us but we are faced with practical…limitations in terms of adverse effects And what are some of those things that you're navigating through in your in your practice with patients in terms of limitations of these drugs? 

ANDREA DARBY STEWART:
Sure Most recently I've had to help a patient understand that just because She's on her medication…before, her diabetes and chronic kidney disease. her glucoses are terrific. that doesn't mean she can liberalize her diet because the mechanism of action is that she is urinating help more glucose and she is giving herself uritory tract infections and candidal infections. So it's been kind of an interesting, discussion with her to basically be like look you need to still follow the dietary modifications. urinary related issues, are some of the biggest that I've seen here I've also had some challenges, with a couple of patients who we had on loop diuretics and these medications reduce the dose or stop the loop diuretic but because of auto prescriptions they received another prescription for a loop diuretic and then resumed them and, resulted in some substantial changes in renal function because they were being over diarized and we've had to kind of reiterate with people that when we do stop these medications, we want you to stop them regardless of whether or not they get sent to you or somebody calls you and says hey we've noticed you haven't filled your prescription. so so those are some of the some of the more recent challenges that we've run into here. 

CRAIG WILLIAMS:
The thing I think you have coming Jeff is the ketoacidosis been an interesting thing that we've kinda had to navigate our way around and practice and then we'll spend some time on that But but aside from that it's really some thought about acute kidney injury and that is you know keep in mind if they're already on a diuretic And then as Andrea said the urinary tract infections which you know definitely…yeast infections in our female patients, whether or not you really increase bacterial…cystitis and pilomyritis risk that literature still debates that In the labeling and we should be aware of it And if someone wasn't having any UTIs before the SGLT2 and now they are absolutely it could do it. But increasing it seems like the risk really is local yeast infections definitely and we still kinda debate in the labelings and kinda not clear is there a really different between placebo…and the drug because you know patients with diabetes have glucose in their urine already Now they have more So It's a little hard to tease out the real UTI risk but absolutely possible by the mechanism. 

JEFF LANGFORD:
Okay Well, dig into that ketoacidosis point for just a minute Craig as we wrap things up, in our content we've emphasized that it is while it is possible it is also rare occurring in in less than point one percent of patients. But the real caveat I think is that it obviously can be very serious potentially life threatening and it's easy to miss these patients may present with a blood glucose This is only modestly elevated perhaps in the range of two fifty to three hundred. So I would wonder if you could tell me which patients you think first of all should not get an SGLT2 inhibitor because of this risk I think that's the foundational question. 

CRAIG WILLIAMS:
Yeah It's it's among our patients with type two diabetes that's a little hard to sort out but absolutely patients with type one diabetes so…should not really get SGLT2s. But because of the way these drugs work like they will add some benefit in type one I mean this is not an insulin dependent. Mechanism so anytime blood sugar's high these drugs gonna help you kind of flush out some of that blood sugar. But yeah our patient type one diabetes are are certainly where the vast risk of ketoacidosis comes from. And if they are on a happy dose of insulin that well for them And I come along with the SGLT2 for whatever reason, it will slightly decrease their insulin need and so they might reduce their dose and arrange where they're at risk for ketoacidosis. So really we should kind of put them out of our mind in my opinion for type one diabetes. It's a tougher question among our type twos who's really at risk Cause that it's so rare It's been really difficult for us to really sort that out at the clinical level. 

JEFF LANGFORD:
Okay We'll want to quickly look at just some practical things that we can tell patients about reducing the risk If we're using an SGLT2 inhibitor for them, we have some practical tips that we could consider to reduce that risk such as providing a sick day management plan for patients, encouraging them to hold the SGLT2 inhibitor, perhaps if they're having severe vomiting or diarrhea, kind of steering away from these drugs for patient or steering patients away from using a low carb diet are following a very low carb diet if they're taking an SGLT2 inhibitor because they're already in kind of this myelikitotic state So that might be enough to tip them over to a more over ketoacidosis, and then appropriately stopping on SGLT2 inhibitor with a an event like surgery. For the appropriate amount of time typically three to four days before, and then resuming once they're eating normally again. Our content does have We do have a nice resource that has some more tips on managing this ketoacidosis…piece and how to manage that if it occurs in our patients that are hospitalized so I do hope that our listeners will take a look at that resource for some more details there.

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We hope you enjoyed and gained practical insights from listening in to this discussion!
 
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