MJM MedTalks
Let's Talk LMCC (S01E05): 37-2 Antihyperglycemic Agents

S01E05

Meryem K. Talbo1, Tricia M Peters1, Susan Joanne Wang1, Esther SH Kang1, Renée-Claude Bider1, Katherine Lan1, Samy Amghar1, Vanessa Ross1, Masha (Maryia) Samuel1, Khiran Arumugam1, Jan Pack1 for the McGill Journal of Medicine
Published online: July 4, 2024

1McGill University
mjm.med@mcgill.ca

Abstract

Welcome to the McGill Journal of Medicine (MJM) LMCC review. This podcast series was created to aid medical students studying for the Canadian Medical Council (MCC)’s licensing exam. Each episode is created based on specific LMCC objectives and is divided into 2 parts. In part one we provide an overview of the topic with the help of experts in the field, followed by Part 2 where we review LMCC styled questions to help consolidate knowledge. In this episode, we welcome our expert advisor, Dr. Tricia Peters, Endocrinologist and Associate Professor in the Faculty of Medicine and Health Sciences at McGill University to complete our series on LMCC Objective 37-2: Diabetes Mellitus by speaking about antihyperglycemic agents. This episode was written by Susan Wang, Meryem Talbo and Dr. Tricia Peters, with feedback from the entire MJM Podcast Team. Please see our website www.mjmmed.com for more information, including a link to show notes.

     

Content overview

Glossary

Links and papers

Diabetes canada clinical practice guidelines

Links for Dr Peter’s works: https://pubmed.ncbi.nlm.nih.gov/?sort=date&size=200&term=Peters+TM&cauthor_id=31388772

Transcript

0:12 Meryem Talbo (MT): Welcome to the McGill Journal of Medicine Let's Talk LMCC podcast. My name is Meryem Talbo. I'm a PhD candidate and a member of the MJM podcast team. This podcast series was created to help medical students preparing for their Canadian medical licensing exam. Each episode is created based on MCC objectives and divided into two parts. We first provide an overview of the topic with the help of experts in the field. Then we review some LMCC style questions for practice. Today's episode will complete our series on glucose abnormalities and diabetes. We will be discussing blood sugar management using antihyperglycemic medications, but to review glucose abnormality such as hyperglycemia or hypoglycemia, types of diabetes diagnosis, please refer to our earlier episodes.

1:06: Joining us today is our expert advisor, Dr. Tricia Peters. Dr. Peters is an endocrinologist and assistant professor of medicine at McGill University. And you can find more information about Dr. Peters work in the episode description. I want to first start by welcoming Dr. Peters. Thank you very much, Dr. Peters for sharing your time with us today.

Dr Tricia Peters (TP): Thank you very much, Meryem, for inviting me to be part of your podcast.

1:36 MT: So in the last episode we discussed the ABCDEs of diabetes management and to start today's episode, let us just revisit the “A” part of diabetes management, which is the A1C. So Dr. Peters, can tell us a little bit more about the glycated hemoglobin A1C, or HbA1C, and what are the targets for diabetes management?

1:59 TP: Sure. So according to diabetes Canada guidelines, a hemoglobin A1C of less than 7% is the goal for the average adult with type 1 or type 2 diabetes. However, in adults with type 2 diabetes at low risk for hypoglycemia, we target even lower, an A1C of less than 6.5, which is recommended to further reduce the risk of microvascular complications such as chronic kidney disease or nephropathy, or diabetic retinopathy. Targets could also be higher for those individuals who are functionally dependent. So individuals who older, have limited life expectancy or with dementia, or those who might have hypoglycemia unawareness. And when we aim for a higher target, we typically aim for a hemoglobin A1C of 8.5% or less, which is recommended to minimize hypoglycemia in those individuals, but also limit the risk symptomatic hyperglycemia and increasing the risk of acute or chronic complications of hyperglycemia.

3:08 MT: So to reach those targets and avoid hyper or hypoglycemia, pharmacotherapy is quite important and sometimes essential. However, there are also lifestyle recommendations. Can you tell us what are the current recommendations in terms of lifestyle that can help us reach those A1C targets?

TP: Yeah, so lifestyle changes are indeed the first line of management for anyone diagnosed with type 2 diabetes, and are generally recommended for anyone with diabetes, regardless of type, in order to help control blood glucose levels and reduce the risk of cardiovascular disease and mortality.

MT: Absolutely. Thank very much Dr. Peters, and we will be putting the links to diabetes Canada clinical practice guidelines specifically for the recommendations on lifestyle as in the episode description. So now we will be jumping to the topic of today's episode and I would like to first start by asking Dr. Peters, so please tell us a bit about the different classes of medication or pharmacotherapy for diabetes or antihyperglycemic agents and how we can use them to achieve those A1C targets or those glycemia targets in different populations.

4:23 TP: Yeah, so there are two main categories of medications for diabetes and we would normally break this up into insulin and non-insulin pharmacotherapies. When we consider non-insulin medications, we could divide these into oral and injectable medications and we can also look into their mechanism of action and where they act in the body to help remember these agents as well. So we have some that act on the liver, some on the kidneys, gut or pancreas.

4:55 MT: Well, that sounds like such a neat way to categorize the different agents, or the different medications and also to try to memorize them as well. So can you please tell us a bit more about each of these classes? And where do they work or where- where do they act?

TP: Yup. So first off we have the biguanides. So metformin, as many of you may have heard of and then the thiazolidinediones or TZDs, which are some examples are pioglitazone and rosiglitazone. And both of these classes of medications act on peripheral and hepatic tissues to improve or increase insulin sensitivity. Metformin activates AMP kinase whereas the TZDs act on the PPAR gamma receptors. And although both work in the same tissues, metformin mainly works to reduce hepatic gluconeogenesis while the TZDs work primarily in skeletal tissues.

5:54: Next we have a class of medications called the sodium glucose transporter-2 inhibitors, or SGLT-2 inhibitors, which act on the kidneys. And some examples of these medications are empagliflozin, dapagliflozin, and canagliflozin. And SGLT-2 inhibitors lower circulating glucose by inhibiting the reabsorption of glucose as well as sodium into the bloodstream by blocking the sodium-glucose linked transporter 2, which is located in the- in the proximal tubule of the kidney. In addition, we have medications that act on the gut to decrease glucose absorption. And one of these examples are the, or is the alpha-glucosidase inhibitor and that is acarbose. Also acting in the gut are incretins. So these are the GLP-1 agonists and DPP-4 inhibitors. GLP-1 agonists, and some examples are semaglutide, liraglutide, exenatide, dulaglutide, and lixisenatide, these medications act in multiple ways. They act centrally to inhibit appetite, they act on the gut to delay gastric emptying. They also act on the liver to reduce hepatic glucose production and on the pancreas itself, where they inhibit glucagon secretion and promote glucose-dependent insulin secretion.

7:24: The DPP-4 inhibitors, so some examples sitagliptin, saxagliptin, linagliptin and alogliptin, work to inhibit the enzyme that breaks down GLP-1. A more recent medication is Trezepitide, which is a dual agonist working both as a glucose dependent insulinotropic polypeptide. So GIP agonist and a GLP-1 receptor agonist. This also acts to stimulate insulin release in response to food, can suppress intake, delay gastric emptying, and reduce glucagon secretion.

8:00: Next we have insulin secretagogues that act directly on the pancreatic beta cells to stimulate insulin release and these are the insulin secretagogues which are sulfonylureas. And some examples are gliclazide, glyburide and glimepiride, as well as the meglitinides, an example is repaglinide, and these both act on the sulfonylurea channels on the beta cells to depolarize the cell and secrete insulin. And lastly we have insulin itself. So insulin is an injectable medication which directly replaces missing or insufficient endogenous insulin. It acts on insulin receptors throughout the body to regulate carbohydrate, protein, fat metabolism and glucose uptake and there are various formulations, which we’ll discuss later.

8:54 MT: Yes, so we will discuss insulin a little bit later, but for now that we're still talking about the agents or the medication mentioned before so far, now that we know more about how they work or where they work, can you tell us a bit about, or how to choose which ones to prescribe and for which, for which patient?

TP: Sure, so generally we take into, a few things into consideration. Some things we consider are the risk of a medication for hypoglycemia, the effects on body weight, and consideration of the presence or absence of coexisting renal or cardiovascular disease. So we must consider aspects of the medication itself as well as the individual patient in front of us. First line treatment is typically with metformin due to its low risk hypoglycemia, and it's minimization of weight gain, it doesn't necessarily cause weight loss, but it's considered to be weight neutral. In addition, we'd always want to consider the level of hemoglobin A1C of a patient, if they need, and symptomatic hyperglycemia, to know if they need acute and intensive glucose lowering or if we can start with different oral medications as opposed to beginning with insulin.

10:17: So let's start with the risk of hypoglycaemia. And if we think about that, it's really insulin and the insulin secretagogues which we want to avoid. If our- we have an elderly patient, someone with dementia or a functional dependency, or as we mentioned before someone with hypoglycemia unawareness, we'd want to maybe consider avoiding these medications if possible. Medications like GLP-1 agonists and SGLT-2 inhibitors are less likely to cause hypoglycemia, so we would consider those. For body weight, insulin, the insulin secretagogues and TZDs, albeit by a different mechanism, are associated with weight gain. So if we have a patient who would benefit from weight loss, which is a common comorbidity with type 2 diabetes, is overweight and obesity, we would want to consider more the SGLT-2 inhibitors and GLP-1 agonists, which are associated with weight loss. So that might be something you would start with in addition to metformin. Other weight neutral medications would be acarbose, the alpha glucosidase inhibitor or a DPP-4 inhibitor.

11:34: Furthermore the presence of kidney disease might limit our ability to prescribe some agents. So this is an important thing to look at in terms of a patient's laboratory profile, since many of these agents are renally cleared and have a risk of accumulation. So we have to be cautious with certain medications in patients with chronic kidney disease. In addition, we counsel patients for several of these medications to hold them on “sick days” where there's risk for dehydration and acute kidney injury. Specifically metformin and SLGT-2 inhibitors should not to be initiated in a patient with an estimated glomerular filtration rate less than 30, and should be stopped when patients reach an eGFR of less than 15. When patients have chronic kidney disease or acute kidney injuries sulfonylureas have a higher risk of causing hypoglycemia. So we would tend away from those, although there's not a definitive contraindication to their prescription among patients with CKD, but certain of the sulfonylureas we would typically avoid. So generally speaking if we're CKD stage 3 or 4, we’d avoid metformin, sulfonylureas and the SGLT-2 inhibitors.

12:54 MT: And are there any exceptions to these contraindications or the contraindications you mentioned before as well or any other things that we need to take into account when… to help us have a broader profile of the medication that we can provide or prescribe to our patients?

TP: Yeah, definitely. So several of the newer classes of medications now have to be tested for cardio-renal benefits. And so we have many medications that confer benefits for cardiovascular and renal disease and one example of these are the SGLT-2 inhibitors, which do show cardio renal benefits for patients with pre-existing CKD stage 1 to 2, and atherosclerotic cardiovascular disease. These have been shown in several studies to reduce the risk of major adverse cardiac cardiovascular events or MACE, which is defined as myocardial infarction, stroke or cardiovascular death, as well as heart failure and progression of nephropathy. Most of the studies are looking at secondary, so reduced risk secondary events, but they've also been shown to reduce heart failure incidence and progression of nephropathy, and these studies really included individuals, older individuals, those aged over 60 years and those with cardiovascular risk factors such as smoking, dyslipidemia, and hypertension. Also like the SGLT-2 inhibitors, GLP-1 agonists have shown cardio-renal benefits. Specifically liraglutide, semaglutide and dulaglutide have all been shown to confer a reduction in MACE in patients with atherosclerotic cardiovascular disease, chronic kidney disease, or age above 60 with established cardiovascular risk factors. Exenatide and lixisenatide are safe to prescribe in those with known cardiovascular disease, but have not been shown to have such substantial benefit. And then for medications that you would want to avoid in patients with heart failure or that which have been shown that with an increased risk of exacerbating or even causing heart failure, there two to remember, so the DPP-4 inhibitor saxagliptin and any of the TZDs.

15:14 MT: And are there any additional considerations that we need to take into account when prescribing these medications?

TP: Certainly. Yes. There are other things to consider in terms of contraindications that would make you choose one agent over another. So if the patient is being considered for repaglinide, we would want to avoid this medication if the patient is also taking clopidogrel, which is an antiplatelet medication, or gemfibrozil, a fibrate. For patients with a known history of bladder cancer, we would avoid pioglitazone or dapagliflozin. And in those patients with a history of pancreatitis or pancreatic cancer, we avoid DPP-4 inhibitors and GLP-1 agonists. GLP-1 agonists are also contraindicated in individuals with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2.

16:10 MT: So now that we covered these hard contraindications, namely drug interactions or possible patient-specific factors that would make the medication contraindicated for prescription, are there any other considerations that we need to also take into account when consuming or when taking this medication and after it's been prescribed?

TP: Yes, definitely. So certain medications as we briefly mentioned before require sick day management and education. In particular metformin, sulfonylureas and SGLT-2 inhibitors. These should all be held in case of illness, dehydration or fasting. Metformin because of this risk of lactic acidosis. SGLT-2 inhibitors can cause euglycemic diabetic ketoacidosis if not held in the case of acute illness or typically two to three days before major surgery. In addition, SGLT-2 inhibitors are also associated with genital mycotic infections and urinary tract infections because these medications work by helping you pee out the sugar. And they can also be associated with dizziness or orthostatic hypotension as sodium is leaving the body in the urine along with the glucose. The TZDs are associated rarely with incidents of macular edema. Have also been shown to increase the risk of fracture. And as we said they can cause heart failure and their mechanism of increasing weight gain is actually by causing edema. DPP-4 inhibitors as we said are contraindication- contraindicated in patients with a history of pancreatitis because they can increase the risk of pancreatitis itself. And also in rare cases, there have been reports of severe joint pain. GLP-1 agonists are associated with, in some patients, gastrointestinal side effects due to their mechanisms. So nausea, vomiting, diarrhea, bloating, because they do delay gastric emptying. In addition, because hemoglobin A1C can rapidly lowered with these medications in some individuals, they need to have close monitoring for progression of diabetic retinopathy. Furthermore the alpha glucosidase inhibitor, acarbose, causes gastrointestinal side effects, bloating, diarrhea, etc. As well as it needs to be taken three times a day, so this is something to consider, many patients don't really adhere to that very well. So we don't commonly prescribe it. Meglitinides or repaglinide are also taken three times a day, and because of this might be less- less likely to be prescribed.

19:10 MT: So we still have one last medication that we did not discuss yet. And that's insulin. So Dr. Peters, what should mwe know about insulin?

TP: Sure. So insulin is an injectable antihyperglycemic that directly activates the insulin receptor to regulate the metabolism of carbohydrates, fat, protein and glucose uptake. It’s associated with hypoglycemia and weight gain. It's used in type 1 diabetes where it replaces missing endogenous insulin, but also in usually more advanced type 2 diabetes where the pancreatic beta cells are considered to be almost ‘burnt out’ and we cannot achieve target glycemic management with just the oral antihyperglycemic medications alone. Also would be indicated in patients with chronic kidney disease at a low eGFR. As such, insulin is not contraindicated for kidney or cardiac disease, but also doesn't really give any cardio-renal benefit. So we'll talk about two major kinds of insulin you'll encounter in your practice: that's basal insulin and bolus insulin.

20:23: So basal insulin is our long acting insulin and these act like a background endogenous insulin secretion by providing a steady level of insulin. They have a longer half-life and they handle, or manage our glucose levels outside of mealtimes, that is throughout the day. And these include long acting formulations. So we Glargine, and some brand names you might hear are Basiglar, Lantus and Tujeo, Degludec or Tresiba. And then more intermediate acting insulin such as Detemir, or Levemir, and NPH. You hear of these called Humulin or Novolin N. Basal insulins are usually taken once a day, could be in the morning or at night. Or with the more intermediate-lasting versions, these would be taken once or twice a day. So NPH or Levemir could be taken either once or twice a day depending on the patient. And typically in individuals with poorly controlled type 2 diabetes, we start with adding a basal insulin to any oral hypoglycemics.

MT: So Dr. Peters, you mentioned that there is basal and bolus insulin. Can you tell us a little bit more about how is bolus insulin different from a basal?

TP: Bolus insulins are insulins taken at mealtimes and act more rapidly to mimic the endogenous insulin spike that occurs after eating, with eating and this works to lower postprandial blood glucose. Some examples include the ultra rapid insulin analogs, like faster acting Aspart or Fiasp, the rapid acting analogs like Aspart, Novolog or Novorapid, Glulisine which is Apidra, Lispro, which is Humalog or Admelog, the biosimilar form, or regular acting insulins, Humulin R and Novolin R. And these all have a bit of a different time of onset and duration of action and are usually injected somewhere between 10 and 30 minutes before the meal depending on the exact formulation. And will be injected after measuring capillary or interstitial blood glucose to confirm the dose and the safety of injection and they be adjusted based on these glucose measurements.

22:44 MT: Great. Thank you so much for going over all of these different antihyperglycemic medications, telling us when and when not to consider or prescribe them and what to expect as well once the patient uses them. So now we will be going over some sample LMCC questions.

23:12 MT: So the first case is a 54 year old woman who comes to your office for a checkup. She has type 2 diabetes and is already on metformin, gliclazide, an ACE inhibitor and a statin and has made appropriate lifestyle changes. Despite maximizing her doses of her current medications. Her A1C is 7.5, eGFR is over 60 and she has recurrent UTIs. Her blood pressure is 134 over 82. Her BMI is 32 and her LDL cholesterol is below 2. What medication would you add? So would you add a:

  1. GLP-1 receptor agonist? So for example semaglutide or a
  2. SLGT-2 inhibitor? So for example empagliflozin, or
  3. long acting insulin or maybe
  4. sulfonylureas or
  5. insulin NPH, so an intermediate acting insulin?

TP: So considering the options given and this patient at hand, I would choose A: semaglutide and this is primarily due to her BMI. So her body mass index is 32, so in the obese range. Her hemoglobin A1C is 7.5. So above our target of 7, but not to the point where I would think she needs multiple additional medications, and adding semaglutide will help with her glycemic management as well as her weight loss. And with this history of recurrent UTIs, that would lead me toward semaglutide, a GLP-1 agonist, as opposed to an SGLT-2 inhibitor like empagliflozin. Insulin, I wouldn't think would be necessary at this point with her current hemoglobin A1C and would confer further weight gain often, as well, similarly to a sulfonylurea. So either C or E for insulins and then question answer D with the sulfonylurea will all contribute to weight gain.

25:20 MT: Our second case is an 88 year old man with dementia, coronary artery disease, congestive heart failure and type 2 diabetes who comes to your office for a checkup. He is on metformin sulfonylureas, perindopril, a statin, aspirin, lasix and candesartan. His A1C is 8%. So what changes would you make to his glucose management? Would you:

  1. add semaglutide? Would you
  2. add insulin, a long acting insulin, or would you
  3. change nothing as his A1C is appropriate given his age and comorbidities, or would you
  4. stop the sulfonylureas?

TP: So for this patient, although his A1- hemoglobin A1C is 8%, so not at our typical target of less than seven, I would look at his age, 88 years old. His status with dementia, and despite his cardiovascular comorbidities, I would really focus on the age and the vulnerability that accompanies his dementia with respect to hypoglycemia. So I think we don't have his renal function, but we assume it's normal. So I would start by lowering his risk of hypoglycemia by removing the sulfonylurea. Adding any additional medications I don't think is necessary in this case because of the hemoglobin A1C I would target would be more around the less than 8.5 mark which is… he's at already! However, he has elevated risk hypoglycemia with the sulfonylurea. So I think more appropriate than “change nothing” is, stop the sulfonylurea.

27:02 MT: Our third case is a 68 year old man with stage 4 CKD or chronic kidney disease from polycystic kidney disease. He has a new diagnosis of type 2 diabetes and an A1C of 7.2%. He has normal BMI, normal blood pressure and no history of cardiovascular disease. What would be the agent to start him on? Would it be

  1. metformin, would it be
  2. a long-acting insulin,
  3. a semaglutide or
  4. empagliflozin?

TP: So for this case, I think with the current stage of his chronic kidney disease and the risk of progression of this to end stage kidney disease considering that he has polycystic kidney disease, I would probably err on the side of caution with a long acting insulin. Metformin we might consider depending on how long he’s had the chronic kidney disease and what his exact eGFR might be but he doesn't have any benefits, requirements, I would say, to benefit from semaglutide or empagliflozin and if this is a new diagnosis, just for safety sake I think I would start with insulin.

28:15 MT: All right. So our last case is a 74 year old woman with type 2 diabetes, coronary artery disease and chronic kidney disease, who presents to your clinic with an A1C of 11.2% and a recent decrease in her eGFR from 30 to 14. She's already on metformin, gliclazide and sitagliptin. What changes would you make to her diabetes management? So would you

  1. stop the metformin and the gliclazide? Would you
  2. just stop the gliclazide and start a long acting insulin or
  3. stop the gliclazide and start empagliflozin? Or would you
  4. stop metformin and gliclazide and start a long acting insulin? Or
  5. stop metformin and gliclazide and then start empagliflozin?

TP: So for this case with poorly managed type 2 diabetes with a rather high hemoglobin A1C and progressive chronic kidney disease, with now an eGFR less than 15, we would need to reassess all of her medications. And in this instance, we would need to stop the metformin, stop the gliclazide, which is a sulfonylurea. We would need to dose-adjust the sitagliptin. It's safe to continue the sitagliptin, but it must be adjusted in terms of the dosing. And then due to the poor glycemic management,we would start a long acting insulin to help better control her glucose levels.

29:48 MT: Great. Thank you very much, Dr. Peters. With this we bring up the end of our episode today. Thank you again very much for sharing your time and your expertise with us and for being on our podcast.

TP: Thank you for having me on the podcast.

30:09 MT: All right, and that is a wrap on our episode today and the LMCC diabetes-specific series as well. Thank you for joining us and we hope you enjoyed this episode and it was helpful for you as well. This episode was written by Susan Wang and Meryem Talbot with input from our expert advisor. For details about the LMCC objectives, diabetes resources, and information about our expert advisor, Dr. Peters, please check out the episode description below. As this is a podcast made in the spirit of learning, we would love to hear your feedback. Let us know what you think about our episode by sending us an email at mcgilljmed.podcasts@gmail.com.



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