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Non-insulin Diabetes Mellitus Medications with Case

by Michael Lazarus, MD

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    00:01 <b>In this case, a 57-year-old man presents to his primary care physician for follow-up of his</b> <b>diabetes. He has been diagnosed with type 2 diabetes 3 months ago and has been started on metformin</b> <b>and lifestyle modifications. The patient does not have any current complaints except for occasional</b> <b>numbness in both hands and feet. His hemoglobin A1c is 8.5% and his serum glucose is 240 mg/dL.</b> <b>What is the best next step for managing this patient? The best next step is to obviously add a</b> <b>second agent to treat his diabetes. Once lifestyle modifications have been initiated and metformin</b> <b>has been started and dose maximized, if the patient continues to have elevations of hemoglobin</b> <b>A1c and serum glucose, a second oral agent is usually indicated. Second line therapy for type 2</b> <b>diabetes after dosing metformin. After initiating metformin, if the hemoglobin A1c remains above</b> <b>goal, the best next step is to add ato add a Glucagon Like Peptide-1 receptor agonist or GLP1RA </b> <b>because there is clinical evidence of neuropathy, a complication of persistent hyperglycemia, which needs urgent A1C improvement. </b> <b>GLP-1 RA also offers the strongest A1C reduction of the second-line agents, </b> <b>it provides cardiovascular protection in a relatively young patient (57 yrs),</b> <b> and is safe to use with a low hypoglycemia risk</b> <b>Let me walk you through the five diabetes medications you'll encounter most often in clinical practice. </b> <b>Everything starts with metformin - it's our foundation and first-line treatment. </b> <b>We love metformin because it's effective, inexpensive, and doesn't cause weight gain. </b> <b>Just remember to start low and go slow to avoid GI upset and keep an eye on the patient's kidney function - </b> <b>you'll need to stop it if the eGFR drops below 30.</b> <b>After metformin, we have some powerful options. </b> <b>The GLP-1 receptor agonists, like semaglutide and dulaglutide, are game-changers. </b> <b>They're especially useful in patients who need weight loss or have underling heart disease.</b> <b> They’re administered as weekly injections, and while they can cause some nausea initially, </b> <b>most patients tolerate them well over time. </b> <b>The main drawback? They're expensive.</b> <b>The Sodium-glucose cotransporter-2 or SGLT2 inhibitors, such as empagliflozin and dapagliflozin, </b> <b>are another modern class that's revolutionized diabetes care. </b> <b>These are particularly valuable in patients with heart failure or kidney disease. </b> <b>They work by reducing the reabsorption of filtered glucose and promote urinary glucose excretion in the urine - </b> <b>which means you need to monitor for urinary tract infections, </b> <b>and you can't use them if kidney function is too low (eGFR below 30).</b> <b>Dipeptidyl peptidase-4 or DPP-4 inhibitors, like sitagliptin, are the gentle members of our diabetes arsenal. </b> <b>They're well tolerated, weight-neutral, and less likely to cause hypoglycemia. </b> <b>They are not as powerful as the GLP-1s or SGLT2s.</b> <b> Just use caution with saxagliptin in patients with heart failure.</b> <b>Finally, don't forget about our old friends, the sulfonylureas like glipizide. </b> <b>They're not fancy, but they're inexpensive and effective. The main concerns are weight gain and hypoglycemia,</b> <b> so you will need to counsel patients carefully.</b> <b>The key to success is matching the right drug to the right patient. </b> <b>After metformin, think about your patient's main issue - is it heart disease? Kidney problems?</b> <b>Excessive Weight? Or is cost the biggest barrier? Let that guide your choice of your second agent.</b> <b>That's really all you need to know to get started. Remember, every drug has its place in our toolkit - it's just about using them wisely.</b> <b>it's just about using them wisely.</b> <b>Let's explore further the SGLT2 inhibitors, a fascinating class of medications that has transformed our approach to treating type 2 diabetes. </b> <b>What makes these drugs particularly interesting is that they work in a completely different way from our traditional diabetes medications.</b> <b>Let's start with their unique mechanism of action. Unlike other diabetes medications</b> <b>that work through insulin pathways, SGLT2 inhibitors work on the kidneys by blocking glucose reabsorption in the proximal tubule.</b> <b> This leads to increased glucose excretion in the urine, effectively lowering blood sugar independently of insulin.</b> <b>These medications have proven beneficial in three major clinical areas:</b> <b>First, in Type 2 diabetes, they not only improve glycemic control, lowering A1C by 0.5-0.7%,</b> <b>but also promote weight loss and reduce blood pressure - </b> <b>benefits that are particularly valuable in our diabetic population.</b> <b>Second, and quite remarkably, they've shown significant benefits in heart failure,</b> <b>particularly in patients with reduced ejection fraction (HFrEF).</b> <b>What's fascinating is that these benefits occur whether or not the patient has diabetes.</b> <b>Third, they've demonstrated impressive effects in chronic kidney disease,</b> <b>slowing disease progression and reducing cardiovascular mortality, again independent of diabetes status.</b> <b>Among the available medications, empagliflozin, marketed as Jardiance,</b> <b>has shown the strongest cardiovascular outcomes data, -</b> <b>while Farxiga has particularly strong data in heart failure and kidney disease.</b> <b>It's worth noting that while canagliflozin (Invokana) has strong kidney disease data,</b> <b> we need to be cautious about its use due to a slightly higher limb amputation risk.</b> <b>However, we must be mindful of their limitations. These drugs shouldn't be used in </b> <b>patients with severely reduced kidney function (eGFR <30 mL/min),</b> <b>and we need to avoid them in patients with a history of diabetic ketoacidosis.</b> <b>Regular monitoring for UTIs, yeast infections, and avoiding dehydration is essential.</b> <b>Let me tell you about three older diabetes medications that you'll still encounter,</b> <b> though less frequently than our modern options.</b> <b>They're important to understand because you'll see patients taking them, and sometimes they're still useful in specific situations.</b> <b>and sometimes they're still useful in specific situations.</b> <b>First, there's pioglitazone, a thiazolidinedione or "TZD." </b> <b>Think of it as the complicated cousin in the diabetes medication family. </b> <b>While it effectively lowers blood sugar, it comes with a lot of baggage - weight gain, fluid retention</b> <b>that can worsen heart failure, risk of bone fractures, and concerns about macular edema.</b> <b>Back in the day, there was also rosiglitazone, but it fell out of favor due to cardiovascular concerns.</b> <b>We still occasionally use pioglitazone, but we're very selective about which patients get it.</b> <b>Then there's acarbose, an alpha-glucosidase inhibitor.</b> <b>It works differently from our other diabetes drugs - it blocks carbohydrate absorption in the intestine.</b> <b>Sounds good in theory, but in practice, it's not very popular in the U.S. </b> <b>Why? It's not very powerful in lowering blood sugar, and it causes a lot of gas and bloating. </b> <b>Patients often vote with their feet on this one and stop taking it.</b> <b>Finally, we have repaglinide, a meglitinide. </b> <b>Think of it as a short-acting cousin of the sulfonylureas.</b> <b>It stimulates insulin release but doesn't last as long in the body. </b> <b>While this shorter action might seem advantageous, it needs to be taken multiple times daily with meals,</b> <b>which isn't great for adherence. Like sulfonylureas, it can cause weight gain and low blood sugar.</b> <b>The bottom line? While these medications aren't first-line choices anymore, they're part of our history,</b> <b>and occasionally, they might be the right choice for specific patients.</b> <b>For instance, if someone can't take any of our preferred agents, or if cost is a major issue,</b> <b>these might become relevant options.</b> <b>That's your quick tour of our "reserve bench” of diabetes medications. </b> <b>Not stars of the show anymore, but still worth knowing about.</b> <b>Let's break down diabetes treatment in a way that's easy to remember for your board exam and on the wards.</b> <b>Every patient with type 2 diabetes starts with the basics: diet, exercise, and diabetes education.</b> <b> Metformin is our foundation medication - we start low at 500mg and gradually increase to 2000mg daily,</b> <b>as long as their kidneys are okay (eGFR should be above 30).</b> <b>Our target A1C is typically less than 7%, and we check it every 3 months.</b> <b>If we're not hitting that target on metformin alone, we add a second drug.</b> <b>This is where it gets interesting - but stay with me, because it's actually pretty straightforward.</b> <b>Choosing the second drug is all about matching it to your patient's main problem.</b> <b>Does your patient have heart disease? Go with a GLP-1 receptor agonist.</b> <b>Heart failure or kidney disease? Choose an SGLT2 inhibitor (as long as their eGFR is above 30).</b> <b>Need weight loss? GLP-1 receptor agonist is your best bet.</b> <b>If cost is the main concern, a sulfonylurea is still a reasonable option.</b> <b>There's one emergency scenario you need to know: </b> <b>if your patient shows up with an A1C above 9% and has symptoms, start both insulin and metformin.</b> <b>Don't worry - you can often transition them to other medications once they're stable.</b> <b>For your exams, remember that these drugs lower A1C differently: </b> <b>GLP-1 receptor agonists and sulfonylureas give you about a 1-1.5% drop,</b> <b>while SGLT2 inhibitors provide a more modest 0.5-0.8% reduction.</b> <b>That's really all there is to it - start with metformin, add a second drug based on your patient's main problem, </b> <b>and adjust as needed. Keep it simple!</b> <b>This is the first of 3 additional challenging board-type clinical cases that highlight different aspects of diabetes management </b> <b>based on renal, cardiovascular, stroke, and all-cause mortality benefits,</b> <b>using the provided algorithm as a guide.</b> <b>In managing diabetes with conditions like chronic kidney disease (CKD) and heart failure,</b> <b>choosing medications that support both glucose control and organ protection is crucial.</b> <b>Let’s review a case to reinforce key decision-making principles in diabetes management,</b> <b>particularly when comorbidities like kidney disease and heart failure are present.</b> <b>Case Summary: A 65-year-old woman with recently diagnosed type 2 diabetes is here for follow-up.</b> <b>Her history includes chronic kidney disease (eGFR 35 mL/min/1.73 m²) and heart failure (NYHA Class II). </b> <b>She has been on metformin, titrated up to 2000 mg/day, and has worked on dietary changes. Her A1c is 8.2%.</b> <b>Which of the following is the most appropriate medication to add for optimal diabetes management?</b> <b>A. Sulfonylurea</b> <b>B. Thiazolidinedione</b> <b>C. Glucagon-like peptide-1 (GLP-1) receptor agonist</b> <b>D. Sodium-glucose co-transporter 2 (SGLT-2) inhibitor</b> <b>E. Dipeptidyl peptidase-4 (DPP-4) inhibitor</b> <b>(Pause here to allow time for consideration)</b> <b>The correct answer is D - SGLT-2 inhibitor. </b> <b>In our question about selecting the best add-on diabetes medication for this 65-year-old patient,</b> <b>SGLT-2 inhibitors stand out as the optimal choice. Why? </b> <b>Because they offer a unique combination of benefits targeting both heart failure and chronic kidney disease, which are key concerns in our patient.</b> <b>These medications have proven ability to reduce heart failure hospitalizations</b> <b>and protect kidney function, even in patients with reduced eGFR like our case.</b> <b>Let's quickly review why the other options aren't as suitable:</b> <b>Sulfonylureas, while effective at lowering blood sugar, come with two major drawbacks:</b> <b>hypoglycemia risk and weight gain. Plus, they don't offer any cardiovascular or renal protection.</b> <b>Thiazolidinediones are actually contraindicated in this case. </b> <b>Why? Because they can cause fluid retention, potentially worsening our patient's heart failure.</b> <b>GLP-1 receptor agonists are excellent medications, especially for patients with atherosclerotic cardiovascular disease.</b> <b>However, when it comes to heart failure specifically, SGLT-2 inhibitors have shown better benefits.</b> <b>Finally, DPP-4 inhibitors, while safe, simply don't provide the cardiovascular and renal benefits that our patient needs.</b> <b>They're missing an opportunity for organ protection.</b> <b>The key lesson here is that modern diabetes management isn't just about blood sugar control -</b> <b> it's about choosing medications that can address multiple comorbidities simultaneously.</b> <b>For patients with both heart failure and chronic kidney disease, SGLT-2 inhibitors are currently our best option.</b> <b>This next case is a 52-year-old man with type 2 diabetes and a history of ischemic stroke presents for follow-up. </b> <b>He has been on metformin and following lifestyle modifications since his diabetes diagnosis six months ago. </b> <b>His hemoglobin A1c is 8.7%. The patient is asymptomatic and has no other significant medical issues.</b> <b>Which of the following is the best next step in managing this patient’s diabetes?</b> <b>A. Add a sulfonylurea</b> <b>B. Add a glucagon-like peptide-1 (GLP-1) receptor agonist</b> <b>C. Add an SGLT-2 inhibitor</b> <b>D. Initiate insulin therapy</b> <b>E. Add a thiazolidinedione</b> <b>The optimal medication choice for a patient with a history of ischemic stroke and elevated A1c of 8.7% is answer B:</b> <b>Add a GLP-1 receptor agonist. Let me explain why this is our best choice and then discuss the other options.</b> <b>GLP-1 receptor agonists have emerged as a premier choice for patients with cardiovascular disease, </b> <b>particularly those with a history of stroke. These medications do double duty - </b> <b>they not only provide excellent A1c reduction but also significantly reduce the risk of recurrent cardiovascular events, including stroke.</b> <b>but also significantly reduce the risk of recurrent cardiovascular events, including stroke.</b> <b>Now, let's look at why the other options aren't as suitable. </b> <b>Sulfonylureas, while effective at lowering blood glucose, come with some concerning drawbacks.</b> <b>They can cause both hypoglycemia and weight gain, and importantly, </b> <b>they don't offer any cardiovascular protection - something crucial for our stroke patient.</b> <b>SGLT-2 inhibitors are excellent medications, and they do provide cardiovascular benefits.</b> <b>However, their benefits are particularly strong in heart failure and kidney disease rather than stroke prevention, </b> <b> </b> <b>where GLP-1 RAs have shown superior outcomes.</b> <b>Insulin therapy is a powerful tool for glucose control, but it doesn't offer the cardiovascular benefits we're looking for in this case.</b> <b>We typically reserve insulin for cases requiring rapid glucose control</b> <b>or for symptomatic patients, neither of which applies here.</b> <b>Finally, thiazolidinediones improve insulin sensitivity, but they come with their own concerns -</b> <b>particularly fluid retention, which isn't ideal in patients with cardiovascular histories.</b> <b>They also lack the specific cardiovascular protection our patient needs.</b> <b>The key takeaway here is that in patients with established cardiovascular disease, particularly stroke,</b> <b>we want to choose a medication that goes beyond just glucose control to provide proven cardiovascular benefits.</b> <b>This makes GLP-1 receptor agonists our optimal choice in this scenario.</b> <b>Let's look at this question about managing newly diagnosed diabetes.</b> <b>We have a 63-year-old woman presenting to the ED with classic diabetes symptoms:</b> <b>increased thirst, polyuria, and fatigue. She's showing signs of dehydration but isn't in acute distress.</b> <b>Her labs reveal significant hyperglycemia with a glucose of 485 and A1c of 10.5%, </b> <b>along with mild electrolyte changes and normal kidney function.</b> <b>She doesn’t have any ketones in her urine and her calculated anion gap is normal.</b> <b>This implies that she does not have either diabetic hyperosmolar state or diabetic ketoacidosis.</b> <b>For initial treatment, we're given five options: A. Starting metformin alone</b> <b>B. Using insulin by itself </b> <b> C. Combining metformin with a sulfonylurea</b> <b>D. Start insulin and add metformin prior to hospital discharge</b> <b>E. Starting an SGLT-2 inhibitor with a </b> <b>GLP-1 receptor agonist</b> <b>Let me explain why D - starting insulin and adding metformin before discharge</b> <b> is the correct answer for this patient.</b> <b>This patient's severe hyperglycemia with </b> <b>glucose of 485 and A1c of 10.5%, </b> <b>along with symptoms, she requires </b> <b>immediate, effective intervention.</b> <b>When we see numbers this high with symptoms, </b> <b> we need both rapid control and long-term management.</b> <b>This is exactly what the insulin </b> <b>and metformin combination provides.</b> <b>Let's look at why the other options aren't optimal:</b> <b>Metformin alone, while it's our first-line medication, works too slowly to address this level of hyperglycemia.</b> <b> Using it by itself would leave </b> <b>the patient symptomatic for too long. </b> <b> Insulin alone would work quickly, but we'd miss the opportunity to start metformin,</b> <b>which offers excellent long-term benefits and can help reduce insulin requirements over time.</b> <b>The combination of metformin and sulfonylurea isn't aggressive enough for this degree of hyperglycemia.</b> <b> While both are oral agents, they won't provide the rapid control this patient needs.</b> <b>As for SGLT2-inhibitors and GLP-1 agonists, while they're excellent medications, </b> <b>they're not appropriate as initial therapy for severe hyperglycemia. </b> <b>They work too slowly for this acute situation.</b> <b>Remember: When A1c is above 10% </b> <b>and a patient is symptomatic,</b> <b>combining insulin for immediate control and adding metformin for long-term benefit</b> <b> a few days before the patient leaves </b> <b>the hospital is the best strategy.</b> <b>She would also benefit from teaching </b> <b>by the dietitian and diabetes educator </b> <b>on low carbohydrate diet, how to check</b> <b> her blood glucose and self insulin administration</b>


    About the Lecture

    The lecture Non-insulin Diabetes Mellitus Medications with Case by Michael Lazarus, MD is from the course Diabetes Mellitus. It contains the following chapters:

    • Case 57-year-old Man with Type 2 DM and Numbness
    • Non-Insulin DM Medications

    Included Quiz Questions

    1. Lifestyle modifications → oral metformin → GLP-1 agonist → insulin
    2. Lifestyle modifications → SGLT2 antagonist -> oral metformin -> insulin
    3. Lifestyle modifications → insulin → oral metformin → second oral agent
    4. Lifestyle modifications → insulin → oral metformin → second injectable agent
    5. Lifestyle modifications → empagliflozin → oral metformin → insulin
    1. A 54-year-old man with CKD V
    2. A 36-year-old woman who had chest CT with contrast two weeks ago
    3. A 79-year-old man with an HbA1c level of 7.6% who is receiving insulin therapy alone
    4. A 45-year-old woman with an eGFR of 51
    5. A 15-year-old boy with newly diagnosed type 2 diabetes
    1. Insulin and weight gain
    2. Metformin and weight gain
    3. Sulfonylureas and hyperglycemia
    4. Thiazolidinediones with cardiovascular protection
    5. GLP-1 agonist with increased risk of UTI
    1. Addition of a second oral hypoglycemic agent
    2. Bariatric surgery
    3. Switching to a subcutaneous insulin pump
    4. Increasing the dosage of metformin

    Author of lecture Non-insulin Diabetes Mellitus Medications with Case

     Michael Lazarus, MD

    Michael Lazarus, MD


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