Mounjaro and the Evolution of Type 2 Diabetes Treatment Guidelines
Sherwin D’Souza, MD, FACE: Welcome. I’m Dr. Sherwin D’Souza, an endocrinologist working in Boise, Idaho, and today I’m here with Ms. Ellen Neylon and Dr. Eugene Wright. We’re going to talk about how type 2 diabetes treatment guidelines have evolved over time, how we each use the guidelines in our treatment decision-making, and how Mounjaro® fits into our approaches to managing adults with type 2 diabetes. Would you both introduce yourselves?
Ellen Neylon, MSN, FNP-BC, RN: Sure thing. I’m Ellen Neylon, and I work at an endocrinology practice as a nurse practitioner. I’m based in Las Vegas, Nevada.
Eugene E. Wright, Jr, MD: And I’m Dr. Eugene Wright. I’m a primary care physician in North Carolina.
Dr. D’Souza: Great, thank you, I’m looking forward to talking with you today. First, let’s review the Indication and Boxed Warning for Mounjaro.
Mounjaro is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Mounjaro also has a Boxed Warning related to the risk of thyroid C-cell tumors.
In both male and female rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether Mounjaro causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined.
Mounjaro is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of Mounjaro and inform them of symptoms of thyroid tumors (for example, a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Mounjaro.
Now let’s kick off our conversation about type 2 diabetes treatment guidelines. Could you both share how you’ve seen guidelines evolve over time?
Dr. Wright: Well, since I have the most gray hair, I’ll go first. When I started practicing, we had limited treatment options for type 2 diabetes. Over time, I’ve seen many different therapies come to market that not only lower blood glucose but also reduce the risk for certain diabetes-related complications.
Ms. Neylon: Absolutely, I agree with that. I’ve been practicing within the diabetes space for going on 10 years, and I appreciate that the guidelines have been updated to reflect individual patient needs.
Dr. D’Souza: I agree with what you’re both saying. This is my 24th year in practice, and when I started, there were fewer options—it was metformin, a sulfonylurea, and basal insulin. Thiazolidinediones, or TZDs, had also just arrived on the market. Over time, I’ve seen the guidelines evolve to incorporate the many therapies we have today. Most clinicians typically start with metformin, but what comes after metformin is where I think confusion may arise. Clinicians may not be sure which treatment option to use next; they may not be sure how to position one drug in relation to another. Dr. Wright, as a primary care clinician, could you comment on that?
Dr. Wright: That is a valid point, Dr. D’Souza. As a primary care physician, I would say that the time between when guidelines are written or revised and when they are fully implemented in primary care is often several years. And you just brought up how metformin is typically used first, but it doesn’t have to be. Guidelines note that you can start with metformin or other medications that provide sufficient effectiveness to help patients achieve and maintain their treatment goals with consideration of comorbid conditions. One of the reasons I find guidelines for type 2 diabetes useful is because they provide information needed to make evidence-based treatment decisions. However, it can be hard to keep track of the latest recommendations in a busy primary care practice where type 2 diabetes is not the only condition you have to address in the patients you see.
Ms. Neylon: And teaching is an important part of this as well. We have a residency and a fellowship program within our endocrinology practice, and we’re quoting these guidelines all of the time to our fellows. We remind our residents to think about the core defects that contribute to type 2 diabetes and consider medications that cover as many of those defects as possible. We ask, “Why are you choosing that medication? What benefits does it provide? What is the reason that you’re choosing that medication over this one? What is the rationale?” In these clinical conversations, we focus on picking the right medication for the individual patient based on what we know about their type 2 diabetes diagnosis, risk factors, and overall medical history.
Dr. D’Souza: We’ve been talking about guidelines in general, but I’d love to know more specifically what guidelines you tend to use. Both the American Diabetes Association, or ADA, and the American Association of Clinical Endocrinology, or AACE, have type 2 diabetes treatment guidelines. For me, a lot of what I do depends on the patient. AACE recommends a glycated hemoglobin, or A1C, target of 6.5% or below, whereas ADA states that an A1C less than 7% is an appropriate target for adult patients who are not pregnant, but I tend to individualize A1C targets for my patients. I might be more aggressive with a younger patient who is at an early stage in their disease as opposed to an older patient with more complications. So, the glycemic targets may vary, but in terms of selecting medications, I always try to remember the pathophysiology of hyperglycemia. l believe targeting type 2 diabetes from a variety of angles is a good approach.
Dr. Wright: I absolutely agree with individualizing goals for the patient. I target the lowest A1C I can safely get a patient to reach. Many people think that 7% is the magic number; once you get to 7% you stop, work done. But I think the data and the evidence are starting to show that there’s still opportunity to see further improvements below 7% and below 6.5%. So I like to talk to my patients about how our goal is to get them to the lowest A1C we can safely achieve. And I think guidelines are a great resource that help with clinical decision-making and the process of choosing a glucose-lowering therapy.
Dr. D’Souza: Thank you so much, Dr. Wright. Ms. Neylon, what about you?
Ms. Neylon: We reference AACE guidelines probably more in our office than we do ADA guidelines, but we know both are in existence and that the guidelines have evolved to recommend the most effective medications early after type 2 diabetes diagnosis. As I said before, I think the guidelines play a big role in training new providers, but they are also good guidance for those of us who’ve been in practice for many years, as a reminder of what therapy choices we have—from metformin and insulin to some of the newer incretin-based therapies.
Dr. D’Souza: And would you like to comment on A1C goals?
Ms. Neylon: I would just add to Dr. Wright’s point about A1C that we also look at continuous glucose monitoring, or CGM, data in my practice. A1C is definitely important, but the spikes and dips in blood glucose you can see with CGM can also be telling. Even just knowing that a patient’s blood glucose isn’t going up as much after they eat can be a win.
Dr. D’Souza: Excellent point about CGM. I also like to use CGM data to help evaluate glycemic outcomes.
So far, we’ve talked about guidelines and A1C goals, but I’d also like to touch on a more recent addition to the ADA guidelines. They cite the disease-modifying effects that weight reduction of greater than 10% can have on patients with type 2 diabetes who also have overweight or obesity. Reducing body weight has the potential to alter the course of type 2 diabetes, so it’s an important part of my strategy to help patients improve control of their disease.
Dr. Wright: I appreciate that the guidelines are starting to note that weight is important to consider for patients who have type 2 diabetes and overweight or obesity. Since about 90% of patients with type 2 diabetes also have overweight or obesity, therapies targeting both A1C and weight may be beneficial.
Dr. D’Souza: Thank you both—this has been a great conversation about guidelines. Now, I want to turn our focus to one specific type 2 diabetes treatment option—Mounjaro, a glucose-dependent insulinotropic polypeptide, or GIP, and glucagon-like peptide-1, or GLP-1, receptor agonist. How does Mounjaro fit into your approach for type 2 diabetes management?
Dr. Wright: I like to follow a shared decision-making model, which is supported by the guidelines; I make sure my patients know the potential risk and benefits, as well as what to expect from different therapies. I’ve found that when we choose a therapy together, the patient is more likely to stay on it than if I recommend and choose a therapy for them. So, we’ll discuss what worries the patient the most about their type 2 diabetes and what types of medications we have that could impact those areas of concern. For many of my adult patients with type 2 diabetes, Mounjaro comes up as an effective treatment option with the potential to address both glucose and excess body weight concerns. In my clinic, I’ve seen a variety of patients successfully reach their A1C goals on Mounjaro and, although Mounjaro is not indicated for weight loss, they’ve also reduced their excess body weight.
Ms. Neylon: Dr. Wright hit on shared decision-making, so I want to emphasize the patient education piece. I like to have an educational discussion with my patients about medication types, diet, and movement. In my conversations with patients, I discuss the dual receptor agonism of Mounjaro, and how it works differently than GLP-1 receptor agonists. As a single molecule that activates both the GIP and GLP-1 receptors in the body, Mounjaro works by enhancing insulin secretion, improving insulin sensitivity, decreasing food intake, delaying gastric emptying, and reducing glucagon levels, resulting in lower glucose concentrations in both fasting and postprandial states.
Folks with type 2 diabetes who are already on a GLP-1 receptor agonist may come in to see me, and I talk to them about other options, including Mounjaro. I’ve prescribed Mounjaro to some adults in this situation who don’t have any contraindications or other safety concerns and have seen it help them make progress toward their treatment goals.
Dr. D’Souza: What you’re both saying resonates with me. I think knowledge is power. Empowering patients is critical and gives them a sense of ownership of their treatment. Every patient has unique needs, so I really try to individualize my approach while keeping in mind guideline recommendations. With drugs like Mounjaro that have the potential to not only improve A1C but also reduce excess weight, I have another medication in my treatment toolbox.
Dr. Wright: Knowing your options is important. I had a patient come in with an elevated A1C and excess weight. They were frustrated and wanted to learn more about treatment options beyond their 2 current antihyperglycemic medications. They had no contraindications to Mounjaro, so after we discussed how it works, along with the efficacy and safety profile of the medication, we decided to give Mounjaro a try. I am happy to report that the patient and I were both satisfied with the progress they made toward their A1C goal and with their reductions in excess weight on Mounjaro. As clinicians, we need to continue to get the word out about treatments like Mounjaro.
Dr. D’Souza: I see that in my endocrinology practice too, Dr. Wright. Patients are sent to me because their glycemic control is poor despite being on multiple medications, and often they haven’t been treated according to guideline recommendations. I tend to consider Mounjaro early, especially for patients who have glycemic goals and concerns about excess weight, because of the glucose and weight results seen in clinical trials. Now, in the real world, Mounjaro might be given second, third, or fourth line—depending on when and where someone like me or you ends up seeing these patients—but I think that’s why it’s important to talk about where Mounjaro can fit within a patient’s type 2 diabetes treatment journey.
Ms. Neylon: Right, I see patients at various points in their treatment journey, and many of them have been appropriate candidates for Mounjaro. I consider Mounjaro early after type 2 diabetes diagnosis since there’s no limitation in the label about using Mounjaro as a first-line therapy.
Dr. D’Souza: I can echo that, Ms. Neylon, and I would just add that Mounjaro is an option that all healthcare professionals who see patients with type 2 diabetes can consider. It isn’t a specialty drug and doesn’t have to be prescribed by an endocrinologist. I’ve seen Mounjaro effectively support my patients’ individualized treatment goals in many scenarios. I had a patient come to me who, despite being on 3 antihyperglycemic medications, had an A1C that was rising and excess weight. Her A1C was at such a level that it would have been common practice to initiate basal insulin, but we discussed how she was frustrated by both her high A1C and weight, and I took that into account when we discussed treatment options. Ultimately, we decided to try Mounjaro, and her A1C decreased and she had a reduction in excess body weight. I saw her for follow-up not long ago and she’s still doing well on Mounjaro.
Dr. Wright: That’s a great reminder about how shared decision-making hinges on listening to your patient’s concerns.
Dr. D’Souza: Agreed.
Thank you both for your insights on this topic. It was great chatting with you.
To give some additional context to our conversation about Mounjaro, I want to discuss the efficacy and safety of Mounjaro across the SURPASS phase 3 registrational studies.
The effectiveness of Mounjaro as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes was established in 5 trials. A similar study design was used in each trial. Patients were randomized to receive Mounjaro 5, 10, or 15 milligrams, placebo, or an active comparator.
In trials that allowed background glucose-lowering therapy, various combinations of metformin, SGLT2 inhibitors, a sulfonylurea, and titrated insulin glargine were permitted. Comparator treatments included placebo, Ozempic® 1 milligram, titrated Tresiba®, and titrated insulin glargine.
The primary endpoint across the SURPASS studies was the mean change in A1C from baseline at 40 or 52 weeks. Mounjaro delivered superior A1C reductions across the range of background therapies and comparators studied.
Similarly, for the key secondary endpoint of mean change in weight from baseline, Mounjaro consistently demonstrated greater weight reductions versus comparators. As a reminder, Mounjaro is not indicated for weight loss.
In the pool of placebo-controlled studies, adverse reactions reported in at least 5% of patients taking Mounjaro included nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain.
In placebo-controlled trials, when Mounjaro was used as a monotherapy, 0% of patients in the Mounjaro treatment groups reported hypoglycemia or severe hypoglycemia. In the placebo group, the incidence of hypoglycemia was 1% and the incidence of severe hypoglycemia was 0% after 40 weeks.
In placebo-controlled trials, when Mounjaro was used as an add-on to basal insulin with or without metformin, the incidence of hypoglycemia after 40 weeks in patients receiving Mounjaro 5, 10, or 15 milligrams ranged from 14 to 19% and was 13% for placebo. The incidence of severe hypoglycemia ranged from 0 to 2% in the Mounjaro groups, with no reported incidence for placebo.
Thanks for joining us.
[Select Important Safety Information]
Contraindications
Mounjaro is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2, and in patients with known serious hypersensitivity to tirzepatide or any of the excipients in Mounjaro. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with Mounjaro.
Risk of Thyroid C-cell Tumors
Counsel patients regarding the potential risk for MTC with the use of Mounjaro and inform them of symptoms of thyroid tumors (for example, a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Mounjaro. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values greater than 50 nanograms per liter. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
Acute Pancreatitis
Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, or Mounjaro. Observe patients for signs and symptoms, including persistent severe abdominal pain sometimes radiating to the back, which may or may not be accompanied by vomiting. If pancreatitis is suspected, discontinue Mounjaro and initiate appropriate management.
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
Concomitant use with an insulin secretagogue (for example, sulfonylurea) or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. The risk of hypoglycemia may be lowered by reducing the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
Hypersensitivity Reactions
Serious hypersensitivity reactions (for example, anaphylaxis and angioedema) have been reported in patients treated with Mounjaro. If hypersensitivity reactions occur, discontinue use of Mounjaro; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous serious hypersensitivity to tirzepatide or any of the excipients in Mounjaro. Use caution in patients with a history of angioedema or anaphylaxis with a GLP-1 receptor agonist because it is unknown if such patients will be predisposed to these reactions with Mounjaro.
Acute Kidney Injury Due to Volume Depletion
There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists, or Mounjaro. The majority of reported events occurred in patients who experienced gastrointestinal adverse reactions leading to dehydration such as nausea, vomiting, or diarrhea. Monitor renal function in patients reporting adverse reactions to Mounjaro that could lead to volume depletion, especially during dosage initiation and escalation of Mounjaro.
Severe Gastrointestinal Adverse Reactions
Use of Mounjaro has been associated with gastrointestinal adverse reactions, sometimes severe. In the pool of placebo-controlled trials, severe gastrointestinal adverse reactions occurred more frequently among patients receiving Mounjaro (5 milligrams 1.3%, 10 milligrams 0.4%, 15 milligrams 1.2%) than placebo (0.9%). Mounjaro is not recommended in patients with severe gastroparesis.
Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy
Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Mounjaro has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.
Acute Gallbladder Disease
In clinical trials, acute gallbladder disease was reported by 0.6% of Mounjaro-treated patients and 0% of placebo-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.
Pulmonary Aspiration During General Anesthesia or Deep Sedation
Mounjaro delays gastric emptying. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking Mounjaro.
Adverse Reactions
The most common adverse reactions reported in greater than or equal to 5% of Mounjaro-treated patients in placebo-controlled trials were nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain.
Drug Interactions
When initiating Mounjaro, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia. Mounjaro delays gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications, so caution should be exercised.
Pregnancy
Limited data on Mounjaro use in pregnant women are available to inform on drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Based on animal reproduction studies, there may be risks to the fetus from exposure to tirzepatide. Use only if potential benefit justifies the potential risk to the fetus.
Lactation
There are no data on the presence of tirzepatide in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Mounjaro and any potential adverse effects on the breastfed infant from Mounjaro or from the underlying maternal condition.
Females of Reproductive Potential
Advise females using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation.
Pediatric Use
Safety and effectiveness of Mounjaro have not been established and use is not recommended in pediatric patients.
Please see the Full Prescribing Information, including Boxed Warning about possible thyroid tumors, including thyroid cancer, and Medication Guide by clicking the links within www.mounjaro.lilly.com/hcp.
Please see Instructions for Use included with the pen.
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