It has been 12 years since the first GLP-1 receptor agonist, liraglutide (Saxenda), was approved as a weight loss medication. This breakthrough was followed in 2021 by the approval of semaglutide (Wegovy) and in 2023 by the approval of tirzepatide (Zepbound), which have transformed obesity treatment
To understand the clinical considerations and nuances of month-to-month patient management, Director of The Clinical Advisor, Nikki Kean, met with Melissa Glassford, DNP, MSN, APRN, FNP-BC, to discuss how to titrate dosages, high and low, address manufacturing shortages, and ensure insurance coverage for these medications. Dr Glassford is a family nurse practitioner and an assistant professor at the Vanderbilt University School of Nursing in Nashville, Tennessee
Ms Kean: Access to GLP-1 agents has been an issue from the start. When you think of access issues, is this typically driven by manufacturing or insurance companies denying coverage requests?
Dr Glassford: One of the most significant clinical pain points we currently see in practice involves patients who are going on and off the [obesity] medication a lot. While manufacturing shortages have largely resolved, access and insurance coverage issues remain. Because of this, patients frequently experience interruptions in care or find themselves switching from one medication to another. I want to emphasize to clinicians that rather than prematurely labeling these scenarios as ‘treatment failure,’ we must evaluate the external circumstances interrupting the flow of treatment.
Insurance requirements vary wildly; some plans require reauthorization every 3 months, while others look at it every 6 months or annually. When these renewal periods arrive, administrative delays can cause gaps in therapy lasting several weeks or even longer
Furthermore, insurance formularies shift unpredictably. A patient might stabilize on semaglutide (Wegovy) only for their formulary to drop it, forcing a sudden transition to tirzepatide (Zepbound), or vice versa. Clinically managing these transitions smoothly can be quite challenging
Ms Kean: There are positive shifts regarding Medicare coverage for these agents. How is that reshaping patient access?
Dr Glassford: The expansion of Medicare coverage is a monumental milestone for patient access. Medicare now covers Wegovy for patients with established cardiovascular disease and elevated BMI, and Zepbound has gained substantial traction for indications like severe obstructive sleep apnea
Additionally, expanded access initiatives — including manufacturer partnerships with GoodRx, Amazon Pharmacy, and direct cash-pay platforms — have allowed seniors and individuals without comprehensive commercial insurance to purchase these medications at a substantially reduced cost. Ensuring universal, equitable access is critical because the long-term health benefits span across all patient demographics
Ms Kean: Medication shortages also drove patients toward compounding pharmacies. For patients who were previously obtaining their medications through compounding pharmacies, are those avenues effectively closed due to these regulatory shifts?
Dr Glassford:Regulatory frameworks have shifted significantly. The Food and Drug Administration (FDA) has closed that loop. Some smaller compounding pharmacies attempt to leverage legal loopholes by adding vitamins, such as vitamin B12, to the formulation to justify continued compounding. However, the commercials has dwindled.
Clinical Consequences of Medication Gaps
Ms Kean: When a patient experiences a long gap in therapy, what clinical consequences do you observe?
Dr Glassford: During a 1-month gap, weight loss will almost certainly stall, and patients may experience a slight increase in weight. Within a few weeks of missing doses, patients notice their appetite coming back
If a patient was maintained on a maximum dose and misses 4 weeks of therapy, they have to restart the medication at a lower dose. We titrate the dosage back up from a lower baseline, which essentially resets their progress
Ms Kean: Having their appetite and food noise return must be incredibly distressing for patients. How do you address that?
Dr Glassford: It induces a tremendous amount of anxiety. Many of these individuals have spent decades attempting to lose weight, experiencing temporary success followed by signals that drive them back to a certain level of hunger
When they start a GLP-1 receptor agonist, they describe a profound sense of relief. I see people who are able to eat intuitively for the first time in their lives. The “food noise” disappears, and it restores their relationship with food, which is amazing. When a gap in medication occurs, anxiety re-emerges immediately. They worry the medication has failed or that they will never regain that feeling where their hunger felt normal. Navigating that distress requires substantial clinical support and reassurance.
Ultimately, we must teach our patients that clinical success is never defined solely by the scale; it is defined by optimizing their body composition, preserving structural bone health, and improving their quality of life
Managing the Medication Plateau
Ms Kean: Can you describe the phenomenon of a weight-loss plateau? Is this plateau similar to what we see in traditional dieting, or is it distinct because of the titration schedule?
Dr Glassford: It is distinct and highly individualized. Clinical trial data demonstrate that these medications provide an average total body weight loss of 15% to 25%, depending on the specific agent. Some patients are losing weight consistently month over month. Others experience a stair-step pattern: losing weight, stalling briefly, and losing again
We define a true clinical plateau when a patient has been on the maximum tolerated dose of a medication consistently for several months, yet their weight loss has completely halted. For instance, a patient’s BMI may have dropped from 35 kg/mg2to 30 kg/mg2. They have had great success but remain in a category where further reduction would offer additional therapeutic benefits
When a true plateau is identified, Dr Glassford evaluates several strategies:
- Pharmacotherapeutic Switch: Moving a patient from a selective GLP-1 receptor agonist (such as max-dose Wegovy) to a dual GLP-1/GIP receptor agonist (such as Zepbound) can re-engage weight-loss mechanisms.
- Adjuvant Therapy: For patients with underlying insulin resistance or comorbid conditions like polycystic ovary syndrome (PCOS), adding metformin can successfully disrupt a plateau. It is not a replacement but a complementary tool.
- Shift in Clinical Focus: Sometimes, it is vital to pivot away from the number on the scale and evaluate body composition — components of the overall clinical picture. We partner with nutritional therapists to adjust macronutrient percentages — specifically increasing protein intake — and if they haven’t already incorporated weight-lifting and resistance training, we work to introduce structured activity to preserve and build lean muscle mass. This reset frequently helps patients resume a downward weight trajectory.
Long-Term Maintenance and the Chronic Disease Model
Ms Kean: I imagine that once patients experience a steady, healthy weight decline and begin feeling physically better, they become much more enthusiastic about incorporating exercise and lifestyle changes
Dr Glassford: Absolutely. I see many patients who finally experience enough physical relief from joint pain and systemic inflammation to exercise comfortably. They join gyms, set strength goals, and train for 5Ks or half-marathons. However, clinicians must recognize that for a subset of patients with severe obesity, achieving a baseline level of weight loss is a functional prerequisite to exercising safely and comfortably without debilitating pain
Ms Kean: Now that these medications have been widely used for several years, what does long-term maintenance look like? How do you determine the optimal maintenance dose to prevent weight regain and keep food noise under control?
Dr Glassford: Maintenance is highly individualized. Some patients remain on the maximum dose long-term, and their weight naturally stabilizes at a healthy equilibrium. However, if a patient is approaching a normal BMI but maintains an aggressive weight-loss trajectory (losing 2% to 4% of their body weight monthly), we proactively taper the dose. Finding the optimal maintenance dose takes time; the objective is to avoid overshooting and driving the BMI into an unhealthily low range
Other patients stabilize comfortably on medium or lower doses. Anecdotally, I have patients who successfully maintain their weight and suppress food noise by taking a low dose on an extended off-label schedule, such as every 2 weeks. This prevents the weight regain, which clinical trials have shown is common when therapy is stopped entirely
Obesity is a chronic, progressive metabolic disease. Discontinuing a GLP-1 receptor agonist once a patient reaches their goal weight is equivalent to discontinuing an antihypertensive medication once a patient’s blood pressure normalizes. We must treat it with the same long-term mindset we apply to hypertension or hyperlipidemia.
Although a small percentage of patients discontinue the medication and maintain their weight through lifestyle modifications alone, the vast majority prefer to remain on maintenance therapy. They appreciate escaping the restrictive cycle of chronic dieting, calorie counting, and food obsession, allowing them to live normally and healthily
Ms Kean: What is the longest duration you have continuously maintained a patient on these therapies?
Dr Glassford: I have patients who have been on these medications for approximately 5 years now, with excellent long-term safety and efficacy profiles
Management of Adverse Gastrointestinal Effects
Ms Kean: For the percentage of patients who experience gastrointestinal side effects during the initial 6 to 12 weeks of therapy, how do you manage their care to ensure they adhere to treatment?
Dr Glassford: Anticipatory guidance and patient education are critical. Patients must understand ahead of time that transient nausea, reflux, and bowel changes are common. To minimize these effects, we must adhere to a conservative titration schedule. I often see patients who come from outside practices where they were started on excessively high doses because they were anxious to lose weight rapidly. This invariably backfires
- Nausea: Small, frequent meals; hydration; judicious Zofran use; evaluate for hidden acid reflux
- Constipation:Preemptive fluid optimization; dietary fiber scaling; short-term osmotic laxatives
- Acid Reflux: Identification of dietary triggers; lifestyle modifications; time-limited PPI or H2RA therapy.
If a patient experiences severe constipation, we emphasize drinking more fluids and increasing dietary fiber. When appetite is profoundly suppressed, patients frequently forget to drink fluids and consume adequate fiber, which exacerbates lower GI stasis
For nausea, we can prescribe ondansetron for short-term relief, but I discourage long-term reliance on it because it can cause constipation, sometimes significant, and carries potential drug interaction risks. Some patients want to stay on the maximum dose of a GLP-1 and take ondansetron daily, but that is clinically counterproductive
Nausea mimics the physiology of morning sickness in pregnancy; it is frequently exacerbated by an empty stomach. Because their appetite is gone, patients assume they should not eat, but consuming a small amount of bland food or a few crackers often alle
Ms Kean: Gastroesophageal reflux is another common complaint. Given the long-term risks associated with over-the-counter proton pump inhibitors (PPIs), what specific guidance do you give patients experiencing severe heartburn?
Dr Glassford: Acid reflux can be miserable and is a frequent hidden trigger for nausea. During our initial intake, I screen thoroughly for a pre-existing history of gastroesophageal reflux disease (GERD). Interestingly, once patients achieve a modest percentage of weight loss, their baseline reflux often resolves entirely because of decreased intra-abdominal pressure
In the acute titration phase, I recommend lifestyle modifications: eating smaller, more frequent meals, avoiding recumbency after eating, and identifying personal dietary triggers like alcohol, chocolate, carbonated beverages, or highly acidic and spicy foods. For occasional symptoms, calcium carbonate antacids are sufficient. If symptoms persist, we may utilize H2 receptor antagonists or short-term PPI therapy
If a patient requires a daily PPI for longer than a month, I refer them to their primary care clinician or a gastroenterologist to ensure we are not overlooking underlying esophagitis or structural issues. My clinical goal is to avoid polypharmacy; one of the most rewarding aspects of weight loss is helping patients discontinue chronic medications, so we want to manage side effects behaviorally whenever possible
Ms Kean: Have you treated multiple generations within the same family, and do you see familial or genetic patterns regarding tolerability?
Dr Glassford: I treat many couples simultaneously, as well as several parent-adult child pairs. Familial experiences are often a great starting point for selecting an agent; if a patient’s mother had an excellent response to semaglutide with minimal side effects, that provides a logical and reassuring clinical starting point. However, even within families, the side effect profiles can vary significantly
Expanded Indications and Evolving Health Care Coverage
Ms Kean: The evolving clinical research into off-label indications — such as substance use disorders, alcohol reduction, and smoking cessation — is fascinating. What are you observing in your practice regarding these disorders?
Dr Glassford: We ask about weekly alcohol consumption for all patients initiating therapy. The drop-off in alcohol intake is staggering. Even patients who previously enjoyed regular social drinking report a reduction in their desire to consume alcohol. The medication appears to fundamentally blunt the reward pathways associated with these cravings, which opens up incredible therapeutic possibilities for addiction medicine
Bone Mineral Density, Body Composition, and Holistic Health Metrics
Ms Kean: To touch on long-term safety, there is growing concern regarding accelerated bone density loss and the subsequent risk of osteoporosis, particularly in older female patients. Do you routinely screen your patients with dual-energy X-ray absorptiometry (DEXA) scans?
Dr Glassford: Yes, absolutely. For any female patient within the appropriate age demographic or with independent risk factors for bone loss, I ensure their screening DEXA scans are up to date. However, clinicians should interpret short-term DEXA data cautiously; a scan performed 6 to 12 months into rapid weight loss may show transient bone remodeling that does not accurately reflect long-term fracture risk. Current long-term data indicate that the weight loss itself, rather than the drug peptide, drives changes in bone mineral density.
This risk underscores why setting realistic, clinically meaningful weight goals is essential. Many patients present with an idealized weight goal based on what they weighed in their early 20s, but achieving that number may offer no additional health benefits and can actually introduce harm. A patient with a BMI of 24 who engages in rigorous resistance training possesses a far superior health and longevity profile than a patient with a BMI of 20 who has lost significant lean muscle mass and bone density.
If a patient is losing weight too rapidly, I tell them that they are likely depleting muscle tissue and bone mineral density rather than adipose tissue. We must prioritize a slow, steady, and deliberate weight-loss trajectory. Ultimately, we must teach our patients that clinical success is never defined solely by the scale; it is defined by optimizing their body composition, preserving structural bone health, and improving their quality of life
Note: This interview was edited for clarity and length
Hear directly from Dr Melissa Glassford below or at TheObesityAdvisor.com
Glassford M. GLP-1s unlocked: from plateau to progress. Presented at: AANP 2026; June 23-27, 2026; Las Vegas, NV
