Wellness Wednesday: A Doctor’s Guide to Who Should (and Shouldn’t) Take GLP-1 Medications
The use of GLP-1 receptor agonists such as semaglutide and the dual GLP-1/GIP agonist tirzepatide has expanded rapidly in recent years, driven by their dual role in type 2 diabetes management and weight loss. These medications have delivered remarkable results in lowering blood sugar, reducing cardiovascular risk, and producing meaningful weight loss where other strategies often fall short. But with their rapid rise in popularity has come an important question: Are GLP-1 medications safe for everyone? While headlines often frame these medications as breakthrough solutions for obesity and metabolic disease, the clinical reality is more nuanced. As with any powerful therapy, safety and appropriateness depend on the patient’s health profile, risk factors, and long-term care plan.
As an endocrinologist and obesity medicine physician, I regularly see patients who are both excited by the potential of these therapies and concerned about the risks. However, as with most medical interventions, prescribing GLP-1 therapies requires balancing their undeniable benefits with the potential risks that may not make them suitable for every individual.
How GLP-1 Medications Work in the Body
GLP-1 receptor agonists mimic the natural hormone glucagon-like peptide-1, secreted from the gut in response to food intake. Their effects span several key physiological pathways: they stimulate insulin release in a glucose-dependent manner, reduce glucagon secretion, slow gastric emptying, and act on the central nervous system to reduce appetite. The dual incretin agonist tirzepatide also activates GIP (glucose-dependent insulinotropic polypeptide) receptors, providing an added boost to insulin sensitivity and appetite regulation.
For many patients with type 2 diabetes and obesity, these mechanisms translate into improved glycemic control, reduced cardiovascular risk factors, and significant weight loss. However, the same pathways can also interact with underlying health conditions in ways that may be unsafe.
Who Benefits Most From GLP-1 Medications
The strongest evidence for GLP-1 medications comes from individuals with type 2 diabetes and/or obesity. Clinical trials consistently show that patients with a BMI ≥30 (or ≥27 with weight-related comorbidities like hypertension, sleep apnea, or dyslipidemia) experience not just weight loss but improvements in blood sugar control, blood pressure, and cardiovascular outcomes.
For patients with type 2 diabetes, these medications offer advantages beyond glucose lowering. Large trials such as SUSTAIN-6 and REWIND demonstrated reductions in major cardiovascular events, making GLP-1s a preferred option in patients with both diabetes and established cardiovascular disease. For patients with obesity, GLP-1s are now among the most effective non-surgical options available, often achieving 10–15% body weight loss.
These benefits are especially impactful for patients who have struggled with lifestyle-only interventions. While diet and exercise remain foundational, we now understand that biological drivers of obesity, such as altered gut hormones, hunger signaling, and insulin resistance, make long-term weight loss extremely difficult for many people without medical support.
Current prescribing guidelines and clinical data show the most benefit for:
Patients with type 2 diabetes and poor glycemic control despite lifestyle modification or other therapies. GLP-1s are often recommended before insulin due to their weight-neutral or weight-reducing effects.
Individuals with obesity (BMI ≥30, or ≥27 with weight-related comorbidities) who struggle with sustainable weight loss through diet and exercise alone.
Patients with cardiovascular disease or high risk for cardiovascular events. Large trials such as SUSTAIN-6 and REWIND have shown GLP-1 therapies can reduce the risk of major adverse cardiovascular events.
In these populations, the benefits, improved glycemic control, reduced cardiovascular morbidity, and clinically meaningful weight loss, often outweigh the risks.
Who Should Not Take GLP-1 Medications
Despite their benefits, GLP-1s are not safe or appropriate for everyone. Current guidelines and regulatory labeling recommend avoiding these drugs in several key situations:
History of medullary thyroid carcinoma or MEN2: Animal studies raised concerns about thyroid C-cell tumors. While this has not been observed in humans to date, it remains a clear contraindication.
Severe gastrointestinal disease (gastroparesis, severe GERD, or bowel obstruction): Because GLP-1s slow gastric emptying, they can worsen these conditions.
History of hypersensitivity reactions: Rare but potentially severe allergic responses have been documented.
Pregnancy and breastfeeding: Safety has not been established, so GLP-1s are not recommended during these times.
Additionally, patients with a history of pancreatitis warrant special caution. Although the overall evidence does not show a significant increase in pancreatitis risk across large trials, both the FDA and EMA advise close monitoring, and in some cases alternative options may be safer.
The Real Risk
For most patients, the most common side effects of GLP-1 medications are gastrointestinal, nausea, vomiting, diarrhea, and constipation. These symptoms usually improve with slow titration, dietary adjustments, and hydration.
More serious but less common risks include:
Gallbladder disease: Rapid weight loss and GLP-1 therapy both increase the risk of gallstones, which can occasionally lead to pancreatitis.
Acute pancreatitis: Very rare, but should prompt immediate drug discontinuation if symptoms arise.
Renal complications: Secondary to dehydration in patients with persistent vomiting or diarrhea.
Potential mental health signals: Regulatory bodies are currently reviewing data on reports of suicidal ideation, though causality has not been established.
It’s important to distinguish common, transient effects (like nausea) from rare, serious complications. With proper monitoring, most patients tolerate therapy safely.
Special Populations That Need Extra Consideration
GLP-1 medications are being used more broadly than ever before, which makes it critical to identify populations where risks may outweigh benefits:
Older adults: While generally safe, frail adults or those at risk of muscle and bone loss need closer monitoring. Preserved protein intake and resistance training are essential alongside therapy.
Adolescents: Semaglutide is now approved for ages 12+, but long-term safety in this group is not fully established. Monitoring for growth, nutrient adequacy, and disordered eating is essential.
Patients with eating disorders: Because GLP-1s suppress appetite and alter food reward pathways, they may worsen restrictive eating behaviors. Careful psychological screening is recommended.
Patients with limited access to follow-up care: These medications require monitoring and ongoing clinical support. Without access, risks increase.
Safety Considerations Beyond Contraindications
Even for patients without absolute contraindications, safety depends on careful management. Common side effects include nausea, vomiting, diarrhea, and constipation, symptoms that can usually be mitigated by slow dose titration and dietary adjustments. More concerning, though rare, are reports of gallbladder disease, pancreatitis, and potential suicidal ideation.
Additionally, compounded versions of GLP-1s, widely marketed online, present unique dangers. These unregulated products may be dosed incorrectly, contaminated, or lack proper efficacy testing, posing serious risks to patients who obtain them outside of medical supervision.
Practical Safety Guidance for Patients and Providers
Safe use of GLP-1 medications is not just about who takes them, but how they are prescribed and monitored. A thoughtful approach includes:
Baseline evaluation: Assess history of pancreatitis, gallstones, thyroid cancer, triglyceride levels, renal function, and mental health.
Gradual dose escalation: Reduces GI side effects and improves long-term tolerability.
Patient education: Teach red-flag symptoms such as severe abdominal pain, dehydration, or mood changes that should prompt urgent care.
Lifestyle foundation: Reinforce that GLP-1s work best when paired with balanced nutrition, adequate protein, resistance training, and healthy routines.
Avoiding compounded products: Stick to FDA-approved formulations to ensure dosing accuracy, sterility, and safety.
Long-Term Use
Long-term safety data are still accumulating, though several large trials have provided reassurance. Semaglutide has been studied for over five years in patients with type 2 diabetes, showing durable benefits in glucose control, cardiovascular risk reduction, and weight management without new safety concerns. Tirzepatide, while newer, has shown similar promise in early long-term studies, but additional surveillance is needed to confirm safety beyond clinical trial populations.
Still, these trials emphasize that outcomes are most favorable when medications are used within their intended patient populations, those with obesity, type 2 diabetes, or high cardiometabolic risk, not as general lifestyle drugs.
Cost, Access, and Ethical Questions
Another reality is that not all patients who might benefit from GLP-1 medications can access them. High monthly costs and inconsistent insurance coverage create disparities. Many patients with diabetes, who may benefit most, are unable to afford therapy, while others may use these drugs primarily for aesthetic weight loss.
This raises important ethical and equity questions. From a public health perspective, it’s critical to ensure that limited supplies are prioritized for patients with the greatest medical need. At the same time, long-term solutions must address affordability and insurance coverage to prevent widening health disparities.
Looking Ahead
While the evidence so far is reassuring, several unknowns remain. Long-term effects beyond 10 years are not fully understood, particularly in non-diabetic populations using GLP-1s primarily for weight management. Theoretical risks around thyroid tumors remain unresolved. Questions also persist about what happens when patients discontinue therapy, since weight regain is common without ongoing lifestyle support.
At the same time, exciting new areas of research are emerging. Trials are examining GLP-1s in conditions such as non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and cardiovascular disease prevention in patients without diabetes. These findings could broaden their role in metabolic medicine even further.
Balancing the Promise and the Precautions
GLP-1 receptor agonists and dual agonists like tirzepatide represent some of the most effective tools to date in the treatment of obesity and type 2 diabetes. For the right patients, they can significantly improve health outcomes and quality of life. But they are not a “one size fits all” solution. Clear contraindications exist, risks must be carefully managed, and long-term unknowns remain.
The best approach is personalized prescribing rooted in shared decision-making. Patients should feel empowered with accurate information, while providers must weigh benefits and risks in the context of each individual’s health history, values, and goals. When used thoughtfully and responsibly, GLP-1 medications can be safe, effective, and life-changing.
