Does Glucagon-like peptide-1 (GLP-1) receptor agonist therapy help with weight gain induced by steroid use?

GLP-1 Receptor Agonists and Steroid-Induced Weight Gain

GLP-1 receptor agonists have not been specifically studied for steroid-induced weight gain, but their mechanisms of action—appetite suppression, delayed gastric emptying, and reduced caloric intake—directly counter the increased appetite and central fat deposition caused by glucocorticoids. 1, 2

Understanding Steroid-Induced Weight Gain

Glucocorticoid therapy causes weight gain through multiple mechanisms that GLP-1 receptor agonists could theoretically address 1:

• Increased appetite and failure to trigger satiety are primary drivers of steroid weight gain, with patients experiencing behavioral changes mimicking starvation despite excess energy storage 1
• Central adipose tissue deposition occurs with marked catabolic effects on bone and muscle 1
• Weight gain timing typically occurs early after glucocorticoid initiation, with most gain happening in the first 9 months and then plateauing 1
• Cumulative dose relationship shows increasing odds ratios from OR 1.42 at 1.7-2.8 grams cumulative prednisolone to OR 2.20 at >4.7 grams 1

GLP-1 Receptor Agonist Mechanisms That Counter Steroid Effects

GLP-1 receptor agonists work through pathways that directly oppose glucocorticoid-induced weight gain 2, 3:

• Appetite suppression via hypothalamic and brainstem GLP-1 receptors counteracts the steroid-induced increase in appetite 2, 3
• Delayed gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone, leading to prolonged feelings of fullness 4
• Reduced caloric intake through central nervous system signaling that influences both insulin secretion and metabolism 2
• Activation of vagal nerve endings in the intestinal mucosa generates satiety signals 2

Evidence-Based Medication Selection

For steroid-induced weight gain, tirzepatide 15mg weekly should be the first-line choice, achieving 20.9% weight loss at 72 weeks, followed by semaglutide 2.4mg weekly with 14.9% weight loss if tirzepatide is unavailable or not tolerated. 2

Tirzepatide (First Choice)

• Superior weight loss efficacy of 20.9% at 72 weeks with the 15mg dose 2
• Dual GIP/GLP-1 receptor activation provides enhanced metabolic benefits including delayed gastric emptying, suppressed appetite, and improved insulin secretion 2
• Starting dose of 5mg weekly with titration upward every 4 weeks to maximum 15mg weekly 2
• Cost approximately $1,272 per 30-day supply 2

Semaglutide 2.4mg Weekly (Second Choice)

• Weight loss of 14.9% at 68 weeks with 64.9% of patients achieving ≥10% weight loss 2
• Proven cardiovascular benefit with 20% reduction in cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.80) if patient has established cardiovascular disease 2
• Titration schedule: 0.25mg weekly for 4 weeks, then 0.5mg for 4 weeks, then 1.0mg for 4 weeks, then 1.7mg for 4 weeks, reaching maintenance dose of 2.4mg at week 17 2
• Cost approximately $1,557-$1,619 per 30-day supply 2

Liraglutide 3.0mg Daily (Third Choice)

• Weight loss of 5.24-6.1% in clinical trials, substantially less than weekly injectable options 2
• Daily injection requirement may reduce compliance compared to weekly options 2
• Consider only when weekly injections are refused or not tolerated 2

Eligibility Criteria for Treatment

Patients qualify for GLP-1 receptor agonist therapy with BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity such as hypertension, dyslipidemia, or type 2 diabetes. 2

Absolute Contraindications

• Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2) 2, 1
• Pregnancy (women using oral contraceptives should switch to non-oral methods or add barrier contraception for 4 weeks after initiation and each dose escalation) 2

Relative Cautions

• History of pancreatitis requires careful monitoring, though causality has not been definitively established 1, 2
• Severe gastroparesis or GI motility disorders may worsen with GLP-1 therapy 2
• Recent heart failure decompensation should avoid GLP-1 receptor agonists 2

Essential Lifestyle Modifications

GLP-1 receptor agonists must be combined with a 500-kcal reduction below daily requirements and minimum 150 minutes per week of physical activity, including resistance training to preserve lean body mass. 2

• Caloric deficit of 500 kcal below daily requirements is mandatory for optimal results 2
• Resistance training specifically helps preserve lean body mass during weight loss 2
• Behavioral interventions should accompany pharmacotherapy 2

Monitoring and Follow-Up Schedule

Assess patients every 4 weeks during titration for gastrointestinal tolerance, weight loss progress, and blood pressure, then every 3 months minimum after reaching maintenance dose. 2

Initial Titration Phase (First 3-4 Months)

• Monthly visits during dose escalation to assess tolerance and adjust dosing 2
• Monitor for gastrointestinal side effects including nausea, vomiting, diarrhea, and constipation 2
• Blood pressure monitoring as weight loss may necessitate antihypertensive medication adjustment 2

Maintenance Phase

• Quarterly assessments for weight stability, cardiovascular risk factors, and medication adherence 2
• Evaluate treatment efficacy at 12-16 weeks on maximum tolerated therapeutic dose 2
• Discontinue if weight loss <5% after 3 months at therapeutic dose 2

Managing Adverse Effects

Gastrointestinal effects occur in 17-44% of patients but are typically mild-to-moderate and decrease over time, with slow titration being the most effective mitigation strategy. 2

Common Side Effects

• Nausea occurs in 17-44% of patients, typically mild-to-moderate 2
• Diarrhea in 12-32%, vomiting in 7-25%, and constipation in 10-23% 2
• Headache may occur due to GLP-1 receptor distribution in the central nervous system 2

Mitigation Strategies

• Slow titration with gradual dose escalation every 4 weeks minimizes adverse effects 2
• Reducing meal size and limiting alcohol and carbonated beverages helps manage GI symptoms 2
• Dietary modifications can help manage gastrointestinal side effects 2

Serious But Rare Risks

• Pancreatitis reported in clinical trials, though causality not definitively established 2
• Gallbladder disease including cholelithiasis and cholecystitis 2
• Monitor for persistent severe abdominal pain and discontinue if pancreatitis suspected 2

Critical Considerations for Steroid Users

Weight loss following glucocorticoid discontinuation occurs naturally, with patients losing an average of 3.1 kg one year after stopping prednisolone, so timing of GLP-1 initiation should consider steroid duration. 1

• For short-term steroid courses (<3 months), consider waiting to see if weight normalizes after discontinuation before initiating GLP-1 therapy 1
• For long-term steroid users (>6 months), where 60% report weight gain, GLP-1 therapy is more clearly indicated 1
• Patients treated with steroids for ≤1 year had mean weight increase of 2.7 kg, while those treated >1 year had lower mean weight at last visit compared to baseline 1

Long-Term Treatment Expectations

GLP-1 receptor agonists require lifelong treatment to maintain weight loss, as sudden discontinuation results in regain of one-half to two-thirds of lost weight within 1 year. 2

• Weight regain is substantial and rapid after stopping medication 2
• Cardiometabolic improvements reverse with weight regain, including beneficial effects on blood pressure, lipid profiles, and glucose metabolism 2
• Intensifying lifestyle interventions immediately upon discontinuation is essential if stopping is necessary 2

Cost and Insurance Considerations

The average wholesale price ranges from $1,272-$1,619 per 30-day supply, requiring long-term financial planning and insurance authorization. 2

• Insurance authorization may be challenging particularly for obesity management without diabetes 2
• Payors should cover evidence-based obesity treatments to reduce barriers to treatment access 2
• Lifelong treatment necessity means cumulative costs will be substantial 2