Is there any indication to initiate GLP‑1 receptor agonist therapy in a patient without diabetes, obesity, or established atherosclerotic cardiovascular disease?

GLP-1 Receptor Agonist Therapy Without Diabetes or Obesity

No, there is no established indication to initiate GLP-1 receptor agonist therapy in patients without diabetes, obesity, or established atherosclerotic cardiovascular disease. The evidence-based indications are strictly limited to specific clinical scenarios where cardiovascular or metabolic benefit has been demonstrated.

FDA-Approved Indications and Guideline Recommendations

Type 2 Diabetes with Cardiovascular Disease

• GLP-1 receptor agonists are recommended for patients with type 2 diabetes and established atherosclerotic cardiovascular disease to reduce major adverse cardiovascular events by approximately 20-26%, with semaglutide demonstrating a hazard ratio of 0.74 (95% CI 0.58-0.95) for the composite of cardiovascular death, nonfatal MI, or nonfatal stroke 1.

Obesity Management

• Adults with BMI ≥30 kg/m² qualify for GLP-1 receptor agonist therapy without additional requirements, while those with BMI ≥27 kg/m² require at least one weight-related comorbidity such as hypertension, dyslipidemia, or obstructive sleep apnea 1, 2.
• Semaglutide 2.4 mg weekly achieves mean weight loss of 14.9% at 68 weeks, with 64.9% of patients achieving ≥10% weight loss 2.

Cardiovascular Disease with Overweight/Obesity (Without Diabetes)

• The most recent evidence from 2024 supports semaglutide 2.4 mg for patients with established cardiovascular disease and BMI ≥27 kg/m², even without diabetes, demonstrating a 20% reduction in cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.80) 1, 2.
• This represents the only scenario where GLP-1 therapy is indicated in non-diabetic patients—but obesity or overweight status remains a prerequisite 1.

Why No Indication Exists for Your Patient

Absence of Proven Benefit

• Cardiovascular outcome trials have exclusively enrolled patients with either type 2 diabetes OR obesity/overweight, meaning there is zero evidence for efficacy or safety in metabolically healthy individuals 1, 3.
• The pleiotropic cardiovascular effects—including blood pressure reduction (1-6 mmHg), LDL cholesterol reduction (up to 16%), and anti-inflammatory effects—have only been demonstrated in populations with underlying metabolic dysfunction 1.

Guideline Consensus

• The 2024 DCRM guidelines explicitly state that GLP-1 receptor agonists should be initiated based on the presence of prediabetes, type 2 diabetes, obesity, or established cardiovascular disease 1.
• The 2018 ACC Expert Consensus Decision Pathway restricts GLP-1 therapy to patients with type 2 diabetes and clinical ASCVD 1.
• The 2025 KDOQI guidelines note that GLP-1 receptor agonists are underutilized even in appropriate candidates (only 6.3-17% of eligible patients), suggesting the focus should be on treating those with established indications rather than expanding use 1.

Clinical Decision Algorithm

For a patient presenting without diabetes, obesity, or cardiovascular disease:

1. Screen for undiagnosed conditions:

   • Measure HbA1c to exclude prediabetes (5.7-6.4%) or diabetes (≥6.5%) 1
   • Calculate BMI to confirm absence of overweight (≥27 kg/m²) or obesity (≥30 kg/m²) 1, 2
   • Assess for established ASCVD (prior MI, stroke, peripheral arterial disease, or revascularization) 1

2. If all screening is negative:

   • Do not initiate GLP-1 receptor agonist therapy 1
   • Focus on evidence-based primary prevention: lifestyle modification, statin therapy if indicated by cardiovascular risk, and blood pressure management 1

3. If screening reveals prediabetes:

   • GLP-1 receptor agonists may be considered for patients with prediabetes at high risk of progression to type 2 diabetes, particularly if obesity is present 1
   • However, lifestyle intervention (diet and physical activity) remains first-line therapy 1

Critical Contraindications and Safety Concerns

Absolute Contraindications

• Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN 2) is an absolute contraindication to all GLP-1 receptor agonists based on animal studies showing thyroid C-cell tumors 1, 2, 4.

Adverse Effects Without Therapeutic Benefit

• In the absence of metabolic disease, patients would experience the full burden of adverse effects without proven benefit:
  • Gastrointestinal effects (nausea 17-44%, diarrhea 12-32%, vomiting 7-25%) 2
  • Increased risk of pancreatitis and gallbladder disease (38% higher rate of serious gallbladder events versus placebo) 2
  • Delayed gastric emptying with aspiration risk during anesthesia 2
  • Cost burden of approximately $1,272-$1,619 per 30-day supply 2

Real-World Prescribing Patterns and Concerns

• Recent data from 2024-2025 show concerning trends of GLP-1 receptor agonist prescribing in patients without established indications, with semaglutide prescriptions rising to 60% share in non-diabetic obese/overweight groups 5.
• However, less than 9% of patients without diabetes at the time of GLP-1 initiation received a diabetes or prediabetes diagnosis within 30 days, suggesting potential inappropriate prescribing 5.
• Paradoxically, GLP-1 receptor agonists remain underutilized in patients with established ASCVD and type 2 diabetes (only 6.3-17% of eligible patients), where cardiovascular benefit is proven 1, 6.

Common Pitfalls to Avoid

• Do not prescribe GLP-1 receptor agonists for "cardiovascular protection" in metabolically healthy individuals—this represents off-label use without supporting evidence 1.
• Do not initiate therapy based solely on family history of diabetes or cardiovascular disease without documented metabolic abnormalities 1.
• Do not use GLP-1 receptor agonists as a substitute for lifestyle modification in primary prevention—diet and exercise remain the foundation 1.
• Do not assume that cardiovascular benefits observed in diabetic or obese populations extrapolate to healthy individuals—the mechanisms may be dependent on underlying metabolic dysfunction 1, 7.

Future Directions

• Ongoing research is exploring GLP-1 receptor agonist effects in non-diabetic atherosclerosis, but these remain investigational applications 7.
• The TRIUMPH program (launched 2023) is evaluating novel triple-receptor agonists, but enrollment criteria still require obesity or metabolic disease 2.
• Until randomized controlled trial data demonstrate benefit in metabolically healthy populations, prescribing remains contraindicated by evidence-based guidelines 1.