What is the recommended approach to using new Glucagon-like peptide (GLP)/Glucose-dependent insulinotropic polypeptide (GIP)/glucagon/Insulin-like growth factor 1 (IGF1) peptides in patients with diabetes or growth disorders?

Recommended Approach to Using New GLP/GIP/Glucagon/IGF1 Peptides in Diabetes and Growth Disorders

For patients with diabetes or metabolic disorders, GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists should be prioritized as second-line therapy after metformin, particularly in patients with cardiovascular disease, obesity, or chronic kidney disease. 1

Peptide Selection in Diabetes Management

First-Line Approach

• Begin with lifestyle modifications and metformin
• If A1C remains >1-2% above individualized goal, consider combination therapy 1

Second-Line Options (Evidence-Based Hierarchy)

1. GLP-1 RAs or dual GIP/GLP-1 RAs - Preferred for:

   • Patients with established ASCVD
   • Obesity or overweight
   • Need for significant weight reduction
   • High cardiovascular risk

2. SGLT2 inhibitors - Preferred for:

   • Heart failure
   • Chronic kidney disease
   • Established ASCVD

Important Precautions

• Do not combine incretin classes (GLP-1 RA, GIP/GLP-1 RA, DPP4i) 1
• Use caution when combining insulin with sulfonylureas, SGLT2 inhibitors, or TZDs 1
• Monitor for gastrointestinal side effects with GLP-1 RAs and dual GIP/GLP-1 RAs 1

Administration Guidelines

Injection Technique for Peptides

• Deposit into healthy subcutaneous fat tissue, avoiding intradermal and intramuscular spaces 1
• Recommended sites: abdomen (2 fingerbreadths from umbilicus), upper third of thighs, posterior lateral buttocks, middle third of upper arm 1
• Use 4-mm pen needles inserted at 90° for all adults regardless of BMI 1
• Rotate injection sites to prevent lipohypertrophy 1

Perioperative Management

• Continue GLP-1 RAs throughout the perioperative period 1
• Consider risk of pulmonary aspiration due to delayed gastric emptying 1
• Monitor for stress hyperglycemia in patients using GLP-1 RAs for obesity 1

Combination Therapy Approaches

When to Intensify Therapy

• If basal insulin has been titrated to acceptable fasting glucose but A1C remains above goal
• If significant postprandial hyperglycemia is present
• If signs of overbasalization appear (high bedtime-to-morning glucose differential, hypoglycemia) 1

Combination Injectable Options

1. Add GLP-1 RA or dual GIP/GLP-1 RA to basal insulin (preferred approach)

   • Reduces risk of hypoglycemia and weight gain compared to adding prandial insulin 1
   • Can use fixed-ratio combination products if available

2. Add prandial insulin to basal insulin (if GLP-1 RA not appropriate)

   • Start with single prandial dose at largest meal (4 units or 10% of basal dose)
   • Can advance to multiple prandial doses if necessary 1

Special Considerations

Monitoring and Adjustments

• When starting GLP-1 RAs or dual GIP/GLP-1 RAs:
  • If HbA1c is well-controlled or patient has history of hypoglycemia:
    • Consider reducing sulfonylurea dose or discontinuing
    • Consider reducing total daily insulin dose by ~20% 1
  • Monitor glucose more closely for first 4 weeks of therapy 1

Patient Education

• Educate about potential gastrointestinal side effects (nausea, vomiting, diarrhea)
• For patients on SGLT2 inhibitors, educate about genital mycotic infections and importance of genital hygiene 1
• Inform about symptoms of dehydration and diabetic ketoacidosis 1

Cautions and Contraindications

• Active gallbladder disease (caution with GLP-1 RAs)
• History of medullary thyroid cancer or MEN2 (avoid GLP-1 RAs)
• History of gastroparesis (caution with GLP-1 RAs)
• History of proliferative retinopathy (caution with semaglutide or dulaglutide) 1

Emerging Research

• Dual GIP/GLP-1 receptor agonists like tirzepatide show superior efficacy compared to selective GLP-1 receptor agonists for both glycemic control and weight reduction 2, 3
• Novel peptides show promising neuroprotective effects in models of Alzheimer's and Parkinson's disease 4, 5
• Triple GIP/GLP-1/glucagon receptor agonists are in development 6

Important Warning

• Avoid non-FDA approved "cash pay" peptides due to limited regulatory oversight, inconsistent quality control, and potential safety concerns 7