What is the difference between Glucose-dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide-1 (GLP-1) and when to use each in treatment?

GIP vs GLP-1: Mechanisms and Clinical Applications

Key Physiological Differences

GIP and GLP-1 are both incretin hormones that stimulate glucose-dependent insulin secretion, but they differ fundamentally in their effects on glucagon, gastric emptying, and clinical applications. 1

Insulin Secretion

• Both GIP and GLP-1 bind to G-protein coupled receptors on pancreatic β cells, stimulating insulin secretion only when blood glucose is elevated, explaining the low hypoglycemia risk 1
• GLP-1 is released from L-cells in the terminal ileum and colon in response to nutrients 1
• GIP is released from the small intestine after meals 1

Glucagon Regulation (Critical Difference)

• GLP-1 inhibits glucagon secretion from pancreatic α cells, reducing hepatic glucose production 1
• GIP has a dual, glucose-dependent effect: augments glucagon during euglycemia/hypoglycemia but inhibits it during hyperglycemia 1, 2
• This glucagonotropic property of GIP during hypoglycemia was demonstrated in type 1 diabetes patients, where GIP increased glucagon responses during recovery from hypoglycemia and reduced exogenous glucose requirements 2

Gastric Emptying (Critical Difference)

• GLP-1 receptor activation delays gastric emptying by inhibiting gastric peristalsis and increasing pyloric tone 1
• GIP does not significantly affect gastric emptying 1
• The gastric emptying delay with GLP-1 shows tachyphylaxis with continuous exposure, with short-acting agents maintaining this effect longer than long-acting formulations 3, 1

Appetite and Weight Effects

• Both GLP-1 and GIP receptors in the hypothalamus and brainstem mediate appetite, satiety, and energy regulation 3, 1
• GLP-1's gastric emptying delay contributes significantly to satiety and weight loss 1

When to Use Each Therapeutically

GLP-1 Receptor Agonists: Primary Indications

Use GLP-1 receptor agonists for type 2 diabetes and obesity, particularly when cardiovascular protection is needed. 3

Type 2 Diabetes

• Recommended as second-line therapy after metformin for glycemic control 4, 5
• Liraglutide is FDA-approved to reduce MACE risk in adults with type 2 diabetes and established cardiovascular disease 3
• Liraglutide reduced 3-point MACE by 13% (HR 0.87, p=0.01) and all-cause mortality by 15% in the LEADER trial 3
• Semaglutide reduced 3-point MACE by 26% (HR 0.74) in SUSTAIN-6, though not powered for superiority 3

Obesity Management

• Liraglutide 3 mg daily and semaglutide 2.4 mg weekly are FDA-approved for weight management in patients with BMI >30 or >27 with comorbidities 3
• Semaglutide achieved 14.9% mean weight loss in non-diabetic patients in the STEP trial 3
• Greater weight loss occurs in non-diabetic patients (6.1-17.4%) compared to diabetic patients (4-6.2%) 3

MASLD/MASH

• GLP-1 receptor agonists cannot currently be recommended as MASH-targeted therapies due to lack of phase III histological endpoint data 3
• However, they are safe to use in MASH (including compensated cirrhosis) for their approved indications of diabetes and obesity 3
• Substantial weight loss induced by GLP-1RAs could provide hepatic histological benefit, though not extensively documented 3

Cardiovascular and Renal Protection

• Use in patients with type 2 diabetes at high cardiovascular risk or with established atherosclerotic cardiovascular disease 3, 5
• Beneficial effects on cardiovascular and renal outcomes demonstrated in multiple trials 3

Dual GIP/GLP-1 Receptor Agonists: Enhanced Efficacy

Tirzepatide (dual GIP/GLP-1 agonist) produces superior glycemic control and weight loss compared to selective GLP-1 agonists. 1

When to Choose Tirzepatide Over GLP-1 Alone

• Tirzepatide achieved greater HbA1c reductions and body weight loss compared to semaglutide and dulaglutide 1
• Mean weight loss of 15% at 72 weeks in non-diabetic obese patients, with 20.9% reduction at 15 mg dose 3
• Weight loss comparable to bariatric surgery 3
• Significantly reduced liver and visceral fat in type 2 diabetes patients 3

Mechanism of Superior Efficacy

• The dual agonism provides synergistic effects: GLP-1's gastric emptying delay and appetite suppression combined with GIP's metabolic benefits 1
• GIP's glucagonotropic effect during euglycemia may provide metabolic flexibility while maintaining glucose-dependent insulin secretion 1

GIP Receptor Antagonists: Investigational

• GIP receptor antagonists are being studied for type 2 diabetes, as blocking GIP might reduce fasting hyperglucagonemia and paradoxical postprandial glucagon excursions 6
• May inhibit GIP-induced fat deposition, potentially beneficial for overweight patients with type 2 diabetes 6
• Currently no approved GIP antagonists for clinical use; this remains investigational 6

Clinical Decision Algorithm

For Type 2 Diabetes:

1. First-line: Metformin with lifestyle modification 5
2. Second-line with obesity or cardiovascular disease: GLP-1 receptor agonist (liraglutide or semaglutide for proven cardiovascular benefit) 3, 5
3. For maximum weight loss and glycemic control: Consider tirzepatide (dual GIP/GLP-1 agonist) 1
4. Not achieving targets on basal insulin: Add GLP-1 receptor agonist if not already receiving one 5

For Obesity Without Diabetes:

1. Proven options: Liraglutide 3 mg daily or semaglutide 2.4 mg weekly 3
2. Maximum weight loss: Tirzepatide 15 mg weekly 3

Important Caveats:

• GLP-1 receptor agonists should be withheld for at least three half-lives before elective surgery due to delayed gastric emptying and aspiration risk 3
• Most common adverse effects are gastrointestinal, transient, and less common with long-acting formulations 4, 5
• In type 1 diabetes, exogenous GIP (not clinically available) augments glucagon responses to hypoglycemia, but this is not a therapeutic application 2