What is the role of Glucagon-like peptide-1 (GLP-1) and Gastric inhibitory polypeptide (GIP) in managing type 2 diabetes?

GLP-1 and GIP Receptor Agonists in Type 2 Diabetes Management

Primary Recommendation

For patients with type 2 diabetes, GLP-1 receptor agonists are preferred for glycemic management due to lower hypoglycemia risk and cardiovascular event reduction, while dual GIP/GLP-1 receptor agonists (tirzepatide) offer superior weight loss and glycemic control but lack proven cardiovascular outcome benefits. 1

Mechanism of Action

GLP-1 Receptor Agonists

GLP-1 receptor agonists work through multiple complementary mechanisms 2:

• Pancreatic effects: Stimulate glucose-dependent insulin secretion and suppress glucagon release, with insulin secretion subsiding as glucose approaches normal levels 2
• Gastric effects: Delay gastric emptying, reducing the rate at which postprandial glucose enters circulation 2
• Central nervous system: Suppress appetite through hypothalamic pathways and brainstem signaling 3
• Cardiovascular protection: Improve myocardial substrate utilization, reduce inflammation, and improve lipid profiles 3

The glucose-dependent nature of insulin stimulation explains the low likelihood of hypoglycemia with GLP-1 receptor agonists 3

Dual GIP/GLP-1 Receptor Agonists

Tirzepatide activates both GIP and GLP-1 receptors, though its affinity for the GLP-1 receptor is approximately five times less than endogenous GLP-1 1, 3. The dual mechanism provides 4, 5:

• Enhanced metabolic benefits: Delayed gastric emptying, suppressed appetite, improved insulin secretion, and increased energy expenditure 3
• Lipid metabolism: GIP improves lipid and glucose metabolism, especially when paired with GLP-1's anorexigenic mechanism 5
• Synergistic weight loss: The combination produces profound weight loss beyond either hormone alone 5

Clinical Efficacy Comparison

Glycemic Control

• Tirzepatide: Achieves HbA1c reductions of 1.87-2.59%, representing the most potent glucose-lowering effect of any currently available diabetes medication 6
• Semaglutide: Produces HbA1c reductions of approximately 1.4-1.48% from baseline 3, 6
• Liraglutide: Reduces HbA1c by approximately 0.8-1.6% 6

Weight Loss

• Tirzepatide 15mg weekly: 20.9% total body weight loss at 72 weeks 1, 3
• Semaglutide 2.4mg weekly: 14.9% weight loss at 68 weeks 3
• Liraglutide 3.0mg daily: 5.24-6.1% weight loss 3

Tirzepatide demonstrates a 6% absolute advantage over semaglutide for weight loss 3

Cardiovascular and Renal Benefits

Proven Cardiovascular Outcomes (GLP-1 RAs Only)

Semaglutide has demonstrated cardiovascular benefit with a 26% reduction in composite cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.74,95% CI 0.58-0.95) in patients with type 2 diabetes and established cardiovascular disease. 3, 6

For patients with obesity and established cardiovascular disease without diabetes, semaglutide 2.4mg reduces cardiovascular events by 20% (HR 0.80) 3

Tirzepatide Cardiovascular Data

Tirzepatide meets cardiovascular safety criteria with hazard ratios <1.0 and upper confidence bounds <1.3 for MACE-4 events, but does not reduce all-cause mortality compared to usual care 3. Cardiovascular outcome trials are ongoing, and tirzepatide currently lacks proven cardiovascular benefit unlike semaglutide. 3

Renal Protection

Both GLP-1 receptor agonists and dual GIP/GLP-1 agonists 3, 6:

• Reduce albuminuria and slow eGFR decline
• Require no dose adjustment across all CKD stages, including eGFR <30 mL/min/1.73 m²
• Are preferred for patients with advanced CKD due to lower hypoglycemia risk

Clinical Decision Algorithm

When to Choose GLP-1 RA (Semaglutide/Liraglutide)

Prioritize GLP-1 receptor agonists for: 1, 3, 6

• Patients with established cardiovascular disease requiring proven cardiovascular benefit
• Patients with recent heart failure decompensation (avoid tirzepatide)
• Patients requiring documented cardiovascular risk reduction
• First-line injectable therapy before insulin for type 2 diabetes

When to Choose Dual GIP/GLP-1 RA (Tirzepatide)

Prioritize tirzepatide for: 1, 3

• Patients requiring maximum weight loss (BMI ≥35 kg/m²)
• Patients with significantly elevated HbA1c (≥1.5% above goal) requiring aggressive glycemic control
• Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) or MASH
• Patients without established cardiovascular disease where weight loss is the primary goal

Special Populations

For chronic kidney disease (eGFR <30 mL/min/1.73 m²): GLP-1 receptor agonists are preferred due to lower hypoglycemia risk and cardiovascular event reduction 1, 6

For heart failure with preserved ejection fraction: Consider GLP-1 receptor agonists for symptom improvement, though SGLT2 inhibitors remain preferred 6

Combination Therapy Considerations

Essential Combinations

• Combine with metformin unless contraindicated 6
• When combined with insulin: Reduce basal insulin by 20% immediately to prevent hypoglycemia 3
• With sulfonylureas: Reduce dose by 50% or discontinue to prevent hypoglycemia 3, 6

Prohibited Combinations

Never combine DPP-4 inhibitors with GLP-1 receptor agonists or dual GIP/GLP-1 agonists due to lack of additional glucose lowering beyond GLP-1 RA alone. 1, 6

Safety Profile and Adverse Effects

Common Gastrointestinal Effects

Both GLP-1 and dual GIP/GLP-1 agonists cause predominantly gastrointestinal side effects 1, 3:

• Nausea: 17-44% of patients (typically mild-to-moderate, decreases over time)
• Diarrhea: 12-32% of patients
• Vomiting: 7-25% of patients
• Constipation: 10-23% of patients

Mitigation strategies: Slow titration with gradual dose escalation every 4 weeks, reducing meal size, and limiting alcohol and carbonated beverages 3, 6

Serious Adverse Events

Both medication classes carry identical serious risks 1, 3:

• Pancreatitis: Reported in clinical trials, though causality not definitively established
• Gallbladder disease: Including cholelithiasis and cholecystitis
• Delayed gastric emptying: Creates aspiration risk during anesthesia, with retained gastric contents documented even after extended fasting periods

Absolute Contraindications

Both GLP-1 and dual GIP/GLP-1 agonists are contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2). 1, 3, 7

Dosing and Administration

Semaglutide (Ozempic)

Standard titration schedule 3, 7:

• Start at 0.25mg weekly for 4 weeks
• Increase to 0.5mg weekly for at least 4 weeks
• If additional glycemic control needed, increase to 1mg weekly

Tirzepatide (Mounjaro)

FDA-approved titration schedule 1, 3:

• Start at 5mg weekly (designed to minimize gastrointestinal adverse events)
• Titrate upward every 4 weeks based on tolerance
• Maximum dose: 15mg weekly

Liraglutide (Victoza)

• Administered as daily subcutaneous injection 2
• Titrate gradually to minimize gastrointestinal side effects 6

Critical Clinical Caveats

Perioperative Management

For elective surgery requiring anesthesia, discontinue GLP-1 RAs well in advance due to delayed gastric emptying and aspiration risk: 1, 3

• Semaglutide/tirzepatide: 3 weeks before surgery
• Liraglutide: 3 days before surgery

Retained gastric contents persist even after extended fasting, with 24.2% of semaglutide users showing increased residual gastric content versus 5.1% of controls 1, 3

Weight Regain After Discontinuation

Sudden discontinuation results in regain of one-half to two-thirds of weight loss within 1 year, making lifelong treatment necessary for sustained benefits. 3

Hypoglycemia Risk

GLP-1 and dual GIP/GLP-1 agonists have minimal intrinsic hypoglycemia risk when used as monotherapy due to their glucose-dependent mechanism 3, 6. However, when combined with insulin or sulfonylureas, hypoglycemia risk increases significantly, requiring dose reduction of these agents 1, 6

Cost Considerations

Average wholesale prices 3:

• Semaglutide: ~$1,600 per 30-day supply
• Tirzepatide: ~$1,272 per 30-day supply
• Liraglutide: ~$1,619 per 30-day supply

Payors should cover evidence-based obesity treatments to reduce barriers to treatment access. 3