What are the potential side effects of incretin-based therapies, such as GLP-1 (Glucagon-Like Peptide-1) receptor agonists and DPP-4 (Dipeptidyl Peptidase-4) inhibitors, in patients with type 2 diabetes?

Side Effects of Incretin-Based Therapies in Type 2 Diabetes

GLP-1 receptor agonists and DPP-4 inhibitors have distinct side effect profiles, with GLP-1 receptor agonists commonly causing gastrointestinal effects and DPP-4 inhibitors potentially increasing risk of heart failure hospitalization in certain patients.

GLP-1 Receptor Agonists Side Effects

Gastrointestinal Effects

• Nausea, vomiting, and diarrhea are the most common side effects associated with GLP-1 receptor agonists 1
• These gastrointestinal effects may lead to dehydration in some patients, potentially contributing to acute kidney injury 2
• Delayed gastric emptying is a known effect that can contribute to the gastrointestinal symptoms 2

Weight Loss Effects

• Weight loss (typically 2-5 kg) is considered a beneficial effect for most patients but may be undesirable in some older adults or frail patients 1, 3
• This weight loss effect distinguishes GLP-1 receptor agonists from DPP-4 inhibitors, which are weight-neutral 3

Cardiovascular Effects

• GLP-1 receptor agonists can increase heart rate by 3-10 beats per minute while lowering systolic blood pressure by 2-3 mmHg 1
• These medications have shown cardiovascular benefits in large trials but should be used with caution in patients with established heart failure with reduced ejection fraction (HFrEF) 1

Other Significant Side Effects

• Acute pancreatitis: Rare but serious potential complication that requires immediate discontinuation of the medication 2
• Acute gallbladder disease: Cholelithiasis and cholecystitis have been reported in clinical trials and post-marketing 2
• Hypoglycemia: Risk is low when used as monotherapy but increases when combined with insulin or sulfonylureas 2
• Hypersensitivity reactions: Including anaphylaxis and angioedema have been reported 2
• Pulmonary aspiration: Risk during general anesthesia or deep sedation due to delayed gastric emptying 2

DPP-4 Inhibitors Side Effects

Minimal Side Effect Profile

• DPP-4 inhibitors generally have few side effects and minimal risk of hypoglycemia when used as monotherapy 1
• They are weight-neutral, which distinguishes them from GLP-1 receptor agonists 3, 4

Heart Failure Concerns

• Some DPP-4 inhibitors, particularly saxagliptin, have been associated with an increased risk of hospitalization for heart failure 1
• The SAVOR-TIMI 53 trial showed a 27% relative increase in the risk of heart failure hospitalization with saxagliptin compared to placebo 1
• This risk appears to vary among different DPP-4 inhibitors, with sitagliptin showing no increased risk in the TECOS trial 1

Other Reported Side Effects

• Joint pain has been reported with DPP-4 inhibitors 1
• Acute pancreatitis, though rare, has been reported 1
• Peripheral edema is a common side effect 1

Special Considerations for Older Adults

• DPP-4 inhibitors may be preferred in older adults due to their minimal side effects and low risk of hypoglycemia 1
• However, cost may be a barrier for some older patients 1
• GLP-1 receptor agonists require visual, motor, and cognitive skills for proper administration, which may limit their use in some older adults 1
• Weight loss with GLP-1 receptor agonists may not be desirable in frail older adults 1

Practical Considerations for Clinical Use

Monitoring Recommendations

• Monitor for signs and symptoms of pancreatitis (persistent severe abdominal pain) in patients on either class of medication 2
• For patients on GLP-1 receptor agonists, monitor for dehydration, especially if gastrointestinal side effects are prominent 2
• Consider renal function monitoring, particularly when initiating or escalating doses of GLP-1 receptor agonists 2

Risk Mitigation Strategies

• For GLP-1 receptor agonists, starting with a lower dose and gradually titrating can help minimize gastrointestinal side effects 5
• When combining with insulin or sulfonylureas, consider dose reduction of these agents to prevent hypoglycemia 2
• For patients with a history of heart failure or at high risk for heart failure, consider avoiding saxagliptin and other DPP-4 inhibitors with known heart failure risk 1

Contraindications

• GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 1
• Both medication classes should be used with caution in patients with a history of pancreatitis 2

By understanding these side effect profiles, clinicians can make more informed decisions about which incretin-based therapy might be most appropriate for individual patients with type 2 diabetes, considering their comorbidities, age, and other risk factors.