What are the effects of Glucagon-like peptide-1 (GLP-1) inhibitors?

From the Guidelines

GLP-1 receptor agonists, not inhibitors, are the recommended medications for managing type 2 diabetes, offering benefits beyond glycemic control, including weight loss and cardiovascular protection, as evidenced by the most recent study 1.

Key Points

• GLP-1 receptor agonists are administered as subcutaneous injections, with frequencies ranging from twice daily to once weekly, depending on the specific drug.
• These medications stimulate insulin secretion, suppress glucagon release, slow gastric emptying, and reduce appetite through central nervous system effects.
• Common GLP-1 agonists include semaglutide (Ozempic, Wegovy), liraglutide (Victoza, Saxenda), dulaglutide (Trulicity), tirzepatide (Mounjaro), and exenatide (Byetta).
• The LEADER trial showed a benefit in cardiovascular outcomes with GLP-1 receptor agonists, with a 13% reduction in the primary composite outcome of cardiovascular death, non-fatal myocardial infarction or stroke 1.
• The SUSTAIN 6 trial also confirmed the cardiovascular benefit of GLP-1 receptor agonists, with a 26% reduction in the primary outcome of cardiovascular death, non-fatal myocardial infarction or stroke 1.

Side Effects and Management

• Nausea, vomiting, and diarrhea are the most frequently reported adverse effects of GLP-1 receptor agonists, which are dose-dependent and more frequent with short-acting drugs.
• Slow titration is helpful in increasing gastrointestinal tolerability, and side effects often improve over time.
• Management of common adverse effects includes:
  • Nausea and vomiting: avoid in gastroparesis
  • Dyspepsia: start GLP-1 receptor agonist at low dose and titrate upward slowly
  • Diarrhea: reduce meal size
  • Gastrointestinal reflux: limit alcohol and carbonated drinks
  • Constipation: avoid high fat diet

Recommendations

• GLP-1 receptor agonists should be initiated at lower doses and gradually increased to minimize gastrointestinal side effects.
• They are contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2, and caution is advised in patients with history of pancreatitis.
• The most recent study 1 supports the use of GLP-1 receptor agonists as a valuable treatment option for patients with type 2 diabetes, offering benefits beyond glycemic control.

From the FDA Drug Label

1. 1 Risk of Thyroid C-cell Tumors In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures.

5.1 Risk of Thyroid C-cell Tumors One case of MTC was reported in a patient treated with TRULICITY in a clinical trial. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period;

• GLP1 inhibitors may increase the risk of thyroid C-cell tumors, including medullary thyroid carcinoma (MTC).
• The human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.
• TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2.
• Patients should be counseled regarding the potential risk for MTC with the use of TRULICITY and informed of symptoms of thyroid tumors 2.
• Liraglutide, another GLP-1 receptor agonist, has also been associated with MTC in the postmarketing period 3.

From the Research

GLP-1 Inhibitors Overview

• GLP-1 receptor agonists (GLP-1 RAs) are a class of glucose-lowering agents used to treat type 2 diabetes 4.
• They work by augmenting hyperglycemia-induced insulin secretion, suppressing glucagon secretion, decelerating gastric emptying, and reducing calorie intake and body weight 4.

Types of GLP-1 Inhibitors

• Short-acting agents: exenatide b.i.d., lixisenatide 4.
• Long-acting agents: liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide 4.
• Oral preparation: semaglutide, recently approved 4.

Efficacy and Safety

• GLP-1 RAs have been shown to be effective in reducing HbA1c levels, body weight, and cardiovascular risk 4, 5, 6.
• They have a low risk of hypoglycemia and are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes 4.
• Oral semaglutide has been shown to be effective in achieving adequate glycemic control in patients with type 2 diabetes inadequately controlled with metformin monotherapy 5, 6.

Comparison with Other Therapies

• GLP-1 RAs have been compared to SGLT-2 inhibitors and have been shown to be more effective in reducing HbA1c levels and body weight 5.
• They have also been compared to insulin therapy and have been shown to be effective in reducing HbA1c levels and body weight, with a low risk of hypoglycemia 6.

Switching Therapies

• Switching from liraglutide or dulaglutide to semaglutide has been shown to improve glycemic control and treatment satisfaction in patients with type 2 diabetes 7.
• Semaglutide has also been shown to improve metabolic parameters, such as body weight and lipid profiles, when switched from other GLP-1 RAs 7.