From the Guidelines
GLP-1 Receptor Agonists are Generally Safe and Effective for Long-Term Use in Patients with Type 2 Diabetes GLP-1 receptor agonists, such as liraglutide, semaglutide, and dulaglutide, have been shown to be effective in improving glycemic control, reducing cardiovascular risk, and promoting weight loss in patients with type 2 diabetes 1. However, they may also be associated with increased risks of pancreatitis, thyroid cancer, and kidney problems, particularly in patients with a history of these conditions 1.
Benefits of GLP-1 Receptor Agonists
The benefits of GLP-1 receptor agonists include:
- Improved glycemic control 1
- Reduced cardiovascular risk, including major adverse cardiovascular events (MACE) and heart failure hospitalization 1
- Weight loss and improved renal outcomes 1
- Low risk of hypoglycemia compared to other diabetes medications 1
Safety Considerations
To minimize potential risks, it's recommended to:
- Start with a low dose and gradually increase as needed and tolerated 1
- Monitor kidney function, liver enzymes, and thyroid function regularly 1
- Be aware of the signs and symptoms of pancreatitis, such as severe abdominal pain, and seek medical attention immediately if they occur 1
- Use GLP-1 receptor agonists with caution in patients with a history of thyroid cancer or pancreatitis 1
Specific Medications and Dosing
The typical dose range for GLP-1 receptor agonists is:
- Liraglutide: 1.2-1.8 mg/day 1
- Semaglutide: 0.5-1.0 mg/day 1
- Dulaglutide: 0.75-1.5 mg/day 1 The duration of treatment should be individualized, but most studies have shown benefits with long-term use, typically 12-26 weeks or longer 1.
From the FDA Drug Label
INDICATIONS AND USAGE OZEMPIC is a glucagon-like peptide 1 (GLP-1) receptor agonist indicated: • as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1). • to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (1). • to reduce the risk of sustained eGFR decline, end-stage kidney disease and cardiovascular death in adults with type 2 diabetes mellitus and chronic kidney disease (1).
The safety and long-term effects of GLP-1 receptor agonist medications, such as semaglutide, on patients with type 2 diabetes include:
- Improved glycemic control
- Reduced risk of major adverse cardiovascular events
- Reduced risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death However, the label does not provide comprehensive information on all potential long-term effects. 2
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility A 2-year carcinogenicity study was conducted with dulaglutide in male and female rats at doses of 0.05,0.5,1. 5, and 5 mg/kg (0.2-, 3-, 8-, and 24-fold the MRHD of 4. 5 mg once weekly based on AUC) administered by subcutaneous injection twice weekly. In rats, dulaglutide caused a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) compared to controls, at ≥3-fold the MRHD based on AUC.
Additionally, dulaglutide has been associated with an increased incidence of thyroid C-cell tumors in rats. 3
From the Research
Safety of GLP-1 Receptor Agonists
- The main safety concern about GLP-1 receptor agonists is the possible association with increased risk of pancreatitis and/or tumors, however, clinical studies and post-marketing analyses have failed to demonstrate a significant association 4.
- The use of GLP-1 receptor agonists was associated with a significant reduction of cardiovascular and all-cause mortality, with a safe profile related to pancreatitis or thyroid cancer, as compared with placebo 5.
- GLP-1 receptor agonists have a reliable hypoglycaemic and weight-loss effect that can intervene in obesity, which is the basis of type 2 diabetes pathology, and have shown potential benefits in reducing the risk of major adverse cardiovascular events and improving kidney outcomes in patients with diabetes at high risk for cardiovascular disease 6.
Long-term Effects of GLP-1 Receptor Agonists
- Long-term studies are needed to confirm the true benefits of GLP-1 receptor agonists in the treatment of diabetes mellitus, including the durability of the weight loss, the ability to preserve functional beta-cell mass, and the applicability in other than type 2 diabetes 7.
- Some sub-analyses of large clinical trials suggest that GLP-1 receptor agonist and sodium-glucose cotransporter 2 inhibitor combination therapy may provide more significant reductions in heart failure hospitalization and renal composite events than each alone 6.
- Six cardiovascular outcome trials of GLP-1 receptor agonists have been published, analyzing lixisenatide, liraglutide, semaglutide, long-acting exenatide, dulaglutide, and oral semaglutide, with a follow-up duration of 2-4 years, and have demonstrated a reduction in rates of major adverse cardiovascular events with active GLP-1 receptor agonist treatment in some trials, but not others 8.
Cardiovascular Benefits of GLP-1 Receptor Agonists
- GLP-1 receptor agonists have emerged as a new antidiabetic drug class with multiple metabolic effects, including cardiovascular benefits, through other mechanisms than glycemic control 5.
- Semaglutide and liraglutide demonstrated a reduction in cardiovascular events, with similar rates on cardiovascular mortality, and exenatide and liraglutide demonstrated the decrease of blood pressure values, weight reduction, and improvement of dyslipidemia 5.
- Liraglutide induced an improvement of blood circulation, increasing the nitric oxide level and inhibiting the adhesion and procoagulant factors, and demonstrated beneficial effects on cardiac remodeling after myocardial infarction 5.