From the Guidelines
For third and fourth-line agents in type 2 diabetes management, consider adding a GLP-1 receptor agonist (such as semaglutide 0.25-1 mg weekly, dulaglutide 0.75-4.5 mg weekly, or liraglutide 0.6-1.8 mg daily) or an SGLT-2 inhibitor (like empagliflozin 10-25 mg daily, dapagliflozin 5-10 mg daily, or canagliflozin 100-300 mg daily) as recommended by the 2019 ESC guidelines 1. These agents are typically added after metformin and often a sulfonylurea have proven insufficient for glycemic control. The choice between these classes should be guided by patient-specific factors:
- GLP-1 agonists offer greater A1C reduction and weight loss but require injection and may cause gastrointestinal side effects
- SGLT-2 inhibitors provide moderate A1C reduction with cardiovascular and renal benefits, weight loss, and the convenience of oral administration. For patients with established cardiovascular disease or high risk, these agents are particularly beneficial as they've demonstrated cardiovascular outcome benefits, as noted in the 2019 ESC guidelines 1 and the 2016 Israel National Diabetes Council recommendations 1. If these agents don't achieve target glycemic control, consider adding the other class or insulin therapy, taking into account the patient's medical condition and personal preference, as suggested by the 2016 Israel National Diabetes Council recommendations 1. Combination therapy targeting different physiological pathways often provides synergistic effects for improved glucose management. Key considerations include the patient's BMI, with GLP-1 RAs being more suitable for patients with higher BMI due to their greater potential for weight loss, and the importance of minimizing side effects and costs, as discussed in the 2012 ADA/EASD position statement 1. Ultimately, the selection of third and fourth-line agents should prioritize the patient's individual needs, glycemic targets, and cardiovascular risk profile, aligning with the recommendations from the 2019 ESC guidelines 1 and other evidence-based guidelines.
From the Research
Third and Fourth Agents for Diabetes Type 2
When considering the addition of a third or fourth agent for the treatment of type 2 diabetes, several options are available. The choice of agent depends on various factors, including the patient's current treatment regimen, glycemic control, and presence of comorbidities.
- SGLT2 Inhibitors and GLP-1 Receptor Agonists: These agents have been shown to have beneficial effects on glycemic control, weight loss, and cardiovascular risk factors 2, 3. They can be considered as second-line or even first-line therapies in patients with cardiorenal disease, regardless of glycemic control.
- Thiazolidinediones, Insulins, and Dipeptidyl Peptidase-4 Inhibitors: These agents can be considered as additional therapy options for patients with type 2 diabetes who are not achieving adequate glycemic control with metformin and sulfonylureas 4.
- Combination Therapy: Combination therapy with an SGLT2 inhibitor and a GLP-1 receptor agonist has been shown to have complementary effects on glycemic control, weight loss, and cardiovascular risk factors 3.
Considerations for Third and Fourth Agent Selection
When selecting a third or fourth agent, clinicians should consider the following factors:
- Efficacy and Safety: The efficacy and safety of the agent in improving glycemic control and reducing cardiovascular risk factors.
- Cost: The cost of the agent and its potential impact on the patient's quality of life.
- Patient Preferences: The patient's preferences and values, including their willingness to inject medications or take oral medications.
- Comorbidities: The presence of comorbidities, such as cardiovascular disease, kidney disease, or obesity, which may influence the choice of agent.
Evidence-Based Recommendations
Based on the available evidence, the following recommendations can be made:
- SGLT2 Inhibitors: Can be considered as a third or fourth agent in patients with type 2 diabetes who have established cardiovascular disease or are at high risk of cardiovascular events 2, 5.
- GLP-1 Receptor Agonists: Can be considered as a third or fourth agent in patients with type 2 diabetes who have established cardiovascular disease or are at high risk of cardiovascular events 2, 3, 5.
- Insulin Therapy: Can be considered as a third or fourth agent in patients with type 2 diabetes who are not achieving adequate glycemic control with oral medications 4, 6.