From the Guidelines
GLP-1 agonists have a low risk of causing hypoglycemia when used as monotherapy, but the risk increases significantly when combined with insulin or insulin secretagogues. Medications in this class, such as semaglutide, dulaglutide, liraglutide, and tirzepatide, work by stimulating insulin secretion in a glucose-dependent manner, meaning they primarily increase insulin when blood glucose levels are elevated, as noted in the 2018 consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) 1. This glucose-dependent mechanism provides a built-in safety feature that minimizes hypoglycemia risk. However, when GLP-1 agonists are combined with insulin or insulin secretagogues like sulfonylureas, the risk of hypoglycemia increases, as these medications can enhance the insulin-stimulating effects of GLP-1 agonists, leading to excessive insulin secretion and hypoglycemia.
Some key points to consider when using GLP-1 agonists include:
- The risk of hypoglycemia is low when GLP-1 agonists are used alone, but increases when combined with other diabetes medications, as reported in a 2024 systematic review and network meta-analysis for the American College of Physicians 1.
- GLP-1 agonists have a heterogeneous class effect, with varying potencies and dosing regimens, which can impact their efficacy and safety profiles, including the risk of hypoglycemia.
- Patients should be educated to recognize hypoglycemia symptoms, such as shakiness, sweating, confusion, and irritability, and instructed to keep fast-acting carbohydrates available.
- Blood glucose monitoring is crucial during the initial weeks of therapy and after dose adjustments, especially in elderly patients or those with renal impairment who may have altered drug clearance.
When initiating a GLP-1 agonist in patients already on insulin or sulfonylureas, consider reducing the insulin dose by 20% or the sulfonylurea dose by half to prevent hypoglycemia, as suggested by the evidence 1. By taking these precautions and carefully monitoring patients, the risk of hypoglycemia associated with GLP-1 agonists can be minimized, and their benefits in improving glycemic control and reducing cardiovascular risk can be maximized.
From the FDA Drug Label
Adult patients receiving liraglutide injection in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When OZEMPIC is used with an insulin secretagogue or insulin, consider lowering the dose of the secretagogue or insulin to reduce the risk of hypoglycemia.
The risk of hypoglycemia is increased when GLP-1 agonists such as liraglutide and semaglutide are used in combination with insulin secretagogues or insulin. To reduce this risk, consider lowering the dose of the insulin secretagogue or insulin 2 3.
- Key points:
- Increased risk of hypoglycemia with combination therapy
- Consider dose reduction of insulin secretagogue or insulin
- Monitor patients for signs and symptoms of hypoglycemia
From the Research
Risk of Hypoglycemia with GLP-1 Agonist
- The risk of hypoglycemia with GLP-1 agonists is generally considered to be low 4, 5, 6, 7, 8.
- GLP-1 receptor agonists have been shown to have a low intrinsic risk of hypoglycemic episodes 4.
- Studies have demonstrated that GLP-1 RAs can effectively lower blood glucose levels without increasing the risk of hypoglycemia 5, 6, 7, 8.
- Oral semaglutide, a GLP-1 receptor agonist, has been shown to have a low risk of hypoglycemia when used as monotherapy or in combination with other glucose-lowering therapies 5, 8.
Mechanisms of Action
- GLP-1 receptor agonists work by augmenting hyperglycemia-induced insulin secretion, suppressing glucagon secretion, and decelerating gastric emptying 4.
- These mechanisms of action help to reduce blood glucose levels and body weight, while minimizing the risk of hypoglycemia 4, 5, 6, 7, 8.
Clinical Evidence
- Clinical trials have demonstrated the efficacy and safety of GLP-1 receptor agonists in reducing blood glucose levels and body weight, with a low risk of hypoglycemia 5, 6, 7, 8.
- Head-to-head clinical studies have shown that GLP-1 receptor agonists are effective therapeutic options for reducing A1C and weight, with differences in terms of magnitude of effect and frequency of adverse effects 6.