GLP-1 receptor agonists: reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued

Diabetic ketoacidosis has been reported in patients with type 2 diabetes on a combination of a GLP-1 receptor agonist and insulin who had doses of concomitant insulin rapidly reduced or discontinued. GLP-1 receptor agonists are not substitutes for insulin, and any reduction of insulin should be done in a stepwise manner with careful glucose self-monitoring. Abrupt discontinuation or reduction in insulin doses can lead to poor glycaemic control, with a risk of diabetic ketoacidosis.

Advice for healthcare professionals:

  • serious and life-threatening cases of diabetic ketoacidosis have been reported in association with exenatide, liraglutide, and dulaglutide, particularly after discontinuation or reduction of concomitant insulin
  • blood glucose self-monitoring is necessary when adjusting the dose of insulin, particularly when GLP-1 receptor agonist therapy is initiated and insulin is reduced

  • if the insulin dose is to be reduced, a stepwise approach is recommended

  • discuss with patients the risk factors for and signs and symptoms of diabetic ketoacidosis (see below) and advise them to seek immediate medical advice if these develop

  • report suspected adverse drug reactions on a Yellow Card

Background

Exenatide (Bydureon, Byetta), liraglutide (Victoza, Saxenda▼, Xultophy▼[combination product with insulin]), and dulaglutide (Trulicity▼) are glucagon-like peptide-1 (GLP-1) receptor agonists (also known as GLP-1 mimetic therapies) and are authorised for use in adults with type 2 diabetes to improve glycaemic control, except for Saxenda, which is indicated for weight management. GLP-1 receptor agonists act by stimulating insulin secretion from the pancreas in a glucose-dependent manner, as well as slowing gastric emptying and suppressing glucagon secretion. GLP-1 receptor agonists are not substitutes for insulin.

Review of cases of diabetic ketoacidosis

Serious and life-threatening cases of diabetic ketoacidosis have been reported in association with exenatide, liraglutide, and dulaglutide, particularly after rapid reduction or discontinuation of concomitant insulin. An EU review of these reports concluded that the cases could be attributed to abrupt discontinuation or dose reduction of insulin while initiating GLP-1 receptor agonist therapy, resulting in a poor glycaemic control.

This review did not identify euglycaemic diabetic ketoacidosis as a safety concern specific to treatment with GLP-1 receptor agonist therapies. A few cases in the review reported reactions suggestive of euglycaemic diabetic ketoacidosis; however, these were attributed to concomitant use of sodium-glucose co-transporter-2 inhibitor (SGLT2) medicines, which are known to be associated with euglycaemic diabetic ketoacidosis (see Drug Safety Update April 2016).

Recommendations for reducing the risk of ketoacidosis

When GLP-1 receptor agonist therapy is added to existing treatment with insulin, a reduction in the dose of insulin may be considered to reduce the risk of hypoglycaemia. A stepwise approach to insulin dose adjustment is recommended, taking into account a patient’s glucose levels and individual insulin requirements.

The Summaries of Product Characteristics and Patient Information Leaflets for exenatide, liraglutide, and dulaglutide are being updated to note that a stepwise approach is recommended for insulin dose reduction and to advise that blood glucose self-monitoring is necessary when adjusting the dose of insulin, particularly during initiation of GLP-1 receptor agonist therapy.

The GLP-1 receptor agonists lixisenatide (Lyxumia) and semaglutide (Ozempic▼) are also authorised for use in the UK. Lixisenatide and semaglutide were not subject to the EU review. At the time of publication, we have not received any UK reports of diabetic ketoacidosis in association with lixisenatide and semaglutide. However, the theoretical risk of diabetic ketoacidosis when changes are made to insulin dose cannot be excluded.

Characteristics of reactions reported

Up until the end of May 2019, the MHRA’s Yellow Card Scheme has received 26 reports of diabetic ketoacidosis, and 10 reports of reactions relating to ketone body formation (increased blood ketones, ketonuria) in patients taking exenatide, liraglutide, and dulaglutide. This corresponds to a UK estimated exposure to these 3 medicines of about 2 million patient-years of treatment between 2007 and 2018.1

In around a third of the UK cases reported, insulin was either discontinued or the dose was rapidly reduced at initiation of the GLP-1 receptor agonist. In the remaining cases, it is difficult to establish the role of these agents due to possible precipitating factors for diabetic ketoacidosis, such as other medicines or underlying conditions. Although nausea and vomiting may be considered adverse drug reactions of GLP-1 receptor agonists, these are also well-known symptoms of diabetic ketoacidosis and should be taken seriously when initiating GLP-1 receptor agonists and adjusting insulin doses.

Many of the cases of diabetic ketoacidosis and related reactions occurred within 2 weeks of initiation of GLP-1 receptor agonists. Nausea and vomiting were commonly co-reported reactions.

Signs and symptoms of diabetic ketoacidosis

Inform patients of the signs and symptoms of diabetic ketoacidosis (nausea, vomiting, abdominal pain, excessive thirst, increased frequency of urination, difficulty breathing, confusion, unusual fatigue, or sleepiness) and the need for urgent medical attention if they occur.

Report suspected adverse drug reactions on a Yellow Card

Please continue to report suspected adverse drug reactions (ADRs) associated with GLP-1 receptor agonists on a Yellow Card. Reporting suspected ADRs, even those known to occur in association with the medicine, adds to knowledge about the frequency and severity of these reactions and can be used to identify patients who are most at risk. Your report helps the safer use of medicines.

Healthcare professionals, patients, and caregivers can report suspected ADRs via the Yellow Card website or via the Yellow Card app. Download the app today via iTunes Yellow Card for iOS devices or via PlayStore Yellow Card for Android devices.

Further information

PRAC recommendations on signals at the 26-29 November 2018 meeting.

Article citation: Drug Safety Update volume 12, issue 11: June 2019: 2.

  1. Data derived from IQVIA MIDAS Q1 2006 to Q4 2018, by the MHRA, March 2019. Patient-years estimated from the data by using defined daily doses (DDD) as provided by WHO. 

Published 19 June 2019