Sodium-glucose cotransporter-2 (SGLT2) inhibitors and risk of serious diabetic ketoacidosis (DKA)

In the September 2015 issue of the HSA Adverse Drug Reaction News Bulletin, HSA issued an interim safety update on the potential risk of DKA with SGLT2 inhibitors while evaluating this safety signal.¹ Subsequently, in February 2016, HSA issued a Dear Healthcare Professional Letter to communicate its benefit-risk assessment outcomes and recommendations.² This article serves to remind healthcare professionals on HSA’s recommendations to minimise the risk of SGLT2 inhibitor-associated DKA.  

Background

There are three SGLT2 inhibitor-containing products registered in Singapore since 2014. They are Invokana™ (canagliflozin, Johnson & Johnson Pte Ltd), Forxiga^® (dapagliflozin, AstraZeneca Singapore Pte Ltd) and Jardiance^® (empagliflozin, Boehringer Ingelheim Singapore Pte Ltd). These drugs are indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus (T2DM), as monotherapy or as an add-on combination therapy with other glucose-lowering agents including insulin. Forxiga^® is also indicated as an initial combination therapy with metformin.

HSA’s benefit-risk assessment

HSA’s review took into account the findings from scientific publications as well as information from local and overseas cases of DKA associated with SGLT2 inhibitors. The review of the published clinical studies noted that although SGLT2 inhibitors use was associated with an increase in blood ketone body levels, the vast majority of patients with ketonaemia were clinically asymptomatic.^3,4 For the patients on SGLT2 inhibitors who developed DKA, it was noted that they had contributory risk factors, such as recent surgery, infection, low caloric/carbohydrate intake, late-onset type 1 diabetes mellitus, long standing T2DM  and pancreatic insufficiency.^5-9 In a number of cases, euglycaemic DKA have also been observed in patients treated with SGLT2 inhibitors. Hence, this highlights the importance of blood ketone testing even when the blood glucose levels are not high, should ketoacidosis be suspected during treatment with SGLT2 inhibitors.

Local case reports of DKA

As of 1 February 2016, HSA has received five local cases of DKA and one case of ketonaemia associated with SGLT2 inhibitors use, all of which had resulted in the patients being hospitalised. Four cases were associated with canagliflozin and two cases were associated with dapagliflozin. The time-to-onset of DKA from the initiation of treatment with SGLT2 inhibitors ranged from 11 to 169 days while that of ketonaemia was unknown. In two cases, the patients presented with euglycaemic DKA (blood glucose levels less than 13.9 mmol/L). Similar underlying and/or concomitant risk factors as those reported in publications, such as infection, reduction in insulin dose, late-onset type 1 diabetes mellitus and long standing T2DM, were also observed in these local cases, which could have precipitated the development of DKA.

In consideration of the expert opinions from local endocrinologists and HSA’s Pharmacovigilance Advisory Committee (PVAC), as well as the regulatory developments in other international jurisdictions, HSA has assessed that while the benefit-risk profile of SGLT2 inhibitors remains favourable for their approved indications, the possibility of SGLT2 inhibitors leading to an increased risk of DKA cannot be excluded, particularly in the presence of predisposing factors.  

International regulatory action

The United States Food and Drug Administration (US FDA), the European Medicines Agency (EMA) and Health Canada have also initiated safety reviews on SGLT2 inhibitors following reports of ketoacidosis with the use of SGLT2 inhibitors.^10-12 To-date, both the EMA and US FDA have completed their respective reviews. The EMA’s Pharmacovigilance Risk Assessment Committee advised healthcare professionals to be aware of possible euglycaemic DKA cases.¹³ The US FDA added a new warning to the US package inserts for SGLT2 inhibitors to warn of the risk of ketoacidosis.¹⁴ Manufacturers of SGLT2 inhibitors are also required by the US FDA to conduct post-marketing studies to collect and analyse spontaneous reports of ketoacidosis with SGLT2 inhibitors and follow-up data for a period of 5 years.

HSA’s advisory

Healthcare professionals are advised on the following to minimise the risk of SGLT2 inhibitor-associated DKA:

• SGLT2 inhibitors should be used in accordance to its approved indications

• SGLT2 inhibitors should be used with caution in patients at risk of developing DKA. Predisposing factors for DKA include a low beta-cell function reserve resulting from pancreatic disorders (e.g. Type 1 diabetes mellitus, history of pancreatitis or pancreatic surgery), insulin dose reduction, reduced caloric intake or increased insulin requirements due to infections, illness or surgery, and alcohol abuse

• Patients should be advised on the possible signs and symptoms of metabolic acidosis, such as tachypnoea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy or mental status changes, and to seek medical attention promptly upon experiencing such symptoms

• Atypical or euglycaemic DKA presentations were observed in some patients (i.e. blood glucose levels lower than usually associated with DKA) while in other cases, no alternative explanation for metabolic acidosis could be identified

• Patients presenting with metabolic acidosis should be assessed for ketoacidosis and tested for blood ketones, even when the blood glucose levels are not high

• If ketoacidosis is suspected, treatment with SGLT2 inhibitor should be discontinued

HSA is working with the product licence holders to strengthen the local package inserts of the SGLT2 inhibitor products, to warn of the risk of developing DKA during treatment with these medications. HSA has also required the product licence holders to submit Periodic Benefit-Risk Evaluation Reports. HSA will continue to closely monitor the local and international developments regarding the risk of DKA with SGLT2 inhibitors use and will update healthcare professionals of any new significant findings.

Healthcare professionals are encouraged to report any suspected serious adverse reactions relating to SGLT2 inhibitors use to the Vigilance and Compliance Branch.

References

1. HSA ADR News Bulletin 2015 Sep; 17:1-2

2. https://www.hsa.gov.sg/announcements/Dear-Healthcare-Professional-Letters

3. Expert Opin Pharmacother 2015;16:1577-91

4. Cardiovasc Diabetol 2014;13:65

5. Diabetes Care 2015;38:1687-93

6. https://endo.confex.com/endo/2015endo/webprogram/
   Paper21461.html

7. http://onlinelibrary.wiley.com/doi/10.1111/jdi.12330/epdf

8. Lancet Diabetes Endocrinol 2015;3:503-4

9. Diabetes Care 2015; 38:1680-6

10. http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm

11. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/SGLT2_inhibitors/
    human_referral_prac_000052.jsp&mid=WC0b01ac05805c516f

12. http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/53892a-eng.php

13. http://www.ema.europa.eu/docs/en_GB/document_library/
    Referrals_document/SGLT2_inhibitors__20/
    Recommendation_provided_by_Pharmacovigilance_Risk_
    Assessment_Committee/WC500201886.pdf

14. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm