INTERNATIONAL JOURNAL OF ARTIFICIAL INTELLIGENCE
ISSN: 2692-5206, Impact Factor: 12,23
American Academic publishers, volume 05, issue 09,2025
Journal:
https://www.academicpublishers.org/journals/index.php/ijai
page 221
DIABETIC KETOACIDOSIS ASSOCIATED WITH EMPAGLIFLOZIN THERAPY :
MECHANISMS, RISC FACTORS AND CLINICAL IMPLICATIONS
Professor
Najmutdinova D.K.,
Kurbanova A.B.
, TMA
Tashkent, Uzbekistan
Abstract:
Empagliflozin, a sodium–glucose co-transporter 2 (SGLT2) inhibitor, is widely
prescribed for type 2 diabetes mellitus (T2DM) and heart failure. Despite its proven
cardiovascular and renal benefits, rare but serious cases of diabetic ketoacidosis (DKA),
including euglycemic DKA (euDKA), have been reported. This article reviews the incidence,
mechanisms, risk factors, clinical features, and management strategies of empagliflozin-
associated DKA. Early recognition and preventive strategies are essential to balance risks and
benefits of therapy.
Introduction
Empagliflozin (Jardiance) is an oral SGLT2 inhibitor that improves glycemic control, reduces
cardiovascular events, and provides renal protection in patients with T2DM [1]. However,
since 2015, regulatory agencies have highlighted the risk of DKA, particularly euDKA, in
patients treated with SGLT2 inhibitors [2]. EuDKA is characterized by significant ketosis and
metabolic acidosis despite only mild-to-moderate hyperglycemia, creating diagnostic
challenges [3].
Methods
A narrative review was conducted using PubMed, Scopus, and Web of Science databases.
Search terms included “empagliflozin,” “SGLT2 inhibitors,” “diabetic ketoacidosis,” and
“euglycemic DKA.” Articles published between 2015 and 2025, including randomized
controlled trials (RCTs), meta-analyses, case reports, and regulatory advisories, were included.
Results
Incidence
Meta-analyses and real-world studies report low but clinically significant incidence of
empagliflozin-associated DKA. A 2024 network meta-analysis found empagliflozin 10 mg
increased odds of DKA compared with placebo (OR 2.68; 95% CI 1.11–6.49) [4]. Another
meta-analysis of 10 RCTs including 71,553 subjects reported a threefold increased risk of
DKA with SGLT2 inhibitors (RR 3.0; 95% CI 1.36–3.63) [5].
In Uzbekistan, empagliflozin-associated DKA incidence was estimated at 0.23% (2.3 per
1,000 patient-years) [6]. Perioperative studies show elevated risk: 0.17% after non-emergency
surgery and 1.1% after emergency procedures [7].
Pathophysiology
INTERNATIONAL JOURNAL OF ARTIFICIAL INTELLIGENCE
ISSN: 2692-5206, Impact Factor: 12,23
American Academic publishers, volume 05, issue 09,2025
Journal:
https://www.academicpublishers.org/journals/index.php/ijai
page 222
Empagliflozin promotes ketogenesis by:
1. Increasing glucosuria, lowering insulin secretion, and stimulating glucagon release [5].
2. Enhancing renal ketone reabsorption [5].
3. Inducing osmotic diuresis, volume depletion, and impaired glucose utilization [3].
Risk Factors
Major risk factors include:
Acute illness, infection, dehydration, or perioperative fasting [2,7].
Low-carbohydrate diets, alcohol intake, and prolonged fasting [2,6].
Insulin dose reduction or discontinuation in insulin-dependent patients [5].
Ethnic differences: higher incidence among NZ Europeans compared to Māori and Asian
populations [6].
Clinical Presentation
Patients typically present with nausea, vomiting, abdominal pain, dyspnea, malaise, and
metabolic acidosis. Blood glucose is often <14 mmol/L (<250 mg/dL), which may delay
diagnosis [2,3].
Management
Immediate discontinuation of empagliflozin.
Standard DKA protocol: IV fluids, insulin infusion, and electrolyte replacement [3,8].
Perioperative prevention: discontinue empagliflozin ≥3 days before elective surgery and
resume only after clinical stabilization [1,2].
EuDKA may require longer ketone clearance but carries higher risk of hypoglycemia due to
insulin therapy [8].
Prevention
Preventive strategies include patient education on “sick day rules,” perioperative
discontinuation, avoidance of ketogenic diets, and maintaining appropriate insulin therapy
[2,6].
Discussion
Although the absolute incidence of empagliflozin-associated DKA is low, the condition is
clinically significant. RCTs report mixed findings, with some showing no significant increase
in DKA compared to placebo, but real-world evidence and case reports confirm the risk in
susceptible patients [4–6]. The atypical presentation of euDKA emphasizes the need for
clinical vigilance. Preventive strategies and patient education can help minimize risk while
preserving empagliflozin’s cardiovascular and renal benefits.
INTERNATIONAL JOURNAL OF ARTIFICIAL INTELLIGENCE
ISSN: 2692-5206, Impact Factor: 12,23
American Academic publishers, volume 05, issue 09,2025
Journal:
https://www.academicpublishers.org/journals/index.php/ijai
page 223
Conclusion
Empagliflozin remains an important therapeutic option for T2DM and heart failure. However,
clinicians must be aware of the rare risk of DKA, especially in perioperative and high-risk
scenarios. Vigilance, patient education, and adherence to preventive protocols are essential to
maximize benefits and minimize risks.
References (Vancouver Style)
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and
mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128.
2. Medicines and Healthcare products Regulatory Agency. SGLT2 inhibitors: updated advice
on the risk of diabetic ketoacidosis. Drug Safety Update. 2016. Available
from:https://www.gov.uk/drug safety update/sglt2-inhibitors updated
Advice on the risk of diabetic ketoacidosis
3. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable,
and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38(9):1638–1642.
4. Li Y, Sun H, Jiang F, et al. Risk of diabetic ketoacidosis with SGLT2 inhibitors in adults
with type 1 diabetes: a network meta-analysis. Front Endocrinol. 2024;15:1453067.
5. Tang H, Li D, Wang T, et al. Risk of diabetic ketoacidosis with sodium-glucose
cotransporter-2 inhibitors: a meta-analysis of randomized controlled trials. Front Pharmacol.
2023;14:1145587.
6. Braatvedt G, et al. The incidence of diabetic ketoacidosis associated with empagliflozin use
in Aotearoa New Zealand: a preliminary review. N Z Med J. 2022;135(1555):94–102.
7. Meyer EJ, et al. Perioperative risk of diabetic ketoacidosis in patients taking SGLT2
inhibitors: a population-based cohort study. Anaesthesia. 2025;80(3):259–268.
8. Tuttle KR, et al. Euglycemic DKA management in patients on SGLT2 inhibitors: protocol
evaluation. Curr Diab Rep. 2025;25(2):163–170.
