Pillar or poison? Evaluating overdose and safety challenges in newer diabetic kidney disease medications

To the editor,

Sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and non-steroidal mineralocorticoid receptor antagonists (nsMRA) now form the foundation of the pillar-based pharmacological approach for the management of chronic kidney disease (CKD) in individuals with type 2 diabetes mellitus. As the use of these agents continues to expand globally, incidence of overdose—whether accidental, resulting from therapeutic misadventure, or intentional—is expected to rise. Despite this, many clinicians have limited familiarity in relation to the toxicological profiles of these medications, and may be insufficiently prepared to manage cases of overdose when they present. We conducted a scoping review aiming to provide insights on the clinical outcomes associated with supratherapeutic exposure to these medications.

A scoping literature search was conducted for publications published between 1 January 2013 and 30 September 2025 using PubMed, MEDLINE, Cochrane Review, and Google Scholar. The search process was completed as per the PRISMA-ScR principles, and the study is registered on PROSPERO (CRD420251251433). Combination keywords used in the search process included: ‘SGLT2 inhibitor’, ‘empagliflozin’, ‘dapagliflozin’, ‘canagliflozin’, ‘GLP-1 receptor agonist’, ‘liraglutide’, ‘semaglutide’, ‘finerenone’, ‘overdose’, ‘toxicity’, ‘intoxication’, ‘acute kidney injury’, ‘osmotic nephropathy’, and ‘tubular injury’. Following initial screening, publications were eligible for full-text review if they met the following criteria: (i) they reported overdose, high-dose exposure, or severe toxicity involving SGLT2i, GLP-1RA, and/or nsMRA medications; and (ii) they described evidence of biochemical or structural kidney injury. Case reports, case series, retrospective analysis, and/or conference abstracts were eligible for inclusion. Publications reporting only adverse effects associated with therapeutic dosages of SGLT2i, GLP-1RA, and/or nsMRA and those involving established therapies for diabetic kidney disease (e.g. angiotensin converting enzyme inhibitors, angiotensin receptor blockers) without co-ingestion of SGLT2i, GLP-1RA, and/or nsMRA were excluded, as were publications not in English and animal toxicology studies.

Table 1 summarizes the findings from our scoping review [1–3] (Supplementary references S1–S23). Four publications addressing overdose involving SGLT2i were identified [1, 2] (Supplementary references S1, S2). A cohort of 88 patients from US poison centres [1] represented the largest dataset on SGLT2i overdose, in which cases were associated with mild adverse effects and acute kidney injury (AKI) was uncommon. However, several individual case reports described clinically significant kidney injury following large intentional ingestions of dapagliflozin or related agents. These included biopsy-proven osmotic nephropathy, acute tubular injury, and stage 3 AKI, in some cases necessitating dialysis [2] (Supplementary references S1, S2). Of note, Kawata et al. [2] reported marked swelling of proximal tubular epithelial cells and evidence of vacuolization on renal histology after ingestion of dapagliflozin at 29 times the recommended daily dose (290 mg). Despite severe presentation in some cases, most instances of AKI resolved with supportive therapy and did not progress to CKD [2] (Supplementary references S2).

Table 1:

Summary of the literature reporting supratherapeutic and toxic exposures to SGLT2 inhibitors and GLP-1 receptor agonists.

Author, year	Type of study	Number of patients	Name of drug (number of subtherapeutic exposures)	Range of toxic doses	Renal side effects	Other side effects
SGLT2i
Schaeffer et al. [1], 2018	Retrospective poison centres database study	88	Empagliflozin (n = 2), Dapagliflozin (n = 1), Canagliflozin (n = 1)	Empagliflozin 125 mg– 900 mg Canagliflozin 900 mg	None observed	Nausea, vomiting, tachycardia, hypertension, urinary incontinence
Kawata et al. [2], 2025	Case report	1	Dapagliflozin	290 mg	AKI necessitating dialysis. Biopsy-proven osmotic nephropathy and tubular vacuolization
Baig et al. [S1], 2022	Case report	1	Ertugliflozin	150 mg	None observed	Dizziness
Nakamura et al. [S2], 2020	Case report	1	Ipragliflozin	1500 mg	AKI	Hypotension, hypoglycaemia
GLP-1RA
Acosta et al. [3], 2025	Case report	1	Semaglutide	4.8 mg SC injection	None observed	Euglycaemic non-diabetic DKA in context of pancreatitis, nausea, vomiting, abdominal pain
Wiener et al. [S3], 2024	Case series	3	Semaglutide (n = 3)	1.7 mg–2.4 mg SC Injection	None observed	Non-specific GI symptoms
Marshall et al. [S4], 2024	Single poison centre + retrospective cohort	152	Semaglutide (n = 65), Dulaglutide (n = 38), Liraglutide (n = 22), Exenatide (n = 18), Tirzepatide (n = 9)	Not specified	None observed	Non-specific GI symptoms, hypoglycaemia
Muschler et al. [S5], 2025	Single poison centre retrospective cohort	237	Semaglutide most common (n = 72)	Not specified	None observed	Hypoglycaemia
Gaw et al. [S6], 2024	Multiple poison centre retrospective cohort	1 209	Semaglutide 42.5%L, iraglutide 23.5%, Others 34.1%	Not specified	One case of renal failure	Non-specific GI symptoms, abdominal pain, pancreatitis, ileus
Gartner et al. [S7], 2025	Retrospective emergency department cohort study	152	Semaglutide (n = 109), Dulaglutide (n = 18), Liraglutide (n = 14), Tirzepatide (n = 8) GLP-1RA type unconfirmed (n = 3)	Semaglutide IQR 1.3–4.9 mgDulaglutide IQR 1.3–4 mgLiraglutide IQR 1.3–3.7 mgTirzepatide IQR 1.3–5 mg	None observed	Non-specific GI symptoms, hypoglycaemia, abdominal pain, tachycardia
Elmehdawi & Elbarsha [S8], 2014	Case report	1	Liraglutide	18 mg SC injection	None observed	Nausea and vomiting
Diec et al. [S9], 2024	Case report	1	Semaglutide	1 mg SC injection daily for 7 days	None observed	Not specified
Zamir et al. [S10], 2025	Case report	1	Semaglutide	8 mg SC injection	AKI recovered with conservative treatment	Hypoglycaemia, Elevated liver enzymes, pancreatitis
Krishnan et al. [S11], 2013	Case report	1	Exenatide	1800 mcg SC injection	None observed	Nausea and vomiting
Solverson et al. [S12], 2018	Case report	1	Liraglutide	36 mg SC injection	None observed	Nausea and vomiting, hypoglycaemia, reduced GCS
Al Saadoun et al. [S13], 2022	Case report	1	Liraglutide	2.4 mg SC injection	None observed	Pancreatitis, nausea, and vomiting
Nafisah et al. [S14], 2020	Case report	1	Liraglutide	18 mg SC injection	None observed	Nausea and vomiting, abdominal pain, hypoglycaemia
Payen et al. [S15], 2014	Case series	3	Exenatide (n = 3)	60 mcg–600 mcg SC injection	None observed	Nausea, vomiting, hypoglycaemia
Lambson et al. [S16], 2023	Case series	3	Semaglutide (n = 3)	Not specified	None observed	Nausea, vomiting, abdominal pain
Foo et al. [S17], 2024	Case report	1	Semaglutide (combined with insulin)	3 ml Ozempic	None observed	Prolonged refractory hypoglycaemia requiring renal replacement therapy
Moore et al. [S18], 2024	Case report	1	Dulaglutide	1.5 mg SC injection on 6 consecutive days	None observed	Hypoglycaemia
Nakanishi et al. [S19], 2013	Case report	1	Liraglutide	72 mg SC injection	None observed	Nausea and vomiting
Cohen et al. [S20], 2008	Letter to the editor	1	Exenatide	90 microgram SC injection	None observed	Nausea and vomiting, dizziness
Bode et al. [S21], 2013	Letter to the editor	1	Liraglutide	18 mg daily for 7 months	None observed	Nausea and vomiting, diarrhoea
McIntyre et al. [S22], 2024	Retrospective national database study	3 348	Not specified	Not specified	None observed	Not specified
Branch et al. [S23], 2024	Case report	1	Semaglutide	Not specified	None observed	Not specified

DKA, diabetic ketoacidosis; GCS, Glasgow Coma Score; SC, subcutaneous.

A total of 22 publications were related to GLP-1RA overdose [3] (Supplementary references S3–S23), most of which manifested as gastrointestinal (GI) symptoms, with no reports of AKI [3] (Supplementary references S3, S4, S7, S8, S11, S13–S16, S19, S21). Rare but serious complications have been reported, with one article reporting semaglutide-induced pancreatitis and euglycemic non-diabetic ketoacidosis requiring intensive care admission [3]. The observed renal toxicity in this class appears to be more closely related to volume depletion and immunological mechanisms, rather than direct dose-related toxicity (Supplementary references S6, S10, S17).

Other than the case report by Kawata et al.[2] in which the patient took an overdose of eplerenone (725 mg) in addition to dapagliflozin, esomeprazole, and azosemide, there were no further articles identified relating to overdose of nsMRA resulting in biochemical or structural kidney injury. Nevertheless, current trial and pharmacovigilance data observed functional declines in eGFR, acid–base dysregulation and hyperkalaemia without tubular or histological injury [4]. Therefore, adverse renal effects are very possible in the context of subtherapeutic ingestion.

The findings from this review highlight that, despite the widespread global use of SGLT2i, GLP-1RA, and nsMRA, there remains a paucity of literature describing the effects of supratherapeutic exposure and drug toxicity. Present evidence suggests that SGLT2i overdose is generally well-tolerated, with kidney dysfunction and volume disturbances rare and often self-limiting. GLP-1RA overdose typically presents with GI and systemic side effects, with supportive management sufficing in most cases. Literature around nsMRAs overdose is minimal, with potential toxicities largely theoretical and related to electrolyte disturbances. The lack of well-defined toxicity profiles poses challenges for clinicians, including uncertainty around monitoring, admission thresholds, and escalation of care. In addition, the risk of under-recognition or delayed diagnosis, particularly outside tertiary centres is high. To address these gaps, enhanced pharmacovigilance, systematic data collection, and targeted clinician education are essential to improve preparedness and standardize care pathways as the use of these therapies continue to expand.

CONFLICT OF INTEREST STATEMENT

None declared.

Authors’ contributions

E.M.: Methodology, Investigation, Writing – Original draft and preparation, Writing – Review and editing; A.A.: Methodology, Investigation, Writing – Original draft and preparation, Writing – Review and editing; H.H.L.W.: Conceptualization, Writing – Review and editing, Visualization, Project administration; S.K.L.: Writing – Review and editing, Visualization; L.F.: Conceptualization, Methodology, Writing – Review and editing, Visualization, Project administration, Supervision