a b s t r a c t

Objectives: Biguanides and sulfonylureas are anti-hyperglycemic drugs commonly used in the United States. Poi- soning with these drugs may lead to serious consequences. The diagnosis of biguanide and sulfonylurea poison- ing is based on history, clinical manifestations, and laboratory studies.

Methods: This study is a six-year retrospective cohort analysis based on the National Poison Data System. Clinical effects of 6183 biguanide and sulfonylurea exposures were identified using binary logistic regression.

Results: The mean age of patients with biguanide and sulfonylurea exposure was 39.27 +- 28.91 and 28.91 +-

30.41 years, respectively. Sulfonylurea exposure is most commonly seen via unintentional exposure, while biguanide exposure frequently occurs as a result of Intentional ingestion. Minor and moderate outcomes com- monly developed following biguanide and sulfonylurea exposure, respectively. Sulfonylurea exposure was less likely to develop clinical effects abdominal pain, metabolic acidosis, diarrhea, nausea, vomiting, and elevated cre- atinine than patients ingesting biguanides. However, sulfonylurea exposure was more likely to cause dizziness or vertigo, tremor, drowsiness or lethargy, agitation, diaphoresis, and hypoglycemia. Conclusions: Our study is the first to use a wide range of national data to describe the clinical characteristics that differentiate the toxicologic exposure to biguanides and sulfonylureas. Sulfonylurea exposure is commonly seen via unintentional exposure, while metformin exposure is frequently seen via intentional exposure. sulfonylurea toxicity is more likely to cause agitation, dizziness or vertigo, tremor, diaphoresis, and hypoglycemia, while met- formin exposure induces abdominal pain, acidosis, diarrhea, nausea, vomiting, and elevated creatinine.

(C) 2022 Published by Elsevier Inc.

1. Introduction

Sulfonylurea and biguanide agents are commonly used to treat type 2 diabetes mellitus. The biguanides include buformin, phenformin, and metformin. Only the latter is still available in the United States (US) [1]. Data derived from the American Association of Poison control centers (AAPCC) Toxic Exposure Surveillance System (TESS) show that reported cases of metformin toxicity were more serious than other anti-diabetic medications [2].

Notwithstanding the comparability in Glycemic control effectiveness of metformin and sulfonylureas, metformin does not increase insulin

* Corresponding author.

E-mail address: [email protected] (O. Mehrpour).

secretion. Rather, it exerts its anti-diabetic effects by inhibiting mito- chondrial complex I and increasing insulin sensitivity, decreasing hepatic glucose uptake, increasing peripheral glucose absorption, in- creasing intestinal glucose consumption, and decreasing fatty acid oxi- dation [3]. Lactic acidosis is the most potentially lethal clinical effect of biguanides. Although the prevalence of biguanide-associated lactic acidosis is low, its mortality rate is estimated to be 30-50% [4,5]. Renal dysfunction is the primary risk factor for metformin-induced lactic acidosis [6].

In contrast, neuroglycopenic effects and counter-regulatory hor- monal reactions are clinical features following sulfonylurea overdose [7]. Sulfonylureas inhibit adenosine triphosphate (ATP)-sensitive potas- sium efflux channels in pancreatic beta-cell membranes, raising intra- cellular potassium concentrations causing depolarization. Calcium

https://doi.org/10.1016/j.ajem.2022.03.023 0735-6757/(C) 2022 Published by Elsevier Inc.

influx is thereby induced due to the depolarization, promoting insulin release by exocytosis [8]. Sulfonylureas are more likely than biguanides to lead to weight gain and hypoglycemia [9]. Poor nutrition, excessive alcohol consumption, and renal and hepatic disease are risk factors for developing hypoglycemia caused by sulfonylureas [8].

A growing body of studies have reported wide ranges of adverse clinical effects associated with these two classes of anti-diabetic medications. The clinical diagnosis of sulfonylurea and biguanide toxicity is dependent on medical history and laboratory studies. Nevertheless, since some effects of these agents are nonspecific, their toxicity may be difficult to diagnose. Given that there may be some overlap in the clinical manifestations of biguanides and sulfo- nylurea poisoning, distinguishing between the two can be challeng- ing. The primary aim of the present research was to determine those clinical manifestations that might allow for a differential diagnostic strategy to discern which of these poisonings might be present using a broad cohort from TESS’s National Poison Data System (NPDS).

1. Material and methods
   1. Study population and definition of terms

This is a retrospective study for which we included all single ex- posures to biguanides or sulfonylureas between 1 January 2012 and 31 December 2017, not meeting exclusion criteria, from the NPDS. The NPDS is a database that provides all of the substance ex- posure reports from poison control centers around the US. Irrelevant medical outcomes, duplicate data, or missing demographic data were all exclusion criteria. Variables obtained included sex, age, the reason for exposure, medical history, outcomes, signs, and symp- toms related to the exposure. The NPDS categorizes medical out- comes as minor, moderate, or major [10]. Reasons for exposure

were also classified as unintentional, intentional, and other [10]. We used the worst/highest biological parameters to define the ob- served complications and outcomes in each record.

Per standard procedures to determine outcomes, regional poison center follow-up was conducted unless the first call occured long enough after the exposure that there was rational certainty that the clinical effect(s) would not get worse. Patients with signs or symptoms were followed to the point where they were resolving unless they were predicted to be permanent or long-term.

• 1. Clinical features definition suggested by NPDS

The full definitions for clinical effects were those in the NPDS coding manual version 3.1 [11] as presented in Table 1.

• 1. Statistical analysis

Descriptive statistics were reported as mean and standard devia- tion for continuous variables and percentages (absolute numbers) for categorical variables. Independent sample t-tests and One-way ANOVA were performed to compare continuous variables and the Pearson chi-square test, or Fisher exact test (if >20% of expected cell counts are less than 5), for the categorical variables. Finally, lo- gistic regression analysis was used to identify risk factors associated with the biguanide and sulfonylurea poisoning, and the results are presented by multivariate-adjusted odds ratios (ORs) with 95% con- fidence intervals (CIs). Analyses were performed using SPSS version 26 (IBM, Armonk, NY). Variable importance was done using the varImp function in the caret R package. All variables with p-values

<0.2 in univariate logistic regression were used for logistic regres- sions. All reported P-values are two-sided, and P < 0.05 was consid- ered statistically significant.

Table 1

Full definitions for Clinical features suggested by NPDS Clinical features Definitions

The patient showed some symptoms due to the exposure, but they were minimally annoying to the patient. The symptoms usually resolve

Minor effect

Moderate effect

quickly and often include skin or mucous membrane manifestations. The patient has returned to a pre-exposure state and has no remaining disability or deformity.

The patient showed symptoms due to exposure that are more pronounced, prolonged, or more systemic than minor effects. Usually, some treatment is or would have been indicated. However, the symptoms are not life-threatening, and the patient has returned to a pre-exposure state without any disability or deformity.

Major effect The patient has been shown life-threatening symptoms which resulted in significant disability or disfigurement as a result of the exposure

Other LFT abnormality Abnormalities in GGT (? glutamyltransferase), ammonia, alkaline phosphatase, bromsulphalein excretion, 5? nucleotidase, LDH (unless -of nonhepatic origin), albumin or other.

Agitated/irritable Hyperactivity, excessive restlessness, combativeness, fussiness, tremor, nervousness, or anxiety.

Coma All levels of central nervous system (CNS) depression in which the patient cannot be awakened with a stimulus. Confusion Disturbed orientation or inability to think with normal speed and clarity.

Dizziness/vertigo A debilitating sensation in which the patient feels that he/his surroundings are constantly moving. Include lightheadedness and other nonvertiginous complaints of dizziness.

Drowsiness/lethargy Fatigue or sleep or minor levels of CNS depression through which the patient can wake up with a stimulus. Hypotension Systolic Blood pressure less than 90 mmHg or more than 15 mmHg less than the patient’s normal systolic BP Hypertension Transient or persistent elevation of arterial BP. Diastolic BP > 90 mmHg in adults.

Tachycardia Heart rate more than 100 beats/min in adults.

Bradycardia Heart rate less than 60 beats/ min in adults.

Asystole: Cardiac arrest; absence of cardiac contractions.

Conduction disturbance Prolonged electrocardiographic intervals or any degree of heart block. ECG change (other) Other ECG changes not listed (ST-segment elevation, inverted T-waves, etc.) Creatinine increased: Creatinine elevation of more than 1.5 mg/dL or 133 umol/L.

Oliguria/anuria The production of abnormally low volume of urine or no urine production

Renal failure Acute and chronic renal failure that has resulted in significant azotemia and loss of renal function. Hyperventilation/tachypnea Tachypnea at rest; arterial blood gas diagnosis is usually made.

Dyspnea Labored or difficult breathing; shortness of breath.

Acidosis Acid accumulation or decreased alkaline reserve; diagnosis is usually made using an ABG

Electrolyte abnormality imbalance in any of the electrolytes, including sodium, potassium, calcium, bicarbonate, chloride, magnesium, and phosphate Hypoglycemia Blood glucose deficiency, glucose concentrations lower than 70 mg/dL or 3.9 mmol/L.

ADR to treatment Patient experiences an adverse reaction (ADR) to a treatment used for the patient’s overdose

Rhabdomyolysis creatine kinase more than 500 IU/L and/or the presence of myoglobinuria

1. Diagnostic characteristics“>Results
   1. Baseline characteristics

We identified 6183 patients who met our inclusion criteria, of whom 3336 and 2847 were diagnosed with metformin and sulfonylurea expo- sure, respectively. Table 2 presents the subjects’ baseline characteristics. The mean age of patients with metformin and sulfonylurea exposure was 39 +- 29 and 29 +- 30, respectively. Among patients with metformin exposure, 55% and 36% were from intentional and unintentional expo- sures, respectively. Sixty percent of patients with metformin exposure developed minor effects. Abdominal pain, nausea, vomiting, diarrhea, and acidosis were observed among 13.5%, 36%, 34.5%, 16.5%, and 25.3% respectively. Among patients exposed to sulfonylureas, the reason for exposures of 15% and 71% were intentional and unintentional exposure, respectively. Seventy-seven percent of patients developed moderate

effects. Nausea, abdominal pain, vomiting, diarrhea, and acidosis were observed among 2.9%, 0.6%, 2.7%, 0.3%, and 0.8% respectively.

• 1. Diagnostic characteristics

The result of multiple logistic regression for comparing the clinical and laboratory characteristics to distinguish the diagnosis of sulfonyl- urea and metformin poisoning is presented in Table 3. Our model showed no significant association between sulfonylurea exposure and gender [OR = 0.87, 95% CI: 0.65-1.05] compared to metformin expo- sures. Patients with intentional exposure were 74% [OR = 0.26, 95% CI: 0.17-0.41] less likely to be exposed to sulfonylureas than metformin. In terms of gastrointestinal manifestations, those with diarrhea and ab- dominal pain were 99.4% [OR = 0.06, 95% CI: 0.03-0.13] and 87% [OR = 0.13, 95% CI: 0.07-0.25] less likely to be poisoned by sulfonylureas com- pared to metformin. Acidosis was associated with a 99.2% [OR = 0.02,

Table 2

Baseline characteristics of patients

Variable	Biguanide		Sulfonylurea	p-value
	N (%)		N (%)
Sociodemographic Age (mean +- SD)	39 +- 29		29 +- 30	<0.001
Gender (female)	2209 (66.2)		1497 (52.6)	<0.001
Intentional	1828 (54.8)		418 (14.7)	<0.001
Reason for exposure Unintentional	1189 (35.6)		2010 (70.6)	<0.001
Other	319 (5.1)		419 (6.8)	0.01
Major effect	213 (6.3)		210 (7.3)	0.07
Medical outcome Moderate effect	1079 (31.9)		2187 (76.6)	<0.001
Minor effect	2044 (60.3)		450 (15.8)	<0.001
AST, ALT, and gamma- ?-glutamyl transpeptidase (GGT) levels;>100 and <= 1000	17 (0.5)		1 (0.04)	<0.001
Abdominal Pain	450 (13.5)		17 (0.6)	<0.001
Nausea	1202 (36.0)		83 (2.9)	<0.001
Gastrointestinal findings Vomiting	1150 (34.5)		76 (2.7)	<0.001
LFT abnormality - other	10 (0.3)		1 (0.04)	0.01
Hematemesis	7 (0.2)		1 (0.04)	0.04
Diarrhea	551 (16.5)		9 (0.3)	<0.001
Anorexia	10 (0.3)		1 (0.04)	0.03
Agitation	39 (1.2)		49 (1.7)	0.08
Confusion	92 (2.8)		149 (5.2)	<0.001
Dizziness/vertigo	138 (4.1)		148 (5.2)	0.048
Seizure (single)	9 (0.3)		53 (1.9)	<0.001
Neurological findings Seizures (multi/discrete)	5 (0.1)		12 (0.4)	0.04
Tremor	12 (0.4)		58 (2.0)	<0.001
Slurred speech	16 (0.5)		24 (0.8)	0.07
Headache	104 (3.1)		26 (0.9)	<0.001
Drowsiness/lethargy	264 (7.9)		322 (11.3)	<0.001
Coma	47 (1.4)		81 (2.8)	<0.001
Tachycardia	314 (9.4)		70 (2.5)	<0.001
Asystole	19 (0.6)		2 (0.1)	0.001
Hypertension	159 (4.8)		32 (1.1)	<0.001
Hypotension	54 (1.6)		17 (0.6)	<0.001
ECG change (other/N O S)	9 (0.3)		3 (0.1)	0.16
Cardiovascular findings Ventricular tachycardia/ventricular fibrillation	2 (0.1)		0 (0.0)	0.5
Chest pain (including non-cardiac)	18 (0.5)		2 (0.1)	0.001
Respiratory arrest	13 (0.4)		5 (0.2)	0.11
Respiratory depression	23 (0.7)		9 (0.3)	0.05
Conduction disturbance	18 (0.5)		4 (0.1)	0.006
Cardiac arrest	30 (0.9)		4 (0.1)	<0.001
Coagulation findings Coagulopathy (other)	7 (0.2)		1 (0.04)	0.07
Cough/choke	11 (0.3)		3 (0.1)	0.06
Respiratory findings Hyperventilation/tachypnea	90 (2.7)		8 (0.3)	<0.001
Dyspnea	21 (0.6)		7 (0.2)	0.04
Oliguria/anuria	29 (0.9)		1 (0.0)	<0.001
Renal findings Renal failure	79 (2.4)		6 (0.2)	<0.001
Creatinine increased	233 (7.0)		12 (0.4)	<0.001
Dermatology findings Pallor	4 (0.1)		10 (0.4)	0.06
Endocrinology findings Hypoglycemia	153 (4.6)		2493 (87.6)	<0.001
Musculoskeletal findings Elevated Creatine phosphokinase	16 (0.5)		4 (0.1)	0.02
Rhabdomyolysis	7 (0.2)		1 (0.04)	0.04
Laboratory findings Acidosis	843 (25.3)		23 (0.8)	<0.001
Electrolyte abnormality	216 (6.5)		48 (1.7)	<0.001
Miscellaneous findings ADR to treatment	42 (1.3)		22 (0.8)	0.08
Diaphoresis	31 (0.9)		163 (5.7)	<0.001

AST: Aspartate transaminase, ALT: Alanine transaminase, LFT: Liver function test, ADR: Adverse drug reaction, ECG: Electrocardiography, NOS: Not Otherwise Specified.

Multiple logistics regression analysis of biguanide versus sulfonylurea poisoning clinical characteristics. All biguanide cases were due to metformin

Variable	OR (95% CI)	P-value
Sociodemographic Age	0.99 (0.98-0.99)	<0.001
Gender (female)	0.87 (0.65-1.05)	0.11
Intentional	0.26 (0.17-0.41)	<0.001
Reason of exposure Unintentional	0.85 (0.56-1.30)	0.27
Other	1.26 (0.83-1.91)	0.48
Major effect	0.76 (0.06-10.16)	0.68
Medical outcome Minor effect	1.81 (0.11-30.78)	0.95
Moderate effect	1.68 (0.09-29.46)	0.72
AST, ALT, and gamma-GT;>100 and <= 1000	0.42 (0.03-6.28)	0.52
Abdominal Pain	0.13 (0.07-0.25)	<0.001
Nausea	0.21 (0.15-0.29)	<0.001
Gastrointestinal findings Vomiting	0.24 (0.18-0.35)	<0.001
LFT abnormality - other	0.06 (0.001-3.61)	0.18
Hematemesis	2.42 (0.15-38.98)	0.52
Diarrhea	0.06 (0.03-0.13)	<0.001
Anorexia	0.07 (0.001-3.26)	0.17
Agitation	2.38 (1.03-5.55)	0.04
Confusion	1.18 (0.64-2.20)	0.63
Dizziness/vertigo	1.99 (1.36-2.92)	<0.001
Seizure (single)	3.23 (0.63-16.76)	0.16
Neurological findings Seizures (multi/discrete)	0.73 (0.04-15.35)	0.82
Tremor	4.31 (1.79-10.40)	0.001
Slurred speech	1.52 (0.49-4.63)	0.52
Headache	0.93 (0.51-1.72)	0.84
Drowsiness/lethargy	1.62 (1.13-2.30)	0.007
Coma	1.64 (0.58-4.68)	0.36
Tachycardia	0.99 (0.61-1.63)	0.96
Asystole	2.13 (0.05-84.42)	0.68
Hypertension	0.43 (0.09-1.95)	0.83
Hypotension	0.74 (0.29-1.85)	0.52
ECG change (other/N O S)	1.96 (0.09-1.95)	0.66
Cardiovascular findings Ventricular tachycardia/ventricular fibrillation	0.99 (0.61-1.63)	0.99
Chest pain (including non-cardiac)	0.29 (0.04-2.31)	0.24
Respiratory arrest	1.13 (0.22-58.33)	0.95
Respiratory depression	1.42 (0.20-9.87)	0.72
Conduction disturbance	1.40 (0.19-10.23)	0.74
Cardiac arrest	0.35 (0.02-7.81)	0.51
Coagulation findings Coagulopathy (other)	12.24 (0.52-290.3)	0.12
Cough/choke	0.45 (0.11-1.81)	0.26
Respiratory findings Hyperventilation/tachypnea	0.43 (0.09-1.95)	0.27
Dyspnea	4.13 (0.92-18.62)	0.07
Oliguria/anuria	0.88 (0.06-13.46)	0.93
Renal findings Renal failure	0.91 (0.21-3.81)	0.89
Creatinine increased	0.19 (0.06-0.63)	0.0.007
Dermatology findings Pallor	4.21 (0.41-42.44)	0.23
Endocrinology findings Hypoglycemia	72.5 (51.5-101.96)	<0.001
Musculoskeletal findings Elevated CK	0.98 (0.07-14.35)	0.98
Rhabdomyolysis	1.03 (0.13-80.60)	0.99
Laboratory findings Acidosis	0.02 (0.01-0.05)	<0.001
Electrolyte abnormality	0.49 (0.24-1.03)	0.06
Miscellaneous findings ADR to treatment	1.50 (0.61-3.74)	0.4
Diaphoresis	7.27 (4.05-13.05)	<0.001

AST: Aspartate transaminase, ALT: Alanine transaminase, LFT: Liver function test, ADR: Adverse drug reaction, ECG: Electrocardiography, NOS: Not Otherwise Specified, CK: Creatine Phosphokinase.

95% CI: 0.01-0.05] decreased risk of sulfonylureas exposure compared to metformin. In the presence of diaphoresis and hypoglycemia, it was

7.27 [OR = 7.27, 95% CI: 4.05-13.05] and 72.5 [OR = 72.5, 95% CI:

51.5-101.96] times more likely to be exposed to sulfonylureas com- pared to metformin. As shown in Table 4, even though the primary

reason of exposure of individuals younger than 5 years old was uninten- tional, those who were older than 5 years old commonly report the in- tentional exposure. The characteristics of patients based on reason of exposure is also shown in Table 5. The rank order of the important var- iables of our study is presented in Fig. 1.

Table 4

Characteristics of exposure reason based on different age groups

<0.001

Reason	Age group							P-value
	0-5		5-13		13-18		>18
	N (%)		N (%)		N (%)		N (%)
Intentional	0 (0.0)		129 (48.1)		488 (85.3)		1629 (41.7)
Unintentional	1430 (99.3)		135 (50.4)		77 (13.5)		1557 (39.9)
Other	10 (0.7)		4 (1.5)		7 (1.2)		717 (18.4)
Total	1440 (100.0)		268 (100.0)		572 (100.0)		3903 (100.0)

1. Discussion

The current study included characteristics of exposure with anti- hyperglycemic agents. Our findings indicated that hypoglycemia, acido- sis, nausea, vomiting, diarrhea, diaphoresis, intentional exposure, ab- dominal pain, dizziness, age, and tremor are the most crucial factors for distinguishing these two agents.

In our study, approximately 70% of the exposures with sulfonylureas were unintentional. The reason might be due to exploratory behaviors of children. A 5-year retrospective study of children with exposure to

Table 5

Characteristics of patients based on the reason of exposure

Variable	Intentional N (%)	Unintentional N (%)	Other	p-value
Sociodemographic Age (mean +- SD)	35 +- 18	31 +- 26	61 +- 18	<0.001
Gender (female)	1489 (66.3)	1382 (43.2)	338 (45.8)	<0.001
Major effect	175 (7.8)	161 (5.0)	142 (19.2)
Medical outcome Moderate effect	1089 (48.5)	1725 (53.9)	430 (58.3)	<0.001
Minor effect	982 (43.7)	1313 (41.0)	166 (22.5)
AST, ALT, and gamma- ?-glutamyl transpeptidase (GGT) levels;>100 and <= 1000	7 (0.3)	9 (1.2)	2 (0.1)	<0.001
Abdominal Pain	246 (11.0)	181 (5.7)	40 (5.4)	<0.001
Nausea	651 (29.0)	542 (16.9)	77 (10.4)	<0.001
Gastrointestinal findings Vomiting	772 (34.4)	367 (11.5)	68 (9.2)	<0.001
LFT abnormality - other	6 (0.3)	2 (0.1)	3 (0.4)	0.03
Hematemesis	3 (0.1)	2 (0.1)	3 (0.4)	0.07
Diarrhea	232 (10.3)	247 (8.6)	47 (6.4)	0.002
Anorexia	0 (0.0)	7 (0.2)	4 (0.5)	0.03
Agitation	44 (2.0)	33 (1.0)	11 (1.5)	0.08
Confusion	68 (3.0)	63 (2.0)	109 (14.8)	<0.001
Dizziness/vertigo	61 (2.7)	170 (5.3)	52 (7.0)	<0.001
Seizure (single)	13 (0.6)	39 (1.2)	10 (1.4)	0.03
Neurological findings Seizures (multi/discrete)	4 (0.2)	8 (0.3)	4 (0.5)	0.4
Tremor	12 (0.5)	46 (1.4)	11 (1.5)	0.002
Slurred speech	12 (0.5)	12 (0.4)	16 (2.2)	0.07
Headache	41 (1.8)	75 (2.3)	11 (1.5)	<0.001
Drowsiness/lethargy	227 (10.1)	275 (8.6)	81 (11.0)	<0.001
Coma	49 (2.2)	38 (1.2)	40 (5.4)	<0.001
Tachycardia	280 (12.5)	55 (1.7)	43 (5.8)	<0.001
Asystole	9 (0.4)	2 (0.1)	10 (1.4)	0.001
Hypertension	47 (2.1)	13 (0.4)	11 (1.5)	<0.001
Hypotension	102 (4.5)	21 (0.7)	66 (8.9)	<0.001
ECG change (other/N O S)	6 (0.3)	4 (0.1)	2 (0.3)	0.6
Cardiovascular findings Ventricular tachycardia/ventricular fibrillation	1 (0.04)	1 (0.03)	0 (0.0)	0.99
Chest pain (including non-cardiac)	9 (0.4)	9 (0.3)	2 (0.3)	0.7
Respiratory arrest	6 (0.3)	0 (0.0)	12 (1.6)	<0.001
Respiratory depression	14 (0.6)	3 (0.1)	15 (2.0)	<0.001
Conduction disturbance	15 (0.7)	3 (0.1)	4 (0.5)	0.001
Cardiac arrest	12 (0.5)	3 (0.1)	19 (2.6)	<0.001
Coagulation findings Coagulopathy (other)	1 (0.04)	0 (0.0)	7 (0.9)	<0.001
Cough/choke	1 (0.04)	10 (0.3)	3 (0.4)	0.03
Respiratory findings Hyperventilation/tachypnea	71 (3.2)	10 (0.3)	16 (2.2)	<0.001
Dyspnea	8 (0.4)	2 (0.1)	18 (2.4)	<0.001
Oliguria/anuria	12 (0.5)	1 (0.03)	17 (2.3)	<0.001
Renal findings Renal failure	28 (1.2)	9 (0.3)	48 (6.5)	<0.001
Creatinine increased	149 (6.6)	23 (0.7)	72 (9.8)	<0.001
Dermatology findings Pallor	5 (0.2)	8 (0.3)	1 (0.1)	0.8
Endocrinology findings Hypoglycemia	427 (19.0)	179 (56.1)	406 (55.0)	<0.001
Musculoskeletal findings Elevated creatine phosphokinase	13 (0.6)	1 (0.03)	6 (0.8)	<0.001
Rhabdomyolysis	6 (0.3)	0 (0.0)	2 (0.3)	0.004
Laboratory findings Acidosis	598 (26.6)	102 (3.2)	163 (22.1)	<0.001
Electrolyte abnormality	164 (7.3)	35 (1.1)	65 (8.8)	<0.001
Miscellaneous findings ADR to treatment	31 (1.4)	23 (0.7)	10 (1.4)	0.03
Diaphoresis	46 (2.0)	121 (3.8)	27 (3.7)	0.001

sulfonylureas showed that 86% of the patients were younger than 6 years old [12].

Also, as expected, we found that creatinine increase, and acidosis are less common in sulfonylurea than metformin exposure. This finding is consistent with what is already well-known. Acidosis is the most seri- ous adverse effect of metformin toxicity and correlates with poisoning severity [13].

Metformin inhibits mitochondrial complex I of electron transport chain, causing inhibition of proton entry into the mitochondria resulting in a decrease in ATP synthesis, increasing adenosine monophosphate, the production of Reactive oxygen species, and subsequently a metabolic acidosis. Furthermore, metformin inhibits mitochondrial glycerophos- phate dehydrogenase, blocking the conversion of glycerol-3-phosphate to dihydroxyacetone phosphate and inhibiting gluconeogenesis from glycerol [14]. Mitochondrial dysfunction induced by metformin can lead to tubular ischemia potentially worsening the metabolic acidosis [15].

A meta-analysis of 347 comparative trials and cohort studies re- ported that metformin users do not have an increased risk of acidosis compared to other individuals receiving other anti-hyperglycemic treatments. [16]. However, our study of patients where consultation

with a poison control center was sought, by either the patient, their family, or a health care provider, clearly demonstrated that the OR for acidosis a sulfonylurea compared to metformin was 0.02. Because it is known that sulfonylureas do not cause metabolic acidosis, our data demonstrates that metabolic acidosis is major reason why patients with metformin toxicity require medical care.

Our findings demonstrate that abdominal pain, diarrhea, nausea, and vomiting are more common following metformin than sulfonylurea exposure. A growing body of studies has reported gastrointestinal ef- fects, including nausea, vomiting, diarrhea, abdominal pain, and acidosis following metformin overdose [17-20]. The mechanism by which met- formin overdose results in these Gastrointestinal complications is un- clear [21]. However, it might be due to increased Glucagon-like Peptide 1, intestinal glucose turnover elevation, and changing the gut microbiotic flora [22]. It has also been reported that metformin over- dose changes the bile acid turnover by decreasing the reabsorption of bile salt in the ileum and increasing the concentrations of bile salt in the colon [11]. Heaney et al. reported a 29-year-old man who suffers from hypoglycemia, nausea, abdominal pain, increased creatinine, and acidosis following metformin poisoning [23]. Likewise, Teale et al.

Fig. 1. The rank order of the important variables.

reported three metformin overdose cases presented to the emergency department with metabolic acidosis, abdominal pain, and vomiting [24]. However, these symptoms have also been described in sulfonyl- urea poisoning [25].

Our findings showed that agitation, dizziness, or vertigo, tremor, drowsiness or lethargy, diaphoresis, and hypoglycemia are more com- mon in sulfonylurea poisoning. Unlike what is seen with sulfonylureas, hypoglycemia is reported to be an uncommon occurrence in the setting of metformin poisoning [26,27] [28]. This finding is consistent with our data that shows an OR of 72.5 for hypoglycemia following sulfonylureas poisoning. Hypoglycemia in metformin toxicity might happened in se- vere cases [29], however, while metformin increase insulin sensitivity, it does not increase insulin release. However, hypoglycemia following sulfonylurea exposure is more common due to neuroglycopenic effects

and counterregulatory hormonal response [7]. Sulfonylureas increase insulin release from Pancreatic beta cells by acting on ATP-sensitive po- tassium channels leading to hypoglycemia [30]. As a result of hypogly- cemia induced by chronic exposure to sulfonylureas, intracellular ATP of the central nervous system decreased, leading to clinical manifesta- tions including dizziness or vertigo, tremor, agitation, and drowsiness or lethargy. On the other hand, hormone released, such as epinephrine, norepinephrine, and cortisol, results in diaphoresis [7].

Neurological findings might accompany Sulfonylurea-induced hy- poglycemia. For example, Gunaratne et al. reported a 56 year old man with new-onset hypoglycemia, lethargy, and confusion following unintentional sulfonylurea exposure [31]. Moreover, Spiller et al. reported a lethargic 6-year-old girl with agitation and hypoglycemia after glyburide ingestion [32].

Prior studies documenting clinical manifestations of metformin and sulfonylurea poisoning have been comprised of a small numbers of pa- tients [33,34]. We leveraged a very large sample size that allowed us to determine the clinical manifestations that help differentiate the diagnosis of metformin from sulfonylurea toxicity. However, some limitations of our study should be noted. First, the data collection of the National Poison Data System was limited. NPDS data does not represent the overall inci- dence of substance exposure, or of clinical syndromes engendered by these exposures, in the US since it only reflects calls made to poison con- trol centers. poison centers do not generally confirm the information ob- tained. Therefore, not all exposures, even if correctly reported, represent true poisoning episodes. Second, this study only evaluated characteristics of single-agent exposure to anti-hyperglycemic agents. Third, since case records are dependent on self-report, it is very difficult for AAPCC to val- idate exposures as poisoning.

1. Conclusion

Although the results of this study do not change the clinical manage- ment of these two poisons, they help us understand the clinical charac- teristics of these poisoning. Sulfonylurea exposure is commonly seen via unintentional exposure, while metformin exposure is frequently seen via intentional exposure. Sulfonylurea toxicity is more likely to cause agitation, dizziness or vertigo, tremor, diaphoresis, and hypoglycemia, while metformin exposure induces abdominal pain, acidosis, diarrhea, nausea, vomiting, and elevated creatinine.

Disclaimers

The American Association of Poison Control Center (AAPC) main- tains the National Poison Data system (NPDS), which houses de- identified case records of all self-reported information collected from callers during exposure management and poison information calls man- aged by the country’s poison control centers (PCCs). NPDS data do not reflect the entire universe of exposures to a particular substance as ad- ditional exposures may be underreported to PCCs; accordingly, NPDS data should not necessarily represent a poisoning or overdose, and AAPCC cannot completely verify the accuracy of every report. Finding based on NPDS data do not necessarily reflect the opinion of AAPCC.

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Data availability

The data of this study is available upon any request.

Authors’ contribution

OM conceptualized and designed the study. All of the authors con- tributed in drafting and writing.

CRediT authorship contribution statement

Omid Mehrpour: Writing - review & editing, Validation, Supervi- sion, Data curation, Conceptualization. Farhad Saeedi: Writing - origi- nal draft. Christopher Hoyte: Writing - review & editing. Ali Hadianfar: Methodology, Formal analysis. Samaneh Nakhaee: Writing - review & editing. Jeffrey Brent: Writing - review & editing.

Declaration of Competing Interest

Authors declare no conflict of interest.

Acknowledgment

The authors want to thank National Poison Data System for provid- ing the data of this study.

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