Clopidogrel as a Distinctive Cause of Insulin Autoimmune Syndrome: A Systematic Case Review

Figures & data

Figure 1 Flowchart of case identification.

Notes: *Cases from literature databases, FAERS, and the index case were combined into one clopidogrel-induced IAS (CIAS) series. After combination, cases with the same age, sex, race, and report time were removed to avoid possible duplication. PRISMA figure adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372. Creative Commons.

Table 1 Reported Demography of CIAS and Comparison to All IAS

	CIAS (n=51)	All IAS (n=287)	p-value
Age (years)	74.8±8.6	53.0±20.0	<0.001
Sex (male/female/not reported)	92.2/7.8/0	43.5/55.8/0.7	<0.001
Race (East Asian/non-East Asian)	49.0/51.0	50.5/49.5	0.9456

Notes: The data of age are shown as mean ± SD; the data of sex and race were shown as percentage; significant p‐values (p<0.05) are indicated in bold; in the difference tests of sex, the “not reported” category was excluded.

Abbreviations: IAS, insulin autoimmune syndrome; CIAS, clopidogrel-induced IAS.

Table 2 Reported HLA Alleles of CIAS and Comparison to IAS from Various Causes

	CIAS				IAS from Various Causes				p-value CIAS vs IAS
	Total (n=9)	EA (n=6)	NEA (n=3)	p-value: EA vs NEA	Total (n=98)	EA (n=52)	NEA (n=46)	p-value: EA vs NEA	EA	NEA
DRB1*0403	4	3	1	1.000	20	3	17	<0.001	0.046	1.000
DRB1*0404	2	1	1	0.427	10	2	8	0.027	0.404	0.463
DRB1*0406	2	2	0	1.000	40	35	5	<0.001	0.032	1.000
DQB1*0302	2	2	0	1.000	13	6	7	0.592	0.605	1.000
Other	7	5	2	1.000	47	24	23	0.704	0.761	0.640

Notes: Significant p‐values (p<0.05) are indicated in bold; p-values: EA vs NEA of IAS from various causes were extracted from the reference systematic case review.

Abbreviations: IAS, insulin autoimmune syndrome; CIAS, clopidogrel-induced IAS; EA, East Asian; NEA, non‐East Asian.

Table 3 Reported Clinical Onset and Symptoms of CIAS and Comparison to All IAS

	CIAS	All IAS	p-value
Type of hypoglycemia	n=11	n=124
Fasting hypoglycemia	9	79	0.153
Postprandial hypoglycemia	3	83	0.087
Exercise‐induced hypoglycemia	1	7	0.454
Symptoms	n=11	n=141
Sweating	6	81	0.805
Palpitations/ tachycardia	2	47	0.753
Loss of consciousness	1	38	0.491
Fatigue	2	29	1.000
Tremor	3	36	0.728
Dizziness	3	27	0.427
Polyphagia	0	26	0.395
Confusion	5	19	0.013
Coma	1	10	0.525
Weight loss	0	6	1.000
Blurred vision	0	6	1.000
Somnolence	0	5	1.000
Polydipsia	0	4	1.000
Seizure	3	Not mentioned	NA

Note: Significant p‐values (p<0.05) are indicated in bold.

Abbreviations: IAS, insulin autoimmune syndrome; CIAS, clopidogrel-induced IAS.

Table 4 Reported GC/Immunotherapy Use in the Treatment of Clopidogrel-Induced IAS

	GC/Immunotherapy (n=9)	No GC/Immunotherapy (n=4)	p-value
Age (years)	71.7±10.6	76.0±8.5	0.457
Sex (male/female)	77.8/22.2	100.0/0	1.000
Race (EA/NEA)	33.3/66.7	100.0/0	0.070
Recovery time (months)	6.0±5.8	5.0±1.6	0.683

Notes: The data of age and recovery time are shown as mean ± SD; the data of sex and race were shown as percentage; in the calculation of average recovery time, two cases were removed due to vague description or extremum number.

Abbreviations: GC, glucocorticoids; EA, East Asian; NEA, non‐East Asian.

Table 5 Reports Related to IAS or Autoimmune Hypoglycemia of Antiplatelet Drugs

Drug	PubMed Search Result	Embase Search Result	Reports Related to IAS/Hypoglycemia
Clopidogrel	7	21	12
Aspirin	158	7	0
Ticagrelor	0	1	0
Prasugrel	0	0	0
Dipyridamole	0	1	0
Tirofiban	0	1	0
Rivaroxaban	0	3	0