Increased Frequency of Severe Hypoglycemia with the Modified-Release Gliclazide Compared to Glimepiride in Diabetic Older Adults; Propensity Score-Adjusted Analysis

Figures & data

Figure 1 Study flow diagram.

Notes: ^aThose patients had a gliclazide MR or glimepiride prescription but had no dispensing history. This may be because they were visitors to the country or followed up in private hospitals or other reasons. We excluded them because we doubt they received any of the study medications and had incomplete files.

Table 1 Baseline Characteristics of the Study Groups

	Total	Glimepiride	Gliclazide	p-value
ED admission count	N=2320	N=534	N=1786
Age, years; mean (SD)	73.4 (6.8)	73.6 (7.1)	73.4 (6.8)	0.56
Age groups^a				0.12
65–74	1440 (62.1%)	318 (59.6%)	1122 (62.8%)
75–84	700 (30.2%)	164 (30.7%)	536 (30.0%)
≥ 85	180 (7.8%)	52 (9.7%)	128 (7.2%)
Gender, Male	1153 (49.7%)	300 (56.2%)	853 (47.8%)	<0.001
BMI, Kg/m^2; mean (SD)	31.2 (7.4)	32.1 (8.8)	30.9 (7.0)	0.002
BMI Stages^a				<0.001
Below 18.5	12 (0.5%)	8 (1.5%)	4 (0.2%)
18.5–24.9	378 (16.3%)	70 (13.1%)	308 (17.2%)
25.0–29.9	743 (32.0%)	179 (33.5%)	564 (31.6%)
30.0–34.9	692 (29.8%)	161 (30.1%)	531 (29.7%)
35.0–39.9	307 (13.2%)	57 (10.7%)	250 (14.0%)
Above 40	178 (7.7%)	53 (9.9%)	125 (7.0%)
Missing	10 (0.4%)	6 (1.1%)	4 (0.2%)
eGFR, mL/min/1.73m2; mean (SD)	69.7 (25.4)	67.9 (25.9)	70.3 (25.2)	0.057
CKD Stages^a				<0.001
G1	593 (25.6%)	120 (22.5%)	473 (26.5%)
G2	985 (42.5%)	228 (42.7%)	757 (42.4%)
G3a	306 (13.2%)	47 (8.8%)	259 (14.5%)
G3b	220 (9.5%)	94 (17.6%)	126 (7.1%)
G4	135 (5.8%)	43 (8.1%)	92 (5.2%)
G5	79 (3.4%)	2 (0.4%)	77 (4.3%)
Missing	2 (0.1%)	0 (0.0%)	2 (0.1%)
Last HbA1c %, mean (SD)	7.6 (1.5)	7.7 (1.5)	7.5 (1.5)	0.005
Diabetes control^a				<0.001
Tight control, <6.5%	533 (23.0%)	93 (17.4%)	440 (24.6%)
Near target, 6.5–8.5%	1241 (53.5%)	285 (53.4%)	956 (53.5%)
Uncontrolled, >8.5%	506 (21.8%)	148 (27.7%)	358 (20.0%)
Missing	40 (1.7%)	8 (1.5%)	32 (1.8%)
Antidiabetic medications
Insulin	998 (43.0%)	269 (50.4%)	729 (40.8%)	<0.001
Insulin regimen				<0.001
No insulin	1322 (57.0%)	265 (49.6%)	1057 (59.2%)
Basal only	501 (21.6%)	150 (28.1%)	351 (19.7%)
Bolus only	6 (0.3%)	2 (0.4%)	4 (0.2%)
Basal bolus	281 (12.1%)	62 (11.6%)	219 (12.3%)
Mixed insulin	210 (9.1%)	55 (10.3%)	155 (8.7%)
Biguanides	1941 (83.7%)	434 (81.3%)	1507 (84.4%)	0.089
Alpha-glucosidase inhibitors	16 (0.7%)	5 (0.9%)	11 (0.6%)	0.43
Thiazolidinediones	388 (16.7%)	107 (20.0%)	281 (15.7%)	0.019
Glinides	48 (2.1%)	36 (6.7%)	12 (0.7%)	<0.001
DPP4Is	1626 (70.1%)	375 (70.2%)	1251 (70.0%)	0.94
GLP1 Agonists	194 (8.4%)	61 (11.4%)	133 (7.4%)	0.004
SGLT2 Inhibitors	305 (13.1%)	90 (16.9%)	215 (12.0%)	0.004
Chronic Medications
Calcium channel blockers	1309 (56.4%)	280 (52.4%)	1029 (57.6%)	0.034
ACEIs or ARBs	1791 (77.2%)	386 (72.3%)	1405 (78.7%)	0.002
Beta Blockers	1206 (52.0%)	241 (45.1%)	965 (54.0%)	<0.001
Statin	2056 (88.6%)	444 (83.1%)	1612 (90.3%)	<0.001
Aspirin	1572 (67.8%)	348 (65.2%)	1224 (68.5%)	0.14
SU. Interacting Medications
Fluconazole	196 (8.4%)	67 (12.5%)	129 (7.2%)	<0.001
Quinolones	745 (32.1%)	168 (31.5%)	577 (32.3%)	0.71
Sulfa Drugs	129 (5.6%)	47 (8.8%)	82 (4.6%)	<0.001
Type I DM	57 (2.5%)	2 (0.4%)	55 (3.1%)	<0.001
Comorbidities
Depression	248 (10.7%)	34 (6.4%)	214 (12.0%)	<0.001
Hypothyroidism	441 (19.0%)	125 (23.4%)	316 (17.7%)	0.003
Cognitive impairment	437 (18.8%)	92 (17.2%)	345 (19.3%)	0.28
Heart Failure	640 (27.6%)	126 (23.6%)	514 (28.8%)	0.019
CAD	902 (38.9%)	184 (34.5%)	718 (40.2%)	0.017
Diabetes complications
Neuropathy	865 (37.3%)	151 (28.3%)	714 (40.0%)	<0.001
Retinopathy	518 (22.3%)	108 (20.2%)	410 (23.0%)	0.18
PAD	121 (5.2%)	17 (3.2%)	104 (5.8%)	0.016
Diabetic foot	174 (7.5%)	32 (6.0%)	142 (8.0%)	0.13

Notes: Count and percentage are mentioned unless the mean and SD are specified in the most left column. ^aCategorized variables that are not included in the propensity score production model.

Abbreviations: ACEIs, Angiotensin-Converting Enzyme Inhibitors; ARBs, Angiotensin II Receptor Blockers; BMI, Body Mass Index; CAD, Coronary Artery Disease; CKD, Chronic Kidney Disease; DPP4Is, DiPeptidyl Peptidase 4 Inhibitors; eGFR, estimated Glomerular Filtration Rate; GLP1, Glucagon-Like Peptide 1; PAD, Peripheral Artery Disease; SD, Standard deviation; SGLT2Is, Sodium-GLucose coTransporter 2 Inhibitors.

Table 2 Univariate and Propensity Score-Adjusted Analysis Results

Outcome Measures	Univariate Analysis
	Total N (%)	Glimepiride n (%), Control	Gliclazide MR n (%), Exposure	OR	95% CI	P-value
Total	N=2320	N=534	N=1786
ED Hypoglycemia	58 (2.5)	3 (0.6)	55 (3.1)	5.62	(1.75–18.05)	0.004
Any Documented Hypoglycemia	582 (25.1)	117 (21.9)	465 (26.0)	1.25	(0.99–1.58)	0.054
Falls	663 (28.6)	123 (23.0)	540 (30.2)	1.45	(1.16–1.81)	0.001
Fractures	468 (20.2)	81 (15.2)	387 (21.7)	1.55	(1.19–2.01)	0.001
CVEA	597 (25.7)	101 (18.9)	496 (27.8)	1.65	(1.30–2.10)	<0.001
Recurrent ED Admissions	1438 (62.0)	289 (54.1)	1149 (64.3)	1.53	(1.26–1.86)	<0.001
	PS Adjusted Analysis
Total	N=2270	N=520	N=1750	AOR	95% CI	P-value
ED Hypoglycemia	58 (2.6)	3 (0.6)	55 (3.1)	6.74	(2.02–22.55)	0.002
Any Documented Hypoglycemia	580 (25.6)	117 (22.5)	463 (26.5)	1.17	(0.92–1.49)	0.209
Falls	657 (28.9)	120 (23.1)	537 (30.7)	1.43	(1.13–1.82)	0.003
Fractures	467 (20.6)	81 (15.6)	386 (22.1)	1.43	(1.09–1.89)	0.01
CVEA	589 (25.9)	101 (19.4)	488 (27.9)	1.66	(1.29–2.15)	<0.001
Recurrent ED Admissions	1421 (62.6)	285 (54.8)	1136 (64.9)	1.39	(1.13–1.72)	0.002
	PS Adjusted Analysis After MI
Total	N=2320	N=534	N=1786	AOR	95% CI	P-value
ED Hypoglycemia	58 (2.5)	3 (0.6)	55 (3.1)	6.69	(2.00–22.32)	0.002
Any Documented Hypoglycemia	582 (25.1)	117 (21.9)	465 (26.0)	1.17	(0.92–1.49)	0.201
Falls	663 (28.6)	123 (23.0)	540 (30.2)	1.40	(1.10–1.77)	0.006
Fractures	468 (20.2)	81 (15.2)	387 (21.7)	1.46	(1.11–1.93)	0.006
CVEA	597 (25.7)	101 (18.9)	496 (27.8)	1.75	(1.36–2.26)	<0.001
Recurrent ED Admissions	1438 (62.0)	289 (54.1)	1149 (64.3)	1.41	(1.15–1.74)	0.001

Abbreviations: AOR, Adjusted Odds Ratio; CI, Confidence Interval; CVEA, Cardio Vascular Emergency Admission; ED, Emergency Department; MI, Multiple Imputation; OR, Odds Ratio; PS, Propensity Score.

Table 3 Odds Ratio of Gliclazide MR Using Glimepiride as a Baseline in the Study Measures in Patients Using Low Doses

Outcome Measures	Total N (%)	Glimepiride n (%), Baseline	Gliclazide MR n (%), Exposure	OR of Exposure	95 Confidence Interval	P-value
	Univariate Analysis
Total low dosing users	189	16	173
ED Hypoglycemia	0 (0.0)	0 (0.0)	0 (0.0)	-	-	-
Any Documented Hypoglycemia	58 (30.7)	0 (0.0)	58 (33.5)	-	-	-
Falls	61 (32.3)	0 (0.0)	61 (35.3)	-	-	-
Fractures	51 (27.0)	1 (6.3)	50 (28.9)	6.1	(0.78–47.4)	0.084
CVEA	41 (21.7)	6 (37.5)	35 (20.2)	0.42	(0.14–1.24)	0.117
Recurrent ED Admissions	105 (55.6)	8 (50.0)	97 (56.1)	1.28	(0.46–3.56)	0.641
	Propensity Score Adjusted Analysis
Total low dosing users	182	16	166
ED Hypoglycemia	0 (0.0)	0 (0.0)	0 (0.0)	-	-	-
Any Documented Hypoglycemia	58 (31.9)	0 (0.0)	58 (34.9)	-	-	-
Falls	61 (33.5)	0 (0.0)	61 (36.7)	-	-	-
Fractures	51 (28.0)	1 (6.3)	50 (30.1)	6.23	(0.79–48.93)	0.082
CVEA	37 (20.3)	6 (37.5)	31 (18.7)	0.44	(0.14–1.35)	0.149
Recurrent ED Admissions	101 (55.5)	8 (50.0)	93 (56.0)	1.11	(0.38–3.19)	0.851
	Propensity Score Adjusted Analysis After MI
Total low dosing users	189	16	173
ED Hypoglycemia	0 (0.0)	0 (0.0)	0 (0.0)	-	-	-
Any Documented Hypoglycemia	58 (30.7)	0 (0.0)	58 (33.5)	-	-	-
Falls	61 (32.3)	0 (0.0)	61 (35.3)	-	-	-
Fractures	51 (27.0)	1 (6.3)	50 (28.9)	5.72	(0.73–44.82)	0.097
CVEA	41 (21.7)	6 (37.5)	35 (20.2)	0.55	(0.17–1.72)	0.302
Recurrent ED Admissions	105 (55.6)	8 (50.0)	97 (56.1)	1.16	(0.4–3.3)	0.788

Abbreviations: ED, Emergency Department; CVEA, Cardiovascular Emergency Admission, MI; Multiple Imputation. A dash is used where the regression is not possible.

Table 4 Odds Ratio of Gliclazide MR Using Glimepiride as a Baseline in the Study Measures in Patients Using Mod-High Doses

Outcome Measures	Total N (%)	Glimepiride n (%), Baseline	Gliclazide MR n (%), Exposure	OR of Exposure	95 Confidence Interval	P-value
	Univariate Analysis
Total mod-high dosing users	2131	518	1613
ED Hypoglycemia	58 (2.7)	3 (0.6)	55 (3.4)	6.06	(1.89–19.45)	0.002
Any Documented Hypoglycemia	524 (24.6)	117 (22.6)	407 (25.2)	1.16	(0.91–1.46)	0.224
Falls	602 (28.2)	123 (23.7)	479 (29.7)	1.36	(1.08–1.71)	0.009
Fractures	417 (19.6)	80 (15.4)	337 (20.9)	1.45	(1.11–1.89)	0.007
CVEA	556 (26.1)	95 (18.3)	461 (28.6)	1.78	(1.39–2.28)	<0.001
Recurrent ED Admissions	1333 (62.6)	281 (54.2)	1052 (65.2)	1.58	(1.29–1.93)	<0.001
	Propensity Score Adjusted Analysis
Total mod-high doses	2088	504	1584
ED Hypoglycemia	58 (2.8)	3 (0.6)	55 (3.5)	7.31	(2.18–24.47)	0.001
Any Documented Hypoglycemia	522 (25.0)	117 (23.2)	405 (25.6)	1.04	(0.81–1.33)	0.773
Falls	596 (28.5)	120 (23.8)	476 (30.1)	1.36	(1.06–1.74)	0.014
Fractures	416 (19.9)	80 (15.9)	336 (21.2)	1.33	(1–1.76)	0.05
CVEA	552 (26.4)	95 (18.8)	457 (28.9)	1.8	(1.38–2.34)	<0.001
Recurrent ED Admissions	1320 (63.2)	277 (55.0)	1043 (65.8)	1.45	(1.17–1.8)	0.001
	Propensity Score Adjusted Analysis After MI
Total mod-high doses	2131	518	1613
ED Hypoglycemia	58 (2.7)	3 (0.6)	55 (3.4)	7.3	(2.18–24.39)	0.001
Any documented hypoglycemia	524 (24.6)	117 (22.6)	407 (25.2)	1.04	(0.81–1.34)	0.74
Falls	602 (28.2)	123 (23.7)	479 (29.7)	1.33	(1.05–1.7)	0.02
Fractures	417 (19.6)	80 (15.4)	337 (20.9)	1.37	(1.03–1.81)	0.029
CVEA	556 (26.1)	95 (18.3)	461 (28.6)	1.87	(1.44–2.43)	<0.001
Recurrent ED Admissions	1333 (62.6)	281 (54.2)	1052 (65.2)	1.47	(1.18–1.82)	<0.001

Abbreviations: CVEA, Cardiovascular Emergency Admission; ED, Emergency Department; MI, Multiple Imputation.