Safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (STELLA-ELDER): Interim results of a post-marketing surveillance study

Figures & data

Table 1. Patient characteristics at baseline.

Variable	Number of patients (%) or mean ± SD
Total	7170 (100.0)
Sex
Male	3531 (49.2)
Female	3639 (50.8)
Age, years
Mean ± SD	72.2 ± 5.8
Age
<75 years	4947 (69.0)
≥75 years	2223 (31.0)
Inpatient/outpatient
Inpatient	87 (1.2)
Outpatient	7083 (98.8)
Duration of diabetes, years*
Mean ± SD	10.5 ± 7.5
Duration of diabetes
<5 years	1005 (14.0)
≥5 years	3448 (48.1)
Unknown	2717 (37.9)
BMI, kg/m^2 †
Mean ± SD	26.9 ± 4.5
BMI category 1
<18.5 kg/m^2	59 (0.8)
≥18.5 to <22.0 kg/m^2	429 (6.0)
≥22.0 to <25.0 kg/m^2	1001 (14.0)
≥25.0 to <30.0 kg/m^2	1835 (25.6)
≥30.0 kg/m^2	934 (13.0)
Unknown	2912 (40.6)
BMI category 2
<25.0 kg/m^2	1489 (20.8)
≥25.0 kg/m^2	2769 (38.6)
Unknown	2912 (40.6)
Complications
No	1377 (19.2)
Yes	5692 (79.4)
Unknown	101 (1.4)
Type of complication
Diabetic neuropathy	606 (8.5)
Diabetic nephropathy	796 (11.1)
Diabetic retinopathy	410 (5.7)
Urinary tract infection	27 (0.4)
Genital infection	7 (0.1)
Dyslipidemia	3539 (49.4)
Hypertension	4058 (56.6)
Other	407 (5.7)
Hepatic function status§
Normal	6222 (86.8)
Mild impairment	633 (8.8)
Moderate impairment	45 (0.6)
Severe impairment	3 (0.0)
Unknown	267 (3.7)
Renal function status¶
Normal	5802 (80.9)
Mild impairment	1035 (14.4)
Moderate impairment	103 (1.4)
Severe impairment	6 (0.1)
Unknown	224 (3.1)
eGFR, ml/min/1.73 m^2 ‡
Mean ± SD	70.2 ± 18.9
Classification of eGFR
≥90 ml/min/1.73 m^2	566 (7.9)
≥60 to <90 ml/min/1.73 m^2	2552 (35.6)
≥45 to <60 ml/min/1.73 m^2	953 (13.3)
≥30 to <45 ml/min/1.73 m^2	281 (3.9)
<30 ml/min/1.73 m^2	43 (0.6)
Unknown	2775 (38.7)

*n = 4453; †n = 4258; ‡n = 4395.

§Assessed by total bilirubin, aspartate aminotransferase and alanine aminotransferase levels.

¶Assessed by blood urea nitrogen and creatinine levels.

BMI: body mass index; eGFR: estimated glomerular filtration rate; SD: standard deviation.

Table 2. Treatments used at baseline.

Variable	Number of patients (%) or mean ± SD
Evaluable patients	7170 (100.0)
Daily dose of ipragliflozin, mg*	47.5 ± 8.3
Initial dose of ipragliflozin, mg
25	890 (12.4)
50	6266 (87.4)
75	0 (0.0)
100	9 (0.1)
Others	4 (0.1)
Unknown	1 (0.0)
Concomitant antidiabetic drugs
No	1159 (16.2)
Yes	5961 (83.1)
Unknown	50 (0.7)
Number of concomitant antidiabetic drugs
Mean ± SD	2.0 ± 1.0
None	1159 (16.2)
1	2159 (30.1)
2	2055 (28.7)
3	1274 (17.8)
≥4	473 (6.6)
Unknown	50 (0.7)
Type of concomitant antidiabetic drug
DPP-4 inhibitor	4292 (59.9)
Sulfonylurea	2545 (35.5)
Metformin	1960 (27.3)
α-glucosidase inhibitor	949 (13.2)
Thiazolidine	731 (10.2)
Insulin	731 (10.2)
Fast-acting insulin secretagogue	235 (3.3)
GLP-1 receptor agonist	107 (1.5)
Other	509 (7.1)
Concomitant diuretic drug
No	6242 (87.1)
Yes	868 (12.1)
Unknown	60 (0.8)
Type of diuretic drug
Loop diuretic	321 (4.5)
Thiazide diuretic	269 (3.8)
Potassium-sparing diuretic	172 (2.4)
Carbonate dehydratase inhibitor	1 (0.0)
Osmotic diuretic	1 (0.0)
Vasopressin antagonist	3 (0.0)
Other	232 (3.2)
Other concomitant drugs, n (%)
No	2212 (30.9)
Yes	4863 (67.8)
Unknown	95 (1.3)
Type of concomitant drugs
Antihypertensive drugs	3165 (44.1)
ARB	1624 (22.6)
CCB	1547 (21.6)
ARB + CCB	815 (11.4)
Statin	2324 (32.4)
Antipeptic ulcer drug	891 (12.4)
Antiplatelet drug	759 (10.6)
Antihyperuricemia drug	307 (4.3)
Other	542 (7.6)

*n = 7167.

ARB: angiotensin receptor blocker; CCB: calcium channel blocker; SD: standard deviation.

Table 3. Adverse drug reactions.

	At approval	Post-marketing survey
Number of participating institutions	144	2242
Number of evaluable patients	1669	7170
Number of patients with an ADR (%)	549 (32.89)	721 (10.06)
Number of ADRs	887	898
Type of ADR, number of patients (%)*
Skin and subcutaneous tissue disorders	48 (2.88)	163 (2.27)
Renal and urinary disorders	176 (10.55)	120 (1.67)
Infections and infestations	62 (3.71)	89 (1.24)
General disorders and administration site conditions	101 (6.05)	80 (1.12)
Gastrointestinal disorders	102 (6.11)	73 (1.02)
Reproductive system and breast disorders	25 (1.50)	72 (1.00)
Metabolism and nutrition disorders	20 (1.20)	71 (0.99)
Investigations	133 (7.97)	64 (0.89)
Nervous system disorders	42 (2.52)	63 (0.88)
Musculoskeletal and connective tissue disorders	13 (0.78)	11 (0.15)
Cardiac disorders	10 (0.60)	10 (0.14)
Vascular disorders	7 (0.42)	9 (0.13)
Respiratory, thoracic and mediastinal disorders	7 (0.42)	8 (0.11)
Hepatobiliary disorders	8 (0.48)	7 (0.10)
Eye disorders	17 (1.02)	5 (0.07)
Neoplasms benign, malignant and unspecified (including cysts and polyps)	4 (0.24)	2 (0.03)
Blood and lymphatic system disorders	8 (0.48)	2 (0.03)
Psychiatric disorders	3 (0.18)	2 (0.03)
Injury, poisoning and procedural complications	0	2 (0.03)
Immune system disorders	0	1 (0.01)
Ear and labyrinth disorders	5 (0.30)	0

*By system organ class (MedDRA version 18.0).

ADR: adverse drug reaction.

Table 4. Adverse drug reactions of special interest.

	All	Serious	Non-serious
All ADRs	721 (10.06)	44 (0.61)	688 (9.60)
Types of ADRs
Skin complications	160 (2.23)	8 (0.11)	152 (2.12)
Volume depletion	136 (1.90)	7 (0.10)	131 (1.83)
Genital infection	104 (1.45)	1 (0.01)	103 (1.44)
Polyuria/pollakiuria	95 (1.32)	2 (0.03)	93 (1.30)
Urinary tract infection	55 (0.77)	4 (0.06)	51 (0.71)
Renal disorder	25 (0.35)	3 (0.04)	22 (0.31)
Hypoglycemia	23 (0.32)	0 (0.00)	23 (0.32)
Cerebrovascular disease	10 (0.14)	6 (0.08)	4 (0.06)
Cardiovascular disease	7 (0.10)	6 (0.08)	1 (0.01)
Hepatic impairment	6 (0.08)	0 (0.00)	6 (0.08)
Malignant tumor	2 (0.03)	2 (0.03)	0 (0.00)
Ketone body increased	1 (0.01)	0 (0.00)	1 (0.01)
Fracture	0 (0.00)	0 (0.00)	0 (0.00)

Table 5. Variables associated with the incidence of adverse drug reactions in univariate analyses.

ADR	Number of patients (%)	Significant variables (p-value)*
Hypoglycemia	23 (0.32)	Low BMI (category 1, p = 0.001†)
		BMI <25.0 (category 2, p = 0.025‡)
		Impaired renal function (p = 0.018†)
		Concomitant insulin use (p = 0.001‡)
Genital infection	104 (1.45)	Female (p < 0.001‡)
		High BMI (category 1, p = 0.001†)
		BMI ≥25.0 (category 2, p = 0.001‡)
		Impaired hepatic function (p = 0.022†)
Urinary tract infection	55 (0.77)	Female (p < 0.001‡)
		Duration of diabetes ≥5 years (p = 0.006‡)
		Impaired hepatic function (p = 0.007†)
Polyuria/pollakiuria	95 (1.32)	Male (p = 0.002‡)
Volume depletion	136 (1.90)	Age ≥75 years (p < 0.001‡)
		BMI <25.0 (category 2, p = 0.046‡)
		Impaired renal function (p = 0.006†)
		Low eGFR (p < 0.001†)
		Concomitant diuretic use (p = 0.002‡)
Skin complications	160 (2.23)	Inpatient status (p = 0.045‡)
		Duration of diabetes ≥5 years (p = 0.024‡)

*BMI category 1 (kg/m²): <18.5, ≥18.5 to <22.0, ≥22.0 to <25.0, ≥25.0 to <30.0, ≥30.0 and unknown.

BMI category 2 (kg/m²): <25.0, ≥25.0 and unknown.

Renal function: normal, mild disorder, moderate disorder, severe disorder and unknown.

Hepatic function: normal, mild disorder, moderate disorder, severe disorder and unknown.

Duration of diabetes group (years): <5, ≥5 and unknown.

Age group (years): <75 and ≥75.

eGFR (ml/min/1.73 m²): ≥90, ≥60 to <90, ≥45 to <60, ≥30 to <45, <30 and unknown.

†Cochran–Armitage trend test.

‡Fisher’s exact test.

ADR: adverse drug reaction; BMI: body mass index; eGFR: estimated glomerular filtration rate.

Table 6. Surrogate markers, vital signs and laboratory variables.

Variable	Baseline	Final visit	Change at 1 month	Change at 3 months	Change at 6 months	Change at 9 months	Change at 12 months	Change at final visit
HbA1c, %	7.8 ± 1.3	7.3 ± 1.1	−0.3 ± 0.6*	−0.5 ± 1.0*	−0.6 ± 1.0*	−0.6 ± 1.0*	−0.7 ± 1.1*	−0.6 ± 1.0*
	(6005)	(6507)	(3977)	(4880)	(4322)	(774)	(777)	(5771)
FPG, mg/dl	163.0 ± 57.8	140.5 ± 45.7	−18.4 ± 48.6*	−22.6 ± 54.2*	−25.7 ± 53.5*	−22.7 ± 46.1*	−28.8 ± 43.3*	−22.7 ± 53.6*
	(3734)	(4338)	(2374)	(2859)	(2532)	(423)	(396)	(3493)
Body weight, kg	67.4 ± 12.8	65.1 ± 12.5	−1.4 ± 1.4*	−2.2 ± 1.9*	−2.5 ± 2.4*	−2.3 ± 2.2*	−2.6 ± 2.3*	−2.3 ± 2.4*
	(4925)	(5172)	(3247)	(3792)	(3273)	(595)	(608)	(4575)
BMI, kg/m^2	26.9 ± 4.5	26.0 ± 4.4	−0.5 ± 0.6*	−0.9 ± 0.8*	−1.0 ± 1.0*	−0.9 ± 0.9*	−1.1 ± 1.0*	−0.9 ± 1.0*
	(4258)	(4403)	(2844)	(3279)	(2846)	(530)	(548)	(3965)
SBP, mmHg	133.2 ± 15.2	130.1 ± 14.3	−4.1 ± 14.6*	−4.6 ± 14.9*	−2.9 ± 14.8*	−2.5 ± 14.4*	−3.8 ± 14.8*	−3.1 ± 15.1*
	(5551)	(5941)	(3835)	(4429)	(3924)	(750)	(763)	(5300)
DBP, mmHg	73.5 ± 10.0	72.4 ± 9.7	−2.0 ± 9.2*	−2.2 ± 9.3*	−1.1 ± 9.8*	−1.2 ± 9.5*	−1.6 ± 9.8*	−1.2 ± 9.8*
	(5548)	(5939)	(3831)	(4428)	(3922)	(749)	(763)	(5297)
Hematocrit, %	41.0 ± 4.3	42.9 ± 4.5	0.8 ± 2.1*	1.7 ± 2.4*	2.0 ± 2.6*	2.3 ± 2.6*	2.0 ± 2.9*	1.8 ± 2.7*
	(3849)	(4788)	(2133)	(2803)	(2513)	(411)	(403)	(3513)
Serum Cr, mg/dl	0.77 ± 0.25	0.79 ± 0.27	0.04 ± 0.09*	0.03 ± 0.10*	0.01 ± 0.10*	0.00 ± 0.09	0.00 ± 0.11	0.02 ± 0.11*
	(4395)	(5301)	(2481)	(3172)	(2859)	(496)	(483)	(4048)
BUN, mg/dl	17.0 ± 5.2	17.8 ± 5.1	0.7 ± 3.9*	0.7 ± 4.0*	0.8 ± 4.0*	0.9 ± 3.6*	1.0 ± 3.6*	0.8 ± 4.1*
	(3648)	(4443)	(2094)	(2580)	(2338)	(410)	(398)	(3347)
eGFR, ml/min/1.73 m^2	70.2 ± 18.9	69.3 ± 19.6	−3.1 ± 10.4*	−2.6 ± 9.6*	−1.0 ± 9.8*	−0.3 ± 9.9	0.8 ± 11.1	−1.1 ± 10.4*
	(4395)	(5301)	(2481)	(3172)	(2859)	(496)	(483)	(4048)

*p < 0.001 vs. before administration (paired t-test).

Values are presented as the mean ± standard deviation (number of patients).

BMI: body mass index; BUN: blood urea nitrogen; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; FPG: fasting plasma glucose; HbA1c: glycated hemoglobin; SBP: systolic blood pressure; Cr: creatinine.

Glucose: 1 mmol/l = 18.02 mg/dl.

Creatinine: 1 μmol/l = 0.01 mg/dl.

Urea nitrogen: 1 mmol/l = 2.80 mg/dl.