Real-world evidence for the safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (STELLA-ELDER): final results of a post-marketing surveillance study

Figures & data

Table 1. Patient characteristics at baseline.

	No. of patients (%) or mean ± SD
Safety analysis set	8505 (100.0)
Sex
Male	4181 (49.2)
Female	4324 (50.8)
Age, years	72.3 ± 5.9
Age category 1
<75 years	5800 (68.2)
≥75 years	2705 (31.8)
Age category 2
≥65 to <70 years	3287 (38.6)
≥70 to <75 years	2513 (29.5)
≥75 to <80 years	1602 (18.8)
≥80 to <85 years	802 (9.4)
≥85 years	301 (3.5)
Inpatient/outpatient status
Inpatient	147 (1.7)
Outpatient	8358 (98.3)
Duration of diabetes, years*	10.6 ± 7.52
Duration of diabetes category
<5 years	1177 (13.8)
≥5 years	4150 (48.8)
Unknown	3178 (37.4)
BMI (kg/m^2)†	27.0 ± 4.56
BMI category
<18.5 kg/m^2	73 (0.9)
≥18.5 to <22.0 kg/m^2	518 (6.1)
≥22.0 to <25.0 kg/m^2	1171 (13.8)
≥25.0 to <30.0 kg/m^2	2168 (25.5)
≥30.0 kg/m^2	1138 (13.4)
Unknown	3437 (40.4)
Complications
No	1477 (17.4)
Yes	6917 (81.3)
Unknown	111 (1.3)
Type of complication
Diabetic neuropathy	749 (8.8)
Diabetic nephropathy	990 (11.6)
Diabetic retinopathy	521 (6.1)
Urinary tract infection	38 (0.4)
Genital infection	9 (0.1)
Dyslipidemia	4294 (50.5)
Hypertension	5047 (59.3)
Hyperuricemia	532 (6.3)
Dementia	177 (2.1)
Macrovascular disorders	1701 (20.0)
Coronary artery disease	1023 (12.0)
Cerebral vascular disease	604 (7.1)
Arteriosclerosis obliterans	357 (4.2)
Other	3737 (43.9)
Hepatic function status§
Normal	7357 (86.5)
Mild impairment	764 (9.0)
Moderate impairment	55 (0.6)
Severe impairment	3 (0.0)
Unknown	326 (3.8)
Renal function status
Normal	6777 (79.7)
Mild impairment	1295 (15.2)
Moderate impairment	145 (1.7)
Severe impairment	11 (0.1)
Unknown	277 (3.3)
eGFR, mL/min/1.73 m^2‡	69.7 ± 19.4
eGFR category
≥90 mL/min/1.73 m^2	671 (7.9)
≥60 to <90 mL/min/1.73 m^2	2961 (34.8)
≥45 to <60 mL/min/1.73 m^2	1172 (13.8)
≥30 to <45 mL/min/1.73 m^2	366 (4.3)
<30 mL/min/1.73 m^2	67 (0.8)
Unknown	3268 (38.4)

*n = 5327; †n = 5068; ‡n = 5237.

§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. Prescribed treatments.

	No. of patients (%) or mean ± SD
Safety analysis set	8505 (100.0)
Initial dose of ipragliflozin
25 mg	1152 (13.5)
50 mg	7344 (86.3)
75 mg	0 (0.0)
100 mg	9 (0.1)
Dose changes during treatment
25 mg to 25 mg	856 (10.1)
25 mg to 50 mg	263 (3.1)
50 mg to 50 mg	7168 (84.3)
50 mg to 100 mg	78 (0.9)
Other	140 (1.6)
Duration of treatment with ipragliflozin, days	277.6 ± 129.6
Concomitant antidiabetic drug
No	1257 (14.8)
Yes	7192 (84.6)
Unknown	56 (0.7)
Type of concomitant antidiabetic drug
DPP-4 inhibitor	5165 (60.7)
Sulfonylurea	3089 (36.3)
Biguanide	2400 (28.2)
α-Glucosidase inhibitor	1190 (14.0)
Insulin	914 (10.7)
Thiazolidine	898 (10.6)
Fast-acting insulin secretagogue	305 (3.6)
GLP-1 receptor agonist	143 (1.7)
Other	660 (7.8)
Concomitant diuretic drug
No	7285 (85.7)
Yes	1136 (13.4)
Unknown	84 (1.0)
Type of concomitant diuretic drug
Loop diuretic	423 (5.0)
Thiazide diuretic	346 (4.1)
Potassium-sparing diuretic	230 (2.7)
Vasopressin antagonist	5 (0.1)
Carbonate dehydratase inhibitor	2 (0.0)
Osmotic diuretic	1 (0.0)
Other	309 (3.6)
Other concomitant drugs
No	2464 (29.0)
Yes	5930 (69.7)
Unknown	111 (1.3)
Type of other concomitant drugs
Antihypertensive drugs	4031 (47.4)
ARB	2007 (23.6)
CCB	2158 (25.4)
ARB + CCB	999 (11.7)
Statin	3018 (35.5)
Antiplatelet drug	1253 (14.7)
Antipeptic ulcer drug	1181 (13.9)
Antihyperuricemia drug	447 (5.3)
Other	5704 (67.1)

ARB: angiotensin receptor blocker; CCB: calcium channel blocker; DPP-4: dipeptidyl peptidase-4; GLP-1: glucagon-like peptide-1; SD: standard deviation.

Table 3. Adverse drug reactions.

	This survey	Preapproval clinical trials
No. of participating institutions	2588	144
No. of evaluable patients	8505	1669
Number of patients with an ADR (%)	1438 (16.91)	549 (32.89)
Number of ADRs	1880	887
Type of ADR, number of patients (%)*
Infections and infestations	190 (2.23)	64 (3.83)
Neoplasms benign, malignant, and unspecified (including cysts and polyps)	11(0.13)	4 (0.24)
Blood and lymphatic system disorders	5 (0.06)	8 (0.48)
Immune system disorders	1 (0.01)	0 (0)
Endocrine disorders	2 (0.02)	0 (0)
Metabolism and nutrition disorders	156 (1.83)	20 (1.20)
Psychiatric disorders	11 (0.13)	3 (0.18)
Nervous system disorders	144 (1.69)	42 (2.52)
Eye disorders	10 (0.12)	17 (1.02)
Ear and labyrinth disorders	2 (0.02)	5 (0.30)
Cardiac disorders	35 (0.41)	10 (0.60)
Vascular disorders	33 (0.39)	7 (0.42)
Respiratory, thoracic, and mediastinal disorders	14 (0.16)	7 (0.42)
Gastrointestinal disorders	146 (1.72)	101 (6.05)
Hepatobiliary disorders	15 (0.18)	8 (0.48)
Skin and subcutaneous tissue disorders	276 (3.25)	48 (2.88)
Musculoskeletal and connective tissue disorders	42 (0.49)	13 (0.78)
Renal and urinary disorders	233 (2.74)	176 (10.55)
Reproductive system and breast disorders	125 (1.47)	25 (1.50)
General disorders and administration site conditions	152 (1.79)	101 (6.05)
Investigations	162 (1.90)	133 (7.97)
Injury, poisoning and procedural complications	4 (0.05)	0 (0)

*By system organ class (MedDRA version 18.1).

ADR: adverse drug reaction.

Table 4. Adverse drug reactions of special interest.

	This survey
	All	Serious	Pre-approval clinical trials*
All ADRs, no. of patients (%)	1438 (16.91)	127 (1.49)	(32.9)
Type of ADRs, no. of ADRs or patients (%)
Skin complications	269 (3.16)	11 (0.13)	(2.9)
Volume depletion	266 (3.13)	19 (0.22)	(5.8)
Polyuria/pollakiuria	170 (2.00)	1 (0.01)	(12.8)
Genital infection	166 (1.95)	1 (0.01)	(2.1)
Urinary tract infection	118 (1.39)	11 (0.13)	(2.2)
Renal disorder	118 (1.39)	7 (0.08)	(4.2)
Hypoglycemia	58 (0.68)	2 (0.02)	(1.8)
Cerebrovascular disease	36 (0.42)	31 (0.36)	(0.2)
Cardiovascular disease	24 (0.28)	16 (0.19)	(0.6)
Malignant tumor	11 (0.13)	11 (0.13)	(0.2)
Fracture	2 (0.02)	2 (0.02)	0
Ketone body-related events	2 (0.02)	1 (0.01)	0

*Definition of the ADRs at approval: skin complications, skin and subcutaneous tissue disorders; renal disorder, renal impairment + β-2 microglobulin increased + urinary β 2-microglobulin increased + β-N-acetyl-d-glucosaminidase increased + serum creatinine increased + urinary albumin-to-creatinine ratio (ACR) increased + serum alpha 1-microglobulin increased; cerebrovascular disease, cerebral infarction + transient ischemic attack; cardiovascular disease, cardiac disorder; ketone body-related events, ketoacidosis + ketone body increased + ketosis + metabolic acidosis.

ADR: adverse drug reaction.

Table 5. Factors associated with the incidence of adverse drug reactions of special interest in the multivariable regression analyses.

ADR class	Factors included in the model*	Odds ratio (95% CI)
All	Female (vs. male)	1.549 (1.297–1.850)
	BMI ≥30.0 kg/m^2 (vs. ≥22.0 to <25.0 kg/m^2)	1.294 (1.003–1.669)
	Moderately impaired hepatic function (vs. normal)	2.298 (1.011–5.225)
	Mildly impaired renal function (vs. normal)	1.376 (1.097–1.725)
Hypoglycemia	BMI <18.5 kg/m^2 (vs. ≥22.0 to <25.0 kg/m^2)	9.356 (2.692–32.514)
	Concomitant insulin use (vs. no)	4.946 (2.540–9.629)
Genital infection	Female (vs. male)	5.927 (3.477–10.104)
	BMI ≥25.0 to <30.0 kg/m^2 (vs. ≥22.0 to <25.0 kg/m^2)	2.061 (1.139–3.728)
	BMI ≥30.0 kg/m^2 (vs. ≥22.0 to <25.0 kg/m^2)	2.363 (1.273–4.387)
Urinary tract infection	Female (vs. male)	5.063 (2.467–10.389)
	Duration of diabetes ≥5 years (vs. <5 years)	5.288 (1.637–17.082)
	Moderately impaired hepatic function (vs. normal)	6.652 (1.452–30.478)
Polyuria/pollakiuria	Concomitant antidiabetic drug use (vs. no)	3.679 (1.143–11.841)
Volume depletion	Age ≥75 years (vs. <75 years)	1.737 (1.209–2.497)
	Concomitant loop diuretic use (vs. no)	2.105 (1.141–3.881)
Renal disorder	Mildly impaired renal function (vs. normal)	3.203 (2.131–4.816)
	Moderately impaired renal function (vs. normal)	7.003 (3.579–13.703)
	Severely impaired renal function (vs. normal)	22.389 (5.412–92.617)
	Concomitant diuretic use (vs. no)	2.631 (1.754–3.949)
Skin complications	Female (vs. male)	1.428 (1.115–1.829)

*The final models were built using a stepwise procedure with p-values of <0.15 for entry and staying in the model.

ADR: adverse drug reaction; CI: confidence interval; BMI: body mass index.

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 1 year	Change at final visit	Change at final visit in preapproval trials*
HbA1c, %	7.84 ± 1.33	7.28 ± 1.12	−0.33 ± 0.61†	−0.54 ± 0.97†	−0.64 ± 1.05†	−0.59 ± 1.01†	−0.67 ± 1.03†	−0.56 ± 1.04†	−0.51 ± 0.81†
	(6853)	(6853)	(4725)	(5719)	(5004)	(4090)	(4154)	(6853)
HbA1c (50 mg), %	7.84 ± 1.33	7.26 ± 1.11	−0.34 ± 0.61†	−0.56 ± 0.98†	−0.65 ± 1.05†	−0.59 ± 1.00†	−0.68 ± 1.01†	−0.57 ± 1.04†	−0.64 ± 0.66†
	(5751)	(5751)	(3960)	(4786)	(4245)	(3454)	(3551)	(5751)
FPG, mg/dL	164.3 ± 59.3	141.3 ± 48.2	−18.1 ± 50.7†	−22.5 ± 55.1†	−25.5 ± 54.8†	−21.9 ± 51.2†	−28.1 ± 51.1†	−23.0 ± 55.7†	−32.7 ± 31.7†
	(4154)	(4154)	(2792)	(3318)	(2895)	(2313)	(2323)	(4154)
Body weight, kg	67.64 ± 12.84	65.09 ± 12.51	−1.35 ± 1.43†	−2.20 ± 1.98†	−2.51 ± 2.51†	−2.56 ± 2.82†	−2.91 ± 3.08†	−2.56 ± 2.88†	−3.41 ± 2.30†
	(5481)	(5481)	(3845)	(4445)	(3817)	(3114)	(3149)	(5481)
BMI, kg/m^2	27.0 ± 4.54	26.0 ± 4.42	−0.53 ± 0.58†	−0.87 ± 0.79†	−1.00 ± 1.02†	−1.02 ± 1.14†	−1.14 ± 1.25†	−1.01 ± 1.16†	–
	(4734)	(4734)	(3364)	(3847)	(3307)	(2676)	(2717)	(4734)
SBP, mmHg	133.3 ± 15.3	130.0 ± 14.4	−4.1 ± 14.9†	−4.7 ± 15.1†	−2.9 ± 15.0†	−2.3 ± 15.1†	−3.7 ± 15.1†	−3.3 ± 15.6†	−6.4 ± 11.78†
	(6317)	(6317)	(4517)	(5188)	(4525)	(3725)	(3769)	(6317)
DBP, mmHg	73.4 ± 10.2	71.9 ± 9.9	−1.9 ± 9.4†	−2.1 ± 9.5†	−1.2 ± 9.9†	−1.0 ± 9.9†	−1.8 ± 9.9†	−1.5 ± 10.1†	−3.3 ± 7.82†
	(6313)	(6313)	(4512)	(5187)	(4523)	(3722)	(3768)	(6313)
Heart rate, beat/min	74.4 ± 11.1	73.9 ± 11.1	−0.1 ± 8.4	−0.5 ± 8.8	−0.5 ± 9.0	−0.4 ± 9.2	−0.9 ± 8.8†	−0.5 ± 9.2†	–
	(3760)	(3760)	(2711)	(2984)	(2616)	(2184)	(2191)	(3760)
Hematocrit, %	40.9 ± 4.5	42.6 ± 4.7	0.8 ± 2.1†	1.7 ± 2.5†	2.0 ± 2.6†	2.1 ± 3.0†	1.8 ± 3.0†	1.7 ± 3.0†	–
	(4272)	(4272)	(2531)	(3309)	(2928)	(2462)	(2479)	(4272)
Serum albumin, g/dL	4.21 ± 0.44	4.22 ± 0.42	0.04 ± 0.24†	0.01 ± 0.30	0.04 ± 0.30†	0.04 ± 0.31†	0.02 ± 0.34	0.02 ± 0.34	–
	(2343)	(2343)	(1410)	(1726)	(1505)	(1239)	(1257)	(2343)
Serum Cr, mg/dL	0.78 ± 0.27	0.80 ± 0.29	0.04 ± 0.10†	0.03 ± 0.12†	0.01 ± 0.11†	0.01 ± 0.11	0.01 ± 0.12†	0.02 ± 0.13†	–
	(4889)	(4889)	(2947)	(3745)	(3323)	(2743)	(2796)	(4889)
BUN, mg/dL	17.2 ± 5.5	18.2 ± 5.8	0.8 ± 4.0†	0.8 ± 4.4†	0.8 ± 4.1†	0.9 ± 4.2†	1.1 ± 4.3†	1.0 ± 4.6†	–
	(4054)	(4054)	(2485)	(3048)	(2716)	(2272)	(2302)	(4054)
eGFR, ml/min/1.73 m^2	69.7 ± 19.3	68.8 ± 20.8	−3.1 ± 10.3†	−2.6 ± 9.6†	−0.9 ± 9.7†	−0.2 ± 13.1	−0.6 ± 12.2	−1.0 ± 11.3†	–
	(4889)	(4889)	(2947)	(3745)	(3323)	(2743)	(2796)	(4889)

*Data from 52-week study (Kashiwagi A, et al. Japanese Pharmacology & Therapeutics 2015; 43: 85–100)

†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.

Albumin: 1 μmol/l = 689.66 mg/dL.

Creatinine: 1 μmol/l = 0.01 mg/dL.

Urea nitrogen: 1 mmol/l = 2.80 mg/dL.