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

ABSTRACT

Objective: To determine the incidence of adverse drug reactions (ADRs) associated with ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus.

Research design and methods: We report interim results of a postmarketing surveillance survey. Japanese physicians recorded ADRs in elderly patients (≥65 years old) who were first prescribed with ipragliflozin within 3 months of its launch (April 2014).

Main outcome measures: Incidence of ADRs within 1 year of starting treatment with ipragliflozin.

Results: 898 ADRs occurred in 721/7,170 patients (10.06%). Skin complication-, volume depletion-, genital infection-, polyuria/pollakiuria-, urinary tract infection-, and hypoglycemia-related ADRs occurred in 2.23%, 1.90%, 1.45%, 1.32%, 0.77%, and 0.32%, respectively. ADRs were classified as serious in 44 (0.61%) patients. Half of the ADRs occurred within 30 days of starting treatment. There were no cases of Stevens-Johnson syndrome or toxic epidermal necrolysis. Most (92.1%) of the ADRs resolved or improved. Glycated hemoglobin, fasting blood glucose, body weight, and systolic blood pressure decreased by 0.6% (baseline 7.8%), 22.7 mg/dL (baseline 163.0 mg/dL), 2.3 kg (baseline 67.4 kg), and 3.1 mmHg (baseline 133.2 mmHg), respectively, from baseline to treatment discontinuation/last visit.

Conclusions: Ipragliflozin is well tolerated and reduced surrogate endpoints in elderly Japanese patients with type 2 diabetes mellitus.

Clinicaltrials.gov identifier: NCT02297620

KEYWORDS:

• elderly
• ipragliflozin
• post-marketing surveillance
• SGLT2 inhibitors
• type 2 diabetes mellitus

1. Introduction

Sodium–glucose cotransporter 2 (SGLT2) inhibitors represent a new class of oral antidiabetic drugs that lower blood glucose concentrations in an insulin-independent manner by increasing urinary glucose excretion.[1]

Ipragliflozin was the first SGLT2 inhibitor to be approved in Japan for the treatment of type 2 diabetes mellitus as monotherapy or in combination with other antidiabetic drugs. Several randomized placebo-controlled studies in Japanese patients with type 2 diabetes mellitus have demonstrated that ipragliflozin was effective in terms of improving glycemic control over 12–52 weeks.[2–7] In these studies, ipragliflozin was associated with a favorable safety profile, with low rates of mild-to-moderate treatment-emergent adverse events (TEAEs) including genital infection and hypoglycemia.

In these clinical trials, low-grade TEAEs, including pollakiuria and constipation, were more common in the metformin+ipragliflozin group [2] while pollakiuria and thirst were more common in the sulfonylurea+ipragliflozin group [7] than in the placebo groups, but the incidence of TEAEs was not increased in the pioglitazone+ipragliflozin group compared with the placebo group.[5]

These earlier trials enrolled Japanese patients aged 20–75 years. However, Japan is an aging society with more than 25% of its population aged ≥65 years; moreover, many patients with type 2 diabetes mellitus are of an advanced age.[8,9] Because the prior studies enrolled relatively few elderly patients and because of the increased risk of comorbidities or TEAEs in elderly patients, it is important to confirm the safety of ipragliflozin in this patient population. Accordingly, Astellas Pharma Inc. and the Pharmaceutical and Medical Device Agency (PMDA) of Japan agreed that an all-case post-marketing surveillance (PMS) survey of elderly patients should be carried out to confirm its safety in elderly Japanese patients (≥65 years), with a particular focus on the adverse drug reactions (ADRs) associated with volume depletion and the clinical factors associated with these ADRs. Therefore, a 1-year PMS survey (STELLA-ELDER, Specified drug use resulTs survEy of ipragLifLozin treAtment in ELDERly type 2 diabetic patients) was implemented in April 2014 in compliance with the ministerial ordinance on Good Post-Marketing Study Practice (GPSP), and registered all elderly Japanese patients with type 2 diabetes mellitus who were prescribed ipragliflozin within 3 months of its launch.

After the launch of ipragliflozin, the safety of SGLT2 inhibitors has become an important issue in Japan owing to the large number of serious AEs reported in the first 3 months of using these drugs. While the present post-marketing surveillance survey had been planned at the pre-approval stage before the safety concern was revealed and its purpose was to confirm the safety of ipragliflozin in elderly patients, we decided to report interim results of the survey to communicate safety data for ipragliflozin administered in a large population in clinical practice. We did this to help inform clinicians on the real-world safety of ipragliflozin and to detect any potential safety concerns occurring in this population.

2. Patients and methods

All patients with type 2 diabetes mellitus aged ≥65 years who were first prescribed ipragliflozin within 3 months after its launch in April 2014 were to be registered and their clinical data were to be recorded for up to 1 year after registration, at all survey sites in Japan.

In accordance with the approved label, patients were prescribed 50 mg ipragliflozin once daily, to be administered before or after breakfast. If the efficacy of 50 mg ipragliflozin was judged to be insufficient by the attending physician, the dose could be increased to 100 mg and the patient’s clinical course should be monitored carefully in accordance with the prescribing information. All treatment decisions, including the decision to prescribe ipragliflozin, were made at the attending physician’s discretion. Because this study involved the collection of anonymous data from clinical settings, it was not necessary to obtain informed consent from patients. This approach was fully compliant with Japanese regulations for post-marketing surveillance studies. All of the medical institutions that agreed to provide data signed a contract with Astellas Pharma Inc.

2.1. Survey design

The survey was conducted between April 2014 and July 2015, and the data collected up to 16 July 2015 were analyzed for this interim report. All data were to be recorded immediately in an electronic database using case report forms for each patient. The survey items included the following demographic characteristics: age, sex, date of the start of administration, height, body weight, body mass index (BMI), inpatient/outpatient status, duration of diabetes, diabetic complications (neuropathy, nephropathy, retinopathy), presence of urinary tract infection, presence of genital infection, and the degree of renal and hepatic function at the start of drug administration. Information regarding the administration of ipragliflozin (daily dose, daily administration frequency, administration period, reason of termination or discontinuation of administration) and the use of concomitant drugs was also recorded using the case report form. The type and dose were to be recorded for concomitant antidiabetic drugs and diuretics. Vital signs and laboratory data to be recorded included: blood pressure, pulse, glycated hemoglobin (HbA1c), fasting blood glucose, hematocrit, serum albumin, serum creatinine and blood urea nitrogen (BUN).

For the purpose of monitoring safety, any adverse events (AEs) and ADRs that occurred during treatment with ipragliflozin were to be recorded at each visit. The physician noted the type of AE/ADR during or after drug administration, the date of onset, seriousness, outcome (resolved, improved or worsened), causal relationship to ipragliflozin, causative relationship to factors other than ipragliflozin and laboratory data at the time of the event. AEs and ADRs were categorized according to system organ class and preferred term using MedDRA version 18.0.[10]

2.2. Statistical analysis

All statistical analyses were performed using SAS statistical software version 9.1 (BASE/SAS®, SAS/STAT®, SAS Institute Inc., Cary, NC, USA). Data are presented as the mean and standard deviation (SD) for continuous variables, and as the frequency and proportion for categorical variables. The changes in continuous variables from baseline were tested using paired t-tests. Differences in the incidences of ADRs between groups of patients were tested using Fisher’s exact test and the trends in the incidences of ADRs across ordered-categorical variables were determined using the Cochran–Armitage test. All p-values are derived from two-tailed tests. The sample size was not pre-determined.

3. Results

3.1. Patient disposition and characteristics

A total of 8687 patients were enrolled from 2634 medical institutions in Japan. A total of 1431 patients were excluded from the analyses because their survey form was not collected and a further 86 were excluded for the following reasons: no hospital visit after the initial visit (n = 76), existence of AEs uncertain (n = 4), unable to check required form (n = 2), not eligible (n = 2), drug not administered (n = 1) and overlapping patient (n = 1). Therefore, the safety analysis population included 7170 patients, of which 1140 had completed the 1-year survey period at a cut-off date for this interim analysis. Patient characteristics at baseline are shown in Table 1. The proportions of males and females were similar. The mean ± SD age of patients was 72.2 ± 5.8 years. Patients aged 75 years or older accounted for 31% (2223) of patients, with the remaining two-thirds aged between 65 and 74 years. The majority of patients were outpatients (7083, 98.8%). The mean ± SD duration of diabetes, BMI and estimated glomerular filtration rate (eGFR) were 10.5 ± 7.5 years, 26.9 ± 4.5 kg/m² and 70.2 ± 18.9 ml/min/1.73 m², respectively.

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.

Most patients (87.4%) were prescribed 50 mg ipragliflozin daily and 12.4% were prescribed 25 mg/day. Overall, 83.1% of patients received concomitant antidiabetic drugs, with a mean number of 2 per patient. The most commonly used antidiabetic drugs were DPP-4 inhibitors (4292, 59.9%), sulfonylureas (2545, 35.5%) and metformin (1960, 27.3%) (Table 2). Other concomitant drugs included diuretics in 868 patients (12.1%), antihypertensive drugs in 3165 patients (44.1%) and statins in 2324 patients (32.4%).

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.

Overall, 1727 patients discontinued treatment for the following reasons: AE (538, 7.5%); patient request (excluding AEs) (442, 6.2%); no change or worsening of diabetes (322, 4.5%); did not visit the medical institution during the survey period (213, 3.0%); improvement in diabetes (86, 1.2%); ipragliflozin was stopped for ≥2 consecutive months (3, 0.17%); or another reason (249, 3.5%). In some cases, patients discontinued treatment because of more than two reasons.

3.2. Safety

The incidence rates of ADRs (overall and by system organ class) for ipragliflozin at approval and in the current survey are summarized in Table 3.

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.

At approval, 549 patients (32.89%) had experienced 887 ADRs in the phase 2 and 3 clinical trials.[2–7] The most common ADRs by system organ class in the pre-approval trials were renal and urinary disorders (176 patients, 10.55%), investigations (133 patients, 7.97%), gastrointestinal disorders (102 patients, 6.11%), and general disorders and administration site conditions (101 patients, 6.05%).

Of the 7170 patients enrolled in this survey, 721 patients (10.06%) experienced 898 ADRs. The most common ADRs (by system organ class) were skin and subcutaneous tissue disorders (163 patients, 2.27%) followed by renal and urinary disorders (120 patients, 1.67%), infections and infestations (89 patients, 1.24%), general disorders and administration site conditions (80 patients, 1.12%) and gastrointestinal disorders (73 patients, 1.02%).

The incidence rates of ADRs of special interest (hypoglycemia, genital infection, urinary tract infection, polyuria/pollakiuria, volume depletion, cardiovascular/cerebrovascular disease and skin complications) are shown in Table 4, and ranged from 0.14 to 2.23%. Volume depletion-related events were defined as all events associated with potential reductions in body fluid volume and dehydration. ‘Skin complications’ included all ADRs related to skin. All ADRs related to hypoglycemia were recorded as hypoglycemia and none were classified as serious. The most common type of genital infection-related ADR was pruritus genital (56 patients, 0.78%). Urinary tract infection-related ADRs included cystitis (24 patients, 0.33%) and urinary tract infection (24 patients, 0.33%). ADRs associated with polyuria/pollakiuria were predominantly pollakiuria, which occurred in 71 patients (0.99%). The most common types of ADR associated with volume depletion were thirst and dehydration, which occurred in 27 (0.38%) and 26 patients (0.36%), respectively. The most common cardiovascular/cerebrovascular ADR was cerebral infarction, which occurred in 7 patients (0.10%). The most common ADRs associated with skin complications were drug eruption in 48 patients (0.67%), rash in 26 patients (0.36%) and eczema in 24 patients (0.33%). The seriousness of ADRs is also shown in Table 4. Of 721 patients with an ADR, the event was classified as serious in 44 patients (0.61%) and ranged from 0.0 to 0.11%.

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)

Regarding the time to the onset of ADRs, 443/898 ADRs (49.3%) occurred within 30 days of starting treatment, especially skin complications (102/170, 60.0%), volume depletion (84/169, 49.7%) and polyuria/pollakiuria (64/97, 66.0%).

Importantly, 92.1% (827/898) of all ADRs were classified as resolved or improved, with similar rates for the individual categories of ADR, including polyuria/pollakiuria (87/97, 89.7%), skin disorders (162/170, 95.3%) and volume depletion (153/169, 90.5%).

Table 5 shows the factors that were significantly associated with ADRs in univariate analyses. Gender, BMI, renal/hepatic functions and age, in particular, were significantly associated with the incidences of ADRs.

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.

3.3. Effects of ipragliflozin on laboratory variables and vital signs

The effects of ipragliflozin on the changes in laboratory variables and vital signs were also evaluated as surrogate markers (Table 6). Significant decreases in HbA1c, fasting blood glucose, body weight, BMI, systolic blood pressure and diastolic blood pressure were observed at 1, 3, 6, 9 and 12 months, and at the final visit compared with the baseline values (all p < 0.001, Table 6). Hematocrit, serum creatinine and blood urea nitrogen increased significantly from baseline to the last visit/treatment discontinuation (all p < 0.001), although the magnitudes of these changes were very small (Table 6). In addition, eGFR was significantly lower at 1, 3 and 6 months, and at the final visit or treatment discontinuation compared with baseline.

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.

4. Discussion

The safety of SGLT2 inhibitors has become an important issue in Japan. This is because of the large number of serious AEs including urogenital infections, hypoglycemia, dehydration, and skin complications reported in the first 3 months of using ipragliflozin or other SGLT2 inhibitors in Japanese patients with type 2 diabetes mellitus.[11] Concerns about serious AEs are less apparent in countries other than Japan, so there is a need to perform long-term observational studies of Japanese patients treated with SGLT2 inhibitors in clinical practice in order to determine the real risk of these AEs in the treated patients. Here, we report interim results of a PMS survey to determine the long-term safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus. We focused on elderly patients in this survey because of the large number of elderly patients with type 2 diabetes mellitus in Japan and because these patients are rarely enrolled in pre-approval clinical trials, limiting our knowledge about the safety of ipragliflozin in this population. In fact, about 28% of patients treated with ipragliflozin in actual clinical practice are ≥65 years old and only 8% of elderly patients were ≥75 years old when they were first prescribed ipragliflozin. This indicates that ipragliflozin is used with some caution in this age-group. In addition, ipragliflozin is rarely prescribed to elderly patients with a very low BMI, as illustrated in the present survey.

In the present survey, 898 ADRs were reported in 721 patients, with skin and subcutaneous tissue disorders, and renal and urinary disorders being the most common classes of events according to the system organ class. These results compare favorably with the data obtained at approval, in which 887 ADRs were reported in 549/1669 patients (32.89%). Notably, most of the individual ADRs (92.1%) either resolved or improved and only 44 ADRs were classified as serious, demonstrating the good safety profile of ipragliflozin.

The results of the current PMS survey revealed a lower incidence of skin complications than was previously reported by Yabe et al. in an analysis of approved SGLT2 inhibitors (ipragliflozin, dapagliflozin, tofogliflozin and luseogliflozin) from the Japan Medical Data Center Claims Database.[11] Instead, our data on skin complications and the overall safety of ipragliflozin showed similar trends to those observed in the pre-approval clinical trials [2–7] and there were no cases of Stevens–Johnson syndrome or toxic epidermal necrolysis in the present survey. Regarding AEs/ADRs reported in studies conducted outside of Japan, a pooled analysis of patients aged 18–92 years (mean 56.9 years) found that hypersensitivity-type reactions, which included skin events, occurred in 270/5936 (4.5%) patients, including in 21/1050 (2.0%) Asian patients treated with dapagliflozin for 12–208 weeks.[12] The incidence of hypersensitivity AEs in the non-Asian population in the same study was similar, occurring in 249/4886 (5.1%) patients. Rash and eczema were the most frequent hypersensitivity-type reactions, occurring in 1.1% (63/5936) and 0.6% (38/5936) of patients, although these rates were similar to those in the placebo groups [1.1% (36/3403) and 0.8% (26/3403), respectively). Although we did not assess hypersensitivity-type reactions per se, the incidence of skin complications-related ADRs (2.23%) was similar to that of reported for dapagliflozin in Asian patients. Furthermore, in the product information for dapagliflozin and canagliflozin marketed in the US, hypersensitivity-type reactions including rash, pruritus, urticaria and angioedema are reported.[13,14]

A number of variables including low BMI, impaired renal function, concomitant use of insulin, female, impaired hepatic function, duration of diabetes ≥5 years, age ≥75 years, and concomitant use of a diuretic were significantly associated with the incidence of various classes of ADRs. These variables and other clinical factors may need to be considered when prescribing ipragliflozin. For example, four episodes of hypoglycemia were reported as ADRs in patients with a BMI of <18.5 kg/m² who were also prescribed other concomitant antidiabetic drugs (insulin + ipragliflozin in one patient, ipragliflozin + DPP-4 inhibitor + sulfonylurea + metformin in one patient, ipragliflozin + sulfonylurea in one patient and ipragliflozin + DPP-4 inhibitor in one patient).

It is also notable that age ≥75 years was significantly associated (p < 0.001) with volume depletion-related ADRs, such as dehydration. Elderly patients are particularly likely to experience reduced thirst sensation [15], which can lead to dehydration. Dehydration is also a symptom of hyperglycemia and increased urine output. We observed small but statistically significant increases in hematocrit, serum creatinine and blood urea nitrogen, which might be indicative of slight volume depletion. Volume depletion is potentially serious if untreated and may result in renal, cardiovascular or cerebrovascular events. In the current study, one case each of stroke (classified as severe) and transient ischemic attack (classified as mild) were judged to be associated with volume depletion, but both events were resolved. Therefore, when managing elderly patients to be treated with ipragliflozin, it is important to evaluate potential risk factors, such as dehydration, in regular medical checks by assessing the patient’s physical status and general well-being and to control hyperglycemia-related symptoms such as dehydration and encouraging the consumption of fluids.[16,17]

Urinary tract and genital tract infections were more common with the SGLT2 inhibitors dapagliflozin and canagliflozin, marketed in the US and the EU, than with other antidiabetic drugs.[18] However, these episodes were often reported to be mild and resolved or improved following appropriate treatments.[19–22] Other possible safety concerns identified include genital mycotic infections (more common in women than men), urinary tract infection and volume depletion (especially among the elderly), although these events are usually mild to moderate in severity and their associations with SGLT2 inhibitors are not entirely clear.[23] The incidence of non-serious genital infections was lower with ipragliflozin in the present study (1.45%) than with dapagliflozin (5.5%) in a pooled analysis of patients with a mean age of about 58 years.[24] In that study, the incidence of genital infections tended to increase with increasing BMI and a similar finding was observed in the present survey.

Other safety issues of SGLT2 inhibitors outside Japan have been identified, including possible adverse effects on bone, considering the frequency of treatment-emergent bone fractures that has been reported.[25] However, there were no cases of fracture in the current PMS survey.

This PMS survey focusing on the safety of ipragliflozin was the first to be reported of all SGLT2 inhibitors approved in Japan and is significant in terms of the size of the treated population (7170 elderly patients). The data may be useful not only for patients in Japan but also for those in other countries in East Asia where patients share similar characteristics to those of Japanese patients (e.g. lower BMI compared with Western patients). These data are also important in terms of demonstrating the safety of ipragliflozin in patients with advanced age because advanced age (≥75 years) was not associated with the specific classes of ADRs, except for volume depletion-related ADRs.

In the present survey, ADRs related to cerebrovascular disease and cardiovascular disease occurred in about 0.1% of patients, although most of the events were classified as serious. A subgroup analysis of the EMPA-REG OUTCOME study [26], showed that the SGLT2 inhibitor empagliflozin was effective at reducing major adverse cardiovascular events and cardiovascular death in elderly patients. Similar studies are also needed to examine the impact of SGLT2 inhibitors on major adverse cardiovascular events in elderly Japanese patients at high risk of such events.

Finally, we observed significant improvements in clinically relevant surrogate markers, including HbA1c, FPG, body weight, BMI and systolic blood pressure in this cohort of elderly Japanese patients with type 2 diabetes mellitus. These results support those observed in the pre-approval clinical trials of ipragliflozin in younger patients.[2–7]

The findings of this study should be interpreted in light of its limitations. First, the criteria for renal/hepatic impairment may not have been strictly observed among physicians, because in each case, an individual physician judged the impairment based on laboratory data. Second, physicians were asked to determine if any ADR was possibly associated with volume depletion, but there may have been some variability in the adjudication of such events by the physician. Third, some episodes of hypoglycemia were not determined on the basis of objective laboratory data. Nevertheless, the objective of this survey was to obtain data regarding the incidence of ADRs and the most common types of ADRs in elderly patients treated with ipragliflozin in actual clinical practice and this was achieved by performing a PMS survey, a common method in this setting.

5. Conclusions

In conclusion, the current PMS survey revealed that ipragliflozin has a good safety profile and is an effective treatment in terms of improving glycemic control in elderly Japanese patients with type 2 diabetes mellitus. The incidence of ADRs in the present survey was similar to that in pre-approval clinical trials, while the incidence of volume depletion, a particular concern for elderly patients, was high in patients aged ≥75 years and those treated with a diuretic. Thus, both subgroups of patients should be managed carefully to avoid volume depletion. Nevertheless, the majority of events were classified as non-serious and resolved/improved. The final results of the 1-year survey are awaited.

Declaration of interest

This study was sponsored by Astellas Pharma Inc., Japan. Y Terauchi has received honoraria for speakers bureau from Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Company Limited, Dainippon Sumitomo Pharma Co., Ltd., Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Company Ltd., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K., Shionogi & Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited; and grants from Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Company Limited, Dainippon Sumitomo Pharma Co., Ltd., Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Company Ltd., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K., Shionogi & Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited.

K Yokote has received grants/research support from Astellas Pharma Inc., Daiichi Sankyo Company Limited, Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation; honoraria for speakers bureau and consulting fees from Astellas Pharma Inc., AstraZeneca K.K., Daiichi Sankyo Company Limited, Kowa Pharmaceutical Company Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceuticals Ltd, MSD K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Shionogi & Co., Ltd, and Takeda Pharmaceutical Company Limited; funded research department from MSD K.K.

I Nakamura and H Sugamori are employees of Astellas Pharma Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance provided by Dr. Nicholas D. Smith and Dr. J. Ludovic Croxford of Edanz Group Ltd., and by ELMCOM™ was utilized in the production of this manuscript and funded by Astellas Pharma Inc.