ABSTRACT
Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective treatments for type 2 diabetes mellitus (T2DM). We present the interim findings of an ongoing post-marketing surveillance (PMS) study in Japanese patients with T2DM receiving empagliflozin.
Research design and methods: This 3-year, prospective, observational, multicenter PMS evaluated the safety and effectiveness of empagliflozin in Japanese clinical practice. Patients with T2DM who had not been treated with empagliflozin before enrollment were eligible. Assessments, including the primary endpoint of incidence of adverse drug reactions (ADRs), were based on electronic case report forms (eCRF).
Results: Of 8,180 registered patients from 1,103 sites, 7,618 patients had an eCRF including a follow-up visit and were treated (mean age, 58.8 years; 10.5% aged ≥75 years; 63.2% male; mean HbA1c, 8.01%; 41.8% with HbA1c ≥8.0%; 24.8% and 61.8% with at least mild hepatic and renal impairment, respectively). Mean treatment duration was 98.4 weeks; 644 (8.5%) patients had ≥1 ADR, including 8.5% of patients aged ≥75 years. Hypoglycemia, urinary tract infection, genital infections, volume depletion, diabetic ketoacidosis, and lower limb amputation occurred in 0.28%, 0.62%, 0.53%, 0.33%, 0%, and 0.03% of patients, respectively.
Conclusions: The reported ADRs were consistent with the known safety profile of empagliflozin.
Trial registration: ClinicalTrials.gov identifier: NCT02489942.
1. Introduction
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are glucose-lowering agents with an insulin-independent mechanism of action that supports their use as monotherapy and in combination with other antidiabetic agents to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) [Citation1]. Since the approval of the first SGLT2 inhibitor in Japan in 2014, the class has become widely used. In several post-marketing surveillance (PMS) studies, including in elderly patients, adverse drug reactions (ADRs) occurred at similar or lower frequencies to clinical trials, with no new safety concerns [Citation2–Citation5].
Empagliflozin is a highly selective SGLT2 inhibitor with potent blood glucose–lowering effects and modest benefits in terms of reductions in body weight and blood pressure (BP) [Citation1,Citation6]. Beyond these metabolic benefits, the EMPA-REG OUTCOME trial showed that empagliflozin additionally had cardioprotective and renoprotective benefits, reducing cardiovascular death, all-cause mortality, hospitalization for heart failure (HHF), and kidney disease progression in patients with T2DM and established cardiovascular disease (CVD) [Citation1,Citation7,Citation8]. An interim report of the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) study further showed that, relative to a dipeptidyl peptidase-4 inhibitor, the initiation of empagliflozin was associated with a decreased risk of HHF among patients with or without a history of CVD who were treated in routine care in the United States [Citation9]. Cardiovascular and renal benefits have also been demonstrated for other SGLT2 inhibitors, specifically canagliflozin and dapagliflozin [Citation10,Citation11]. Currently, empagliflozin is the only SGLT2 inhibitor with proven cardiovascular and all-cause mortality benefits in patients with T2DM and established CVD [Citation8,Citation10,Citation11].
Because side effects such as urinary tract infections (UTIs), genital tract infections, and diabetic ketoacidosis (DKA) are predicted on the basis of the mechanism of action of SGLT2 inhibitors, it is necessary to conduct ongoing monitoring of such events [Citation12]. To mitigate their likelihood, a committee of experts has issued recommendations for the appropriate use of SGLT2 inhibitors [Citation13].
Previously, we reported the findings of large-scale pooled analyses of overall and East Asian patients with T2DM who were treated with empagliflozin 10 mg or 25 mg in phase 1–3 clinical trials [Citation14,Citation15]. Compared with placebo, empagliflozin treatment in the overall and East Asian cohorts was associated with similar incidences of adverse events (AEs), including severe AEs, serious AEs (SAEs), and AEs leading to discontinuation [Citation14,Citation15]. AEs that occurred more frequently compared with placebo were genital infections and, in patients aged ≥75 years, volume depletion. The rates of UTIs, bone fractures, malignancy, renal events, hepatic injury, lower limb amputations, and DKA were similar between empagliflozin and placebo. Thus, in clinical trials, empagliflozin was well tolerated in overall and East Asian patients with T2DM. However, large-scale observational data of the safety and effectiveness of empagliflozin in the real-world clinical setting in Japan have yet to be published.
Given the importance of confirming the long-term, real-world safety and effectiveness of empagliflozin for the treatment of patients with T2DM, particularly elderly patients, we commenced PMS of empagliflozin in 2015. In order to provide early feedback because there are currently limited data regarding the safety and effectiveness of empagliflozin in actual clinical practice, we herein report interim results, including maximum-to-date 3-year findings. Consistent with the broad, real-world use of empagliflozin in Japan, we aimed to include a significant proportion of elderly patients.
2. Patients and methods
2.1. Study design
This PMS study is an ongoing, prospective, observational, single-arm, 3-year, multicenter study (Study 1245.94; ClinicalTrials.gov NCT02489942) conducted at 1,103 centers in Japan. The study is being conducted in routine clinical practice without restriction and in accordance with Japanese Ministry of Health and Welfare Ordinance GPSP and Good Vigilance Practice regulations, as well as standard operating procedures of the sponsor. As an observational study, independent review board/ethics committee approval and patient informed consent were not sought. Enrollment started in June 2015 and was completed in May 2017. For the present interim analysis, data were collected via electronic case report form (eCRF) at weeks 12, 52, 104, and 156 of empagliflozin treatment, and at treatment discontinuation (last observation). Adverse event reports were collected continuously. Data cutoff was 17 October 2018.
2.2. Study population
Male and female patients with T2DM from Japan who had not previously been treated with empagliflozin before enrollment were eligible. Prior use of other SGLT2 inhibitors was permitted. Patients without T2DM or who had received empagliflozin prior to enrollment were excluded.
2.3. Assessments
The primary safety endpoint was the incidence of ADRs coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 21.0. Investigators assessed whether an AE constituted an ADR. An ADR was defined as any adverse reaction with the possibility of a reasonable causal relationship between empagliflozin and the AE, or when the causal relationship was unknown due to insufficient or contradictory information. Causality was established if either the investigator or sponsor or both assessed the causal relationship of empagliflozin with the AE as ‘possibility high,’ ‘possibility low,’ or ‘unknown.’ The sponsor assessed the causal relationship independently from the investigator and did not influence the investigator’s assessment.
Other safety endpoints were the incidences of serious ADRs and priority survey items. Priority survey items were AEs of hypoglycemia, UTI, genital infection, volume depletion, cardiovascular event, DKA, renal impairment, liver injury, bone fracture, malignancy, excessive urination/frequent urination, and AEs relating to an increase in ketone. Liver injury was captured based on reported AEs; for non-serious AEs, the degree of liver injury (eg, based on liver function tests) was not captured. Although not a priority survey item, lower limb amputations were also evaluated. Sarcopenia was assessed via the MedDRA preferred terms ‘Muscular weakness’, ‘Sarcopenia’, ‘Muscle atrophy’, ‘Muscle fatigue’, and ‘Myopathy’. An ADR was considered to be serious if it resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, or was a congenital anomaly/birth defect.
The effectiveness endpoint was the change in glycosylated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) from baseline to the last observation on treatment. Other measures included assessment of BP and pulse rate (vital signs), body weight, and laboratory assessments, including hematocrit, hemoglobin, total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, bilirubin, creatinine, and estimated glomerular filtration rate (eGFR).
2.4. Statistical analysis
The analyses used in this PMS study were descriptive and exploratory; as such, no formal hypothesis testing was undertaken. The PMS aimed to enroll at least 3,000 patients who completed a 3-year observation period. On the basis of 3,000 completers, an ADR with a true incidence of 0.10% was expected to occur in at least one patient with a probability of 95%. Safety was evaluated using the safety analysis set (SAS), which included patients who received empagliflozin at least once regardless of dose, but excluded those patients with invalid registration, no observation following enrollment, or invalid site contract. Effectiveness was evaluated using the effectiveness analysis set (EAS), which included patients in the SAS, but excluded those without available effectiveness data and, to discourage off-label use according to the package insert in Japan [Citation16], those who initiated empagliflozin at 25 mg/day and those who had a baseline eGFR of <30 ml/min/1.73 m2.
In addition to descriptive statistics to report the incidence of ADRs in patients enrolled in the PMS, data were compared with a pooled safety analysis using data from three phase 2b/3 clinical trials conducted in Japanese patients with T2DM who were treated for ≥52 weeks with empagliflozin at 10 mg/day or 25 mg/day [Citation17]. The incidence rate of ADRs of special interest was expressed per 1,000 patient-years. SAS version 9.4 software (SAS Institute Inc., Cary, NC, USA) was used for statistical analyses.
3. Results
3.1. Patient disposition
Of 8,180 enrolled patients, eCRFs were collected for 7,717 patients (Supplemental Figure S1). The SAS consisted of 7,618 patients, with 99 patients excluded for reasons of no visit recorded after entry (n = 95), multiple registration (n = 1), and no T2DM (n = 3). The EAS consisted of 7,099 patients, with 519 patients excluded for reasons of no baseline and/or post-baseline HbA1c and FPG values.
3.2. Patient demographics and baseline characteristics
The mean (standard deviation [SD]) overall age was 58.8 (12.8) years, with 63.4% of patients aged <65 years, 26.1% aged ≥65 to <75 years, and 10.5% aged ≥75 years at baseline (). Overall, 63.2% of patients were male, 62.4% had a body mass index ≥25 kg/m2, and 24.8% had at least mild hepatic impairment. The mean (SD) duration of diabetes was 8.20 (7.3) years; 34.8% of patients had diabetes for >5 years. At baseline, mean (SD) HbA1c was 8.01% (1.45); 40.7% of patients had an HbA1c level ≥8.0%. Mean (SD) FPG was 160.0 (55.7) mg/dl and mean (SD) eGFR was 82.52 (24.6) ml/min/1.73 m2. Most (83.5%) patients had ≥1 concomitant disease, most commonly hypertension (57.2%) and dyslipidemia (40.7%).
Table 1. Patient demographics and baseline characteristics (safety analysis set)*.
3.3. Treatment
In this interim analysis, 71.4% of patients at data cutoff were treated with empagliflozin for ≥52 weeks. A total of 691 (8.9%) patients discontinued prior to week 52 for reasons of AE (n = 94), no change or progressive disease (n = 56), improvement in their disease (n = 62), patient request (n = 170), or other reasons (n = 309). Patients were treated with empagliflozin for a mean (SD) duration of 98.4 (42.0) weeks (median 106.9 weeks, range 0.1–175.1) (Supplemental Table S1). Approximately 95% of patients were initiated with empagliflozin 10 mg/day. At the last dose, 8.1% of patients were receiving empagliflozin 25 mg/day; 3.8% of patients were up-titrated from 10 mg/day to 25 mg/day during treatment. At baseline, 23.8% of patients initiated empagliflozin as monotherapy; 45.3% initiated empagliflozin together with ≥2 additional glucose-lowering medications. Concomitant medications at baseline included a dipeptidyl peptidase-4 inhibitor (44.4%), biguanide (36.2%), sulfonylurea (20.2%), and insulin (11.9%).
3.4. Safety
3.4.1. Incidence of ADRs, serious ADRs, and deaths
In this interim analysis, 644 of 7,618 (8.5%) patients experienced ≥1 ADR during treatment with empagliflozin, including 8.0% of patients aged <65 years, 9.6% of patients aged ≥65 to <75 years, and 8.5% of patients aged ≥75 years. An empagliflozin pooled safety analysis of Japanese patients treated for ≥52 weeks in three clinical trials (pre-approval pooled Japanese safety data) [Citation17] showed that the incidence of ADRs was 14.7% for those receiving empagliflozin 10 mg/day and 16.1% for patients receiving the 25 mg/day dose (). ADRs for the present PMS study are summarized by system organ class in Supplemental Table S2. Less than 5% of patients in each age subgroup were pretreated with another SGLT2 inhibitor; the frequency of drug-related AEs was not different between patients who had received pretreatment and those who had not (data not shown).
Table 2. Adverse drug reactions of special interest: comparison by age subgroup and pre-approval pooled safety data for patients treated ≥52 weeks (safety analysis set).
Serious ADRs occurred in 74 of 7,618 (0.97%) patients (Supplemental Table S3). Serious ADRs by preferred term that occurred in at least two patients were 12 (0.16%) cases of cerebral infarction, four (0.05%) cases of angina pectoris, three (0.04%) cases of acute myocardial infarction, and two (0.03%) cases each of cardiac failure, cerebellar infarction, bile duct cancer, pyelonephritis, fall, and diabetic gangrene. A total of 17 deaths were reported, including 14 deaths that were considered to be unrelated to empagliflozin and three deaths for which empagliflozin could not be excluded as having a relationship. The cause of death in these cases was bile duct cancer in a 67-year-old woman, malignant ascites in a 69-year-old man, and bacterial arthritis in a 70-year-old man.
3.4.2. ADRs of special interest
The incidences of ADRs of special interest compared favorably with pre-approval pooled Japanese safety data () [Citation17]. Hypoglycemia occurred in 21 (0.28%) patients overall, including 13 (0.27%) patients aged <65 years, five (0.25%) patients aged ≥65 to <75 years, and three (0.37%) patients aged ≥75 years (). Of the 21 hypoglycemia events, seven occurred in patients receiving concomitant sulfonylureas, and 12 occurred in patients receiving insulin. No patient experienced a serious ADR of hypoglycemia.
UTIs and genital infections occurred in 47 (0.62%) and 40 (0.53%) patients, respectively, in the PMS compared with 2.0%/1.1% and 1.1%/0.7%, respectively, for patients treated with empagliflozin 10 mg and 25 mg in pre-approval pooled Japanese safety data (). In the PMS, UTIs occurred in 30 (0.62%) patients aged <65 years, 10 (0.50%) patients aged ≥65 to <75 years, and seven (0.87%) patients aged ≥75 years. Genital infections occurred in similar proportions of patients in each age subgroup. UTIs occurred in 1.28% of women and 0.23% of men. Three patients experienced a serious UTI, including two patients with serious pyelonephritis. Genital infections occurred in 1.03% of women and 0.23% of men. One patient had vulvitis as a concomitant disease before receiving empagliflozin.
Volume depletion occurred in 25 (0.33%) patients, including 0.35% of patients aged <65 years, 0.35% of those aged ≥65 to <75 years, and 0.12% of patients aged ≥75 years. In comparison, volume depletion–related events occurred in 0.7% and 0.1% of patients treated with empagliflozin 10 mg and 25 mg in pre-approval pooled Japanese safety data. In the PMS, dehydration occurred in 22 cases, including nine cases in summer with no evidence of seasonal differences. Use of diuretics was associated with three cases of volume depletion, including two patients using a loop diuretic. Two (0.03%) patients with volume depletion had serious events, including one patient each with BP decreased and dehydration.
Cardiovascular events occurred in 29 (0.38%) patients overall, including 14 (0.29%), 10 (0.50%), and five (0.62%) patients aged <65, ≥65 to <75, and ≥75 years, respectively. There were no incidences of cardiovascular events in patients treated with empagliflozin 10 mg or 25 mg in pre-approval pooled Japanese safety data. In the PMS, cardiovascular events included 13 (0.17%) patients overall with cardiac disorders and 16 (0.21%) with cerebral events. Cardiac disorders included six (0.08%) patients with angina pectoris, three (0.04%) with acute myocardial infarction, two (0.03%) with cardiac failure, and one each (0.01%) with myocardial ischemia and silent myocardial infarction. Cerebral events included cerebral infarction (n = 12; 0.16%), cerebellar infarction (n = 2; 0.03%), and one patient (0.01%) each with carotid artery stenosis, lacunar infarction, and thrombotic cerebral infarction.
Seven (0.09%) patients experienced renal ADRs (none serious) and 26 (0.34%) had liver injury (one serious). The serious liver injury was of hepatic function abnormal.
The most commonly reported ADR of special interest, excessive/frequent urination, which occurred in 80 (1.05%) patients overall, did not result in any serious cases. In contrast, the incidences among patients treated with empagliflozin 10 mg and 25 mg in the pre-approval pooled Japanese safety data were 5.0% and 5.7%, respectively.
AEs relating to an increase in ketone occurred in 26 (0.34%) patients overall, with a single serious event, which was not DKA, in a patient aged 50 years. Following a hospital visit for appetite loss, this patient (receiving insulin combination therapy) was diagnosed with diabetic ketosis by increased ketones in the urine. Two (0.03%) lower limb amputations were reported, with both cases involving diabetic gangrene and requiring toe amputation. Other ADRs are reported in .
The median time to onset of ADRs of special interest ranged from 4.1 weeks for excessive/frequent urination to 50.7 weeks for malignancy (). Hypoglycemic events and increased urination were reported mostly within the first 12 weeks, with no clear pattern seen for the other ADRs of special interest.
Table 3. Adverse drug reactions of special interest: time to onset of first episode (safety analysis set).
Patients who up-titrated from empagliflozin 10 mg to 25 mg (N = 293) reported ADRs of special interest (Supplemental Table S4). No notable increase in the risk of these ADRs was observed, except for an increase in ADRs related to an increase in ketone (3.41% in patients who up-titrated vs 0.34% in the overall population, with no ADR of DKA in either population).
3.5. Effectiveness
Among patients with baseline eGFR ≥30 ml/min/1.73 m2 who were treated with empagliflozin at an initial dose of 10 mg/day and constituted the EAS, treatment was associated with reductions from baseline over time in HbA1c and FPG (). At the last observation, empagliflozin reduced HbA1c by a mean of –0.80% (95% CI: –0.83, –0.77) and FPG by a mean of –31.0 mg/dl (95% CI: –33.3, –28.8).
Figure 1. Effect of treatment with empagliflozin at an initial dose of 10 mg/day. Change from baseline over time in (a) HbA1c and (b) FPG (effectiveness analysis set). Change from baseline over time in (c) body weight (safety analysis set). Absolute values for eGFR (d) over time (safety analysis set). Values are mean ± SD. Data for the overall population are indicated by black squares; data for age subgroups <65 years, ≥65 to <75 years, and ≥75 years are indicated by closed circles, open circles, and triangles, respectively. CI: confidence interval. eGFR: estimated glomerular filtration rate. FPG: fasting plasma glucose. HbA1c: glycosylated hemoglobin A1c. Last obs.: last observation. SD, standard deviation.
A subgroup analysis of change from baseline in HbA1c and FPG at last observation showed reductions in these variables independent of age category (). HbA1c decreased by a mean (SD) of –0.88% (1.33) in patients aged <65 years, by –0.67% (1.10) in patients aged ≥65 to <75 years, and by –0.62% (1.19) in patients aged ≥75 years. FPG decreased by a mean (SD) of –34.1 mg/dl (55.3) in patients aged <65 years, by –23.8 (46.3) mg/dl in patients aged ≥65 to <75 years, and by –29.9 (57.2) mg/dl in patients aged ≥75 years. With respect to baseline eGFR category, reductions in HbA1c and FPG tended to be somewhat greater in people with eGFR ≥90 ml/min/1.73 m2 than in those with lower eGFR; however, significant reductions in both HbA1c and FPG were observed in all of the eGFR categories (Supplemental Table S5). Mean (SD) reductions in HbA1c ranged from –1.04% (1.43) for patients with baseline eGFR of ≥90 ml/min/1.73 m2 to –0.55% (1.21) for patients with baseline eGFR of 45 to <60 ml/min/1.73 m2 and –0.69% (1.28) for patients with baseline eGFR of 30 to <45 ml/min/1.73 m2. Mean (SD) reductions in FPG ranged from –38.2 mg/dl (58.0) for patients with baseline eGFR of ≥90 ml/min/1.73 m2 to –24.0 (50.8) mg/dl for those with baseline eGFR of 30 to <45 ml/min/1.73 m2.
Among patients in the EAS who had an empagliflozin dose increase from 10 mg to 25 mg, HbA1c decreased at last observation by a mean of –0.75% (95% CI: –0.92, –0.59; mean HbA1c at baseline: 8.03%) and FPG decreased by a mean of –25.4 mg/dl (95% CI: –35.0, –15.9; mean FPG at baseline: 155.7 mg/dl). When compared with values before dose increase at last observation, the mean reduction associated with up-titration of empagliflozin was –0.28% (95% CI: –0.40, –0.16) for HbA1c and –11.0 mg/dl (95% CI: –18.8, –3.1) for FPG (Supplemental Table S6).
3.6. Other findings
In the SAS, empagliflozin treatment was associated with significant reductions from baseline over time in body weight (); ). At the last observation, empagliflozin reduced body weight by a mean of –2.62 kg (95% CI: –2.73, –2.51). Changes from baseline in body weight were also consistent between age subgroups. In patients aged <65 years, mean body weight decreased by –2.70 kg (95% CI: –2.84, –2.55). In patients aged ≥65 to <75 years, and in those aged ≥75 years, the corresponding mean decreases in body weight were –2.56 kg (95% CI: –2.78, –2.34) and –2.26 kg (95% CI: –2.58, –1.93), respectively ()).
Table 4. Change from baseline in body weight and laboratory parameters (safety analysis set).
Reductions in body weight were consistent regardless of baseline eGFR. In patients with baseline eGFR of ≥90, 60 to <90, 45 to <60, and 30 to <45 ml/min/1.73 m2, the corresponding mean (95% CI) reductions from baseline in body weight at last observation were –2.61 kg (95% CI: –2.83, –2.38), –2.62 kg (95% CI: –2.76, –2.47), –2.50 kg (95% CI: –2.81, –2.18), and –2.32 kg (95% CI: –3.04, –1.59), respectively (Supplemental Table S7).
Overall, eGFR decreased from a mean (SD) baseline value of 81.83 (24.61) ml/min/1.73 m2. However, with a mean reduction at last observation of –3.10 ml/min/1.73 m2 (95% CI: –3.58, –2.61), the absolute reduction of 3.8% over a mean treatment duration of 98.4 weeks was consistent with the pre-approval pooled Japanese safety data. ()). Other vital signs and laboratory measures are described in .
4. Discussion
Following recommendations of the expert committee regarding the appropriate use of SGLT2 inhibitors [Citation13], the present PMS study provides the opportunity to investigate the safety and effectiveness of empagliflozin in different patient subgroups in routine clinical care in Japan. We therefore investigated the safety and effectiveness of empagliflozin according to age subgroup at baseline. For comparative purposes, we used empagliflozin pre-approval pooled safety data from clinical trials of Japanese patients treated with empagliflozin 10 mg or 25 mg for ≥52 weeks [Citation17]. We further investigated the incidence of ADRs of special interest that require ongoing attention in order to demonstrate the long-term safety of empagliflozin. In this interim report, we show that the incidences of ADRs were consistent with these data. In particular, the present findings provide real-world evidence of the safety of empagliflozin in relation to ADRs of special interest and laboratory test parameters. Importantly, these interim surveillance results also provide real-world evidence of the long-term effectiveness of empagliflozin in different patient subgroups.
Consistent with the results of randomized controlled trials and with the insulin-independent mechanism of action of empagliflozin [Citation14,Citation15,Citation18,Citation19], the incidence of hypoglycemia was low, with an overall incidence of 0.28% compared with 2.6% of patients treated with empagliflozin in the pre-approval pooled Japanese safety data. Further, hypoglycemia occurred at a similar frequency in each of the age subgroups. Of the 21 observed cases of hypoglycemia, 18 were associated with concomitant sulfonylurea or insulin use. Therefore, when empagliflozin is used in combination with a sulfonylurea or insulin, a lower dose of the sulfonylurea or insulin should be considered to reduce the risk of hypoglycemia, as recommended by the expert committee [Citation13].
Increases in natriuresis and diuresis have been noted with SGLT2 inhibitors, which, in vulnerable patients, may contribute to volume depletion [Citation18]. We previously reported that initiation of empagliflozin treatment in Japanese patients with T2DM was associated with transient diuresis [Citation20]. In this earlier study, 24-hour urine volume increased dose dependently on day 1 and returned to baseline levels within 4 weeks of initiating treatment [Citation20]. Similarly, Heise et al. reported that in European patients with T2DM, multiple-dose administration of empagliflozin was associated with transient increases in urine volume and urinary sodium excretion that returned to baseline levels after 5 days [Citation21]. Transient increases in urine volume were also seen with another SGLT2 inhibitor, dapagliflozin, in healthy volunteers [Citation22]. Further, mathematical modeling was used to show that dapagliflozin is expected to produce substantially greater reductions in interstitial volume compared with blood volume, unlike loop diuretics [Citation22]. In the current PMS study, empagliflozin initiation was associated with increased urination in 1.05% of patients (no serious cases) over the short term. This was lower than the 5.3% of patients who experienced increased urination in the pre-approval pooled Japanese safety data. The incidence of volume depletion (0.33% overall), which led to dehydration in 22 cases (including two cases associated with concomitant diuretic use), was generally similar across age subgroups. These findings were similar to the pre-approval pooled Japanese safety data, in which volume depletion occurred in 0.4% of patients overall. In Japan, increased fluid intake and hydration for elderly patients are especially recommended during initial treatment with SGLT2 inhibitors when administered in combination with diuretics [Citation13].
Genital infections and UTIs may result from the increased urinary glucose excretion elicited by SGLT2 inhibitors [Citation18]. In this study, the incidences of both genital infections (0.53%) and UTIs (0.62%) were low, occurring at similar frequencies across the age subgroups. Although no incident cases of genital infection were serious, three patients experienced serious UTIs, including two cases of pyelonephritis. In comparison, 1.6% of patients treated with empagliflozin in the pre-approval pooled Japanese safety data experienced UTIs, and 0.9% had genital infections. Both types of infection predominantly occurred de novo following empagliflozin initiation. Consistent with earlier reports of empagliflozin treatment in overall and East Asian patients with T2DM, the incidences of UTIs and genital infections were higher in women than in men [Citation14,Citation15].
An increased incidence of lower limb amputation compared with placebo was reported in the canagliflozin CANVAS cardiovascular outcomes trial program [Citation10]. However, a similar signal was not seen with empagliflozin in the EMPA-REG OUTCOME trial [Citation23]. Consistent with this observation for empagliflozin, large-scale safety analyses revealed that the rate of lower limb amputations was low in both overall and East Asian patients with T2DM (1.1% and 0.1%, respectively) and was similar for empagliflozin and placebo [Citation14,Citation15]. The pre-approval pooled Japanese safety data did not include any lower limb amputation events. In the present study, two patients (incidence rate 0.14 per 1,000 patient-years) had lower limb amputations, both involving toe amputation in response to diabetic gangrene. This incidence rate is similar to that reported in a prospective cohort study of the Fukuoka Diabetes Registry, which observed lower limb amputation at a rate of 0.47 per 1,000 person-years in Japanese patients with T2DM [Citation24]. Although there was a low incidence of lower limb amputation with empagliflozin treatment in the present analysis, efforts to collect surveillance data are ongoing.
Several cases of DKA, a rare but potentially life-threatening condition, were reported soon after SGLT2 inhibitors were launched in the United States, prompting the Food and Drug Administration to issue a safety warning [Citation12,Citation18,Citation25]. Although an increase in ketone levels was reported in 26 cases (one serious) in the present PMS study, no cases of DKA were reported. In earlier large-scale safety analyses, DKA occurred in 0.1–0.3% of placebo-treated patients compared with <0.1% of patients treated with empagliflozin 10 mg or 25 mg in overall and East Asian patients with T2DM [Citation14,Citation15].
Some ADRs of special interest, such as cardiovascular event, renal impairment, and liver injury, were higher in this study compared with pre-approval pooled safety data. This is likely because patients with previous cardiovascular events, previous liver dysfunction, and lower eGFR were included in this real-world, post-marketing surveillance study.
Concerns have been raised regarding the potential for SGLT2 inhibitors to activate gluconeogenesis in the liver, lipolysis in adipose tissue, and proteolysis in skeletal muscle [Citation26]. Such proteolysis may, in turn, lead to sarcopenia, particularly in elderly patients with T2DM in whom sarcopenia increases the risk of falls, fractures, and dysphagia [Citation26]. However, there were no AEs of sarcopenia in this study.
Although the primary focus of this PMS study was safety, the effectiveness of empagliflozin in daily clinical practice was also evaluated. Consistent with clinical trial reports [Citation14,Citation15,Citation17,Citation27,Citation28] and a meta-analysis [Citation19], empagliflozin treatment was associated with sustained reductions from baseline in HbA1c and FPG. We observed significant reductions in both HbA1c and FPG irrespective of baseline eGFR status. Furthermore, the effectiveness of empagliflozin was similar irrespective of age subgroup. Among patients who had an empagliflozin dose increase from 10 mg/day to 25 mg/day, the findings suggested that additional glycemic control was achieved compared with the reduction in both HbA1c and FPG at the observation prior to the dose increase. Further research is needed to confirm this finding as the current study did not include a comparator arm and there is a lack of randomized controlled trials designed to evaluate the glycemic effects of dose escalation.
The strengths of this PMS study include its large sample size (7,618 patients) compared with the pre-approval pooled analysis populations (empagliflozin 10 mg: 700 patients; empagliflozin 25 mg: 703 patients) and real-world generalizability to Japanese patients with T2DM. The study population was indicative of the real-world clinical setting. The PMS study included a significant proportion of elderly patients, which permitted the assessment of safety in this patient subgroup. However, as an interim analysis, the results may change with further maturation of the data. As a non-interventional study without a comparator, it is not possible to make any cause and effect associations. Another limitation is the potential underreporting of adverse events. As a long-term surveillance, reporting bias may influence the study findings because patients in the real-world setting may choose not to disclose all AEs. Other confounding variables may also have impacted the study findings, including concomitant medications, comorbidities, and support by healthcare providers.
5. Conclusions
In conclusion, in this interim analysis of an ongoing long-term PMS study, the reported ADRs and ADRs of special interest for empagliflozin were consistent with the known safety profile from previous trials of this agent, including the pre-approval pooled Japanese safety data. No new safety concerns suggesting additional caution were observed. The findings additionally support the real-world effectiveness of empagliflozin. The safety, tolerability, and effectiveness of empagliflozin will continue to be investigated in Japanese patients in this long-term PMS study.
Role of the sponsor
Nippon Boehringer Ingelheim Co. Ltd. and Eli Lilly K.K. were involved in the study design, data collection, data analysis, and preparation of the manuscript.
Declaration of interest
K. Kaku has acted in an advisory role for Astellas Pharma, Sanwa Kagaku Kenkyusho, Nippon Boehringer Ingelheim, and Novo Nordisk Pharma; received honoraria or fees for promotional materials from Astellas Pharma, AstraZeneca, Daiichi Sankyo, MSD, Ono Pharmaceutical, Novo Nordisk Pharma, Nippon Boehringer Ingelheim, Taisho-Toyama Pharmaceutical, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, and Kowa Pharmaceutical; and received scholarships or donations from Nippon Boehringer Ingelheim, Taisho-Toyama Pharmaceutical, Mitsubishi Tanabe Pharma, and Kowa Pharmaceutical. R. Chin is an employee of Eli Lilly Japan K.K. Y. Naito, R. Ikeda, and A. Yasui are employees of Nippon Boehringer Ingelheim Co. Ltd. H. Iliev is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. K. Ochiai is an employee of EPS Corporation.
Reviewer disclosures
A peer reviewer of this manuscript discloses being an employee of Janssen. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.
Role of contributors
All authors participated in the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. K. Kaku, R. Ikeda, and A. Yasui were involved in the study design, R. Ikeda was involved in data collection, and R. Chin, Y. Naito, and K. Ochiai conducted the statistical analysis. All authors agree to be accountable for all aspects of this work.
Data availability
The data that support the findings of this study are available from the corresponding author, Yusuke Naito, upon reasonable request.
Previous presentations
This research was presented in part at the 34th Annual Meeting of the Japan Diabetes Complications Society, Osaka, Japan, September 27–28, 2019.
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.
Empagliflozin_PMS_Supplemental_Material.docx
Download MS Word (177.8 KB)Acknowledgments
The authors would like to thank all physicians and patients who participated in this study.
Supplementary material
The supplementary data for this article can be accessed here.
Additional information
Funding
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