Abstract
Objective: To evaluate the safety and efficacy of canagliflozin in elderly patients with type 2 diabetes mellitus (T2DM) in clinical settings.
Methods: The authors conducted a 1-year post-marketing surveillance (PMS) of canagliflozin in almost all the elderly patients (≥65 years old) with T2DM who began taking canagliflozin during the first 3 months after its launch in Japan. The main outcomes included the incidences of adverse drug reactions (ADRs), serious ADRs, and the changes of laboratory tests as well as efficacy variables.
Results: An ADR was reported in 9.09% (125 of 1375 patients) in the safety analysis set. The main ADRs were dehydration, constipation, thirst, pollakiuria, dizziness, cystitis, eczema, pruritus, and rash. The incidence of serious ADRs was 1.02% (14 patients), which included urinary tract infection, dehydration, hypoglycemia, and cerebral infarction (two patients each). ADRs of special interest that had been reported in clinical trials of SGLT2 inhibitors, such as hypoglycemia, volume depletion-related events, genital/urinary tract infection, polyuria/pollakiuria, and ketone body increased were also observed in this PMS. The safety profiles were similar to the results of a previous clinical study of canagliflozin, and new safety concerns were not identified in this survey. The mean change in HbA1c was –0.77% after 12 months of treatment in the efficacy analysis set.
Conclusion: In this PMS, the safety and efficacy profiles of canagliflozin in elderly patients with T2DM were obtained in the clinical settings in Japan and the drug was well tolerated and effective in improving glycemic control.
Introduction
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-diabetic drugs that lower blood glucose concentrations by suppressing renal glucose reabsorption via the inhibition of SGLT2 localized in the proximal renal tubule, thereby increasing urinary glucose excretionCitation1–3. SGLT2 inhibitors exert a glucose lowering effect in an insulin-independent manner and improve glycemic control in the treatment of type 2 diabetes mellitus (T2DM) as monotherapy or in combination with other anti-diabetic drugsCitation1–3. One of the SGLT2 inhibitors, canagliflozin, has been approved for the treatment of T2DM by the regulatory authorities of numerous countries across North America, Europe, Latin America, and Asia-Pacific, including JapanCitation4.
Diabetes in elderly patients is related to higher mortality, reduced functional status, and an increased risk of acute and chronic microvascular and cardiovascular complicationsCitation5. Additionally, elderly patients are at increased risk for adverse drug reactions to various medications due to age-related changes in pharmacokinetics and pharmacodynamics, but there is poor clinical evidence for medication use in elderly patients, because many clinical trials exclude the elderly population from enrollment by setting an upper age limit in the protocol. Therefore, special attention is needed for the treatment of elderly patients with T2DM in the clinical settingCitation6. Besides adverse drug reactions (ADRs) such as hypoglycemia, in common with other anti-diabetic drugs, and genital/urinary tract infection, dehydration, polyuria/pollakiuria, or ketone body increased, as special ADRs of SGLT2 inhibitors, were reported in the clinical studies at the development stage of SGLT2 inhibitorsCitation3. These agents possibly cause a great change in the energy metabolism and body fluid volume in elderly patients with T2DM, which might lead to severe side-effects. Therefore, a committee of experts in the field released a recommendation on the appropriate usage of SGLT2 inhibitors based on the characteristics of reported serious adverse events (SAEs). We thought that it was very important to clarify the safety and efficacy profiles of canagliflozin in elderly patients in the clinical settings. We conducted a post-marketing surveillance (PMS) among elderly patients (≥65 years old) with T2DM who were treated with canagliflozin during the first 3 months after its launch in Japan (September 2014) to confirm the safety and efficacy of canagliflozin in these patients in the clinical settings.
Patients and methods
Study design and patients
This PMS was a 1-year prospective observational study designed to investigate the safety and efficacy of canagliflozin in Japanese patients aged 65 years or older with T2DM in the clinical settings. The collected patient’ data in this study came from actual clinical practices, and the physician at each site decided the courses of treatment such as additional use, dose change, or discontinuation of concomitant drugs at a physician’s own discretion. Whenever possible, all patients who started treatment with canagliflozin within 3 months of its launch in September 2014 were registered using a central registration system, and their clinical data were recorded up to 12 months after the initiation of treatment at all survey sites. This surveillance was performed in accordance with the ministerial ordinance on Good Post-marketing Study Practice (GPSP) in Japan, and registered as JapicCTI-153049.
Data collection and assessment
The survey items included the following demographic and baseline characteristics: sex, age, duration of T2DM, body weight, body mass index (BMI), estimated glomerular filtration rate (eGFR), hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and presence/absence of complications: diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, kidney disease, liver disease, hypertension, hyperlipidemia, and dementia. Information on the administration of canagliflozin was also collected, including the duration of treatment, reasons for termination or discontinuation of treatment, and previous and/or concomitant treatments.
For the safety evaluation, all adverse events (AEs), including abnormal laboratory tests results that occurred during the survey period, were recorded. The AEs were identified by physicians, based on self-reports by patients during their clinical visits or medical records, including medical interviews and laboratory test data. Specifics about the AEs including the type, date of onset, seriousness, treatment, outcome, and causal relationship with the administration of canagliflozin were investigated, and ADRs were defined as AEs whose causal relationship with drug administration could not be ruled out. In addition, the development of ADRs of special interest for SGLT2 inhibitor treatment were monitored, which included hypoglycemia, volume depletion-related event (definition; blood pressure decreased, dehydration, postural vertigo, hypotension, oligemia, oligemic shock, orthostatic hypotension, presyncope, shock, syncope, oliguria, orthostatic tachycardia syndrome, orthostatic intolerance, diastolic hypotension, and orthostatic blood pressure decreased), genital infections, urinary tract infections, polyuria/pollakiuria, ketoacidosis/ketone body increased, renal disorders, hepatic disorders, bone fracture, and skin disorders. Severe hypoglycemia was defined as a blood glucose level ≤50 mg/dL, or if a physician at each site judged the condition as severe based on the patient’s report.
Malignancy and cardiovascular events were also evaluated as AEs of special interest. Cardiovascular events were defined using two broad standardized MedDRA queries (SMQ): myocardial infarction and central nervous system bleeding and cerebrovascular disease. The ADRs and AEs of special interest in this survey were selected because these events have been frequently or specifically reported in the pre-approval study or post-marketing use of SGLT2 inhibitors. The ADRs and AEs, based on the physicians’ reports, were coded using the Medical Dictionary for Regulatory Activities/Japanese edition (MedDRA/J) version 19.1.
Efficacy measures studied included the changes from baseline in HbA1c and FPG, and laboratory variables such as body weight, BMI, and blood pressure.
Analyses
The safety analysis set consisted of all patients for whom case report forms were collected, excluding patients with no verification of canagliflozin dosing, whose AE incidences were not evaluated, or who enrolled after changing hospitals. The efficacy analysis set included patients in the safety analysis set with any efficacy data.
All statistical analyses were performed using descriptive statistics. The mean, standard deviation (SD), and median were calculated for continuous variables, and the frequency number and proportion were calculated for categorical variables. The changes from baseline to 12 months after the treatment initiation and last observation point were also evaluated for some efficacy and laboratory measures, and statistically tested using paired t-tests. The p-value was set at .05 to determine significance. All statistical analyses were performed using SAS version 9.1.3 (SAS institute Japan Ltd., Tokyo, Japan).
Results
Demographic and clinical characteristics of patients
A total of 1395 patients were enrolled at 445 medical institutions in Japan. The patient disposition is summarized in . The safety and efficacy analysis sets in this PMS included 1375 and 1291 patients, respectively; 474 patients withdrew from the survey due to AEs (n = 109), no response or worsening of T2DM (n = 86), patient’s request (n = 115), no follow-up visit (n = 80), recovery or remission of T2DM (n = 22), and other reasons (n = 101), where patients may have two or more reasons for discontinuation. Although we did not inquire into the more detailed reasons, we identified some reasons in the collected case report forms, such as requests for switching to other anti-hyperglycemic agents, moving, changing the hospital, and placing the therapeutic priority on the treatment for the comorbidity.
Figure 1. Patient disposition. Abbreviations. CRF, case report form.
summarizes the demographic and clinical characteristics of patients in the safety analysis set. Male patients accounted for 49.8% of the set, the mean ± SD age was 72.7 ± 6.1 years, and 469 patients (34.1%) were 75 years of age or older. The mean duration of T2DM was 10.44 ± 9.26 years. The mean body weight, BMI, and eGFR were 65.22 ± 11.81 kg, 26.15 ± 4.13 kg/m2, and 67.98 ± 18.78 mL/min/1.73 m2, respectively. At baseline, 383 patients (27.9%) had diabetic complications: nephropathy (17.3%), neuropathy (12.5%), and retinopathy (8.6%). Other complications included hypertension (64.9%), hyperlipidemia (54.8%), and dementia (2.6%).
Table 1. Demographic and clinical characteristics of patients in the safety analysis set.
Status of treatment
The mean duration of canagliflozin treatment was 286.3 ± 122.6 days (). The majority (83.3%) of patients received anti-diabetic drugs concomitantly, and the most commonly used drug was dipeptidyl peptidase-4 inhibitors (65.5%), followed by sulfonylureas (32.4%) and biguanides (27.5%). Meanwhile, the patients received concomitant non-anti-diabetic therapy with anti-hypertensives (64.7%), anti-hyperlipidemics (51.9%), and diuretics (11.9%) ().
Table 2. Status of treatment.
Safety
Incidences of ADRs and serious ADRs
Among the safety analysis set, 125 patients (9.09%) experienced 173 ADRs during the survey period. The main ADRs, which were defined as occurring in five or more patients in this study, were dehydration and constipation (10 patients each, 0.73%), thirst (nine patients, 0.65%), dizziness and pollakiuria (seven patients each, 0.51%), cystitis, eczema, pruritus, and rash (six patients each, 0.44%), hypoglycemia, pruritus genital, and malaise (five patients each, 0.36%). Serious ADRs were observed in 14 patients (1.02%, 18 events), including urinary tract infection, hypoglycemia, dehydration, and cerebral infarction (two patients each, 0.15%), underweight, dizziness, loss of consciousness, retinal detachment, cardiac failure, acute coronary syndrome, shock symptom, cholecystitis acute, rash, and renal impairment (one patient each, 0.07%) ().
Table 3. Incidences of ADRs.
Incidences of ADRs of special interest
A summary for the incidences of ADRs of special interest is presented in , and their outcomes are provided in Supplemental Table 1.
Table 4. Incidences of ADRs of special interest.
Hypoglycemia: Hypoglycemia was observed in five patients (0.36%; five events). Although two of them were classified as serious, all patients recovered. All these patients had been administered concomitantly with insulin, sulfonylureas, and/or glynides.
Volume depletion-related event: Ten patients (0.73%) had 11 volume depletion-related events, including dehydration (10 events) and orthostatic hypotension (one event), and the median time to onset of these events was 24.0 days after the start of treatment. All patients either recovered or were recovering at the end of the study, excluding one patient whose outcome was unknown.
Genital infection: Ten genital infection-related ADRs were reported in nine patients (0.65%), including one man and eight women. These events comprised pruritus genital (five events), vulvovaginal pruritus (two events), vulvitis, vaginal infection, and vulvovaginal pain (one event each). Three patients had a previous history of genital infections. None of them were classified as serious, and all patients with those events recovered or were recovering at the end of the study.
Urinary tract infection: Eleven ADRs of urinary tract infections occurred in one male and 10 female patients (0.80%; 11 events). These events included cystitis (six events), urinary tract infections (four events), and urethritis (one event). Four patients had a previous history of urinary tract infections. Two patients with urinary tract infections were classified as serious ADR. All these patients recovered or were recovering at the end of the study, excluding two patients whose outcomes were unknown.
Polyuria/pollakiuria: Polyuria or pollakiuria ADRs were observed in 18 patients (1.31%; 23 events). These events included thirst (nine events), pollakiuria (seven events), nocturia, (four events), polyuria (two events), and urine volume increased (one event). None of these cases were classified as serious. Consequently, of the 23 ADRs, the patients recovered or were recovering from 20 ADRs, while they did not recover from two ADRs, and one patient had an unknown outcome at the end of the study.
Skin disorders: Skin-related ADRs were observed in 26 patients (1.89%; 27 events). These events comprised pruritus, eczema, rash (six events each), drug eruption (three events), alopecia, dermatitis (two events each), generalized erythema, and rash macular (one event each). One patient with rash experienced a serious skin-related ADR. The median time to onset of events was 63.0 days after starting treatment. Of the 27 ADRs, the patients recovered or were recovering from the 24 ADRs, and one patient did not recover from pruritus, and two patients had unknown outcomes at the end of the study.
Others: Renal impairment was reported in four patients (0.29%, four events), and the condition of one patient was serious. Two patients were recovering, and two did not recover by the end of the study. The serious case was complicated with diabetic retinopathy, diabetic nephropathy, hypertension, and hyperlipidemia, had high serum creatinine at baseline, and eGFR decreased from 34.3 mL/min/1.73 m2 to 16.6 mL/min/1.73 m2 at 3 month after the start of treatment. This patient did not recover by the end of the study. Hepatic function abnormalities were reported in three patients (0.22%, three events), and all patients recovered or were recovering at the end of the study. Body weight reduction (underweight and weight decreased in ) occurred in three patients (0.22%, three events), and one patient experienced serious “underweight”. All patients recovered or were recovering at the end of the study. A case of “ketone body increased” was reported, but ketoacidosis was not observed.
Malignancies occurred in eight patients (10 events), however, all events were not related to canagliflozin. Of the nine patients who had AEs of cardiovascular events, cerebral infarction occurred in three patients, unstable angina occurred in two patients, and myocardial infarction, transient ischemic attack, acute coronary syndrome, and cerebrovascular stenosis occurred in one patient each. Four of these patients had a previous history of cardiac or cerebral disease. Three patients experienced serious ADRs, such as cerebral infarction (two patients) and acute coronary syndrome (one patient), and all of them recovered or were recovering at the end of the study.
Laboratory test parameters
Laboratory test parameters are shown in . The systolic and diastolic blood pressures were significantly decreased without change in heart rate after the treatment with canagliflozin. The body weight and BMI were significantly (p < .001) decreased at a month after treatment with canagliflozin, and the decrease continued for 12 months. As attention should be paid to malnutrition and decreased muscle mass, especially in more elderly patients such as the patients aged ≥75 years, changes in body weight were evaluated in patients aged ≥75 and <75 years, respectively. Changes in body weight after 12 months of treatment were –2.73 kg for patients aged ≥75 years and –2.91 kg for those <75 years, and the changes were similar between these patient populations. Additionally, no sarcopenia was reported in this survey. Mean hematocrit values and blood urea nitrogen/creatinine ratios, as parameters of volume status, were increased during the treatment period. AST and ALT were decreased with treatment, and the decreases were continuously observed until the end of the treatment period. The mean eGFR value was 67.86 mL/min/1.73 m2 at baseline and reduced by –1.63 mL/min/1.73 m2 and –0.50 mL/min/1.73 m2 at 1 month and 12 months after starting treatment, respectively.
Table 5. Changes in the laboratory test, physical, and clinical parameters.
Efficacy
The mean HbA1c value was 7.62 ± 1.34% at baseline and was significantly (p < .001) reduced by −0.77 ± 1.11% at 12 months after starting the treatment and by −0.60 ± 1.18% at the last observation (). The patient population with HbA1c ≥7.0 to <8.0% accounted for the largest proportion (35.7%) of the total at baseline; however, at 12 months after treatment, the number of patients with HbA1c ≥6.0 to <7.0% became the largest (52.1%) (Supplemental Figure 1). The proportion of patients who achieved HbA1c < 7.0% at 12 months after treatment was 62.3%.
Figure 2. Changes in HbA1c and FPG. Data are expressed as mean ± SD. The number of patients [n] at each point is shown in parentheses. **p < .001 (paired t-test, vs baseline). Abbreviations. FPG, fasting plasma glucose; SD, standard deviation.
![Figure 2. Changes in HbA1c and FPG. Data are expressed as mean ± SD. The number of patients [n] at each point is shown in parentheses. **p < .001 (paired t-test, vs baseline). Abbreviations. FPG, fasting plasma glucose; SD, standard deviation.](/cms/asset/b6d0184f-51ab-42eb-9035-1bf73dc7e6a6/icmo_a_1392293_f0002_b.jpg)
The mean FPG value was 164.4 ± 70.0 mg/dL at baseline and decreased by –35.3 ± 71.3 mg/dL at 12 months after the initiation of treatment and by –26.8 ± 67.7 mg/dL at the last observation, respectively ().
Discussion
In this PMS, we investigated the safety and efficacy of canagliflozin in Japanese elderly patients aged ≥65 years with T2DM who received the drug in the clinical settings. The demographic and baseline clinical characteristics of patients in this survey (e.g. sex ratio, average age, duration of diabetes, comorbidities of diabetic complications, hypertension, hyperlipidemia and concomitant use of other anti-diabetics) were similar to those reported in PMS previously conducted in Japan for other SGLT2 inhibitorsCitation7,Citation8, showing no major differences in the actual prescription status between the SGLT2 inhibitors in Japan. Four-hundred and seventy-four patients (34.5%) withdrew from this survey. Although this withdrawal rate was high, it was similar to the PMS results of other SGLT2 inhibitors for elderly patients with T2DM; 39.4% of patients discontinued ipraglifloizinCitation7, and 36.4% of patients discontinued tofogliflozinCitation8, respectively. As for safety, a total of 9.09% (125/1375) of patients experienced ADRs during the survey period, which was lower than the 29.1% (474/1629) reported in previous Japanese clinical trials of canagliflozinCitation9. On the other hand, our survey had high withdrawal rate due to AEs (7.9%); however, such a high withdrawal rate is common to the PMS results of other SGLT2 inhibitors for elderly diabetic patients; ipragliflozin: 11.9%Citation7 and tofogliflozin: 12.6%Citation8, respectively. Most of the patients who experienced ADRs (total number of 125 patients) also withdrew from this survey. Taking these results into account, we guessed that Japanese physicians may be cautious of ADRs potentially caused by SGLT2 inhibitors after the issue of recommendation for SGLT2 inhibitors, resulting in the increase of withdrawal rate due to AEs. All ADRs observed in this survey were already known events that were reported in the previous clinical trials of canagliflozin conducted in JapanCitation9–13, and there were no clinically significant concerns in the changes of laboratory variables during our survey period. Recently, the Food and Drug Administration (FDA) and the European Medicines Agency also warned of the risk of ketoacidosis with SGLT2 inhibitorsCitation14. FDA revised the label of canagliflozin to include a warning regarding bone fracture risk and decrease in bone mineral densityCitation14. However, no ketoacidosis or fracture were reported in this survey. Therefore, new safety concerns were not identified in this survey.
We evaluated the incidences of ADRs of special interest when using a SGLT2 inhibitor, including hypoglycemia, volume depletion-related events, genital infection, urinary tract infection, polyuria/pollakiuria, ketone body increased, renal disorders, hepatic disorders, body weight reduction, and skin disorders.
Generally, special attention is needed to prevent hypoglycemia, especially in elderly patients, because severe hypoglycemia is more likely to occur in these patientsCitation15, and hypoglycemia may induce cognitive dysfunction and the risk of fracture in elderly patientsCitation16,Citation17. In this PMS of canagliflozin, five patients, who received other anti-diabetics concomitantly such as insulin preparations, sulfonylureas, and/or glynides, for which the association with hypoglycemia is widely knownCitation18, experienced a hypoglycemia. For these reasons, an appropriate dose adjustment of insulin preparations and/or insulin secretagogues should be considered to prevent hypoglycemia when using these drugs concomitantly with SGLT2 inhibitors, especially in elderly patients with T2DM.
Ten patients experienced volume depletion-related events, and serious dehydration was observed in two patients. Of these 10 patients, more than half experienced dehydration within 30 days after the start of canagliflozin treatment. Hematocrit values, a parameter of volume status, were slightly increased after canagliflozin treatment. However, it has been reported that transient increase in urine volume without a change in hematocrit was also observed after initiation of canagliflozinCitation19. The mechanism of the increase in hematocrit when using SGLT2 inhibitors is unclearCitation20, and there is also no strong relationship to an elevation in risk of CV eventsCitation21. The relationship between CV events, such as cerebral infarction or myocardial infarction, and hydration was also unclear in this PMS. Nevertheless, elderly adults become dehydrated more easily than younger adults due to their reduced physiological functionsCitation22. In a pooled analysis based on eight randomized controlled studies of canagliflozin, the onset of AEs related to volume depletion is commonly reported in patients aged ≥75 yearsCitation23. Taken together, although there are some controversies to be elucidated, it is necessary to take preventive measures against the potential onset of dehydration in the elderly patients.
Genital and urinary tract infections are already known risks for SGLT2 inhibitors, and a systematic review and meta-analysis of randomized trials for SGLT2 inhibitors revealed that these incidences were more common with SGLT2 inhibitors compared with placebo or other medication for T2DMCitation24. Genital and urinary tract infections incidence rates were generally higher in female diabetic patients than maleCitation25,Citation26, and clinical study of canagliflozin in Japanese T2DM patients also showed genital infections were more frequently observed in female patientsCitation12. In this PMS, genital and urinary tract infection-related ADRs were reported in eight and 10 women, respectively, which were consistent with the previous reports.
Polyuria/pollakiuria, as well as volume depletion-related events, are thought to be the ADRs related to the mechanism of action of the SGLT2 inhibitors, wherein they inhibit SGLT2 localized in the proximal renal tubule, suppress renal glucose reabsorption, and increase urinary glucose excretionCitation1–3. The incidence of polyuria/pollakiuria was 1.31% in this survey, and the rate is almost the same with those (2.00% and 2.92%) reported in the analyses of PMS conducted in Japan for other SGLT2 inhibitorsCitation7,Citation8.
In this PMS of canagliflozin, skin-related ADRs occurred in 26 patients (1.89%), which were similar to the PMS of other SGLT2 inhibitors in Japanese elderly patients: 3.16% with ipragliflozin and 2.39% tofogliflozin, respectivelyCitation7,Citation8. Over half of the ADRs related to skin complications are reported to occur within 30 days after the start of ipragliflozin treatmentCitation7, and the onsets are reported to be within the 4 weeks of tofogliflozin treatment among the one-third of the patients who experienced these disordersCitation8. On the other hand, these ADRs seemed not to occur in a specified period after the start of administration of canagliflozin in this PMS.
The incidences of AEs such as malignancy and cardiovascular events were 0.58% and 0.65% in this PMS, respectively. Their incidences were low because this PMS had a short treatment period. Long-term safety of canagliflozin for malignancy and cardiovascular events needs to be evaluated.
Regarding efficacy, the mean HbA1c and FPG values were decreased by canagliflozin treatment and remained at well-controlled low levels through 12 months in this survey. The mean decreases of HbA1c and FPG after 12-month treatment in this PMS were –0.77% and –35.3 mg/dL, respectively, and the mean decreases in HbA1c and FPG after 52-week treatment with 100 mg/day of canagliflozin were reported to range –0.80 to –1.06% and –24.2 to –37.5 mg/dL, respectively, in the previous Japanese clinical study (the mean subject age =55.3–59.1 years)Citation12. The efficacies in the reduction of HbA1c and FPG in these two studies were similar, and the results demonstrated that canagliflozin improved glucose control over a long period of time also in the treatment of elderly patients aged ≥65 years with T2DM.
The limitations of this study include a short survey period of 1-year and the possible influence of reporting bias. This PMS was initiated after the recommendations on the proper use of SGLT2 inhibitors were issued by a committee of experts in the fieldCitation27, and the physicians’ prescription behavior and the level of attention to the safety of an SGLT2 inhibitor might have been influenced by the recommendation. In addition, this PMS was conducted in the Japanese specific medical conditions including healthcare system and drug utilization of anti-diabetic drugs; therefore, the survey results may not be the same in other countries that have different medical conditions from Japan. For example, the prescription pattern by physicians is different based on the guidelines in Japan and other countries. More than 60% of patients were prescribed canagliflozin add-on to dipeptidyl peptidase-4 inhibitors in this surveillance. On the other hand, approximately half of patients received canagliflozin concomitantly with metformin in a real-world setting in the USCitation28.
Conclusion
The PMS results showed the safety and efficacy profiles of canagliflozin in Japanese elderly patients aged ≥65 years with T2DM. Canagliflozin was well tolerated and effective in improving glycemic control in these patients in the clinical settings.
Transparency
Declaration of funding
This post-marketing surveillance of canagliflozin was funded by Mitsubishi Tanabe Pharma Corporation, and Daiichi Sankyo Co., Ltd.
Declaration of financial/other relationships
All authors are employees of Mitsubishi Tanabe Pharma Corporation. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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The authors thank all physicians and medical staff of the 445 participating institutions in this survey. Medical writing support was provided by Interscience Co., Ltd. with funding by Mitsubishi Tanabe Pharma Corporation.
References
- DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab 2012;14:5-14
- Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 2015;75:33-59
- Dardi I, Kouvatsos T, Jabbour SA. SGLT2 inhibitors. Biochem Pharmacol 2016;101:27-39
- Rosenthal N, Meininger G, Ways K, et al. Canagliflozin: a sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus. Ann NY Acad Sci 2015;1358:28-43
- Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults. Diabetes Care 2012;35:2650-64
- Scheen AJ. SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment. Expert Opin Drug Saf 2015;14:1879-904
- Yokote K, Terauchi Y, Nakamura I, et al. 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. Expert Opin Pharmacother 2016;17:1995-2003
- Utsunomiya K, Shimmoto N, Senda M, et al. Safety and effectiveness of tofogliflozin in elderly Japanese patients with type 2 diabetes mellitus: a post-marketing study (J-STEP/EL study). J Diabetes Investig 2017;8:766-75
- Package insert of CANAGLU tablets 100mg. Mitsubishi Tanabe Pharma Corporation. [in Japanese] http://weba939.intra.sharedom.net/kdi-web/packins/files/packins.10002986/can_a.pdf Accessed November 6, 2017
- Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab 2013;15:1136-45
- Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo-controlled, Phase III study. Expert Opin Pharmacother 2014;15:1501-15
- Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin alone or as add-on to other oral antihyperglycemic drugs in Japanese patients with type 2 diabetes: a 52-week open-label study. J Diabetes Investig 2015;6:210-18
- Inagaki N, Harashima S, Maruyama N, et al. Efficacy and safety of canagliflozin in combination with insulin: a double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2016;15:89
- Carlson CJ, Santamarina ML. Update review of the safety of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with type 2 diabetes mellitus. Expert Opin Drug Saf 2016;15:1401-12
- Seltzer HS. Drug-induced hypoglycemia. A review of 1418 cases. Endocrinol Metab Clin North Am 1989;18:163-83
- Bordier L, Doucet J, Boudet J, et al. Update on cognitive decline and dementia in elderly patients with diabetes. Diabetes Metab 2014;40:331-7
- Puar TH, Khoo JJ, Cho LW, et al. Association between glycemic control and hip fracture. J Am Geriatr Soc 2012;60:1493-7
- McIntosh B, Cameron C, Singh SR, et al. Second-line therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a systematic review and mixed-treatment comparison meta-analysis. Open Med 2011;5:e35-48
- Tanaka H, Takano K, Iijima H, et al. Factors affecting canagliflozin-induced transient urine volume increase in patients with type 2 diabetes mellitus. Adv Ther 2017;34:436-451
- Sano M, Takei M, Shiraishi Y, et al. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res 2016;8:844-7
- Zinman B, Inzucchi SE, Lachin JM, et al.; on behalf of the EMPA-REG OUTCOME Investigators (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke 2017;48:1218-25
- Phillips PA, Rolls BJ, Ledingham JG, et al. Reduced thirst after water deprivation in healthy elderly men. N Engl J Med 1984;311:753-9
- Sinclair AJ, Bode B, Harris S, et al. Efficacy and safety of canagliflozin in individuals aged 75 and older with type 2 diabetes mellitus: a pooled analysis. J Am Geriatr Soc 2016;64:543-52
- Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013;159:262-74
- Hirji I, Guo Z, Andersson SW, et al. Incidence of urinary tract infection among patients with type 2 diabetes in the UK General Practice Research Database (GPRD). J Diabetes Complications 2012;26:513-16
- Hirji I, Andersson SW, Guo Z, et al. Incidence of genital infection among patients with type 2 diabetes in the UK General Practice Research Database. J Diabetes Complications 2012;26:501-5
- Yabe D, Nishikino R, Kaneko M, et al. Short-term impacts of sodium/glucose co-transporter 2 inhibitors in Japanese clinical practice: considerations for their appropriate use to avoid serious adverse events. Expert Opin Drug Saf 2015;14:795-800
- Buysman EK, Chow W, Henk HJ, et al. Characteristics and short-term outcomes of patients with type 2 diabetes mellitus treated with canagliflozin in a real-world setting. Curr Med Res Opin 2015;31:137-43