Abstract
Aims
We aimed to investigate potential predictors of effectiveness of SGLT2 inhibitors (SGLT2i) in individuals with type 1 diabetes (T1D) on sensor-augmented pump (SAP) therapy.
Methods
We included individuals with T1D receiving SAP therapy at our hospital who were newly initiated on SGLT2i between 2019 and 2020 and were followed for at least 1 year. Data on BMI, blood tests, and continuous glucose monitoring (CGM) were compared before and 12 months after initiation of SGLT2i. Predictors of incremental increases in time in range (ΔTIR) were explored using a multiple regression analysis. Cutoff values for the predictors were determined using an ROC curve analysis.
Results
A total of 17 individuals (females, 70.6%; median age, 44.0 years) were included, excluding three individuals who discontinued SGLT2i due to side effects. During follow-up, their median BMI decreased significantly (P = 0.013), while no significant change was seen in their total daily dose of insulin, basal-to-total insulin ratio. Again, their HbA1c, TIR, and time above range (TAR) improved significantly (P = 0.004, P = 0.003, and P = 0.003, respectively), while their time below range (TBR) showed no significant change. The predictor of increased ΔTIR was high urinary albumin-to-creatinine ratio (UACR) at baseline (P = 0.026) only, with the cutoff value determined to be 28.0 mg/g Cr or higher (AUC = 0.82, P = 0.003).
Conclusions
It may be suggested that individuals with T1D on SAP therapy and having near-microalbuminuria or higher could be expected to show significant improvement in TIR.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13340-024-00743-4.
Keywords: Type 1 diabetes, SGLT2 inhibitors, Sensor augmented pump therapy, Urinary albumin
Introduction
Reportedly, sensor augmented pump (SAP) therapy has been shown likely to result in greater improvements in glycemic control in individuals with type 1 diabetes (T1D) than multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) therapy [1–3]. Of note, in SAP therapy with a predictive low glucose management (PLGM) function, insulin injections are suspended well before the imminent onset of hypoglycemia [4–7], while hybrid closed-loop (HCL) therapy, which allows insulin injection volumes to be adjusted and thus allows hyperglycemia to be reduced [8–12]. However, a certain proportion of individuals does fail to achieve the target time in range (TIR) of 70% despite the use of SAP therapy.
On the other hand, SGLT2 inhibitors (SGLT2i) have been reported in multiple, large-scale clinical studies not only to produce improvements in glycemic control and reductions in body weight but to provide additional benefits such as reductions in heart failure or renal protection [13–17]. To turn attention to their use in Japan, of all SGLT2i, only dapagliflozin and ipragliflozin are approved for clinical use in combination with insulin therapy for T1D [18, 19]. With regard to the effectiveness of SGLT2i in type 1 diabetes, they have been reported in studies conducted to date to provide reductions in HbA1c, body weight and glycemic variability, as well as improvements in TIR, in addition to reductions in systolic blood pressure [20–23]. Also of note, a study of SGLT2i (given 12 weeks or longer) was conducted in Japanese individuals with T1D on MDI or CSII therapy using continuous glucose monitoring (CGM), demonstrating that the SGLT2i led to a reduction of 9.4% in their total daily dose (TDD) of insulin without increasing their time below range (TBR), while significantly increasing their TIR but significantly decreasing their time above range (TAR) [24].
This is in stark contrast to the use of SGLT2i in individuals with type 1 diabetes in the rest of the world, which has largely been restricted by relevant regulatory authorities, with the European Medicines Agency (EMA) having restricted their use to obese or overweight individuals with BMI ≥ 27 kg/m2 alone and the US Food and Drug Administration (FDA) not having approved their use in T1D individuals for lack of evidence establishing their efficacy and safety in these individuals, to date.
Particular precautions to be taken in using SGLT2i in individuals with T1D include giving full attention to the associated risk of diabetic ketoacidosis (DKA) and euglycemic DKA. Again, the caveat for the use of insulin pumps in individuals with T1D as described in an international consensus statement is that their use and failure are likely to place these individuals at low-to-intermediate and intermediate-to-high risk of DKA, respectively [25].
Despite these issues and caveats, however, individuals with T1D on SAP therapy may indeed benefit from the use of SGLT2i in improving their glycemic control, with full attention given to risk management. Indeed, a Canadian study of SGLT2i in individuals with T1D on HCL or SAP therapy demonstrated that treatment with SGLT2i led to an increase in TIR of 7.2% and 11.4% in those on HCL and SAP therapy, respectively [26]. While Asian and Western individuals with T1D may likely differ in their physique versus required insulin dose, no studies evaluated SGLT2i in Asian individuals with T1D on SAP therapy, to date. Therefore, we investigated the effectiveness of SGLT2i given for 12 months in Japanese individuals with T1D on SAP therapy and sought to explore predictors for improvement of glycemic control.
Materials and methods
Study population
Of all individuals with T1D 20 years of age or older being treated in an outpatient setting at four Jikei University School of Medicine-affiliated hospitals, the study population comprised those on SAP therapy who had newly been initiated on SGLT2i between January 2019 and December 2020. The exclusion criteria of the study included: those who had previously been prescribed an SGLT2i prior to the study period; those being treated with other modalities than SAP therapy; those who had discontinued the SGLT2i due to associated side effects during the study; and those not available for follow-up 12 months or longer.
Their data (i.e., age, age at diagnosis of T1D, sex, blood/urinary test results, and medications prescribed and their doses) were extracted for the study drawing on the Standard Structured Medical Information eXchange (SS-MIX2). Again, their physical data (i.e., height and body weight) were collected from their medical records as part of their electronic charts. The SAP device used was either the Minimed 640G, which has the PLGM function, or the Minimed 620G, which does not have the PLGM function (Medtronic Inc., Tokyo, Japan) in all individuals evaluated, and CGM data were collected from the CareLink™ System software.
Study protocol
The study collected data on height, body weight, blood test results (i.e., HbA1c and estimated glomerular filtration rate [eGFR]), urinary test results (i.e., urinary albumin-to-creatinine ration [UACR]) as well as those derived from CGM at baseline (before initiation of SGLT2i), 1, 3, 6 and 12 months after SGLT2i initiation. With the date of each blood test performed defined as an index date, their TDD, bolus insulin dose, basal insulin dose, glucose management indicator (GMI), percent coefficient of variation (%CV), TIR, TAR, TBR, and glucose values sensor-measured every five minutes during the one month preceding each index date were derived from CGM data. Incidentally, individuals and/or their attending physicians were allowed to adjust their insulin doses with reference to their CGM data during the study.
Outcome variables
Outcome variables evaluated included: (1) body weight, body mass index (BMI), TDD, basal-to-total insulin (B/T) ratio, renal function (i.e., eGFR and UACR) and parameters for glycemic variability (i.e., GMI, %CV, TIR, TAR, and TBR) as compared before and 12 months after SGLT2i initiation; (2) changes in parameters for glycemic variability from before to 1, 3, 6, and 12 months after SGLT2i initiation; (3) glycemic profile as compared before and 12 months after SGLT2i initiation; and (4) predictive factors identified for incremental increases in TIR (ΔTIR).
Statistical analysis
All statistical analyses were performed using SPSS Ver. 26.0 (SPSS Inc., Chicago, IL, USA; www.spss.com). All outcome parameters were presented as median (interquartile range) and were compared before and 12 months after SGLT2i initiation by using the Wilcoxon signed-rank test. Furthermore, single and multiple regression analyses were performed, with duration of T1D, baseline variables (BMI, TDD, B/T ratio, HbA1c and UACR) serving as independent variables, to identify predictive factors for ΔTIR. For any predictive factor thus identified, the cutoff value for predicting ΔTIR in excess of its median value was determined by using a receiver operating characteristic (ROC) curve analysis.
The present study was conducted with the approval of the Institutional Review Board (IRB) of Jikei University School of Medicine, Tokyo, Japan (approval number: 30-273 [9294]) and in accordance with the provisions of the Declaration of Helsinki (as revised in Fortaleza, Brazil in October 2013).
Results
Patient characteristics
Of the 328 individuals with T1D prescribed SGLT2i between January 2019 and December 2020, the study eventually included a total of 17 after excluding all those who had met the exclusion criteria of the study (Fig. 1). Three individuals used the Minimed 620G, while the remaining fourteen used the Minimed 640G. The main characteristics of the individuals included were: males/females, 5/12; age, 44.0 (40.0–51.0) years; and duration of type 1 diabetes, 14.0 (10.0–23.0) years (Table 1).
Fig. 1.
Flowchart for selection of research subjects
Table 1.
Patient characteristics and comparison of parameters before and after SGLT2i initiation
| Parameters | Baseline | 12 months | P value | Difference | P value | |
|---|---|---|---|---|---|---|
| Male (%) | 5 (29.4%) | – | – | – | – | |
| Age (years) | 44.0 (40.0–51.0) | – | – | – | – | |
| History of T1D (years) | 14.0 (10.0–23.0) | – | – | – | – | |
| Height (cm) | 164.0 (159.8–169.8) | – | – | – | – | |
| Weight (kg) | 67.0 (61.0–74.6) | 66.0 (61.4–70.2) | 0.016* | – | – | |
| BMI (kg/m2) | 25.3 (22.8–27.2) | 23.9 (21.8–25.9) | 0.013* | – | – | |
| Total daily insulin dose (U) | 40.1 (35.0–53.5) | 41.0 (31.50–55.1) | 0.084 | – | – | |
| Basal-to-total insulin ratio (%) | 40.1 (31.4–49.3) | 38.5 (30.6–54.0) | 0.266 | – | – | |
| eGFR (ml/min/1.73 m2) | 79.0 (69.0–88.1) | 73.0 (64.0–83.1) | 0.002* | – | – | |
| UACR (mg/gCr) | 7.0 (5.0–52.7) | 3.0 (1.0–17.5) | 0.345 | – | – | |
| HbA1c (%) | 8.2 (7.7–8.9) | 7.8 (7.3–8.4) | 0.004* | – | – | |
| GMI (%) | 7.7 (7.4–8.3) | 7.2 (7.0–7.7) | 0.003* | – | – | |
| %CV | 32.5 (29.2–36.7) | 33.2 (29.5–35.4) | 0.501 | – | – | |
| TIR (%) | Whole day | 53.0 (33.0–59.6) | 61.0 (49.0–73.0) | 0.003* | – | – |
| 0:00–6:00 | 51.0 (32.7–68.8) | 72.9 (55.8 – 86.1) | 0.002* | 17.8 (9.2–26.6) | 0.039* | |
| 6:00–24:00 | 51.2 (32.8–57.9) | 59.0 (47.9–69.2) | 0.009* | 9.7 (− 0.9–19.1) | ||
| TAR (%) | Whole day | 47.0 (40.0–66.8) | 36.0 (25.5–50.0) | 0.003* | – | – |
| 0:00–6:00 | 49.0 (29.4–65.9) | 26.5 (11.9 – 44.2) | 0.003* | − 19.8 (− 29.3 to − 7.9) | 0.028* | |
| 6:00–24:00 | 47.8 (41.8–66.9) | 38.2 (29.3 – 50.7) | 0.007* | − 11.6 (− 19.9–1.2) | ||
| TBR (%) | Whole day | 0.4 (0.0–1.0) | 0.8 (0.0–2.0) | 0.309 | – | – |
| 0:00–6:00 | 0.0 (0.0–0.8) | 0.6 (0.0–2.7) | 0.071 | 0.0 (0.0–1.8) | 0.492 | |
| 6:00–24:00 | 0.5 (0.1–1.1) | 0.6 (0.2–2.5) | 0.163 | 0.0 (− 0.1–0.9) | ||
Data are represented as median (25–75 percentiles [interquartile range])
BMI body mass index, UACR urinary albumin-to-creatinine ratio, GMI glucose management indicator, TIR time in range, TAR time above range, TBR time below range, Difference 12 months difference
*p < 0.05 (Wilcoxon’s signed-rank test)
Comparisons before and 12 months after SGLT2i initiation revealed a significant decrease in BMI (25.3 [22.8–27.2] to 23.9 [21.8–25.9] kg/m2 [P = 0.013]), but no significant change in TDD or in B/T ratio (40.1 [35.0–53.6] to 41.0 [31.5–55.1] U/day [P = 0.084], 40.1 [31.4–49.3] to 38.5 [30.6–54.0]% [P = 0.266], respectively); they also demonstrated a significant decrease in eGFR (79.0 [69.0–88.1] to 73.0 [64.0–83.1] mL/min/1.73 m2 [P = 0.002]), but no significant change in UACR (7.0 [5.0–52.7] to 3.0 [1.0–17.5] mg/g Cr [P = 0.345]).
Glycemic control
Of the parameters evaluated for glycemic variability, HbA1c, GMI, TIR, and TAR were shown to be significantly improved 12 months after SGLT2i initiation (HbA1c, 8.2 [7.7–8.9] to 7.8 [7.3–8.4]%, P = 0.004; GMI, 7.7 [7.4–8.3] to 7.2 [7.0–7.7]%, P = 0.003; TIR, 53.0 [33.0–59.6] to 61.0 [49.0–73.0]%, P = 0.003; and TAR, 47.0 [40.0–66.8] to 36.0 [25.5–50.0]%, P = 0.003), while %CV and TBR were not shown to be significantly different (%CV, 32.5 [29.2–36.7] to 33.2 [29.5–35.4], P = 0.501; TBR, 0.4 [0.0–1.0] to 0.8 [0.0–2.0] %, P = 0.309) (Table 1). Furthermore, when examined over time, the extent of improvements in HbA1c, GMI, TIR and TAR was shown to be greatest one month after SGLT2i initiation (Fig. 2).
Fig. 2.
Change over time in glycemic control
Glycemic profile
A comparison of the glycemic profiles in the individuals as determined based on the CGM data obtained during the one month before and 12 months after SGLT2i initiation revealed an overall decrease in glucose values throughout the day 12 months after SGLT2 initiation, i.e., not only in median but in 25th (Q1) and 75th percentile (Q3) values (Fig. 3). In addition, a comparison of 24 h TIR, TAR and TBR as divided between nighttime (0–6 h) and daytime (6–24 h) showed a significant improvement in TIR and TAR during both nighttime and daytime, but no significantly change in TBR during nighttime or daytime. Again, in a comparison of ΔTIR and ΔTAR during nighttime and daytime, ΔTIR was shown to be significantly larger, and ΔTAR was shown to be significantly smaller, during nighttime than during daytime (Table 1).
Fig. 3.
Glucose profile before and 12 months after SGLT2i initiation
Predictors of increased TIR
High baseline UACR value was the only factor shown to be significantly associated with ΔTIR 12 months after SGLT2i initiation not only in single regression analysis (β = 0.10; 95% CI, 0.05–0.16; P = 0.001), but also in multiple regression analysis (β = 0.12; 95% CI, 0.05–0.18; P = 0.002) (Table 2). The cutoff value for baseline UACR predicting ΔTIR in excess of its median value 12 months after SGLT2i initiation was determined by an ROC curve analysis as 28.0 mg/g Cr or higher (AUC = 0.82; sensitivity, 0.625; specificity, 1.00; P = 0.003).
Table 2.
Univariate and multivariate analysis of predictors for increased ΔTIR
| Parameters | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| β (95%CI) | P value | β (95%CI) | P value | |
| Duration of T1D (years) | 0.04 (− 0.54–0.62) | 0.876 | − 0.33 (− 0.82–0.16) | 0.161 |
| Baseline BMI (kg/m2) | 0.85 (− 0.69–2.39) | 0.257 | 0.82 (− 0.92–2.56) | 0.317 |
| Baseline TDD (U) | 0.09 (− 0.24–0.42) | 0.568 | 0.05 (− 0.36–0.47) | 0.784 |
| Baseline B/T (%) | 0.13 (− 0.20–0.46) | 0.415 | 0.18 (− 0.16–0.52) | 0.269 |
| Baseline HbA1c (%) | 1.21 (− 6.54–8.96) | 0.745 | − 4.50 (− 11.52–2.52) | 0.184 |
| Baseline UACR (mg/gCr) | 0.10 (0.05–0.16) | 0.001* | 0.12 (0.05–0.18) | 0.002** |
Data are represented as median (25–75 percentiles [interquartile range])
T1D Type 1 diabetes, BMI body mass index, TDD total daily dose of insulin, B/T basal-to-total insulin ratio, UACR urinary albumin-to-creatinine ratio
*p < 0.05 (simple regression analysis), **p < 0.05 (multiple regression analysis test)
Discussion
Conducted to initiate SGLT2i as an add-on in individuals with T1D on SAP therapy using Minimed 620G or 640G and to follow them up for one year thereafter, this study found that the combined modality treatment led to improvements in TIR, TAR, and BMI without increasing hypoglycemia; it also identified a UACR value of 28 mg/g Cr or higher at baseline (prior to SGLT2i initiation) as a factor predicting increased ΔTIR after SGLT2i initiation. To date, the present study is the first to explore predictive factors for improvements in glycemic control in individuals with T1D on SAP therapy following SGLT2i initiation.
The study demonstrated an 8% improvement in TIR as well as an 11% improvement in TAR 12 months after SGLT2i initiation, suggesting, in agreement with earlier studies [20–23], that add-on SGLT2i may prove useful in improving glycemic control in individuals with T1D on SAP therapy. Again, a review of the individual data obtained 1, 3, 6 and 12 months after SGLT2i initiation also revealed that both their TIR and TAR had tended to improve from 1 month after SGLT2i initiation onwards, thus likely suggesting the immediate onset of action of SGLT2i. Furthermore, of note, a comparison of its effectiveness by time of day suggested that SGLT2i may prove useful particularly in lowering glucose values in these individuals during nighttime. Additionally, the lack of significant improvement in %CV versus the target of 36% or lower recommended by international consensus guidelines may be accounted for by the fact that the individuals had a median baseline %CV value of 32.6% at baseline and represented a group exhibiting relatively small glycemic variability, thus failing to show improvements in %CV [27]. Again, the outcome for TBR (no improvement with SGLT2i) may also be attributable to the action of the PLGM function as part of SAP, which led to low TBR at baseline in the participants.
While many studies in the literature report decreases in TDD 2–4 weeks after SGLT2i initiation, eventually resulting in a decrease in TDD on the order of 10% [21, 22, 24], the present study demonstrated a decrease in TDD of only 1.2 U (3%) 1 and 3 months after SGLT2i initiation but no decrease 12 months after SGLT2i initiation, which may be accounted for by the possibility that given the increase in bolus insulin dose as well as the decrease in basal insulin dose observed in 4 of the 5 individuals whose TDD were shown to be increased, TDD tended to increase in those in whom postprandial hyperglycemia became conspicuous after SGLT2i initiation.
The transition of eGFR following initiation of SGLT2i showed a decline at one month, followed by improvement over the subsequent 6 months, and then a subsequent decline at 12 months (Figure S1). While the cause of the decline in eGFR at 12 months is not clearly elucidated, it is suggested to be attributable to factors distinct from the initial dip associated with SGLT2 inhibitor administration.
Again, this study demonstrated a significant reduction in BMI in the individuals, with a tendency for gradual decrease observed at 1, 3, 6, and 12 months after SGLT2i initiation.
An attempt to explore factors responsible for ΔTIR in this study led to high baseline UACR value being identified as the sole responsible factor, where the higher the baseline UACR, the greater the ΔTIR (Figure S2). Of interest here is an earlier study which reported a correlation between the % increase in TIR and the decrease in UACR value in individuals with T1D with baseline UACR values 30 mg/g Cr or higher who had newly been initiated on SAP therapy and followed up for 1 year and demonstrated a 10% decrease in UACR value for every 10% increase in TIR [28], suggesting that as the ΔTIR value becomes elevated, the UACR value becomes decreased in individuals with T1D.
Consistently with the earlier observation that the greater the baseline UACR, the greater the decrease in UACR in individuals receiving SGLT2i [29], it is highly likely that the use of SGLTi in this study accounted for the greater extent of decrease in UACR values in those with high baseline UACR values. Considering this and the correlation between the improvement in TIR and the decrease in UACR [28], it may be possible that the higher the baseline UACR, the greater the ΔTIR. However, there have been a report suggesting that there is no correlation between the improvement in UACR and the change in HbA1c in the study where SGLT2i were administered to patients with type 2 diabetes [30]. Therefore, the results of this study cannot be considered definitive, and further research is warranted. In this study, we also intended to examine whether UACR decreased or the extent of change, but due to the limited number of individuals with measured UACR values at 12 months, this assessment could not be conducted. Given their ability to inhibit glucose and sodium reabsorption in the proximal tubule, SGLT2i are shown not only to ameliorate hyperglycemia but to lower intraglomerular pressure, suggesting the possibility that the greater the expression of SGLT2 in the proximal tubule, the greater the effect of SGLT2i in lowering glucose and albuminuria in these individuals. At present, however, reports from basic research vary as to whether or not SGLT2 expression is increased in individuals with T1D [31–34] or, if so, it remains unclear which background characteristics may contribute to an increase in SGLT2 expression in these individuals. Thus, further study is required to address these issues.
Again, given the cutoff value for UACR predicting ΔTIR after SGLT2i initiation determined as 28 mg/g Cr, the new finding of this study could be that add-on SGLT2i may further improve glycemic control in individuals with T1D on SAP therapy, particularly in those with microalbuminuria or more advanced renal dysfunction.
Despite these potential benefits of add-on SGLT2i, the caveat is that attention needs to be given to the side effects of SGLT2i in individuals initiating SGLT2i, which include not only general ones, such as urinary tract infection, genital infection, dehydration, and skin symptoms, but DKA, particularly euglycemic DKA, which are due to insulin insufficiency in individuals with T1D. With the use of SGLT2i, the risk of DKA is shown to increase 5–10-fold and dose-dependently in individuals with T1D [25, 35]. Thus, it is recommended in a review of dapagliflozin that of all individuals with T1D, physicians consider prescribing SGLT2i in those shown to have a BMI of 27 kg/m2 or higher, an insulin dose of > 0.5 U/kg, a normal blood ketone concentration, and an eGFR value of > 60 mL/min/1.73 m2. Furthermore, caution is recommended in prescribing SGLT2i due to the risk of DKA, in those with a history of DKA within the last 2 years and in those scheduled for insulin pump therapy (36). It should also be kept in mind that the US FDA has clearly voted against approving the use of SGLT2i in individuals with T1D. Again, it should also be noted that, of all insulin pumps available, insulin pumps equipped with a PLGM function, e.g., the one used in this study, and those used as part of HCL therapy allow insulin injections to be suspended when a hypoglycemic episode is predicted to occur, thus increasing the risk of DKA in individuals with T1D. In this study, 3 individuals had been excluded due to the side effects of SGLT2i, i.e., one with DKA, one who self-discontinued SGLT2i after having experienced a weight loss of 4 kg 3 months later, and one who discontinued SGLT2i after having experienced anorexia. It was also found that, of these, the one excluded due to DKA had failed to respond to the alert calling for insulin replenishment, despite being aware of it. Therefore, in prescribing SGLT2i, care should be taken to instruct individuals with T1D and their guardians not only on the associated risk of DKA, but on how to avoid insulin insufficiency and how to measure ketone bodies in the individuals at first presentation and repeatedly at each visit thereafter.
The present study has several limitations that need to be taken into account. First, this was a single-center, pilot study involving a small number of individuals and thus further study is required in a larger number of individuals to validate the findings reported herein. Second, the study involved spot measurements of urinary albumin, suggesting that the measured values may not be as accurate as desired. Third, the participants in this study represented a small group characterized as having relatively low UACR values, which may have contributed to the cutoff value being lower for UACR predicting ΔTIR than otherwise. Thus, further study is required in individuals with overt albuminuria. Fourth, this study utilized real-world data, and there were very few individuals who could be followed for UACR values after initiation of SGLT2i. Fifth, the study included only individuals on SAP therapy using Minimed 620G or 640G, to the exclusion of those on HCL therapy using other insulin pumps.
In conclusion, the study found that SGLT2i as an add-on improved glycemic control in Japanese individuals with T1D on SAP therapy and that near-microalbuminuria or more advanced renal dysfunction at baseline represented a factor predicting elevated ΔTIR. Thus, SGLT2i may be considered in individuals exhibiting little improvement in hyperglycemia despite SAP therapy, particularly in those with microalbuminuria or more advanced renal dysfunction, based on assessment of their risk for DKA and with the informed consent of the individuals.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors would like to extend their heartfelt thanks to all individuals for their participation in the study.
Funding
This work was partially supported by a grant from the Ministry of Health, Labor and Welfare of Japan (H29-CVD etc.-General-006). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Data availability
The datasets analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
The authors of this manuscript have the following competing interests: RN has participated in speakers’ bureaus/advisory panels for Boehringer Ingelheim, Eli Lilly, Kissei, Medtronic, Novo Nordisk, Sanofi, Takeda, Ono, Taisho-Toyama, Tanabe-Mitsubishi, Terumo, MSD, Abbott, Daiichi-Sankyo, Suntory and Dainihon-Sumitomo. None of the other authors have any conflict of interest to declare.
Ethical approval
Approval of the research protocol: the Institutional Review Board (IRB) of Jikei University School of Medicine, Tokyo, Japan. Approval date of Registry and the Registration No. of the study/trial: approval date: Nov 5th, 2018, approval number: 30–273 [9294].
Animal studies
N/A.
Informed consent
N/A.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets analyzed during the current study are available from the corresponding author on reasonable request.