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A multicentre, prospective, non-interventional study evaluating the safety of dapagliflozin in patients with type 2 diabetes in routine clinical practice in China (DONATE)

BMC Medicine volume 21, Article number: 212 (2023) Cite this article

Abstract

Background

There are few large-scale studies evaluating the safety of the sodium-glucose cotransporter-2 inhibitor, dapagliflozin, in Chinese patients with type 2 diabetes. DONATE, a multicentre, single-arm, prospective, non-interventional study, is the first real-world study evaluating the safety of dapagliflozin in Chinese patients with type 2 diabetes in routine clinical practice.

Methods

Between August 2017 and July 2020, patients with type 2 diabetes who had initiated dapagliflozin therapy and received ≥1 dose were prospectively recruited from 88 hospitals in China. Patients were subsequently followed up for 24 weeks; if patients discontinued dapagliflozin they were followed up for an additional 7 days after treatment discontinuation. The primary outcome was the proportion of patients with adverse events and serious adverse events, particularly key adverse events of special interest (AESI) including urinary tract infection, genital tract infection (typical symptoms with or without microbiological diagnosis) and hypoglycaemia (typical symptoms with or without blood glucose ≤3.9 mmol/L, or blood glucose ≤3.9 mmol/L without symptoms). Exploratory outcomes included the absolute change in metabolic parameters and the proportion of patients with other AESI including volume depletion, abnormal blood electrolytes, polyuria, renal impairment, diabetic ketoacidosis, hepatic impairment and haematuria.

Results

A total of 3000 patients were enrolled, of whom 2990 (99.7%) were included in the safety analysis set. Mean (SD) age was 52.6 (12.0) years, and 65.8% of patients were male. Mean (SD) duration of type 2 diabetes at enrolment was 8.4 (7.1) years. Mean (SD) treatment duration of dapagliflozin was 209.1 (157.6) days. Adverse events were reported in 35.4% (n = 1059) of patients during the 24-week follow-up period. Overall, 9.0% (n = 268) were related to treatment and 6.2% (n = 186) were serious. Urinary tract infection, genital tract infection and hypoglycaemia were reported in 2.3% (n = 70), 1.3% (n = 39) and 1.1% (n = 32) of patients, respectively. The proportion of patients with other AESI was also low: polyuria (0.7%; n = 21), volume depletion (0.3%; n = 9), renal impairment (0.3%; n = 8), hepatic impairment (0.2%; n = 7), haematuria (0.2%; n = 6) and diabetic ketoacidosis (0.1%; n = 2).

Conclusions

This study demonstrated that once-daily dapagliflozin was well tolerated in Chinese patients with type 2 diabetes and the overall safety profile of dapagliflozin in clinical practice in China was consistent with that reported in clinical trials.

Trial registration

ClinicalTrials.gov, NCT03156985. Registered on 16 May, 2017.

Peer Review reports

Background

Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance and a progressive loss of beta cell function [1], and it independently increases the risk of vascular and renal death by 2.3- and three-fold, respectively [2]. China has the largest number of adults with diabetes worldwide (140.9 million individuals in 2021), with an estimated overall prevalence of 12.4% in 2018 [3, 4]. Management of T2DM requires multifactorial behavioural and pharmacological treatment to manage blood-glucose levels, weight, and cardiovascular risk factors while ensuring cardiorenal protection [5]. Despite the availability of a wide variety of glucose-lowering medications, many patients with T2DM are inadequately treated and do not achieve glycaemic control (glycated haemoglobin [HbA1c] <7.0%), highlighting the need for more effective T2DM management [6, 7].

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a novel class of glucose-lowering agents with a unique insulin-independent mechanism of action [8]. Dapagliflozin is a highly selective, orally active SGLT2i approved in 2017 by the Chinese National Medical Products Administration (NMPA) to improve glycaemic control in adults with T2DM. International and Chinese guidelines recommend SGLT2i for patients with T2DM with a compelling need to minimise hypoglycaemia and/or weight gain or to promote weight loss [9, 10]. Additionally, SGLT2i are recommended for patients at increased risk of cardiovascular events, with established atherosclerotic cardiovascular disease, with heart failure or with chronic kidney disease in light of evidence for the cardiovascular and renal benefits of SGLT2i in cardiovascular outcome trials [5, 9, 10].

Several adverse events (AEs) were associated with SGLT2i, albeit some (such as urinary and genital tract infections and volume depletion) are expected due to the specific class mechanism of action [9, 11, 12]. Nonetheless, safety data from clinical trials in international [13, 14] and Asian and Chinese [15, 16] populations have demonstrated that dapagliflozin treatment in patients with T2DM has a favourable and predictable safety profile. However, there is still a lack of large-scale studies evaluating the safety of dapagliflozin in Chinese patients with T2DM [15, 16]. In China, the NMPA requires that the safety of all newly approved drugs be assessed in ≥3000 patients within the first 5 years after approval. As such, the primary objective of the DONATE study was to evaluate the safety of dapagliflozin by assessment of AEs during a 24-week follow-up in Chinese patients with T2DM in clinical practice.

Methods

Study design and participants

DONATE was a multicentre, single-arm, prospective, non-interventional study (ClinicalTrials.gov Identifier: NCT03156985). Chinese patients were consecutively enrolled during routine clinical visits between 16 August 2017 and 30 July 2020 from 88 secondary and tertiary hospitals across eight regions in China. Eligible patients were required to have been diagnosed with T2DM according to the 2013 Chinese guidelines for diabetes treatment [17]: typical diabetes symptoms (e.g., polydipsia, polyuria, polyphagia, weight loss) with random plasma glucose ≥11.1 mmol/L and/or fasting plasma glucose ≥7.0 mmol/L and/or 2-h post-challenged plasma glucose ≥11.1 mmol/L; in patients without typical symptoms testing was repeated on a separate day. Patients were also required to have been prescribed dapagliflozin by their physician according to clinical practice, and to have received ≥1 dose of dapagliflozin (see Additional file 1: Table S1 for a full list of eligibility criteria) [17]. Dapagliflozin treatment was confirmed at the first study visit; patients already receiving dapagliflozin prior to enrolment were also eligible. The dosing of dapagliflozin and concomitant medications was at the discretion of the physicians according to current clinical practice [18]. After enrolment, patients were followed up for 24 weeks; if dapagliflozin was discontinued during the study period, patients were followed up for an additional 7 days after discontinuation. Treatment discontinuation was based on the patient’s own decision or the physician’s professional discretion. Patients who discontinued dapagliflozin treatment prior to study completion were followed up via telephone contact if a face-to-face visit was not feasible.

The study comprised three on-site visits: at enrolment (Day 0), at 12 weeks ± 7 days (Week 12) and at 24 weeks ± 7 days (Week 24) (Additional file 1: Table S2 and Additional file 1: Fig. S1). The last observation prior to the first dose of dapagliflozin treatment was used as the baseline measurement. If there was no value prior to the first dose of study treatment, then the baseline value was set to missing. Patient demographics, clinical characteristics and medical and diabetes history were recorded at enrolment (Additional file 1: Table S2). AEs and serious AEs (SAEs) were collected from the time of granting informed consent until 7 days after the last visit. Information on vital signs, laboratory tests and concomitant medication was collected, if available, at enrolment, Week 12 and Week 24 (Additional file 1: Table S2). Prior and concomitant antidiabetic medications were coded by the WHO Drug Dictionary [19].

The study was designed and conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and local clinical practice regulations in China. Ethics approval was provided by the Institutional Review Board of Beijing Hospital (2017BJYYEC-054-02). Written informed consent was obtained from all patients prior to study screening. Patients were reimbursed for incurred travel expenses up to the value of 300 RMB (100 RMB per visit).

Outcomes

The primary endpoint was the proportion of patients with AEs and SAEs, particularly key adverse events of special interest (AESI), including hypoglycaemia (typical symptoms with or without blood glucose ≤3.9 mmol/L, or blood glucose ≤3.9 mmol/L without symptoms), urinary tract infections (UTIs), and genital tract infections (GTIs; typical symptoms with or without microbiological diagnosis). AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA). The definitions of AEs, SAEs and adverse drug reactions (ADRs) are described in Additional file 1: Table S3. The definitions of individual AESIs are described in Additional file 1: Table S4 [20]. Exploratory endpoints included the proportion of patients who experienced other AESI (defined in Additional file 1: Table S4) as well as the absolute change in HbA1c, fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2h-PPG), body weight, waist circumference, blood pressure and the proportion of patients achieving HbA1c <7.0%.

Statistical analysis

A target sample size of 3000 patients was determined based on the post-authorisation drug intensive monitoring programme criteria. Based on a previous study in Chinese patients, the proportion of patients with UTI, GTI and hypoglycaemia following treatment with dapagliflozin was 3.9–5.3%, 3.1–4.5% and 0.8%, respectively [21]. If the proportion of patients with any AE is assumed at 50.0%, 3000 evaluable patients will achieve a precision (or half-width) of 1.8%; if the proportion of patients with any AE is assumed at 0.8%, the precision achieved from 3000 evaluable patients is 0.3%. Accordingly, we estimated that 3000 patients would be sufficient to derive a 95% probability of observing at least one case if the proportion of patients with any AE is ≥0.1%.

The safety analysis set (SAS) was used as the primary analysis set for all safety analyses and included all patients who received ≥1 dose of dapagliflozin. The metabolic analysis set (MAS) included all patients who were treated with dapagliflozin continuously for ≥90 days and had baseline data with at least one post-baseline datapoint available.

For continuous variables, mean, median, standard deviation (SD) and range were calculated, while percentages were calculated for categorical variables. No imputation method for missing data was utilised. Change from baseline was calculated as the post-baseline assessment value minus the baseline assessment value; if either value was missing, the change from baseline was also missing. The Kaplan–Meier method was used to estimate the incidence of hypoglycaemia, UTI and GTI at Week 12 and Week 24. Estimated time to incidence was defined as the time from the first dose of dapagliflozin to the onset of a specific AE. Patients were censored on the day of their last dose of dapagliflozin or discontinuation of the study, whichever happened first. Univariate and multivariate Cox regression models were performed to further explore the association of patient characteristics with the incidence of hypoglycaemia, UTI and GTI. AEs were grouped according to AE severity and relationship to study treatment. Statistical analysis was performed using Statistical Analysis System version 9.4.

Results

Patient demographics and characteristics

In total, 3000 patients were enrolled (Fig. 1). Of these, 2990 (99.7%) received ≥1 dose of dapagliflozin and were included in the SAS, while 2548 (84.9%) were included in the MAS. A total of 700 (23.3%) enrolled patients withdrew from the study; the main reasons for withdrawal were patients’ own decision (13.4%), AEs (3.7%) and loss to follow-up (3.4%).

Fig. 1
figure 1

Patient disposition. aAll patients who received at least one dose of dapagliflozin. bPatients who were treated with dapagliflozin consistently for at least 90 days. T2DM, type 2 diabetes mellitus

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Patient demographics and clinical characteristics at study enrolment (SAS) are shown in Table 1. Briefly, patients were aged (mean [SD]) 52.6 (12.0) years, with 8.35 (7.1) years of diabetes duration. Most patients were male (65.8%). Patients had a mean (SD) HbA1c and FPG of 9.1 (2.0)% and 10.22 (4.0) mmol/L, respectively.

Table 1 Patient demographics and clinical characteristics at study enrolment (safety analysis set)
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At study enrolment, patients included in the MAS had a mean (SD) HbA1c, FPG and 2 h-PPG of 9.0 (1.94)%, 10.15 (3.98) mmol/L and 15.75 (5.10) mmol/L, respectively. Patient body weight, body mass index (BMI) and waist circumference (mean [SD]) were 77.10 (13.89) Kg, 27.23 (4.00) Kg/m2 and 95.94 (10.32) cm, respectively. Mean (SD) systolic blood pressure (SBP) and diastolic blood pressure (DBP) for the enrolled patients were 131.60 (15.53) mmHg and 81.20 (10.21) mmHg, respectively.

Real-world use of dapagliflozin and concomitant medications

Mean (SD) dapagliflozin treatment duration was 209.1 (157.6) days. Most patients (2989/2990) received the preferred once-daily dose of dapagliflozin. Details on exposure to dapagliflozin, including exposure among patients with/without dapagliflozin treatment prior to study enrolment, are summarised in Additional file 1: Table S5.

In the SAS, 94.9% of patients received concomitant antidiabetic therapy (Additional file 1: Table S6 [19]. See Additional file 1: Table S7 for the most frequently prescribed concomitant glucose-lowering medications.

AEs

A total of 1059 (35.4%) patients in the SAS reported ≥1 AE during the 24-week follow-up period (Table 2). This was similar between patients with exposure to dapagliflozin before enrolment (35.5%) and patients without exposure before enrolment (35.1%) (Additional file 1: Table S8). Among the overall population, 186 (6.2%) experienced SAEs and 268 (9.0%) reported ADRs, as assessed by study investigators. The most common AEs (MedDRA preferred terms) were upper respiratory tract infection (3.6%), UTI (2.1%) and constipation (1.4%); the majority of AEs were mild in severity (Table 3). The most common SAEs were inadequate control of T2DM (0.7%), diabetic ketosis (0.3%) and pneumonia (0.3%) (Table 4). The most common ADRs were UTI (1.6%), hypoglycaemia (0.6%), weight decreased (0.6%) and diabetic ketosis (0.5%) (Table 4). Overall, 4.7% of patients discontinued dapagliflozin due to AEs; the most common AEs leading to treatment discontinuation were UTI (0.5%) and weight decreased (0.3%) (Table 4); all patients who discontinued due to weight decreased had a baseline BMI <28 kg/m2.

Table 2 Overall summary of adverse events and adverse events of special interest (safety analysis set)
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Table 3 Summary of adverse events by severity and relationship to study treatment (safety analysis set)
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Table 4 Summary of serious adverse events, adverse drug reactions, and AEs leading to discontinuation (safety analysis set)
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AESIs

UTI, GTI and hypoglycaemia were reported in 70 (2.3%), 39 (1.3%) and 32 (1.1%) patients (Table 2), with 1.6%, 0.1% and 0.6% patients reporting events related to treatment, respectively (Table 3). UTI, GTI and hypoglycaemia were reported in 31 (1.6%), 12 (0.6%) and 23 (1.2%) male patients, and 39 (3.8%), 27 (2.6%) and 9 (0.9%) female patients. The proportion of patients experiencing other AESIs was relatively low (0.1%–0.7%), and no abnormal electrolyte events were reported (Table 2).

The estimated incidence of UTI, GTI and hypoglycaemia for the first 12 weeks was 0.9% (95% confidence interval [CI]: 0.645–1.349), 0.6% (95% CI: 0.376–0.946) and 0.6% (95% CI: 0.349–0.902), respectively; and for 24 weeks, the incidence was 1.7% (95% CI: 1.301–2.270), 1.0% (95% CI: 0.672–1.407) and 0.8% (95% CI: 0.491–1.131).

In the multivariate analysis, sex showed a predictive trend for incidence of UTI (hazard ratio [HR] 2.244, 95% CI: 1.047–4.810) and GTI (HR 6.723, 95% CI: 2.135–21.167) (Table 5). Presence of T2DM complications showed a predictive trend for GTI (HR 0.153 95% CI: 0.048–0.481), as did diabetes duration (>5 years and ≤10 years vs ≤5 years: HR 6.107, 95% CI: 1.212–30.785; >20 years vs ≤5 years: HR 20.580, 95% CI: 3.448–122.828) (Table 5).

Table 5 Analysis of risk factors for hypoglycaemia, urinary tract infection and genital tract infection (safety analysis set)
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Change in metabolic factors (MAS)

At Week 12, mean (SD) change from baseline in HbA1c, FPG and 2h-PPG was –1.522 (1.794)%, –2.022 (3.498) mmol/L and –1.967 (7.882) mmol/L, respectively. At Week 24, mean (SD) change from baseline was –1.318 (1.871)%, –1.826 (3.470) mmol/L and –5.466 (5.473) mmol/L, respectively (Additional file 1: Figs. S2-4). Mean (SD) body weight, BMI and waist circumference were 74.90 (13.34) Kg, 26.51 (3.73) Kg/m2 and 93.34 (10.45) cm at Week 12, and 74.64 (12.88) Kg, 26.37 (3.57) Kg/m2 and 92.87 (10.17) cm at Week 24, respectively. Mean (SD) SBP and DBP were 127.50 (13.72) mmHg and 78.90 (9.27) mmHg at Week 12, and 127.40 (13.18) mmHg and 78.50 (8.72) mmHg at Week 24, respectively. Mean (SD) changes from baseline for all metabolic factors and vital signs are shown in Additional file 1: Figs. S2–9. The proportions of patients achieving HbA1c <7.0% and HbA1c <7.0% without hypoglycaemia are shown in Additional file 1: Fig. S10.

Discussion

This is the largest non-interventional study undertaken in Chinese patients with T2DM evaluating the safety of dapagliflozin in clinical practice, as well as the largest study investigating the safety of any SGLT2i in China to date. Results from this observational study show that dapagliflozin treatment was associated with a low frequency of AEs, including AESIs, demonstrating a favourable safety profile and tolerability in Chinese patients with T2DM in a real-world setting. Overall, no new safety findings were reported and the safety profile of dapagliflozin was consistent with that established in dapagliflozin clinical trials [22,23,24,25].

Overall, baseline patient demographics and clinical characteristics, including metabolic factors and vital signs, were similar to those reported in two Phase 3 studies evaluating the safety of dapagliflozin in Asian (predominantly Chinese) populations [15, 16]. However, there were notable differences, including the longer duration of T2DM, and increased HbA1c, body weight, waist circumference, SBP and DBP in our study. These differences suggest that in a real-world setting, Chinese patients with T2DM receive dapagliflozin at a more advanced stage of the disease and have poorer glycaemic control and metabolic markers than patients with T2DM included in clinical trials.

Most patients received a once-daily dose of dapagliflozin and had a mean treatment duration of 209.1 days, indicating good real-world treatment compliance. The majority of patients (94.9%) received concomitant antidiabetic therapy during the study, most frequently metformin (68.3%). The dapagliflozin and metformin combination is widely used in clinical practice together with lifestyle management in patients with T2DM, indicating that the study population was representative of the real world in terms of clinical management [22].

In the present study, the proportion of patients reporting AEs of any grade (35.4%) was lower than that found in clinical trials in international (60.0–61.7%), Asian (53.6–58.7%) and Chinese (52.4–61.7%) populations [14,15,16, 26, 27], confirming that dapagliflozin is well tolerated in Chinese patients with T2DM in clinical practice. We hypothesise that this difference could be due to physicians using a high degree of caution when selecting appropriate patients, as dapagliflozin had only recently launched in China at the time of study initiation and was the only SGLT2i with approval.

Several prespecified AESIs were carefully monitored during the 24-week follow-up period. These AESIs are potentially associated with treatment with dapagliflozin and other SGLT2i [11], and some of these appear to be related to dapagliflozin’s mechanism of action [26, 28, 29]. Overall, the proportion of patients experiencing ≥1 AESI in this study was low (6.4%), including UTI, GTI and hypoglycaemia (2.3%, 1.3% and 1.1%, respectively). In a study of patients treated with dapagliflozin in Korea, GTI and hypoglycaemia were reported in 3.4% and 13.0% of patients, respectively [30]. In pooled analyses of international dapagliflozin clinical trials, the proportions of patients reporting hypoglycaemia, UTI and GTI were 10.2–13.7%, 4.3–4.7% and 4.8–5.5%, respectively [14, 26], although these AESIs appear to be less frequent in Asian (1.6–1.9%, 3.5–4.7% and 1.8–2.6%, respectively) [27] and Chinese (0.0–1.4%, 3.6–6.6% and 0.9–‍2.0%, respectively) [15, 16] populations. The low proportion of patients reporting UTI and GTI in DONATE may have been influenced by the predominantly male population (65.8% male), although the proportion of male patients is consistent with that reported in dapagliflozin and empagliflozin pooled safety analyses (57.5%–65.4%) [14, 31]. It is possible, however, that a higher degree of caution was used by clinicians when considering dapagliflozin treatment in females due to the known risk of GTI and UTI and the recent approval of dapagliflozin in China at the time of study initiation. A meta-analysis of six randomised, placebo-controlled trials (N = 2033; up to 24 weeks of follow-up) showed that dapagliflozin treatment was associated with an increased relative risk of 1.74 (95% CI: 1.21–2.49; p = 0.003) for UTI and 3.52 (95% CI: 2.06–6.03; p <1 × 10–5) for GTI [32]. Multivariate analyses in the present study showed that the incidence of UTI and GTI in females was increased by approximately 2.2- and 6.7-fold, respectively, compared with males. Sex has previously shown a strong association with UTI and GTI in patients with T2DM receiving dapagliflozin [28, 29, 33], although this has also been shown in patients with and without T2DM irrespective of dapagliflozin treatment [34]. Results of the DONATE study suggest that the incidence of UTI, GTI and hypoglycaemia is low in clinical practice in China (estimated incidence: 0.9%, 0.6% and 0.6% at Week 12, and 1.7%, 1.0% and 0.8% at Week 24, respectively). Nonetheless, we found that UTI was the most frequent AE leading to treatment discontinuation.

We additionally found that longer duration of diabetes was associated with increased incidence of GTI, but was not associated with incidence of UTI or hypoglycemia. However, an association between disease duration and hypoglycaemia has been previously shown in patients with T2DM [35], which could be due to a decline in islet function over time. Treatment with SGLT2i improves glycaemic control independent of insulin secretion [8], which may account for differences between these studies. Another study has reported no association between diabetes duration and GTI [33]; this study also reported no association between HbA1c and GTI, but there is evidence that poor glycaemic control may increase incidence of GTI [36, 37]. It is interesting that in DONATE, longer duration of diabetes but not glycemic control (measured by HbA1c) was associated with incidence of GTI. Although, while HbA1c reflects average blood glucose levels over 3 months, this measurement may not fully reflect the impact of longer-term glucose toxicity. In the setting of uncontrolled glucose levels, patients with T2DM have impaired immune system function and thus are at increased risk of infections [38]. Therefore, good control of blood glucose levels and regular check-ups may help to reduce the risk of GTI. Further research is required to confirm the risk factors for GTI in patients with diabetes, particularly for patients treated with SGLT2i given the increased risk conferred by treatment [14, 39, 40]. In the present study, the proportion of patients reporting other AESIs was low, including the frequency of diabetic ketoacidosis (0.1%). A UK study reported the frequency of diabetic ketoacidosis in patients treated with dapagliflozin in clinical practice to be 1.9% [41]. Of note, the proportion of patients with renal impairment was lower than in the pooled safety analysis by Jabbour and colleagues (0.3% vs 0.8%) [14].

This study, which provides a comprehensive real-world analysis of dapagliflozin treatment in routine clinical practice, identified ‘weight decreased’ as an adverse drug reaction in 17 patients. While weight loss is an expected and desirable effect of SGLT2i [42], it may be perceived differently from patient to patient and could potentially be deemed an adverse effect by some, especially those who are elderly or not overweight/obese. Clinicians should be aware of the potential unintended consequences of excessive or rapid weight loss, including malnutrition and anxiety. However, weight loss is a significant metabolic effect of dapagliflozin and even modest reductions in weight can lead to improvements in glycemia and other cardiovascular risk factors [43]. In DONATE, where the majority of patients were classified as overweight or obese, dapagliflozin treatment resulted in an overall decrease in mean weight over the study period.

Other metabolic parameters of interest such as HbA1c, FPG and 2h-PPG improved throughout the 24-week follow-up, although all results using the metabolic analysis set should be interpreted with caution due to substantial missing data. The mean (SD) absolute change from baseline in HbA1c at Week 24 was consistent with that observed in clinical practice in the UK (–1.06 [1.49]%) [41]. An improvement was also observed in the proportion of patients achieving HbA1c <7.0% throughout the present study. This is consistent with two randomised clinical trials of Chinese patients treated with dapagliflozin 10 mg, in which HbA1c <7.0% was achieved in 33.0−49.8% of patients at the 24-week follow-up [15, 16]. In a real-world analysis of US databases evaluating glycaemic control in patients with T2DM, 25.1% of patients treated with dapagliflozin 10 mg achieved HbA1c <7.0% at 6 months [44]. Current integrated glycaemic control targets for T2DM in China include HbA1c <7.0% [17, 45]. Results of the DONATE study suggest that dapagliflozin treatment resulted in an increase in the proportion of patients with T2DM meeting this criteria, demonstrating its valuable role in the integrated management of patients with T2DM in a real-world setting [17].

Strengths of the study include the large sample size and wide variety of contemporary clinical practice settings across diverse regions of China. However, the results should be viewed in the context of the following limitations. Firstly, data on AEs prior to study enrolment were not collected retrospectively; therefore, early AEs may have been omitted from the analyses due to the time of data collection. Secondly, there was a limited number of patients with available post-baseline data for all parameters. Patients who provided data may have been those with a high level of diabetes management compliance; thus, data from the present study should be interpreted with caution. The lack of available post-baseline records for the change in metabolic parameters and vital signs suggests that patients with T2DM may not be routinely followed up in clinical practice in China. A recent focus group study evaluating the encounters between Chinese general practitioners (GPs) and patients with T2DM identified key challenges that GPs face, from short consultation time to inadequate patient information resources and healthcare support [46]. These issues may explain the lack of periodic follow-up in the DONATE study. Thirdly, the effects of concomitant glucose-lowering medications cannot be easily separated from the effects of dapagliflozin. Fourthly, while there are many interesting observations in DONATE, the data we collected does not allow us to investigate them all. For instance, we did not collect data on the reason(s) for initiation of dapagliflozin and so we are unable to evaluate adherence to the local clinical guidelines [18]. In addition, we did not collect detailed information on diabetes complications, which hinders interpretation of the association of diabetes complications with risk of GTI. We encourage further research in these areas. Finally, and as with observational studies in general, confounding could have influenced the results.

Conclusions

In conclusion, dapagliflozin use under varied clinical practice settings in China was associated with a favourable safety profile and a low incidence of AEs, especially those of special interest (GTI, UTI and hypoglycaemia). Moreover, improvements were observed in glycaemic control and other metabolic parameters.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ADR:

Adverse drug reaction

AE:

Adverse event

AESI:

Adverse event of special interest

BMI:

Body mass index

CI:

Confidence interval

DBP:

Diastolic blood pressure

FPG:

Fasting plasma glucose

GP:

General practitioner

GTI:

Genital tract infection

HR:

Hazard ratio

MAS:

Metabolic analysis set

MedDRA:

Medical Dictionary for Regulatory Activities

NMPA:

National Medical Products Administration

2h-PPG:

2-Hour postprandial plasma glucose

SAE:

Serious adverse event

SAS:

Safety analysis set

SBP:

Systolic blood pressure

SD:

Standard deviation

SGLT2i:

Sodium-glucose cotransporter-2 inhibitors

T2DM:

Type 2 diabetes mellitus

UTI:

Urinary tract infection

References

  1. Kaku K, Inoue S, Matsuoka O, Kiyosue A, Azuma H, Hayashi N, et al. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2013;15:432–40.

    Article  CAS  PubMed  Google Scholar 

  2. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364:829-41.

  3. Wang L, Peng W, Zhao Z, Zhang M, Shi Z, Song Z, et al. Prevalence and treatment of diabetes in China, 2013–2018. JAMA. 2021;326:2498–506.

    Article  PubMed  PubMed Central  Google Scholar 

  4. International Diabetes Federation. IDF Diabetes Atlas 10th edition. 2021. https://diabetesatlas.org/atlas/tenth-edition/. Accessed 15 Jul 2022.

  5. Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J, Maruthur NM, et al. Management of hyperglycaemia in type 2 diabetes, A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2022;2022(65):1925–66.

    Article  Google Scholar 

  6. Ji LN, Lu JM, Guo XH, Yang WY, Weng JP, Jia WP, et al. Glycemic control among patients in China with type 2 diabetes mellitus receiving oral drugs or injectables. BMC Public Health. 2013;13:602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chan JCN, Lim LL, Luk AOY, Ozaki R, Kong APS, Ma RCW, et al. From Hong Kong Diabetes Register to JADE Program to RAMP-DM for Data-Driven Actions. Diabetes Care. 2019;42:2022–31.

    Article  PubMed  Google Scholar 

  8. Hsia DS, Grove O, Cefalu WT. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2017;24:73–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes-2021. Diabetes Care. 2021;44:S111–24.

    Article  Google Scholar 

  10. Chinese Diabetes Society. Guideline for the prevention and treatment of type 2 diabetes mellitus in China (2020 edition). Chin J Diabetes Mellitus. 2021;13:315–409.

    Google Scholar 

  11. Scheen AJ. An update on the safety of SGLT2 inhibitors. Expert Opin Drug Saf. 2019;18:295–311.

    Article  CAS  PubMed  Google Scholar 

  12. Xu D, Chandler O, Wee C, Ho C, Affandi JS, Yang D, et al. Sodium-glucose cotransporter-2 inhibitor (SGLT2i) as a primary preventative agent in the healthy individual: a need of a future randomised clinical trial? Front Med (Lausanne). 2021;8:712671.

    Article  PubMed  Google Scholar 

  13. Anderson SL. Dapagliflozin efficacy and safety: a perspective review. Ther Adv Drug Saf. 2014;5:242–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jabbour S, Seufert J, Scheen A, Bailey CJ, Karup C, Langkilde AM. Dapagliflozin in patients with type 2 diabetes mellitus: A pooled analysis of safety data from phase IIb/III clinical trials. Diabetes Obes Metab. 2018;20:620–8.

    Article  CAS  PubMed  Google Scholar 

  15. Yang W, Han P, Min KW, Wang B, Mansfield T, T’Joen C, et al. Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: a randomized controlled trial. J Diabetes. 2016;8:796–808.

    Article  CAS  PubMed  Google Scholar 

  16. Ji L, Ma J, Li H, Mansfield TA, T’Joen CL, Iqbal N, et al. Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Ther. 2014;36(84–100):e9.

  17. Chinese Diabetes Society. Chinese type 2 diabetes mellitus treatment guidelines: 2013 edition. Chin J Diabetes Mellit. 2014;6:447–98.

    Google Scholar 

  18. Chinese Medical Association Diabetes Branch. Guidelines for the prevention and treatment of type 2 diabetes in China (2017 Edition). Chin J Diabetes Mellit. 2018;10:4–67.

    Google Scholar 

  19. World Health Organization. WHO Drug Dictionary by the Uppsala Monitoring Centre. 2021. https://www.who-umc.org/whodrug/. Accessed 5 May 2022.

  20. Andrassy KM. Comments on “KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.” Kidney Int. 2013;84:622–3.

    Article  CAS  PubMed  Google Scholar 

  21. Ji L, Ma J, Li H, Mansfield TA, T’Joen CL, Iqbal N, et al. Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Ther. 2014;36(84–100):e9.

    Google Scholar 

  22. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:2223–33.

    Article  CAS  PubMed  Google Scholar 

  23. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33:2217–24.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2011;13:928–38.

    Article  CAS  PubMed  Google Scholar 

  25. Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012;156:405–15.

    Article  PubMed  Google Scholar 

  26. Ptaszynska A, Johnsson KM, Parikh SJ, de Bruin TW, Apanovitch AM, List JF. Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Saf. 2014;37:815–29.

    Article  CAS  PubMed  Google Scholar 

  27. Yang W, Ji L, Zhou Z, Cain VA, Johnsson KM, Sjostrom CD. Efficacy and safety of dapagliflozin in Asian patients: a pooled analysis. J Diabetes. 2017;9:787–99.

    Article  CAS  PubMed  Google Scholar 

  28. Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27:473–8.

    Article  PubMed  Google Scholar 

  29. Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27:479–84.

    Article  PubMed  Google Scholar 

  30. Ku EJ, Lee D-H, Jeon HJ, Oh TK. Long-term effectiveness and safety of quadruple combination therapy with empagliflozin versus dapagliflozin in patients with type 2 diabetes: 3-year prospective observational study. Diabetes Res Clin Pract. 2021;182:109123.

  31. Kohler S, Zeller C, Iliev H, Kaspers S. Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I-III clinical trials. Adv Ther. 2017;34:1707–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Feng M, Lv H, Xu X, Wang J, Lyu W, Fu S. Efficacy and safety of dapagliflozin as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials. Medicine (Baltimore). 2019;98:e16575.

    Article  CAS  PubMed  Google Scholar 

  33. Thong KY, Yadagiri M, Barnes DJ, Morris DS, Chowdhury TA, Chuah LL, et al. Clinical risk factors predicting genital fungal infections with sodium-glucose cotransporter 2 inhibitor treatment: the ABCD nationwide dapagliflozin audit. Prim Care Diabetes. 2018;12:45–50.

    Article  PubMed  Google Scholar 

  34. Nichols GA, Brodovicz KG, Kimes TM, Deruaz-Luyet A, Bartels DB. Prevalence and incidence of urinary tract and genital infections among patients with and without type 2 diabetes. J Diabetes Complications. 2017;31:1587–91.

    Article  PubMed  Google Scholar 

  35. Torimoto K, Okada Y, Hajime M, Tanaka K, Tanaka Y. Risk factors of hypoglycemia in patients with type 2 diabetes mellitus: a study based on continuous glucose monitoring. Diabetes Technol Ther. 2018;20:603–12.

    Article  CAS  PubMed  Google Scholar 

  36. Hirji I, Andersson SW, Guo Z, Hammar N, Gomez-Caminero A. Incidence of genital infection among patients with type 2 diabetes in the UK General Practice Research Database. J Diabetes Complications. 2012;26:501–5.

    Article  PubMed  Google Scholar 

  37. Rizzi M, Trevisan R. Genitourinary infections in diabetic patients in the new era of diabetes therapy with sodium-glucose cotransporter-2 inhibitors. Nutr Metab Cardiovasc Dis. 2016;26:963–70.

    Article  CAS  PubMed  Google Scholar 

  38. Berbudi A, Rahmadika N, Tjahjadi AI, Ruslami R. Type 2 diabetes and its impact on the immune system. Curr Diabetes Rev. 2020;16:442–9.

    PubMed  PubMed Central  Google Scholar 

  39. Ptaszynska A, Johnsson KM, Parikh SJ, de Bruin TW, Apanovitch AM, List JF. Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Saf. 2014;37:815–29.

    Article  CAS  PubMed  Google Scholar 

  40. Xu C, He L, Zhang J, Xu L, Dong J, Liao L. The cardiovascular benefits and infections risk of SGLT2i versus metformin in type 2 diabetes: a systemic review and meta-analysis. Metabolites. 2022;12:979.

  41. McGurnaghan SJ, Brierley L, Caparrotta TM, McKeigue PM, Blackbourn LAK, Wild SH, et al. The effect of dapagliflozin on glycaemic control and other cardiovascular disease risk factors in type 2 diabetes mellitus: a real-world observational study. Diabetologia. 2019;62:621–32.

    Article  CAS  PubMed  Google Scholar 

  42. Bolinder J, Ljunggren O, Kullberg J, Johansson L, Wilding J, Langkilde AM, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97:1020–31.

    Article  CAS  PubMed  Google Scholar 

  43. American Diabetes Association. Standards of care in diabetes-2023 abridged for primary care providers. Clin Diabetes. 2022;41:4–31.

    Article  Google Scholar 

  44. Blonde L, Patel C, Bookhart B, Pfeifer M, Chen YW, Wu B. A real-world analysis of glycemic control among patients with type 2 diabetes treated with canagliflozin versus dapagliflozin. Curr Med Res Opin. 2018;34:1143–52.

    Article  CAS  PubMed  Google Scholar 

  45. Jia W, Weng J, Zhu D, Ji L, Lu J, Zhou Z, et al. Standards of medical care for type 2 diabetes in China 2019. Diabetes Metab Res Rev. 2019;35:e3158.

    Article  PubMed  Google Scholar 

  46. Yao M, Zhang DY, Fan JT, Lin K, Haroon S, Jackson D, et al. The experiences of Chinese general practitioners in communicating with people with type 2 diabetes-a focus group study. BMC Fam Pract. 2021;22:156.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank the participants, their families and all investigators involved in the DONATE study. The authors also thank J. Ventura, BScBiotech, MSc and A. Carruthers, BSc (Hons), PhD, of Nucleus Global for providing medical writing assistance funded by AstraZeneca China. The authors would also like to thank J. Zhang (MM, AstraZeneca), L. Li (MM, AstraZeneca) for review and critical suggestions for improvement.

Funding

This study was funded by AstraZeneca. AstraZeneca provided funding for medical writing, editorial support and publication fees in accordance with Good Publication Practice (GPP3) guidelines. AstraZeneca also played a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Department of Endocrinology, Beijing Hospital, National Centre of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1, Dongdan Dahua Road, Dongcheng District, Beijing, 100730, People’s Republic of China

    Lixin Guo

  2. Weifang Municipal Hospital, Weifang, People’s Republic of China

    Jing Wang

  3. The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China

    Li Li

  4. Zhuhai People’s Hospital, Zhuhai, People’s Republic of China

    Lin Yuan

  5. The People’s Hospital of Liuyang, Liuyang, People’s Republic of China

    Sheng Chen

  6. Yancheng Tinghu District People’s Hospital, Yancheng, People’s Republic of China

    Hui Wang

  7. The 81st Hospital of People’s Liberation Army, Nanjing, People’s Republic of China

    Tonghuan Li

  8. Present Address: The Second Hospital of Nanjing, Nanjing, People’s Republic of China

    Tonghuan Li

  9. Beijing Yanhua Hospital, Beijing, People’s Republic of China

    Lin Qi

  10. Rui’an People’s Hospital, Rui’an, People’s Republic of China

    Hong Yang

Authors
  1. Lixin Guo
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  3. Li Li
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  4. Lin Yuan
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  9. Hong Yang
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Contributions

LG had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. LG, JW, LL, LY, SC, HW, TL, LQ and HY contributed to the study investigations, including recruitment, follow-up, and data collection. LG, was a major contributor in writing the manuscript, and LG, JW and LL contributed to critical revision of the manuscript for important intellectual content. LG was additionally responsible obtaining funding, statistical analysis and interpretation, and administrative, technical, or material support. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lixin Guo.

Ethics declarations

Ethics approval and consent to participate

Ethics approval was provided by the Institutional Review Board of Beijing Hospital (2017BJYYEC-054-02). Written informed consent was obtained from all patients prior to study screening.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Supplementary Information

Additional file 1: Table S1.

Eligibility criteria. Table S2. Schedule of visits and data collection. Table S3. Outcome definitions. Table S4. Definition of adverse events of special interest. Table S5. Summary of dapagliflozin exposure. Table S6. Concomitant medications. Table S7. Most common concomitant antidiabetic medications. Table S8. Overall summary of adverse events and adverse events of special interest by timing of exposure to dapagliflozin. Fig. S1. Study design. Fig. S2. Mean change from baseline in HbA1c during the 24-week study follow-up. Fig. S3. Mean change from baseline in FPG during the 24-week study follow-up. Fig. S4. Mean change from baseline in 2h-PPG during the 24-week study follow-up. Fig. S5. Mean change from baseline in body weight during the 24-week study follow-up. Fig. S6. Mean change from baseline in BMI during the 24-week study follow-up. Fig. S7. Mean change from baseline in waist circumference during the 24-week study follow-up. Fig. S8. Mean change from baseline in SBP during the 24-week study follow-up. Fig. S9. Mean change from baseline in DBP during the 24-week study follow-up. Fig. S10. Proportion of patients achieving HbA1c <7.0% throughout the 24-week study follow-up.

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Guo, L., Wang, J., Li, L. et al. A multicentre, prospective, non-interventional study evaluating the safety of dapagliflozin in patients with type 2 diabetes in routine clinical practice in China (DONATE). BMC Med 21, 212 (2023). https://doi.org/10.1186/s12916-023-02906-7

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Keywords

BMC Medicine

ISSN: 1741-7015

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