Search

Aims: To evaluate the effects of initiating sodium‐glucose cotransporter‐2 (SGLT2) inhibitors on cardiorenal outcomes and mortality compared to dipeptidyl peptidase‐4 (DPP‐4) inhibitors as active comparators in patients diagnosed with type 2 diabetes with a history of percutaneous coronary intervention (PCI). Materials and Methods: We used an active‐comparator, new‐user design and nationwide data from the National Health Insurance Service in South Korea from 2014 to 2019. Of the 56 392 patients who underwent PCI, 4610 new SGLT2 inhibitor users were paired 1:1 with DPP‐4 inhibitor users for analysis using propensity‐score matching. Results: During 13 708.59 person‐years of follow‐up, the initiation of SGLT2 inhibitors, compared with the initiation of DPP‐4 inhibitors, was associated with a significantly lower risk of composite repeat revascularization, myocardial infarction, stroke, heart failure (HF), all‐cause death and end‐stage renal disease (ESRD). The beneficial effects of SGLT2 inhibitor use were consistent with the components of stroke, HF, all‐cause death and ESRD. In the cohort that included health examination data, including anthropometric and metabolic factors, new use of SGLT2 inhibitors was associated with a significantly lower risk of HF (hazard ratio [HR] 0.574, 95% confidence interval [CI] 0.36–0.915), all‐cause death (HR 0.731, 95% CI 0.567–0.942), and ESRD (HR 0.076, 95% CI 0.018–0.319). The effects of SGLT2 inhibitor use were consistent regardless of the timing of the previous PCI. Conclusions: The initiation of SGLT2 inhibitors in patients with type 2 diabetes and a history of PCI was significantly associated with a reduced risk of cardiorenal consequences and mortality, irrespective of time since the last PCI. [ABSTRACT FROM AUTHOR]

Concomitant use of sodium glucose cotransporter‐2 inhibitors (SGLT‐2i) and overactive bladder (OAB) drugs potentially poses a risk of urinary tract infections (UTIs) due to the urinary retention of highly concentrated glucose in the urine. Thus, this study aimed to investigate the risk of UTIs among patients who initiated SGLT‐2i treatment while taking OAB drugs. This population‐based cohort study included new‐users of SGLT‐2i or comparator antidiabetics (dipeptidyl peptidase‐4 inhibitor (DPP‐4i); glucagon‐like peptide‐1 receptor agonist (GLP‐1RA)) with OAB drugs between 2014 and 2020 using claim data from Korea. Primary outcome was a composite UTI event composite end point comprising pyelonephritis, cystitis, and urethritis, using both inpatient and outpatient diagnoses. Propensity score fine stratification was used to adjust for potential confounding factors. Weighted hazard ratios (HR) were calculated using the Cox proportional hazards model. In the first cohort, 796 and 9,181 new‐users of SGLT‐2i and DPP‐4i with OAB drugs were identified, respectively. This study found a similar risk of UTIs in concomitant users of SGLT‐2i and DPP‐4i (weighted HR 1.08, 95% confidence interval: 0.88–1.32) with OAB drugs. In the second cohort, 2,387 and 280 new‐users of SGLT‐2i and GLP‐1RA with OAB drugs were identified, respectively. Initiation of SGLT‐2i while on OAB treatment was not associated with increased risk of UTI (0.89, 0.50–1.60), compared with initiation of GLP‐1RA. These results show that the concomitant use of SGLT‐2i with OAB drugs was not associated with an increased risk of UTI compared with the concomitant use of DPP‐4i or GLP‐1RA with OAB drugs. [ABSTRACT FROM AUTHOR]

Background: Recent diabetes management guidelines recommend that sodium-glucose cotransporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1RAs) with proven cardiovascular benefits should be prioritized for combination therapy in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD). This study was aimed at evaluating SGLT2i or GLP-1RA usage rates and various related factors in patients with T2DM and established CVD. Methods: We enrolled adults with T2DM aged =30 years who were hospitalized due to established CVD from January 2019 to May 2020 at 13 secondary and tertiary hospitals in Korea in this retrospective observational study. Results: Overall, 2,050 patients were eligible for analysis among 2,107 enrolled patients. The mean patient age, diabetes duration, and glycosylated hemoglobin level were 70.0 years, 12.0 years, and 7.5%, respectively. During the mean follow-up duration of 9.7 months, 25.7% of the patients were prescribed SGLT2is after CVD events. However, only 1.8% were prescribed GLP-1RAs. Compared with SGLT2i non-users, SGLT2i users were more frequently male and obese. Furthermore, they had a shorter diabetes duration but showed worse glycemic control and better renal function at the time of the event. GLP-1RA users had a longer duration of diabetes and worse glycemic control at the time of the event than GLP-1RA non-users. Conclusion: The SGLT2i or GLP-1RA prescription rates were suboptimal in patients with T2DM and established CVD. Sex, body mass index, diabetes duration, glycemic control, and renal function were associated with the use of these agents. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated the effectiveness and safety of sodium-glucose cotransporter 2 inhibitor (SGLT2i) add-on treatment in patients with type 2 diabetes mellitus (T2DM) in the real-world setting. Methods: This single-center retrospective study used the clinical database of Seoul National University Hospital in South Korea. Patients who received metformin monotherapy or combination therapy with ≥ 1 other oral hypoglycemic medication and had a baseline glycosylated hemoglobin (HbA1c) between 7.0% and 10.5% were included. Propensity score matching was applied between patients treated with and without SGLT2 inhibitors (SGLT2i and non-SGLT2i groups, respectively). Changes in HbA1c from baseline to week 26 were compared between the SGLT2i and non-SGLT2i groups, and risk of adverse events (AE) were also assessed. Results: A total of 1106 patients were included. At week 26, HbA1c was significantly more reduced by 0.35 percentage points in the SGLT2i group than in the non-SGLT2i group (95% CI 0.30–0.41, P < 0.001). Likewise, the proportion of patients achieving HbA1c < 7% was also significantly higher (51.9% vs. 37.6%, P < 0.05) in the SGLT2i group than in the non-SGLT2i group. The risk of adverse events in the SGLT2i group was mostly comparable with those in the non-SGLT2i group except for diseases of the liver, pain, hypertensive diseases, and metabolic disorders, which showed significantly higher odds in the SGLT2i group. Conclusions: SGLT2i add-on treatment is an effective and safe therapeutic option for patients with T2DM in the real-world practice setting. [ABSTRACT FROM AUTHOR]

Background: There is no clinical evidence about the effect of sodium–glucose cotransporter-2 (SGLT2) inhibitors on diabetic patients who have been diagnosed with coronavirus disease 19 (COVID-19). Methods: The dataset is based on insurance benefit claims sent to the Health Insurance Review and Assessment Service of Korea from January, 2018 to April, 2022. Among 9,822,577 patients who were involved in the claims, diabetic patients were divided into two groups based on whether they had a prescription for an SGLT2 inhibitor. The primary outcome was major adverse cardiac and cerebrovascular events (MACCEs), which were a composite of all-cause mortality, myocardial infarction, stroke, and revascularization over 90 days. Results: A total of 172,682 patients was analyzed. In the propensity score-matched analysis, the rate of MACCE was lower in the SGLT2 inhibitor group compared to the non-SGLT2 inhibitor group (0.89% vs. 1.31%; hazard ratio, 0.71; 95% confidence interval, 0.53–0.94; p =0.020). Each of the MACCEs showed no differences between the two groups. The rate of pneumonia was similar between the two groups (4.45% vs. 4.39%; hazard ratio, 1.06; 95% confidence interval, 0.91–1.16; p = 0.620). Conclusions: In the diabetic patients who were diagnosed with COVID-19, SGLT2 inhibitors were associated with improved clinical outcomes in terms of MACCEs. SGLT2 inhibitors might be considered for prescription to diabetic patients in the current context of long COVID-19. [ABSTRACT FROM AUTHOR]

Enavogliflozin is a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor approved for clinical use in South Korea. As SGLT2 inhibitors are a treatment option for patients with diabetes, enavogliflozin is expected to be prescribed in various populations. Physiologically based pharmacokinetic (PBPK) modelling can rationally predict the concentration–time profiles under altered physiological conditions. In previous studies, one of the metabolites (M1) appeared to have a metabolic ratio between 0.20 and 0.25. In this study, PBPK models for enavogliflozin and M1 were developed using published clinical trial data. The PBPK model for enavogliflozin incorporated a non-linear urinary excretion in a mechanistically arranged kidney model and a non-linear formation of M1 in the liver. The PBPK model was evaluated, and the simulated pharmacokinetic characteristics were in a two-fold range from those of the observations. The pharmacokinetic parameters of enavogliflozin were predicted using the PBPK model under pathophysiological conditions. PBPK models for enavogliflozin and M1 were developed and validated, and they seemed useful for logical prediction. [ABSTRACT FROM AUTHOR]

Background : Impaired respiratory function remains underrecognized in patients with type 2 diabetes (T2D), despite common pulmonary impairment. Meanwhile, there is little data available on the respiratory effects of sodium glucose cotransporter 2 inhibitors (SGLT2i). Hence, we examined the association between SGLT2i use and the risk of adverse respiratory events in a real-world setting. Methods: We conducted a population-based, nationwide cohort study using an active-comparator new-user design and nationwide claims data of South Korea from January 2015 to December 2020. Among individuals aged 18 years or older, propensity score matching was done to match each new user of SGLT2is with dipeptidyl peptidase 4 inhibitors (DPP4is), with patients followed up according to an as-treated definition. The primary outcome was respiratory events, a composite endpoint of acute pulmonary edema, acute respiratory distress syndrome (ARDS), pneumonia, and respiratory failure. Secondary outcomes were the individual components of the primary outcome and in-hospital death. Cox models were used to estimate hazard ratios (HRs) and 95% CIs. Results: Of 205,534 patient pairs in the propensity score matched cohort, the mean age of the entire cohort was 53.8 years and 59% were men, with a median follow-up of 0.66 years; all baseline covariates achieved balance between the two groups. Incidence rates for overall respiratory events were 4.54 and 7.54 per 1000 person-years among SGLT2i and DPP4i users, respectively, corresponding to a rate difference of 3 less events per 1000 person-years (95% CI − 3.44 to − 2.55). HRs (95% CIs) were 0.60 (0.55 to 0.64) for the composite respiratory endpoint, 0.35 (0.23 to 0.55) for acute pulmonary edema, 0.44 (0.18 to 1.05) for ARDS, 0.61 (0.56 to 0.66) for pneumonia, 0.49 (0.31 to 0.76) for respiratory failure, and 0.46 (0.41 to 0.51) for in-hospital death. Similar trends were found across individual SGLT2is, subgroup analyses of age, sex, history of comorbidities, and a range of sensitivity analyses. Conclusions: These findings suggest a lower risk of adverse respiratory events associated with patients with T2D initiating SGLT2is versus DPP4is. This real-world evidence helps inform patients, clinicians, and guideline writers regarding the respiratory effects of SGLT2i in routine practice. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA) are novel anti-diabetic drugs whose glucose-lowering effect and cardiovascular and renal benefits were evidenced in clinical trials. We investigated the real-world efficacy and safety of the combination of SGLT2i and GLP-1RA in patients with type 2 diabetes mellitus in Korea. The medical records of 104 patients who maintained the combination for at least 1 year were retrospectively reviewed. The change in glycosylated hemoglobin (HbA1c) after 6 months and 1 year of treatment was evaluated. The mean age was 51 years, and 41% were female. The mean baseline HbA1c, body mass index, and duration of diabetes were 9.0%, 28.8 kg/m², and 11.7 years, respectively. Compared with baseline, the HbA1c decreased by 1.5% (95% confidence interval [CI], 1.27 to 1.74; P<0.001) after 6 months and by 1.4% (95% CI, 1.19 to 1.70; P<0.001) after 1 year. Over 1 year, the bodyweight change was -2.8 kg (95% CI, -4.21 to -1.47; P<0.001). The combination of SGLT2i and GLP-1RA is effective and tolerable in type 2 diabetes mellitus patients in realworld practice. [ABSTRACT FROM AUTHOR]

Aims/Introduction: This study aimed to determine whether sodium–glucose cotransporter 2 inhibitors (SGLT2i) were related to increased fracture risk in adults with type 2 diabetes compared with dipeptidyl peptidase‐4 inhibitors (DPP‐4i). Materials and Methods: Between 1 May 2016 and 31 December 2018, we carried out a new‐user cohort study using the Korean National Health Insurance Service database. Propensity score matching was carried out on 478,826 new users of an SGLT2i or DPP‐4i. After propensity score matching on >80 covariates, 84,460 individuals were initiated on SGLT2i or DPP‐4i, with 42,230 individuals in each treatment group. The time to first fracture event was compared between the SGLT2i and DPP‐4i groups using Cox proportional hazards models, and the results are reported as hazard ratios with 95% confidence intervals for fracture occurrence. Subgroup analyses investigated fractures between treatment groups according to baseline characteristics. Results: Individuals who were started on SGLT2i were not linked with increased fracture risk in both as‐treated and intention‐to‐treat analyses (as‐treated: hazard ratio 0.98, 95% confidence interval 0.92–1.04; intention‐to‐treat: hazard ratio 0.94, 95% confidence interval 0.89–1.00). We identified no significant interaction between the individuals' age, sex, fracture history or thiazolidinedione use in any subgroup analyses, showing that none of these variables appeared to be impact modifiers in the connection between SGLT2i and fractures. Conclusions: Our study found no increase in the risk of fracture among individuals treated with SGLT2i in a real‐world clinical setting for type 2 diabetes. [ABSTRACT FROM AUTHOR]

What is known and objectives: In Korea, the side effects of sodium‐glucose cotransporter 2 inhibitors (SGLT2i) have not been clearly reported, aside from voluntary reporting. We aimed to develop detection algorithms for SGLT2i‐related genital tract infections (GTIs) and urinary tract infections (UTIs) via a common data model (CDM), an electronic medical record–based database for supporting multi‐hospital clinical research. We estimated the occurrence of GTIs and UTIs and—by assessing the status of each step of the algorithm—we also aimed to determine how clinicians responded to the SGLT2i‐related GTIs and UTIs. Methods: We targeted all patients who were prescribed SGLT2i at Catholic University Seoul St. Mary's Hospital and Hallym University Dongtan Sacred Heart Hospital from January 2014 to August 2018. We developed algorithms for detection of SGLT2i‐related GTIs or UTIs that divided patients into "most likely," "possibly" or "less likely" categories of GTIs or UTIs. The numbers of patients at each step were extracted. Results and discussion: A total of 4253 patients received their first prescription of SGLT2i. According to the algorithm used in this study, the proportions of "most likely GTI" and "possibly GTI" were 0.9% (37 out of 4253) and 19.4% (826 out of 4253 patients), respectively. Similarly, the proportions of "most likely UTI" and "possibly UTI" were 0.9% (38 out of 4253) and 20.2% (858 out of 4253 patients), respectively. Compared to the various existing prospective studies, both GTIs and UTIs showed lower occurrence among patients who met "most likely" criteria and higher occurrence among those who met "possibly" criteria. When a GTI or UTI occurred or was suspected, the overall rate of discontinuing SGLT2i was 51.8% (1721 out of 3323). Despite a confirmed or suspected GTI and an UTI, 62.8% (1460 out of 2323) and 14.2% (142 out of 1000) of patients continued to take SGLT2i, respectively. The discontinuation rate for suspected GTIs was significantly lower than that for suspected UTIs (37.2% vs. 85.8%, p < 0.001). What is new and conclusion: In this study, although the GTIs appeared to have a similar occurrence as UTIs, however, the discontinuation rate of SGLT2i for suspected GTIs was relatively lower. Our study is novel in that we identified how the physicians approached SGLT2i‐related GTIs or UTIs at each step in a real‐world clinical practice setting. Although we could estimate SGLT2i‐related GTIs and UTIs via CDM, we were limited in our ability to accurately detect mild drug side effects via CDM, which lacked data for operational definition. [ABSTRACT FROM AUTHOR]

Background: Using real-world data, cardiovascular safety was investigated in metformin users newly starting sodium glucose cotransporter 2 (SGLT2) inhibitors compared with other glucose-lowering drugs in Korea. Methods: This was a retrospective observational study using the National Health Insurance Service claims database in Korea. The study period was from September 2014 to December 2016. The study included subjects who were newly prescribed SGLT2 inhibitors or other glucose-lowering drugs while on metformin monotherapy; cohort 1 was composed of new users of SGLT2 inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors and cohort 2 included new users of SGLT2 inhibitors versus sulfonylureas. To balance the patient characteristics, propensity score matching was performed at a 1:1 ratio. Cardiovascular outcomes included hospitalization for heart failure (HHF), all-cause mortality, HHF plus all-cause mortality, myocardial infarction (MI), stroke, and modified major adverse cardiovascular events (MACEs). Results: After propensity score matching, each cohort group was well balanced at baseline (21,688 pairs in cohort 1 and 20,120 pairs in cohort 2). As the second-line treatment, use of SGLT2 inhibitors was associated with a lower risk of HHF and HHF plus all-cause mortality compared with DPP-4 inhibitors. In addition, use of SGLT2 inhibitors versus sulfonylurea as add-on therapy to metformin was associated with decreased risks of HHF, all-cause mortality, HHF plus all-cause mortality, MI, stroke, and modified MACEs. Conclusion: SGLT2 inhibitors can be a good second-line drug to reduce the incidence of cardiovascular diseases compared with DPP-4 inhibitors or sulfonylureas in people with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effectiveness of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors on the risk of progression to end‐stage renal disease (ESRD) and all‐cause mortality in a broad range of patients with type 2 diabetes (T2D) using a Korean nationwide cohort. Materials and Methods: Using data from the Korean National Health Insurance Service database from January 2014 to December 2017, a total of 701 674 patients were identified with T2D. We divided these patients into new users of SGLT2 inhibitors and new users of other glucose‐lowering drugs (oGLDs). Using propensity scores, patients in the two groups were matched 1:1. We assessed the risk of ESRD and all‐cause death. Results: There were 45 016 patients in each group, and baseline characteristics were well balanced between the groups. The patients' mean age was 58.1 ± 10.6 years and mean estimated glomerular filtration rate (eGFR) was 89.2 ± 27.4 mL/min/1.73m2, and 8% of patients had proteinuria. We identified 167 incident ESRD cases and 1070 all‐cause deaths during follow‐up. Use of SGLT2 inhibitors versus oGLDs was associated with a lower risk of ESRD (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.34 to 0.65) and all‐cause death (HR 0.82, 95% CI 0.73 to 0.93). In a subgroup analysis by eGFR, initiation of SGLT2 inhibitor treatment, compared with oGLD treatment, was associated with lower risk of progression to ESRD among patients with eGFR 60 to 90 mL/min/1.73m2 and those with eGFR < 60 mL/min/1.73m2, and a lower risk of all‐cause death was associated with SGLT2 inhibitors versus oGLDs in patients with eGFR ≥90 and 60 to 90 mL/min/1.73m2. Conclusion: In this large nationwide study of Korean patients with T2D, initiation of SGLT2 inhibitors versus oGLDs was associated with lower risk of ESRD and all‐cause death. [ABSTRACT FROM AUTHOR]

Diabetes is a leading cause of end-stage renal disease. Therefore, prevention of renal dysfunction is an important treatment goal in the management of diabetes. The data of landmark cardiovascular outcome trials of sodium-glucose cotransporter-2 (SGLT2) inhibitor showed profound reno-protective effects. The Korean Diabetes Association and the Korean Society of Nephrology reviewed clinical trials and performed meta-analysis to assess the effects of SGLT2 inhibitors on the preservation of estimated glomerular filtration rate (eGFR). We limited the data of SGLT2 inhibitors which can be prescribed in Korea. Both eGFR value and its change from the baseline were significantly more preserved in the SGLT2 inhibitor treatment group compared to the control group after 156 weeks. However, some known adverse events were increased in SGLT2 inhibitor treatment, such as genital infection, diabetic ketoacidosis, and volume depletion. We recommend the long-term use SGLT2 inhibitor in patients with type 2 diabetes mellitus (T2DM) for attenuation of renal function decline. However, we cannot generalize our recommendation due to lack of long-term clinical trials testing reno-protective effects of every SGLT2 inhibitor in a broad range of patients with T2DM. This recommendation can be revised and updated after publication of several large-scale renal outcome trials. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is a multifactorial condition characterized by high level of sugar in the blood. To control hyperglycemia, combination therapy is recommended if monotherapy fails to achieve glycemic control. The combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a sodium-glucose cotransporter type 2 (SGLT2) inhibitor is a promising option of the combination therapies in terms of safety as well as efficacy. Despite of the value of combination therapy of these two agents, the pharmacokinetic drug interactions between these two classes of agents have been evaluated in a few drugs. Thus, we reviewed the potential pharmacokinetic drug interaction based on the in vitro metabolism- and transporter-mediated drug interaction information as well as drug interaction studies in human, between a DPP-4 inhibitor and a SGLT2 inhibitor which are marketed in South Korea. [ABSTRACT FROM AUTHOR]