The sodium glucose co-transporter 2 (SGLT2) functions in the proximal tubule to reabsorb the bulk of filtered glucose. SGLT2 inhibitors have been developed to promote renal glucose excretion to improve glycemic control in diabetes. Regulatory guidance mandated adequately powered studies to detect increased cardiovascular risk from emerging hypoglycemic medications. This led to recognition of remarkable improvement in cardiovascular and kidney outcomes with SGLT2 inhibition. Moreover, cardiovascular and kidney benefits extend beyond patients with diabetes. The dramatic kidney benefits of SGLT2 inhibitors documented in CKD in adult patients underscores the need for pediatric nephrologists to familiarize themselves with SGLT2 inhibitor therapies. This review explores the currently available body of knowledge regarding the kidney protective effects of SGLT2 inhibitors in adults and mechanisms thought to contribute to improved kidney outcomes. The limited data for SGLT2i treatment in pediatric kidney disease are reviewed and highlight the need for randomized controlled trials of this drug class in pediatric kidney patients as has been done for pediatric diabetes. Dosing patterns for SGLT2 inhibitors from other pediatric settings are reviewed as well as guidance for initiating SGLT2 inhibition in young adults remaining in pediatric nephrology care.

To assess the effect of dapagliflozin plus calorie restriction on remission of type 2 diabetes.

Multicentre, double blind, randomised, placebo controlled trial.

16 centres in mainland China from 12 June 2020 to 31 January 2023.

328 patients with type 2 diabetes aged 20-70 years, with body mass index >25 and diabetes duration of <6 years.

Calorie restriction with dapagliflozin 10 mg/day or placebo.

Primary outcome: incidence of diabetes remission (defined as glycated haemoglobin <6.5% and fasting plasma glucose <126 mg/dL in the absence of all antidiabetic drugs for at least 2 months); secondary outcomes: changes in body weight, waist circumference, body fat, blood pressure, glucose homoeostasis parameters, and serum lipids over 12 months.

Remission of diabetes was achieved in 44% (73/165) of patients in the dapagliflozin group and 28% (46/163) of patients in the placebo group (risk ratio 1.56, 95% confidence interval (CI) 1.17 to 2.09; P=0.002) over 12 months, meeting the predefined primary endpoint. Changes in body weight (difference -1.3 (95% CI -1.9 to -0.7) kg) and homoeostasis model assessment of insulin resistance (difference -0.8, -1.1 to -0.4) were significantly greater in the dapagliflozin group than in the placebo group. Likewise, body fat, systolic blood pressure, and metabolic risk factors were significantly more improved in the dapagliflozin group than in the placebo group. In addition, no significant differences were seen between the two groups in the occurrence of adverse events.

The regimen of dapagliflozin plus regular calorie restriction achieved a much higher rate of remission of diabetes compared with calorie restriction alone in overweight or obese patients with type 2 diabetes.

ClinicalTrials.gov NCT04004793.

Glucose metabolism is associated with several endocrine disorders. Anti-diabetes drugs are crucial in controlling diabetes and its complications; nevertheless, few studies have been carried out involving endocrine function. This study aimed to investigate the association between anti-diabetes drugs and endocrine parameters.

We performed a study of 180 consecutive patients with type 2 diabetes who attended a medical center. Laboratory measurements of metabolic values and endocrine parameters were assessed after a stable treatment regimen of more than 12 weeks. The differences in various endocrine parameters were compared between subjects with or without certain anti-diabetes drugs, with the administrated anti-diabetes drugs being analyzed to find independent risks associated with elevated endocrine parameters.

After maintaining stable treatment, acceptable glycemic control was noted with an average HbA1c of 7.55% in females and 7.43% in males. Participants taking sulfonylurea (55.8 vs 26.34 ng/L, P=0.043), dipeptidyl peptidase-4 inhibitor (DPP4i) (47.14 vs 32.26 ng/L, P=0.096), or sodium-glucose co-transporter 2 inhibitor (SGLT2i) (64.58 vs 28.11 ng/L, P=0.117) had higher plasma renin concentrations compared to those without this drug but the aldosterone levels did not differ, as well as for other adrenal tests and thyroid function. Under linear regression modeling, SGLT2i was found to be independently associated with a risk of high renin level (beta coefficient: 30.186, 95% confidence interval: 1.71─58.662, P=0.038), whereas sulfonylurea only had borderline associations (B: 21.143, 95% CI: -2.729─45.014, P=0.082). Additionally, renin-angiotensin-aldosterone system (RAAS) blockade (B: 36.728, 95% CI: 12.16─61.295, P=0.004) or diuretics (B: 47.847, 95% CI: 2.039─93.655, P=0.041) was also independently associated with increased renin levels.

SGLT2i was the only class of anti-diabetes drugs independently associated with elevated renin levels, with results similar to RAAS blockade and diuretics. Although SGLT2i appears to protect reno- and cardio-function, the clinical impact of increased renin warrants further precise study for verification.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have been shown to reduce visceral (VAT) and subcutaneous (SAT) adipose tissue. Although many systematic reviews have examined SGLT2i's effect on VAT and SAT, a focus analysis of dapagliflozin, one of the more commonly prescribe SGLT2i, has yet to been done. This study aims to determine the effect of dapagliflozin on reducing VAT and SAT in patients with chronic disease.

SCOPUS, PubMed, EBSCO, and LILACS databases were searched until December 26, 2023. Heterogeneity was determined using Cochran's Q test and quantified using the inconsistency index. The random-effects model was used to calculate the pooled standardize difference in means (SDM) and 95% confidence intervals (95% CI). Duval and Tweedie trim and fill (DT), Egger's test, and Beggs-Muzamar's test were used to assess publication bias. PROSPERO: CRD42023426208.

Twelve reports were included (treated = 299 and controls = 301). Overall, dapagliflozin treatment reduced VAT (SDM = - 0.406, 95% CI: - 0.526 to - 0.286, p < 0.001) and SAT (SDM = - 0.439, 95% CI: - 0.601 to - 0.278, p < 0.001). These results were stable as determined with a sensitivity analysis; however, there was potential publication bias. Two and three imputed studies were determined by the DT method for VAT and SAT, respectively. When stratified by pathology (obesity, T2D, and T2D/NAFLD), dapagliflozin treatment decreased VAT and SAT for all conditions. However, for specifically SAT, only when compared between T2D and T2D/NAFLD, T2D/NAFLD was associated with a twofold decrease (p = 0.003).

Treatment with dapagliflozin resulted in a significant reduction in VAT and SAT in patients with obesity, T2D, or T2D/NAFLD.

The online version contains supplementary material available at 10.1007/s13340-024-00765-y.

SGLT2 (Sodium-Glucose Co-transporter 2) inhibitors, also known as gliflozin class, are a novel family of oral drugs being used to treat type 2 diabetes. SGLT2 inhibitors can work alone or in conjunction with other medications. This class includes five drugs, including canagliflozin, ertugliflozin, sotagliflozin, dapagliflozin, and empagliflozin. SGLT2 inhibitors inhibit the SGLT2 cotransporter in the proximal tubules of the kidney, reducing glucose and sodium reabsorption. It promotes the elimination of sugar in urine (diabetes mellitus) and lowers blood sugar levels. SGLT2 inhibitors also have pleiotropic effects on cardiac and renal function, broadening their therapeutic applications in heart failure. Despite the clinical benefits, regulators have placed secondary warnings in product information since the medications first hit the market. SGLT2 inhibitors, in particular, have had a significant impact on a variety of risk factors. This can lead to hypoglycaemia, urinary tract infections, diabetic ketoacidosis, lower limb amputation, and fractures. Although some of these events are uncommon, they can lead to severe and deadly consequences; therefore, patients must be closely monitored. In general, SLGT2 inhibitors are an efficient diabetes treatment with strong cardiovascular and renal protection and a favourable safety overview. This review sought to summarise the safety overview of commercially available SGLT2 inhibitors.

Nocturia impairs the quality of life in patients with type 2 diabetes mellitus. Although sodium glucose co-transporter 2 inhibitors (SGLT2i) such as tofogliflozin increase urine volume, their impact on nocturia, in conjunction with dietary salt restriction, is less clear.

This multicenter, open-label, randomized, parallel-group trial included 80 subjects with type 2 diabetes and nocturia. The patients were divided into two groups: one receiving tofogliflozin, the shortest half-life, without salt restriction, and the other receiving both tofogliflozin and dietary salt restriction. The primary endpoint was nocturia frequency at 12 weeks. The secondary outcomes included changes in daytime urination frequency, urine volume, and home blood pressure.

At 12 weeks, there were no significant differences in nocturia changes between both groups. Nocturia frequency did not change in the tofogliflozin without salt restriction group from 1.5 ± 0.8 to 1.3 ± 1.1 times per night (P = 0.297), and significantly decreased from 1.6 ± 1.0 to 1.3 ± 0.7 times per night in the tofogliflozin and dietary salt restriction group (P = 0.049). There was a trend toward increased urine volume and frequency during the daytime in the group with salt restriction, indicating a time-shift effect of the short half-life tofogliflozin and salt restriction on urinary time.

The frequency of nocturia after tofogliflozin did not increase. Tofogliflozin reduced nocturia when combined with salt restriction. Furthermore, daytime urine volume and frequency showed an increasing trend, suggesting a shift in urine production to daytime hours due to the short half-life of tofogliflozin. Dietary modifications can enhance the therapeutic benefits of tofogliflozin in managing nocturia in people with type 2 diabetes.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) induce body weight loss, but their effect on skeletal muscle mass (SMM) and strength needs to be better elucidated.

This study aimed to evaluate the effects of SGLT2i on SMM in a real-life population setting of patients with type 2 diabetes (T2D). Secondary outcomes included changes in liver steatosis and in anthropometric and glucometabolic parameters.

Seventy-one patients were treated with SGLT2is as an add-on to metformin for 52 consecutive weeks. Visits were scheduled at baseline (T0) and after 6 (T6) and 12 months of therapy (T12) and included the checking of laboratory tests, measurement of anthropometric parameters, bioimpedance analysis of body composition, and abdominal ultrasound (US).

Fat mass (FM) and visceral adipose tissue (VAT) progressively decreased compared to the baseline (FM: -2.9 ± 0.6 kg at T6; -2.8 ± 0.6 kg at T12; VAT: -0.3 ± 0.1 L at T6; -0.4 ± 0.1 L at T12; all p < 0.01). Changes in SMM were less pronounced (-0.4 ± 0.3 kg at T6, ns; -0.7 ± 0.4 kg at T12, p < 0.05), yielding a beneficial increase in the SMM/FM ratio (+0.3 ± 0.05 at T6 and +0.2 ± 0.05 at T12, all p < 0.01). No significant changes in sarcopenia, sarcopenic obesity, fat-free mass, muscle strength, and water compartments were observed at the end of the follow-up period. Anthropometric and glucometabolic parameters, insulin resistance, liver enzymes, and biometric indices and US grading of hepatic steatosis improved throughout this study.

In a real-life setting, SGLT2i therapy is associated with weight loss attributable to FM rather than SMM loss without any relevant deterioration in muscle strength. In addition, SGLT2is proved to have beneficial effects on steatotic liver disease.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.

There is still a lack of information regarding the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on bone and mineral metabolism in patients with diabetes and chronic kidney disease (CKD). Therefore, we aimed to investigate the effects of SGLT2i in a cohort of patients suffering from diabetic kidney disease (DKD).

In this prospective observational study, patients with type 2 diabetes and biopsy-proven diabetic nephropathy or presumptive DKD with eGFR levels ≥20 ml/min/1.73m2 and 25-OH vitamin D levels ≥20 ng/dl were included. 41 used SGLT2i (study group) and 39 continued their current treatment regimens (control group). Serum FGF-23, sclerostin, osteoprotegerin (OPG), and hydroxyproline levels were measured at baseline, 1 month and 3 months after treatment.

Mean age of all patients was 67±9.3 years, and 48 (60%) were female. All patients in the study group used dapagliflozin. Taking into account the renal functions at the commencement of the study, the eGFR values for the study group and the control group were 51.2±15.6 and 44.6±16.9ml/min/1.73m2, respectively (p=0.01). After three months, these values were observed to be 47.4±16.7 and 44.3±18.8 ml/min/1.73m2 (p=0.43), respectively. At baseline, OPG levels were higher in the study group (p=0.025) but there were no differences between the groups in terms of FGF-23 and sclerostin levels (p=0.670 and p=0.467, respectively). Levels of OPG, FGF-23, and sclerostin significantly decreased throughout 3 months of treatment with dapagliflozin (p<0.001 for all). Hydroxyproline levels also declined but did not reach to statistical significance (p=0.075). Multiple linear regression models revealed that treatment with SGLT2i was associated with the change in levels of sclerostin (β=0.303, p=0.011) and OPG (β=0.210, p=0.010), but not with FGF-23 (β=0.089, p=0.150).

FGF-23, sclerostin and OPG levels significantly declined after treatment with dapagliflozin for 3 months.

Implantable cardioverter defibrillators (ICDs) are the standard treatment for patients with reduced left ventricular ejection fraction (LVEF ≤35%) to reduce the risk of sudden cardiac death. Loop diuretics can cause electrolyte imbalances, leading to an increased incidence of ICD shocks. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have shown cardiovascular benefits in patients with heart failure (HF), but their effects on ventricular arrhythmias and ICD shocks, particularly in patients receiving different doses of loop diuretics, are not fully understood. This study evaluated the effects of furosemide dose and SGLT2i use on ICD shocks in HF patients with reduced left ventricular ejection fraction (HFrEF).

HFrEF patients using oral furosemide and undergoing ICD implantation in our clinic were followed for 12 months to monitor ICD shocks for ventricular arrhythmias. They were grouped according to daily oral furosemide dose and SGLT2i use.

Out of 175 patients, the use of high-dose furosemide (>80 mg/day) was significantly higher in the ICD shock group compared to the non-shock group (38.8% vs. 16.7%, p = 0.001), while the use of SGLT2i was lower (19.4% vs. 45.4%, p < 0.001). ICD shocks occurred in 67.6% of patients on high-dose furosemide without SGLT2i and 30.0% with SGLT2i (p < 0.001). Multivariate analysis identified the absence of SGLT2i as an independent predictor of ICD shocks.

SGLT2i was associated with reduced ventricular arrhythmias and ICD shocks in HF patients, even when high doses of furosemide were used. The absence of SGLT2i in HF treatment was an independent predictor of ICD shocks.

Implantable cardioverter defibrillators (ICDs) are the standard treatment for patients with reduced left ventricular ejection fraction (LVEF ≤35%) to reduce the risk of sudden cardiac death. Loop diuretics can cause electrolyte imbalances, leading to an increased incidence of ICD shocks. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have shown cardiovascular benefits in patients with heart failure (HF), but their effects on ventricular arrhythmias and ICD shocks, particularly in patients receiving different doses of loop diuretics, are not fully understood. This study evaluated the effects of furosemide dose and SGLT2i use on ICD shocks in HF patients with reduced left ventricular ejection fraction (HFrEF).

HFrEF patients using oral furosemide and undergoing ICD implantation in our clinic were followed for 12 months to monitor ICD shocks for ventricular arrhythmias. They were grouped according to daily oral furosemide dose and SGLT2i use.

Out of 175 patients, the use of high-dose furosemide (>80 mg/day) was significantly higher in the ICD shock group compared to the non-shock group (38.8% vs. 16.7%, p = 0.001), while the use of SGLT2i was lower (19.4% vs. 45.4%, p < 0.001). ICD shocks occurred in 67.6% of patients on high-dose furosemide without SGLT2i and 30.0% with SGLT2i (p < 0.001). Multivariate analysis identified the absence of SGLT2i as an independent predictor of ICD shocks.

SGLT2i was associated with reduced ventricular arrhythmias and ICD shocks in HF patients, even when high doses of furosemide were used. The absence of SGLT2i in HF treatment was an independent predictor of ICD shocks.

Right ventricular (RV) fibrosis is an important pathological change that occurs during the development of right heart failure (RHF) induced by pulmonary hypertension (PH). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to play a major role in left heart failure, but it is unclear whether it has a positive effect on RHF. This study aimed to clarify the effect of DAPA on PH-induced RHF and investigate the underlying mechanisms.

We conducted experiments on two rat models with PH-induced RHF and cardiac fibroblasts (CFs) exposed to pathological mechanical stretch or transforming growth factor-beta (TGF-β) to investigate the effect of DAPA.

In vivo, DAPA could improve pulmonary hemodynamics and RV function. It also attenuated right heart hypertrophy and RV fibrosis. In vitro, DAPA reduced collagen expression by increasing the production of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). Additionally, DAPA was found to reduce reactive oxygen species (ROS) levels in CFs and the right heart in rats. Similar to DAPA, the ROS scavenger N-acetylcysteine (NAC) exerted antifibrotic effects on CFs. Therefore, we further investigated the mechanism by which DAPA promoted collagen degradation by reducing ROS levels.

In summary, we concluded that DAPA ameliorated PH-induced structural and functional changes in the right heart by increasing collagen degradation. Our study provides new ideas for the possibility of using DAPA to treat RHF.

The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on calcium phosphate homeostasis in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) remain uncertain.

A retrospective observational cohort study of patients with T2DM at CKD stage G3b-5ND who received SGLT2i as compared to control from 1 January 2015 through 31 December 2021 was recruited. Propensity score assignment at 1:3 ratio by logistic regression was done. All patients were followed for 12 months. Outcomes were changes in phosphate level.

We analyzed 1,450 SGLT2i users and 4,350 control subjects. At the 12th month, SGLT2i users had a slower increase in phosphate levels (absolute change: -0.01 ± 0.28 vs + 0.14 ± 0.34 mmol/L; percentage change: -0.74 % ± 25.56 vs + 10.88 ± 28.15 %, P for both < 0.001). The proportion of patients with high phosphate was lower with SGLT2i (8.2 % vs 24.6 % increase). In the generalized estimating equation, SGLT2i was linked to a longitudinal reduction in phosphate (B -0.039, P<0.001).

SGLT2i can effectively slow down the progression of phosphate retention in advanced CKD with T2DM.

We evaluated the pharmacokinetics, safety, and tolerability of a fixed-dose combination (FDC) of dapagliflozin/sitagliptin versus individual component (IC) tablets in healthy Western and Korean participants. The combination of these antihyperglycemic drugs provides efficient glucose control, and the use of FDC has generally been shown to improve medication adherence in individuals with type 2 diabetes mellitus (T2DM).

Two randomized, open-label, two-period, two-treatment, single-dose, single-center, crossover bioequivalence studies conducted on healthy fasted German participants (aged 18-55 years; Western study) and South Korean participants (aged 19-55 years; Korean study) were included. In both studies, pharmacokinetic parameters (maximum [peak] plasma concentration [Cmax], area under the plasma concentration-time curve from zero to the last quantifiable concentration [AUClast], and area under the plasma concentration-time curve from zero to infinity [AUCinf]) were used to assess the bioequivalence of 10 mg dapagliflozin/100 mg sitagliptin FDC (Treatment A) with their ICs (Treatment B) under fasted conditions. Safety and tolerability were assessed throughout the study.

Forty-six healthy participants (male, 60.9%; mean age, 39.5 years; mean body mass index [BMI], 23.9 kg/m2) were randomized in the Western study, and 51 healthy participants (male, 100.0%; mean age, 24.6 years; mean BMI, 23.9 kg/m2) were randomized in the Korean study. In both studies, the participants were randomized 1:1 into treatment sequence AB and treatment sequence BA. Dapagliflozin/sitagliptin FDC was bioequivalent to IC tablets in both Western and Korean studies, as the 90% confidence interval of the FDC to IC ratios of the geometric least-squares means of the pharmacokinetic parameters for both dapagliflozin and sitagliptin was within the 0.8000-1.2500 bioequivalence criterion limit. The observed differences in pharmacokinetic parameters, such as Cmax, AUClast, and AUCinf, between the Western and Korean studies were not clinically meaningful. Dapagliflozin/sitagliptin FDC and their ICs were well tolerated, with no serious adverse events reported in any of the study populations.

The 10 mg dapagliflozin/100 mg sitagliptin FDC and IC formulations were bioequivalent in fasted healthy Western and Korean participants, with no new safety concerns identified, thus offering a useful alternative for patients currently receiving individual medications as part of their treatment regimen.

Western study (clinicaltrials.gov: NCT05266404) and Korean study (clinicaltrials.gov: NCT05453786).

To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D).

This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104.

HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT.

Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients.

This study aimed to assess the efficacy of combined administration of dipeptidyl peptide-4 (DPP4) and sodium-glucose cotransporter-2 (SGLT2) inhibitors on metabolic disorders and their preferable and complementary effects.

The effectiveness of a 24-week intervention on metabolic parameters (including glucose profile), physical functions (grip strength and calf circumference), and health-related quality of life (HR-QOL) was analyzed using the International Physical Activity Questionnaire and Geriatric Depression Scale 5. A total of 39 patients with type-2 diabetes mellitus (T2DM) treated with the combination of DPP4 and SGLT2 inhibitors were included in this multicenter pilot study.

Combination therapy significantly reduced the HbA1c level (median [interquartile range]) after 24 weeks (pretreatment: 7.7% [7.3-8.2] vs. posttreatment: 7.1% [6.6-7.9], P < 0.001). The grip strength significantly increased after 24 weeks (1.7 ± 2.7 kg, P < 0.001), while the mean calf circumference and body mass index significantly decreased. In particular, administration of the SGLT2 inhibitor significantly increased total physical activity in participants aged ≥65 years (P = 0.003), while psychological QOL did not significantly improve.

Combination therapy with DPP4 and SGLT2 inhibitors decreased HbA1c levels and improved physical function in patients with T2DM. This study confirmed the effectiveness of combination therapy for metabolic disorders and suggested its beneficial and complementary effects. Therefore, advances in treatment plans to achieve further improvements in glucose profiles using DPP4 and SGLT2 inhibitors are recommended to enhance the QOL of patients with T2DM. Clinical trial number: University Hospital Medical Information Network Center: UMIN000045375.

In this video, Javed Butler, MD, introduces the series on the use of SGLT2 inhibitors in heart failure. He discusses the epidemiology of heart failure and the effects of SGLT2 inhibitors on heart failure outcomes. Jonathan Rich, MD, joins to summarize the effects of SGLT2 inhibitors from dedicated trials in patients with heart failure.

Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential.

The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment.

DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance.

Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70).

Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).

The dose-dependent pharmacological response to dapagliflozin in patients with type 2 diabetes mellitus (T2DM) with regard to weight loss remain unknown. The aim of the present study was to investigate the effects of dapagliflozin on weight loss in patients with T2DM. A total of 8,545 patients with T2DM from 24 randomized controlled trials reported in the literature were selected for inclusion in the study. Data from these trials were analyzed using maximal effect (Emax) models with nonlinear mixed effects modeling; the evaluation index was the body weight change rate from baseline values. Patients treated with 2.5 mg/day dapagliflozin exhibited an Emax of -3.04%, and the time taken for therapy to reach half of the Emax (ET50) was estimated to be 30.8 weeks for patients treated with this dose. Patients treated with 5, 10 and 20 mg/day dapagliflozin exhibited Emax values of -6.57, -4.12 and -3.23%, respectively, and their ET50 values were estimated to be 27.3, 20.4 and 4.23 weeks, respectively. The data indicated ideal linear relationships between individual predictions and observations, suggesting the optimal fitting of the final models. The present study is the first systematic analysis of the effect of dapagliflozin on weight loss in patients with T2DM. The application of dapagliflozin at 5 mg/day exhibited a greater weight loss effect compared with the other doses used, and the weight loss onset time shortened as the dose of dapagliflozin increased.

Multiple randomized controlled trials have extensively examined the therapeutic effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors, ushering in a transformative approach to treating individuals with type 2 diabetes mellitus (DM). Notably, emerging reports have drawn attention to the potential positive impacts of SGLT2 inhibitors in nondiabetic patients. In an effort to delve into this phenomenon, a comprehensive systematic literature review spanning PubMed (NLM), Medline (Ovid), and Cochrane Library, covering publications from 2000 to 2024 was undertaken. This systematic review encompassed twenty-six randomized control trials (RCTs) involving 35,317 participants. The findings unveiled a multifaceted role for SGLT2 inhibitors, showcasing their ability to enhance metabolic control and yield cardioprotective effects through a reduction in cardiovascular death (CVD) and hospitalization related to heart failure (HF). Additionally, a renalprotective effect was observed, evidenced by a slowdown in chronic kidney disease (CKD) progression and a decrease in albuminuria. Importantly, these benefits were coupled with an acceptable safety profile. The literature also points to various biological plausibility and underlying mechanistic pathways, offering insights into the association between SGLT2 inhibitors and these positive outcomes in nondiabetic individuals. Current research trends indicate a continual exploration of additional role for SGLT2 inhibitors in. Nevertheless, further research is imperative to fully elucidate the mechanisms and long-term outcomes associated with the nondiabetic use of SGLT2 inhibitors.

Syncope is a symptom that poses an important diagnostic and therapeutic challenge, and generates significant cost for the healthcare system. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated beneficial cardiovascular effects, but their possible effects on incident syncope have not been fully investigated. This study compared the effects of SGLT2i and dipeptidyl peptidase-4 inhibitors (DPP4i) on new-onset syncope.

This was a retrospective, territory-wide cohort study enrolling type 2 diabetes mellitus (T2DM) patients treated with SGLT2i or DPP4i between 1 January 2015 and 31 December 2020, in Hong Kong, China. The outcomes were hospitalization of new-onset syncope, cardiovascular mortality, and all-cause mortality. Multivariable Cox regression and different approaches using the propensity score were applied to evaluate the association between SGLT2i and DPP4i with incident syncope and mortality. After matching, a total of 37 502 patients with T2DM were included (18 751 SGLT2i users vs. 18 751 DPP4i users). During a median follow-up of 5.56 years, 907 patients were hospitalized for new-onset syncope (2.41%), and 2346 patients died from any cause (6.26%), among which 471 deaths (1.26%) were associated with cardiovascular causes. Compared with DPP4i users, SGLT2i therapy was associated with a 51% lower risk of new-onset syncope [HR 0.49; 95% confidence interval (CI) 0.41-0.57; P < 0.001], 65% lower risk of cardiovascular mortality (HR 0.35; 95% CI 0.26-0.46; P < 0.001), and a 70% lower risk of all-cause mortality (HR 0.30; 95% CI 0.26-0.34; P < 0.001) in the fully adjusted model. Similar associations with syncope were observed for dapagliflozin (HR 0.70; 95% CI 0.58-0.85; P < 0.001), canagliflozin (HR 0.48; 95% CI 0.36-0.63; P < 0.001), and ertugliflozin (HR 0.45; 95% CI 0.30-0.68; P < 0.001), but were attenuated for empagliflozin (HR 0.79; 95% CI 0.59-1.05; P = 0.100) after adjusting for potential confounders. The subgroup analyses suggested that, compared with DPP4i, SGLT2i was associated with a significantly decreased risk of incident syncope among T2DM patients, regardless of gender, age, glucose control status, Charlson comorbidity index, and the association remained constant amongst those with common cardiovascular drugs and most antidiabetic drugs at baseline.

Compared with DPP4i, SGLT2i was associated with a significantly lower risk of new-onset syncope in patients with T2DM, regardless of gender, age, degree of glycaemic control, and comorbidity burden.

To compare the effects of different selective sodium-glucose cotransporter-2 inhibitors (SGLT2i) on hemoglobin and hematocrit in patients with type 2 diabetes mellitus (T2DM) with a network meta-analysis (NMA).

Randomized controlled trials (RCTs) on SGLT2i for patients with T2DM were searched in PubMed, Embase, Cochrane Library, and Web of Science from inception of these databases to July 1, 2023. The risk of bias (RoB) tool was used to evaluate the quality of the included studies, and R software was adopted for data analysis.

Twenty-two articles were included, involving a total of 14,001 T2DM patients. SGLT2i included empagliflozin, dapagliflozin, and canagliflozin. The NMA results showed that compared with placebo, canagliflozin 100mg, canagliflozin 300mg, dapagliflozin 10mg, dapagliflozin 2mg, dapagliflozin 50mg, dapagliflozin 5mg, empagliflozin 25mg, and dapagliflozin 20mg increased hematocrit in patients with T2DM, while canagliflozin 100mg, canagliflozin 200mg, canagliflozin 300mg increased hemoglobin in patients with T2DM. In addition, the NMA results indicated that canagliflozin 100mg had the best effect on the improvement of hematocrit, and canagliflozin 200mg had the best effect on the improvement of hemoglobin.

Based on the existing studies, we concluded that SGLT2i could increase hematocrit and hemoglobin levels in patients with T2DM, and canagliflozin 100mg had the best effect on the improvement of hematocrit, while canagliflozin 200mg had the best effect on the improvement of hemoglobin.

https://www.crd.york.ac.uk/PROSPERO/#loginpage, identifier PROSPERO (CRD42023477103).

The safety results of different recommended doses of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) for patients with type 2 diabetes mellitus (T2DM) remain uncertain. This study aims to comprehensively estimate and rank the relative safety outcomes with different doses of SGLT-2i for T2DM.

PubMed, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Chinese National Knowledge Infrastructure, WanFang database, and SinoMed database were searched from the inception to 31 May 2023. We included double-blind randomized controlled trials (RCTs) comparing SGLT-2i with placebo or another antihyperglycemic as oral monotherapy in the adults with a diagnosis of T2DM.

Twenty-five RCTs with 12,990 patients randomly assigned to 10 pharmacological interventions and placebo were included. Regarding genital infections (GI), all SGLT-2i, except for ertugliflozin and ipragliflozin, were associated with a higher risk of GI compared to placebo. Empagliflozin 10mg/d (88.2%, odds ratio [OR] 7.90, 95% credible interval [CrI] 3.39 to 22.08) may be the riskiest, followed by empagliflozin 25mg/d (83.4%, OR 7.22, 95%CrI 3.11 to 20.04)) and canagliflozin 300mg/d (70.8%, OR 5.33, 95%CrI 2.25 to 13.83) based on probability rankings. Additionally, dapagliflozin 10mg/d ranked highest for urinary tract infections (UTI, OR 2.11, 95%CrI 1.20 to 3.79, 87.2%), renal impairment (80.7%), and nasopharyngitis (81.6%) when compared to placebo and other treatments. No increased risk of harm was observed with different doses of SGLT-2i regarding hypoglycemia, acute kidney injury, diabetic ketoacidosis, or fracture. Further subgroup analysis by gender revealed no significantly increased risk of UTI. Dapagliflozin 10mg/d (91.9%) and canagliflozin 300mg/d (88.8%) ranked first in the female and male subgroups, respectively, according to the probability rankings for GI.

Current evidence indicated that SGLT-2i did not significantly increase the risk of harm when comparing different doses, except for dapagliflozin 10mg/d, which showed an increased risk of UTI and may be associated with a higher risk of renal impairment and nasopharyngitis. Additionally, compared with placebo and metformin, the risk of GI was notably elevated for empagliflozin 10mg/d, canagliflozin 300mg/d, and dapagliflozin 10mg/d. However, it is important to note that further well-designed RCTs with larger sample sizes are necessary to verify and optimize the current body of evidence.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023396023.

Prenatal programming with dexamethasone increases the risk of the development of hyperglycaemia and insulin resistance, leading to diabetes in adulthood. Dexamethasone also causes a decline in renal glomerular filtration in the adult offspring. Sodium-glucose cotransporter-2 (SGLT2) plays a significant role in regulating blood glucose and renal haemodynamics in diabetic patients. However, the role of SGLT2 in dexamethasone-induced programming and the putative sex-dependent effects on the changes named earlier is unknown. Therefore, this study aimed to investigate the impact of maternal dexamethasone treatment on glucose tolerance, insulin sensitivity, renal perfusion and renal function in adult male and female offspring and the possible contribution of SGLT2 to these changes.

Pregnant Sprague Dawley rats (F0 ) were treated with either vehicle or dexamethasone (0.2 mg/kg ip) from gestation Day 15 to 20. F1 males and F1 females were randomly selected from each mother at 4 months of age. There was no change in serum Na+ , Na+ excretion rate, glucose tolerance or insulin sensitivity in F1 male or female rats. However, dexamethasone caused significant glomerular hypertrophy and decreases in CSinistrin and CPAH indicating decreased glomerular filtration rate and renal plasma flow, respectively, in dexamethasone-treated F1 male but not female rats. Dexamethasone did not affect SGLT2 mRNA or protein expression in F1 males or females.

We conclude that dexamethasone-mediated prenatal programming of glomerular volume, renal function and haemodynamics is sex-dependent, occurring only in adult male offspring.

In this study, the summarized WMDs and RRs were calculated using a pairwise analysis and a network meta-analysis with a random effects model, to compare and rank the efficacy and safety of SGLT-2i for renal outcomes in patients with T2DM. Among 1894 identified articles, 30 trials including 50,244 patients with T2DM were evaluated. Network analysis revealed that the administration of canagliflozin was associated with a reduced risk of renal impairment (surface under the cumulative ranking: 90.8%). Further, although the administration of SGLT-2i was not associated with the risk of renal impairment (RR = 0.88, 95%CI = 0.68-1.15, p = 0.354), the administration of empagliflozin was associated with a reduced risk of renal impairment compared to that with the administration of placebo (RR = 0.74, 95%CI = 0.62-0.90, p = 0.002). Moreover, compared with the administration of a placebo, the administration of 50, 100, and 200 mg of canagliflozin was associated with lower serum creatinine levels. Furthermore, compared with the administration of a placebo, the administration of 100 mg canagliflozin, 2.5 mg dapagliflozin, and 25 mg empagliflozin was associated with a lower reduction in the estimated glomerular filtration rate. Except for 300 mg canagliflozin, all SGLT-2i were associated with greater increases in blood urea nitrogen levels (WMD = 1.39, 95%CI = 1.20-1.59, p < 0.001). Finally, the administration of all SGLT-2i significantly increased the ratio of urinary glucose to creatinine compared with the ratio upon administration of placebo (WMD = 36.21, 95%CI = 31.50-40.92, p < 0.001). Briefly, canagliflozin exerts the greatest therapeutic effect in terms of reducing the risk of renal impairment. Empagliflozin and canagliflozin may be more effective than other SGLT-2i in preventing renal impairment.

Evogliptin (EV) is a novel dipeptidyl peptidase-4 inhibitor (DPP4i) for glycemic control in patients with type 2 diabetes mellitus (T2DM). This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between EV and sodium glucose cotransporter-2 inhibitors (SGLT2i) in healthy volunteers since combination therapy of DPP4i and SGLT2i has been considered as an effective option for T2DM treatment. A randomized, open-label, multiple-dose, two-arm, three-period, three treatments, two-sequence crossover study was conducted in healthy Korean volunteers. In arm 1, subjects were administered 5 mg of EV once daily for 7 days, 25 mg of empagliflozin (EP) once daily for 5 days, and the combination once daily for 5 days (EV + EP). In arm 2, subjects were administered 5 mg of EV once daily for 7 days, 10 mg of dapagliflozin (DP) once daily for 5 days, and the combination once daily for 5 days (EV + DP). Serial blood samples were collected for PK analysis, and oral glucose tolerance tests were conducted for PD analysis. In each arm, a total of 18 subjects completed the study. All adverse events (AEs) were mild with no serious AEs. The geometric mean ratio and confidence interval of the main PK parameters (maximum concentration of the drug in plasma at steady state and area under the plasma drug concentration-time curve within a dosing interval at a steady state) between EV and either EP or DP alone were not significantly altered by co-administration. Administration of EV + EP or EV + DP did not result in significant PD changes, as determined by the glucose-lowering effect. Administration of EV + EP or EV + DP had no significant effects on the PK profiles of each drug. All treatments were well-tolerated.

A fixed-dose combination (FDC) product combining dapagliflozin and metformin may increase medication adherence in patients with type 2 diabetes mellitus (T2DM) by minimizing pill burden associated with co-administration of individual component (IC) formulations and, consequently, improve cost-efficiency and compliance. This study evaluated the bioequivalence of the dapagliflozin/metformin FDC product versus IC administration in healthy volunteers from a Chinese population and assessed the safety profile of the FDC product. In addition, pharmacokinetic (PK) and safety comparisons of dapagliflozin and metformin across different regions were conducted to evaluate regional differences.

This single-center, open-label, parallel-cohort, randomized, 2-period, crossover study enrolled Chinese adults (aged 18-55 years). Volunteers in cohort 1 received either a single FDC tablet of dapagliflozin/metformin extended release (XR) (5/500 mg) or IC tablets (dapagliflozin [5 mg] and metformin XR [500 mg]). Volunteers in cohort 2 received a higher dosage in a similar manner (dapagliflozin [10 mg] and metformin XR [1000 mg]). Volunteers in each cohort were subsequently crossed over to receive the alternate cohort treatment. Plasma concentrations of dapagliflozin and metformin were determined, and bioequivalence analyses were performed under standard fed conditions.

Eighty healthy Chinese volunteers (89.9% male; mean age, 28.7 years) were randomized into cohort 1 (n = 40) and cohort 2 (n = 39; 1 volunteer withdrew before receiving study treatment). The mean plasma concentration-time profiles of the dapagliflozin and metformin FDC and IC formulations for both doses were found to be nearly superimposable. Dapagliflozin and metformin XR FDC were bioequivalent to the IC tablets, with 90% CIs for each pairwise comparison contained within the 80% to 125% bioequivalence limits. Both the FDC and IC formulations were well tolerated, with no serious adverse events/death. PK parameters for dapagliflozin in the Chinese volunteers were slightly to moderately higher than those from studies conducted in Brazil, Russia, and the United States, and the safety profile of the dapagliflozin/metformin FDC product was consistent with that of other studies. The difference in PK parameters among the 4 regions was not clinically meaningful.

The bioequivalence of the dapagliflozin/metformin FDC and IC formulations in healthy Chinese adults was established without any new safety concerns. Notably, the observed bioequivalence may be extrapolated to patients with T2DM as the PK parameters of dapagliflozin and metformin in healthy adults are similar to those reported in patients with T2DM.

gov identifier: NCT04856007.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are commonly used in the management of type 2 diabetes mellitus (T2DM) and have been found to worsen the reduction of skeletal muscle mass in individuals with T2DM. This study aims to examine the potential of exercise in mitigating the skeletal muscle atrophy induced by SGLT2i treatment.

A rat model of T2DM (40 male Sprague-Dawley rats; T2DM induced by a combination of high-fat diet and streptozotocin) was used to examine the effects of six-week treatment with Dapagliflozin (DAPA, SGLT2i) in combination with either aerobic exercise (AE) or resistance training (RT) on skeletal muscle. T2DM-eligible rats were randomized into the T2DM control group (CON, n = 6), DAPA treatment group (DAPA, n = 6), DAPA combined with aerobic exercise intervention group (DAPA + AE, n = 6), and DAPA combined with resistance training intervention group (DAPA + RT, n = 6). To assess the morphological changes in skeletal muscle, myosin ATPase and HE staining were performed. mRNA expression levels of Atrogin-1, MuRF1, and Myostatin were determined using quantitative PCR. Furthermore, protein expression levels of AKT, p70S6K, mTOR, FoXO1/3A, NF-κB, and MuRF1 were examined through western blotting.

Both the administration of DAPA alone and the combined exercise intervention with DAPA resulted in significant reductions in blood glucose levels and body weight in rats. However, DAPA alone administration led to a decrease in skeletal muscle mass, whereas RT significantly increased skeletal muscle mass and muscle fiber cross-sectional area. The DAPA + RT group exhibited notable increases in both total protein levels and phosphorylation levels of AKT and p70S6K in skeletal muscle. Moreover, the DAPA, DAPA + AE, and DAPA + RT groups demonstrated downregulation of protein expression (FoXO1/3A) and mRNA levels (Atrogin-1, MuRF1, and Myostatin) associated with muscle atrophy.

Our findings provide support for the notion that dapagliflozin may induce skeletal muscle atrophy through mechanisms unrelated to protein metabolism impairment in skeletal muscle, as it does not hinder protein metabolic pathways while reduces muscle atrophy-related genes. Additionally, our observations reveal that RT proves more effective than AE in enhancing skeletal muscle mass and muscle fiber cross-sectional area in rats with T2DM by stimulating protein anabolism within the skeletal muscle.

To explore the effects of empagliflozin (25 mg) on metabolic and renal parameters in patients with type 2 diabetes mellitus (T2DM).

This retrospective observational comparative study was conducted at a military hospital in southern Saudi Arabia. All adults (aged >18 years) with T2DM who attended diabetic clinics between October 2021 to March 2022 (6 months), with or without insulin treatment, were eligible for inclusion in the study.

Following the initiation of empagliflozin treatment, statistically significant reductions in patient weight (kg) were observed at 1, 3-5, and 6 months. In addition, low-density lipoprotein levels significantly decreased 3-5 months post-treatment initiation (p=0.011). However, serum creatinine level decreased gradually with time during the treatment with empagliflozin, from 87.45±31.78 (0.105) to 78.39±27.43 (0.033). Furthermore, after empagliflozin treatment, the urinary albumin-to-creatinine ratio significantly decreased at 3-5 and 6 months. Moreover, HbA1c levels exhibited statistically significant decreases at 3-5 months (p<0.001) and at 6 months (p<0.001) following the initiation of empagliflozin treatment. Notably, systolic and diastolic blood pressure significantly reduced 6 months after empagliflozin treatment.

In the current study, empagliflozin has demonstrated efficacy in controlling blood pressure and body weight, and improving renal function, short-term dyslipidemia, and glycemic control in patients with T2DM.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a relatively new class of oral glucose-lowering agents that reduce adverse cardiovascular and kidney outcomes among individuals with chronic kidney disease (CKD). Emerging evidence suggests that SGLT2i may also affect bone and mineral metabolism. This review analyzes recent evidence on the safety of SGLT2i with respect to bone and mineral metabolism in people with CKD, and discusses potential underlying mechanisms and clinical implications.

Recent studies have documented the beneficial effects of SGLT2i on cardiovascular and renal outcomes among individuals with CKD. SGLT2i may alter renal tubular phosphate reabsorption and are associated with increased serum concentrations of phosphate, fibroblast growth factor-23 (FGF-23), parathyroid hormone (PTH), decreased 1,25-hydroxyvitamin D levels, as well as increased bone turnover. Clinical trials have not demonstrated an increased risk of bone fracture associated with SGLT2i use among patients with CKD with or without diabetes mellitus.

Although SGLT2i are associated with abnormalities of bone and mineral metabolism, they have not been linked to a higher risk of fracture among patients with CKD. More research is needed on the association between SGLT2i and fracture risk in this population.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by abnormally high blood glucose concentrations due to dysfunction of the insulin-producing beta-cells in the pancreas. Dapagliflozin, an inhibitor of renal glucose reabsorption, has the potential to improve often suboptimal glycemic control in patients with T1DM through insulin-independent mechanisms and to partially mitigate the adverse effects associated with long-term insulin administration. In this work, we have adapted a systems pharmacology model of type 2 diabetes mellitus to describe the T1DM condition and characterize the effect of dapagliflozin on short- and long-term glycemic markers under various treatment scenarios. The developed platform serves as a quantitative tool for the in silico evaluation of the insulin-glucose-dapagliflozin crosstalk, optimization of the treatment regimens, and it can be further expanded to include additional therapies or other aspects of the disease.

Two open-label, randomized, two-period crossover studies were conducted to investigate the pharmacokinetic (PK) properties, safety, and bioequivalence of the test formulation (KD4004), a new fixed-dose combination (FDC) formulation of dapagliflozin and metformin extended release (XR) tablets, relative to the reference formulation (10 mg dapagliflozin/1,000 mg metformin XR FDC tablet) in healthy subjects under fasting (Part A) and fed (Part B) conditions. After giving the dose, serial blood samples were collected for a period of 48 hours. Primary PK parameters (AUC_0-t and C_max) were used to assess bioequivalence between two dapagliflozin/metformin XR (10/1,000 mg) FDC formulations under fed and fasting conditions. Safety and tolerability were also evaluated. Part A and Part B were completed by 32 and 37 subjects, respectively. Bioequivalence of the two FDC formulations of dapagliflozin and metformin XR tablets was established in both the fasted and the fed conditions as the 90% confidence interval of the ratios of adjusted geometric means for AUC_0-t and C_max were contained within the predefined range of 0.800-1.250 bioequivalence criteria. Single-dose administration of dapagliflozin and metformin XR was safe and well tolerated as the two FDC formulations. In conclusion, both FDC formulations of dapagliflozin and metformin XR tablets were bioequivalent in fed and fasted subjects. All treatments were well tolerated.

Clinical Research Information Service Identifier: KCT0004026.

Effective pharmacological treatments to achieve significant and sustained weight loss in obese individuals remain limited. Here, we apply a 'reverse engineering' approach to cancer cachexia, an extreme form of dysregulated energy balance resulting in net catabolism. We discuss three phenotypic features of the disease, summarize the underlying molecular checkpoints, and explore their translation to obesity research. We then provide examples for established pharmaceuticals, which follow a reverse engineering logic, and propose additional targets that may be of relevance for future studies. Finally, we argue that approaching diseases from this perspective may prove useful as a generic strategy to fuel the development of innovative therapies.

Hypertension is a global public health issue and the leading cause of premature death in humans. Despite more than a century of research, hypertension remains difficult to cure due to its complex mechanisms involving multiple interactive factors and our limited understanding of it. Hypertension is a condition that is named after its clinical features. Vascular function is a factor that affects blood pressure directly, and it is a main strategy for clinically controlling BP to regulate constriction/relaxation function of blood vessels. Vascular elasticity, caliber, and reactivity are all characteristic indicators reflecting vascular function. Blood vessels are composed of three distinct layers, out of which the endothelial cells in intima and the smooth muscle cells in media are the main performers of vascular function. The alterations in signaling pathways in these cells are the key molecular mechanisms underlying vascular dysfunction and hypertension development. In this manuscript, we will comprehensively review the signaling pathways involved in vascular function regulation and hypertension progression, including calcium pathway, NO-NOsGC-cGMP pathway, various vascular remodeling pathways and some important upstream pathways such as renin-angiotensin-aldosterone system, oxidative stress-related signaling pathway, immunity/inflammation pathway, etc. Meanwhile, we will also summarize the treatment methods of hypertension that targets vascular function regulation and discuss the possibility of these signaling pathways being applied to clinical work.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to improve cardiovascular and renal outcomes in patients with established cardiovascular disease, chronic kidney disease (CKD), and heart failure (HF) with reduced or preserved ejection fraction. Clinical benefit has been substantiated in patients with and without type 2 diabetes (T2D). Consequently, SGLT2is have an increasingly important role in HF and CKD management that extends beyond T2D treatment. Their pleiotropic pharmacological effects underlying their cardiovascular and renal benefits are not completely understood but include significant effects beyond blood glucose reduction. SGLT2is inhibit the reabsorption of glucose and sodium in the proximal tubule which, in addition to lowering blood glucose, activates tubuloglomerular feedback, leading to reduced glomerular hydrostatic pressure and the mitigation of glomerular filtration rate loss. SGLT2is have diuretic and natriuretic effects, leading to decreased blood pressure, preload, and left ventricular (LV) filling pressure, and improvements in other surrogates of afterload. In HF, SGLT2is mitigate the risks of hyperkalemia and ventricular arrhythmia and improve LV dysfunction. SGLT2is also reduce sympathetic tone and uric acid levels, increase hemoglobin levels, and are postulated to have anti-inflammatory properties. This narrative review discusses the multifactorial and interrelated pharmacological mechanisms underlying the cardiovascular and renal benefits of SGLT2is.

To investigate whether dapagliflozin (as a selective inhibitor of sodium-glucose cotransporter 2), increases the risk of urinary tract infection (UTI) in the treatment of type 2 diabetes mellitus (T2DM) remains an ongoing issue. We performed a systematic review and meta-analysis of randomized clinical trials (RCTs) to estimate the short-term and long-term risks of UTI in patients with T2DM who received dapagliflozin at different doses.

The PubMed, EMBASE, and the Cochrane Library and ClinicalTrials.gov website were searched up to December 31, 2022. Only RCTs involving adult T2DM patients with a trial duration of at least 12 weeks were included. The data were summarized using random- or fixed-effects models based on overall heterogeneity. A subgroup analysis was also performed. The review protocol was previously registered in the PROSPERO database (CRD42022299899).

In total, 42 RCTs involving 35,938 patients were assessed for eligibility. The results showed that dapagliflozin imposed a higher risk of UTI compared to placebo and other active treatments, with a heterogeneity of 11% (odds ratio [OR] 1.17, 95% CI 1.04-1.31, p = 0.006). In the subgroup analysis, dapagliflozin 10 mg/day with a treatment period of > 24 weeks was associated with a significantly higher UTI risk than placebo or other active treatments (OR 1.27, 95% CI 1.13-1.43, p < 0.0001). The ORs for dapagliflozin as monotherapy and combination therapy in the control group were 1.05 (95% CI 0.88-1.25, p = 0.571) and 1.27 (95% CI 1.09-1.48, p = 0.008), respectively.

High-dose, long-term treatment, and add-on therapy of dapagliflozin call for careful consideration of the risk of UTI in T2DM patients.

Background: Sodium-glucose cotransporter 2 inhibitors have proved to be extremely effective and reliable in reducing hyperglycemia, and have also been used for the treatment of cardiovascular and renal disease in patients with or without type 2 diabetes. Thousands of research articles on SGLT2 inhibitors have been published in the past, but few bibliometric analyses have systematically been studied this field. We aimed to visualize the global research hotspots and trends of SGLT2 inhibitors using a bibliometric analysis to provide new evidence and ideas for researchers and clinicians in this field. Methods: We retrieved publications from Science Citation Index Expanded of Web of Science Core Collection in 2004-2022 on 1 July 2022. Microsoft Excel, CiteSpace and VOSviewer were employed to collect publication data, analyze publication trends, and visualize relevant results. Results: We identified 4,419 original research articles on SGLT2 inhibitors published between 2004 and the first half of 2022. Global SGLT2 inhibitors-related research increased rapidly from 2004 to 2022, especially recently. United States made the greatest contribution to the topic, with (1,629, 36.86%) publications and citations (88,892). AstraZeneca was the most prolific institutions (272, 6.16%). Heerspink HJL published the most related articles (98), whereas Zinman B was cited the most frequently (1,784 citations). Diabetes Obesity and Metabolism was the journal with the most studies (406, 9.19%), and The New England Journal of Medicine was the most commonly cited journal (11,617 citations), with nine of the top 10 co-cited references published in this journal. The emerging keywords "heart failure," "diabetic cardiomyopathy," "ejection fraction," "mortality," "biomarker," "fibrosis," "ampk," and "guideline" appeared the most recently as research frontiers. Conclusion: United States is the leader in SGLT2 inhibitor research. Recently, the research on SGLT2 inhibitors has focused on clinical trials, related mechanisms, and therapy. In the future, the research on SGLT2 inhibitors will delve into molecular mechanisms, especially those related to fibrosis and AMPK, revealing the link between SGLT2 inhibitors and heart failure and diabetic cardiomyopathy will be the next research hotspot.

Sodium-glucose cotransporter type 2 inhibitors have evolved into a novel drug class utilized for reductions in cardiovascular risk and heart failure hospitalization. We aimed to describe the impact of sodium-glucose cotransporter type 2 inhibitors on diuretic prescribing patterns and intermediate laboratory outcomes in patients with and without diuretic use.

This retrospective cohort study included patients taking empagliflozin as of 1 July, 2021. Patients were assigned to the intervention group if prescribed a diuretic concomitantly or a control group otherwise. The primary outcome was the impact of empagliflozin on diuretic prescribing (i.e., no change, discontinuation, decrease, increase). Secondary outcomes were change in weight, hemoglobin A1c, estimated glomerular filtration rate, hemoglobin, hematocrit, blood pressure, and electrolytes at 90 and 180 days. Mean differences were compared using the t-test between groups or the paired t-test within groups. Patients without diuretic use were matched 1:1 to patients taking diuretics using propensity scores.

This study included 1189 patients: 750 in the control group and 439 in the intervention group. After propensity score matching, baseline characteristics were well balanced. Of the 439 patients in the intervention group, 118 had changes in the diuretic regimen. There were 131 changes: 109 (83.2%) discontinuations, 13 (9.92%) decreases, and nine (6.87%) increases. The mean furosemide equivalent loop dose was reduced after empagliflozin initiation (50.62 mg vs 43.13 mg; p < 0.001). Among all patients, there was a decrease in weight (p = 0.01), estimated glomerular filtration rate (p < 0.001), and hemoglobin A1c (p < 0.001). There was an increase in hemoglobin (p < 0.001), hematocrit (p < 0.001), and magnesium (p < 0.001). In the propensity score-matched cohort, there was a significant reduction from baseline in mean weight in the intervention group compared with the control group (p < 0.001).

This hypothesis-generating study suggests that sodium-glucose cotransporter type 2 inhibitors may lower diuretic requirements, further supported by a reduction in weight in the intervention cohort.