Canagliflozin Mitigates Diabetic Cardiomyopathy through Enhanced PINK1-Parkin Mitophagy.

Diabetic cardiomyopathy (DCM) is a major determinant of mortality in diabetic populations, and the potential strategies are insufficient. Canagliflozin has emerged as a potential cardioprotective agent in diabetes, yet its underlying molecular mechanisms remain unclear. We employed a high-glucose challenge (60 mM for 48 h) in vitro to rat cardiomyocytes (H9C2), with or without canagliflozin treatment (20 µM). In vivo, male C57BL/6J mice were subjected to streptozotocin and a high-fat diet to induce diabetes, followed by canagliflozin administration (10, 30 mg·kg-1·d-1) for 12 weeks. Proteomics and echocardiography were used to assess the heart. Histopathological alterations were assessed by the use of Oil Red O and Masson's trichrome staining. Additionally, mitochondrial morphology and mitophagy were analyzed through biochemical and imaging techniques. A proteomic analysis highlighted alterations in mitochondrial and autophagy-related proteins after the treatment with canagliflozin. Diabetic conditions impaired mitochondrial respiration and ATP production, alongside decreasing the related expression of the PINK1-Parkin pathway. High-glucose conditions also reduced PGC-1α-TFAM signaling, which is responsible for mitochondrial biogenesis. Canagliflozin significantly alleviated cardiac dysfunction and improved mitochondrial function both in vitro and in vivo. Specifically, canagliflozin suppressed mitochondrial oxidative stress, enhancing ATP levels and sustaining mitochondrial respiratory capacity. It activated PINK1-Parkin-dependent mitophagy and improved mitochondrial function via increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Notably, PINK1 knockdown negated the beneficial effects of canagliflozin on mitochondrial integrity, underscoring the critical role of PINK1 in mediating these protective effects. Canagliflozin fosters PINK1-Parkin mitophagy and mitochondrial function, highlighting its potential as an effective treatment for DCM.

Fixed-Dose Combination of Canagliflozin and Metformin as an Adjunct to Diet and Exercise in Indian Adults with Type 2 Diabetes Mellitus: Results from a Multicentric, Open-Label, Single-Arm, Phase IV Study.

BACKGROUND: Canagliflozin and metformin fixed-dose combination (CANA/MET FDC), an approved treatment for type 2 diabetes mellitus (T2DM) in India, effectively lowers glycated hemoglobin (HbA1c), promotes weight loss, and improves patient adherence. As a regulatory requirement, we aimed to evaluate the safety and efficacy of CANA/MET FDC in Indian patients with T2DM. RESEARCH DESIGN AND METHODS: This prospective, multicenter, open-label, single-arm, phase IV study included Indian patients with T2DM (aged 18-65 years) inadequately controlled on diet and exercise. Patients received CANA/MET (50/500 and 50/1000 mg) immediate-release (IR) FDC twice daily for 24 weeks. The primary endpoint was safety assessment, including adverse events (AEs) and serious AEs (SAEs). The secondary endpoint included a change in HbA1c from baseline to weeks 12 and 24. Descriptive statistics were used for all continuous safety variables and efficacy parameters. RESULTS: Of the 310 patients screened, 276 were enrolled. 114/274 (41.6%) patients had ≥1 treatment-emergent AE [treatment-emergent AEs (TEAEs), among which 29 (10.6%) were related to study intervention]. The most common TEAEs were dyslipidemia (4.7%), pyrexia (4.7%), genital infections (3.3%), hypoglycemia (3.3%), and urinary tract infections (2.6%). Three (1.1%) patients had serious TEAEs, and all cases were resolved. No deaths were reported. The mean change in HbA1c from baseline was -0.92 and -0.93% at weeks 12 and 24, respectively. CONCLUSION: The study demonstrates the safety and efficacy of CANA/MET FDC in Indian patients with T2DM, presenting a safe therapeutic option for diabetes management in India.

Diverse Strategies for Modulating Insulin Resistance: Causal or Consequential Inference on Metabolic Parameters in Treatment-Naïve Subjects with Type 2 Diabetes.

Bacground and Objectives: The objective of this study is to investigate how different therapies modulating insulin resistance, either causally or consequently, affect metabolic parameters in treatment-naïve subjects with T2DM. Subjects and Methods: A total of 212 subjects were assigned to receive either a tight Japanese diet (n = 65), pioglitazone at doses ranging from 15-30 mg/day (n = 70), or canagliflozin at doses ranging from 50-100 mg/day (n = 77) for a duration of three months. Correlations and changes (Δ) in metabolic parameters relative to insulin resistance were investigated. Results: Across these distinct therapeutic interventions, ΔHOMA-R exhibited significant correlations with ΔFBG and ΔHOMA-B, while demonstrating a negative correlation with baseline HOMA-R. However, other parameters such as ΔHbA1c, ΔBMI, ΔTC, ΔTG, Δnon-HDL-C, or ΔUA displayed varying patterns depending on the treatment regimens. Participants were stratified into two groups based on the median value of ΔHOMA-R: the lower half (X) and upper half (Y). Group X consistently demonstrated more pronounced reductions in FBG compared to Group Y across all treatments, while other parameters including HbA1c, HOMA-B, TC, TG, HDL-C, non-HDL-C, TG/HDL-C ratio, or UA exhibited distinct regulatory responses depending on the treatment administered. Conclusions: These findings suggest that (1) regression to the mean is observed in the changes in insulin resistance across these therapies and (2) the modulation of insulin resistance with these therapies, either causally or consequentially, results in differential effects on glycemic parameters, beta-cell function, specific lipids, body weight, or UA.

SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells.

BACKGROUND: Sodium-glucose transporter 2 (SGLT2) inhibitors (iSGLT2) are approved medications for type 2 diabetes. Recent studies indicate that iSGLT2 inhibit the growth of some cancer cells. However, the mechanism(s) remains to be fully elucidated. METHODS: The SGLT2 levels were determined in normal colon CCD 841 CoN and, HCT 116, HT-29, SW480 and LoVo colorectal cancer (CRC) cell lines by quantitative real-time PCR and western blot. The effect of iSGLT2 canagliflozin on cell proliferation was examined using CCK-8, as its role on CRC cells metabolism and tumorigenesis has been evaluated by XF HS Seahorse Bioanalyzer and flow cytometric analyses. Transient gene silencing experiments and analysis of protein-protein interaction network were conducted to evaluate the SGLT2 molecular targets in CRC cells. RESULTS: Data showed that the treatment with iSGLT2 (50 µM) for 72 h induced cell cycle arrest (p < 0.001), impaired glucose and energetic metabolism (p < 0.001), promoted apoptotic cell death and ER stress flowing into autophagy (p < 0.001) in HCT 116 and HT-29 cells. These cellular events were accompanied by sirtuin 3 (SIRT3) upregulation (p < 0.01), as also supported by SIRT3 transient silencing experiments resulting in the attenuation of the effects of iSGLT2 on the cellular metabolic/energetic alterations and the induction of programmed cell death. The identification and validation of dipeptidyl peptidase 4 (DPP4) as potential common target of SGLT2 and SIRT3 were also assessed. CONCLUSIONS: These results deepened knowledge on the iSGLT2 contribution in limiting CRC tumorigenesis unveiling the SGLT2/SIRT3 axis in the cytotoxic mechanisms.

Comparative Genitourinary Safety of In-class Sodium-Glucose Cotransporter-2 Inhibitors among Patients with Heart Failure with Preserved Ejection Fraction: A Cohort Study.

PURPOSE: The American Heart Association recommended sodium-glucose cotransporter-2 inhibitors (SGLT2i) for the management of heart failure with preserved ejection fraction (HFpEF). However, little is known about their real-world in-class comparative safety in patients with HFpEF. We aimed to assess the comparative safety of SGLT2i in the risk of urinary tract infection (UTI) or genital infection separately or as a composite outcome among patients with HFpEF. METHODS: This cohort study using MarketScan® Commercial and Medicare supplemental databases (2012-2020) included patients aged ≥ 18 years with a diagnosis of HFpEF who initiated SGLT2i therapy. Three pairwise comparison groups were established: cohort 1, dapagliflozin versus canagliflozin; cohort 2, empagliflozin versus canagliflozin; and cohort 3, dapagliflozin versus empagliflozin. After stabilized inverse probability treatment weighting, Cox proportional hazards regression was used to compare the risk of UTI or genital infection separately or as a composite outcome in each cohort. RESULTS: The risk of the composite outcome did not significantly differ between canagliflozin and dapagliflozin (adjusted hazard ratio [aHR] 0.64; 95% confidence interval [CI] 0.36-1.14) or between empagliflozin and canagliflozin (aHR 1.25; 95% CI 0.77-2.05). Similarly, there was no evidence of difference between dapagliflozin and empagliflozin in this risk (aHR 0.76; 95% CI 0.48-1.21). The results of analyses separately assessing UTI or genital infection were similar. CONCLUSIONS: There was no significant difference in the risk of UTI or genital infection among patients with HFpEF who initiated canagliflozin, dapagliflozin, or empagliflozin.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are used for the management of heart failure with preserved ejection fraction (HFpEF). It is important to assess their comparative risk of urinary tract infection (UTI) or genital infection among patients with HFpEF. We compared patients with HFpEF using SGLT2i in three pairwise groups: cohort 1, dapagliflozin versus canagliflozin; cohort 2, empagliflozin versus canagliflozin; and cohort 3, dapagliflozin versus empagliflozin. We found that there was no significant difference in the risk of genitourinary infections including UTI or genital infections among dapagliflozin, empagliflozin, and canagliflozin.

SGLT2 inhibition eliminates senescent cells and alleviates pathological aging.

It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.

Pioglitazone reduces serum ketone bodies in sodium-glucose cotransporter-2 inhibitor-treated non-obese type 2 diabetes: A single-centre, randomized, crossover trial.

AIM: To examine the effects of the thiazolidinedione (TZD) pioglitazone on reducing ketone bodies in non-obese patients with T2DM treated with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin. METHODS: Crossover trials with two periods, each treatment period lasting 4 weeks, with a 4-week washout period, were conducted. Participants were randomly assigned in a 1:1 ratio to receive pioglitazone combined with canagliflozin (PIOG + CANA group) versus canagliflozin monotherapy (CANA group). The primary outcome was change (Δ) in ß-hydroxybutyric acid (ß-HBA) before and after the CANA or PIOG + CANA treatments. The secondary outcomes were Δchanges in serum acetoacetate and acetone, the rate of conversion into urinary ketones, and Δchanges in factors related to SGLT2 inhibitor-induced ketone body production including non-esterified fatty acids (NEFAs), glucagon, glucagon to insulin ratio, and noradrenaline (NA). Analyses were performed in accordance with the intention-to-treat principle. RESULTS: Twenty-five patients with a mean age of 49 ± 7.97 years and a body mass index of 25.35 ± 2.22 kg/m2 were included. One patient discontinued the study during the washout period. Analyses revealed a significant increase in the levels of serum ketone bodies and an elevation in the rate of conversion into urinary ketones after both interventions. However, differernces in levels of ketone bodies (except for acetoacetate) in the PIOG + CANA group were significantly smaller than in the CANA group (219.84 ± 80.21 µmol/L vs. 317.69 ± 83.07 µmol/L, p < 0.001 in ß-HBA; 8.98 ± 4.17 µmol/L vs. 12.29 ± 5.27 µmol/L, p = 0.018 in acetone). NEFA, glucagon, glucagon to insulin ratio, and NA were also significantly increased after both CANA and PIOG + CANA treatments; while only NEFAs demonstrated a significant difference between the two groups. Correlation analyses revealed a significant association between the difference in Δchanges in serum NEFA levels with the differences in Δchanges in ketones of ß-HBA and acetoacetate. CONCLUSION: Supplementation of pioglitazone could alleviate canagliflozin-induced ketone bodies. This benefit may be closely associated with decreased substrate NEFAs rather than other factors including glucagon, fasting insulin and NA.

Sodium-Glucose Cotransporter-2 Inhibitors and Cardiovascular Protection Among Patients With Type 2 Diabetes Mellitus: A Systematic Review.

Background: Accumulating evidence has demonstrated the positive effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in managing patients with type 2 diabetes mellitus (T2DM). SGLT2 inhibitors protect patients with T2DM from cardiovascular complications and are generally safe. Aim: The aim of this study is to assess the cardiovascular effects of SGLT2 inhibitors in patients with T2DM. Methods: A systematic review was conducted using published English literature in PubMed and Google Scholar databases. Results: Most of the studies showed significant positive cardiovascular effects of SGLT2 inhibitors in patients with and without established cardiovascular disease (CVD). Empagliflozin reduced the risk of cardiovascular death, hospitalization for heart failure (HHF), cardiovascular death or heart failure, and major adverse cardiovascular events (MACE) such as nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death regardless of the number of cardiovascular risk factors. The effects of empagliflozin on cardiovascular events and mortality in patients with coronary artery bypass graft (CABG) were assessed. Further, the efficacy of empagliflozin in three different phenotypic groups, namely, younger patients with shorter duration of T2DM and highest glomerular filtration rate, women without coronary artery disease, and older adults with advanced coronary artery disease plus several comorbidities, was also assessed. The effects of canagliflozin were evaluated in patients with and without a history of CVD and with different body weights, and in those with and without prior heart failure. Treatment with canagliflozin based on multivariable-predicted cardiovascular risk factors prevented heart failure events more than treatment based on glycated hemoglobin and albuminuria alone. The efficacy of dapagliflozin was evaluated in patients with or at risk of atherosclerotic cardiovascular disease (ASCVD), heart failure status, and left ventricular ejection fraction (LVEF), as well as the elderly population. A reduction in HHF or cardiovascular death and insignificant reduction in MACE were noted. Furthermore, significant reduction in the risk of cardiovascular death and all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF) was also observed. Sotagliflozin was studied for its cardiovascular outcomes in patients with chronic kidney disease with or without albuminuria and resulted in a reduction in cardiovascular-related deaths and HHF. Conclusion: SGLT2 inhibitors have beneficial cardiovascular effects in patients with T2DM and should be incorporated into their management.

SGLT2-independent effects of canagliflozin on NHE3 and mitochondrial complex I activity inhibit proximal tubule fluid transport and albumin uptake.

Beyond glycemic control, SGLT2 inhibitors (SGLT2is) have protective effects on cardiorenal function. Renoprotection has been suggested to involve inhibition of NHE3 leading to reduced ATP-dependent tubular workload and mitochondrial oxygen consumption. NHE3 activity is also important for regulation of endosomal pH, but the effects of SGLT2i on endocytosis are unknown. We used a highly differentiated cell culture model of proximal tubule (PT) cells to determine the direct effects of SGLT2i on Na+-dependent fluid transport and endocytic uptake in this nephron segment. Strikingly, canagliflozin but not empagliflozin reduced fluid transport across cell monolayers and dramatically inhibited endocytic uptake of albumin. These effects were independent of glucose and occurred at clinically relevant concentrations of drug. Canagliflozin acutely inhibited surface NHE3 activity, consistent with a direct effect, but did not affect endosomal pH or NHE3 phosphorylation. In addition, canagliflozin rapidly and selectively inhibited mitochondrial complex I activity. Inhibition of mitochondrial complex I by metformin recapitulated the effects of canagliflozin on endocytosis and fluid transport, whereas modulation of downstream effectors AMPK and mTOR did not. Mice given a single dose of canagliflozin excreted twice as much urine over 24 h compared with empagliflozin-treated mice despite similar water intake. We conclude that canagliflozin selectively suppresses Na+-dependent fluid transport and albumin uptake in PT cells via direct inhibition of NHE3 and of mitochondrial function upstream of the AMPK/mTOR axis. These additional targets of canagliflozin contribute significantly to reduced PT Na+-dependent fluid transport in vivo.NEW & NOTEWORTHY Reduced NHE3-mediated Na+ transport has been suggested to underlie the cardiorenal protection provided by SGLT2 inhibitors. We found that canagliflozin, but not empagliflozin, reduced NHE3-dependent fluid transport and endocytic uptake in cultured proximal tubule cells. These effects were independent of SGLT2 activity and resulted from inhibition of mitochondrial complex I and NHE3. Studies in mice are consistent with greater effects of canagliflozin versus empagliflozin on fluid transport. Our data suggest that these selective effects of canagliflozin contribute to reduced Na+-dependent transport in proximal tubule cells.

The Effect of Canagliflozin on High-Density Lipoprotein Cholesterol and Angiopoietin-Like Protein 3 in Type 2 Diabetes Mellitus.

Background: Diabetes mellitus is often accompanied by dyslipidemia. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, as a novel therapeutic agent for the treatment of type 2 diabetes mellitus (T2DM), have been reported to exert effects on lipid, while the results remain controversial. This study is aimed at exploring the effect of SGLT2 inhibitor canagliflozin on lipid profile. Methods: This study was a single-center, open-label, nonrandomized, prospective study. Metformin (500 mg three times per day) or canagliflozin (100 mg, once daily) was administered for 12 weeks. Fasting blood samples were collected before and 12 weeks after treatment. Serum lipid profile levels and angiopoietin-like protein 3 (ANGPTL3) were determined. In animal experiment, C57BL/6 J mice were divided into three groups including control, STZ + HFD, and STZ + HFD + canagliflozin. Lipid profile and plasma ANGPTL3 level were measured after 12 week's treatment. Moreover, the expression of ANGPTL3 was detected in the liver tissues. Results: There was a decreased trend in low-density lipoprotein cholesterol (LDL-c) and triglycerides (TG) after canagliflozin treatment, while canagliflozin significantly increased high-density lipoprotein cholesterol (HDL-c) level and decreased plasma ANGPTL3 level. In addition, the expression of ANGPTL3 in liver tissues decreased obviously in diabetic mice with canagliflozin treatment. Conclusions: Canagliflozin increases HDL-c level and suppresses ANGPTL3 expression in patients with T2DM and diabetic mice. The reduction of ANGPTL3 may contribute to the increase of HDL-c. However, the specific mechanism needs further research. This trial is registered with ChiCTR1900021231.

Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates artery remodeling in MCT-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) was a devastating disease characterized by artery remodeling, ultimately resulting in right heart failure. The aim of this study was to investigate the effects of canagliflozin (CANA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i) with mild SGLT1 inhibitory effects, on rats with PAH, as well as its direct impact on pulmonary arterial smooth muscle cells (PASMCs). PAH rats were induced by injection of monocrotaline (MCT) (40 mg/kg), followed by four weeks of treatment with CANA (30 mg/kg/day) or saline alone. Pulmonary artery and right ventricular (RV) remodeling and dysfunction in PAH were alleviated with CANA, as assessed by echocardiography. Hemodynamic parameters and structural of pulmonary arteriole, including vascular wall thickness and wall area, were reduced by CANA. RV hypertrophy index, cardiomyocyte hypertrophy, and fibrosis were decreased with CANA treatment. PASMCs proliferation was inhibited by CANA under stimulation by platelet-derived growth factor (PDGF)-BB or hypoxia. Activation of AMP kinase (AMPK) was induced by CANA treatment in cultured PASMCs in a time- and concentration-dependent manner. These effects of CANA were attenuated when treatment with compound C, an AMPK inhibitor. Abundant expression of SGLT1 was observed in PASMCs and pulmonary arteries, while SGLT2 expression was undetectable. SGLT1 increased in response to PDGF-BB or hypoxia stimulation, while PASMCs proliferation was inhibited and beneficial effects of CANA were counteracted by knockdown of SGLT1. Our research demonstrated for the first time that CANA inhibited the proliferation of PASMCs by regulating SGLT1/AMPK signaling and thus exerted an anti-proliferative effect on MCT-induced PAH.

A comparative in vitro study on the effect of SGLT2 inhibitors on chemosensitivity to doxorubicin in MCF-7 breast cancer cells.

Cancer frequently develops resistance to the majority of chemotherapy treatments. This study aimed to examine the synergistic cytotoxic and antitumor effects of SGLT2 inhibitors, specifically Canagliflozin (CAN), Dapagliflozin (DAP), Empagliflozin (EMP), and Doxorubicin (DOX), using in vitro experimentation. The precise combination of CAN+DOX has been found to greatly enhance the cytotoxic effects of doxorubicin (DOX) in MCF-7 cells. Interestingly, it was shown that cancer cells exhibit an increased demand for glucose and ATP in order to support their growth. Notably, when these medications were combined with DOX, there was a considerable inhibition of glucose consumption, as well as reductions in intracellular ATP and lactate levels. Moreover, this effect was found to be dependent on the dosages of the drugs. In addition to effectively inhibiting the cell cycle, the combination of CAN+DOX induces substantial modifications in both cell cycle and apoptotic gene expression. This work represents the initial report on the beneficial impact of SGLT2 inhibitor medications, namely CAN, DAP, and EMP, on the responsiveness to the anticancer properties of DOX. The underlying molecular mechanisms potentially involve the suppression of the function of SGLT2.

Prediction of new-onset heart failure in patients with type 2 diabetes derived from ALTITUDE and CANVAS.

AIM: To create and validate a prediction model to identify patients with type 2 diabetes (T2D) at high risk of new-onset heart failure (HF), including those treated with a sodium-glucose cotransporter-2 (SGLT2) inhibitor. METHODS: A prediction model was developed from the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE), a trial in T2D patients with albuminuria or cardiovascular disease. We included 5081 patients with baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) measurement and no history of HF. The model was developed using Cox regression and validated externally in the placebo arm of the Canagliflozin Cardiovascular Assessment Study (CANVAS), which included 996 participants with T2D and established cardiovascular disease or high cardiovascular risk, and in patients treated with canagliflozin. RESULTS: ALTITUDE participants (mean age 64 ± 9.8 years) had a median serum NT-proBNP level of 157 (25th-75th percentile 70-359) pg/mL. Higher NT-proBNP level, troponin T (TnT) level and body mass index (BMI) emerged as significant and independent predictors of new-onset HF in both cohorts. The model further contained urinary albumin-to-creatinine ratio, glycated haemoglobin, age, haematocrit, and use of calcium channel blockers. A prediction model including these variables had a C-statistic of 0.828 (95% confidence interval [CI] 0.801-0.855) in ALTITUDE and 0.800 (95% CI 0.720-0.880) in CANVAS. The C-statistic of this model increased to 0.847 (95% CI 0.792-0.902) in patients after 1 year of canagliflozin treatment. CONCLUSION: In patients with T2D, higher NT-proBNP level, TnT level and BMI are independent and externally validated predictors of new-onset HF, including patients using an SGLT2 inhibitor. This newly developed model may identify patients at high risk of new-onset HF, contributing to early recognition and possibly prevention.

Adherence to newer second-line oral antidiabetic drugs among people with type 2 diabetes-A systematic review.

The adherence to oral antidiabetic drugs (OADs) among people with type 2 diabetes (T2D) is suboptimal. However, new OADs have been marketed within the last 10 years. As these new drugs differ in mechanism of action, treatment complexity, and side effects, they may influence adherence. Thus, the aim of this study was to assess the adherence to newer second-line OADs, defined as drugs marketed in 2012-2022, among people with T2D. A systematic review was performed in CINAHL, Cochrane Trials, Embase, PubMed, PsycINFO, and Scopus. Articles were included if they were original research of adherence to newer second-line OADs and reported objective adherence quantification. The quality of the articles was assessed using JBI's critical appraisal tools. The overall findings were reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines and summarized in a narrative synthesis. All seven included articles were European retrospective cohort studies investigating alogliptin, canagliflozin, dapagliflozin, empagliflozin, and unspecified types of SGLT2i. Treatment discontinuation and medication possession ratio (MPR) were the most frequently reported adherence quantification measures. Within the first 12 months of treatment, 29%-44% of subjects on SGLT2i discontinued the treatment. In terms of MPR, 61.7%-94.9% of subjects on either alogliptin, canagliflozin, dapagliflozin, empagliflozin or an unspecified SGLT2i were adherent. The two investigated adherence quantification measures, treatment discontinuation and MPR, suggest that adherence to the newer second-line OADs may be better than that of older OADs. However, a study directly comparing older and newer OADs should be done to verify this.

Canagliflozin or acarbose versus placebo to ameliorate post-bariatric hypoglycaemia - The HypoBar I randomized clinical trial protocol.

INTRODUCTION: Post-bariatric hypoglycaemia (PBH) is a rare yet disabling clinical condition, mostly reported after Roux-en-Y gastric bypass (RYGB) surgery. RYGB is one of the most widely used and effective bariatric procedures. The pathophysiology of PBH remains unclear, and treatment options are limited in effectiveness and/or carry significant side effects. Acarbose slows carbohydrates digestion and absorption and is generally considered first-line pharmacological treatment for PBH but its gastrointestinal side effects limit patient compliance. Canagliflozin inhibits intestinal and renal sodium-dependent glucose absorption and reduces postprandial excursions of glucose, insulin and incretins after RYGB - effects that could be beneficial in ameliorating PBH. AIMS: The trial aims to investigate how blood glucose levels are affected during daily living in subjects with PBH during treatment with canagliflozin or acarbose compared with placebo, and to study the meal-induced entero-endocrine mechanisms implied in the treatment responses. METHODS: In a double-blinded, randomized, crossover clinical trial, HypoBar I will investigate the effectiveness in reducing the risk of PBH, safety, ambulatory glucose profile and entero-endocrine responses when PBH is treated with canagliflozin 300 mg twice daily during a 4-week intervention period, compared with acarbose 50 mg thrice daily or placebo. ETHICS AND DISSEMINATION: HypoBar I is approved by the Local regulatory entities. Results will be published in peer-reviewed journals. CONCLUSION: If effective, well-tolerated and safe, canagliflozin could be a novel treatment for people with PBH. HypoBar I might also unravel new mechanisms underlying PBH, potentially identifying new treatment targets. TRIAL REGISTRATION: EudraCT number 2022-000157-87.

The effect of canagliflozin on gut microbiota and metabolites in type 2 diabetic mice.

BACKGROUND: Sodium glucose cotransporter 2 inhibitor (SGLT2i) represent a new type of hypoglycemic medicine that can cause massive loss of glucose from the urine, which have several benefits of reducing body weight and improving the prognosis of cardiovascular and kidney diseases. Although they are oral medicated hypoglycemic agents, their effects on the gut microbiome and function have been unclear. OBJECTIVE: In order to describe the effects of canagliflozin on intestinal flora and metabolites, diabetic mice were randomized to receive canagliflozin or isoconcentration carboxymethylcellulose sodium by gavage for 8 weeks. Feces were collected for 16 S rRNA gene and LC-MS/MS analysis and enriched metabolic pathways through Kyoto Encyclopedia of Genes and Genomes (KEGG). Liver, muscle, intestinal, fat were collected for qRT-PCR according to KEGG enriched metabolic pathways. RESULTS: Our results showed that canagliflozin significantly increased GLP-1 level and impacted on the composition of gut microbiota and metabolites. It mainly increased Muribaculum, Ruminococcaceae_UCG_014, Lachnospiraceae-UCG-001, decreased ursodeoxycholic acids (UDCA) and hyodeoxycholic acids (HDCA), and increased fatty acids metabolites in feces. CONCLUSION: In conclusion, we analyzed the changes of intestinal microbial composition and metabolites in diabetic mice after canagliflozin intervention and found that canagliflozin influenced intestinal fatty acid and bile acid (BA) metabolism. This study will provide reference for subsequent SGLT2i and intestinal related research.

Effect of sodium-glucose cotransporter 2 inhibitor canagliflozin on interstitial glucose concentration in insulin-treated diabetic dogs.

BACKGROUND: The utility of sodium-glucose cotransporter 2 inhibitors (SGLT2i) has not been reported in insulin-treated diabetic dogs. HYPOTHESIS: Canagliflozin, a PO-administered SGLT2i, decreases interstitial glucose concentration (IG) in insulin-treated diabetic dogs. ANIMALS: Five insulin-treated diabetic dogs. METHODS: Uncontrolled open label longitudinal study. Canagliflozin (2-4 mg/kg/day PO) was added to an unchanged insulin dose for 7 days. Fractional excretion of glucose was calculated by dividing the product of urine glucose and serum creatinine concentrations by the product of serum glucose and urine creatinine concentrations. Hypoglycemia was defined as IG <60 mg/dL. RESULTS: Median IG in 2869 measurements obtained while dogs were treated with insulin and canagliflozin was 87 mg/dL (range, 40-500 mg/dL) and was significantly lower than median IG in 1426 measurements obtained while dogs were treated with insulin alone (212 mg/dL; range, 41-500 mg/dL; P < .001). Median fractional excretion of glucose when dogs were treated with insulin and canagliflozin was 1.1% (range, 0.9%-2.0%), significantly higher than when dogs were treated with insulin alone (0.3%; range, 0.01%-1.0%; P = .04). The frequency of hypoglycemia was higher in dogs treated with insulin and canagliflozin (544 of 2869 IG measurements, 19%) compared with the frequency of hypoglycemia in dogs treated with insulin alone (52 of 1426 IG measurements, 4%; P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Canagliflozin may have a role in improving glycemic control in insulin-treated diabetic dogs, but the dose of insulin should be decreased when adding canagliflozin to insulin treatment.

Sensitization of cancer cells to paclitaxel-induced apoptosis by canagliflozin.

Cancer cells consume more glucose and usually overexpress glucose transporters which have become potential targets for the development of anticancer drugs. It has been demonstrated that selective SGLT2 inhibitors, such as canagliflozin and dapagliflozin, display anticancer activity. Here we demonstrated that canagliflozin and dapagliflozin synergistically enhanced the growth inhibitory effect of paclitaxel in cancer cells including ovarian cancer and oral squamous cell carcinoma cells. Canagliflozin also inhibited glucose uptake via GLUTs. The combination of paclitaxel and WZB117, a GLUT inhibitor, exhibited a strong synergy, supporting the notion that inhibition of GLUTs by canagliflozin may also account for the synergy between canagliflozin and paclitaxel. Mechanistic studies in ES-2 ovarian cancer cells revealed that canagliflozin potentiated paclitaxel-induced apoptosis and DNA damaging effect. Paclitaxel in the nanomolar range elevated abnormal mitotic cells as well as aneuploid cells, and canagliflozin further enhanced this effect. Furthermore, canagliflozin downregulated cyclin B1 and phospho-BUBR1 upon spindle assembly checkpoint (SAC) activation by paclitaxel, and may consequently impair SAC. Thus, paclitaxel disturbed microtubule dynamics and canagliflozin compromised SAC activity, together they may induce premature mitotic exit, accumulation of aneuploid cells with DNA damage, and ultimately apoptosis.