SGLT2i improves kidney senescence by down-regulating the expression of LTBP2 in SAMP8 mice.

Senescent kidney can lead to the maladaptive repairment and predispose age-related kidney diseases. Here, we explore the renal anti-senescence effect of a known kind of drug, sodium-dependent glucose transporters 2 inhibitor (SGLT2i). After 4 months intragastrically administration with dapagliflozin on senescence-accelerated mouse prone 8 (SAMP8) strain mice, the physiologically effects (lowering urine protein, enhancing glomerular blood perfusion, inhibiting expression of senescence-related biomarkers) and structural changes (improving kidney atrophy, alleviating fibrosis, decreasing glomerular mesangial proliferation) indicate the potential value of delaying kidney senescence of SGLT2i. Senescent human proximal tubular epithelial (HK-2) cells induced by H2 O2 also exhibit lower senescent markers after dapagliflozin treatment. Further mechanism exploration suggests LTBP2 have the great possibility to be the target for SGLT2i to exert its renal anti-senescence role. Dapagliflozin down-regulate the LTBP2 expression in kidney tissues and HK-2 cells with senescent phenotypes. Immunofluorescence staining show SGLT2 and LTBP2 exist colocalization, and protein-docking analysis implies there is salt-bridge formation between them; these all indicate the possibility of weak-interaction between the two proteins. Apart from reducing LTBP2 expression in intracellular area induced by H2 O2 , dapagliflozin also decrease the concentration of LTBP2 in cell culture medium. Together, these results reveal dapagliflozin can delay natural kidney senescence in non-diabetes environment; the mechanism may be through regulating the role of LTBP2.

Sex Differences in Characteristics, Outcomes, and Treatment Response With Dapagliflozin Across the Range of Ejection Fraction in Patients With Heart Failure: Insights From DAPA-HF and DELIVER.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of sodium-glucose cotransporter-2 inhibitors remains unclear. Our analyses aim to assess the effect of sex on the efficacy and safety of dapagliflozin. METHODS: In a prespecified patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), clinical outcomes were compared by sex (including the composite of cardiovascular death or worsening HF events, cardiovascular death, all-cause death, total events [first and recurrent HF hospitalization and cardiovascular death], and Kansas City Cardiomyopathy Questionnaire scores) across the spectrum of left ventricular ejection fraction. RESULTS: Of a total of 11 007 randomized patients, 3856 (35%) were women. Women with HF were older and had higher body mass index but were less likely to have a history of diabetes and myocardial infarction or stroke and more likely to have hypertension and atrial fibrillation compared with men. At baseline, women had higher ejection fraction but worse Kansas City Cardiomyopathy Questionnaire scores than men did. After adjustment for baseline differences, women were less likely than men to experience cardiovascular death (adjusted hazard ratio, 0.69 [95% CI, 0.60-0.79]), all-cause death (adjusted hazard ratio, 0.69 [95% CI, 0.62-0.78]), HF hospitalizations (adjusted hazard ratio, 0.82 [95% CI, 0.72-0.94]), and total events (adjusted rate ratio, 0.77 [95% CI, 0.71-0.84]). Dapagliflozin reduced the primary end point in both men and women similarly (Pinteraction=0.77) with no sex-related differences in secondary outcomes (all Pinteraction>0.35) or safety events. The benefit of dapagliflozin was observed across the entire ejection fraction spectrum and was not modified by sex (Pinteraction>0.40). There were no sex-related differences in serious adverse events, adverse events, or drug discontinuation attributable to adverse events. CONCLUSIONS: In DAPA-HF and DELIVER, the response to dapagliflozin was similar between men and women. Sex did not modify the treatment effect of dapagliflozin across the range of ejection fraction.

SGLT2 inhibitor as a potential therapeutic approach in hyperthyroidism-induced cardiopulmonary injury in rats.

Hyperthyroidism-induced cardiac disease is an evolving health, economic, and social problem affecting well-being. Sodium-glucose cotransporter protein 2 inhibitors (SGLT2-I) have been proven to be cardio-protective when administered in cases of heart failure. This study intended to investigate the potential therapeutic effect of SGLT2-I on hyperthyroidism-related cardiopulmonary injury, targeting the possible underlying mechanisms. The impact of the SGLT2-I, dapagliflozin (DAPA), (1 mg/kg/day, p.o) on LT4 (0.3 mg/kg/day, i.p)-induced cardiopulmonary injury was investigated in rats. The body weight, ECG, and serum hormones were evaluated. Also, redox balance, DNA fragmentation, inflammatory cytokines, and PCR quantification in heart and lung tissues were employed to investigate the effect of DAPA in experimentally induced hyperthyroid rats along with histological and immunohistochemical examination. Coadministration of DAPA with LT4 effectively restored all serum biomarkers to nearly average levels, improved ECG findings, and reinstated the redox balance. Also, DAPA could improve DNA fragmentation, elevate mtTFA, and lessen TNF-α and IGF-1 gene expression in both organs of treated animals. Furthermore, DAPA markedly improved the necro-inflammatory and fibrotic cardiopulmonary histological alterations and reduced the tissue immunohistochemical expression of TNF-α and caspase-3. Although further clinical and deep molecular studies are required before transposing to humans, our study emphasized DAPA's potential to relieve hyperthyroidism-induced cardiopulmonary injury in rats through its antioxidant, anti-inflammatory, and anti-apoptotic effects, as well as via antagonizing the sympathetic over activity.

Acute antiarrhythmic effects of SGLT2 inhibitors-dapagliflozin lowers the excitability of atrial cardiomyocytes.

In recent years, SGLT2 inhibitors have become an integral part of heart failure therapy, and several mechanisms contributing to cardiorenal protection have been identified. In this study, we place special emphasis on the atria and investigate acute electrophysiological effects of dapagliflozin to assess the antiarrhythmic potential of SGLT2 inhibitors. Direct electrophysiological effects of dapagliflozin were investigated in patch clamp experiments on isolated atrial cardiomyocytes. Acute treatment with elevated-dose dapagliflozin caused a significant reduction of the action potential inducibility, the amplitude and maximum upstroke velocity. The inhibitory effects were reproduced in human induced pluripotent stem cell-derived cardiomyocytes, and were more pronounced in atrial compared to ventricular cells. Hypothesizing that dapagliflozin directly affects the depolarization phase of atrial action potentials, we examined fast inward sodium currents in human atrial cardiomyocytes and found a significant decrease of peak sodium current densities by dapagliflozin, accompanied by a moderate inhibition of the transient outward potassium current. Translating these findings into a porcine large animal model, acute elevated-dose dapagliflozin treatment caused an atrial-dominant reduction of myocardial conduction velocity in vivo. This could be utilized for both, acute cardioversion of paroxysmal atrial fibrillation episodes and rhythm control of persistent atrial fibrillation. In this study, we show that dapagliflozin alters the excitability of atrial cardiomyocytes by direct inhibition of peak sodium currents. In vivo, dapagliflozin exerts antiarrhythmic effects, revealing a potential new additional role of SGLT2 inhibitors in the treatment of atrial arrhythmias.

Treatment recommendations for glycogen storage disease type IB- associated neutropenia and neutrophil dysfunction with empagliflozin: Consensus from an international workshop.

Glycogen storage disease type Ib (GSD Ib, biallelic variants in SLC37A4) is a rare disorder of glycogen metabolism complicated by neutropenia/neutrophil dysfunction. Since 2019, the SGLT2-inhibitor empagliflozin has provided a mechanism-based treatment option for the symptoms caused by neutropenia/neutrophil dysfunction (e.g. mucosal lesions, inflammatory bowel disease). Because of the rarity of GSD Ib, the published evidence on safety and efficacy of empagliflozin is still limited and does not allow to develop evidence-based guidelines. Here, an international group of experts provides 14 best practice consensus treatment recommendations based on expert practice and review of the published evidence. We recommend to start empagliflozin in all GSD Ib individuals with clinical or laboratory signs related to neutropenia/neutrophil dysfunction with a dose of 0.3-0.4 mg/kg/d given as a single dose in the morning. Treatment can be started in an outpatient setting. The dose should be adapted to the weight and in case of inadequate clinical treatment response or side effects. We strongly recommend to pause empagliflozin immediately in case of threatening dehydration and before planned longer surgeries. Discontinuation of G-CSF therapy should be attempted in all individuals. If available, 1,5-AG should be monitored. Individuals who have previously not tolerated starches should be encouraged to make a new attempt to introduce starch in their diet after initiation of empagliflozin treatment. We advise to monitor certain safety and efficacy parameters and recommend continuous, alternatively frequent glucose measurements during the introduction of empagliflozin. We provide specific recommendations for special circumstances like pregnancy and liver transplantation.

Dapagliflozin attenuates LPS-induced myocardial injury by reducing ferroptosis.

Septic cardiomyopathy is a severe cardiovascular disease with a poor prognosis. Previous studies have reported the involvement of ferroptosis in the pathogenesis of septic cardiomyopathy. SGLT2 inhibitors such as dapagliflozin have been demonstrated to improve ischemia-reperfusion injury by alleviating ferroptosis in cardiomyocyte. However, the role of dapagliflozin in sepsis remains unclear. Therefore, our study aims to investigate the therapeutic effects of dapagliflozin on LPS-induced septic cardiomyopathy. Our results indicate that dapagliflozin improved cardiac function in septic cardiomyopathy experimental mice. Mechanistically, dapagliflozin works by inhibiting the translation of key proteins involved in ferroptosis, such as GPX4, FTH1, and SLC7A11. It also reduces the transcription of lipid peroxidation-related mRNAs, including PTGS2 and ACSL4, as well as iron metabolism genes TFRC and HMOX1.

Heart Failure, Investigator-Reported Sleep Apnea and Dapagliflozin: A Patient-Level Pooled Meta-Analysis of DAPA-HF and DELIVER.

BACKGROUND: Sleep apnea is more common in patients with heart failure (HF) than in the general population, but little is known about its association with clinical outcomes in various HF phenotypes or how it might modify the effect of HF therapy. OBJECTIVES: To examine the prevalence of sleep apnea, its association with outcomes and the effects of dapagliflozin in patients with HF with and without sleep apnea in a pooled analysis of 2 trials comparing dapagliflozin to placebo in HFrEF (DAPA-HF trial) and HFmrEF/HFpEF (DELIVER trial). METHODS: A history of sleep apnea was investigator-reported. The primary outcome was a composite of worsening HF or cardiovascular death. RESULTS: The prevalence of sleep apnea was 5.7% and 7.8% in patients with HFrEF and HFmrEF/HFpEF, respectively. The primary outcome occurred at a rate of 16.0 in participants with sleep apnea compared to 10.6 per 100 person-years in those without (adjusted HR 1.29 [95%CI, 1.10-1.52]). Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients with (HR 0.78 [95% CI, 0.59-1.03]) and without sleep apnea (HR 0.79 [0.72-0.87]) [Pinteraction = 0.93]. The beneficial effects of dapagliflozin on other clinical outcomes and symptom burden, physical function, and quality of life were consistent in participants with and without sleep apnea. CONCLUSIONS: In DAPA-HF and DELIVER, the true prevalence of sleep apnea was likely underestimated. An investigator-reported history of sleep apnea was associated with higher rates of worsening HF events. The benefits of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. CLINICAL TRIAL REGISTRATION: Unique identifiers: NCT01920711 CONDENSED ABSTRACT: In a pooled analysis of the DAPA-HF and DELIVER trials of more than 11,000 patients with heart failure (HF) across the range of ejection fractions, an investigator-reported history of sleep apnea was associated with higher rates of worsening HF events but not mortality. The beneficial effects of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. These findings provide further evidence for dapagliflozin as a new treatment option for patients with heart failure across the range of ejection fractions.

Is there any robust evidence showing that SGLT2 inhibitor predisposes to cancer?

BACKGROUND: The exact pathophysiological mechanisms of SGLT-2 inhibitors in the development, progression or treatment of malignancies are not fully understood, but multiple hypotheses have been proposed. SGLT-2 inhibitors have potential anti-proliferative roles due to several underlying pathophysiological mechanisms, such as inhibition of ATP production, activation of AMPK signalling, induction of apoptosis and ferroptosis, inhibition of glutamate dehydrogenase activity and inhibition of DNA and RNA synthesis. However, heterogeneity among tumour cells and SGLT-2 inhibitor drugs limit the generalizability of pre-clinical studies. METHODS: This is a narrative review discussing the potential anti-cancer effects of SGLT-2 inhibitors, an oral glucose-lowering medication used in patients with type II diabetes mellitus. This review discusses underlying mechanisms, pre-clinical and clinical trial data, epidemiological data and future perspectives on the use of SGLT-2 inhibitors in cancer treatment. RESULTS: Type II diabetes is linked to various comorbidities and malignancies, but some glucose-slowering medications may have a preventive role in cancer. The use of SGLT-2 inhibitors was associated with bladder cancer based on mice studies. However, meta-analyses showed no significant increase in overall malignancy incidence of any specific type, except for empagliflozin and bladder cancer association. SGLT-2 inhibitors can potentially reduce the heart damage caused by doxorubicin and sunitinib, while enhancing the anti-cancer effects of doxorubicin. Combining SGLT-2 inhibitors with doxorubicin may allow higher doses of chemotherapy use. Multiple ongoing clinical trials are investigating the potential therapeutic potential of SGLT-2 inhibitors in various types of cancer. CONCLUSION: More large-scale pre-clinical and clinical studies are needed to explore their potential preventive and therapeutic roles of SGLT-2 inhibitors in cancer treatment. In this narrative review, our aim is to explore the pre-clinical and clinical data regarding the potential anti-cancer effects of SGLT-2 inhibitors including the hypothetical pathophysiological mechanisms.

Dapagliflozin dampens liver fibrosis induced by common bile duct ligation in rats associated with the augmentation of the hepatic Sirt1/AMPK/PGC1α/FoxO1 axis.

Liver fibrosis is considered an epidemic health problem due to different insults that lead to death. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, is one of the newer anti-diabetic drugs used to manage type 2 diabetes mellitus (T2DM). DAPA exerted beneficial effects in many human and rat models due to its antioxidant, anti-inflammatory and antifibrotic activities. AIM: Due to previously reported capabilities related to DAPA, we designed this study to clarify the beneficial role of DAPA in liver fibrosis triggered by common bile duct ligation (CBL) in male rats. METHODS: For 14 or 28 days after CBL procedures, DAPA was administered to the rats orally at a dose of 10 mg/kg once daily. The effects of DAPA were evaluated by assaying liver enzymes, hepatic oxidant/antioxidant parameters, serum levels of tumor necrotic factor alpha (TNF-α), and AMP-activated protein kinase (AMPK). In addition, we measured the hepatic expression of fibrosis regulator-related genes along with evaluating liver histological changes. KEY FINDINGS: DAPA successfully decreased hepatic enzymes and malondialdehyde levels, increased superoxide dismutase activity, elevated catalase levels, decreased serum levels of TNF-α, elevated serum levels of AMPK, decreased liver hydroxyproline content, upregulated Sirt1/PGC1α/FoxO1 liver gene expressions, down-regulated fibronectin-1 (Fn-1), collagen-1 genes in liver tissues, and improved the damaged liver tissues. Deteriorated biochemical parameters and histological liver insults associated with CBL were more pronounced after 28 days, but DAPA administration for 14 and 28 days showed significant improvement in most parameters and reflected positively in the histological structures of the liver. SIGNIFICANCE: The significance of this study lies in the observation that DAPA mitigated CBL-induced liver fibrosis in rats, most likely due to its antioxidant, anti-inflammatory, and antifibrotic effects. These results suggest that DAPA's beneficial impact on liver fibrosis might be attributed to its interaction with the Sirt1/AMPK/PGC1α/FoxO1 pathway, indicating a potential mechanistic action for future exploration.

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2023 American Heart Association Scientific Sessions.

PURPOSE OF REVIEW: Focused review highlighting ten select studies presented at the 2023 American Heart Association (AHA) Scientific Sessions. RECENT FINDINGS: Included studies assessed semaglutide and cardiovascular outcomes in overweight or obese patients without diabetes (SELECT); dapagliflozin in patients with acute myocardial infarction without diabetes (DAPA-MI); effects of dietary sodium on systolic blood pressure in middle-aged individuals (CARDIA-SSBP); long-term blood pressure control after hypertensive pregnancy with physician guided self-management (POP-HT); effect and safety of zilebesiran, an RNA interference therapy, for sustained blood pressure reduction (KARDIA-1); recaticimab add-on therapy in patients with non-familial hypercholesterolemia and mixed hyperlipidemia (REMAIN-2); efficacy and safety of lepodisiran an extended duration short-interfering RNA targeting lipoprotein(a); safety and pharmacodynamic effects of an investigational DNA base editing medicine that inactivates the PCSK9 gene and lowers LDL cholesterol (VERVE-101); automated referral to centralized pharmacy services for evidence-based statin initiation in high-risk patients; and effects of intensive blood pressure lowering in reducing risk of cardiovascular events (ESPRIT). Research presented at the 2023 AHA Scientific Sessions emphasized innovative strategies in cardiovascular disease prevention and management.

Dapagliflozin improves erectile dysfunction in patients with type 2 diabetes mellitus: An open-label, non-randomized pilot study.

INTRODUCTION: The role of dapagliflozin on erectile dysfunction (ED), a condition widely affecting patients with type 2 diabetes mellitus (T2DM), has not yet been studied. AIM: The aim of the study was to evaluate the effects of dapagliflozin alone or in combination with tadalafil on ED in patients with T2DM. METHODS: This was an open-label, non-randomized pilot study involving 30 Caucasian male patients with T2DM and severe ED. They were equally divided into three groups, assigned to treatment with tadalafil 5 mg/day (Group 1), tadalafil 5 mg/day plus dapagliflozin 10 mg/day (Group 2) and dapagliflozin 10 mg/day (Group 3) for 3 months. The presence and the severity of ED were evaluated at enrolment and after treatment, by the International Index of Erectile Function 5-item (IIEF-5) questionnaire and the dynamic penile echo colour Doppler ultrasound (PCDU) examination. RESULTS: At the end of treatment, the three groups showed a significant improvement in IIEF-5 score, by 294%, 375% and 197%, in Groups 1, 2 and 3, respectively. PCDU evaluation showed a significant increase in peak systolic velocity by 178.9%, 339% and 153%; acceleration time was significantly shortened in Group 2 (-26.2%) and was significantly lower than in Group 1 and 3 (-7.2% and -6.6%), while no significant difference was found in end-diastolic velocity after treatment. The greatest rates of improvement were observed in Group 2 for all the end points. CONCLUSIONS: Dapagliflozin improves ED in patients with T2DM and enhances the efficacy of tadalafil. Further studies are needed to confirm our results explain the mechanism(s) by which dapagliflozin exerts its effects on ED.

Dapagliflozin Ameliorates Ovulation Disorders via Attenuating Activated Microglia-Mediated Hypothalamic Inflammation in HFD-Fed Mice.

INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown neuroprotective effects in obese mice. However, whether SGLT2i can ameliorate high-fat diet (HFD)-related ovulation disorders remains unknown. The aim of this research was to investigate whether dapagliflozin improves HFD-induced ovulatory dysfunction by attenuating microglia-mediated hypothalamic inflammation. METHODS: C57BL/6J female mice fed HFD were treated with dapagliflozin (1 mg/kg) for 22 weeks. Plasma insulin, leptin, luteinizing hormone (LH), estradiol (E2), and IL-1ß levels were also tested. Microglial morphology, cell numbers, and SGLT2 expression were evaluated using immunofluorescence. The expression of IL-1ß, NLRP3, kisspeptin, gonadotropin-releasing hormone (GnRH), SGLT2, insulin, and leptin receptors in the hypothalamus was determined using immunohistochemical staining. We also examined the effects of dapagliflozin on glucose metabolism and the release of inflammatory factor in palmitic acid (PA)-treated HMC3 cells. RESULTS: As expected, dapagliflozin improved HFD-induced metabolic disturbances, peripheral versus central insulin and leptin resistance and also restored the regular estrous cycle. Furthermore, dapagliflozin blunted microglia activation, NLRP3 inflammasome priming, hypothalamic inflammation, and increased the expression of GnRH and kisspeptin at proestrus in the hypothalamus. Additionally, dapagliflozin markedly reduced IL-6 and NO release and fat accumulation, decreased lactic acid production and glucose consumption, and inhibited mammalian target of rapamycin (mTOR) and hexokinase 2 (HK2) expression in PA-treated HMC3 cells. These effects suggest that dapagliflozin reduced the mTOR/HK2-mediated aerobic glycolysis. CONCLUSIONS: Dapagliflozin improved HFD-related ovulation disorders by regulating glucose metabolism through mTOR/HK2 signaling and attenuating microglia-mediated hypothalamic inflammation. These results validate the novel role for the neuroprotection of SGLT2i in HFD-induced obesity and ovulation disorders.

Efficacy and safety of zibotentan and dapagliflozin in patients with chronic kidney disease: study design and baseline characteristics of the ZENITH-CKD trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) are part of the standard of care for patients with chronic kidney disease (CKD), both with and without type 2 diabetes. Endothelin A (ETA) receptor antagonists have also been shown to slow progression of CKD. Differing mechanisms of action of SGLT2 and ETA receptor antagonists may enhance efficacy. We outline a study to evaluate the effect of combination zibotentan/dapagliflozin versus dapagliflozin alone on albuminuria and estimated glomerular filtration rate (eGFR). METHODS: We are conducting a double-blind, active-controlled, Phase 2b study to evaluate the efficacy and safety of ETA receptor antagonist zibotentan and SGLT2i dapagliflozin in a planned 415 adults with CKD (Zibotentan and Dapagliflozin for the Treatment of CKD; ZENITH-CKD). Participants are being randomized (1:2:2) to zibotentan 0.25 mg/dapagliflozin 10 mg once daily (QD), zibotentan 1.5 mg/dapagliflozin 10 mg QD and dapagliflozin 10 mg QD alone, for 12 weeks followed by a 2-week off-treatment wash-out period. The primary endpoint is the change in log-transformed urinary albumin-to-creatinine ratio (UACR) from baseline to Week 12. Other outcomes include change in blood pressure from baseline to Week 12 and change in eGFR the study. The incidence of adverse events will be monitored. Study protocol-defined events of special interest include changes in fluid-related measures (weight gain or B-type natriuretic peptide). RESULTS: A total of 447 patients were randomized and received treatment in placebo/dapagliflozin (n = 177), zibotentan 0.25 mg/dapagliflozin (n = 91) and zibotentan 1.5 mg/dapagliflozin (n =  179). The mean age was 62.8 years, 30.9% were female and 68.2% were white. At baseline, the mean eGFR of the enrolled population was 46.7 mL/min/1.73 m2 and the geometric mean UACR was 538.3 mg/g. CONCLUSION: This study evaluates the UACR-lowering efficacy and safety of zibotentan with dapagliflozin as a potential new treatment for CKD. The study will provide information about an effective and safe zibotentan dose to be further investigated in a Phase 3 clinical outcome trial. CLINICAL TRIAL REGISTRATION NUMBER: NCT04724837.

Programmed death of cardiomyocytes in cardiovascular disease and new therapeutic approaches.

Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.

A multicentre, double-blind, placebo-controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add-on therapy in type 2 diabetic patients treated with metformin and dapagliflozin.

AIM: To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In a multicentre study, with a randomized, double-blind, placebo-controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24-week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. RESULTS: Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% ± 0.72% to 7.27% ± 0.82%) compared with placebo (from 7.79% ± 0.76% to 7.69% ± 0.86%, corrected mean difference: -0.42% ± 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high-density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. CONCLUSIONS: Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference.

Dual add-on therapy of gemigliptin and dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin alone: The SOLUTION 2 study.

AIM: To evaluate the efficacy and safety of gemigliptin and dapagliflozin dual add-on therapy (GEMI + DAPA) to metformin in type 2 diabetes (T2D) patients who had inadequate glycaemic control on metformin alone, compared with a single add-on of either gemigliptin (GEMI) or dapagliflozin (DAPA) to metformin. MATERIALS AND METHODS: In this randomized, double-blind, double-dummy, active-controlled, parallel-group, phase 3 study, 469 T2D patients treated with a stable dose of metformin for 8 weeks or longer were randomized to receive GEMI + DAPA (n = 157) and either GEMI (n = 156) or DAPA (n = 156). The primary endpoint was change in HbA1c levels from baseline at week 24. RESULTS: Baseline characteristics including body mass index and T2D duration were similar among groups. At week 24, the least square mean changes in HbA1c from baseline were -1.34% with GEMI + DAPA, -0.90% with GEMI (difference between GEMI + DAPA vs. GEMI -0.44% [95% confidence interval {CI}: -0.58% to -0.31%], P < .01) and -0.78% with DAPA (difference between GEMI + DAPA vs. DAPA -0.56% [95% CI: -0.69% to -0.42%], P < .01). Both upper CIs were less than 0, demonstrating the superiority of GEMI + DAPA for lowering HbA1c. The rates of responders achieving HbA1c less than 7% and less than 6.5% were greater with GEMI + DAPA (84.9%, 56.6%) than with GEMI (55.3%, 32.2%) and DAPA (49.3%, 15.3%). The incidence rate of adverse events was similar across groups, with low incidence rates of hypoglycaemia, urinary tract infection and genital infection. CONCLUSIONS: These results suggest that the addition of GEMI + DAPA to metformin as triple combination therapy was effective, safe and well-tolerated, especially for T2D patients who experienced poor glycaemic control on metformin alone.

The effect of sodium-glucose cotransporter-2 inhibitors on inflammatory biomarkers: A meta-analysis of randomized controlled trials.

AIMS: To conduct a meta-analysis of randomized controlled trials (RCTs) to assess the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors on inflammatory biomarkers. METHODS: Medline, Embase and the Cochrane Library were searched for RCTs investigating the effect of SGLT2 inhibitors on inflammatory biomarkers, adipokine profiles and insulin sensitivity. RESULTS: Thirty-eight RCTs were included (14 967 participants, 63.3% male, mean age 62 ± 8.6 years) with a median (interquartile range) follow-up of 16 (12-24) weeks. Meta-analysis showed that SGLT2 inhibitors significantly improved adiponectin, interleukin-6, tumour necrosis factor receptor-1 (vs. placebo alone: standardized mean difference [SMD] 0.34 [95% confidence interval {CI} 0.23, 0.45], mean difference [MD] -0.85 pg/mL [95% CI -1.32, -0.38], SMD -0.13 [95% CI -0.20, -0.06], respectively), leptin and homeostatic model assessment of insulin resistance index (vs. CONTROL: SMD -0.20 [95% CI -0.33, -0.07], MD -0.83 [95% CI -1.32, -0.33], respectively). There were no significant changes in C-reactive protein (CRP), tumour necrosis factor-α, plasminogen activator inhibitor-1, fibroblast growth factor-21 or monocyte chemoattractant protein-1. CONCLUSIONS: Our analysis shows that SGLT2 inhibitors likely improve adipokine biomarkers and insulin sensitivity, but there is little evidence that SGLT2 inhibitors improve other inflammatory biomarkers including CRP.

Glomerular and tubular effects of dapagliflozin, eplerenone and their combination in patients with chronic kidney disease: A post-hoc analysis of the ROTATE-3 study.

AIM: Sodium-glucose co-transporter 2 inhibitors and mineralocorticoid receptor antagonists reduce albuminuria and the risk of kidney failure. The aim of this study was to investigate the effects of both agents alone and in combination on markers of the glomerular endothelial glycocalyx and tubular function. METHODS: This post-hoc analysis utilized data of the ROTATE-3 study, a randomized cross-over study in 46 adults with chronic kidney disease and urinary albumin excretion ≥100 mg/24 h, who were treated for 4 weeks with dapagliflozin, eplerenone or its combination. The effects of dapagliflozin, eplerenone and the combination on outcome measures such as heparan sulphate, neuro-hormonal markers and tubular sodium handling were assessed with mixed repeated measures models. RESULTS: The mean percentage change from baseline in heparan sulphate after 4 weeks treatment with dapagliflozin, eplerenone or dapagliflozin-eplerenone was -34.8% (95% CI -52.2, -10.9), -5.9% (95% CI -32.5, 31.3) and -28.1% (95% CI -48.4, 0.1) respectively. The mean percentage change from baseline in plasma aldosterone was larger with eplerenone [38.9% (95% CI 2.8, 87.7)] and dapagliflozin-eplerenone [32.2% (95% CI -1.5, 77.4)], compared with dapagliflozin [-12.5% (95% CI -35.0, 17.8)], respectively. Mean percentage change from baseline in copeptin with dapagliflozin, eplerenone or dapagliflozin-eplerenone was 28.4% (95% CI 10.7, 49.0), 4.2% (95% CI -10.6, 21.4) and 23.8% (95% CI 6.6, 43.9) respectively. Dapagliflozin decreased proximal absolute sodium reabsorption rate by 455.9 mmol/min (95% CI -879.2, -32.6), while eplerenone decreased distal absolute sodium reabsorption rate by 523.1 mmol/min (95% CI -926.1, -120.0). Dapagliflozin-eplerenone decreased proximal absolute sodium reabsorption [-971.0 mmol/min (95% CI -1411.0, -531.0)], but did not affect distal absolute sodium reabsorption [-9.2 mmol/min (95% CI -402.0, 383.6)]. CONCLUSIONS: Dapagliflozin and eplerenone exert different effects on markers of glomerular and tubular function supporting the hypothesis that different mechanistic pathways may account for their kidney protective effects.

A 52-week efficacy and safety study of enavogliflozin versus dapagliflozin as an add-on to metformin in patients with type 2 diabetes mellitus: ENHANCE-M extension study.

AIM: To evaluate the long-term safety and efficacy of enavogliflozin 0.3 mg/day added to metformin in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: After 24 weeks of a randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 101) or dapagliflozin 10 mg/day (n = 99) added to metformin, all patients received enavogliflozin 0.3 mg/day plus metformin for an additional 28 weeks during the open-label extension period. RESULTS: Eighty-two patients continued enavogliflozin (maintenance group), and 77 were switched from dapagliflozin to enavogliflozin (switch group). All adverse drug reactions (ADR) were mild in severity. In the maintenance group, ADRs (cystitis and vaginal infection) were reported in two patients (2.44%) during 52 weeks. In the switch group, ADR (hypoglycaemia) was reported in one patient (1.30%) during a 28-week open-label extension period. At week 52, glycated haemoglobin and fasting plasma glucose were significantly lower than at the baseline, by 0.85% and 29.08 mg/dl, respectively, in the maintenance group (p < .0001 for both), and by 0.81% and 32.77 mg/dl, respectively, in the switch group (p < .0001 for both). At week 52, 68.92% of patients from the maintenance group and 64.29% from the switch group achieved glycated haemoglobin <7%. A significant increase in the urine glucose-creatinine ratio was observed at week 52, by 58.81 g/g and 63.77 g/g in the maintenance and switch groups, respectively (p < .0001). CONCLUSIONS: Enavogliflozin added to metformin was tolerated well for up to 52 weeks and provided continual glycaemic control in type 2 diabetes mellitus, along with a significant increase in the urine glucose-creatinine ratio.

Dapagliflozin pharmacokinetics is similar between patients with heart failure with reduced ejection fraction and patients with type 2 diabetes mellitus.

Dapagliflozin was recently approved for use in adults with chronic heart failure with reduced ejection fraction (HFrEF) with/without type 2 diabetes mellitus (T2DM). The objectives of this analysis were to characterize dapagliflozin pharmacokinetics in patients with HFrEF and to compare dapagliflozin systemic exposure between adults with HFrEF with/without T2DM and adults with T2DM. A nonlinear mixed-effects modelling approach was applied; the population-pharmacokinetic model was developed using 9735 dapagliflozin plasma concentrations from 2744 patients. The final two-compartmental model adequately described the observed dapagliflozin concentrations, with a similar estimated apparent clearance compared with a previous estimate in patients with T2DM without HF and in healthy subjects (23.0 [95% CI: 22.6-23.9] L/h vs. 22.9 [95% CI: 22.1-23.7] L/h). The model-predicted median area under the dapagliflozin concentration-time profile was ≤1.2-fold higher in patients with HFrEF vs. those with T2DM without HFrEF, which is not considered clinically relevant. Dapagliflozin exposure was similar between patients with HFrEF with/without T2DM and T2DM patients without HFrEF.