Search Results (21)

SGLT2 inhibitors have become increasingly used due to their effectiveness in improving not only type 2 diabetes but also cardiovascular, renal and hepatic diseases, as well as the obesity found in metabolic syndrome. Starting from the structure of gliflozins, modifications of the carbohydrate part, aglycone, and also the glycosidic bond between them can determine variations in pharmacokinetic and pharmacodynamic properties. SGLT2 inhibitors, in addition to reducing blood glucose levels, improve alterations in lipid metabolism by diverting excessively accumulated lipids in tissues towards mobilization, lipolysis, β-oxidation, ketogenesis and the utilization of ketone bodies. This enhances anti-inflammatory properties by decreasing the levels of some proinflammatory mediators and by modulating some cell signaling pathways. Thus, in this review, the intimate mechanisms by which SGLT2 inhibitors achieve these therapeutic effects in the various conditions belonging to metabolic syndrome and beyond were described, along with the structure–effect relationship with some specific features of each gliflozin. Starting from these findings, further modeling of these molecules may lead to the creation of new therapeutic uses. Further research is needed to broaden the range of indications and also eliminate adverse effects, such as phenomena leading to lower limb amputations. Full article

Background/Objectives: Current guidelines for the management of type 2 diabetes (T2D) strongly recommend the use of sodium–glucose cotransporter 2 inhibitors (SGLT2is) in patients with chronic kidney disease (CKD) to alleviate cardiorenal risk. However, the implementation of this guidance in daily practice remains limited. In a real-world setting, we evaluated the frequency of SGLT2i use in elderly people with T2D and CKD and compared patient profiles between SGLT2i users and non-users. Methods: We retrospectively analyzed the medical records of individuals over 65 years of age followed in outpatient internal medicine clinics in Greece. Demographic and laboratory parameters, comorbidity profiles, and medication use were recorded and compared between the SGLT2i and non-SGLT2i groups. Results: The analysis included 135 patients with T2D and CKD, of whom the majority (57.8%) did not receive SGLT2i treatment. The patients in the SGLT2i group were younger (p = 0.006), had higher creatinine (p = 0.001) and hemoglobin (p = 0.001) values, and lower levels of uric acid (p = 0.025) than the participants not treated with SGLT2is. Heart failure rates were similar between the groups (p = 0.252). There was no difference in the use of renin–angiotensin–aldosterone system inhibitors (p = 0.210); in contrast, treatment with glucagon-like peptide 1 receptor agonists was more frequent in the group receiving SGLT2is compared to the group not treated with gliflozins (p = 0.002). Conclusions: Real-world data confirm the benefits of SGLT2i treatment for elderly people with T2D and CKD. However, our findings indicate that the use of gliflozins in this population of patients remains suboptimal, highlighting the need for greater vigilance among prescribers to align with existing guidelines. Full article

Background: Lafora disease (LD) is an ultra-rare and fatal neurodegenerative disorder with limited therapeutic options. Current treatments primarily address symptoms, with modest efficacy in halting disease progression, thus highlighting the urgent need for novel therapeutic approaches. Gene therapy, antisense oligonucleotides, and recombinant enzymes have recently been, and still are, under investigation. Drug repurposing may offer a promising approach to identify new, possibly effective, therapies. Methods: This study aims to investigate the conditions for repurposing empagliflozin, an SGLT2 (sodium/glucose cotransporter-2) inhibitor, as a potential treatment for LD and to establish a clinical protocol. Clinical phase: This 12-month prospective observational study will assess the safety and clinical efficacy of empagliflozin in two patients with early to intermediate LD stage. The primary endpoints will include changes in the severity of epilepsy and cognitive function, while the secondary endpoints will assess motor function, global function, and autonomy. Multiple clinical and instrumental evaluations (including MRI and PET with ¹⁸F-fluorodeoxyglucose) will be performed before and during treatment. Safety monitoring will include regular clinical assessments and reports of adverse events. Preclinical phase: In silico studies (using both molecular docking calculations and reverse ligand-based screening) and in vitro cell-based assays will allow us to investigate the effects of empagliflozin (and other gliflozins) on some key targets likely implicated in LD pathogenesis, such as GLUT1, GLUT3, glycogen synthase (hGYS), and glycogen phosphorylase (GP), as suggested in the literature and digital platforms for in silico target fishing. Results: The expected outcome of this study is twofold, i.e., (i) assessing the safety and tolerability of empagliflozin in LD patients and (ii) gathering preliminary data on its potential efficacy in improving clinical and neurologic features. Additionally, the in silico and in vitro studies may provide new insights into the mechanisms through which empagliflozin may exert its therapeutic effects in LD. Conclusion: The findings of this study are expected to provide evidence in support of the repurposing of empagliflozin for the treatment of LD. Full article

Diabetes mellitus (DM) is a chronic disease associated with numerous complications, including cardiovascular diseases, nephropathy, and neuropathy. Sodium–glucose cotransporter 2 (SGLT-2) inhibitors, a class of novel antidiabetic agents, have demonstrated promising therapeutic effects beyond glycemic control, with potential benefits extending to the cardiovascular and renal systems. Recently, research has increasingly focused on exploring the potential role of SGLT-2 inhibitors in preventing dementia. The aim of this review is to summarize the current research suggesting that SGLT-2 inhibitors, such as empagliflozin and dapagliflozin, may have neuroprotective effects that reduce dementia risk and improve cognitive function in type 2 diabetes patients. These benefits are likely due to better glycemic control, reduced oxidative stress, and less advanced glycation end-product (AGE) formation, all linked to neurodegeneration. Despite these promising findings, existing studies are limited by small sample sizes and short follow-up durations, which may not adequately capture long-term outcomes. To establish more robust evidence, larger-scale, long-term randomized controlled trials (RCTs) involving diverse populations are needed. These studies should involve diverse populations and focus on understanding the mechanisms behind the neuroprotective effects. Addressing these limitations will provide clearer guidelines for using SGLT-2 inhibitors in dementia prevention and management. This will help improve therapeutic strategies for cognitive health in diabetic patients. Full article

Atrial fibrillation (AF) is the most prevalent arrhythmia among adults worldwide, frequently co-occurring with comorbidities such as Heart Failure (HF) and Type 2 Diabetes Mellitus (T2DM). This association contributes to increased morbidity and mortality, elevated healthcare costs, and diminished quality of life. Consequently, preventing or delaying the onset and recurrence of AF is crucial for reducing the incidence of complications. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), due to their multifaceted pharmacological actions, have been proposed as potential therapeutic agents in the management of AF. However, current evidence from both animal models and clinical studies remains inconclusive. This narrative literature review aims to provide a comprehensive analysis of existing evidence on the impact of SGLT2is on the prevalence, incidence of new-onset, and recurrence of AF in diabetic populations and patients with HF. Numerous observational studies, predominantly retrospective, suggest a consistent reduction in AF risk with SGLT2is, while randomized controlled trials (RCTs) have yielded mixed results, with some demonstrating benefits and others not reaching statistical significance. The heterogeneity in study outcomes, population characteristics, follow-up duration, and specific SGLT2is used, as well as potential biases, underscore the need for further extensive and rigorous RCTs to establish definitive conclusions and elucidate the underlying mechanisms. Full article

(1) Background: This single-center retrospective study aimed to evaluate whether sodium–glucose cotransporter-2 inhibitors (SGLT2-i) therapy may have a nephroprotective effect to prevent contrast-induced acute kidney injury (CI-AKI) in patients with heart failure (HF) undergoing iodinated contrast medium (ICM) invasive procedures. (2) Methods: The population was stratified into SGLT2-i users and SGLT2-i non-users according to the chronic treatment with gliflozins. The primary endpoint was CI-AKI incidence during hospitalization. Secondary endpoints were all-cause mortality and the need for continuous renal replacement therapy (CRRT). (3) Results: In total, 86 patients on SGLT2-i and 179 patients not on SGLT2-i were enrolled. The incidence of CI-AKI in the gliflozin group was lower than in the non-user group (9.3 vs. 27.3%, p < 0.001), and these results were confirmed after propensity matching analysis. Multivariable logistic regression showed that only SGLT2-i treatment was an independent preventive factor for CI-AKI (OR: 0.41, 95% CI: 0.16–0.90, p = 0.045). The need for CRRT was reported only in five patients in the non-SGLT2-i-user group compared to zero patients in the gliflozin group (p = 0.05). (4) Conclusions: SGLT2-i therapy was associated with a lower risk of CI-AKI in patients with HF undergoing ICM invasive procedures. Full article

The goal of the second volume of this Special Issue was to build upon the success of the first one and to continue to highlight the ever-expanding list of pharmacological properties of the sodium/glucose co-transporter (SGLT) type 2 (SGLT2) inhibitor (SGLT2i) drug class (also known as gliflozins) [...] Full article

Sodium–glucose cotransporter-2 (SGLT-2) inhibitors, also called gliflozins or flozins, are a class of drugs that have been increasingly used in the management of type 2 diabetes mellitus (T2DM) due to their glucose-lowering, cardiovascular (CV), and renal positive effects. However, recent studies suggest that SGLT-2 inhibitors might also have a ketogenic effect, increasing ketone body production. While this can be beneficial for some patients, it may also result in several potential unfavorable effects, such as decreased bone mineral density, infections, and ketoacidosis, among others. Due to the intricate and multifaceted impact caused by SGLT-2 inhibitors, this initially anti-diabetic class of medications has been effectively used to treat both patients with chronic kidney disease (CKD) and those with heart failure (HF). Additionally, their therapeutic potential appears to extend beyond the currently investigated conditions. The objective of this review article is to present a thorough summary of the latest research on the mechanism of action of SGLT-2 inhibitors, their ketogenesis, and their potential synergy with the ketogenic diet for managing diabetes. The article particularly discusses the benefits and risks of combining SGLT-2 inhibitors with the ketogenic diet and their clinical applications and compares them with other anti-diabetic agents in terms of ketogenic effects. It also explores future directions regarding the ketogenic effects of SGLT-2 inhibitors. Full article

Sodium–glucose cotransporter 2 inhibitors (SGLT2i), or gliflozins, have recently been shown to reduce cardiovascular death and hospitalization in patients with heart failure, representing a revolutionary therapeutic tool. The purpose of this review is to explore their multifaceted mechanisms of actions, beyond their known glucose reduction power. The cardioprotective effects of gliflozins seem to be linked to the maintenance of cellular homeostasis and to an action on the main metabolic pathways. They improve the oxygen supply for cardiomyocytes with a considerable impact on both functional and morphological myocardial aspects. Moreover, multiple molecular actions of SGLT2i are being discovered, such as the reduction of both inflammation, oxidative stress and cellular apoptosis, all responsible for myocardial damage. Various studies showed controversial results concerning the role of SGLT2i in reverse cardiac remodeling and the lowering of natriuretic peptides, suggesting that their overall effect has yet to be fully understood. In addition to this, advanced imaging studies evaluating the effect on all four cardiac chambers are lacking. Further studies will be needed to better understand the real impact of their administration, their use in daily practice and how they can contribute to benefits in terms of reverse cardiac remodeling. Full article

Brain swelling is a major cause of death and disability in ischemic stroke. Drugs of the gliflozin class, which target the Na⁺-coupled D-glucose cotransporter, SGLT2, are approved for type 2 diabetes mellitus (T2DM) and may be beneficial in other conditions, but data in cerebral ischemia are limited. We studied murine models of cerebral ischemia with middle cerebral artery occlusion/reperfusion (MCAo/R). Slc5a2/SGLT2 mRNA and protein were upregulated de novo in astrocytes. Live cell imaging of brain slices from mice following MCAo/R showed that astrocytes responded to modest increases in D-glucose by increasing intracellular Na⁺ and cell volume (cytotoxic edema), both of which were inhibited by the SGLT2 inhibitor, canagliflozin. The effect of canagliflozin was studied in three mouse models of stroke: non-diabetic and T2DM mice with a moderate ischemic insult (MCAo/R, 1/24 h) and non-diabetic mice with a severe ischemic insult (MCAo/R, 2/24 h). Canagliflozin reduced infarct volumes in models with moderate but not severe ischemic insults. However, canagliflozin significantly reduced hemispheric swelling and improved neurological function in all models tested. The ability of canagliflozin to reduce brain swelling regardless of an effect on infarct size has important translational implications, especially in large ischemic strokes. Full article

The drug metabolism and drug degradation pathways may overlap, resulting in the formation of similar constituents. Therefore, the metabolism data can be helpful for deriving safe levels of degradation impurities and improving the quality of respective pharmaceutical products. The present article contains considerations on possible links between metabolic and degradation pathways for new antidiabetic drugs such as glutides, gliflozins, and gliptins. Special attention was paid to their reported metabolites and identified degradation products. At the same time, many interesting analytical approaches to conducting metabolism as well as degradation experiments were mentioned, including chromatographic methods and radioactive labeling of the drugs. The review addresses the analytical approaches elaborated for examining the metabolism and degradation pathways of glutides, i.e., glucagon like peptide 1 (GLP-1) receptor agonists, and gliflozins, i.e., sodium glucose co-transporter 2 (SGLT2) inhibitors. The problems associated with the chromatographic analysis of the peptide compounds (glutides) and the polar drugs (gliflozins) were addressed. Furthermore, issues related to in vitro experiments and the use of stable isotopes were discussed. Full article

Heart failure (HF) is a complex, multifactorial, progressive clinical condition affecting 64.3 million people worldwide, with a strong impact in terms of morbidity, mortality and public health costs. In the last 50 years, along with a better understanding of HF physiopathology and in agreement with the four main models of HF, many therapeutic options have been developed. Recently, the European Society of Cardiology (ESC) HF guidelines enthusiastically introduced inhibitors of the sodium-glucose cotransporter (SGLT2i) as first line therapy for HF with reduced ejection fraction (HFrEF) in order to reduce hospitalizations and mortality. Despite drugs developed as hypoglycemic agents, data from the EMPA-REG OUTCOME trial encouraged the evaluation of the possible cardiovascular effects, showing SGLT2i beneficial effects on loading conditions, neurohormonal axes, heart cells’ biochemistry and vascular stiffness, determining an improvement of each HF model. We want to give a boost to their use by increasing the knowledge of SGLT2-I and understanding the probable mechanisms of this new class of drugs, highlighting strengths and weaknesses, and providing a brief comment on major trials that made Gliflozins a cornerstone in HF therapy. Finally, aspects that may hinder SGLT2-i widespread utilization among different types of specialists, despite the guidelines’ indications, will be discussed. Full article

Gliflozins are a new class of antidiabetic drugs with renoprotective properties. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to high-glucose conditions in the presence or absence of dapagliflozin, we evaluated cellular senescence pathways. High glucose increased sodium–glucose cotransporter-2 (SGLT-2) expression and glucose consumption, enhancing reactive oxygen species production. The latter induced DNA damage, ataxia telangiectasia mutated kinase (ATM), and p53 phosphorylation. Stabilized p53 increased the cell cycle inhibitor p21, resulting in cell cycle arrest and increasing the cellular senescence marker beta-galactosidase (GLB-1). RPTECs under high glucose acquired a senescence-associated secretory phenotype, which was detected by the production of IL-1β, IL-8, and TGF-β1. By decreasing SGLT-2 expression and glucose consumption, dapagliflozin inhibited the above pathway and prevented RPTEC senescence. In addition, dapagliflozin reduced the cell cycle inhibitor p16 independently of the glucose conditions. Neither glucose concentration nor dapagliflozin affected the epithelial-to-mesenchymal transition when assessed with α-smooth muscle actin (α-SMA). Thus, high glucose induces p21-dependent RPTEC senescence, whereas dapagliflozin prevents it. Since cellular senescence contributes to the pathogenesis of diabetic nephropathy, delineating the related molecular mechanisms and the effects of the widely used gliflozins on them is of particular interest and may lead to novel therapeutic approaches. Full article

Gliflozins (sodium-glucose transporter-2 inhibitors) exhibited renoprotective effects not only in diabetic but also in non-diabetic patients with chronic kidney disease (CKD). Controversial results were reported in experimental non-diabetic models of CKD. Therefore, we examined empagliflozin effects in three CKD models, namely, in fawn-hooded hypertensive (FHH) rats, uninephrectomized salt-loaded (UNX + HS) rats, and in rats with Goldblatt hypertension (two-kidney, one-clip 2K1C) that were either untreated or treated with empagliflozin (10 mg/kg/day) for eight weeks. Plethysmography blood pressure (BP) was recorded weekly, and renal parameters (proteinuria, plasma urea, creatinine clearance, and sodium excretion) were analyzed three times during the experiment. At the end of the study, blood pressure was also measured directly. Markers of oxidative stress (TBARS) and inflammation (MCP-1) were analyzed in kidney and plasma, respectively. Body weight and visceral adiposity were reduced by empagliflozin in FHH rats, without a significant effect on BP. Experimentally induced CKD (UNX + HS and 2K1C) was associated with a substantial increase in BP and relative heart and kidney weights. Empagliflozin influenced neither visceral adiposity nor BP in these two models. Although empagliflozin increased sodium excretion, suggesting effective SGLT-2 inhibition, it did not affect diuresis in any experimental model. Unexpectedly, empagliflozin did not provide renoprotection because proteinuria, plasma urea, and plasma creatinine were not lowered by empagliflozin treatment in all three CKD models. In line with these results, empagliflozin treatment did not decrease TBARS or MCP-1 levels in either model. In conclusion, empagliflozin did not provide the expected beneficial effects on kidney function in experimental models of CKD. Full article