Sodium-glucose transport protein-2 (SGLT2) inhibitors, initially developed for glycemic control in type 2 diabetes mellitus (T2DM), have emerged as potential cardioprotective agents, reducing cardiovascular mortality and improving heart failure outcomes. Recent evidence suggests that SGLT2 inhibitors exert anti-inflammatory effects, particularly through modulating the inflammasome pathway. This review explores the role of the inflammasome in acute myocardial infarction (AMI) in T2DM and discusses the mechanisms by which SGLT2 inhibitors influence this pathway. We evaluate current studies on the impact of SGLT2 inhibitors on key inflammatory mediators, particularly the NLRP3 inflammasome, and discuss their potential therapeutic implications for reducing inflammation and myocardial injury in patients with T2DM experiencing AMI. In summary, the key novelties in this review lie in its focused mechanistic approach on the inflammasome pathway, its integration of diabetes and cardiovascular research, and its potential to influence future therapeutic strategies for AMI in T2DM patients. It offers a novel angle by tying together molecular mechanisms of inflammation with clinical implications in a specific patient population that faces high cardiovascular risk.

(1) Background: Arterial stiffness, often measured by carotid-femoral pulse wave velocity (cf-PWV), is crucial in cardiovascular disease. Dapagliflozin has shown rapid effects on arterial stiffness, but there is limited evidence of empagliflozin's acute effects, especially in type 2 diabetes (T2D) patients. This study evaluated the acute effects of empagliflozin and dapagliflozin on arterial stiffness and blood pressure (BP). (2) Methods: A one-week double-blind randomized trial involved 30 T2D patients on stable metformin therapy. Participants received empagliflozin (25 mg/day), dapagliflozin (10 mg/day), or a placebo. Arterial stiffness was assessed via cf-PWV, and BP was measured with an automated sphygmomanometer. (3) Results: Both SGLT2 inhibitors significantly reduced cf-PWV compared to the placebo after one week (p < 0.05), with dapagliflozin showing a more pronounced effect. No significant differences were observed in BP changes. (4) Conclusion: Short-term treatment with SGLT2 inhibitors acutely reduces arterial stiffness in T2D patients, with empagliflozin demonstrating a stronger effect, supporting the potential vascular benefits of SGLT2 inhibitors beyond glucose control.

Background: Cardiovascular disease (CVD) is a leading cause of mortality in Type 2 diabetes mellitus (T2DM). Sodium-glucose co-transporter 2 (SGLT2) inhibitors are known to provide cardioprotective effects, but their influence on validated cardiovascular risk models remains underexplored. This study assessed the impact of SGLT2 inhibitors on cardiovascular risk scores, metabolic parameters, and laboratory profiles over six months. Methods: This study was conducted on 152 T2DM patients initiating SGLT2 inhibitors. Cardiovascular risk was evaluated using the SCORE2-DM model at baseline and after six months. Generalized Estimating Equation (GEE) analysis assessed temporal risk stratification changes. Metabolic parameters and laboratory profiles were analyzed using repeated-measures ANOVA. Results: Cardiovascular risk scores decreased significantly, i.e., from 21.68 to 17.43 (p < 0.001). Systolic and diastolic blood pressure were reduced by 9.21 mmHg and 6.16 mmHg, respectively (p < 0.001). BMI declined by 1.27 kg/m2 (p < 0.001), and HbA1c decreased by 1.38% (p < 0.001). Triglyceride levels dropped by 22.91 mg/dL (p < 0.001), while renal parameters remained stable. The GEE analysis confirmed significant shifts to lower cardiovascular risk categories (β = -0.777, p < 0.001), with comparable efficacy between empagliflozin and dapagliflozin (p = 0.922). Conclusions: SGLT2 inhibitor therapy significantly reduces cardiovascular risk and improves metabolic and laboratory parameters in T2DM patients. These findings highlight the importance of integrating SGLT2 inhibitors into comprehensive cardiometabolic management strategies.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is mainly secreted by the liver, and plays a crucial role in lipid metabolism disorder. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) can regulate lipid metabolism through various pathways, including reducing visceral fat accumulation, modulating serum lipoprotein levels and alleviating hepatic steatosis. However, the specific regulatory mechanisms remain unclear.

We built a model of glucose and lipid metabolism disorder in vivo and in vitro, and explored the regulatory mechanism of dapagliflozin in regulating liver lipid metabolism.

We found that the SGLT2i dapagliflozin significantly reduced serum levels of PCSK9, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) in high-fat diet (HFD)-fed mice, while also improving hepatic steatosis. In vitro studies confirmed that dapagliflozin increased LDL receptor (LDLR) expression in HepG2 cells, enhancing their ability to uptake LDL-C.

Further mechanistic studies revealed that the hepatocyte nuclear factor-1-alpha (HNF1α)/PCSK9/LDLR signalling pathway may be involved in dapagliflozin's regulation of lipid metabolism homeostasis.

Metabolic syndrome-related diseases frequently involve disturbances in skeletal muscle lipid metabolism. The accumulation of lipid metabolites, lipid-induced mitochondrial stress in skeletal muscle cells, as well as the inflammation of adjacent adipose tissue, are associated with the development of insulin resistance and metabolic dysfunction. Consequently, when antidiabetic medications are used to treat various chronic conditions related to hyperglycaemia, the impact on skeletal muscle lipid metabolism should not be overlooked. However, current research has predominantly focused on muscle mass rather than skeletal muscle lipid metabolism and its interplay with glucose metabolism. In this review, we summarised the latest research on the effects of antidiabetic drugs and certain natural compounds with antidiabetic activity on skeletal muscle lipid metabolism, focusing on data from preclinical to clinical studies. Given the widespread use of antidiabetic drugs, a better understanding of their effects on skeletal muscle lipid metabolism merits further attention in future research.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally formulated to reduce blood glucose levels in individuals with diabetes. Recent clinical trials indicate that this compound can be repurposed for other critical conditions. A literature search was performed on PubMed, Scopus, Embase, ProQuest, and Google Scholar, utilizing key terms such as SGLT2i, diabetes, and oxidative stress. SGLT2i has significant beneficial effects not only in cardiovascular disease but also in renal dysfunction. SGLT2i therapy can mitigate critical cardiovascular complications like heart attacks, strokes, mortality rates, and hospitalization duration, as well as delay the necessity for dialysis irrespective of diabetic condition. Evidence supports potential advantages of SGLT2 inhibitors for individuals with renal problems and heart failure, regardless of diabetes status. In addition to diabetic mellitus, this analysis explores the latest updates on SGLT2i and the therapeutic advantages it offers in many renal and cardiovascular diseases (CVDs).

Beyond glucose-lowering, sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardioprotective effects with unclear mechanisms. We examined changes in an extensive panel of plasma lipids, lipoproteins, and apolipoproteins and whether these changes were independent of weight loss, hemoglobin A1c, and hematocrit in patients treated with empagliflozin vs placebo to better understand the observed cardioprotective effects.

Post-hoc analyses of 2 double-blind, placebo-controlled trials, the Empire HF trial including 190 patients with heart failure and reduced ejection fraction and the SIMPLE trial including 90 patients with type 2 diabetes randomized to, respectively, 10 mg and 25 mg empagliflozin daily or placebo for 12 weeks.

In studies combined, empagliflozin reduced age and sex adjusted body weight by 1.40 kg (SEM: 0.10; P < .001) and hemoglobin A1c by 2.71 mmol/mol (SEM: 0.24; P < .001); and increased hematocrit by 1.9% (SEM: 0.12; P < .001) compared to placebo. No mean changes were seen in concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, small dense LDL cholesterol, very low-density lipoprotein cholesterol, triglyceride rich lipoprotein cholesterol, non-high-density lipoprotein (non-HDL) cholesterol, apolipoprotein B, lipoprotein(a), HDL cholesterol, and triglycerides adjusted for body weight, hemoglobin A1c, and hematocrit with empagliflozin compared to placebo.

Empagliflozin treatment reduced body weight and hemoglobin A1c, and increased hematocrit. No changes were seen in concentrations of lipids and lipoproteins with empagliflozin compared to placebo. This suggests that the cardioprotective effects of SGLT2 inhibitors are independent of lipid and lipoprotein concentrations.

Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving treatment of diseases. We employed a cross-disciplinary approach to identify potential treatments for metabolic dysfunction associated steatotic liver disease (MASLD) using humans as a model organism. We identified 212 putative causal genes associated with MASLD using data from a large multi-ancestry genetic association study, of which 158 (74.5%) are novel. From this set we identified 57 genes that encode for druggable protein targets, and where the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. These potential targets were then evaluated for evidence of efficacy using Mendelian randomization, pathway analysis, and protein structural modeling. Using these approaches, we present compelling evidence to suggest activation of FADS1 by icosopent ethyl as well as S1PR2 by fingolimod could be promising therapeutic strategies for MASLD.

High-density lipoprotein (HDL) exhibits multiple metabolic protective functions, such as facilitating cellular cholesterol efflux, antioxidant, anti-inflammatory, anti-apoptotic and anti-thrombotic properties, showing antidiabetic and renoprotective potential. Diabetic kidney disease (DKD) is considered to be associated with high-density lipoprotein cholesterol (HDL-C). The hyperglycemic environment, non-enzymatic glycosylation, carbamylation, oxidative stress and systemic inflammation can cause changes in the quantity and quality of HDL, resulting in reduced HDL levels and abnormal function. Dysfunctional HDL can also have a negative impact on pancreatic β cells and kidney cells, leading to the progression of DKD. Based on these findings, new HDL-related DKD risk predictors have gradually been proposed. Interventions aiming to improve HDL levels and function, such as infusion of recombinant HDL (rHDL) or lipid-poor apolipoprotein A-I (apoA-I), can significantly improve glycemic control and also show renal protective effects. However, recent studies have revealed a U-shaped relationship between HDL-C levels and DKD, and the loss of protective properties of high levels of HDL may be related to changes in composition and the deposition of dysfunctional particles that exacerbate damage. Further research is needed to fully elucidate the complex role of HDL in DKD. Given the important role of HDL in metabolic health, developing HDL-based therapies that augment HDL function, rather than simply increasing its level, is a critical step in managing the development and progression of DKD.

Sodium-glucose co-transporter type 2 inhibitors (SGLT2i) have emerged as a class of agents relevant for managing diabetic nephropathy and cardiopathy. In a previous report, we noticed that these drugs share, with other drugs with "nephroprotective" effects, the ability to reduce the glomerular filtration rate (GFR), thus suggesting the kidney hemodynamic effect as a proxy for optimal drug dosage. We also noticed that all known nephroprotective drugs exert cardioprotective functions, suggesting the possibility of activities not mediated by the kidney. Finally, we observe that nephroprotective drugs can be grouped according to their effects on hemoglobin levels, thus suggesting their mechanism of action. While the primary mechanism of SGLT2i involves glycosuria and natriuria, growing evidence suggests broader therapeutic effects beyond hemodynamic modulation. Specifically, the evidence that SGLT2 can be expressed in several atypical regions under pathological conditions, supports the possibility that its inhibition has several extratubular effects. Evidence supports the hypothesis that SGLT2i influence mitochondrial function in various cell types affected by diabetes, particularly in the context of diabetic nephropathy. Notably, in SGLT2i-treated patients, the extent of albumin-creatinine ratio (ACR) reduction post-treatment may be correlated with mitochondrial staining intensity in glomerular endothelial cells. This implies that the anti-proteinuric effects of SGLT2i could involve direct actions on glomerular endothelial cell. Our investigation into the role of SGLT2 inhibitors (SGLT2i) in endothelial function suggests that the aberrant expression of SGLT2 in endothelial cells in T2DM would lead to intracellular accumulation of glucose; therefore, SGLT2i are the first type of endothelial protective drugs available today, with potential implications for ageing-related kidney disease. The review reveals two major novel findings: SGLT2 inhibitors are the first known class of endothelial-protective drugs, due to their ability to prevent glucose accumulation in endothelial cells where SGLT2 is aberrantly expressed in Type 2 Diabetes. Additionally, the research demonstrates that SGLT2 inhibitors share a GFR-reducing effect with other nephroprotective drugs, suggesting both a mechanism for optimal drug dosing and potential broader applications in ageing-related kidney disease through their effects on mitochondrial function and glomerular endothelial cells.

Our study aimed to elucidate the impact of sodium-glucose cotransporter-2 inhibitor on left ventricular systolic function using global longitudinal strain in type 2 diabetes mellitus patients and to assess its protective effect depending on disease duration. Type 2 diabetes mellitus patients treated at our institute were included. According to whether sodium-glucose cotransporter-2 inhibitor was used in drug treatment, the patients were divided into SGLT2i group and control group, and propensity score matching was performed. For subgroup analysis, patients were further classified based on disease duration (1-5 years, 5-10 years, and 10-20 years). A total of 256 patients with type 2 diabetes mellitus were enrolled. Significantly better global longitudinal strain results were observed at the 6-month follow-up in the SGLT2i group than those of the control group and its baseline (p < 0.001). A significantly lower proportion of subclinical cardiac dysfunction was observed in the SGLT2i group (p < 0.001). Significantly greater global longitudinal strains were observed in the SGLT2i subgroups compared with control subgroups (p all < 0.05). Furthermore, sodium-glucose cotransporter-2 inhibitor use and epicardial adipose tissue thickness change were independently associated with global longitudinal strain change according to multivariate analysis. Sodium-glucose cotransporter-2 inhibitor significantly improved left ventricular function in type 2 diabetes mellitus patients without cardiovascular complications, regardless of disease duration, with more prominent outcomes observed in patients with early-stage disease.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-Like peptide-1 receptor agonists (GLP-1 RA) are recommended in people with type 2 diabetes (T2D) for glycaemic control and for people with high cardiovascular risk. However, current guidelines do not specifically address the role of initial early combination therapy with SGLT2i and GLP-1 RA or dual gastric inhibitory polypeptide (GIP)/GLP-1 RA, but rather sequential initiation with either in T2D. This review synthesizes the available evidence on the use of SGLT2i and GLP-1-based therapies for T2D and provides a rationale for their combination. The combination of SGLT2i with GLP-1-based therapies addresses complementary pathophysiological mechanisms and enhances efficacy in achieving target haemoglobin A1C (HbA1c) levels. SGLT2i and GLP-1 RA also have been shown to prevent complications of T2D. While both classes reduce adverse cardiorenal events, SGLT2i has a predominant effect on prevention of kidney dysfunction and heart failure, whereas GLP-1 RA has a more marked effect on the risk of atherosclerotic cardiovascular disease. Both drug classes have favourable safety profiles. Finally, weight loss with combination therapy may have disease-modifying effects that may reverse T2D progression. We propose that the combination of SGLT2i with GLP-1 RA or dual GIP/GLP-1 RA should be considered for most patients with T2D who do not have contraindications.

Dyslipidemia is a major risk factor for cardiovascular disease, and its impact may be exacerbated when accompanied by metabolic dysfunction-associated steatotic liver disease (MASLD). The simultaneous management of these conditions poses multiple challenges for healthcare providers. Insulin resistance has been implicated in the pathogenesis of both dyslipidemia and MASLD, necessitating a holistic approach to managing dyslipidemia, glucose levels, body weight, and MASLD. This review explores the intricate pathophysiological relationship between MASLD and dyslipidemia. It also examines current guidance regarding the use of lipid-lowering agents (including statins, ezetimibe, fibrates, omega-3 polyunsaturated fatty acids, and proprotein convertase subtilisin/kexin type 9 inhibitors) as well as glucose-lowering medications (such as pioglitazone, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors) in patients with MASLD, with or without metabolic dysfunction-associated steatohepatitis (MASH), and dyslipidemia. Additionally, the review addresses the potential of emerging drugs to concurrently target both MASLD/MASH and dyslipidemia. Our hope is that a deeper understanding of the mechanisms underlying MASLD and dyslipidemia may assist clinicians in the management of these complex cases.

The metabolic and lipid profiles of horses treated with sodium-glucose cotransporter 2 inhibitors are not well understood. This retrospective study evaluated blood parameters in hyperinsulinemic horses treated with either ertugliflozin (0.05 mg/kg) or dapagliflozin (0.02 mg/kg) orally once daily. Blood samples were collected at baseline (day 0) and after 7 and/or 30 days of treatment. Statistical analyses were conducted using Wilcoxon signed-rank, Mann-Whitney and Spearman's rank correlation tests. Thirty-four horses received dapagliflozin and 24 received ertugliflozin. Significant (p<0.05) within-horse changes between day 0 and day 30 included [median, inter-quartile range (IQR)]: basal serum [Insulin] (uU/ml) reduced 170 (92-280) to 28.7 (14.5-90); [triglycerides] (mmol/l) increased 0.5 (0.3-0.6) to 1.0 (0.6-1.56), [β-hydroxybutyrate] (umol/l) increased 0.22 (0.17-2.7) to 0.30 (0.24-0.35); [total cholesterol] (mmol/l) increased 2.36 (2-2.6) to 2.84 (2.4-3.7); and GGT (IU/ml) increased 21 (16-32) to 25 (18-38). As a percentage of total serum lipids, high-density lipoprotein (HDL) reduced 52.4 % (47.9 %-61.0 %) to 50 % (41 %-54.8 %) and very-low density lipoprotein (VLDL) increased 10.4 % (6.4 %-14.4 %) to 12.3 % (9.9 %-16.8 %) (all p<0.05). Differences between ertugliflozin and dapagliflozin groups were not significant in any of these parameters at days 0, 7 or 30. At day 30, 10/48 (21 %) cases had [triglycerides] > 2.0 mmol/l (maximum = 10.8mmol/l). Day 30 [triglyceride] correlated with day 0: basal insulin (rho=0.47); [triglyceride] (rho=0.42); %VLDL (rho=0.34) day 30: [total cholesterol] (rho=0.67), %HDL (rho=-0.432) and %VLDL (rho=0.708). Our findings suggest that SGLT2 inhibitors induce minor changes in lipid profiles, with occasional cases of marked hypertriglyceridemia, and that dapagliflozin and ertugliflozin exhibit similar biochemical effects.

We aim to investigate the causal effect of blood lipids mediating sodium-glucose cotransporter 2 (SGLT2) inhibition in cardiovascular disease (CVD) using Mendelian randomization (MR).

A two-sample two-step MR study was conducted to evaluate the association of SGLT2 inhibition with CVDs and the mediation effects of blood lipids linking SGLT2 inhibition with CVDs. Genetic instruments for SGLT2 inhibition were identified as genetic variants, which were associated with the expression of the SLC5A2 gene and glycated haemoglobin level (HbA1c). SGLT2 inhibition was associated with reduced risk of heart failure (HF) (OR 0.44 [95% CI 0.32-0.61]; P = 6.0 × 10-7), atrial fibrillation (AF) (0.47 [0.37-0.61]; P = 1.81 × 10-8), coronary artery disease (CAD) (0.47 [0.30-0.73]; P = 7.46 × 10-4), myocardial infarction (MI) (0.30 [0.15-0.61]; P = 7.44 × 10-4), any stroke (AS) (0.28 [0.18-0.42]; P = 1.14 × 10-9), and ischaemic stroke (IS) (0.27 [0.17-0.44]; P = 1.97 × 10-7). Our results indicated that the proportion mediated of the mediating effect of total cholesterol was 1.7% (OR 0.99 [95% CI 0.98, 0.99], P = 0.004), 4.7% (0.96 [0.95, 0.98], P = 0.002), and 2.7% (0.97 [0.95, 0.98], P = 0.002) in the association between SGLT2 inhibition and the risk of HF, CAD, and MI, respectively. For low-density lipoprotein cholesterol, the proportion mediated of the mediating effect was 2.2% for HF (OR 0.98 [95% CI 0.98, 0.99], P = 0.003), 8.6% for CAD (0.93 [0.91, 0.95], P = 5.74 × 10-4), and 5.0% for MI (0.95 [0.94, 0.96], P = 6.97 × 10-4). For non-high-density lipoprotein cholesterol, the proportion mediated of the mediating effect was 3.4% for HF (OR 0.98 [95% CI 0.97, 0.98], P = 4.42 × 10-6), 11.8% for CAD (0.92 [0.90, 0.93], P = 7.23 × 10-8), 5.7% for MI (0.94 [0.92, 0.95], P = 8.17 × 10-7), 1.5% for AS (0.98 [0.98, 0.99], P = 0.001), and 1.4% for IS (0.98 [0.98, 0.99], P = 0.004).

Our study showed the association of SGLT2 inhibition with the reduced risk of CVDs and blood lipids might mediate this association.

Beyond their established hypoglycemic, cardioprotective, and nephroprotective properties, sodium-glucose cotransporters 2 (SGLT2) inhibitors exert other pleiotropic actions on blood pressure levels, body weight, and lipid metabolism. Blood pressure (BP) reduction varies based on the background history, including an effect on systolic, diastolic BP, and 24 h BP measurements. The reduction in body weight between 1 and 2 kg for the first months is caused by a reduction in visceral and subcutaneous fat due to glycosuria and loss of calories. Regarding lipid metabolism, a reduction in triglycerides and an increase in total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) have been reported, although these alterations are small and could provide additional cardiovascular protection. Various pathophysiologic mechanisms have been proposed to explain the above-mentioned pleiotropic actions of SGLT2 inhibitors. Natriuresis, osmotic diuresis, body weight reduction, amelioration of endothelial dysfunction and arterial stiffness, sympathetic tone decrease, and uric acid reduction are among those that have been suggested for BP reduction. Apart from glycosuria and calorie loss, other mechanisms seem to contribute to body weight reduction, such as the beiging of white adipose tissue, while the mechanisms involved in lipid metabolism alterations have not been clearly determined.

Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S donor in two preclinical models of cardiometabolic HFpEF was investigated.

Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H2S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8 weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols.

SGLT2i treatment improved E/e' ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end-diastolic function (E/e' ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow-up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology.

SGLT2i monotherapy remediated pathological complications exhibited by two well-established HFpEF models. Adjunctive H2S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow-up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.

Lecithin-cholesterol acyltransferase (LCAT) serves as a pivotal enzyme in preserving cholesterol homeostasis via reverse cholesterol transport, a process closely associated with the onset of atherosclerosis. Impaired LCAT function can lead to severe LCAT deficiency disorders for which no pharmacological treatment exists. LCAT-based therapies, such as small molecule positive allosteric modulators (PAMs), against LCAT deficiencies and atherosclerosis hold promise, although their efficacy against atherosclerosis remains challenging. Herein we utilized a quantitative in silico metric to predict the activity of novel PAMs and tested their potencies with in vitro enzymatic assays. As predicted, sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), sucrose and flavonoids activate LCAT. This has intriguing implications for the mechanism of action of gliflozins, which are commonly used in the treatment of type 2 diabetes, and for the endogenous activation of LCAT. Our results underscore the potential of molecular dynamics simulations in rational drug design.

Inhibitors of sodium-glucose cotransporter-2 (SGLT2) lower renal glucose reabsorption and, thus, are used to treat patients with type 2 diabetes mellitus. Clinical trials coincidentally showed that SGLT2 inhibitors also benefitted patients with heart failure. This review explores the impact of SGLT2 inhibitors on other aspects of cardiovascular disease and skeletal health.

In some, but not all, clinical and preclinical studies, SGLT2 inhibitors are found to reduce serum levels of free fatty acids and triglycerides. Their effects on total and low-density lipoprotein cholesterol and cardiac function also vary. However, SGLT2 inhibitors reduce lipid accumulation in the liver, kidney, and heart, and alter expression of lipid metabolism genes. Effects on free fatty acid uptake in abdominal fat depots depend on the location of adipose tissue. In male, but not female, mice, SGLT2 inhibitors reduce the atherosclerotic lesions and aortic calcium deposition. With respect to skeletal health, recent literature has reported conflicting associations with the risks of fracture and amputation.

Studies suggest that SGLT2 inhibitors reduce tissue lipid accumulation, and in a sex-dependent manner, atherosclerosis and vascular calcification. However, their effects on lipid levels and bone health are complex and remain to be established.

Obesity and type 2 diabetes mellitus are closely associated with each other and require careful management. This study aimed to assess the impact of sodium-glucose co-transporter 2 (SGLT2) inhibitors on glycemic control and body composition in diabetic patients, stratified by obesity status.

We enrolled patients diagnosed with type 2 diabetes mellitus, categorized as obese (BMI≥30) or non-obese (BMI<30), from our outpatient clinic. SGLT2 inhibitor therapy was added to their existing treatment regimen without altering dietary habits or exercise routines. Anthropometric measurements and laboratory parameters were compared between baseline and the third month of treatment.

The study included 40 participants, evenly split between obese and non-obese groups. At the third-month follow-up, significant reductions were observed in BMI, weight, waist and hip circumference, and body fat percentage across both groups (p < 0.001). Conversely, muscle mass percentage significantly increased (p < 0.001). Additionally, there were statistically significant decreases in HbA1c, glucose, CRP, ALT, LDL, and total cholesterol levels from baseline to the third month of treatment (p < 0.001 for HbA1c and glucose; p = 0.009, p = 0.022, p = 0.003, and p = 0.021, respectively, for CRP, ALT, LDL, and total cholesterol).

The findings of the present study suggest that SGLT2 inhibitors may offer substantial benefits, particularly in the management of obesity-related type 2 diabetes.

Background: No comprehensive meta-analysis has evaluated the efficacy and safety of ertugliflozin compared to a placebo in patients with Type 2 diabetes (T2D) until now. This meta-analysis fills this gap in knowledge. Methods: A systematic search was carried out in electronic databases to identify randomized controlled trials (RCTs) that included patients with T2D receiving ertugliflozin in the treatment group and placebo in the control group. The change in HbA1c from the baseline values was the primary outcome, whereas changes in plasma glucose and other metabolic parameters and adverse events (AEs), including hypoglycemia, were the secondary outcomes. Results: Seven RCTs involving 7283 subjects met the inclusion criteria. Ertugliflozin outperformed placebo in reducing HbA1c in both 5 mg (MD -0.62%, 95% CI [-0.80, -0.44], p < 0.00001, I 2 = 91%) and 15 mg (MD -0.69%, 95% CI [-0.91, -0.47], p < 0.00001, I 2 = 93%) doses. A higher proportion of patients achieved HbA1c < 7.0% with ertugliflozin than with placebo. Ertugliflozin was also superior to placebo in lowering fasting plasma glucose (FPG), body weight, and systolic and diastolic blood pressure (BP). Ertugliflozin and placebo had comparable AE profiles, including urinary tract infection (UTI) and hypoglycemia, except for the greater risk of genital mycotic infections (GMIs) with ertugliflozin. Ertugliflozin 5 and 15 mg have equivalent efficacy and safety profiles except for greater weight reduction with ertugliflozin 15 mg. Conclusion: Ertugliflozin has a good glycemic efficacy and a reassuring safety profile in managing T2D. Trial Registration: Registration number: CRD42023456450.

Currently, Sodium-glucose cotransporter 2 (SGLT2) inhibitors demonstrate additional effects beyond glucose control on the gut microbiota and circulating metabolites. The gut microbiota and metabolites have been found to be useful in elucidating potential biological mechanisms of pulmonary diseases. Therefore, our study aims to investigate the effects of gut microbiota and metabolites mediating SGLT2 inhibition in 10 pulmonary diseases through Mendelian randomization (MR) research.

We conducted a two-sample, two-step MR study to assess the association between SGLT2 inhibition and 10 pulmonary diseases and to investigate the mediating effects of gut microbiota and metabolite. Gene-fine mapping and annotation of mediators by FUMA and Magma analyses were performed, and causal associations of mapped genes with diseases were assessed by muti-omics MR analyses. Possible side effects of SGLT2 inhibition were assessed by PheWAS analysis.

SGLT2 inhibition was linked to a reduced risk of T2DM, Interstitial lung disease (ILD), Pneumoconiosis, Pulmonary tuberculosis, and Asthma(OR=0.457, 0.054, 0.002, 0.280, 0.706). The family Enterobacteriaceae and order Enterobacteriales were associated with SGLT2 inhibition and ILD(95% CI:0.079-0.138). The family Alcaligenaceae and X-12719 were linked to pneumoconiosis (95% CI: 0.042-0.120, 0.050-0.099). The genus Phascolarctobacterium was connected to pulmonary tuberculosis (95% CI: 0.236-0.703).The degree of unsaturation (Fatty Acids), ratio of docosahexaenoic acid to total fatty acids, and 4-androsten-3beta,17beta-diol disulfate 2, were associated with asthma(95% CI: 0.042-0.119, 0.039-0.101, 0.181-0.473). Furthermore, Fuma and Magma analyses identified target genes for the four diseases, and proteomic MR analysis revealed six overlapping target genes in asthma. PheWAS analysis also highlighted potential side effects of SGLT2 inhibition.

This comprehensive study strongly supports a multi-omics association between SGLT2 inhibition and reduced risk of interstitial lung disease, tuberculosis, pneumoconiosis, and asthma. Four identified gut microbiota, four metabolites, sixteen metabolic pathways, and six target genes appear to play a potential role in this association. The results of the comprehensive phenome-wide association analysis also identified the full effect of SGLT2 inhibitors.

Background/Objectives: The health burden of metabolic dysfunction-associated fatty liver disease (MASLD) has been increasing lately. Cardiovascular disease (CVD) is the main cause of death in MASLD patients; therefore, the treatments for MASLD should improve both CV risk factors such as obesity, diabetes, and dyslipidemia, in addition to an improvement in liver function. The evidence on the long-term effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on the progression of MASLD in Asian populations is very limited. Methods: The retrospective longitudinal study was performed by using the medical records at our institute. We picked up patients with type 2 diabetes who had taken SGLT2is for at least 3 years or longer between 1 April 2014 and 31 March 2018. We collected the data on metabolic parameters, including laboratory data and anthropometric parameters, and compared the data before and after the initiation of SGLT2is treatment. Results: During the observation period, 324 patients had taken SGLT2is for 3 years. Three-year SGLT2is treatment significantly reduced body weight, hemoglobin A1c, low-density lipoprotein cholesterol, triglyceride, and non-high-density lipoprotein cholesterol (non-HDL-C). Such favorable changes in serum lipids were remarkable in patients with statins. Furthermore, this treatment significantly improved liver function and the markers for hepatic steatosis and hepatic fibrosis. Conclusions: Considering that the development of CVD determines the prognosis of MASLD patients, long-term SGLT2is treatment may be an ideal therapy for MASLD patients.

Remogliflozin is a novel SGLT-2 inhibitor used for the management of Type 2 Diabetes Mellitus (T2DM). Since its introduction medical literature is scarce on its quantitative effects. We performed this meta-analysis to ascertain its safety and efficacy in the treatment of T2DM. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Handbook, six studies involving 1,605 participants were analyzed. Our analysis found comparable reductions in glycated hemoglobin (HbA1c) by remogliflozin in comparison to the comparators. It was found to be inferior to other anti-diabetic drugs in decreasing fasting plasma glucose and post-prandial glucose. A significant reduction was obtained in body weight and a significant increase was also found in high-density lipoprotein cholesterol (HDL-C) levels. Remogliflozin did not significantly increase the risk for total adverse events, severe adverse events, or hypoglycemic episodes. The results were accompanied by high heterogeneity, which necessitates conducting high-quality randomized control trials for more robust evidence synthesis. Overall Remogliflozin can be considered a safe drug with beneficial effects on body weight and HDL-C levels for the treatment of people with T2DM.

Diabetes is considered a significant risk factor for the development of atrial fibrillation/flutter (AF/AFL). However, there is still insufficient evidence to determine the varying effects of different hypoglycemic drugs (HDs) on the incidence of new-onset AF/AFL in diabetic patients. To address this gap, we conducted a network meta-analysis to investigate whether various HDs have different effects on the risk of new-onset AF/AFL compared with insulin.

We conducted a comprehensive search in PubMed, EMBASE, Cochrane Library, and Web of Science to identify all clinical trials investigating the association between various HDs or insulin and incident AF/AFL up until April 1, 2024. Bayesian random-effects model was used for network meta-analysis, and the results were expressed as relative risk (RR) and 95% confidence interval (CI).

After searching 2070 articles, a total of 12 studies (2,349,683 patients) were included in the network meta-analysis. The treatment regimen comprised insulin and 8 HDs hypoglycemic drugs, which are sodium-dependent glucose transporters 2 inhibitor (SGLT2i), glucagon-like peptide 1 receptor agonist (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), metformin (Met), sulfonylureas (SU), non-sulfonylureas (nSU), thiazolidinedione (TZD) and α-glycosidase inhibitors (AGI). The use of SGLT2i [RR 0.23, 95%CI (0.11, 0.49)], GLP-1RA [RR 0.28, 95%CI (0.13, 0.57)], and DPP4i [RR 0.34, 95%CI (0.17, 0.67)] demonstrated significant efficacy in reducing the incidence of new-onset AF/AFL when compared to insulin. When HDs were compared in pairs, SGLT2i is more effective than Met [RR 0.35, 95% CI (0.19, 0.62)], SU (RR 0.27, 95% CI (0.14, 0.51)], nSU [RR 0.28, 95% CI (0.08, 0.95)], TZD [RR 0.34, 95% CI (0.17, 0.7)], GLP-1RA is more effective Met [RR 0.42, 95% CI (0.25, 0.71)], SU (RR 0.33, 95% CI (0.18, 0.6)], TZD [RR 0.41, 95% CI (0.21, 0.82)], while Met[RR 1.98, 95% CI (1.23, 3.23)], SU [RR 2.54, 95% CI (1.46, 4.43)], TZD [RR 2.01, 95% CI (1.05, 3.79)] was not as effective as DPP4i.

SGLT-2i, GLP-1RA, and DPP4i showed a superior efficacy in reducing the risk of new-onset AF/AFL compared to insulin therapy.

Renal outcomes in patients with type 2 diabetes following treatment with sodium-glucose co-transporter-2 inhibitors (SGLT2is) or glucagon-like peptide-1 receptor agonists (GLP1RAs) have not been directly compared. This study compared the impact of SGLT2i and GLP1RA therapy on renal function and metabolic parameters.

Patients with type 2 diabetes who initiated SGLT2i or GLP1RA therapy in a tertiary hospital between January 2009 and August 2023 were included to assess composite renal outcomes, such as a 40% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease, renal death, or new-onset macroalbuminuria. Alterations in blood pressure, glucose regulation parameters, lipid profile, and anthropometric parameters, including body fat and muscle masses, were examined over 4-years.

A total of 2,112 patients were enrolled using a one-to-three propensity-score matching approach (528 patients for GLP1RAs, 1,584 patients for SGLT2i). SGLT2i treatment was favoured over GLP1RA treatment, though not significantly, for composite renal outcomes (hazard ratio [HR], 0.63; p = 0.097). SGLT2i therapy preserved renal function effectively than GLP1RAs (decrease in eGFR, ≥ 40%; HR, 0.46; p = 0.023), with improving albuminuria regression (HR, 1.72; p = 0.036). SGLT2i therapy decreased blood pressure and body weight to a greater extent. However, more patients attained HbA1c levels < 7.0% with GLP1RAs than with SGLT2is (40.6% vs 31.4%; p < 0.001). GLP1RA therapy enhanced β-cell function and decreased LDL-cholesterol levels below baseline values.

SGLT2is were superior for preserving renal function and reducing body weight, whereas GLP1RAs were better for managing glucose dysregulation and dyslipidaemia.

Sodium glucose co-transporter 2 (SGLT2)-inhibitors were developed as glucose-lowering drugs. Surprisingly, SGLT2-inhibitors also reduced risk of cardiovascular disease. The impact of SGLT2-inhibitors on lipids and lipoproteins is unclear, but an effect might contribute to the observed lower cardiovascular risk. We conducted a meta-analysis to examine this, overall and by dose, ethnicity, and drug type.

PubMed, EMBASE and Web of Science were searched for randomized controlled trials examining all available SGLT2-inhibitors. Studies with available lipid measurements were included. Quantitative data synthesis was performed using random and fixed effects models.

We identified 60 randomized trials, including 147,130 individuals. Overall, using random effects models, SGLT2-inhibitor treatment increased total cholesterol by 0.09 mmol/L (95% CI: 0.06, 0.13), low-density lipoprotein (LDL) cholesterol by 0.08 mmol/L (0.05, 0.10), and high-density lipoprotein (HDL) cholesterol by 0.06 mmol/L (0.05, 0.07), while it reduced triglycerides by 0.10 mmol/L (0.06, 0.14). Fixed effects estimates were similar but with smaller effect sizes for HDL cholesterol and triglycerides. For higher SGLT2-inhibitor doses, there was a nominally higher non-significant effect on lipids and lipoproteins. In Asian compared to non-Asian populations, a slightly larger increase in HDL cholesterol and a decrease in triglycerides were observed, but with similar results for total and LDL cholesterol. Treatment effects on lipids and lipoproteins were generally robust across different SGLT2-inhibitor drugs.

In meta-analyses, SGLT2-inhibition increased total, LDL, and HDL cholesterol and decreased triglycerides. Effect sizes varied slightly by drug dose and ethnicity but were generally robust by drug type.

Despite the risk of atherosclerosis has progressively declined over the past few decades, subjects with type 2 diabetes mellitus (T2DM) continue to experience substantial excess of atherosclerotic cardiovascular disease (ASCVD)-related events. Therefore, there is urgent need to treat ASCVD disease in T2DM earlier, more intensively, and with greater precision. Many factors concur to increase the risk of atherosclerosis, and multifactorial intervention remains the basis for effective prevention or reduction of atherosclerotic events. The role of anti-hyperglycemic medications in reducing the risk of ASCVD in subjects with T2DM has evolved over the past few years. Multiple cardiovascular outcome trials (CVOTs) with new and emerging glucose-lowering agents, namely SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RA), have demonstrated significant reductions of major cardiovascular events and additional benefits. This robust evidence has changed the landscape for managing people with T2DM. In addition to glycemic and ancillary extra-glycemic properties, SGLT2i and GLP1-RA might exert favorable effects on subclinical and clinical atherosclerosis. Therefore, the objective of this review is to discuss the available evidence supporting anti-atherosclerotic properties of SGLT2i and GLP1-RA, with a quick nod to sotagliflozin and tirzepatide.

This study aimed to investigate the association between clinical and laboratory parameters and response to therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2D).

We retrospectively analyzed the medical records of people with T2D in whom SGLT2i was started. Clinical and laboratory parameters were recorded before, 3 and 6 months after starting treatment. Specific criteria were applied to classify participants into good and poor responders in terms of weight loss (primary outcome) and glycemic control (secondary outcome), separately.

Fifty individuals (64% men) with a mean age of 65.8 ± 8.5 years were included in the analysis. 86% and 64% of the participants were classified into good response categories for glycemic control and weight loss, respectively. Good responders in terms of glycemic control had lower high-density lipoprotein cholesterol levels at baseline compared to poor responders (43.3 vs 57.4 mg/dl, p = 0.044). In the logistic regression analysis, a higher baseline weight was associated with a better response to therapy in terms of weight loss (p = 0.04).

Our findings suggest that specific clinical and laboratory parameters are associated with response to SGLT2i treatment and can contribute to a more personalized approach to T2D care.

Diabetic atherosclerosis is a complex process that is characterized by diffuse and unstable lesions increasing 2-4-fold the risk of adverse cardiovascular (CV) events. Diabetic dyslipidemia has a predominant role in coronary artery disease (CAD) and has been the target of classical and emerging pharmaceutical agents with established or promising CV benefits. The aim of the present narrative review was to summarize the effects of classical and novel lipid-lowering pharmaceutical agents on lipid profile and CV outcomes in diabetic patients with established CAD or high risk of CAD. Statins remain the first-line treatment for all diabetic patients since they considerably ameliorate lipid parameters and non-lipid CV risk factors, leading to reduced CV morbidity and mortality. Complementary to statins, ezetimibe exerts lipid-lowering properties with modest but significant reductions in major adverse cardiovascular events (MACEs) and CV mortality. PCSK9 inhibitors considerably reduce LDL-C levels and lower MACEs in diabetic patients. On the other hand, fibrates may confer a very modest decline in MACE incidence, while the CV impact of omega-3 fatty acids is promising but remains questionable. Bempedoic acid and inclisiran have a potential therapeutic role in the management of diabetic dyslipidemia, but this is still not adequately documented. Given the heightened CV risk among individuals with diabetes, more decisive results would be of great importance in the utility of all these drugs.

Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This post hoc prespecified analysis of the EXCEED-BHS3 trial compared the effects of a 16-week therapy with empagliflozin (E) alone or in combination with evolocumab (EE) on the lipid profile and cholesterol content in HDL subspecies in individuals with T2D divided equally into two groups of 55 patients. Both treatments modestly increased HDL-C. The cholesterol content in HDL subspecies 2a (7.3%), 3a (7.2%) and 3c (15%) increased from baseline in the E group, while the EE group presented an increase from baseline in 3a (9.3%), 3b (16%) and 3c (25%). The increase in HDL 3b and 3c was higher in the EE group when compared to the E group (p < 0.05). No significant interactive association was observed between changes in hematocrit and HDL-C levels after treatment. Over a 16-week period, empagliflozin with or without the addition of evolocumab led to a modest but significant increase in HDL-C. The rise in smaller-sized HDL particles was heterogeneous amongst the treatment combinations.

Bexagliflozin and dapagliflozin are sodium-glucose cotransporter-2 (SGLT2) inhibitors. No direct comparison of SGLT2 inhibitors in a randomized controlled trial has been reported to date.

This was a multicenter, randomized, double-blind, active-controlled trial comparing bexagliflozin to dapagliflozin for the treatment of type 2 diabetes mellitus in adults with disease inadequately controlled by metformin. Subjects (n = 406) were randomized to receive bexagliflozin (20 mg) or dapagliflozin (10 mg) plus metformin. The primary endpoint was noninferiority of bexagliflozin to dapagliflozin for the change in glycated hemoglobin (HbA1c) from baseline to week 24. Secondary endpoints included intergroup differences in fasting plasma glucose (FPG), 2-h-postprandial glucose (PPG), body weight, and systolic blood pressure (SBP) from baseline to week 24. The trial also evaluated the safety profiles.

The model-adjusted mean change from baseline to week 24 HbA1c was -1.08% for bexagliflozin and -1.10% for dapagliflozin. The intergroup difference of 0.03% (95% confidence interval [CI] -0.14% to 0.19%) was below the prespecified margin of 0.4%, confirming the noninferiority of bexagliflozin. The changes from baseline in FPG, PPG, body weight, and SBP were -1.95 mmol/L, -3.24 mmol/L, -2.52 kg, and -6.4 mm Hg in the bexagliflozin arm and -1.87 mmol/L, -3.07 mmol/L, -2.22 kg, and -6.3 mm Hg in the dapagliflozin arm. Adverse events were experienced in 62.6% and 65.0% and serious adverse events affected 4.4% and 3.5% of subjects in the bexagliflozin and dapagliflozin arm, respectively.

Bexagliflozin showed nearly identical effects and a similar safety profile to dapagliflozin when used in Chinese patients on metformin.

Beyond glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been proposed to reduce the risk of cardiovascular events. The aim of the present systematic review and meta-analysis is to demonstrate the effects of GLP-1 RA and SGLT2is on intima-media thickness (IMT).

PubMed, EMBASE, Web of Science, SCOPUS, and Google Scholar databases were searched from inception to September 9, 2023. All interventional and observational studies that provided data on the effects of GLP-1 RAs or SGLT2is on IMT were included. Critical appraisal was performed using the Joanna Briggs Institute checklists. IMT changes (preintervention and postintervention) were pooled and meta-analyzed using a random-effects model. Subgroup analyses were based on type of medication (GLP-1 RA: liraglutide and exenatide; SGLT2i: empagliflozin, ipragliflozin, tofogliflozin, and dapagliflozin), randomized clinical trials (RCTs), and diabetic patients.

The literature search yielded 708 related articles after duplicates were removed. Eighteen studies examined the effects of GLP-1 RA, and eleven examined the effects of SGLT2i. GLP-1 RA and SGLT2i significantly decreased IMT (MD = -0.123, 95% CI (-0.170, -0.076), P < 0.0001, I2 = 98% and MD = -0.048, 95% CI (-0.092, -0.004), P = 0.031, I2 = 95%, respectively). Metaregression showed that IMT change correlated with baseline IMT, whereas it did not correlate with gender, duration of diabetes, and duration of treatment.

Treatment with GLP-1 RA and SGLT2i can lower IMT in diabetic patients, and GLP-1 RA may be more effective than SGLT2i.

Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are a class of drugs with modest antidiabetic efficacy, weight loss effect, and cardiovascular benefits as proven by multiple randomised controlled trials (RCTs). However, real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse.

To study the comparative efficacy and safety of SGLT-2i using real-world clinical data.

We evaluated the comparative efficacy data of 3 SGLT-2i drugs (dapagliflozin, canagliflozin, and empagliflozin) used for treating patients with type 2 diabetes mellitus. Data on the reduction of glycated hemoglobin (HbA1c), body weight, blood pressure (BP), urine albumin creatinine ratio (ACR), and adverse effects were recorded retrospectively.

Data from 467 patients with a median age of 64 (14.8) years, 294 (62.96%) males and 375 (80.5%) Caucasians were analysed. Median diabetes duration was 16.0 (9.0) years, and the duration of SGLT-2i use was 3.6 (2.1) years. SGLT-2i molecules used were dapagliflozin 10 mg (n = 227; 48.6%), canagliflozin 300 mg (n = 160; 34.3%), and empagliflozin 25 mg (n = 80; 17.1). Baseline median (interquartile range) HbA1c in mmol/mol were: dapagliflozin - 78.0 (25.3), canagliflozin - 80.0 (25.5), and empagliflozin - 75.0 (23.5) respectively. The respective median HbA1c reduction at 12 months and the latest review (just prior to the study) were: 66.5 (22.8) & 69.0 (24.0), 67.0 (16.3) & 66.0 (28.0), and 67.0 (22.5) & 66.5 (25.8) respectively (P < 0.001 for all comparisons from baseline). Significant improvements in body weight (in kilograms) from baseline to study end were noticed with dapagliflozin - 101 (29.5) to 92.2 (25.6), and canagliflozin 100 (28.3) to 95.3 (27.5) only. Significant reductions in median systolic and diastolic BP, from 144 (21) mmHg to 139 (23) mmHg; (P = 0.015), and from 82 (16) mmHg to 78 (19) mmHg; (P < 0.001) respectively were also observed. A significant reduction of microalbuminuria was observed with canagliflozin only [ACR 14.6 (42.6) at baseline to 8.9 (23.7) at the study end; P = 0.043]. Adverse effects of SGLT-2i were as follows: genital thrush and urinary infection - 20 (8.8%) & 17 (7.5%) with dapagliflozin; 9 (5.6%) & 5 (3.13%) with canagliflozin; and 4 (5%) & 4 (5%) with empagliflozin. Diabetic ketoacidosis was observed in 4 (1.8%) with dapagliflozin and 1 (0.63%) with canagliflozin.

Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c, body weight, and better than those reported in RCTs, with low side effect profiles. A review of large-scale real-world data is needed to inform better clinical practice decision making.

Recent studies have shown that the imbalance of intestinal flora is related to the occurrence and progression of diabetic nephropathy (DN) and can affect lipid metabolism. Sodium-dependent glucose transporters 2 (SGLT2) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist are commonly used hypoglycemic drugs and have excellent renal safety. The purpose of this study was to compare the protective effects of empagliflozin and liraglutide on kidneys, lipid metabolism, and intestinal microbiota in diabetic mice.

We established a mouse model of type two diabetes by feeding rats a high-fat diet (HFD) followed by an intraperitoneal injection of STZ. The mice were randomly divided into groups: normal control (NC), diabetic model (DM), liraglutide treatment (LirT), empagliflozin treatment (EmpT), and liraglutide combined with empagliflozin treatment (Emp&LirT) groups. Blood glucose, lipids, creatinine, and uric acid, as well as urinary nitrogen and albumin levels were measured. The renal tissues were subjected to HE, PAS and Masson's staining. These parameters were used to evaluate renal function and histopathological changes in mice. Mice feces were also collected for 16sRNA sequencing to analyze the composition of the intestinal flora.

All the indexes related to renal function were significantly improved after treatment with drugs. With respect to lipid metabolism, both drugs significantly decreased the serum triglyceride levels in diabetic mice, but the effect of liraglutide on reducing serum cholesterol was better than that of empagliflozin. However, empagliflozin had a better effect on the reduction of low-density lipoproteins (LDL). The two drugs had different effects on intestinal flora. At the phylum level, empagliflozin significantly reduced the ratio of Firmicutes to Bacteroidota, but no effect was seen with liraglutide. At the genus level, both of them decreased the number of Helicobacter and increased the number of Lactobacillus. Empagliflozin also significantly increased the abundance of Muribaculaceae, Muribaculum, Olsenella, and Odoribacter, while liraglutide significantly increased that of Ruminococcus.

Liraglutide and empagliflozin were both able to improve diabetes-related renal injury. However, the ability of empagliflozin to reduce LDL was better compared to liraglutide. In addition, their effects on the intestine bacterial flora were significantly different.

The aim of this study is to evaluate the safety of this drug in diabetic patients with comorbidities of all systems.

In this review, the beneficial effects of this drug and its mechanism on the disorders of every system of humans in relation to diabetes have been studied, and finally, its adverse effects have also been discussed. The search for relevant information is carried out in the PubMed and Google Scholar databases by using the following terms: diabetes mellitus type 2, SGLT, SGLT2 inhibitors, (SGLT2 inhibitors) AND (Pleiotropic effects). All English-published articles from 2016 to 2023 have been used in this study. It should be noted that a small number of articles published before 2016 have been used in the introduction and general informations.

Its beneficial effects on improving cardiovascular disease risk factors and reducing adverse events caused by cardiovascular and renal diseases have proven in most large clinical studies that these effects are almost certain. It also has beneficial effects on other human systems such as the respiratory system, the gastrointestinal system, the circulatory system, and the nervous system; more of them are at the level of clinical and pre-clinical trials but have not been proven in large clinical trials or meta-analyses.

With the exception of a few adverse effects, this drug is considered a good choice and safe for all diabetic patients with comorbidities of all systems.