GLP-1 receptor agonists have emerged as important therapeutic agents for type 2 diabetes mellitus (T2DM), but their comparative efficacy and broader applications remain subjects of ongoing research. The aim of the study was to evaluate and compare the efficacy, safety, and clinical applications of three GLP-1 receptor agonists - Semaglutide, Dulaglutide, and Exenatide - through systematic review and meta-analysis. A comprehensive search of PubMed/MEDLINE, Embase, Cochrane Library, Scopus, and Web of Science (2015-2023) identified 20 randomized controlled trials and observational studies. Primary outcomes included changes in HbA1c and body weight. Risk of bias was assessed using the Cochrane Collaboration's Risk of Bias tool. Semaglutide demonstrated superior efficacy with mean HbA1c reduction of 1.45% and weight loss of 1.44 kg. Dulaglutide showed consistent reductions in HbA1c (1.1%) and weight (1.2 kg). while Exenatide exhibited moderate effects. Meta-analysis revealed a significant pooled effect estimate favoring GLP-1 receptor agonists. with a mean HbA1c difference of -0.81 (95% CI: -0.92 to -0.70). Gastrointestinal side effects were most common, with Semaglutide showing the highest incidence. This meta-analysis establishes Semaglutide as the most effective GLP-1 receptor agonist for glycemic control and weight reduction, while Dulaglutide and Exenatide offer viable alternatives with fewer side effects. These findings support evidence-based decision-making in T2DM management and highlight the potential broader therapeutic applications of GLP-1 receptor agonists beyond diabetes care.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as groundbreaking therapeutic agents in managing a spectrum of metabolic disorders, demonstrating remarkable efficacy across multiple organ systems and disease states. These compounds are not only well-established in the treatment of type 2 diabetes (T2D) and obesity-conditions for which they have received widespread approval-but also exhibit promising potential in addressing cardiovascular disease (CVD) and Metabolic dysfunction-associated steatotic liver disease (MASLD). Recent investigations have begun to illuminate the utility of GLP-1RAs in the management of type 1 diabetes (T1D), as well as neurodegenerative disorders such as Alzheimer's and Parkinson's disease and various behavioral disorders. A plethora of clinical trials have consistently validated the capacity of GLP-1RAs to improve glycemic control, promote weight loss, and mitigate cardiovascular risk factors in individuals with T2D and obesity. While their application in T1D remains limited due to safety concerns-particularly regarding the risks of hypoglycemia and hyperglycemic ketoacidosis-emerging data suggest that GLP-1RAs may offer hepatoprotective benefits, potentially reducing liver fat content and decelerating the progression of MASLD. The neuroprotective attributes of GLP-1 RAs have garnered significant interest, with research indicating their potential to alleviate cognitive decline associated with neurodegenerative diseases. Furthermore, preliminary findings highlight the role of GLP-1 RAs in addressing behavioral disorders, emphasizing their extensive therapeutic promise. This comprehensive review synthesizes the current evidence supporting the diverse therapeutic applications of GLP-1RAs, positioning them as "magic drug" therapies for metabolic and neurological disorders. As ongoing research continues to explore innovative applications and combinations of GLP-1RAs, the landscape of disease management in metabolic and neurological contexts is poised for transformative advancements. This review will also critically assess safety considerations and underscore the need for personalized treatment strategies to optimize patient outcomes in these complex and often comorbid conditions.

Treating type 2 diabetes has shifted from a gluco-centric approach to broader cardio-renal-metabolic strategy, driven by the use of disease-modifying medications. Traditionally, diabetes management has relied on stepwise medication addition based on failures in glucose control. However, the benefits and risks of combining glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) remain inadequately understood.

This study conducted a scoping review to examine the available clinical research on the benefits and risks of combining GLP1-RAs and SGLT2is. Additionally, the nominal group technique was used to gather insights from medical experts from different areas regarding the combined therapy's daily clinical use, concerns, and limitations. The review followed the guidelines outlined in the Joanna Briggs Institute Reviewer's Manual and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews).

The final report includes 50 studies. The most common designs are observational studies. The median (IQR) number of patients across studies was 355 (1295). Studies reporting metabolic outcomes were the most common. The follow-up time ranges from 1.5 to 60 months. Although limited, the available evidence seems to support the combined use of GLP1-RAs and SGLT2is. The experts agreed that the underlying mechanisms appear synergistic rather than antagonistic for most outcomes.

Combining medical therapy is common in diabetes treatment and may occur naturally in everyday practice. Limited evidence suggests that combined SGLT2is/GLP1-RAs therapy can potentially improve most but not all outcomes. Quality evidence and better-defined outcomes are paramount to guide the selection of patients for combined therapy.

Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease and significantly increases cardiovascular risk and mortality. Despite conventional therapies, including renin-angiotensin-aldosterone system inhibitors, substantial residual risk remains. The emergence of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists has reshaped DKD management. Beyond glycemic control, these agents provide distinct and complementary cardiorenal benefits through mechanisms such as hemodynamic modulation, anti-inflammatory effects, and metabolic adaptations. Landmark trials, including CREDENCE, DAPA-CKD, EMPA-KIDNEY, and FLOW, have demonstrated their efficacy in preserving kidney function and reducing adverse outcomes. SGLT2 inhibitors appear more effective in mitigating glomerular hyperfiltration and lowering heart failure risk, whereas GLP-1 receptor agonists are particularly beneficial in reducing albuminuria and atherosclerotic cardiovascular events. Although indirect comparisons suggest that SGLT2 inhibitors may offer greater protection against kidney function decline, direct head-to-head trials are lacking. Combination therapy holds promise, however further studies are needed to define optimal treatment strategies. This review synthesizes current evidence, evaluates comparative effectiveness, and outlines future directions in DKD management, emphasizing precision medicine approaches to enhance clinical outcomes. The integration of these therapies represents a paradigm shift in diabetes care, expanding treatment options for people with diabetes mellitus at risk of kidney failure.

Aims: The study is aimed at assessing gender bias in Phase III clinical trials (CTs) of sodium-glucose cotransporter type 2 (iSGLT2) inhibitors in adults with Type 2 diabetes mellitus (T2DM). Methods: We searched PubMed and EMBASE databases until June 2023. To estimate sex bias in recruitment, the difference between F-Particip (fraction of women recruited) and F-Prev (prevalence fraction of women with T2DM) was calculated. A significant sex bias in recruitment was considered to exist when the difference between F-Particip and F-Prev was greater than 0.05, 0.1, and 0.2. The analysis was considered to have a sex bias when the efficacy variables were not analyzed by sex. Gender of the first, last, and corresponding author was also assessed. Results: In total, 70 articles met all inclusion criteria. Sex bias in recruitment showed variable results depending on the reference value. No significant sex bias in recruitment was found in the total number of included patients. Examining each CT individually, using values of significant sex bias in recruitment of ±0.05, ±0.1, or ±0.2, we found that 41.4%, 20%, and 5.7% of the trials, respectively, showed this bias. In 34.3% of the articles, women were the first, last, or corresponding authors. Sex-based analysis of the results was performed in five studies. Conclusions: Although the proportion of women included in iSGLT2 CTs seems acceptable, gender bias persists in the analysis of variables and in the study authors. However, the lack of gender focus may be explained by the characteristics of the patients included in the CTs.

Atherosclerosis is a closely related complication of diabetes mellitus (DM), driven by endothelial dysfunction, inflammation, and oxidative stress. The progression of atherosclerosis is accelerated by hyperglycemia, insulin resistance, and hyperlipidemia. Novel antidiabetic agents, SGLT2 inhibitors, and GLP-1 agonists improve glycemic control and offer cardiovascular protection, reducing the risk of major adverse cardiovascular events (MACEs) and heart failure hospitalization. These agents, along with nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), promise to mitigate metabolic disorders and their impact on endothelial function, oxidative stress, and inflammation. This review explores the potential molecular mechanisms through which these drugs may prevent the development of atherosclerosis and cardiovascular disease (CVD), supported by a summary of preclinical and clinical evidence.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown promising results in reducing hospitalizations from heart failure (HF) and cardiovascular mortality. However, their effect on arrhythmia and sudden cardiac death (SCD) is not well established.

The authors sought to evaluate the association between SGLT2i and the risk of arrhythmias and SCD in patients with type 2 diabetes mellitus, HF, or chronic kidney disease.

We performed a systematic literature search on PubMed, EMBASE, and Scopus for relevant randomized controlled trials from inception until February 10, 2023. ORs and 95% CIs were pooled using a random effect model.

A total of 38 randomized controlled trials with 88,704 patients (48,435 in the SGLT2i group and 40,269 in the control group) were included in the study. The mean age of patients among SGLT2i and control groups was 56.8 and 56.7 years, respectively. The mean follow-up duration was 1.6 years. Pooled analysis of primary and secondary outcomes showed that SGLT2i significantly reduced the risk of incident atrial arrhythmia (OR: 0.85 [95% CI: 0.75-0.98], P = 0.02), SCD (OR: 0.72 [95% CI: 0.55-0.94], P = 0.02) compared with placebo. However, the risk of ventricular arrhythmia (OR: 1.03 [95% CI: 0.84-1.26], P = 0.77) and cardiac arrest (OR: 0.94 [95% CI: 0.72-1.23] P = 0.67) was comparable between both groups of patients.

SGLT2i therapy was associated with an overall lower risk of atrial arrythmia and SCD in patients with type 2 diabetes mellitus and/or HF or chronic kidney disease. However, SGLT2i therapy was not associated with a lower risk of ventricular arrhythmia.

The potential benefits and risks of combination therapy with sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus monotherapy remain a subject of debate to optimize metabolic and cardiovascular outcomes in patients with type 2 diabetes mellitus. This study aims to systematically review and meta-analyze the available evidence from randomized controlled trials.

A comprehensive search identified relevant randomized controlled trials comparing combination therapy with SGLT-2i and GLP-1RA to monotherapy or treatment as usual (TAU). The main outcome was the incidence of hospitalization for heart failure. Other outcomes included major adverse cardiovascular events (MACE) (cardiovascular mortality, all-cause mortality, stroke, and myocardial infarction), changes in metabolic parameters, and adverse events. Random-effects meta-analysis estimated risk ratios (RRs), mean difference (MD), and 95% confidence intervals (CIs). We assessed the risk of bias in included studies using the Cochrane ROB 2.0 tool.

The meta-analysis included 10 randomized controlled trials with 42,651 participants, of which 2,820 were on combination therapy and the rest on SGLT-2i (37.1%), GLP-1RA (20.1%) monotherapies or TAU (42.8%). Combination therapy had a lower risk of hospitalization for heart failure versus GLP-1RA monotherapy (RR = 0.37, 95% CI 0.22; 0.65), SGLT-2i monotherapy (RR = 0.37, 95% CI 0.19; 0.75), and TAU (RR = 0.43, 95% CI 0.24; 0.75), respectively. Combination therapy also had a significantly lower risk of MACE versus TAU (RR = 0.73, 95% CI 0.61; 0.88). Combination therapy showed greater weight loss and hemoglobin A1c reduction versus SGLT-2i monotherapy (MD = -2.20, 95% CI -3.09; -1.31 and MD = -0.74, 95% CI -1.21; -0.27), respectively, while no difference was noted versus GLP-1RA monotherapy. The incidence of nausea and diarrhea was higher with combination therapy versus SGLT-2i monotherapy (MD = 3.34, 95% CI 1.74; 6.43 and MD = 1.75, 95% CI 1.10; 2.77), respectively.

Combination therapy with SGLT-2i and GLP-1RA may provide superior cardiovascular, weight, and Hemoglobin A1c outcomes versus monotherapy despite higher gastrointestinal adverse events. These results may impact the management of patients with metabolic and cardiovascular diseases and highlight the need for further research on combination therapy to optimize outcomes.

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.

We evaluate whether the combination of sodium-glucose cotransporter-2 inhibitor(SGLT2i) and glucagon-like peptide-1 receptor agonist(GLP1RA) disproportionally increases the reporting of adverse events compared with SGLT2i or GLP1RA monotherapy in the FDA adverse event reporting system (FAERS).

Adverse events related to SGLT2i and GLP1RA were screened and selected, then data from the FAERS was underwent thorough disproportionality analysis. The proportional reporting ratio(PRR) of SGLT2i-related adverse events were compared between patients using SGLT2i alone and those using both SGLT2i and GLP1RA. Similarly, the PRR of GLP1RA-related adverse events were compared between patients using GLP1RA alone and those using both SGLT2i and GLP1RA. The results showed that the PRR of SGLT2i-related adverse events including diabetic ketoacidosis(DKA), ketosis, reproductive tract adverse events, urinary tract infection, and other adverse events, decreased in individuals using both SGLT2i and GLP1RA compared with those using SGLT2i alone, and the signal of fracture was not detected. Likewise, the PRR of GLP1RA-related adverse events including gastrointestinal adverse events, gallbladder and biliary tract disease, pancreatitis, and other adverse events, decreased in individuals using both SGLT2i and GLP1RA compared with those using GLP1RA alone, the PRR of hyperlipasaemia and hyperamylasaemia increased in the combination therapy and no signal of depression, suicidal and self-injurious behaviour was detected.

Adverse events reporting are not disproportionally higher among those using both SGLT-2i and GLP1RA compared with SGLT2i or GLP1RA monotherapy.

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

To evaluate the efficacy and safety of combination therapy with sodium-glucose cotransporter2(SGLT-2) inhibitors and glucagon-like peptide-1(GLP-1) receptor agonists in the treatment of type 2 diabetes mellitus (T2DM).

To construct an exhaustive database of randomized controlled trials (RCTs) concerning SGLT-2 inhibitors and GLP-1 agonists, a methodical search was undertaken across a range of databases, such as Embase, PubMed, and the Cochrane Central Register of Controlled Trials, from their inception to January 2023. Following this, a meta-analysis was executed to amalgamate the collected data, which allowed for the calculation of standardized mean differences (SMDs), odds ratios (ORs), and 95 % confidence intervals (CIs) for a spectrum of outcomes. This analytical approach was designed to yield a quantitative evaluation of the therapeutic efficacy and safety profile of SGLT-2 inhibitors and GLP-1 agonists for the treatment of diabetes mellitus.

When compared to GLP-1 agonist therapy alone, the combination therapy did not significantly reduce fasting plasma glucose (FPG) levels (95 % confidence interval [CI]: -0.27, 0.10; p = 0.35), body weight (95 % CI: -0.18, 0.18; p = 1.00), Glycosylated Hemoglobin, Type A1C (HbA1c) (95 % CI: -0.29, 0.07; p = 0.22), or systolic blood pressure (SBP) values (95 % CI: -0.29, 0.06; p = 0.21). In contrast, when compared to SGLT-2 inhibitor therapy alone, combination therapy significantly decreased FPG by 0.24 mmol/L (95 % CI: -0.43, -0.05; p = 0.01), HbA1c by 0.45 % (95 % CI: -0.72, -0.18; p = 0.001), and SBP by 0.12 mmHg (95 % CI: -0.24, 0.00; p = 0.05). However, the combination therapy failed to demonstrate a significant reduction in body weight when compared with either SGLT-2 inhibitor therapy (95 % CI: -0.20, 0.05; p = 0.24) or GLP-1 agonist therapy (95 % CI: -0.18, 0.18; p = 1.00). Additionally, the combination therapy did not increase the incidence of hypoglycemia. It should be noted that data regarding mortality and cardiovascular outcomes were limited.

The combination treatment of SGLT-2 inhibitors and GLP-1 receptor agonists effectively reduces HbA1c, FPG, and SBP without elevating the risk of hypoglycemia when compared to monotherapy with SGLT-2 inhibitors. However, these beneficial effects were not observed when the combination therapy was compared with GLP-1 receptor agonist treatment alone.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven efficacy and safety in randomized clinical trials and observational real-life studies. Besides improving glucose control, reducing body weight, and lowering arterial blood pressure (surrogate endpoints), the breakthroughs were the demonstration of a significant reduction in cardiovascular and renal events in patients with type 2 diabetes at high risk. GLP-1RAs reduce events linked to atherogenic cardiovascular disease (especially ischemic stroke) and also renal outcomes (FLOW trial with semaglutide), with a limited effect on heart failure. The most striking protective effects of SGLT2is were a marked reduction in hospitalization for heart failure and a remarkable reduced progression of chronic kidney disease. These benefits have been attributed to numerous pleiotropic effects beyond glucose-lowering action. Underlying mechanisms contributing to cardiovascular and renal protection are at least partially different between GLP-1RAs (mainly anti-atherogenic and vascular effects) and SGLT2is (mainly systemic and intrarenal hemodynamic changes). Thus, patients at high risk may benefit from complementary actions when being treated with a GLP-1RA/SGLT2i combination. Such combination has proven its efficacy on surrogate endpoints. Furthermore, post hoc subgroup analyses of cardiovascular outcome trials have suggested a greater cardiorenal protection in patients treated with a combination versus either monotherapy. The benefits of a combined therapy have been confirmed in a few retrospective cohort studies. A dedicated prospective trial comparing a combined therapy versus either monotherapy is ongoing (PRECIDENTD); however, several challenges still remain, especially the higher cost of a combined therapy and the worldwide underuse of either GLP-1RAs or SGLT2is in clinical practice, even in patients at high cardiorenal risk.

Diabetic Kidney Disease (DKD) is the main cause of end-stage renal disease in the developed world. The current treatment of the DKD with renin-angiotensin system (RAS) blockade does not totally halt the progression to end stage kidney disease. Currently, several drugs have shown to delay DKD progression such as sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like-1 receptor agonists (GLP-1RA). We hypothesized that by combining several drugs that prevent DKD progression on top of RAS blockade a synergistic effect would be achieved in terms of cardiorenal protection. In the present study, we analysed if the combination of a RAS blocker (ramipril) with a SGLT2i (empagliflozin) and/or GLP-1RA (semaglutide) in a type 2 diabetic mouse model could have add-on effects in kidney and heart protection.

Male and female uninephrectomized type 2 diabetic db/db mice were treated with empagliflozin and/or semaglutide on top of ramipril during 8 weeks. During the study body weight, water and food intake were weekly monitored, glycaemia biweekly and albuminuria and glomerular filtration rate (GFR) before and after the treatment. At the end of the experiment, kidney and heart were isolated for histological and gene expression studies as well as for intrarenal RAS state assessment.

Semaglutide combined with ramipril and/or empagliflozin significantly decreased albuminuria but only when combined with both compounds, semaglutide further decreased blood glucose, glomerular hyperfiltration in male mice and glomerular mesangial matrix expansion. In kidney, only the triple treatment with empagliflozin, semaglutide and ramipril reduced the expression of the proinflammatory and profibrotic genes ccl2 and TGFß1. In addition, the combination of empagliflozin and semaglutide on top of RAS blockade was superior in decreasing cardiomyocyte hypertrophy and heart fibrosis in db/db mice.

Our results suggest that the combination of SGLT2i with GLP-1RA is superior in cardiorenal protection in DKD than the drugs administered alone on top of RAS blockade.

Gliflozins are recommended as first-line treatment in patients with heart failure and/or cardiovascular comorbidities and are demonstrated to reduce atrial fibrillation (AF) occurrence. However, it is not well known which gliflozin yields the larger cardioprotection in terms of AF occurrence reduction. Hence, we aimed to compare data regarding AF recurrence associated with different gliflozins.

An accurate search of online scientific libraries (from inception to June 1, 2023) was performed. Fifty-nine studies were included in the meta-analysis involving 108 026 patients, of whom 60 097 received gliflozins and 47 929 received placebo.

Gliflozins provided a statistically significant reduction of AF occurrence relative to standard of care therapy in the overall population (relative risks [RR]: 0.8880, 95% CI: [0.8059; 0.9784], p = .0164) and in patients with diabetes and cardiorenal diseases (RR: 0.8352, 95% CI: [0.7219; 0.9663], p = .0155). Dapagliflozin significantly decreased AF occurrence as compared to placebo (0.7259 [0.6337; 0.8316], p < .0001) in the overall population, in patients with diabetes (RR: 0.2482, 95% CI: [0.0682; 0.9033], p = .0345), with diabetes associated with cardiorenal diseases (RR: 0.7192, 95% CI: [0.5679; 0.9110], p = .0063) and in the subanalysis including studies with follow-up ≥1 year (RR: 0.7792, 95% CI: [0.6508; 0.9330], p = .0066). No significant differences in terms of AF protection were found among different gliflozins.

Dapagliflozin use was associated with significant reduction in AF risk as compared to placebo in overall population and patients with diabetes, whereas the use of other gliflozins did not significantly reduce AF occurrence.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially developed for their glucose-lowering effects and have shown a modest glycaemic benefit in people with type 2 diabetes mellitus (T2DM). In the past decade, a series of large, robust clinical trials of these therapies have demonstrated striking beneficial effects for various care goals, transforming the chronic disease therapeutic landscape. Cardiovascular safety studies in people with T2DM demonstrated that SGLT2 inhibitors reduce cardiovascular death and hospitalization for heart failure. Subsequent trials in participants with heart failure with reduced or preserved left ventricular ejection fraction demonstrated that SGLT2 inhibitors have beneficial effects on heart failure outcomes. In dedicated kidney outcome studies, SGLT2 inhibitors reduced the incidence of kidney failure among participants with or without diabetes. Post hoc analyses have suggested a range of other benefits of these drugs in conditions as diverse as metabolic dysfunction-associated steatotic liver disease, kidney stone prevention and anaemia. SGLT2 inhibitors have a generally favourable adverse effect profile, although patient selection and medication counselling remain important. Concerted efforts are needed to better integrate these agents into routine care and support long-term medication adherence to close the gap between clinical trial outcomes and those achieved in the real world.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents, including canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Risk of urinary tract infections (UTIs) and genital mycotic infections (GMIs) associated with SGLT‑2 inhibitors is of great clinical significance. The study aimed to assess the association between SGLT-2 inhibitors and occurrences of UTIs and GMIs using the FDA Adverse Event Reporting System (FAERS) database.

We used OpenVigil 2.1-MedDRA-v24 to query the FAERS database. Disproportionality analysis was performed to detect adverse event signals. Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) were calculated to measure the disproportionality.

A total of 45,256 reports related to the use of SGLT-2 inhibitors, including 1,714 UTI cases and 438 GMI cases, were retrieved. Potential positive signals for UTIs and GMIs were identified for canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin in adult patients of all ages and both sexes.

Data mining in the FAERS database suggests strong association between SGLT-2 inhibitors and UTIs/GMIs. These findings provide real-world evidence on the potential risk of UTIs/GMIs related to SGLT-2 inhibitors.

To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 receptor agonist (GLP-1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP-1RA first.

We included 438 patients with CKD (GLP-1RA-first group, n = 223; SGLT2 inhibitor-first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)-matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only.

Using the PS-matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP-1RA-first group, 10%; SGLT2 inhibitor-first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was 1.83 (95% CI 1.71 to 1.95; p < 0.001).

Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was significant. These results suggest that, in GLP-1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP-1RA treatment may lead to more favourable renal outcomes.

The benefits of new glucose-lowering agents on cardiovascular disease have been demonstrated in randomized clinical trials. However, more evidence is required to assess the additive value of a combined therapy based on sodium-glucose transporter inhibitors (SGLT2i) and glucagon-like peptide receptor agonists (GLP1ra) in a real-world population.

A nonconcurrent prospective study was conducted using integrated electronic medical records from primary care and hospitals obtained through "big data" technologies in a healthy area in Galicia. The study involved patients who were given SGLT2i, GLP1ra, or both treatments between January 2018 and June 2022 and were categorized as either mono- or combined therapy (SGLT2i, GLP1ra, or both). The cumulative risk for different events: hospitalization or mortality, or both, for 1) coronary artery disease, 2) heart failure, 3) cerebrovascular accident, and all-cause mortality were represented by Kaplan-Meier curves and multivariate Cox regression analysis to obtain the hazard ratio (HR) and (95% confidence interval [CI]). Validation was performed in a subpopulation with propensity score matching.

The patients (15,549) who were included were median (standard deviation) 68 (12) years old, with 41% of them being female and 46% experiencing obesity. The median (interquartile range) of follow-up was 19 (8-33) months. The Kaplan-Meier analysis determined that the cumulative risk for coronary artery disease and cerebrovascular accident events was similar among the 3 different therapy groups. However, the combined therapy vs SGLT2i reduced the risk of heart failure events (HR 0.69; 95% CI, 0.56-0.87) or all-cause mortality (HR 0.68; 95% CI, 0.54-0.86). Multivariate Cox regression analysis, after matching with a propensity score, confirmed the benefits of combined therapy regarding SGLT2i or GLP1ra monotherapy.

Compared with SGLT2i or GLP1ra alone, combined therapy SGLT2i + GLP1ra reduces heart failure risk and all-cause mortality in a real-world population.

To determine if the dispensing of glucagon-like peptide (GLP)-1 receptor agonists is associated with increased dispensing of antidepressants.

We used cross-sectional, case-control and retrospective cohort study designs to examine the association between dispensed GLP-1 receptor agonists and antidepressants between 2012 and 2022 in the 10% random sample of the Australian Pharmaceutical Benefits Scheme (PBS) data. PBS-listed GLP-1 receptor agonists, exenatide, dulaglutide and semaglutide were the exposures. Outcomes were the odds ratio [ORs; 99% confidence interval (CI)] and hazard ratio (99% CI) of being dispensed any antidepressant. Analyses were adjusted for demographic measures and the dispensing of medicines to manage cardiovascular diseases or anxiety/insomnia. Statistical tests were two-sided at the 1% level of significance.

In total, 358 075 of 1 746 391 individuals were dispensed antidepressants, and 8495 of the 24 783 dispensed a GLP-1 receptor agonist were also dispensed an antidepressant in 2022 (OR 1.44; 99% CI 1.38-1.50); 24 103 of the 1 746 391 participants had been dispensed a GLP-1 receptor agonist between 2012 and 2021, and of these 8083 were dispensed antidepressants in 2022 (OR 1.52; 99% CI 1.46-1.59). The 2012 cohort included 1 213 316 individuals who had not been dispensed antidepressants that year. The hazard ratio of being dispensed an antidepressant between 2013 and 2022 following the dispensing of a GLP-1 receptor agonist was 1.19 (99% CI 1.12-1.27). Additional analyses restricting the time of exposure confirmed these associations for all PBS-listed GLP-1 receptor agonists.

Individuals exposed to GLP-1 receptor agonists are at greater risk of being dispensed antidepressants. The possible impact of GLP-1 receptor agonists on the mood of consumers requires ongoing vigilance and further research.

Dapagliflozin possesses the capacity to cure a wide range of diseases, however, there are many adverse events (AEs) that have not yet been acknowledged or recorded.

Safety assessment of dapagliflozin based on the Food and Drug Administration Adverse Event Reporting System (FAERS) database, to explore differences between the reported AEs to provide a overview of the safety profile of dapagliflozin.

We extracted data from the United States FAERS database, including from the fourth quarter of 2012 to the third quarter of 2023. Reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric average (EBGM) were used to evaluate the relationship between dapagliflozin and its associated AEs.

A total of 13,593,946 case reports were gathered from the Food and Drug Administration Adverse Event Reporting System database for this investigation. Among these, there were 44,506 episodes of adverse events that were associated with dapagliflozin. Included in the analysis were 341 preferred words and 2 system organ classes that showed statistical significance according to all four methods simultaneously. The system organ classes encompassed illnesses related to metabolism and nutrition, as well as problems affecting the renal and urinary systems. PT levels were screened for adverse drug reaction signals including scrotal gangrene, scrotal cellulitis, perineal cellulitis, diabetic ketoacidosis, and pancreatitis.

The majority of our findings aligned with the specification, however, certain novel indicators of AEs such as acute pancreatitis were not accounted for. The analysis of the AE signals may provide support for clinical monitoring and risk identification of dapagliflozin. Due to the inherent limitations of FAERS data, well-designed studies are required to demonstrate the safety of dapagliflozin.

Membrane transporters interact not only with endogenous substrates but are also engaged in the transport of xenobiotics, including drugs. While the coordinated function of uptake (solute carrier family-SLC and SLCO) and efflux (ATP-binding cassette family-ABC, multidrug and toxic compound extrusion family-MATE) transporter system allows vectorial drug transport, efflux carriers alone achieve barrier functions. The modulation of transport functions was proved to be effective in the treatment strategies of various pathological states. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are the drugs most widely applied in clinical practice, especially in the treatment of diabetes mellitus and heart failure. Sodium taurocholate co-transporting polypeptide (NTCP) serves as virus particles (HBV/HDV) carrier, and inhibition of its function is applied in the treatment of hepatitis B and hepatitis D by myrcludex B. Inherited cholestatic diseases, such as Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) can be treated by odevixibat and maralixibat, which inhibit activity of apical sodium-dependent bile salt transporter (ASBT). Probenecid can be considered to increase uric acid excretion in the urine mainly via the inhibition of urate transporter 1 (URAT1), and due to pharmacokinetic interactions involving organic anion transporters 1 and 3 (OAT1 and OAT3), it modifies renal excretion of penicillins or ciprofloxacin as well as nephrotoxicity of cidofovir. This review discusses clinically approved drugs that affect membrane/drug transporter function.

Despite the increasing use of combination treatment with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, data are limited on the effects of combination treatment on markers of cardiovascular disease. This study aimed to investigate the effect of empagliflozin, semaglutide, and their combination on vascular function.

In total, 120 patients with type 2 diabetes were randomized into four groups (n = 30 in each) for 32 weeks: placebo, semaglutide, empagliflozin, and their combination. The study had two co-primary outcomes: change in arterial stiffness and kidney oxygenation. This paper reports on arterial stiffness assessed as carotid-femoral pulse wave velocity. Secondary outcomes included 24-h blood pressure (BP), 24-h central BP, urinary albumin to creatinine ratio and glycaemic control assessed by both continuous glucose monitoring and glycated haemoglobin.

The carotid-femoral pulse wave velocity did not change significantly in any of the groups compared with placebo. Twenty-four-hour systolic BP was reduced by 10 mmHg (95% CI 6-14), p < .001 in the combination group, significantly superior to both placebo and monotherapy (p < .05). Combination treatment increased glycaemic time in range from 72% at baseline to 91% at week 32, p < .001, without increasing time below range. The urinary albumin to creatinine ratio decreased by 36% (95% CI 4-57), p = .03 in the combination group compared with placebo.

Empagliflozin, semaglutide, or their combination did not reduce arterial stiffness. Combination treatment showed a substantial and clinically important reduction in 24-h systolic BP compared with either treatment alone. Combination treatment increased glycaemic time in range without increasing the risk of hypoglycaemia.

To determine whether the combined use of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors is associated with a decreased risk of major adverse cardiovascular events and serious renal events compared with either drug class alone among patients with type 2 diabetes, and to assess the effect of the combination on the individual components of major adverse cardiovascular events, heart failure, and all cause mortality.

Population based cohort study using a prevalent new-user design, emulating a trial.

UK Clinical Practice Research Datalink linked to Hospital Episode Statistics Admitted Patient Care and Office for National Statistics databases.

Two prevalent new-user cohorts were assembled between January 2013 and December 2020, with follow-up until the end of March 2021. The first cohort included 6696 patients who started GLP-1 receptor agonists and added on SGLT-2 inhibitors, and the second included 8942 patients who started SGLT-2 inhibitors and added on GLP-1 receptor agonists. Combination users were matched, in a 1:1 ratio, to patients prescribed the same background drug, duration of background drug, and time conditional propensity score.

Cox proportional hazards models were fitted to estimate the hazard ratios and 95% confidence intervals of major adverse cardiovascular events and serious renal events, separately, comparing the GLP-1 receptor agonist-SGLT-2 inhibitor combination with the background drug, either GLP-1 receptor agonists or SGLT-2 inhibitors, depending on the cohort. Secondary outcomes included associations with the individual components of major adverse cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular mortality), heart failure, and all cause mortality.

Compared with GLP-1 receptor agonists, the SGLT-2 inhibitor-GLP-1 receptor agonist combination was associated with a 30% lower risk of major adverse cardiovascular events (7.0 v 10.3 events per 1000 person years; hazard ratio 0.70, 95% confidence interval 0.49 to 0.99) and a 57% lower risk of serious renal events (2.0 v 4.6 events per 1000 person years; hazard ratio 0.43, 0.23 to 0.80). Compared with SGLT-2 inhibitors, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a 29% lower risk of major adverse cardiovascular events (7.6 v 10.7 events per 1000 person years; hazard ratio 0.71, 0.52 to 0.98), whereas serious renal events generated a wide confidence interval (1.4 v 2.0 events per 1000 person years; hazard ratio 0.67, 0.32 to 1.41). Secondary outcomes generated similar results but with wider confidence intervals.

In this cohort study, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a lower risk of major adverse cardiovascular events and serious renal events compared with either drug class alone.

Objective: To determine whether Glucagon-Like Peptide 1 (GLP-1) agonists or Sodium Glucose Transporter 2 (SGLT-2) inhibitors result in greater A1c reduction, weight loss, and reduction of insulin requirements in veterans using multiple daily doses of insulin. Methods: This retrospective, single-site, cohort study included patients of VA Eastern Kansas Health Care System with a diagnosis of Type II Diabetes utilizing multiple daily dose insulin and an SGLT-2 inhibitor or GLP-1 agonist. SAS Enterprise Guide was utilized to complete a multivariate analysis of variance to evaluate all outcomes. Key Findings: 150 patients met selection criteria. The GLP-1 group averaged a .65% reduction in A1c compared to a 1.05% reduction in the SGLT-2 group (P = .1397). The Basal insulin dose was reduced by 5.5 units in the GLP-1 group vs 2.45 units in the SGLT-2 group (P = .3132), and 7.12 units vs 8.14 units respectively for short-acting insulin (P = .8170). The resulting weight reduction was 4.1 Kg in the GLP-1 group compared to 3.6 Kg in the SGLT-2 group (P = .6993). Conclusion: The results suggest there is not a statistically significant difference in changes to A1c, insulin requirements, or weight after 1 year of treatment with an SGLT-2 vs GLP-1 in patients using multiple daily insulin injections.

Ischaemic cardiovascular diseases, including peripheral and coronary artery disease, myocardial infarction, and stroke, remain major comorbidities for individuals with type 2 diabetes (T2D) and obesity. During cardiometabolic chronic disease (CMCD), hyperglycaemia and excess adiposity elevate oxidative stress and promote endothelial damage, alongside an imbalance in circulating pro-vascular progenitor cells that mediate vascular repair. Individuals with CMCD demonstrate pro-vascular 'regenerative cell exhaustion' (RCE) characterized by excess pro-inflammatory granulocyte precursor mobilization into the circulation, monocyte polarization towards pro-inflammatory vs. anti-inflammatory phenotype, and decreased pro-vascular progenitor cell content, impairing the capacity for vessel repair. Remarkably, targeted treatment with the sodium-glucose cotransporter-2 inhibitor (SGLT2i) empagliflozin in subjects with T2D and coronary artery disease, and gastric bypass surgery in subjects with severe obesity, has been shown to partially reverse these RCE phenotypes. SGLT2is and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped the management of individuals with T2D and comorbid obesity. In addition to glucose-lowering action, both drug classes have been shown to induce weight loss and reduce mortality and adverse cardiovascular outcomes in landmark clinical trials. Furthermore, both drug families also act to reduce systemic oxidative stress through altered activity of overlapping oxidase and antioxidant pathways, providing a putative mechanism to augment circulating pro-vascular progenitor cell content. As SGLT2i and GLP-1RA combination therapies are emerging as a novel therapeutic opportunity for individuals with poorly controlled hyperglycaemia, potential additive effects in the reduction of oxidative stress may also enhance vascular repair and further reduce the ischaemic cardiovascular comorbidities associated with T2D and obesity.

Sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone all individually reduce cardiovascular, kidney, and mortality outcomes in patients with type 2 diabetes and albuminuria. However, the lifetime benefits of combination therapy with these medicines are not known.

We used data from 2 SGLT2i trials (CANVAS [Canagliflozin Cardiovascular Assessment] and CREDENCE [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation]), 2 ns-MRA trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease]), and 8 GLP-1 RA trials to estimate the relative effects of combination therapy versus conventional care (renin-angiotensin system blockade and traditional risk factor control) on cardiovascular, kidney, and mortality outcomes. Using actuarial methods, we then estimated absolute risk reductions with combination SGLT2i, GLP-1 RA, and ns-MRA in patients with type 2 diabetes and at least moderately increased albuminuria (urinary albumin:creatinine ratio ≥30 mg/g) by applying estimated combination treatment effects to participants receiving conventional care in CANVAS and CREDENCE.

Compared with conventional care, the combination of SGLT2i, GLP-1 RA, and ns-MRA was associated with a hazard ratio of 0.65 (95% CI, 0.55-0.76) for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). The corresponding estimated absolute risk reduction over 3 years was 4.4% (95% CI, 3.0-5.7), with a number needed to treat of 23 (95% CI, 18-33). For a 50-year-old patient commencing combination therapy, estimated major adverse cardiovascular event-free survival was 21.1 years compared with 17.9 years for conventional care (3.2 years gained [95% CI, 2.1-4.3]). There were also projected gains in survival free from hospitalized heart failure (3.2 years [95% CI, 2.4-4.0]), chronic kidney disease progression (5.5 years [95% CI, 4.0-6.7]), cardiovascular death (2.2 years [95% CI, 1.2-3.0]), and all-cause death (2.4 years [95% CI, 1.4-3.4]). Attenuated but clinically relevant gains in event-free survival were observed in analyses assuming 50% additive effects of combination therapy, including for major adverse cardiovascular events (2.4 years [95% CI, 1.1-3.5]), chronic kidney disease progression (4.5 years [95% CI, 2.8-5.9]), and all-cause death (1.8 years [95% CI, 0.7-2.8]).

In patients with type 2 diabetes and at least moderately increased albuminuria, combination treatment of SGLT2i, GLP-1 RA, and ns-MRA has the potential to afford relevant gains in cardiovascular and kidney event-free and overall survival.

Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor and semaglutide, a glucagon-like peptide 1 receptor agonist, have both demonstrated efficacy in glycemic control, reducing blood pressure, body weight, risk of renal and heart failure in type 2 diabetes mellitus. In this observational, real-world, study we aimed to investigate the efficacy of the combination therapy with those two agents over glycemic control. We thus obtained the data of 1335 patients with type 2 diabetes followed by 11 Diabetes centers in Lombardia, Italy. A group of 443 patients was treated with dapagliflozin alone, the other group of 892 patients was treated with the combination therapy of dapagliflozin plus oral semaglutide. We analyzed changes in glycated hemoglobin from baseline to 6 months of follow-up, as well as changes in fasting glycemia, body weight, body mass index, systolic and diastolic pressure, heart rate, creatinine, estimated glomerular filtration rate and albuminuria. Both groups of patients showed an improvement of glycometabolic control after 6 months of treatment; indeed, the treatment with dapagliflozin plus oral semaglutide showed a reduction of glycated hemoglobin of 1.2% as compared to the 0.5% reduction observed in the dapagliflozin alone group. Significant changes were observed in body mass index, fasting plasmatic glucose, blood pressure, total cholesterol, LDL and albumin to creatinine ratio, with a high rate (55%) of near-normalization of glycated hemoglobin. Our real world data confirmed the potential of the oral combination therapy dapagliflozin with semaglutide in inducing pharmacological remission of type 2 diabetes mellitus.

Empagliflozin, a sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, are commonly recognized for their cardiovascular benefits in individuals with type 2 diabetes (T2D). In prior studies, we have demonstrated that both drugs, alone or in combination, were able to protect cardiomyocytes from injury induced by diabetes. Mechanistic investigations also suggested that the cardioprotective effect may be independent of diabetes In this study, we utilized a hypoxia-reoxygenation (H/R) model to investigate the cardiovascular benefits of SGLT2 inhibitor empagliflozin and GLP-1 receptor (GLP-1R) agonist liraglutide, both alone and in combination, in the absence of T2D. Our hypothesis was that empagliflozin and liraglutide, either individually or in combination, would demonstrate cardioprotective properties against H/R-induced injury, with an additive and/or synergistic effect anticipated from combination therapy.

In this study, the cardiac muscle cell line, HL-1 cells, were treated with vehicle, empagliflozin, liraglutide, or a combination of the two drugs. The cells were then subjected to a hypoxia-reoxygenation (H/R) protocol, consisting of 1 h of hypoxia followed by 24 h of reoxygenation. The effects of the treatments on cytotoxicity, oxidative stress, endothelial nitric oxide synthase (eNOS) activity, phospho-protein kinase C (PKC) beta and phospho-eNOS (Thr495) expression were subsequently evaluated at the end of the treatments.

We found that H/R increased cytotoxicity and reduces eNOS activity, empagliflozin, liraglutide or combination treatment attenuated some or all of these effects with the combination therapy showing the greatest improvement.

Empagliflozin, liraglutide or combination of these two have cardioprotective effect regardless of diabetes. Cardioprotective effects of SGLT2 inhibitor and GLP-1R agonist is additive and synergistic.

To investigate whether combined treatment with empagliflozin (a sodium-glucose cotransporter-2 inhibitor) and semaglutide (a glucagon-like peptide-1 receptor agonist) can reduce urinary albumin-creatinine ratio (UACR) compared to treatment with empagliflozin alone in individuals with type 2 diabetes (T2D) and albuminuria.

We conducted a randomized, placebo-controlled, double-blind, parallel study including 60 individuals with T2D and albuminuria. All participants initiated open-label empagliflozin 25 mg once daily, on top of renin-angiotensin system inhibition, in a run-in period of 26 weeks. Subsequently, participants were randomized to semaglutide or placebo 1 mg once weekly for 26 weeks. The primary endpoint was change in UACR. Secondary endpoints were change in: (i) measured glomerular filtration rate (GFR); (ii) 24-hour systolic blood pressure; (iii) glycated haemoglobin (HbA1c) level; (iv) body weight; and (v) plasma renin and aldosterone levels.

Addition of semaglutide to empagliflozin provided no additional change in UACR from randomization to end-of-treatment. The mean (95% confidence interval) difference in UACR was -22 (-44; 10)% (P = 0.15) between treatment groups. Neither GFR, 24-hour blood pressure, body weight, nor plasma renin activity was changed with semaglutide. HbA1c (-8 [-13; -3] mmol/mol; P = 0.003) and plasma aldosterone (-30 [-50; -3] pmol/L; P = 0.035) were reduced with semaglutide compared to placebo.

Semaglutide added to empagliflozin did not change UACR, measured GFR, 24-hour systolic blood pressure, body weight or plasma renin levels in individuals with T2D and albuminuria. Semaglutide improved glycaemic control and plasma aldosterone levels compared to placebo.

Individuals diagnosed with chronic kidney disease (CKD) continue to increase globally. This group of patients experience a disproportionately higher risk of cardiovascular (CV) events compared to the general population. Despite multiple guidelines-based medical management, patients with CKD continue to experience residual cardiorenal risk. Several potential mechanisms explain this excessive CV risk observed in individuals with CKD. Several new drugs have become available that could potentially transform CKD care, given their efficacy in this patient population. Nevertheless, use of these drugs presents certain benefits and challenges that are often underrecognized by prescribing these drugs. In this review, we aim to provide a brief discussion about CKD pathophysiology, limiting our discussion to recent published studies. We also explore benefits and limitations of newer drugs, including angiotensin receptor/neprilysin inhibitors (ARNI), sodium glucose transporter 2 inhibitors (SGLT2i), glucagon-like peptides-1 (GLP-1) agonists and finerenone in patients with CKD. Despite several articles covering this topic, our review provides an algorithm where subgroups of patients with CKD might benefit the most from such drugs based on the selection criteria of the landmark trials. Patients with CKD who have nephrotic range proteinuria beyond 5000 mg/g, or those with poorly controlled blood pressure (systolic ≥160 mm Hg or diastolic ≥100 mm Hg) remain understudied.

We aimed to investigate the factors associated with UTI in patients with T2D whether being treated with SGLT-2i or not.

Adult patients with T2D, whose urine culture results were available, were analyzed retrospectively. Urine culture was obtained from mid-flow urine. Antibacterial treatment was given to the patients with UTI, which was defined by positive urine cultures and/or clinical findings. We grouped the patients as follows: Group A, those treated with SGLT-2i; and Group B, those not treated with SGLT-2i.

A total of 101 patients were included. Median age was 56 (45-67), 56.4% (n = 57) of the patients were female. Urine culture was positive in 54.9% (n = 28) and 16% (n = 8) of Group A (n = 51) and Group B (n = 50), respectively. Of those for whom urine culture was positive, Escherichia coli was isolated in 83.3% (n = 30), and both Escherichia coli and Klebsiella pneumoniae (K.pneumoniae) were isolated in 16.7% (n = 6). Klebsiella pneumoniae was isolated only from Group A. The need for and duration of hospitalization were higher in Group A (p < 0.001). UTI was detected in 60 patients. ROC analysis showed that a HbA1c of > 5.8% was associated with UTI with good accuracy (AUC: 0.835, p < 0.001). In multiple logistic regression analysis, SGLT-2i use and glucosuria were positive predictors for UTI (p = 0.004, Odds Ratio: 1984.013; and p = 0.028, and Odds Ratio: 12.480, respectively).

Besides the association of HbA1c and BMI with UTI, SGLT-2i use and glucosuria predicted UTI. Urine culture is important with respect to the choice of antibacterial treatment, especially in those patients under SGLT-2i treatment. The effect of SGLT-2i on the development of UTI is independent of baseline BMI score or HbA1c.

As the prevalence of obesity rises in the United States, so does the incidence of obesity-related kidney disease. Obesity itself is an independent risk factor for chronic kidney disease where the pathophysiology is complex, involving altered hemodynamics, renin-angiotensin-aldosterone system overactivation, and adipokines leading to inflammation and fibrosis. Obesity-related kidney disease comprises both obesity-related glomerulopathy and fatty kidney disease. Obesity-related glomerulopathy is a consequence of glomerular hyperfiltration and often presents clinically with subnephrotic proteinuria and pathologically with glomerulomegaly with or without focal glomerulosclerosis. Fatty kidney disease is the effect of renal ectopic fat contributing to chronic kidney disease. Whether the renal ectopic fat is a distinct clinical entity or a pathologic mechanism contributing to obesity-related glomerulopathy, the treatment paradigm of weight and proteinuria reduction remains the same. We present the pathophysiology behind obesity-related kidney disease, clinical outcomes, and treatment strategies, which include lifestyle interventions, use of renin-angiotensin-aldosterone system inhibitors, glucagon-like peptide 1 receptor agonists, sodium-glucose co-transporter-2 inhibitors, and bariatric surgery. With old and novel therapeutics, we are attempting to stave off the silent epidemic that obesity-related kidney disease is becoming.

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

To compare the effectiveness and safety of empagliflozin and dulaglutide in patients with type 2 diabetes (T2D) inadequately controlled by oral triple therapy.

In this 24-week, multi-center, randomized trial, patients with T2D and HbA1c level ≥7.5% (58 mmol/mol) on metformin, sulfonylurea, and dipeptidyl peptidase 4 inhibitor (DPP4-i) were randomly assigned into two groups: daily empagliflozin add-on or once-weekly dulaglutide switched from DPP4-i. The primary endpoint was changes from baseline HbA1c at 24 weeks.

In total, 152 patients were recruited to the empagliflozin-added quadruple group (n = 76) or the switched-to-dulaglutide triple group (n = 76). At week 24, both groups showed significant reduction in HbA1c level from baseline with greater reduction with empagliflozin (the mean treatment difference: -0.27% [95% CI -0.50 to -0.04, p = 0.024]) (-2.88 mmol/mol [95% CI -5.37 to -0.39], p = 0.024). Empagliflozin significantly reduced body weight from baseline to week 24 (-1.72 kg [95% CI -1.98 to -0.59, p < 0.001]). No serious adverse events were reported with either empagliflozin or dulaglutide.

Empagliflozin, compared with once-weekly dulaglutide switched from DPP4-i, demonstrated greater HbA1c reduction and weight loss in patients with T2D inadequately controlled with metformin, sulfonylurea, and DPP4-i.

cris.nih.go.kr (KCT0006157).

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 receptor agonists (GLP-1 RAs) reduce adverse cardiovascular outcomes in type 2 diabetes (T2D). However, the efficacy of combination therapy is unclear.

The aim of this study was to evaluate the effects of GLP-1 RAs on cardiovascular outcomes in patients with T2D treated with or without SGLT2 inhibitors.

Post hoc analysis of Harmony Outcomes (Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease) evaluating the effect of albiglutide in T2D with cardiovascular disease by background SGLT2 inhibitor use. Additionally, a trial-level meta-analysis of Harmony Outcomes and AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes), which evaluated T2D with cardiovascular or renal disease, was performed, combining the treatment effect estimates according to SGLT2 inhibitor use.

Of the 9,462 participants in Harmony Outcomes, 575 (6.1%) were treated with SGLT2 inhibitors at baseline. The effect of albiglutide on reducing the composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events) was consistent with or without SGLT2 inhibitors (P interaction = 0.70). The effect of albiglutide on secondary outcomes and adverse events was not modified by SGLT2 inhibitors. A meta-analysis of Harmony Outcomes and AMPLITUDE-O included 13,538 patients, of whom 1,193 (8.8%) used SGLT2 inhibitors. Compared to placebo, GLP1-RAs reduced major adverse cardiovascular events without effect modification by SGLT2 inhibitor use (HR: 0.77; 95% CI: 0.68-0.87 without SGLT2 inhibitors; and HR: 0.78; 95% CI: 0.49-1.24 with SGLT2 inhibitors) (P for interaction = 0.95) and reduced heart failure hospitalization (HR: 0.72; 95% CI: 0.55-0.92 vs HR: 0.34; 95% CI: 0.12-0.96) (P for interaction = 0.18).

In patients with T2D and cardiovascular disease, GLP-1 RAs reduced cardiovascular events independently of SGLT2 inhibitor use. These findings suggest that the combination of GLP-1 RAs with SGLT2 inhibitors may further reduce cardiovascular risk. Clinical trials with combination therapy are needed.

Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RA) are frequently used for the management of diabetes. The impact of GLP-1 RA on cardiovascular outcomes is unclear. We aim to assess the effect of GLP-1 RA on mortality, atrial and ventricular arrhythmias, and sudden cardiac death in patients with type II diabetes.

We searched databases including Ovid MEDLINE, EMBASE, Scopus, Web of Science, Google Scholar and CINAHL, from inception to May 2022, for randomized controlled trials reporting the relationship between GLP-1 RA (including albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide) and mortality, atrial arrhythmias, and the combined incidence of ventricular arrhythmias and sudden cardiac death. The search was not restricted to time or publication status.

A total of 464 studies resulted from literature search, of which 44 studies, including 78,702 patients (41,800 GLP-1 agonists vs 36,902 control), were included. Follow up ranged from 52 to 208 weeks. GLP-1 RA were associated with lower risk of all-cause mortality (odds ratio 0.891, 95% confidence interval 0.837-0.949; P < 0.01) and reduced cardiovascular mortality (odds ratio 0.88, 95% confidence interval 0.881-0.954; P < 0.01). GLP-1 RA were not associated with increased risk of atrial (odds ratio 0.963, 95% confidence interval 0.869-1.066; P 0.46) or ventricular arrhythmias and sudden cardiac death (odds ratio 0.895, 95% confidence interval 0.706-1.135; P 0.36).

GLP-1 RA are associated with decreased all-cause and cardiovascular mortality, and no increased risk of atrial and ventricular arrhythmias and sudden cardiac death.