Case reports of postoperative diabetic ketoacidosis in patients using sodium-glucose cotransporter 2 inhibitor (SGLT2i) medications underlie guidance by the US Food and Drug Administration to withhold SGLT2i medication for at least 3 days prior to surgery. Given the potential negative consequences associated with preoperative medication withholding, a large-scale evaluation of the risk of diabetic ketoacidosis in this population is needed.

To estimate the association between preoperative SGLT2i medication use and postoperative diabetic ketoacidosis in a population of patients who underwent a variety of emergency surgeries. Emergency surgery was chosen given the assumption that a patient would be unable to withhold their SGLT2i medication per the current guidance.

This retrospective cohort study was conducted among a nationwide sample of patients aged 18 years or older with type 2 diabetes who were enrolled in commercial or Medicare fee-for-service insurance plans and who underwent 1 of 13 emergency surgeries between January 1, 2016, and December 15, 2022. Emergency surgeries were defined as those occurring on the same day or the 1 to 2 days after an emergency department claim. Data were analyzed from November 2023 through December 2024.

SGLT2i medication use.

Diabetic ketoacidosis, defined by diagnosis codes, in the 0 to 14 days after surgery.

Among 34 671 patients with type 2 diabetes who underwent emergency surgery (mean [SD] age, 63.9 [14.0] years; 19 175 female [55.3%] and 15 496 male [44.7%]), the most common surgeries were laparoscopic cholecystectomy (9385 patients) and transurethral procedures (12 246 patients). There were 2607 patients (7.5%) who used SGLT2i medications and 32 064 patients (92.5%) who did not. Unadjusted incidence of diabetic ketoacidosis was 127 patients (4.9%) for those exposed to SGLT2i medications and 1115 patients (3.5%) for those unexposed. After accounting for covariates, including demographic characteristics, indicators of diabetic severity, comorbidities, and surgery type, the incidence of the outcome was 3.8% for those exposed to SGLT2i medications and 3.5% for those unexposed. The average treatment effect [ATE] was 0.2% (95% CI, -1.7% to 2.2%). Results were robust to alternate specifications (eg, intensive care unit-level care as the outcome: ATE, -1.0%; 95% CI, -2.9% to 1.1%).

This study found that preoperative use of SGLT2i medications in patients undergoing emergency surgery was not associated with an increased risk for postoperative diabetic ketoacidosis compared with no use of SGLT2i medications. These findings may justify liberalizing current guidance on preoperative SGLT2i medication withholding periods.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been associated with lower rates of cardiac arrhythmias in post hoc analyses. The real-world effect on cardiac arrhythmias is incompletely defined.

The purpose of this study was to determine the effects of SGLT2i on cardiac arrhythmias in a real-world, hospitalized population.

A retrospective cohort study was performed in South Australia, Australia. Patients (n = 882) with type 2 diabetes mellitus (T2DM) on oral diabetic therapy (33.6% females, median age 62.3 years) who received SGLT2i (for T2DM) were identified through public hospital admissions from 2011-2019. Patients were matched with 3282 contemporaneous controls with T2DM who did not receive SGLT2i. Baseline characteristics were adjusted using inverse probability treatment weighting. The primary outcome was incidence of atrial arrhythmias. Secondary outcomes included incidence of ventricular arrhythmias and cardiac arrest at 2 years.

All-cause mortality was higher in the SGLT2i group (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.55-2.63, P <.001) despite propensity matching, highlighting the greater unmeasured comorbidity burden of the SGLT2i-treated group. Despite this, SGLT2i treatment was associated with fewer atrial arrhythmias (HR 0.17, 95% CI 0.07-0.41, P <.001) at 2 years. The relationship between SGLT2i use and ventricular arrhythmias (HR 0.25, 95% CI 0.06-1.03, P = .055) and cardiac arrest (HR 0.82, 95% CI 0.20-3.45, P = .796) did not reach statistical significance.

In this real-world, comorbid inpatient cohort, SGLT2i treatment was associated with a lower incidence of atrial arrhythmias. Prospective randomized trials evaluating SGLT2i as specific atrial fibrillation pharmacotherapy are underway.

Several studies showed higher risks of cardiovascular complications to have been observed in patients with type 2 diabetes mellitus (T2DM). Atrial fibrillation (AF) and atrial flutter have been more pronounced in patients with hyperglycemia. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are now considered as second-line treatment for patients with T2DM following inadequate glycemic control with first line agents. In this analysis, we aimed to compare the risk of AF in patients with T2DM who were treated with SGLT-2 inhibitors versus DPP-4 inhibitors.

Relevant publications comparing AF in patients with T2DM treated by SGLT-2 inhibitors versus DPP-4 inhibitors were searched through electronic databases. AF was the clinical endpoint in this analysis. Revman 5.4 software was used to carry out this analysis. Risk ratios (RR) with 95% confidence intervals (CIs) were used to assess the outcome.

Eleven studies with a total number of 1,019,476 participants with T2DM were included in this analysis whereby 480,549 patients were assigned to SGLT-2 inhibitors and 538,927 patients were assigned to DPP-4 inhibitors. Result of this analysis showed SGLT-2 inhibitors to be associated with a significantly lower risk of AF compared to DPP-4 inhibitors in these patients with T2DM (RR: 0.57, 95% CI: 0.39 - 0.85; P = 0.006).

Based on the result of this analysis, the risk of AF was significantly reduced with SGLT-2 inhibitors when compared to DPP-4 inhibitors in these patients with T2DM. This hypothesis should be confirmed in future larger studies.

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.

Type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease (diabetic MASLD) frequently coexist and worsen liver and non-liver outcomes, but effective pharmacological therapies are limited. We aimed to evaluate the long-term effect of sodium-glucose cotransporter-2 inhibitor (SGLT-2i) on liver and non-liver outcomes among patients with diabetic MASLD.

This population-based cohort study retrieved patients with diabetic MASLD from Merative Marketscan Research Databases (April 2013 and December 2021). The active comparator was other glucose-lowering drugs (oGLDs). Primary outcomes were liver complications including hepatocellular carcinoma (HCC) and liver cirrhosis, as well as non-liver complications including cardiovascular disease (CVD), chronic kidney disease (CKD) and non-liver cancer. Propensity score matching was applied and Cox regression models were conducted.

Compared with oGLD, SGLT-2i users had significantly lower risk of HCC (HR 0.76, 95% CI 0.62 to 0.93), liver cirrhosis (HR 0.80, 95% CI 0.76 to 0.84), CVD (HR 0.82, 95% CI 0.79 to 0.85) and CKD (HR 0.66, 95% CI 0.62 to 0.70), non-liver cancer (HR 0.81, 95% CI 0.76 to 0.86). Compared with patients without metformin and SGLT-2i, a stepwise decreasing risk was observed in users of either metformin or SGLT-2i (HRs 0.76-0.97) and in users of both medications (HRs 0.58-0.79). The lower risk also was shown in liver decompensation, compensated cirrhosis, major CVD, end-stage renal disease and specific common cancers (HRs 0.61-0.84).

In a nationwide cohort, SGLT-2i users were associated with a substantially lower risk of liver and non-liver complications than oGLD users among patients with diabetic MASLD. The risk was further reduced with concomitant metformin use.

Sodium-glucose co-transporter inhibitors (SGLTis) are the latest class of anti-hyperglycemic agents. In addition to inhibiting the absorption of glucose by the kidney causing glycosuria, these drugs also demonstrate cardio-renal benefits in diabetic subjects. miR-30 family, one of the most abundant microRNAs in the heart, has recently been linked to a setting of cardiovascular diseases and has been proposed as novel biomarkers in kidney dysfunctions as well; their expression is consistently dysregulated in a variety of cardio-renal dysfunctions. The mechanistic involvement and the potential interplay between miR-30 and SGLT2i effects have yet to be thoroughly elucidated. Recent research has stressed the relevance of this cluster of microRNAs as modulators of several pathological processes in the heart and kidneys, raising the possibility of these small ncRNAs playing a central role in various cardiovascular complications, notably, endothelial dysfunction and pathological remodeling. Here, we review current evidence supporting the pleiotropic effects of SGLT2is in cardiovascular and renal outcomes and investigate the link and the coordinated implication of the miR-30 family in endothelial dysfunction and cardiac remodeling. We also discuss the emerging role of circulating miR-30 as non-invasive biomarkers and attractive therapeutic targets for cardiovascular diseases and kidney diseases. Clinical evidence, as well as metabolic, cellular, and molecular aspects, are comprehensively covered.

Objective: To evaluate the effectiveness of empagliflozin in reducing all-cause mortality (ACM), hospitalization for heart failure (HHF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), and end-stage renal disease (ESRD) in routine clinical practice in the Nordic countries of the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) study. Methods: This noninterventional, multicountry cohort study used secondary data from four Nordic countries (Denmark, Sweden, Finland, and Norway). Propensity score (PS) matched (1:1) adults with type 2 diabetes (T2D) initiating empagliflozin (a sodium-glucose cotransporter-2 inhibitor) during 2014-2018 who were compared to those initiating a dipeptidyl peptidase-4 inhibitor (DPP-4i). Cox proportional hazards regression modelling was used to assess the risk for ACM, HHF, MI, stroke, CVM, and ESRD. Meta-analyses were conducted and hazard ratios (HRs) with 95% confidence intervals (CIs) from random-effects models were calculated. Results: A total of 43,695 pairs of PS-matched patients were identified. Patients initiating empagliflozin exhibited a 49% significantly lower risk of ACM (HR: 0.51, 95% CI 0.40-0.64) compared to DPP-4i. Additionally, empagliflozin was associated with a 36% significantly lower risk of HHF (HR: 0.64, 95% CI 0.46-0.89), a 52% significantly lower risk of CVM (HR: 0.48, 95% CI 0.37-0.63), and a 66% significantly lower risk of ESRD (HR: 0.34, 95% CI 0.15-0.77) compared to DPP-4i. No significant differences were observed in the risk of stroke and MI between patients initiating empagliflozin compared with those initiating a DPP-4i. Results were generally consistent for subgroups (with/without pre-existing CV disease or congestive heart failure) and in sensitivity analyses. Conclusion: Empagliflozin initiation was associated with a significantly reduced risk of ACM, HHF, CVM, and ESRD compared with initiation of DPP-4i in patients with T2D when examining routine clinical practice data from Nordic countries.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally designed to manage blood sugar levels in individuals with type 2 diabetes (T2D), have emerged as a crucial class of drugs for managing cardio-renal diseases. These drugs work by targeting the SGLT2 protein in the kidneys, promoting the excretion of glucose and influencing metabolic pathways beyond glucose control. The relationship between cardio-renal diseases and SGLT2 inhibitors has been explored through landmark trials and real-world evidence (RWE) studies, demonstrating significant reductions in cardio-renal complications. This review discusses the importance of RWE studies alongside randomized controlled trials in understanding the real-world effectiveness and safety of SGLT2 inhibitors. It outlines the advantages and disadvantages of RWE compared to RCTs, highlighting their complementary roles in providing comprehensive insights into treatment outcomes. By examining a range of RWE studies, the review underscores the cardio-renal benefits of SGLT2 inhibitors across various patient populations. Safety assessments indicate that SGLT2 inhibitors are generally well tolerated, with severe adverse events being rare. Common issues, such as genital mycotic infections and urinary tract infections, are acknowledged, alongside less frequent but significant adverse events including diabetic ketoacidosis, lower-limb amputations, and bone fractures. In summary, SGLT2 inhibitors show promising cardio-renal protective effects in real-world scenarios across diverse populations in T2D, indicating their potential as early intervention measures. Continued research is essential for gaining a thorough understanding of their long-term effects and safety profiles.

Background: Diabetes mellitus (DM) is a prevalent disease in the general population and also a well-established risk factor for the development of ischemic stroke. Patients who have been diagnosed with diabetes have a 20% higher risk for developing ischemic stroke in comparison to non-diabetic individuals. The aim of the current systematic review is to provide the latest evidence regarding the association between antidiabetic treatment and the prevention of ischemic stroke. Methods: A comprehensive search in scientific literature databases PUBMED, COCHRANE, and SCOPUS was conducted. The studies that were deemed as eligible for this review were those that examined the clinical benefits of therapeutic strategies in terms of preventing ischemic strokes. Results: A total of 32 studies met the established selection criteria. The included studies showed that pioglitazone treatment significantly reduced the risk for recurrent stroke in patients with DM. Furthermore, in the context of primary prevention, the improvement in glycemic control after treatment with the glucagon-like peptide-1 receptor agonists (GLP-1RA) semaglutide and dulaglutide was associated with a reduction in the risk of ischemic stroke in diabetic subjects. Metformin monotherapy may reduce stroke risk, while dipeptidyl peptidase 4 inhibitors, sodium-glucose co-transporter 2 inhibitors, and insulin do not seem to affect the incidence of stroke. Conclusions: The findings of the present systematic review suggest that pioglitazone and GLP-1RA may decrease the risk of stroke. Further studies are needed to provide additional data regarding the preventive effect of novel antidiabetic drugs, such as dual glucose-dependent insulinotropic polypeptide/GLP-1RA agents, on stroke.

GLP-1 receptor agonists and SGLT2 inhibitors are increasingly being used in people with type 2 diabetes on the basis of findings from randomised clinical trials; however, little is known of whether clinical outcomes are affected by frailty in real-world settings. We aimed to compare the clinical effectiveness and safety of GLP-1 receptor agonists and SGLT2 inhibitors in managing type 2 diabetes, with a specific focus on stratifying people by their frailty status.

In this retrospective, nationwide, longitudinal study, we identified people (aged ≥20 years) with type 2 diabetes who newly initiated either a GLP-1 receptor agonist or an SGLT2 inhibitor during the period Jan 1, 2017 to Dec 31, 2019 from the Taiwan National Health Insurance database. Individuals were excluded if they had been diagnosed with cancer, received dialysis for kidney failure, or had prescriptions for a GLP-1 receptor agonist or an SGLT2 inhibitor, within 1 year before the index date. Mortality data were collected from the Taiwan National Death Registry. Eligible individuals were categorised into three frailty subgroups-fit, mild frailty, and moderate or severe frailty-on the basis of the multimorbidity frailty index. Propensity score matching (1:1) was used to balance covariates between recipients of GLP-1 receptor agonists and SGLT2 inhibitors among each frailty subgroup. Clinical outcomes of interest included three-point major adverse cardiovascular events (non-fatal acute myocardial infarction, non-fatal stroke, and fatal cardiovascular disease), all-cause mortality, hospitalisation for heart failure, dialysis or renal transplant, severe diabetic foot complications, retinopathy, hospitalisation for severe hyperglycaemia, and hospitalisation for severe hypoglycaemia. The association between the use of a GLP-1 receptor agonist versus an SGLT2 inhibitor and the risk of the outcomes of interest among each frailty subgroup was examined using a subdistribution hazard model.

We identified 320 210 people with type 2 diabetes, of whom 280 163 met the eligibility criteria, who initiated either a GLP-1 receptor agonist (n=22 968; mean age 57·7 years [SD 13·9], 11 338 [49·4%] were female, and 11 630 [50·6%] were male) or SGLT2 inhibitor (n=257 195; mean age 58·8 years [12·3], 107 988 [42·0%] were female, and 149 207 [58·0%] were male) during 2017-19. After matching, 11 882, 7210, and 3414 pairs of GLP-1 receptor agonist and SGLT2 inhibitor users were assigned in the fit, mild frailty, and moderate or severe frailty subgroups. All clinical outcomes were comparable between users of GLP-1 receptor agonists and SGLT2 inhibitors among each frailty subgroup, except for a higher risk of hospitalisation for severe hyperglycaemia with GLP-1 receptor agonists than with SGLT2 inhibitors in the mild frailty subgroup (subdistribution hazard ratio 1·25 [95% CI 1·13-1·38]; p<0·0001) and a higher risk of dialysis or renal transplant with GLP-1 receptor agonists than with SGLT2 inhibitors in the fit (2·43 [1·82-3·23]; p<0·0001), mild frailty (3·93 [3·03 -5·09]; p<0·0001), and moderate or severe frailty (2·60 [2·03-3·31]; p<0·0001) subgroups.

Formulating clear and updated guidelines on the use of GLP-1 receptor agonists and SGLT2 inhibitors according to frailty status could improve management of type 2 diabetes.

Ministry of Education, Taiwan.

People with type 2 diabetes mellitus (T2DM) are at higher risk of developing cardiovascular disease, heart failure, chronic kidney disease, and premature death than people without diabetes. Therefore, treatment of diabetes aims to reduce these complications. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown beneficial effects on cardiorenal and metabolic health beyond glucose control, making them a promising class of drugs for achieving the ultimate goals of diabetes treatment. However, despite their proven benefits, the use of SGLT2 inhibitors in eligible patients with T2DM remains suboptimal due to reports of adverse events. The use of SGLT2 inhibitors is particularly limited in older patients with T2DM because of the lack of treatment experience and insufficient long-term safety data. This article comprehensively reviews the risk-benefit profile of SGLT2 inhibitors in older patients with T2DM, drawing on data from prospective randomized controlled trials of cardiorenal outcomes, original studies, subgroup analyses across different age groups, and observational cohort studies.

Acute coronary syndrome (ACS) poses a significant global health burden despite advancements in its management. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, primarily used in type 2 diabetes mellitus (T2DM), have gained recent consideration as potential agents for ACS management due to their cardiovascular benefits beyond glycemic control. This study aimed to assess the effects of empagliflozin on left cardiac parameters in ACS patients. PubMed, Cochrane, Scopus, and Web of Science were searched thoroughly to identify relevant randomized controlled trials (RCTs). Four RCTs involving 701 patients were included. Compared to placebo, empagliflozin significantly reduced left ventricular end-systolic volume index (mean difference (MD): -2.38, 95% CI: -3.95 to -0.80, p = 0.0032), left ventricular mass index (MD: -2.76, 95% CI: -4.95 to -0.56, p = 0.0137), and left ventricular filling pressure (MD: -0.59, 95% CI: -1.07 to -0.10, p = 0.0189). However, empagliflozin treatment did not yield a statistically significant change in left ventricular ejection fraction (MD: 1.21, 95% CI: -0.05 to 2.48, p = 0.0603) nor a significant change in left ventricular end-diastolic volume (MD: -4.49, 95% CI: -14.24 to 5.26, p = 0.37), left ventricular end-systolic volume (MD: -5.19, 95% CI: -10.77 to 0.39, p = 0.0682), and left ventricular end-diastolic volume index (MD: -2.20, 95% CI: -4.59 to 0.19, p = 0.0718). Empagliflozin provides favorable effects on left cardiac structural parameters in ACS patients. This suggests a potential role for SGLT2 inhibitors as adjunctive therapy in ACS management, warranting further investigation into their mechanisms and long-term clinical outcomes.

In 2022, in Italy, general practitioners (GPs) have been allowed to prescribe SGLT2i in Type 2 Diabetes (T2D) under National Health Service (NHS) reimbursement. In the pivotal clinical trial named DECLARE-TIMI 58, dapagliflozin reduced the risk of hospitalization for heart failure, CV death and kidney disease progression compared to placebo in a population of T2D patients. This study evaluated the health and economic impact of dapagliflozin for T2D patients who had or were at risk for atherosclerotic cardiovascular disease in the Italian GPs setting.

A budget impact model was developed to assess the health and economic impact of introducing dapagliflozin in GPs setting. The analysis was conducted by adopting the Italian NHS perspective and a 3-year time horizon. The model estimated and compared the health outcomes and direct medical costs associated with a scenario with dapagliflozin and other antidiabetic therapies available for GPs prescription (scenario B) and a scenario where only other antidiabetic therapies are available (scenario A). Rates of occurrence of cardiovascular and renal complications as well as adverse events were captured from DECLARE-TIMI 58 trial and the literature, while cost data were retrieved from the Italian tariff and the literature. One-way sensitivity analyses were conducted to test the impact of model parameters on the budget impact.

The model estimated around 442.000 patients eligible for the treatment with dapagliflozin in the GPs setting for each simulated year. The scenario B compared to scenario A was associated with a reduction in the occurrence of cardiovascular and renal complication (-1.83%) over the 3 years simulated. Furthermore, the scenario A allowed for an overall cost saving of 102,692,305€: 14,521,464€ in the first year, 33,007,064€ in the second and 55,163,777€ in the third. The cost of cost of drug acquisition, the probability of cardiovascular events and the percentage of patients potentially eligible to the treatment were the factor with largest impact on the results.

The use of dapagliflozin in GPs setting reduce the number of CVD events, kidney disease progression and healthcare costs in Italy. These data should be considered to optimize the value produced for the T2D patients who had or were at risk for atherosclerotic cardiovascular disease.

In patients with bilateral primary hyperaldosteronism (PA) and those with unilateral PA who are unwilling or unable to undergo adrenalectomy an increase in plasma renin activity (PRA) provided by mineralocorticoid receptor antagonists (MRAs) therapy reflects sufficient antagonism for elevated aldosterone. Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) have cardiovascular, renal protective properties and some clinical data have shown an increase in PRA levels with SGLT2-i. Here, we present our experience of using SGLT2-i in PA patients with suppressed PRA despite 100 mg/day spironolactone therapy.

We prospectively evaluate the laboratory values of seven patients who were diagnosed with bilateral hyperaldosteronism. All of them were diabetic and had an HbA1c <7% with metformin treatment alone. Spironolactone was started in all of the patients after diagnosis and although the dose was increased to 100 mg/day, PRA levels remained <1 ng/ml/h. Metformin treatment was changed to empagliflozin in all patients and PRA was checked again at the sixth month of treatment.

Metformin treatment was changed to empagliflozin in all patients and PRA was checked again at the sixth month of treatment. Mean PRA levels were 0.464 ± 0.189 ng/ml/h before the treatment change and increased to mean 3.257 ± 1.881 ng/ml/h in the sixth month ( P  = 0.008). The mean PRA was >1 ng/ml/h except for one patient in the sixth month of treatment.

Larger molecular and clinical studies are needed to understand whether the increase in PRA after empagliflozin treatment indicates interference, whether spironolactone treatment has become more effective, or whether empagliflozin has aldosterone receptor antagonism apart from its known effects.

Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.

Accumulating evidence shows that sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce adverse cardiovascular outcomes. However, whether SGLT2i, compared with other antidiabetic drugs, reduce the new development of atrial fibrillation (AF) is unclear. In this study, we compared SGLT2i with dipeptidyl peptidase-4 inhibitors (DPP-4is) in terms of reduction in the risk of AF in individuals with type 2 diabetes.

We included 42,786 propensity score-matched pairs of SGLT2i and DPP-4i users without previous AF diagnosis using the Korean National Health Insurance Service database between May 1, 2016, and December 31, 2018.

During a median follow-up of 1.3 years, SGLT2i users had a lower incidence of AF than DPP-4i users (1.95 vs. 2.65 per 1,000 person-years; hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.55-0.97; p=0.028]). In individuals without heart failure, SGLT2i users was associated with a decreased risk of AF incidence (HR, 0.70; 95% CI, 0.52-0.94; p=0.019) compared to DPP-4i users. However, individuals with heart failure, SGLT2i users was not significantly associated with a change in risk (HR, 1.04; 95% CI, 0.44-2.44; p=0.936).

In this nationwide cohort study of individuals with type 2 diabetes, treatment with SGLT2i was associated with a lower risk of AF compared with treatment with DPP-4i.

This study investigated whether initial SGLT2 (sodium-glucose cotransporter 2) inhibitor-based treatment is superior to metformin-based regimens as a primary prevention strategy among low-risk patients with diabetes.

In this nationwide cohort study, a total of 38 496 patients with diabetes with low cardiovascular risk were identified (age 62.0±11.6 years, men 50%) from January 1 to December 31, 2016. Patients receiving SGLT2 inhibitors-based and metformin-based regimens were 1:2 matched by propensity score. Study outcomes included all-cause mortality, cardiovascular death, hospitalization for heart failure, stroke, and progression to end-stage renal disease. Compared with 1928 patients receiving metformin-based regimens, 964 patients receiving SGLT2 inhibitor-based regimens had similar all-cause mortality (hazard ratio [HR], 0.75 [95% CI, 0.51-1.12]), cardiovascular death (HR, 0.69 [95% CI, 0.25-1.89]), hospitalization for heart failure (HR, 1.06 [95% CI, 0.59-1.92]), stroke (HR, 0.78 [95% CI, 0.48-1.27]), and progression to end-stage renal disease (HR, 0.88 [95% CI, 0.32-2.39]). However, SGLT2 inhibitors were associated with a lower risk of all-cause mortality (HR, 0.47 [95% CI, 0.23-0.99]; P for interaction=0.008) and progression to end-stage renal disease (HR, 0.22 [95% CI, 0.06-0.82]; P for interaction=0.04) in patients under the age of 65.

In comparison to metformin-based regimens, SGLT2 inhibitor-based regimens showed a similar risk of all-cause mortality and adverse cardiorenal events. SGLT2 inhibitors might be considered as first-line therapy in select low-risk patients, for example, younger patients with diabetes.

We aimed to assess the effect of SGLT2i on arrhythmias by conducting a meta-analysis using data from randomized controlled trials(RCTs).

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have shown cardioprotective effects via multiple mechanisms that may also contribute to decrease arrhythmias risk.

We searched in databases (PubMed, Embase, Cochrane Library, and clinicaltrials.gov) up to April 2023. RCTs comparing SGLT2i with placebo were included. The effects of SGLT2i on atrial fibrillation(AF), atrial flutter(AFL), composite AF/AFL, ventricular fibrillation(VF), ventricular tachycardia(VT), ventricular extrasystoles(VES), sudden cardiac death(SCD) and composite VF/VT/SCD were evaluated.

33 placebo-controlled RCTs were included, comprising 88,098 patients (48,585 in SGLT2i vs. 39,513 in placebo). The mean age was 64.9 ± 9.4 years, 63.0% were male. The mean follow-up was 1.4 ± 1.1 years. The pooled-results showed that SGLT2i was associated with a significantly lower risk of AF [risk ratio(RR): 0.88, 95% confidence interval(CI) 0.78-1.00, P = 0.04] and composite AF/AFL (RR: 0.86, 95%CI 0.77-0.96, P = 0.01). This favorable effect appeared to be substantially pronounced in patients with HFrEF, male gender, dapagliflozin, and > 1 year follow-up. For SCD, only in heart failure patients, SGLT2i were found to be associated with a borderline lower risk of SCD (RR: 0.67, P = 0.05). No significant effects of SGLT2i on other ventricular arrhythmic outcomes were found.

SGLT2i lowers the risks of AF and AF/AFL, and this favorable effect appeared to be particularly pronounced in patients with HFrEF, male gender, dapagliflozin, and longer follow-up (> 1 year). SGLT2i lowers the risk of SCD only in heart failure patients.

Dapagliflozin, one of the sodium-glucose cotransporter-2 inhibitors, has been widely used for the treatment of type 2 diabetes mellitus (T2DM) and heart failure. In this study, we sought to determine the impact of dapagliflozin on the outcome of radiofrequency catheter ablation (RFCA) for patients with T2DM and atrial fibrillation (AF).

This retrospective study included patients who underwent AF ablation between January 2019 to February 2021 at the First Affiliated Hospital of Zhengzhou University. All patients had a history of T2DM and were divided into the dapagliflozin group (n = 79) and the control group (n = 247) according to whether the patients were treated with dapagliflozin after ablation. The definition of AF recurrence was documented atrial arrhythmias over 30 s after a 1-month blanking period. Cox regression models were used to analyze the risk of AF recurrence.

Overall, 326 patients were analyzed (mean age, 63.7±10.0 years old; male, 58.9%; paroxysmal AF, 52.8%; recurrence rate, 40.8%). We found that hemoglobin A1c before ablation was higher in the dapagliflozin group than in the control group (7.7±1.4 vs. 7.3±1.2, P = 0.007). After a mean follow-up of 15.5±8.9 months, the dapagliflozin group had a lower recurrence rate than the control group (27.8% vs. 44.9%, P = 0.007). Treatment with dapagliflozin (HR 0.614, ±95%CI 0.387-0.974, P = 0.038) was associated with a lower risk of recurrence of atrial arrhythmias (ATa) after ablation in multivariable Cox regression models that adjusted for duration of AF, BMI, AF type, left atrial diameter (LAD), and eGFR. The Cox regression model that incorporated hemoglobin A1c and other antidiabetic agents also demonstrated a similar reduction in the risk of recurrent atrial arrhythmias with dapagliflozin treatment (HR 0.611, ±95% CI 0.379-0.985, P = 0.043).

In patients with T2DM, treatment with dapagliflozin appears to be independently associated with a significant reduction in the risk of recurrent atrial arrhythmias after RFCA.

Coronary heart disease is a narrowing or obstruction of the vascular cavity caused by atherosclerosis of the coronary arteries, which leads to myocardial ischemia and hypoxia. At present, percutaneous coronary intervention (PCI) is an effective treatment for coronary atherosclerotic heart disease. Restenosis is the main limiting factor of the long-term success of PCI, and it is also a difficult problem in the field of intervention. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new oral glucose-lowering agent used in the treatment of diabetes in recent years. Recent studies have shown that SGLT2 inhibitors can effectively improve the prognosis of patients after PCI and reduce the occurrence of restenosis. This review provides an overview of the clinical studies and mechanisms of SGLT2 inhibitors in the prevention of restenosis, providing a new option for improving the clinical prognosis of patients after PCI.

Metabolic effects of empagliflozin treatment include lowered glucose and insulin concentrations, elevated free fatty acids and ketone bodies and have been suggested to contribute to the cardiovascular benefits of empagliflozin treatment, possibly through an improved cardiac function. We aimed to evaluate the influence of these metabolic changes on cardiac function in patients with T2D.

In a randomized cross-over design, the SGLT2 inhibitor empagliflozin (E) was compared with insulin (I) treatment titrated to the same level of glycemic control in 17 patients with type 2 diabetes, BMI of > 28 kg/m2, C-peptide > 500 pM. Treatments lasted 5 weeks and were preceded by 3-week washouts (WO). At the end of treatments and washouts, cardiac diastolic function was determined with magnetic resonance imaging from left ventricle early peak-filling rate and left atrial passive emptying fraction (primary and key secondary endpoints); systolic function from left ventricle ejection fraction (secondary endpoint). Coupling between cardiac function and fatty acid concentrations, was studied on a separate day with a second scan after reduction of plasma fatty acids with acipimox. Data are Mean ± standard error. Between treatment difference (ΔT: E-I) and treatments effects (ΔE: E-WO or ΔI: I -WO) were evaluated using Students' t-test or Wilcoxon signed rank test as appropriate.

Glucose concentrations were similar, fatty acids, ketone bodies and lipid oxidation increased while insulin concentrations decreased on empagliflozin compared with insulin treatment. Cardiac diastolic and systolic function were unchanged by either treatment. Acipimox decreased fatty acids with 35% at all visits, and this led to reduced cardiac diastolic (ΔT: -51 ± 22 ml/s (p < 0.05); ΔE: -33 ± 26 ml/s (ns); ΔI: 37 ± 26 (ns, p < 0.05 vs ΔE)) and systolic function (ΔT: -3 ± 1% (p < 0.05); ΔE: -3 ± 1% (p < 0.05): ΔI: 1 ± 2 (ns, ns vs ΔE)) under chronotropic stress during empagliflozin compared to insulin treatment.

Despite significant metabolic differences, cardiac function did not differ on empagliflozin compared with insulin treatment. Impaired cardiac function during acipimox treatment, could suggest greater cardiac reliance on lipid metabolism for proper function during empagliflozin treatment in patients with type 2 diabetes.

EudraCT 2017-002101-35, August 2017.

Dapagliflozin has been widely used for the treatment of type 2 diabetes mellitus (T2DM) and heart failure (HF). However, data concerning the association between dapagliflozin and the recurrence of atrial fibrillation (AF), especially in patients following Cox-Maze IV (CMIV), are rare. We aim to explore the effect of dapagliflozin on the recurrence of AF after CMIV with and without T2DM or HF.

The study of dapagliflozin evaluation in AF patients followed by CMIV (DETAIL-CMIV) is a prospective, double-blind, randomized, placebo-controlled trial. A total of 240 AF patients who have received the CMIV procedure will be randomized into the dapagliflozin group (10 mg/day, n = 120) and the placebo group (10 mg/day, n = 120) and treated for 3 months. The primary endpoint is any documented atrial tachyarrhythmia (AF, atrial flutter or atrial tachycardia) lasting 30 s following a blanking period of 3 months after CMIV.

DETAIL-CMIV will determine whether the sodium-glucose cotransporter-2 inhibitor dapagliflozin, added to guideline-recommended post-operative AF therapies, safely reduces the recurrence rate of AF in patients with and without T2DM or HF.

Aims: This study aimed to investigate the association between the use of sodium-glucose transporter 2 inhibitors (SGLT-2i) and the risk of diabetic ketoacidosis (DKA), lower limb amputation (LLA), urinary tract infections (UTI), genital tract infections (GTI), bone fracture, and hypoglycemia in cohort studies. Methods: A systematic search was conducted in the PubMed and Embase databases to identify cohort studies comparing the safety of SGLT-2i versus other glucose-lowering drugs (oGLD) in patients with type 2 diabetes mellitus (T2DM). The quality of the studies was assessed using the Newcastle-Ottawa Scale. Primary endpoints were DKA and LLA, while secondary endpoints included UTI, GTI, bone fracture, and hypoglycemia. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Results: A total of 9,911,454 patients from 40 cohort studies were included in the analysis. SGLT-2i use was associated with a higher risk of DKA (HR: 1.21, 95% CI: 1.07-1.38, p = 0.003) and GTI (HR: 2.72, 95% CI: 2.48-2.98, p < 0.01). However, it was not associated with an increased risk of LLA (HR: 1.06, 95% CI: 0.92-1.23, p = 0.42), UTI (HR: 0.99, 95% CI: 0.89-1.10, p = 0.83), or bone fracture (HR: 0.99, 95% CI: 0.94-1.04, p = 0.66). Furthermore, SGLT-2i was associated with a reduced risk of hypoglycemia. Furthermore, compared to dipeptidyl peptidase 4 inhibitors, SGLT-2i as a class and individually was associated with an increased risk of DKA. Canagliflozin specifically increased the risk of LLA (HR: 1.19, 95% CI: 1.04-1.36, p = 0.01). The subgroup analysis suggested that SGLT-2i increased the risk of LLA among patients with a history of cardiovascular disease. Conclusion: SGLT-2i versus oGLD was associated with a similar occurrence of LLA, UTI, and bone fracture. However, SGLT-2i was associated with a higher risk of DKA and GTI than oGLD. These findings provide valuable information on the safety profile of SGLT-2i in patients with T2DM and can help inform clinical decision-making.

Acute coronary syndrome (ACS) remains the leading cause of death and disability worldwide, especially when combined with type 2 diabetes mellitus (T2DM). Many multicenter randomized controlled trials have established the cardiovascular benefits of Sodium-Glucose cotransporter 2 inhibitors (SGLT-2i) in patients with T2DM at high cardiovascular risk. However, these studies did not include patients in the early stages of acute coronary events. This study investigated the cardiovascular protective effects of SGLT-2i in patients with ACS and T2DM.

A total of 232 hospitalized patients with ACS and T2DM were enrolled and divided into two groups based on their hypoglycemic drug treatment: the SGLT-2i and the non-SGLT-2i groups. Kaplan-Meier analysis and Cox regression were used to compare adverse cardiovascular outcomes in both groups.

There were no significant differences in the hospital clinical outcomes between the SGLT-2i and non-SGLT-2i groups. The adverse cardiovascular outcomes did not significantly differ between both groups (hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.35-1.25, P = 0.195). Moreover, the rehospitalization rates for ACS or heart failure (HF) were not significantly different between both groups (adjusted HR 0.56, 95%CI 0.28-1.10, P = 0.093). When analyzed separately, there was no significant difference in rehospitalizations for ACS (HR 0.87, 95% CI 0.40-1.87, P = 0.713). However, the SGLT-2i group showed lower rates of rehospitalizations for HF (adjusted HR 0.20, 95% CI 0.04-0.96, P = 0.045). Additionally, there was no significant difference in cardiovascular mortality between both groups (HR 1.75, 95% CI 0.28-10.97, P = 0.543). Notably, the SGLT-2i group exhibited a higher angina symptom control rate than the non-SGLT-2i group (adjusted odd ration (OR) 0.45, 95%CI 0.21-0.93, P = 0.031).

In recently diagnosed patients with ACS, who have T2DM, early initiation of SGLT-2i was associated with a lower risk of rehospitalization for HF and a higher rate of angina symptom control.

A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.

We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.

Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.

Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.

Endothelial dysfunction is a critical and initiating factor of the vascular complications of diabetes. Inflammation plays an important role in endothelial dysfunction regulated by epigenetic modifications. N6-methyladenosine (m6A) is one of the most prevalent epigenetic modifications in eukaryotic cells. In this research, we identified an m6A demethylase, fat mass and obesity-associated protein (FTO), as an essential epitranscriptomic regulator in diabetes-induced vascular endothelial dysfunction. We showed that enhanced FTO reduced the global level of m6A in hyperglycemia. FTO knockdown in endothelial cells (ECs) resulted in less inflammation and compromised ability of migration and tube formation. Compared with EC Ftofl/fl diabetic mice, EC-specific Fto-deficient (EC FtoΔ/Δ) diabetic mice displayed less retinal vascular leakage and acellular capillary formation. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) combined with RNA-Seq indicated that Tnip1 served as a downstream target of FTO. Luciferase activity assays and RNA pull-down demonstrated that FTO repressed TNIP1 mRNA expression by erasing its m6A methylation. In addition, TNIP1 depletion activated NF-κB and other inflammatory factors, which aggravated retinal vascular leakage and acellular capillary formation, while sustained expression of Tnip1 by intravitreal injection of adeno-associated virus alleviated endothelial impairments. These findings suggest that the FTO-TNIP1-NF-κB network provides potential targets to treat diabetic vascular complications.

Studies that have reported lower risk for cardiovascular outcomes in users of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF).

Adults initiating empagliflozin and DPP-4i in 2014-2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64-0.86), CVM (HR 0.55; 95% CI 0.38-0.80), HHF or CVM (HR 0.57; 95% CI 0.48-0.67) and stroke (HR 0.79; 95% CI 0.67-0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF.

These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status.

Use of sodium glucose cotransporter 2 inhibitors (SGLT2i) was associated with a reduction in atrial fibrillation hospitalizations. Therefore, we aim to evaluate the effects of SGLT2i on atrial tachy-arrhythmias (ATA) in patients with cardiac implantable electronic devices (CIEDs).

All 13 888 consecutive patients implanted with a CIED in two tertiary medical centers were enrolled. Treatment with SGLT2i was assessed as a time dependent variable. The primary endpoint was the total number of ATA. Secondary endpoints included total number of ventricular tachy-arrhythmias (VTA), ATA and VTA, and death. All events were independently adjudicated blinded to the treatment. Multivariable propensity score modeling was performed.

During a total follow-up of 24 442 patient years there were 62 725 ATA and 10 324 VTA events. Use of SGLT2i (N = 696) was independently associated with a significant 22% reduction in the risk of ATA (hazard ratio [HR] = 0.78 [95% confidence interval {CI} = 0.70-0.87]; p < .001); 22% reduction in the risk of ATA/VTA (HR = 0.78 [95% CI = 0.71-0.85]; p < .001); and with a 35% reduction in the risk of all-cause mortality (HR = 0.65 [95% CI = 0.45-0.92]; p = .015), but was not significantly associated with VTA risk (HR = 0.92 [95% CI = 0.80-1.06]; p = .26). SGLT2i were associated with a lower ATA burden in heart failure (HF) patients but not among diabetes patients (HF: HR = 0.68, 95% CI = 0.58-0.80, p < .001 vs. Diabetes: HR = 0.95, 95% CI = 0.86-1.05, p = .29; p < .001 for interaction between SGLT2i indication and ATA burden).

Our real world findings suggest that in CIED HF patients, those with SGLT2i had a pronounced reduction in ATA burden and all-cause mortality when compared with those not on SGLT2i.

Background Whether the early use of sodium-glucose cotransporter-2 (SGLT2) inhibitors have cardioprotective effects following acute myocardial infarction is unknown. Thus, we aimed to evaluate the association between the early initiation of SGLT2 inhibitors and cardiac event rates in patients with diabetes with acute myocardial infarction undergoing percutaneous coronary intervention. Methods and Results Based on the National Health Insurance claims data in South Korea, patients who received percutaneous coronary intervention for acute myocardial infarction between 2014 and 2018 were analyzed. Patients given SGLT2 inhibitors or other glucose-lowering drugs were matched based on a propensity score. The primary end point was a composite of all-cause mortality and hospitalizations for heart failure. Major adverse cardiac events (a composite of all-cause death, nonfatal myocardial infarction, and ischemic stroke) were compared as the secondary end point. After 1:2 propensity score matching, the SGLT2 inhibitors group (938 patients) and the no use of SGLT2 inhibitors group (1876 patients) were compared. During a median follow-up of 2.1 years, the early use of SGLT2 inhibitors was associated with lower risks of both the primary end point (9.8% versus 13.9%; adjusted hazard ratio [HR], 0.68 [95% CI, 0.54-0.87]; P=0.002) and secondary end point (9.1% versus 11.6%; adjusted HR, 0.77 [95% CI, 0.60-0.99]; P=0.04). All-cause mortality and hospitalizations for heart failure were also significantly lower in early users of SGLT2 inhibitors. Conclusions The early use of SGLT2 inhibitors in patients with diabetes treated with percutaneous coronary intervention for acute myocardial infarction was associated with a significantly lower risk of cardiovascular events, including all-cause mortality, hospitalizations for heart failure, and major adverse cardiac events.

Endothelial cells (ECs) angiogenesis is the process of sprouting new vessels from the existing ones, playing critical roles in physiological and pathological processes such as wound healing, placentation, ischemia/reperfusion, cardiovascular diseases and cancer metastasis. Although mitochondria are not the major sites of energy source in ECs, they function as important biosynthetic and signaling hubs to regulate ECs metabolism and adaptations to local environment, thus affecting ECs migration, proliferation and angiogenic process. The understanding of the importance and potential mechanisms of mitochondria in regulating ECs metabolism, function and the process of angiogenesis has developed in the past decades. Thus, in this review, we discuss the current understanding of mitochondrial proteins and signaling molecules in ECs metabolism, function and angiogeneic signaling, to provide new and therapeutic targets for treatment of diverse cardiovascular and angiogenesis-dependent diseases.

To assess the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and other second-line diabetes therapies with risk of cardiovascular disease (CVD), as well as conduct head-to-head comparisons between SGLT2 inhibitors.

Using data from the MarketScan databases (January 1, 2013, through December 31, 2019), SGLT2 inhibitor users were matched with up to five other second-line therapy users by age, sex, date of enrollment, and date of second-line therapy initiation. The primary composite outcome included stroke, atrial fibrillation, myocardial infarction, and heart failure. Hazard ratios were estimated, adjusting for demographics and a propensity score reflecting comorbidities and medications.

In this study population of 313,396 patients (mean age 53±10 years; 47% female), 9787 incident CVD events occurred over a median follow-up of 1.36 years. After multivariable adjustments, SGLT2 inhibitor users had a lower risk of CVD than other second-line therapy users (HR, 0.66; 95% CI, 0.62 to 0.71). Significant associations were also observed when each CVD outcome was assessed separately. No differences were noted when comparing individual SGLT2 inhibitors.

SGLT2 inhibitors were associated with a clinically meaningfully lower CVD risk in the real-world setting. In head-to-head comparisons, the different SGLT2 inhibitors were consistent in their protective associations with CVD. This suggests that as a class, SGLT2 inhibitors may have widespread benefit in preventing CVD among patients with type 2 diabetes.

A precision medicine approach in type 2 diabetes requires identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.

We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes.

After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review. The majority of papers had methodological limitations precluding robust assessment of treatment effect heterogeneity. For glycaemic outcomes, most cohorts were observational, with multiple analyses identifying lower renal function as a predictor of lesser glycaemic response with SGLT2-inhibitors and markers of reduced insulin secretion as predictors of lesser response with GLP1-receptor agonists. For cardiovascular and renal outcomes, the majority of included studies were post-hoc analyses of randomized control trials (including meta-analysis studies) which identified limited clinically relevant treatment effect heterogeneity.

Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.

This review identifies research that helps understand which clinical and biological factors that are associated with different outcomes for specific type 2 diabetes treatments. This information could help clinical providers and patients make better informed personalized decisions about type 2 diabetes treatments. We focused on two common type 2 diabetes treatments: SGLT2-inhibitors and GLP1-receptor agonists, and three outcomes: blood glucose control, heart disease, and kidney disease. We identified some potential factors that are likely to lessen blood glucose control including lower kidney function for SGLT2-inhibitors and lower insulin secretion for GLP1-receptor agonists. We did not identify clear factors that alter heart and renal disease outcomes for either treatment. Most of the studies had limitations, meaning more research is needed to fully understand the factors that influence treatment outcomes in type 2 diabetes.

Continued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies.

The EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014-2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary endpoints included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined.

Among 83,946 matched patient pairs, (0·7 years overall mean follow-up time), initiation of empagliflozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0·70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0·55; 0·48 to 0·63), stroke (0·82; 0·71 to 0·96), and end-stage renal disease (0·43; 0·30 to 0·63) were lower and risk for myocardial infarction, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1·97; 1·28 to 3·03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions.

Results from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors.

Type 2 diabetes mellitus (T2DM) is a highly prevalent health condition in the aging population. Older adults with T2DM have higher risks of cardiovascular disease, heart failure (long underestimated) and premature death than those without diabetes. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven their ability to improve cardiovascular prognosis and reduce the risk of hospitalization for heart failure (hHF). However, several adverse events have been reported, whose incidence and severity might be increased in the elderly population. The aims of this comprehensive review were to analyze the benefit-risk ratio of SGLT2i therapy in older patients with T2DM by collecting data from (i) large prospective placebo-controlled cardiovascular outcome trials (including those dedicated to heart failure), using both original publications and dedicated post-hoc analyses across different age groups and (ii) observational cohort studies, describing the effects of SGLT2is versus other glucose-lowering agents on cardiovascular outcomes and hHF in elderly patients or these effects in different age groups. Overall, consistent results showed a similar relative risk reduction in cardiovascular mortality and hHF with SGLT2is independently of age. The absolute risk reduction may be greater in elderly because of a higher background risk in older versus younger patients. Similarly, the safety profile of SGLT2is appeared comparable in older versus younger patients. In conclusion, the benefit/risk balance favors the use of SGLT2is in older patients at risk of cardiovascular disease and/or heart failure. Caution may be required in very old frail patients, especially those exposed to an increased risk of volume depletion.