SGLT2 Inhibitors Research Articles

All cause mortality in people with type 2 diabetes using SGLT-2 inhibitors compared to DPP4 inhibitors using the danish registries

Abstract Background The SGLT-2 inhibitors outcome trials such as EMPA-REG have had significant impact on the treatment and management of patients with type 2 diabetes. Using real world danish data simulating EMPA-REG criteria can demonstrate the efficacy of SGLT-2 in real world clinical settings. Aim The purpose of this study is to evaluate the efficacy of SGLT-2 in reducing all-cause mortality in people with type 2 diabetes (T2D) over a 5-year period, using real world data. We compared all cause mortality between those prescribed SGLT-2 and DPP4 inhibitors in a population resembling the EMPA-REG trial. DPP4 is selected as a comparator to SGLT-2 given it is known to be neutral with regards to cardiovascular disease (CVD). Methods Individuals were identified using Danish nationwide registries. This estimate was performed using in/exclusion criteria from EMPA-REG. We defined time zero as the first date the patient redeems either SGLT-2/DPP4. Individuals >=50 years of age with verified T2D and established CVD were included. CVD included myocardial infarctions, ischemic heart disease, stroke and heart failure. Individuals were only included if they had Hba1c at baseline > 53 mmol/mol (7.0%) The primary endpoint was all cause mortality. Survival was estimated using a Kaplan-Meier estimator in both arms. P values of less than 5% are considered significant. Results A total of 150.313 patients were identified to be on either DPP4-inhibitors or SGLT2 between 2012 and 2022. After applying EMPA-REG inclusion and exclusion criteria 15.461 patients remained (8518 on DPP4 and 6943 on SGLT2). The 5 year survival rate of SGLT2 and DPP4 was 0.780 and 0.657 respectively (p-value<0.0001). Conclusion In conclusion, we demonstrate, using EMPA-REG trial criteria in real-world data based on Danish nationwide registries, that five year mortality of people with T2D treated with SGLT-2 inhibitor was lower than those treated with DPP4 inhibitor.

SGLT2 inhibitors in patients with amyloidosis and heart failure: a worldwide retrospective cohort study

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the combined risk of death and hospitalization in patients with heart failure with reduced or preserved left ventricular ejection fraction. However, evidence of their impact on patients with heart failure due to amyloidosis is lacking. Purpose To evaluate the effects of SGLT2 inhibitors on mortality and hospitalization in patients with amyloidosis and heart failure. Methods In this retrospective cohort study, we used real-world data from 108 healthcare organizations worldwide from the global health research collaborative network TriNetX. We identified 24,619 patients with amyloidosis and heart failure without exposure to SGLT2 inhibitors (control group) and 2,988 patients with amyloidosis and heart failure under treatment with SGLT2 inhibitors (SGLTi group). We performed propensity score matching for demographic and clinical characteristics and Kaplan–Meier plots, log-rank tests, and Cox proportional hazard models were calculated. The outcomes were 12-month all-cause death and 12-month hospitalization. Results After propensity score matching, 2,237 patients were analyzed in each group. During the 12-month follow-up, 198 (8.8%) patients died in the SGLT2i group, and 431 (19.2%) patients died in the control group (hazard ratio 0.51, 95% CI 0.43-0.61). In the SGLT2i group, 974 (44.5%) patients were hospitalized, and in the control group, 1508 (53.5%) patients were hospitalized (hazard ratio 0,79, 95% CI 0.72-0.86). The Kaplan-Meier curves are shown in Figure 1. Conclusions In conclusion, in this retrospective cohort study with a large number of patients with amyloidosis and heart failure, SGLT2 inhibitors were associated with a lower 12-month all-cause mortality and hospitalization. Further evidence from randomized controlled studies are needed to confirm the efficacy of SGLT2 inhibitors in patients with cardiac amyloidosis.Figure 1.Kaplan-Meier curves

Risk of Incident colorectal carcinoma in patients with type 2 diabetes on SGLT-2 inhibitor users: a population-based cohort study

Abstract Background Patients with type 2 diabetes (T2D) are at substantially higher risk for developing colorectal carcinoma (CC) than the general population. Clinical studies have investigated the effects of sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use on the development of incident CC in patients with T2D, but the findings are inconsistent. Purpose This study aimed to examine the association between SGLT-2i use and incident CC risk in patients with T2D. Methods We conducted a nationwide retrospective cohort study using the National Health Insurance Research Database (2015–2021). The primary outcome was the risk of incident CC by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Therefore, multiple Cox regression modeling was conducted to analyze the association between SGLT-2i use and incident CC risk in patients with T2D. Results 268,495 propensity score-matched pairs of patients with T2D using SGLT-2i and non-using SGLT-2i, 1557 and 1264 incident CCs were recorded, respectively. There was a decreased risk of incident CC for SGLT-2i users after adjusting for the index year, sex, age, comorbidities, and concurrent medication (adjusted HR 0.79, 95% CI 0.74–0.84) compared with non-SGLT-2i users. The sensitivity test for the propensity score 1:2-matched analyses showed similar result (adjusted HR 0.79, 95% CI 0.74–0.85). Conclusions This population-based cohort study found that SLGT2i user was associated with a lower risk of CC by 21% compared to non-SGLT-2i users in T2D patients. More studies are needed to credibly evaluate the effects of SGLT-2i therapy on CC prevention in patients with T2D.

Empaglifozin modifies the arterial stiffness in type-2 diabetic patients: a preliminary report.

Abstract Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors demonstrated beneficial effects on cardiovascular and renal events in patients with type 2 diabetes mellitus. The mechanisms underlying these effects are not fully elucidated. Aim of this study was to investigate whether empagliflozin is able to modify the arterial stiffness in type 2 diabetic patients. Methods Pulse wave velocity (PWV) and other parameters of arterial stiffness were assessed before and after adding empagliflozin to a traditional antidiabetic treatment in 16 consecutive T2DM outpatients folowed for 3 months. Arterial stiffness were evaluted using SphygmoCor ECEL measuring the pulse waveform of the arterial pulse moving from tha descending aorta to the femoral artery (PWV). Data obtained from the diabetic population has been compared to 16 T2DM outpatients not treated with SGLT2 inhibitors. Results In the two groups differences according gender distribution or duration of diabetes mellitus did not emerge. However the empagliflozin group was younger compared to controls (64.1±8.68 vs 74.45±8.13, P < 0.05). Empagliflozin treatment significantly decreased HbA1c after 12 weeks of treatment (7.9±0.78 vs 7.04±1.09%, P < 0.008.). After 12 weeks’ treatment, empagliflozin significantly improved PWV compared to controls not treated with SGLT2-i (ΔPWVV -0.68±1.1 vs 0.89±1,6 p <0.004, P = 0.0065 with age and HbA1c as covariates). Moreover body weight significantly decreased in the empagliflozin group (86.75±16.16 vs 81.71±16.5 kg, p =0.001) compared to controls (in whom remained unchanged) as long as BMI (30.48±5.4 versus 28.75±5.66 kg/m2, P < 0.002) compared to controls (in whom remained unchanged). Estimated glomerular filtration rate (eGFR) remained unchanged in the two groups during the study whereas urine Albumin to Creatinine ratio significantly improved using empagliflozin (17.8±46.8 vs 12.2±35.7 mg/mmol, P = 0.049). Conclusion In this ‘real clinical practice’ experience, the potential effect of empagliflozin treatment on arterial stiffness in T2DM patients was extensively investigated. Arterial stiffness was significantly decreased adding empaglifozin to the traditional treatment and this result has been obtained after 3-month. Significantly improvement in urine Albumin to Creatinine ratio might suggest an amelioration of endothelial function in those patients that could be involved in reducing arterial stiffness.

SGLT2 inhibitors are associated with development of heart failure with improved ejection fraction

Abstract Background Heart failure (HF) with improved ejection fraction (EF), termed HFimpEF, has been proposed as a new HF classification associated with better clinical outcomes. Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce cardiovascular death and hospitalization for HF irrespective of diabetes. Purpose Analyze the effect of SGLT2 inhibitors on the development of HFimpEF. Methods Consecutive HF with reduced EF (HFrEF) patients with follow-up echocardiogram at around 12 months were enrolled from 2017 to 2022. Patients were classified into HFimpEF (follow-up EF > 40% and ≥ 10% absolute increase) or otherwise persistent HFrEF based on repeat echocardiograms after 12 months. A 1:2 propensity score matched analysis was performed. Results Of all the HFrEF patients in the cohort, 46.6% of patients developed HFimpEF. We matched 93 and 186 patients treated with or without SGLT2 inhibitors according to propensity score. In the matched cohort, treatment with SGLT2 inhibitors was associated with nearly a doubled likelihood of the development of HFimpEF (OR: 1.978 [95% CI 1.184~3.346]). Subgroup analysis revealed this association was only present in HF patients with an ischemic etiology (OR: 3.427 [95% CI 1.614~7.573], P for interaction=0.022). There was no significant interaction term between SGLT2 inhibitors and the presence of diabetes for the development of HFimpEF. Conclusions This study reveals that treatment with SGLT2 inhibitors is associated with increased likelihood of HFimpEF, especially in those with an ischemic etiology.

Comparative outcomes between empagliflozin and dapagliflozin in heart failure: real world multi-center cohort study

Abstract Introduction Heart failure (HF) is a significant global health concern, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as dapagliflozin and empagliflozin, have emerged as important therapeutic options. However, their comparative effectiveness in a real-world population remains uncertain. Purpose The purpose of this multicenter, population-based cohort study was to investigate and compare the outcomes associated with dapagliflozin and empagliflozin use in patients with heart failure. We sought to understand whether these SGLT2 inhibitors had differential effects on cardiovascular events in a real-world setting. Methods We analysed data from a clinical data warehouse encompassing seven medical centers. Subjects diagnosed with heart failure between January 2021 and November 2023, who were prescribed dapagliflozin or empagliflozin, were included. We conducted one-to-one propensity-score matching, ensuring that the dapagliflozin and empagliflozin groups were comparable in baseline characteristics. The primary outcome was a composite of cardiovascular (CV) death or hospitalization for HF, analysed as the first event occurring after starting each medication. Secondary outcomes included individual components, all-cause death, and CV hospitalization. Results Propensity-score matching made a balanced cohort of 6,281 patients (3,111 in the dapagliflozin group and 3,170 in the empagliflozin group). The median follow-up duration was 16.0 months. In the propensity-score matched cohort, dapagliflozin and empagliflozin showed no significant difference in the primary outcome (8.8% versus 7.8%, hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.77-1.08, p=0.276). Similar findings were observed in secondary outcomes. Subgroup analysis revealed potential benefits of empagliflozin in patients with diabetes mellitus (DM) (7.8% versus 5.6%, HR 0.73, 95% CI 0.55-0.98, p=0.039). Conclusion This study suggests that dapagliflozin and empagliflozin have similar clinical outcomes in the management of heart failure in a real-world setting. However, empagliflozin showed result in improving outcomes for HF patients with DM. Further research is warranted to validate these findings and guide clinical decision-making in the individualized management of heart failure.Baseline characteristicsSubgroup analysis

Impact of SGLT2 inhibitors on liver-related outcomes in patients with heart failure - a population-based study in HK

Abstract Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now recommended for heart failure with preserved ejection fraction (HFpEf). While their side effects on respiratory and renal outcomes in patients with type 2 diabetes have been studied, the impact on liver-related diseases within HF patients is not well-established. Purpose This study aims to evaluate the association between SGLT2 inhibitor use and the risks of adverse liver events among HF patients. Methods We conducted a retrospective cohort study using the Hong Kong Clinical Data Analysis and Reporting System (CDARS) to identify 80,248 HF patients (mean age 73.37 ± 12.88 years; 49.2% male) between 2013 and 2022. Propensity score matching was applied to achieve a 1:3 ratio of SGLT2 users to non-users, ensuring balanced baseline characteristics. Competing risk regression within Cox proportional hazards frameworks quantified the risks for cirrhosis, hepatocellular carcinoma, liver-related death, and significant elevations in liver enzymes (ALT or AST >3x normal and bilirubin >2x normal). Results During a median follow-up of 6.02 years (interquartile range: 3.48–9.25 years), there were 12,103 liver-related deaths. SGLT2 was associated with a 52% reduced risk of cirrhosis (adjusted subdistribution hazard ratio [SHR]: 0.48; 95% confidence interval [CI]: 0.36-0.65), a 61% lower risk of hepatocellular carcinoma (SHR: 0.39; 95% CI: 0.26-0.42), a 13% decreased risk of liver-related death (SHR: 0.87; 95% CI: 0.77-0.98), and a 19% risk reduction in elevated liver enzymes (SHR: 0.81; 95% CI: 0.68-0.96). 5-year cumulative incidences were 1.7%, 0.62%, 13%, and 5.4%, respectively, for SGLT2 users compared to 3.7%, 1.9%, 16%, and 7.0% for SGLT2 nonusers. Conclusion SGLT2 use is associated with a decreased risk of adverse liver outcomes in HF patients. This suggests a potential protective role for SGLT2 in liver health within this population.

Combined ARNI and SGLT2i impacts on peak tricuspid regurgitant velocity and echocardiographic probability of pulmonary hypertension

Abstract Background In heart failure with reduced ejection fraction (HFrEF), the development of pulmonary hypertension (PH) is associated with poor prognosis. Recent medical advancements have substantially improved both survival rates and HF hospitalization. However, the impact of combining angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on peak tricuspid regurgitant velocity (TRV) and PH echocardiographic probability remains unexplored. Purpose We aimed to evaluate the effect of ARNI alone versus ARNI combined with SGLT2i on peak TRV and PH probability in a real-life population of outpatients with HFrEF. Methods This was an observational monocentric study including patients treated with either ARNI alone or with SGLT2i on top of ARNI. Echocardiographic examinations were performed by fully accredited operators and all parameters were analysed offline by expert operators blinded to clinical data. We performed echocardiographic evaluation in all patients before initiating treatment and at 12 months follow-up. We excluded patients who discontinued ARNI within 6 months of introduction and those who did not complete at least 6 months of follow-up with both drugs. Results 80 HFrEF patients were included, 41 receiving ARNI+SGLT2i and 39 receiving ARNI alone. Baseline mean peak TRV was similar between the two groups (280±44 cm/s and 259±48 cm/s respectively, p=0.09). At follow-up, mean peak TRV was 232±32 cm/s in ARNI+SGLT2i group and 258±45 cm/s in ARNI alone group (p=0.02). The decrease in peak TRV was significant in ARNI+SGLT2i group, p=0.0004 (Table). At baseline the echocardiographic probability of PH was comparable between both groups, p=0.53 (Figure). Nevertheless, during follow-up, the proportion of patients with high probability of PH decreased in the ARNI+SGLT2i group (from 22% to 2%), while in the ARNI alone group it did not change (Figure). Conclusions In HFrEF the combination of ARNI+SGLT2i demonstrates high effectiveness in TRV reduction, downgrading PH probability class. In our population, this evidence is primarily driven by the decrease TRV. These results may suggest the positive effect of SGLT2i on pulmonary vascular remodelling and right heart hemodynamic worth of full investigation in further studies aimed at targeting left-sided PH and its prevention strategies.

Effect of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on carotid intima-media thickness

Abstract Background/Introduction Type 2 diabetes mellitus (T2DM) is an additional factor for exacerbation of atherosclerosis increasing the risk for ischemic attacks such as coronary artery disease and ischemic stroke. Evaluation of carotid artery atherosclerosis through ultrasound techniques is a useful tool for risk stratification in type 2 diabetic patients. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on carotid intima-media thickness (cIMT) of T2DM patients. Methods A total of 320 T2DM patients were randomized to receive insulin (n = 80), liraglutide (n = 80), empagliflozin (n = 80) or their combination (GLP-1RA+SGLT-2i) (n = 80) as add-on to metformin. At baseline, at 6 and at 12 months of treatment, we measured the maximal thickness of six major points including right and left common carotid, carotid bifurcation and internal carotids. Finally, we calculated the average cIMT of all six segments (three on each side) to get mean cIMT. Results Compared to baseline, all patients had significantly reduced cIMT at 6 and at 12 months of treatment (p < 0.001; Table). A significant interaction of follow-up time with the type of treatment was observed regarding cIMT levels (F = 7.203, p for interaction < 0.001) in a model including age, sex, smoking, baseline body mass index, glucose levels, glycosylated hemoglobin, levels of blood lipids and their changes at 6 and 12 months of treatment as covariates. At 6 months, patients who were treated with GLP-1RA, SGLT-2i and those under the combination GLP-1RA+SGLT-2i showed a greater reduction of cIMT (-2.5%, -2.4% and -5.8%) compared to insulin (-0.8%; p = 0.008, p = 0.022, and p < 0.001, respectively). Moreover, at 12 months patients under GLP-1RA, SGLT-2i and their combination achieved remarkable reduction of cIMT (-7.4%, -4.9% and -10%) than those under insulin (-1.7%, p < 0.001 for all comparisons). Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i and their combination resulted in reduction of cIMT in T2DM. The combined treatment was superior and additive to each regimen separately.Table

Disparities in SGLT2i utilization among heart failure patients with different ejection fraction in China: findings from chinese cardiovascular association database-heart failure center registry

Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are recommended for heart failure (HF) patients regardless of left ventricular ejection fraction (LVEF). Although Chinese HF guidelines still recommend traditional renin–angiotensin–aldosterone system inhibitors, beta blockers, mineralocorticoid receptor antagonists, the Chinese Cardiovascular Association (CCA) HF Center Registry has launched a project to promote the guideline-directed medical therapy (GDMT) for HF patients in China. However, data on the utilization of GDMT in Chinese HF patients is scarce, especially SGLT2i. Purpose We aimed to investigate the usage status of SGLT2i in HF patients with different LVEFs and explore associated factors with SGLT2i adoption in hospitalized HF Chinese patients. Methods This is a retrospective real world study using data from the CCA Database-HF Center Registry. The study included HF patients hospitalized in 52 secondary or tertiary hospitals, including 26 accredited heart failure centers (HFC) and 26 non-accredited heart failure centers (NHFC). Centers that meet the 25 quality control standards established by CCA can be accredited as HFC. We evaluated the use rate of SGLT2i overall and by HF type, as well as the change of SGLT2i usage rate at discharge during the study period from 1st July 2022 to 31st March 2023. LASSO and multivariable logistic regression were also used to explore associated factors of SGLT2i adoption at discharge. Result We included 8,843 hospitalized HF patients: 5,326 (60.2%) were male, 2,980 (33.7%) HFrEF, 1,624 (18.4%) HFmrEF, 3,653 (41.3%) HFpEF and 586 (6.6%) lacked EF data. Overall, SGLT2i were adopted in 3,666 (41.5%) HF patients at discharge (58.1% in HFrEF, 45.3% in HFmrEF, 28.8% in HFpEF). Overall, the usage rate of SGLT2i at discharge rose from 35.2% to 50.2%. Specifically, for HFrEF patients, there was a rise from 56.2% to 64.4%. For HFmrEF and HFpEF patients, the usage rate increased from 37.5% to 54.4% and from 22.2% to 35.7%, respectively (Figure 1). The usage rate of SGLT2i was higher in HFC compared with NHFC (47.1% vs. 35.8%, p<0.001). In multivariable logistic regression, older age, new-onset heart failure, hospital location, etc. were associated with a lower usage rate of SGLT2i at discharge. In contrast, HFC, dilated cardiomyopathy, obesity, etc. were associated with a higher utilization rate of SGLT2i (Figure 2). HF classification by LVEF was also an independent influencing factor even after adjusting other factors; when HFrEF was used as a reference, the use rate of SGLT2i was lower in HFmrEF (OR 0.79, 95% CI 0.69 - 0.91) and HFpEF (OR 0.44, 95% CI 0.39 - 0.49). Conclusion In clinical practice in China, the usage rate of SGLT2i for HF treatment is increasing but needs to be further improved. Disparities exist in usage rates among HF patients with different LVEFs. Addressing this disparity necessitates a targeted approach, emphasizing increased utilization in HF patients regardless of LVEF.SGLT2i usage rate in HFFactors affecting SGLT2i adoption in HF

Sodium-glucose cotransporter 2 inhibitor attenuates left ventricular dysfunction in post-myocardial infarction in rats via reducing cardiac mitochondrial impairment

Abstract Background Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a class of antidiabetic drugs that has demonstrated cardiovascular benefits in heart failure patients, regardless of diabetic status. Although current evidence regarding the role of SGLT2i in myocardial infarction (MI) is still limited, a recent randomized study reported the favorable effects of dapagliflozin on cardiometabolic outcomes in post-MI patients. Nevertheless, the evidence of the underlying mechanism of SGLT2i in post-MI is still unclear. Purpose We aimed to investigate the cardioprotective effects and cellular mechanisms of SGLT2i in post-MI rats. Methods 72 male Wistar rats were divided into two groups: the MI group, which underwent surgery involving permanent ligation of the left anterior descending coronary artery to induce MI (n=58), and the sham group, which underwent a sham operation (n=14). One-week post-surgery, echocardiography was performed. For inclusion in the MI group, only rats exhibiting anterior wall akinesia and a left ventricular ejection fraction (LVEF) < 50% were considered. Subsequently, MI rats were stratified into three groups to receive different interventions: 1) MI+VEH (distilled water, PO, n=13), 2) MI+DAPA (dapagliflozin, 1 mg/kg, PO, n=11), and 3) MI+ENA (enalapril, 10 mg/kg, PO, n=14). After 8 weeks of treatment, echocardiography was performed again. Then, the rats were sacrificed, and heart tissues were used to determine mitochondrial function and protein expressions. Results After 8 weeks of treatment, the MI+VEH group exhibited a decrease in LVEF compared to the sham group (Fig. 1A). The MI+VEH group was associated with cardiac mitochondrial dysfunction, as indicated by increased mitochondrial oxidative stress, mitochondrial membrane depolarization, and mitochondrial swelling, and impaired mitochondrial biogenesis, as indicated by decreasing peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expressions (Fig. 1B-F). Treatment with dapagliflozin and enalapril effectively attenuated left ventricular (LV) systolic dysfunction, reversed mitochondrial dysfunction, and restored mitochondrial biogenesis induced by MI (Fig. 1A-F). Conclusion SGLT2i could attenuate LV dysfunction and restore mitochondrial dysfunction in post-MI rats. These findings demonstrate SGLT2i as a novel cardioprotection against post-MI complications.

Heterogeneous effect of sodium-glucose cotransporter 2 inhibitors on cardiovascular events among people with type 2 diabetes: an application of machine learning to target trial emulation

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are widely used to reduce cardiovascular risk in patients with type 2 diabetes. However, certain patient subgroups, including younger individuals or those with lower body mass index (BMI), have been underrepresented in previous randomized clinical trials. Therefore, the consistency of the effectiveness of SGLT2i has not been thoroughly investigated. Purpose This research aims to investigate the individual benefit of SGLT2i on cardiovascular risk reduction across the diverse patient population with type 2 diabetes Methods We investigated the effectiveness of SGLT2i versus active comparators (dipeptidyl peptidase 4 inhibitors [DPP4i]) using a target trial emulation framework, prevalent new-user design, and a nationwide insurer-based database covering more than 30 million working-age citizens in Japan. Participants were identified using data from April 2015 to March 2022 and were followed until March 2023. The primary endpoint was the composite of all-cause death, myocardial infarction, stroke, or heart failure. We then applied the machine learning causal forest algorithm to the emulated trial cohort to predict the individualized benefit of SGLT2i in reducing cardiovascular outcomes. After describing the characteristics of patients with predicted benefits above the median (high-benefit group) and those with predicted benefits below the median (low-benefit group), we compared the long-term survival outcomes between the high-benefit group and the low-benefit group using adjusted Cox proportional hazard models. Results The study included 274,886 participants (SGLT2i, n=137,443; DPP4i, n=137,443) with a mean age of 55.7 years, 17.3% (n=47,517) female, and a mean BMI of 27.3kg/m2. Over a median follow-up of 36 months, 3.6% (n=9,896) experienced the primary outcome. SGLT2i were associated with a reduced incidence of the primary endpoint in the entire cohort (hazard ratio [HR] = 0.94 [95% confidence interval (95%CI): 0.90–0.97]). The causal forest model showed that the effects of SGLT2i were heterogeneous across individuals. Patients in the low-benefit group were characterized by older age, female gender, lower BMI, lower blood pressure, worse kidney function, and milder diabetes status than those in the high-benefit group. While we found the preventive effect of SGLT2i on long-term cardiovascular outcomes in the high-benefit group (HR [95%CI] = 0.86 [0.82–0.90]), the effect was not observed in the low-benefit group (HR [95%CI] = 1.05 [1.00–1.11]; p-for-interaction < 0.001). Conclusion By applying a machine-learning causal forest to a target trial emulation cohort in the general population, we found heterogeneity in the effect of SGLT2i on cardiovascular outcomes, and identified characteristics of patients who are less likely to benefit from SGLT2i. The findings suggest personalized treatment strategies for cardiovascular risk reduction in patients with type 2 diabetes.Graphical summary

What does routinely-collected electronic health record data tell us about the use of heart failure medication among older people in Wales? Making progress but could do better

Abstract Background European Society of Cardiology 2021 guidelines recommend 4 pillars of treatment to reduce mortality for those with heart failure (HF) and reduced ejection fraction (HFrEF): pillar 1) angiotensin converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), pillar 2) beta-blocker (BB), pillar 3) mineralocorticoid receptor antagonist (MRA), pillar 4) sodium-glucose co-transporter 2 inhibitor (SGLT2i). When there is heart failure with preserved ejection fraction (HFpEF), guidelines recommend diuretics to alleviate congestion and treatment of risk factors such as hypertension and diabetes. Prior to 2021, United Kingdom guidelines did not include SGLT2i. Purpose To examine how HF treatment is recorded in routinely-collected electronic health record (EHR) data for older people in Wales, and to explore how that has changed since 2015. Methods We conducted a retrospective, population-level, observational study using linked anonymised EHR data in Wales (2015-22). 737,230 individuals were aged 65y+ in the study period (21.5% of population in 2022). Of these, 65,010 had a code for heart failure in their primary or secondary care records. We excluded 13,990 individuals with fewer than 12 months data pre- or post-diagnosis. We looked forward, from HF diagnosis, for codes associated with specific medications. Results The final cohort comprised 51,020 individuals aged 65y and over with a diagnosis of heart failure between 2015-2022. Incidence and prevalence of heart failure increased across the study period (1.4-1.5% and 8.5-9.1% respectively). Preceding cardiovascular diagnoses included hypertension (69.5%), atrial fibrillation (36.7%), myocardial infarction (30.5%), coronary artery disease (25.7%), and valve disease (17.7%). Diabetes (41.7%), chronic kidney disease (30.9%) and cancer (26.4%) were the most common comorbidities. The subtype of HF (HFrEF or HFpEF) was only evident in 5,850. Treatments recorded most often were loop diuretics, ACE-I, and BB (Table 1). SGLT2i codes increased in 2020/2021(Figure 1). At 10-12 months post diagnosis, the proportion with simultaneous pillar combinations was; 27.4% 1 + 2, 12.5% 1, 2 + 3, and only 2% 1, 2, 3 + 4. Conclusions In Wales, there is a need to improve the coding of HF subtype in primary care records. We suggest interpreting data with the assumption that approximately half of the cohort are likely to have HFrEF. While the cohort proportion on ACE-I or beta-blockers may be appropriate, the proportion with more than 1 simultaneous pillar of treatment recorded appears low. The use of SGLT2i in codes is increasing. These results are important in evaluating health service delivery and in establishing baseline data from which to monitor improvements.

SGLT2-'eyes' on the reno-protection prize: reduction of post-PCI contrast-associated AKI in diabetic patients using SGLT2 inhibitors

Abstract Background Chronic therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2i) is associated with long term reno-protective benefits. There are limited data on the benefits of these agents against the risk of contrast-associated acute kidney injury (CA-AKI). Purpose The goal of our study was to assess the comparative efficacy of SGLT2i for the prevention of CA-AKI in diabetic patients undergoing PCI. Methods The study population included all diabetic patients enrolled in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium Percutaneous Coronary Intervention (BMC2PCI) registry, a clinical registry of all PCI cases at non-federal hospitals in the state of Michigan, USA. Included patients underwent PCI between January 2022 and September 2023. Patients on dialysis were excluded. Predicted AKI risk was calculated using a previously validated and published machine learning BMC2 risk model. The primary outcome of CA-AKI was defined as an elevation in serum creatinine of ≥0.5 mg/dL following PCI. Risk-adjusted AKI rates were estimated by the product of event observed/expected ratio and overall collaborative AKI rate. Propensity matching on 23 covariates was used to adjust for the non-random use of SGLT2i. Results A total of 19,078 diabetic patients were included, of whom 3,087 (16.2%) were prescribed SGLT2i prior to PCI. Patients treated with SGLT2i were younger (66.1 vs 68.3 years), more likely to be men (73.3% vs 65.3%), have heart failure (50.4% vs 42.4%), have prior PCI (58.4% vs 48.8%), and have co-prescription of insulin (43.8% vs 37.3%) (p<0.001 for all). After propensity matching, no significant baseline difference between cohorts remained, with an absolute standardized difference less than 10% on all covariates. The pre-procedural use of SGLT2i was associated with a lower incidence of CA-AKI in unadjusted analysis (2.7% vs 3.8%, p=0.003) and after adjusting for the baseline predicted risk of CA-AKI (2.2% vs 2.8%, adjusted OR 0.69, 95% CI 0.54-0.89, p=0.0045). In a propensity-matched analysis, the use of SGLT2i was strongly associated with a reduced adjusted risk for CA-AKI (2.2 % vs 2.8%, adjusted OR 0.72, 95% CI 0.62-0.84, p=0.026). Conclusions Among patients with diabetes presenting for PCI, pre-procedural use of SGLT2i was associated with a significant reduction in the risk of CA-AKI. These results should compel further investigation into the beneficial effects of SGLT2 inhibitors in reducing the risk of CA-AKI.

The effect of empagliflozin on circulating endothelial progenitor cells in patients with diabetes and stable coronary artery disease.

Diabetes mellitus (DM) is associated with premature atherosclerotic disease, coronary artery disease (CAD) and chronic heart failure (HF), leading to increased morbidity and mortality. Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2i) exhibit cardioprotective benefits beyond glucose lowering, reducing the risk of major cardiovascular events (MACE) and HF hospitalizations in patients with DM and CAD. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in vascular repair, mobilized in response to vascular injury. The number and function of circulating EPCs (cEPCs) are negatively affected by cardiovascular risk factors, including DM. This study aimed to examine the response of cEPCs to SGLT2i treatment in DM patients with stable CAD. A prospective single-center study included patients with DM and stable CAD who were started on an SGLT2i (empagliflozin). Peripheral blood samples were collected at baseline, 1 month, and 3 months to evaluate cEPC levels and function by flow cytometry, immunohistochemistry and MTT assays. Eighteen patients were included in the study (median age 73, (IQR 69, 77) years, 67% male). After 1 month of treatment with empagliflozin, there was no significant change in cEPCs level or function. However, following 3 months of treatment, a significant increase was observed both in cell levels (CD34(+)/VEGFR-2(+): from 0.49% (IQR 0.32, 0.64) to 1.58% (IQR 0.93, 1.82), p = 0.0006; CD133(+)/VEGFR-2(+): from 0.38% (IQR 0.27, 0.6) to 0.82% (IQR 0.7, 1.95), p = 0.0001) and in cell function (from 0.25 CFUs (IQR 0, 0.5) at baseline, to 2 CFUs (IQR 1, 2) at 3 months, p = 0.0012). Empagliflozin treatment in patients with DM and stable CAD increases cEPC levels and function, implying a cardioprotective mechanism. These findings highlight the potential of SGLT2i in treating cardiovascular diseases, warranting further research to explore these effects and their long-term implications.

Left ventricular dysfunction, pulmonary congestion, or both and cardiovascular risk after acute myocardial infarction

Abstract Background Patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD), pulmonary congestion, or both are at increased risk for adverse cardiovascular events, including long-term heart failure. The EMPACT-MI trial studied the efficacy and safety of early initiation of a sodium-glucose cotransporter-2 inhibitor (SGLT2i) in this population. We set out to evaluate the contemporary real-world risk associated with AMI presenting with LVSD and/or congestion and the projected impact of implementing early SGLT2i post-MI across the spectrum of risk. Purpose To evaluate the independent risk of presenting with LVSD, congestion, or both in patients with AMI. We will further explore the potential impact of the implementation of early initiation of SGLT2i in real-world clinical practice. Methods We conducted a retrospective population-based cohort study in Ontario, Canada, analyzing AMI hospitalizations from April 2009 to March 2022, emulating the EMPACT-MI trial cohort. Patients that survived to hospital discharge were stratified by baseline presentation with LVSD (defined as LVEF<50%), signs or symptoms of congestion or both and compared with a referent group without either risk factor (none). Exclusion criteria were previously established heart failure, prior SGLT2i use, eGFR < 20 ml/min/1.73m2 or chronic dialysis. The primary outcome was a composite of HF hospitalization or all-cause mortality at 30 days and 1 year. We used a multivariable logistic regression model to report an odds ratio (OR) and 95% confidence intervals (CI) adjusted for clinical risk factors. Results Among 36,837 AMI patients, 3% presented with congestion, 55% with LVSD, 10% with both, and 32% with none. Age/sex-adjusted 30-day event rates for the primary endpoint were 30%, 22%, 57%, and 7%, respectively. The corresponding adjusted ORs were 3.34 (95% CI: 2.05-5.46) for congestion, 3.58 (95% CI: 2.72-4.71) for LVSD, and 7.01 (95% CI: 5.09-9.65) for both, versus the reference group (none) (Figure 1). At year 1, a similar pattern of risk was observed (Figure 2). Based on the results of the EMPACT-MI trial being reported at the ACC conference in April 2024, relative and absolute risk differences in outcomes with implementation of early initiation of SGLT2i post-MI in real-world clinical practice across the spectrum of presentation will be reported. Conclusion Patients presenting with pulmonary congestion and/or LVSD remain at high risk of adverse cardiovascular events following AMI. This high-risk group represents an unmet need with a potential impact for improvement with novel interventions such as SGLT2i.

Sodium-glucose co-transporter-2 inhibitors : a potential cardioprotective agent?

Abstract Background Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are one of the cornerstones in the treatment of patients with heart failure (HF) , regardless the ejection fraction (EF) or the presence of diabetes mellitus (DM). Other types of medications used in the treatment of heart failure , like angiotensin converting enzyme inhibitors (ACEi) or beta-blockers (BB) have shown some degree of cardioprotection in high risk patients receiving cardiotoxic chemotherapy, but data on SGLT2i are very limited. Purpose To examine the possible differences in the development of anthracycline cardiotoxicity in diabetic patients receiving SGLT2i compared to those who don’t. Methods We retrospectively analysed the data from the oncological as well as hematological patients of our hospital. Group 1 (SGLT2) included patients with cancer who received anthracycline treatment and diabetes on treatment with SGLT2i. Group 2 (control) included patients with cancer who received anthracycline treatment and diabetes but with treatment other than SGLT2i. We recorded the basic demographic parameters, the development of cardiotoxicity (heart failure incidence, heart failure admissions, new cardiomyopathy [>10% decline in ejection fraction to <50%], and clinically significant arrhythmias) as well as the abnormal levels of troponin I (tnI) and natriuretic peptides (NTproBNP). Results Age, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. The mean duration of the follow up was 2 years. In the SLT2 group were included 86 patients and in the control group 97. The rates of the cardiotoxicity events were recorded as follow : (SGLT2 vs control) Heart failure (7.4% vs 31.9%, p<0.01), heart failure admissions (3.4% vs 12.3%, p<0.05), new cardiomyopathy (6.1% vs 27.2%, p<0.05), arrhythmias (2.7% vs 24.3%, p<0.01), abnormal tnI levels (4.2% vs 14.7% , p< 0.01), abnormal NTproBNP levels (6.4% vs 30.9%, p<0.01) Conclusions SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Further studies are needed in order to test the possible cardioprotective effects of SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines.

Secondary erythrocytosis / polycythemia due to sodium glucose co-transporter 2 inhibitors: a real world heart failure cohort

Abstract Background Sodium glucose co-transporter 2 inhibitors (SGLT2-i) are one of the four pillars of guideline-directed medical therapy in heart failure with reduced ejection fraction and preserved ejection fraction according to the current ESC and AHA/ACC heart failure guidelines 1,2. As a result, there has been a significant increase in their use worldwide. Although SGLT2 inhibitors are known to increase hemoglobin and hematocrit levels, there is a lack of data on the burden of erythrocytosis or polycythemia in pivotal trials 3,4. Purpose In this retrospective cohort study, we investigated the prevalence and clinical outcomes of SGLT2-i related erythrocytosis in a tertiary heart failure outpatient clinic. Methods We reviewed clinical data from heart failure patients treated with an SGLT2 inhibitor at our tertiary centre between September 2019 and October 2023. Patients were included if they were taking SGLT2-i continuously for more than one month. Data were collected on Hb/Hct levels at baseline before initiation of SGLT2-i, at peak levels during therapy and at the last follow-up. Erythrocytosis was defined according to the 2017 WHO classification as Hb> 10.3 mmol/L and/or Hct> 49% in men and Hb> 10.0 mmol/L and/or Hct> 48% in females. Results A total of 173 patients with heart failure were included (median age 58 [49-66] years, 65% male). One hundred and fifty-six patients (90%) were using dapagliflozin, while 16 patients (9%) were using empagliflozin. The overall prevalence of SGLT2i related erythrocytosis was 39/173 (22.5%; median age 60 and 82% males). Eleven (6.3%) patients had pre-existing erythrocytosis at baseline. During a mean follow-up of 14±10 months, 28/173 (16.2%) patients developed new onset erythrocytosis. The median time to the peak of the Hb/Hct level was 6.5 months. Although the group with erythrocytosis had significantly higher Hb and Hct at baseline compared to the group without erythrocytosis (Hb 9.7 mmol/L ± 1.0 vs. 8.5 mmol/L ± 1.0; p<0.001 in men and 9.1 mmol/L ± 0.8 mmol/L vs. 8.1 ± 0.8; p=0.006 in females), they also experienced a significantly greater median increase in Hb from baseline to peak (1.05 mmol/L vs. 0.60mmol/L; p=0.01) (see Figure 1) There were significantly more males (82% vs 60%; p=0.01) in the erythrocytosis group compared to the non-erythrocytosis group. In addition, the prevalence of OSAS was significantly higher in the group with erythrocytosis compared to the group without erythrocytosis (31% vs. 8%; p<0.001). Conclusion Secondary erythrocytosis or polycythemia is common in patients with chronic heart failure. It is particularly common in men and in patients with obstructive sleep apnoea syndrome (OSAS). There were no excess thrombotic or thromboembolic events, probably because of the routine use of anticoagulants/antiplatelets and limited follow-up. To avoid unnecessary haematological referrals and potential clinical adverse events, increased awareness among clinicians is needed.Table 1.Baseline and clinical outcomesFig1.Hemoglobin levels over time

Treatment with flozins across the whole spectrum of heart failure in Poland between February 2022 and June 2023 based on Heart Failure Observational Study by Polish Cardiac Society.

Abstract Since the introduction of the ESC guidelines in 2021 and the increased level of recommendations in 2023, SGLT2 inhibitors (SGLT2i) have been widely used in all patients with heart failure (HF), improving their prognosis. Current guidelines recommend the use of SGLT2i across the entire spectrum of HF regardless of ejection fraction. The aim of the study was to summarize the usage of SGLT2i in patients with HF in Poland, based on data gathered in the Heart Failure Observational Study (HEROES) conducted by the Polish Cardiac Society. Overall, 1176 patients (enrolled between Feb 2022 and Jun 2023) were included in the analysis (hospitalizations: N=918, outpatient visits: N=258). Most of them were men (71.7%) with a median age of 69 years (IQR: 60-75). Patients with reduced ejection fraction (HFrEF) were the most numerous group (48%, N=565) followed by preserved (HFpEF, 22%, N=259) and mildly reduced (HFmrEF, 14%, N=166) ejection fraction. In 16% of cases, ejection fraction was not reported. Only fewer than 60% of subjects were reported to be treated with SGLT2i (overall: 59.5%; HFrEF: 82.3%; HFmrEF: 48.8%, HFpEF: 32.4%). We divided the whole study group into 4 even quartiles based on the number of consecutive patients enrolled (Q1: Feb 2022-Dec 2022; Q2: Sep 2022; Q3: Mar 2023; Q4: Jun 2023). Results showed an overall increasing number of patients treated with SGLT2i in consecutive quartiles, especially in HFmrEF group (Fig. 1). However, in the last quartile (Q4), less than 40% usage of SGLT2i in HFpEF patients was observed (38.2%). The analyzed period ended before the release of the 2023 focused update of HF guidelines that strengthened recommendations for SGLT2i use to the first class of recommendations regardless of ejection fraction. This document will probably further increase the usage of SGLT2i in the Polish HF population. Nevertheless, our data are worrying, as overall more than 1/3 of HF patients in the last quartile were not treated with one of the basic and effective drugs in HF. It is worth mentioning that the 2021 HF guidelines recommended SGLT2i in the first class of recommendations only in HFrEF, but by that time, current clinical trial results had already shown great benefit in HFmrEF and HFpEF patients.SGLT2i treatment in PL (Feb2022-Jun2023)

Beneficial effect of sodium-glucose cotransporter-2 inhibitors on mortality among patients with cancer and diabetes mellitus.

The work attempts to describe mortality outcomes of sodium-glucose cotransporter-2 inhibitor (SGLT2I) in patients with diabetes mellitus (DM) and cancer. Using Taiwan's National Health Insurance Research Database to analyze the prognosis of cancer patients with coexisting DM, comparing those receiving SGLT2I with those who do not. After index-year and matching (age, sex, some comorbidities and medications), weobtain two groups of 20,339 patients. After further adjustment for age, sex and comorbidities, those with SGLT2I had a lower adjusted hazard ratio of mortality (aHR: 0.64 [95% CI: 0.60-0.68]). We conclude that SGLT2I medication should be considered first choice in patients suffering from DM and cancer.