Effects of Different Types of Intermittent Fasting Interventions on Metabolic Health in Healthy Individuals (EDIF): A Randomised Trial with a Controlled-Run in Phase.

The effects of intermittent fasting (IF) on health promotion in the healthy population remain controversial. Therefore, our study aimed to analyse the efficacy and feasibility of different IF protocols and evaluated the effects within a cohort with a controlled-run in phase on the body mass index (BMI) as the primary outcome, the body composition, and metabolic and haematological markers in healthy participants. A total of 25 individuals were randomised into three fasting groups: 16/8 fasting (n = 11), 20/4 fasting (n = 6), and alternate-day fasting (ADF, n = 8). Assessments were conducted at baseline (visit 1), after a four-week controlled-run in phase (visit 2), and after eight weeks of fasting (visit 3). Both the BMI (p = 0.01) and bodyweight (p = 0.01) were significantly reduced in the ADF group, which was not seen in the 16/8 and 20/4 groups (p > 0.05). Adherence was different but not statistically among the groups (16/8: 84.5 ± 23.0%; 20/4: 92.7 ± 9.5%; and ADF: 78.1 ± 33.5%, p = 0.57). Based on our obtained results, the data suggest that some fasting interventions might be promising for metabolic health. However, adherence to the specific fasting protocols remains challenging even for the healthy population.

From classical dualistic antagonism to hormone synergy: potential of overlapping action of glucagon, insulin and GLP-1 for the treatment of diabesity.

The increasing prevalence of 'diabesity', a combination of type 2 diabetes and obesity, poses a significant global health challenge. Unhealthy lifestyle factors, including poor diet, sedentary behaviour, and high stress levels, combined with genetic and epigenetic factors, contribute to the diabesity epidemic. Diabesity leads to various significant complications such as cardiovascular diseases, stroke, and certain cancers. Incretin-based therapies, such as GLP-1 receptor agonists and dual hormone therapies, have shown promising results in improving glycaemic control and inducing weight loss. However, these therapies also come with certain disadvantages, including potential withdrawal effects. This review aims to provide insights into the cross-interactions of insulin, glucagon, and GLP-1, revealing the complex hormonal dynamics during fasting and postprandial states, impacting glucose homeostasis, energy expenditure, and other metabolic functions. Understanding these hormonal interactions may offer novel hypotheses in the development of 'anti-diabesity' treatment strategies. The article also explores the question of the antagonism of insulin and glucagon, providing insights into the potential synergy and hormonal overlaps between these hormones.

Ketone body levels and its associations with cardiac markers following an acute myocardial infarction: a post hoc analysis of the EMMY trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to exert cardioprotective effects in patients with heart failure, possibly by improving the metabolism of ketone bodies in the myocardium. METHODS: This post hoc analysis of the EMMY trial investigated the changes in serum ß-hydroxybutyrate (3-ßOHB) levels after acute myocardial infarction (AMI) in response to 26-week of Empagliflozin therapy compared to the usual post-MI treatment. In addition, the association of baseline and repeated measurements of 3-ßOHB with cardiac parameters and the interaction effects of Empagliflozin were investigated. Cardiac parameters included N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), and left ventricular filling pressure (E/é ratio). RESULTS: The mean 3-ßOHB levels increased from baseline (46.2 ± 3.0 vs. 51.7 ± 2.7) to 6 weeks (48.8 ± 2.2 vs. 42.0 ± 2.3) and 26 weeks (49.3 ± 2.2 vs. 35.8 ± 1.9) in the Empagliflozin group compared to a consistent decline in placebo over 26 weeks (pinteraction < 0.001). Baseline and longitudinal measurements of 3-ßOHB were not significantly associated with NT-proBNP and E/é ratio. Baseline 3-ßOHB value was negatively associated with LVEF (coefficient: - 0.464, 95%CI - 0.863;- 0.065, p = 0.023), while an increase in its levels over time was positively associated with LVEF (0.595, 0.156;1.035, 0.008). The baseline 3-ßOHB was positively associated with LVESV (1.409, 0.186;2.632, 0.024) and LVEDV (0.640, - 1.170;- 2.449, 0.488), while an increase in its levels over time was negatively associated with these cardiac parameters (LVESV: - 2.099, - 3.443;- 0.755, 0.002; LVEDV: - 2.406, - 4.341;- 0.472, 0.015). Empagliflozin therapy appears to modify the association between 3-ßOHB, LVEF (pinteraction = 0.090), LVESV (pinteraction = 0.134), and LVEDV (pinteraction = 0.168), particularly at 26 weeks; however, the results were not statistically significant. CONCLUSION: This post hoc analysis showed that SGLT2i increased 3-ßOHB levels after AMI compared to placebo. Higher baseline 3-ßOHB levels were inversely associated with cardiac function at follow-up, whereas a sustained increase in 3-ßOHB levels over time improved these markers. This highlights the importance of investigating ketone body metabolism in different post-MI phases. Although more pronounced effect of 3-ßOHB on cardiac markers was observed in the SGLT2i group, further research is required to explore this interaction effect.

Effects of empagliflozin in women and men with acute myocardial infarction: An analysis from the EMMY trial.

OBJECTIVE: Women have a higher comorbidity burden and a lower survival rate after acute myocardial infarction (AMI) than men. This analysis aimed to investigate the impact of sex on the effect of treatment with the sodium glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin immediately after an AMI. METHODS: Participants were randomized to either empagliflozin or placebo and followed for 26 weeks after initiating the treatment no later than 72 hours after a percutaneous coronary intervention following an AMI. We analyzed the impact of sex on the beneficial effects of empagliflozin observed for heart failure biomarkers as well as structural and functional cardiac parameters. RESULTS: Women had higher NT-proBNP levels at baseline (median 2117pg/mL, IQR 1383-3267 pg/mL versus 1137 pg/mL, IQR 695-2050 pg/mL; p < 0.001) and were older than men (median 61y, IQR 56-65y versus 56y, IQR 51-64y, p = 0.005). The beneficial effects of empagliflozin on NT-proBNP levels (Pinteraction = 0.984), left ventricular ejection fraction (Pinteraction = 0.812), left ventricular end systolic volume (Pinteraction = 0.183), or left ventricular end diastolic volume (Pinteraction = 0.676) were independent of sex. CONCLUSIONS: Empagliflozin exhibited similar benefits in women and men when administered immediately after an AMI.

Impact of a 4-week intensive track and field training intervention on glycaemia in adolescents with type 1 diabetes: The ChilDFiT1 study.

AIM: To investigate the safety and efficacy of track and field training compared with intensification of insulin treatment only in adolescents with type 1 diabetes (T1D). MATERIALS AND METHODS: Eighteen adolescents (seven females) with T1D were included (age 15.1 ± 1.1 years, HbA1c 7.3% ± 1.0% [56.3 ± 10.9 mmol/mol]). After a 4-week observational control phase, participants were randomized to either stand-alone intensive glycaemic management (IT; telemedicine or on-site visits, three times/week) or additionally performed track and field exercise (EX; three 60-minute sessions/week) for 4 weeks. Glycaemia was assessed via continuous glucose monitoring during observational control and intervention phases. RESULTS: Time in range (70-180 mg/dL; 3.9-10.0 mmol/L) significantly improved from the observational control phase to the exercise intervention phase in EX (69% ± 13% vs. 72% ± 11%, P = .049), but not in IT (59% ± 22% vs. 62% ± 16%, P = .399). Time below range 1 (54-69 mg/dL; < 3.9 mmol/L) improved in IT (3.1% ± 1.9% vs. 2.0% ± 0.8%, P = .017) and remained stable in EX (2.0% ± 1.7 vs. 1.9% ± 1.1%, P = .999). The EX group's HbA1c ameliorated preintervention to postintervention (mean difference: ΔHbA1c -0.19% ± 0.17%, P = .042), which was not seen within the IT group (ΔHbA1c -0.16% ± 0.37%, P = .40). Glucose standard deviation was reduced significantly in EX (55 ± 11 vs. 51 ± 10 mg/dL [3.1 ± 0.6 vs. 2.8 ± 0.6 mmol/L], P = .011), but not in IT (70 ± 24 vs. 63 ± 18 mg/dL [3.9 ± 1.3 vs. 3.5 ± 1.0 mmol/L], P = .186). CONCLUSION: Track and field training combined with intensive glycaemic management improved glycaemia in adolescents with T1D, which was not observed in the non-exercise group.

Glycated haemoglobin, HOMA2-B, C-peptide to glucose ratio and type 2 diabetes clusters as predictors for therapy failure in individuals with type 2 diabetes without insulin therapy: A registry analysis.

AIM: Some people with type 2 diabetes mellitus (T2D) and declining ß-cell function do require insulin over time. Various laboratory parameters, indices of glucose metabolism or phenotypes of T2D (clusters) have been suggested, which might predict future therapy failure (TF), indicating the need for insulin therapy initiation. This analysis evaluated glycated haemoglobin (HbA1c), homeostatic model assessment (HOMA)2-B, C-peptide to glucose ratio (CGR) and diabetes clusters as predictive parameters for the occurrence of glycaemic TF in individuals diagnosed with T2D without previous insulin therapy. MATERIALS AND METHODS: In total, 159 individuals with T2D [41% female, median age 50 (IQR: 53-69) years, diabetes duration 9 (5-15) years], without insulin therapy were prospectively evaluated for the occurrence of a composite primary endpoint, including HbA1c increasing or remaining >8.0% (64 mmol/mol) 3 months after baseline on non-insulin glucose-lowering agents, insulin initiation or hospital admissions because of acute hyperglycaemic events. Diabetes clusters were formed according to previously described characteristics. Only severe autoimmune diabetes clusters were excluded because of a small amount of glutamate decarboxylase antibody-positive participants. The other clusters were distributed as mild age-related diabetes 33%; severe insulin-deficient diabetes 31%; mild obesity-related diabetes 20%; and severe insulin-resistant diabetes 15%. RESULTS: During a median observation of 57 months, higher tertiles of HbA1c at baseline, HOMA2-B, as well as a lower CGR were significantly predictive for the occurrence of the primary endpoint. The probability of meeting the primary endpoint was the highest for mild obesity-related diabetes [hazard ratio 3.28 (95% confidence interval 1.75-6.2)], followed by severe insulin-deficient diabetes [hazard ratio 2.03 (95% confidence interval 1.1-3.7)], mild age-related diabetes and the lowest for severe insulin-resistant diabetes. The best performance to predict TF with an area under the curve (AUC) of 0.77 was HbA1c at baseline, followed by HOMA2-B (AUC 0.69) and CGR (AUC 0.64). CONCLUSION: HbA1c, indices of insulin secretion capacity (HOMA2-B and CGR) and T2D clusters might be applicable tools to guide practitioners in the decision of whether insulin is required in people already diagnosed with T2D. These findings need to be validated in prospective studies.

SGLT2 Inhibitors in Long COVID Syndrome: Is There a Potential Role?

The coronavirus disease (COVID)-19 has turned into a pandemic causing a global public health crisis. While acute COVID-19 mainly affects the respiratory system and can cause acute respiratory distress syndrome, an association with persistent inflammatory stress affecting different organ systems has been elucidated in long COVID syndrome (LCS). Increased severity and mortality rates have been reported due to cardiophysiological and metabolic systemic disorders as well as multiorgan failure in COVID-19, additionally accompanied by chronic dyspnea and fatigue in LCS. Hence, novel therapies have been tested to improve the outcomes of LCS of which one potential candidate might be sodium-glucose cotransporter 2 (SGLT2) inhibitors. The aim of this narrative review was to discuss rationales for investigating SGLT2 inhibitor therapy in people suffering from LCS. In this regard, we discuss their potential positive effects-next to the well described "cardio-renal-metabolic" conditions-with a focus on potential anti-inflammatory and beneficial systemic effects in LCS. However, potential beneficial as well as potential disadvantageous effects of SGLT2 inhibitors on the prevalence and long-term outcomes of COVID-19 will need to be established in ongoing research.

(Hybrid) Closed-Loop Systems: From Announced to Unannounced Exercise.

Physical activity and exercise have many beneficial effects on general and type 1 diabetes (T1D) specific health and are recommended for individuals with T1D. Despite these health benefits, many people with T1D still avoid exercise since glycemic management during physical activity poses substantial glycemic and psychological challenges - which hold particularly true for unannounced exercise when using an AID system. Automated insulin delivery (AID) systems have demonstrated their efficacy in improving overall glycemia and in managing announced exercise in numerous studies. They are proven to increase time in range (70-180 mg/dL) and can especially counteract nocturnal hypoglycemia, even when evening exercise was performed. AID-systems consist of a pump administering insulin as well as a CGM sensor (plus transmitter), both communicating with a control algorithm integrated into a device (insulin pump, mobile phone/smart watch). Nevertheless, without manual pre-exercise adaptions, these systems still face a significant challenge around physical activity. Automatically adapting to the rapidly changing insulin requirements during unannounced exercise and physical activity is still the Achilles' heel of current AID systems. There is an urgent need for improving current AID-systems to safely and automatically maintain glucose management without causing derailments - so that going forward, exercise announcements will not be necessary in the future. Therefore, this narrative literature review aimed to discuss technological strategies to how current AID-systems can be improved in the future and become more proficient in overcoming the hurdle of unannounced exercise. For this purpose, the current state-of-the-art therapy recommendations for AID and exercise as well as novel research approaches are presented along with potential future solutions - in order to rectify their deficiencies in the endeavor to achieve fully automated AID-systems even around unannounced exercise.

Low glucose availability potentiates the effects of metformin on model T cell activation and exhaustion markers in vitro.

Modulation of immune cell metabolism is one of promising strategies to improve cancer immunotherapies. Metformin is an anti-diabetic drug with potential anti-cancer effects, ranging from normalization of blood glucose and insulin levels, direct anti-proliferative effects on cancer cells to emerging immunomodulatory effects on anti-tumor immunity. Metformin can reduce tumor hypoxia and PD-L1 expression, as well as normalize or improve T cell function and potentiate the effect of immune checkpoint inhibitors, making it a promising adjuvant to immunotherapy of tumors with poor response such as triple negative breast cancer (TNBC). However, although the effects of metformin on cancer cells are glucose-dependent, the role of glucose in modulating its effect on T cells has not been systematically studied. We thus investigated the effect of metformin as a function of glucose level on Jurkat cell and PBMC T cell models in vitro. While low metformin concentrations had little effect on T cell function, high concentration reduced proliferation and IFN-γ secretion in both models and induced a shift in T cell populations from memory to effector subsets. The PD-1/CD69 ratio was improved by high metformin in T cells from PBMC. Low glucose and metformin synergistically reduced PD-1 and CD69 expression and IFN-γ secretion in T cells from PBMC. Low glucose level itself suppressed Jurkat cell function due to their limited metabolic plasticity, but had limited effects on T cells from PBMC apart from reduced proliferation. Conversely, high glucose did not strongly affect either T cell model. Metformin in combination with glycolysis inhibitor 2-deoxy-D-glucose (2DG) reduced PD-1 in Jurkat cells, but also strongly suppressed their function. However, low, physiologically achievable 2DG concentration itself reduced PD-1 while mostly maintaining IL-2 secretion and, interestingly, even strongly increased IFN-γ secretion regardless of glucose level. Overall, glucose metabolism can importantly influence some of the effects of metformin on T cell functionality in the tumor microenvironment. Additionally, we show that 2DG could potentially improve the anti-tumor T cell response.

Incidence of Diabetes Mellitus and Its Impact on Outcomes in Patients Undergoing Surgical Pancreatectomy for Non-Malignant and Malignant Pancreatobiliary Diseases-A Retrospective Analysis.

Diabetes mellitus (DM) is a prominent risk factor for malignant and non-malignant pancreatic diseases. Furthermore, the presence of DM predicts an unfavourable outcome in people with pancreatic cancer. This retrospective observational study investigated 370 patients who underwent pancreatic resection surgery for various indications (84.3% in malignant indication) in a single surgery centre in Graz, Austria. The preoperative and postoperative diabetes statuses were evaluated according to surgery method and disease entity and predictors for diabetes development after surgery, as well as outcomes (survival and cancer recurrence) according to diabetes status, were analysed. In the entire cohort, the postoperative diabetes (postopDM) incidence was 29%. PostopDM occurred significantly more frequently in malignoma patients than in those with benign diseases (31.3% vs. 16.7%; p = 0.040, OR = 2.28). In the malignoma population, BMI, longer surgery duration, and prolonged ICU and hospital stay were significant predictors of diabetes development. The 1- and 2-year follow-ups showed a significantly increased mortality of people with postopDM in comparison to people without diabetes (HR 1-year = 2.02, p = 0.014 and HR 2-years = 1.56, p = 0.034). Local cancer recurrence was not influenced by the diabetes status. Postoperative new-onset diabetes seems to be associated with higher mortality of patients with pancreatic malignoma undergoing pancreatobiliary surgery.

Changes in Lipoprotein(a) Levels in People after ST Elevation Myocardial Infarction-The STEMI-Lipids Study.

Lipoprotein(a) (Lp(a)) is considered an independent risk factor for cardiovascular diseases. The plasma concentration of Lp(a) is largely genetically determined but varies over a wide range within the population. This study investigated changes in Lp(a) levels after an acute myocardial infarction. Patients who underwent coronary angiography due to an ST elevation myocardial infarction were enrolled (n = 86), and Lp(a) levels were measured immediately after the intervention, one day, two days, and at a post-discharge follow-up visit at 3 to 6 months after the acute myocardial infarction. Median Lp(a) levels increased from a median of 7.9 mg/dL (3.8-37.1) at hospital admission to 8.4 mg/dL (3.9-35.4) on the following day, then to 9.3 mg/dL (3.7-39.1) on day two (p < 0.001), and to 11.2 mg/dL (4.4-59.6) at the post-discharge follow-up (p < 0.001). Lp(a) levels were the lowest during the acute myocardial infarction and started to increase significantly immediately thereafter, with the highest levels at the post-discharge follow-up. The moderate but significant increase in Lp(a) in people with acute myocardial infarction appears to be clinically relevant on an individual basis, especially when specific Lp(a) cut-off levels are supposed to determine the initiation of future treatment. Hence, a repeated measurement of Lp(a) after myocardial infarction should be performed.

Albumin of People with Diabetes Mellitus Is More Reduced at Low HbA1c.

Oxidative stress is involved in the development, progression, and complications of diabetes mellitus (DM). Oxidative modification of human serum albumin's cysteine-34 is a marker for oxidative stress-related pathological conditions. We aimed to evaluate the redox state of albumin in patients with DM to investigate possible correlations with age, diabetes duration, and disease control status. Plasma aliquots were collected from 52 participants (26 type 1 and 26 type 2 DM). Patients were divided into two groups according to their glycated hemoglobin levels less than or equal to and greater than 58 mmol/L. Albumin redox state was assessed with high-performance liquid chromatography by fractionating it into human mercaptalbumin (HMA) and human nonmercaptalbumin 1 and 2 (HNA1 and HNA2). Albumin redox fractions were differently related to the age of study participants. In age-matched T1DM and T2DM groups, the albumin redox state was essentially the same. Irreversibly oxidized HNA2 was positively correlated with diabetes duration, especially in the T1DM group. HNA was increased in people with an increased HbA1c (>58 mmol/mol). Our results support the hypothesis that oxidative stress plays a crucial role in DM pathogenesis and emphasize the importance of diabetes control on systemic oxidative burden.

Speckle-Tracking Analysis of the Right and Left Heart after Peak Exercise in Healthy Subjects with Type 1 Diabetes: An Explorative Analysis of the AppEx Trial.

In eight healthy participants with Type 1 diabetes (T1D) exercise-related dynamic cardiac remodeling was analyzed by performing two-dimensional echocardiography, including deformation analysis of the left-ventricular (LV) global longitudinal strain (LV-GLS), and the deformation pattern of the left atrium (LA) and right ventricle (RV) at rest and post-peak performance on a bicycle. The feasibility echocardiographic speckle-tracking analysis was performed on eight asymptomatic participants with T1D (n = 8, male n = 5, age: 23-65 years). The obtained echocardiographic data were compared for various echocardiographic parameters at rest and post exercise. Across our participating T1D individuals no structural echocardiographic abnormalities of concern could be revealed. All participating T1D subjects showed preserved contractile reserve of the LV and no significant diastolic dysfunction. Significant differences were found for the phasic LA contractile strain pattern at rest and post exercise (p < 0.001), whereby the dynamic RV (p = 0.5839 and p = 0.7419) and LV strain pattern (p = 0.5952) did not reveal significant differences in comparison to resting conditions. This descriptive secondary outcome analysis describes preserved contractile reserve of the LV and elucidates dynamic modification of the phasic LA contractile deformation pattern in asymptomatic T1D individuals after exhaustive exercise on a bicycle.

Retinal venular vessel diameters are smaller during ten days of bed rest.

Older individuals experience cardiovascular dysfunction during extended bedridden hospital or care home stays. Bed rest is also used as a model to simulate accelerated vascular deconditioning occurring during spaceflight. This study investigates changes in retinal microcirculation during a ten-day bed rest protocol. Ten healthy young males (22.9 ± 4.7 years; body mass index: 23.6 ± 2.5 kg·m-2) participated in a strictly controlled repeated-measures bed rest study lasting ten days. High-resolution images were obtained using a hand-held fundus camera at baseline, daily during the 10 days of bed rest, and 1 day after re-ambulation. Retinal vessel analysis was performed using a semi-automated software system to obtain metrics for retinal arteriolar and venular diameters, central retinal artery equivalent and central retinal vein equivalent, respectively. Data analysis employed a mixed linear model. At the end of the bed rest period, a significant decrease in retinal venular diameter was observed, indicated by a significantly lower central retinal vein equivalent (from 226.1 µm, CI 8.90, to 211.4 µm, CI 8.28, p = .026), while no significant changes in central retinal artery equivalent were noted. Prolonged bed rest confinement resulted in a significant (up to 6.5%) reduction in retinal venular diameter. These findings suggest that the changes in retinal venular diameter during bedrest may be attributed to plasma volume losses and reflect overall (cardio)-vascular deconditioning.

Comparative Analysis of Predictive Interstitial Glucose Level Classification Models.

BACKGROUND: New methods of continuous glucose monitoring (CGM) provide real-time alerts for hypoglycemia, hyperglycemia, and rapid fluctuations of glucose levels, thereby improving glycemic control, which is especially crucial during meals and physical activity. However, complex CGM systems pose challenges for individuals with diabetes and healthcare professionals, particularly when interpreting rapid glucose level changes, dealing with sensor delays (approximately a 10 min difference between interstitial and plasma glucose readings), and addressing potential malfunctions. The development of advanced predictive glucose level classification models becomes imperative for optimizing insulin dosing and managing daily activities. METHODS: The aim of this study was to investigate the efficacy of three different predictive models for the glucose level classification: (1) an autoregressive integrated moving average model (ARIMA), (2) logistic regression, and (3) long short-term memory networks (LSTM). The performance of these models was evaluated in predicting hypoglycemia (<70 mg/dL), euglycemia (70-180 mg/dL), and hyperglycemia (>180 mg/dL) classes 15 min and 1 h ahead. More specifically, the confusion matrices were obtained and metrics such as precision, recall, and accuracy were computed for each model at each predictive horizon. RESULTS: As expected, ARIMA underperformed the other models in predicting hyper- and hypoglycemia classes for both the 15 min and 1 h horizons. For the 15 min forecast horizon, the performance of logistic regression was the highest of all the models for all glycemia classes, with recall rates of 96% for hyper, 91% for norm, and 98% for hypoglycemia. For the 1 h forecast horizon, the LSTM model turned out to be the best for hyper- and hypoglycemia classes, achieving recall values of 85% and 87% respectively. CONCLUSIONS: Our findings suggest that different models may have varying strengths and weaknesses in predicting glucose level classes, and the choice of model should be carefully considered based on the specific requirements and context of the clinical application. The logistic regression model proved to be more accurate for the next 15 min, particularly in predicting hypoglycemia. However, the LSTM model outperformed logistic regression in predicting glucose level class for the next hour. Future research could explore hybrid models or ensemble approaches that combine the strengths of multiple models to further enhance the accuracy and reliability of glucose predictions.

Timing of SGLT2i initiation after acute myocardial infarction.

BACKGROUND: Pharmacological post-MI treatment is routinely initiated at intensive/cardiac care units. However, solid evidence for an early start of these therapies is only available for dual platelet therapy and statins, whereas data on beta blockers and RAAS inhibitors are heterogenous and mainly limited to STEMI and heart failure patients. Recently, the EMMY trial provided the first evidence on the beneficial effects of SGLT2 inhibitors (SGLT2i) when initiated early after PCI. In patients with type 2 diabetes mellitus, SGLT2i are considered "sick days drugs" and it, therefore, remains unclear if very early SGLT2i initiation following MI is as safe and effective as delayed initiation. METHODS AND RESULTS: The EMMY trial evaluated the effect of empagliflozin on NT-proBNP and functional and structural measurements. Within the Empagliflozin group, 22 (9.5%) received early treatment (< 24 h after PCI), 98 (42.2%) within a 24 to < 48 h window (intermediate), and 111 (48.1%) between 48 and 72 h (late). NT-proBNP levels declined by 63.5% (95%CI: - 69.1; - 48.1) in the early group compared to 61.0% (- 76.0; - 41.4) in the intermediate and 61.9% (- 70.8; - 45.7) in the late group (n.s.) within the Empagliflozin group with no significant treatment groups-initiation time interaction (pint = 0.96). Secondary endpoints of left ventricular function (LV-EF, e/e`) as well as structure (LVESD and LVEDD) were also comparable between the groups. No significant difference in severe adverse event rate between the initiation time groups was detected. CONCLUSION: Very early administration of SGLT2i after acute myocardial infarction does not show disadvantageous signals with respect to safety and appears to be as effective in reducing NT-proBNP as well as improving structural and functional LV markers as initiation after 2-3 days.

Identification of Novel Intronic SNPs in Transporter Genes Associated with Metformin Side Effects.

Metformin is a widely used and effective medication in type 2 diabetes (T2DM) as well as in polycystic ovary syndrome (PCOS). Single nucleotide polymorphisms (SNPs) contribute to the occurrence of metformin side effects. The aim of the present study was to identify intronic genetic variants modifying the occurrence of metformin side effects and to replicate them in individuals with T2DM and in women with PCOS. We performed Next Generation Sequencing (Illumina Next Seq) of 115 SNPs in a discovery cohort of 120 metformin users and conducted a systematic literature review. Selected SNPs were analysed in two independent cohorts of individuals with either T2DM or PCOS, using 5'-3'exonucleaseassay. A total of 14 SNPs in the organic cation transporters (OCTs) showed associations with side effects in an unadjusted binary logistic regression model, with eight SNPs remaining significantly associated after appropriate adjustment in the discovery cohort. Five SNPs were confirmed in a combined analysis of both replication cohorts but showed different association patterns in subgroup analyses. In an unweighted polygenic risk score (PRS), the risk for metformin side effects increased with the number of risk alleles. Intronic SNPs in the OCT cluster contribute to the development of metformin side effects in individuals with T2DM and in women with PCOS and are therefore of interest for personalized therapy options.