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Sodium-glucose cotransporter 2 inhibitors were first discovered as glucose-lowering drugs because of their glycosuric action and good safety profile. Subsequently, they were studied in cardiovascular outcome trials in people with type 2 diabetes, and their cardiovascular benefit was consistently observed as regards heart failure hospitalizations and cardiovascular death. Investigation of the underlying mechanisms granting such benefit is continuously engaging researchers all over the world. The findings described in this article paved the way to a larger use of these drugs in patients with heart failure, with the aim of improving their clinical outcomes and quality of life.

Objectives The antiphospholipid syndrome is defined by antiphospholipid antibodies (aPL) together with arterial and/or venous thromboembolism and/or obstetric morbidities. aPL are overrepresented in SLE and acute myocardial infarction, but it is unknown whether aPL are associated with calcific aortic valve stenosis (CAVS) in the general population. The prevalence of aPL and other SLE-associated autoantibodies and their impact on aortic valve transcriptomics were therefore determined. Methods A total of 233 tricuspid CAVS cases (median age 74, 69% male) and an age- and sex-matched control population were included. aPL were measured as anti-cardiolipin and anti-β2Glycoprotein-I of IgG/M/A isotypes. Resilient, thickened and calcified aortic valve (AV) tissue derived from five aPL positive and five matched aPL negative CAVS patients undergoing surgical aortic valve replacement were analysed by microarrays. Results The prevalence of positivity for any aPL (IgG/M/A) in patients with CAVS was 6.4% (95% CI 3.6% – 10.4%: n = 233). aPL IgG was significantly more prevalent in CAVS cases vs controls (4.6% vs 0.6%, P = 0.04). AV tissue from aPL IgG/IgM-positive patients was negatively enriched in pathways related to interferon signalling. One hundred differentially expressed genes could predict local AV CAVS progression with supervised machine learning algorithms. Conclusions aPL IgG was more common in CAVS patients compared with matched controls and aPL positivity was associated with altered AV transcriptomics related to local disease progression and interferon pathways. Further studies should aim to establish aPL as a possible risk marker and/or causal factor for CAVS and could offer new precision therapeutic targets.

Background: We investigated eligibility for dapagliflozin and empagliflozin in a real-world heart failure (HF) cohort based on selection criteria of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure), and EMPEROR (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction and Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with APreserved Ejection Methods and Results: Selection criteria were applied to the Swedish HF registry outpatient population according to 3 scenarios: (i) a "trial scenario" applying all selection criteria; (ii) a "pragmatic scenario" applying the most clinically relevant criteria; and (iii) a "label scenario" following the regulatory agencies labels. Of the 49,317 patients, 55% had an ejection fraction of less than 40% and were assessed for eligibility based on DAPA-HF and EMPEROR-Reduced, 45% had ejection fraction of 40% or greater and were assessed based on EMPEROR-Preserved and DELIVER. Eligibility using trial, pragmatic, and label scenarios was 35%, 61%, and 80% for DAPA-HF; 31%, 55%, and 81% for EMPEROR-Reduced; 30%, 61%, and 74% for DELIVER; and 32%, 59%, and 75% for EMPEROR-Preserved, respectively. The main selection criteria limiting eligibility were HF duration and N-terminal pro-B type natriuretic peptide levels. Eligible patients had more severe HF, more comorbidities, higher use of HF treatments and higher mortality and morbidity. Clinical Highlights: Large clinical trials for the approval of new drugs in heart failure often apply numerous selection criteria, limiting the generalizability of trial findings to real-world populations. We assessed eligibility for dapagliflozin and empagliflozin according to trial criteria, the more practical criteria usually applied in daily practice for treatment selection, and the criteria mandated by regulatory agencies, in a real-word heart failure population. Our results from the Swedish Heart Failure Registry show that a great number of patients with heart failure might be candidates for these therapies, which have been shown to significantly decrease morbidity and mortality; therefore, their use should be implemented in clinical practice. Lay summary: When strictly applying selection criteria used in clinical trials, only one-third of a real-world heart failure population is eligible for treatment with empagliflozin and dapagliflozin. Adopting approaches that consider the most meaningful criteria, that is, those most clinically relevant or those mandated by regulatory agencies, significantly broadened eligibility. These results might contribute to future trial design taking into consideration the characteristics of real-world populations, feasibility, and potential cost benefits. Conclusions: In a real-world HF setting, eligibility for sodium glucose co-transporter-2 inhibi-tors was similar whether selection criteria from DAPA-HF or EMPEROR-Reduced were applied in HFrEF, or EMPEROR-Preserved or DELIVER in HFpEF. These data might help stakeholders assessing the consequences of future trial eligibility. (J Cardiac Fail 2022;28:1050-1062) Funding Agencies|AstraZeneca; Boehringer Ingelheim

Objectives. To assess whether the use of cardioprotective therapies for type 2 diabetes varies by gender and whether the risk of cardiovascular events is higher in women versus men in the REWIND trial, including an international type 2 diabetes patient population with a wide range of baseline risk. Design. Gender differences in baseline characteristics, cardioprotective therapy, and the achieved clinical targets at baseline and two years were analyzed. Hazards for cardiovascular outcomes (fatal/nonfatal stroke, fatal/nonfatal myocardial infarction, cardiovascular death, all-cause mortality, and heart failure hospitalization), in women versus men were analyzed using two Cox proportional hazard models, adjusted for randomized treatment and key baseline characteristics respectively. Time-to-event analyses were performed in subgroups with or without history of cardiovascular disease using Cox proportional hazards models that included gender, subgroup, randomized treatment, and gender-by-subgroup interactions. Results. Of 9901 participants, 46.3% were women. Significantly fewer women than men had a cardiovascular disease history. Although most women met treatment targets for blood pressure (96.7%) and lipids (72.8%), fewer women than men met the target for cardioprotective therapies at baseline and after two years, particularly those with prior cardiovascular disease, who used less renin-angiotensin-aldosterone system inhibitors, statins, and aspirin than men. Despite these differences, women had lower hazards than men for all outcomes except stroke. No significant gender and cardiovascular disease history interactions were identified for cardiovascular outcomes. Conclusions. In REWIND, most women met clinically relevant treatment targets, but in lower proportions than men. Women had a lower risk for all cardiovascular outcomes except stroke. Clinical trials.gov registration number: NCT01394952

Aims Type 2 diabetes (T2DM) in patients with coronavirus disease-19 (COVID-19) is associated with a worse prognosis. We separately investigated the associations between the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and dipeptidyl peptidase-4 inhibitors (DPP-4i), and the risk of COVID-19 hospitalization and death. Methods and results Patients with T2DM registered in the Swedish National Patient Registry and alive on 1 February 2020 were included. ‘Incident severe COVID-19’ was defined as the first hospitalization and/or death from COVID-19. A modified Poisson regression approach was applied to a 1:1 propensity score-matched population receiving vs. not receiving SGLT2i, GLP-1 RA, and DPP-4i to analyse the associations between their use and (I) incident severe COVID-19 and (II) risk of 30-day mortality in patients hospitalized for COVID-19. Among 344 413 patients, 39 172 (11%) were treated with SGLT2i, 34 290 (10%) with GLP-1 RA, and 53 044 (15%) with DPP-4i; 9538 (2.8%) had incident severe COVID-19 by 15 May 2021. SGLT2i and DPP-4i were associated with a 10% and 11% higher risk of incident severe COVID-19, respectively, whereas there was no association for GLP-1 RA. DPP-4i was also associated with a 10% higher 30-day mortality in patients hospitalized for COVID-19, whereas there was no association for SGLT2i and GLP-1 RA. Conclusion SGLT2i and DPP-4i use were associated with a higher risk of incident severe COVID-19. DPP-4i use was associated with higher 30-day mortality in patients with COVID-19, whereas SGLT2i use was not. No increased risk for any outcome was observed with GLP-1 RA.

Background Gender disparities in the management of dysglycaemia, defined as either impaired glucose tolerance (IGT) or type 2 diabetes (T2DM), in coronary artery disease (CAD) patients are a medical challenge. Recent data from two nationwide cohorts of patients suggested no gender difference as regards the risk for diabetes-related CV complications but indicated the presence of a gender disparity in risk factor management. The aim of this study was to investigate gender differences in screening for dysglycaemia, cardiovascular risk factor management and prognosis in dysglycemic CAD patients. Methods The study population (n = 16,259; 4077 women) included 7998 patients from the ESC-EORP EUROASPIRE IV (EAIV: 2012–2013, 79 centres in 24 countries) and 8261 patients from the ESC-EORP EUROASPIRE V (EAV: 2016–2017, 131 centres in 27 countries) cross-sectional surveys. In each centre, patients were investigated with standardised methods by centrally trained staff and those without known diabetes were offered an oral glucose tolerance test (OGTT). The first of CV death or hospitalisation for non-fatal myocardial infarction, stroke, heart failure or revascularization served as endpoint. Median follow-up time was 1.7 years. The association between gender and time to the occurrence of the endpoint was evaluated using Cox survival modelling, adjusting for age. Results Known diabetes was more common among women (32.9%) than men (28.4%, p Conclusions Guideline-recommended risk factor control is poorer in dysglycemic women than men. This may contribute to the worse prognosis in CAD women with known diabetes.

Established dysglycaemia (impaired glucose tolerance [IGT] or type 2 diabetes [T2DM]) is a risk factor for further cardiovascular events in patients with coronary artery disease. Sodium-glucose cotransporter 2 inhibitors reduce this risk. The aim of the present investigation was to test the hypothesis that empagliflozin exerts beneficial effects on myocardial function in patients with a recent acute coronary syndrome and newly detected dysglycaemia.Forty-two patients (mean age 67.5 years, 81 % male) with recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected IGT (n = 27) or T2DM (n = 15) were randomised to 25 mg of empagliflozin daily (n = 20) or placebo (n = 22) on top of ongoing therapy. They were investigated with oral glucose tolerance tests, stress-perfusion cardiac magnetic resonance imaging (CMR) and echocardiography at three occasions: before randomisation, after seven months on study drug and three months following cessation of such drug. Primary outcome was a change in left ventricular (LV) end-diastolic volume (LVEDV) and secondary outcomes were a change in a) systolic and diastolic LV function; b) coronary flow reserve; c) myocardial extracellular volume (ECV) in non-infarcted myocardium; d) aortic pulse wave velocity.Empagliflozin induced a significant decrease in fasting and post load glucose (p 0.05) and body weight (p 0.01). Empagliflozin did not influence LVEDV, LV systolic or mass indexes, coronary flow reserve, ECV or aortic pulse wave velocity. Echocardiographic indices of LV diastolic function (E/e' and mitral E/A ratio) were not influenced. No safety concerns were identified.Empagliflozin had predicted effects on the dysglycaemia but did not influence variables expressing LV function, coronary flow reserve and ECV. An explanation may be that the LV function of the patients was within the normal range.

Digital, Objective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. Research design and methods Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection. Results Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81–1.05) vs. 0.78 (CI 0.61–0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin. Conclusion This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy., Ciencias Médicas y de la Salud

This study is aimed at investigating gender differences in the medical management of patients with coronary heart disease (CHD). Analyses were based on the ESC EORP EUROASPIRE V (European Survey Of Cardiovascular Disease Prevention And Diabetes) survey. Consecutive patients between 18 and 80 years, hospitalized for a coronary event, were included in the study. Information on cardiovascular medication intake at hospital discharge and at follow-up (≥ 6 months to 0.01) at discharge and follow-up respectively. However, a statistically significant difference was found in the use of statins at follow-up, in disfavor of women (82.8% vs. 77.7%; P 0.01). Furthermore, women were less likely than men to have received a CABG (20.4% vs. 13.2%; P

Type 2 diabetes represents a major threat to global health mainly because of its strong link to atherosclerotic vascular disease. From position 15 among the 20 leading causes of loss of disability-adjusted life-years in 2000, type 2 diabetes climbed to position 8 in 2016. The fact that ischemic heart disease and stroke, conditions for which diabetes is a major risk factor, hold the two leading positions confirms that diabetes is an important threat to health (1). Combining this information with a predicted increase in adults living with diabetes from 9.3% of the global population (463 million) in 2019 to 10.9% (700 million) in 2045, the majority with type 2 diabetes, further underlines that this menace is truly of an immense magnitude. In addition, impaired glucose tolerance (IGT) has been shown to be a risk factor for cardiovascular disease. The proportion of IGT is estimated to increase from 7.5% (374 million) of the adult population in 2019 to 8.6% (548 million) in 2045, with the largest increase in low- to middle-income countries. Of great concern is that about one-half of people with type 2 diabetes are undiagnosed, varying from 38% in high-income countries to 67% in low-income countries, limiting the possibility to prevent the development of diabetes-related complications. Diabetes already puts a strain on health economics; diabetes-related expenditure was estimated to be US$760 billion in 2019 and is expected to increase to US$845 billion in 2045 (2), with costs associated with cardiovascular complications dominating (3). Cardiovascular complications of diabetes were unknown until the Nobel Prize–awarded discovery of insulin a century ago allowed people with diabetes to survive longer (4). Not until the 1960s–1970s did the first reports on an increased cardiovascular risk associated with diabetes make their appearance from several research groups (5–8). One of the first long-term …

Background The optimal screening strategy for dysglycaemia, including type 2 diabetes (T2DM) and impaired glucose tolerance (IGT), in patients with coronary artery disease (CAD) is debated. Purpose We tested the hypothesis that measures of insulin resistance by homeostasis model assessment (HOMA) indexes may constitute accurate screening methods in a CAD population. Methods Insulin, C-peptide, glycated haemoglobin A1c (HbA1c) and an oral glucose tolerance test (OGTT) were centrally assessed in 3534 CAD patients without known dysglycaemia from the EUROASPIRE V survey. Three different HOMA indexes were calculated: HOMA-IR, HOMA2 based on insulin (HOMA2-ins), and HOMA2 based on C-peptide (HOMA2-Cpep). Dysglycaemia was diagnosed based on the two-hour postload glucose (2hPG) value obtained from the OGTT. Information on study participants was obtained by standardised visits. The optimal thresholds of the three HOMA indexes for dysglycaemia diagnosis were obtained by the maximum value of Youden's J statistic on receiver operator characteristics curves. The diagnostic performance of such thresholds was tested for both T2DM (i.e. in reference to a 2hPG value ≥11 mmol/L) and dysglycaemia (i.e. in reference to 2hPG value ≥7.8 mmol/L) and their correlation with several clinical parameters was assessed by Spearman's coefficients. Results The mean age of the patients was 63 years and 25% were women. Fifty-four percent of the patients had central obesity, 18% were current smokers, mean blood pressure was 133/80 mmHg and mean LDL-cholesterol 2.4 mmol/L. The OGTT revealed that 41% were dysglycaemic (IGT = 24% and T2DM = 16%). Mean insulin, C-peptide and HOMA indexes were significantly higher in patients with vs. without newly detected dysglycaemia (all p Conclusion Screening for dysglycaemia in CAD patients by insulin, C-peptide, HOMA-IR, HOMA2-ins and HOMA2-Cpep had insufficient diagnostic performance to detect dysglycaemia with reference to the yield of an OGTT, which should still be prioritized. Further studies are warranted to assess whether measures of insulin resistance might be better markers of unfavourable metabolic derangement beyond dysglycaemia. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): European Society of CardiologyErling-Perssons Stiftelse

Aims This study aims to provide an overview on contemporary gender differences in the risk factor control of coronary heart disease (CHD) patients. Methods and results Analyses were based on the cross-sectional ESC (European Society of Cardiology) EORP (EurObservational Research Programme) EUROASPIRE V (European Survey of Cardiovascular Disease Prevention and Diabetes) survey including data on CHD patients across 27 European countries. Men and women between 18 and 80 years old, hospitalized for a first or recurrent coronary event were included in the study. Data were available for 8261 patients of which 25.8% women. Overall, women had a worse risk factor control compared with men. Whereas women were more likely to be non-smokers (79.3% vs. 87.2%; P 0.05). Moreover, a lower proportion of women reached low-density lipoprotein cholesterol (LDL-C) target levels (31.4% vs. 22.1%; P Conclusion The risk factor control of CHD women is substantial worse compared with men despite little gender differences in cardiovascular medication intake. Further actions are needed to increase the awareness of the worse risk factor control in female CHD patients.

An oral glucose tolerance test (OGTT) combining fasting (FPG) and 2-hour plasma glucose (2hPG) is the most sensitive method for detecting type 2 diabetes (T2DM). Since it is considered time-consuming, we aim at validating a previously proposed screening algorithm based on a 1-hour plasma glucose (1hPG) with a 12 mmol/L threshold.Nine-hundred-eighteen patients with coronary artery disease (CAD) without known T2DM from the EUROASPIRE V cross-sectional survey underwent an OGTT. The reference for T2DM was 2hPG ≥ 11.1 mmol/L. T2DM diagnosis by HbA1c ≥ 6.5%(48 mmol/mol), FPG ≥ 7.0 mmol/L, and 1hPG ≥ 12 mmol/L were compared with the outcome of 2hPG.Mean FPG, HbA1c and 2hPG were 6.1 mmol/L, 5.6%(38 mmol/mol) and 7.8 mmol/L respectively. Ninety-six patients (10%) were diagnosed with T2DM according to 2hPG. Using this definition, in the group with FPG 6.5 mmol/L and 1hPG 12 only 5 (1%) were misdiagnosed as false negatives. All patients with a FPG 8.0 mmol/L and 1hPG 15.0 mmol/L were identified as having T2DM. According to the algorithm, in 79% of patients T2DM could be excluded by combining FPG 6.5 mmol/L and 1hPG 12 mmol/L.T2DM Screening by means of an algorithm combining FPG and 1hPG limits the demand of a 2hOGTT in 79% of CAD patients without known T2DM. HbA1c did not add to the information derived from this algorithm.

Background Lifestyle management is essential in the secondary care of coronary heart disease (CHD) patients. Little evidence is available about gender differences in lifestyle counselling and lifestyle compliance. This study aimed to provide an overview on potential gender differences in lifestyle advice provided by a healthcare professional and patients’ lifestyle compliance. Methods and results Analyses were based on the cross-sectional ESC EORP EUROASPIRE V survey including data on CHD patients across 27 European countries. Consecutive patients 0.05). However, a closer look at the particular actions to adopt a healthy diet revealed that women reported more frequently a reduction of their salt (68.6% vs. 73.7%; P = 0.002), fat (70.8% vs. 74.7%; P = 0.003), and calorie intake (56.8% vs. 60.5%; P = 0.004) compared to men. In contrast, women were less likely to increase their physical activity levels (55.5% vs. 48.0%; P Conclusion Despite little gender differences in lifestyle advice provided by a healthcare professional, lifestyle compliance for physical activity is worse in CHD women. Further actions are needed to increase physical activity levels in female CHD patients.

Sodium-glucose transporter-2 inhibitors (SGLT2i), originally launched as glucose-lowering drugs, have been studied in large cardiovascular outcome trials to ascertain safety. Surprisingly, these compounds reduced the risk of cardiovascular events (cardiovascular death, non-fatal myocardial and non-fatal stroke) and total mortality. The mechanisms behind this benefit are only partly understood, but a major contributor is the reduction of heart failure hospitalisations, evident already within weeks after the initiation of the SGLT2i. SGLT2 inhibition increases urinary glucose excretion, thereby improving glycaemic control in an insulin-independent manner. Moreover, SGLT2i potentially impact the cardiovascular system both indirectly via weight loss and blood pressure lowering and directly through osmotic diuresis and increased sodium excretion and presumably by improving myocardial energetics. The aim of this review is to summarise evidence from all major outcome trials investigating SGLT2i in patients with diabetes, as well as recent evidence from trials in heart failure patients without glucose perturbations, which pave the way for novel treatment of large groups of patients. The results of these studies have been taken into account in recently issued guidelines for the management of diabetes and cardiovascular disease. An important task for diabetologists, cardiologists and general practitioners is to incorporate them into clinical practice to the benefit of many patients.

Aims Use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in real-world heart failure (HF) is poorly characterised. In contemporary patients with HF and type 2 diabetes mellitus (T2DM) we assessed over time SGLT2i use, clinical characteristics and outcomes associated with SGLT2i use. Methods and results Type 2 diabetes patients enrolled in the Swedish HF Registry between 2016-2018 were considered. We performed multivariable logistic regression models to assess the independent predictors of SGLT2i use and Cox regression models in a 1:3 propensity score-matched cohort and relevant subgroups to investigate the association between SGLT2i use and outcomes. Of 6805 eligible HF patients with T2DM, 376 (5.5%) received SGLT2i, whose use increased over time with 12% of patients on treatment at the end of 2018. Independent predictors of SGLT2i use were younger age, HF specialty care, ischaemic heart disease, preserved kidney function, and absence of anaemia. Over a median follow-up of 256 days, SGLT2i use was associated with a 30% lower risk of cardiovascular (CV) death/first HF hospitalisation (hazard ratio 0.70, 95% confidence interval 0.52-0.95), which was consistent regardless of ejection fraction, background metformin treatment and kidney function. SGLT2i use was also associated with a lower risk of all-cause and CV death, HF and CV hospitalisation, and CV death/myocardial infarction/stroke. Conclusion In a contemporary HF cohort with T2DM, SGLT2i use increased over time, was more common with specialist care, younger age, ischaemic heart disease, and preserved renal function, and was associated with lower mortality and morbidity. Funding Agencies|AstraZenecaAstraZeneca; EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant [116074]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2019-01059]; Swedish Heart and Lung FoundationSwedish Heart-Lung Foundation

Background The 2019 ESC/EASD European Guidelines for Diabetes, Prediabetes and Coronary Artery Disease introduced a paradigm shift in the management of patients with type 2 diabetes (T2D) at high risk for or already established cardiovascular (CV) disease by recommending a GLP-1 receptor agonist (GLP-1 RA) as initial glucose lowering therapy in patients without any previous antihyperglycaemic treatment. This recommendation has been questioned since outcome trials of GLP-1-RA were usually conducted with metformin as background therapy. Purpose The aim of this report is to determine whether the effect of dulaglutide on cardiovascular events varies according to baseline metformin therapy. It was tested by a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. Methods REWIND, a multicentre, double-blind, placebo-controlled trial, comprised 9901 participants (women: 46.3%; mean age: 66.2 years) with T2D and either a previous CV event (31%) or a high CV risk (69%). They were randomised (1:1) to either sc. dulaglutide (1.5 mg/week) or placebo in addition to standard of care. The primary outcome was the first of a composite of non-fatal myocardial infarction or stroke or CV death. Secondary outcomes were a microvascular composite endpoint, all-cause death and heart failure. The effect of dulaglutide study outcomes in patients with and without baseline metformin was evaluated by means of a Cox regression hazard model with baseline metformin, dulaglutide assignment and the interaction between dulaglutide and metformin as independent variables. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using a Cox regression model with additional adjustments for factors that differed at baseline between people on vs. those not on baseline metformin selected by a backward regression model. A p Results Patients without metformin at baseline (n=1864; 19%) were older, leaner, more likely to be women and had a higher proportion of prior CV events, heart failure and renal disease than patients with metformin (n=8037; 81%). During a median follow-up of 5.4 years (IQR 5.1–5.9), the primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without metformin. There was no significant difference in the effect of dulaglutide on the primary outcome in the groups with vs. without metformin at baseline (HR 0.93 [CI 0.82–1.06] vs. 0.78 [CI 0.61–0.99]; p for interaction=0.16). The effect of dulaglutide on the secondary outcomes was also not modified by concomitant metformin use (all interaction p>0.1). Conclusion This exploratory analysis suggests that the cardioprotective effect of dulaglutide does not depend on baseline metformin therapy. This supports the recommendation of using agents with proven cardioprotective efficacy without metformin in patients with diabetes and additional cardiac risk factors. Figure 1. Forest plot Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Eli Lilly and Company

Background Fulminant myocarditis is a catastrophic disease with high mortality and complications. A viral aetiology is frequent and the implication of SARS-CoV-2 is not yet known. Case summary A 38-year-old woman who recently arrived from Spain presented with palpitations that started suddenly 3 days prior to presentation and were associated with haemodynamic instability, without dyspnoea or chest pain. We found features of myopericarditis on the electrocardiogram and severe systolic dysfunction on the echocardiogram. The chest tomography showed findings which suggested COVID-19 infection, and PCR for SARS-CoV-2 was positive. The cardiac magnetic resonance image showed Lake Louise criteria for myocarditis. The patient was treated with immunomodulatory, steroid, and immunoglobulin therapy, with a favourable clinical response. Discussion The importance of this case lies in highlighting the severe cardiac involvement in a young patient, without previous risk factors, positive for COVID-19, and the favourable response to the medical treatment given.

Background COVID-19 infection is the most serious global public health crisis of the century. With no approved treatments against it, investigational treatments are being used despite limited safety data. Besides being at higher risk of complications of COVID-19 infection, patients with underlying cardiovascular disease are more likely to develop cardiac-related side effects of treatment. We present a case of sinus arrest with junctional escape related to lopinavir–ritonavir. Case summary A 67-year-old man, with underlying stable ischaemic heart disease, acquired COVID-19 infection. He had a prolonged duration of fever and cough. He subsequently developed acute respiratory distress and required intensive care unit (ICU) care. Given his severe infection, he was started on lopinavir–ritonavir. Hydroxychloroquine was not used as he had a prolonged QTc interval. During observation in the ICU, the patient developed recurrent episodes of sinus arrest with junctional escape. Initial concerns were of myocarditis, but he had no ST-segment changes on ECG, with mild elevations of highly sensitive troponin I and a normal transthoracic echocardiogram. A multidisciplinary team discussion involving the intensivist, infectious disease physicians, and cardiologist; the decision was made to stop treatment with lopinavir–ritonavir. Within 48 h, the bradyarrhythmia resolved. The patient did not require transvenous and permanent pacemaker insertion. Conclusion Current efficacy and safety evidence of lopinavir–ritonavir as a treatment in COVID-19 patients is limited. Although uncommonly reported, those with underlying cardiovascular disease are at increased risk of bradyarrhythmia-related adverse effects of lopinavir–ritonavir. When initiating investigational therapies, especially in patients with cardiovascular conditions, adequate counselling and close monitoring are required.

Aims An oral glucose tolerance test (OGTT) combining fasting (FPG) and 2-hour plasma glucose (2hPG) is the most sensitive method for detecting type 2 diabetes (T2DM). Since it is considered time-consuming, we aim at validating a previously proposed screening algorithm based on a 1-hour plasma glucose (1hPG) with a 12 mmol/L threshold. Methods Nine-hundred-eighteen patients with coronary artery disease (CAD) without known T2DM from the EUROASPIRE V cross-sectional survey underwent an OGTT. The reference for T2DM was 2hPG≥11.1mmol/L. T2DM diagnosis by HbA1c≥6.5%(48mmol/mol), FPG≥7.0mmol/L, and 1hPG≥12mmol/L were compared with the outcome of 2hPG. Results Mean FPG, HbA1c and 2hPG were 6.1mmol/L, 5.6%(38mmol/mol) and 7.8mmol/L respectively. Ninety-six patients (10%) were diagnosed with T2DM according to 2hPG. Using this definition, in the group with FPG 8.0 mmol/L and 1hPG>15.0 mmol/L were identified as having T2DM. According to the algorithm, in 79% of patients T2DM could be excluded by combining FPG Conclusions T2DM Screening by means of an algorithm combining FPG and 1hPG limits the demand of a 2hOGTT in 79% of CAD patients without known T2DM. HbA1c did not add to the information derived from this algorithm.

OBJECTIVE Coronary artery disease (CAD) is a major challenge in patients with type 2 diabetes (T2D). Coronary computed tomography angiography (CCTA) provides a detailed anatomic map of the coronary circulation. Proteomics are increasingly used to improve diagnostic and therapeutic algorithms. We hypothesized that the protein panel is differentially associated with T2D and CAD. RESEARCH DESIGN AND METHODS In CAPIRE (Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation—a cohort of 528 individuals with no previous cardiovascular event undergoing CCTA), participants were grouped into CAD− (clean coronaries) and CAD+ (diffuse lumen narrowing or plaques). Plasma proteins were screened by aptamer analysis. Two-way partial least squares was used to simultaneously rank proteins by diabetes status and CAD. RESULTS Though CAD+ was more prevalent among participants with T2D (HbA1c 6.7 ± 1.1%) than those without diabetes (56 vs. 30%, P < 0.0001), CCTA-based atherosclerosis burden did not differ. Of the 20 top-ranking proteins, 15 were associated with both T2D and CAD, and 3 (osteomodulin, cartilage intermediate-layer protein 2, and HTRA1) were selectively associated with T2D only and 2 (epidermal growth factor receptor and contactin-1) with CAD only. Elevated renin and GDF15, and lower adiponectin, were independently associated with both T2D and CAD. In multivariate analysis adjusting for the Framingham risk panel, patients with T2D were “protected” from CAD if female (P = 0.007), younger (P = 0.021), and with lower renin levels (P = 0.02). CONCLUSIONS We concluded that 1) CAD severity and quality do not differ between participants with T2D and without diabetes; 2) renin, GDF15, and adiponectin are shared markers by T2D and CAD; 3) several proteins are specifically associated with T2D or CAD; and 4) in T2D, lower renin levels may protect against CAD.

In the above article, all mentions of “cartilage intermediate-layer protein” refer to “cartilage intermediate-layer protein 2.” The isoform number was misstated in the abstract and one place in the …

Background:Cardiovascular disease is a serious complication in patients with dysglycaemia, defined as either type 2 diabetes or impaired glucose tolerance. Research focusing on the identification of potential markers for atherothrombotic disease in these subjects is warranted. The antiphospholipid syndrome is a common acquired prothrombotic condition, defined by a combination of thrombotic events and/or obstetric morbidity and positivity of specific antiphospholipid antibodies. Available information on antiphospholipid antibodies in dysglycaemia is scarce.Objective:This study investigates the association between antiphospholipid antibodies and dysglycaemia.Patients/Methods:The PAROKRANK (periodontitis and its relation to coronary artery disease) study included 805 patients, investigated 6–10 weeks after a first myocardial infarction, and 805 matched controls. Participants without known diabetes (91%) underwent an oral glucose tolerance test. Associations between antiphospholipid antibodies (anti-cardiolipin and anti-β2 glycoprotein-I IgG, IgM and IgA) and dysglycaemia were analysed.Results:In total, 137 (9%) subjects had previously known type 2 diabetes and 371 (23%) newly diagnosed dysglycaemia. Compared with the normoglycaemic participants, those with dysglycaemia had a higher proportion with first myocardial infarction (61% vs 45%, p Conclusions:This study reports an association between antiphospholipid antibody IgG positivity and dysglycaemia. Further studies are needed to verify these findings and to investigate if antithrombotic therapy reduces vascular complications in antiphospholipid antibody positive subjects with dysglycaemia.

Cardiovascular (CV) disease (CVD) is the main cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Despite optimal glycaemic control, standard antihyperglycaemic therapy failed to impact CV events in intervention trials; therefore, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued a guidance to the pharmaceutical industry to specifically assess the CV outcomes and safety of new glucose-lowering drugs. Amongst them, sodium-glucose transporter 2 (SGLT2) inhibitors proved to not only provide good tolerance, few adverse effects, and good glycometabolic control, but also striking reduction in the risk of CV events. In this review, data from the main randomised controlled trials are presented, including post-hoc analyses looking into several aspects of CV protection. Moreover, the main findings from observational real-world studies to date are described, overall reassuring as regards to CV safety and efficacy of SGLT2 inhibitors. Finally, several mechanisms which might contribute to the cardioprotective effect of SGLT2 inhibition are depicted, including findings from recent mechanistic studies.

Biochemical growth hormone deficiency is prevalent among human immunodeficiency virus-infected patients, but if this condition is clinically relevant remains challenging. The aim is to prospectively compare the growth hormone deficiency/insulin-like growth factor-1 status of 71 human immunodeficiency virus-infected patients with impaired growth hormone response to growth hormone releasing hormone + Arginine with that of 65 hypopituitary patients affected by a true growth hormone deficiency secondary to pituitary disease. The main outcomes were: basal serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein 3, growth hormone peak and area under the curve after growth hormone response to growth hormone releasing hormone + Arginine test, body mass index, waist and hip circumference, and body composition by dual energy X-ray absorptiometry. Insulin-like growth factor-1 binding protein 3, basal growth hormone (p

OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibitors cause substantially less weight loss than expected from the energy excreted via glycosuria. Our aim was to analyze this phenomenon quantitatively. RESEARCH DESIGN AND METHODS Eighty-six patients with type 2 diabetes (HbA1c 7.8 ± 0.8% [62 ± 9 mmol/mol], estimated glomerular filtration rate [eGFR] 89 ± 19 mL ⋅ min−1 ⋅ 1.73 m−2) received empagliflozin (25 mg/day) for 90 weeks with frequent (n = 11) assessments of body weight, eGFR, and fasting plasma glucose (FPG). Time-dependent glucose filtration was calculated as the product of eGFR and FPG; time-dependent glycosuria was estimated from previous direct measurements. The relation of calorie-to-weight changes was estimated using a mathematical model of human energy metabolism that simulates the time course of weight change for a given change in calorie balance and calculates the corresponding energy intake changes. RESULTS At week 90, weight loss averaged −3.2 ± 4.2 kg (corresponding to a median calorie deficit of 51 kcal/day [interquartile range (IQR) 112]). However, the observed calorie loss through glycosuria (206 kcal/day [IQR 90]) was predicted to result in a weight loss of –11.3 ± 3.1 kg, assuming no compensatory changes in energy intake. Thus, patients lost only 29 ± 41% of the weight loss predicted by their glycosuria; the model indicated that this difference was accounted for by a 13% (IQR 12) increase in calorie intake (269 kcal/day [IQR 258]) coupled with a 2% (IQR 5) increase in daily energy expenditure (due to diet-induced thermogenesis). This increased calorie intake was inversely related to baseline BMI (partial r = −0.34, P < 0.01) and positively to baseline eGFR (partial r = 0.29, P < 0.01). CONCLUSIONS Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss.