Glucagon-like peptide-1 receptor agonists use and associations with outcomes in heart failure and type 2 diabetes. Data from the Swedish Heart Failure and Swedish National Diabetes Registries.

AIMS: To assess use and associations with outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in a real-world population with heart failure (HF) and type 2 diabetes (T2DM). METHODS AND RESULTS: The Swedish HF Registry was linked with the National Diabetes Registry and other national registries. Independent predictors of GLP-1 RA use were assessed by multivariable logistic regressions, and associations with outcomes by Cox regressions in a 1:1 propensity score-matched cohort. Of 8188 patients enrolled in 2017-2021, 9% received a GLP-1 RA. Independent predictors of GLP-1 RA use were age<75, worse glycaemic control, impaired renal function, obesity and reduced ejection fraction (EF). GLP-1 RA use was not significantly associated with a composite of HF hospitalization (HHF) or cardiovascular (CV) death regardless of EF, but was associated with lower risk of major adverse CV events (CV death, non-fatal stroke/transient ischemic attack or myocardial infarction), CV and all-cause death. In patients with body mass index≥30 kg/m2, GLP-1 RA use was also associated with lower risk of HHF/CV death and HHF alone. CONCLUSIONS: In patients with HF and T2DM, GLP-1 RA use was independently associated with more severe T2DM, reduced EF and obesity, and was not associated with a higher risk of HHF/CV death but with longer survival and less major CV adverse events. An association with lower HHF/CV death and HHF was observed in obese patients. Our findings provide new insights into GLP-1 RA use and its safety in HF and T2DM.

Universal screening for early detection of chronic autoimmune, metabolic and cardiovascular diseases in the general population using capillary blood (UNISCREEN): low-risk interventional, single-centre, pilot study protocol.

INTRODUCTION: Chronic autoimmune (type 1 diabetes and coeliac disease) and metabolic/cardiovascular (type 2 diabetes, dyslipidaemia, hypertension) diseases are highly prevalent across all age ranges representing a major public health burden. Universal screening for prediction/early identification of these conditions is a potential tool for reducing their impact on the general population. The aim of this study is to assess whether universal screening using capillary blood sampling is feasible at a population-based level. METHODS AND ANALYSIS: This is a low-risk interventional, single-centre, pilot study for a population-based screening programme denominated UNISCREEN. Participants are volunteers aged 1-100 who reside in the town of Cantalupo (Milan, Italy) undergoing: (1) interview collecting demographics, anthropometrics and medical history; (2) capillary blood collection for measurement of type 1 diabetes and coeliac disease-specific autoantibodies and immediate measurement of glucose, glycated haemoglobin and lipid panel by point-of-care devices; (3) venous blood sampling to confirm autoantibody-positivity; (4) blood pressure measurement; (5) fulfilment of a feasibility and acceptability questionnaire. The outcomes are the assessment of feasibility and acceptability of capillary blood screening, the prevalence of presymptomatic type 1 diabetes and undiagnosed coeliac disease, distribution of glucose categories, lipid panel and estimate of cardiovascular risk in the study population. With approximately 3000 inhabitants, the screened population is expected to encompass at least half of its size, approaching nearly 1500 individuals. ETHICS AND DISSEMINATION: This protocol and the informed consent forms have been reviewed and approved by the San Raffaele Hospital Ethics Committee (approval number: 131/INT/2022). Written informed consent is obtained from all study participants or their parents if aged <18. Results will be published in scientific journals and presented at meetings. CONCLUSIONS: If proven feasible and acceptable, this universal screening model would pave the way for larger-scale programmes, providing an opportunity for the implementation of innovative public health programmes in the general population. TRIAL REGISTRATION NUMBER: NCT05841719.

Sex differences in the association between insulin resistance and non-fatal myocardial infarction across glycaemic states.

BACKGROUND: Females are generally less prone to cardiovascular (CV) events than males, but this protection is trumped by diabetes. The mechanism behind the increased relative risk in females with diabetes is not fully understood. Insulin resistance (IR) is suggested to be a more important contributor to CV morbidity in females than in males. We aim to investigate differences in the association between IR indexes (Homeostatic Model Assessment of IR - HOMA-IR, visceral adiposity index - VAI, and triglycerides/high-density lipoprotein-cholesterol - TG/HDL-C index), and a first non-fatal myocardial infarction (MI) across different glycaemic states. METHODS: IR indexes were calculated in a population with (n = 696) and without (n = 707) a first non-fatal MI, free from known diabetes. MI cases were investigated at least six weeks after the event. All participants were categorized by an oral glucose tolerance test as having normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance, or newly diagnosed diabetes. Comparison of proportion of glycaemic states by sex was tested by chi-square test. The associations between sex, a first non-fatal MI, IR indexes, and traditional CV risk factors were analysed by multivariate logistic regression models. Continuous variables were logarithmically transformed. RESULTS: Of the total population 19% were females and 81% males, out of whom 47% and 50% had a first non-fatal MI, respectively. Compared with males, females were older, less often smokers, with lower body mass index and higher total cholesterol and high-density lipoprotein cholesterol levels. The proportion of glycaemic states did not differ between the sexes (p = 0.06). Females were less insulin resistant than males, especially among cases and with normal glucose tolerance. In logistic regression models adjusted for major CV risk factors including sex, the associations between VAI and TG/HDL-C index and a first non-fatal MI remained significant only in females (odds ratios and 95% confidence intervals: 1.7, 1.0-2.9, and 1.9, 1.1-3.4 respectively). CONCLUSIONS: These results support the assumption that IR indexes based on anthropometrics and lipid panel, i.e., VAI and TG/HDL-C, could be a better measure of IR and CV-predictor for non-fatal MI in females, even without glycaemic perturbations.

High Mannose Correlates With Surrogate Indexes of Insulin Resistance and Is Associated With an Increased Risk of Cardiovascular Events Independently of Glycemic Status and Traditional Risk Factors.

OBJECTIVE: To explore the associations among mannose, indexes of insulin resistance (IR) and secretion, and long-term cardiovascular outcomes. RESEARCH DESIGN AND METHODS: Fasting mannose was assayed in 1,403 participants, one-half of which had a first myocardial infarction (MI) with either normal glucose tolerance (n = 1,045) or newly detected dysglycemia (i.e., impaired glucose tolerance or type 2 diabetes; n = 358). Regression models were used to explore mannose associations with surrogate indexes of IR/insulin secretion. Multivariate Cox models were used to investigate the independent association between high (higher quartile) versus low (lower three quartiles) mannose and major adverse cardiac events (MACE) (n = 163) during the 10-year follow-up. RESULTS: Mannose was independently associated with IR indexes (all P ≤ 0.001). High versus low mannose was independently associated with MACE (hazard ratio 1.54, 95% CI 1.07-2.20) in the overall population. CONCLUSIONS: Mannose might represent a new biomarker able to track early, potentially detrimental glucometabolic alterations independently of glycemic state.

N-terminal pro-B-type natriuretic peptide concentrations, testing and associations with worsening heart failure events.

AIMS: In patients with heart failure (HF), we aimed to assess (i) the time trends in N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing; (ii) patient characteristics associated with NT-proBNP testing; (iii) distribution of NT-proBNP levels, focusing on the subgroups with (WHFE) vs. without (NWHFE) a worsening HF event, defined as an HF hospitalization; and (iv) changes of NT-proBNP levels over time. METHODS AND RESULTS: NT-proBNP testing and levels were investigated in HF patients enrolled in the Swedish Heart Failure Registry (SwedeHF) linked with the Stockholm CREAtinine Measurements project from January 2011 to December 2018. Index date was the first registration in SwedeHF. Patterns of change in NT-proBNP levels before (in the previous 6 ± 3 months) and after (in the following 6 ± 3 months) the index date were categorized as follows: (i) <3000 ng/L at both measurements = stable low; (ii) <3000 ng/L at the first measurement and ≥3000 ng/L at the second measurement = increased; (iii) ≥3000 ng/L at the first measurement and <3000 ng/L at the second measurement = decreased; and (iv) ≥3000 ng/L at both measurements = stable high. Univariable and multivariable logistic regression models, expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs), were performed to assess the associations between (i) clinical characteristics and NT-proBNP testing and (ii) changes in NT-proBNP from 6 months prior to the index date and the index date and a WHFE. Consistency analyses were performed in HF with reduced ejection fraction (HFrEF) alone. A total of 4424 HF patients were included (median age 74 years, women 34%, HFrEF 53%), 33% with a WHFE. NT-proBNP testing increased over time, up to 55% in 2018, and was almost two-fold as frequent, and time to testing was less than half, in patients with WHFE vs. NWHFE. Independent predictors of testing were WHFE, higher heart rate, diuretic use, and preserved ejection fraction. Median NT-proBNP was 3070 ng/L (Q1-Q3: 1220-7395), approximately three-fold higher in WHFE vs. NWHFE. Compared with stable low NT-proBNP levels, increased (OR 4.27, 95% CI 2.47-7.37) and stable high levels (OR 2.48, 95% CI 1.58-3.88) were independently associated with a higher risk of WHFE. Results were consistent in the HFrEF population. CONCLUSIONS: NT-proBNP testing increased over time but still was only performed in half of the patients. Testing was associated with a WHFE, with features of more severe HF and for differential diagnosis purposes. Increased and stable high levels were associated with a WHFE. Overall, our data highlight the potential benefits of carrying further implementation of NT-proBNP testing in clinical practice.

Empagliflozin improves insulin sensitivity in patients with recent acute coronary syndrome and newly detected dysglycaemia : Experiences from the randomized, controlled SOCOGAMI trial.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM) and high cardiovascular risk via mechanisms which have not been fully explained. The mechanisms of such benefit have not been fully understood, and whether empagliflozin can be safely administered as first-line treatment in patients with CVD at the initial stages of glycaemic perturbations remains to be established. We investigated the effects of empagliflozin on insulin resistance, insulin sensitivity and ß-cell function indexes in patients with a recent acute coronary event and newly detected dysglycaemia, i.e., impaired glucose tolerance (IGT) or T2DM. METHODS: Forty-two patients (mean age 67.5 years, 19% females) with a recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected dysglycaemia were randomized to either empagliflozin 25 mg daily (n = 20) or placebo (n = 22). Patients were investigated with stress-perfusion cardiac magnetic resonance imaging before randomization, 7 months after the start of study drug and 3 months following its cessation. Indexes of insulin resistance, sensitivity and ß-cell function were calculated based on glucose and insulin values from 2-hour oral glucose tolerance tests (OGTT) and fasting C-peptide. The differences in glucose, insulin, C-peptide, mannose levels and indexes between the two groups were computed by repeated measures ANOVA including an interaction term between the treatment allocation and the time of visit. RESULTS: After 7 months, empagliflozin significantly decreased glucose and insulin values during the OGTT, whereas C-peptide, mannose and HbA1c did not differ. Empagliflozin significantly improved insulin sensitivity indexes but did not impact insulin resistance and ß-cell function. After cessation of the drug, all indexes returned to initial levels. Insulin sensitivity indexes were inversely correlated with left ventricular mass at baseline. CONCLUSIONS: Empagliflozin improved insulin sensitivity indexes in patients with a recent coronary event and drug naïve dysglycaemia. These findings support the safe use of empagliflozin as first-line glucose-lowering treatment in patients at very high cardiovascular risk with newly diagnosed dysglycaemia. TRIAL REGISTRATION NUMBER: EudraCT number 2015-004571-73.

Real-world use of sodium-glucose cotransporter 2 inhibitors in patients with heart failure and reduced ejection fraction: Data from the Swedish Heart Failure Registry.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce mortality/morbidity in heart failure (HF). We explored the implementation of SGLT2i over time, and patient characteristics associated with their use, in a large, nationwide population with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Patients with HFrEF (ejection fraction <40%), no type 1 diabetes, estimated glomerular filtration rate (eGFR) <20 ml/min/1.73 m2 and/or on dialysis, registered in the Swedish HF Registry between 1 November 2020 and 5 August 2022 were included. Independent predictors of use were investigated by multivariable logistic regressions. Of 8192 patients, 37% received SGLT2i. Use increased overall from 20.5% to 59.0% over time, from 46.2% and 12.5% to 69.8% and 55.4% in patients with and without type 2 diabetes, from 14.7% and 22.3% to 58.0% and 59.8% in eGFR <60 versus ≥60 ml/min/1.73 m2 , from 21.0% and 18.9% to 61.6% and 52.0% in males versus females, from 24.2% and 18.0% to 60.8% and 57.7% in patients with versus without recent HF hospitalization, from 26.1% and 19.8% to 54.7% and 59.6% in inpatients versus outpatients, and from 20.2% and 21.2% to 59.2% and 58.7% in those with HF duration <6 versus ≥6 months, respectively. Important characteristics associated with SGLT2i use were male sex, recent HF hospitalization, specialized HF follow-up, lower ejection fraction, type 2 diabetes, higher education level, use of other HF/cardiovascular interventions. Older age, higher blood pressure, atrial fibrillation and anaemia were associated with less use. Discontinuation rate at 6 and 12 months was 13.1% and 20.0%, respectively. CONCLUSIONS: Use of SGLT2i increased three-fold over 2 years. Although this indicates a more rapid translation of trial results and guidelines into clinical practice compared to previous HF drugs, further efforts are advocated to complete the implementation process while avoiding inequities across different patient subgroups and discontinuations.

Eligibility for vericiguat in a real-world heart failure population according to trial, guideline and label criteria: Data from the Swedish Heart Failure Registry.

AIM: We investigated the eligibility for vericiguat in a real-world heart failure (HF) population based on trial, guideline and label criteria. METHODS AND RESULTS: From the Swedish HF registry, 23 573 patients with HF with reduced ejection fraction (HFrEF) enrolled between 2000 and 2018, with a HF duration ≥6 months, were considered. Eligibility for vericiguat was calculated based on criteria from (i) the Vericiguat Global Study in Subjects with Heart Failure and Reduced Ejection Fraction (VICTORIA) trial; (ii) European and American guidelines on HF; (iii) product labelling according to the Food and Drug Administration and European Medicines Agency. Estimated eligibility for vericiguat in the trial, guidelines, and label scenarios was 21.4%, 47.4%, and 47.4%, respectively. Prior HF hospitalization within 6 months was the criterion limiting eligibility the most in all scenarios (met by 49.1% of the population). In the trial scenario, other criteria meaningfully limiting eligibility were elevated N-terminal pro-B-type natriuretic peptide levels and nitrate use. In all scenarios, eligibility was higher among patients hospitalized for HF at baseline (44.3% vs. 21.4% [trial scenario] and 97.3% vs. 47.4% [guideline/label scenarios] for hospitalized vs. non-hospitalized patients). Overall, eligible patients were older, had more severe HF, more comorbidities, and consequently higher cardiovascular mortality and HF hospitalization rates compared with ineligible patients across all scenarios. CONCLUSION: In a large and contemporary real-world HFrEF cohort, we estimated that 21.4% of patients would be eligible for vericiguat according to the VICTORIA trial selection criteria, 47.4% based on guidelines and labelling. Eligibility for vericiguat translated into the selection of a population at high risk of morbidity/mortality.

Extremes of both weight gain and weight loss are associated with increased incidence of heart failure and cardiovascular death: evidence from the CANVAS Program and CREDENCE.

BACKGROUND: Obesity is an independent risk factor for cardiovascular disease (CVD) in patients with type 2 diabetes (T2D). However, it is not known to what extent weight fluctuations might be associated with adverse outcomes. We aimed at assessing the associations between extreme weight changes and cardiovascular outcomes in two large randomised controlled trials of canagliflozin in patients with T2D and high cardiovascular (CV) risk. METHODS: In the study populations of the CANVAS Program and CREDENCE trials, weight change was evaluated between randomization and week 52-78, defining subjects in the top 10% of the entire distribution of weight changes as gainers, subjects in the bottom 10% as losers and the remainder as stable. Univariate and multivariate Cox proportional hazards models were used to test the associations between weight changes categories, randomised treatment and covariates with heart failure hospitalisation (hHF) and the composite of hHF and CV death. RESULTS: Median weight gain was 4.5 kg in gainers and median weight loss was 8.5 kg in losers. The clinical phenotype of gainers as well as that of losers were similar to that of stable subjects. Weight change within each category was only slightly larger with canagliflozin than placebo. In both trials, gainers and losers had a higher risk of hHF and of hHF/CV death compared with stable at univariate analysis. In CANVAS, this association was still significant by multivariate analysis for hHF/CV death in both gainers and losers vs. stable (hazard ratio - HR 1.61 [95% confidence interval - CI: 1.20-2.16] and 1.53 [95% CI 1.14-2.03] respectively). Results were similar in CREDENCE for gainers vs. stable (adjusted HR for hHF/CV death 1.62 [95% CI 1.19-2.16]) CONCLUSIONS: Extremes of weight gain or loss were independently associated with a higher risk of the composite of hHF and CV death. In patients with T2D and high CV risk, large changes in body weight should be carefully assessed in view of individualised management. TRIALS REGISTRATION: CANVAS ClinicalTrials.gov number: NCT01032629. CREDENCE ClinicalTrials.gov number: NCT02065791.

Gender differences in cardiovascular risk, treatment, and outcomes: a post hoc analysis from the REWIND trial.

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.

Antiphospholipid antibodies in patients with calcific aortic valve stenosis.

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-ß2Glycoprotein-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.

SOdium-glucose CO-transporter inhibition in patients with newly detected Glucose Abnormalities and a recent Myocardial Infarction (SOCOGAMI).

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

SGLT2 Inhibitors in Type 2 Diabetes Mellitus.

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.

Plasma mannose as a novel marker of myocardial infarction across different glycaemic states: a case control study.

BACKGROUND: Plasma mannose, an emerging novel biomarker of insulin resistance, is associated with both diabetes mellitus and coronary atherosclerosis, but the relationship between mannose concentrations and myocardial infarction (MI) across different glycaemic states remains to be elucidated. The aim of this study was to investigate the independent association between mannose and a first MI in a group of subjects characterized according to their glycaemic state. METHODS: Fasting plasma mannose concentrations were analysed in 777 patients 6-10 weeks after a first myocardial infarction and in 770 matched controls by means of high-performance liquid chromatography coupled to tandem mass spectrometry. Participants without known diabetes mellitus were categorized by an oral glucose tolerance test (OGTT) as having normal glucose tolerance (NGT, n = 1045), impaired glucose tolerance (IGT, n = 246) or newly detected type 2 diabetes (T2DM, n = 112). The association between mannose and MI was investigated across these glycaemic states by logistic regression. RESULTS: Mannose levels increased across the glycaemic states (p < 0.0001) and were significantly associated with a first MI in the whole study population (odds ratio, OR: 2.2; 95% CI 1.4 to - 3.5). Considering the different subgroups separately, the association persisted only in subjects with NGT (adjusted OR: 2.0; 95% CI 1.2-3.6), but not in subgroups with glucose perturbations (adjusted OR: 1.8, 95% CI 0.8-3.7). CONCLUSIONS: Mannose concentrations increased across worsening levels of glucose perturbations but were independently associated with a first MI only in NGT individuals. Thus, mannose might be a novel, independent risk marker for MI, possibly targeted for the early management of previously unidentified patients at high cardiovascular risk.

Association between use of novel glucose-lowering drugs and COVID-19 hospitalization and death in patients with type 2 diabetes: a nationwide registry analysis.

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.

Long-term prognosis after a first myocardial infarction: eight years follow up of the case-control study PAROKRANK.

Objective. To explore long-term cardiovascular outcomes and mortality in patients after a first myocardial infarction (MI) compared with matched controls in a contemporary setting. Methods. During 2010-2014 the Swedish study PAROKRANK recruited 805 patients <75 years with a first MI and 805 age-, gender-, and area-matched controls. All study participants were followed until 31 December 2018, through linkage with the National Patient Registry and the Cause of Death Registry. The primary endpoint was the first of a composite of all-cause death, non-fatal MI, non-fatal stroke, and heart failure hospitalization. Event rates in cases and controls were calculated using a Cox regression model, subsequently adjusted for baseline smoking, education level, and marital status. Kaplan-Meier curves were computed and compared by log-rank test. Results. A total of 804 patients and 800 controls (mean age 62 years; women 19%) were followed for a mean of 6.2 (0.2-8.5) years. The total number of primary events was 211. Patients had a higher event rate than controls (log-rank test p < .0001). Adjusted hazard ratio (HR) for the primary outcome was 2.04 (95% CI 1.52-2.73). Mortality did not differ between patients (n = 38; 4.7%) and controls (n = 35; 4.4%). A total of 82.5% patients and 91.3% controls were event-free during the follow up. Conclusions. In this long-term follow up of a contemporary, case-control study, the risk for cardiovascular events was higher in patients with a previous first MI compared with their matched controls, while mortality did not differ. The access to high quality of care and cardiac rehabilitation might partly explain the low rates of adverse outcomes.

Liver function markers predict cardiovascular and renal outcomes in the CANVAS Program.

BACKGROUND: Raised liver function tests (LFTs) have been correlated with multiple metabolic abnormalities and variably associated with cardiorenal outcomes. We sought to systematically test the relationship between LFT levels within the accepted range and major cardiorenal outcomes in a large clinical trial in type 2 diabetes, and the possible impact of placebo-controlled canagliflozin treatment. METHODS: We measured serum alanine aminotransferase (ALT), aspartic aminotransferase (AST), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), and bilirubin concentrations in 10,142 patients, at baseline and repeatedly over follow-up. The relation of LFTs to first hospitalized heart failure (HHF), cardiovascular (CV) and all-cause mortality, and progression of renal impairment was investigated using multivariate proportional-hazards models. RESULTS: In univariate association, ALT was reciprocally predictive, and ALP was positively predictive, of all adjudicated outcomes; γGT also was directly associated with CV-but not renal-outcomes. In multivariate models including all 5 LFTs and 19 potential clinical confounders, ALT was independently associated with lower, and γGT with higher, CV outcomes risk. Canagliflozin treatment significantly reduced ALT, AST, and γGT over time. In a fully adjusted model including updated LFT levels and treatment, γGT was independently associated with CV and all-cause mortality, ALP with renal dysfunction progression, and canagliflozin treatment with significant reduction in HHF and renal risk. CONCLUSIONS: Higher γGT levels are top LFT markers of risk of HHF and death in patients with diabetes and high CV risk, while ALT are protective. Canagliflozin lowers the risk of HHF and renal damage independently of LFTs and potential confounders.

Mannose-binding lectin does not explain the dismal prognosis after an acute coronary event in dysglycaemic patients. A report from the GAMI cohort.

BACKGROUND: Mannose binding lectin (MBL) has been suggested to be associated with an impaired cardiovascular prognosis in dysglycaemic conditions, but results are still contrasting. Our aims are (i) to examine whether MBL levels differ between patients with an acute myocardial infarction (MI) and healthy controls and between subgroups with different glucose tolerance status, and (ii) to investigate the relation between MBL and future cardiovascular events. METHODS: MBL levels were assessed at discharge and after 3 months in 161 AMI patients without any previously known glucose perturbations and in 183 age- and gender-matched controls from the Glucose metabolism in patients with Acute Myocardial Infarction (GAMI) study. Participants were classified as having dysglycaemia, i.e. type 2 diabetes or impaired glucose tolerance, or not by an oral glucose tolerance test. The primary outcome was a composite of cardiovascular events comprising cardiovascular death, AMI, stroke or severe heart failure during 11 years of follow-up. Total and cardiovascular mortality served as secondary outcomes. RESULTS: At hospital discharge patients had higher MBL levels (median 1246 µg/L) than three months later (median 575 µg/L; p < 0.01), the latter did not significantly differ from those in the controls (801 µg/L; p = 0.47). MBL levels were not affected by dysglycaemia either in patients or controls. Independent of glycaemic state, increasing MBL levels did not predict any of the studied outcomes in patients. In unadjusted analyses increasing MBL levels predicted cardiovascular events (hazard ratio HR: 1.67, 95% confidence interval CI 1.06-2.64) and total mortality (HR 1.53, 95% CI 1.12-2.10) in the control group. However, this did not remain in adjusted analyses. CONCLUSIONS: Patients had higher MBL levels than controls during the hospital phase of AMI, supporting the assumption that elevated MBL reflects acute stress. MBL was not found to be independently associated with cardiovascular prognosis in patients with AMI regardless of glucose state.