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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

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.

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 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.

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.

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 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.

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

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 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.

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.