Metabolic syndrome traits differentially and cumulatively influence micro- and macrovascular disease risk in patients with MASLD.

INTRODUCTION: The cumulative impact of metabolic syndrome (MetS) components on micro- and macrovascular disease in metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. We aimed to determine whether the number of the MetS components increases the risk of micro- and macrovascular disease in patients with MASLD. METHODS: We performed a retrospective cohort study of electronic medical records using the TriNetX network, a global federated database. The exposure arm was patients with hepatic steatosis (defined via International Classification of Diseases, 10th Revision coding, or modified hepatic steatosis index), and ≥1 MetS components (obesity/central adiposity, insulin resistance, hypertension, or dyslipidaemia), compared with a reference arm of adults without any MetS components or hepatic steatosis. Our propensity score matched (1:1) for confounders with 5 years of follow-up. Primary outcomes included microvascular (peripheral neuropathy, retinopathy, and nephropathy) and macrovascular (cardiovascular events, cerebrovascular accidents, and peripheral vascular disease) disease. Secondary analyses assessed the impact of additional MetS components on these outcomes, as well as the impact of sex. RESULTS: MASLD, defined by hepatic steatosis and insulin resistance (n = 15 937), carried the highest risk of microvascular disease (HR 13.93 (95% CI 8.55-22.68)), whilst MASLD, defined by hepatic steatosis and hypertension (n = 53 028), carried the highest risk of macrovascular disease (7.23 (6.45-8.13)). MASLD with all MetS components carried greatest risk of both micro- (31.20 (28.88-33.70) (n = 462 789)) and macrovascular (8.04 (7.33-8.82) (n = 336 010)) disease. CONCLUSION: We demonstrate a differential effect of MetS components on micro- and macrovascular disease risk in patients with MASLD, with a cumulative impact of multiple MetS on overall risk. The impact of MetS components was most pronounced in women. Aggressive metabolic risk factor management is critical for prevention of micro- and macrovascular complications.

Current type 2 diabetes guidelines: Individualized treatment and how to make the most of metformin.

Evidence-based guidelines provide the premise for the delivery of quality care to preserve health and prevent disabilities and premature death. The systematic gathering of observational, mechanistic and experimental data contributes to the hierarchy of evidence used to guide clinical practice. In the field of diabetes, metformin was discovered more than 100 years ago, and with 60 years of clinical use, it has stood the test of time regarding its value in the prevention and management of type 2 diabetes. Although some guidelines have challenged the role of metformin as the first-line glucose-lowering drug, it is important to point out that the cardiovascular-renal protective effects of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists were gathered from patients with type 2 diabetes, the majority of whom were treated with metformin. Most national, regional and international guidelines recommend metformin as a foundation therapy with emphasis on avoidance of therapeutic inertia and early attainment of multiple treatment goals. Moreover, real-world evidence has confirmed the glucose-lowering and cardiovascular-renal benefits of metformin accompanied by an extremely low risk of lactic acidosis. In patients with type 2 diabetes and advanced chronic kidney disease (estimated glomerular filtration rate 15-30 mL/min/1.73m2), metformin discontinuation was associated with an increased risk of cardiovascular-renal events compared with metformin persistence. Meanwhile, it is understood that microbiota, nutrients and metformin can interact through the gut-brain-kidney axis to modulate homeostasis of bioactive molecules, systemic inflammation and energy metabolism. While these biological changes contribute to the multisystem effects of metformin, they may also explain the gastrointestinal side effects and vitamin B12 deficiency associated with metformin intolerance. By understanding the interactions between metformin, foods and microbiota, healthcare professionals are in a better position to optimize the use of metformin and mitigate potential side effects. The United Kingdom Prospective Diabetes Study and the Da Qing Diabetes Prevention Program commenced 40 years ago provided the first evidence that type 2 diabetes is preventable and treatable. To drive real-world impact from this evidence, payors, practitioners and planners need to co-design and implement an integrated, data-driven, metformin-based programme to detect people with undiagnosed diabetes and prediabetes (intermediate hyperglycaemia), notably impaired glucose tolerance, for early intervention. The systematic data collection will create real-world evidence to bring out the best of metformin and make healthcare sustainable, affordable and accessible.

Dysregulation of long non-coding RNA gene expression pathways in monocytes of type 2 diabetes patients with cardiovascular disease.

BACKGROUND: Monocytes play a central role in the pathophysiology of cardiovascular complications in type 2 diabetes (T2D) patients through different mechanisms. We investigated diabetes-induced changes in lncRNA genes from T2D patients with cardiovascular disease (CVD), long-duration diabetes, and poor glycemic control. METHODS: We performed paired-end RNA sequencing of monocytes from 37 non-diabetes controls and 120 patients with T2D, of whom 86 had either macro or microvascular disease or both. Monocytes were sorted from peripheral blood using flow cytometry; their RNA was purified and sequenced. Alignments and gene counts were obtained with STAR to reference GRCh38 using Gencode (v41) annotations followed by batch correction with CombatSeq. Differential expression analysis was performed with EdgeR and pathway analysis with IPA software focusing on differentially expressed genes (DEGs) with a p-value < 0.05. Additionally, differential co-expression analysis was done with csdR to identify lncRNAs highly associated with diabetes-related expression networks with network centrality scores computed with Igraph and network visualization with Cytoscape. RESULTS: Comparing T2D vs. non-T2D, we found two significantly upregulated lncRNAs (ENSG00000287255, FDR = 0.017 and ENSG00000289424, FDR = 0.048) and one significantly downregulated lncRNA (ENSG00000276603, FDR = 0.017). Pathway analysis on DEGs revealed networks affecting cellular movement, growth, and development. Co-expression analysis revealed ENSG00000225822 (UBXN7-AS1) as the highest-scoring diabetes network-associated lncRNA. Analysis within T2D patients and CVD revealed one lncRNA upregulated in monocytes from patients with microvascular disease without clinically documented macrovascular disease. (ENSG00000261654, FDR = 0.046). Pathway analysis revealed DEGs involved in networks affecting metabolic and cardiovascular pathologies. Co-expression analysis identified lncRNAs strongly associated with diabetes networks, including ENSG0000028654, ENSG00000261326 (LINC01355), ENSG00000260135 (MMP2-AS1), ENSG00000262097, and ENSG00000241560 (ZBTB20-AS1) when we combined the results from all patients with CVD. Similarly, we identified from co-expression analysis of diabetes patients with a duration ≥ 10 years vs. <10 years two lncRNAs: ENSG00000269019 (HOMER3-AS10) and ENSG00000212719 (LINC02693). The comparison of patients with good vs. poor glycemic control also identified two lncRNAs: ENSG00000245164 (LINC00861) and ENSG00000286313. CONCLUSION: We identified dysregulated diabetes-related genes and pathways in monocytes of diabetes patients with cardiovascular complications, including lncRNA genes of unknown function strongly associated with networks of known diabetes genes.

Diabetes-Related Macrovascular Complications Are Associated With an Increased Risk of Diabetic Microvascular Complications: A Prospective Study of 1518 Patients With Type 1 Diabetes and 20 802 Patients With Type 2 Diabetes in the UK Biobank.

BACKGROUND: Diabetic vascular complications share common pathophysiological mechanisms, but the relationship between diabetes-related macrovascular complications (MacroVCs) and incident diabetic microvascular complications remains unclear. We aimed to investigate the impact of MacroVCs on the risk of microvascular complications. METHODS AND RESULTS: There were 1518 participants with type 1 diabetes (T1D) and 20 802 participants with type 2 diabetes from the UK Biobank included in this longitudinal cohort study. MacroVCs were defined by the presence of macrovascular diseases diagnosed after diabetes at recruitment, including coronary heart disease, peripheral artery disease, stroke, and ≥2 MacroVCs. The primary outcome was incident microvascular complications, a composite of diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy. During a median (interquartile range) follow-up of 11.61 (5.84-13.12) years and 12.2 (9.50-13.18) years, 596 (39.3%) and 4113 (19.8%) participants developed a primary outcome in T1D and type 2 diabetes, respectively. After full adjustment for conventional risk factors, Cox regression models showed significant associations between individual as well as cumulative MacroVCs and the primary outcome, except for coronary heart disease in T1D (T1D: diabetes coronary heart disease: 1.25 [0.98-1.60]; diabetes peripheral artery disease: 3.00 [1.86-4.84]; diabetes stroke: 1.71 [1.08-2.72]; ≥2: 2.57 [1.66-3.99]; type 2 diabetes: diabetes coronary heart disease: 1.59 [1.38-1.82]; diabetes peripheral artery disease: 1.60 [1.01-2.54]; diabetes stroke: 1.50 [1.13-1.99]; ≥2: 2.66 [1.92-3.68]). Subgroup analysis showed that strict glycemic (glycated hemoglobin <6.5%) and blood pressure (<140/90 mm Hg) control attenuated the association. CONCLUSIONS: Individual and cumulative MacroVCs confer significant risk of incident microvascular complications in patients with T1D and type 2 diabetes. Our results may facilitate cost-effective high-risk population identification and development of precise prevention strategies.

A prospective observational study to evaluate a possible relationship between vitamin K antagonist therapy and risk of peripheral arterial disease in patients with type 2 diabetes.

AIM: The use of vitamin K antagonists (VKAs) may increase the risk of peripheral arterial disease (PAD) because vitamin K is a strong inhibitor of medial arterial calcification. Type 2 diabetes (T2D) exposes patients to an increased risk of PAD. We examined how the use of VKAs modulates the risk of incident PAD in people with T2D. MATERIALS AND METHODS: SURDIAGENE is a French cohort including 1468 patients with T2D with a prospective follow-up from 2002 to 2015. The primary outcome of the current analysis was the first occurrence of PAD, a composite of lower-limb amputation (LLA) or lower-limb revascularization. LLA and lower-limb revascularization were considered individually as secondary outcomes. RESULTS: During a 7-year median follow-up, PAD occurred in 147 (10%) of the 1468 participants. The use of VKAs was not significantly associated with the risk of PAD [multivariable adjusted hazard ratio (HR) 1.42, 95% confidence interval (CI), 0.88-2.31]. During the study period, LLA and lower-limb revascularization occurred in 82 (6%) and 105 (7%) participants, respectively. The use of VKAs was significantly associated with increased risk of LLA [multivariable adjusted HR 1.90 (95% CI, 1.04-3.47)], but not lower-limb revascularization [multivariable adjusted HR 1.08 (95% CI, 0.59-1.97)]. CONCLUSIONS: In this prospective study, we did not observe any excess risk of PAD requiring lower-limb revascularization in people with type 2 diabetes using VKAs. However, our data suggest a high risk of LLA in VKA users. Further studies are required to confirm this observation.

Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: The LIFE-T1D model.

AIMS: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. MATERIALS AND METHODS: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. RESULTS: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. CONCLUSIONS: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation.

Separate and combined effects of empagliflozin and semaglutide on vascular function: A 32-week randomized trial.

AIM: Despite the increasing use of combination treatment with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, data are limited on the effects of combination treatment on markers of cardiovascular disease. This study aimed to investigate the effect of empagliflozin, semaglutide, and their combination on vascular function. MATERIALS AND METHODS: In total, 120 patients with type 2 diabetes were randomized into four groups (n = 30 in each) for 32 weeks: placebo, semaglutide, empagliflozin, and their combination. The study had two co-primary outcomes: change in arterial stiffness and kidney oxygenation. This paper reports on arterial stiffness assessed as carotid-femoral pulse wave velocity. Secondary outcomes included 24-h blood pressure (BP), 24-h central BP, urinary albumin to creatinine ratio and glycaemic control assessed by both continuous glucose monitoring and glycated haemoglobin. RESULTS: The carotid-femoral pulse wave velocity did not change significantly in any of the groups compared with placebo. Twenty-four-hour systolic BP was reduced by 10 mmHg (95% CI 6-14), p < .001 in the combination group, significantly superior to both placebo and monotherapy (p < .05). Combination treatment increased glycaemic time in range from 72% at baseline to 91% at week 32, p < .001, without increasing time below range. The urinary albumin to creatinine ratio decreased by 36% (95% CI 4-57), p = .03 in the combination group compared with placebo. CONCLUSIONS: Empagliflozin, semaglutide, or their combination did not reduce arterial stiffness. Combination treatment showed a substantial and clinically important reduction in 24-h systolic BP compared with either treatment alone. Combination treatment increased glycaemic time in range without increasing the risk of hypoglycaemia.

Association between depression and macrovascular disease: a mini review.

Depression and macrovascular diseases are globally recognized as significant disorders that pose a substantial socioeconomic burden because of their associated disability and mortality. In addition, comorbidities between depression and macrovascular diseases have been widely reported in clinical settings. Patients afflicted with coronary artery disease, cerebrovascular disease or peripheral artery disease exhibit an elevated propensity for depressive symptoms. These symptoms, in turn, augment the risk of macrovascular diseases, thereby reflecting a bidirectional relationship. This review examines the physiological and pathological mechanisms behind comorbidity while also examining the intricate connection between depression and macrovascular diseases. The present mechanisms are significantly impacted by atypical activity in the hypothalamic-pituitary-adrenal axis. Elevated levels of cortisol and other hormones may disrupt normal endothelial cell function, resulting in vascular narrowing. At the same time, proinflammatory cytokines like interleukin-1 and C-reactive protein have been shown to disrupt the normal function of neurons and microglia by affecting blood-brain barrier permeability in the brain, exacerbating depressive symptoms. In addition, platelet hyperactivation or aggregation, endothelial dysfunction, and autonomic nervous system dysfunction are important comorbidity mechanisms. Collectively, these mechanisms provide a plausible physiological basis for the interplay between these two diseases. Interdisciplinary collaboration is crucial for future research aiming to reveal the pathogenesis of comorbidity and develop customised prevention and treatment strategies.

Does nutritional guidance reduce cardiovascular events in patients with type 2 diabetes mellitus? A retrospective cohort study using a nationwide claims database.

AIM: To examine the effect of nutritional guidance (NG) provided by a registered dietitian under the direction of a physician on the development of subsequent cardiovascular events in patients with early-stage type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This retrospective cohort study used the JMDC claims database to explore patients aged 18 years or older who first met the diagnostic criteria for T2DM at a health checkup between January 2011 and January 2019. The last day of the observation period was set for 28 February, 2021. Exposure was defined as receiving NG within 180 days of diagnosis of T2DM. The primary outcome was a composite endpoint of coronary artery disease (CAD) and cerebrovascular disease, and the secondary outcomes were each event, and time to event was compared. The propensity score weighting method was used for adjusting the distribution of confounding variables. Cox regression was conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Overall, 31,378 patients met the eligibility criteria at an annual health checkup. 9.6% received NG (n = 3013). Patients who attended ≥ 1 NG after diagnosis had significantly reduced risk of cardiovascular composite (adjusted HR 0.75, 95% CI 0.58-0.97) and cerebrovascular disease (adjusted HR 0.65, 95% CI 0.47-0.90) during approximately 3.3 years of follow-up. In contrast, no difference was observed for CAD. CONCLUSIONS: Receiving NG in early-stage diabetes may reduce the incidence of cardiovascular events, especially cerebrovascular events.

Diabetes and cognitive decline: Challenges and future direction.

There is growing evidence that diabetes can induce cognitive decline and dementia. It is a slow, progressive cognitive decline that can occur in any age group, but is seen more frequently in older individuals. Symptoms related to cognitive decline are worsened by chronic metabolic syndrome. Animal models are frequently utilized to elucidate the mechanisms of cognitive decline in diabetes and to assess potential drugs for therapy and prevention. This review addresses the common factors and pathophysiology involved in diabetes-related cognitive decline and outlines the various animal models used to study this condition.

Hypomagnesemia and Cardiovascular Risk in Type 2 Diabetes.

Hypomagnesemia is 10-fold more common in individuals with type 2 diabetes (T2D) than in the healthy population. Factors that are involved in this high prevalence are low Mg2+ intake, gut microbiome composition, medication use, and presumably genetics. Hypomagnesemia is associated with insulin resistance, which subsequently increases the risk to develop T2D or deteriorates glycemic control in existing diabetes. Mg2+ supplementation decreases T2D-associated features like dyslipidemia and inflammation, which are important risk factors for cardiovascular disease (CVD). Epidemiological studies have shown an inverse association between serum Mg2+ and the risk of developing heart failure (HF), atrial fibrillation (AF), and microvascular disease in T2D. The potential protective effect of Mg2+ on HF and AF may be explained by reduced oxidative stress, fibrosis, and electrical remodeling in the heart. In microvascular disease, Mg2+ reduces the detrimental effects of hyperglycemia and improves endothelial dysfunction; however, clinical studies assessing the effect of long-term Mg2+ supplementation on CVD incidents are lacking, and gaps remain on how Mg2+ may reduce CVD risk in T2D. Despite the high prevalence of hypomagnesemia in people with T2D, routine screening of Mg2+ deficiency to provide Mg2+ supplementation when needed is not implemented in clinical care as sufficient clinical evidence is lacking. In conclusion, hypomagnesemia is common in people with T2D and is involved both as cause, probably through molecular mechanisms leading to insulin resistance, and as consequence and is prospectively associated with development of HF, AF, and microvascular complications. Whether long-term supplementation of Mg2+ is beneficial, however, remains to be determined.

Advancing a causal role of type 2 diabetes and its components in developing macro- and microvascular complications via genetic studies.

The role of diabetes in developing microvascular and macrovascular complications has been subject to extensive research. Despite multiple observational and genetic studies, the causal inference of diabetes (and associated risk factors) on those complications remains incomplete. In this review, we focused on type 2 diabetes, as the major form of diabetes, and investigated the evidence of causality provided by observational and genetic studies. We found that genetic studies based on Mendelian randomization provided consistent evidence of causal inference of type 2 diabetes on macrovascular complications; however, the evidence for causal inference on microvascular complications has been somewhat limited. We also noted high BMI could be causal for several diabetes complications, notable given high BMI is commonly upstream of type 2 diabetes and the recent calls to target weight loss more aggressively. We emphasize the need for further studies to identify type 2 diabetes components that mostly drive the risk of those complications. Even so, the genetic evidence summarized broadly concurs with the need for a multifactorial risk reduction approach in type 2 diabetes, including addressing excess adiposity.

The association between macrovascular complications and intensive care admission, invasive mechanical ventilation, and mortality in people with diabetes hospitalized for coronavirus disease-2019 (COVID-19).

BACKGROUND: It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. METHODS: We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020-October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. RESULTS: Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83-2.45 with an I2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29-1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31-0.75], I2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40-0.68], I2 37%) were significantly lower for people with previous macrovascular disease. CONCLUSIONS: This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup.

Reconsidering the role of glycaemic control in cardiovascular disease risk in type 2 diabetes: A 21st century assessment.

It is well known that the multiple factors contributing to the pathogenesis of type 2 diabetes (T2D) confer an increased risk of developing cardiovascular disease (CVD). Although the relationship between hyperglycaemia and increased microvascular risk is well established, the relative contribution of hyperglycaemia to macrovascular events has been strongly debated, particularly owing to the failure of attempts to reduce CVD risk through normalizing glycaemia with traditional therapies in high-risk populations. The debate has been further fuelled by the relatively recent discovery of the cardioprotective properties of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors. Further, as guidelines now recommend individualizing glycaemic targets, highlighting the importance of achieving glycated haemoglobin (HbA1c) goals safely, the previously observed negative influences of intensive therapy on CVD risk might not present if trials were repeated using current-day treatments and individualized HbA1c goals. Emerging longitudinal data illuminate the overall effect of excess glucose, the impacts of magnitude and duration of hyperglycaemia on disease progression and risk of CVD complications, and the importance of glycaemic control at or early after diagnosis of T2D for prevention of complications. Herein, we review the role of glucose as a modifiable cardiovascular (CV) risk factor, the role of microvascular disease in predicting macrovascular risk, and the deleterious impact of therapeutic inertia on CVD risk. We reconcile new and old data to offer a current perspective, highlighting the importance of effective, early treatment in reducing latent CV risk, and the timely use of appropriate therapy individualized to each patient's needs.

The Contribution of Wnt Signaling to Vascular Complications in Type 2 Diabetes Mellitus.

Vascular complications are the leading cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). These vascular abnormalities result in a chronic hyperglycemic state, which influences many signaling molecular pathways that initially lead to increased oxidative stress, increased inflammation, and endothelial dysfunction, leading to both microvascular and macrovascular complications. Endothelial dysfunction represents the initial stage in both types of vascular complications; it represents "mandatory damage" in the development of microvascular complications and only "introductory damage" in the development of macrovascular complications. Increasing scientific evidence has revealed an important role of the Wnt pathway in the pathophysiology of the vascular wall. It is well known that the Wnt pathway is altered in patients with T2DM. This review aims to be an update of the current literature related to the Wnt pathway molecules that are altered in patients with T2DM, which may also be the cause of damage to the vasculature. Both microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications (coronary artery disease, cerebrovascular disease, and peripheral arterial disease) are analyzed. This review aims to concisely concentrate all the evidence to facilitate the view on the vascular involvement of the Wnt pathway and its components by highlighting the importance of exploring possible therapeutic strategy for patients with T2DM who develop vascular pathologies.

Rating the importance of outcomes from diabetes trials. A survey of patients' and doctors' opinions.

Purpose: To investigate and compare how patients with diabetes mellitus and doctors rate the importance of outcomes used as part of composite endpoints in clinical diabetes trials. Secondly, to compare the ratings of outcomes between patients with low and high education. Methods: Using a pre-piloted questionnaire, patients with diabetes and doctors working with diabetes were asked to rate the importance of 36 different outcomes commonly used in trials assessing intervention effects in patients with diabetes. The respondents were asked to rate individual outcomes as being either critical, of major importance, of moderate importance, or of minor importance. Results: The study population consisted of 139 patients with a mean age of 56.6 years and an average duration of diabetes for 13.6 years and 45 doctors with a mean time of practice of 19.6 years. There was no difference between patients' and doctors' rating of risk of mortality and non-fatal myocardial infarction, and percutaneous coronary intervention (all p-values > 0.34). Non-fatal stroke, admission for heart failure or angina was perceived more severely by patients compared to doctors (all p-values < 0.03). Patients rated risk of foot-ulcers, amputations and quality of life as more important compared to doctors (p-values < 0.01). Conclusion: The current study suggest that patients and doctors weigh some diabetic outcomes used as part of composite endpoints in clinical diabetes trials differently. These findings call for more studies on patient reported outcomes and patient education for improved personal care. Highlights: • We performed this study to assess how patients and practicing physicians rate the importance of outcomes commonly used in diabetes trials.• We found that patients and doctors rate the importance of some outcomes used in clinical diabetes trials differently.• These findings suggest that shared decision making is pivotal when taking clinical decisions and that future diabetes studies incorporate end points relevant to both patients and clinicians and do not combine end points which are not equally important.

Increased frequency of proangiogenic tunica intima endothelial kinase 2 (Tie2) expressing monocytes in individuals with type 2 diabetes mellitus.

BACKGROUND: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk for developing macrovascular disease (MVD) manifested by atherosclerosis. Phenotypically and functionally different monocyte subsets (classical; CD14++CD16-, non-classical; CD14+CD16++, and intermediate; CD14++CD16+) including pro-angiogenic monocytes expressing Tie2 (TEMs) can be identified. Here we investigated monocyte heterogeneity and its association with T2DM and MVD. METHODS: Individuals with (N = 51) and without (N = 56) T2DM were recruited and allocated to "non-MVD" or "with MVD" (i.e., peripheral or coronary artery disease) subgroups. Blood monocyte subsets were quantified based on CD14, CD16 and Tie2 expression levels. Plasma levels of Tie2-ligands angiopoietin-1 and angiopoietin-2 were determined using ELISA. Carotid endarterectomy samples from individuals with (N = 24) and without (N = 22) T2DM were stained for intraplaque CD68+ macrophages (inflammation) and CD34+ (angiogenesis), as plaque vulnerability markers. RESULTS: Monocyte counts were similar between individuals with T2DM and healthy controls (non-diabetic, non-MVD). Non-classical monocytes were reduced (p < 0.05) in T2DM, whereas the percentage of TEMs within the intermediate subset was increased (p < 0.05). T2DM was associated with increased angiopoietin-1 (p < 0.05) and angiopoietin-2 (p = 0.0001) levels. Angiopoietin-2 levels were higher in T2DM individuals with MVD compared with non-MVD (p < 0.01). Endarterectomized plaques showed no differences in macrophage influx and microvessel number between individuals with and without T2DM. CONCLUSIONS: Monocyte subset distribution is altered in T2DM with reduced non-classical monocytes and increased TEM percentage in the intermediate monocyte subset. Increased angiopoietin-2 levels together with increased frequency of TEMs might promote plaque vulnerability in T2DM which could however not be confirmed at tissue level in advanced atherosclerotic lesions.

Cardiovascular efficacy of liraglutide and semaglutide in individuals with diabetes and peripheral artery disease.

AIM: To evaluate the cardiovascular (CV) efficacy of liraglutide and semaglutide in patients with type 2 diabetes (T2D) and peripheral artery disease (PAD). MATERIALS AND METHODS: LEADER and SUSTAIN 6 trials investigated subcutaneous liraglutide (≤1.8 mg/day) and semaglutide (0.5 or 1.0 mg/week), respectively, versus placebo in patients with T2D and high CV risk (median follow-up: 3.8 and 2.1 years, respectively). The primary outcome was a composite of CV death, non-fatal myocardial infarction or non-fatal stroke (major adverse CV event [MACE]) according to the presence of PAD at baseline. RESULTS: Overall, 1184/9340 (12.7%) patients in LEADER and 460/3297 (14.0%) in SUSTAIN 6 had PAD at baseline. Patients with PAD were at an ~35% increased risk of MACE versus those without (LEADER: hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.17-1.58; SUSTAIN 6: HR 1.33, 95% CI 0.94-1.83). The effects of both therapies on MACE were consistently beneficial in patients with PAD (liraglutide: HR 0.77, 95% CI 0.58-1.01; semaglutide: 0.61, 0.33-1.13) and without (liraglutide: HR 0.89, 95% CI 0.79-1.00; semaglutide: HR 0.77, 95% CI 0.58-1.01; Pinteraction  = .34 for liraglutide and .49 for semaglutide). Absolute risk reductions for MACE were higher in patients with PAD (liraglutide: 4.13%-point, 95% CI -0.15-8.42; semaglutide: 4.63%-point, 95% CI -0.58-9.84) versus without (liraglutide:1.42%-point, 95% CI -0.03-2.87; semaglutide: 1.90%-point, 95% CI 0.00-3.80). CONCLUSION: Both liraglutide and semaglutide reduce MACE with consistent CV efficacy regardless of PAD status.

Sotagliflozin for patients with type 2 diabetes: A systematic review and meta-analysis.

AIM: To assess the efficacy and safety of sotagliflozin in patients with type 2 diabetes. METHODS: We searched Medline, Embase, the Cochrane Library, and grey literature sources up to August 2021 for randomized controlled trials (RCTs) that compared sotagliflozin with placebo or other antidiabetic agents in patients with type 2 diabetes. Our primary outcome was change in HbA1c from baseline. We additionally assessed three secondary efficacy and 15 safety outcomes. We synthesized data using weighted mean differences (WMDs) and odds ratios (ORs), along with 95% confidence intervals (CIs). RESULTS: We included 11 RCTs comprising 16 411 subjects in the meta-analysis. Compared with placebo, sotagliflozin reduced HbA1c (WMD -0.42%, 95% CI -0.56 to -0.29), body weight (WMD -1.33 kg, 95% CI -1.57 to -1.09), and systolic blood pressure (WMD -2.44 mmHg, 95% CI -2.81 to -2.07). No difference was evident against other active comparators. Sotagliflozin reduced myocardial infarction (OR 0.72, 95% CI 0.54 to 0.97) and heart failure (OR 0.68, 95% CI 0.58 to 0.79) compared with placebo, and had a neutral effect on all-cause mortality, cardiovascular mortality, and stroke. Treatment with sotagliflozin was safe regarding the incidence of serious adverse events, hypoglycaemia, and diabetic ketoacidosis. Nevertheless, it was associated with an increased incidence of diarrhoea, genital infections, and volume depletion events. CONCLUSIONS: Sotagliflozin reduces blood glucose, body weight, and systolic blood pressure, and demonstrates a beneficial effect on heart failure and myocardial infarction. Its overall safety profile is comparable with other sodium-glucose co-transporter-2 inhibitors.

A higher non-severe hypoglycaemia rate is associated with an increased risk of subsequent severe hypoglycaemia and major adverse cardiovascular events in individuals with type 2 diabetes in the LEADER study.

AIMS/HYPOTHESIS: Hypoglycaemia is a common side effect of insulin and some other antihyperglycaemic agents used to treat diabetes. Severe hypoglycaemia has been associated with adverse cardiovascular events in trials of intensive glycaemic control in type 2 diabetes. The relationship between non-severe hypoglycaemic episodes (NSHEs) and severe hypoglycaemia in type 2 diabetes has been documented. However, an association between more frequent NSHEs and cardiovascular events has not been verified. This post hoc analysis of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial aimed to confirm whether there is an association between NSHEs and severe hypoglycaemic episodes in individuals with type 2 diabetes. In addition, the possible association between NSHEs and major adverse cardiac events (MACE), cardiovascular death and all-cause mortality was investigated. METHODS: LEADER was a double-blind, multicentre, placebo-controlled trial that found that liraglutide significantly reduced the risk of MACE compared with the placebo. In this post hoc analysis, we explored, in all LEADER participants, whether the annual rate of NSHEs (defined as self-measured plasma glucose <3.1 mmol/l [56 mg/dl]) was associated with time to first severe hypoglycaemic episode (defined as an episode requiring the assistance of another person), time to first MACE, time to cardiovascular death and time to all-cause mortality. Participants with <2 NSHEs per year were used as reference for HR estimates. Cox regression with a time-varying covariate was used. RESULTS: We demonstrate that there is an association between NSHEs (2-11 NSHEs per year and ≥12 NSHEs per year) and severe hypoglycaemic episodes (unadjusted HRs 1.98 [95% CI 1.43, 2.75] and 5.01 [95% CI 2.84, 8.84], respectively), which was consistent when baseline characteristics were accounted for. Additionally, while no association was found between participants with 2-11 NSHEs per year and adverse cardiovascular outcomes, higher rates of NSHEs (≥12 episodes per year) were associated with higher risk of MACE (HR 1.50 [95% CI 1.01, 2.23]), cardiovascular death (HR 2.08 [95% CI 1.17, 3.70]) and overall death (HR 1.80 [95% CI 1.11, 2.92]). CONCLUSIONS/INTERPRETATION: The analysis of data from the LEADER trial demonstrated that higher rates of NSHEs were associated with both a higher risk of severe hypoglycaemia and adverse cardiovascular outcomes in individuals with type 2 diabetes. Therefore, irrespective of the cause of this association, it is important that individuals with high rates of hypoglycaemia are identified so that the potentially increased risk of cardiovascular events can be managed and steps can be taken to reduce NSHEs. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01179048).