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Purpose: There are large disparities in the impact of diabetes on cardiovascular disease (CVD) risk and outcomes by sex and gender. Achieving health equity requires understanding risks and medication efficacy in female patients, especially now, as novel pharmacologic treatments are transforming the diabetes and CVD treatment landscape. This review examines 2 bodies of research that can inform sex differences in CVD in patients with diabetes: female-specific risk factors for CVD and sex-related limitations of clinical trial research in evaluating novel diabetes and CVD treatments., Methods: Two literature searches were performed using Ovid Medline(R) All. The first retrieved manuscripts covering sex and gender differences related to CVD risk and therapies and diabetes. The second focused on randomized controlled trial data on sex/gender differences and GLP-1/SGLT-2/DPP-4 drugs., Results: Female-specific risk factors for CVD include early menarche, premature or early menopause, irregular cycles and polycystic ovary syndrome; pregnancy; adverse pregnancy outcomes; history of breast cancer; and autoimmune diseases. Clinical trials of novel pharmacological treatments for diabetes and CVD have undersampled female populations, and clinical characteristics of male and female participants have differed significantly. Thus, evidence to evaluate potential sex differences in treatment efficacy and side effects has been lacking., Conclusion: To improve health of female patients with diabetes, sex-specific cardiovascular risk factors should be taken into account in screening and treatment decisions. Further, studies of cardiovascular and diabetes medications must ensure adequate representation by sex and report participant characteristics and outcomes by sex., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objective: To investigate the association of diabetes duration with cardiovascular disease (CVD) risk and to examine the relationship between lipid levels and CVD risk over the duration., Methods: Using the Korean National Health Insurance Service Cohort database, we identified 2 359 243 subjects with type 2 diabetes aged ≥ 20 years in 2015 to 2016. Baseline lipid levels and diabetes duration were evaluated and followed up until December 2020 (mean follow-up, 3.9 years). Subjects were categorized according to diabetes duration (new-onset, < 5 years, 5-9 years, or ≥ 10 years). We analyzed the new-onset diabetes group with low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL as the reference group. The hazard ratios (HRs) and 95% CIs of myocardial infarction (MI) and ischemic stroke (IS) were estimated using a Cox proportional hazards model adjusted for potential confounders., Results: During follow-up, 45 883 cases of MI and 53 538 cases of IS were identified. The risk of MI or IS began to increase at LDL-C ≥ 160 mg/dL in the new-onset diabetes group, and at LDL-C ≥ 130 mg/dL in the group with diabetes duration < 5 years. Among subjects with diabetes duration of 5 to 9 years, LDL-C levels of 100-129 mg/dL, 130-159 mg/dL, and ≥ 160 mg/dL were significantly associated with the risk of MI (HR [95% CI] 1.13 [1.04-1.22], 1.28 [1.17-1.39], and 1.58 [1.42-1.76], respectively). MI risk in the diabetes duration ≥ 10 years group was increased by 16%, even in the LDL-C 70-99 mg/dL population (HR [95% CI] 1.16 [1.08-1.25])., Conclusion: This population-based longitudinal study revealed that the LDL-C cutoff level for increasing the risk of CVD varied with diabetes duration and that the target LDL-C level should depend on the duration., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Given the limited head-to-head comparison of cardiovascular and renal outcomes between liraglutide and dulaglutide, our study aimed to investigate the clinical outcomes between dulaglutide and liraglutide in a real-world setting. In this new-user design, comparative and retrospective cohort study, patients with type 2 diabetes mellitus with prescription for GLP-1RAs from January 1, 2016 to December 31, 2022 (n = 8,278) were included. Primary outcome was composite cardiovascular outcomes which was composed of cardiovascular death, non-fatal myocardial infarction, and non-fatal ischemic stroke. The composite renal outcome was also interested, including new macroalbuminuria, doubling of serum creatinine, worsening of estimated glomerular filtration rate (eGFR), and progression to dialysis. A total of 3,210 subjects receiving liraglutide and 5,068 subjects receiving dulaglutide were identified. In the adjusted cohort by applying inverse probability of treatment weighting, the incidence of composite cardiovascular outcomes was 18.4 and 18.7 events per 1000 person-years in the liraglutide and dulaglutide groups, respectively. The risk of cardiovascular outcomes did not significantly differ between groups (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.85-1.15). Moreover, the risk of composite renal outcomes was also comparable between groups (subdistribution HR 1.07, 95% CI 0.995-1.16). Liraglutide and dulaglutide demonstrated comparable cardiovascular and renal outcomes in a real-world setting., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Aims: Hypoalbuminemia can lead to underestimations of the true anion gap levels. There are few data on albumin-corrected serum anion gap (ACAG) status and mortality in the diabetes. The study aimed to examine the association between ACAG and all-cause, cardiovascular, and cancer mortality in type 2 diabetes (T2D) patients., Methods: Herein, 8,161 diabetic adults were included in the National Health and Nutrition Examination Survey (NHANES) 1999-2018. National Mortality Index (NDI) data were used for determining mortality outcomes through 31 December 2019. Cox proportional hazards models were used to estimate the risk of all-cause, cardiovascular, and cancer mortality. We conducted a mediation analysis using the counterfactual framework method to estimate how ACAG may be indirectly associated with increased mortality risk through mediators., Results: A total of 2,309 deaths were documented over 8,161 person-years of follow up, including 659 cardiovascular and 399 cancer deaths. In multivariate analyses, higher ACAG levels had a significant correlation with an increase in all-cause (HR, 1.58; 95% CI, 1.38-1.81; P=0.001), cardiovascular (HR, 1.34; 95% CI, 1.05-1.72; P=0.019), and cancer (HR, 1.41; 95% CI, 1.02-1.96; P=0.018) mortality rates than the controls. Results of the mediation analysis showed that altered levels of C-reactive protein and estimated glomerular filtration rate (eGFR) explained 7.867% and 7.669% of the relation between serum ACAG and all-cause mortality, respectively (all P<0.05). Total cholesterol and HbA1c mediated 15.402% and 14.303% of the associations with cardiovascular mortality, respectively (all P<0.05)., Conclusions: Higher ACAG levels were significantly associated with increased all-cause, cardiovascular, and cancer mortality. Researchers suggest that patients with T2D who control ACAG in a normal state may be at a lower risk of mortality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Yang, Deng, Wu, He, Li, Dong, Zhang and Li.)

Source Citation: Lingvay I, Deanfield J, Kahn SE, et al; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes by baseline HbA 1c and change in HbA 1c in people with overweight or obesity but without diabetes in SELECT. Diabetes Care. 2024;47:1360-1369. 38907684., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Diet and lifestyle modifications remain the foundation of obesity treatment, but they have historically proven insufficient for significant, long-term weight loss. As a result, there is a high demand for new pharmacologic treatments to promote weight loss and prevent life-threatening diseases associated with obesity. Researchers are particularly interested in 1 type of drug, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), because of its promising potential in addressing the limitations of non-pharmacologic treatments. In addition to their role in weight loss, these drugs have shown promising early evidence of cardiovascular benefits in obese patients, further enhancing their clinical relevance. Semaglutide and liraglutide, which were initially approved for the treatment of type 2 diabetes, have since been approved by the Food and Drug Administration as weight loss medications due to their effectiveness in promoting significant and sustained weight loss. In this narrative review, we will explore the mechanism of GLP-1 RAs, their effects on weight loss, cardiovascular risk factors and outcomes, common adverse effects, and strategies for managing these effects., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Metabolic dysfunction-associated steatotic liver disease (MASLD), represents a growing health concern due to its strong association with metabolic syndrome, obesity, and type 2 diabetes mellitus (T2DM). This condition, characterized by excessive fat accumulation in the liver not attributed to alcohol consumption, has emerged as a leading cause of chronic liver disease globally. MASLD significantly elevates the risk of major adverse cardiovascular events (MACE) through mechanisms like increased oxidative stress, insulin resistance, and chronic inflammation, all of which contribute to the development of atherosclerosis and endothelial dysfunction. Effective management of MASLD is crucial not only for liver health but also for cardiovascular disease (CVD) prevention. Lifestyle modifications, particularly weight loss achieved through dietary changes and increased physical activity, are the cornerstone of MASLD treatment. Additionally, pharmacological interventions, especially antihyperglycemic agents, play a pivotal role in treating MASLD in patients with T2DM. Novel therapeutic agents targeting various pathways of metabolic and liver dysfunction are under investigation, offering hope for more effective management strategies. This review explores the interconnectedness of MASLD and CVD, highlighting current and emerging therapeutic approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: To investigate the impact of diagnosis age of type 2 diabetes mellitus (T2DM) on subsequent adverse outcomes within the Chinese population., Methods: 549,959 eligible T2DM patients were included from Ningbo and Jinhua city in Zhejiang province, China. Standardized ratio was used to evaluate the risks of coronary heart disease (CHD), stroke, cancer and all-cause death in different T2DM diagnosis age groups., Results: For all adverse outcomes, higher excess risks were observed in the youngest age group (30-39) than in the oldest age group (≥80) with T2DM. The standardized incidence ratios (SIR) were 5.93 (95% CI: 3.46, 10.14) for CHD, 5.45 (95% CI: 3.72, 7.99) for stroke and 1.85 (95% CI: 1.38, 2.49) for cancer in the youngest age group, and were 1.32 (95% CI: 1.08, 1.60) for CHD, 1.25 (95% CI: 1.08, 1.44) for stroke, and 0.78 (95% CI: 0.56, 1.09) for cancer, respectively, in the oldest age group. The standardized mortality ratios (SMR) for all-cause death were 3.15 (1.69, 5.84) vs. 1.12 (0.88, 1.43). These excess risks decreased with increasing diagnosis age (all P value < 0.001). Consistent results were observed when individuals were stratified by sex or further excluded with the time from T2DM diagnosis to endpoints less than 1 or 2 years., Conclusions: Th earlier the diagnosis of T2DM, the higher the risk for subsequent adverse outcomes. It is imperative to enhance the management and monitoring of early-onset patients during follow-up., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: To identify unique clinical phenotypes in type 2 diabetes (T2D) and investigate their treatment response to canagliflozin using latent class analysis., Methods: This was a pooled latent class analysis of the individuals in the CANVAS Program and CREDENCE trial. The co-primary endpoints were hospitalization for heart failure (HHF) and the composite of cardiovascular death (CVD) or HHF. Secondary endpoints included three-point major adverse CV events, its individual components, and all-cause mortality. We completed Cox proportional hazards models to evaluate the effect of canagliflozin across phenotypes., Results: Four distinct phenotypes were identified: Phenotype 1 (n = 966, 6.6%), with the lowest prevalence of heart failure, kidney dysfunction and hypertension; Phenotype 2 (n = 4169, 28.7%), primarily comprising females with a high prevalence of atherosclerotic vascular disease (ASCVD); Phenotype 3 (n = 7108, 48.9%), predominately males with a high prevalence of ASCVD; and Phenotype 4 (n = 2300, 15.8%), possessing the highest prevalences of HF and renal dysfunction. A hierarchical increase in the risk of the primary endpoint was observed across the phenotypes, with the highest CV risk observed for Phenotype 4 (hazard ratio for HHF: 7.57 [95% CI: 4.19-13.69]). Canagliflozin significantly reduced HHF and the composite CVD or HHF across phenotypes (all P values for interaction > .05)., Conclusion: We identified four clinically distinct T2D phenotypes with differential CV risks. Canagliflozin reduced the risk of CV events, irrespective of the phenotype, emphasizing its broad therapeutic acceptability., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose of Review: Body fat distribution plays a significant role in the cardiometabolic consequences of obesity. We review the impact of visceral and hepatic fat and highlight important interventions., Recent Findings: Several epidemiologic studies have established a clear association between visceral fat and cardiovascular disease. The association between hepatic fat and cardiovascular disease is less clear with discordant results. Novel evidence demonstrates sodium glucose co-transporter-2 (SGLT2) inhibitors facilitate modest weight loss and reductions in ectopic fat depots in patient with type 2 diabetes. Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with decreased visceral/hepatic fat and reductions in MACE in populations with type 2 diabetes and with overweight/obesity. Clear associations between visceral fat and cardiometabolic outcomes have been established, whereas the impact of hepatic fat remains less clear. Lifestyle modification and pharmacologic interventions remain the initial therapies, while surgical intervention is associated with improved long-term outcomes. Emerging therapies have demonstrated a profound impact on body fat distribution and cardiometabolic risk., (© 2024. The Author(s).)

Purpose of Review: Cardiovascular disease (CVD) is the leading cause of death globally and is closely associated with obesity and type 2 diabetes mellitus (T2DM). This review examines the interplay between obesity, T2DM, and CVD, highlighting the increasing prevalence and economic burden of these conditions., Recent Findings: Pharmacologic therapies, particularly glucagon-like peptide-1 receptor agonists, show promise in substantial weight loss and subsequent reduction of adverse cardiovascular events in obese individuals with and without diabetes. Obesity significantly contributes to the development of insulin resistance and T2DM, further escalating CVD risk. The common co-occurrence of these three conditions may involve several other pathophysiological mechanisms, such as chronic inflammation, increased visceral adiposity, and endothelial dysfunction. Until recently, lifestyle modifications and bariatric surgery had been the primary methods for weight loss and mitigating obesity-associated cardiovascular risk. Newer pharmacological options have led to a paradigm shift in our approach to obesity management as they provide substantial benefits in weight loss, glycemic control, and cardiovascular risk reduction., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: To investigate whether the physician-encounter interval for patients with type 2 diabetes (T2D) can be optimized from 2-3 to 4-6 months among those with a calculated 10-year cardiovascular disease (CVD) risk score of less than 20% without compromising their long-term outcomes., Materials and Methods: Using territory-wide public electronic medical records in Hong Kong, we emulated a target trial to compare the effectiveness of the physician-encounter intervals of 4-6 versus 2-3 months for T2D patients without prior CVDs and with a predicted risk for CVDs of less than 20% (i.e. those patients not in the high-risk category). Propensity score matching was used to emulate the randomization of participants at baseline, where 42 154 matched individuals were included for analysis. The marginal structural model was applied to estimate the hazard ratio (HR) for CVD incidence and all-cause mortality, the incidence rate ratio of secondary and tertiary care utilization, as well as the between-group differences in HbA1c, blood pressure and cholesterol levels., Results: During a follow-up period of up to 12 (average: 5.1) years, there was no significantly increased risk of CVD in patients with physician-encounter intervals of 4-6 months compared with those patients with physician-encounter intervals of 2-3 months (HR [95% confidence interval {CI}]: 1.01 [0.90, 1.14]; standardized 10-year risk difference [95% CI]: -0.1% [-0.7%, 0.6%]), nor for all-cause mortality (HR: 1.00 [0.84, 1.20]; standardized 10-year risk difference: -0.1% [-0.5%, 0.3%]). Additionally, there was no observable difference in the utilization of secondary and tertiary care or key clinical parameters between these two follow-up frequencies., Conclusions: For T2D patients with a calculated 10-year CVD risk of less than 20%, the interval of regular physician encounters can be optimized from 2-3 to 4-6 months without compromising patients' long-term outcomes and saving substantial service resources in primary care., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To evaluate the association between changes in haemoglobin A1c (HbA1c) and the concurrent incidence of cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) patients., Method: We conducted a retrospective cohort study among T2DM patients with HbA1c measurement after T2DM diagnosis between August 2009 and September 2010. The patients were classified into six subgroups based on baseline HbA1c (<7%; 7%-7.9%; ≥8%) and age (<65; ≥65 years), and then clustered into classes by HbA1c trajectory and CVD incidence over the 12-year follow-up period using joint latent class mixture models. We explored the HbA1c trajectories and CVD incidences in each latent class. Multinomial logistic regression was used to compare the baseline characteristics among different latent classes., Results: A total of 128 843 T2DM patients were included with a median follow-up period of 11.7 years. Ten latent classes were identified in patients with baseline HbA1c ≥ 8% and age <65 years, while seven classes were identified in the other five groups. Among all the identified latent classes, patients with fluctuating HbA1c trajectories, characterized by alternating periods of increase and decrease, had higher CVD incidences. Male patients, and patients with higher baseline HbA1c and use of antidiabetic drugs were more likely to have a fluctuating HbA1c trajectory. More specifically, patients aged < 65 years with younger age or a smoking habit, and patients aged ≥ 65 years with a longer duration of T2DM were more likely to have a fluctuating HbA1c trajectory., Conclusion: We found that T2DM patients with fluctuating HbA1c trajectories could have a higher CVD risk. Different trajectory-associated characteristics in age subgroups highlight the need for individualized management of T2DM patients., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Estimating how type 2 diabetes (T2D) affects the rate of depression in cardiovascular disease (CVD) can help identify high-risk patients. The aim is to investigate how T2D affects the rate of depression according to specific subtypes of CVD., Methods: Incident CVD patients, free of psychiatric disease, with and without T2D, were included from nationwide registries between 2010 and 2020. We followed patients from CVD diagnosis until the first occurrence of depression, emigration, death, 5 years, or end of study (December 31, 2021). We used time-dependent Poisson regression to estimate the incidence rates and rate ratios (IRR) of depression following subtypes of CVD with and without T2D. The model included age, sex, comorbidities, calendar year, T2D duration, educational level, and living situation as covariates., Results: A total of 165,096 patients were included; 45,845 had a myocardial infarction (MI), 63,691 had a stroke, 19,959 had peripheral artery disease (PAD), 35,568 had heart failure (HF), and 979 were diagnosed with 2 or more CVD subtypes (= > 2 CVD's). Baseline T2D in each CVD subtype ranged from 11 to 17%. The crude incidence rate of depression per 1000 person-years (95% confidence intervals) was: MI + T2D: 131.1 (109.6;155.6), MI: 82.1 (65.3;101.9), stroke + T2D: 287.4 (255.1;322.6), stroke: 222.4(194.1;253.6), PAD + T2D: 173.6 (148.7;201.4), PAD:137.5 (115.5;162.5), HF + T2D: 244.3 (214.6;276.9), HF: 199.2 (172.5;228.9), =  > 2 CVD's + T2D: 427.7 (388.1;470.2), =  > 2 CVD's: 372.1 (335.2;411.9). The adjusted IRR of depression in MI, stroke, PAD, HF, and =  > 2 CVD's with T2D compared to those free of T2D was: 1.29 (1.23;1.35), 1.09 (1.06;1.12), 1.18 (1.13;1.24), 1.05 (1.02;1.09), and 1.04 (0.85;1.27) (p-value for interaction < 0.001)., Conclusion: The presence of T2D increased the rate of depression differently among CVD subtypes, most notable in patients with MI and PAD., (© 2023. The Author(s).)

Background: Empagliflozin and dapagliflozin have proven cardiovascular benefits in people with type 2 diabetes at high cardiovascular risk, but their comparative effectiveness is unknown., Methods: This study used nationwide, population-based Danish health registries to emulate a hypothetical target trial comparing empagliflozin versus dapagliflozin initiation, in addition to standard care, among people with treated type 2 diabetes from 2014 through 2020. The outcome was a composite of myocardial infarction, ischemic stroke, heart failure (HF), or cardiovascular death (major adverse cardiovascular event). Participants were followed until an outcome, emigration, or death occurred; 6 years after initiation; or December 31, 2021, whichever occurred first. Logistic regression was used to compute inverse probability of treatment and censoring weights, controlling for 57 potential confounders. In intention-to-treat analyses, 6-year adjusted risks, risk differences, and risk ratios, considering noncardiovascular death competing events, were estimated. Analyses were stratified by coexisting atherosclerotic cardiovascular disease and HF. A per-protocol design was performed as a secondary analysis., Results: There were 36 670 eligible empagliflozin and 20 606 eligible dapagliflozin initiators. In the intention-to-treat analysis, the adjusted 6-year absolute risk of major adverse cardiovascular event was not different between empagliflozin and dapagliflozin initiators (10.0% versus 10.0%; risk difference, 0.0% [95% CI, -0.9% to 1.0%]; risk ratio, 1.00 [95% CI, 0.91 to 1.11]). The findings were consistent in people with atherosclerotic cardiovascular disease (risk difference, -2.3% [95% CI, -8.2% to 3.5%]; risk ratio, 0.92 [95% CI, 0.74 to 1.14]) and without atherosclerotic cardiovascular disease (risk difference, 0.3% [95% CI, -0.6% to 1.2%]; risk ratio, 1.04 [95% CI, 0.93 to 1.16]) and in people with HF (risk difference, 1.1% [95% CI, -6.5% to 8.6%]; risk ratio, 1.04 [95% CI, 0.79 to 1.37]) and without HF (risk difference, -0.1% [95% CI, -1.0% to 0.8%]; risk ratio, 0.99 [95% CI, 0.90 to 1.09]). The 6-year risks of major adverse cardiovascular event were also not different in the per-protocol analysis (9.1% versus 8.8%; risk difference, 0.2% [95% CI, -2.1% to 2.5%]; risk ratio, 1.03 [95% CI, 0.80 to 1.32])., Conclusions: Empagliflozin and dapagliflozin initiators had no differences in 6-year cardiovascular outcomes in adults with treated type 2 diabetes with or without coexisting atherosclerotic cardiovascular disease or HF., Competing Interests: Dr Hennessy consults for the Medullary Thyroid Cancer Registry Consortium (Novo Nordisk Inc, AstraZeneca Pharmaceuticals LP, and Eli Lilly and Company). The other authors report no disclosures.

Background: Cardiovascular diseases (CVDs) are the most common cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). There is a paucity of data on the pattern of first manifestation of CVD and the outcome among patients with T2DM in Cameroon., Objectives: We aimed to examine the pattern of the first manifestation of CVD and the outcome among patients with T2DM., Methods: Between January 2017 and December 2023, files of patients with T2DM hospitalized for the first observed CVD were reviewed. We identified cases of three incident overt clinically manifest CVD complications (acute myocardial infarction [AMI], stroke, and heart failure) in hospitalized T2DM patients. Patients with a previous history of CVD were excluded., Results: Out of the 1091 patients hospitalized with T2DM, we identified 261(23.9%) patients with clinically overt CVD, of whom 129 (49.4%) were females. The mean age was 63.9 ± 12.1 years and ranged from 15 to 91 years. Women were significantly older compared to men (65.4 ± 11.4 years vs. 62.5 ± 12.6 years; p = 0.042). Hypertension was reported in 201 (77%; 95% CI: 71.4-82) patients. Any form of chronic kidney disease was seen in 15 (5.8%; 95% CI: 3.3-9.3) patients. HIV infection was seen in 5 (1.9%; 95% CI: 0.6-4.4) patients. Stroke was the most common incident clinically overt CVD in 144 (55.2%; 95% CI: 48.9-61.3) patients, followed by heart failure in 105 (40.2%; 95% CI: 34.2-46.5) patients, and Acute MI in 12 (4.6%; 95% CI: 2.4-7.9) patients. The mean length of hospital stay was 9.7 ± 6.6 days. Patients with stroke had a significantly longer hospital stay > 7 days (63% vs. 48.7%, p = 0.021). The in-hospital case fatality was seen in 35 (13.4%; 95% CI: 9.5-18.2) patients., Conclusion: Nearly 1 out of 4 hospitalized patients with T2DM was hospitalized for a first CVD. Stroke and heart failure are the most common initial manifestations of CVD. More than three-quarters of the patients had concomitant hypertension and the in-hospital case fatality was high., Clinical Trial Number: Not applicable., (© 2024. The Author(s).)

Background: The evidence regarding the relationship between different types of beverages and cardiovascular health in individuals with type 2 diabetes (T2D) is scarce., Aims: To prospectively examine the associations between individual beverage consumption, genetic predisposition, and risk of incident cardiovascular disease (CVD) among adults with T2D., Methods: We analyzed the associations of individual beverage intake with risks of CVD and ischemic heart disease (IHD) in 7315 participants with T2D, overall or stratified by genetic risk to CVD, using data from the UK Biobank study., Results: During a median follow-up of 6.1 years, 878 incident CVD cases were identified, including 517 IHD cases. Higher intakes of sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and natural juices were each linearly associated with a higher CVD (Pnonlinearity > .05). Comparing the highest to lowest groups of beverage consumption, the multivariable-adjusted hazard ratios (95% confidence intervals) of CVD were 1.54 (1.14, 2.07) for SSBs, 1.34 (1.07, 1.69) for ASBs, and 1.33 (1.01, 1.76) for natural juices. Similar results were observed for incident IHD. Moreover, no significant interactions between these beverages and the CVD genetic risk score were observed. Replacing half-unit/day of SSBs or natural juices with coffee, tea, or yogurt, but not ASBs, was associated with a 20% to 46% lower risk of CVD and IHD., Interpretation: Higher intakes of SSBs, ASBs, and natural juices were each linearly associated with an increased risk of CVD among individuals with T2D, regardless of genetic predisposition. Our findings highlight the importance of selecting healthy beverage options to improve cardiovascular health in patients with T2D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To investigate the associations of serum gamma-glutamyl transferase (GGT) levels with the risk of cardiovascular disease (CVD) and its subtypes in patients with type 2 diabetes mellitus (T2DM) in Jiangsu Province. Methods: The participants were enrolled in the Comprehensive Research project regarding 'Prevention and Control of Diabetes' in Jiangsu Province. The baseline survey was conducted from 2013 to 2014, and follow-up until December 31, 2021. After excluding the participants who self-reported with chronic liver disease/stroke/coronary heart disease at baseline survey and those with incomplete information on GGT, a total of 16 147 T2DM patients were included in the final analysis. Cox proportional hazard regression models were used to calculate the hazard ratio ( HR ) and their 95% CI of GGT for CVD, myocardial infarction, and stroke. Restricted cubic spline models were applied to analyze the dose-response relationship between GGT and the risk of CVD and its subtypes. Results: During the median follow-up time of 8.02 years, 2 860 CVD cases were registered, including 196 cases of myocardial infarction and 2 730 cases of stroke. Multivariate Cox proportional risk regression model indicated that compared to the lowest serum GGT level group, the highest GGT level group had a 24% increased risk of CVD ( HR =1.24, 95% CI : 1.09-1.41) and a 23% increased risk of stroke ( HR =1.23, 95% CI : 1.08-1.40). The restricted cubic spline model showed a nonlinear dose-response relationship between GGT and the risk of CVD, myocardial infarction, and stroke in T2DM patients. Conclusions: High levels of GGT may be associated with an increased risk of cardiovascular disease in T2DM patients, which needs further exploration and validation in future clinical practice.

Aims: Identifying patients with established cardiovascular disease (CVD) who are at high risk of type 2 diabetes (T2D) may allow for early interventions, reducing the development of T2D and associated morbidity. The aim of this study was to develop and externally validate the CVD2DM model to estimate the 10-year and lifetime risks of T2D in patients with established CVD., Methods and Results: Sex-specific, competing risk-adjusted Cox proportional hazard models were derived in 19 281 participants with established CVD and without diabetes at baseline from the UK Biobank. The core model's pre-specified predictors were age, current smoking, family history of diabetes mellitus, body mass index, systolic blood pressure, fasting plasma glucose, and HDL cholesterol. The extended model also included HbA1c. The model was externally validated in 3481 patients from the UCC-SMART study. During a median follow-up of 12.2 years (interquartile interval 11.3-13.1), 1628 participants with established CVD were diagnosed with T2D in the UK Biobank. External validation c-statistics were 0.79 [95% confidence interval (CI) 0.76-0.82] for the core model and 0.81 (95% CI 0.78-0.84) for the extended model. Calibration plots showed agreement between predicted and observed 10-year risk of T2D., Conclusion: The 10-year and lifetime risks of T2D can be estimated with the CVD2DM model in patients with established CVD, using readily available clinical predictors. The model would benefit from further validation across diverse ethnic groups to enhance its applicability. Informing patients about their T2D risk could motivate them further to adhere to a healthy lifestyle., Competing Interests: Conflict of interest: M.W. has received consultancy fees from Amgen and Freeline. The other authors have nothing to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Type 2 diabetes mellitus (T2DM) and its consequences are a serious global public health issue. By 2030, the number of people with type 2 diabetes is predicted to reach 439 million. The purpose of this study is to evaluate the plasma levels of glucose, HbA1c, insulin, and lipid profile in Sudanese T2DM patients. Methods: This case control study included 165 Sudanese patients with diabetic type 2 and a cardiovascular condition as cases and 165 diabetic type 2 volunteers without a cardiovascular disorder as controls. The concentrations of plasma glucose, HbA1c, and lipid profile were assessed using a Mindray BS-480 auto-chemistry analyzer, and insulin was analyzed using a Cobase 411 auto analyzer. The collected data were analyzed using statistical tools for social science computer programs (SPSS version 21). Results: According to the findings, (59.4%) of patients between the ages of (50-69). Females made up 50.9%. (38.2%) of patients had an illness duration of between (8-15 years). (41.8%) of individuals did not have hypertension. There was a substantial rise in BMI, FBG, HbA1c, HDL-C, and insulin among diabetics with cardiovascular disease compared to diabetics without cardiovascular disease (p-value = 0.001, 0.000, 0.018, and 0.000). Females had significantly higher blood TC, LDL-C, HDL-C, and BMI than males (p-values = 0.000, 0,001, and 0.000, respectively). There were significant positive correlation between FBS, HBA1c, insulin and duration of disease (r=0.155, p, value=0.005) (r=0.160, p, value=0.004)(r=0.103, p. value=0.061)respectively, while there were significant negative correlation between TC, TG,LDL-C, HDL-C and duration of disease (r=-0.152, p, value= 0.006)(r=-0.023, p, value=0.678)(r=-0.113, p, value= 0.040)(r=-0.145, p, value=0.008)respectively. Conclusion: When comparing diabetics with cardiovascular disease to diabetics without cardiovascular disease, there was a substantial rise in BMI, FBG, HbA1c, HDL-C, and insulin. FBS, HBA1c, insulin, and illness duration all had a strong positive connection., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Abdallah SI et al.)

Importance: Cardiovascular disease (CVD) can be recurrent during type 2 diabetes (T2D) progression in this aging population. The effectiveness of sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy on total (ie, first and subsequent) CVD among patients with T2D in clinical practice remains uncertain., Objective: To analyze the comparative association of SGLT2i vs dipeptidyl peptidase 4 inhibitor (DPP4i) therapy with total CVD among patients with T2D in clinical practice., Design, Setting, and Participants: This retrospective cohort study used electronic medical records at the National Cheng Kung University Hospital, a leading medical center in Taiwan, from 2015 through 2021. Adult patients with T2D who initiated first use of the study drugs from 2016 through 2019, with up to 6 years of follow-up, were identified., Main Outcomes and Measures: The primary outcomes included total composite CVD events and individual CVD subtypes (ie, atrial fibrillation, coronary heart disease, heart failure, stroke, myocardial infarction, and transient ischemic attack). A shared frailty model analysis was used to assess the association of treatment with repeat CVD events. Data from patients at high risk for CVD recurrence were further analyzed. Data were analyzed from September 1, 2022, to December 31, 2023., Results: Overall, 8384 patients with T2D were identified (mean [SD] age, 63.7 [12.4] years; 4645 [55.4%] male). A total of 1632 propensity score-matched pairs of SGLT2i (mean [SD] age, 57.8 [12.0] years; 673 [41.2%] female and 959 [58.8%] male) and DPP4i (mean [SD] age, 58.2 [12.9] years; 655 [40.1%] female and 977 [59.9%] male) users were included. SGLT2i was associated with reduced total CVD risk vs DPP4i therapy (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98]) but not the first CVD event (with the use of SGLT2i therapy were more prominent for patients at high risk of CVD (ie, HR, 0.70 [95% CI, 0.62-0.80] for individuals with estimated glomerular filtration rate lower than 60 mL/min/1.73 m2; HR, 0.70 [95% CI, 0.64-0.78]; for individuals having any diabetes-related complications; and HR, 0.72 [95% CI, 0.65-0.80] for individuals with a history of CVD) compared with the overall cohort. Among patients at high risk of CVD, greater reduced total CVD burden associated with SGLT2i therapy was observed for women vs men (eg, HR, 0.59 [95% CI, 0.49-0.72] in the subgroup with CVD history)., Conclusions and Relevance: In this cohort study of patients with T2D, the use of SGLT2is vs DPP4is was associated with reduced total cardiovascular burden, suggesting that long-term use of this therapy may optimize treatment benefit among patients with chronic CVD. The SGLT2i-associated benefit among patients with high risk of CVD encourages the prioritization of SGLT2i use for these vulnerable individuals.

Background: Cardiovascular diseases are a common cause of death among patients with type 2 diabetes (T2DM). Major adverse cardiovascular event (MACE) risks can be significantly reduced under adequate glycemic control (GC). This study aims to identify factors that influence MACE risk among patients with T2DM, including Hemoglobin A1c variability score (HVS) and early use of MACE-preventive glucose-lowering medications (GLMs)., Methods: We conducted a longitudinal cohort study to retrospectively review electronic health records between 2011 and 2022. Patients with T2DM ≥18 years without previous stroke or acute myocardial infarction (AMI) were included. Cox regression was utilized to investigate MACE risk factors and compare MACE risk reduction associated with early use of MACE-preventive GLMs., Results: A total of 19 685 subjects were included, with 5431 having MACE, including 4453 strokes, 977 AMI, and 1 death. There were 11 123 subjects with good baseline GC. Subjects with good baseline GC had 0.837 (confidence interval [CI]: 0.782-0.895) times lower MACE risk than their counterpart. Subjects with a single MACE-preventive GLM at baseline with continuous use >365 days showed a decreased MACE hazard ratio (0.681; CI: 0.635-0.731). Among all MACE-preventive GLMs, semaglutide provided a more significant MACE-preventive effect., Conclusions: This study identified that GLM, early GC, and HVS are MACE determinants among patients with T2DM. Novel GLM, adequate GC, and reduction of HVS can benefit MACE outcomes., (© 2024 The Author(s). Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Backgruound: This study investigated the prognostic importance of the hemoglobin glycation index (HGI) for macrovascular and microvascular outcomes, mortality, and hypoglycemia occurrence in a type 2 diabetes cohort and compared it to glycated hemoglobin (HbA1c)., Methods: Baseline and mean first-year HGI and HbA1c, and the variability thereof, were assessed in 687 individuals with type 2 diabetes (median follow-up, 10.6 years). Multivariable Cox regression was conducted to evaluate the associations of HGI and HbA1c parameters with macrovascular (total and major cardiovascular events) and microvascular outcomes (microalbuminuria, advanced renal failure, retinopathy, and peripheral neuropathy), mortality (all-cause and cardiovascular), and moderate/severe hypoglycemia occurrence., Results: During follow-up, there were 215 total cardiovascular events (176 major) and 269 all-cause deaths (131 cardiovascular). Microalbuminuria developed in 126 patients, renal failure in 104, retinopathy in 161, and neuropathy in 177. There were 90 hypoglycemia episodes. Both HGI and HbA1c predicted all adverse outcomes, except microalbuminuria and hypoglycemia. Their adjusted risks were roughly equivalent for all outcomes. For example, the adjusted hazard ratios (HRs) with 95% confidence intervals (CIs), estimated for 1 standard deviation increments, of mean first-year HGI were 1.23 (1.05 to 1.44), 1.20 (1.03 to 1.38), 1.36 (1.11 to 1.67), 1.28 (1.09 to 1.67), and 1.29 (1.09 to 1.54), respectively, for cardiovascular events, all-cause mortality, renal failure, retinopathy, and neuropathy; whereas the respective HRs (95% CIs) of mean HbA1c were 1.31 (1.12 to 1.53), 1.28 (1.11 to 1.48), 1.36 (1.11 to 1.67), 1.33 (1.14 to 1.55), and 1.29 (1.09 to 1.53)., Conclusion: HGI was no better than HbA1c as a predictor of adverse outcomes in individuals with type 2 diabetes, and its clinical use cannot be currently advised.

Aim: The 2019 ESC/EASD guidelines categorize cardiovascular disease risk (CVD) in patients with diabetes mellitus (DM). Assessing CVD risk is necessary to identify individuals at very high risk of CVD, enabling tailored and precise intervention for this high-risk population. This study aims to evaluate the severity of a very high risk for CVD stratification among patients with type 2 DM (T2DM) across different regions in China., Methods: We conducted a cross-sectional screening study from 1 January 2020 to 30 December 2022. Disease duration, body mass index (BMI), targeted organ damage, such as atherosclerotic heart disease, proteinuria, impaired renal function, left ventricular hypertrophy, retinopathy and known CVD risk factors, were collected from diabetic patients by professionally trained physicians. The risk of CV in patients with DM was categorized into two groups: very high risk and others, according to the 2019 ESC/EASD guidelines., Results: In total, 1 870 720 participants from 1669 hospitals in 30 provinces of China, excluding Tibet, Taiwan, Hong Kong and Macao, were enrolled from 2020 to 2022, among whom 67.50% of patients with T2DM were at very high risk for CVD. The proportions of very high-risk T2DM were higher in Northeast China (75.82%), Central China (73.65%) and Southwest China (72.66%), while the lowest prevalence of very high-risk T2DM was found in Southern China (60.15%). The multivariate binary logistic regression analyses suggested that the category of very high risk for CVD is associated with age [odds ratio (OR) = 1.04; 95% confidence interval (CI): 1.04-1.04; p < .0001], BMI (OR = 1.07; 95% CI: 1.07-1.07; p < .0001), duration of DM (OR = 1.05; 95% CI: 1.05-1.05; p < .0001), hypertension (OR = 3.75; 95% CI: 3.72-3.78; p < .0001), dyslipidaemia (OR = 5.22; 95% CI: 5.18-5.27; p < .0001) and smoking (OR = 2.92; 95% CI: 2.89-2.95; p < .0001)., Conclusions: This study represented the largest observational study of CVD risk assessment in patients with T2DM in China. The CVD risk situation of patients with diabetes in China is critical, and comprehensive control and management of CVD risk factors, such as hypertension, BMI and dyslipidaemia, in patients with DM need to be strengthened in patients with T2DM in China., (© 2024 John Wiley & Sons Ltd.)

In the US, approximately 11% of the population have diagnosed diabetes and nearly 40% have prediabetes. In addition, chronic kidney disease (CKD) affects 14% of the US population including up to 40% of those with diabetes. Cardiovascular disease (CVD) remains the leading cause of death worldwide where it affects approximately half of adults. The presence of CKD or diabetes doubles the risk of cardiovascular events. When both CKD and diabetes occur in the same patient the risks are further increased. The clinical problems of hypertension, hyperglycemia, and hyperlipidemia are all closely related with obesity, metabolic syndrome, Type 2 diabetes, CKD, atherosclerotic cardiovascular disease, heart failure and non-alcoholic fatty liver disease and metabolic dysfunction-associated steatohepatitis. The increasing frequency of obesity has driven increases in all of these medical comorbidities. These conditions frequently cluster together in the same patient exacerbating the risk of morbidity and mortality. They are also associated with cognitive dysfunction/dementia, pulmonary diseases, cancers, gastrointestinal diseases, immune system abnormalities, and inflammatory disorders. Only 6.8% of adults in US meet all targets for cardiovascular risk management with significant disparities based on race and ethnicity. Given the complexity of these multisystem problems in people with diabetes and obesity, it would seem reasonable to attempt to diagnose and treat many of the comorbidities earlier in the course of disease rather than wait for substantial end organ dysfunction to occur. The American Diabetes Association (ADA) has recently published a consensus statement recommending early screening for the diagnosis of heart failure, CKD and diabetes, recognizing both the frequency and gravity of this combination. Likewise, there are recommendations in the guidelines to facilitate screening for microalbuminuria, blood pressure, glycemic control and lipids earlier in patients at risk rather than wait and treat as a secondary prevention program. Thus, the general principle is to facilitate earlier recognition and diagnosis and provide treatment before downstream target organ complications occur. This review will focus on CVD and risk management based on newest recommendations and standards of care in people with diabetes by the ADA. The main considerations in the treatment of people with diabetes are glycemic control, blood pressure, lipids, and the use of medications with proven cardiorenal disease progression capability to prevent or delay., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: The distribution of fat and muscle mass in different regions of the body can reflect different pathways to mortality in individuals with diabetes. Therefore, we investigated the associations between whole-body and regional body fat and muscle mass with cardiovascular disease (CVD) and non-CVD mortality in type 2 diabetes (T2D)., Methods: Within the National Health and Nutrition Examination Survey 1999-2006, 1417 adults aged ≥50 years with T2D were selected. Dual-energy X-ray absorptiometry was used to derive whole-body, trunk, arm, and leg fat mass and muscle mass indices (FMI and MMI). Mortality data until 31 December 2019 were retrieved from the National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models., Results: A total of 1417 participants were included in this study (weighted mean age [standard error]: 63.7 [0.3] years; 50.5% female). Over a median follow-up of 13.6 years, 797 deaths were recorded (371 CVD-related and 426 non-CVD deaths). Higher FMI in the arm was associated with increased risk of non-CVD mortality (fourth quartile [Q4] vs. first quartile [Q1]: HR 1.82 [95% CI 1.13-2.94]), whereas higher FMI in the trunk or leg was not significantly associated with CVD or non-CVD mortality. Conversely, higher arm MMI was associated with a lower risk of both CVD (Q4 vs. Q1: HR 0.51 [95% CI 0.33-0.81]) and non-CVD (Q4 vs. Q1: HR 0.56 [95% CI 0.33-0.94]) mortality. There was a significant interaction between smoking status and arm FMI on non-CVD mortality (P for interaction = 0.007). Higher arm FMI was associated with a higher risk of non-CVD mortality among current or former smokers (Q4 vs. Q1: HR 2.67 [95% CI 1.46-4.88]) but not non-smokers (Q4 vs. Q1: HR 0.85 [95% CI 0.49-1.47])., Conclusions: Fat mass and muscle mass, especially in the arm, are differently associated with CVD and non-CVD mortality in people with T2D. Our findings underscore the predictive value of body compositions in the arm in forecasting mortality among older adults with T2D., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally designed to manage blood sugar levels in individuals with type 2 diabetes (T2D), have emerged as a crucial class of drugs for managing cardio-renal diseases. These drugs work by targeting the SGLT2 protein in the kidneys, promoting the excretion of glucose and influencing metabolic pathways beyond glucose control. The relationship between cardio-renal diseases and SGLT2 inhibitors has been explored through landmark trials and real-world evidence (RWE) studies, demonstrating significant reductions in cardio-renal complications. This review discusses the importance of RWE studies alongside randomized controlled trials in understanding the real-world effectiveness and safety of SGLT2 inhibitors. It outlines the advantages and disadvantages of RWE compared to RCTs, highlighting their complementary roles in providing comprehensive insights into treatment outcomes. By examining a range of RWE studies, the review underscores the cardio-renal benefits of SGLT2 inhibitors across various patient populations. Safety assessments indicate that SGLT2 inhibitors are generally well tolerated, with severe adverse events being rare. Common issues, such as genital mycotic infections and urinary tract infections, are acknowledged, alongside less frequent but significant adverse events including diabetic ketoacidosis, lower-limb amputations, and bone fractures. In summary, SGLT2 inhibitors show promising cardio-renal protective effects in real-world scenarios across diverse populations in T2D, indicating their potential as early intervention measures. Continued research is essential for gaining a thorough understanding of their long-term effects and safety profiles., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: This systematic review was aimed to assess the association between magnitude of body weight loss (BWL) in type 2 diabetes (T2D) patients and cardiovascular (CV) risk in CV outcome trials (CVOTs)., Methods: We searched electronic databases (PubMed, Cochrane and Scopus) for available CVOTs, observational cohort studies or post hoc analyses of clinical trials of adult T2D patients investigated the association of BWL with CV outcomes and/or all-cause mortality., Results: 19 RCTs of novel glucose-lowering drugs (GLP-1RA, DPP-4i and SGLT2i) and 6 RCT or observational trial of different strategies (intensive treatment or standard care) were included (379.904 T2D patients). Higher BWL during GLP-1RA treatment, in comaprison to lower BWL, was associated with higher decrease in risk of MACE, while DPP-4i had not that effect. With SGLT2i the higher decrease in risk of MACE was associated with lower BWL. In contrast, in other different strategies, higher BWL lead to increase in risk for MACE and all-cause mortality., Conclusions: In CVOTs, treatment of T2D patients resulted in BWL, which correlated with reduction in risk for CV outcomes, particularly with GLP-1 RAs. However, interventional non-CVOTs are warning that in the absence of structured behavioral intervention and relevant medication, the large BWL might be harmful for CV outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Physical frailty has been found to increase the risk of multiple adverse outcomes including cardiovascular disease (CVD) in diabetic patients, but whether this could be modified by traditional risk factor control remains unknown. We aimed to explore the joint and interaction effects of frailty and traditional risk factor control on the risk of CVD., Design: A population-based cohort study., Setting and Participants: We included 15,753 participants with type 2 diabetes at baseline from UK Biobank., Measurements: Physical frailty was assessed by Fried criteria's frailty phenotype. The degree of risk factor control was determined by the numbers of the following factors controlled within the target range, including glycated hemoglobin, blood pressure, low-density lipoprotein cholesterol, smoking, and kidney condition. Incident CVD included coronary heart disease, stroke, or heart failure. Cox proportional hazard models were used to assess the individual and joint effects of frailty and risk factor control on the risk of CVD., Results: After a median follow-up of 13.5 years, 1129 incident CVD events were observed. Compared with non-frailty, both prefrailty and frailty were significantly associated with increased risk of CVD (HR 1.22, 95% CI [1.13, 1.31] for pre-frailty and 1.70 [1.53, 1.90] for frailty). For the joint effects, participants with frailty and a low degree of risk factor control (control of 0-1 risk factors) had the highest risk of CVD (2.92 [2.04, 4.17]) compared to those with non-frailty and optimal risk factor control (control of 4-5 risk factors). Moreover, a significant additive interaction between frailty and risk factor control was observed, with around 3.8% of CVD risk attributed to the interactive effects., Conclusions: Both prefrailty and frailty were associated with a higher risk of CVD in participants with type 2 diabetes. Moreover, physical frailty could interact with the degree of risk factor control in an additive manner to increase the CVD risk., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Backgruound: Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined., Methods: This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months., Conclusion: This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Aims: To provide an overview of the primary outcomes and key clinical implications of the CANVAS Program and CREDENCE trial, which were event-driven, double-blind randomized controlled trials that established the efficacy and safety of canagliflozin in those with type 2 diabetes (T2D) and high cardiovascular risk (CV) or albuminuric chronic kidney disease (CKD)., Methods and Results: The CANVAS programme (CANVAS and CANVAS-R trials) randomized 10 142 people with T2D and high CV risk to canagliflozin or placebo and followed them for a median of 126 weeks. The primary efficacy outcome was met, with canagliflozin treatment associated with a 14% reduction in major adverse CV events (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.75 to 0.97; p < 0.001) as compared to placebo. The CREDENCE trial randomized 4401 individuals with T2D and albuminuric CKD to canagliflozin or placebo and followed them for 109 weeks. The CREDENCE trial also met its primary endpoint; canagliflozin treatment was associated with a 30% reduction in the composite of kidney failure, sustained doubling of serum creatinine level, or death from kidney or CV causes (HR 0.70, 95% CI 0.59 to 0.82; p < 0.001). Substantial reductions in hospitalization for heart failure (CANVAS: HR 0.67, 95% CI 0.52 to 0.87; CREDENCE: HR 0.61, 95% CI 0.47 to 0.80) and other key CV and kidney outcomes were also identified. Relative clinical benefits were consistent across subgroups defined by baseline age, sex, kidney function and history of CV disease but absolute benefits were greatest in those at highest baseline risk. Total serious adverse events were less common with canagliflozin treatment. Concerns about amputation and fracture risk observed in the CANVAS Program were not seen in CREDENCE and appear to have been spurious chance findings., Conclusion: Canagliflozin reduced important CV, kidney and mortality outcomes in those with T2D and high CV risk or CKD across diverse patient groups, with a good safety profile. Taken together with the other sodium-glucose cotransporter-2 inhibitor CV and renal outcomes trials, these landmark findings have changed the treatment landscape for patients worldwide., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular disease (CVD) risk, but whether T2DM directly causes adverse cardiac remodelling is uncertain. We performed a comprehensive Mendelian randomization (MR) analysis to investigate the causal relevance of T2DM to CVD outcomes and cardiac structure/function., Methods and Results: Bidirectional two-sample MR was conducted using summary-level data from European-ancestry genome-wide association studies. The T2DM GWAS data included 80 154 cases and 853 816 controls from the DIAGRAM consortium. Outcomes included coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure, atrial fibrillation, and various quantitative cardiac imaging traits assessed by magnetic resonance imaging. MR analysis revealed causal associations between genetic predisposition to T2DM and increased risk of CAD (odds ratio [OR] 1.104, 95% confidence interval [CI] 1.078-1.130, P = 2.59e-16), MI (OR 1.129, 95% CI 1.094-1.166, P = 6.02e-14) and stroke (OR 1.086, 95% CI 1.064-1.109, P = 1.02e-14). These associations were validated in the FinnGen cohort (CAD: OR 1.117, 95% CI 1.075-1.158, P = 1.56e-9; MI: OR 1.132, 95% CI 1.083-1.184, P = 4.27e-8; stroke: OR 1.138, 95% CI 1.107-1.170, P = 3.52e-20). Multivariable MR show consistent findings (CAD: OR 1.063, 95% CI 1.031-1.097, P = 1.11e-4; MI: OR 1.088, 95% CI 1.042-1.135, P = 1.12e-4; stroke: OR 1.066, 95% CI 1.032-1.101, P = 1.18e-4) after adjusting for cardiometabolic traits. T2DM was causally associated with higher left ventricular mass index (β = 0.473, 95% CI 0.193 to 0.752, P = 0.001), lower indexed right atrial minimum (β = -0.048, 95% CI -0.073 to -0.022, P = 2.1e-5), and maximum (β = -0.042, 95% CI -0.065 to -0.019, P = 4.12e-5) areas. The effects on right atrial size remained significant after adjusting for risk factors (minimum area: β = -0.041, 95% CI -0.072 to -0.010, P = 0.009; maximum area: β = -0.039, 95% CI -0.069 to -0.008, P = 0.012). Both apolipoprotein A1 and SBP are important mediators in the causal relationship between T2DM and left ventricular mass index. No reverse causal associations were identified., Conclusions: Our MR study demonstrates that genetic liability to T2DM plays causal roles in CAD, MI, stroke, and cardiac structure changes including left ventricular hypertrophy and reduced right atrial dimensions. These findings provide genetic evidence supporting glycaemic control in T2DM to mitigate cardiovascular complications and adverse cardiac remodelling., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: The decline in estimated glomerular filtration rate (eGFR), a significant predictor of cardiovascular disease (CVD), occurs heterogeneously in people with diabetes because of various risk factors. We investigated the role of eGFR decline in predicting CVD events in people with type 2 diabetes in both primary and secondary CVD prevention settings., Materials and Methods: Bayesian joint modelling of repeated measures of eGFR and time to CVD event was applied to the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to examine the association between the eGFR slope and the incidence of major adverse CV event/hospitalization for heart failure (MACE/hHF) (non-fatal myocardial infarction, non-fatal stroke, CV death, or hospitalization for heart failure). The analysis was adjusted for age, sex, smoking, systolic blood pressure, baseline eGFR, antihypertensive and lipid-lowering medication, diabetes duration, atrial fibrillation, high-density cholesterol, total cholesterol, HbA1c and treatment allocation (once-weekly exenatide or placebo)., Results: Data from 11 101 trial participants with (n = 7942) and without (n = 3159) previous history of CVD were analysed. The mean ± SD eGFR slope per year in participants without and with previous CVD was -0.68 ± 1.67 and -1.03 ± 2.13 mL/min/1.73 m 2 , respectively. The 5-year MACE/hHF incidences were 7.5% (95% CI 6.2, 8.8) and 20% (95% CI 19, 22), respectively. The 1-SD decrease in the eGFR slope was associated with increased MACE/hHF risks of 48% (HR 1.48, 95% CI 1.12, 1.98, p = 0.007) and 33% (HR 1.33, 95% CI 1.18,1.51, p < 0.001) in participants without and with previous CVD, respectively., Conclusions: eGFR trajectories over time significantly predict incident MACE/hHF events in people with type 2 diabetes with and without existing CVD, with a higher hazard ratio for MACE/hHF in the latter group., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Glucagon-like peptide-1 receptor agonists (GLP1Ra) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce major adverse cardiovascular events (MACE). We assessed whether the effect differs in patients with and without cardiovascular (CV) disease, and rated the certainty of evidence by conducting a systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials. Certainty of the evidence (CoE) was rated using the Grading of Recommendations, Assessment, Development, and Evaluation guidelines. The reduction in the risk of MACE was significant for both medications (high CoE), and the effect was similar in patients with and without CV disease (moderate CoE). GLP1Ra and SGLT2i reduced the risk of CV death (with high and moderate CoE, respectively), and the effects were consistent in the subgroups, but with very low CoE. While SGLT2i reduced the risk of fatal or non-fatal MI with a consistent effect in the subgroups, GLP1Ra reduced the risk of fatal or non-fatal stroke (with high CoE). In conclusion, GLP1Ra and SGLT2 inhibitors reduce the MACE to a similar extent in patients with and without CV disease, but have a differential effect on the reduction of fatal or non-fatal MI and stroke., Competing Interests: Declaration of Conflict of InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Mustafa Kilickap has received honoraria from NovoNordisk (for lectures and consultancy), Daiichi Sankyo (for consultancy), Amgen (for consultancy), and Astra-Zeneca (for lecture). Other authors do not have conflict of interest to disclose.

Aims: To assess whether and to what extent excess risk of all-cause death is reduced in individuals with type 2 diabetes by achieving optimal control of traditional cardiovascular risk factors., Methods: This observational, prospective, cohort study enrolled 15,773 Caucasian patients in 19 Italian centres in 2006-2008. Participants were stratified according to the number of the following risk factors outside target: haemoglobin A 1c , blood pressure, micro/macroalbuminuria, current smoking, LDL cholesterol, and triglycerides. All-cause mortality was retrieved for 15,656 patients (99.3 %) on 31 October 2015., Results: Age-adjusted mortality rates and hazard ratios were significantly higher in the whole RIACE cohort (by ∼20 %) and in patients with (by ∼100 %) but not in those without prior cardiovascular disease (CVD), as compared with the coeval Italian general population. In all patients and in those without prior CVD, the relationship with mortality according to the number of risk factors outside target was J-shaped, an effect that was attenuated after either excluding "overtreated " patients, i.e., those with haemoglobin A 1c ≤6.0 % on anti-hyperglycaemic agents causing hypoglycaemia and/or systolic blood pressure ≤120 mmHg on anti-hypertensive agents, or adjusting for "overtreatment". Conversely, in patients with prior CVD, mortality remained higher than in the general population in all categories and increased progressively from +70 % to +314 %, without J-effect., Conclusions: In patients with type 2 diabetes, optimal treatment of traditional cardiovascular risk factors completely eliminated the excess mortality risk versus the general population, provided that they were not "overtreated". However, this effect was observed only in participants without history of CVD., Trial Registration: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July 2008., Competing Interests: Declaration of Competing Interest Monia Garofolo: consultant fees from Eli Lilly, and lecture fees from Eli Lilly, Merck Sharp & Dohme, and Novo Nordisk. Giuseppe Penno: consultant fees from Bayer and Eli Lilly, and lecture fees from AstraZeneca, Boerhinger Ingelheim, Eli-Lilly, Merck Sharp & Dohme, Mundipharma, Novo Nordisk, and Takeda. Anna Solini: consultant fees from Axxam, Bayer, and Novo Nordisk, and lecture fees from Eli Lilly, Novo Nordisk, and Sanofi-Aventis. Emanuela Orsi: consultant fees from Eli Lilly and Novo Nordisk, and lecture fees from Astellas. Martina Vitale: lecture fees from MundiPharma and Novo Nordisk. Veronica Resi: lecture fees from Astra-Zeneca, Eli Lilly, and Sanofi-Aventis. Enzo Bonora: consultant fees from Abbott, Bayer, Becton Dickinson, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, and Novo Nordisk. Cecilia Fondelli: lecture fees from Abbot, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Merck Sharp & Dohme, Mundipharma, and Theras Lifetech. Roberto Trevisan: consultant fees from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, and Sanofi-Aventis, and lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Monica Vedovato: lecture fees from Lifescan and Novo Nordisk. Antonio Nicolucci: consultant fees from AstraZeneca, lecture fees from Eli Lilly, Medtronic, and Novo Nordisk, and grant support from AlfaSigma, Novo Nordisk, Pikdare, Sanofi, Shionogi, SOBI, and Theras. Giuseppe Pugliese: consultant fees from Abbot, Bayer, and Novo Nordisk, and lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Mundipharma, and Novo Nordisk., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Cardiovascular disease is the leading cause of morbidity and mortality among patients with diabetes, and for this reason, all guidelines for CV risk management provide the same targets in controlling traditional CV risk factors in patients with type 1 or type 2 diabetes at equal CV risk class. Aim of our study was to evaluate and compare CV risk management in patients with type 1 and type 2 diabetes included in AMD Annals Database paying particular attention to indicators of clinical inertia., Methods: This was a multicenter, observational, retrospective study of AMD Annals Database during year 2022. Patients with diabetes were stratified on the basis of their cardiovascular risk, according to ESC-EASD guidelines. The proportion of patients not treated with lipid-lowering despite LDL cholesterol > to 100 mg/dl or the proportion of patients not treated with antihypertensive drug despite BP > 140/90 mmhg and proportion of patients with proteinuria not treated with angiotensin converting enzyme inhibitors or angiotensinogen receptor blockers (ACE/ARBs) were considered indicators of clinical inertia. The proportion of patients reaching at the same time HbA1c < 7% LDL < 70 mg/dl and BP < 130/80 mmhg were considered to have good multifactorial control. Overall quality of health care was evaluated by the Q-score., Results: Using the inclusion criteria and stratifying patients by ESC/EASD Cardiovascular Risk categories, we included in the analysis 118.442 patients at High Cardiovascular risk and 416.246 patients at Very High Cardiovascular risk. The proportion of patients with good multifactorial risk factor control was extremely low in both T1D and T2D patients in each risk class. At equal risk class, the patients with T1D had lower proportion of subjects reaching HbA1c, LDL, or Blood Pressure targets. Indicators of clinical inertia were significantly higher compared with patients with T2D at equal risk class. Data regarding patients with albuminuria not treated with RAAS inhibitors were available only for those at Very High risk and showed that the proportion of patients not treated was again significantly higher in patients with T1DM., Conclusions: In conclusion, this study provides evidence of wide undertreatment of traditional cardiovascular risk factors among patients with diabetes included in AMD Annals Database. Undertreatment seems to be more pronounced in individuals with T1D compared to those with T2D and is frequently due to clinical inertia., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Aim: To investigate the associations between ketone bodies (KB) and multiple adverse outcomes including cardiovascular disease (CVD), chronic kidney disease (CKD) and all-cause mortality according to diabetes status., Methods: This prospective study included 222 824 participants free from CVD and CKD at baseline from the UK Biobank. Total KB including β-hydroxybutyrate, acetoacetate and acetone were measured by nuclear magnetic resonance. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between KB and adverse outcomes among participants with normoglycaemia, prediabetes and type 2 diabetes, respectively., Results: During a mean follow-up of 14.1 years, 24 088 incident CVD events (including 17 303 coronary heart disease events, 5172 stroke events and 5881 heart failure [HF] events), 8605 CKD events and 15 813 deaths, were documented. Higher total KB significantly increased the risk of HF among participants with normoglycaemia (HR, 1.32 [95% CI, 1.17-1.49], per 10-fold increase in total KB) and prediabetes (1.35 [1.04-1.76]), and increased the risk of CKD among those with normoglycaemia (1.20 [1.09-1.33]). Elevated KB levels were associated with an increased risk of all-cause mortality across the glycaemic spectrum (1.32 [1.23-1.42] for normoglycaemia, 1.45 [1.24-1.71] for prediabetes and 1.47 [1.11-1.94] for diabetes). Moreover, a significant additive interaction between KB and diabetes status was observed on the risk of death (P = .009), with 4.9% of deaths attributed to the interactive effects., Conclusions: Our study underscored the variation in association patterns between KB and adverse outcomes according to diabetes status and suggested that KB could interact with diabetes status in an additive manner to increase the risk of mortality., (© 2024 John Wiley & Sons Ltd.)

The prevalence of cardiovascular diseases (CVDs) is well known. According to the World Health Organization (WHO), almost 18 million people die from CVDs worldwide every year, accounting for 31% of all causes of death [1]. CVDs often develop concomitantly with diabetes mellitus (DM), with approximately 20% of cardiovascular deaths attributed to elevated blood glucose levels [2]. Notably, CVDs are the leading cause of death among patients with type 2 diabetes (T2DM). Based on data from the Federal Register of Diabetes 2022 in Russia, chronic heart failure was the direct cause of death in 24.2% of T2DM cases, followed by acute heart failure (13.1%), cerebrovascular events (10.0%), and myocardial infarction (3.7%) [3].The pathophysiological interplay between atherosclerotic cardiovascular disease and DM has led to a situation where cardiologists are increasingly involved in the treatment of patients with DM, while endocrinologists are encountering a growing number of patients with CVDs. This association has become so apparent that in a recent article published in the European Journal of Cardiology, Yu. Braunwald speculated about the emergence of a new subspecialty - diabetocardiology [4]. Unfortunately, experts predict that the global number of diabetic patients will reach 783 million [5].Recent data on the CV benefits of certain hypoglycemic drugs (primarily, certain SGLT2 inhibitors, several GLP-1 receptor agonists, and a novel non-steroidal mineralocorticoid receptor antagonist finerenone) prove the need for a unified interdisciplinary approach to managing CVDs and DM.Given the importance of integrated and coordinated efforts in managing patients with CVD and DM, the Task Force of the -European Society of Cardiology (ESC) updated, formulated, and published clinical guidelines on the treatment of CVD in diabetic patients in 2023 [6]. This article provides a concise overview of the key provisions outlined in the guidelines.

Background: Cardiovascular autonomic neuropathy (CAN) is known to affect patients with diabetes mellitus (DM) and cause adverse renal outcomes. We aimed to analyze the association between CAN and diabetic kidney disease (DKD)., Method: We enrolled 254 DM patients (mean age, 56.7 ± 15.2 years; male: female ratio, 1.17:1) with 19 (7.5%) type 1 DM patients and 235 (92.5%) type 2 DM patients. All patients had undergone cardiovascular autonomic function tests between January 2019 and December 2021 in a tertiary hospital in Korea. Cardiovascular autonomic neuropathy was categorized as normal, early, or definite after measuring three heart rate variability parameters. Diabetic kidney disease refers to a persistently elevated urinary albumin-creatinine ratio (uACR ≥30 mg/g) or reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m 2 ). Logistic and Cox regression analyses were performed., Results: Patients with elevated uACR (n=107) and reduced eGFR (n=32) had a higher rate of definite CAN. After adjusting for covariates, definite CAN was associated with elevated uACR (OR=2.4, 95% CI 1.07-5.36) but not with reduced eGFR (OR=3.43, 95% CI 0.62-18.90). A total of 94 patients repeated uACR measurements within 2 years (mean follow-up, 586.3 ± 116.8 days). Both definite and early CAN were independent risk factors for elevated uACR (HR=8.61 and 8.35, respectively; both p <0.05). In addition, high-density lipoprotein cholesterol, ACE inhibitors/angiotensin receptor blockers and glucagon-like peptide-1 receptor agonists were independent protective factors for elevated uACR (HR=0.96, 0.25, and 0.07, respectively; all p <0.05)., Conclusion: Cardiovascular autonomic neuropathy is a potential indicator of DKD. Comprehensive management of DKD in the early stages of CAN may prevent microalbuminuria., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cho, Lim, Kwon, Chung, Moon, Yoon and Won.)

Background: In the past, there has been a clear conclusion regarding the sole impact of serum neurofilament light chain (sNfL) levels or type 2 diabetes mellitus (DM) on the risk of death. However, the combined effect of sNfL levels and type 2 DM on all-cause and cardiovascular mortality is still uncertain., Methods: This study was a prospective cohort study based on data from the National Health and Nutrition Examination Survey (NHANES). The sNfL levels were measured through immunological methods using blood samples collected during the survey. The diagnosis of diabetes was based on rigorous criteria, and participants' mortality data were followed up until December 31, 2019. Firstly, we separately examined the effects of sNfL and type 2 DM on all-cause and cardiovascular mortality, and finally studied the comprehensive impact of the combination of sNfL and type 2 DM on the risk of mortality. Cumulative Kaplan-Meier curves, multivariate logistic regression and sensitivity analysis were incorporated throughout the entire study., Results: Participants in the highest quartile of sNfL were observed. Multivariable COX regression model showed that increased sNfL levels and type 2 DM were respectively associated with an increased risk of all-cause and cardiovascular mortality. Furthermore, elevated sNfL levels were significantly associated with an increased risk of all-cause mortality and cardiovascular mortality after adjustment for confounding factors. When considering both elevated sNfL levels and type 2 DM, individuals had a significantly increased risk of mortality. Sensitivity analysis confirmed the robustness of the findings., Conclusions: These results suggest that elevated levels of sNfL and type 2 DM are associated with an increased risk of all-cause and cardiovascular mortality, and that participants with increased sNfL levels associated with type 2 DM have higher all-cause mortality and cardiovascular mortality., (© 2024. The Author(s).)

Background and Aims: The purpose of this meta-analysis was to investigate the effect of vitamin D supplementation on hemoglobin A1C (HbA1C), fasting blood sugar (FBS), low-density lipoprotein (LDL), high-density lipoprotein (HDL), systolic blood pressure (SBP), and the total vitamin D level in patients with Type 2 diabetes (T2DM). Methods: A systematic search was conducted in databases such as PubMed (Medline), Scopus, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov using relevant keywords from January 1990 to January 2024. After screening and extracting data, a qualitative evaluation of articles was performed using the Cochrane risk-of-bias tool for randomized trials (RoB 2). Results: The findings revealed that vitamin D supplementation significantly decreased the mean HbA1C (SMD: -0.15; 95% CI: -0.29, -0.20; I square : 79.76%; p value < 0.001) and mean FBS (SMD: -0.28; 95% CI: -0.40, -0.15; I square : 70.13%; p value < 0.001), lowered SBP (SMD: -0.06; 95% CI: -0.16, -0.05; I square : 39.63%; p value = 0.23), and reduced LDL (SMD: -0.11; 95% CI: -0.28, -0.05; I square : 73.66%; p value < 0.001). Furthermore, vitamin D supplementation increased the average HDL (SMD: 0.13; 95% CI: 0.04, 0.29; I The results also indicated that taking vitamin D supplements in the amount of 50,000 IU had a significant effect on reducing the indicators related to diabetes control. Based on the combined evidence, the findings of this meta-analysis suggest that vitamin D supplementation can significantly improve glycemic control and reduce the risk of complications associated with T2DM, especially cardiovascular diseases (CVDs).square : 79.33%; p value < 0.001) and vitamin D levels (SMD: 1.78; 95% CI: 1.53, 2.04; I square : 91.92%; p value < 0.001) in patients with T2DM. Subgroup analyses showed that weight gain, BMI, and duration of the disease could reduce the effect of vitamin D supplementation on diabetes control in affected patients. Conclusion: The results also indicated that taking vitamin D supplements in the amount of 50,000 IU had a significant effect on reducing the indicators related to diabetes control. Based on the combined evidence, the findings of this meta-analysis suggest that vitamin D supplementation can significantly improve glycemic control and reduce the risk of complications associated with T2DM, especially cardiovascular diseases (CVDs)., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Maryam Afraie et al.)

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials., Objectives: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM., Methods: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis., Results: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13])., Conclusions: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD., Competing Interests: Funding Support and Author Disclosures This study was partially funded through National Institutes of Health grants R01 HL167858, K23 HL153775, R01 LM006910, R01 HG006139, and R01 HL169954 and the U.S. Department of Veterans Affairs under the research priority to “Put VA Data to Work for Veterans” (VA ORD 22-D4V). The funders had no role in the design and conduct of the protocol; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr Khera is an associate editor at JAMA; and has received support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (awards R01 HL167858 and K23 HL153775) and the Doris Duke Charitable Foundation (award 2022060); has received research support, through Yale University, from Bristol Myers Squibb, Novo Nordisk, and BridgeBio; is a coinventor of U.S. provisional patent applications WO2023230345A1, US20220336048A1, 63/346,610, 63/428,569, 63/484,426, 63/508,315, 63/580,137, 63/606,203, 63/619,241, and 63/562,335, unrelated to the present work; and is a cofounder of Evidence2Health and Ensight-AI, precision health platforms to improve evidence-based cardiovascular care and cardiovascular diagnostics. Dr DuVall has received grants from Alnylam Pharmaceuticals, AstraZeneca Pharmaceuticals, Biodesix, Celgene, Cerner Enviza, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis International, and Parexel International through the University of Utah or the Western Institute for Veteran Research (outside the submitted work). Dr Man has received support from the C.W. Maplethorpe Fellowship, the National Institute of Health Research, European Commission Framework Horizon 2020, the Hong Kong Research Grant Council, and the Innovation and Technology Commission of the Hong Kong Special Administration Region Government outside the submitted work). Dr Morales is supported by a Wellcome Trust Clinical Research Fellowship (214588/Z/18/Z). In the past 3 years, Dr Krumholz has received expenses and/or personal fees from UnitedHealth, Element Science, Aetna, Reality Labs, Tesseract/4Catalyst, F-Prime, the Siegfried and Jensen Law Firm, the Arnold and Porter Law Firm, and the Martin/Baughman Law Firm; is a cofounder of Refactor Health, HugoHealth, and Ensight-AI; and is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare and Medicaid Services and, through Yale University, from Johnson & Johnson. Dr You is chief technology officer of PHI Digital Healthcare. Dr Ross has received research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation program (grant U01 FD005938), from the Agency for Healthcare Research and Quality (grant R01 HS022882), and from Arnold Ventures; has received research support from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology and from the National Heart, Lung, and Blood Institute of the National Institutes of Health (grants R01 HS025164 and R01 HL144644); and was an expert witness at the request of the relator’s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled September 2022. Dr Thangaraj is a coinventor on provisional patent 63/606,203, unrelated to the present work, and is funded by grant 5T32 HL155000-03. Ms Blacketer, Dr Ostropolets, and Dr Ryan are employees of Johnson & Johnson. Dr Schuemie is an employee and shareholder of Johnson & Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)

Background: The role of the common FTO gene variant rs9939609 in obesity has been well established, and the FTO gene has a strong association with T2DM. Objective: To investigate the association of FTO gene variant rs9939609 with obesity-related parameters in T2DM and CVD patients. Materials and Methods: In this cross-sectional study, 280 subjects of either sex aged 45.10 ± 9.6 years were randomly divided into four groups, that is, T2DM, T2DM with CVD, nondiabetic with CVD disease, and normal control. These samples were genotyped by ARMS-PCR. The FTO gene association with obesity-related parameters in T2DM and CVD patients was analyzed by SPSS 22. Results: The TT genotype was the most common genotype (46.80%) in our study groups. The minor allele frequency (MAF) was significantly higher in T2DM patients (0.39 vs. 0.28), T2DM patients with CVD (0.43 vs. 0.28), and nondiabetic patients with CVD (0.35 vs. 0.28) as compared to control with p < 0.005. Carriers of the AA genotype of the FTO gene rs9939609 were significantly associated with increased BMI, WC, HbA1C, SBP, DBP, and TGs and lowered HDL cholesterol as compared to the TA and TT genotypes in T2DM and CVD patients with p < 0.005. The FTO gene variant rs9939609 showed a significant association with T2DM and CVD. The AA genotype odds ratio (OR) in T2DM was 1.48 (1.06-2.32), p = 0.006, and in CVD, it was 1.56 (1.04-2.4), p = 0.003. Conclusion: The FTO gene variant rs9939609 has a strong association with T2DM and CVD. The AA genotype of FTO gene variants rs9939609 showed a strong association with most of the risk factors of CVD and T2DM., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Mazhar Hussain et al.)

Aim: To explore the effect of canagliflozin on kidney and cardiovascular events and safety outcomes in individuals with type 2 diabetes and chronic kidney disease across geographic regions and racial groups., Materials and Methods: A stratified Cox proportional hazards model was used to assess efficacy and safety outcomes by geographic region and racial group. The primary composite outcome was a composite of end-stage kidney disease (ESKD), doubling of the serum creatinine (SCr) level, or death from kidney or cardiovascular causes. Secondary outcomes included: (i) cardiovascular death or heart failure (HF) hospitalization; (ii) cardiovascular death, myocardial infarction (MI) or stroke; (iii) HF hospitalization; (iv) doubling of the SCr level, ESKD or kidney death; (v) cardiovascular death; (vi) all-cause death; and (vii) cardiovascular death, MI, stroke, or hospitalization for HF or for unstable angina., Results: The 4401 patients were divided into six geographic region subgroups: North America (n = 1182, 27%), Central and South America (n = 941, 21%), Eastern Europe (n = 947, 21%), Western Europe (n = 421, 10%), Asia (n = 749, 17%) and Other (n = 161, 4%). The analyses included four racial groups: White (n = 2931, 67%), Black or African American (n = 224, 5%), Asian (n = 877, 20%) and Other (n = 369, 8%). Canagliflozin reduced the relative risk of the primary composite outcome in the overall trial by 30% (hazard ratio 0.70, 95% confidence interval 0.59-0.82; P = 0.00001). Across geographic regions and racial groups, canagliflozin consistently reduced the primary composite endpoint without evidence of heterogeneity (interaction P values of 0.39 and 0.91, respectively) or significant safety outcome differences., Conclusions: Canagliflozin reduces the risk of kidney and cardiovascular events similarly across geographic regions and racial groups., (© 2024 John Wiley & Sons Ltd.)

Aims/introduction: Individuals with diabetes are at high risk of developing cardiovascular events. The present study investigated the predictive value of the cardio-ankle vascular index (CAVI) when added to the Systematic Coronary Risk Evaluation 2-Diabetes (SCORE2-Diabetes) risk algorithm to predict cardiovascular events in the Asian population., Materials and Methods: The SCORE2-Diabetes risk was assessed in 1,502 patients with diabetes, aged 40-69 years. Then, we further stratified each 10-year risk category with a CAVI value of 9.0. The primary outcomes (composite of all causes of death, myocardial infarction, stroke and hospitalization for heart failure) were assessed over 5 years., Results: The mean age of the population was 59.8 ± 6.4 years. The proportion of 10-year risk according to the SCORE2-Diabetes risk of low, moderate, high and very high risk identified at 7.2, 30.0, 27.2 and 35.6%, respectively. The mean CAVI value was 8.4 ± 1.4, and approximately 35.4% of the patients had CAVI ≥9.0. The SCORE2-Diabetes risk algorithm independently predicted the primary outcomes in patients with diabetes (hazard ratio 1.18, 95% confidence interval [CI] 1.13-1.22), whereas CAVI did not (hazard ratio 1.03, 95% CI 0.89-1.18). The C-index for the primary outcomes of the SCORE2-Diabetes risk algorithm alone was 0.72 (95% CI 0.67-0.77). The combination of SCORE2-Diabetes and CAVI, both in the continuous value and risk groups, did not improve discrimination (C-index 0.72, 95% CI 0.67-0.77 and 0.68, 95% CI 0.64-0.74, respectively)., Conclusions: Adding the CAVI to the SCORE2-Diabetes risk algorithm did not improve individual risk stratification in patients with diabetes., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective for glycemic control, with many also demonstrating cardiovascular (CV) benefit, in people with type 2 diabetes (T2D). This study aimed to find a consensus on the barriers and strategies for the optimal use of GLP-1 RAs in people with T2D and high CV risk or established cardiovascular disease (CVD) in Spain., Methods: A two-round Delphi survey (53 questions) was conducted among members of four national scientific societies in Spain, including physicians experienced in the management of people with T2D. The degree of consensus was evaluated with a 7-point Likert scale, establishing consensus when ≥ 70% of the panelists agreed (6-7) or disagreed (1-2)., Results: A total of 97 physicians participated in the first round (endocrinology: 34%, family and community medicine: 21%, internal medicine: 23%, and cardiology: 23%), and 96 in the second round. The main barriers identified were: therapeutic inertia and late use of GLP-1 RAs; lack of a comprehensive approach to CV risk; lack of knowledge on the usefulness of GLP-1 RAs in CVD prevention and treatment; and economic/administrative barriers. Strategies with a highest consensus included: the need to establish simple protocols that integrate awareness of CV risk monitoring; training professionals and patients; and the use of new technologies., Conclusion: Physicians identified clinical, healthcare, and economic/administrative barriers that limit the use of GLP-1 RAs in people with T2D and high CV risk or established CVD in Spain, highlighting the importance of integrating these therapies according to clinical practice guidelines., (© 2024. The Author(s).)

Aim: The guidelines recommend statins to prevent cardiovascular events in patients with type 2 diabetes (T2D) however, the importance of baseline LDL-Cholesterol (LDL-C) levels remains controversial. This study aimed to determine the association of statin use in T2D patients with major adverse cardiovascular events (MACE) and all-cause mortality and whether this association differs by baseline LDL-C levels., Data Synthesis: Medline, Embase, and Web of Science were systematically searched from inception until January 2022. Observational studies in patients with T2D comparing statin users vs non-users, with reports of the baseline LDL-C levels, were included. Random-effects meta-analysis and meta-regression were performed to estimate the overall effect on the risk of all-cause mortality and MACE (a composite of myocardial infarction, heart failure, stroke, and revascularization events) and the modification in the association by baseline LDL-C levels. We categorized studies according to their baseline LDL-C levels into 1) <100 mg/dl (2.59 mmol/l), 2) 100-130 mg/dl (2.59-3.37 mmol/l) and 3) >130 mg/dl (3.37 mmol/l) categories. A total of 9 cohort studies (n = 403,411 individuals) fulfilled our criteria. The follow-up duration ranged from 1.7 to 8 years. The overall combined estimate showed that statin therapy was associated with a significantly lower risk of MACE (Hazard Ratio (HR): 0.70 [95% CI 0.59 to 0.83], Absolute risk reduction percentage (ARR%): 3.19% [95%CI 0.88 to 5.50%) and all-cause mortality (HR: 0.60 [95% CI 0.46 to 0.79], ARR%: 5.23% [95% CI 2.18 to 8.28%), but varied, albeit not statistically significant, by baseline LDL-C levels. Studies with baseline LDL-C levels higher than 130 mg/dl had the greatest reduction of MACE (HR: 0.58 [95% CI 0.37 to 0.90]) and all-cause mortality risk (HR: 0.51 [95% CI [ 0.29 to 0.90]). The HRs of MACE in studies with LDL-C levels of 100-130 mg/dl and <100 mg/dl categories were respectively (0.70 [95% CI 0.59 to 0.83]) and (0.83 [95% CI [0.68 to 1.00]); and that of all-cause mortality were respectively (0.62 [95% CI 0.38 to 1.01]) and (0.67 [95% CI [0.44 to 1.02]). Statin use changes the HRs of MACE (0.99 [95%CI, 0.98 to 0.99]; P = 0.04) and all-cause mortality (0.99 [95% CI 0.98 to 1.01]; P = 0.8) per each mg/dl increase in baseline LDL-C level in meta-regression analyses., Conclusion: Statin therapy in patients with T2D was associated with reduced risk of MACE and all-cause mortality. Significant differences across studies with different baseline LDL-C levels were not observed., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To develop 10-year cardiovascular disease (CVD) risk prediction models in Chinese patients with type 2 diabetes mellitus (T2DM) managed in primary care using machine learning (ML) methods., Methods: In this 10-year population-based retrospective cohort study, 141 516 Chinese T2DM patients aged 18 years or above, without history of CVD or end-stage renal disease and managed in public primary care clinics in 2008, were included and followed up until December 2017. Two-thirds of the patients were randomly selected to develop sex-specific CVD risk prediction models. The remaining one-third of patients were used as the validation sample to evaluate the discrimination and calibration of the models. ML-based methods were applied to missing data imputation, predictor selection, risk prediction modelling, model interpretation, and model evaluation. Cox regression was used to develop the statistical models in parallel for comparison., Results: During a median follow-up of 9.75 years, 32 445 patients (22.9%) developed CVD. Age, T2DM duration, urine albumin-to-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), systolic blood pressure variability and glycated haemoglobin (HbA1c) variability were the most important predictors. ML models also identified nonlinear effects of several predictors, particularly the U-shaped effects of eGFR and body mass index. The ML models showed a Harrell's C statistic of >0.80 and good calibration. The ML models performed significantly better than the Cox regression models in CVD risk prediction and achieved better risk stratification for individual patients., Conclusion: Using routinely available predictors and ML-based algorithms, this study established 10-year CVD risk prediction models for Chinese T2DM patients in primary care. The findings highlight the importance of renal function indicators, and variability in both blood pressure and HbA1c as CVD predictors, which deserve more clinical attention. The derived risk prediction tools have the potential to support clinical decision making and encourage patients towards self-care, subject to further research confirming the models' feasibility, acceptability and applicability at the point of care., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)