High-risk Type 2 Diabetes Patients Research Articles

Coronary microvascular dysfunction and left heart filling pressures in patients with type 2 diabetes.

Patients with type 2 diabetes (T2D) have a high prevalence of diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF), which in turn leads to an increased risk of hospitalization and death. However, the factors of risk and their relative importance in leading to higher left ventricular filling pressures are still disputed. We sought to clarify the associations of a wide range of invasive and non-invasive risk factors with cardiac filling pressures in high-risk T2D patients. Patients with T2D at high risk of cardiovascular events were prospectively enrolled in this study. Participants were thoroughly phenotyped including right heart catheterization at rest and during exercise, echocardiography, urinary excretion of albumin (UACR), and quantification of their myocardial blood flow rate (MFR) using cardiac 82Rb-PET/CT. Of the 37 patients included in the study, 22 (59%) patients met invasive criteria for HFpEF. Only 2 out of 39 variables emerged as independent factors associated with left ventricular filling pressure as assessed by pulmonary capillary wedge pressure (PCWP) at rest; history of hypertension (coefficient: 2.6mmHg [0.3; 5.0], P=0.030) and MFR (P=0.026). We found a significant inverse association between MFR and PCWP with a coefficient of -2.3mmHg (-4.3; -0.3) in PCWP per integer change of MFR. The MFR ranged from 1.18 to 3.68 in our study, which corresponds to a difference in PCWP of approximately 6mmHg between patients with the lowest compared to the highest MFR. During exercise, only 2 variables emerged as borderline independent factors associated with PCWP: myocardial flow reserve (coefficient: -4.4 [-9.6; 0.8], P=0.091) and beta-blockers use (coefficient: 6.1 [-0.1; 12.4], P=0.053). In patients with type 2 diabetes without known HFpEF but risk factors for cardiovascular disease, myocardial blood flow rate was independently associated with PCWP at rest across the range from normal to abnormal left heart filling pressures. A clinically significant difference of 6mmHg in PWCP was attributable to differences in MFR in patients with the lowest compared with the highest MFR values. This suggests that strategies than attenuate microvascular dysfunction could slow progression of increased left ventricular left heart filling pressures in patients at increased risk.

Association of plasma angiogenin with risk of major cardiovascular events in type 2 diabetes

BackgroundAngiogenin, an enzyme belonging to the ribonucleases A superfamily, plays an important role in vascular biology. Here, we sought to study the association of plasma angiogenin and major adverse cardiovascular events (MACEs) in patients with type 2 diabetes (T2D).MethodsThis prospective study included 1083 T2D individuals recruited from a secondary hospital and a primary care facility. The primary outcome was a composite of four-point MACE (nonfatal myocardial infarction, stroke, unstable angina pectoris leading to hospitalization and cardiovascular death). Circulating angiogenin was measured by a proximity extension assay. Cox regression models were used to evaluate the association of baseline plasma angiogenin with the risk of MACE.ResultsDuring a median follow-up of 9.3 years, 109 (10%) MACE were identified. Plasma angiogenin was significantly higher in participants with MACE than in those without MACE (P < 0.001). Doubling of plasma angiogenin concentration was associated with a 3.10-fold (95% CI 1.84–5.22) increased risk for MACE. The association was only moderately attenuated after adjustment for demographic and cardiometabolic risk factors (adjusted HR 2.38, 95% CI 1.34–4.23) and remained statistically significant after additional adjustment for estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (uACR) (adjusted HR 1.90, 95% CI 1.02–3.53). A consistent outcome was obtained when plasma angiogenin was analysed as a categorical variable in tertiles.ConclusionsPlasma angiogenin was associated with the risk of future cardiovascular events in patients with T2D and may be a promising novel biomarker for identifying high-risk T2D patients for early management.

Prediction of clinical events by liver stiffness and chronic kidney disease by NAFLD in patients with type-2 diabetes

Background & AimsNon-alcoholic fatty liver disease (NAFLD) is associated with poorer glycemic control and a higher risk of type-2 diabetes (T2D) complications, extrahepatic and cardiovascular disease (CVD). Our study aim was to evaluate the association between NAFLD, T2D complications, and the development of overall clinical events (OCE) (CV, liver-related, and mortality) in patients with T2D. MethodsProspective single-center study comprising T2D subjects with no history of CVD and non-T2D matched controls. Patients were selected from the Outpatient Diabetes Clinic of Vall d’Hebron Hospital and related primary care centers. Results186 diabetics and 57 controls were included. Amongst T2D, 124/186 subjects had NAFLD (66.6%). T2D-NAFLD subjects showed a heavier metabolic burden and higher median liver stiffness (5.6kPa [4.5–7.3] vs 4.8 [4.2–5.8]; p=0.004) compared to non-NAFLD diabetics. During a median follow-up of 5.6 years, 33 (17.7%) T2D patients developed OCE vs 4 (7.0%) controls (p=0.049). No differences were found for OCE between NAFLD and non-NAFLD diabetics (16.9% vs 19.4%; p=0.68). CV was the most reported outcome and only one liver event occurred. NAFLD diabetics showed more often chronic kidney disease (CKD), whereas T2D complications and subclinical CVD rates were similar. A higher liver stiffness, older age, and male gender were independently associated with OCE amongst the entire T2D population and NAFLD diabetics. ConclusionsNAFLD and liver stiffness were associated with CKD and clinical outcomes in diabetics, respectively. A hepatic evaluation is recommended to identify high-risk T2D patients that would benefit from early referral to specialized care.

Prognostic Factors for COVID-19 Hospitalized Patients with Preexisting Type 2 Diabetes

Background Type 2 diabetes (T2D) as a worldwide chronic disease combined with the COVID-19 pandemic prompts the need for improving the management of hospitalized COVID-19 patients with preexisting T2D to reduce complications and the risk of death. This study aimed to identify clinical factors associated with COVID-19 outcomes specifically targeted at T2D patients and build an individualized risk prediction nomogram for risk stratification and early clinical intervention to reduce mortality. Methods In this retrospective study, the clinical characteristics of 382 confirmed COVID-19 patients, consisting of 108 with and 274 without preexisting T2D, from January 8 to March 7, 2020, in Tianyou Hospital in Wuhan, China, were collected and analyzed. Univariate and multivariate Cox regression models were performed to identify specific clinical factors associated with mortality of COVID-19 patients with T2D. An individualized risk prediction nomogram was developed and evaluated by discrimination and calibration. Results Nearly 15% (16/108) of hospitalized COVID-19 patients with T2D died. Twelve risk factors predictive of mortality were identified. Older age (HR = 1.076, 95% CI = 1.014–1.143, p=0.016), elevated glucose level (HR = 1.153, 95% CI = 1.038–1.28, p=0.0079), increased serum amyloid A (SAA) (HR = 1.007, 95% CI = 1.001–1.014, p=0.022), diabetes treatment with only oral diabetes medication (HR = 0.152, 95%CI = 0.032–0.73, p=0.0036), and oral medication plus insulin (HR = 0.095, 95%CI = 0.019–0.462, p=0.019) were independent prognostic factors. A nomogram based on these prognostic factors was built for early prediction of 7-day, 14-day, and 21-day survival of diabetes patients. High concordance index (C-index) was achieved, and the calibration curves showed the model had good prediction ability within three weeks of COVID-19 onset. Conclusions By incorporating specific prognostic factors, this study provided a user-friendly graphical risk prediction tool for clinicians to quickly identify high-risk T2D patients hospitalized for COVID-19.

Genome-wide analysis reflects novel 5-hydroxymethylcytosines implicated in diabetic nephropathy and the biomarker potential

Aim: Diabetic nephropathy (DN) has become the most common cause of end-stage renal disease in most countries for patients with type 2 diabetes (T2D). Elucidating novel epigenetic contributors to DN can not only enhance our understanding of this complex disorder but also lay the foundation for developing more effective monitoring tools and preventive interventions in the future, thus contributing to our ultimate goal of improving patient care. Methods: 5-hydroxymethylcytosines (5hmC)-Seal, a highly selective chemical labeling technique, was used to profile genome-wide 5hmC, a stable cytosine modification type marking gene activation, in circulating cell-free DNA (cfDNA) samples from a cohort of patients recruited at Zhongnan Hospital, including T2D patients with nephropathy (DN, n = 12), T2D patients with non-DN vascular complications (non-DN, n = 29), and T2D patients without any complication (controls, n = 14). Differential analysis was performed to find DN-associated 5hmC features, followed by the exploration of biomarker potential of 5hmC in cfDNA for DN using a machine learning approach. Results: Genome-wide analyses of 5hmC in cfDNA detected 427 and 336 differential 5hmC modifications associated with DN, compared with non-DN individuals and controls, and suggested relevant pathways such as NOD-like receptor signaling pathway and tyrosine metabolism. Our exploration using a machine learning approach revealed an exploratory model comprised of ten 5hmC genes showing the possibility to distinguish DN from non-DN individuals or controls. Conclusion: Genome-wide analysis suggests the possibility of exploiting novel 5hmC in patient-derived cfDNA as a non-invasive tool for monitoring DN in high-risk T2D patients in the future.

Diuretics and risk of lower extremity amputation amongst patients with insulin-treated type 2 diabetes – exploring the mechanism of possible sodium glucose co-transporter 2 inhibitor induced risk of lower extremity amputations

Aims and background Sodium-glucose cotransporter-2 (SGLT2) inhibitor has been linked to an increased risk of lower extremity amputation (LEA) in patients with Type 2 Diabetes (T2D) and is known to induce volume depletion through osmotic diuresis. We investigated the potential association between diuretics use and the LEA risk in insulin-treated T2D patients. Methods and materials A retrospective cohort study was conducted on 10,320 insulin-treated T2D patients within the UK population. Cox proportional hazard models were utilised to estimate LEA hazard ratios. Amputation risk was compared between a propensity score-matched cohort of diuretics users versus non-users over a 20-year period. Results Among 10,320 subjects, 6454 (52.3%) were on diuretics. In the full cohort, diuretic-treated patients had significantly higher risk of LEA than the non-diuretic individuals (HR: 1.89; 95%CI: 1.34–2.68). When adjusting for possible confounding effects, a 2.3-fold higher risk of amputation was observed (aHR: 2.45; 95%CI: 1.63–3.69). In the matched cohort (n = 580), this association is marginally significant (HR: 3.33; 95%CI: 1.17–18.9; p = .029). Conclusion While diuretic use appeared to be associated with an increased risk of LEA among insulin-treated T2D patients, this association is marginally significant after controlling for confounding factors by cohort matching. These results suggest that volume depletion may be a factor in increasing the risk of LEA amongst high-risk T2D patients, but the strength of this association is weak when adjusted for all other risk factors. Thus, patient selection is crucial when determining the safe use of agents that induce volume depletion in high risk patients with T2D.

304-OR: 5-Hydroxymethylcytosines in Circulating Cell-Free DNA Reveal Diabetic Nephropathy

Background: Long-term complications of type 2 diabetes (T2D) are the major causes for T2D-related disability and mortality. Notably, diabetic nephropathy (DN) has become the most frequent cause of end-stage renal disease in most countries. A clinically convenient, noninvasive approach for monitoring the development of DN would improve the overall life quality of patients with T2D and help reduce healthcare burden through preventive interventions. Methods: A selective chemical labeling strategy, the 5hmC-Seal, was used to profile genome-wide 5-hydroxymethylcytosines (5hmC), an emerging class of epigenetic markers implicated in complex diseases including diabetes, in patient-derived circulating cell-free DNA (cfDNA) in plasma. Differentially modified 5hmC marker genes were identified through the pair-wise comparisons among T2D patients with DN (DN) (n=12), T2D patients with non-DN complications(non-DN) (n=29), and T2D controls with no complications (T2D) (n=14),respectively. Results: A panel of 271 differentially modified genes (fold-change &amp;gt; 10% and nominal p-value &amp;lt; 0.05) were detected between T2D and DN, involving genes and pathways relevant to synthesis of bile acids and bile salts, fatty acid metabolism(ACAA2), mitochondrial gene expression (POLRMT), and ion transport (OTX1, SRI). In addition, a 4-gene 5hmC marker panel (DNAH1, RAB11FIP4, POLRMT, RAB36) was found to be differentially modified among T2D, DN and non-DN patients. Further analysis indicated that this 4-gene signature showed capacity for differentiating DN from T2D (AUC= 83%; 95% confidence interval [66-100%]), healthy individuals (AUC= 83% [64-100%]), and non-DN (AUC = 88% [76-100%]). Conclusion: The 5hmC profiles in cfDNA reflect epigenetic changes in T2D and DN that have the potential to be a clinically convenient, noninvasive approach for monitoring the presence and severity of diabetic retinopathy in high risk T2D patients. Disclosure C. Zeng: None. Y. Yang: None. Z. Zhang: None. C. He: Advisory Panel; Self; Shanghai Epican Genetech Co., Ltd. W. Zhang: Advisory Panel; Self; Shanghai Epican Genetech Co., Ltd. S. Liu: None.

404-P: Cardiovascular Risk Scoring and Stratification in Patients with Type 2 Diabetes Enrolled in a Medicare Advantage Plan

Current tools to identify patients at risk for cardiovascular (CV) disease or events are variable, limiting their utility and generalizability. The purpose of this study was to develop a predictive model to identify patients with type 2 diabetes (T2D) who are ≥65 years of age, enrolled in a Medicare Advantage Prescription Drug (MAPD) plan and at risk for future CV events. This retrospective cohort study used administrative claims, laboratory and enrollment data from 1/2011-12/2018. Patients with T2D were identified from 1/2012-12/2013 using diagnosis codes and/or claims for antihyperglycemic medications. The dependent variable was the first composite CV event defined as ≥1 inpatient hospitalization for myocardial infarction, ischemic stroke, unstable angina, or heart failure or any evidence of revascularization. Independent variables for the prediction survival model included baseline demographic and clinical characteristics prognostic for the dependent variable. C-statistic, accuracy, sensitivity, and specificity were used to assess model performance. Risk ranking was conducted, whereby patients were classified as low, medium or at high risk of an event based on probability distribution derived cut-points. A total of 362,791 patients with T2D were identified. The proportion of patients with ≥1 CV event was 18.0% up to 5 years after T2D identification. The final model included 42 demographic and clinical variables. The C-statistic was 0.68, and accuracy, sensitivity and specificity were 0.63. Results were consistent across the training, test and holdout datasets suggesting internal validity. Up to 5 years after identification, 11% of patients classified as low, 27% as medium, and 51% as high risk had a future CV event. A predictive model for composite CV events utilizing administrative claims to identify and risk stratify patients may be used to scale focused interventions to high-risk T2D patients in a MAPD population to prevent future CVD events. Disclosure J.D. Hayden: Employee; Self; Humana. P. Pimple: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Employee; Spouse/Partner; CVS Caremark. R. Luthra: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. T.G. Prewitt: None. V. Chiguluri: None. M. Kattan: Consultant; Self; GlaxoSmithKline plc. Research Support; Self; Boehringer Ingelheim (Canada) Ltd., Novo Nordisk Inc. R. Harvey: None. A.M. Goss: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. E.O. Caplan: Employee; Self; Humana. Funding Boehringer Ingelheim; Humana

1484-P: Association between Bariatric Surgery and Cardiovascular Events, Mortality, and Glycemic Control among Diabetes Patients: Evidence from a Large EMR Network

Introduction: Studies show that cardiovascular (CV) risk among patients with type 2 diabetes (T2D) and obesity is not always well managed by lifestyle changes. The following study used RWD to examine the effect of bariatric surgery (BS) on CV outcomes and glycemic control (GC) among high risk T2D patients. Methods: In a 1:1 matched propensity score (PS) analysis using the TriNetX database, a federated EMR network representing over 40M patients, T2D patients undergoing BS were compared to T2D patients who were not. Definitions were based on ICD9/10, CPT, RxNorm, and LOINC codes. Patients aged 18-90 were required to have two T2D diagnosis codes 6 months apart, no type 1 diabetes, and a BMI ≥ 30 kg/m2 in the year prior to the index event (IE). The IE was defined by the first BS code in the treated group and the first RxNorm or CPT code in the comparison group. Outcomes of interest were a combined CV event (stroke, MI, or angina) and overall survival (OS). GC (HbA1c &amp;lt; 6.5%) was examined among patients with a HbA1c greater than 9% at baseline. Risk ratios (RR; 95% CIs) and KM curves were calculated for each outcome. Results: In two matched cohorts of 2,972 patients each, a standardized mean difference of &amp;lt;10% was observed for all variables used to calculate the PS. At the time of the IE, patients were 51 (11) and 50 (13) years old, 69% and 68% female, and 62% and 64% white in the BS and comparison groups, respectively. Patients undergoing BS were 60% (70-50%) less likely to experience a CV event (n = 65 events and 173 events, respectively). The 5-year OS was 97% compared to 94% (p&amp;lt;0.01). In a matched subsample of 904 patients with a HbA1c of &amp;gt; 9% in the year prior to the IE, patients undergoing BS were 3.6 (2.4-5.5) times more likely to achieve a HbA1c of &amp;lt; 6.5 in the 12-18 months after the IE. Conclusion: This analysis provides RWE to support a growing body of literature that BS reduces the risk of CV events and mortality, and increase glycemic control, among high risk T2D patients. Disclosure S. Kuranz: Employee; Self; TriNetX, Inc.

Clinical Characteristics of Type 2 Diabetics Who are at High Risk for Obstructive Sleep Apnea.

Introduction:Obstructive sleep apnea (OSA) has been associated with insulin resistance and glucose intolerance. Recent reports have indicated that the majority of patients with type 2 diabetes (T2D) are also having OSA.Aim/Objective:The primary goal of the study is to assess the risk of OSA among T2D patients and its impact on T2D related control and complications.Method:A cross-sectional study for the adult patients with T2D who had a routine follow up visit from Jun 2013- Aug 2014 was asked to participate. We excluded patients with existed psychiatric illness and those with history of diagnosed OSA. To screen for OSA we used Berlin Questionnaire.Result:A total of 265 T2D patients were included in the study with a mean age of 57.2+12.5 years and long standing T2D. Around 53.2% were classified as high risk for OSA. Compared to those who are considered low risk for OSA, those who are high risk for OSA have higher BMI (p <0.001), higher mean SBP (p 0.002), less likely to be male (p 0.003), more likely to have hyperlipidemia (p 0.058), more likely have neuropathy (p 0.021), more likely to report sedentary lifestyle (p 0.046), and more likely to report low income (p 0.068).Conclusion:High risk T2D patients for OSA tend to be older, have significantly higher BMI, systolic BP and tend to have significantly higher risk for neuropathy.

Diabetic Kidney Disease in Adolescents With Type 2 Diabetes: New Insights and Potential Therapies.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) and dialysis in the Western world. Early DKD, including microalbuminuria and renal hyperfiltration, is common in adolescents with type 2 diabetes (T2D). Furthermore, youth-onset T2D carries a higher risk of progressive DKD than adult-onset T2D of similar diabetes duration. DKD is characterized by a long clinically silent period without signs of disease. Therefore, a major challenge in preventing DKD is the difficulty in identifying high-risk T2D patients at an early stage. The Type 2 Diabetes in Adolescents and Youth (TODAY) study demonstrated a high initial prevalence that increased over time, irrespective of treatment arm. This key observation underscores the importance of discovering new therapeutic targets to supplement conventional management, in order to reduce DKD risk. In this review, we focus on early DKD in T2D and summarize potential novel biomarkers and therapeutic targets.

Screening for silent myocardial ischaemia in type 2 diabetic patients with additional atherogenic risk factors: applicability and accuracy of the exercise stress test.

Coronary artery disease (CAD), a major cause of mortality in patients with type 2 diabetes (T2D), is often diagnosed late because of silent myocardial ischaemia (SMI). Exercise electrocardiogram testing (ECG) stress is the most utilized screening test for SMI. Its applicability and accuracy, which have never been reported in asymptomatic high-risk T2D patients, have been investigated in this study. A cross-sectional study with coronary angiography as the gold standard for detecting CAD was used. Two hundred and six consecutive T2D patients, without symptoms and resting ECG signs of ischaemia but with peripheral vascular disease (PVD) and/or > or = two atherogenic factors, were studied. Ischaemia at ECG stress was indicated by horizontal or downsloping ST segment depression > or =1 mm at 0.08 s after the J point. CAD was defined by stenosis > or =70%. Only 141/206 (68%) patients had a diagnostic test: 27 (19%) tested positive and 114 (81%) tested negative. Coronary angiography in 71 patients (the 27 who tested positive and 44 randomly selected patients who tested negative) indicated a CAD prevalence of 29% and the ECG stress accuracy was 79%. 'False negative' patients (18%) had a higher prevalence (P<0.01) of long duration of diabetes and PVD. This is the first study which provides insights into the applicability and accuracy of ECG stress in screening SMI in high-risk patients with T2D. Due to the high prevalence of CAD, alternative screening tests in patients unable to perform the test and in those with a high chance of being 'false negative' should be looked for and validated.