Risk Of Microvascular Disease Research Articles

Weight Change and the Risk of Micro and Macro Vascular Complications of Diabetes: A Systematic Review.

Type 2 diabetes mellitus (T2DM) is a metabolic disease that can be a significant cause of cardiovascular disease (CVD), leading to macrovascular and microvascular diseases. Many researchers around the world have investigated the effects of weight change on micro and macro CVD in patients with T2DM. This study aimed to investigate the effect of weight change (weight gain and loss) on microvascular and macrovascular complications in patients with T2DM. We searched PubMed, Scopus and Google Scholar from the database until January 2023. We screened the title, abstract, and full text of articles, and after quality assessment, we extracted data from interrelated ones into this systematic review. Reviewing the results of 11 cohort studies with 219,839 individuals (T2DM patients) showed that weight loss caused an increase in the mortality rate in diabetic patients, while weight gain after diabetes diagnosis increased the risk of CVD, chronic kidney disease (CKD), microvascular disease, stroke and mortality. It should be noted that severe body weight variability increases the mortality rate and the risk of microvascular disease. Unlike other studies, one study showed that more than 5% weight gain positively affected CVD and coronary heart disease in T2DM patients. Generally, weight change in patients with T2DM is an essential sign of cardiovascular complications. According to our findings, the risk of cardiovascular complications in patients with weight loss is seen to be higher than in patients with weight gain. In regular patients with body mass index (BMI), stable weight in a healthy range is reported to decrease the risk of CVD.

Association between lung function and risk of microvascular diseases in patients with diabetes: A prospective cohort and Mendelian randomization study

Background and aimsTo investigate causal relationships of lung function with risks microvascular diseases among participants with diabetes, type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM), respectively, in prospective and Mendelian randomization (MR) study. Methods and results14,617 participants with diabetes and without microvascular diseases at baseline from the UK Biobank were included in the prospective analysis. Of these, 13,421 had T2DM and 1196 had T1DM. The linear MR analyses were conducted in the UK Biobank with 6838 cases of microvascular diseases and 10,755 controls. Lung function measurements included forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). The study outcome was microvascular diseases, a composite outcome including chronic kidney diseases, retinopathy and peripheral neuropathy. During a median follow-up of 12.1 years, 2668 new-onset microvascular diseases were recorded. FVC (%predicted) was inversely associated with the risk of new-onset microvascular diseases in participants with diabetes (Per SD increment, adjusted HR = 0.86; 95%CI:0.83–0.89), T2DM (Per SD increment, adjusted HR = 0.86; 95%CI:0.82–0.90) and T1DM (Per SD increment, adjusted HR = 0.87; 95%CI: 0.79–0.97), respectively. Similar results were found for FEV1 (%predicted). In MR analyses, genetically predicted FVC (adjusted RR = 0.55, 95%CI:0.39–0.77) and FEV1 (adjusted RR = 0.48, 95%CI:0.28–0.83) were both inversely associated with microvascular diseases in participants with T1DM. No significant association was found in those with T2DM. Similar findings were found for each component of microvascular diseases. ConclusionThere was a causal inverse association between lung function and risks of microvascular diseases in participants with T1DM, but not in those with T2DM.

Association between macro- and microvascular damage and sarcopenia index in individuals with type 2 diabetes mellitus.

Sarcopenia was recently reported to be relevant to an increased macro-and microvascular disease risk. Sarcopenia index (SI) has been identified as a surrogate marker for sarcopenia. The aim of the present study was to investigate the association between macro- and microvascular disease and SI in patients with type 2 diabetes mellitus (T2DM). A total of 783 patients with T2DM were enrolled in this cross-sectional study. The SI was calculated by (serum creatinine [mg/dL]/cystatin C [mg/L])×100. The subjects were divided into three groups according to SI tertiles: T1 (41.27-81.37), T2 (81.38- 99.55), and T3 (99.56-192.31). Parameters of macro- and microvascular complications, including diabetic retinopathy (DR), micro- and macroalbuminuria (MAU), diabetic peripheral neuropathy (DPN), and lower extremity peripheral artery disease (LEAD) were evaluated. Multivariate logistic regression analysis revealed that when taking the top tertile of SI as a reference, an increasing trend of the prevalence of DR, MAU, DPN, and LEAD were presented (all P for trend <0.05), where the OR (95% CI) for DR prevalence was 1.967 (1.252-3.090) in T2, 2.195 (1.278-3.769) in T1, for MAU was 1.805 (1.149-2.837) in T2, 2.537 (1.490-4.320) in T1, for DPN was 2.244 (1.485-3.391) in T2, 3.172 (1.884-5.341) in T1, and for LEAD was 2.017 (1.002-4.057) in T2, 2.405 (1.107-5.225) in T1 (all P<0.05). Patients with lower SI were more inclined to have an increased risk of macro- and microvascular damage in T2DM population, which may be related to sarcopenia.

Frailty and risk of microvascular disease in adults with prediabetes

Background and aimsTo assess the relationship between frailty phenotypes and the risk of MVD among prediabetics in two prospective cohorts. MethodsThe study included 66,068 and 226 participants with prediabetes from the UK Biobank (UKB) and Chinese Ocular Imaging Project (COIP) in Guangzhou, China, respectively. Frailty was evaluated using the Fried phenotype, which includes weight loss, fatigue, low grip strength, low physical activity, and slow walking pace. The outcome was incident microvascular diseases, including diabetic retinopathy, nephropathy, and neuropathy in UKB, and decline rate of retinal capillary density in COIP. Cox models were used to calculate hazard ratios (HRs) and 95 % confidential intervals (CIs), and mixed linear model was used to determine the β and 95 % CIs. ResultsAt baseline, 27,491 (41.6 %) and 3332 (5.0 %) prediabetics were classified as pre-frail and frail, respectively in UKB. During a median follow-up of 8.9 years, 3784 cases of incident microvascular diseases were identified. Pre-frailty and frailty were significantly associated with a higher risk of microvascular diseases (HR 1.21 [1.12, 1.30] for pre-frailty; HR 1.60 [1.42, 1.81] for frailty). Compared to no frailty, the adjusted HRs for frailty were 1.42 (0.73, 2.76) for retinopathy, 1.49 (1.31, 1.70) for nephropathy, and 2.37 (1.69, 3.33) for neuropathy. Fatigue and walking pace were the strongest mediators of frailty and microvascular diseases. In the COIP, the lowest handgrip strength group exhibited 62%–63 % faster annually decline in retinal capillary density compared with the highest group (all P<0.05). ConclusionsEach frailty point is important for prediabetics because both pre-frailty and frailty phenotypes are strongly associated with an increased risk of microvascular diseases and its subtypes. Lower handgrip strength presents with faster decline in retinal capillary density.

160-LB: Circulating MicroRNAs as Predictors of Microvascular Complications in Youth Onset Type 2 Diabetes—The TODAY Study

From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, 60% of the participants demonstrated diabetes-related complications by 10 years. We aimed to identify circulating microRNA (miRNA) species associated with microvascular disease in TODAY participants with youth-onset type 2 diabetes. Using nCounter Human v3 miRNA Panel (NanoString Technologies) to identify relevant miRNAs in two groups of participants who lost glycemic control and either developed microvascular complications during follow-up (n=6) or not (n=11), 53 miRNA species were differentially expressed at baseline (p&amp;lt;0.05) and 2 at the end of study visit (p&amp;lt;0.05). Polymerase chain reaction validations were carried out for 17 miRNAs from 365 participants with samples obtained at baseline, 24, 60, 96, and 120 months. During follow-up, 250 (68%) of the participants (mean 14 years old and diabetes duration &amp;lt;2 years at entry) developed at least one microvascular complication. Using backward elimination modeling and adjusting for demographic characteristics, a set of four baseline miRNA log2 fold changes remained significant predictors of microvascular complications (p&amp;lt;0.05). Increased levels of miR-122 (OR:1.17, 95%CI:1.03-1.32) and miR-221 (OR:1.51, 95%CI: 1.51-1.98) were associated with higher risk of complication, while increased levels of miRNA-let 7g (OR:0.75, 95%CI: 0.60-0.94) and miRNA-130a (OR:0.82, 95%CI: 0.68-0.99) were associated with lower risk of complication. miR-122 abundance was also positively correlated with urine albumin/creatinine ratio at baseline and 24-months (R=0.11, p=0.041 and R=0.16, p=0.005, respectively). The alterations in miR-122, 221, 130a, and let 7g in circulation are all consistent with in vitro alterations that promote endothelial dysfunction suggesting that these early alterations in circulation may predict those at highest risk of microvascular disease in the future. Disclosure D. Redling: None. S. Bialek: None. S. Chernausek: Advisory Panel; Ascendis Pharma A/S. L. El ghormli: None. J. B. Tryggestad: None. Funding National Institutes of Health (5U01DK061230-16)

Association of Retinal Microangiopathy with Albuminuria in Patient with Chronic Kidney Disease: a Meta-analysis Study.

Chronic kidney disease (CKD) patients suffer renal and cardiovascular problems and early death. In 2016, 13.4% of all ages globally had CKD. Kidney disease, diabetes, and hypertension have a microvascular component. Diabetic retinopathy (DR) and diabetic nephropathy (DN) commonly occur concurrently, indicating that the same mechanisms may be at action in the eyes and kidneys. Chronic kidney disease (CKD) has been a tough medical problem because of late signs and late treatment. Retinal vessels are a non-invasive technique to examine systemic microvasculature. Novel predictors may enhance microvascular disease risk categorization, leading to better therapy. Retinal vascular diameter and retinopathy are reported most often. Numerous investigations have linked this condition to kidney or other systemic disorders. The retinal microvasculature was linked with both the incidence and prevalence of renal illness in this investigation. We wanted to determine whether retinal microvasculature might be utilized to diagnose renal disease. Initial searching found 625 papers, of which 542 articles were rejected due to primary screening unrelated titles and/or abstracts. There were a total of 81 papers selected for full-text evaluation and due to insufficient data provided and duplication, we got 5 papers to enter the next step. In five investigations, retinal microvascular symptoms correlated with albuminuria. All studies connected retinal vascular diameter with albuminuria. As a categorical variable, CRAE narrowed. There was a U-shaped relationship between CRAE and albuminuria in quintiles 1 and 5. There were relationship between albuminuria to a larger CRVE and a narrower CRAE. Studies relate AVR to albuminuria were associated as well. Our investigation demonstrated retinal vascular symptoms are linked to renal illness. Retinopathy correlates with CKD and ESRD in diabetic and nondiabetic individuals. Evidence linking retinal vascular width to early renal disease implies fundus photography might be a useful screening technique for CKD patients. Insufficient evidence links retinal vascular diameter to kidney-related morbidity and death. Future studies should stratify by age, gender, obesity, hypertension, ethnicity, and others.

The Theory of Hyperlipidemic Memory of Type 1 Diabetes.

Literature Search CriteriaA literature search was conducted to identify publications addressing the early phases of lipid phenotypes in children and adults with either type 1 diabetes or type 2 diabetes. Medline, EMBASE, and Ovid were searched using the following search terms: clinical remission, partial remission, partial clinical remission, honeymoon phase, C-peptide, type 1 or 2 diabetes, children, pediatric type 1 or 2 diabetes, and paediatrics type 1 or 2 diabetes, adults, adult type 1 or type 2 diabetes. Partial clinical remission (PR) of type 1 diabetes (T1D) is characterized by continued endogenous production of insulin and C-peptide following the diagnosis and the introduction of exogenous insulin therapy. PR is associated with improved glycemic control and reduced prevalence of diabetes complications. The theory of hyperglycemic memory was proposed to explain this concept of improved glycemic outcomes in remitters (those who experienced PR) versus non-remitters (those who did not experience PR). However, this theory is incomplete as it does not explain the dichotomy in early lipid phenotypes in T1D based on PR status, which is an understudied area in diabetology and lipidology. To fill this knowledge gap, we propose the Theory of Hyperlipidemic Memory of T1D. This theory is premised on our 5-year research on early post-diagnostic dichotomy in lipid phenotypes between remitters and non-remitters across the lifespan. It provides a more rigorous explanation for the differences in lifelong atherosclerotic cardiovascular disease (ASCVD) risk between remitters and non-remitters. We conducted 4 clinical studies in pediatric and adult subjects with diabetes mellitus to characterize the particulars of the hyperlipidemic memory. In the first investigation, we explored the impact of the presence or absence of PR on lipid parameters in children and adolescents with T1D. In the second, we investigated whether pubertal maturation influenced our findings in T1D; and whether these findings could be replicated in healthy, non-diabetic children and adolescents. In the third, we leveraged our findings from T1D and controls to investigate the mechanisms of early lipid changes in T2D by comparing the earliest lipid phenotype of subjects with type 2 diabetes (T2D) to those of remitters, non-remitters, and controls. In the fourth, we investigated the impact of PR on the earliest lipid phenotypes in adults with T1D and compared these early lipid data to those of T2D subjects and controls. This body of work across the lifespan in children, adolescents, and adults supports the Theory of Hyperlipidemic Memory. This new theory clarifies why PR largely determines the risks for early-phase dyslipidemia, mid-term microvascular disease risk, and long-term ASCVD risk in subjects with T1D.

Association Between Obesity and Microvascular Diseases in Patients With Type 2 Diabetes Mellitus.

This study aimed to evaluate the association between obesity, evaluated by fat mass index (FMI) with the risk of microvascular diseases in patients with type 2 diabetes mellitus (T2DM) and compare the magnitude of associations of FMI, body mass index (BMI), and waist circumference (WC) with the risk of microvascular diseases. We performed a post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes study. The primary microvascular outcomes of the present study included chronic kidney disease (CKD) progression, retinopathy, and neuropathy. Cox proportional-hazards models were performed to evaluate the association of FMI with microvascular diseases. A discordant analysis was performed to compare the magnitude of associations of FMI, BMI, and WC with the risk of microvascular diseases. Our study included 10,251 T2DM participants with a median of 5 years (interquartile range, 4.2–5.7) of follow-up. A total of 6,184 participants developed CKD progression, 896 participants had retinopathy, and 3,213 participants developed neuropathy (Michigan Neuropathy Screening Instrument, >2.0). After the confounding factors were adjusted for, patients in the highest FMI quartile had a higher risk of CKD progression (HR: 1.26, 95%CI: 1.16–1.36) and neuropathy (HR: 1.93, 95% CI: 1.74–2.15), except for retinopathy (HR: 1.17, 95% CI: 0.96–1.43), than those in the lowest quartile. Discordant analyses found that FMI and WC are better in identifying individuals with obesity-related risk of neuropathy, compared with BMI; neither is better in identifying individuals with obesity-related risk of CKD progression and retinopathy. Obesity is associated with CKD progression and neuropathy in T2DM participants. Further randomized trials are needed to test whether obesity control can improve the outcomes of T2DM participants with CKD or neuropathy. FMI and WC are more useful in identifying obesity-related risk of neuropathy compared with BMI in T2DM patients.Clinical Trial Registration http://www.clinicaltrials.gov, NCT00000620.

Increased risk for microvascular complications among women with gestational diabetes in the third trimester

AimsThe risk of microvascular disease has been thought to commence with the onset of overt diabetes. Women with gestational diabetes have only had a short-term exposure to frank hyperglycemia, but, due to underlying β-cell dysfunction, they may also have had long-term exposure to mild degrees of hyperglycemia. The aim of the study was to determine whether women with gestational diabetes are at increased risk for microalbuminuria and retinopathy compared to women with normal glucose tolerance in pregnancy. MethodsWe recruited women aged ≥ 25 years with singleton pregnancies at 32 to 40 weeks’ gestational age, with and without gestational diabetes. Women with hypertension, preeclampsia, or pre-gestational diabetes were excluded. ResultsOf 372 women included in the study, 195 had gestational diabetes. The prevalence of microalbuminuria was 15% among those with gestational diabetes versus 6% in those with normal glucose tolerance (adjusted odds ratio 2.4, 95% confidence interval 1.1 to 5.2, p = 0.006). Diastolic blood pressure and HbA1c were associated with microalbuminuria. The prevalence of retinopathy did not differ between groups (10% versus 11%). ConclusionsWomen with gestational diabetes have an increased risk of microalbuminuria in the third trimester, despite having been exposed to only a brief period of overt hyperglycemia.

A nationwide cohort study for comparative vascular safety of long-acting insulin analogue versus intermediate-acting human insulin in type 2 diabetes

Little is known about the comparative vascular safety of basal insulins (intermediate-acting human insulin [IAHI] or long-acting insulin analogue [LAIA]) in type 2 diabetes (T2D). This study sought to examine the vascular and hypoglycemic effects associated with IAHI versus LAIA in real-world patients with T2D. We utilized Taiwan’s National Health Insurance Research Database to identify T2D patients who stably used IAHI (N = 11,521) or LAIA (N = 37,651) in the period 2004–2012. A rigorous three-step matching algorithm that considered the initiation date of basal insulin, previous exposure of antidiabetic treatments, comorbidities, diabetes severity and complications, and concomitant medications was applied to achieve the between-group comparability. Study outcomes, including cardiovascular diseases (CVDs), microvascular diseases (MVDs), and hypoglycemia, were assessed up to the end of 2013. Compared with LAIA, the use of IAHI was associated with greater risks of composite CVDs (adjusted hazard ratio [aHR]: 1.79; 95% confidence interval [CI] 1.20–2.67) and hospitalized hypoglycemia (aHR: 1.82; 95% CI 1.51–2.20), but a lower risk of composite MVDs (aHR: 0.88; 95% CI 0.84–0.91). Subgroup and sensitivity analyses showed a consistent trend of results with that in the primary analyses. In summary, although the use of IAHI versus LAIA among T2D patients in usual practice may be associated with a lower risk of MVDs, strategies should be optimized for minimizing the risks of hypoglycemia and CVDs in this population.

Relationship between insulin-sensitive obesity and retinal microvascular abnormalities.

Obesity and insulin resistance (IR) are risk factors for microvascular disease (MVD). Whether insulin-sensitive obese individuals are at higher risk for MVD is still debated. We aimed to investigate whether insulin-sensitive obesity is associated with retinal microvascular abnormalities. This cross-sectional study recruited a total of 8,313 participants (3,604 males and 4,709 females) aged 21 years or older from 13 villages in rural area and 8 communities in urban area in Fujian province in China between 2011 to 2012. Participants were categorized by insulin-sensitive/-resistant and general/ abdominal obese status. IR was defined as homeostasis model assessment of IR >1.99 (75% percentile). Direct ophthalmoscopic examination was used to diagnose MVD, which was defined as the presence of retinal microvascular abnormalities. Among the older subjects (aged 65-79 years), those who were obese had a markedly higher risk for MVD, both in insulin-sensitive [odds ratio (OR): 2.259, 95% confidence interval (CI): 1.041-4.904, P=0.039] and insulin-resistant (OR: 2.356, 95% CI: 1.064-5.218, P=0.035) individuals. Additionally, insulinsensitive/-resistant abdominal obesity in middle-aged people showed an increased risk for prevalent MVD in women (OR: 2.061, 3.322; 95% CI: 1.004-4.233, 1.645-6.709; P values: 0.049, <0.001). In this study, obesity was closely related to an elevated higher risk of MVD, regardless of IR, especially in older people and abdominally obese middle-aged women. Obesity may be similar to diabetes mellitus, with chronic complications that not only cause cardiovascular diseases but also MVD. Direct ophthalmoscopy may be a noninvasive and meaningful method of early screening for obesity-related MVD. Insulin-sensitive obesity, like impaired glucose tolerance, is a pre-existing state of insulin resistant obesity.

LDL-Cholesterol versus Glucose in Microvascular and Macrovascular Disease.

The causal relationships between increased concentrations of low density lipoprotein (LDL)-cholesterol and glucose and risk of ischemic heart disease are well established. The causal contributions of LDL-cholesterol and glucose to risk of peripheral micro- and macrovascular diseases are less studied, especially in prediabetic stages and in a general population setting. This review summarizes the current evidence for a causal contribution of LDL-cholesterol and glucose to risk of a spectrum of peripheral micro- and macrovascular diseases and reviews possible underlying disease mechanisms, including differences between vascular compartments, and finally discusses the clinical implications of these findings, including strategies for prevention and treatment. Combined lines of evidence suggest that LDL-cholesterol has a causal effect on risk of peripheral arterial disease and chronic kidney disease, both of which represent manifestations of macrovascular disease due to atherosclerosis and accumulation of LDL particles in the arterial wall. In contrast, there is limited evidence for a causal effect on risk of microvascular disease. Glucose has a causal effect on risk of both micro- and macrovascular disease. However, most evidence is derived from studies of individuals with diabetes. Further studies in normoglycemic and prediabetic individuals are warranted. Overall, LDL-cholesterol-lowering reduces risk of macrovascular disease, while evidence for a reduction in risk of microvascular disease is inconsistent. Glucose-lowering has a beneficial effect on risk of microvascular diseases and on risk of chronic kidney disease and estimated glomerular filtration rate (eGFR) in some studies, while results on risk of peripheral arterial disease are conflicting.

Association of sedentary time with blood pressure in women of reproductive age.

While the beneficial impact of moderate-vigorous physical activity (MVPA) on blood pressure is well-understood, the relationship between sedentary time (ST) and blood pressure is less clear. We aimed to evaluate the associations between ST and BP in reproductive-age women. This cross-sectional analysis consisted of 431 women enrolled in the Placenta as a Window to Maternal Microvascular Disease Risk study at Magee-Womens Hospital. Blood pressure and self-reported physical activity and ST were collected 8–10 years after delivery at study enrollment. Logistic and linear regression models examined associations between ST and blood pressure and adjusted for MVPA. Women with the highest amount of ST were less likely to be normotensive and more likely to have elevated blood pressure and Stage II hypertension (p = 0.02). Each additional hour of ST was associated with an increased risk of Stage II hypertension (OR 1.12 [1.01–1.24]) and higher systolic blood pressure (0.45 mmHg [0.08–0.82]), diastolic blood pressure (0.29 mmHg [0.02–0.56]), and mean arterial pressure (0.34 mmHg [0.05–0.63]), after adjustment for covariates. This relationship was more apparent in women who participated in less MVPA (bottom 50th percentile) versus more MVPA (top 50th percentile). ST is associated with higher blood pressure, particularly in women who engage in less aerobic activity, and could serve as an important intervention target for reducing blood pressure and hypertension during the reproductive years.

Association between Obesity and Microvascular Diseases in Patients with Type 2 Diabetes Mellitus

Background: The association between obesity and microvascular diseases, especially in extremely obese patients with type 2 diabetes mellitus, has not been well examined. This study aimed to investigate this association and further compare the magnitude of the associations of fat mass index (FMI), body mass index (BMI), waist circumference (WC), and waist-to-height (W-t-H), with the risk of microvascular diseases in type 2 diabetes mellites(T2DM). Methods: We mainly used FMI as an indicator of obesity to study the association with microvascular diseases and performed a post hoc analysis of the ACCORD study. The primary microvascular outcomes of the present study included severe renal hypofunction, retinopathy, or neuropathy. Findings: After confounding factors were adjusted for, patients with the highest quartile of FMI had a higher risk of severe renal hypofunction (hazard ratio [HR]: 1·26, 95% confidence interval [CI]: 1·16–1·36) and neuropathy (HR: 1·93, 95% CI: 1·74–2·15) but not higher risk of retinopathy (HR: 1·17, 95% CI: 0·96–1·43) than those with the lowest quartile. A “plateau phenomenon” for severe renal hypofunction and neuropathy was found when the extent of obesity exceeded a certain point. Quartiles, deciles or standardized measure (1-SD increment) of obesity indicators analysis showed inconsistent results on which obesity indicator had a stronger association with the risk of microvascular disease. Interpretation: Obesity is associated with renal function deterioration and neuropathy but not with retinopathy. Compared to BMI, WC, and W-t-H, FMI did not show a stronger association with the risk of microvascular diseases. Funding Statement: None. Declaration of Interests: All authors declare to have no conflict of interest.

Progression of Diabetic Complications in Subgroups of People with Long Term Diabetes Type 1 According to Clinical Course.

Prevention and prediction of microvascular complications are important aims of medical care in people with type 1 diabetes. Since the course of the disease is heterogenous, we tried to identify subgroups with specific risk profiles for microvascular complications. Retrospective analysis of a cohort of 285 people (22637 consultations) with >10 years of type 1 diabetes. Persons were grouped into slow (<15 years), fast (>15 years) and non progressors according to the average onset of microvascular complications. Generalized estimating equations for binary outcomes were applied and pseudo coefficients of determination were calculated. Progression to microvascular disease was associated with age (OR: 1.034 [1.001-1.068]; p=0.04), diabetes duration (OR: 1.057 [1.021-1.094]; p=0.002), HbA1c (OR: 1.035 [1.011-1.060]; p=0.005), BMI (OR: 0.928 [0.866-0.994]; p=0.034) and the social strata index (OR: 0.910 [0.830-0.998]; p=0.046). Generalized estimating equations predicted 31.02% and exclusion of HbA1c marginally reduced the value to 28.88%. The proportion of patients with LADA was higher in fast than slow progressors [13 (26.5%) vs. 14 (11.9%); p=0.019]. A generalized estimating equation comparing slow to fast progressors revealed no significant markers. In our analysis, we were able to confirm known risk factors for microvascular disease in people with type 1 diabetes. Overall, prediction of individual risk was difficult, the effect of individual markers minor and we could not find differences regarding slow or fast progression. We therefore emphasis the need for additional markers to predict individual risk for microvascular disease.

Comparative predictive ability of visit-to-visit HbA1c variability measures for microvascular disease risk in type 2 diabetes

BackgroundTo assess the associations of various HbA1c measures, including a single baseline HbA1c value, overall mean, yearly updated means, standard deviation (HbA1c-SD), coefficient of variation (HbA1c-CV), and HbA1c variability score (HVS), with microvascular disease (MVD) risk in patients with type 2 diabetes.MethodsLinked data between National Cheng Kung University Hospital and Taiwan’s National Health Insurance Research Database were utilized to identify the study cohort. The primary outcome was the composite MVD events (retinopathy, nephropathy, or neuropathy) occurring during the study follow-up. Cox model analyses were performed to assess the associations between HbA1c measures and MVD risk, with adjustment for patients’ baseline HbA1c, demographics, comorbidities/complications, and treatments.ResultsIn the models without adjustment for baseline HbA1c, all HbA1c variability and mean measures were significantly associated with MVD risk, except HVS. With adjustment for baseline HbA1c, HbA1c-CV had the strongest association with MVD risk. For every unit of increase in HbA1c-CV, the MVD risk significantly increased by 3.42- and 2.81-fold based on the models without and with adjustment for baseline HbA1c, respectively. The associations of HbA1c variability and mean measures with MVD risk in patients with baseline HbA1c < 7.5% (58 mmol/mol) were stronger compared with those in patients with baseline HbA1c ≥ 7.5% (58 mmol/mol).ConclusionsHbA1c variability, especially HbA1c-CV, can supplement conventional baseline HbA1c measure for explaining MVD risk. HbA1c variability may play a greater role in MVD outcomes among patients with relatively optimal baseline glycemic control compared to those with relatively poor baseline glycemic control.

75-LB: Machine-Learned, Biophysical Prediction of Glucose Response for 1,000 Subjects

Background: Reducing glycemic excursions following oral intake decreases the risk for microvascular disease in those with type 2 diabetes (T2D) and prevents conversion to T2D in those with prediabetes. Currently there are no accurate methods by which to predict a real world subject’s glycemic response to a particular meal. We developed a novel machine learning tool to infer personalized physiological parameters using consumer sensors for the accurate prediction of glycemic responses to food and activity. Method: We prospectively recruited 1,000 healthy, prediabetic and type 2 diabetic subjects instructed to wear a Freestyle Libre Continuous Glucose Monitor (CGM) and Heart Rate Monitor (HRM) and logged foods for 10 days. A novel biophysical, machine-learned model was trained on CGM, HRM data and food logs to predict and tune glucose responses to food and activity. The training used a separate deep-learning network trained to predict the infusion of glucose into subject bloodstream using known glycemic index (GI) values. Results: 715 nondiabetic, 35 prediabetic, and 246 T2D subjects were enrolled. Our novel biophysical, machine-learned model predicted glucose excursions over a database of many million foods and activity rates and exceeded 99.9% on the Clarke Error Grid regions A and B for a wide variety of individuals. Many correlations exist between caloric intake and composition, fiber intake, household income, sleep quality, and inferred physiological parameters. Conclusion: Precise prediction of glycemic responses will allow accurate counterfactual analysis of lifestyle choices and allow all individuals to better plan and select foods and activities to match their lifestyle, physiology, and psychological predispositions. This novel technology has potential novel applications for both diabetes treatment and prevention. Disclosure P. Dalal: Advisory Panel; Spouse/Partner; Arc Bio, Caribou Biosciences, Inc., January, Inc. Employee; Self; January, Inc. Other Relationship; Spouse/Partner; Illumina. M. Yazdani: None. M. Snyder: Stock/Shareholder; Self; January, Inc. S. Rahili: Employee; Self; January, Inc. S.S. Torbaghan: None.

Prolonged Circulation of Ultra-Large Von Willebrand Factor and a Reduction in ADAMTS13 Activity Promotes Microvascular Disease Following Traumatic Injury

Introduction: Increases in plasma von Willebrand Factor (vWF) levels, accompanied by decreases in its respective metalloprotease, ADAMTS13, have been demonstrated in diseases of microvascular injury. We hypothesized that following severe trauma, a burst of ultra-large vWF (UL-vWF) is released into the bloodstream by damaged endothelium, resulting in increased thrombogenicity due to circulating vWF multimers. We further hypothesized that traumatic injury would lead to a deficit of ADAMTS13, promoting the accumulation of UL-vWF forms and, ultimately, the increased risk of microvascular disease, such as acute kidney injury (AKI). Methods: A cohort of 37 severely injured trauma patients was analyzed for antigen levels of plasma vWF and ADAMTS13 at 0- and 24-hours after admission. Circulating vWF multimeric composition from both time points was determined by vertical agarose gel electrophoresis. Multivariate analyses were performed with data abstracted from the electronic medical records to identify further dependences. A similar analysis was also performed on plasma from a cohort of 8 patients with trauma induced AKI at 0-, 24-, and 72-hours after admission; these patients were well matched against trauma patients without AKI. Finally, we utilized a murine model of polytrauma and hemorrhage, in conjunction with qRT-PCR of ADAMTS13 in total liver RNA, to specifically address how the expression of ADAMTS13 is altered by the systemic effects of traumatic injury. Results: Circulating vWF levels were increased in severe trauma patients when compared to healthy controls at presentation (189% (110-263) vs. 95% (74-120)) and persisted through 24-hours (213% (146-257) vs. 132% (57-160)). Ultra-large vWF forms were elevated at both 0- and 24-hours when compared to pooled normal plasma ((10.0% (8.9-14.3) and 11.3% (9.1-21.2), respectively, vs 0.6%). The largest vWF forms within trauma patient plasma circulated at 33±4 dimers vs 18±1 dimer in length within pooled normal plasma. Severe trauma patient ADAMTS13 activity was decreased at 0-hours (66% (47-86) vs. 100% (98-100)) and at 24-hours (72.5% (56-87.3) vs 103% (103-103)) when compared to healthy patients. Furthermore, the proportion of circulating low molecular weight multimeric (LMWM) vWF to total circulating vWF forms was directly dependent upon ADAMTS13 activity at 24-hours (Decreased ADAMTS13 Activity: 20.4% (15.0-22.7) LMWM vWF vs Normal Activity: 25.8% (22.7-35.2) LMWM vWF). Strikingly, ADAMTS13 activity independently predicted the development of coagulopathy, correlating with presentation INR (ρ =-0.63), activated clotting time of thromboelastography (TEG) (ρ=-0.36), and TEG maximum amplitude (ρ=0.36). ADAMTS13 activity also closely correlated with injury severity (ISS) (ρ=-0.34) and blood product transfusion (ρ =-.45). The cohort of 8 trauma patients who went on to develop AKI showed a 1.54-fold (1.02-2.05) increase in plasma vWF antigen levels between 0 and 72 hours, while those who did not develop AKI showed no change in vWF levels over this time period. Furthermore, those who developed AKI demonstrated a smaller proportion of LMWM vWF in plasma than those who did not (25.4% (23.4-28.0) vs 31.2% (27.2-35.6)), suggesting the increased thrombogenicity of their circulating vWF forms. Finally, qRT-PCR of total liver RNA in 6 mice demonstrated a 2-fold decrease in ADAMTS13 RNA expression levels between the times immediately before and 24-hours after trauma. Altogether, these data indicate that both circulating ADAMTS13 and its production are deficient in the days following severe injury. Conclusions: Severe traumatic injury alters the circulating composition of ADAMTS13 and its target, vWF, shifting their equilibrium to one that promotes thrombosis. Not only is the concentration of circulating ADAMTS13 decreased following traumatic injury, but hepatic expression of the enzyme is lacking as well. In the immediate moments following injury, these mechanisms contribute to life-saving hemostasis; however, as these changes extend into the following days, the early hemostatic benefit quickly shifts to burden that may exacerbate microvascular disease. Disclosures Ragni: Bioverativ/Sanofi: Consultancy, Research Funding; Sangamo: Research Funding; Shire/Takeda: Consultancy, Other: Study drug; Alnylam/Sanofi: Consultancy, Research Funding; Bayer: Consultancy; Spark Therapeutics: Consultancy, Research Funding; ICER: Consultancy; OPKO: Research Funding; Biomarin: Consultancy, Research Funding. Rollins-Raval:Bayer, Inc: Membership on an entity's Board of Directors or advisory committees. Raval:Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer, Inc: Research Funding. Neal:Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees.

Regression From Prediabetes to Normal Glucose Regulation and Prevalence of Microvascular Disease in the Diabetes Prevention Program Outcomes Study (DPPOS).

OBJECTIVERegression from prediabetes to normal glucose regulation (NGR) was associated with reduced incidence of diabetes by 56% over 10 years in participants in the Diabetes Prevention Program Outcomes Study (DPPOS). In an observational analysis, we examined whether regression to NGR also reduced risk for microvascular disease (MVD).RESEARCH DESIGN AND METHODSGeneralized estimating equations were used to examine the prevalence of aggregate MVD at DPPOS year 11 in people who regressed to NGR at least once (vs. never) during the Diabetes Prevention Program (DPP). Logistic regression assessed the relationship of NGR with retinopathy, nephropathy, and neuropathy, individually. Generalized additive models fit smoothing splines to describe the relationship between average A1C during follow-up and MVD (and its subtypes) at the end of follow-up.RESULTSRegression to NGR was associated with lower prevalence of aggregate MVD in models adjusted for age, sex, race/ethnicity, baseline A1C, and treatment arm (odds ratio [OR] 0.78, 95% CI 0.65–0.78, P = 0.011). However, this association was lost in models that included average A1C during follow-up (OR 0.95, 95% CI 0.78–1.16, P = 0.63) or diabetes status at the end of follow-up (OR 0.92, 95% CI 0.75–1.12, P = 0.40). Similar results were observed in examination of the association between regression to NGR and prevalence of nephropathy and retinopathy, individually. Risk for aggregate MVD, nephropathy, and retinopathy increased across the A1C range.CONCLUSIONSRegression to NGR is associated with a lower prevalence of aggregate MVD, nephropathy, and retinopathy, primarily due to lower glycemic exposure over time. Differential risk for the MVD subtypes begins in the prediabetes A1C range.

Personalizing Second-Line Type 2 Diabetes Treatment Selection: Combining Network Meta-analysis, Individualized Risk, and Patient Preferences for Unified Decision Support.

Personalizing medical treatment often requires practitioners to compare multiple treatment options, assess a patient's unique risk and benefit from each option, and elicit a patient's preferences around treatment. We integrated these 3 considerations into a decision-modeling framework for the selection of second-line glycemic therapy for type 2 diabetes. Based on multicriteria decision analysis, we developed a unified treatment decision support tool accounting for 3 factors: patient preferences, disease outcomes, and medication efficacy and safety profiles. By standardizing and multiplying these 3 factors, we calculated the ranking score for each medication. This approach was applied to determining second-line glycemic therapy by integrating 1) treatment efficacy and side-effect data from a network meta-analysis of 301 randomized trials ( N = 219,277), 2) validated risk equations for type 2 diabetes complications, and 3) patient preferences around treatment (e.g., to avoid daily glucose testing). Data from participants with type 2 diabetes in the U.S. National Health and Nutrition Examination Survey (NHANES 2003-2014, N = 1107) were used to explore variations in treatment recommendations and associated quality-adjusted life-years given different patient features. Patients at the highest microvascular disease risk had glucagon-like peptide 1 agonists or basal insulin recommended as top choices, whereas those wanting to avoid an injected medication or daily glucose testing had sodium-glucose linked transporter 2 or dipeptidyl peptidase 4 inhibitors commonly recommended, and those with major cost concerns had sulfonylureas commonly recommended. By converting from the most common sulfonylurea treatment to the model-recommended treatment, NHANES participants were expected to save an average of 0.036 quality-adjusted life-years per person (about a half month) from 10 years of treatment. Models can help integrate meta-analytic treatment effect estimates with individualized risk calculations and preferences, to aid personalized treatment selection.