Intensive Glycemic Control Research Articles

Subcellular mass spectrometric detection unveils hyperglycemic memory in the diabetic heart.

Intensive glycemic control is insufficient to reduce the risk of heart failure in patients with diabetes mellitus. While the hyperglycemic memory in the diabetic cardiomyopathy has been well documented, its underlying mechanisms are not fully understood. The present study tried to investigate whether the dysregulated proteins/biological pathways, which persistently altered in diabetic hearts during normoglycemia, participate in the hyperglycemic memory. Hearts of streptozotocin-induced diabetic mice, with or without intensive glycemic control using slow-release insulin implants, were collected. Proteins from total heart samples and subcellular fractions were assessed by mass spectrometry, Western blotting, and KEGG pathway enrichment analysis. mRNA sequencing was used to determine whether the persistently altered proteins were regulated at the transcriptional or post-transcriptional level. Western blot validation of several proteins with high pathophysiological importance, including MYH7, HMGCS2, PDK4, and BDH1, indicated that mass spectrometry was able to qualitatively, but not quantitatively, reflect the fold changes of certain proteins in diabetes. Pathway analysis revealed that the peroxisome, PPAR pathway, and fatty acid metabolism could be efficiently rescued by glycemic control. However, dysregulation of oxidative phosphorylation and reactive oxygen species persisted even after normalization of hyperglycemia. Notably, mRNA sequencing revealed that dysregulated proteins in the oxidative phosphorylation pathway were not accompanied by coordinated changes in mRNA levels, indicating post-transcriptional regulation. Moreover, literature review and bioinformatics analysis suggested that hyperglycemia-induced persistent alterations of miRNAs targeted genes from the persistently dysregulated oxidative phosphorylation pathway, whereas, oxidative phosphorylation dysfunction-induced ROS regulated miRNA expression, which thereby might sustained the dysregulation of miRNAs. Glycemic control cannot rescue hyperglycemia-induced alterations of subcellular proteins in the diabetic heart, and persistently altered proteins are involved in multiple functional pathways, including oxidative phosphorylation. These findings might provide novel insights into hyperglycemic memory in diabetic cardiomyopathy.

Real-World Treatment Patterns in Drug Naïve Type 2 Diabetes Population: Initial Combination Therapy vs. Sequential Step-Therapy

BackgroundDespite evidence-based guidelines and available therapies, many patients with type 2 diabetes (T2D) have suboptimal glycemic control. The current standard of care suggests initial monotherapy followed by add-on therapy to achieve and maintain target HbA1c. However, clinical trials revealed that intensive glycemic control, especially at the early stages of the disease, could result in earlier and better long-term glycemic control in addition to reducing diabetes-related complications and mortality risk. ObjectivesThis population-based study aimed to investigate treatment initiation patterns among newly diagnosed drug-naïve patients with T2D in real-world clinical settings, focusing on two recommended approaches: initial combination therapy and step-therapy. MethodsA retrospective study was conducted using claims data from the Merative™ MarketScan® Research Databases between 2017 and 2019. The study included drug-naïve patients with T2D with continuous enrolment in medical and pharmacy plans. Patients were categorized into the initial combination therapy or step-therapy cohorts based on their initial treatment regimen. Baseline characteristics of the cohorts were recorded, and logistic regression analysis was performed to identify factors associated with receiving each approach. ResultsThe study included a total of 117,419 patients in the Commercial/Medicare population and 18,574 patients in the Medicaid population. About 10-12% of patients received initial combination therapy as their initial pharmacotherapy regimen. Several patient demographic and clinical characteristics were significantly associated with the use of initial combination therapy vs. step-therapy. Results also showed a greater usage of loose-dose combination pills over fixed-dose combinations. ConclusionsGiven the lack of real-world studies on combination vs. step-therapy, the study findings provide insights into the current treatment initiation patterns and associated factors among drug-naïve patients with T2D. These findings contribute to understanding the real-world clinical practices in diabetes management and may help guide clinicians in making informed decisions regarding pharmacotherapy approaches.

Paradigm shift from glucocentric to organ protection for the management of hyperglycemia in patients with type 2 diabetes

The UK Prospective Diabetes Study was the first study to investigate the effectiveness of glycemic control in patients with type 2 diabetes. Since then, many studies have evaluated the impact of intensive glycemic control on diabetes-related morbidities and mortality. The results of these studies were intended to change the paradigm for controlling glycated hemoglobin and preventing diabetes-related complications, but the beneficial outcomes were limited to microvascular diseases rather than diabetes-related cardiorenal diseases and deaths. This has emphasized the need for comprehensive management of other risk factors (hypertension, dyslipidemia, renal failure, etc.) in addition to hyperglycemia to prevent atherosclerotic cardiovascular diseases and end-stage renal disease in type 2 diabetes. Since 2008, clinical trials to demonstrate cardiovascular safety have shown a beneficial effect of sodium-glucose transporter 2 inhibitors or glucagon-like peptide-1 receptor agonists on macrovascular or renal complications in patients with type 2 diabetes. Recently, major societies around the world including the Korean Diabetes Association, have shifted the goals of diabetes management from the typical glucocentric view to cardiorenal outcome-oriented (organ protection) care, which has been widely accepted and is gradually applied to primary care.

Association between average glucose concentration or glucose variability and acute kidney injury among CAD patients with prediabetes

Abstract Background Prediabetes, impacting approximately 10% of adults, lacks comprehensive attention, and there is limited data on effective glycemic control strategies. Meta-analysis suggests that intensive glycemic control is linked to a lower incidence of major adverse cardiovascular events, mainly driven by decreased reinfarction and reduced microvascular complications in coronary artery disease (CAD) patients. However, despite these associations, existing evidence does not conclusively establish the efficacy of intensive glycemic control in enhancing cardio-renal outcomes. Purpose In the present study, we aimed to validate the utility of intensive glycaemic control on acute kidney injury (AKI) prevention using a prospective, pragmatic clinical data of patients with CAD. Methods This study utilized data from the Prospective Registry of the Current Status of Care for Patients with Coronary Artery Disease database, a nationwide and pragmatic registry project initiated on January 17th, 2022. Data, including demographics, medical history, and lab results, were collected from electronic medical records. The time-weighted average glucose (TWAG) and glucose variability (CV) for each patient to assess glycaemic control, and outcomes including AKI were assessed. Statistical analysis involved logistic models and sensitivity analyses. SAS 9.4 and R software were used, with p<0.05 considered significant. Results Between January 2022 and June 2023, 2,454 CAD patients with prediabetes were included for final analysis. Among them, the average age was 62.6 ± 10.3 years, of whom 27.1% were females. In univariate model, the incidence of AKI was 1.51 (1.36,1.68) times higher in patients with an increasing TWAG per mmol/L. After the stepwise adjusting of covariates, the OR was 1.50 (1.35,1.67). CV of glucose also had positive association with AKI. An increasing of 0.1 unit of CV increased the risk of about 44%. When adjusting the TWAG and CV of glucose at the same time, both still had positive association with AKI. A restricted cubic splines plot showed an increasing trend of the ORs for AKI as both TWAG and CV of glucose increased. Subgroups analyses also showed stable positive association between TWAG, CV and AKI. Conclusions Our study reveals an association between TWAG or CV and AKI in individuals with both CAD and prediabetes. These findings underscore the importance of continuous glucose monitoring and the implementation of intensive glycaemic control for CAD patients coexistence of prediabetes.Restricted cubic splines function

Recent Advances Associated with Cardiometabolic Remodeling in Diabetes-induced Heart Failure.

Diabetes mellitus (DM) is characterized by chronic hyperglycemia, and despite intensive glycemic control, the risk of heart failure in diabetic patients remains high. Diabetes-induced heart failure (DHF) presents a unique metabolic challenge, driven by significant alterations in cardiac substrate metabolism, including increased reliance on fatty acid oxidation, reduced glucose utilization, and impaired mitochondrial function. These metabolic alterations lead to oxidative stress, lipotoxicity, and energy deficits, contributing to the progression of heart failure. Emerging research has identified novel mechanisms involved in the metabolic remodeling of diabetic hearts, such as autophagy dysregulation, epigenetic modifications, polyamine regulation, and branched-chain amino acid (BCAA) metabolism. These processes exacerbate mitochondrial dysfunction and metabolic inflexibility, further impairing cardiac function. Therapeutic interventions targeting these pathways-such as enhancing glucose oxidation, modulating fatty acid metabolism, and optimizing ketone body utilization-show promise in restoring metabolic homeostasis and improving cardiac outcomes. This review explores the key molecular mechanisms driving metabolic remodeling in diabetic hearts and advanced methodology, highlighting the latest therapeutic strategies to mitigate the progression of DHF. Understanding these emerging pathways offers new opportunities to develop targeted therapies that address the root metabolic causes of heart failure in diabetes.

Risk of Infection in Older Adults With Type 2 Diabetes With Relaxed Glycemic Control.

To compare the risk of hospitalization for infection among patients who achieve intensive versus relaxed glycemic control. This retrospective cohort study included adults age ≥65 years with type 2 diabetes from an integrated health care delivery system. Negative binomial models were used to estimate incidence rates and relative risk (RR) of hospitalization for infections (respiratory; genitourinary; skin, soft tissue, and bone; and sepsis), comparing two levels of relaxed (hemoglobin A1c [HbA1c] 7% to <8% and 8% to <9%) with intensive (HbA1c 6% to <7%) glycemic control from 1 January 2019 to 1 March 2020. Among 103,242 older patients (48.5% with HbA1c 6% to <7%, 35.3% with HbA1c 7% to <8%, and 16.1% with HbA1c 8% to <9%), the rate of hospitalization for infections was 51.3 per 1,000 person-years. Compared with HbA1c 6% to <7%, unadjusted risk of hospitalization for infections was significantly elevated among patients with HbA1c 8% to <9% (RR 1.25; 95% CI 1.13, 1.39) but not among patients with HbA1c 7% to <8% (RR 0.99; 95% CI 0.91, 1.08), and the difference became nonsignificant after adjustment. Across categories of infections, the adjusted RR of hospitalization was significantly higher among patients with HbA1c 8% to <9% only for skin, soft tissue, and bone infection (RR 1.33; 95% CI 1.05, 1.69). Older patients with type 2 diabetes who achieve relaxed glycemic control levels endorsed by clinical guidelines are not at significantly increased risk of hospitalization for most infections, but HbA1c 8% to <9% is associated with an increased risk of hospitalization for skin, soft tissue, and bone infections.

When does metabolic memory start? Insights from the AMD Annals Initiative on stringent HbA1c targets.

Early, intensive glycemic control in T2D patients is associated with long-term benefits on cardiovascular disease (CVD) development. Evidence on benefits of achieving HbA1c targets close to normal values is scant. Subjects with newly-diagnosed T2D, without CVD at baseline, were identified in an Italian clinical registry (N=251,339). We adopted three definitions of early exposure periods (0-1, 0-2 and 0-3 years). Mean HbA1c was categorized into HbA1c < 5.7%, 5.7-6.4%, 6.5-7.0%, 7.1-8.0%, and >8.0%. The outcome was the incidence of major cardiovascular events. After a mean follow-up of 4.6±2.9 years, at multivariate Cox regression analysis, compared with mean HbA1c <5.7% during the first year after diagnosis, the increase in the risk of CVD was 24%, 42%, 49% and 56% for patients with HbA1c of 5.7%-6.4%, 6.5%-7.0%, 7.1%-8.0%, and >8.0%, respectively. The same trend was documented in all exposure periods. In conclusion, our data support that an early achievement of stringent targets of HbA1c <5.7% is worthy for CVD prevention.

Younger-onset compared with later-onset type 2 diabetes: an analysis of the UK Prospective Diabetes Study (UKPDS) with up to 30 years of follow-up (UKPDS 92).

Younger-onset type 2 diabetes is associated with accelerated complications. We assessed whether complications and mortality rates differed for younger age compared with older age at diagnosis over 30 years of follow-up. In this study, we used data from the UKPDS, collected between 1977 and 2007, of participants aged 25-65 years with newly diagnosed type 2 diabetes with younger-onset (younger than 40 years) or later-onset (40 years or older), and without diabetes autoantibodies. We analysed standardised mortality ratios (SMR) using UK general population data, and incidence rates of prespecified outcomes by 10-year age intervals at diagnosis. Of 4550 participants testing negative to all measured autoantibodies, 429 (9·4%) had younger-onset type 2 diabetes. 2704 (59·4%) were male, and mean HbA1c was 76 mmol/mol (SD 24·6). The median follow-up was 17·5 years (IQR 12·7-20·8). SMR for younger-onset type 2 diabetes was higher (3·72 [95% CI 2·98-4·64]) compared with later-onset type 2 diabetes (1·54 [1·47-1·61]). The incidence rate was higher for all outcomes in later-onset type 2 diabetes, except for microvascular disease (younger-onset 14·5 (11·9-17·7) vs later-onset 12·1 (11·3-13·0) per 1000 person-years). However, at any given age, the 5-year incidence of any diabetes-related endpoint, all-cause mortality, microvascular disease, and myocardial infarction was higher with younger age at diagnosis. Annual mean HbA1c was higher in the first 20 years in younger-onset compared with later-onset type 2 diabetes. Among participants randomised to intensive versus conventional glycaemic control, we observed no interactions by subgroup of younger-onset versus later-onset type 2 diabetes for any outcome. The risk of dying relative to the general population is even greater for people diagnosed with type 2 diabetes at younger ages. The increased risk of complications and poorer glycaemic control in younger-onset type 2 diabetes calls for the development of services to identify and manage these individuals. National Institute of Health and Care Research's Biomedical Research Centre.

Periodontal tissue susceptibility to glycaemic control in type 2 diabetes.

To assess the direct effect of intensive glycaemic control on periodontal tissues in patients with diabetes mellitus. Twenty-nine patients with type 2 diabetes were enrolled and hospitalized to receive a 2-week intensive glycaemic control regimen. We observed and analysed the systemic and oral disease indicators before and after treatment and clarified the indicators related to periodontal inflammation. A significant reduction in glycaemic and periodontal parameters, including glycated albumin levels and periodontal inflamed surface area (PISA), was observed after treatment. The changes in PISA per tooth, indicative of periodontal healing, exhibited a bimodal distribution; the patients were divided into two groups on this basis. Correlations were observed between the changes in PISA per tooth and fasting plasma glucose, acetoacetic acid, and beta-hydroxybutyrate levels in the PISA-improved group. Significantly lower levels of C-peptide, coefficient of variation of R-R interval, and ankle-brachial pressure index were observed before treatment in the PISA non-improved group. Glycaemic control treatment can effectively improve periodontitis in patients with type 2 diabetes, even in the absence of specific periodontal treatments. However, the periodontal responsiveness to glycaemic control treatment depends on the systemic condition of the patient.

Legacy effect of intensive glycaemic control in type 2 diabetes—the UKPDS

Legacy effect of intensive glycaemic control in type 2 diabetes—the UKPDS

Heterogeneous Effects of Intensive Glycemic and Blood Pressure on Cardiovascular Events Among Diabetes by Living Arrangements.

Although living alone versus with others is a key social element for cardiovascular prevention in diabetes, evidence is lacking about whether the benefit of intensive glycemic and blood pressure (BP) control differs by living arrangements. We thus aim to investigate heterogeneity in the joint effect of intensive glycemic and BP control on cardiovascular events by living arrangements among participants with diabetes. This study included 4731 participants with diabetes in the ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) trial. They were randomized into 4 study arms, each with glycated hemoglobin target (intensive, <6.0% versus standard, 7.0-7.9%) and systolic BP target (intensive, <120 mm Hg versus standard <140 mm Hg). Cox proportional hazard models were used to estimate the joint effect of intensive glycemic and BP control on the composite cardiovascular outcome according to living arrangements. At a mean follow-up of 4.7 years, the cardiovascular outcome was observed in 445 (9.4%) participants. Among participants living with others, intensive treatment for both glycemia and BP showed decreased risk of cardiovascular events compared with standard treatment (hazard ratio [HR], 0.68 [95% CI, 0.51-0.92]). However, this association was not found among participants living alone (HR, 0.96 [95% CI, 0.58-1.59]). P for interaction between intensive glycemic and BP control was 0.53 among participants living with others and 0.009 among those living alone (P value for 3-way interaction including living arrangements was 0.049). We found benefits of combining intensive glycemic and BP control for cardiovascular outcomes among participants living with others but not among those living alone. Our study highlights the critical role of living arrangements in intensive care among patients with diabetes.

Emerging Therapeutics Targeting Cellular Stress Pathways to Mitigate End-Organ Damage in Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by insulin deficiency and impaired glucose regulation. While daily insulin therapy is life-saving, many patients struggle to achieve optimal glycemic control, leading to microvascular complications affecting various organs, including the kidneys and the liver. This review aims to summarize the current state of knowledge regarding the pathogenesis of hepatic and renal complications in T1D, highlight recent advances in potential therapeutic targets, and provide evidence-based recommendations for mitigating end-organ damage. Chronic hyperglycemia drives diabetic complications through several interrelated mechanisms, including increased polyol pathway flux, advanced glycation end-product (AGE) formation, protein kinase C activation, and mitochondrial reactive oxygen species overproduction. In the liver, these processes contribute to non-alcoholic fatty liver disease, with up to 50% of T1D patients developing hepatic steatosis. Diabetic nephropathy, affecting 25%–40% of long-term T1D patients, is characterized by glomerular basement membrane thickening, mesangial expansion, and tubulointerstitial fibrosis. Recent innovations in T1D management include genomics and precision medicine approaches, gut microbiome modulation, nanomedicine, and artificial intelligence-driven glucose monitoring systems. Emerging immunotherapies aim to fundamentally modify the autoimmune response in T1D. Mitigating T1D complications requires intensive glycemic control, targeted pharmacotherapy, and lifestyle modifications. Emerging therapies and precision medicine approaches offer promising avenues. Ongoing research into molecular mechanisms remains crucial for developing novel interventions and improving long-term outcomes in T1D patients.

The Renoprotective Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i)-A Narrative Review.

Chronic kidney disease (CKD) is a noncommunicable condition that has become a major healthcare burden across the globe, often underdiagnosed and associated with low awareness. The main cause that leads to the development of renal impairment is diabetes mellitus and, in contrast to other chronic complications such as retinopathy or neuropathy, it has been suggested that intensive glycemic control is not sufficient in preventing the development of diabetic kidney disease. Nevertheless, a novel class of antidiabetic agents, the sodium-glucose cotransporter-2 inhibitors (SGLT2i), have shown multiple renoprotective properties that range from metabolic and hemodynamic to direct renal effects, with a major impact on reducing the risk of occurrence and progression of CKD. Thus, this review aims to summarize current knowledge regarding the renoprotective mechanisms of SGLT2i and to offer a new perspective on this innovative class of antihyperglycemic drugs with proven pleiotropic beneficial effects that, after decades of no significant progress in the prevention and in delaying the decline of renal function, start a new era in the management of patients with CKD.

174-OR: Genetic Variation in GLP-1R Modify the Risk of Hypoglycemia in Response to Intensive Glycemic Control in Adults with Type 2 Diabetes

174-OR: Genetic Variation in GLP-1R Modify the Risk of Hypoglycemia in Response to Intensive Glycemic Control in Adults with Type 2 Diabetes

Type 2 Diabetes.

Type 2 diabetes (T2D) is a prevalent disease that increases risk for vascular, renal, and neurologic complications. Prevention and treatment of T2D and its complications are paramount. Many advancements in T2D care have emerged over the past 5 years, including increased understanding of the importance of early intensive glycemic control, mental health, social determinants of health, healthy eating patterns, continuous glucose monitoring, and the benefits of some drugs for preventing cardiorenal disease. This review summarizes the evidence supporting T2D prevention and treatment, focusing on aspects that are commonly in the purview of primary care physicians.

The impact of intensive glycemic control on prognosis in diabetes patients with severe coronary artery disease across different age groups

The impact of intensive glycemic control on prognosis in diabetes patients with severe coronary artery disease across different age groups

Post-trial monitoring of a randomised controlled trial of intensive glycaemic control in type 2 diabetes extended from 10 years to 24 years (UKPDS 91)

The 20-year UK Prospective Diabetes Study showed major clinical benefits for people with newly diagnosed type 2 diabetes randomly allocated to intensive glycaemic control with sulfonylurea or insulin therapy or metformin therapy, compared with conventional glycaemic control. 10-year post-trial follow-up identified enduring and emerging glycaemic and metformin legacy treatment effects. We aimed to determine whether these effects would wane by extending follow-up for another 14 years. 5102 patients enrolled between 1977 and 1991, of whom 4209 (82·5%) participants were originally randomly allocated to receive either intensive glycaemic control (sulfonylurea or insulin, or if overweight, metformin) or conventional glycaemic control (primarily diet). At the end of the 20-year interventional trial, 3277 surviving participants entered a 10-year post-trial monitoring period, which ran until Sept 30, 2007. Eligible participants for this study were all surviving participants at the end of the 10-year post-trial monitoring period. An extended follow-up of these participants was done by linking them to their routinely collected National Health Service (NHS) data for another 14 years. Clinical outcomes were derived from records of deaths, hospital admissions, outpatient visits, and accident and emergency unit attendances. We examined seven prespecified aggregate clinical outcomes (ie, any diabetes-related endpoint, diabetes-related death, death from any cause, myocardial infarction, stroke, peripheral vascular disease, and microvascular disease) by the randomised glycaemic control strategy on an intention-to-treat basis using Kaplan-Meier time-to-event and log-rank analyses. This study is registered with the ISRCTN registry, number ISRCTN75451837. Between Oct 1, 2007, and Sept 30, 2021, 1489 (97·6%) of 1525 participants could be linked to routinely collected NHS administrative data. Their mean age at baseline was 50·2 years (SD 8·0), and 41·3% were female. The mean age of those still alive as of Sept 30, 2021, was 79·9 years (SD 8·0). Individual follow-up from baseline ranged from 0 to 42 years, median 17·5 years (IQR 12·3-26·8). Overall follow-up increased by 21%, from 66 972 to 80 724 person-years. For up to 24 years after trial end, the glycaemic and metformin legacy effects showed no sign of waning. Early intensive glycaemic control with sulfonylurea or insulin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 10% (95% CI 2-17; p=0·015) for death from any cause, 17% (6-26; p=0·002) for myocardial infarction, and 26% (14-36; p<0·0001) for microvascular disease. Corresponding absolute risk reductions were 2·7%, 3·3%, and 3·5%, respectively. Early intensive glycaemic control with metformin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 20% (95% CI 5-32; p=0·010) for death from any cause and 31% (12-46; p=0·003) for myocardial infarction. Corresponding absolute risk reductions were 4·9% and 6·2%, respectively. No significant risk reductions during or after the trial for stroke or peripheral vascular disease were observed for both intensive glycaemic control groups, and no significant risk reduction for microvascular disease was observed for metformin therapy. Early intensive glycaemic control with sulfonylurea or insulin, or with metformin, compared with conventional glycaemic control, appears to confer a near-lifelong reduced risk of death and myocardial infarction. Achieving near normoglycaemia immediately following diagnosis might be essential to minimise the lifetime risk of diabetes-related complications to the greatest extent possible. University of Oxford Nuffield Department of Population Health Pump Priming.

Haptoglobin phenotype and intensive glycemic control for coronary artery disease risk reduction in people with type two diabetes: The Veterans Affairs Diabetes Trial

BackgroundIntensive glycemic control reduced the risk of coronary artery disease (CAD) events among White ACCORD study participants with the haptoglobin (Hp)2-2 phenotype, and not among participants without the Hp2-2 phenotype. It is unknown whether these results persist in a population with more severe diabetes. MethodsHaptoglobin phenotype was measured in 1746 (97 %) samples from the Veterans Affairs Diabetes Trial (VADT) randomized controlled trial. Multivariable-adjusted Cox regression models assessed the effect of intensive therapy on CAD risk among participants with and without the Hp2-2 phenotype separately and when stratified within pre-specified race/ethnicity-based subgroups. Time-varying (achieved) HbA1c data (<7.0 % or ≥8.0 % compared to 7.0–7.9, updated every 3 months) were also analyzed in relation to CAD risk within each phenotype. Results567 (32.5 %) participants had the Hp2-2 phenotype. Compared to standard therapy, intensive glycemic control was not associated with risk of CAD among participants with the non-Hp2-2 or the Hp2-2 phenotype or for any race/ethnicity-based group. Compared to HbA1c of 7.0–7.9 %, having HbA1c <7.0 % was not associated with CAD risk for either phenotype or among any race/ethnicity-based group. Having HbA1c ≥8.0 % was associated with an increased risk of CAD among Hispanic participants without the Hp2-2 phenotype (HR= 3.61, 95 % CI: 1.54–8.41, p-interaction=0.53). ConclusionThe effect of intensive glycemic therapy on CAD events was not dependent on Hp phenotype in the VADT study of veterans with severe diabetes who may represent a population where Hp phenotype information would not be useful for personalizing diabetes management. However, further research is needed to determine if these results are conclusive.

A GENETIC RISK SCORE OF EARLY-ONSET TYPE 2 DIABETES PREDICTS EARLY DEATH AND BENEFITS OF INTENSIVE GLYCEMIC CONTROL IN ADVANCE TRIAL

Objective: Context: Early-onset type 2 diabetes (T2D) increases rapidly worldwide, alongside obesity, and carries an excess risk of microvascular complications and early death compared to when it started later in life. We have developed a multi-polygenic risk score (multiPRS) that predicts the risk of major micro- and macrovascular complications of T2D. We showed that individuals with high multiPRS scores for macrovascular events benefited more from tight blood pressure control while those with high multiPRS scores for microvascular events benefited from glycemic control. Early-onset T2D is genetically determined. Objective: To develop a genetic risk score that identifies individuals who are more susceptible to early-onset T2D and assess whether they could benefit from tight glycemic control. Design and method: We developed a genetic risk score (GRS) composed of 22 SNPs associated with early-onset T2D. We analysed 545 participants of European descent of ADVANCE with the highest GRS values and 526 subjects with the lowest GRS for early-onset T2D. Results: The median age at diagnosis of T2D was 54.9 in the high GRS and 64.6 in the low GRS group. Compared to participants with low GRS, those with high GRS were slightly heavier with a BMI of 30.8 (5.1 SD) vs 29.6 (4.9 SD), p = 7.2 x 10-5, they received more antidiabetic drugs (n= 1.5 (0.8) vs 1.2 (0.8), p = 1.2 x 10-7) and they died 5.7 years earlier (70.8 vs 76.5 years old p = 9 x 10-7). Contrary to the low GRS group, intensive glycemic control reduced mortality significantly in the high GRS group. Combination of intensive blood pressure and glycemia control led to a relative risk reduction of 52% (p = 0.028) and a number needed to treat of only 10 in the high GRS group while no significant effects were observed in the low GRS group. Conclusions: This novel GRS can identify individuals at risk of early-onset T2D who can benefit from tight glycemic control while its combination with blood pressure control is the most effective in reducing cardiorenal outcomes and death rate.

Glycemic control and clinical outcomes in diabetic patients with heart failure and reduced ejection fraction: insight from ventricular remodeling using cardiac MRI

BackgroundGlycemic control, as measured by glycosylated hemoglobin (HbA1c), is an important biomarker to evaluate diabetes severity and is believed to be associated with heart failure development. Type 2 diabetes mellitus (T2DM) and heart failure with reduced ejection fraction (HFrEF) commonly coexist, and the combination of these two diseases indicates a considerably poorer outcome than either disease alone. Therefore, glycemic control should be carefully managed. The present study aimed to explore the association between glycemic control and clinical outcomes, and to determine the optimal glycemic target in this specific population.MethodsA total of 262 patients who underwent cardiac MRI were included and were split by HbA1c levels [HbA1c < 6.5% (intensive control), HbA1c 6.5-7.5% (modest control), and HbA1c > 7.5% (poor control)]. The biventricular volume and function, as well as left ventricular (LV) systolic strains in patients in different HbA1c categories, were measured and compared. The primary and secondary outcomes were recorded. The association of different HbA1c levels with adverse outcomes was assessed.ResultsDespite similar biventricular ejection fractions, both patients with intensive and poor glycemic control exhibited prominent deterioration of LV systolic strain in the longitudinal component (P = 0.004). After a median follow-up of 35.0 months, 55 patients (21.0%) experienced at least one confirmed endpoint event. Cox multivariable analysis indicated that both patients in the lowest and highest HbA1c categories exhibited a more than 2-fold increase in the risk for primary outcomes [HbA1c < 6.5%: hazard ratio (HR) = 2.42, 95% confidence interval (CI) = 1.07–5.45; P = 0.033; HbA1c > 7.5%: HR = 2.24, 95% CI = 1.01–4.99; P = 0.038] and secondary outcomes (HbA1c < 6.5%: HR = 2.84, 95% CI = 1.16–6.96; P = 0.022; HbA1c > 7.5%: HR = 2.65, 95% CI = 1.08–6.50; P = 0.038) compared with those in the middle HbA1c category.ConclusionsWe showed a U-shaped association of glycemic control with clinical outcomes in patients with T2DM and HFrEF, with the lowest risk of adverse outcomes among patients with modest glycemic control. HbA1c between 6.5% and 7.5% may be served as the optimal hypoglycemic target in this specific population.