Standard Glucose Control Research Articles

Renal function as an effect modifier of intensive glucose control in delaying cognitive function decline among individuals with type 2 diabetes: A revisit to the ACCORD MIND trial.

Dysglycaemia accelerates cognitive decline. Intensive glucose control may help delay or prevent cognitive function decline (CFD). We aimed to determine how patient characteristics influence the effect of intensive glucose control [glycated haemoglobin (HbA1c) <6.0%] on delaying CFD in people with type 2 diabetes. In this post-hoc analysis of 2977 type 2 diabetes participants from the ACCORD MIND trial, we applied the causal forest and causal tree algorithms to identify the effect modifier of intensive glucose control in delaying CFD from 68 variables (demographics, disease history, medications, vitals and baseline biomarkers). The exposure was intensive versus standard glucose control (HbA1c <6.0% vs. 7.0%-7.9%). The main outcome was cognitive function changes from baseline to the 40th month follow-up, which were evaluated using the digit symbol substitution test, Rey auditory verbal learning test, mini-mental state examination and Stroop test. We used Cohen's d, a measure of standardized difference, to quantify the effect size of intensive glucose control on delaying CFD. Among all the baseline characteristics, renal function was the most significant effect modifier. Participants with urinary albumin levels <0.4 mg/dl [absolute function change (AFC): 0.51 in mini-mental state examination, 95% confidence interval (CI): 0.04, 0.98, Cohen's d: 0.25] had slower CFD with intensive glucose control. Patients with preserved renal function (estimated glomerular filtration rate between 60 and 90 ml/min/1.73 m2) were associated with small benefits (AFC: 1.28 in Stroop, 95% CI: 0.28, 2.27, Cohen's d: 0.12) when undergoing intensive glucose control. Conversely, participants with an estimated glomerular filtration rate <60 ml/min/1.73 m2 (AFC: -0.57 in the Rey auditory verbal learning test, 95% CI: -1.09, -0.05, Cohen's d: -0.30) exhibited faster CFD when undergoing intensive glucose control. Participants who were <60 years old showed a significant benefit from intensive glucose control in delaying CFD (AFC: 1.08 in the digit symbol substitution test, 95% CI: 0.06, 2.10, Cohen's d: 0.13). All p < .05. Our findings linked renal function with the benefits of intensive glucose control in delaying CFD, informing personalized HbA1c goals for those with diabetes and at risk of CFD.

Some patients with type 2 diabetes may benefit from intensive glycaemic and blood pressure control: A post-hoc machine learning analysis of ACCORD trial data.

The action to control cardiovascular risk in diabetes (ACCORD) trial showed a neutral average treatment effect of intensive blood glucose and blood pressure (BP) controls in preventing major adverse cardiovascular events (MACE) in individuals with type 2 diabetes. Yet, treatment effects across patient subgroups have not been well understood. We aimed to identify patient subgroups that might benefit from intensive glucose or BP controls for preventing MACE. As a post-hoc analysis of the ACCORD trial, we included 10 251 individuals with type 2 diabetes. We applied causal forest and causal tree models to identify participant characteristics that modify the efficacy of intensive glucose or BP controls from 68 candidate variables (demographics, comorbidities, medications and biomarkers) at the baseline. The exposure was (a) intensive versus standard glucose control [glycated haemoglobin (HbA1c) <6.0% vs. 7.0%-7.9%], and (b) intensive versus standard BP control (systolic BP <120 vs. <140 mmHg). The primary outcome was MACE. Compared with standard glucose control, intensive one reduced MACE in those with baseline HbA1c <8.5% [relative risk (RR): 0.79, 95% confidence interval (CI): 0.67-0.93] and those with estimated glomerular filtration rate ≥106 ml/min/1.73 m2 (RR: 0.74, 95% CI: 0.55-0.99). Intensive BP control reduced MACE in those with normal high-density lipoprotein levels (women >55 mg/dl, men >45 mg/dl; RR: 0.51, 95% CI: 0.34-0.74). Risk reductions were not significant in other patient subgroups. Our findings suggest heterogeneous treatment effects of intensive glucose and BP control and could provide biomarkers for future clinical trials to identify more precise HbA1c and BP treatment goals for individualized medicine.

Short- and Long-Term Effects on Glucose Control of Nonadherence to Insulin Therapy in People With Type 2 Diabetes An In Silico Study.

Strict adherence to multiple daily insulin (MDI) therapy is a cornerstone for the achievement of good glucose control in people with advanced type 2 diabetes (T2D). Here, we aim to in silico assess glucose control in T2D subjects with poor adherence to MDI therapy. We tuned the Padova T2D Simulator, originally describing early-stage T2D physiology, around advanced T2D people. One hundred in silico advanced T2D subjects were generated and equipped with optimal MDI therapy: specifically, basal and bolus insulin amounts and injection times were individualized for each subject by applying titration algorithms that iteratively update insulin dose based on glucose deviation from its target. Then, the effect of nonadhering to MDI therapy was assessed using standard glucose control metrics calculated in two 6-month 3-meal/day in silico scenarios: in Scenario 1, subjects received the optimal basal and prandial insulin bolus at each meal; in Scenario 2, subjects received optimal basal insulin and randomly delayed or skipped the prandial insulin bolus in 3 lunches during working days and 1 dinner during weekends. A statistically significant degradation was found in all glucose control outcome metrics in Scenario 2 versus Scenario 1: e.g., percent time above 180 mg/dL increased by 22.2% and glucose management index by 0.2%. Impaired adherence to MDI therapy in T2D leads to glucose control deteriorations in both short and long terms. Interestingly, short-term hyperglycemia seems being contrasted by residual endogenous insulin secretion, which statistically increased by 3-fold after delayed/skipped insulin boluses compared with optimal ones.

Intensive glucose control and recurrent cardiovascular events: 14-year follow-up investigation of the ACCORDION study.

While cardiovascular disease in patients with type 2 diabetes commonly progresses with the occurrence of repeated events, most trials consider the effect of glucose-lowering strategies only on the first event. We examined the Action to Control Cardiovascular Risk in Diabetes trial and its observational follow-up study (ACCORDION) to investigate the effect of intensive glucose control on multiple events and further identify any subgroup effects. A recurrent events analysis, using a negative binomial regression model, was applied to estimate the treatment effect on different consecutive cardiovascular disease events, including non-fatal myocardial infarction, non-fatal stroke, hospitalisation from heart failure, and cardiovascular death. Interaction terms were used to identify potential effect modifiers. The robustness of the results was confirmed in sensitivity analyses using alternative models. The median duration of follow-up was 7.7years. Of the 5128 participants in the intensive and 5123 in the standard glucose control arm, respectively, 822 (16.0%) and 840 (16.4%) participants experienced a single event; 189 (3.7%) and 214 (4.2%) participants experienced two events; 52 (1.0%) and 40 (0.8%) experienced three events; and 1 (0.02%) and 1 (0.02%) experienced four events. There was no evidence of a treatment effect, with a rate difference of 0.0 (-0.3, 0.3) per 100 person-years comparing intensive versus standard intervention, although with non-significantly lower event rates in younger patients with HbA1c < 7% and higher event rates in older patients with HbA1c≥9%. Intensive glucose control may not affect cardiovascular disease progression except in select subgroups. Since time-to-first event analysis may miss beneficial or harmful effects of glucose control on the risk of cardiovascular disease, recurrent events analysis should be routinely analysed in cardiovascular outcome trials, particularly when investigating long-term treatment effects. NCT00000620, clinicaltrials.gov.

Effects of Intensive Blood Glucose Control on Surgical Site Infection for Liver Transplant Recipients: A Randomized Controlled Trial

The evidence supporting intensive blood glucose control to prevent surgical site infections (SSIs) among liver transplant recipients is insufficient. We aimed to assess the effects of postoperative intensive blood glucose control (IBGC) against standard blood glucose control (SBGC) on the incidence of SSIs among adult liver transplant recipients. We performed a randomized controlled trial (ClinicalTrials.gov identifier NCT03474666). The IBGC target was 80 to 130 mg/dL, and the SBGC target was below 180 mg/dL. Analyses were made on an intention-to-treat basis. Of the 41 recipients enrolled onto the trial, 20 were randomly allocated to the IBGC group and 21 to the SBGC group. There were no significant differences in SSIs among recipients allocated to either group (relative risk [RR], 0.78; 95% confidence interval [CI], 0.21-2.88; P=.69). Mean (SD) blood glucose levels were significantly lower in the IBGC group in the 24-hour period after surgery (145.0 [20.7] mg/dL and 230.2 [51.6] mg/dL; P=.001). While there were fewer episodes of hypoglycemia in the IBGC group, this was not statistically significant. There were no episodes of severe hypoglycemia in either group. Hyperglycemia and severe hyperglycemia were significantly more frequent in the SBGC group (RR, 0.70; 95% CI, 0.52-0.93; P=.001 and RR, 0.07; 95% CI, 0.01-0.48; P=.001, respectively). Length of hospital stay was significantly shorter for recipients in the IBGC group (13.1 [5.5] days vs 19.3 [12.1] days; P=.04). Although this small trial did not find intensive control reduced SSI, it was associated with lower blood glucose levels, fewer episodes of hyperglycemia and severe hyperglycemia, and shorter length of hospital stay.

Effects of glucose and blood pressure reduction on subclinical cardiac damage: Results from ADVANCE

ObjectiveObservational data suggest a potential for subclinical cardiac damage from intensive blood glucose or blood pressure (BP) control, particularly in adults with very low blood glucose and BP levels. However, this has not been tested in a randomized trial. MethodsThe Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Research Controlled Evaluation (ADVANCE) study was a factorial, randomized trial designed to test the effects of intensive blood glucose (hemoglobin A1c ≤6.5% versus usual care) and intensive BP (combination of perindopril-indapamide versus placebo) control on vascular events in adults with diabetes. Using mixed effects tobit models, we determined the effect of the randomized interventions on change in subclinical cardiac injury (high sensitivity cardiac troponin T [hs-cTnT]) and strain (N-terminal b-type pro natriuretic peptide [NT-proBNP]), 1 year after randomization. ResultsAmong the 682 participants, mean age was 66.1 (SD, 6.5) years; 40% were women. Mean baseline hemoglobin A1c was 7.4% (SD, 1.5) and systolic/diastolic BP was 147 (SD,21)/81 (SD,11) mmHg. After 1 year, intensive versus standard glucose control did not significantly change hs-cTnT (1.5%; 95%CI:-4.9,8.2) or NT-proBNP (−10.3%; 95%CI: −20.2%,0.9%). Intensive versus standard BP control also did not affect hs-cTnT (−2.9%; 95%CI: −8.9,3.6), but did significantly lower NT-proBNP by 21.6% (95%CI:-30.2%,-11.9%). Changes in systolic BP at 1 year (versus baseline) were strongly associated with NT-proBNP (P = 0.004), but not hs-cTnT (P = 0.95). ConclusionsIn adults with diabetes, intensive BP control reduced NT-proBNP without increasing hs-cTnT, supporting the benefits and safety of intensive BP control in adults with diabetes.This trial is registered at clinicaltrials.gov, number: NCT00145925.

LOWER EXTREMITY PHERIPHERALARTERIAL DISEASE - AN UPDATE

Lower-extremity arterial disease (LEAD) is a major endemic disease with an alarming increased prevalence worldwide. It is a common and severe condition with excess risk of major cardiovascular events and death. It also leads to a high rate of lower-limb adverse events and non-traumatic amputation. The American Diabetes Association recommends a widespread medical history and clinical examination to screen for LEAD. The ankle brachial index (ABI) is the first non-invasive tool recommended to diagnose LEAD although its variable performance in patients with diabetes. The performance of ABI is particularly affected by the presence of peripheral neuropathy, medial arterial calcification, and incompressible arteries. There is no strong evidence today to support an alternative test for LEAD diagnosis in these conditions. The management of LEAD requires a strict control of cardiovascular risk factors including diabetes, hypertension, and dyslipidaemia. The benefit of intensive versus standard glucose control on the risk of LEAD has not been clearly established. Antihypertensive, lipid-lowering, and antiplatelet agents are obviously worthful to reduce major cardiovascular adverse events, but few randomised controlled trials (RCTs) have evaluated the benefits of these treatments in terms of LEAD and its related adverse events. Smoking cessation, physical activity, supervised walking rehabilitation and healthy diet are also crucial in LEAD management. Several advances have been achieved in endovascular and surgical revascularization procedures, with obvious improvement in LEAD management. The revascularization strategy should take into account several factors including anatomical localizations of lesions, medical history of each patient and operator experience. Further studies, especially RCTs, are needed to evaluate the interest of different therapeutic strategies on the occurrence and progression of LEAD and its related adverse events in patients with diabetes.

Evaluation of Serum Glucose and Kidney Disease Progression Among Patients With Diabetes

The appropriate target of glycemic control in diabetic kidney disease is unclear. To investigate optimal on-treatment glycemic levels associated with slowing of diabetic kidney disease progression. This retrospective cohort study was conducted using nationwide Korean cohorts from the National Health Information Database from 2005 to 2019. Included individuals were adults with diabetes using antihyperglycemic agents with and without chronic kidney disease (CKD) identified from participants aged 40 to 74 years in a nationwide health screening survey conducted from 2009 to 2010. Data were analyzed from October 2020 through March 2021. On-treatment fasting blood glucose (FBG) level. The primary outcome was a composite of doubling of serum creatinine, end-stage kidney disease, or death from CKD. Among 183 049 adults with diabetes using antihyperglycemic agents (mean [SD] age, 61.7 [8.4] years; 99 110 [54.1%] men), there were 131 401 individuals with dipstick albuminuria or an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2 (mean [SD] age, 62.4 [8.3] years; 71 280 [54.2%] men) and 51 648 individuals with no CKD (mean [SD] age, 59.6 [8.4] years; 27 830 [53.9%] men). During 9 years of follow-up, the primary outcome occurred among 13 802 individuals with CKD (10.5%) and 1421 individuals with no CKD (2.8%). On-treatment FBG level had a J-shaped hazard ratio (HR) curve for the primary outcome. Among patients with albuminuria, FBG levels of 126 mg/dL to less than 140 mg/dL (HR, 0.87; 95% CI, 0.81-0.94) and 140 mg/dL to less than 160 mg/dL (HR, 0.90; 95% CI, 0.84-0.96) were associated with decreased risk and levels of 160 mg/dL to less than 180 mg/dL were associated with increased risk (HR, 1.10; 95% CI, 1.03-1.18) compared with FBG levels of 110 mg/dL to less than 126 mg/dL. Among patients with decreased eGFR, FBG levels of 80 mg/dL to less than 100 mg/dL (HR, 1.30; 95% CI, 1.20-1.42) and levels of 160 mg/dL to less than 180 mg/dL (HR, 1.13; 95% CI, 1.04-1.23) were associated with increased risk of the primary outcome compared with FBG levels of 110 mg/dL to less than 126 mg/dL. Among patients with no CKD, FBG levels of 80 mg/dL to less than 100 mg/dL (HR, 1.29; 95% CI, 1.01-1.65) and levels of 126 mg/dL to less than 140 mg/dL (HR, 1.23; 95% CI, 1.03-1.47) were associated with increased risk compared with FBG levels of 110 mg/dL to less than 126 mg/dL. Among patients with no albuminuria at baseline, FBG levels of 140 mg/dL to less than 160 mg/dL (HR, 1.14; 95% CI, 1.09-1.20) were associated with increased risk of new-onset albuminuria, while levels of 100 mg/dL to less than 110 mg/dL were not associated with increased risk compared with FBG levels of 110 mg/dL to less than 126 mg/dL. For all-cause mortality, while FBG levels of 160 mg/dL to less than 180 mg/dL (HR, 1.20; 95% CI, 1.12-1.28) were associated with increased risk among patients with albuminuria, FBG levels of 140 mg/dL to less than 160 mg/dL were associated with increased risk among patients with decreased eGFR (HR, 1.10; 95% CI, 1.04-1.16) and those with no CKD (HR, 1.10; 95% CI, 1.00-1.21) compared with levels of 110 mg/dL to less than 126 mg/dL. These findings suggest that intensive vs standard glucose control may not be associated with increased protection for the progression of established diabetic kidney disease and that timely control is important for prevention. However, careful glycemic control would still be associated with improved overall outcomes among patients with CKD, particularly those with no albuminuria.

Black Patients with Ischemic Stroke and Hyperglycemia have Worse outcome than Whites if given Intensive Glucose Control

BackgroundHyperglycemia is common after acute ischemic stroke and is associated with worse outcome, but intensive glucose control has not improved outcome. There is also a racial disparity in outcome after stroke, with Black patients more likely to have functional impairment than whites. We aimed to evaluate if there were racial differences in outcomes in acute ischemic stroke patients treated with intensive glucose control. MethodsWe performed a post-hoc analysis of the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial to determine if Black patients had worse functional outcome than whites and if standard versus intensive glucose control modified that association. We included non-Hispanic white and Black patients. The primary outcome was excellent functional outcome (90-day modified Rankin Score of 0-1). To account for patient clustering by study site, we fit mixed-effects logistic regression models to our outcome and tested the interaction of treatment and race. ResultsWe included 895 patients, of which 304 (34%) were Black and 591 (66%) were white. The rate of excellent outcome was 31.6% in Black patients versus 41.0% in white patients (p=0.006). After adjusting for potential confounders, the odds ratio for excellent outcome in Black patients was 0.54 (95% CI 0.38-0.77). The interaction term between treatment and race was significant (p=0.067). In the intensive treatment arm, Black patients had a predicted probability of excellent outcome of 26.4% (20.1-32.8) versus 42.7% (37.6-47.9) for white patients (p<0.001), while in the standard treatment arm the difference was not significant. ConclusionsBlack patients with acute ischemic stroke and hyperglycemia had worse functional outcome at 90 days than white patients, particularly if given intensive glucose control. These findings are from a post-hoc analysis and may be confounded, thus warrant additional study.

Effect of Intensive Glucose Control on Outcomes of Hyperglycemic Stroke Patients Receiving Mechanical Thrombectomy: Secondary Analysis of the SHINE Trial.

Hyperglycemia is common among patients presenting with acute ischemic stroke (AIS) and is associated with poor clinical outcomes. We studied the effects of intensive blood glucose control among AIS patients presenting with hyperglycemia treated with mechanical thrombectomy (MT). We analyzed publicly available data from the Stroke Hyperglycemia Insulin Network Effort trial. In this nonpreplanned secondary analysis, we compared hyperglycemic AIS patients treated with MT who received intensive blood glucose control (80 to 130 mg/dL) with those who received standard blood glucose control (80 to 179 mg/dL). Outcomes included rates of favorable 90-day outcome (modified Rankin Scale score ≤2) and death. This analysis included 146 patients (74 in the intensive treatment group and 72 in the standard treatment group). Intensive blood glucose was not associated with higher rates of 90-day favorable outcomes (intensive 31.1% vs. standard 30.6%, P =1.0; odds ratio 1.025, 95% confidence interval 0.51 to 2.07) or a decrease in rates of death (intensive 20.3% vs. standard 22.2%, P =0.84; odds ratio 0.98, 95% confidence interval 0.40 to 1.97). Intensive blood glucose control among AIS patients presenting with hyperglycemia and treated with MT was not associated with lower rates of death or higher rates of long-term favorable outcomes when compared with standard treatment.

Coagulation markers and functional outcome in acute ischemic stroke: Impact of intensive versus standard hyperglycemia control

ObjectiveAlterations in coagulation could mediate functional outcome in patients with hyperglycemia after acute ischemic stroke (AIS). We prospectively studied the effects of intensive versus standard glucose control on coagulation markers and their relationships to functional outcomes in patients with AIS. ApproachThe Insights on Selected Procoagulation Markers and Outcomes in Stroke Trial measured the coagulation biomarkers whole blood tissue factor procoagulant activity (TFPCA); plasma factors VII (FVII), VIIa (FVIIa), and VIII (FVIII); thrombin‐antithrombin (TAT) complex; D‐dimer; tissue factor pathway inhibitor, and plasminogen activator inhibitor‐1 (PAI‐1) antigen in patients enrolled in the Stroke Hyperglycemia Insulin Network Effort trial of intensive versus standard glucose control on functional outcome at 3 months after AIS. Changes in biomarkers over time (from baseline ≈12 hours after stroke onset) to 48 hours, and changes in biomarkers between treatment groups, functional outcomes, and their interaction were analyzed by two‐way analysis of variance. ResultsA total of 125 patients were included (57 in the intensive treatment group and 68 in the standard treatment group). The overall mean age was 66 years; 42% were women. Changes from baseline to 48 hours in coagulation markers were significantly different between treatment groups for TFPCA (P= 0.02) and PAI‐1 (P= .04) and FVIIa (P= .04). Increases in FVIIa and decreases in FVIII were associated with favorable functional outcomes (P= .04 and .04, respectively). In the intensive treatment group, reductions in TFPCA and FVIII and increases in FVIIa were greater in patients with favorable than unfavorable outcomes (P= .02, 0.002, 0.03, respectively). In the standard treatment group, changes in FVII were different by functional outcome (P= .006). ConclusionsIntensive glucose control induced greater alterations in coagulation biomarkers than standard treatment, and these were associated with a favorable functional outcome at 3 months after AIS.

Cost-Effectiveness of Gliclazide-Based Intensive Glucose Control vs. Standard Glucose Control in Type 2 Diabetes Mellitus. An Economic Analysis of the ADVANCE Trial in Vietnam.

Introduction: ADVANCE was a large, multinational clinical study conducted over 5 years in type 2 diabetes mellitus (T2DM). In all, 11,140 patients were randomly assigned to receive gliclazide-based intensive glucose control (IGC) or standard glucose control (SGC). IGC was shown to significantly reduce the incidence of major macrovascular and microvascular events (composite endpoint) or major microvascular events compared with SGC, primarily by enhancing renal protection. We assessed the cost-effectiveness of IGC vs. SGC, based on the ADVANCE results, from a Vietnamese healthcare payer perspective.Materials and Methods: A partitioned survival times model across five health states (no complications, myocardial infarction, stroke, end-stage renal disease [ESRD], and diabetes-related eye-disease) was designed. Time-to-event curves were informed by the cumulative incidence of events and corresponding hazard ratios from the ADVANCE study. Health outcomes were expressed in terms of ESRD avoided and quality-adjusted life years (QALYs). Costs (in US $) comprised treatment costs and health state costs. Utility weights and costs were documented from literature reporting Vietnamese estimates. For sensitivity analyses, all parameters were individually varied within their 95% confidence interval bounds (when available) or within a ±30% range.Results: Over a 5-year horizon, IGC avoided 6.5 additional ESRD events per 1,000 patients treated compared with SGC (IGC, 3.5 events vs. SGC, 10.0 events) and provided 0.016 additional QALYs (IGC, 3.570 QALYs vs. SGC, 3.555 QALYs). Total costs were similar for the two strategies (IGC, $3,786 vs. SGC, $3,757). Although the total drug costs were markedly higher for IGC compared with SGC ($1,703 vs. $873), this was largely offset by the savings from better renal protection with IGC (IGC, $577 vs. SGC, $1,508). The incremental cost-effectiveness ratio (ICER) of IGC vs. SGC was $1,878/QALY gained, far below the threshold recommended by the World Health Organization (i.e., 1–3 × gross domestic product per inhabitant ≈$7,500 in Vietnam). The ICER of IGC vs. SGC per ESRD event avoided was $4,559/event. The findings were robust to sensitivity analysis.Conclusion: In Vietnam, gliclazide-based IGC was shown to be cost-effective compared with SGC from a healthcare payer perspective, as defined in the ADVANCE study.

Review of the veteran affairs diabetes trial: Lessons learned.

Despite robust evidence linking long-term hyperglycemia with cardiovascular complications, several large randomized trials found only modest benefits from intensive compared to standard glucose control. Of these trials, the Veteran Affairs Diabetes Trial (VADT), offers a unique long-term perspective in that there were analyses of outcomes at the end of the intervention trial, 5-years post-trial, and after 10-years post-trial. From the VADT and other large trials, we draw several valuable lessons that are relevant to the care of patients with type 2 diabetes. Intensive glucose control reduces development of nephropathy and retinopathy but not neuropathy, though evaluations of neuropathy are less consistent and conclusions regarding outcomes less reliable. While the VADT did not demonstrate reduction in cardiovascular outcomes at completion of the glucose lowering intervention, it did demonstrate a 17% reduction 5-years post-trial, which waned by 10-years post-trial observation. Of interest, the 5-year post trial period included 3 additional years of HbA1c separation between treatment groups which suggests that longer-term glucose control may be needed before benefits are seen. Other factors including hypoglycemia and increased glucose variation are also associated with cardiovascular events and are more prevalent during intensive glucose control, potentially lessening the benefit of lowering average glucose levels. Finally, intensive glucose control requires substantial effort from both the patient and clinician perspective. All of these factors must be kept in mind when considering the benefits of aggressive glucose control for each patient.

Intensive vs. standard treatment of hyperglycemia and functional outcome in patients with acute ischemic stroke: The SHINE randomized clinical trial

Emergency Medicine Physicians are often the first to evaluate and treat patients with acute ischemic strokes. Clinical outcomes decline when there is associated hyperglycemia and thus hyperglycemic control is crucial. There are few studies however, that demonstrate a favorable association between aggressive blood glucose control and clinical outcome compared to standard glucose control.

Renal protection: What have we learnt from ADVANCE about kidney disease in type 2 diabetes?

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial was a landmark randomized controlled clinical trial in 11 140 type 2 diabetic patients from 215 centers in 20 countries with a two-by-two factorial design. In the blood pressure-lowering arm, patients were treated using a fixed combination of the ACE-inhibitor, perindopril, and the thiazide-like diuretic, indapamide, or placebo, whereas in the glucose-lowering arm, the intervention compared the sulphonylurea gliclazide plus other glucose-lowering drugs, targeting a glycated hemoglobin value of 6.5% or less, with standard glucose control. Primary end-points were major macro- and microvascular events in both arms. This review gives an overview of the results of the primary randomized trial, results from observational follow-up studies, and results of several biomarker studies and discusses the perspectives of these data in the context of recent major outcome trials for current medical treatment.

Observational analyses from ADVANCE and ADVANCE-ON.

To explain, and document, the epidemiological work associated with the action in diabetes and vascular disease: preterax and diamicron-modified release controlled evaluation (ADVANCE) clinical trial. ADVANCE was designed as a randomized controlled multicentre factorial trial in high-risk patients with diabetes. The two interventions were blood pressure lowering medications versus placebo, and intensive glucose control versus standard glucose control. Following termination of the trial, an observational study of surviving participants, able to join, was mounted: the ADVANCE - observational study (ADVANCE-ON). Other epidemiological analyses that were undertaken treated the trial as a cohort study, including using biomarkers from the blood samples taken from ADVANCE subjects as risk exposures. More than 50 publications have reported epidemiological results from ADVANCE. The main results from ADVANCE-ON suggested attenuated benefits of ADVANCE's blood pressure lowering treatment on all-cause and cardiovascular death, but no such long-term benefits for intensive glucose control, although this did give persistent benefit for end-stage renal disease. The other epidemiological studies found, amongst other things, strong effects of NT-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T on macrovascular events, microvascular events and all-cause death. Embedding post-randomization and epidemiological analyses into clinical trials is worthwhile and can be highly productive in advancing scientific knowledge.

Intensive Versus Standard Glucose Control in Patients with Ischemic Stroke: A Meta-Analysis of Randomized Controlled Trials

Hyperglycemia is common in patients with ischemic stroke (IS) and has been proven to be associated with worse clinical outcomes. However, it is controversial whether intensive glucose control (IGC) is superior to standard glucose control (SGC). Therefore, we carried out this meta-analysis based on randomized controlled trials (RCTs). We systematically searched databases for RCTs that evaluated the efficacy of IGC versus SGC in patients with IS. The retrieval time was limited from the establishment of the database to October 2019. The retrieval databases included PubMed, Medline, Embase, OVID, Web of Science, Google Scholar, and a Chinese literature database. Two researchers independently screened and evaluated the quality of literature. We used Stata 11.0 software for data analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to compare the results. Finally, 7 RCTs including 1691 participants were included in this study. Among the patients, 857 patients were in the IGC group and 834 were in the SGC group. Our results show that IGC significantly increased the risk of hypoglycemia compared with SGC (OR, 4.76; 95% CI, 1.17-19.45). No significant differences were observed in modified Rankin scale score ≤2 (OR, 0.97; 95% CI, 0.75-1.25), National Institutes of Health Stroke Scale score ≤2(OR, 1.48; 95% CI, 0.54-4.06), and death (OR, 0.74; 95% CI, 0.53-1.02) between the 2 groups within 3 months. Our results suggest there is no evidence that IGC is superior to SGC in patients with IS, but IGC increases the risk of hypoglycemia.

Full title: High glucose protects mesenchymal stem cells from metformin-induced apoptosis through the AMPK-mediated mTOR pathway

Micro- and macro-vascular events are directly associated with hyperglycemia in patients with type 2 diabetes mellitus (T2DM), but whether intensive glucose control decreases the risk of diabetic cardiovascular complications remains uncertain. Many studies have confirmed that impaired quality and quantity of mesenchymal stem cells (MSCs) plays a pathogenic role in diabetes. Our previous study found that the abundance of circulating MSCs was significantly decreased in patients with T2DM, which was correlated with the progression of diabetic complications. In addition, metformin-induced MSC apoptosis is one of the reasons for the decreased quantity of endogenous or exogenous MSCs during intensive glucose control. However, the role of glucose in metformin-induced MSC apoptosis during intensive glucose control in T2DM remains unknown. In this study, we found that metformin induces MSC apoptosis during intensive glucose control, while high glucose (standard glucose control) could significantly reverse its adverse effect in an AMPK-mTOR pathway dependent manner. Thus, our results indicate that the poorer clinical benefit of the intensive glucose control strategy may be related to an adverse effect due to metformin-induced MSC apoptosis during intensive glucose control therapy in patients with T2DM.

Long-term follow-up of intensive glycaemic control in type 2 diabetes

In a 15-year follow-up of the VADT study, no differences in major cardiovascular outcomes were found among individuals with type 2 diabetes mellitus who underwent either intensive or standard glucose control. These results indicate that intensification of glycaemic control might not be expected to mitigate the risk of cardiovascular events.

Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke

Hyperglycemia during acute ischemic stroke is common and is associated with worse outcomes. The efficacy of intensive treatment of hyperglycemia in this setting remains unknown. To determine the efficacy of intensive treatment of hyperglycemia during acute ischemic stroke. The Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial included adult patients with hyperglycemia (glucose concentration of >110 mg/dL if had diabetes or ≥150 mg/dL if did not have diabetes) and acute ischemic stroke who were enrolled within 12 hours from stroke onset at 63 US sites between April 2012 and August 2018; follow-up ended in November 2018. The trial included 1151 patients who met eligibility criteria. Patients were randomized to receive continuous intravenous insulin using a computerized decision support tool (target blood glucose concentration of 80-130 mg/dL [4.4-7.2 mmol/L]; intensive treatment group: n = 581) or insulin on a sliding scale that was administered subcutaneously (target blood glucose concentration of 80-179 mg/dL [4.4-9.9 mmol/L]; standard treatment group: n = 570) for up to 72 hours. The primary efficacy outcome was the proportion of patients with a favorable outcome based on the 90-day modified Rankin Scale score (a global stroke disability scale ranging from 0 [no symptoms or completely recovered] to 6 [death]) that was adjusted for baseline stroke severity. Among 1151 patients who were randomized (mean age, 66 years [SD, 13.1 years]; 529 [46%] women, 920 [80%] with diabetes), 1118 (97%) completed the trial. Enrollment was stopped for futility based on prespecified interim analysis criteria. During treatment, the mean blood glucose level was 118 mg/dL (6.6 mmol/L) in the intensive treatment group and 179 mg/dL (9.9 mmol/L) in the standard treatment group. A favorable outcome occurred in 119 of 581 patients (20.5%) in the intensive treatment group and in 123 of 570 patients (21.6%) in the standard treatment group (adjusted relative risk, 0.97 [95% CI, 0.87 to 1.08], P = .55; unadjusted risk difference, -0.83% [95% CI, -5.72% to 4.06%]). Treatment was stopped early for hypoglycemia or other adverse events in 65 of 581 patients (11.2%) in the intensive treatment group and in 18 of 570 patients (3.2%) in the standard treatment group. Severe hypoglycemia occurred only among patients in the intensive treatment group (15/581 [2.6%]; risk difference, 2.58% [95% CI, 1.29% to 3.87%]). Among patients with acute ischemic stroke and hyperglycemia, treatment with intensive vs standard glucose control for up to 72 hours did not result in a significant difference in favorable functional outcome at 90 days. These findings do not support using intensive glucose control in this setting. ClinicalTrials.gov Identifier: NCT01369069.