Effect Of Intensive Glycemic Control Research Articles

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

Effects of intensive glycemic control on microvascular outcomes in type 2 diabetes mellitus are modified by long-term HbA1c variability: A post hoc analysis of the ACCORD trial

AimsTo assess the impact of long-term visit-to-visit variability in HbA1c on microvascular outcomes in type 2 diabetes mellitus (T2DM), and its influence on the effects of intensive glycemic control. MethodsIncluded were participants with T2DM enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) who had at least three measurements of HbA1c prior to new-onset microvascular outcomes, namely nephropathy, retinopathy and neuropathy. Variability in HbA1c was defined as the coefficient of variation (CV) across HbA1c measurements obtained from enrollment to the transition from intensive to standard glycemic therapy. ResultsDuring a median of 22,005, 23,121, and 13,080 person-years of follow-up, 2,905 nephropathy, 2,655 retinopathy, and 1,974 neuropathy cases were recorded, respectively. Median CV (IQR) was 7.91 % (5.66 %-10.76 %) in the standard treatment group and 9.79 % (7.32 %-13.35 %) in the intensive treatment group. In the standard treatment group, lower HbA1c-CV (the first versus the second quartile) was associated with a higher risk of all microvascular outcomes, while higher HbA1c-CV (the fourth quartile) was associated with a higher risk of nephropathy only. In the intensive treatment group, only higher HbA1c-CV was associated with a higher risk of developing the microvascular outcomes. Intensive therapy reduced all microvascular outcomes among individuals with lower HbA1c-CV, but increased the risk among those with the highest HbA1c-CV (all P values for interaction < 0.0001). For example, hazard ratios (95 % CI) of retinopathy comparing intensive with standard treatments were 0.65 (0.56–0.75), 0.84 (0.71–0.98), 0.97 (0.82–1.14) and 1.28 (1.08–1.53) across the lowest to the highest quartiles of HbA1c variability. ConclusionsThe effects of intensive glycemic control on microvascular outcomes in T2DM appear to be modified by the variability of HbA1c during the treatment process, suggesting the significance of dynamic monitoring of HbA1c levels and timely adjustments to the therapeutic strategy among individuals with a high HbA1c variability.

Heterogeneous Treatment Effects of Intensive Glycemic Control on Kidney Microvascular Outcomes and Mortality in ACCORD.

Identifying and quantifying treatment effect variation across patients is the fundamental challenge of precision medicine. Here we quantify heterogeneous treatment effects of intensive glycemic control in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, considering three outcomes of interest-a composite kidney outcome (driven by macroalbuminuria), all-cause mortality, and first assisted hypoglycemic event. We demonstrate that the effects of intensive glycemic control vary with risk of kidney failure, as predicted by the kidney failure risk equation (KFRE). Participants at highest risk of kidney failure gain the largest absolute kidney benefit of intensive glycemic control but also experience the largest absolute risk of death and hypoglycemic events. Our findings illustrate the value of identifying clinically meaningful treatment heterogeneity, particularly when treatments have different effects on multiple end points. Clear criteria to individualize glycemic targets in patients with type II diabetes are lacking. In this post hoc analysis of the ACCORD, we evaluate whether the KFRE can identify patients for whom intensive glycemic control confers more benefit in preventing kidney microvascular outcomes. We divided the ACCORD trial population into quartiles on the basis of 5-year kidney failure risk using the KFRE. We estimated conditional treatment effects within each quartile and compared them with the average treatment effect in the trial. The treatment effects of interest were the 7-year restricted mean survival time (RMST) differences between intensive and standard glycemic control arms on ( 1 ) time-to-first development of severely elevated albuminuria or kidney failure and ( 2 ) all-cause mortality. We found evidence that the effect of intensive glycemic control on kidney microvascular outcomes and all-cause mortality varies with baseline risk of kidney failure. Patients with elevated baseline risk of kidney failure derived the most from intensive glycemic control in reducing kidney microvascular outcomes (7-year RMST difference of 114.8 [95% confidence interval 58.1 to 176.4] versus 48.4 [25.3 to 69.6] days in the entire trial population) However, this same patient group also experienced a shorter time to death (7-year RMST difference of -56.7 [-100.2 to -17.5] v. -23.6 [-42.2 to -6.6] days). We found evidence of heterogenous treatment effects of intensive glycemic control on kidney microvascular outcomes in ACCORD as a function of predicted baseline risk of kidney failure. Patients with higher kidney failure risk experienced the most pronounced reduction in kidney microvascular outcomes but also experienced the highest risk of all-cause mortality.

The evolution of type 2 diabetes management: glycemic control and beyond with SGLT-2 inhibitors and GLP-1 receptor agonists.

Diabetes mellitus (DM) is one of the most prevalent diseases encountered by the primary care physician on a daily basis. Complications associated with DM can include nephropathy, neuropathy, and retinopathy ("microvascular complications"), along with cardiovascular disease (CVD), which can include myocardial infarction (MI) and strokes ("macrovascular complications"). In the 1990s, landmark clinical trials demonstrated that intensive glycemic control can reduce the risk of developing microvascular complications, but reduction in macrovascular complications with intensive glycemic control was not clearly demonstrated. At this point, intensive glycemic control became the standard of care (SOC). In the 2000s, additional trials evaluating the effect of intensive glycemic control in patients with type 2 diabetes mellitus (T2D) and established CVD, or risk factors for CVD, subsequently failed to identify a macrovascular benefit from intensive glycemic control, and one of the trials was terminated early because of an increase in the risk of mortality observed among patients assigned to receive intensive glycemic control. These results led to less strict glycemic targets being recommended in older patients, particularly those with established CVD. In 2007, everything changed after a report surfaced suggesting that rosiglitazone was associated with a significant increase in the risk of MI, as well as an increase in the risk of cardiovascular death that was of borderline significance. As a result, in 2008, the FDA mandated that all new diabetes medications must exclude an unacceptable level of risk for atherosclerotic cardiovascular disease (ASCVD) prior to drug approval, and thus undergo additional cardiovascular safety trials. Accordingly, through these trials, some of the newer agents, particularly sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), were demonstrated to reduce the risk of major adverse cardiovascular events (MACEs), independent of their effect on glycemic control. These findings subsequently led to further trials to evaluate the effects of some of these therapies on the risk of chronic kidney disease (CKD) progression, as well as adverse heart failure-related outcomes. SGLT-2 inhibitors have been demonstrated to reduce the risk of CKD progression, as well as a reduction in the risk of cardiovascular death or hospitalization secondary to heart failure in patients with both reduced ejection and preserved ejection fractions. A trial evaluating the effects of GLP-1RA on CKD outcomes is ongoing. The aim of this narrative review article, compiled by identifying relevant studies via the utilization of PubMed, is to provide a broad overview over the various clinical trials and analyses that have led to current diabetes management guidelines, and ultimately, help guide primary care physicians in selecting therapies that will not only improve glycemic control and reduce the risk of microvascular complications, but also reduce the risk of macrovascular disease in their patients with T2D.

The Effect Of Intensive Glycemic Control On Outcomes In Diabetic Patients Admitted With Decompensated Heart Failure

The Effect Of Intensive Glycemic Control On Outcomes In Diabetic Patients Admitted With Decompensated Heart Failure

Effect of Intensive Glycemic Control on Myocardial Infarction Outcome in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

The effect of intensive glucose-lowering treatment on the risk of cardiovascular events in type 2 diabetes remains uncertain, especially the effect on the occurrence of myocardial infarction in patients with type 2 diabetes is still unclear. The purpose of this study was to conduct a systematic review and meta-analysis of relevant RCTs. We performed a systematic review of randomized clinical trials (RCTS) and observational studies relevant to this study question. We searched the PubMed and Cochrane databases until June 2022. We included data on 14 RCTs and 144,334 patients, all of whom had type 2 diabetes. When all studies were considered, intensive glucose-lowering treatment significantly reduced the incidence of MI compared with conventional therapy and the total OR value is 0.90 (CI 0.84, 0.97; P = 0.004) when considering all the studies. When the target value of intensive glucose-lowering treatment was considered as HbA1c decrease of more than 0.5%, there was no significant protective effect on MI, the total OR value is 0.88 (CI 0.81, 0.96; P = 0.003). When considering all available RCTS, the intensive glucose-lowering treatment group had a protective effect for MACE compared to the conventional treatment group, and the total OR value is 0.92 (CI 0.88, 0.96; P < 0.00001). In the available RCTs, for the patients with a history of prior CAD, the total OR value is 0.94 (CI 0.89, 0.99; P = 0.002). And there was no difference in the incidence of hypoglycemic events between the intensive and conservative treatment groups. Our data support the positive protective effect of glucose-lowering therapy on MI in patients with T2DM, but there is no significant effect of intensive glucose-lowering. In addition, we found no greater protective effect of enhanced glucose control in the HbA1c reduction of more than 0.5%, and no difference in the incidence of adverse events compared with the HbA1c reduction of less than 0.5%.

Effects of Intensive Glycemic Control on Serum Exosome miR-126-3p and miR-125b-1-3p Levels and Wound Healing in Patients with Diabetic Ulcers.

Intensive glycemic control and exosomal miRNAs have both been reported to improve wound repair in diabetic ulcers. In this study, we aimed to investigate the effects of intensive glycemic control on serum exosome microRNA-126-3p (miR-126-3p), microRNA-125b-1-3p (miR-125b-1-3p), and wound healing in patients with diabetic ulcers. Herein, 45 diabetic patients with an ulcer, aged 35-75 years old, were randomly assigned to the intensive glycemic control group (n = 21) and the conventional glycemic control group (n = 24). Serum exosomes were extracted in the laboratory and assessed by Western blotting, transmission electron microscopy, and nanoparticle tracking analysis. The expression of miR-126-3p and miR-125b-1-3p was validated using quantitative real-time polymerase chain reaction. The wound healing of each diabetic ulcer patient was measured and imaged; additionally, clinical and follow-up data were collected. Finally, the clinical and laboratory data were combined for statistical analysis. Intensive glycemic control was significantly more conducive to wound healing and infection control than conventional glycemic control (P < 0.05). Serum exosomal miR-126-3p was negatively correlated with fasting plasma glucose levels (r = 0.34, P < 0.05) and positively associated with the wound healing rate (r = 0.45, P < 0.01). The level of miR-126-3p in the intensive glycemic control group was significantly higher than that in the conventional glycemic control group (P < 0.01). Serum exosomal miR-125b-1-3p was not correlated with blood glucose levels (r = 0.03, P > 0.05) and was positively associated with the wound healing rate (r = 0.33, P < 0.05). No significant difference was observed in the level of miR-125b-1-3p between the intensive and conventional glycemic control groups. Regarding the prognosis of diabetic ulcers, the intensive glycemic control group was better than the conventional group (Z = -2.02, P < 0.05). Serum exosome (miR-125b-1-3p and miR-126-3p) levels are correlated with wound healing in diabetic ulcers. Intensive glycemic control increases the serum exosomal miR-126-3p level, which might be one of the mechanisms that promotes wound healing in diabetic ulcers.

Heterogeneous treatment effects of intensive glycemic control on major adverse cardiovascular events in the ACCORD and VADT trials: a machine-learning analysis

BackgroundEvidence to guide type 2 diabetes treatment individualization is limited. We evaluated heterogeneous treatment effects (HTE) of intensive glycemic control in type 2 diabetes patients on major adverse cardiovascular events (MACE) in the Action to Control Cardiovascular Risk in Diabetes Study (ACCORD) and the Veterans Affairs Diabetes Trial (VADT).MethodsCausal forests machine learning analysis was performed using pooled individual data from two randomized trials (n = 12,042) to identify HTE of intensive versus standard glycemic control on MACE in patients with type 2 diabetes. We used variable prioritization from causal forests to build a summary decision tree and examined the risk difference of MACE between treatment arms in the resulting subgroups.ResultsA summary decision tree used five variables (hemoglobin glycation index, estimated glomerular filtration rate, fasting glucose, age, and body mass index) to define eight subgroups in which risk differences of MACE ranged from − 5.1% (95% CI − 8.7, − 1.5) to 3.1% (95% CI 0.2, 6.0) (negative values represent lower MACE associated with intensive glycemic control). Intensive glycemic control was associated with lower MACE in pooled study data in subgroups with low (− 4.2% [95% CI − 8.1, − 1.0]), intermediate (− 5.1% [95% CI − 8.7, − 1.5]), and high (− 4.3% [95% CI − 7.7, − 1.0]) MACE rates with consistent directions of effect in ACCORD and VADT alone.ConclusionsThis data-driven analysis provides evidence supporting the diabetes treatment guideline recommendation of intensive glucose lowering in diabetes patients with low cardiovascular risk and additionally suggests potential benefits of intensive glycemic control in some individuals at higher cardiovascular risk.

Effect of Intensive Glycemic and Blood Pressure Control on QT Prolongation in Diabetes: The ACCORD Trial.

Compared with standard glycemic control, intensive glycemic control caused increased mortality in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Preliminary data from several studies suggest that intensive glycemic control is associated with QT prolongation, which may lead to ventricular arrhythmias as a possible explanation of this increased mortality. We sought to assess the effects of intensive glycemic control and intensive blood pressure control on the risk of incident QT prolongation. Cox proportional hazards models were used to compare the risk of incident QT prolongation (>460 ms in women or >450 ms in men) in the intensive versus standard glycemic control arms. Over a combined 48,634 person-years of follow-up (mean 4.9), 634 participants (6.4%) developed a prolonged QTc. Participants in the intensive glycemic control arm did not have an increased risk of QT prolongation. Similarly, a strategy of intensive blood pressure control did not result in a significant change in risk of prolonged QTc. Sensitivity analyses using alternative QT correction formulas (Hodges and Bazett) yielded overall similar findings. In conclusion, the increased mortality observed in the intensive glycemic control arm in the ACCORD trial is not likely to be explained by QT prolongation leading to lethal ventricular arrhythmias.

A 'Speed-Dating' Model of Wound Care? Rapid, High-Volume Assessment of Patients With Diabetes in a Multidisciplinary Foot Wound Clinic.

Diabetes is a major risk factor for foot ulceration and leg amputation, but the effect of intensive glycaemic control on wound healing is unknown. While an interdisciplinary approach has been shown to be important in the management of diabetic foot ulcer (DFU), there is no standardised definition of such an interdisciplinary team. To investigate the role of an opportunistic, rapid-access, inter-disciplinary model of diabetes care at a foot wound clinic. A retrospective case-control study of patients with DFUs attending a diabetes foot wound clinic over a 6-month period. Outcomes in patients who were seen by a rapid-access interdisciplinary team (RAIT) consisting of an endocrinologist, diabetes educator and dietician during the standard wound care those who were not seen by this team were compared. Fifty-five patients were seen by the RAIT and 64 control patients were not seen by this team during their attendance of a diabetes foot wound clinic. Patients in the intervention group had non-significantly higher baseline HbA1c and a significantly larger proportion were active cigarette smokers. Both groups achieved comparable reduction in the total number of DFUs per patient (p=0.971). Patients in the intervention group had a 60.1% reduction in wound size compared to 52.4% reduction in control group (p=0.526). Our study shows that the use of a rapid-access interdisciplinary team to assess and manage patients' diabetes in a foot wound clinic is feasible. Patients with higher-risk diabetes foot wounds exposed to RAIT had comparable wound healing outcomes to lower risk patients.

Effects of Intensive Glycemic Control on Clinical Outcomes Among Patients With Type 2 Diabetes With Different Levels of Cardiovascular Risk and Hemoglobin A1c in the ADVANCE Trial

To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A1c (HbA1c) at baseline. We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models. During 5 years' follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83-0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA1c level (P for interaction = 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk (P = 0.15) or HbA1c levels (P = 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41-2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA1c at baseline (P = 0.09 and 0.18, respectively). The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA1c.

Abstract P439: Generalizability of Heterogeneous Treatment Effects of Intensive Glycemic Control on All-cause Mortality Across Two Randomized Trials

Background: Machine learning is an attractive tool for identifying patient subgroups that exhibit heterogeneous treatment effects (HTE) of an intervention. Whether HTE identified using machine learning methods generalize across clinical studies is unclear. Prior work using a causal forest machine learning approach identified hemoglobin glycation index (HGI), body mass index (BMI), and age as determinants of HTE of intensive versus standard glycemic control on all-cause mortality in the ACCORD randomized trial. We examined whether the same three variables defined HTE in the VA Diabetes Trial (VADT), an independent randomized trial of intensive versus standard glycemic control in type 2 diabetes patients. Methods: The VADT study randomized participants to intensive (median hemoglobin A1c [HbA1c] achieved of 6.9%) or standard (median HbA1c achieved of 8.4%) glycemic control. In this secondary analysis comparing results with the ACCORD trial, we included 1789 out of 1791 VADT participants who had non-missing data at baseline for fasting glucose, HbA1c, BMI, age, and lab values and comorbidities included in prior machine learning analysis of the ACCORD trial; median follow-up was 5.6 years. We examined the absolute risk difference in all-cause mortality in four subgroups with HTE for mortality in the ACCORD trial: group 1, HGI &lt; 0.44, BMI &lt; 30kg/m 2 , Age &lt; 61 years; group 2, HGI &lt; 0.44, BMI &lt; 30kg/m 2 , Age ≥ 61 years; group 3, HGI &lt; 0.44, BMI ≥ 30kg/m 2 ; and group 4, HGI ≥ 0.44. We repeated the analysis after using inverse odds of sampling weights to standardize VADT study participants to the ACCORD study participants using individual-level data from both studies. Methods: The absolute all-cause mortality difference between intensive and standard glycemic control in all VADT participants included in this study was 0.8%. The absolute mortality difference did not vary significantly across subgroups: 2.2% (95% CI -6.0, 10) in group 1 (n=140), 3.4% (-7.3, 14.2) in group 2 (n=192), 2.4% (-2.9, 7.7) in group 3 (n=517), and -0.8% (-4.8, 3.1) in group 4 (n=940), where negative values indicate lower mortality in the intensive glycemic control intervention arm. The absolute mortality differences for the corresponding subgroups in the ACCORD trial were: -2.3% (-4.3, -0.2), 0.7% (-1.6, 3.1), 0.9% (0.4, 2.1), 3.7% (1.5, 6.0) in groups 1, 2, 3, and 4 respectively. The pattern of absolute mortality differences across groups 1 through 4 in the ACCORD study did not reproduce in the VADT study even after standardization of study population characteristics with the ACCORD study. Conclusions: Machine learning methods to define HTE subgroups from randomized trials may not be generalizable across study samples and are likely sensitive to variability in the intervention and differences in study populations. Additional work is needed to define consistent HTE that can guide individualized diabetes treatment.

Diabetes drugs and stroke risk: Intensive versus conventional glucose-lowering strategies, and implications of recent cardiovascular outcome trials.

People with diabetes mellitus are at higher risk of ischaemic stroke and worse outcomes thereafter. However, whether it is better to prescribe intensive glucose-lowering treatment compared with conventional treatment in people with diabetes to prevent recurrent stroke is debated. It is also crucial to consider whether specific antidiabetic agents are more efficacious and safer than others for prevention of stroke. In this review, we provide an overview of the efficacy of intensive and conventional glucose-lowering treatment in post-stroke management. Our conclusion is that the overall evidence for a beneficial effect of intensive glycaemic control on risk of stroke is limited. We also discuss evidence from recent large clinical trials of thiazolidinediones and new antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose co-transporter-2 inhibitors. On the basis of the findings of these trials, our conclusion is that pioglitazone and the GLP-1RA class (other than short-acting lixisenatide) are likely to lessen the occurrence of cerebrovascular disease (by mechanisms not dependent on glucose-lowering per se), whereas there is no consistent evidence for other drug classes.

SAT-294 RANDOMISED EFFECTS OF INTENSIVE GLUCOSE-LOWERING THERAPY ON THE RISK OF MAJOR CLINICAL OUTCOMES IN TYPE 2 DIABETES ACCORDING TO eGFR AND UACR LEVELS

There is ongoing uncertainty regarding the risk-benefit ratio of intensive glucose-lowering therapy in the prevention of clinically important outcomes among people with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We sought to assess the effects of intensive glycaemic control on the risk of major clinical outcomes in T2DM according to level of eGFR and UACR in the ADVANCE trial.

The Cardiovascular Legacy of Good Glycemic Control: Clues About Mediators From the DCCT/EDIC Study.

Diabetes is defined by hyperglycemia, but whether optimizing glycemic control can reduce its complications was long in doubt. In 1968 Siperstein et al. proposed the hypothesis that microvascular injury accompanying diabetes could be genetically determined (1), and there was concern that, even if the “glucose hypothesis” (2,3) were valid, seeking good control of hyperglycemia was overly risky. Nevertheless, epidemiologic evidence linking hyperglycemia with both microvascular and cardiovascular complications prompted assessment of the effects of intensive glycemic control in the Diabetes Control and Complications Trial (DCCT) for type 1 diabetes (T1D) and the UK Prospective Diabetes Study (UKPDS) for type 2 diabetes (T2D). When the results of the DCCT were reported in Las Vegas on a hot (>110°F) day in June 1993, many people were surprised by the approximately 50% reduction of microvascular changes that was associated with 6.5 years of maintaining hemoglobin A1c (HbA1c) close to 7% (53 mmol/mol) compared with 9% (75 mmol/mol) in the control arm (4). Because the DCCT participants were young, cardiovascular events were too few to analyze and long-term effects on cardiovascular risk remained unknown. Results in T2D from the UKPDS reinforced the message of the DCCT. More intensive glycemic control attaining about a 1% difference in HbA1c in T2D for 10 years led to 25% lower rates of microvascular outcomes (5) and a nonsignificant 16% lower rate of myocardial infarction (5). For more than two decades after these reports the dominant view has been that improving glycemic control reduces eye, nerve, and kidney complications but not cardiovascular risk. Four large randomized clinical trials testing whether seeking HbA1c levels at or below 7% could reduce cardiovascular events showed limited benefits during their periods of active treatment (5–8). Although analysis of data pooled from these four trials …

Therapeutic Targeting of the Proinflammatory IL-6-JAK/STAT Signalling Pathways Responsible for Vascular Restenosis in Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is increasing worldwide, and it is associated with increased risk of coronary artery disease (CAD). For T2DM patients, the main surgical intervention for CAD is autologous saphenous vein grafting. However, T2DM patients have increased risk of saphenous vein graft failure (SVGF). While the mechanisms underlying increased risk of vascular disease in T2DM are not fully understood, hyperglycaemia, insulin resistance, and hyperinsulinaemia have been shown to contribute to microvascular damage, whereas clinical trials have reported limited effects of intensive glycaemic control in the management of macrovascular complications. This suggests that factors other than glucose exposure may be responsible for the macrovascular complications observed in T2DM. SVGF is characterised by neointimal hyperplasia (NIH) arising from endothelial cell (EC) dysfunction and uncontrolled migration and proliferation of vascular smooth muscle cells (SMCs). This is driven in part by proinflammatory cytokines released from the activated ECs and SMCs, particularly interleukin 6 (IL-6). IL-6 stimulation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT) pathway is a key mechanism through which EC inflammation, SMC migration, and proliferation are controlled and whose activation might therefore be enhanced in patients with T2DM. In this review, we investigate how proinflammatory cytokines, particularly IL-6, contribute to vascular damage resulting in SVGF and how suppression of proinflammatory cytokine responses via targeting the JAK/STAT pathway could be exploited as a potential therapeutic strategy. These include the targeting of suppressor of cytokine signalling (SOCS3), which appears to play a key role in suppressing unwanted vascular inflammation, SMC migration, and proliferation.

Long-Term Effects of Intensive Glycemic and Blood Pressure Control and Fenofibrate Use on Kidney Outcomes.

In people with type 2 diabetes, aggressive control of glycemia, BP, and lipids have resulted in conflicting short-term (<5 years) kidney outcomes. We aimed to determine the long-term kidney effects of these interventions. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) was a multifactorial intervention study in people with type 2 diabetes at high risk for cardiovascular disease (n=10,251), to examine the effects of intensive glycemic control (hemoglobin A1c <6.0% versus 7%-7.9%), BP control (systolic BP <120 mm Hg versus <140 mm Hg) or fenofibrate versus placebo added to simvastatin on cardiovascular events and death. The glycemia trial lasted 3.7 years and participants were followed for another 6.5 years in ACCORDION, the ACCORD Follow-On Study. The post hoc primary composite kidney outcome was defined as incident macroalbuminuria, creatinine doubling, need for dialysis, or death by any cause. Cox proportional hazards regression estimated the effect of each intervention on the composite outcome and individual components. In secondary outcome analyses, competing risk regression was used to account for the risk of death in incident kidney outcomes. Analyses were adjusted for sociodemographics, randomization groups, and clinical factors. There were 988 cases of incident macroalbuminuria, 954 with doubling of creatinine, 351 requiring dialysis, and 1905 deaths. Hazard ratios (HRs) for the composite outcome with intensive glycemic, BP control, and fenofibrate use compared with standard therapy were 0.92 (95% confidence interval [95% CI], 0.86 to 0.98), 1.16 (95% CI, 1.05 to 1.28), and 1.16 (95% CI, 1.06 to 1.27). Multivariable, secondary outcome analyses showed that in the glycemia trial, only macroalbuminuria was significantly decreased (HR, 0.68; 95% CI, 0.59 to 0.77). In the BP and lipid trials, only creatinine doubling was affected (HR, 1.64; 95% CI, 1.30 to 2.06 and HR, 2.00; 95% CI, 1.61 to 2.49, respectively). In people with type 2 diabetes at high risk for cardiovascular disease, intensive glycemic control may result in a long-term reduction in macroalbuminuria; however, intensive BP control and fenofibrates may increase the risk for adverse kidney events.

Effect of Intensive Glycemic Control on Risk of Lower Extremity Amputation

Diabetes mellitus is a major risk factor for peripheral arterial disease and lower extremity amputation (LEA). We evaluated the effects of intensive glucose control (IGC) on risk of LEA in patients with type 2 diabetes during a randomized-controlled multicenter trial. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial randomized patients with type 2 diabetes to IGC (HbA1c target < 6.0%) or standard glycemic control (SGC; HbA1c target 7.0% to 7.9%). Using analysis of mean HbA1c, we examined relationships between glycemic control and incident/recurrent LEA during the clinical trial/follow-up. Mean post-randomization HbA1c over the course of the trial and post-trial follow-up was 7.3% ± 0.9% (6.8% ± 0.8% in the IGC arm, 7.7% ± 0.7% in the SGC arm). There were 124 participants who had at least 1 LEA during the study period; 73 were randomized to the SGC arm and 51 to the IGC arm (p= 0.049). Randomization to IGC was associated with decreased LEA rate (HR 0.69, 95% CI 0.483 to 0.987, p= 0.042). In multivariable models, mean HbA1c was a powerful predictor of LEA (HR 2.07 per 1% increase in HbA1c, 95% CI 1.67 to 2.57, p < 0.0001). Post-randomization mean HbA1c remained a strong predictor of LEA after controlling for other important covariates and competing risk of death (HR 1.94 per 1% increase in HbA1c, 95% CI 1.52 to 2.46, p < 0.0001). In patients with type 2 diabetes, IGC was associated with a reduction in the risk for LEA. After 3.7 years of IGC, there was an enduring protective effect against LEA. Improved glycemic control was a strong predictor of decreased risk for subsequent LEA. This study suggests that tight glycemic control, even over a short time period, has potential to reducerisk of limb loss.

Effects of intensive interventions compared to standard care in people with type 2 diabetes and microalbuminuria on risk factors control and cardiovascular outcomes: A systematic review and meta-analysis of randomised controlled trials

AimsThe effect of intensive glycaemic control, blood pressure control and lipid levels control alone or as part of a multifactorial intervention has not been fully evaluated. We aimed to estimate the effects of more intensive interventions, compared with standard care, on risk factor control and cardiovascular outcomes in people with type 2 diabetes and microalbuminuria. MethodsWe searched MEDLINE, Embase and the Cochrane library without language restrictions from inception to August 10, 2018. We included randomised controlled trials that evaluated intensive interventions in adults with type 2 diabetes and microalbuminuria. The review was registered on PROSPERO (registration number 42017055208). We used random effects meta-analysis to calculate overall pooled effect estimates across studies. ResultsA total of seven (n = 1210) randomised controlled trials were included, four studies (n = 758) reported HbA1c, six studies (n = 950) reported blood pressure measurements, and three studies (n = 896) examined non-fatal MI, non-fatal stroke, cardiovascular mortality, and all-cause mortality. Intensive interventions indicated statistically significant reductions in both systolic and diastolic blood pressure, and a nonsignificant trend for reduction in HbA1c, total cholesterol, LDL, triglycerides and urinary albumin excretion rate. There was no evidence to suggest that compared with standard care, intensive interventions reduced the risk of non-fatal MI [risk ratio (RR) 0·50; 95% CI 0·20, 1·22; P = 0·127], non-fatal stroke (RR 0·44; 95% CI 0·10, 1·91; P = 0·275), CV mortality (RR 0·95; 95% CI 0·48, 1·86; P = 0·874) or all-cause mortality (RR 0·80; 95% CI 0·51, 1·25; P = 0·324). ConclusionsApart from blood pressure outcomes, there was no evidence that intensive interventions improve or worsen HbA1c, total cholesterol, LDL, triglycerides, urinary albumin excretion rate, risk of cardiovascular or mortality outcomes in people with type 2 diabetes and microalbuminuria. Results of this review are mainly influenced by one small trial, hence uncertainty surrounding the effect of intensive interventions in people with type 2 diabetes and microalbuminuria still exists. Large studies are urgently required in this high risk cardiovascular group of patients.