Intradialytic hypotension (IDH) is common in hemodialysis patients and can lead to several complications. Risk factors for IDH include demographic characteristics, comorbidities, dialysis procedure factors, and so on. Clinical studies on predictive models for dialysis-induced hypotension have shown inconsistent results. This systematic review aims to evaluate published prediction models for IDH, analyzing their characteristics, predictors, efficacy, and the methodological quality and applicability. The protocol has been prepared using the Preferred Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidelines. The systematic review protocol for IDH prediction in hemodialysis patients has been registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY2023110081, DOI: 10.37766/inplasy2023.11.0081). A comprehensive search across five major databases (PubMed, Web of Science, Cochrane Library, CNKI, and Wanfang) will be conducted for studies on prediction models of IDH among hemodialysis patients. Two researchers will independently screen literature, extract data, and evaluate the bias risk and applicability of included studies using prediction modelling study tools. This systematic review will provide critical insights into the efficacy and quality of reporting of the IDH model in hemodialysis patients. This will guide clinical staff in selecting the most appropriate IDH prediction model and inform future research endeavors in IDH prediction.

Hypoglycemia is a known risk of intensive postoperative glucose control in neurosurgical patients. However, the impact of postoperative hypoglycemia after craniotomy remains unexplored. This study aimed to determine the association between postoperative hypoglycemia and mortality in patients undergoing elective craniotomy.

This study involved adult patients who underwent elective craniotomy at the West China Hospital, Sichuan University, between January 2011 and March 2021. We defined moderate hypoglycemia as blood glucose levels below 3.9 mmol/L (70 mg/dL) and severe hypoglycemia as blood glucose levels below 2.2 mmol/L (40 mg/dL). The primary outcome was postoperative 90-day mortality.

This study involved 15 040 patients undergoing an elective craniotomy. Overall, 504 (3.4%) patients experienced moderate hypoglycemia, whereas 125 (0.8%) patients experienced severe hypoglycemia. Multivariable analysis revealed that both moderate hypoglycemia (adjusted odds ratio [aOR] 1.86, 95% CI 1.24-2.78) and severe (aOR 2.94, 95% CI 1.46-5.92) hypoglycemia were associated with increased 90-day mortality compared with patients without hypoglycemia. Moreover, patients with moderate (aOR 2.78, 95% CI 2.28-3.39) or severe (aOR 16.70, 95% CI 10.63-26.23) hypoglycemia demonstrated a significantly higher OR for major morbidity after adjustment, compared with those without hypoglycemia. Patients experiencing moderate (aOR 3.20, 95% CI 2.65-3.88) or severe (aOR 14.03, 95% CI 8.78-22.43) hypoglycemia had significantly longer hospital stays than those without hypoglycemia. The risk of mortality and morbidity showed a tendency to increase with the number of hypoglycemia episodes in patients undergoing elective craniotomy (P for trend = .01, <.001).

Among patients undergoing an elective craniotomy, moderate hypoglycemia and severe hypoglycemia are associated with increased mortality, major morbidity, and prolonged hospital stays. In addition, the risk of mortality and major morbidity increases with the number of hypoglycemia episodes.

Previous studies have reported an association between hypoglycemia and cardiovascular (CV) events in people with type 2 diabetes (T2D), but it is unclear if this association is causal or identifies a high-risk patient phenotype.

To evaluate the associations between hypoglycemia and CV outcomes.

This secondary analysis was a post hoc assessment of the multinational, double-blind CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; 2013-2016) and CAROLINA (Cardiovascular Outcome Trial of Linagliptin vs Glimepiride in Type 2 Diabetes; 2010-2018) randomized clinical trials of the antihyperglycemic drug, linagliptin, a dipeptidyl peptidase 4 inhibitor. Participants were adults with T2D at high CV risk with or without high kidney risk. By design, participants in the CARMELINA trial had longer duration of T2D and had a higher CV risk than participants in the CAROLINA trial. Data analyses were conducted between June 2021 and June 2023.

Linagliptin or placebo in the CARMELINA trial, and linagliptin or glimepiride in the CAROLINA trial.

The primary outcome for both trials was CV death, myocardial infarction (MI), or stroke (3-point major adverse CV events [3P-MACE]). For the present analyses, hospitalization for heart failure (HF) was added. Hypoglycemia was defined as plasma glucose less than 54 mg/dL or severe hypoglycemia (episodes requiring the assistance of another person). Associations between the first hypoglycemic episode and subsequent CV events and between nonfatal CV events (MI, stroke, hospitalization for HF) and subsequent hypoglycemic episodes were assessed using multivariable Cox proportional hazards regression models. Sensitivity analyses explored the risk of CV events within 60 days after each hypoglycemic episode.

In the CARMELINA trial (6979 patients; 4390 males [62.9%]; mean [SD] age, 65.9 [9.1] years), there was an association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (hazard ratio [HR], 1.23; 95% CI, 1.04-1.46) as well as between nonfatal CV events and subsequent hypoglycemia (HR, 1.39; 95% CI, 1.06-1.83). In the CAROLINA trial (6033 patients; 3619 males (60.0%); mean [SD] age, 64.0 [9.5] years), there was no association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (HR, 1.00; 95% CI, 0.76-1.32) and between nonfatal CV events and subsequent hypoglycemia (HR, 1.44; 95% CI, 0.96-2.16). In analyses of CV events occurring within 60 days after hypoglycemia, there was either no association or too few events to analyze.

This study found bidirectional associations between hypoglycemia and CV outcomes in the CARMELINA trial but no associations in either direction in the CAROLINA trial, challenging the notion that hypoglycemia causes adverse CV events. The findings from the CARMELINA trial suggest that both hypoglycemia and CV events more likely identify patients at high risk for both.

ClinicalTrials.gov Identifier: NCT01897532 (CARMELINA) and NCT01243424 (CAROLINA).

Diabetes and hyperglycemic events in cardiac surgical patients are associated with postoperative morbidity and mortality. The causes of dysglycemia, the abnormal fluctuations in blood glucose concentrations, in the perioperative period include surgical stress, surgical techniques, medications administered perioperatively, and patient factors. Both hyperglycemia and hypoglycemia lead to poor outcomes after cardiac surgery. While trying to control blood glucose concentration tightly for better postoperative outcomes, hypoglycemia is the main adverse event. Currently, there is no definite consensus on the optimum perioperative blood glucose concentration to be maintained in cardiac surgical patients. This review provides an overview of perioperative glucose homeostasis, the pathophysiology of dysglycemia, factors that affect glycemic control in cardiac surgery, and current practices for glycemic control in cardiac surgery.

Hypoglycemia is associated with increased mortality, though the mechanisms underlying this association are not established. Hypoglycemia impairs the counterregulatory hormonal and autonomic responses to subsequent hypoglycemia. It is unknown whether hypoglycemia elicits a generalized impairment in autonomic control of cardiovascular function in individuals with type 2 diabetes. We tested the hypothesis that in individuals with type 2 diabetes, hypoglycemia impairs a key measure of cardiovascular autonomic homeostasis, baroreflex sensitivity.

Sixteen individuals with well-controlled type 2 diabetes and without known cardiovascular disease were exposed to two 90-min episodes of experimental hypoglycemia (2.8 mmol/L, 50 mg/dL) on the same day. All individuals experienced a hypoglycemic-hyperinsulinemic clamp in the morning (AM clamp) and again in the afternoon (PM clamp). Baroreflex sensitivity was assessed using the modified Oxford method before the initiation of each hypoglycemic-hyperinsulinemic clamp, during the last 30 min of hypoglycemia, and the following morning. A mixed effects model adjusting for sex, age, BMI, and insulin level, demonstrated a significant effect of hypoglycemia on baroreflex sensitivity. The study is registered at ClinicalTrials.gov (NCT03422471).

Baroreflex sensitivity during PM hypoglycemia was reduced compared to baseline, during AM hypoglycemia, and the next day. Insulin levels positively correlated with baroreflex sensitivity at baseline and during AM hypoglycemia.

Exposure to hypoglycemia impairs a key measure of autonomic control of cardiovascular function and, thus, may increase the risk of cardiac arrhythmias and blood pressure lability in individuals with type 2 diabetes. This effect is attenuated in part by increased insulin levels.

It has long been known that administering insulin or insulin secretagogues to treat diabetes has the unfavorable side effect of hypoglycemia. Because hypoglycemia can disrupt normal brain function, it can have a profound impact on people's lives. Studies have shown a connection between hypoglycemia and a higher risk of death and cardiovascular disease. Through experimental studies, numerous potential reasons for the start of cardiovascular events have been discovered. In addition, studies on people have demonstrated that hypoglycemia can result in ventricular arrhythmias. According to recent studies, a number of factors may affect the relationship between hypoglycemia, cardiovascular events, and mortality. Confounding factors may explain the apparent correlation, at least in part. People with comorbidities may experience more hypoglycemia, increasing their risk of mortality. Those who have type 1 or type 2 diabetes, however, seem to be more susceptible to the negative effects of hypoglycemia on the cardiovascular system. When choosing appropriate glucose-lowering treatments and setting glycemic objectives with patients, clinicians should be aware of this risk.

Maintenance of plasma glucose (PG) homeostasis is due to a complex network system. Even a minor fall in PG activates multiple neuroendocrine actions promoting hormonal, metabolic and behavioral responses, which prevent and ultimately recover hypoglycemia, primarily neuroglycopenia. Among these responses, gastric emptying (GE) plays an important role by coordinated mechanisms which regulate transit and absorption of nutrients through the small intestine. A bidirectional relationship between GE and glycemia has been established: GE may explain the up to 30-40 % variance in glycemic response following a carbohydrate-rich meal. In addition, acute and chronic hyperglycemia induce deceleration of GE after meals. Hypoglycemia accelerates GE, but its role in counterregulation has been poorly investigated. The role of GE as a counterregulatory mechanism has been confirmed in pathophysiological conditions, such as gastroparesis or following recurrent hypoglycemia. Therefore, it could represent an "ancestral" mechanism, highly conservative and effective in all individuals, conditions and clinical contexts. Recent guidelines recommend GLP-1 receptor agonists (GLP-1RAs) either as the first injectable therapy for type 2 diabetes mellitus or in combination with insulin. Considering the potential impact on GE, it would be important to study subjects on GLP-1 RAs during hypoglycemia, to establish whether a possible deceleration of GE impairs glucose counterregulation.

Hypoglycaemia has been linked to an increased risk of cardiac arrhythmias by causing autonomic and metabolic alterations, which may be associated with detrimental outcomes in individuals with diabetes(IWD), such as cardiovascular diseases (CVDs) and mortality, especially in multimorbid or frail people. However, such relationships in this population have not been thoroughly investigated. For this reason, we conducted a systematic review and meta-analysis.

Relevant papers published on PubMed, Embase, Cochrane, Web of Knowledge, Scopus, and CINHAL complete from inception to December 22, 2022 were routinely searched without regard for language. All of the selected articles included odds ratio, hazard ratio, or relative risk statistics, as well as data for estimating the connection of hypoglycaemia with cardiac arrhythmia, CVD-induced death, or total death in IWD. Regardless of the heterogeneity assessed by the I2 statistic, pooled relative risks (RRs) and 95% confidence intervals (CI) were obtained using random-effects models.

After deleting duplicates and closely evaluating all screened citations, we chose 60 studies with totally 5,960,224 participants for this analysis. Fourteen studies were included in the arrhythmia risk analysis, and 50 in the analysis of all-cause mortality. Hypoglycaemic patients had significantly higher risks of arrhythmia occurrence (RR 1.42, 95%CI 1.21-1.68), CVD-induced death (RR 1.59, 95% CI 1.24-2.04), and all-cause mortality (RR 1.68, 95% CI 1.49-1.90) compared to euglycaemic patients with significant heterogeneity.

Hypoglycaemic individuals are more susceptible to develop cardiac arrhythmias and die, but evidence of potential causal linkages beyond statistical associations must await proof by additional specifically well planned research that controls for all potential remaining confounding factors.

In patients with type 2 diabetes (T2D), levels of hypoglycemia and their risk of mortality are not well understood. The aim of this study was to ascertain the correlation among disparate levels of hypoglycemia and patients with T2D's achieved mean glycated hemoglobin A1c (HbA1c) with all-cause and cardiovascular mortality.

27,932 T2D patients taking hypoglycemic medications at outpatient visits for more than 6 months between 2008 and 2018 were linked to Taiwan's National Death Registry. We determined the respective mortality rates with Poisson assumption, and explored the relative risks of all-cause and cardiovascular mortality according to dissimilar levels of hypoglycemia with their achieved mean HbA1c by Cox proportional hazard regression model with adjustment of potential confounders.

T2D patients with level 3 hypoglycemia had the highest rates of all-cause and cardiovascular mortality. Compared with those who never encountered hypoglycemia, study subjects with level 1 and level 2 hypoglycemia did not show excessive risks of either all-cause or cardiovascular mortality. Only those with level 3 hypoglycemia revealed marginal risk of all-cause (Hazard ratio [HR]: 1.18; 95% Confidence Interval [CI] 1.04-1.33) but not cardiovascular mortality (HR: 1.16; 95% CI 0.88-1.53). In T2D patients with hypoglycemia, only those with mean HbA1c ≥9.0% increased all-cause mortality in level 3 hypoglycemia, and cardiovascular mortality in level 1 hypoglycemia.

Elevated risk of all-cause mortality was exclusively found in patients with level 3 hypoglycemia. In T2D patients with hypoglycemia, mean HbA1c ≥ 9% increased all-cause or cardiovascular mortality. Aggressive treatment of accompanying serious illness in severe hypoglycemia may help reduce mortality in patients with T2DM.

Diabetes is a highly prevalent disease associated with considerable cardiovascular end organ damage and mortality. Despite significant changes to the management of acute myocardial infarction over the last two decades, people with diabetes remain at risk of complications and mortality following a myocardial infarct for a multitude of reasons, including increased coronary atherosclerosis, associated coronary microvascular dysfunction, and diabetic cardiomyopathy. Dysglycaemia causes significant endothelial dysfunction and upregulation of inflammation within the vasculature and epigenetic changes mean that these deleterious effects may persist despite subsequent efforts to tighten glycaemic control. Whilst clinical guidelines advocate for the avoidance of both hyper- and hypoglcyaemia in the peri-infarct period, the evidence base is lacking, and currently there is no consensus on the benefits of glycaemic control beyond this period. Glycaemic variability contributes to the glycaemic milieu and may have prognostic importance following myocardial infarct. The use of continuous glucose monitoring means that glucose trends and parameters can now be captured and interrogated, and its use, along with newer medicines, may provide novel opportunities for intervention after myocardial infarction in people with diabetes.

In the century since the discovery of insulin, diabetes has changed from an early death sentence to a manageable chronic disease. This change in longevity and duration of diabetes coupled with significant advances in therapeutic options for patients has fundamentally changed the landscape of diabetes management, particularly in patients with type 1 diabetes mellitus. However, hypoglycemia remains a major barrier to achieving optimal glycemic control. Current understanding of the mechanisms of hypoglycemia has expanded to include not only counter-regulatory hormonal responses but also direct changes in brain glucose, fuel sensing, and utilization, as well as changes in neural networks that modulate behavior, mood, and cognition. Different strategies to prevent and treat hypoglycemia have been developed, including educational strategies, new insulin formulations, delivery devices, novel technologies, and pharmacologic targets. This review article will discuss current literature contributing to our understanding of the myriad of factors that lead to the development of clinically meaningful hypoglycemia and review established and novel therapies for the prevention and treatment of hypoglycemia.

There are limited data on the link between cardiac autonomic neuropathy (CAN) and severe hypoglycemia in type 2 diabetes. Here, we evaluated the associations of CAN with severe hypoglycemia among 7,421 adults with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes study. CAN was defined using ECG-derived measures. Cox's and Andersen-Gill regression models were used to generate HRs (HRs) for the first and recurrent severe hypoglycemic episodes, respectively. Over 4.7 years, there were 558 first and 811 recurrent hypoglycemic events. Participants with CAN had increased risks of a first episode or recurrent episodes of severe hypoglycemia. The intensity of glycemic management modified the CAN association with hypoglycemia. In the standard glycemic management group, compared with those of participants without CAN, HRs for a first severe hypoglycemia event and recurrent hypoglycemia were 1.58 and 1.96, respectively. In the intensive glycemic management group, HRs for a first severe hypoglycemia event and recurrent hypoglycemia were 1.10 and 1.24, respectively. In summary, CAN was independently associated with higher risks of a first hypoglycemia event and recurrent hypoglycemia among adults with type 2 diabetes, with the highest risk observed among those on standard glycemic management.

The prognostic implication of elevated or decreased blood glucose (BG) level in acute decompensated heart failure (ADHF) has been still controversial. Indices of stress hyperglycemia, expressed by the ratio of BG and chronic BG control, has been reported to be associated with poor outcome in different disease population. We sought to assess BG at admission and %ΔBG, an index of BG deviation from estimated average BG calculated from glycated hemoglobin (HbA1c), on the long-term outcome in ADHF patients.

The West Tokyo Heart Failure (WET-HF) Registry is a prospective multicenter registry enrolling consecutive hospitalized ADHF patients. Among the patients (N = 3078, 77 [67-84] years, male 59%), BG at admission discriminated the long-term (1000 days) incidence of ADHF rehospitalization, but not cardiac death. BG at admission showed a U-shape relationship with the long-term incidence of ADHF rehospitalization after adjustment for covariates. Especially, in patients with HbA1c ≥ 6.5%, the lowest quartile showed the highest risk of ADHF rehospitalization. On the contrary, %ΔBG showed U-shape relationship with the long-term incidence of cardiac death after discharge, rather than ADHF rehospitalization after adjustment for covariates. In addition, elevated %ΔBG was associated with the long-term risk of sudden cardiac death (SCD) even after adjustment for covariates.

For ADHF patients, BG at admission and %ΔBG might be a simple, useful tool for predicting and stratifying long-term risk of cardiac events. Especially, elevated %ΔBG might be an important in predicting hard events such as cardiac death or SCD.

Stress can be classified as either psychosocial or physiologic. Physiologic stress refers to stresses due to acute illness, trauma, pain, hypoglycemia, and sleep deprivation-much less is known regarding its health consequences. This review focuses on hypoglycemia as a model to further investigate physiological stress. Experimental mild to moderate hypoglycemia is a paradigmatic physiological stress that evokes autonomic, neuroendocrine, and immune responses. Hypoglycemic stress is an ideal model to examine the interactions and consequences of physiological stress on the autonomic nervous system. Acute hypoglycemia has been demonstrated to increase inflammatory markers, prolong QTc, and impair cardiac-vagal baroreflex sensitivity. Some of these consequences may not reverse completely when euglycemia is restored. For example, there is attenuation of the cardiac-vagal baroreflex, attenuation of the vascular sympathetic baroreflex (muscle sympathetic nerve activity response to transient hypotension), and attenuation of the catecholamine response to lower body negative pressure that is present the next day after hypoglycemia has resolved.

Critically ill patients with premorbid diabetes can suffer from relative hypoglycemia (RHG), falling below the normal blood glucose (BG) target. However, these events have not been well defined or studied. In the present study, we aimed to explore the incidence and clinical significance of RHG events in critically ill patients with diabetes.

Patients with a history of diabetes who stayed in the intensive care unit (ICU) for more than three days with at least 12 BG recordings were retrospectively included in the study. A BG level > 30% below the estimated average according to patient hemoglobin A1c measured at admission was defined as a single RHG event. Outcomes were compared between patients with and those without RHG events.

In total, 113 patients were included in the final analysis. RHG was detected in 73 patients (64.6%). Those who experienced RHG events had a significantly higher incidence of ICU delirium. They also had a higher risk of 28-day mortality, but this was not statistically significant. However, patients with a higher frequency of RHG events did have a significantly higher risk of overall mortality (57.1% for more than four events vs 15.4% for three to four events, P=0.006 and 15.1% for one to two events, P=0.003).

In conclusion, RHG is a common finding in critically ill patients with diabetes and is associated with mortality and the occurrence of delirium.

Diabetes mellitus is a leading cause of chronic kidney disease (CKD) that confers faster kidney disease progression, higher mortality, and various metabolic derangements including hypoglycemia.

Even in the absence of diabetes mellitus, growing research demonstrates that CKD patients are at heightened risk for hypoglycemia via multiple pathways. In CKD patients transitioning to end-stage renal disease (ESRD), spontaneous resolution of hyperglycemia and frequent hypoglycemia resulting in reduction and/or cessation of glucose-lowering medications are frequently observed in a phenomenon described as 'burnt-out diabetes'. In non-CKD patients, it is well established that hypoglycemia is causally associated with mortality, with pathways including arrhythmias, sudden cardiac death, stroke, and seizures. Increasing evidence shows that, in CKD and ESRD patients with and without diabetes mellitus, hypoglycemia is associated with cardiovascular complications and mortality risk.

Given the high prevalence of hypoglycemia in CKD patients and the morbidity and mortality associated with this metabolic complication, a multimodal strategy is needed to prevent dysglycemia, including individualization of glycemic targets, selection of glucose-lowering medications less likely to induce hypoglycemia, medical nutrition therapy administered by trained dietitians, and accurate and precise hypoglycemia detection methods, such as self-monitored blood glucose or continuous glucose monitoring including during dialysis treatment.

HbA_1c is the most used parameter to assess glycaemic control. However, evidence suggests that the concept of hyperglycaemia has profoundly changed and that different facets of hyperglycaemia must be considered. A modern approach to glycaemic control should focus not only on reaching and maintaining optimal HbA_1c concentrations as early as possible, but to also do so by reducing postprandial hyperglycaemia, glycaemic variability, and to extend as much as possible the time in range in near-normoglycaemia. These goals should be achieved while avoiding hypoglycaemia, which, should it occur, should be reverted to normoglycaemia. Modern technology, such as intermittently scanned glucose monitoring and continuous glucose monitoring, together with new drug therapies (eg, ultra-fast insulins, SGLT2 inhibitors, and GLP-1 receptor agonists), could help to change the landscape of glycaemia management based on HbA_1c in favour of a more holistic approach that considers all the different aspects of this commonly oversimplified pathophysiological feature of diabetes.

Insulin represents a mainstay of glucose-lowering therapy for many adults with type 2 diabetes mellitus (T2DM). Insulin treatments prescribed as standard care for the majority of people with T2DM, such as basal human insulin, may not be optimal in the treatment of frail older adults because of the increased demand on health care staff to administer multiple daily injections and monitor the patient. When choosing an insulin regimen for a frail older person with T2DM, predictability of glucose lowering effect, risk of hypoglycaemia, ease of administration, and simplicity and flexibility of dosing are major determining factors. Multiple daily injections may be too complex for older frail adults, whilst providing an unnecessary degree of tight glycaemic control and low doses of once-daily basal insulin analogues such as insulin degludec may be a reasonable option as cognitive decline or functional disability increases. Although insulin degludec has a substantially higher acquisition cost than routinely used basal human insulin, it has a longer, more predictable pharmacological profile and is more amenable to once-daily administration, translating into a reduced burden of care and potential cost savings for insulin-treated frail older adults. Insulin acquisition cost represents only a small proportion of the total cost of treatment, and it is important to consider the value perspective of insulin therapy in frail older adults from all stakeholders in the health care system.

30-80% of patients being treated in intensive care units in the perioperative period develop hyperglycemia. This stress hyperglycemia is induced and maintained by inflammatory-endocrine and iatrogenic stimuli and generally requires treatment. There is uncertainty regarding the optimal blood glucose targets for patients with diabetes mellitus.

This review is based on pertinent publications retrieved by a selective search in PubMed and Google Scholar.

Patients in intensive care with pre-existing diabetes do not benefit from blood sugar reduction to the same extent as metabolically healthy individuals, but they, too, are exposed to a clinically relevant risk of hypoglycemia. A therapeutic range from 4.4 to 6.1 mmol/L (79-110 mg/dL) cannot be justified for patients with diabetes mellitus. The primary therapeutic strategy in the perioperative setting should be to strictly avoid hypoglycemia. Neurotoxic effects and the promotion of wound-healing disturbances are among the adverse consequences of hyperglycemia. Meta-analyses have shown that an upper blood sugar limit of 10 mmol/L (180 mg/dL) is associated with better outcomes for diabetic patients than an upper limit of less than this value. The target range of 7.8-10 mmol/L (140-180 mg/dL) proposed by specialty societies for hospitalized patients with diabetes seems to be the best compromise at present for optimizing clinical outcomes while avoiding hypoglycemia. The method of choice for achieving this goal in intensive care medicine is the continuous intravenous administration of insulin, requirng standardized, high-quality monitoring conditions.

Optimal blood sugar control for diabetic patients in intensive care meets the dual objectives of avoiding hypoglycemia while keeping the blood glucose concentration under 10 mmol/L (180 mg/dL). Nutrition therapy in accordance with the relevant guidelines is an indispensable pre - requisite.

Decreased heart rate variability (HRV) has been reported to be associated with cardiac autonomic dysfunction. Hypopituitarism in nonfunctioning pituitary adenoma (NFPA) is often linked to increased cardiovascular mortality. We therefore hypothesized that postoperative NFPA patients with hormone deficiency have an elevated risk of HRV alterations indicating cardiac autonomic dysfunction.

A total of 22 patients with NFPA were enrolled in the study. Between 3 and 6 months after surgery, a combined pituitary function test (CPFT) was performed, and HRV was measured. The period of sleep before the CPFT was deemed the most stable period, and the hypoglycemic period that occurred during the CPFT was defined as the most unstable period. Changes in HRV parameters in stable and unstable periods were observed and compared depending on the status of hormone deficiencies.

In patients with adrenocorticotropic hormone (ACTH) deficiency with other pituitary hormone deficiencies, the low frequency to high frequency ratio, which represents overall autonomic function and is increased in the disease state, was higher (P=0.005). Additionally, the standard deviation of the normal-to-normal interval, which decreases in the autonomic dysfunction state, was lower (P=0.030) during the hypoglycemic period. In panhypopituitarism, the low frequency to high frequency ratio during the hypoglycemic period was increased (P=0.007).

HRV analysis during CPFT enables estimation of cardiac autonomic dysfunction in patients with NFPA who develop ACTH deficiency with other pituitary hormone deficiencies or panhypopituitarism after surgery. These patients may require a preemptive assessment of cardiovascular risk.

There is very limited information about glycemic control after discharge from the ICU. The aims of this study were to evaluate the prevalence of hypoglycemia in ICU survivors with type-2 diabetes and determine whether hypoglycemia is associated with cardiac arrhythmias.

Prospective, observational, two-center study. Participants underwent up to 5 days of simultaneous blinded continuous interstitial glucose monitoring and ambulatory 12-lead electrocardiogram monitoring immediately after ICU discharge during ward-based care. Frequency of arrhythmias, heart rate variability, and cardiac repolarization markers were compared between hypoglycemia (interstitial glucose ≤ 3.5 mmol/L) and euglycemia (5-10 mmol/L) matched for time of day.

Mixed medical-surgical ICUs in two geographically distinct university-affiliated hospitals.

Patients with type-2 diabetes who were discharged from ICU after greater than or equal to 24 hours with greater than or equal to one organ failure and were prescribed subcutaneous insulin were eligible.

Thirty-one participants (mean ± sd, age 65 ± 13 yr, glycated hemoglobin 64 ± 22 mmol/mol) were monitored for 101 ± 32 hours post-ICU (total 3,117 hr). Hypoglycemia occurred in 12 participants (39%; 95% CI, 22-56%) and was predominantly nocturnal (40/51 hr) and asymptomatic (25/29 episodes). Participants experiencing hypoglycemia had 2.4 ± 0.7 discrete episodes lasting 45 minutes (interquartile range, 25-140 min). Glucose nadir was less than or equal to 2.2 mmol/L in 34% of episodes. The longest episode of nocturnal hypoglycemia was 585 minutes with glucose nadir less than 2.2 mmol/L. Simultaneous electrocardiogram and continuous interstitial glucose monitoring recordings were obtained during 44 hours of hypoglycemia and 991 hours of euglycemia. Hypoglycemia was associated with greater risk of bradycardia but did not affect atrial or ventricular ectopics, heart rate variability, or cardiac repolarization.

In ICU survivors with insulin-treated type-2 diabetes, hypoglycemia occurs frequently and is predominantly nocturnal, asymptomatic, and prolonged.

A novel, multi-dimensional protocol named GENIE has been in use for intensive insulin therapy (IIT, target glucose <140 mg/dL) in the surgical intensive care unit (SICU) after open heart surgery (OHS) at VA Pittsburgh since 2005. Despite concerns over increased mortality from IIT after the publication of the NICE-SUGAR Trial, it remains in use, with ongoing monitoring under the MAGIC GENIE Project showing that GENIE performance over 12 years (2005-2016) aligns with the current consensus that IIT with target blood glucose (BG) <140 mg/dL is advisable only if it does not provoke severe hypoglycemia (SH). Two studies have been conducted to monitor glucometrics and outcomes during GENIE use in the SICU. One compares GENIE (n = 382) with a traditional IIT protocol (FORMULA, n = 289) during four years of contemporaneous use (2005-2008). The other compares GENIE's impact overall (n = 1404) with a cohort of patients who maintained euglycemia after OHS (euglycemic no-insulin [ENo-I], n = 111) extending across 12 years (2005-2016). GENIE performed significantly better than FORMULA during contemporaneous use, maintaining lower time-averaged glucose, provoking less frequent, severe, prolonged, or repetitive hypoglycemia, and achieving 50% lower one-year mortality, with no deaths from mediastinitis (0 of 8 cases vs 4 of 9 on FORMULA). Those benefits were sustained over the subsequent eight years of exclusive use in OHS patients, with an overall one-year mortality rate (4.2%) equivalent to the ENo-I cohort (4.5%). The results of the MAGIC GENIE Project show that GENIE can maintain tight glycemic control without provoking SH in patients undergoing OHS, and may be associated with a durable survival benefit. The results, however, await confirmation in a randomized control trial.

This article provides a summary of the autonomic neuropathies, including neuropathies associated with diabetes mellitus, neuropathies due to amyloid deposition, immune-mediated autonomic neuropathies (including those associated with a paraneoplastic syndrome), inherited autonomic neuropathies, and toxic autonomic neuropathies. The presenting features, diagnostic investigations, and natural history of these neuropathies are discussed.

Recent findings in autonomic peripheral neuropathy include data on the epidemiology and atypical presentations of diabetic autonomic neuropathy, treatment-induced neuropathy of diabetes mellitus, the presentation of immune-mediated neuropathies, and advances in hereditary neuropathy associated with amyloidosis and other hereditary neuropathies.

Knowledge and recognition of the clinical features of the autonomic neuropathies, combined with appropriate laboratory and electrophysiologic testing, will facilitate accurate diagnosis and management.

To investigate the association of severe hypoglycemia (SH) with all-cause mortality and complication risks among Chinese patients with type 2 diabetes mellitus (T2DM).

Cohort study and nested case-control studies were conducted based on medical insurance database 2008-2015. The incidence of outcomes or the exposure of previous SH was compared among matched patients, respectively. The association between SH and outcomes was investigated and validated by different models.

Among cohort study participants (mean age of 59.0 ± 11.2 years), SH was associated with higher risk of all-cause mortality (HR = 1.80, P < 0.001) and transient ischemic attacks (TIA, HR = 1.51, P < 0.001), while no association was observed between SH and complications including myocardial infarction (MI), angina, arrhythmia and stroke. Similarly, SH was associated with about doubled all-cause mortality (OR = 1.76, P < 0.001) and TIA (OR = 2.00, P < 0.001), but not associated with risk of MI or stroke in nested case-control studies.

In Chinese patients with T2DM, SH is associated with increased risk of all-cause mortality and TIA, but no significant differences were found regard to the other examined complication risks, which need to be further explored in future studies.

Impaired awareness of hypoglycemia (IAH) is a reduction in the ability to recognize low blood glucose levels that would otherwise prompt an appropriate corrective therapy. Identified in approximately 25% of patients with type 1 diabetes, IAH has complex pathophysiology, and might lead to serious and potentially lethal consequences in patients with diabetes, particularly in those with more advanced disease and comorbidities. Continuous glucose monitoring systems can provide real-time glucose information and generate timely alerts on rapidly falling or low blood glucose levels. Given their improvements in accuracy, affordability and integration with insulin pump technology, continuous glucose monitoring systems are emerging as critical tools to help prevent serious hypoglycemia and mitigate its consequences in patients with diabetes. This review discusses the current knowledge on IAH and effective diagnostic methods, the relationship between hypoglycemia and cardiovascular autonomic neuropathy, a practical approach to evaluating cardiovascular autonomic neuropathy for clinicians, and recent evidence from clinical trials assessing the effects of the use of CGM technologies in patients with type 1 diabetes with IAH.

This article provides an up-to-date review of the manifestations of neuropathy seen in the setting of diabetes and other metabolic disorders.

Although a number of metabolic disorders cause or are associated with peripheral neuropathy, the neuropathies associated with glucose dysregulation make up the vast majority of cases. Recent investigations have determined major differences in the neuropathies associated with type 1 and type 2 diabetes. Neuropathy in type 1 diabetes is closely linked to glycemic control, whereas neuropathy in type 2 diabetes is linked to dyslipidemia, central obesity, hypertension, insulin resistance, and glucose control. Although length-dependent axonal distal symmetric polyneuropathy is the most common clinical presentation, diabetes is also associated with acute, asymmetric, painless, and autonomic neuropathies.

The prevalence of diabetes and metabolic syndrome is increasing across the globe. The need to recognize and treat the wide array of clinical manifestations of neuropathy detected in individuals with metabolic disorders will continue to grow. As a consequence, an increasing number of well-trained physicians who can manage these patients is needed. At present, treatment is largely focused on prevention and symptomatic management. Investments into funding for both basic and clinical science are necessary to bring novel therapeutic interventions into clinical practice.

Impaired awareness of hypoglycaemia (IAH) affects around a quarter of patients with diabetes who receive insulin treatment. This condition is characterised by a progressive reduction in symptomatic and behavioural responses to hypoglycaemia, increasing risk of deeper drops in blood glucose, unconsciousness, and collapse. Thus, patients with IAH experience severe hypoglycaemic episodes more frequently, resulting in significant morbidity and mortality. IAH is thought to develop as a consequence of whole-body adaptations to repeated insulin-induced hypoglycaemia (RH), with widespread deficits in the hypoglycaemia counter-regulatory response (CRR). Despite this important insight, the precise pathophysiology by which RH leads to an attenuated CRR is unknown. Studies into the underlying mechanisms of IAH have employed a variety of protocols in humans and experimental species. The use of animal models has many investigational benefits, including the unprecedented increase in the availability of transgenic strains. However, modelling impaired hypoglycaemia-associated counter-regulation remains challenging and appropriate interpretation of findings across species and protocols even more so. Here, we review the experimental modelling of IAH and impaired hypoglycaemia-associated counter-regulation, with a focus on understanding species-specific variation in glucose homeostasis. This review will aid investigators in interpreting outputs from different studies in IAH and aid progress in the field.

Hypoglycemia attenuates cardiovascular homeostatic autonomic control. This attenuation, known as the cardiovascular component of hypoglycemia-associated autonomic failure (HAAF), is characterized most notably by decreased baroreflex sensitivity (BRS) that begins during hypoglycemia and persists until at least the next day, despite return to euglycemia. Understanding the mechanisms underlying this reduction in BRS is important because BRS attenuation is associated with increased morbidity and mortality.

The objective of this work is to investigate the role of the adrenocorticotropin (ACTH)-adrenal axis in decreasing BRS. We tested the hypothesis that infusion of ACTH 1-24 (cosyntropin), as compared to placebo, would acutely suppress BRS, and that this decrease in BRS would be present the next day.

A double-blind, placebo-controlled, random-order, cross-over study was conducted.

This study took place in a clinical research center.

Participants included healthy men and women.

Interventions included an intravenous infusion of cosyntropin (70 μg/hour for 2.5 hours in the morning and again in the early afternoon) vs normal saline placebo.

Outcome measures included BRS during and 16 hours after cosyntropin vs placebo infusions.

Cosyntropin infusion attenuated BRS (mm Hg/ms) as compared to placebo (baseline 17.8 ± 1.38 vs 17.0 ± 2.07; during 14.4 ± 1.43 vs 17.3 ± 1.65; and next day 14.8 ± 1.42 vs 18.9 ± 2.04; P < .05, time by treatment, analysis of variance). BRS was decreased during the final 30 minutes of the morning cosyntropin infusion as compared to baseline (P < .01) and remained suppressed the next day (16 hours after afternoon infusion) (P < .025). Placebo infusion did not significantly change BRS. Corrected QT interval was not affected.

ACTH attenuates BRS, raising the possibility that hypoglycemia-induced increases in ACTH may contribute to the cardiovascular component of HAAF.

While the association between hypoglycaemia and poor outcomes in diabetes is well established, it is unclear whether such an association is generalizable to those without diabetes.

A total of 8497 participants free of cardiovascular disease and diabetes from the Third National Health and Nutrition Examination Survey were included. We examined the relationship between baseline low (<80 mg/dL) and high (⩾126 mg/dL) fasting plasma glucose compared to normal levels (80-99 mg/dL).

Over a median follow-up of 14 years, 2101 deaths occurred, of which 570 were due to cardiovascular disease. In a model adjusted for sociodemographic and cardiovascular disease risk factors, individuals with low fasting plasma glucose were at increased risk of cardiovascular disease and all-cause mortality [hazard ratio = 1.79 (95% confidence interval = 1.04-3.08) and hazard ratio = 1.35 (95% confidence interval = 1.02-1.78), respectively], compared to those with normal fasting plasma glucose. These associations were stronger among men than women for both cardiovascular disease mortality and all-cause mortality.

Low fasting plasma glucose in individuals without diabetes is a risk factor for cardiovascular disease and all-cause mortality, especially in men.

Previous studies demonstrated that hyperglycemic glucose concentrations are observed in children that are overweight or have obesity. The aim of this study was to evaluate the effect of a 12 month lifestyle intervention on free-living glycemic profiles in children that were overweight or had obesity, and the association of the alterations with changes in cardiovascular risk parameters. BMI z-score, free-living glycemic profiles, continuous overlapping net glycemic action (CONGA), and cardiovascular parameters were evaluated before and after a multidisciplinary lifestyle intervention, in 33 non-diabetic children that were overweight or had obesity. In children with a decrease in BMI z-score, the duration which glucose concentrations were above the high-normal threshold (6.7 mmol/L) and the glycemic variability decreased significantly. In these children, a decrease in median sensor glucose was associated with decreases in LDL-cholesterol, and systolic and diastolic blood pressure z-score. A decrease in BMI z-score was associated with a decrease in CONGA1, 2, and 4. In conclusion, the glycemic profiles in free-living conditions in children that were overweight improved in children with a decrease in BMI z-score after lifestyle intervention. In those children, changes in median sensor glucose concentrations were associated with changes in LDL-cholesterol and blood pressure z-scores. These results suggest that glucose homeostasis can improve after one year of lifestyle intervention and that these improvements are associated with improvements in cardiovascular health parameters.

We sought to confirm a bidirectional association between severe hypoglycemic events (SHEs) and cardiovascular (CV) event risk and to characterize individuals at dual risk.

In a post hoc analysis of 14,752 Exenatide Study of Cardiovascular Event Lowering (EXSCEL) participants, we examined time-dependent associations between SHEs and subsequent major adverse cardiac events (CV death, nonfatal myocardial infarction [MI] or stroke), fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for acute coronary syndrome (hACS), hospitalization for heart failure (hHF), and all-cause mortality (ACM), as well as time-dependent associations between nonfatal CV events and subsequent SHEs.

SHEs were uncommon and not associated with once-weekly exenatide therapy (hazard ratio 1.13 [95% CI 0.94-1.36], P = 0.179). In fully adjusted models, SHEs were associated with an increased risk of subsequent ACM (1.83 [1.38-2.42], P < 0.001), CV death (1.60 [1.11-2.30], P = 0.012), and hHF (2.09 [1.37-3.17], P = 0.001), while nonfatal MI (2.02 [1.35-3.01], P = 0.001), nonfatal stroke (2.30 [1.25-4.23], P = 0.007), hACS (2.00 [1.39-2.90], P < 0.001), and hHF (3.24 [1.98-5.30], P < 0.001) were all associated with a subsequent increased risk of SHEs. The elevated bidirectional time-dependent hazards linking SHEs and a composite of all CV events were approximately constant over time, with those individuals at dual risk showing higher comorbidity scores compared with those without.

These findings, showing greater risk of SHEs after CV events as well as greater risk of CV events after SHEs, validate a bidirectional relationship between CV events and SHEs in patients with high comorbidity scores.

Simultaneous pancreas-kidney (SPK) transplantation is a proven option of treatment for patients with type 1 diabetes mellitus (T1DM) and related end-stage renal disease. There is discrepancy between the results of different studies about the impact of prolonged normalization of glucose metabolism achieved by SPK on the course of diabetic complications including severe forms of diabetic neuropathy. The objective of the study was to evaluate the prevalence of cardiovascular autonomic neuropathy (CAN) in patients undergoing SPK transplantation and its evolution 10 years after transplantation.

Prospective study of 81 patients transplanted in a single center from year 2002 to 2015. Autonomic function was assessed using cardiovascular autonomic reflex tests (CARTs). CARTs were made before SPK transplantation and during the follow-up. Evolution of tests after SPK transplantation was evaluated by contrasting hypotheses (paired tests). Multiple testing was adjusted with the Benjamini-Hochberg procedure with a false discovery rate of 10%.

48 males and 33 females, mean age 37.4 ± 5.7 years, mean BMI 24.0 ± 3.4 kg/m², and mean duration of diabetes 25.5 ± 6.5 years, received SPK transplantation. Ten years after SPK transplantation, 56 patients re tained the pancreatic graft (42 of them with normofunctioning pancreas and 14 with low doses of insulin therapy). These 42 patients were selected for the autonomic study. Before transplant procedure, all CART results were abnormal. After SPK transplantation, paired test analysis showed an improvement of systolic blood pressure (SBP) response to orthostasis at the 5^th year after SPK (p = 0.03), as well as improvement of the Valsalva ratio at the 3^rd (p < 0.001) and 5^th (p = 0.001) year after SPK. After correcting for the false discovery rate, all the variables of autonomic study reached significance at different time points.

Prevalence of CAN in patients who are candidates for SPK transplantation is high and is generally advanced. SPK transplantation improves CAN with improved Valsalva ratio as the most precocious test.

Immune cells are bioenergetically expensive during activation, which requires tightly regulated control of metabolic pathways. Both low and high glycemic conditions can modulate immune function. States of undernourishment depress the immune system, and in the same way, excessive intake of nutrients, such as an obesity state, compromise its functioning. Multicellular organisms depend on two mechanisms to survive: the regulation and ability to store energy to prevent starvation and the ability to fight against infection. Synergic interactions between metabolism and immunity affect many systems underpinning human health. In a chronic way, the breakdown of glycemic homeostasis in the body can influence cells of the immune system and consequently contribute to the onset of diseases such as type II diabetes, obesity, Alzheimer's, and fat and lean mass loss. On the contrary, exercise, recognized as a primary strategy to control hyperglycemic disorders, also induces a coordinated immune-neuro-endocrine response that acutely modulates cardiovascular, respiratory, and muscle functions and the immune response to exercise is widely dependent on the intensity and volume that may affect an immunodepressive state. These altered immune responses induced by exercise are modulated through the "stress hormones" adrenaline and cortisol, which are a threat to leukocyte metabolism. In this context, carbohydrates appear to have a positive acute response as a strategy to prevent depression of the immune system by maintaining plasma glucose concentrations to meet the energy demand from all systems involved during strenuous exercises. Therefore, herein, we discuss the mechanisms through which exercise may promotes changes on glycemic homeostasis in the metabolism and how it affects immune cell functions under higher or lower glucose conditions.

Hypoglycaemia has long been recognised as a dangerous side-effect of treatment of diabetes with insulin or insulin secretagogues. With its potential to disrupt cerebral function, hypoglycaemia can have a major effect on peoples' lives. Study findings have suggested that hypoglycaemia is associated with an increased risk of cardiovascular events and mortality. Different mechanisms by which hypoglycaemia might provoke cardiovascular events have been identified in experimental studies, and in clinical studies cardiac arrhythmias have been reported to be induced by hypoglycaemia, with one report describing sudden death during a severe episode. Emerging evidence suggests that the association between hypoglycaemia and cardiovascular events and mortality is likely to be multifactorial. The association is probably partly caused by confounding, with hypoglycaemia occurring more frequently in people with comorbidities who are also more likely to die than those without. However, people with type 1 or type 2 diabetes also seem at risk of hypoglycaemia-induced cardiovascular effects. This risk should be recognised by clinicians when agreeing glycaemic goals with patients and choosing appropriate glucose-lowering therapies.

To evaluate the association between fasting plasma glucose (FPG) and mortality by gender.

A total of 17 248 eligible participants from a rural Chinese prospective cohort population were included. The same questionnaire interview and anthropometric and laboratory measurements were performed at both baseline (2007-2008) and follow-up (2013-2014). Participants were classified according to baseline FPG and diabetic status by sex. Restricted cubic splines and Cox proportional-hazards regression models, estimating hazard ratio (HR) and 95% confidence interval (CI), were used to assess the FPG-mortality relation.

During the 6-year follow-up, 618 men and 489 women died. The FPG-mortality relation was J shaped for both sexes. For men, risk of all-cause and noncardiovascular disease (CVD)/noncancer mortality was greater with low fasting glucose (LFG) than with normal fasting glucose (adjusted HR [aHR] 1.60; 95% CI, 1.05-2.43; and aHR 2.16; 95% CI, 1.15-4.05). Men with diabetes mellitus (DM) showed increased risk of all-cause (aHR 2.04; 95% CI, 1.60-2.60), CVD (aHR 1.98; 95% CI, 1.36-2.89), and non-CVD/noncancer mortality (aHR 2.62; 95% CI, 1.76-3.91). Men with impaired fasting glucose (IFG) had borderline risk of CVD mortality (aHR 1.34; 95% CI, 1.00-1.79). Women with LFG had increased risk of non-CVD/noncancer mortality (aHR 2.27; 95% CI, 1.04-4.95), and women with DM had increased risk of all-cause (aHR 1.73; 95% CI, 1.35-2.23), CVD (aHR 1.76; 95% CI, 1.24-2.50), and non-CVD/noncancer mortality (aHR 1.97; 95% CI, 1.27-3.08).

LFG is positively associated with all-cause mortality risk in rural Chinese men but not in women.

Diabetic kidney disease (DKD) is the leading cause of end stage kidney disease (ESKD) and is associated with a considerably shortened lifespan. While glucose-lowering therapy targeting glycated hemoglobin (HbA1c) <7% is proven to reduce the risk of developing DKD, its effects on complications of DKD are unclear.

We examined the associations of HbA1c with risks of progression to ESKD and death within a clinic-based study of CKD. We hypothesized that higher HbA1c concentrations would be associated with increased risks of ESKD and death.

We studied 618 participants from the Seattle Kidney Study (mean eGFR 42 ml/min), 308 of whom had diabetes, and tested associations of baseline HbA1c with time to a composite outcome of initiation of renal replacement therapy or death.

During a median follow-up of 4.2 years, there were 343 instances of the composite outcome (11.5 per 100 person-years). Among participants with diabetes, in both crude and adjusted analyses, higher HbA1c levels (examined continuously or categorically) were not associated with the risk of the composite outcome (HR (95% CI): 0.99 (0.88, 1.10) per 1% additional HbA1c, p = 0.79). HbA1c was not associated with ESKD or mortality when the outcomes were examined separately, nor when stratified between insulin users and non-users.

In a referred population of established DKD, higher HbA1c was not associated with higher risk of ESKD or death. These data support current recommendations to be conservative with glycemic control among patients with advanced diabetes complications, such as CKD.

Cardiovascular (CV) disease (CVD) is a well-recognized complication of type 2 diabetes mellitus (T2DM) and there is a clinical need for glucose-lowering therapies that do not further increase CV risk in this population. Although sulfonylureas (SUs) may be used as second-line therapy for patients requiring additional therapy after first-line metformin to improve glycemic control, their long-term effects on CV outcomes remain uncertain, and a wide range of alternative agents exist including dipeptidyl peptidase-4 (DPP-4) inhibitors.

Literature searches in PubMed (2013-2018) were conducted with terms for DPP-4 inhibitors combined with CV terms, with preference given to cardiovascular outcomes trials (CVOTs). Reference lists from retrieved articles and diabetes guidelines were also considered.

This narrative review discusses current evidence for the CV safety of these agents, describes the long-term CV effects of DPP-4 inhibitors, including effects on CV events, mortality, the risk for heart failure hospitalization, and highlights the need for further research into the CV effects of SU therapy. Although SUs remain a treatment option for T2DM, the long-term effects of these agents on CV outcomes are unclear, and further long-term studies are required. For DPP-4 inhibitors, uncertainties have been raised about their long-term effect on hospitalization for heart failure in light of the results of SAVOR-TIMI 53, although the findings of other DPP-4 inhibitor CVOTs in T2DM and data analyses have suggested these agents do not increase the occurrence of adverse CV outcomes.

Based on recent CVOTs and guideline updates, the choice of add-on to metformin therapy for patients with T2DM and established CV disease should be a sodium-glucose co-transporter-2 inhibitor or a glucagon-like peptide-1 agonist with proven CV benefit. Additional treatment options for those individuals who require therapy intensification, as well as in patients with T2DM and without established CVD include DPP-4 inhibitors and SUs. Since few head-to-head trials have compared the effects of different oral glucose-lowering agents on CV outcomes in T2DM, with most CVOTs using placebo as a comparator, the CAROLINA trial will provide important information on the comparative CV safety of a commonly prescribed SU and a DPP-4 inhibitor.

The purpose of this study was to establish the association between continuous glucose monitoring (CGM)-defined glycaemic variability (GV) and cardiovascular autonomic neuropathy (CAN) in type 1 diabetes independent of mean glucose and to examine the relative contribution of each internationally standardized CGM parameter to this association.

This study included 80 adults with type 1 diabetes who underwent 3-day CGM and autonomic function tests within 3 months. The degree of association between internationally standardized CGM parameters and CAN, defined as at least two abnormal parasympathetic tests or the presence of orthostatic hypotension, were analysed by logistic regression, receiver operating characteristics (ROC), and dominance analysis.

A total of 36 subjects (45.0%) were diagnosed with CAN. When adjusted with mean glucose and clinical risk factors of CAN, standard deviation, coefficient of variation, mean amplitude of glycaemic excursion, percent time in level 1 (glucose 54-69 mg/dL) and level 2 (glucose < 54 mg/dL) hypoglycaemia, area under the curve in level 2 hypoglycaemia, low blood glucose index, high blood glucose index, and percent time in glucose 70 to 180 mg/dL were independently associated with CAN. Multivariable ROC analysis and dominance analysis revealed the highest relative contribution of percent time in level 2 hypoglycaemia to the independent associations between CGM parameters and presence of CAN.

CGM-defined GV was associated with CAN independent of mean glucose in adults with type 1 diabetes. Among internationally standardized CGM parameters, those describing the degree of level 2 hypoglycaemia were the most significant contributors to this association.

Hypoglycemia has been linked to persistent increases in cardiovascular (CV) mortality in type 2 diabetes after the event. Our aim was to examine acute and downstream effects of hypoglycemia on markers of thrombosis risk and inflammation in type 2 diabetes.

Twelve individuals with type 2 diabetes with no history of CV disease and 11 age- and BMI-matched volunteers without diabetes underwent paired hyperinsulinemic-euglycemic (glucose 6 mmol/L for two 60-min periods) and hypoglycemic (glucose 2.5 mmol/L for two 60-min periods) clamps on separate occasions on day 0. Fibrin clot properties, platelet reactivity, and inflammatory markers were measured at baseline, end of and after recovery from the initial clamp, day 1, and day 7 using validated assays and electron microscopy.

Euglycemic hyperinsulinemia reduced platelet reactivity, decreased fibrin clot density, and improved fibrinolytic efficiency in both groups. Platelet reactivity and aggregation increased during acute hypoglycemia in both groups, resolving at recovery. In type 2 diabetes, clot lysis times and clot maximum absorbance increased up to day 7 (P = 0.002 and 0.001 vs. euglycemia, respectively), but clots from control subjects without diabetes showed limited changes. Fibrin network density increased Δ 1.15 ± 0.28 fibers/μm² at day 7 after the hypoglycemic clamp (P < 0.01 for glycemic arm), whereas fibrinogen and complement C3 increased after hypoglycemia up to day 7 in type 2 diabetes only.

Antecedent hypoglycemia has acute and persistent prothrombotic effects, lasting at least 7 days, that were enhanced in individuals with type 2 diabetes. These findings identify mechanisms by which hypoglycemia might increase short- and medium-term risk of CV mortality.