Benefits Of Tight Glycemic Control Research Articles

Potential overtreatment of type 2 diabetes therapy in real clinical practice: Omsk Oblast register data

Backgraund: The total number of patients with type 2 diabetes mellitus (T2DM) in the Russian Federation as of 01.01.2019 is 4.24 million. The majority of patients with T2DM are elderly people and older, forming groups with high comorbidity and the risk of severe hypoglycemia, including those associated with excess hypoglycemic therapy. Foreign studies indicate that a significant proportion of older adults with diabetes are potentially exposed to excessive sugar-lowering therapy.Aims: to study the frequency of excessive decrease in HbA1c in a group of patients with T2DM according to a sample from the regional diabetes register.Materials and methods: A content analysis of the regional register of diabetes mellitus was carried out as of ­December 31, 2019. Based on the register data, an individual target level of HbA1c was calculated and the compliance of the achieved HbA1c level with the target level was assessed.Results: The analysis included data from 1202 patients with T2DM, which amounted to 2.35% of the total number of patients with T2DM in the region (n = 51,163). The age of the included individuals was 66 years (LQ 60.0; UQ 72), 360 men (29.95%). The duration of T2DM 8.0 years. The HbA1c level in the general group was 7.1%. Persons over 60 years of age accounted for 75.21% (n = 904). When analyzing HbA1c in the age groups, there were no statistically significant differences (p> 0.05). HbA1c was above the target level in 43.34% of cases (n = 521). The level of HbA1c <6.5% was noted in a quarter of cases (24.62%), including HbA1c <6.0% was recorded in 97 cases, which accounted for a third of all cases of tight glycemic control. At the same time, the majority of observations of HbA1c <6.5% were in patients 60 years and older (79.73%). Among young and middle-aged patients with HbA1c <6.5%, 8.33% of cases had risk factors for severe hypoglycemia in the presence of SU and / or insulin therapy. In the older age group (in comparison with young and middle-aged patients), HbA1c <7% (p <0.05) was significantly more often detected, there was a tendency for a higher frequency of HbA1c <6.5% (p = 0.067). Among elderly and senile patients with HbA1c <6.5%, in 41.53% of cases there were risk factors for severe hypoglycemia, in a quarter of cases in T2DM therapy SU and / or insulin were used (24.58%), almost every fifth patient (19.07%), risk factors for severe hypoglycemia, received SU and / or insulin.Conclusion: According to our data, at least a quarter of patients in the older age group (24.58%) had overtreatment and need de-intensification of therapy. Perhaps that in this group of patients, the risks associated with treatment may outweigh the benefits of tight glycemic control, and these patients require planned de-intensification of glucose-lowering therapy. Taking into account the position of some expert communities on determining the target range of HbA1c in the older age group, the need for de-intensification of antihyperglycaemic therapy may be even higher. Further research is required in order to develop a full-fledged domestic concept of de-intensification of hypoglycemic therapy.

399-P: Deintensification of Diabetes Treatment in Elderly Patients with Type 2 Diabetes Mellitus

The prevalence of type 2 diabetes mellitus (T2DM) is increasing, especially in the elderly population. Many of these patients have co-morbidities like renal insufficiency, cognitive impairment and lack of social support, increasing the risk of hypoglycemia. Moreover, the benefits of tight glycemic control have not been established in the elderly. Therefore, the American Diabetes Association recommends relaxed glycemic goals (HbA1c ∼8%) in the elderly population. De-intensification of diabetes treatment is recommended to prevent potential harm. We conducted a retrospective study to evaluate the rate of de-intensification of antidiabetic treatment in patients aged ≥75 years with HbA1c ≤7% at the time of their clinic visits. All patients with ≥2 clinic visits over 1-year period at a major academic diabetes center were included. Out of 1,417 unique patients treated during 2017, 174 were ≥75 years old on the day of their last clinic visit. Out of these, 80 patients had an HbA1c ≤7%. Medical records of these 80 patients were manually reviewed for comorbidities, hypoglycemic episodes and drug therapy. A mention of de-intensification of antidiabetic treatment was found in physicians’ notes in only 12 cases. After excluding those with type 1 diabetes, inadequate documentation or controlled on medications without hypoglycemia potential, we found 36 patients treated with a sulfonylurea drug or insulin. Only 10 (27%) patients were advised to reduce the dose of sulfonylurea drug or insulin after an HbA1c <7% was noted. Out of patients receiving a sulfonylurea drug or insulin, 17 had at least one episode of hypoglycemia before the visit. Even among patients with documented hypoglycemia, only 7 (41%) were advised to de-intensify therapy. Our study suggests that de-intensification of antidiabetic medications is infrequent despite the potential harm of hypoglycemia in elderly patients with T2DM. Strategies need to be developed to prevent overtreatment of diabetes in the elderly patients. Disclosure D.V. Pirela: None. R. Garg: None.

2199-PUB: Insulin Use and Hypoglycemia Prevalence in an Australian Public Hospital Setting

Aims: Diabetes management in hospital often focuses on tight glycemic control. Insulin use is, therefore, more common in the hospital inpatient setting. We sought to determine the prevalence and patterns of insulin use and hypoglycemia among inpatients with diabetes on medical wards in a tertiary Sydney hospital. Methods: A daily census was conducted on three medical wards (79 beds) over 44 weeks from June 2017. Inpatients with diabetes were audited using a questionnaire based on the UK National Diabetes Inpatient Audit. Those admitted for >7 days were audited for the last 7 days of admission. Results: Among 822 patients with diabetes, 96% had T2DM, mean age (SD) was 69.1(12.3) years, 54.8% male. Overall, 29.6% were on insulin on admission but 44.7% were prescribed insulin during their hospital stay. Hypoglycemia (<4.0mmol/L) occurred in 111 patients (13.5%) with 225 episodes, and severe hypoglycemia (<3.0mmol/L) occurred in 39 patients (4.8%) with 52 episodes. Insulin was prescribed during hospital stay in 78.4% of patients who had hypoglycemia, and 92.3% who had severe hypoglycemia. There was a greater prevalence of hypoglycemia out of hours (5pm-8am) compared to 8am-5pm (167 vs. 58 episodes). Conclusions: Hypoglycemia and severe hypoglycemia were common among hospital inpatients, and insulin use in this group was high. Insulin use was a major risk factor for hypoglycemia, particularly with new insulin initiation and after hours. These data highlight the need to weigh the risk of hypoglycemia against the benefit of tight glycemic control when considering insulin initiation in hospital. Extra vigilance is also needed after hours when there is a higher risk of hypos with fewer staff. Disclosure M.K. Piya: None. T. Fletcher: None. K. Myint: None. R. Zarora: None. D. Simmons: Speaker's Bureau; Self; Sanofi-Aventis. Other Relationship; Self; Medtronic. Funding South Western Sydney Local Health District

Glycemic control, mortality, and hypoglycemia in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials

It is unclear whether tight glycemic control is warranted in all critically ill adults. We employed network meta-analysis to examine the risk of mortality and hypoglycemia associated with different glycemic control targets in critically ill adults. Electronic databases were searched up to 2016 for randomized controlled trials comparing various insulin regimens in critically ill adults with hyperglycemia. Two reviewers independently extracted information and evaluated quality with the Cochrane risk-of-bias tool. Four glycemic control groups were compared: tight (blood glucose: 4.4<6.1mmol/l), moderate (6.1<7.8mmol/l), mild (7.8<10.0mmol/l), and very mild (10.0 to<12.2mmol/l). Network meta-analysis was performed by a frequentist approach with multivariate random effects meta-analysis. Thirty-six randomized trials (17,996 patients) were identified. Compared with very mild control, tight control did not reduce the risk of short-term mortality [relative risk (RR) 0.94 (95% CI 0.83-1.07, p=0.36)], and neither did mild control [RR 0.88 (0.73-1.06), p=0.18] or moderate control [RR 1.1 (0.66-1.84), p=0.72]. However, severe hypoglycemia (<2.2mmol/l) was more frequent with tight control than very mild control [RR 5.49 (3.22-9.38), p<0.001] or mild control [RR 4.47 (2.5-8.03), p<0.001]. Stratified analyses (cause of death, ICU type, time period, or diabetes) did not find significant between-group differences. Ranking analysis revealed the following hierarchy for avoiding death (highest to lowest rank): mild control, tight control, and very mild control. Network meta-analysis showed no mortality benefit of tight glycemic control in critically ill patients, but fivefold more hypoglycemia versus mild or very mild control.

Ketosis After Cardiopulmonary Bypass in Children Is Associated With an Inadequate Balance Between Oxygen Transport and Consumption.

Hyperglycemia after cardiac surgery and cardiopulmonary bypass in children has been associated with worse outcome; however, causality has never been proven. Furthermore, the benefit of tight glycemic control is inconsistent. The purpose of this study was to describe the metabolic constellation of children before, during, and after cardiopulmonary bypass, in order to identify a subset of patients that might benefit from insulin treatment. Prospective observational study, in which insulin treatment was initiated when postoperative blood glucose levels were more than 12 mmol/L (216 mg/dL). Tertiary PICU. Ninety-six patients 6 months to 16 years old undergoing cardiac surgery with cardiopulmonary bypass. None. Metabolic tests were performed before anesthesia, at the end of cardiopulmonary bypass, at PICU admission, and 4 and 12 hours after PICU admission, as well as 4 hours after initiation of insulin treatment. Ketosis was present in 17.9% patients at the end of cardiopulmonary bypass and in 31.2% at PICU admission. Young age was an independent risk factor for this condition. Ketosis at PICU admission was an independent risk factor for an increased difference between arterial and venous oxygen saturation. Four hours after admission (p = 0.05). Insulin corrected ketosis within 4 hours. In this study, we found a high prevalence of ketosis at PICU admission, especially in young children. This was independently associated with an imbalance between oxygen transport and consumption and was corrected by insulin. These results set the basis for future randomized controlled trials, to test whether this subgroup of patients might benefit from increased glucose intake and insulin during surgery to avoid ketosis, as improving oxygen transport and consumption might improve patient outcome.

Outcome studies and safety as guide for decision making in treating patients with type 2 diabetes.

Cardiovascular disease is the leading cause of mortality in patients with diabetes. Over the past 20 years multiple CV outcome studies have been conducted assessing the cardiovascular benefits of tight glycemic control or of particular glucose lowering agents. Improved glycemic control per-se failed to significantly reduce the risk of adverse cardiovascular outcomes in the short term, and it is only after >15 years that a reduction in adverse CV outcomes with tight glycemic control was perceived. Moreover tight glycemic control and increased attendant hypoglycemia led to increased mortality observed in the ACCORD trial. These data highlighted the importance of setting individualized glycemic targets and assessing the CV safety of the individual glucose lowering agents. Three DPP-4 inhibitors have presented CV outcome data to date demonstrating overall CV safety yet the question of increased hospitalization for heart failure with saxagliptin remains unexplained. Lixisenatide was the first GLP-1 receptor agonist to publish CV outcome data which demonstrated overall safety. The SGLT-2 inhibitor empagliflozin demonstrated CV superiority and a reduction in all-cause mortality and hospitalization for heart failure vs. placebo via mechanisms which remain to be fully elucidated. The outcome studies, though large and costly, have had a considerable effect on diabetes guidelines, these now emphasizing the importance of individualization of care. The outcome studies will presumably influence the new guidelines and dictate better tailoring of the drug regimen to the individual patient, matching patient comorbidities to the accumulating data regarding the safety and efficacy of each drug and class.

Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations — Part I

Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations — Part I

Type 1 diabetes in adults: new NICE guidance on diagnosis and management

Type 1 diabetes in adults: new <scp>NICE</scp> guidance on diagnosis and management

Antidiabetic Therapy in End‐Stage Renal Disease

There has been substantial growth in the variety of available antidiabetic agents during the last decade and a half. The role of these newer agents in patients with diabetes and end-stage renal disease (ESRD) population, and their relative benefits and risks in this population compared to patients without ESRD are not yet clear. This stems from the altered state of glucose homeostasis in ESRD, which places patients at high risk for hypoglycemia and, in certainsituations, hyperglycemia. In addition, there is a dearth of evidence to support a benefit of tight glycemic control on either micro- or macrovascular outcomes in ESRD patients; furthermore, the metrics by which glycemic control is conventionally measured are less valid in ESRD. In this review, we will discuss noninsulin and insulin-based therapies as well as unique challenges, contraindications, advantages, and disadvantages to their use in ESRD. We will also review issues pertinent to both hemodialysis (HD) and peritoneal dialysis (PD) patients.

Low HbA1c and Increased Mortality Risk-is Frailty a Confounding Factor?

Diabetes mellitus is increasingly becoming an older person disease due to the increased survival and aging of the population. Previous studies which showed benefits of tight glycemic control and a linear relationship between HbA1c and mortality have largely included younger patients newly diagnosed with diabetes and with less comorbidities. Recent studies, which included older population with diabetes, have shown a U-shaped relationship of increased mortality associated with low HbA1c. The mechanism of such relationship is unclear. There was no direct causal link between low HbA1c and mortality. It appears that malnutrition, inflammation and functional decline are characteristics shared by the populations that showed increased mortality and low HbA1c. In these studies functional status, disability or frailty was not routinely measured. Therefore, although adjustment for comorbidities was made there may be a residual confounding by unmeasured factors such as frailty. Thus, frailty or decline in functional reserve may be the main confounding factor explaining the relationship between increased mortality risk and low HbA1c.

Glucose Homeostasis Disorders in Premature Infants

An abnormal plasma glucose concentration is one of the most commonly encounter­ ed metabolic problems in the intensive care of premature infants. Compared with term infants, glycogen reserves are lower in the preterm neonatal liver. Despite this, preterm infants are at a greater risk of hyperglycemia than term infants are, which is owing to comparable production rate of endogenous glucose and impaired ability to reduce glucose production rate in response to hyperglycemia. Debate continues about the normal plasma glucose concentrations and the guideline for glucose con­ trol in pre mature infants. Some randomized controlled trials in very low birth weight infants demonstrated little clinical benefit of tight glycemic control with early insulin therapy and higher calorie intake in terms of mortality, morbidities and growth para­ meters. Compared with term infants, preterm infants have limited endocrine and metabolic adaptation to hypoglycemia. In any case, hypoglycemia in premature in­ fants should not be considered a physiologic condition. The operational criteria for intervention of hypoglycemia should be different from that in term infants. Con­ tinuous non­invasive glucose monitoring is a promising tool considering the principle of minimal handling of extremely premature infants. However, the clinical implication of abnor mal glucose concentrations, previously undetected on intermittent measure­ ments, is unclear.

Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats.

Recurrent exposure to hypoglycemia can impair the normal counterregulatory hormonal responses that guard against hypoglycemia, leading to hypoglycemia unawareness. This pathological condition known as hypoglycemia-associated autonomic failure (HAAF) is the main adverse consequence that prevents individuals with type 1 diabetes mellitus from attaining the long-term health benefits of tight glycemic control. The underlying molecular mechanisms responsible for the progressive loss of the epinephrine response to subsequent bouts of hypoglycemia, a hallmark sign of HAAF, are largely unknown. Normally, hypoglycemia triggers both the release and biosynthesis of epinephrine through activation of nicotinic acetylcholine receptors (nAChR) on the adrenal glands. We hypothesize that excessive cholinergic stimulation may contribute to impaired counterregulation. Here, we tested whether administration of the nAChR partial agonist cytisine to reduce postganglionic synaptic activity can preserve the counterregulatory hormone responses in an animal model of HAAF. Compared with nicotine, cytisine has limited efficacy to activate nAChRs and stimulate epinephrine release and synthesis. We evaluated adrenal catecholamine production and secretion in nondiabetic rats subjected to two daily episodes of hypoglycemia for 3 days, followed by a hyperinsulinemic hypoglycemic clamp on day 4. Recurrent hypoglycemia decreased epinephrine responses, and this was associated with suppressed TH mRNA induction (a measure of adrenal catecholamine synthetic capacity). Treatment with cytisine improved glucagon responses as well as epinephrine release and production in recurrently hypoglycemic animals. These data suggest that pharmacological manipulation of ganglionic nAChRs may be promising as a translational adjunctive therapy to avoid HAAF in type 1 diabetes mellitus.

Glycaemic control: a balancing act or a different approach?

The prevalence of diabetes is increasing world-wide. Tight glycaemic control has been shown to reduce diabetes complications in a number of landmark trials. Apart from increasing the risk of microvascular and macrovascular disease, poor glycaemic control is also associated with cognitive and memory impairment as well as with mood disturbance. However, tighter glycaemic control with conventional anti-hyperglycaemic medication is also associated with increased risk of hypoglycaemia. There is increasing evidence that hypoglycaemia is much more than a troublesome inconvenience. Indeed it is associated with acute cognitive impairment, dementia, increased risk of falls, rebound hyperglycaemia with consequent loss of glycaemic control, acute coronary syndrome and increased mortality. Hence, a very difficult balance needs to be achieved so as to achieve the best glycaemic control possible, whilst avoiding hypoglycaemia. This paper will briefly discuss the potential benefits of tight glycemic control and reviews the risks associated with hypoglycaemia. A paradigm shift in diabetes care may be needed; use of newer anti-hyperglycemic agents with low hypoglycaemia risk may allow us to achieve good control in most patients whilst avoiding the serious consequences of hypoglycaemia. This may be especially important in those at significant risk of hypoglycaemia (e.g. those with brittle diabetes) or of its consequences such as elderly patients, those in certain occupations or those with cardiovascular disease or epilepsy.

So Much Insulin, So Much Hypoglycemia

So Much Insulin, So Much Hypoglycemia

The benefits of tight glycemic control in critical illness: Sweeter than assumed?

Hyperglycemia has long been observed amongst critically ill patients and associated with increased mortality and morbidity. Tight glycemic control (TGC) is the clinical practice of controlling blood glucose (BG) down to the “normal” 4.4–6.1 mmol/L range of a healthy adult, aiming to avoid any potential deleterious effects of hyperglycemia. The ground-breaking Leuven trials reported a mortality benefit of approximately 10% when using this technique, which led many to endorse its benefits. In stark contrast, the multi-center normoglycemia in intensive care evaluation–survival using glucose algorithm regulation (NICE-SUGAR) trial, not only failed to replicate this outcome, but showed TGC appeared to be harmful. This review attempts to re-analyze the current literature and suggests that hope for a benefit from TGC should not be so hastily abandoned. Inconsistencies in study design make a like-for-like comparison of the Leuven and NICE-SUGAR trials challenging. Inadequate measures preventing hypoglycemic events are likely to have contributed to the increased mortality observed in the NICE-SUGAR treatment group. New technologies, including predictive models, are being developed to improve the safety of TGC, primarily by minimizing hypoglycemia. Intensive Care Units which are unequipped in trained staff and monitoring capacity would be unwise to attempt TGC, especially considering its yet undefined benefit and the deleterious nature of hypoglycemia. International recommendations now advise clinicians to ensure critically ill patients maintain a BG of <10 mmol/L. Despite encouraging evidence, currently we can only speculate and remain optimistic that the benefit of TGC in clinical practice is sweeter than assumed.

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Introduction: In a 2001 landmark trial, the potential benefits of tight glycemic control (TGC) were reported, stimulating support to implement TGC strategies in the ICU. By 2006, evidence opposing TGC was subsequently reported culminating in the publication of NICE-SUGAR in 2009. Published guidelines have since recommended against TGC, however, there is no objective description of how the changing literature has affected practice patterns. The purpose of this study is to evaluate annual ICU glycemic control trends between 2005 and 2012 in a large cohort of ICU patients (pts). Methods: All adult non-trauma ICU admissions in the eICU Research Institute database were included, excluding pts admitted with DKA. Hyperglycemia (HG+) was defined by a time-weighted average daily glucose >180 mg/dL and hypoglycemia (HG-) by a glucose value <50 mg/dL. Incidence rate ratios (IRR) for days with HG+ and HG- per total pt days were calculated yearly using negative binomial regression and a robust variance estimator clustered by each ICU and are reported relative to 2012. Results: Overall, 6,249,767 pt-days were evaluated across all ICU types, including: cardiac (n=1,212,865), cardiothoracic (n=714,051), medical (n=512,309), surgical (n=488.895), neurologic (n=319,629) and mixed (n=3,002,018). Between 2005 and 2007, HG+ rates decreased and HG- rates increased. In 2005, the incidence rate (IR) of HG+ was 17.2% (IRR=1.0; 0.94-1.08) and 1.5% (IRR=0.71; 0.63-0.80) for HG-. In 2007, the IR of HG+ was 14.4% (IRR=0.87; 0.83-0.91) and 2.7% (IRR=1.18; 1.12-1.32) for HG-. Rates of HG+ and HG- were relatively stable between 2007 and the publication of NICE-SUGAR in 2009. The proportion of HG+ days has increased annually since 2009. In 2012, the IR of HG+ and HG- were 18.0% and 2.1% respectively. Trends were similar in all ICU types at both teaching and non-teaching facilities. Conclusions: These data objectively describe broad increased adoption of TGC strategies which began to plateau in 2007 and reversed trajectory after publication of NICE-SUGAR in 2009. ICU practice appears to have changed over time in relation to peer-reviewed research publications, preceding the publication of revised national guidelines regarding glycemic control in ICU pts. These data also confirm the inverse relationship of HG+ and HG- exists in real-world settings outside of randomized controlled trials.

Tsunami of diabetes: Help is on the way

In his presidential address at the 73rd Scientifi c Sessions of the American Diabetes Association (ADA), John Anderson, MD, asked whether the United States is prepared for this “tsunami of diabetes.” Held in June, this year’s 73rd Scientifi c Sessions drew nearly 18,000 participants and included 2,500 abstracts, more than 2,000 research posters, and 92 symposia. The meeting was internationally attended. An estimated 60% of meeting attendees came to Chicago from countries outside of the United States. This year’s program included presentations on treatment strategies for type 1 diabetes, as well as information on the effi cacy of novel agents for diabetes and potential pathways for targeting better control of the disease. Key highlights from the meeting included a look back on important trials such as the Diabetes Control and Complications Trial (DCCT) and a glimpse into the future for the treatment of diabetes, including new drugs and formulations of antidiabetic agents.

Vascular Protection in People with Diabetes

Vascular Protection in People with Diabetes

Targets for Glycemic Control

Targets for Glycemic Control

Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients

To evaluate the literature and identify important aspects of insulin therapy that facilitate safe and effective infusion therapy for a defined glycemic end point. Where available, the literature was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to assess the impact of insulin infusions on outcome for general intensive care unit patients and those in specific subsets of neurologic injury, traumatic injury, and cardiovascular surgery. Elements that contribute to safe and effective insulin infusion therapy were determined through literature review and expert opinion. The majority of the literature supporting the use of insulin infusion therapy for critically ill patients lacks adequate strength to support more than weak recommendations, termed suggestions, such that the difference between desirable and undesirable effect of a given intervention is not always clear. The article is focused on a suggested glycemic control end point such that a blood glucose ≥ 150 mg/dL triggers interventions to maintain blood glucose below that level and absolutely <180 mg/dL. There is a slight reduction in mortality with this treatment end point for general intensive care unit patients and reductions in morbidity for perioperative patients, postoperative cardiac surgery patients, post-traumatic injury patients, and neurologic injury patients. We suggest that the insulin regimen and monitoring system be designed to avoid and detect hypoglycemia (blood glucose ≤ 70 mg/dL) and to minimize glycemic variability.Important processes of care for insulin therapy include use of a reliable insulin infusion protocol, frequent blood glucose monitoring, and avoidance of finger-stick glucose testing through the use of arterial or venous glucose samples. The essential components of an insulin infusion system include use of a validated insulin titration program, availability of appropriate staffing resources, accurate monitoring technology, and standardized approaches to infusion preparation, provision of consistent carbohydrate calories and nutritional support, and dextrose replacement for hypoglycemia prevention and treatment. Quality improvement of glycemic management programs should include analysis of hypoglycemia rates, run charts of glucose values <150 and 180 mg/dL. The literature is inadequate to support recommendations regarding glycemic control in pediatric patients. While the benefits of tight glycemic control have not been definitive, there are patients who will receive insulin infusion therapy, and the suggestions in this article provide the structure for safe and effective use of this therapy.