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      Cardiac resynchronization therapy with a defibrillator (CRTd) in failing heart patients with type 2 diabetes mellitus and treated by glucagon-like peptide 1 receptor agonists (GLP-1 RA) therapy vs. conventional hypoglycemic drugs: arrhythmic burden, hospitalizations for heart failure, and CRTd responders rate

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          Abstract

          Objectives

          To evaluate clinical outcomes in patients with diabetes, treated by cardiac resynchronization therapy with a defibrillator (CRT-d), and glucagon-like peptide 1 receptor agonists (GLP-1 RA) in addition to conventional hypoglycemic therapy vs. CRTd patients under conventional hypoglycemic drugs.

          Background

          Patients with diabetes treated by CRTd experienced an amelioration of functional New York Association Heart class, reduction of hospital admissions, and mortality, in a percentage about 60%. However, about 40% of CRTd patients with diabetes experience a worse prognosis.

          Materials and methods

          We investigated the 12-months prognosis of CRTd patients with diabetes, previously treated with hypoglycemic drugs therapy (n 271) vs. a matched cohort of CRTd patients with diabetes treated with GLP-1 RA in addition to conventional hypoglycemic therapy (n 288).

          Results

          At follow up CRTd patients with diabetes treated by GLP-1 RA therapy vs. CRTd patients with diabetes that did not receive GLP-1 RA therapy, experienced a significant reduction of NYHA class (p value < 0.05), associated to higher values of 6 min walking test (p value < 0.05), and higher rate of CRTd responders (p value < 0.05). GLP-1 RA patients vs. controls at follow up end experienced lower AF events (p value < 0.05), lower VT events (p value < 0.05), lower rate of hospitalization for heart failure worsening (p value < 0.05), and higher rate of CRTd responders (p value < 0.05). To date, GLP-1 RA therapy may predict a reduction of AF events (HR 0.603, CI [0.411–0.884]), VT events (HR 0.964, CI [0.963–0.992]), and hospitalization for heart failure worsening (HR 0.119, CI [0.028–0.508]), and a higher CRT responders rate (HR 3.707, CI [1.226–14.570]).

          Conclusions

          GLP-1 RA drugs in addition to conventional hypoglycemic therapy may significantly reduce systemic inflammation and circulating BNP levels in CRTd patients with diabetes, leading to a significant improvement of LVEF and of the 6 min walking test, and to a reduction of the arrhythmic burden. Consequently, GLP-1 RA drugs in addition to conventional hypoglycemic therapy may reduce hospital admissions for heart failure worsening, by increasing CRTd responders rate.

          Trial registration NCT03282136. Registered 9 December 2017 “retrospectively registered”

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          Most cited references 34

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          American Association of Clinical Endocrinologists and American Diabetes Association Consensus Statement on Inpatient Glycemic Control

          People with diabetes are more likely to be hospitalized and to have longer durations of hospital stay than those without diabetes. A recent survey estimated that 22% of all hospital inpatient days were incurred by people with diabetes and that hospital inpatient care accounted for half of the 174 billion USD total U.S. medical expenditures for this disease (1). These findings are due, in part, to the continued expansion of the worldwide epidemic of type 2 diabetes. In the U.S. alone, there are ∼1.6 million new cases of diabetes each year, with an over all prevalence of 23.6 million people (7.8% of the population, with one-fourth of the cases remaining undiagnosed). An additional 57 million American adults are at high risk for type 2 diabetes (2). Although the costs of illness-related stress hyperglycemia are not known, they are likely to be considerable in light of the poor prognosis of such patients (3 –6). There is substantial observational evidence linking hyperglycemia in hospitalized patients (with or without diabetes) to poor outcomes. Cohort studies as well as a few early randomized controlled trials (RCTs) have suggested that intensive treatment of hyperglycemia improved hospital outcomes (5 –8). In 2004, this evidence led the American College of Endocrinology (ACE) and the American Association of Clinical Endocrinologists (AACE), in collaboration with the American Diabetes Association (ADA) and other medical organizations, to develop recommendations for treatment of inpatient hyperglycemia (9). In 2005, the ADA added recommendations for treatment of hyperglycemia in the hospitalto itsannual Standards of Medical Care (10). Recommendations from the ACE and the ADA generally endorsed tight glycemic control in critical care units. For patients in general medical and surgical units, where RCT evidence regarding treatment targets was lacking, glycemic goals similar to those advised for outpatients were advocated (9,10). In 2006, the ACE and the ADA partnered on a joint “call to action” for inpatient glycemic control, addressing a number of systematic implementation barriers in hospitals (11). These efforts contributed to a growing national movement viewing the management of inpatient hyperglycemia as a quality-of-care measure. Although hyperglycemia is associated with adverse patient outcomes, intervention to normalize glycemia has yielded inconsistent results. Indeed, recent trials in critically ill patients have failed to showa significant improvement in mortality with intensive glycemic control (12,13) or have even shown increased mortality risk (14). Moreover, these recent RCTs have highlighted the risk of severe hypoglycemia resulting from such efforts (12 –17). These outcomes have contributed to confusion regarding specific glycemic targets and the means for achieving them in both critically ill and noncritically ill patients. Recognizing the importance of glycemic control across the continuum of care, the AACE and the ADA joined forces to develop this updated consensus statement on inpatient glycemic management. The central goals were to identify reasonable, achievable, and safe glycemic targets and to describe the protocols, procedures, and system improvements needed to facilitate their implementation. This document is addressed to health care professionals, supporting staff, hospital administrators, and other stakeholders focused on improved management of hyperglycemia in inpatient settings. Consensus panel members extensively reviewed the most current literature and considered the following questions: Does improving glycemic control improve clinical outcomes for inpatients with hyperglycemia? What glycemic targets can be recommended in different patient populations? What treatment options are available for achieving optimal glycemic targets safely and effectively in specific clinical situations? Does inpatient management of hyperglycemia represent a safety concern? What systems need to be in place to achieve these recommendations? Is treatment of inpatient hyperglycemia cost-effective? What are the optimal strategies for transition to outpatient care? What are areas for future research? QUESTION 1: DOES IMPROVING GLYCEMIC CONTROL IMPROVE CLINICAL OUTCOMES FOR INPATIENTS WITH HYPERGLYCEMIA? Hyperglycemia in hospitalized patients, irrespective of its cause, is unequivocally associated with adverse outcomes (5,6,18 –25). Hyperglycemia occurs in patients with known or undiagnosed diabetes, or it occurs during acute illness in those with previously normal glucose tolerance (termed “stress hyperglycemia”) (8,26). Intervention directed at reducing blood glucose (BG) levels has resulted in improved outcomes in some, but not all, studies (5,18 –25). Several recent clinical trials in critically ill patients have reported no reduction in mortality from intensive treatment targeting near-euglycemia versus conventional management targeting BG 200 randomized patients) a Trial N Setting Blood glucose target [mg/dl (mmol/l)] Blood glucose achieved [mg/dl (mmol/l)] b Primary outcome End point rate (%) ARR (%) c RRR (%) c Odds ratio (95% CI) Intensive Conventional Intensive Conventional Intensive Conventional DIGAMI (ref. 33), 1995 620 CCU (AMI) 126–196 (7–10.9) Usual care 173 (9.6) 211 (11.7) 1-year mortality 18.6 26.1 7.5 29 d NR Van den Berghe et al. (ref. 5), 2001 1,548 SICU 80–110 (4.4–6.1) 180–200 (10–11) 103 (5.7) 153 (8.5) ICU mortality 4.6 8.0 3.4 42 0.58(0.38–0.78) d DIGAMI 2 (ref. 34), 2005 1,253 CCU (AMI) 126–180 (7–10) (groups 1 and 2) Usual care (group 3) 164 (9.1) 180 (10) 2-year mortality Group 1, 23.4; group 2, 21.2 Group 3, 17.9 — e — e NR Van den Berghe et al. (ref. 16), 2006 1,200 MICU 80–110 (4.4–6.1) 180–200 (10–11) 111 (6.2) 153 (8.5) Hospital mortality 37.3 40.0 2.7 7.0 0.94(0.84–1.06) e HI-5 (ref. 35), 2006 240 CCU (Ami) (GIK) 72–180 (4–10) Usual care 0.05). fPresented as abstract only. gComposite of death, sternal infection, prolonged ventilation, cardiac arrhythmias, stroke, and renal failure at 30 days. hOnly patients with sepsis. iPersonal communication, Dr. Frank Brunkhorst. The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study reported no decrease in mortality and higher rates of severe hypoglycemia with intensive insulin therapy in patients with severe sepsis (17 vs. 4.1%; P 95%) required mechanical ventilation (14). The 90-day mortality was significantly higher in the intensively treated versus the conventionally treated group (78 more deaths; 27.5 vs. 24.9%; P = 0.02) in both surgical and medical patients. Mortality from cardiovascular causes was more common in the intensively treated group (76 more deaths; 41.6 vs. 35.8%; P = 0.02). Severe hypoglycemia was also more common in the intensively treated group (6.8 vs. 0.5%; P 200 mg/dl [11.1 mmol/l]) were found to have a 2.2-fold higher rate of mortality than those with admission glucose of 140 mg/dl (>7.8 mmol/l). Levels that are significantly and persistently above this level may necessitate treatment in hospitalized patients. In patients without a previous diagnosis of diabetes, elevated BG concentrations may be due to stress hyperglycemia, a condition that can be established by a review of prior medical records or measurement of A1C. A1C values of >6.5–7.0% suggest that diabetes preceded hospitalization (87). Hypoglycemia is defined as any BG level <70 mg/dl (<3.9 mmol/l) (88). This is the standard definition in outpatients and correlates with the initial threshold for the release of counterregulatory hormones (89). Severe hypoglycemia in hospitalized patients has been defined by many clinicians as <40 mg/dl (<2.2 mmol/l), although this value is lower than the approximate 50 mg/dl (2.8 mmol/l) level at which cognitive impairment begins in normal individuals (89 –91). As with hyperglycemia, hypoglycemia among inpatients is also associated with adverse short-term and long-term outcomes. Early recognition and treatment of mild to moderate hypoglycemia (40 and 69 mg/dl [2.2 and 3.8 mmol/l], respectively) can prevent deterioration to a more severe episode with potential adverse sequelae (91,92). Treatment of hyperglycemia in critically ill patients On the basis of the available evidence, insulin infusion should be used to control hyperglycemia in the majority of critically ill patients in the ICU setting, with a starting threshold of no higher than 180 mg/dl (10.0 mmol/l). Once IV insulin therapy has been initiated, the glucose level should be maintained between 140 and 180 mg/dl (7.8 and 10.0 mmol/l). Greater benefit may be realized at the lower end of this range. Although strong evidence is lacking, somewhat lower glucose targets may be appropriate in selected patients. Targets <110 mg/dl (6.1 mmol/l), however, are not recommended. Use of insulin infusion protocols with demonstrated safety and efficacy, resulting in low rates of occurrence of hypoglycemia, is highly recommended. Treatment of hyperglycemia in noncritically ill patients With no prospective, RCT data for establishing specific guidelines in noncritically ill patients, our recommendations are based on clinical experience and judgment. For the majority of noncritically ill patients treated with insulin, premeal glucose targets should generally be <140 mg/dl (<7.8 mmol/l) in conjunctionwith random BG values <180 mg/dl (<10.0 mmol/l), as long as these targets can be safely achieved. For avoidance of hypoglycemia, consideration should be given to reassessing the insulin regimen if BG levels decline below 100 mg/dl (5.6 mmol/l). Modification of the regimen is necessary when BG values are <70 mg/dl (<3.9 mmol/l), unless the event is easily explained by other factors (such as a missed meal). Occasional clinically stable patients with a prior history of successful tight glycemic control in the outpatient setting may be maintained with a glucose range below the aforementioned cut points. In contrast, higher glucose ranges may be acceptable in terminally ill patients or in patients with severe comorbidities, as well as in those in patient-care settings where frequent glucose monitoring or close nursing supervision is not feasible. We emphasize that clinical judgment in combination with ongoing assessment of the patient's clinical status, including changes in the trajectory of glucose measures, the severity of illness, the nutritional status, or the concurrent use of medications that might affect glucose levels (for example, corticosteroids or octreotide), must be incorporated into the day-to-day decisions regarding insulin dosing (93,94). Inpatient glucose metrics Hospitals attempting to improve the quality of their glycemic control and clinical investigators who analyze glycemic management require standardized glucose measures for assessment of baseline performance and the effect of any intervention (11). Several methods have been proposed for determining the adequacyof glycemic control across a hospital or unit. A recent study indicated that a simple measure of mean BG (39) provides information similar to that from more complex metrics (hyperglycemic index, time-averaged glucose) (14,48). The “patient-day” unit of measure is anotherproposedmetric of hospital glucose data, especially when there is substantial variability in the duration of hospital stay (95). The patient-day metric may yield a more accurate assessment of the frequency of hypoglycemia and severe hyperglycemic events, providing an approach for obtaining measures of performance for clinical investigation (95). The absolute definition of high-quality BG control has not been determined. Of course, one should aim for the highest percentage of patients within a prespecified BG target range. The opposite holds true for hypoglycemia. What is reasonable for a hospital to achieve and with what consistency have not been studied, and information regarding best practices in this area is needed. QUESTION 3: WHAT TREATMENT OPTIONS ARE AVAILABLE FOR ACHIEVING OPTIMAL GLYCEMIC TARGETS SAFELY AND EFFECTIVELY IN SPECIFIC CLINICAL SITUATIONS? In the hospital setting, insulin therapy is the preferred method for achieving glycemic control in most clinical situations (8). In the ICU, IV infusion is the preferred route of insulin administration. Outside of critical care units, subcutaneous administration of insulinis usedmuch more frequently. Orally administered agents have a limited role in the inpatient setting. IV insulin infusions In the critical care setting, continuous IV insulin infusion has been shown to be the most effective method for achieving specific glycemic targets (8). Because of the very short half-life of circulating insulin, IV delivery allows rapid dosing adjustments to address alterations in the status of patients. IV insulin therapy is ideally administered by means of validated written or computerized protocols that allow for predefined adjustments in the insulin infusion rate based on glycemic fluctuations and insulin dose. An extensive review of the merits and deficiencies of published protocols is beyond the intent of this statement, and readers are referred to several available reports and reviews (96 –101). Continued education of staff in conjunction with periodic ongoing review of patient data is critical for successful implementation of any insulin protocol (97 –101). Patients who receive IV insulin infusions will usually require transition to subcutaneously administered insulin when they begin eating regular meals or are transferred to lower-intensity care. Typically, a percentage (usually 75–80%) of the total daily IV infusion dose isproportionately divided into basal and prandial components (see subsequent material). Importantly, subcutaneously administered insulin must be given 1–4 h before discontinuation of IV insulin therapy in order to prevent hyperglycemia (102). Despite these recommendations, a safe and effective transition regimen has not been substantiated. Subcutaneously administered insulin Scheduled subcutaneous administration of insulin is the preferred method for achieving and maintaining glucose control in non-ICU patients with diabetes or stress hyperglycemia. The recommended components of inpatient subcutaneous insulin regimens are a basal, a nutritional, and a supplemental (correction) element (8,103). Each component can be met by one of several available insulin products, depending on the particular hospital situation. Readers are referred to severalrecentpublications and reviews that describe currently available insulin preparations and protocols (101 –106). A topic that deserves particular attention is the persistent overuse of what has been branded as sliding scale insulin (SSI) for management of hyperglycemia. The term “correction insulin,” which refers to the use of additional short- or rapid-acting insulin in conjunction with scheduled insulin doses to treat BG levels above desired targets, is preferred (8). Prolonged therapy with SSI as the sole regimen is ineffective in the majority of patients (and potentially dangerous in those with type 1 diabetes) (106 –112). Noninsulin agents Noninsulin agents are inappropriate in most hospitalized patients. Continued use of such agents may be appropriate in selected stable patients who are expected to consume meals at regular intervals. Caution must be exercised with use of metformin because of the potential development of a contraindication during the hospitalization, such as renal insufficiency, unstable hemodynamic status, or need for imaging studies with radiocontrast dye (8,113). Injectable noninsulin therapies such as exenatide and pramlintide have limitations similar to those with orally administered agents in the hospital setting. Specific clinical situations Patients using an insulin pump. Patients who use continuous subcutaneous insulin infusion (pump) therapy in the outpatient setting can be candidates for diabetes self-management in the hospital, provided they have the mental and physical capacity to do so (8,103,114,115). Of importance, nursing personnel must document basal rates and bolus doses on a regular basis (at least daily). The availability of hospital personnel with expertise in continuous subcutaneous insulin infusion therapy is essential (115). Patients receiving enteral nutrition. Hyperglycemia is a common side effect of inpatient enteral nutrition therapy (116,117). A recent study, in which a combination of basal insulin and correction insulin was used, achieved a mean glucose value of 160 mg/dl (8.9 mmol/l). Similar results were achieved in the group randomized to receive SSI only; however, 48% of patients required the addition of intermediate-acting insulin to achieve glycemic targets (109). Patients receiving parenteral nutrition. The high glucose load in standard parenteral nutrition frequently results in hyperglycemia, which is associated with a higher incidence of complications and mortality in critically ill patients in the ICU (118). Insulin therapy is highly recommended, with glucose targets as defined previously on the basis of the severity of illness. Patients receiving glucocorticoid therapy. Hyperglycemia is a common complication of corticosteroid therapy (93). Several approaches have been proposed for treatment of this condition, but no published protocols or studies have investigated the efficacy of these approaches. A reasonable approach is to institute glucose monitoring for at least 48 h in all patients receiving high-dose glucocorticoid therapy and to initiate insulin therapy as appropriate (94). In patients who are already being treated for hyperglycemia, early adjustment of insulin doses is recommended (119). Importantly, during corticosteroid tapers, insulin dosing should be proactively adjusted to avoid hypoglycemia. QUESTION 4: DOES INPATIENT MANAGEMENT OF HYPERGLYCEMIA REPRESENT A SAFETY CONCERN? Overtreatment and undertreatment of hyperglycemia represent major safety issues in hospitalized patients with and without diabetes (90,120,121). Fear of hypoglycemia, clinical inertia, and medical errors are major barriers to achieving optimal blood glucose control (90,122 –131). In most clinical situations, safe and reasonable glycemic control can be achieved with appropriate use of insulin, adjusted according to results of bedside glucose monitoring (102,106,109). Clinical situations that increase the risk for hypoglycemia and hyperglycemia in the hospital include the following: Changes in caloric or carbohydrate intake (“nothing by mouth” status, enteral nutrition, or parenteral nutrition) (94,128) Change in clinical status or medications (for example, corticosteroids or vasopressors) (93,98) Failure of the clinician to make adjustments to glycemic therapy based on daily BG patterns (102,128) Prolonged use of SSI as monotherapy (107,108) Poor coordination of BG testing and administration of insulin with meals (121,129) Poor communication during times of patient transfer to different care teams (120,121) Use of long-acting sulfonylureas in elderly patients and those with kidney or liver insufficiency Errors in order writing and transcription (102,120) Hypoglycemia is a major safety concern with use of insulin and insulin secretagogues. Hypoglycemia can occur spontaneously in patients with sepsis (130) orin patients who receive certain medications, including quinolone antibiotics and β-adrenergic agonists. Although not all hypoglycemic episodes are avoidable, the use of nurse-driven hypoglycemia treatment protocols that prompt early therapy for any BG levels <70 mg/dl (<3.9 mmol/l) can prevent deterioration of potentially mild events—for example, BG values of 60–69 mg/dl (3.3–3.8 mmol/l)—to more severe events—for example, BG concentrations <40 mg/dl (<2.2 mmol/l) (88,90 –92,98,131). Particular attention is required in high-risk patients, including those with malnutrition; advanced age; a history of severehypoglycemia (88,132); or autonomic, kidney, liver, or cardiac failure. Clinical inertia can be defined as not adjusting glycemic therapy in response to persistently abnormal results on BG determination (123). Often, there is a lack of ownership for diabetes management, particularly in hospitalized patients admitted with a primary diagnosis other than diabetes (128). This inaction may be due in part to insufficient knowledge or confidence in diabetes management (123,133). Improvements in care can be achieved by ongoing education and training (134,135). Insulin errors Insulin has consistently been designated as a high-alert medication because of the risk of harm that can accompany errorsin prescribing, transcribing, or dosing (136). The true frequency of such errors is unknown because the available data sources depend on voluntary reporting of errors (102,137) and mechanisms forreal-time root-cause analysis are not available in most hospitals. BG monitoring Bedside BG monitoring with use of point-of-care (POC) glucose meters is performed before meals and at bedtime in most inpatients who are eating usual meals. It is important to avoid routineuse ofcorrection insulin at bedtime. In patients who are receiving continuousenteralor parenteral nutrition, glucose monitoring is optimally performed every 4–6 h. In patients who are receiving cycled enteral nutrition or parenteral nutrition, the schedule for glucose monitoring can be individualized but should be frequent enough to detect hyperglycemia during feedings and the risk of hypoglycemia when feedings are interrupted (109,112). More frequent BG testing, ranging from every 30 min to every 2 h, is required for patients receiving IV insulin infusions. Glucose meters Safe and rational glycemic management relies on the accuracy of BG measurements performed with use of POC glucose meters, which have several important limitations. Although the U.S. Food and Drug Administration allows a 20% error for glucose meters, questions have been raised about the appropriateness of this criterion (138). Glucose measurements differ significantly between plasma and whole blood, terms that are often used interchangeably and can lead tomisinterpretation. Most commercially available capillary glucose meters introduce a correction factor of ∼1.12 to report a “plasma adjusted” value (139). Significant discrepancies among capillary, venous, and arterial plasma samples have been observed in patients with low or high hemoglobin concentrations, hypoperfusion, or the presence of interfering substances (139,140). Analytical variability has been described with several POC glucose meters (141). Any glucose result that does not correlate withthe patient's clinical status should be confirmed through conventional laboratory sampling of plasma glucose. Although laboratory measurement of plasma glucose has less variability and interference, multiple daily phlebotomies are not practical. Moreover, the use of indwelling lines as the sampling source poses risks for infection. Studies performed with use of continuous interstitial glucose-monitoring systems in the critical care setting (142,143) currently are limited by the lack of reliability of BG measurements in the hypoglycemic range as well as by cost. QUESTION 5: WHAT SYSTEMS NEED TO BE IN PLACE TO ACHIEVE THESE RECOMMENDATIONS? The complexity of inpatient glycemic management necessitates a systems approach that facilitates safe practices and reduces the risk for errors (120,121). Systems that facilitate the appropriate use of scheduled insulin therapy, with institutional support for inpatient personnel who are knowledgeable in glycemic management, are essential for achieving safe and reasonable levels of glycemic control in hospitalized patients. Readers are referred to the 2006 ACE/ADA consensus statement, which outlines the systems that must be in place to promote effective glycemic management in the hospital (11). Some of these recommendations are reviewed briefly in the following paragraphs. The success of any glycemic management program depends on the ability to obtain financial support from hospital administrators, who should be made aware of the potential for cost savings with reductions in morbidity, durations of hospital stay, and need for readmission. This support is necessary for covering the costs of staff education, equipment, and personnel to oversee an inpatient diabetes management program (144). The creation of a multidisciplinary steering committee guided by local diabetes experts can establish reasonable and achievable glycemic management goals with use of protocols and order sets (90). Preprinted order sets or computerized ordering systems with adequate technical support are useful tools for facilitating appropriate glycemic therapy (8,11,145). These tools can advance orders that contain contingencies that promote patient safety, such as withholding prandial insulin if a patient will not eat (102). Protocols need to be reviewed periodically and revised in accordance with available evidence. Inpatient providers often have insufficient knowledge about the many aspects of inpatient diabetes care (133). Thus, education of personnel is essential, especially early during the implementation phase (101,127). Formal communication among various disciplines and services helps to garner support from hospital personnel for new practices and protocols, as well as providing a venue for identifying concerns. Many hospitals are challenged by poor coordination of meal delivery and prandial insulin administration (130), as well as variability in the carbohydrate content of meals (94). Ensuring appropriate administration of insulin with respect to meals despite variations in food delivery necessitates coordination between dietary and nursing services (122). A systems approach can also promote the coordination of glucose monitoring, insulin administration, and meal delivery, particularly during change of shifts and times of patient transfer (121,122). Electronic health records and computerized physician order entry systems have the potential to improve the sharing of information, including POC glucose results and associated medication administration—which can contribute to the reduction of medical errors. These systems can also provide access to algorithms, protocols, and decision support tools that can help guide therapy (146,147). QUESTION 6: IS TREATMENT OF INPATIENT HYPERGLYCEMIA COST-EFFECTIVE? A program of inpatient glycemic control with prespecified glycemic targets will have associated costs attributable to an increase in time needed from physicians, nurses, pharmacists, and other services. These costs are best viewed as short-term investments that ultimately provide long-term cost savings because of improved clinical outcomes, with observed decreases in LOS, inpatient complications, and need for rehospitalization (148 –155). Pharmacoeconomic analyses haveexaminedthe cost-effectiveness of improved glycemic control in the hospital setting (148,149). In the Portland Diabetic Project, a 17-year prospective nonrandomized study of 4,864 patients with diabetes who underwent open-heart surgical procedures, institution of continuous IV insulin therapy to achieve predetermined target BG levels reduced the incidence of deep sternal wound infections by 66%, resulting in a total net savings to the hospital of 4,638 USD per patient (148). In another study, intensive glycemic control in 1,600 patients treated in a medical ICU was associated with a total cost savings of 1,580 USD per patient (149). Van den Berghe et al. (150) reported cost savings of 3,476 USD per patient by strict normalization of BG levels with use of a post hoc health careresourceutilization analysis of their randomized mechanically ventilated surgical ICU patients. In a retrospective analysis of patients undergoing coronary artery bypass grafting, each 50 mg/dl (2.8 mmol/l) increase in BG values on the day of and after the surgical procedure was associated with an increase in hospital cost of 1,769 USD and an increase in duration of hospital stay of 0.76 days (151). In a tertiary care trauma center, implementation of a diabetes management program to reduce the monthly mean BG level by 26 mg/dl (1.4 mmol/l) (177–151 mg/dl [9.8–8.4 mmol/l]) resulted in significant reductions in LOS (0.26 days) in association with estimated hospital savings of more than two million USD per year (152). In another study, implementation of a subcutaneous insulin protocol for treatment of patients with hyperglycemia in the emergency department resulted in a subsequent reduction of hospital stay by 1.5 days (153). The use of an intensified inpatient protocol by a diabetes management team resulted in correct coding and treatment of patients with previously unrecognized hyperglycemia. The LOS was reduced for both primary and secondary diagnoses of diabetes, and readmission rates declined (154). In a different study, the use of diabetes team consultation resulted in a 56% reduction in LOS and a cost reduction of 2,353 USD per patient (155). Thus, intensive glycemic control programs have reported substantial cost savings, primarily attributable to decreases in laboratory, pharmacy, and radiology costs; fewer inpatient complications; decreased ventilator days; and reductionsin ICUand hospital LOS. These reports demonstrate that optimization of inpatient glycemic management not only iseffective in reducing morbidity and mortality but also is cost-effective. The business case for hospital support of glycemic management programs is based on opportunities for improving the accuracy of documentation and coding for diabetes-related diagnoses. The case for revenue generation through billing for clinical services is based on opportunities to increase the provision of glycemic management services in the hospital. It is imperative to involve hospital administration in providing the necessary financial support for inpatient glycemic management programs that will ultimately result in cost savings in conjunction with improved patient outcomes. QUESTION 7: WHAT ARE THE OPTIMAL STRATEGIES FOR TRANSITION TO OUTPATIENT CARE? Preparation for transition to the outpatient setting is an important goal of inpatient diabetes management and begins with the hospital admission. This entails a fundamental shift in responsibility from a situation in which hospital personnel provide the diabetes care to one in which the patient is capable of self-management. Successful coordination of this transition requires a team approach that may involve physicians, nurses, medical assistants, dietitians, case managers, and social workers (8). Hospitals with certified diabetes educators benefit from their expertise during the discharge process. Admission assessment obtains information regarding any prior history of diabetes or hyperglycemia, its management, and the level of glycemic control. Early assessment of a patient's cognitive abilities, literacy level, visual acuity, dexterity, cultural context, and financial resources for acquiring outpatient diabetic supplies allows sufficient time to prepare the patient and address problem areas. Hospitalization provides a unique opportunity for addressing a patient's education in diabetes self-management (3). Because the mean hospital LOS is usually <5 days (2) and the capacity to learn new material may be limited during acute illness, diabetes-related education is frequently limited to an inventory of basic “survival skills.” It is recommended that the following areas be reviewed and addressed before the patient is discharged from the hospital (8): Level of understanding related to the diagnosis of diabetes Self-monitoring of BG and explanation of home BG goals Definition, recognition, treatment, and prevention of hyperglycemia and hypoglycemia Identification of health care provider who will be responsible for diabetes care after discharge Information on consistent eating patterns When and how to take BG-lowering medications, including administration of insulin (if the patient is receiving insulin for ongoing management at home) Sick day management Proper use and disposal of needles and syringes Medication errors and adverse drug events have been linked to poor communication of instructions to the patient at the time of discharge (156,157). This is particularly true for insulin regimens, which are inherently more complex. Because the day of discharge is not always conducive to retention of verbal instructions (158), clearly written instructions provide a reference for patients and their outpatient providers, and they provide a format for medication reconciliation between inpatient and outpatient settings. In one recent study, an insulin-specific discharge instruction form provided greater clarity and more consistent directions for insulin dosing and self-testing of BG in comparison with a generic hospital discharge form (159). An outpatient follow-up visit with the primary care provider, endocrinologist, or diabetes educator within 1 month after discharge from the hospital is advised for all patients having hyperglycemia in the hospital (8). Clear communication with outpatient providers either directly or by means of hospital discharge summaries facilitates safe transitions to outpatient care. Providing information regarding the cause or the plan for determining the cause of hyperglycemia, related complications and comorbidities, and recommended treatments can assist outpatient providers as they assume ongoing care. QUESTION 8: WHAT ARE AREAS FOR FUTURE RESEARCH? The following are selected research topics and questions proposed for guiding the management of patients with hyperglycemia in various hospital settings. Stress hyperglycemia What are the underlying mechanisms? What abnormalities lead to variability in insulin resistance observed in some critically ill patients? What therapeutic modalities, in addition to glycemic control, would improve outcomes in critically ill patients with hyperglycemia? Are there optimal and safe glycemic targets specific to certain populations of critically ill patients? Severe hypoglycemia What is the profile of inpatients at greatest risk for severe hypoglycemia? What are the short-term and long-term outcomes of patients experiencing severe hypoglycemia? What are the true costs of inpatient hypoglycemia? Glycemic targets on general medical and surgical wards What are optimal and safe glycemic targets in noncritically ill patients on medical and surgical wards? Recommended end points for an RCT include rates of hypoglycemia, hospital-acquired infections, other in-hospital complications, LOS, and readmission. Glycemic variability What is the effect of glycemic variability and the rate of change in glycemia on short-term and long-term outcomes, both in ICU and non-ICU settings? Hospital systems and safety What hospital systems and safety measures are important for improving glycemic control and patient outcomes? What teams and support systems are required for safe and effective transition of patients to the outpatient setting? Insulin treatment and monitoring instruments What are safe and effective strategies for inpatient use of insulin and insulin analogues? What is the role of continuous glucose- monitoring systems in inpatient settings? Pediatric inpatient populations What are the optimal and safe glycemic targets in noncritically ill hospitalized children? SUMMARY OF RECOMMENDATIONS I. Critically ill patients Insulin therapy should be initiated for treatment of persistent hyperglycemia, starting at a threshold of no greater than 180 mg/dl (10.0 mmol/l). Once insulin therapy has been started, a glucose range of 140–180 mg/dl (7.8–10.0 mmol/l) is recommended for the majority of critically ill patients. Intravenous insulin infusions are the preferred method for achieving and maintaining glycemic control in critically ill patients. Validated insulin infusion protocols with demonstrated safety and efficacy, and with low rates of occurrence of hypoglycemia, are recommended. With IV insulin therapy, frequent glucose monitoring is essential to minimize the occurrence of hypoglycemia and to achieve optimal glucose control. II. Noncritically ill patients For the majority of noncritically ill patients treated with insulin, the premeal BG target should generally be <140 mg/dl (<7.8 mmol/l) in conjunction with random BG values <180 mg/dl (<10.0 mmol/l), provided these targets can be safely achieved. More stringent targets may be appropriate in stable patients with previous tight glycemic control. Less stringent targets may be appropriate in terminally ill patients or in patients with severe comorbidities. Scheduled subcutaneous administration of insulin, with basal, nutritional, and correction components, is the preferred method for achieving and maintaining glucose control. Prolonged therapy with SSI as the sole regimen is discouraged. Noninsulin antihyperglycemic agents are not appropriate in most hospitalized patients who require therapy for hyperglycemia. Clinical judgment and ongoing assessment of clinical status must be incorporated into day-to-day decisions regarding treatment of hyperglycemia. III. Safety issues Overtreatment and undertreatment of hyperglycemia represent major safety concerns. Education of hospital personnel is essential in engaging the support of those involved in the care of inpatients with hyperglycemia. Caution is required in interpreting results of POC glucose meters in patients with anemia, polycythemia, hypoperfusion, or use of some medications. Buy-in and financial support from hospital administration are required for promoting a rational systems approach to inpatient glycemic management. IV. Cost Appropriate inpatient management of hyperglycemia is cost-effective. V. Discharge planning Preparation for transition to the outpatient setting should begin at the time of hospital admission. Discharge planning, patient education, and clear communication with outpatient providers are critical for ensuring a safe and successful transition to outpatient glycemic management. VI. Needed research A selected number of research questions and topics for guiding the management of inpatient hyperglycemia in various hospital settings are proposed.
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            Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial.

            Cardiac resynchronization therapy (CRT) through biventricular pacing is an effective treatment for heart failure (HF) with a wide QRS; however, the outcomes of patients requiring CRT and implantable cardioverter defibrillator (ICD) therapy are unknown. To examine the efficacy and safety of combined CRT and ICD therapy in patients with New York Heart Association (NYHA) class III or IV congestive HF despite appropriate medical management. Randomized, double-blind, parallel-controlled trial conducted from October 1, 1999, to August 31, 2001, of 369 patients with left ventricular ejection fraction of 35% or less, QRS duration of 130 ms, at high risk of life-threatening ventricular arrhythmias, and in NYHA class III (n = 328) or IV (n = 41) despite optimized medical treatment. Of 369 randomized patients who received devices with combined CRT and ICD capabilities, 182 were controls (ICD activated, CRT off) and 187 were in the CRT group (ICD activated, CRT on). The primary double-blind study end points were changes between baseline and 6 months in quality of life, functional class, and distance covered during a 6-minute walk. Additional outcome measures included changes in exercise capacity, plasma neurohormones, left ventricular function, and overall HF status. Survival, incidence of ventricular arrhythmias, and rates of hospitalization were also compared. At 6 months, patients assigned to CRT had a greater improvement in median (95% confidence interval) quality of life score (-17.5 [-21 to -14] vs -11.0 [-16 to -7], P =.02) and functional class (-1 [-1 to -1] vs 0 [-1 to 0], P =.007) than controls but were no different in the change in distance walked in 6 minutes (55 m [44-79] vs 53 m [43-75], P =.36). Peak oxygen consumption increased by 1.1 mL/kg per minute (0.7-1.6) in the CRT group vs 0.1 mL/kg per minute (-0.1 to 0.8) in controls (P =.04), although treadmill exercise duration increased by 56 seconds (30-79) in the CRT group and decreased by 11 seconds (-55 to 12) in controls (P<.001). No significant differences were observed in changes in left ventricular size or function, overall HF status, survival, and rates of hospitalization. No proarrhythmia was observed and arrhythmia termination capabilities were not impaired. Cardiac resynchronization improved quality of life, functional status, and exercise capacity in patients with moderate to severe HF, a wide QRS interval, and life-threatening arrhythmias. These improvements occurred in the context of underlying appropriate medical management without proarrhythmia or compromised ICD function.
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              Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme.

              To determine whether the risk of adverse cardiovascular (CV) outcomes associated with diabetes differs in patients with low and preserved ejection fraction (EF) heart failure (HF). We analysed outcomes in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme which randomized 7599 patients with symptomatic HF and a broad range of EF. The prevalence of diabetes was 28.3% in patients with preserved EF (>40%) and 28.5% in those with low EF (
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                Author and article information

                Contributors
                +39 0815665110 , drsarducele@gmail.com
                pasquale.paolisso@gmail.com
                cosimo.sacra@fgps.it
                matteo.santamaria@fgps.it
                claudio.delucia@temple.edu
                anruocco70@gmail.com
                ciro.mauro3@tin.it
                giuseppe.paolisso@unicampania.it
                mariarosaria.rizzo@unicampania.it
                michelangela.barbieri@unicampania.it
                raffaele.marfella@unicampania.it
                Journal
                Cardiovasc Diabetol
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central (London )
                1475-2840
                22 October 2018
                22 October 2018
                2018
                : 17
                Affiliations
                [1 ]ISNI 0000 0001 2200 8888, GRID grid.9841.4, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, , University of Campania “Luigi Vanvitelli”, ; Piazza Miraglia, 2, 80138 Naples, Italy
                [2 ]Cardiovascular and Arrhythmias Department, John Paul II Research and Care Foundation, Campobasso, Italy
                [3 ]ISNI 0000 0001 2248 3398, GRID grid.264727.2, Center for Translational Medicine, , Temple University, ; Philadelphia, USA
                [4 ]GRID grid.413172.2, Cardiovascular Diseases Department, , Cardarelli Hospital, ; Naples, Italy
                Article
                778
                10.1186/s12933-018-0778-9
                6196445
                30348145
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Categories
                Original Investigation
                Custom metadata
                © The Author(s) 2018

                Endocrinology & Diabetes

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