Mikhail Kosiborod

Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials: A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association

Diabetes is defined by its association with hyperglycemia-specific microvascular complications; however, it also imparts a two- to fourfold risk of cardiovascular disease (CVD). Although microvascular complications can lead to significant morbidity and premature mortality, by far the greatest cause of death in people with diabetes is CVD. Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 1 (1,2) and type 2 diabetes (3–5). In the Diabetes Control and Complications Trial (DCCT), there was an ∼60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A1C <6.05%, mean achieved A1C ∼7%) and the standard group (A1C ∼9%) over an average of 6.5 years. The relationship between glucose control (as reflected by the mean on-study A1C value) and risk of complications was log-linear and extended down to the normal A1C range (<6%) with no threshold noted. In the UK Prospective Diabetes Study (UKPDS), participants newly diagnosed with type 2 diabetes were followed for 10 years, and intensive control (median A1C 7.0%) was found to reduce the overall microvascular complication rate by 25% compared with conventional treatment (median A1C 7.9%). Here, too, secondary analyses showed a continuous relationship between the risk of microvascular complications and glycemia extending into the normal range of A1C, with no glycemic threshold. On the basis of these two large controlled trials, along with smaller studies and numerous epidemiologic reports, the consistent findings related to microvascular risk reduction with intensive glycemic control have led the American Diabetes Association (ADA) to recommend an A1C goal of <7% for most adults with diabetes (6), recognizing that more or less stringent goals may be appropriate for certain patients. Whereas many epidemiologic studies and meta-analyses …

Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline

OBJECTIVE The aim was to formulate practice guidelines on the management of hyperglycemia in hospitalized patients in the non-critical care setting. PARTICIPANTS The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, six additional experts, and a methodologist. EVIDENCE This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society members, American Diabetes Association, American Heart Association, American Association of Diabetes Educators, European Society of Endocrinology, and the Society of Hospital Medicine reviewed and commented on preliminary drafts of this guideline. CONCLUSIONS Hyperglycemia is a common, serious, and costly health care problem in hospitalized patients. Observational and randomized controlled studies indicate that improvement in glycemic control results in lower rates of hospital complications in general medicine and surgery patients. Implementing a standardized sc insulin order set promoting the use of scheduled basal and nutritional insulin therapy is a key intervention in the inpatient management of diabetes. We provide recommendations for practical, achievable, and safe glycemic targets and describe protocols, procedures, and system improvements required to facilitate the achievement of glycemic goals in patients with hyperglycemia and diabetes admitted in non-critical care settings.

Admission Glucose and Mortality in Elderly Patients Hospitalized With Acute Myocardial Infarction Implications for Patients With and Without Recognized Diabetes

Background—The relationship between admission glucose levels and outcomes in older diabetic and nondiabetic patients with acute myocardial infarction is not well defined. Methods and Results—We evaluated a national sample of elderly patients (n=141 680) hospitalized with acute myocardial infarction from 1994 to 1996. Admission glucose was analyzed as a categorical (≤110, >110 to 140, >140 to 170, >170 to 240, >240 mg/dL) and continuous variable for its association with mortality in patients with and without recognized diabetes. A substantial proportion of hyperglycemic patients (eg, 26% of those with glucose >240 mg/dL) did not have recognized diabetes. Fewer hyperglycemic patients without known diabetes received insulin during hospitalization than diabetics with similar glucose levels (eg, glucose >240 mg/dL, 22% versus 73%; P<0.001). Higher glucose levels were associated with greater risk of 30-day mortality in patients without known diabetes (for glucose range from ≤110 to >240 mg/dL, 10% to 39%) compared with diabetics (range, 16% to 24%; P for interaction <0.001). After multivariable adjustment, higher glucose levels continued to be associated with a graded increase in 30-day mortality in patients without known diabetes (referent, glucose ≤110 mg/dL; range from glucose >110 to 140 mg/dL: hazard ratio [HR], 1.17; 95% CI, 1.11 to 1.24; to glucose >240 mg/dL: HR, 1.87; 95% CI, 1.75 to 2.00). In contrast, among diabetic patients, greater mortality risk was observed only in those with glucose >240 mg/dL (HR, 1.32; 95% CI, 1.17 to 1.50 versus glucose ≤110 mg/dL; P for interaction <0.001). One-year mortality results were similar. Conclusions—Elevated glucose is common, rarely treated, and associated with increased mortality risk in elderly acute myocardial infarction patients, particularly those without recognized diabetes.

Trends in length of stay and short-term outcomes among Medicare patients hospitalized for heart failure, 1993-2006.

CONTEXT Whether decreases in the length of stay during the past decade for patients with heart failure (HF) may be associated with changes in outcomes is unknown. OBJECTIVE To describe the temporal changes in length of stay, discharge disposition, and short-term outcomes among older patients hospitalized for HF. DESIGN, SETTING, AND PARTICIPANTS An observational study of 6,955,461 Medicare fee-for-service hospitalizations for HF between 1993 and 2006, with a 30-day follow-up. MAIN OUTCOME MEASURES Length of hospital stay, in-patient and 30-day mortality, and 30-day readmission rates. RESULTS Between 1993 and 2006, mean length of stay decreased from 8.81 days (95% confidence interval [CI], 8.79-8.83 days) to 6.33 days (95% CI, 6.32-6.34 days). In-hospital mortality decreased from 8.5% (95% CI, 8.4%-8.6%) in 1993 to 4.3% (95% CI, 4.2%-4.4%) in 2006, whereas 30-day mortality decreased from 12.8% (95% CI, 12.8%-12.9%) to 10.7% (95% CI, 10.7%-10.8%). Discharges to home or under home care service decreased from 74.0% to 66.9% and discharges to skilled nursing facilities increased from 13.0% to 19.9%. Thirty-day readmission rates increased from 17.2% (95% CI, 17.1%-17.3%) to 20.1% (95% CI, 20.0%-20.2%; all P < .001). Consistent with the unadjusted analyses, the 2005-2006 risk-adjusted 30-day mortality risk ratio was 0.92 (95% CI, 0.91-0.93) compared with 1993-1994, and the 30-day readmission risk ratio was 1.11 (95% CI, 1.10-1.11). CONCLUSION For patients admitted with HF during the past 14 years, reductions in length of stay and in-hospital mortality, less marked reductions in 30-day mortality, and changes in discharge disposition accompanied by increases in 30-day readmission rates were observed.

Hyperglycemia and Acute Coronary Syndrome A Scientific Statement From the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism

Hyperglycemia is common and associated with markedly increased mortality rates in patients hospitalized with acute coronary syndromes (ACS). Despite the fact that several studies have documented this association, hyperglycemia remains underappreciated as a risk factor, and it is frequently untreated in ACS patients. This is in large part due to limitations of prior studies, and the remaining critical gaps in our understanding of the relationship between hyperglycemia and poor outcomes. The main objective of the present statement is to summarize the current state of knowledge regarding the association between elevated glucose and patient outcomes in ACS and to outline the most important knowledge gaps in this field. These gaps include the need to specifically define hyperglycemia, develop optimal ways of measuring and tracking glucose values during ACS hospitalization, and better understand the physiological mechanisms responsible for poor outcomes associated with hyperglycemia. The most important issue, however, is whether elevated glucose is a direct mediator of adverse outcomes in ACS patients or just a marker of greater disease severity. Given the marked increase in short- and long-term mortality associated with hyperglycemia, there is an urgent need for definitive large randomized trials to determine whether treatment strategies aimed at glucose control will improve patient outcomes and to define specific glucose treatment targets. Although firm guidelines will need to await completion of these clinical trials, the present statement also provides consensus recommendations for hyperglycemia management in patients with ACS on the basis of the available data.

Glucometrics in Patients Hospitalized With Acute Myocardial Infarction Defining the Optimal Outcomes-Based Measure of Risk

Background— Hyperglycemia on admission is associated with an increased mortality rate in patients with acute myocardial infarction. Whether metrics that incorporate multiple glucose assessments during acute myocardial infarction hospitalization are better predictors of mortality than admission glucose alone is not well defined. Methods and Results— We evaluated 16 871 acute myocardial infarction patients hospitalized from January 2000 to December 2005. Using logistic regression models and C indexes, 3 metrics of glucose control (mean glucose, time-averaged glucose, hyperglycemic index), each evaluated over 3 time windows (first 24 hours, 48 hours, entire hospitalization), were compared with admission glucose for their ability to discriminate hospitalization survivors from nonsurvivors. Models were then used to evaluate the relationship between mean glucose and in-hospital mortality. All average glucose metrics performed better than admission glucose. The ability of models to predict mortality improved as the time window increased (C indexes for admission, mean 24 hours, 48 hours, and hospitalization glucose were 0.62, 0.64, 0.66, 0.70; P<0.0001). Statistically significant but small differences in C indexes of mean glucose, time-averaged glucose, and hyperglycemic index were seen. Mortality rates increased with each 10-mg/dL rise in mean glucose ≥120 mg/dL (odds ratio, 1.8; P=0.003 for glucose 120 to <130 mg/dL) and with incremental decline <70 mg/dL (odds ratio, 6.4; P=0.01 versus glucose 100 to <110 mg/dL). The slope of these relationships was steeper in patients without diabetes. Conclusions— Measures of persistent hyperglycemia during acute myocardial infarction are better predictors of mortality than admission glucose. Mean hospitalization glucose appears to be the most practical metric of hyperglycemia-associated risk. A J-shaped relationship exists between average glucose and mortality, with both persistent hyperglycemia and hypoglycemia associated with adverse prognosis.

Relationship Between Spontaneous and Iatrogenic Hypoglycemia and Mortality in Patients Hospitalized With Acute Myocardial Infarction

CONTEXT While glucose control is recommended by professional societies for patients with hyperglycemia hospitalized with acute myocardial infarction (AMI), enthusiasm for glucose lowering is tempered, in part, by concerns of inducing hypoglycemia. Yet, whether episodic hypoglycemia that occurs as a result of glucose-lowering therapy is harmful in patients with AMI is unknown. OBJECTIVE To determine whether the mortality risk associated with hypoglycemic events is similar in patients who develop hypoglycemia spontaneously and those who develop it as a result of insulin therapy. DESIGN, SETTING, AND PATIENTS Retrospective cohort study using data from Health Facts, a contemporary database of patients hospitalized across the United States in 40 hospitals between January 1, 2000, and December 31, 2005. Of all the patients in the database, 7820 patients were hospitalized with AMI and were hyperglycemic on admission (glucose level > or = 140 mg/dL). Patients were stratified based on whether they developed a hypoglycemic event (random glucose level < 60 mg/dL) during subsequent hospitalization. Logistic regression models were used to evaluate the association between hypoglycemia and in-hospital mortality within subgroups of patients who were and were not treated with insulin therapy. MAIN OUTCOME MEASURE All-cause in-hospital mortality. RESULTS Among patients treated or not treated with insulin, those with hypoglycemia were older and had more comorbidity. Hypoglycemia was associated with increased mortality in patients not treated with insulin (18.4% [25/136] mortality in patients with hypoglycemia vs 9.2% [425/4639] in those without hypoglycemia; P<.001), but not in those treated with insulin (10.4% [36/346] mortality in patients with hypoglycemia vs 10.2% [276/2699] in those without hypoglycemia; P = .92). After multivariable adjustment, there was a significant interaction between hypoglycemia and insulin therapy (P value for interaction = .01). Hypoglycemia was a predictor of higher mortality in patients who were not treated with insulin (odds ratio, 2.32 [95% confidence interval, 1.31-4.12] vs patients without hypoglycemia), but not in patients treated with insulin (odds ratio, 0.92 [95% confidence interval, 0.58-1.45] vs patients without hypoglycemia). CONCLUSIONS While hypoglycemia was associated with increased mortality in patients with AMI, this risk was confined to patients who developed hypoglycemia spontaneously. In contrast, iatrogenic hypoglycemia after insulin therapy was not associated with higher mortality risk.

Glycemic Control and Excess Mortality in Type 1 Diabetes

BACKGROUND The excess risk of death from any cause and of death from cardiovascular causes is unknown among patients with type 1 diabetes and various levels of glycemic control. We conducted a registry-based observational study to determine the excess risk of death according to the level of glycemic control in a Swedish population of patients with diabetes. METHODS We included in our study patients with type 1 diabetes registered in the Swedish National Diabetes Register after January 1, 1998. For each patient, five controls were randomly selected from the general population and matched according to age, sex, and county. Patients and controls were followed until December 31, 2011, through the Swedish Register for Cause-Specific Mortality. RESULTS The mean age of the patients with diabetes and the controls at baseline was 35.8 and 35.7 years, respectively, and 45.1% of the participants in each group were women. The mean follow-up in the diabetes and control groups was 8.0 and 8.3 years, respectively. Overall, 2701 of 33,915 patients with diabetes (8.0%) died, as compared with 4835 of 169,249 controls (2.9%) (adjusted hazard ratio, 3.52; 95% confidence interval [CI], 3.06 to 4.04); the corresponding rates of death from cardiovascular causes were 2.7% and 0.9% (adjusted hazard ratio, 4.60; 95% CI, 3.47 to 6.10). The multivariable-adjusted hazard ratios for death from any cause according to the glycated hemoglobin level for patients with diabetes as compared with controls were 2.36 (95% CI, 1.97 to 2.83) for a glycated hemoglobin level of 6.9% or lower (≤52 mmol per mole), 2.38 (95% CI, 2.02 to 2.80) for a level of 7.0 to 7.8% (53 to 62 mmol per mole), 3.11 (95% CI, 2.66 to 3.62) for a level of 7.9 to 8.7% (63 to 72 mmol per mole), 3.65 (95% CI, 3.11 to 4.30) for a level of 8.8 to 9.6% (73 to 82 mmol per mole), and 8.51 (95% CI, 7.24 to 10.01) for a level of 9.7% or higher (≥83 mmol per mole). Corresponding hazard ratios for death from cardiovascular causes were 2.92 (95% CI, 2.07 to 4.13), 3.39 (95% CI, 2.49 to 4.61), 4.44 (95% CI, 3.32 to 5.96), 5.35 (95% CI, 3.94 to 7.26), and 10.46 (95% CI, 7.62 to 14.37). CONCLUSIONS In our registry-based observational study, patients with type 1 diabetes and a glycated hemoglobin level of 6.9% or lower had a risk of death from any cause or from cardiovascular causes that was twice as high as the risk for matched controls. (Funded by the Swedish Society of Medicine and others.).

The prognostic importance of anemia in patients with heart failure

Physiologic studies have suggested that anemia could adversely affect the cardiovascular condition of patients with heart failure. Yet, the prognostic importance of this treatable condition is not well established by epidemiologic studies. We sought to determine the prognostic value of hematocrit level in a cohort of elderly patients hospitalized with heart failure. We studied a consecutive sample of 2281 patients aged 65 years or older who had been admitted with a principal discharge diagnosis of heart failure. Multivariate Cox proportional hazards regression was conducted to test whether hematocrit level was an independent predictor of 1-year mortality and of hospital readmission. The mean (+/- SD) age of the patients was 79 +/- 8 years; 58% (n = 1324) were women. Their median hematocrit was 38% (25th to 75th percentile, 33% to 42%). Lower hematocrits were associated with a higher mortality. After adjusting for demographic and clinical factors, each 1% lower hematocrit was associated with a 2% greater 1-year mortality (P = 0.007). Compared with patients with a hematocrit >42%, those with a hematocrit < or =27% had a 40% greater 1-year mortality (hazard ratio [HR] = 1.40; 95% confidence interval [CI]: 1.02 to 1.92; P = 0.04). This increased risk was similar to that conferred by traditional risk factors, including a left ventricular ejection fraction < or =20% (HR = 1.50; 95% CI: 1.20 to 1.86). Lower hematocrits were also associated with a greater risk of hospital readmission. Anemia is associated with an increased risk of death and rehospitalization in older patients with heart failure. Whether anemia is a direct cause of worse outcomes, or a marker for other causal factors, is not known.

Hospital-wide Code Rates and Mortality Before and After Implementation of a Rapid Response Team

CONTEXT Rapid response teams have been shown in adult inpatients to decrease cardiopulmonary arrest (code) rates outside of the intensive care unit (ICU). Because a primary action of rapid response teams is to transfer patients to the ICU, their ability to reduce hospital-wide code rates and mortality remains unknown. OBJECTIVE To determine rates of hospital-wide codes and mortality before and after implementation of a long-term rapid response team intervention. DESIGN, SETTING, AND PATIENTS A prospective cohort design of adult inpatients admitted between January 1, 2004, and August 31, 2007, at Saint Lukes Hospital, a 404-bed tertiary care academic hospital in Kansas City, Missouri. Rapid response team education and program rollout occurred from September 1 to December 31, 2005. A total of 24 193 patient admissions were evaluated prior to the intervention (January 1, 2004, to August 31, 2005), and 24 978 admissions were evaluated after the intervention (January 1, 2006, to August 31, 2007). INTERVENTION Using standard activation criteria, a 3-member rapid response team composed of experienced ICU staff and a respiratory therapist performed the evaluation, treatment, and triage of inpatients with evidence of acute physiological decline. MAIN OUTCOME MEASURES Hospital-wide code rates and mortality, adjusted for preintervention trends. RESULTS There were a total of 376 rapid response team activations. After rapid response team implementation, mean hospital-wide code rates decreased from 11.2 to 7.5 per 1000 admissions. This was not associated with a reduction in the primary end point of hospital-wide code rates (adjusted odds ratio [AOR], 0.76 [95% confidence interval {CI}, 0.57-1.01]; P = .06), although lower rates of non-ICU codes were observed (non-ICU AOR, 0.59 [95% CI, 0.40-0.89] vs ICU AOR, 0.95 [95% CI, 0.64-1.43]; P = .03 for interaction). Similarly, hospital-wide mortality did not differ between the preintervention and postintervention periods (3.22 vs 3.09 per 100 admissions; AOR, 0.95 [95% CI, 0.81-1.11]; P = .52). Secondary analyses revealed few instances of rapid response team undertreatment or underuse that may have affected the mortality findings. CONCLUSION In this large single-institution study, rapid response team implementation was not associated with reductions in hospital-wide code rates or mortality.