Amit Akirov

Mortality among hospitalized patients with hypoglycemia: insulin-related and non-insulin related

Context: Hypoglycemia is common among hospitalized patients with and without diabetes mellitus. Objective: Investigate the association between spontaneous or insulin-related hypoglycemia and mortality in hospitalized patients. Design: Hypoglycemia was defined as blood glucose <70 mg/dl (3.9 mmol/l), including moderate (40 to 70 mg/dl, 2.2 to 3.9 mmol/l) and severe hypoglycemia (<40 mg/dl, 2.2 mmol/l). Use of insulin during hospitalization defined insulin-related hypoglycemia, thus patients were classified into 6 groups: non-insulin treated (NITC) and insulin-treated controls (ITC), insulin-related hypoglycemia (IH) or severe hypoglycemia (ISH), and non insulin-related hypoglycemia (NIH) and severe hypoglycemia (NISH). Setting and Patients: Historical prospectively data of patients ≥ 18 years of age, hospitalized in medical wards for any cause between January 2011 and December 2013. Main Outcome Measure: All-cause mortality at the end of follow-up. Results: The cohort included 33,675 patients, including 2605 with moderate hypoglycemia (IH, 1011; NIH, 1594) and 342 with severe hypoglycemia (ISH, 201; NISH,141). Overall end-of-follow-up mortality was 31.9% (NITC, 28.0%; ITC, 42.9%; NIH, 50.7%; IH, 55.3%; NISH, 70.9%; ISH, 69.1%). Compared with NITC, unadjusted hazard ratios (95% confidence intervals) for mortality were as follows: ITC, 1.7 (1.6 to 1.8), NIH, 2.2 (2.0 to 2.4), IH, 2.5 (2.2 to 2.7), NISH, 4.2 (3.5 to 5.2), and ISH, 3.8 (3.2 to 4.5); with P < 0.001. Following multivariate analysis, respective hazard ratios were 1.8, 2.1, 2.4, 3.2, and 3.6 (P < 0.001). Cause of admission did not affect the association. Conclusions: In hospitalized patients, hypoglycemia, either with insulin use or spontaneous, is associated with increased short- and long-term mortality.

Elevated TSH in adults treated for hypothyroidism is associated with increased mortality

CONTEXT Numerous studies investigated the link between hypothyroidism and mortality, but a definite conclusion is hard to reach as these were limited by a number of factors, including age of participants, comorbidities and single measurement of thyroid function. OBJECTIVE To evaluate the association between TSH and fT4 levels and mortality in patients with levothyroxine-treated hypothyroidism. DESIGN AND SETTING Observational data of hospitalized patients (2011-2014). TSH and fT4 levels obtained between at least 30 days after discharge and until death or end of follow-up were collected. Median TSH and fT4 levels were stratified into categories. PATIENTS In total, 611 patients with treated hypothyroidism, aged 60-80 years (72% females, mean age 71 ± 6 years) were included in the study. MAIN OUTCOME MEASURE All-cause mortality up to 66 months after discharge, by TSH and fT4 categories. RESULTS During follow-up, the average numbers of TSH and fT4 measurements were 5.5 ± 3.8 and 2.5 ± 4.2 per patient respectively. Mortality rates were 28%, 29% and 54% with median TSH of 0.5-2.5, 2.5-5.0 and 5.0-10.0 IU/L respectively. Adjusted hazard ratios for mortality with median TSH between 5.0 and 10.0 IU/L were 2.3 (95% CI: 1.6-3.4) and 2.2 (95% CI: 1.6-3.2) compared with patients with TSH between 0.5-2.5 IU/L and 2.5-5 IU/L respectively. There was no difference in mortality between patients with median fT4 10-15 or 15-20 pmol/L. CONCLUSION In treated hypothyroid adult patients and serial measurements of thyroid function tests, median TSH levels of 5-10 IU/L are associated with increased mortality with no effect of fT4 levels. Treatment should aim at achieving euthyroidism to improve survival.

Digital therapy in diabetes

Diabetes care is largely dependent on patient self‐management and empowerment, given that patients with diabetes must make numerous daily decisions as to what to eat, when to exercise, and determine their insulin dose and timing if required. In addition, patients and providers are generating vast amounts of data from many sources, including electronic medical records, insulin pumps, sensors, glucometers, and other wearables, as well as evolving genomic, proteomic, metabolomics, and microbiomic data. Multiple digital tools and apps have been developed to assist patients to choose wisely, and to enhance their compliance by using motivational tools and incorporating incentives from social media and gaming techniques. Healthcare teams (HCTs) and health administrators benefit from digital developments that sift through the enormous amounts of patient‐generated data. Data are acquired, integrated, analyzed, and presented in a self‐explanatory manner, highlighting important trends and items that require attention. The use of decision support systems may propose data‐driven actions that, for the most, require final approval by the patient or physician before execution and, once implemented, may improve patient outcomes. The digital diabetes clinic aims to incorporate all digital patient data and provide individually tailored virtual or face‐to‐face visits to those persons who need them most. Digital diabetes care has demonstrated only modest HbA1c reduction in multiple studies and borderline cost‐effectiveness, although patient satisfaction appears to be increased. Better understanding of the barriers to digital diabetes care and identification of unmet needs may yield improved utilization of this evolving technology in a safe, effective, and cost‐saving manner.

Digital health technology and diabetes management

Diabetes care is largely dependent on patient self‐management and empowerment, given that patients with diabetes must make numerous daily decisions as to what to eat, when to exercise, and determine their insulin dose and timing if required. In addition, patients and providers are generating vast amounts of data from many sources, including electronic medical records, insulin pumps, sensors, glucometers, and other wearables, as well as evolving genomic, proteomic, metabolomics, and microbiomic data. Multiple digital tools and apps have been developed to assist patients to choose wisely, and to enhance their compliance by using motivational tools and incorporating incentives from social media and gaming techniques. Healthcare teams (HCTs) and health administrators benefit from digital developments that sift through the enormous amounts of patient‐generated data. Data are acquired, integrated, analyzed, and presented in a self‐explanatory manner, highlighting important trends and items that require attention. The use of decision support systems may propose data‐driven actions that, for the most, require final approval by the patient or physician before execution and, once implemented, may improve patient outcomes. The digital diabetes clinic aims to incorporate all digital patient data and provide individually tailored virtual or face‐to‐face visits to those persons who need them most. Digital diabetes care has demonstrated only modest HbA1c reduction in multiple studies and borderline cost‐effectiveness, although patient satisfaction appears to be increased. Better understanding of the barriers to digital diabetes care and identification of unmet needs may yield improved utilization of this evolving technology in a safe, effective, and cost‐saving manner.

The prognostic significance of admission blood glucose levels in elderly patients with pneumonia (GAP Study).

AIMS Evaluate the association between admission blood glucose (ABG) and short and long-term mortality following hospitalization for pneumonia of elderly patients with and without diabetes mellitus (DM). METHODS Observational data derived from the electronic records of hospitalized patients ≥65years, admitted for pneumonia between January 2011 and December 2013. ABG levels were classified to categories: ≤70 (low), 70-110 (normal), 111-140 (mildly elevated), 141-199mg/dl (moderately elevated) and ≥200mg/dl (markedly elevated). Main outcomes were all-cause mortality rates at various time points. RESULTS Cohort included 2164 patients, 743 with DM (mean age 81, 53% male) and 1421 without it (mean age 83, 52% male). There was a significant interaction between DM, ABG and mortality (p≤0.05). In patients without DM, compared with normal ABG, in-hospital and 30-day mortality rates (adjusted hazard ratio, 95% CI) were higher with moderately (1.5 and 1.4, respectively, p<0.05) and markedly elevated ABG (2.7 and 1.9, respectively, p<0.05). Long-term results were similar at 12 and 36months (1.3 and 1.8, respectively, p<0.05, for moderately and markedly elevated ABG). CONCLUSION In elderly non-diabetic patients hospitalized for pneumonia, moderately and markedly elevated ABG is associated with increased short- and long-term mortality. In diabetic patients there is no association between ABG and mortality.

Calcium levels on admission and before discharge are associated with mortality risk in hospitalized patients

AimInvestigate the association of calcium levels on admission and change in levels during hospitalization with hospitalization outcomes.MethodsHistorical prospective data of patients hospitalized to units of internal medicine between 2011 and 2013. Albumin-corrected-calcium levels were classified to marked hypocalcemia (<7.5 mg/dL), mild hypocalcemia (7.5–8.5 mg/dL), normal calcium (8.5–10.5 mg/dL), mild hypercalcemia (10.5–11.5 mg/dL), marked hypercalcemia (>11.5 mg/dL). Main outcomes were length-of-hospitalization, in-hospital and long-term mortality.ResultsCohort included 30,813 patients (mean age 67 ± 18 years, 51% male). Follow-up (median ± standard deviation) was 1668 ± 325 days. Most patients had normal calcium on admission (93%), 3% had hypocalcemia, 3% had hypercalcemia. Common causes for marked hypercalcemia were malignancy (56%) and hyperparathyroidism (22%). Last calcium levels before discharge or death were normal in 94%, with similar rates of hypercalcemia or hypocalcemia (3% each). Compared to in-hospital mortality with normal calcium on admission (6%), mortality was higher with mild (8%) and marked hypocalcemia (11%), and highest with mild (18%) and marked hypercalcemia (22%). Mortality rate at the end of follow-up was 48% with normal calcium or mild hypocalcemia, 51% with marked hypocalcemia, 68 and 79% with mild and marked hypercalcemia, respectively. Patients with normal calcium on admission and before discharge had the best prognosis. Hypercalcemia on admission or before discharge was associated with a 70% mortality risk at the end of follow-up. Normalization of admission hypercalcemia had no effect on long-term mortality risk.ConclusionsAbnormal calcium on admission is associated with increased short-term and long-term mortality. The excess mortality risk is higher with hypercalcemia than hypocalcemia. Calcium normalization before discharge had no effect on mortality.

Mortality risk in admitted patients with diabetes mellitus according to treatment

AIMS Investigate the importance of treating diabetes by evaluating mortality risk of untreated and medically-treated diabetic patients. METHODS Historical prospectively collected observational data of hospitalized patient ≥18years, admitted for any-cause to medical wards, between January 2011 and December 2013. Main outcome was all-cause mortality at end of follow-up. RESULTS Cohort included 35,340 patients (51% male, median age 70years); 24,159 without diabetes and 11,181 with diabetes. Within the diabetic group, 2,188 patients (20%) were not receiving medical treatment for diabetes and 8993 were being treated as follows: 4550 (41%) non-insulin monotherapy; 1550 (14%) non-insulin combination therapy; 2,893 (26%) insulin. Hazard ratios were compared for the entire follow-up, indicating a significant difference in overall survival between medically untreated DM and all groups, except insulin-treated. Subset analysis with adjustment for age, gender, BMI, alcohol and smoking indicated a significant survival difference between untreated DM and all groups. Rates of hypertension, ischemic heart disease, renal failure, and congestive heart disease were higher in the untreated and insulin-treated diabetic patients than in the nondiabetic and diabetic patients on non-insulin treatment. CONCLUSIONS Lack of treatment for diabetes might have serious consequences. Further studies are needed to see if targeted treatment approach may decrease mortality.

The prognostic significance of admission blood glucose levels in patients with urinary tract infection

AIMS Evaluate the association between admission blood glucose (ABG) and short and long-term outcomes following hospitalization for urinary tract infection (UTI). METHODS Single center, retrospective cohort study of patients admitted to medical wards between January 1, 2011 and December 31, 2013 with a diagnosis of UTI. Patients were classified to those with diabetes mellitus (DM) and those without it. ABG levels were classified to categories: ≤70, 70-110, 111-199, ≥200mg/dl. Primary outcome was all-cause mortality within 30-days and 1-year. Secondary outcomes were hospital readmissions within 30-days and 1-year, and survival rates at end of follow-up. RESULTS Cohort included 3405 patients (median age, 78 years; 44% men), 1106 with DM and 2299 without it. Among patients without DM, compared with ABG between 70 and 110mg/dl (n=852, 37%), there was a significant association between ABG and all-cause mortality: hazard ratios (95% CI) with ABG ≤70mg/dl (n=13, 0.6%), 111-199mg/dl (n=1292, 56%), and ≥200mg/dl (n=142, 6%) were: 3.67 (0.89-15.14, p=0.07, 23% mortality (n=3)), 1.85 (1.29-2.64, p<0.001, 7% mortality (n=89)), and 2.94 (1.71-5.07, p<0.0001, 11% mortality (n=15)) at 30-days, and 3.8 (1.87-7.71, 38% mortality (n=5)), 1.35 (1 1.13-1.60, 7% mortality (n=215)), and 2.02 (1.50-2.71, 25% mortality (n=35)) at 1-year (all p<0.001). In patients with DM there was no significant association between ABG and mortality. There was no association between ABG and readmissions in both groups. CONCLUSION There is a significant association between ABG and short and long-term, all-cause mortality in patients without DM, but not in patients with DM, hospitalized for UTI.

High Glucose Variability Increases Mortality Risk in Hospitalized Patients

Context Glucose variability (GV) is common among hospitalized patients, but the prognostic implications are not understood. Objective Investigate the association between GV, hospital length of stay (LOS), and mortality. Methods GV was assessed by coefficient of variance (CV) and standard deviation (SD) of glucose values during hospitalization. Setting Historical prospectively collected data of patients hospitalized between January 2011 and December 2013. Patients Patients ≥18 years old. Main outcome LOS, and in-hospital and mortality at end of follow-up. Results The cohort included 20,303 patients (mean age ± SD, 70 ± 17 years; 51% men; median follow-up, 1022 days), of whom 8565 patients (42%) had diabetes mellitus (DM). Mean LOS was longer with higher CV or SD tertiles in patients without and with DM. In-hospital mortality was 8.2%, associated with higher tertiles of CV (4%, 10%, 19%) and SD (4%, 11%, 21%) in patients without DM and with DM (3%, 5%, 10%; and 2%, 4%, 9%, respectively). Mortality at the end of follow-up was increased in patients without DM with higher CV (28%, 42%, 55%) and SD (28%, 44%, 57%) tertiles and in patients with DM (26%, 35%, 45%; and 25%, 34%, 44%, respectively). Multivariate analysis indicated increased risk for in-hospital and end of follow-up mortality, in both groups. Adjustment for glucocorticoid treatment or hypoglycemia did not affect the results. Glucose levels during hospitalization and GV were two independent factors affecting LOS and in-hospital mortality. In each CV tertile, mortality was higher with median glucose ≥180 mg/dL, compared with <180 mg/dL. Conclusions In hospitalized patients with and without DM, increased GV is associated with longer hospitalization and increased short- and long-term mortality.

Long-Lived αMUPA Mice Show Attenuation of Cardiac Aging and Leptin-Dependent Cardioprotection

αMUPA transgenic mice spontaneously consume less food compared with their wild type (WT) ancestors due to endogenously increased levels of the satiety hormone leptin. αMUPA mice share many benefits with mice under caloric restriction (CR) including an extended life span. To understand mechanisms linked to cardiac aging, we explored the response of αMUPA hearts to ischemic conditions at the age of 6, 18, or 24 months. Mice were subjected to myocardial infarction (MI) in vivo and to ischemia/reperfusion ex vivo. Compared to WT mice, αMUPA showed functional and histological advantages under all experimental conditions. At 24 months, none of the WT mice survived the first ischemic day while αMUPA mice demonstrated 50% survival after 7 ischemic days. Leptin, an adipokine decreasing under CR, was consistently ~60% higher in αMUPA sera at baseline. Leptin levels gradually increased in both genotypes 24h post MI but were doubled in αMUPA. Pretreatment with leptin neutralizing antibodies or with inhibitors of leptin signaling (AG-490 and Wortmannin) abrogated the αMUPA benefits. The antibodies also reduced phosphorylation of the leptin signaling components STAT3 and AKT specifically in the αMUPA myocardium. αMUPA mice did not show elevation in adiponectin, an adipokine previously implicated in CR-induced cardioprotection. WT mice treated for short-term CR exhibited cardioprotection similar to that of αMUPA, however, along with increased adiponectin at baseline. Collectively, the results demonstrate a life-long increased ischemic tolerance in αMUPA mice, indicating the attenuation of cardiac aging. αMUPA cardioprotection is mediated through endogenous leptin, suggesting a protective pathway distinct from that elicited under CR.