Relationship of glycaemic control and hypoglycaemic episodes to 4-year cardiovascular outcomes in people with type 2 diabetes starting insulin.

AIMS: To examine the relationships between glycated haemoglobin (HbA1c) and cardiovascular (CV) events in people beginning insulin in routine clinical practice in Europe, North America and Asia in a non-interventional study, the Cardiovascular Risk Evaluation in people with Type 2 Diabetes on Insulin Therapy (CREDIT) study. METHODS: Data on 2999 people were collected prospectively over 4 years from physician reports. The primary outcome was the composite of stroke or myocardial infarction (MI) or CV-specific death. Events were blindly adjudicated. The relative hazards of CV events were described from Cox proportional hazards models incorporating patient risk factors, with updated average HbA1c as a time-dependent covariate. The relationship of severe and symptomatic hypoglycaemia (collected during the 6 months before yearly ascertainment) with CV and all-cause mortality was examined. RESULTS: A total of 147 primary events were accrued during up to 54 months of follow-up. In all, 60 CV-specific deaths, 44 non-fatal MIs and 57 non-fatal strokes occurred, totalling 161 events. There was a significant positive relationship between updated mean HbA1c and primary outcome: hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.12-1.40; p < 0.0001]. CV death [HR 1.31 (95% CI 1.10-1.57); p = 0.0027] and stroke [HR 1.36 (95% CI 1.17-1.59); p < 0.0001] were both strongly associated with HbA1c, while MI was not [HR 1.05 (95% CI 0.83-1.32)]. One or more severe hypoglycaemic episodes affected 175 participants, while 1508 participants experienced one or more symptomatic hypoglycaemic events. We found no relationship between severe/symptomatic hypoglycaemic events and CV-specific/all-cause death. CONCLUSIONS: Ongoing poorer glucose control was associated with CV events; hypoglycaemia was not associated with CV-specific/all-cause death.

Planning of pharmacodynamic trials: I. Specificity and possible solutions. II. Stability considerations under placebo and interpretation of drug effects on EEG.

This workshop deals with the concept of quantitative electroencephalography (QEEG) to characterize the central effects of drugs. For proper interpretation, the circumstances under which data are obtained play an important role. To infer the size of variability in standard practice, we elaborated some computations for "placebo-treatment" in healthy volunteers, which helps to determine the threshold of drug effect detection. Simple rules for interpretation of multiple statistical comparisons were proposed and validation of dose effects were carried out with accepted reference compounds. Furthermore, psychotropic agents with comparable therapeutic indications often present similar modifications in EEG spectral composition (pharmaco-EEG profile). To extrapolate this concept, quantified wake-EEG is a rapid, validated technique for early psychopharmacological investigation of new psychotropic compounds (Phase I, healthy volunteers). Classification of drug-induced changes in cerebral activity at this stage forms a useful decision instrument in planning the long-term clinical scenario of drug development (Phases II and higher).

Morning and evening TSH response to TRH and sleep EEG disturbances in major depressive disorder.

1. The aim of this study was to investigate hypothalamo-pituitary-thyroid axis (HPTA) functioning and sleep EEG disturbances in major depressive disorder. 2. Thyroid function was evaluated by determination of TSH levels before and after 8 AM and 11 PM TRH administration on the same day in a sample of 113 consecutively-admitted DSM-IV major depressed inpatients (72 females aged 44.3 +/- 13.0 and 41 males aged 45.7 +/- 10.7) that underwent sleep EEG recordings. 3. A blunted TSH response occurred in 15.9% for 8 AM deltaTSH (maximum increment above baseline at the 8 AM TRH challenge), in 39.8% for 11 PM deltaTSH and in 77% for deltadeltaTSH (difference between 11 PM deltaTSH and 8 AM deltaTSH). A negative correlation between deltadeltaTSH and duration of awakenings after sleep onset, and a shorter sleep onset latency in patients with a blunted 11 PM deltaTSH were found, but these two significant relationships disappeared after controlling for the effects of gender and age. 4. The present findings do not support the hypothesis that, in major depression, HPTA dysfunctioning, as reflected in TSH response to TRH, may be related to sleep EEG disturbances.

Periodic limb movements and obstructive sleep apneas before and after continuous positive airway pressure treatment.

Periodic limb movements during sleep (PLMS) and obstructive sleep apnea syndrome (OSAS) are two common sleep disorders. The similarity in periodicity of periodic limb movements (PLMs) and obstructive sleep apneas (OSAs) led us to hypothesize the existence of a common central generator responsible for the periodicity of both OSAs and PLMs. In order to test this hypothesis, we compared apnea periodicity before continuous positive airway pressure (CPAP) treatment with PLMs periodicity during CPAP treatment in 26 OSA patients, consecutively recorded and treated in our sleep laboratory. The investigation on CPAP was performed twice, once during the initial evaluation and once during a follow-up evaluation after 3 months of home treatment with CPAP. Our results showed that, in this sample, 16 patients out of 26 had an association of OSAS and PLMS, defined as the occurrence of at least 5 PLMs per hour of sleep. The mean apnea interval - measured as the time between the beginning of two successive apneas - was 43.1 s (+/-15.2, SD) and the mean PLM interval - calculated in the same way - was 29.6 s (+/-15.2) during the baseline night, 28.5 s (+/-15.7) during the first CPAP night, and 29.8 s (+/-14.8) during the second CPAP night. Thus, the periodicity of the two phenomena (apneas and PLMs) was different, both before and after CPAP treatment (P< 0.05). When considering the interval between the end of an event (apnea or PLM) and the beginning of the next one the mean apnea interval was 19.5 s (+/-11. 6), and the mean PLM interval was 28.1 s (+/-15.3) during the untreated night, 26.6 s (+/-16) during the first CPAP night and 27.9 s (+/-15) during the second CPAP night. The shortening of apnea intervals with this method of measuring intervals reflects the longer duration of apneas as compared to PLMs. Again the intervals between PLMs were not different between each other but the intervals between apneas were different from the intervals between PLMs (P< 0. 05) These results show that the periodicity of PLMs is different from that of OSAs, suggesting that sleep apneas and PLMs are not generated by a common central generator.

All-night EEG spectral analysis as a tool for the prediction of clinical response to antidepressant treatment.

Earlier investigations have suggested that variables derived from quantified electroencephalographic (EEG) sleep analysis might predict good clinical response in an early phase of antidepressant treatment. In this report we evaluate the predictive value of all-night sleep EEG spectral analysis during the washout period before treatment. We compared the spectral EEG sleep profiles of major depressed inpatients divided into two groups according to an improvement > or = 50% on the Hamilton Rating Scale for Depression. Findings in this population demonstrate the presence of specific characteristics of the responder group compared with the nonresponder group. Delta band relative power was increased in the former group, while theta, alpha, and beta relative power were decreased. All the bands showed decrease in absolute power in the responder group. These results can be interpreted as enhanced sleep intensity in the responder group. All-night sleep EEG spectral variables are valid baseline markers of the functional differences between treatment responders and nonresponders and thus might permit prediction of clinical outcome.