Effect of once-weekly exenatide on clinical outcomes according to baseline risk in patients with type 2 diabetes mellitus: Insights from the EXSCEL trial

Background In the EXSCEL (Exenatide Study of Cardiovascular Event Lowering), exenatide once-weekly resulted in a nonsignificant reduction in major adverse cardiovascular events ( MACEs ) and a nominal 14% reduction in all-cause mortality in 14 752 patients with type 2 diabetes mellitus (T2 DM ) with and without cardiovascular disease. Whether patients at increased risk for events experienced a comparatively greater treatment benefit with exenatide is unknown. Methods and Results In the EXSCEL population, we created risk scores for MACEs and all-cause mortality using step-wise selection of baseline characteristics. A risk score was calculated for each patient, and a time-to-event model for each end point was developed including the risk score, treatment assignment, and risk-treatment interaction. Interaction P values evaluating for a differential treatment effect by baseline risk were reported. Over a median follow-up of 3.2 years (interquartile range, 2.2, 4.4), 1091 (7.4%) patients died and 1744 (11.8%) experienced a MACE . Independent predictors of MACEs and all-cause mortality included age, sex, comorbidities (eg, previous cardiovascular event), body mass index, blood pressure, hemoglobin A1c, and estimated glomerular filtration rate. The all-cause mortality and MACE risk models had modest discrimination with optimism-corrected c-indices of 0.73 and 0.71, respectively. No interaction was observed between treatment effect and risk profile for either end point (both interactions, P>0.1). Conclusions Baseline characteristics (eg, age, previous cardiovascular events) and routine laboratory values (eg, hemoglobin A1c, estimated glomerular filtration rate) provided modest prognostic value for mortality and MACEs in a broad population of patients with type 2 diabetes mellitus. Exenatide's effects on mortality and MACEs were consistent across the spectrum of baseline risk. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 01144338

Distracted by danger: Temporal and spatial dynamics of visual selection in the presence of threat

Threatening stimuli are known to influence attentional and visual processes in order to prioritize selection. For example, previous research showed faster detection of threatening relative to nonthreatening stimuli. This has led to the proposal that threatening stimuli are prioritized automatically via a rapid subcortical route. However, in most studies, the threatening stimulus is always to some extent task relevant. Therefore, it is still unclear if threatening stimuli are automatically prioritized by the visual system. We used the additional singleton paradigm with task-irrelevant fear-conditioned distractors (CS+ and CS-) and indexed the time course of eye movement behavior. The results demonstrate automatic prioritization of threat. First, mean latency of saccades directed to the neutral target was increased in the presence of a threatening (CS+) relative to a nonthreatening distractor (CS-), indicating exogenous attentional capture and delayed disengagement of covert attention. Second, more error saccades were directed to the threatening than to the nonthreatening distractor, indicating a modulation of automatically driven saccades. Nevertheless, cumulative distributions of the saccade latencies showed no modulation of threat for the fastest goal-driven saccades, and threat did not affect the latency of the error saccades to the distractors. Together these results suggest that threatening stimuli are automatically prioritized in attentional and visual selection but not via faster processing. Rather, we suggest that prioritization results from an enhanced representation of the threatening stimulus in the oculomotor system, which drives attentional and visual selection. The current findings are interpreted in terms of a neurobiological model of saccade programming.</p