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AimWe examined eligibility and preventable cardiovascular disease events in US adults with diabetes mellitus from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME).MethodsWe identified adults with diabetes mellitus eligible for EMPA-REG OUTCOME based on trial eligibility criteria available from the National Health and Nutrition Examination Surveys, 2007-2016. We estimated composite cardiovascular disease endpoints, as well as all-cause deaths, death from cardiovascular disease and hospitalizations for heart failure from trial treatment and placebo event rates, the difference indicating the preventable events.ResultsAmong 29,629 US adults aged ⩾18 years (representing 231.9 million), 4672 (27.3 million) had diabetes mellitus, with 342 (1.86 million) meeting eligibility criteria of EMPA-REG OUTCOME. We estimated from trial primary endpoint event rates of 10.5% and 12.1% in the empagliflozin and placebo groups, respectively, that based on the 'treatment' of our 1.86 million estimated EMPA-REG OUTCOME eligible subjects, 12,066 (95% confidence interval: 10,352-13,780) cardiovascular disease events could be prevented annually. Estimated annual preventable deaths from any cause, cardiovascular causes and hospitalizations from heart failure were 17,078 (95% confidence interval: 14,652-19,504), 14,479 (95% confidence interval: 12,422-16,536) and 9467 (95% confidence interval: 8122-10,812), respectively.ConclusionEmpagliflozin, if provided to EMPA-REG OUTCOME eligible US adults, may prevent many cardiovascular disease events, cardiovascular and total deaths, as well as heart failure hospitalizations.

Summary: Anti‐obesity medications (AOMs) have emerged as one element of comprehensive obesity clinical care intended to improve long‐term health outcomes for children and adolescents. The number of pediatric AOM clinical trials has burgeoned in recent years as new pharmacotherapeutics have been developed. Factors related to growth and development in children and adolescents can present unique challenges in terms of designing and conducting clinical trials investigating the safety and efficacy of AOMs. These barriers can delay the AOM development and evaluation process, increase the cost of performing trials, create challenges in the interpretation of results, influence the generalizability of the findings and present ethical dilemmas. In an effort to address these issues and provide guidance to streamline the process of designing and conducting pediatric AOM clinical trials, relevant key stakeholders convened a series of roundtable meetings to discuss, debate and achieve harmonization on design features. Stakeholder participants included a multidisciplinary group of international pediatric obesity experts, patient (parent) representatives and representatives from academic medicine, key regulatory agencies and industry. Topics of discussion included primary efficacy end‐points, secondary end‐points, eligibility criteria, trial run‐in and follow‐up phases, use of active comparators and guidelines for down‐titration and/or stopping rules for excessive weight reduction. Consensus recommendations were agreed upon. Regarding end‐points, emphasis was placed on moving away from BMI z‐score as a primary outcome, incorporating multiple alternative BMI‐related outcomes and measuring adiposity/body fat as a prominent secondary end‐point. Trial eligibility criteria were carefully considered to maximize generalizability while maintaining safety. The limited value of trial run‐in phases was discussed. It was also underscored that designing trials with extended follow‐up periods after AOM withdrawal should be avoided owing to ethical issues (including possible psychological harm) related to weight regain without providing the opportunity to access other treatments. The panel emphasized the value of the randomized, placebo‐controlled trial but recommended the thoughtful consideration of the use of active comparators in addition to, or instead of, placebo to achieve clinical equipoise when appropriate. Finally, the panel recommended that clinical trial protocols should include clear guidance regarding AOM down‐titration to avoid excessive weight reduction when applicable. [ABSTRACT FROM AUTHOR]

Key Points: Question: Can a coordinated, multifaceted intervention increase the prescription of 3 evidence-based therapies among adults with type 2 diabetes and atherosclerotic cardiovascular disease? Findings: In a cluster randomized clinical trial of cardiology clinics across the US, participants in the intervention group were more likely to be prescribed all 3 therapies (high-intensity statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and sodium-glucose cotransporter 2 inhibitors and/or glucagon-like peptide 1 receptor agonists) after an intervention of assessment, education, and feedback vs those in the usual care group (173/457 [37.9%] vs 85/588 [14.5%], respectively, which is a difference of 23.4%). Meaning: A coordinated, multifaceted intervention increased prescription of 3 groups of evidence-based therapies in adults with type 2 diabetes and atherosclerotic cardiovascular disease. Importance: Evidence-based therapies to reduce atherosclerotic cardiovascular disease risk in adults with type 2 diabetes are underused in clinical practice. Objective: To assess the effect of a coordinated, multifaceted intervention of assessment, education, and feedback vs usual care on the proportion of adults with type 2 diabetes and atherosclerotic cardiovascular disease prescribed all 3 groups of recommended, evidence-based therapies (high-intensity statins, angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs], and sodium-glucose cotransporter 2 [SGLT2] inhibitors and/or glucagon-like peptide 1 receptor agonists [GLP-1RAs]). Design, Setting, and Participants: Cluster randomized clinical trial with 43 US cardiology clinics recruiting participants from July 2019 through May 2022 and follow-up through December 2022. The participants were adults with type 2 diabetes and atherosclerotic cardiovascular disease not already taking all 3 groups of evidence-based therapies. Interventions: Assessing local barriers, developing care pathways, coordinating care, educating clinicians, reporting data back to the clinics, and providing tools for participants (n = 459) vs usual care per practice guidelines (n = 590). Main Outcomes and Measures: The primary outcome was the proportion of participants prescribed all 3 groups of recommended therapies at 6 to 12 months after enrollment. The secondary outcomes included changes in atherosclerotic cardiovascular disease risk factors and a composite outcome of all-cause death or hospitalization for myocardial infarction, stroke, decompensated heart failure, or urgent revascularization (the trial was not powered to show these differences). Results: Of 1049 participants enrolled (459 at 20 intervention clinics and 590 at 23 usual care clinics), the median age was 70 years and there were 338 women (32.2%), 173 Black participants (16.5%), and 90 Hispanic participants (8.6%). At the last follow-up visit (12 months for 97.3% of participants), those in the intervention group were more likely to be prescribed all 3 therapies (173/457 [37.9%]) vs the usual care group (85/588 [14.5%]), which is a difference of 23.4% (adjusted odds ratio [OR], 4.38 [95% CI, 2.49 to 7.71]; P <.001) and were more likely to be prescribed each of the 3 therapies (change from baseline in high-intensity statins from 66.5% to 70.7% for intervention vs from 58.2% to 56.8% for usual care [adjusted OR, 1.73; 95% CI, 1.06-2.83]; ACEIs or ARBs: from 75.1% to 81.4% for intervention vs from 69.6% to 68.4% for usual care [adjusted OR, 1.82; 95% CI, 1.14-2.91]; SGLT2 inhibitors and/or GLP-1RAs: from 12.3% to 60.4% for intervention vs from 14.5% to 35.5% for usual care [adjusted OR, 3.11; 95% CI, 2.08-4.64]). The intervention was not associated with changes in atherosclerotic cardiovascular disease risk factors. The composite secondary outcome occurred in 23 of 457 participants (5%) in the intervention group vs 40 of 588 participants (6.8%) in the usual care group (adjusted hazard ratio, 0.79 [95% CI, 0.46 to 1.33]). Conclusions and Relevance: A coordinated, multifaceted intervention increased prescription of 3 groups of evidence-based therapies in adults with type 2 diabetes and atherosclerotic cardiovascular disease. Trial Registration: ClinicalTrials.gov Identifier: NCT03936660 This cluster randomized clinical trial assesses the effect of a coordinated, multifaceted intervention of assessment, education, and feedback vs usual care on the prescribing of all 3 groups of recommended therapies (high-intensity statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and sodium-glucose cotransporter 2 inhibitors and/or glucagon-like peptide 1 receptor agonists) for adults with type 2 diabetes and atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

Previously we demonstrated that GTS-21, a nicotinic cholinergic agonist, ameliorated eyeblink classical conditioning deficits in older rabbits. The present experiment was undertaken to replicate and extend these results by examining the effects of GTS-21 on retention and relearning. Retired breeder rabbits received 15 daily injections of 0.5 mg/kg GTS 21 (n = 8) or sterile saline vehicle (n = 8) during acquisition training, and no further injections occurred. Acquisition of conditioned responses (CRs) was significantly better in GTS-21-treated rabbits. During the first tone-alone retention session in week 6 of the experiment, rabbits initially treated with GTS-21 produced significantly more CRs than vehicle-treated rabbits. There were no group differences in retention at the 13-week retest. Differences in relearning were in the predicted direction but did not attain statistical significance. Results indicate that treatment with GTS-21 ameliorates learning beyond the period when the drug is actually administered. [ABSTRACT FROM AUTHOR]

Background: The cognition-enhancing drug, nefiracetam, is in Phase III clinical trials to treat memory impairment in Alzheimer's disease (AD). Nefiracetam ameliorates acquisition of delay eyeblink classical conditioning in older rabbits, a form of associative learning with striking behavioral and neurobiological similarities in rabbits and humans. In both species, delay eyeblink conditioning engages the septo-hippocampal cholinergic system and is disrupted when the cholinergic system is antagonized. Delay eyeblink classical conditioning is impaired in normal aging and severely disrupted in AD., Material/methods: To test further the efficacy of nefiracetam in an animal model that mimics some of the neurobiological and behavioral effects present in AD, we tested 56 older rabbits assigned to 7 treatment groups in the 750 ms delay eyeblink conditioning procedure. Older rabbits were injected with 1.5 mg/kg scopolamine to simulate disruption of the cholinergic system in AD. Three doses of nefiracetam (5, 10, or 15 mg/kg) were also injected in older rabbits receiving 1.5 mg/kg scopolamine. Control groups were treated with 1.5 mg/kg scopolamine + vehicle, vehicle alone, or explicitly unpaired presentations of conditioning stimuli and vehicle or 1.5 mg/kg scopolamine + 15 mg/kg nefiracetam., Results: Rabbits injected with 1.5 mg/kg scopolamine alone were impaired, but a dose of 15 mg/kg nefiracetam reversed significantly the behavioral impairment., Conclusions: Nefiracetam had ameliorating effects on a task impaired in AD in an animal model of AD: older rabbits with cholinergic system antagonism.