Dapagliflozin therapy for type 2 diabetes in primary care: Changes in HbA1c, weight and blood pressure over 2 years follow-up.

AIMS: To investigate prescribing patterns and effect of dapagliflozin among individuals with T2DM using UK primary care data. METHODS: Adult patients with T2DM initiating dapagliflozin treatment were identified from the Clinical Practice Research Datalink. Changes in HbA1c, body weight and systolic blood pressure were assessed in subgroups defined by glucose lowering treatment at baseline and compliance with the Summary of Product Characteristics. Logistic regression examined the association of baseline characteristics with achievement of target HbA1c (≤53mmol/mol) and weight reduction (by ≥3.0%). RESULTS: Among 5828 eligible individuals, HbA1c was reduced from a baseline mean of 80.0mmol/mol (SD 17.6) by -12.8 (95% CI -13.8, -11.8)mmol/mol at >12-24 months. The corresponding value for weight reduction (baseline mean 101.7kg) was -5.0 (-5.4, -4.5)kg, and for systolic blood pressure reduction (baseline mean 134.1mmHg) was -3.1 (-4.0, -2.2) mmHg. Lower baseline HbA1c values (<69; 69-85 versus ≥86mmol/mol) were positively associated with achievement of target HbA1c <53mmol/mol. CONCLUSIONS: Treatment with dapagliflozin in T2DM was associated with reductions in HbA1c, weight and systolic blood pressure over time periods up to 2 years. Changes in these parameters were consistent with those reported in RCTs.

Weight change and healthcare resource use in English patients with type 2 diabetes mellitus initiating a new diabetes medication class.

AIMS: The aim of this study was to investigate the association between weight change and healthcare resource use (HCRU) and costs in English primary care patients with type 2 diabetes mellitus (T2DM) initiating treatment with a new diabetes medication class. METHODS: Patients diagnosed with T2DM initiating a new diabetes medication class (first-line, switch or add-on treatment) were selected from Clinical Practice Research Datalink. Weight change (index date) was measured 6 months after initiating new treatment. HCRU was derived up to 1 year after index. Adjusted analyses evaluated the association between weight change and HCRU and costs (GBP, 2013 prices). RESULTS: Of 9031 patients, about half (n = 4901) experienced < 3% weight change (weight neutral); the proportions gaining or losing weight were similar. Compared with the weight neutral group, weight gain was associated with significantly increased total costs within a year (3.0-5.4% weight gain: £58.9; p = 0.01, ≥ 5.5% weight gain: £52.9; p = 0.04) and diabetes primary care costs (3.0-5.4% weight gain: £29.2; p < 0.001, ≥ 5.5% weight gain: £34.2; p < 0.001). This included increased rates of prescribing drugs for diabetes and, in ≥ 5.5% weight gain, increased primary care contacts. A ≥ 5.5% weight loss was associated with increased hospital admissions (odds ratio = 1.4; p < 0.0001) and total costs (£126.3; p < 0.001). CONCLUSION: Weight gain after initiating a new glucose-lowering medication is associated with increased prescribing and contact with primary care clinicians, with increased costs in primary care and total spending. This study supports that weight gain in diabetes is associated with increased healthcare costs.

Motivation for alcohol assessed by multiple variable interval schedule behaviour: effects of reward size and alcohol cues.

Altered motivation for drugs of abuse is a central feature of most definitions of drug dependence and the impact of drug-related cues on motivation is of current interest. However, since most studies of cue-reactivity have not used behavioural measures of motivation, their results are often difficult to interpret in motivational terms. In the current paper we describe two experiments in which a behavioural technique, based on multiple variable interval (VI) schedules of reinforcement, was used to study motivation for alcohol in human subjects. In both experiments, subjects attended for several sessions and, during each session, were exposed to a 6-ply VI schedule (values ranged from 1 to 720 s), during which they earned points that were later exchanged for a preferred beer or lager. In Experiment 1 the procedure was validated by showing that changes in the magnitude of reinforcement altered behaviour appropriately. In Experiment 2 we found evidence that the presence of an alcohol-related cue increased the value of alcohol rewards. The results are discussed with reference to a model for the behavioural effects of drug-related cues in triggering relapse and a number of problems we found in using the multiple variable interval schedule procedure.

A naturalistic investigation of the effects of day-long consumption of tea, coffee and water on alertness, sleep onset and sleep quality.

RATIONALE: The effects of caffeine, especially caffeinated coffee, on human performance have been extensively studied. However, few studies have been naturalistic representations of how tea/coffee is normally consumed in terms of dose and time of consumption. OBJECTIVES: This study investigated the effects of day-long consumption of tea, coffee and water on cognitive and psychomotor performance, and sleep quality at night. METHODS: Thirty healthy volunteers received equal volume drinks equivalent to either 1 or 2 cups of tea (containing 37.5 mg or 75 mg caffeine), or coffee (75 mg or 150 mg caffeine), or water, in a randomised five-way crossover design. Drinks were administered on four occasions during the day (0900, 1300, 1700 and 2300 hours). A psychometric battery consisting of critical flicker fusion (CFF), choice reaction time (CRT) and subjective sedation (LARS) tests, was administered pre-dose and at frequent time points post-dose. The Leeds Sleep Evaluation Questionnaire (LSEQ) was completed each morning and a wrist actigraph was worn for the duration of the study. RESULTS: Caffeinated beverages maintained CFF threshold over the whole day (P<0.05), independent of caffeine dose or beverage type. During the acute phase of beverage ingestion, caffeine significantly sustained performance compared to water after the first beverage for CFF and subjective sedation (P<0.05), and after the second beverage for the Recognition component of the CRT task (P<0.05). Additionally, there were significant differences between tea and coffee at 75 mg caffeine after the first drink. Compared to coffee, tea produced a significant increase in CFF threshold between 30 and 90 min post-consumption (P<0.01). However, following the second beverage caffeinated coffee at 75 mg significantly improved reaction time (P<0.05), compared to tea at the same dose, for the Recognition component of the CRT task. Caffeinated beverages had a dose dependent negative effect on sleep onset (P<0.001), sleep time (P<0.001) and sleep quality (P<0.001). CONCLUSIONS: These results indicate that ingestion of caffeinated beverages may maintain aspects of cognitive and psychomotor performance throughout the day and evening when caffeinated beverages are administered repeatedly. This study also demonstrates that day-long tea consumption produces similar alerting effects to coffee, despite lower caffeine levels, but is less likely to disrupt sleep. Other differences between tea and coffee were more subtle, and require further investigation.

Pharmacodynamics of milnacipran in young and elderly volunteers.

AIMS: To investigate the pharmacodynamics of milnacipran in healthy young and elderly volunteers. METHODS: Randomized double-blind crossover designs were employed and a standardized psychometric battery was administered pre and post dose for both studies. In the first study 10 healthy young volunteers received milnacipran 12.5 mg, 25 mg, 50 mg, 100 mg as a single dose or matched placebo. The test battery was administered at baseline and at 1, 2, 4 and 6 h post dose. The second study compared the effects of milnacipran 75 mg (50 mg+25 mg) per day, amitriptyline 50 mg (25 mg+25 mg) per day and placebo for 3 days' dosing in healthy volunteers aged over 65 years. The test battery was administered at baseline and at 2, 10 and 24 h post dose. The psychometric battery included critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking (CTT) and tests of short-term memory (STM), subjective sedation (LARS) and subjective sleep (LSEQ). RESULTS: Milnacipran produced no significant dose related effects in the young volunteers. For the elderly, milnacipran significantly (P<0.05) raised CFF scores compared with placebo but had no significant effects on any of the other measures used. Amitriptyline, in contrast, significantly (P<0. 05) lowered CFF threshold, lengthened CRT and increased error on the CTT. On the subjective variables, LARS and LSEQ, amitriptyline increased ratings both of sedation and of difficulty in waking from sleep. CONCLUSIONS: The results showed that milnacipran at single doses of up to 100 mg in healthy young volunteers is free from disruptive effects on cognitive function and psychomotor performance. In addition, milnacipran 75 mg (50+25 mg) appears to be free of negative effects on cognitive function in elderly volunteers, where it seemingly improves performance on CFF. In contrast, the tricyclic antidepressant amitriptyline, used here as a positive internal control, significantly impaired performance in the elderly on the majority of psychometric measures used in this study. This finding not only validated the sensitivity of this current test battery but also indicates the potential behavioural toxicity of amitriptyline in clinical use in the elderly.

The effects of acute doses of standardized Ginkgo biloba extract on memory and psychomotor performance in volunteers.

This study investigated the effects of acute doses of Ginkgo biloba extract (GBE) on memory and psychomotor performance in a randomized, double-blind and placebo controlled 5-way cross-over design. Thirty-one volunteers aged 30-59 years received GBE 150 mg (50 mg t. d.s), GBE 300 mg (100 mg t.d.s.), GBE 120 mg mane and GBE 240 mg mane and placebo for 2 days. Following baseline measures, the medication was administered at 0900 h for the single doses and at 0900, 1500 and 2100 h for the multiple doses. The psychometric test battery was administered pre-dose (0830 h) and then at frequent intervals until 11 h post dose. The results confirm that the effects of GBE extract on aspects of cognition in asymptomatic volunteers are more pronounced for memory, particularly working memory. They also show that these effects may be dose dependent though not in a linear dose related manner, and that GBE 120 mg produces the most evident effects of the doses examined. Additionally, the results suggest that the cognitive enhancing effects of GBE are more likely to be apparent in individuals aged 50-59 years.

Multiple variable interval schedule behaviour in humans: effects of ethanol, mood, and reinforcer size on responding maintained by monetary reinforcement.

Ethanol is an effective reinforcer but, in common with other drugs of abuse, it may derive some of its reinforcing properties from the effects it has on behaviour maintained by other reinforcers. However, any assessment of ethanol's hypothesized effect on behaviour maintained by other reinforcers must take into account the fact that ethanol may have multiple mechanisms of action. In order to address this problem the experiments reported herein used a procedure based upon Herrnstein's Matching Law which allowed joint assessment of subjects' motor capacity and reinforcer sensitivity. The effect of ethanol (0, 0.3, and 0.6 g/kg) on motor capacity and reinforcer sensitivity was assessed by studying behaviour maintained by monetary reinforcement. In the first experiment the procedure was validated by showing that the behaviour of subjects was sensitive to changes in reinforcer value and in the second experiment 0.6 g/kg ethanol reduced motor capacity but did not affect reinforcer sensitivity. As a secondary hypothesis we also studied the effect of mood on reinforcer sensitivity and motor capacity. It was found that lower mood scores (lower hedonic tone) were associated with reduced reinforcer sensitivity and that male subjects showed higher motor capacity than females. However, there was also a mood by sex interaction, which indicated that higher motor capacity in males was only found in the presence of lower mood scores. The results are discussed in relation to the mechanisms of ethanol's dopaminergic effects, interactions between ethanol and other drugs of abuse, and the changes in reinforcer sensitivity which are thought to occur in depression.