Linagliptin (Trajenta): a selective DPP-4 inhibitor with limited renal elimination

peer reviewedLinagliptin (Trajenta) is a selective inhibitor of dipeptidyl peptidase-4, an enzyme that degrades two incretin hormones, GLP-1 ("Glucagon-Like Peptide-1") and GIP ("Glucose-dependent Insulinotropic Polypeptide"). As other molecules belonging to this pharmacological class, linagliptin improves blood glucose control of type 2 diabetic patients, without increasing hypoglycaemic risk, without promoting weight gain and with a good clinical and biological tolerance profile. Both efficacy and safety have been demonstrated in randomized controlled trials as monotherapy or in combination with other glucose-lowering agents, independent of demographic or clinical patient's characteristics. The pharmacokinetics specificity of linagliptin comprises its biliary excretion, with low hepatic metabolism (no drug-drug interactions) and, in contrast to other gliptins, its negligible renal elimination. Because of these favourable properties, linagliptin may be used without dose adjustment (5 mg once a day) in patients with renal impairment, as well as in elderly people

Sugar: results of a Belgian observational study on the use of sitagliptin in patients with type 2 diabetes

peer reviewedSitagliptin (Januvia), the first selective inhibitor of dipeptidylpeptidase-4, has been assessed in a large Belgian prospective observational study. The aim of the SUGAR study was to evaluate the efficacy of sitagliptin, at a dose of 100 mg once daily, when it was added in patients with uncontrolled type 2 diabetes followed in real life conditions. In the intent-to-treat population (n = 605), mean glycated haemoglobin level decreased from 8.41 +/- 1.18% to 7.29 +/- 0.86% after a follow up averaging 110 days (p < 0.0001). Similarly, mean fasting plasma glucose level decreased from 180 +/- 50 mg/dl to 141 +/- 37 mg/ dl (p < 0.0001). The improvement of these two parameters was observed independently of basal demographic characteristics, but was directly influenced by baseline initial corresponding values. The vast majority of patients included in SUGAR were initially treated by metformin as monotherapy (current criterion for sitagliptin reimbursement in Belgium); metformin daily dose slightly decreased when sitagliptin was added (from 1975 +/- 681 mg to 1919 +/- 667 mg; p = 0.033). Patients receiving other glucose-lowering agents, as single or combined therapies, had also a significant alleviation of their treatment when sitagliptin was added. After 3-6 months of follow up, more than 95% of patients still received sitagliptin, arguing for both the efficacy and the good tolerance of this new oral antidiabetic agent in clinical practice

Act quickly, decide later: long latency visual processing underlies perceptual decisions but not reflexive behavior

Jolij J, Scholte H, Van Gaal S, Hodgson TL, Lamme VAF (2011) Act quickly, decide later: Long latency visual processing underlies perceptual decisions but not reflexive behavior. Journal of Cognitive Neuroscience 23(12), p 3734-3745

Medication of the month...Exenatide (Byetta) incretinomimetic in the treatment of type 2 diabetes after failure and as add-on therapy to oral agents

peer reviewedExenatide (Byetta) is a synthetic derivative of exendin-4 and an agonist of receptors of glucagon-like peptide-1 (GLP-1). It is resistant to the rapid inactivation by dipeptidylpeptidase-4 and acts as an incretin mimetic. It stimulates insulin secretion by the B cell in a glucose-dependent manner whereas it inhibits glucagon secretion. Exenatide improves mainly postprandial glucose concentrations and lowers glycated haemoglobin (HbA(1c)) levels, without being directly responsible for hypoglycaemia or requiring mandatory home blood glucose monitoring. Furthermore, it slows down gastric emptying and promotes sustained body weight reduction, even in absence of frequently reported nausea following treatment initiation. Exenatide is recommended and reimbursed in Belgium for the treatment of type 2 diabetes, in combination with metformin and a sulfonylurea, in patients not adequately controlled with maximal tolerated doses of these oral glucose-lowering agents. Exenatide is presented as pre-filled pens for subcutaneous injection. The recommended initial dose is 5 microg before morning and evening meals, to be up titrated to 10 microg twice daily. Exenatide may represent a valuable alternative to insulin therapy, especially in overweight or obese patients with type 2 diabetes and not ready to perform home blood glucose monitoring

The Flexible Nature of Unconscious Cognition

The cognitive signature of unconscious processes is hotly debated recently. Generally, consciousness is thought to mediate flexible, adaptive and goal-directed behavior, but in the last decade unconscious processing has rapidly gained ground on traditional conscious territory. In this study we demonstrate that the scope and impact of unconscious information on behavior and brain activity can be modulated dynamically on a trial-by-trial basis. Participants performed a Go/No-Go experiment in which an unconscious (masked) stimulus preceding a conscious target could be associated with either a Go or No-Go response. Importantly, the mapping of stimuli onto these actions varied on a trial-by-trial basis, preventing the formation of stable associations and hence the possibility that unconscious stimuli automatically activate these control actions. By eliminating stimulus-response associations established through practice we demonstrate that unconscious information can be processed in a flexible and adaptive manner. In this experiment we show that the same unconscious stimulus can have a substantially different effect on behavior and (prefrontal) brain activity depending on the rapidly changing task context in which it is presented. This work suggests that unconscious information processing shares many sophisticated characteristics (including flexibility and context-specificity) with its conscious counterpart

Unconsciously Triggered Conflict Adaptation

In conflict tasks such as the Stroop, the Eriksen flanker or the Simon task, it is generally observed that the detection of conflict in the current trial reduces the impact of conflicting information in the subsequent trial; a phenomenon termed conflict adaptation. This higher-order cognitive control function has been assumed to be restricted to cases where conflict is experienced consciously. In the present experiment we manipulated the awareness of conflict-inducing stimuli in a metacontrast masking paradigm to directly test this assumption. Conflicting response tendencies were elicited either consciously (through primes that were weakly masked) or unconsciously (strongly masked primes). We demonstrate trial-by-trial conflict adaptation effects after conscious as well as unconscious conflict, which could not be explained by direct stimulus/response repetitions. These findings show that unconscious information can have a longer-lasting influence on our behavior than previously thought and further stretch the functional boundaries of unconscious cognition

Risk of cardiovascular and all-cause mortality: impact of impaired health-related functioning and diabetes: the Australian Diabetes, Obesity and Lifestyle (AusDiab) study.

OBJECTIVE: There is an established link between health-related functioning (HRF) and cardiovascular disease (CVD) mortality, and it is known that those with diabetes predominantly die of CVD. However, few studies have determined the combined impact of diabetes and impaired HRF on CVD mortality. We investigated whether this combination carries a higher CVD risk than either component alone. RESEARCH DESIGN AND METHODS: The Australian Diabetes, Obesity and Lifestyle (AusDiab) study included 11,247 adults aged ≥ 25 years from 42 randomly selected areas of Australia. At baseline (1999-2000), diabetes status was defined using the World Health Organization criteria and HRF was assessed using the SF-36 questionnaire. RESULTS: Overall, after 7.4 years of follow-up, 57 persons with diabetes and 105 without diabetes had died from CVD. In individuals with and without diabetes, HRF measures were significant predictors of increased CVD mortality. The CVD mortality risks among those with diabetes or impaired physical health component summary (PCS) alone were similar (diabetes only: hazard ratio 1.4 [95% CI 0.7-2.7]; impaired PCS alone: 1.5 [1.0-2.4]), while those with both diabetes and impaired PCS had a much higher CVD mortality (2.8 [1.6-4.7]) compared with those without diabetes and normal PCS (after adjustment for multiple covariates). Similar results were found for the mental health component summary. CONCLUSIONS: This study demonstrates that the combination of diabetes and impaired HRF is associated with substantially higher CVD mortality. This suggests that, among those with diabetes, impaired HRF is likely to be important in the identification of individuals at increased risk of CVD mortality

Bivariate genetic modelling of the response to an oral glucose tolerance challenge: A gene x environment interaction approach

AIMS/HYPOTHESIS: Twin and family studies have shown the importance of genetic factors influencing fasting and 2 h glucose and insulin levels. However, the genetics of the physiological response to a glucose load has not been thoroughly investigated. METHODS: We studied 580 monozygotic and 1,937 dizygotic British female twins from the Twins UK Registry. The effects of genetic and environmental factors on fasting and 2 h glucose and insulin levels were estimated using univariate genetic modelling. Bivariate model fitting was used to investigate the glucose and insulin responses to a glucose load, i.e. an OGTT. RESULTS: The genetic effect on fasting and 2 h glucose and insulin levels ranged between 40% and 56% after adjustment for age and BMI. Exposure to a glucose load resulted in the emergence of novel genetic effects on 2 h glucose independent of the fasting level, accounting for about 55% of its heritability. For 2 h insulin, the effect of the same genes that already influenced fasting insulin was amplified by about 30%. CONCLUSIONS/INTERPRETATION: Exposure to a glucose challenge uncovers new genetic variance for glucose and amplifies the effects of genes that already influence the fasting insulin level. Finding the genes acting on 2 h glucose independently of fasting glucose may offer new aetiological insight into the risk of cardiovascular events and death from all causes