Dapagliflozina

Dapagliflozin is a new oral antidiabetic agent whose mechanism of action increases renal glucose excretion, independently of insulin secretion or insulin action. The efficacy of dapagliflozin is dependent on renal function. The use of dapagliflozin has been licensed to improve glycaemic control in patients with type 2 diabetes mellitus as: - monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance. - Add-on combination therapy with other glucose-lowering agents including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. Funding has been restricted to the use of dapagliflozin, prior approval, as dual therapy in combination with metformin. This report aims to assess the efficacy and safety of dapagliflozin in the treatment of type 2 diabetes mellitus, rate the added therapeutic value of dapagliflozin in type 2 diabetes mellitus and identify its current place in therapy. A systematic literature search was carried out, for the purpose of this evaluation, using PubMed, Embase, Cochrane and IDIS databases as well as other secondary sources of evidence-based medicine, therapeutic bulletins and national and international drug agencies. Following the critical reading and analysis of the selected articles, a summary is made out of the scientific evidence available, using Scottish Intercollegiate Guidelines Network (SIGN) criteria. Only one randomised clinical trial, out of the ten trials found, was considered to be a suitable comparison (versus a dual therapy in combination with the sulfonylurea glipizide in patients inadequately controlled with metformin, diet and exercise). No trials have evaluated variables of relevance to patients, except for safety variables. The main efficacy variable in the trials was the change from baseline in HbA1c, except for a study which evaluated the change from baseline in total body weight as main variable. Baseline characteristics of the patients enrolled in the trials significantly differ from those of the population with diabetes in our society which tend to be of an older age and have a longer history of type 2 diabetes mellitus. The major limitation of dapagliflozin derives from its mechanism of action, since its efficacy decreases as renal function declines. The use of dapagliflozin is not recommended in patients with moderate to severe renal impairment ((CrCl<60ml/min or GFG <60 ml/min/1.73 m2) nor in elderly patients, in which a decrease in renal function can be expected. The assessment of safety includes the incidence and rate of discontinuations due to adverse events, episodes of hypoglycaemia, signs or symptoms of genital and urinary tract infections, dehydration, hypovolaemia and hypotension. Further pharmacoepidemiological studies are to be carried out to clarify the long-term effects of dapagliflozin on renal function and the potential effect in the development of breast and bladder tumours. Dapagliflozin as monotherapy has not been evaluated against adequate comparators (sulfonylureas, pioglitazone, gliptins). In combination therapy with metformin, the efficacy of dapagliflozin was shown to be non-inferior to glipizide plus metformin, resulting in a mean reduction of 0.52% in HbA1c, with a difference of 0.00 among both groups (95% CI: -0.11 a 0.11). There are no comparative data against other second-line treatment options. As shown in the studies, the overall incidence of adverse events with dapagliflozin as monotherapy (21.5%) was similar to that observed with placebo, and greater to that observed with metformin (15.4%). Hypoglycaemia of any type was the adverse event more frequently reported. The incidence of severe hypoglycaemic events observed in most of the studies was low. The overall incidence of adverse events observed in the study that compared dapagliflozin+metformin against glipizide+metformin was similar for both groups (27%) and incidence of hypoglycaemic events with dapagliflozin (3.5%) was significantly lower to that observed with glipizide (40.8%). Reductions of body weight of about 2 to 3 kg and a slight decrease in blood pressure (1 to 5 mmHg) have been observed in all studies in the groups treated with dapagliflozin together with diet and exercise. Dosing scheme (every 24 hours) is similar to other oral antidiabetic agents and its cost is similar to that for gliptines and higher to that for sulfonylureas or generic pioglitazone. Funding has been limited to the use of dapagliflozin as dual therapy regimen in combination with metformin as an option for patients with contraindication or intolerance to sulfonylureas, such a those experiencing frequent hypoglycaemic events, weight loss associated risks, as long as they are under 75 years of age and have no moderate to severe renal impairment. In the light of the above, we consider dapagliflozin means no therapeutic innovation in the therapy of type 2 diabetes mellitus over other therapeutic alternatives available.

CB1 blockade potentiates down-regulation of lipogenic gene expression in perirenal adipose tissue in high carbohydrate diet-induced obesity.

De novo lipogenesis and hypercaloric diets are thought to contribute to increased fat mass, particularly in abdominal fat depots. CB1 is highly expressed in adipose tissue, and CB1-mediated signalling is associated with stimulation of lipogenesis and diet-induced obesity, though its contribution to increasing fat deposition in adipose tissue is controversial. Lipogenesis is regulated by transcription factors such as liver X receptor (LXR), sterol-response element binding protein (SREBP) and carbohydrate-responsive-element-binding protein (ChREBP). We evaluated the role of CB1 in the gene expression of these factors and their target genes in relation to lipogenesis in the perirenal adipose tissue (PrAT) of rats fed a high-carbohydrate diet (HCHD) or a high-fat diet (HFD). Both obesity models showed an up-regulated gene expression of CB1 and Lxrα in this adipose pad. The Srebf-1 and ChREBP gene expressions were down-regulated in HFD but not in HCHD. The expression of their target genes encoding for lipogenic enzymes showed a decrease in diet-induced obesity and was particularly dramatic in HFD. In HCHD, CB1 blockade by AM251 reduced the Srebf-1 and ChREBP expression and totally abrogated the remnant gene expression of their target lipogenic enzymes. The phosphorylated form of the extracellular signal-regulated kinase (ERK-p), which participates in the CB1-mediated signalling pathway, was markedly present in the PrAT of obese rats. ERK-p was drastically repressed by AM251 indicating that CB1 is actually functional in PrAT of obese animals, though its activation loses the ability to stimulate lipogenesis in PrAT of obese rats. Even so, the remnant expression levels of lipogenic transcription factors found in HCHD-fed rats are still dependent on CB1 activity. Hence, in HCHD-induced obesity, CB1 blockade may help to further potentiate the reduction of lipogenesis in PrAT by means of inducing down-regulation of the ChREBP and Srebf-1 gene expression, and consequently in the expression of lipogenic enzymes.

Oral and general health-related quality of life in patients treated for oral cancer compared to control group.

BACKGROUND Health-related quality of life (HRQoL) is gaining importance as a valuable outcome measure in oral cancer area. The aim of this study was to assess the general and oral HRQoL of oral and oropharyngeal cancer patients 6 or more months after treatment and compare them with a population free from this disease. METHODS A cross-sectional study was carried out with patients treated for oral cancer at least 6 months post-treatment and a gender and age group matched control group. HRQoL was measured with the 12-Item Short Form Health Survey (SF-12); oral HRQoL (OHRQoL) was evaluated using the Oral Health Impact Profile (OHIP-14) and the Oral Impacts on Daily Performances (OIDP). Multivariable regression models assessed the association between the outcomes (SF-12, OHIP-14 and OIDP) and the exposure (patients versus controls), adjusting for sex, age, social class, functional tooth units and presence of illness. RESULTS For patients (n = 142) and controls (n = 142), 64.1% were males. The mean age was 65.2 (standard deviation (sd): 12.9) years in patients and 67.5 (sd: 13.7) years in controls. Patients had worse SF-12 Physical Component Summary scores than controls even in fully the adjusted model [β-coefficient = -0.11 (95% CI: -5.12-(-0.16)]. The differences in SF-12 Mental Component Summary were not statistically significant. Regarding OHRQoL patients had 11.63 (95% CI: 6.77-20.01) higher odds for the OHIP-14 and 21.26 (95% CI: 11.54-39.13) higher odds for OIDP of being in a worse category of OHRQoL compared to controls in the fully adjusted model. CONCLUSION At least 6 months after treatment, oral cancer patients had worse OHRQoL, worse physical HRQoL and similar psychological HRQoL than the general population.