Pharmacokinetic evaluation of atorvastatin and sitagliptin in combination for the treatment of type 2 diabetes.

peer reviewedINTRODUCTION: Patients with type 2 diabetes (T2DM) are exposed to a high risk of cardiovascular disease (CVD) requiring a global therapeutic approach. Statin therapy has proven its efficacy in reducing CVD events in T2DM patients. Dipeptidylpeptidase-4 inhibitors (gliptins), which are increasingly used to target hyperglycemia, also offer promising preliminary results regarding a possible reduction in CVD events. As most patients with T2DM may be treated with both a statin and a gliptin, dual pharmacological therapy, possibly as a fixed-dose combination (FDC), deserves further consideration. AREAS COVERED: The reader is provided with an update of information on the pharmacokinetics (PK) and pharmacodynamics (PD) of atorvastatin and sitagliptin . The article provides an analysis of the potential PK/PD interactions between the two compounds and puts into perspective the potential cardiovascular protection that such a dual therapy may offer in patients with T2DM. EXPERT OPINION: Atorvastatin and sitagliptin are not prone to PK drug-drug interactions. Their coadministration, either separately or in an FDC, improves both blood glucose levels and cholesterol concentrations, without clinically relevant adverse events. The atorvastatin plus sitagliptin combination may be used to reduce LDL cholesterol and hyperglycemia in patients with T2DM, with the aim to improve CVD prognosis and adherence to therapy

Medications in the kidney.

Patients with chronic kidney disease (CKD) constitute a population at high risk for adverse drug reactions and/or drug-drug interactions. Renal dysfunction-induced pathophysiological changes may alter both medication pharmacodynamics and handling. Most pharmacokinetic parameters are adversely affected by impaired kidney function, among which reduced glomerular filtration and altered tubular secretion and reabsorption lead to the most specific alterations. Dosages of drugs cleared by the kidney should usually be adjusted according to creatinine clearance. Recommended methods for maintenance dosing adjustments are dose reductions, lengthening the dosing interval, or both. Appropriate drug selection and dosing in patients with CKD is imperative to avoid drug adverse events and to ensure optimal patient outcomes

Drug selection guided by known and newly diagnosed comorbidities in a multi-risk patient

peer reviewedRÉSUMÉ : Le patient obèse souffrant de gonarthrose, d’hypertension artérielle, de diabète de type 2, d’hyperuricémie, de dyslipidémie mixte et d’insuffisance rénale modérée est fréquemment rencontré dans la pratique médicale. Outre les mesures hygiéno-diététiques, la prise en charge optimale de ce type de patient impose le recours à une polymédication dont le choix doit tenir compte des synergies pharmacologiques pour garantir la meilleure protection possible, mais aussi des éventuelles contre-indications imposées par la présence des comorbidités ou encore le risque d’interférences médicamenteuses

CB1 receptor blockade and its impact on cardiometabolic risk factors: overview of the RIO programme with rimonabant.

Rimonabant, the first selective CB(1) receptor antagonist in clinical use, has been extensively investigated in the Rimonabant in Obesity (RIO) programme, comprising four 1-2 year placebo-controlled randomised clinical trials recruiting more than 6600 overweight/obese patients with or without co-morbidities. Rimonabant 20 mg daily consistently reduced body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and increased HDL cholesterol concentrations in both non-diabetic and type-2 diabetic overweight/obese patients. Adiponectin levels were increased, an effect that correlated with HDL cholesterol augmentation, while small dense LDL cholesterol levels were decreased in patients receiving rimonabant 20 mg compared with those receiving placebo in RIO Lipids. Furthermore, in RIO Diabetes, a 0.7% reduction in glycated haemoglobin (HbA1c) levels was observed in metformin- or sulphonylurea-treated patients with type-2 diabetes, an effect recently confirmed in the 6-month SERENADE (Study Evaluating Rimonabant Efficacy in drug-NAive DiabEtic patients) trial in drug-naive diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. The positive effects observed after 1 year were maintained after 2 years. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared with placebo. In clinical practice, rimonabant has to be prescribed to the right patient, i.e. overweight/obese subjects with cardiometabolic risk factors and with no major depressive illness and/or ongoing antidepressive treatment, in order to both maximise efficacy and minimise safety issues. New trials are supposed to confirm the potential role of rimonabant in patients with abdominal adiposity, atherogenic dyslipidaemia and/or type-2 diabetes, i.e. at high cardiometabolic risk

Management of the metabolic syndrome.

The metabolic syndrome (MetS) is strongly associated with insulin resistance and consists of a constellation of factors that raise the risk for cardiovascular diseases and diabetes mellitus. Therefore, the primary goals of treating MetS are prevention of type 2 diabetes and cardiovascular events. Three levels of intervention may be considered for individuals with MetS : 1) management of underlying risk conditions by controlling weight excess, enhancing regular physical exercise and promoting healthy diet; 2) management of individual risk factors such as dyslipidaemia, hypertension, hyperglycaemia and prothrombotic state; and 3) targeting insulin resistance by using specific insulin sensitizers such as thiazolidinediones. The most important therapeutic intervention effective in subjects with MetS should focus on modest weight reduction and regular leisure-time physical activities. Although lifestyle modification is the first-line therapy, drug therapy may be necessary in many patients to achieve recommended goals regarding lipid profile, blood pressure and blood glucose control. Rather than to use a magic bullet that might fully reverse the underlying cause of the syndrome, one appealing alternative would be to use a so-called "polypill" targeting each of the components of MetS. However, such a polypill should ideally contain numerous molecules that all have shown a potential interest for the management of MetS such as metformin, acarbose, a thiazolidinedione, a statin, a fibrate, an inhibitor of the renin-angiotensin system, aspirin. The growing prevalence and high-risk nature of MetS highlights the need to identify individuals with this condition and to treat them with an aggressive multitargeted approach

Results of obesity treatment.

Obesity is a chronic disease so that results of obesity treatment should only be evaluated on a long-term basis. The present paper aims at analyzing the long-term (1 year or more) results of three anti-obesity approaches, i.e. lifestyle modifications, pharmacological treatments and surgical procedures. Dietary interventions include diets with moderate calorie restriction and very-low energy diets (VLED). Even if an initial greater weight loss is observed with VLED, no study has conclusively shown that the long-term approaches including VLED are better than non-VLED programmes. Physical activity is not the most efficient method of initial weight loss, but it appears to be more crucial for maintaining weight loss once it has occurred. In general, long-term results of lifestyle modifications are disappointing because of poor compliance. Several 1-2 year large-scale randomized placebo-controlled clinical trials with orlistat, an intestinal lipase inhibitor, and sibutramine, a central appetite regulator, have demonstrated that both drugs significantly, although modestly on average, increase weight reduction, almost double the number of responders (weight loss >=5 or 10% of initial body weight) and improve weight maintenance up to 2 years. Surgical procedures provide a much greater weight reduction than medical interventions in patients with morbid obesity, particularly after a follow-up of several years. Weight loss is greater with gastric bypass, inducing some malbsorption, than with gastroplasty, a pure gastric restriction technique. Associated risk factors such as markers of insulin resistance syndrome and type 2 diabetes are remarkably reduced, but no prospective study of morbidity or mortality is available yet. In all cases, the management of obesity requires a multidisciplinary approach to improve the success rate

Crises financiere, economique, sociale, societale, morale, des reactions en chaine.

peer reviewe

NAVIGATOR: A trial of prevention of cardiovascular complications and type 2 diabetes with valsartan and/or nateglinide

peer reviewedNAVIGATOR ("Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research") is a large international placebo-controlled trial that randomised 9,031 individuals at high risk because of impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors. This trial aimed at investigating whether valsartan (a selective AT1 receptor antagonist) and/or nateglinide (a short-acting insulin-secreting agent) are able to reduce the incidence of type 2 diabetes and cardiovascular events. After a median follow up of 6.5 years, neither valsartan nor nateglinide improved cardiovascular prognosis in the tested population, which already benefited from a protective pharmacotherapy at baseline and a reinforcement of lifestyle modification throughout the trial. Nateglinide did not diminish the risk of new onset diabetes. In contrast, valsartan reduced the incidence of type 2 diabetes by 14%, confirming the potential interest of the blockade of the renin-angiotensin system in this high-risk population