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Empagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has shown a remarkable reduction in cardiovascular and all-cause mortality in patients with type 2 diabetes (T2D) and antecedents of cardiovascular disease in the EMPA-REG OUTCOME trial. This effect has been attributed to a hemodynamic rather than a metabolic effect, partly due to the osmotic/diuretic effect of empagliflozin and to the reduction in arterial blood pressure. The present review will: (1) summarize the results of specific studies having tested the blood pressure lowering effects of SGLT2 inhibitors; (2) describe the results of meta-analyses of trials having evaluated the effects on mortality and cardiovascular outcomes of lowering blood pressure in patients with T2D, with a special focus on baseline and target blood pressures; (3) compare the cardiovascular outcome results in EMPA-REG OUTCOME versus other major trials with antihypertensive agents in patients with T2D; and (4) evaluate post-hoc analyses from EMPA-REG OUTCOME, especially subgroups of patients of special interest regarding the blood pressure lowering hypothesis. Although BP reduction associated to empagliflozin therapy may partly contribute to the benefits reported in EMPA-REG OUTCOME, other mechanisms most probably play a greater role in the overall CV protection and reduction in mortality observed in this trial. [ABSTRACT FROM AUTHOR]

Personalized medicine aims at better targeting therapeutic intervention to the individual to maximize benefit and minimize harm. Type 2 diabetes (T2D) is a heterogeneous disease from a genetic, pathophysiological and clinical point of view. Thus, the response to any antidiabetic medication may considerably vary between individuals. Numerous glucose-lowering agents, with different mechanisms of action, have been developed, a diversified armamentarium that offers the possibility of a patient-centred therapeutic approach. In the current clinical practice, a personalized approach is only based upon phenotype, taking into account patient and disease individual characteristics. If this approach may help increase both efficacy and safety outcomes, there remains considerable room for improvement. In recent years, many efforts were taken to identify genetic and genotype SNP's (Single Nucleotide Polymorphism's) variants that influence the pharmacokinetics, pharmacodynamics, and ultimately the therapeutic response of oral glucose-lowering drugs. This approach mainly concerns metformin, sulphonylureas, meglitinides and thiazolidinediones, with only scarce data concerning gliptins and gliflozins yet. However, the contribution of pharmacogenetics and pharmacogenomics to personalized therapy still needs to mature greatly before routine clinical implementation is possible. This review discusses both opportunities and challenges of precision medicine and how this new paradigm may lead to a better individualized treatment of T2D. [ABSTRACT FROM AUTHOR]

Abstract: Beyond improvement of glucose control, thiazolidinediones exert pleiotropic effects, which may contribute to some cardiovascular protection. PROactive (“PROspective pioglitAzone Clinical Trial In macroVascular Events”) has provided valuable, although controversial, information on the impact of pioglitazone on cardiovascular outcomes in a high-risk population of patients with type 2 diabetes and established macrovascular disease. Since 2005, there has been much debate on the relative value of the statistically non-significant 10% reduction in the quite challenging primary composite endpoint (combining cardiovascular disease-driven and procedural events in all vascular beds) versus the statistically significant 16% decrease in the more robust and conventional main secondary endpoint (all-cause mortality, myocardial infarction, and stroke) observed with pioglitazone. Revisiting PROactive deserves much interest following the report of inconclusive results on cardiovascular efficacy and safety of rosiglitazone in RECORD, the withdrawal (limitation) of rosiglitazone because of cardiovascular safety concern, the recent publication of a statement positioning pioglitazone in type 2 diabetes and the near availability of cheaper generics of pioglitazone. Although subanalyses may have more limited value from a statistical viewpoint, they nonetheless can provide valuable information on the drug efficacy/safety profile and clinical insights into which patients might benefit most (in terms of cardiovascular outcomes) from pioglitazone therapy. [Copyright &y& Elsevier]

Abdominal obesity is associated with numerous metabolic abnormalities, including insulin resistance, impaired glucose tolerance/type-2 diabetes, and atherogenic dyslipidaemia with low high-density lipoprotein (HDL) cholesterol, high triglycerides, and increased small dense low-density lipoprotein (LDL) cholesterol. A proportion of these metabolic disorders may be attributed to increased endocannabinoid activity. The selective cannabinoid 1 (CB1) receptor antagonist rimonabant has been shown to reduce body weight, waist circumference, insulin resistance, triglycerides, dense LDL, C-reactive protein (CRP), and blood pressure, and to increase HDL and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. Besides an improvement in glucose tolerance in non-diabetic subjects, a reduction of 0.5–0.7% in haemoglobin A1C (HbA1c) levels was consistently observed in various groups of patients with type-2 diabetes. Almost half the metabolic changes could not be explained by weight loss, supporting direct peripheral effects of rimonabant. Ongoing studies should demonstrate whether improved metabolic disorders with CB1 receptor antagonists (rimonabant, taranabant, etc.) would translate into fewer cardiovascular complications among high-risk individuals. [Copyright &y& Elsevier]

Type-2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a risk of major cardiovascular disease. Several animal and human observations suggest that the endocannabinoid system is over-active in the presence of abdominal obesity and/or diabetes. Both central and peripheral endocannabinoid actions, via the activation of CB1 receptors, promote weight gain and associated metabolic changes. Rimonabant, the first selective CB1 receptor blocker in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance index and C-reactive protein levels, and to increase high-density lipoprotein (HDL) cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5–0.7% reduction in HbA1c levels was observed in metformin- or sulphonylurea-treated patients with type-2 diabetes and in drug-naïve diabetic patients. Almost half of the metabolic changes, including HbA1c reduction, could not be explained by weight loss, suggesting that there are direct peripheral effects. Rimonabant was generally well-tolerated, and the safety profile was similar in diabetic and non-diabetic patients, with a higher incidence of depressed mood disorders, nausea and dizziness. In conclusion, the potential role of rimonabant in overweight/obese patients with type-2 diabetes and at high risk of cardiovascular disease deserves much consideration. [Copyright &y& Elsevier]

Abstract: Hypocortisolism is an uncommon condition. Its association with myopathy and respiratory failure has only rarely been described. We report the case of a 52 year-old woman presenting with progressive dyspnoea. Work-up revealed a severe restrictive syndrome with hypoxaemia. Further investigations showed hypocortisolism of pituitary origin. Response to hydrocortisone allowed us to conclude to an unusual case of hypocortisolic myopathy affecting the respiratory muscles. [Copyright &y& Elsevier]

Aims: To establish the association between albuminuria and cardiovascular risk factors as well as micro- and macrovascular complications in type 1 and insulin-treated type 2 diabetes, both in the presence and in the absence of reduced estimated glomerular filtration rate (eGFR). Methods: Cross-sectional study including 7640 insulin-treated diabetic patients (33% type 1) treated in specialist diabetes centers. Albuminuria was defined as ≥30 mg/g, 20 mg/L, 20 μg/min or 30 mg/24 h. Reduced eGFR was defined as b60 mL/min/1.73 m² (CKD-EPI equations). Results: Albuminuria, reduced eGFR or a combination was more prevalent in type 2 (21.5%, 15.9% and 16.5%) than in type 1 diabetes (16.1%, 4.7% and 4.0%, all P b 0.001 vs. type 2). Albuminuria was associated with poorer control of blood pressure, blood lipids and glycemia as well as higher prevalence of retinopathy and macrovascular disease, regardless of preserved/reduced eGFR or diabetes type. Reduced eGFR was associated with higher prevalence of micro- and macrovascular complications especially in type 2 diabetes. Combined presence of albuminuria and reduced eGFR was associated with the worst cardiovascular outcomes. Conclusions: Albuminuria and impaired renal function are prevalent in type 1 and insulin-treated type 2 diabetes. Albuminuria, but also normoalbuminuric renal impairment, is associated with micro- and macrovascular complications. [ABSTRACT FROM AUTHOR]

It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammatory therapies could have a place in prevention and treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce [beta]-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1[beta] is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammatory therapies could have a place in prevention and treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]