Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The current obesity pandemic imposes a major global disease burden. Levels of non-communicable diseases such as type 2 diabetes, cardiovascular disease and some cancers will continue to rise unless an effective approach to treat obesity is found. Sustained weight loss of between 5-10% in the obese, by various means, confers marked health benefits. The currently available pharmacotherapies, orlistat and sibutramine, can induce weight loss of between 5-10% over 2 years or more. In trials, orlistat and sibutramine induced weight loss tends to be only between 2-4 kg greater than that produced by placebo control. However, this additional placebo subtracted weight loss produces marked additional improvements in diabetes and cardiovascular risk factors. Moreover, in the 4 year long XENDOS trial, the modest placebo subtracted weight loss produced by orlistat (2.8 kg) reduced the incidence of diabetes by over a third in those with normal glucose tolerance, and by nearly half in those with impaired glucose tolerance. Despite this, prescription sales of sibutramine in the US have apparently remained static and those of orlistat have fallen, with the drug now entering the global over-the-counter medication market. Recent data on potential anti-obesity drugs currently under going phase III trials, such as Rimonabant and Topiramate, demonstrate these drugs produce greater and more prolonged weight loss. Wider use of pharmacotherapy and enhanced efficacy for the next generation of anti-obesity drugs certainly promise to reduce obesity related illness if not halt the rise in obesity per se.
 ...
PMID:Clinical pharmacotherapy for obesity: current drugs and those in advanced development. 1547 53

Rimonabant hydrochloride, the first drug in a new class of selective cannabinoid type 1 (CB1) receptor antagonists, is showing promise in clinical trials for the treatment of obesity and related metabolic risk factors, in addition to tobacco dependence. Results of phase III clinical trials comparing rimonabant with placebo found that overweight or obese patients, with or without untreated dyslipidemia or type 2 diabetes, lost significant body weight when treated with rimonabant 20 mg for a year. The weight loss was accompanied by a decrease in waist circumference, demonstrating a significant reduction in abdominal obesity, which is an independent marker for cardiovascular disease. Significant improvements were also observed in the lipid profile, with an increase in high-density lipoprotein (HDL) cholesterol and a decrease in triglyceride levels. Improvements in glucose tolerance and insulin levels were also found. Moreover, the number of patients diagnosed with the metabolic syndrome at baseline was significantly reduced. These beneficial effects of rimonabant 20 mg were maintained after 2 years of chronic treatment. Other phase III trials have shown that rimonabant helps people to quit smoking without significant post-cessation weight gain. Rimonabant has a favorable safety profile and is generally well tolerated. Rimonabant is proving to be a very promising approach for managing two major and preventable risk factors for cardiovascular disease. This review summarizes the available evidence on the clinical efficacy and safety of rimonabant as a potential therapy for obesity and smoking cessation.
 ...
PMID:Rimonabant hydrochloride: an investigational agent for the management of cardiovascular risk factors. 1623 73

RIO (Rimonabant In Obesity and related disorders) is a large phase 3 programme (>6600 patients) evaluating the efficacy and safety of rimonabant (5 or 20 mg/day), a CBI receptor antagonist of endocannabinoid system, in obese or overweight patients with or without comorbidities (RIO-Europe and RIO-North America), with untreated dyslipidaemia (RIO-Lipids) or with type 2 diabetes treated with metformin or sulfonylurea (RIO-Diabetes). Compared to placebo, rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. Almost half of the metabolic effects, including adiponectin increase, occur beyond weight loss, suggesting a direct peripheral effect of rimonabant.
 ...
PMID:[Rimonabant improves cardiometabolic risk profile in obese or overweight subjects: overview of RIO studies]. 1697 42

Rimonabant is the first drug to target the endocannabinoid (CB) pathway by inhibiting the actions of anandamide and 2-archidonyl-glycerol on CB1 receptors. This review gives an overview of rimonabant and the CB system and how this system relates to obesity. Rimonabant blocks the central effects of this neurotransmitter pathway involved in obesity and weight control and also blocks the direct effects of CBs on adipocyte and hepatocyte metabolism. Blockade of CB1 receptors leads to a decrease in appetite and also has direct actions in adipose tissue and the liver to improve glucose, fat and cholesterol metabolism so improving insulin resistance, triglycerides and high-density lipoprotein cholesterol (HDL-C) and in some patients, blood pressure. The Rimonabant in Obesity (RIO) trials have shown that rimonabant induces weight loss > 5% in 30-40% of patients and > 10% in 10-20% above both a dietary run-in and long-term hypocaloric management over a 2 year period with a low level of drug-related side effects. Rimonabant therapy is associated with an extra 8-10% increase in HDL-C and a 10-30% reduction in triglycerides and improvements in insulin resistance, glycaemic control in patients with diabetes and also adipokines and cytokines including C-reactive protein over hypocaloric diet therapy. In addition rimonabant abolishes the weight gain associated with smoking cessation and improves the chances of quitting smoking. Thus rimonabant has major effects on both the metabolic syndrome and cardiovascular risk factors thus has the potential to reduce the risks of type 2 diabetes and cardiovascular disease associated with the cardiometabolic phenotype.
 ...
PMID:Rimonabant: endocannabinoid inhibition for the metabolic syndrome. 1710 77

Rimonabant is the first of a new class of selective cannabinoid receptor-1 blockers. It reduces the overactivity of the endocannabinoid system, improving lipid and glucose metabolism and regulating food intake and energy balance. In four randomised, double-blind clinical trials in overweight or obese adults with or without type 2 diabetes and/or dyslipidaemia, oral rimonabant 20mg once daily reduced weight and waist circumference to a significantly greater extent than placebo. A significantly greater proportion of rimonabant than placebo recipients achieved the clinically significant weight-loss target of > or =5% or > or =10% of initial weight. Rimonabant was associated with significant improvements in glycaemic control relative to placebo, with approximately equal to 57% of the reduction in glycosylated haemoglobin being independent of the effects of weight loss in one trial. Improvements in other cardiometabolic risk factors (i.e. increases in high-density lipoprotein-cholesterol [HDL-C] and decreases in triglyceride [TG] levels) were significantly greater with rimonabant than with placebo. The improvement in lipid profile also demonstrated a weight-independent effect, with approximately equal to 47-58% of the improvement in HDL-C and TG being beyond that expected through weight loss alone. Rimonabant was generally well tolerated, with most adverse events considered mild to moderate in severity.
 ...
PMID:Rimonabant. 1711 4

Adipose tissue is an active and complex endocrine organ that secretes numerous bioactive substances, including hormones, growth factors, and cytokines. Central obesity, one of the components of metabolic syndrome, is a cardiometabolic risk factor associated with a state of chronic inflammation and coagulation, one in which the expression of certain adipocytokines, including tumor necrosis factor-alpha (TNF-(alpha), interleukin (IL)-6, and plasminogen activator inhibitor-1 (PAI-1) is more abundantly increased, while adiponectin expression is decreased. TNF-alpha initiates and organizes inflammatory changes in vascular tissue. IL-6, an inflammatory cytokine directly implicated in atherogenesis, exerts pleiotropic effects on a variety of tissues. An increased concentration of PAI-1, an important regulator of the endogenous fibrinolytic system, promotes continued clotting. Adiponectin, on the other hand, has potent vasculoprotective, angiogenic, anti-inflammatory, and antiatherogenic properties. Adiponectin levels are low in obese individuals and increase when weight is lost, thereby serving as a marker for cardioprotection. Weight loss has long been promoted as a means to reduce the risk of type 2 diabetes and cardiovascular disease; for example, exercise and a hypocaloric diet have been shown to decrease PAI-1 levels. Weight loss drugs, such as orlistat, a lipase inhibitor, and sibutramine, a serotonin and norepinephrine reuptake inhibitor, have both been shown to produce a decrease in C-reactive protein levels and an increase in serum adiponectin. Rimonabant, a selective cannabinoid 1 receptor antagonist in Phase III studies, also has been shown to increase adiponectin levels. These agents may play a role in the regulation of adipocytokines, which may directly affect the risk for cardiometabolic disease.
 ...
PMID:The relation of adipose tissue to cardiometabolic risk. 1720 62

Rimonabant significantly reduces weight and waist circumference and improves dyslipidemias in overweight and obese patients without diabetes mellitus. Numerous other metabolic changes, including reduced prevalence of the metabolic syndrome and associated cardiovascular disease (CVD) risk factors, reduced fasting glucose, and elevated adiponectin, have been demonstrated with the administration of rimonabant. The Rimonabant-in-Obesity (RIO)-Diabetes trial studied the safety and efficacy of rimonabant in overweight and obese patients with type 2 diabetes who were treated with metformin or sulfonylureas. RIO-Diabetes was a 1-year, randomized, double-blind, placebo-controlled, parallel-group study of 1,047 overweight/obese patients with type 2 diabetes in 151 centers in 11 countries. The body mass index of participants ranged from 27 to 40. Glycosylated hemoglobin (HbA1c) at screening ranged from 6.5% to 10.0%. All patients were receiving either metformin or sulfonylurea therapy and were asked to follow a hypocaloric diet (600 kcal/day deficit [1 kcal = 4.2 kJ]) for the duration of the trial. After a 4-week placebo plus diet run-in period, patients were randomized to receive placebo or rimonabant 5 mg or 20 mg once daily. At 1 year, absolute change in weight from baseline in the intention-to-treat, last observation carried forward analysis of the rimonabant 5 mg and 20 mg groups, respectively, was loss of 2.3 kg and 5.3 kg compared with 1.4 kg in the placebo group (P = 0.013 and P <0.001, respectively). Waist circumference was significantly decreased in the rimonabant 5-mg and 20-mg groups by 2.9 cm and 5.2 cm compared with 1.9 cm in the placebo group (P = 0.034 and P <0.001, respectively). HbA1c reductions of 0.1% and 0.6% were significant in the rimonabant 5-mg and 20-mg groups (P = 0.034 and P <0.001, respectively). Some 57% of the improvements in HbA(1c) and high-density lipoprotein cholesterol could not be attributed to observed weight loss. Compared with placebo, rimonabant 20 mg also demonstrated significant improvements in the prevalence of metabolic syndrome and improvement in its constituents, as well as systolic blood pressure and C-reactive protein levels (assay by ICON Laboratories, Farmingdale, NY and Dublin, Ireland). Rimonabant is the first selective cannabinoid1 blocker studied for type 2 diabetes and associated CVD risk factor therapy. Its ability to improve the numerous metabolic pathologies associated with diabetes and CVD risk and concomitantly to reduce weight and waist circumference introduces a strongly positive new dynamic in type 2 diabetes treatment. Its multifactorial mechanisms warrant further investigation and may provide insights into other pathologies.
 ...
PMID:Endocannabinoid blockade for improving glycemic control and lipids in patients with type 2 diabetes mellitus. 1729 41

The endocannabinoid system has been recently recognized as an important modulatory system in the function of brain, endocrine, and immune tissues. It appears to play a very important regulatory role in the secretion of hormones related to reproductive functions and response to stress. The important elements of this system are: endocannabinoid receptors (types CB1 and CB2), their endogenous ligands (N-arachidonoylethanolamide, 2-arachidonoyl glycerol), enzymes involved in their synthesis and degradation, as well as cannabinoid antagonists. In humans this system also controls energy homeostasis and mainly influences the function of the food intake centers of the central nervous system and gastrointestinal tract activity. The endocannabinoid system regulates not only the central and peripheral mechanisms of food intake, but also lipids synthesis and turnover in the liver and adipose tissue as well as glucose metabolism in muscle cells. Rimonabant, a new and selective central and peripheral cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factor (metabolic syndrome) in obese patients by increasing HDL-cholesterol and adiponectin blood levels as well as decreasing LDL-cholesterol, leptin, and C-reactive protein (a proinflammatory marker) concentrations. It is therefore possible to speculate about a future clinical use of CB1 antagonists, as a means of improving gonadotrophin pulsatility and fertilization capacity as well as the prevention of cardiovasculary disease and type 2 diabetes mellitus. Drugs acting as agonists of CB1 receptors (Dronabinol, Dexanabinol) are currently proposed for evaluation as drugs to treat neurodegenerative disorders (Alzheimer's and Parkinson's diseases), epilepsy, anxiety, and stroke.
 ...
PMID:[The role of the endocannabinoid system in the regulation of endocrine function and in the control of energy balance in humans]. 1736 78

This review considers the use of the first selective blocker of the cannabinoid receptor type 1, rimonabant, to reduce weight and improve cardiovascular disease risk factors in obese patients with metabolic syndrome or multiple cardiovascular disease risk factors. In 4 large trials-Rimonabant in Obesity (RIO)-Lipids, RIO-Europe, RIO-North America, and RIO-Diabetes-after 1 to 2 years of treatment, rimonabant (20 mg/day) led to a significantly greater weight loss and reduction in waist circumference compared with placebo. Treatment with rimonabant was also associated with other favorable changes, including better glycemic control in type 2 diabetes mellitus, improved lipid profile, reduced blood pressure, increased adiponectin levels, fall in high-sensitivity C-reactive protein concentrations, and an overall decrease in the prevalence of the metabolic syndrome. Initial experience with rimonabant shows that it is generally well tolerated with the most common side effect of mild nausea. Rimonabant may be a useful adjunct to lifestyle and behavior modification in the treatment of obese subjects with metabolic syndrome or multiple cardiometabolic risk factors.
 ...
PMID:The role of endocannabinoid system blockade in the treatment of the metabolic syndrome. 1739 96

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. It has been evaluated in the RIO ("Rimonabant In Obesity and related disorders") programme including above 6.600 overweight/obese patients with or without comorbidities followed for 1 to 2 years. Compared to placebo, rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. In patients with type 2 diabetes, rimonabant also diminishes HbA1c levels, an effect confirmed in the recent SERENADE trial. Almost half of the metabolic effects occurs beyond weight loss, suggesting direct peripheral effects of rimonabant. Rimonabant is indicated in Europe as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.
 ...
PMID:[Cardiometabolic effects of rimonabant in obese/overweight subjects with dyslipidaemia or type 2 diabetes]. 1746 Dec 96


1 2 3 Next >>