topiramate and Metabolic-Syndrome

Diabetic peripheral neuropathy and metabolic syndrome (MetS) are both global health challenges with well-established diagnostic criteria and significant impacts on quality of life. Clinical observations, epidemiologic evidence, and animal models of disease have strongly suggested MetS is associated with an elevated risk for cryptogenic sensory peripheral neuropathy (CSPN). MetS neuropathy preferentially affects small unmyelinated axons early in its course, and it may also affect autonomic and large fibers. CSPN risk is linked to MetS and several of its components including obesity, dyslipidemia, and prediabetes. MetS also increases neuropathy risk in patients with established type 1 and type 2 diabetes. In this review we present animal data regarding the role of inflammation and dyslipidemia in MetS neuropathy pathogenesis. Several studies suggest exercise-based lifestyle modification is a promising treatment approach for MetS neuropathy.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diet Therapy; Disease Progression; Dyslipidemias; Exercise; Humans; Hypoglycemic Agents; Metabolic Syndrome; Obesity; Peripheral Nervous System Diseases; Prediabetic State; Risk Factors; Small Fiber Neuropathy; Topiramate

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Patients with schizophrenia have increased prevalence rates for many cardiometabolic risk factors; the prevalence and severity of these risks increase after the institution of antipsychotic medication. Nearly 2 dozen different pharmacologic interventions have been trialed to prevent or attenuate antipsychotic-related cardiometabolic changes. Metformin (usually 1,000-1,500 mg/d) has emerged as the best-studied intervention; in short- and intermediate-duration randomized controlled trials, it has been shown to bring about improvements in weight and other anthropometric indices, in fasting sugar and other glycemic control indices, and in total cholesterol and other lipid metabolism indices. Topiramate and aripiprazole are other possible interventions with support in literature; besides improving metabolic outcomes, these drugs may improve indices of psychopathology, as well. Encouraging though the findings are, there are many unanswered questions that require attention in future research.

Topics: Anti-Obesity Agents; Antipsychotic Agents; Aripiprazole; Cardiovascular Diseases; Fructose; Humans; Hypoglycemic Agents; Metabolic Syndrome; Metformin; Schizophrenia; Topiramate

Topics: Anti-Obesity Agents; Appetite; Appetite Depressants; Benzazepines; Benzoxazines; Bupropion; Clinical Trials as Topic; Drug Approval; Drug Combinations; Drug Discovery; Energy Metabolism; Enzyme Inhibitors; Fructose; Glucagon-Like Peptide 1; Humans; Hypothalamus; Lactones; Lipase; Liraglutide; Metabolic Syndrome; Naltrexone; Obesity; Orlistat; Phentermine; Topiramate

The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, although a return to baseline is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduction in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food ingestion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss, typically 20-35%, effect resolution of co-morbid conditions and improve quality of life. Although mortality is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgical patients experience a reduction in appetite and report changes in food preference. Accentuation of the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent signalling are proposed to induce satiety. Increased understanding of body weight homeostasis and appetite regulation has provided an impressive list of potential targets for drug development, with the promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery.

Topics: Adipose Tissue; Amyloid; Anticonvulsants; Antidepressive Agents; Anxiety; Appetite Regulation; Bariatric Surgery; Body Mass Index; Bupropion; Cholecystokinin; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Depression; Diabetes Mellitus, Type 2; Female; Fluoxetine; Fructose; Ghrelin; Humans; Intra-Abdominal Fat; Islet Amyloid Polypeptide; Isoxazoles; Lactones; Leptin; Metabolic Syndrome; Metformin; Obesity; Obesity, Morbid; Orlistat; Oxyntomodulin; Peptide YY; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Sertraline; Sleep Apnea, Obstructive; Surgical Procedures, Operative; Topiramate; Zonisamide

OBJECTIVE To evaluate over 108 weeks the effect of phentermine and topiramate extended release (PHEN/TPM ER) treatment on progression to type 2 diabetes and/or cardiometabolic disease in subjects with prediabetes and/or metabolic syndrome (MetS) at baseline. RESEARCH DESIGN AND METHODS Subanalysis of a phase 3, randomized, placebo-controlled, double-blind study of overweight/obese subjects (BMI ≥27 to ≤45 kg/m(2)) with two or more comorbidities. Subjects were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg (7.5/46), or PHEN 15 mg/TPM ER 92 mg (15/92) plus lifestyle modifications for 108 weeks. Percent weight loss in the intent-to-treat population using multiple imputation (ITT-MI), annualized incidence rate of progression to type 2 diabetes, and changes in glycemia, lipid parameters, blood pressure, and waist circumference were evaluated. RESULTS At baseline, 475 subjects met the criteria for prediabetes and/or MetS. After 108 weeks, subjects with prediabetes and/or MetS in the placebo, 7.5/46, and 15/92 groups experienced mean percent weight loss of 2.5, 10.9, and 12.1%, respectively (ITT-MI; P < 0.0001 vs. placebo), associated with reductions of 70.5 and 78.7% in the annualized incidence rate of type 2 diabetes for those receiving 7.5/46 and 15/92, respectively (ITT, P < 0.05), versus placebo. The ability of PHEN/TPM ER to prevent diabetes was related to degree of weight lost and was accompanied by significant improvements in cardiometabolic parameters. PHEN/TPM ER was well tolerated by this subgroup over 2 years. CONCLUSIONS PHEN/TPM ER plus lifestyle modification produced significant weight loss and markedly reduced progression to type 2 diabetes in overweight/obese patients with prediabetes and/or MetS, accompanied by improvements in multiple cardiometabolic disease risk factors.

Topics: Anti-Obesity Agents; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Female; Fructose; Humans; Life Style; Male; Metabolic Syndrome; Middle Aged; Phentermine; Placebos; Prediabetic State; Topiramate

Metabolic syndrome has been recognised as a cluster of risk factors contributing to the development of cardiovascular diseases. Different diagnostic criteria have been proposed and the consensus focuses on four major risk factors: obesity, diabetes, dyslipidaemia and hypertension. Although treatment options are available to treat each component separately, a highly effective agent for metabolic syndrome has yet to be developed. To explore the clinical definition of metabolic syndrome and potential molecular targets that can be modulated for treatment purpose, a meeting entitled 'Targeting Metabolic Syndrome' was organised in 2004 by IBC USA Conferences, Inc. This article highlights discussions related to the clinical correlates and pathophysiology of metabolic syndrome, and reviews some of the promising drug discovery efforts. Metabolic syndrome should be treatable and preventable if obesity and insulin resistance are well controlled. New regulatory guidelines need to be developed as new treatment options are being investigated. From a broad spectrum of potential mechanisms encompassing central nervous system targets and peripheral targets for pharmacological intervention, a few promising molecular targets have emerged. Modulating these is expected to treat at least some components of metabolic syndrome.

Topics: Animals; Callithrix; Diabetes Mellitus, Experimental; Disease Models, Animal; Fructose; Humans; Hyperlipidemias; Hypertension; Macaca mulatta; Metabolic Syndrome; Mice; Obesity; Topiramate; Weight Loss