AMP-Activated Protein Kinases/metabolism* ; Adenosine ; Adenosine Monophosphate ; Cell Proliferation ; Endometrial Neoplasms/drug therapy* ; Female ; Humans ; Liraglutide ; Phosphorylation ; Protein Kinases ; Signal Transduction

Glucagon-like peptide-1 (GLP-1) expression is shared by both intestinal cells and neurons of brainstem, which plays anorexigenic role on food intake. However, the exact source of physiological GLP-1 influencing food intake and pertinent mechanism of GLP-1 receptor agonists (GLP-1RA) remain unelucidated. In this study, the immediate early gene product c-Fos was chosen as the specific antigen for immunohistochemistry to show the certain areas of central nervous system (CNS) activation by the GLP-1RA. Thirty normal SD rats were randomly assigned to 3 groups, which were single intraperitoneally injected with Liraglutide (200 μg/kg), Exenatide (10 μg/kg) and saline, respectively. After injection, the amount of food intake and acute glycemic variation were assessed for comparison. The results showed that acute pharmacological dosage of GLP-1RA (Liraglutide or Exenatide) could significantly influence food intake. However, glycemic change indicated that the anorexic effect was dissociated with change in blood glucose in normal rats. Moreover, c-Fos was expressed significantly higher in major critical nuclei related to food intake in GLP-1RA groups when compared with the control group, and its expression was also found in spinal cord. The results suggested that acute administration of pharmacological doses of GLP-1 influences CNS via circulation and vagal pathways, especially on the arcuate nucleus (ARC) and the nucleus of solitary tract (NTS), and GLP-1 modulates autonomic nervous activities.
Animals ; Eating ; drug effects ; Exenatide ; pharmacology ; Glucagon-Like Peptide-1 Receptor ; agonists ; Liraglutide ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley

According to the American Diabetes Association (ADA) and the European Association for the Study of Diabetes guideline for treatment of diabetes, glucagon-like peptide-1 receptor agonist (GLP-1 RA) is recommended in diabetic patients with established atherosclerotic cardiovascular disease. This recommendation is based on the results of recent cardiovascular outcome trials of this kind of medications. GLP-1 RAs have a glucose lowering effect with weight loss and a lower incidence of hypoglycemia, and can improve cardiovascular outcomes such as three-point major cardiovascular events composed of death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke. Also, several GLP-1 RAs have beneficial effects on renal outcomes, mainly due to improvement in macroalbuminuria. In addition, high-dose liraglutide (3 mg/day subcutaneous injection) showed efficacy for reducing body weight. Therefore GLP-1 RA may be effective in patients with established cardiovascular disease, chronic kidney disease, and/or metabolic syndrome.
Body Weight ; Cardiovascular Diseases ; Diabetes Mellitus ; Glucagon-Like Peptide 1 ; Glucagon-Like Peptide-1 Receptor ; Glucose ; Humans ; Hypoglycemia ; Incidence ; Kidney Diseases ; Liraglutide ; Myocardial Infarction ; Obesity ; Renal Insufficiency, Chronic ; Stroke ; Weight Loss

The Korean Ministry of Food and Drug Safety has approved three anti-obesity drugs for long-term management in the past decade. In addition, since 2019, bariatric surgery has been financially supported by National Health Insurance Service in Korea. In this review, the mechanisms of action and the clinical implications of the recently approved anti-obesity drugs, lorcaserin, naltrexone/bupropion, and liraglutide are explained. Lorcaserin stimulates proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurons and inhibits neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, which results in the activation of melanocortin 3/4 receptors. Naltrexone/bupropion stimulates POMC neurons through bupropion; this stimulation is augmented by blocking the autoinhibitory mechanism of POMC with naltrexone. The hypophagic effect of liraglutide is mediated through the direct activation of POMC/CART neurons and the indirect suppression of NPY/AgRP neurons through γ-aminobutyric acid-dependent signaling, with adjunctive suppression of the mesolimbic dopamine reward system. In addition to liraglutide, another glucagon-like peptide-1 receptor agonist, semaglutide, is expected to be added to the list of anti-obesity drugs in the near future. In patients with obesity and high cardiovascular risk, lorcaserin was considered neutral and liraglutide was considered favorable, whereas inconclusive results were obtained for naltrexone/bupropion.
Anti-Obesity Agents ; Bariatric Surgery ; Bupropion ; Dopamine ; Glucagon-Like Peptide-1 Receptor ; Humans ; Korea ; Liraglutide ; Naltrexone ; National Health Programs ; Neurons ; Neuropeptide Y ; Obesity ; Pro-Opiomelanocortin ; Reward

The prevalence of type 2 diabetes mellitus (T2DM), which is associated with cardiovascular morbidity and mortality, is increasing worldwide. Although there have been advances in diabetes treatments that reduce microvascular complications (nephropathy, neuropathy, retinopathy), many clinical studies have found that conventional oral hypoglycemic agents and glucose control alone failed to reduce cardiovascular disease. Thus, incretin-based therapies including glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT-2Is) represent a new area of research, and may serve as novel therapeutics for treating hyperglycemia and modifying other cardiovascular risk factors. Recently, it has been confirmed that several drugs in these classes, including canagliflozin, empagliflozin, semaglutide, and liraglutide, are safe and possess cardioprotective effects. We review the most recent cardiovascular outcome trials on GLP-1RAs and SGLT-2Is, and discuss their implications for treating patients with T2DM in terms of protective effects against cardiovascular disease.
Canagliflozin ; Cardiovascular Diseases ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Glucagon-Like Peptide 1 ; Glucose ; Heart Failure ; Humans ; Hyperglycemia ; Hypoglycemic Agents ; Liraglutide ; Mortality ; Myocardial Ischemia ; Prevalence ; Risk Factors

Over the last 5 years, the Korean Ministry of Food and Drug Safety has approved four anti-obesity drugs for long-term weight management. In this review, the mechanisms of action and clinical applications of lorcaserin, naltrexone/bupropion, liraglutide, and phentermine/topiramate have been clarified. Lorcaserin stimulates proopiomelanocortin/cocaine- and amphetamine-regulated transcript neurons in the arcuate nucleus. Naltrexone/bupropion reduces body weight by controlling the hedonic reward system of food intake. The hypophagic effect of liraglutide depends on the direct activation of the proopiomelanocortin/cocaine- and amphetamine-regulated transcript neurons and indirect suppression of neuropeptide Y/agouti-related peptide neurons through gammaaminobutyric acid-dependent signaling, with an additional thermogenic effect. Phentermine/topiramate induces weight loss by elevating the norepinephrine levels in the hypothalamus, reducing energy deposition in the adipose tissue and skeletal muscle, and elevating the corticotropin-releasing hormone in the hypothalamus. In patients with high cardiovascular risks or type 2 diabetes mellitus, lorcaserin and liraglutide are appropriate. In patients with mood disorders, naltrexone/bupropion could be considered as the first choice of therapy. Notably, lorcaserin and liraglutide are neutral in the aspect of sleep disorder. In case of obese individuals with obstructive sleep apnea, liraglutide or phentermine/topiramate would be selected as the treatment option. These four drugs should be used after considering the patients' co-morbidities of obesity.
Adipose Tissue ; Anti-Obesity Agents ; Arcuate Nucleus of Hypothalamus ; Body Weight ; Corticotropin-Releasing Hormone ; Diabetes Mellitus, Type 2 ; Eating ; Humans ; Hypothalamus ; Korea ; Liraglutide ; Mood Disorders ; Muscle, Skeletal ; Neurons ; Neuropeptides ; Norepinephrine ; Obesity ; Pharmacology ; Reward ; Sleep Apnea, Obstructive ; Sleep Wake Disorders ; Weight Loss

In 2008, the United States Food and Drug Administration issued guidance which mandated long-term cardiovascular outcome trials (CVOTs) to assess the safety of new antidiabetic drugs for type 2 diabetes. Since 2008, three CVOTs that have studied dipeptidyl peptidase-4 (DPP-4) inhibitors and four CVOTs of a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) have been reported. Each of the completed CVOTs showed the noninferiority of respective drugs to placebo for primary CV composite endpoint. Among them, liraglutide and semaglutide showed a reduction of major adverse cardiovascular events. However, the mechanisms for the observed cardiovascular differences between DPP-4 inhibitors and GLP-1RA, and across individual GLP-1RA are not clearly understood. Therefore, this review will summarize the CVOTs of the DPP-4 inhibitors and GLP-1RA, interpretation of cardioprotective results of incretin-based therapy and the possible mechanism of action.
Diabetes Mellitus, Type 2 ; Dipeptidyl-Peptidase IV Inhibitors ; Glucagon-Like Peptide 1 ; Hypoglycemic Agents ; Incretins* ; Liraglutide ; United States Food and Drug Administration

Obesity is a chronic disorder that is a significant risk factor for diabetes, cardiovascular diseases, malignancy, and other chronic diseases. Lifestyle modifications form the basis of most treatments for obesity, but it has become clear that such modifications alone are not enough for many obese patients. When a behavioral approach is insufficient, pharmacological treatment may be recommended. In recent years, the US Food and Drug Administration (FDA) has withdrawn several therapeutic options for obesity due to their side effects, but has approved four novel anti-obesity agents. Until recently, orlistat was the only drug approved for the management of long-term obesity, but the US FDA approved the novel anti-obesity drugs lorcaserin and phentermine/topiramate in 2012, and naltrexone/bupropion and liraglutide in 2014. The present review discusses the different pharmacotherapeutic options for the treatment of obesity.
Anti-Obesity Agents* ; Cardiovascular Diseases ; Chronic Disease ; Humans ; Life Style ; Liraglutide ; Obesity ; Risk Factors ; United States Food and Drug Administration

Objective: Assess safety and effectiveness of liraglutide among Filipino participants with type 2 diabetes (T2D) in routine clinical practice. Methodology: A 26-week, prospective, multicenter, open-label, observational study was conducted in adults with T2D prescribed liraglutide (1.2 mg or 1.8 mg) in routine clinical practice in the Philippines. Primary endpoint: incidence rate and type of serious adverse drug reactions (SADRs). Secondary endpoints included other aspects of safety, and effectiveness. Results: Participants (n=1056) had a mean (standard deviation) age of 53.2 (12.0) years, and glycated hemoglobin (HbA1c) level of 8.8% (2.0). Of 19 ADRs reported in 17 participants, none were SADRs (primary endpoint). No serious adverse events were reported. From baseline to week 26: the proportion of participants with major hypoglycemic episodes (requiring assistance) decreased from 2.0% to 0.2%; and with minor episodes (plasma glucose <3.1 mmol/L [<56 mg/dL]) decreased from 6.1% to 1.5%; serum creatinine remained unchanged. Among secondary effectiveness endpoints, improvements were seen from baseline to week 26 in HbA1c level, fasting and postprandial blood glucose levels, body weight, blood pressure, and fasting lipid profile. Conclusion During routine clinical use of liraglutide for T2D in the Philippines, no new safety concerns were identified and blood glucose was lowered effectively.
Glucagon-Like Peptides ; Liraglutide ; Diabetes Mellitus, Type 2 ; Safety ; Observational Study

Non-alcoholic steatohepatitis (NASH) is the more aggressive form of non-alcoholic fatty liver disease (NAFLD). NASH can progress to hepatic fibrosis, cirrhosis, portal hypertension and primary liver cancer. Therapy is evolving with a substantial number of trials of promising new agents now in progress. In this article however, we will examine data for several older forms of therapy which have been fairly extensively studied over the years: Polyunsaturated Fatty Acid (PUFA) supplements, vitamin E, insulin sensitizing agents with a focus on pioglitazone and statin agents. Early interest in PUFA derived from their potential benefit in cardio-metabolic disease and the close association of NAFLD/NASH with Metabolic Syndrome. Results have been variable although most studies show reduction of liver fat without other major effects and their effects are influenced by concomitant weight loss and underlying genetic factors. Vitamin E has had some efficacy in pediatric NASH but questionable efficacy in even mild NASH among adults. Pioglitazone has shown significant histological benefit in a number of trials but concern over side-effects (especially weight gain) have dampened enthusiasm. A newer insulin sensitizer, liraglutide, has also shown promise in a small randomized, controlled trial. Very limited data exists regarding the histological effects of the statins in NASH and these agents appear to be fairly neutral with neither clear cut benefit nor detriment. Their use is best guided by cardiovascular risks rather than liver histology.
Adult ; Fatty Liver ; Fibrosis ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors* ; Hypertension, Portal ; Insulin* ; Liraglutide ; Liver ; Liver Neoplasms ; Non-alcoholic Fatty Liver Disease ; Vitamin E* ; Vitamins* ; Weight Loss