Recently, incretin hormone-based therapies, including glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors, have become the main therapeutic tools in the hyperglycemia management in patients with type 2 diabetes mellitus. These therapeutic agents could fill an important gap in glycemic control for patients with type 2 diabetes because the incretin response is blunted in type 2 diabetes mellitus. GLP-1 analogues can be classified as exendin-4 backbone (Exenatide, Exenatide LAR and Lixisenatide) and human GLP-1 backbone (Liraglutide, Taspoglutide and Albiglutide). Among these, Exenatide, Exenatide LAR and Liraglutide are currently available. This review will focus on the clinical efficacies of GLP-1 analogues in glycemic control for patients with diabetes.
Diabetes Mellitus, Type 2 ; Glucagon ; Glucagon-Like Peptide 1 ; Humans ; Hyperglycemia ; Incretins ; Peptides ; Venoms ; Liraglutide

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

Obesity has become a global public health problem. The importance of obesity is highlighted by the fact that obesity-related comorbidities, such as type 2 diabetes, cardiovascular disease, and cancer, are a leading cause of death in Westernized countries. As endorsement of lifestyle modifications has proven to be inadequate to combat obesity, pharmacological treatment has become more critical for weight reduction as well as for the treatment of obesity-related morbidity and mortality. However, safety issues dampened the success of the development of anti-obesity drugs, leaving orlistat as the single approved drug for long-term weight management until 2012, when two new anti-obesity drugs were approved by the FDA: lorcaserin and phentermine/topiramate. In 2014, another two drugs were approved by the US FDA for the treatment of obesity: naltrexone/bupropion and liraglutide. In this review, we describe the new FDA-approved anti-obesity drugs and briefly introduce other anti-obesity drugs still under development.
Anti-Obesity Agents ; Cardiovascular Diseases ; Cause of Death ; Comorbidity ; Life Style ; Liraglutide ; Mortality ; Obesity* ; Public Health ; Weight Loss

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

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

There have recently been many advances in obesity treatment, including lifestyle modifications and pharmacological and surgical treatments. Specifically, pharmacological strategies have improved significantly. However, the history of the development of medications aimed at weight loss is complicated. The Federal Drug Administration (FDA) withdrew anti-obesity drugs such as fenfluramine, dexfenfluramine, and phenylpropylamine due to their unwanted side effects. Moreover, sibutramine was voluntarily withdrawn from the market and a new drug, rimonabant, has been suspended in the middle of a clinical trial due to unacceptable side effects. The FDA has approved four new anti-obesity drugs in recent years. Lorcaserin is a selective 5-hydroxytryptamine receptor 2c (5-HT2c) agonist. The pharmacological mechanism of action of this drug is similar to fenfluramine and dexfenfluramine, but lorcaserin is specific for 5-HT2c, which are located almost exclusively in the central nervous system and are not found in heart valves. Three phase 3 clinical trials for lorcaserin have been published recently; weight reduction was successful and no side effects involving the heart were found. Furthermore, the FDA has also approved phentermine/topiramate controlled-release (PHEN/TPM CR), which is composed of a combination of immediate-release phentermine and controlled-release topiramate. Weight reduction achieved with PHEN/TPM CR was demonstrated to be better than all other anti-obesity drugs. Lastly, the combination therapy bupropion/naltrexone activates proopiomelanocortin neurons and inhibits opioid-mediated negative feedback by synergism. Similar to liraglutide, a long-acting analogue of the hormone glucagon-like peptide-1, this treatment showed significant weight loss and metabolic improvements. However, in addition to its efficacy, clinicians should consider its side effects before use.
Anti-Obesity Agents ; Central Nervous System ; Dexfenfluramine ; Fenfluramine ; Glucagon-Like Peptide 1 ; Heart ; Heart Valves ; Life Style ; Neurons ; Obesity* ; Phentermine ; Pro-Opiomelanocortin ; Serotonin ; Weight Loss ; Liraglutide

BACKGROUNDThe pathophysiology of type 2 diabetes is progressive pancreatic beta cell failure with consequential reduced insulin secretion. Glucotoxicity results in the reduction of beta cell mass in type 2 diabetes by inducing apoptosis. Autophagy is essential for the maintenance of normal islet architecture and plays a crucial role in maintaining the intracellular insulin content by accelerating the insulin degradation rate in beta cells. Recently more attention has been paid to the effect of autophagy in type 2 diabetes. The regulatory pathway of autophagy in controlling pancreatic beta cells is still not clear. The aim of our study was to evaluate whether liraglutide can inhibit apoptosis and modulate autophagy in vitro in insulinoma cells (INS-1 cells).

METHODSINS-1 cells were incubated for 24 hours in the presence or absence of high levels of glucose, liraglutide (a long-acting human glucagon-like peptide-1 analogue), or 3-methyadenine (3-MA). Cell viability was measured using the Cell Counting Kit-8 (CCK8) viability assay. Autophagy of INS-1 cells was tested by monodansylcadaverine (MDC) staining, an autophagy fluorescent compound used for the labeling of autophagic vacuoles, and by Western blotting of microtubule-associated protein I light chain 3 (LC3), a biochemical markers of autophagic initiation.

RESULTSThe viability of INS-1 cells was reduced after treatment with high levels of glucose. The viability of INS-1 cells was reduced and apoptosis was increased when autophagy was inhibited. The viability of INS-1 cells was significantly increased by adding liraglutide to supplement high glucose level medium compared with the cells treated with high glucose levels alone.

CONCLUSIONSApoptosis and autophagy were increased in rat INS-1 cells when treated with high level of glucose, and the viability of INS-1 cells was significantly reduced by inhibiting autophagy. Liraglutide protected INS-1 cells from high glucose level-induced apoptosis that is accompanied by a significant increase of autophagy, suggesting that liraglutide plays a role in beta cell apoptosis by targeting autophagy. Thus, autophagy may be a new target for the prevention or treatment of diabetes.

Animals ; Apoptosis ; drug effects ; Autophagy ; drug effects ; Cell Line, Tumor ; Cell Survival ; drug effects ; Glucagon-Like Peptide 1 ; analogs & derivatives ; pharmacology ; Glucose ; pharmacology ; Insulinoma ; pathology ; Liraglutide ; Rats

OBJECTIVETo explore the effect of liraglutide on myocardial ischemia/reperfusion (I/R) injury in rats and related mechanisms.

METHODSTwenty-four male SD rats were divided into sham group, I/R injury group, and liraglutide group by table of random number (n = 8 each). Myocardial I/R injury model was established by occlusion of the left anterior descending artery for 30 min followed by 2 h of reperfusion. HE stain method was used to observe cardiomyocyte status under light microscope, myocardial tissue samples were stained with TTC to measure the myocardial infarction size, protein expression of p53 and caspase-3 was analyzed by immunohistochemical technique and Western blot respectively, xanthine oxidase method was used to detect SOD activity, Thiobarbituric acid method was used to measure the concentration of MDA.

RESULTSCompared with the I/R group, the degree of myocardial damage of liraglutide group was significantly reduced and the myocardial infarct area was significantly lower ((44 ± 8) % vs. (62 ± 8) %, P<0.05) while protein expression of caspase-3 and p53 in liraglutide group was significantly downregulated (0.19 ± 0.03 vs. 0.24 ± 0.02 and 0.27 ± 0.03 vs. 0.39 ± 0.04, P<0.05). SOD activity was significantly increased and MDA concentration was significantly decreased (74.20 ± 11.10 vs. 44.04 ± 14.30 and 4.41 ± 1.07 vs. 8.72 ± 2.20, P<0.05) in liraglutide group compared to I/R group.

CONCLUSIONLiraglutide protects myocardium against I/R injury possibly through reducing cardiomyocytes apoptosis and oxidation.

Animals ; Apoptosis ; Caspase 3 ; Coronary Vessels ; Liraglutide ; Male ; Myocardial Infarction ; Myocardial Reperfusion Injury ; Myocardium ; Myocytes, Cardiac ; Oxidation-Reduction ; Rats ; Rats, Sprague-Dawley

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

Type 2 diabetes and obesity have a complex relationship; obesity is linked to insulin resistance, the precursor to type 2 diabetes. The management of obesity is an important method to delay onset of diabetes and improve the glycemic durability of antidiabetic agents. However, insulin and some of the oral hypoglycemic agents used to treat diabetes cause significant weight gain, and it is difficult for patients with diabetes to reduce and maintain their weight by life-style changes alone. Thus, antiobesity medications or bariatric surgery may be a necessary adjunct for certain obese patients with diabetes. In 2012, the U.S. Food and Drug Administration (FDA) approved lorcaserin and phentermine/topiramate extended-release for the management of chronic weight, and approval for naltrexone/bupropion sustained-release as an adjunct to exercise and reduced caloric intake followed in 2014. Liraglutide is pending FDA approval for antiobesity drug. Here we review the efficacy of approved and new promising drugs for the management of obesity.
Bariatric Surgery ; Drug Therapy* ; Energy Intake ; Humans ; Hypoglycemic Agents ; Insulin ; Insulin Resistance ; Obesity ; United States Food and Drug Administration ; Weight Gain ; Liraglutide