- Open Access
The burden of obesity in the current world and the new treatments available: focus on liraglutide 3.0 mg
© The Author(s) 2017
- Received: 12 December 2016
- Accepted: 25 May 2017
- Published: 31 May 2017
The prevalence of obesity increases worldwide. Treating obesity and its associated health problems has a significant economic impact on health care systems. The unsatisfactory long-term outcomes observed in the obesity treatment are due to its complex pathophysiology and the inherent difficulties associated with maintenance of lifestyle modifications. Determined by genetic and environmental factors, obesity has been officially recognized as a chronic disease, an action that allowed the recognition of anti-obesity drugs as legitimate therapeutic options to address the growing obesity endemic. Like other chronic diseases, obesity requires long-term treatment. Pharmacological interventions, when used as an adjunct to lifestyle changes, are useful to facilitate clinically meaningful weight loss, which may impact on obesity-associated comorbid conditions. In the past, medications for weight reduction were limited. However, the landscape has changed and new drugs provide additional options for weight management. Among the new drugs, liraglutide is the most studied, especially regarding its effects on the limbic system. As an adjunct to a reduced-calorie diet and increased physical activity, treatment with liraglutide 3.0 mg provides a statistically significant and clinically meaningful weight loss. Liraglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist that shares 97% homology to native GLP-1. Receptor agonists of GLP-1, including liraglutide, have emerged as effective therapies for type 2 diabetes and obesity. This review will address the major findings concerning the central regulation of appetite and the main studies that evaluated new drugs for obesity treatment, with a greater focus on liraglutide 3.0 mg.
- Anti-obesity drugs
- Appetite regulation
- Weight loss
More than just a consequence of poor lifestyle choices, obesity is a disease that is complex, polygenic, multifactorial, chronic and resistant to many forms of treatment. Obesity predisposes to the development of cardiovascular diseases (CVD), type 2 diabetes mellitus (T2D), hypertension and numerous other conditions .
During the period between 1980 and 2014, the world prevalence of obesity more than doubled. According to the World Health Organization (WHO) more than 1.9 billion adults over 18 years of age were overweight (38% of men and 40% of women), of these over 600 million were obese (11% of men and 15% of women) in 2014. Forty-two million children under 5 years of age were overweight or obese in 2013. In emerging countries, the increase of childhood overweight and obesity has been more than 30% higher than that of developed countries . For instance, in Brazil, 16.8% of men and 24.4% of women were obese, while 56% of the adult population were overweight in 2013 .
The body mass index (BMI) is an attempt to quantify the amount of tissue mass (muscle, fat, and bone) individually and BMI categories are defined as follows: lean below 18.5, normal weight 18.5–24.9, overweight 25–29.9, and obese over 30 kg/m2 . In accordance with WHO, normal weight East Asians have a BMI 18.5–23, overweight 23–27.4 and obese over 27.5 kg/m2 . BMI has significant limitations since it does not always exhibit the risk of other chronic weight-related conditions . Sharma et al. have proposed a simple clinical and functional staging system, namely Edmonton Obesity Staging System (EOSS). When used together with other anthropometric classification, EOSS provides a more accurate measurement of obesity-related health risks, because it incorporates the presence of comorbidities to aid decision-making in clinical practice , which is important, given that metabolically healthy obese comprise approximately 20% of obese individuals .
In the United States, the increased prevalence of obesity is responsible for almost $40 billion of increased medical spending through 2006, including $7 billion in Medicare prescription drug costs. Finkelstein et al. have shown the extent to which excess weight increased annual medical spending: the costs of overweight and obesity could have been as high as $78.5 billion in 1998 and $147 billion in 2008 . Based on data from 2000 to 2005, Cawley and Meyerhoefer estimated that the United States medical care costs of obesity-related illness in adults is $209.7 billion, which corresponds to 20.6% of the national health expenditures .
Factors leading to the development of obesity have been extensively studied in recent years. The central regulation of appetite, especially with regard to the hedonic appetite, is a field highly exciting. Recently, new medications have been approved for the treatment of obesity in the United States: liraglutide, phentermine/topiramate, naltrexone/bupropion and lorcaserin.
Liraglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist that shares 97% homology to native GLP-1, extending the circulating half-life of GLP-1 from 1 to 2 min to 13 h. Liraglutide was first approved for the treatment of T2D in Europe in 2009 . Among the new obesity drugs, liraglutide is the most studied, especially regarding its important effects through actions on the limbic system .
This review will address the major findings concerning the central regulation of appetite and the main studies with the new anti-obesity drugs, with a greater focus on liraglutide 3.0 mg.
Besides the well-known factors that lead to obesity, such as increase in energy intake by ingestion of high energy-dense processed foods and reduction in physical activity, there are several different factors to be considered. Some putative contributors to obesity include the gut microbiota, endocrine disruptors, epigenetics, increasing maternal age, greater fecundity among people with higher adiposity, assortative mating, sleep debt, pharmaceutical iatrogenesis, reduction in variability of ambient temperatures, and intrauterine and intergenerational effects . Human adiposity and the predisposition towards weight gain are influenced by multiple genes, and the most probable estimate of the heritability of body fat in humans range from about 25 to 75% . Gene mutations that are singly sufficient to cause human obesity are extremely rare. Almost 176 cases of human obesity due to mutations in more than ten different genes have been reported. Noticeably, almost all of these mutations are bounded in the leptin/melanocortin pathway of the hypothalamus, which is critical in the adjustment of whole-body energy homeostasis .
The study of common obesity or polygenic obesity is approached by linkage studies, candidate gene association studies and genome-wide association studies (GWAS), in an attempt to find associations between genetic variations and an obesity-related trait. Until now, GWAS had identified almost 100 loci associated with obesity-related traits, among them, the most relevant is the rs9939609 polymorphism located in the FTO gene [15, 16].
The inability to limit excessive food intake is probably a key process that contributes to uncontrolled weight gain, mainly because it seems to be satisfying to eat a more palatable energetic and obesogenic type of food. The high hedonic value and tempting foods are the main culprits to overeat or eat beyond the immediate metabolic need (food reward behaviour) . The relationship between energy intake and expenditure is modulated not only by environmental and behavioural factors but also by genetic determinants and neuroendocrine feedback mechanisms. These mechanisms are regulated by the hypothalamus, the central site for the homeostatic regulation of body weight. The hypothalamus integrates peripheral hormonal signals from the gastrointestinal tract [ghrelin, cholecystokinin, peptide YY, pancreatic polypeptide (PP), GLP-1], pancreas (insulin) and adipose tissue (leptin), that modify central orexigenic [e.g. neuropeptide Y (NPY)], agouti-related peptide (AgRP) and anorexigenic [e.g. alpha-melanocyte stimulating hormone (α-MSH), a proopiomelanocortin (POMC)-derived peptide], cocaine- and amphetamine-regulated transcript [CART]) neuropeptides .
The hedonic appetite regulation is carried out in the limbic regions such as the hippocampus, amygdala, nucleus accumbens, ventral tegmental area, cingulate gyrus, orbitofrontal cortex, insula and prefrontal cortex. These areas are involved in the development of the conditioned response and reward. Although classical neurotransmitters involved in this network are dopamine, serotonin, and GABA, several animal studies emphasize the contribution of GLP-1 in the system [25, 26]. Hsu et al. assessed the dietary behavior of rats that received exedin-4 in the ventral portion of the hippocampal formation. In addition to reducing total energy intake and weight, it was observed a significant decrease in fat intake and an increase in the standard feed consumption, when they were allowed to choose what food to eat. This finding highlights the importance of GLP-1 in brain regions involved in the control of the learned and motivational behaviors in food consumption .
Farr et at. identified, by immunohistochemical analysis, the presence of GLP-1R in hypothalamic nuclei, medulla oblongata, area postrema and parietal cortex of humans brains . The inferior parietal cortex is part of the attention network, which can be activated by important or highly desirable stimuli, like palatable food. Humans taking liraglutide presented in fMRI a decrease in activation of parietal cortex in response to more desirable food. This parietal activation in response to high-energy food is inversely correlated to weight loss. Patients with the lowest inferior parietal activation reported it would be less pleasant to eat while on liraglutide, when on fasting. In this same study, it was reported a decrease in activation at insula and putamen in patients taking liraglutide when exposed to palatable food cues. The insula participates in the saliency processing and saciety, in turn, putamen seems to contribute in the processing of food reward . A previous study with exenatide, another GLP-1 receptor agonist (derived from exendin-4), also showed a decreased brain response to palatable food pictures in insula, amygdala, putamen, and orbitofrontal cortex .
Another recent study employing fMRI determined the effects of endogenous GLP-1 (using a GLP-1 antagonist) and of liraglutide on central nervous system (CNS) activation in healthy lean individuals as well as in T2D patients. Endogenous GLP-1 was shown to affect central responsiveness to palatable food consumption. In comparison to healthy lean subjects, T2D patients presented reduced activation of the right insula by chocolate milk. In obese T2D patients, liraglutide improved the observed deficit in response to palatable food, which may contribute to the weight loss observed with liraglutide .
An aspect that has been recently considered in the study of obesity is hormonal adaptations to weight loss. Sumithran et al. enrolled 50 overweight or obese nondiabetic patients in a 10-week weight loss program consisting of a very-low-energy diet. At the end of 10 weeks, after a mean weight loss of 13.5 ± 0.5 kg, there were significant reductions in the concentrations of the anorectic peptides leptin, peptide YY, cholecystokinin, insulin and amylin. There were also increases in the concentrations of the orexigenic peptides ghrelin, glucose-dependent insulinotropic polypeptide (GIP) and PP. One year after the initial weight loss, there were still significant differences in the mean concentrations of these peptides in comparison to baseline; GLP-1 levels were also lower than baseline. The authors concluded that the modifications in the circulating mediators of appetite that encourage weight regain persist after one year of the weight loss. They highlight the importance of strategies to counteract this change in order to prevent obesity recidivism, otherwise, the long-term outcomes will remain unsatisfactory .
Non-pharmacological treatment of obesity can be effective, but the long-term success rate is low and regaining lost weight is a major problem. Randomized studies have shown that a greater initial weight loss achieved with changes in lifestyle associated with other strategies (e.g. liquid formula diets or anorectic drugs) improves long-term weight maintenance, provided that it is followed by a 1–2 years of integrated weight maintenance programme consisting of lifestyle interventions involving dietary change, nutritional education, behaviour therapy and increased physical activity. Therefore, a greater initial weight loss as the first step with a pharmacological intervention may result in improved sustained weight maintenance .
Wing et al. demonstrated that the magnitude of weight loss at 1 year was strongly associated with improvements in blood pressure (BP), as well as fasting glucose, triglyceride, and HDL cholesterol levels but not in LDL cholesterol levels. Compared with weight-stable participants, those who lost 5 to <10% (7.25 ± 2.1 kg) of their body weight presented increased odds of achieving a 0.5%-point reduction in HbA1c, a 5-mmHg decrease in diastolic BP, a 5-mmHg decrease in systolic BP, a 5 mg/dL increase in HDL cholesterol, and a 40 mg/dL decrease in triglycerides. In those who lost 10–15% of their body weight, the odds of improvements were even greater .
Pharmacotherapy can be a useful choice for overweight/obese management. In general, long-term pharmacotherapy is recommended for use as an adjunctive treatment to lifestyle modification, enhancing its compliance . Although anti-obesity drugs facilitate weight loss, the long-term therapy is frequently associated with a high dropout rate . In the following subsections, we briefly review the new drugs for the treatment of obesity.
Liraglutide 3.0 mg
The 3.0 mg dose of liraglutide was first approved in December 2014 for the treatment of obesity in the United States of America, being a higher dose than that already approved for second-line treatment of T2D .
In the phase 3 Scale Maintenance Study, obese/overweight individuals (≥18 years, BMI ≥30 or ≥27 kg/m2 with comorbidities) who lost greater than or equal to 5% of initial weight during a low-calorie diet in a 14 week-run-in were randomly assigned to liraglutide 3.0 mg per day or placebo for 56 weeks. Diet and exercise counselling were provided throughout the trial. Co-primary endpoints were the percentage of weight change from randomization, the proportion of participants that maintained the initial weight loss greater than or equal to 5%, and the proportion that lost ≥5% of randomization weight. In addition to the mean weight loss of 6.0 ± 0.9% achieved by the 422 participants during the run-in period, from randomization to week 56, weight decreased an additional mean of 6.2 ± 7.3% with liraglutide and 0.2 ± 7.0% with placebo (P < 0.0001). More participants in liraglutide group (81.4%) maintained the proposed run-in weight loss, compared with those in placebo group (48.9%) (P < 0.0001), and 50.5% vs. 21.8% of the participants lost ≥5% of randomization weight (P < 0.0001) .
Systolic and diastolic BP decreased more in the liraglutide group than in the placebo group by week 56 and levels of fasting lipids, high-sensitivity C-reactive protein, plasminogen activator inhibitor-1, and adiponectin exhibited more improvement in the liraglutide group than in the placebo group . Treatment with liraglutide was linked with improvements in health-related quality of life, notably physical function, as compared with placebo .
Regarding adverse events, gastrointestinal events were the most common side effects and were reported more frequently with liraglutide than placebo. Nausea and vomiting occurred more often in individuals on liraglutide than in those on placebo, mainly in the 4–8 weeks after initiation of treatment, but were mainly transient and rarely led to discontinuation of treatment .
Rare adverse effects consisted of pancreatitis (most gallstone-related pancreatitis), cholelithiasis and cholecystitis. The positive predictive value of isolated lipase or amylase enzyme elevations for diagnosing pancreatitis was very low (<1% for a lipase value ≥3 times the upper limit of normal [ULN] range and among patients who had pancreatitis no one had amylase values ≥3 times the upper limit of the normal range . Lipase may be elevated in asymptomatic obese (5%) and T2D (20%) patients already before treatment. In asymptomatic T2D patients, lipase levels can be greater than 2 times the ULN in 4.5% and 3 times the ULN in 2.1% of them . In a report from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial, nearly 25% of T2D patients had elevated lipase or amylase levels without symptoms of acute pancreatitis, before randomization to liraglutide or placebo . Acute pancreatitis occurred in 18 patients in the liraglutide group and in 23 in the placebo group 54 months after randomization .
Because of an increased incidence of thyroid C-cell tumours in rodents, the FDA states that liraglutide is contraindicated in those with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasias (MEN) syndrome type 2. In the SCALE trial and also in the LEADER trial there were no cases of medullary thyroid carcinoma or C-cell hyperplasia and liraglutide treatment did not increase serum calcitonin concentrations [37, 40]. A meta-analysis including 25 studies aimed to evaluate the risk of serious adverse events associated with liraglutide and exenatide in patients with T2D. Liraglutide did not increase the risk of acute pancreatitis (0.97 [95% CI 0.21–4.39]), cancer (1.35 [95% CI 0.70, 2.59]), or thyroid cancer (1.54 [95% CI 0.40–6.02]) . Pancreatitis seems to be associated with the onset of weight loss-induced gallstone formation .
The long-term cardiovascular outcome safety of liraglutide was formally evaluated in the LEADER trial, which randomized 9.340 T2D patients for treatment with liraglutide 1.8 mg or placebo for a period of up to 5 years. Liraglutide significantly reduced the risk of major adverse cardiovascular events, including death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke .
No weight-loss related effects of liraglutide
It is suggested that liraglutide exerts cardioprotective effects. More detailed explanations regarding the cardiovascular effects of GLP-1R agonists can be found in reviews authored by Saraiva and Sposito  and Drucker . Moreover, this class of drugs has been showing protective effects in several different tissues, including brain . The Imperial College of Science, in London, is conducting phase 2 trials for the treatment of patients with mild Alzheimer’s disease (ClinicalTrials.gov Identifier: NCT01469351).
Lorcaserin is a selective serotonin 2C receptor [5-hydroxytryptamine 2C (5-HT2C) receptor] agonist that acts on the hypothalamus (Fig. 1) to increase satiety . The FDA approved lorcaserin in 2012 at a dose of 10 mg twice daily (BID) for long-term treatment of obesity based on the results of three key randomized clinical trials. The BLOOM (Behavioral Modification and Lorcaserin for Overweight and Obesity Management) study was a double-blind clinical trial, with 3.182 obese or overweight adults to receive lorcaserin at a dose of 10 mg, or placebo, BID for 52 weeks, besides diet and exercise counselling. At week 52, patients in the placebo group continued to receive placebo but patients in the lorcaserin group were randomly reassigned to receive either placebo or lorcaserin. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost 5% or more of their body weight (P < 0.001), corresponding to an average loss of 5.8 ± 0.2 kg with lorcaserin and 2.2 ± 0.1 kg with placebo during year 1 (P < 0.001). Among the patients who received lorcaserin during year 1 and who had lost 5% or more of their baseline weight at 1 year, the loss was maintained in more patients who continued to receive lorcaserin during year 2 (67.9%) than in patients who received placebo during year 2 (50.3%, P < 0.001) .
The BLOSSOM (Behavioral Modification and Lorcaserin Second Study for Obesity Management) was a 1-year randomized placebo-controlled, double-blind, parallel arm trial that included 4008 obese and overweight patients. Patients were randomly assigned in a 2:1:2 ratio to receive lorcaserin 10 mg BID, lorcaserin 10 mg QD, or placebo. All patients received diet and exercise counseling. Significantly more patients treated with lorcaserin 10 mg BID and QD lost at least 5% of baseline body weight (47.2 and 40.2%, respectively) as compared with placebo (25.0%, P < 0.001 vs. lorcaserin BID). Least squares mean (95% confidence interval) weight loss with lorcaserin BID and QD was 5.8% (5.5–6.2%) and 4.7% (4.3–5.2%), respectively, compared with 2.8% (2.5–3.2%) with placebo (P < 0.001 vs. lorcaserin BID; least squares mean difference, 3.0%). Weight loss of at least 10% was achieved by 22.6 and 17.4% of patients receiving lorcaserin 10 mg BID and QD, respectively, and 9.7% of patients in the placebo group (P < 0.001 vs. lorcaserin BID) .
The analysis of pooled data from the BLOOM and the BLOSSOM studies showed that at week 52, more than twice as many lorcaserin-treated patients achieved a weight loss of ≥5% compared with placebo. A significantly greater proportion of lorcaserin-treated patients achieved a weight loss of ≥10% (lorcaserin, 22.4%; placebo, 8.7%). There were also clinically relevant improvements in cardiometabolic parameters, with significant improvements in lipid parameters, glycemic indicators, quality-of-life measures, and vital signs in the lorcaserin group compared with placebo .
At first, some possibly serious safety concerns about lorcaserin have been pointed out, mostly a numerical disproportion in the incidence of valvulopathy. That was worrisome, provided that the weight-loss drugs fenfluramine and dexfenfluramine, activating 5-HT2B receptors on interstitial heart cells, were removed from the market in 1997 owing to an association with valvulopathy. Integrated data analysis from 3 phase 3 trials with 5249 obese and overweight patients treated with 10 mg lorcaserin BID or placebo was 52 weeks showed that the relative risk of valvulopathy in lorcaserin-treated participants as compared with the placebo group, was 1.16 (95% CI, 0.81–1.67). These results may be partially influenced by greater weight loss in the lorcaserin group than in the placebo group. Even though not statistically significant, the 16% increase in the risk gave cause for some concern . Nevertheless, in vitro receptor assays revealed that lorcaserin has a very much greater selectivity for the 5-HT2C than for the 5HT2B receptor and would not be expected to increase the risk of valvulopathy in humans .
The most common adverse events of lorcaserin are headache, nausea, dizziness, fatigue, dry mouth, and constipation, but otherwise, it is well tolerated [48, 50]. In patients on concomitant use of selective serotonin re-uptake inhibitors (SSRIs), lorcaserin can theoretically increase the risk of serotonin syndrome [53, 54].
The value of lorcaserin seems to be on its safety and tolerability, but not on the magnitude of the weight loss. Its efficacy was marginal according to the FDA efficacy standard for weight loss medications (the first benchmark, treated patients met a mean weight loss at least 5% greater than that of patients receiving placebo was not achieved in any study, but it met the second benchmark, with over 35% of subjects losing 5% or more of their baseline weight) .
The combination of phentermine (PHEN) and controlled-release topiramate (TPM CR) is indicated for long-term treatment of obesity. Phentermine acts to reduce appetite through increasing norepinephrine in the hypothalamus and TPM may reduce appetite through its effect on GABA receptors (Fig. 1) . The combination comprises lower doses of PHEN than the ones used as single agent (3.75 mg in the starting dose, 7.5 mg in the recommended dose and 15 mg in the full dose). The doses of TPM CR (23 mg in the starting dose, 46 mg in the recommended dose and 92 mg in the full dose) are also lower than the ones used for migraine prophylaxis or seizures control .
The CONQUER trial included overweight or obese patients with a BMI of 27–45 kg/m2 and at least two metabolic syndrome comorbidities. Of 2.487 patients, 994 were assigned to placebo, 498 to PHEN 7.5 mg plus TPM 46.0 mg, and 995 to PHEN 15.0 mg plus TPM 92.0 mg. The combination PHEN/TPM CR promoted weight losses approaching 10%. The extension for the second year of observation was called SEQUEL , with patients keeping their treatment regimen. At the end of 2 years, patients completing the trial taking 7.5 mg/46 mg maintained a weight loss of 9.3% below baseline and those on the higher doses maintained a 10.5% weight loss from baseline .
In the EQUIP, CONQUER and SEQUEL studies, improvements in risk factors were related to the amount of weight loss, with the greater benefit being observed with greater weight loss. The most commonly observed side effects in these clinical trials were paresthesias, cognitive impairment, dizziness, dysgeusia, insomnia, constipation, metabolic acidosis and dry mouth. Glaucoma is a rare side effect of TPM, and the drug is contraindicated when this condition is present . During the 2-year period in the CONQUER/SEQUEL study, the incidence of reported psychiatric anxiety-related adverse events was dose-related: 3.1, 6.5, and 9.5% for placebo, 7.5/46, and 15/92 arms, respectively. Potentially serious safety concerns regarding PHEN/TPM CR included teratogenicity (orofacial cleft)  and elevations in resting heart rate . Subsequently, the approval of PHEN/TPM CR demanded a risk evaluation and mitigation strategy (REMS). This included a medication guide, a patient brochure, a formal training program for prescribers (both the brochure and the program inform about the teratogenic risk and stress the need for women with reproductive potential to use effective forms of contraception and also recommend pregnancy testing before initiating treatment and monthly during the follow-up) and authorized only especially accredited drugstores to dispense PHEN/TPM CR . The drug’s labeling advises frequent heart rate monitoring and not to use in patients with recent or unstable cardiac or cerebrovascular disease since the combination has not been investigated in this particular patient cohort. It is worth to emphasize that the effect on weight loss observed with this combination is the result of the administration of two active pharmaceutical ingredients.
Naltrexone/bupropion sustained-release (SR)
Naltrexone is an opioid receptor antagonist with minimal effect on weight loss on its own. Bupropion reduces food intake by acting on adrenergic and dopaminergic receptors in the hypothalamus. Even so, the association of both has shown a synergistic effect. Bupropion stimulates the cleavage of POMC and at the same time that increases the agonism of melanocortin-4 receptor by releasing α-MSH. Simultaneously, other cleavage product of POMC, ß-endorphin induces a negative autologous feedback loop in the POMC neuron itself when it binds at the μ opioid receptor, reducing neuronal activity. The ß-endorphin opioid-mediated effect is blocked by the opioid receptor antagonist naltrexone, which amplifies the effect of α-MSH to reduce food intake (Fig. 1) .
The most common adverse effects of this combination were nausea, constipation, headache, vomiting, and dizziness. Bupropion has the potential of increasing the risks for suicidality and for neuropsychiatric symptoms. Nausea and vomiting were the adverse effects that led to a dropout rate of almost 50% in the clinical studies. To improve tolerability, the tablets are presented in a combination of 90 mg bupropion SR and 8 mg naltrexone SR, allowing titration with progressive increase of 1 tablet every week until a final total dose of 2 tablets BID .
The weight loss achieved at 1 year with the naltrexone/bupropion combination was intermediate between PHEN/TPM CR and lorcaserin and associated with improvement in risk factors. However, the decline in blood pressure is not as great as one would expect from the weight loss in the phase 3 trials of naltrexone/bupropion .
Main contraindications, drug interactions, common adverse effects and stopping rules of liraglutide, lorcaserin, phentermine/topiramate and naltrexone/bupropion
Common adverse effects
It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Also it is contraindicated in patients with a personal or family history of MTC or in patients with Multiple endocrine neoplasia syndrome type 2. Pregnant women or women who are nursing
Concurrent oral drug requiring rapid onset (it can delay gastric emptying)
Nausea, hypoglycemia [serious hypoglycemia can only occur when liraglutide is used with an insulin secretagogue (e.g. a sulfonylurea)], diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase
Stop if <4% weight loss at 16 weeks
Pregnant women, or women who are nursing
Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, but not limited to, triptans, monoamine oxidase inhibitors (MAOIs, including linezolid, an antibiotic which is a reversible nonselective MAOI), selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), dextromethorphan, tricyclic antidepressants (TCAs), bupropion, lithium, tramadol, tryptophan, and St. John’s Wort
In patients without diabetes: headache (17%), dizziness (9%), fatigue (7%), nausea (8%), dry mouth (5%), and constipation (6%). In patients with diabetes: hypoglycemia (29%), headache (15%), back pain (12%), cough (8%), and fatigue (7%)
Stop if <5% loss at 12 weeks
Pregnancy (teratogenic risk), glaucoma, hyperthyroidism, during or within 14 days of taking MAOIs, known hypersensitivity or idiosyncrasy to sympathomimetic amines. Should not be used by nursing mothers
Oral contraceptives: altered exposure may cause irregular bleeding but not increased risk of pregnancy; CNS depressants including alcohol: potentiate CNS depressant effects. Non-potassium sparing diuretics: may potentiate hypokalemia. Antiepileptic drugs: concomitant administration of phenytoin or carbamazepine with topiramate in patients with epilepsy, decreased plasma concentrations of topiramate by 48 and 40%, respectively, when compared to topiramate given alone. Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia (with and without encephalopathy) and hypothermia (with and without hyperammonemia)
Paresthesias, dizziness, taste alterations, insomnia, constipation, dry mouth, elevation in heart rate, memory and cognitive changes, secondary acute angle closure glaucoma, suicidal behavior and ideation, fetal toxicity, mood and sleep changes, metabolic acidosis
If 3% weight loss is not achieved with 7.5 mg/46 mg dose after 12 weeks, stop or increase to 11.25 mg/69 mg for 14 days, then 15 mg/92 mg; Stop if <5% loss at 12 weeks on top dose
Uncontrolled hypertension; seizure disorders, anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs; use of other bupropion-containing products; chronic opioid use; during or within 14 days of taking MAOIs; pregnant women or women who are nursing
MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly. Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants, (e.g., selective serotonin reuptake inhibitors and many tricyclics), antipsychotics (e.g., haloperidol, risperidone and thioridazine), beta-blockers (e.g., metoprolol) and Type 1C antiarrhythmics (e.g., propafenone and flecainide). Concomitant treatment with CYP2B6 Inhibitors (e.g., ticlopidine or clopidogrel) can increase bupropion exposure. Do not exceed one tablet twice daily when taken with CYP2B6 inhibitors. CYP2B6 Inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) may reduce efficacy by reducing bupropion exposure, avoid concomitant use. Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with natrexone/buprobion combination. Drug-laboratory test interactions: natrexone/buprobion can cause false-positive urine test results for amphetamines
Constipation, headache, nausea, vomiting, dizziness, insomnia, dry mouth and diarrhea
Stop if <5% loss at 12 weeks
Obesity is a chronic, progressive, multifactorial disease determined by genetic and environmental factors; its complex pathophysiology and the intrinsic difficulties associated with maintenance of lifestyle modifications contribute to the unsatisfactory long-term outcomes observed in the obesity treatment. Just as with other chronic diseases, pharmacological interventions are useful to maximize non-pharmacological approaches in the long-term management of this condition.
MCM and MEM participated in the concept and drafting of the manuscript, figures, table, references and made the critical review for intellectual content. Both authors corrected the manuscript. Both authors read and approved the final manuscript.
MCM is member of the Advisory Board of Novo Nordisk Farmacêutica do Brasil LTDA and of the Obesity Scientific Communications Advisory Board of Novo Nordisk. The authors declare that they have no competing interests influencing the content of this review.
Medical writing and editorial assistance were provided by Springer Healthcare and funded by a grant from Novo Nordisk Farmacêutica do Brasil LTDA. The authors take full responsibility for the content and conclusions stated in this manuscript. Novo Nordisk neither influenced the content of this publication nor was involved in the study design, data collection, analysis or interpretation. This manuscript was prepared according to the International Society for Medical Publication Professionals’ Good Publication Practice for Communicating Company-Sponsored Medical Research: the GPP3 Guidelines.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Garvey WT. New tools for weight-loss therapy enable a more robust medical model for obesity treatment: rationale for a complications-centric approach. Endocr Pract. 2013;19:864–74.View ArticlePubMedPubMed CentralGoogle Scholar
- World Health Organization: Obesity and overweight fact sheet. http://www.who.int/mediacentre/factsheets/fs311/en/. Accessed 04 Nov 2016.
- Ministério do Planejamento, Orçamento e Gestão. Instituto Brasileiro de Geografia e Estatística, 2014. Pesquisa Nacional de Saúde 2013.Google Scholar
- WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004;363:157–63.View ArticleGoogle Scholar
- Wharton S. Current perspectives on long-term obesity pharmacotherapy. Can J Diabetes. 2016;40:184–91.View ArticlePubMedGoogle Scholar
- Sharma AM, Kushner RF. A proposed clinical staging system for obesity. Int J Obes Relat Metab Disord. 2009;33:289–95.View ArticleGoogle Scholar
- Lynch LA, O’Connell JM, Kwasnik AK, Cawood TJ, O’Farrelly C, O’Shea DB. Are natural killer cells protecting the metabolically healthy obese patient? Obesity. 2009;17:601–5.View ArticlePubMedGoogle Scholar
- Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff. 2009;28:w822–31.View ArticleGoogle Scholar
- Cawley J, Meyerhoefer C. The medical care costs of obesity: an instrumental variables approach. J Health Econ. 2012;31:219–30.View ArticlePubMedGoogle Scholar
- Iepsen EW, Torekov SS, Holst JJ. Liraglutide for type 2 diabetes and obesity: a 2015 update. Expert Rev Cardiovasc Ther. 2015;13:753–67.View ArticlePubMedGoogle Scholar
- Rebello CJGF. Reward-induced eating: therapeutic approaches to addressing food cravings. Adv Ther. 2016;33:1853–66.View ArticlePubMedPubMed CentralGoogle Scholar
- McAllister EJ, Dhurandhar NV, Keith SW, Aronne LJ, Barger J, Baskin M, Benca RM, Biggio J, Boggiano MM, Eisenmann JC, Elobeid M, Fontaine KR, Gluckman P, Hanlon EC, Katzmarzyk P, Pietrobelli A, Redden DT, Ruden DM, Wang C, Waterland RA, Wright SM, Allison DB. Ten putative contributors to the obesity epidemic. Crit Rev Food Sci Nutr. 2009;49:868–913.View ArticlePubMedPubMed CentralGoogle Scholar
- Segal NL, Allison DB. Twins and virtual twins: bases of relative body weight revisited. Int J Obes Relat Metab Disord. 2002;26:437–41.View ArticlePubMedGoogle Scholar
- Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, Pérusse L, Bouchard C. The human obesity gene map: the 2005 update. Obesity. 2006;14:529–644.View ArticlePubMedGoogle Scholar
- Loos RJF. Genetic determinants of common obesity and their value in prediction. Best Pract Res Clin Endocrinol Metab. 2012;26:211–26.View ArticlePubMedGoogle Scholar
- Locke A, Kahali B, Berndt S, Justice A, Pers T. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206.View ArticlePubMedPubMed CentralGoogle Scholar
- Buhmann H, le Roux CW, Bueter M. The gut–brain axis in obesity. Best Pract Res Clin Gastroenterol. 2014;28:559–71.View ArticlePubMedGoogle Scholar
- Sweeting AN, Hocking SL, Markovic TP. Pharmacotherapy for the treatment of obesity. Mol Cell Endocrinol. 2015;418:173–83.View ArticlePubMedGoogle Scholar
- Kim GW, Lin JE, Blomain ES, Waldman SA. Antiobesity pharmacotherapy: new drugs and emerging targets. Clin Pharmacol Ther. 2014;95:53–66.View ArticlePubMedGoogle Scholar
- Baggio LL, Drucker DJ. Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight. J Clin Invest. 2014;124:4223–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Wang X-F, Liu J-J, Xia J, Liu J, Mirabella V, Pang ZP. Endogenous glucagon-like peptide-1 suppresses high-fat food intake by reducing synaptic drive onto mesolimbic dopamine neurons. Cell Rep. 2015;12:726–33.View ArticlePubMedPubMed CentralGoogle Scholar
- Secher A, Jelsing J, Baquero AF, Hecksher-Sørensen J, Cowley MA, Dalbøge LS, Hansen G, Grove KL, Pyke C, Raun K, Schäffer L, Tang-Christensen M, Verma S, Witgen BM, Vrang N, Bjerre Knudsen L. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest. 2014;124:4473–88.View ArticlePubMedPubMed CentralGoogle Scholar
- Farr OM, Sofopoulos M, Tsoukas MA, Dincer F, Thakkar B, Sahin-Efe A, Filippaios A, Bowers J, Srnka A, Gavrieli A, Ko BJ, Liakou C, Kanyuch N, Tseleni-Balafouta SMC. GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled. Diabetologia. 2016;59:954–65.View ArticlePubMedPubMed CentralGoogle Scholar
- Farr OM, Tsoukas MA, Triantafyllou G, Dincer F, Filippaios A, Ko BJMC. Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: a randomized, placebo-controlled, crossover study. Metabolism. 2016;65:945–53.View ArticlePubMedGoogle Scholar
- Volkow ND, Wang G-J, Baler RD. Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn Sci. 2011;15:37–46.View ArticlePubMedGoogle Scholar
- Hsu TM, Hahn JD, Konanur VR, Lam A, Kanoski SE. Hippocampal GLP-1 receptors influence food intake, meal size, and effort-based responding for food through volume transmission. Neuropsychopharmacology. 2014;40:327–37.View ArticlePubMedPubMed CentralGoogle Scholar
- van Bloemendaal L, IJzerman RG, Ten Kulve JS, Barkhof F, Konrad RJ, Drent ML, Veltman DJ, Diamant M. GLP-1 receptor activation modulates appetite-and reward-related brain areas in humans. Diabetes. 2014;63:4186–96.View ArticlePubMedGoogle Scholar
- Ten Kulve JS, Veltman DJ, van Bloemendaal L, Groot PFC, Ruhé HG, Barkhof F, Diamant M, Ijzerman RG. Endogenous GLP1 and GLP1 analogue alter CNS responses to palatable food consumption. J Endocrinol. 2016;229:1–12.View ArticlePubMedGoogle Scholar
- Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, Proietto J. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365:1597–604.View ArticlePubMedGoogle Scholar
- Astrup A, Rossner S. Lessons from obesity management programmes: greater initial weight loss improves long-term maintenance. Obes Rev. 2000;1:17–9.View ArticlePubMedGoogle Scholar
- Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, Hill JO, Brancati FL, Peters A, Wagenknecht L. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Patel D. Pharmacotherapy for the management of obesity. Metabolism. 2015;64:1376–85.View ArticlePubMedGoogle Scholar
- Hainer V, Toplak H, Mitrakou A. Treatment modalities of obesity: what fits whom? Diabetes Care. 2008;31(Supplement 2):S269–77.View ArticlePubMedGoogle Scholar
- FDA News Release. FDA approves weight-management drug Saxenda. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427913.htm. Accessed 07 Nov 2016.
- Astrup A, Rossner S, Van Gaal L, Rissanen A, Al Mazin H, Madsen J. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606–16.View ArticlePubMedGoogle Scholar
- Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, Aronne L. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes. 2013;37:1443–51.View ArticleGoogle Scholar
- Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DCW, le Roux CW, Violante Ortiz R, Jensen CB, Wilding JPH. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Eng J Med. 2015;373:11–22.View ArticleGoogle Scholar
- Steinberg W, Rosenstock J, DeVries JH, Thomsen AB, Svendsen CB, Wadden TA. Elevated serum lipase activity in adults with type 2 diabetes and no gastrointestinal symptoms. Gastroenterol. 2012;142:s-93–4.View ArticleGoogle Scholar
- Steinberg WM, Nauck MA, Zinman B, Daniels GH, Bergenstal RM, Mann JF, Steen Ravn L, Moses AC, Stockner M, Baeres FM, Marso SPBJ. LEADER 3—lipase and amylase activity in subjects with type 2 diabetes. Pancreas. 2014;43:1223–31.View ArticlePubMedPubMed CentralGoogle Scholar
- Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.View ArticlePubMedPubMed CentralGoogle Scholar
- Alves C, Batel-Marques F, Macedo AF. A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabetes Res Clin Pract. 2012;98:271–84.View ArticlePubMedGoogle Scholar
- Butsch WS. Obesity medications: what does the future look like? Curr Opin Endocrinol Diabetes Obes. 2015;22:360–6.View ArticlePubMedGoogle Scholar
- Saraiva FK, Sposito AC. Cardiovascular effects of glucagon-like peptide 1 (GLP-1) receptor agonists. Cardiovasc Diabetol. 2014;13:142.View ArticlePubMedPubMed CentralGoogle Scholar
- Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016;24:1–16.View ArticleGoogle Scholar
- Candeias EM, Sebastião IC, Cardoso SM, Correia SC, Carvalho CI, Plácido AI, Santos MS, Oliveira CR, Moreira PI, Duarte AI. Gut-brain connection: the neuroprotective effects of the anti-diabetic drug liraglutide. World J Diabetes. 2015;6:807–27.View ArticlePubMedPubMed CentralGoogle Scholar
- Bays HE. Lorcaserin and adiposopathy: 5-HT2c agonism as a treatment for “sick fat” and metabolic disease. Expert Rev Cardiovasc Ther. 2009;7:1429–45.View ArticlePubMedGoogle Scholar
- Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245–56.View ArticlePubMedGoogle Scholar
- Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, Shanahan WR, Anderson CM. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM Trial. J Clin Endocrinol Metab. 2011;96:3067–77.View ArticlePubMedGoogle Scholar
- O’Neil PM, Smith SR, Weissman NJ, Fidler MC, Sanchez M, Zhang J, Raether B, Anderson CM, Shanahan WR. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity. 2012;20:1426–36.View ArticlePubMedGoogle Scholar
- Aronne L, Shanahan W, Fain R, Glicklich A, Soliman W, Li Y, Smith S. Safety and efficacy of lorcaserin: a combined analysis of the bloom and blossom trials. Postgrad Med. 2014;126:7–18.View ArticlePubMedGoogle Scholar
- Weissman NJ, Sanchez M, Koch GG, Smith SR, Shanahan WR, Anderson CM. Echocardiographic assessment of cardiac valvular regurgitation with lorcaserin from analysis of 3 phase 3 clinical trials. Circ Cardiovasc Imaging. 2013;6:560–7.View ArticlePubMedGoogle Scholar
- Rothman RB, Baumann MH. Serotonergic drugs and valvular heart disease. Expert Opin Drug Saf. 2009;8:317–29.View ArticlePubMedPubMed CentralGoogle Scholar
- Bray GA. Medical treatment of obesity: the past, the present and the future. Best Pract Res Clin Gastroenterol. 2014;28:665–84.View ArticlePubMedGoogle Scholar
- Colman E, Golden J, Roberts M, Egan A, Weaver J, Rosebraugh C. The FDA’s assessment of two drugs for chronic weight management. N Engl J Med. 2012;367:1577–9.View ArticlePubMedGoogle Scholar
- Smith SM, Meyer M, Trinkley KE. Phentermine/topiramate for the treatment of obesity. Ann Pharmacother. 2013;47:340–9.View ArticlePubMedGoogle Scholar
- Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers ML, Najarian T, Tam PY, Troupin B, Day WW. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity. 2012;20:330–42.View ArticlePubMedGoogle Scholar
- Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, Schwiers M, Day WWBC. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297–308.View ArticlePubMedGoogle Scholar
- Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, Day WW. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:1341–52.View ArticlePubMedGoogle Scholar
- Margulis AV, Mitchell AA, Gilboa SM, Werler MM, Mittleman MA, Glynn RJ, Hernandez-Diaz S. Use of topiramate in pregnancy and risk of oral clefts. Am J Obstet Gynecol. 2012;207:405.e1–7.View ArticleGoogle Scholar
- Greenway FL, Whitehouse MJ, Guttadauria M, Anderson JW, Atkinson RL, Fujioka K, Gadde KM, Gupta AK, O’Neil P, Schumacher D, Smith D, Dunayevich E, Tollefson GD, Weber E, Cowley MA. Rational design of a combination medication for the treatment of obesity. Obesity. 2009;17:30–9.View ArticlePubMedGoogle Scholar
- Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, Kim DD, Dunayevich E. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010;376:595–605.View ArticlePubMedGoogle Scholar
- Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, Kim D, Dunayevich E. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity. 2013;21:935–43.View ArticlePubMedPubMed CentralGoogle Scholar
- Wadden TA, Foreyt JP, Foster GD, Hill JO, Klein S, O’Neil PM, Perri MG, Pi-Sunyer FX, Rock CL, Erickson JS, Maier HN, Kim DD, Dunayevich E. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity. 2011;19:110–20.View ArticlePubMedGoogle Scholar
- Hollander P, Gupta AK, Plodkowski R, Greenway F, Bays H, Burns C, Klassen P, Fujioka K. Effects of naltrexone sustained- release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care. 2013;36:4022–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Saxenda® (liraglutide). Full prescribing information. September 2016. http://www.novo-pi.com/saxenda.pdf. Accessed 07 Nov 2016.
- Belviq® (lorcaserin HCl). Full prescribing information. August 2012. https://www.belviq.com/-/media/Files/BelviqConsolidation/PDF/Belviq_Prescribing_information-pdf.pdf?la=en. Accessed 07 Nov 2016.
- Qsymia® (phentermine and topiramate). Full prescribing information. https://qsymia.com/patient/include/media/pdf/prescribing-information.pdf. Accessed 07 Nov 2016.
- Contrave® (naltrexone HCl and bupropion HCl). Full prescribing information. https://www.contrave.com/content/pdf/Contrave_PI.pdf. Accessed 07 Nov 2016.