In obese T2D patients, liraglutide improved the observed deficit in response to palatable food, which may contribute to the weight loss observed with liraglutide [ 28 ]. An aspect that has been recently considered in the study of obesity is hormonal adaptations to weight loss. Sumithran et al. 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 [ 29 ]. 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.
Therefore, a greater initial weight loss as the first step with a pharmacological intervention may result in improved sustained weight maintenance [ 30 ]. Wing et al. In general, long-term pharmacotherapy is recommended for use as an adjunctive treatment to lifestyle modification, enhancing its compliance [ 32 ]. Although anti-obesity drugs facilitate weight loss, the long-term therapy is frequently associated with a high dropout rate [ 33 ].
In the following subsections, we briefly review the new drugs for the treatment of obesity. The 3. Astrup et al. Weight change was analysed by intention to treat ITT and was the primary endpoint. An week open-label extension followed.
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As shown in Fig. Mean weight loss with liraglutide 1. Adapted from Astrup et al. Change in body weight after treatment of obese individuals with four liraglutide doses 1. Proportion of individuals with prediabetes in the ITT population at randomisation and week Individuals included are those with valid assessment at the start and the end of the week trial period. Diet and exercise counselling were provided throughout the trial. In addition to the mean weight loss of 6. More participants in liraglutide group Patients were allocated in a ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.
Patients in the liraglutide group lost a mean of 8. A total of There was a greater reduction in HbA1c, fasting glucose, and fasting insulin levels, as well as in plasma glucose levels during an oral glucose-tolerance test OGTT in the liraglutide rather than in the placebo group and higher insulin and C-peptide levels relative to placebo during the OGTT.
These effects were more noticeable in prediabetic patients than in normoglycaemic ones. At week 56, the prevalence of prediabetes was significantly lower in the liraglutide than in the placebo group and also T2D developed in more patients in the placebo than in the liraglutide group during the course of treatment [ 37 ].
These effects could probably be attributed to the combination of weight loss and improved glycemic control with liraglutide.
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Adapted from Pi-Sunyer et al. I bars indicate standard error, and the separate symbols above the curves represent the week weight change using last-observation-carried-forward LOCF imputation.
Appetite regulation and weight control: the role of gut hormones - Europe PMC Article - Europe PMC
Percentages of weight change in the liraglutide group were 8. In the placebo group, the changes were 2. The full-analysis set comprised patients who underwent randomization, were exposed to at least one treatment dose, and had at least one assessment after baseline 69 patients were excluded from the full-analysis set: 61 owing to lack of an assessment and 8 owing to no exposure. Data shown are the observed means for the full-analysis set with LOCF. Findings from logistic-regression analysis showed an odds ratio of 4.
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 [ 37 ]. Treatment with liraglutide was linked with improvements in health-related quality of life, notably physical function, as compared with placebo [ 37 ].
Regarding adverse events, gastrointestinal events were the most common side effects and were reported more frequently with liraglutide than placebo. Rare adverse effects consisted of pancreatitis most gallstone-related pancreatitis , cholelithiasis and cholecystitis. 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.
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.
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Pancreatitis seems to be associated with the onset of weight loss-induced gallstone formation [ 42 ]. The long-term cardiovascular outcome safety of liraglutide was formally evaluated in the LEADER trial, which randomized 9. Liraglutide significantly reduced the risk of major adverse cardiovascular events, including death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke [ 40 ].
irercanbuy.tk 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 [ 43 ] and Drucker [ 44 ]. Moreover, this class of drugs has been showing protective effects in several different tissues, including brain [ 45 ]. Lorcaserin is a selective serotonin 2C receptor [5-hydroxytryptamine 2C 5-HT2C receptor] agonist that acts on the hypothalamus Fig. 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.
All patients received diet and exercise counseling. The weight reduction remained significantly greater in the lorcaserin groups than in the placebo group throughout the study Fig. Similar results were obtained when data from the subgroup of patients who completed the week trial were analyzed the completer population [ 49 ]. BID, twice daily; QD, once daily.
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 [ 50 ]. 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 owing to an association with valvulopathy. These results may be partially influenced by greater weight loss in the lorcaserin group than in the placebo group. 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 [ 52 ].
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. Phentermine acts to reduce appetite through increasing norepinephrine in the hypothalamus and TPM may reduce appetite through its effect on GABA receptors Fig.
The combination comprises lower doses of PHEN than the ones used as single agent 3. Patients in the placebo, 3. Adapted from Allison et al. The extension for the second year of observation was called SEQUEL [ 57 ], with patients keeping their treatment regimen. 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 [ 53 ].
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 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. In overweight and obese patients without T2D, the placebo-subtracted weight loss ranged from 4.
In patients with T2D, as always, the placebo-subtracted weight loss was less effective [ 61 , 63 ]. Weight loss was maintained with continued double-blind treatment in the NB32 group through week 56 6.
Treatment also was linked to significant improvements in control of eating, weight-related quality of life, and cardiovascular risk factors. Adapted from Apovian et al.