Introduction
Overweight and obesity are significant health challenges, contributing to metabolic and cardiovascular diseases, the leading cause of mortality. In Mexico, a substantial portion of the adult population struggles with these conditions. The complexity of obesity necessitates diverse management approaches, including pharmacological interventions. However, some weight loss drugs have been limited or discontinued due to adverse and sometimes fatal reactions. Glucagon-like peptide-1 (GLP-1) analogues, initially developed for type 2 diabetes mellitus (DM) management, have emerged as a promising option. Liraglutide, a GLP-1 receptor agonist approved by the FDA, not only helps lower glucose levels and improve insulin secretion but also contributes to weight loss and reduces cardiovascular risk factors.
Mechanism of Action
Liraglutide's mechanism of action as an incretin is well-defined. Produced in ileocolic C cells, it stimulates pancreatic insulin secretion by interacting with G protein. At the gastrointestinal level, it decreases acid gastric secretion and delays gastric emptying through antral stimulation, inhibits pylorus propulsion, and reduces digestive tract motility after food intake. Liraglutide induces early satiety via a central nervous system mechanism, potentially involving AMPc stimulation and activation of neuronal receptors in the hypothalamus, specifically the arcuate nucleus. It may also inhibit the solitary tract of the brain stem. These mechanisms collectively reduce caloric intake, leading to weight loss.
Study on Liraglutide's Effect on Weight and Metabolic Parameters
A descriptive, observational, analytical study was conducted to evaluate the effect of liraglutide on body weight and metabolic parameters associated with cardiovascular risk in patients with or without type 2 DM. Clinical files of patients from private cardiology practices in Monterrey, N. L., Mexico, from July 2011 to June 2012, were reviewed. Patients prescribed liraglutide (0.6 to 1.8 mg every 24 hours), following a diet of 2000 kcal for men and 1800 kcal for women, and engaging in moderate exercise for 30 minutes at least 5 times a week, were selected.
Inclusion Criteria
The inclusion criteria included:
- Liraglutide treatment for at least 3 months
- Registered variables at the beginning of the study and after 3 months of treatment: Body weight, body mass index (BMI), blood pressure, plasma glucose after fasting, lipid profile, glycosylated hemoglobin, hepatic function tests, body fat percentage, presence or absence of cardiovascular or digestive symptoms, and medication dosage.
Liraglutide dosage was initiated at 0.6 mg daily during the first week, gradually increased to 1.2 mg and up to 1.8 mg daily based on tolerance and requirement. Metformin was also prescribed to 14 of 15 diabetic patients and 13 of the 23 non-diabetic patients. Statistical analysis involved measures of central tendency and dispersion, Student's T-test, and analysis of variance, with a significance level of p < 0.05.
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Results
The study included 38 cases, with 23 (60%) males and 15 (40%) females, averaging 56 ± 10 years of age. Fifteen patients (40%) were under type 2 DM treatment. Coronary risk factors were detected. The average weight loss after 3 months of treatment was 4.8 kg across all 38 patients, which was statistically significant (p < 0.001). A significant average weight loss of 4.2 kg was observed in diabetic patients and 5.2 kg in non-diabetic patients. Furthermore, several evaluated metabolic parameters improved. The analysis of variance showed a non-significant difference in the behavior between subgroups in weight reduction, BMI, body fat percentage, serum triglycerides, total cholesterol and c-LDL; differences found in systolic arterial pressure and c-LDL were significant. Six patients (16%) reported mild adverse events, such as nausea, dizziness, vomiting, diarrhea, and constipation, during the first 2 weeks of treatment. There were no reports of hypoglycemia episodes or hepatic enzyme alterations. Patients with heart diseases did not show data of cardiac decompensation.
Discussion
The study's findings align with existing research demonstrating liraglutide's effectiveness in weight loss for obese patients, both with and without type 2 DM. Weight losses between 7 to 9 kg in 20 weeks have been reported when using 3 mg of liraglutide a day, with superior results compared to placebo and orlistat. The slightly lower weight loss observed in this study may be attributed to the smaller dose and shorter treatment duration. The study also found a 2.5% average reduction in body fat, slightly greater than previously reported. Improvements in metabolic parameters, including glycosylated hemoglobin and triglycerides, were observed, although to a lesser degree than in some studies. Reductions in blood pressure were slightly superior to those reported in the literature.
Adverse effects, primarily gastrointestinal discomfort, were reported in 16% of patients but resolved within the first two weeks of treatment. The absence of hypoglycemia or pancreatitis cases may be related to patient selection and sample size. The study acknowledges limitations including its retrospective, descriptive, and non-randomized design, small sample size, and short time frame.
Additional Studies and Trials
Liraglutide has been evaluated in two double-blind studies of more than 3,000 obese or overweight patients with hyperlipidemia, hypertension, or diabetes. Liraglutide improves cardiometabolic markers such as blood pressure, waist circumference, body mass index, and A1C, although the clinical relevance of these reductions remains uncertain. Patients may also report improved physical function, as measured by a validated self-reported measure of obesity-related quality of life.
A study on non-diabetic patients with metabolic syndrome who received low-dose liraglutide (0.6 or 1.2 mg per day) for weight reduction for 12 weeks showed statistical weight reduction in both groups, with higher doses demonstrating better efficacy.
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Liraglutide: Safety, Tolerability, and Cost
Liraglutide (Saxenda) is a glucagon-like peptide-1 (GLP-1) receptor agonist that, in addition to stimulating insulin release and inhibiting glucagon secretion, slows gastric emptying and increases satiety after eating. It is labeled as an adjunct to diet and exercise for weight management in overweight or obese adults. Safety concerns with liraglutide include acute gallbladder disease, acute pancreatitis, and risk of severe hypoglycemia. Gallbladder disease and cholecystitis can occur in patients rapidly losing weight by any means, but the rates are higher in patients using liraglutide and rise with increasing weight loss. The risk of pancreatitis is relatively low (0.3%), but transient elevations of pancreatic enzymes of uncertain clinical significance can occur. Although sulfonylureas and other insulin secretagogues are not contraindicated for use with liraglutide, their dose should be lowered by at least 50% if they are continued while patients are taking liraglutide.
Gastrointestinal symptoms are common, and approximately 10% of patients will stop treatment because of adverse effects. Nausea (39%), diarrhea or constipation (20%), and vomiting (15%) are reported with liraglutide.
A one-month supply of liraglutide at the target dosage of 3 mg per day costs approximately $1,194. The starting dosage of liraglutide is 0.6 mg daily, injected subcutaneously at any time of day without regard to meals. The dosage should be increased weekly by 0.6 mg until the target dosage of 3 mg per day is reached. Patients who are unable to tolerate the 3-mg dose should stop treatment, as should patients who do not lose 4% of their baseline body weight after four months. If patients achieve clinically significant weight loss after one year, liraglutide may be continued to maintain weight loss.
Low-Dose Liraglutide in Asian Populations
Considering incretin-based therapy is more effective in Asian populations, the effect of low-dose liraglutide in weight control among these non-diabetic groups has been evaluated. A study retrospectively reviewed non-diabetic obese patients with metabolic syndrome who received low-dose liraglutide for weight control. All patients started medication therapy with liraglutide 0.6 mg per day and were rapidly titrated to 1.2 mg per day if there was no adequate suppression of appetite within the first week.
At 12 weeks of low-dose liraglutide use, the two groups of patients both showed statistical significance in weight reduction. Patients with liraglutide 0.6 mg showed relatively high effectiveness in weight reduction, but this was statistically insignificant compared with patients with liraglutide 1.2 mg (â6.4 vs â5.6%, P = 0.770). Patients receiving 12 weeks of low-dose liraglutide showed an improvement in plasma glucose status. HbA1c showed a statistically significant improvement compared with baseline (â0.5 vs â0.3%). Fasting glucose, serum insulin level, HOMA-IR, insulin and glucose ratio showed numerical improvement compared with baseline; furthermore, there were also improvements in the metabolic factors mentioned above.
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Predictive Factors and the Importance of Early Response
After evaluating the predictive factors for overt weight reduction, only age showed a significant association with weight reduction. Decreased bodyweight with 4.2% from baseline showed a sensitivity of 73.3% and a specificity of 88.9%. This indicates that an early response with rapid weight reduction in the first 4 weeks is observed. The present study also found that younger patients had a better chance of achieving overt weight reduction.
Liraglutide's Broader Health Benefits
In addition to weight reduction, liraglutide has been proven to have direct protective effects in multiple organs, including the brain, pancreatic βâcell function, liver and heart.
Guidelines for Liraglutide Use
Liraglutide improves cardiometabolic markers such as blood pressure, waist circumference, body mass index, and A1C, although the clinical relevance of these reductions remains uncertain.2,3 Patients may also report improved physical function, as measured by a validated self-reported measure of obesity-related quality of life.2,3 As with other pharmacologic treatments, liraglutide has not been studied to determine its effect on cardiovascular- or diabetes-related morbidity, or overall mortality. If patients achieve clinically significant weight loss after one year, liraglutide may be continued to maintain weight loss.
Considerations for Prescribing Liraglutide
Liraglutide, combined with lifestyle counseling, produces a clinically significant and sustained weight loss that continues as long as it is used. Nausea and vomiting, however, are common adverse effects, and about one in 10 patients will discontinue treatment.
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