Introduction
Obesity represents a major public health challenge, affecting over 603 million adults globally. It elevates the risk of various diseases, including hypertension, dyslipidemia, type 2 diabetes (T2D), and coronary artery disease. Initial management typically involves dietary changes, exercise, and behavior modification. Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, has emerged as a potential weight loss drug. While primarily used in obese diabetic patients, its efficacy in non-diabetic obese individuals warrants investigation. This article aims to provide a comprehensive review of the efficacy and safety of liraglutide for weight loss in non-diabetic individuals, drawing upon a systematic review and meta-analysis of relevant studies.
Liraglutide: Mechanism of Action
Liraglutide is a GLP-1 receptor agonist. GLP-1 is a hormone secreted in the intestine, activated after food ingestion by enteroendocrine L cells located in the distal jejunum and ileum. GLP-1 increases insulin concentrations after eating, prior to the elevation of blood glucose levels. GLP-1 receptors are associated with weight loss by attenuating the fall in the anorexigenic hormone leptin that conditions this decrease.
Systematic Review and Meta-Analysis Methodology
A systematic review and meta-analysis were conducted to evaluate the efficacy and safety of liraglutide in non-diabetic obese adults, adhering to the PRISMA-2020 statement guidelines.
Search Strategy
Comprehensive searches were performed in Web of Science, Pubmed, Embase, Cochrane Central, and Scopus from inception to October 7, 2021. Mesh terms, Emtree terms, and TIAB terms were employed to design search strategies for each database. No limitations were imposed based on language or year of publication.
Study Selection
Inclusion criteria comprised: (i) randomized controlled trials (RCTs), (ii) assessment of adults with obesity without type 1 or 2 diabetes, and (iii) evaluation of liraglutide compared with placebo or other drugs. Observational studies, systematic reviews, case series/reports, conference abstracts, and editorials were excluded.
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Two independent authors reviewed titles and abstracts for eligibility, followed by full-text screening. Discrepancies were resolved by a third author. Endnote 20 software was used for managing saved registers.
Outcome Measures
Primary outcomes were decreases in body mass index (BMI) and body weight loss. Secondary outcomes included treatment-emergent adverse events (TEAEs), hypoglycemic episodes, decrease of HbA1c, and blood pressure. Definitions of outcomes were based on the authors' descriptions in each eligible study.
TEAEs were defined as undesirable or unexpected events not present before treatment or a pre-existing event that worsened after treatment. They included gastrointestinal disorders (nausea, abdominal pain, vomiting, or diarrhea), nervous system disorders, infections, infestations, and vascular disorders.
Types of hypoglycemic events included reactive hypoglycemia (glycemia level <70 mg/dL at the time of symptoms and relief after eating) and fasting hypoglycemia (glycemia <50 mg/dL after an overnight fast, between meals, or after physical activity). Author-reported definitions were also used.
Data Extraction
Two independent authors extracted data using a pre-developed standard data extraction form. Disagreements were resolved by consensus, with a third author consulted if needed. Data extracted included author name, year, research type, country, number of participants, mean age, initial and maximum liraglutide dosage, treatment duration, and primary and secondary outcomes per trial arm with baseline values.
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Risk of Bias Assessment
The RoB 2.0 tool from the Cochrane Collaboration was used for risk of bias assessment. Results were judged as low risk, some concerns, or high risk. Two authors independently performed the assessment, resolving discrepancies through discussion or consultation with a third author.
Statistical Analysis
Random effects models and the inverse variance method were used for meta-analysis. The Paule-Mandel estimator assessed between-study variance. Effects of liraglutide on continuous outcomes were expressed as mean difference (MD) with 95% confidence intervals (95% CIs). Relative risk (RR) with 95% CIs were assessed for dichotomous outcomes. Baseline values of continuous outcomes were adjusted for per trial arm. Statistical heterogeneity was evaluated using the I2 statistic, with values indicating low (<30%), medium (30-60%), and high (>60%) levels of heterogeneity. Subgroup analyses by length of treatment (≤16 versus >16 weeks) and maximum dosage (1.8 versus 3.0 mg/day) were performed. Sensitivity analysis involved changing the model to fixed-effects and using the Mantel-Haenzel method for primary outcomes. The metabin and metacont functions of the meta library of R 3.5.1 were used.
Quality of Evidence Assessment
The GRADE methodology was used to rate the quality of evidence (QoE) per outcome. Risk of bias, indirectness, imprecision, inconsistency, and publication bias were assessed, and QoE were rated as high, moderate, low, and very low. QoE was described in summary of findings (SoF) tables created using GRADEpro GDT.
Results of the Meta-Analysis
Study Selection
The search yielded 2171 registers across all databases, with 702 duplicates removed. After screening titles and abstracts, 22 full-text studies were assessed for eligibility, resulting in 12 RCTs being included in the meta-analysis.
Study Characteristics
A total of 8249 adults treated with liraglutide were evaluated. The mean age was 45.9 ± 5.5 years, and 24% of patients were men. Liraglutide was initiated at 0.6 mg/day, with weekly increments of 0.6 mg up to a maximum of 1.8 mg/day and 3.0 mg/day. The mean duration of treatment was 35.1 ± 19.1 weeks. All studies included body weight loss as a primary outcome, with some studies also assessing inflammatory markers, glucose tolerance, the proportion of individuals with T2D, and adverse events. The mean Hb1Ac at baseline was 5.6% ± 0.09% in the liraglutide arm and 5.6% ± 0.07% in the control arm.
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Risk of Bias
Seven RCTs were rated as having a high risk of bias. One RCT exhibited a high risk in the randomization process, three RCTs showed a high risk of deviations from intended interventions, and five RCTs demonstrated a high risk of missing outcome data. The remaining RCTs showed low or unclear risk of bias.
Primary Outcomes
Liraglutide significantly reduced body weight (MD −3.35 kg; 95%CI −4.65 to −2.05; p < 0.0001) and BMI (MD −1.45 kg/m2; 95%CI −1.98 to −0.91; p < 0.0001) compared to placebo.
Secondary Outcomes
Liraglutide did not significantly reduce TEAEs (RR 1.08; 95% CI 0.92 to 1.27; p = 0.25) or Hb1Ac (MD −0.76%; 95% CI −2.24 to 0.72; p = 0.31) compared to placebo. It also did not significantly increase hypoglycemic episodes (RR 2.01; 95% CI 0.37 to 11.02; p = 0.28). However, liraglutide significantly reduced systolic blood pressure (MD −3.07 mmHg; 95%CI −3.66 to −2.48; p < 0.0001) and diastolic blood pressure (MD −1.01 mmHg; 95%CI −1.55 to −0.47; p = 0.0003).
Subgroup and Sensitivity Analyses
Subgroup analyses by length of treatment and maximum dosage yielded results similar to the overall analyses for all outcomes. Sensitivity analyses showed similar effects on primary outcomes, except for TEAEs, where liraglutide was associated with higher TEAEs compared to placebo (RR 1.15; 95% CI 1.12 to 1.18; p < 0.01).
Quality of Evidence
The quality of evidence was low or very low for most primary and secondary outcomes due to the high risk of bias, heterogeneity among the studies, and imprecision of the effect. For systolic blood pressure, the QoE was low due to moderate heterogeneity among the studies.
Publication Bias
The graphical test for publication bias did not reveal significant asymmetry, indicating a low likelihood of publication bias.
Discussion
The systematic review and meta-analysis indicate that liraglutide reduces body weight, BMI, and blood pressure in non-diabetic obese adults. However, it did not significantly reduce TEAEs or HbA1c, nor did it increase the risk of hypoglycemic episodes compared to placebo. Subgroup analyses by duration of treatment and maximum dosage were consistent with the main analyses. The risk of bias was high in 30% of the trials.
Comparison with Existing Literature
These findings align with other studies evaluating liraglutide for weight reduction in non-diabetic obese individuals. A retrospective cohort study found that low-dose liraglutide (0.6 vs. 1.2 mg/day) for 12 weeks led to weight reduction in Taiwanese non-diabetic patients. Similarly, a prospective cohort study evaluating liraglutide 3 mg daily for 12 weeks in non-diabetic overweight women with coronary microvascular dysfunction reported significant weight loss.
A systematic review and Bayesian meta-analysis of RCTs by Khera et al. assessed the effects of different drugs on weight loss and adverse effects in 29,018 patients. The authors found higher odds of >5% weight loss with the liraglutide group compared to placebo. While the Khera et al. study did not evaluate adverse effects or hypoglycemic events, it included fewer patients (4424) for the liraglutide versus placebo comparison compared to the present study (7236).
Another systematic review by Zhang et al. assessed the efficacy and safety of liraglutide in obese, non-diabetic individuals, reporting similar results regarding weight loss and blood pressure reduction. However, Zhang et al. reported a low risk of bias in the included trials, whereas the present study reported a comprehensive risk of bias analysis, indicating a high risk of bias in the majority of trials.
Clinical Implications
Obesity is a global epidemic, and effective interventions for weight reduction are crucial. While lifestyle changes and other medications have shown some success, weight loss is often difficult to achieve and maintain. Liraglutide offers a potential pharmacological approach for weight management in non-diabetic obese individuals.
A retrospective study conducted in Saudi Arabia found that Liraglutide 3.0 mg/day for four to six months resulted in significant weight loss and BMI reduction in obese non-diabetic patients. The study also reported improvements in SBP and HbA1c levels. The most common adverse events were nausea, vomiting, and constipation.
Adverse Effects
Common adverse events associated with liraglutide include nausea, vomiting, and constipation. In the meta-analysis, liraglutide did not significantly reduce TEAEs compared to placebo. However, sensitivity analysis indicated that liraglutide may be associated with higher TEAEs compared to placebo.
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