Journal of Endocrinology and Metabolism, ISSN 1923-2861 print, 1923-287X online, Open Access
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Review

Volume 11, Number 5, October 2021, pages 95-107

Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in the Weight Loss Among Obese Individuals: A Systematic Review

Figure

Figure 1.
Figure 1. Flow chart summarizing the identification and selection of papers for systematic review.

Tables

Table 1. PRISMA Check List That Was Followed for This Review
 
Section and topicChecklist itemLocation where item is reported
TitleIdentify the report as a systematic review.Abstract, Introduction and Methods
AbstractSee the PRISMA 2020 for Abstracts checklist.Seen and followed this guideline.
RationaleDescribe the rationale for the review in the context of existing knowledge.Rationale is described.
ObjectivesProvide an explicit statement of the objective(s) or question(s) the review addresses.Objectives are described.
Eligibility criteriaSpecify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.All required details are in Methods section.
Information sourcesSpecify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.Databases are specified in Methods section.
Search strategyPresent the full search strategies for all databases, registers and websites, including any filters and limits used.A full table of search strategy is made and details are in Methods section.
Selection processSpecify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.All required details are in Methods section.
Data collection processSpecify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.All required details are in Methods section.
Data itemsList and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.All required details are in Methods section.
List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.These are listed in Methods as well as Tables.
Effect measuresSpecify for each outcome the effect measure(s) (e.g., risk ratio, mean difference) used in the synthesis or presentation of results.It is specified in Tables.
Synthesis methodsDescribe the processes used to decide which studies were eligible for each synthesis (e.g., tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).Flow chart is made with details in Methods.
Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.NA
Describe any methods used to tabulate or visually display results of individual studies and syntheses.See the flow chart and Tables.
Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.Since it was not a meta-analysis, we performed qualitative review.
Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).NA
Describe any sensitivity analyses conducted to assess robustness of the synthesized results.NA
Reporting bias assessmentDescribe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).NA
Certainty assessmentDescribe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.NA
Quality assessmentQuality assessment of eligible studies was doneDone using appropriate tools
Study selectionDescribe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.Flow chart and details are in Methods.
Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.Flow chart and details are in Methods.
Study characteristicsCite each included study and present its characteristics.Description is given in Tables and results section.
Results of individual studiesFor all outcomes, present, for each study: 1) summary statistics for each group (where appropriate) and 2) an effect estimate and its precision (e.g., confidence/credible interval), ideally using structured tables or plots.Description is given in Tables and results section.
DiscussionProvide a general interpretation of the results in the context of other evidence.Done
Discuss any limitations of the evidence included in the review.Done
Discuss any limitations of the review processes used.Done
Discuss implications of the results for practice, policy, and future research.Done

 

Table 2. Search Strategy According to PICO Criteria
 
Population“Adults*” [Mesh] OR “women*adults*” OR obese*men or women OR type-2 diabetes mellitus* OR overweight* OR “diabetic*” OR “adults with type-2 diabetes mellitus” OR “obese adults” OR “diabetic women” “diabetic men” OR “obese women” “obese men” [Mesh]
Intervention“GLP-1Ras” OR “Glucagon-like peptide-1 receptor agonists (GLP-1Ras)” OR “Liraglutide” [MeSH Terms] OR “Exenatide” [MeSH Terms] OR Semaglutide [MeSH Terms] OR Dulaglutide [MeSH Terms] OR Exenatide plus changes in the lifestyle [MeSH Terms] OR Dulaglutide plus changes in the lifestyle [MeSH Terms] OR Liraglutide plus changes in the lifestyle [MeSH Terms] OR Semaglutide plus changes in the lifestyle [MeSH Terms] OR Dulaglutide plus changes in life style [MeSH Terms]
ComparisonAdults who were either not randomized to glucagon-like peptide-1 receptor agonists in RCTs or who were not observed to take glucagon-like peptide-1 receptor agonists in observational studies.
Outcome“Obesity management”, OR “weight loss”, OR “reduction in weight” OR “improving weight” OR “reduction in body mass index” OR “reduction in body fat” OR “weight management”

 

Table 3. Characteristics of the Included Studies With Their Settings and Types of Groups (n = 13)
 
Study nameYearCountryStudy designSample sizeGroup 1Group 2Group 3Age (years)BMI (kg/m2)
BMI: body mass index; RCT: randomized controlled trial; SGLT-2: sodium-glucose cotransporter-2; GLP-1: glucagon-like peptide-1.
Rosenstock et al [13]2010USARCT152ExenatidePlaceboNA46 ± 1239.6 ± 7.0
Apovian et al [14]2010USARCT194Exenatide plus changes in the lifestylePlacebo plus changes in the lifestyleNA54.8 ± 9.525 - 39.9
Bergenstal et al [15]2010USA, India, and MexicoRCT491, 170 each in three groupsExenatideSitagliptinPioglitazone≥ 1825 - 45
Astrup et al [16]2012EuropeRCT564LiraglutidePlaceboOrlistat18 - 6530 - 40
Chun-Jun Li et al [17]2014ChinaProspective case series31LiraglutideNANA48.5 ± 11.431.7 ± 3.6
Perna et al [18]2016ItalyRetrospective case series9LiraglutideNANA68.22 ± 3.8632.34 ± 4.89
Rondanelli et al [19]2016ItalyCohort study28LiraglutideNANA58.75 ± 9.3334.13 ± 5.46
Bradley et al [20]2012USAProspective case series18ExenatideNANA39 ± 1130 - 40
Ishoy et al [21]2017DenmarkRCT40ExenatidePlaceboNA19 - 6539.5 ± 3.5
Yin et al [22]2018ChinaRCT37ExenatideGlargineNA48.3 ± 2.328.1 ± 0.5
Hong et al [23]2016KoreaProspective case series32ExenatideNANA49.0 ± 11.232.9 ± 4.7
Semaglutide Blundell et al [24]2017UKRCT30SemaglutidePlaceboNA4230 - 45
Seko et al [25]2017JapanRetrospective case series5DulaglutideNANA66.8 ± 2.728.2 ± 1.2
Di Prospero et al [26]2021USARCT195NJ-64565111, a dual agonist of glucagon-like peptide-1 and glucagon receptors. Three groups were given different doses of NJ-64565111PlaceboNA18 - 7035 - 50
Kim et al [27]2021USARCT35Liraglutide (1.8 mg/day)PlaceboNA40 - 7027 - 40
Frieling et al [28]2021USARetrospective cohort study73SGLT-2 inhibitorsGLP-1 receptor agonistsNA60 - 7530 - 40
Wilding et al [29]202116 countries of Asia, Europe, North America, and South AmericaRCT1,9612.4 mg semaglutide administered subcutaneouslyPlaceboNA18 years of age or older adults> 27
Davies et al [30]202112 countries of Asia, Europe, North and America, and South America, South Africa, and Middle EastRCT1,5952.4 mg semaglutide administered subcutaneously1.0 mg semaglutide administered subcutaneouslyPlacebo18 years of age or older adults> 27
Wadden et al [31]202141 sites in the USARCT6112.4 mg semaglutide administered subcutaneouslyPlaceboNA46 ± 1338.0 ± 6.7
Rubino et al [32]202173 sites in 10 countriesRCT8032.4 mg semaglutide administered subcutaneouslyPlaceboNA46 ± 1238.4 ± 6.9

 

Table 4. Summary of Main Findings Regarding Efficacy of GLP-1 Agonisits in Reducing Weight Loss (n = 13)
 
Study nameYearDuration of treatmentType of populationMain findingsSummary of findings
CI: confidence interval; T2DM: type 2 diabetic mellitus; NAFLD: non-alcoholic fatty liver disease; IQR: intraquartile range; SGLT-2: sodium-glucose cotransporter-2; GLP-1: glucagon-like peptide-1.
Rosenstock et al [13]201024 weeksObeseStudy participants in the intervention group lost 5.1 ± 0.5 kg from baseline as opposed to 1.6 ± 0.5 kg in the placebo group (P < 0.001).Exenatide along with the changes in lifestyle resulted in a decrease in caloric intake, thereby leading to weight reduction and also resulted in improved tolerance to glucose
Apovian et al [14]201024 weeksObese and diabetic individualsExenatide along with the changes in lifestyle revealed a bigger difference in weight (-6.16 ± 0.54 kg as opposed to the placebo group 3.97 ± 0.52 kg (P = 0.003).Exenatide along with the changes in lifestyle resulted in substantial loss of weight, helped to regulate glucose and resulted in reduced blood pressure as opposed to placebo plus changes in lifestyle.
Bergenstal et al [15]201026 weeksDiabetic individualsThere was more weight reduction among study subjects who received exenatide (-2.3 kg, 95% CI: -2.9 to -1.7) vs. sitagliptin (-1.5 kg, 95% CI: -2.4 to -0.7, P = 0.0002) or pioglitazone (-5.1 kg, 95% CI: -5.9 to -4.3, P < 0.0001).Exenatide resulted in more weight reduction than other medications without causing hypoglycemia.
Astrup et al [16]201220 weeksObeseThere was 5.8 kg (95% CI: 3.7 - 8.0) more weight loss in the group 1 as opposed to placebo and there was 3.0 kg more weight loss than orlistat (P < 0.001). There was 20-week body fat reduced by 15.4 among those who took liraglutide and lean tissue by 2.0%.Liraglutide was tolerated very well and there was sustainable weight loss over the period of 2 years and there was also improvement in the risk of cardiovascular diseases.
Chun-Jun Li et al [17]201412 weeksObese and diabetic individualsSubjects treated with liraglutide resulted in a mean weight reduction of 5.03 kg and 61.3% of the patients had a reduction of more than 5% of body weight when contrasted to baseline.The body weight, waist circumference, total fat, lean mass, and fat percentage were substantially decreased when compared to baseline.
Perna et al [18]201615 weeksObese and diabetic individualsThere was a reduction in the mean BMI (-0.78 kg/m2), weight (-2 kg), fat mass (-1.5 kg) and android fat (-0.9%) when compared to baseline.Treatment with liraglutide led to a reduction in the mass of fat and android fat.
Rondanelli et al [19]201624 weeksObese and diabetic individualsSignificant reductions in BMI (-0.86 kg/m2, P = 0.024), fat mass (-2.01 kg, P = 0.015), fat mass index (-0.71 kg/m2, P = 0.014), android fat (-1.72%, P = 0.022), trunk fat (-1.52%, P = 0.016), and waist circumference (-6.86 cm, P < 0.001) were observed when compared to baseline.Treatment with 24-week liraglutide caused decreased fat mass, android fat, trunk fat, and appetite by increasing the lipid profile, glucose control, and insulin sensitivity.
Bradley et al [20]201214 weeksObese individualsThe reduction in the mean weight due to exenatide was 2.0 ± 2.8 kg (P = 0.01). The average change in BMI was 0.7 ± 1.0 kg/m2 (P = 0.01). There was significant reduction in the fat mass by 1.3 ± 1.8 kg (P = 0.01) and fat-free mass was non-significantly reduced by 0.8 ± 2.2 kg (P = 0.14).The variation in the composition of the body relates to an estimated change in body energy stores of 13 ± 28 kcal/day for fat-free mass lost along with 153 ± 205 kcal/day for fat mass lost.
Ishoy et al [21]201714 weeksObese individuals with schizophreniaThere was weight reduction both in intervention and control arms (P = 0.004), however, similar (P = 0.98) weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg.Treatment with exenatide once per week did not lead to weight reduction in obese, patients with schizophrenia who were on anit-psychotic medications as opposed to placebo.
Yin et al [22]201816 weeksObese and diabeticDecreases in weight, BMI, body fat mass, and percent fat mass (except for gynoid) were greater with exenatide than with glargine, and percent lean tissue (other than the limbs) increased with exenatide.Exenatide and glargine attained comparable increases in glycemic control, sensitivity to insulin, and function of β cells. Nevertheless, exenatide created better weight and fat mass decreases, which were beneficial for blood glucose control.
Hong et al [23]201612 weeksObese and diabeticBody weight and fat mass declined substantially (P = 0.002 and P = 0.001, respectively), although muscle mass did not decline (P = 0.289).Impacts of exenatide among obese individuals with comorbid such as cardiometabolic high-risk patients decreased body weight without muscle mass loss, body fat mass, and glycated hemoglobin levels.
Semaglutide Blundell et al [24]201712 weeksObeseSemaglutide led to a reduction from baseline in mean body weight of 5.0 kg, predominantly from body fat mass.Libitum energy intake was significantly shorter with semaglutide vs. placebo with a corresponding loss of body weight observed with semaglutide.
Seko et al [25]201712 weeksDiabeticNot only body weight and hemoglobin A1c but also transaminase activities were significantly decreased after the 12-week therapy with dulaglutide. Total body fat mass and liver stiffness measurement also decreased after the treatment.Dulaglutide, a new glucagon-like peptidase-1 receptor agonist, could be a novel promising agent for the treatment for NAFLD patients with T2DM due to its efficacy in body weight reduction, the nature of weekly injection, and patient preference.
Di Prospero et al [26]202112 weeksObese and diabetic individualsThere was a significant recution in body weight in a dose response manner. More precisely, changes in body weight were -4.6% with 5.0 mg of glucagon receptor agonisits, -5.9% with 7.4 mg, and -7.2% with 10.0 mg. There was more than 5% weight loss in the treatment arm than placebo.Overall, glucagon receptor agonisits resulted in weight reduction in dose dependent manner when compared with placebo. However, there were more side effects reported with glucagon receptor agonisits as compared to placebo. These side effects included nausea and vomiting.
Kim et al [27]202114 weeksObese and pre-diabeticStudy subjects randomized to intervention arm were found to have a significant reduction in mean weight: -3.6% with 95% CI of -5.2% to -2.1%.Liraglutide resulted in improved weight by the end of 14 weeks amon prediabetic individuals.
Frieling et al [28]20216 monthsDiabetic and obese adult patientsThere was a median loss of about -2.8 kg with an IQR of -5.40 to -1.50 among those patients who received SGLT-2 inhibitors, whereas those who received GLP-1 receptor agonisits lost about 1.15 kg with an IQR of -3.38 to 0.975 with a P-value of 0.014.SGLT-2 inhibitors when used in combination with other antidiabetic medications can results in more weight loss than GLP-1 receptor agonisits.
Wilding et al [29]202168 weeksObese adults with at least one attempt of weight unsuccesful weight lossA mean difference in BMI between intervention (semaglutide) and control arm was -12.4 percentage points (95% CI: -13.4 to -11.5 and P < 0.001).There was sustained and clinically meaningful reduction in the body weight among those who were randomized to semaglutide than placebo group.
Davies et al [30]202168 weeksObese and diabetic adultsAn estimated mean difference in BMI between intervention (semaglutide 2.4 mg) and placebo was -6.2 percentage points (95% CI: -7.3 to -5.2 and P < 0.001).Semaglutide 2.4 mg given once a week showed superior findings interms on weight reduction than placebo.
Wadden et al [31]202168 weeksObese and overweight adultsThe mean difference was -10.3 percentage points (95% CI: -12.0 to 8.6 and P < 0.001).Semaglutide 2.4 mg given once a week along with behavioural therapy and low-calorie diet redulted in substantial weight loss than placebo group.
Rubino et al [32]202168 weeksObese and overweight adultsMean change in body weight was -7.9% from baseline to follow-up in the intervention arm versus 6.9% in the placebo arm. The mean difference in the body weight between two groups was -14.8 with 95% CI of -16.0 to -13.50 (P < 0.001).There was substantial weight loss in the group that received Semaglutide 2.4 mg than placebo.