1 Introduction

The obesity epidemic is accelerating globally and is closely associated with an increased risk for a wide range of diseases, including diabetes mellitus (DM) and cardiovascular disease (CVD) [1]. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) exert weight reduction properties, making them promising antiobesity medications. As such, determining the extent to which this weight reduction effect is influenced by specific factors would positively affect their clinical application(s), thereby enabling a more precise estimation of the weight loss outcomes attributed to GLP-1 RAs.

Whether sex significantly influences the efficacy of GLP-1 RAs for weight reduction remains controversial. Some studies have suggested that the extent of weight reduction induced by GLP-1 RAs may be affected by sex [2]. Other studies have indicated that males and females experienced similar weight reductions during treatment with GLP-1 RAs [3, 4]. However, these studies were limited by sample sizes and study designs. Furthermore, labels for GLP-1 RAs did not indicate any discernible sex differences in weight reduction outcomes [5-8]. As such, a comprehensive analysis of this sex difference for GLP-1 RAs is required.

Thus, the objective of the present systematic review and meta-analysis was to identify potential sex differences in the efficacy of GLP-1 RAs for weight loss, complemented by additional analyses to investigate factors that may influence this sex difference.

2 Materials and Methods

This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (i.e., “PRISMA”) guidelines [9]. The study protocol was prospectively registered with PROSPERO (ID: CRD42023480167).

3 Results

3.1 Search Results and Study Characteristics

A flow diagram illustrating the literature search process is presented in Figure 1. Overall, 24,307 references were retrieved in the search. After excluding duplicate studies, those that did not fulfill the inclusion criterion and those that fulfilled the exclusion criteria, 14 were eligible for quantitative data synthesis [4, 14-26]. Five types of GLP-1 RAs were included in the meta-analysis (dulaglutide, exenatide, liraglutide, semaglutide, and retatrutide). The eligible trials lasted from 24 to 104 weeks. Of the included studies, 4 reported results of weight reduction with semaglutide, [4, 23-25] along with 8 studies of dulaglutide, [14-20, 24] 3 studies of exenatide (one with multiple RCTs), [14, 21, 22] 1 study of retatrutide, [26] and 1 study of liraglutide [19]. The average age of the patients in the included studies was 55.3 years. The average BMI among the included studies was 32.8 kg/m², and the average weight was 91.81 kg. The proportion of females ranged from 37.0% to 66.7%. Characteristics of the included studies are summarized in Table 1. More detailed information regarding the included studies is summarized in Tables S2 and S3.

TABLE 1. Study characteristics of included studies.

Trials	Sample size	Treatment duration	Age (year)	Number of males	Number of females	BMI (kg/m2)	Weight at baseline (kg)	Interventions	Weight change from baseline (kg)
AWARD-1 [14]	816	26 weeks	55.66 ± 9.68	477	339	33.34 ± 5.36	96.34 ± 19.99	Exenatide/Dulaglutide	Overall: −0.73 ± 4.82 Male: −0.65 ± 4.52 Female: −0.87 ± 4.38
AWARD-2 [15]	529	52 weeks	56.50 ± 9.51	274	255	31.50 ± 5.02	85.5 ± 17.99	Dulaglutide	Overall: −1.60 ± 3.91 Male: −1.27 ± 3.13 Female: −1.96 ± 3.09
AWARD-3 [16]	530	26 weeks	56.00 ± 10.99	229	301	33.50 ± 6.02	92.5 ± 18.99	Dulaglutide	Overall: −1.83 ± 3.93 Male: −1.33 ± 3.61 Female: −2.24 ± 3.77
AWARD-4 [17]	548	52 weeks	59.10 ± 9.30	286	262	32.55 ± 5.18	91.35 ± 18.09	Dulaglutide	Overall: −0.34 ± 4.50 Male: 0.12 ± 4.08 Female: −0.95 ± 4.27
AWARD-5 [18]	598	104 weeks	54.00 ± 9.99	275	323	31.00 ± 4.53	86.5 ± 17.5	Dulaglutide	Overall: −2.64 ± 4.38 Male: −2.28 ± 3.12 Female: −3.48 ± 3.20
AWARD-6 [19]	593	26 weeks	56.65 ± 9.60	284	309	33.55 ± 5.15	94.1 ± 18.6	Liraglutide/Dulaglutide	Overall: −3.26 ± 3.82 Male: −2.64 ± 3.62 Female: −3.73 ± 3.61
AWARD-8 [20]	236	24 weeks	57.7 ± 10.2	102	134	30.9 ± 5.2	84.5 ± 16.4	Dulaglutide	Overall: −0.91 ± 3.23 Male: −0.24 ± 3.45 Female: −0.75 ± 3.51
DURATION-1-6 [21]	1719	24–30 weeks	55 ± 10.29	944	775	31.3 ± 5.7	87.43 ± 20.48	Exenatide	Overall: −2.37 ± 3.34 Male: −2.1 ± 3.14 Female: −2.7 ± 3.55
DURATION-8 [22]	184	28 weeks	54 ± 10	96	88	32 ± 5.9	89.8 ± 20.2	Exenatide	Overall: −1.55 ± 4.01 Male: −0.56 ± 3.92 Female: −2.63 ± 3.85
Jastreboff 2023 [26]	268	48 weeks	48.2 ± 12.7	139	129	37.3 ± 5.7	107.34 ± 21.5	Retatrutide	Overall: −18.06 ± 10.65 Male: −16.04 ± 9.54 Female: −20.25 ± 10.88
STEP-1 [25]a	228	68 weeks	48 ± 12	76	152	37.6 ± 7.0	105.6 ± 21.8	Semaglutide	Overall: −17.3 ± 9.3 Male: −14.5 ± 8.0 Female: −18.7 ± 9.6
SUSTAIN-6 [23]	1648	104 weeks	64.65 ± 7.20	1013	635	32.80 ± 6.23	92.35 ± 20.7	Semaglutide	Overall: −4.25 ± 12.34 Male: −3.91 ± 10.62 Female: −4.72 ± 10.76
SUSTAIN-7 [24]	1199	40 weeks	55.50 ± 10.63	662	537	33.50 ± 6.78	95.23 ± 22.56	Dulaglutide/Semaglutide	Overall: −4.10 ± 5.03 Male: −3.54 ± 8.38 Female: −4.80 ± 8.56
SUSTAIN-China [4]	578	30 weeks	53.00 ± 11.00	314	264	28.05 ± 5.00	76.85 ± 16.35	Semaglutide	Overall: −3.55 ± 7.14 Male: −2.64 ± 7.07 Female: −3.62 ± 7.10

• Note: Data were shown as mean ± SD.
• Abbreviations: BMI, body mass index; SD, standard deviation.
• ^a The weight change from baseline in STEP-1 is evaluated using the percentage change in body weight; therefore, the unit is percentage rather than kilograms. This study was not included in the meta-analysis that used kilograms as the outcome measure.

3.3 Pooled Effect of GLP-1 RAs and Meta-Regression Analysis

Meta-analysis of 13 studies revealed that females lost more weight than males (MD 1.04 kg [95% CI 0.70–1.38], p < 0.01) (Figure 2A). Another meta-analysis of four studies on the percent of weight change also showed that females lost more weight than males (MD 1.69% [95% CI 0.78–2.61], p < 0.01) (Figure 2B). According to findings, studies that did not find sex differences in weight reduction efficacy reported an average weight reduction of 2.36 kg. Conversely, studies in which sex differences were evident reported an average weight loss of 3.58 kg.

Based on the results of meta-regression, substantial weight reduction was significantly relevant to greater sex disparities (β −0.19 [95% CI −0.29 to −0.09], p < 0.01) (Figure 3). Studies with weight reduction > 5% of baseline body weight were further analyzed and revealed that the sex difference was larger (MD 1.22 kg [95% CI 0.63–1.81], p < 0.01) (Figure S2).

4 Discussion

To the best of our knowledge, this is the first systematic review and meta-analysis to investigate sex differences in the efficacy of GLP-1 RAs for weight reduction, with females losing more weight than males. Sex-based differences in weight reduction became more pronounced as the degree of weight reduction increased. Moreover, the sex difference was greater in trials for weight reduction and longer treatment duration. Sensitivity analysis indicated that the results were robust.

Our results revealed a discernible sex difference in the efficacy of GLP-1 RAs for weight reduction, despite the fact that labels for GLP-1 RAs describe no observable sex differences [5-8]. Labeling for semaglutide states, “The efficacy of Ozempic was not impacted by age, gender, race, ethnicity, BMI at baseline, and body weight (kg) at baseline.” [5] Although some studies have identified sex differences in the efficacy of GLP-1 RAs for weight reduction, [2, 33-36] others have reported comparable weight reduction effects in both sexes treated with GLP-1 RAs [3, 4]. Inconsistent findings among previous studies investigating the efficacy of GLP-1 RAs could be attributed to variations in study settings, including diverse treatment indications and durations, insufficient sample sizes, as well as potential confounding factors. Notably, our research revealed that sex differences became more pronounced as the degree of weight reduction increased, which could potentially account for why previous studies failed to detect any sex differences due to insufficient weight reduction effects. According to our findings, studies that did not report sex differences in weight reduction efficacy reported an average weight reduction of 2.36 kg, while those in which sex differences were evident yielded an average weight loss of 3.58 kg. Although the difference in the efficacy of GLP-1 RAs for weight reduction between females and males was 1.04 kg, this difference increased to 1.22 kg in those with a weight reduction > 5% of baseline body weight. The extent of weight reduction after retatrutide (4/8 mg) treatment reached 23.9 kg, and the difference in weight loss between females and males was 8.7 kg [26]. Even a small weight reduction can reduce the risk of developing DM [37]. In the context of impaired glucose tolerance, every 1 kg of body weight reduction corresponds to a notable 16% decline in the likelihood of developing DM, as well as favorable changes in lipid profiles and blood pressure [38, 39]. Furthermore, women typically have a lower baseline body weight and, thus, higher absolute weight reduction translates into a proportionally larger percentage of overall body weight reduction [40].

Previous studies have confirmed that there is no sex difference in glycemic control or the incidence of major adverse cardiac events (MACE) associated with GLP-1 RAs [33, 34, 41-43]. Thus, there was no sex difference between GLP-1 RAs in glycemic control and MACE, while a sex difference was found in weight reduction, possibly due to a separate mechanism(s) [44]. The inconsistency in observed sex differences between weight reduction and MACE outcomes may stem from the possibility that the achieved weight reductions were not sufficiently substantial to yield a discernible influence on CVD endpoints or that a longer duration of sustained weight reduction is necessary for its effects to manifest in MACE [45, 46]. Moreover, considering the increased sex differences that accompany greater degrees of weight reduction, conducting sex-specific analyses of glycemic control, blood pressure, steatohepatitis, MACE, and additional pertinent health metrics within GLP-1 RAs research featuring substantial weight reduction outcomes would be warranted.

Several specific subgroups have been found to yield more substantial weight reduction, such as obesity-specific therapy indications. This observation suggests that baseline patient characteristics could affect the prediction of potential sex differences in weight reduction outcomes. The degree of weight reduction in trials of GLP-1 RAs for obesity treatment was higher than that in DM treatment. Subgroup analyses stratified according to GLP-1 RA dose, baseline body weight, duration of treatment, background treatment, and type of control revealed that sex differences were also observed in spite of no subgroup differences. In particular, the absolute weight reduction in high and low doses of GLP-1 RAs was 1.10 and 0.76 kg (Figure S7), along with the weight reduction of a high or low dose of semaglutide 1.43 and 0.71 kg (Figure S11). Despite no observed sex-based subgroup differences in weight reduction between high and low doses, our study found different values of weight reduction at high and low doses, which were 1.10 and 0.76 kg for GLP-1 RAs (Figure S7) and 1.43 and 0.71 kg for the semaglutide group (Figure S11), with only marginal differences of 0.34 and 0.72 kg, respectively. As mentioned, the difference in weight reduction between males and females was positively correlated with overall weight reduction. Hence, the current standard approaches to studying low- and high-dose regimens may fail to discern sex-based differences in weight reduction, especially with relatively insufficient efficacy for weight reduction. It is noteworthy that a tendency for sex differences was observed among different doses, although this was not statistically significant, possibly due to the limited number of studies, relatively small sample sizes, and most importantly, the insufficient degree of weight reduction.

Sex may play a vital role in the weight reduction efficacy of GLP-1 RAs via multiple mechanisms. First, sex differences in pharmacokinetics contributing to higher plasma levels of GLP-1 RAs in females may be responsible for greater weight reduction in females compared with males [41, 47, 48]. Increased exposure to GLP-1 RAs was observed in females owing to the lower weight of females compared with males [40, 49]. Decreased clearance of GLP-1 RAs was observed in females compared with weight-matched males [47]. Second, sex hormones may play a role in this difference [50, 51]. GLP-1 RAs and estrogen could act synergistically to activate the supramammillary nucleus, which controls food intake, inducing a greater modification of the food-reward behavior through pro-opiomelanocortin neurons, thus a greater reduction in weight [52, 53]. Moreover, the combination of GLP-1 RAs and estrogen may ameliorate leptin resistance, which contributes to greater weight reduction [53]. Third, the more significant improvement in obesity-related biomarkers and adipocytokine levels, such as C-reactive protein and tumor necrosis factor-alpha, among females compared with males undergoing GLP-1 RA therapy potentially explains their enhanced effectiveness in achieving weight reduction because a decrease in these markers may be linked to the observed weight loss, which is known to contribute to sex-based differences in weight reduction outcomes [2]. Fourth, GLP-1 RAs may cause more gastrointestinal adverse reactions in females than in males, which may also contribute to a lower energy intake [49]. Finally, more stringent adherence to GLP-1 RAs among females may also, in part, account for this difference [2].

The present study had several strengths. To the best of our knowledge, it was the first to systematically confirm sex differences in the efficacy of GLP-1 RAs for weight reduction. Second, in addition to sex differences, we further revealed that the difference increased with greater weight reduction. Third, we subsequently performed subgroup analyses to identify whether baseline characteristics play a role in this sex difference, which was helpful in anticipating sex differences in the use of GLP-1 RAs in clinical practice.

However, our study also had several limitations. First, the number of studies and types of GLP-1 RAs included in our analysis were limited due to the lack of sex-specific data in numerous studies, such as other dual or triple hormone agonists. Although we searched all GLP-1-related medications, including single, dual, and triple hormone agonists, along with oral GLP-1 RAs like orforglipron and danuglipron, we only found data on a triple hormone receptor agonist, retatrutide. Our results remained consistent when the analysis was exclusively confined to GLP-1 RAs. Second, we incorporated post hoc analyses in our meta-analysis, which may have led to an increased risk of bias. Moreover, some studies only provided pooled data from several studies rather than individual data from each, although the data were not reused. Third, the available data represent absolute weight reduction instead of percentage of weight reduction, making it difficult to evaluate relative sex differences in the efficacy of GLP-1 RAs for weight reduction from initial body weight. Fourth, confounders, including adherence, gastrointestinal adverse reactions, lifestyle and diet changes, as well as baseline BMI or weight between females and males, were not available to be evaluated in this study. Finally, the risk of publication bias was inevitable due to the lack of sex-specific data in lots of studies; although publication bias was not detected; therefore, conclusions must be drawn with caution. Further investigation of sex differences in GLP-1 RAs is warranted.

5 Conclusions

Females and males reacted differently to treatment with GLP-1 RAs for weight reduction, with females losing more weight than males. The sex difference in weight reduction became more pronounced as the degree of weight reduction increased. Indications for obesity could magnify this sex difference. Future research could explore the possible mechanism(s) underlying this difference, which would be tremendously beneficial for a more precise prescription of GLP-1 RAs. We recommend that future research investigating GLP-1 RAs should meticulously report sex-specific variations in weight reduction, as well as other outcomes, with the aim of more effectively evaluating the impact of sex differences in weight reduction on diverse health outcomes.

Author Contributions

H.Z. and Y.L. are joint corresponding authors and contributed equally to this work. H.Z., Y.Y., S.H., and Y.L. conceived and designed the study. Y.Y. and S.H. did the relevant literature searches. Y.Y. and S.H. screened the articles for inclusion. Y.Y. and S.H. extracted the data for analysis. Y.Y., L.H., and S.H. were involved in the quality assessment of the eligible studies. Y.Y. and L.H. did the meta-analysis and produced forest plots and summary results under the supervision of H.Z. and Y.L. Y.Y., L.H., and H.Z. drafted the manuscript. F.P., Y.L., X.W., N.Y., Z.L., W.L., L.X., H.Z., and Y.L. critically revised the manuscript for important intellectual content. All authors approved the final manuscript. H.Z. and Y.L. are the guarantors. The corresponding authors (H.Z. and Y.L.) attest that all listed authors meet the authorship criteria and that no others, who meet the criteria have been omitted.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.