Efficacy and safety of liraglutide plus acarbose in obese patients with type 2 diabetes mellitus: A meta-analysis

Efficacy and safety of liraglutide plus acarbose in obese patients with type 2 diabetes mellitus: A meta-analysis | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 3 May 2025 V1 Latest version Share on Efficacy and safety of liraglutide plus acarbose in obese patients with type 2 diabetes mellitus: A meta-analysis Authors : Ying Wang , Wenxuan Fan , Shuang Li , Zhen Wang , Jiaqi Liang , Jie Sun , Shichao Xiao , Lili Jiang , and Yong Liu 0000-0002-6173-8186 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174625036.66012183/v1 387 views 143 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: The effect of combination therapy with liraglutide and acarbose vs. acarbose monotherapy in obese patients with type 2 diabetes mellitus (T2DM) is unknown. In this systematic review and meta-analysis, we compared the clinical efficacy and safety of liraglutide plus acarbose versus acarbose in obese patients with T2DM. Methods: Up until November 2024, searches were done online for relevant publications in PubMed, Web of Science, Embase, the Cochrane Library, CNKI, and Wanfang Database. We obtained randomized controlled trials (RCTs) evaluating the efficacy of liraglutide and acarbose combination therapy versus acarbose monotherapy in obese T2DM. Weighted mean differences (WMDs) and 95% confidence intervals (CI) were pooled using either the random-effect models or the fixed-effect models. Results: Fifteen RCTs (n=1605) were included. Compared with acarbose alone, the addition of liraglutide reduced body mass index (WMD = -2.96, 95% CI: [−3.53,-2.40], p＜0.00001) and blood lipid related indicators: total cholesterol (WMD = -0.98, 95% CI: [−1.47,-0.50], p<0.0001) and triglycerides (WMD = -0.73, 95% CI: [−1.18,-0.29], p=0.001). At the same time, the combination therapy also significantly reduced blood glucose related indexes and insulin resistance related indicators in the patients. In addition, there was no increased risk of gastrointestinal adverse reactions, hypoglycemia, or pruritus. Conclusions: The addition of liraglutide can reduce body mass index (BMI) in obese patients with T2DM compared to acarbose alone. There is no significant difference in the incidence of adverse events between the combination and acarbose alone. 1 Introduction As a serious and common chronic disease, type 2 diabetes mellitus (T2DM) often causes complications including cardiovascular disease, diabetic neuropathy, nephropathy, retinopathy, and so on, with an exponential increase in incidence [1, 2]. For 2045, 783.2 million people (Interval: 6052 to 888.6 million) are expected to have diabetes [3]. Simultaneously, the global prevalence of obesity has almost tripled since 1975 [4]. Accumulating surveys indicated that overweight/obesity might be a major risk factor for T2DM [5, 6]. Additionally, compared with overweight/obesity or T2DM alone, patients with T2DM and overweight/obesity have an increased risk of cardiovascular-related mortality [7]. There is a growing need to consider medication to help with weight loss in so-called diabesity syndrome, since lifestyle-based weight loss strategies do not work for long [8]. First marketed in China in 1995, acarbose is an oral hypoglycemic drug, mainly used to regulate postprandial blood glucose in patients with T2DM. The hypoglycemic effects of acarbose are similar to those of sulfonylureas, metformin, and glinides [9]. It has become one of the most widely used hypoglycemic drugs in combination with multiple drugs [10-12]. The neuroendocrine system’s intestinal L-cells emit the naturally occurring enterotropic hormone known as glucagon-like peptide-1 (GLP-1). By lowering glucagon, delaying stomach emptying, boosting insulin production, and reducing food intake, it can lower blood glucose levels. [13, 14]. Liraglutide is a popular glucagon-like peptide 1 receptor agonist (GLP1-RA) that has been demonstrated to be beneficial for controlling blood sugar levels and helping in weight reduction. Originally used as a diabetes treatment, it is now also used as a weight loss treatment [15]. Liraglutide can be used as a single [16], dual [17] or multidrug [18] for the treatment of obese T2DM patients. As a progressive disease, single hypoglycemic drugs can only address limited pathophysiological indicators, so most T2DM patients need combination therapy [19]. Fixed dose combination administration can potentially improve T2DM patients’ treatment compliance, and optimize the achievement and maintenance of blood glucose by targeting multiple pathogenic mechanisms simultaneously, which may be more effectively delaying disease progression [20]. Although there have been several meta-analysis studies performed with liraglutide [21-25], scientific or systematic reviews about liraglutide and acarbose as combination therapy in the treatment of T2DM is scarce. Moreover, analysis of weight-related indicators in obese T2DM patients is still controversial [25]. Thus, we performed this systematic review and meta-analysis to assess the efficacy and safety of liraglutide and acarbose combination therapy for treatment in obese T2DM patients, with special attention on the effect of combination therapy on patients’ weight index and blood lipid related indexes. 2 Materials and methods This systematic review and meta-analysis was performed and reported according to the items in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. This systematic review’s protocol has already been published in PROSPERO (CRD42022352722). 2.1 Search strategy and study selection Relevant electronic databases including PubMed, Embase, Web of Science, the Cochrane Library, CNKI, Wanfang Database, were searched to identify suitable studies, from inception to November 2024. We used MeSH and Emtree terms, and made minor adjustments to the search method based on the variety of search results in various databases. Furthermore, only RCTs that were published in Chinese or English were considered the applicable studies. 2.2 Eligibility Criteria The studies were deemed to meet the following inclusion criteria: (1) These studies employed randomized controlled trials (RCTs); (2) Obese patients with T2DM were included in the studies; (3) Some patients were treated with acarbose monotherapy, while others were treated with a combination of liraglutide and acarbose in the studies; (4) Body mass index (BMI), blood lipid, blood glucose, insulin resistance and adverse reactions were reported in at least one of the studies. 2.3 Data extraction According to eligibility criteria, screening and identification of the relevant data was done independently by two authors. Disagreements were solved by discussion or the third author. The following information was extracted from the selected studies: Basic information including study design, classification method, population, sample, age, sex ratio, course of T2DM, intervention, duration. The outcome indexes included weight related indicators: body mass index (BMI); Blood lipid related indexes: total cholesterol (TC), triglycerides (TG); Blood glucose related indexes: 2-hour postprandial blood glucose (2hPG), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c); Insulin resistance related indexes: fasting insulin (FINS), homeostasis model assessment for insulin resistance (HOMA-IR), homeostasis model assessment of β cell (HOMA-β) and adverse reactions (Gastrointestinal adverse reactions, hypoglycemia, pruritus). 2.4 Assessment of quality of evidence The publication bias was performed critically using the Cochrane Collaboration Risk of Bias tool by two authors, and disagreements were solved by discussion or the third author equally. The following quality assessment items were considered: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting. selective reporting, publications which were clearly defined details and met or exceeded quality standards were defined as low risk; If not, they were judged as high risk. Ambiguous publications on quality standards were considered to be of unclear risk. 2.5 Statistical analysis We chose the standard deviation (SD) to compare the influences of liraglutide and acarbose combination therapy with acarbose monotherapy on obese type 2 diabetics. If the heterogeneity was considered low (I 2 < 50% and p ≤ 0.05), the DerSimonian-Laird random effects model was applied; If not, the Mantel-Haenszel fixed effects model was used. We chose the mean difference (MD) and 95% confidence intervals (95% CIs) to explore the influences of intervention and the control groups on the continuous outcomes. We used the odds risk (OR) and 95% CIs to assess the dichotomous outcomes. Moreover, a number of sensitivity analyses using the leave-one-out method were performed to look into the impact of each included study on the high heterogeneity. Furthermore, the funnel plot’s symmetry was employed to identify publication bias. 3 Results 3.1 Search results and study characteristics A total of 13411 articles were retrieved in the electronic database using different retrieval strategies, and 9959 articles were left after removing 3452 duplicated articles. After browsing the titles and abstracts, 9175 articles were removed for the following reasons: 1576 articles were reviews, meta-analyses or conference abstracts, 99 articles were animal experiments, and 7500 articles did not meet the requirements. 784 articles were selected and full text were obtained. After evaluating in detail against inclusion criteria, 765 articles were excluded for not meeting the inclusion criteria or not reporting the complete outcomes. Finally, a total of 14 publications [26-39] which met the inclusion requirements could be included in this meta-analysis. More detailed information for searching and selecting was shown in Figure 1. 3.2 Characteristics of eligible studies The search deadline for articles in our meta-analysis was November 2024. A total of 1405 patients were included in the final 14 studies, involving 704 patients in the intervention group and 701 patients in the control group. Of these, 1 study was grouped by admission number, and 9 studies were grouped using the random number table approach. In addition, 1 study was categorized by computer, and 3 studies was categorized by randomization. Thirteen research recorded the gender ratio and average patient age. Data on duration of diabetes were reported by 11 studies. Table 1 displayed comprehensive data on the listed research. 3.3 Risk of bias All 14 studies were described as randomized trials and fully reported data for each major outcome measure, no mention of allocation hiding. The description of blindness in 2 studies was unclear, and there might have been selective reporting of findings in 5 studies. 1 study did not report the duration of treatment, which was considered to have other risks. In Supplementary Figure 1, the particular quality evaluation chart was displayed. 3.4 Effect of interventions 3.4.1 Weight related indicators To evaluate the effect of liraglutide and acarbose combination therapy and acarbose monotherapy on BMI in obese patients with T2DM, forest plots were used to estimate the statistical differences. Patients in the intervention group had decreased BMI (WMD = -2.96, 95% CI: [−3.53, -2.40], p＜0.00001), as seen in Figure 2. 3.4.2 Blood lipid related indexes The WMD of TC (WMD = -1.08, 95% CI: [−1.63, -0.52], p = 0.0001) (Figure 3A) and TG (WMD = -0.81, 95% CI: [−1.44, -0.18], p = 0.01) (Figure 3B) significantly decreased in the intervention group when compared to the control group. 3.4.3 Blood glucose related indexes As shown in Supplementary figure 2, in comparison to acarbose, liraglutide and acarbose combination therapy reduced 2hPG (WMD = -1.16, 95% CI: [− 1.33, -0.99], p＜0.00001), FPG (WMD = -0.92, 95% CI: [−1.16, -0.67], p＜0.00001) and HbA1c (WMD = -0.79, 95% CI: [−1.01, -0.58], p＜0.00001). The outcomes of the combined treatment with liraglutide and acarbose revealed even better blood glucose management. 3.4.4 Insulin resistance related indicators Our meta-analysis’s findings revealed that the levels of FINS (WMD = -0.87, 95% CI: [−1.61, -0.14], p = 0.02) (Supplementary figure 3A) and HOMA-IR (WMD = -0.70, 95% CI: [−1.28, -0.13], p = 0.02) (Supplementary figure 3B) in the liraglutide group and the control group differed significantly. It is proved that liraglutide and acarbose combination therapy is more effective than acarbose therapy in reducing insulin resistance related indicators. Remarkably, the addition of liraglutide had no significant effect on the indicator HOMA-β (WMD = 3.20, 95% CI: [−1.76, 8.17], p = 0.21) (Supplementary figure 3C). 3.4.5 Adverse reactions Liraglutide and acarbose combination therapy had no significant effect on adverse reactions, including gastrointestinal adverse reactions (OR =0.85, 95% CI: [0.46, 1.59], p = 0.62) (Figure 4A), hypoglycemia (OR = 1.15, 95% CI: [0.43, 2.93], p = 0.82) (Figure 4B), pruritus (OR = 0.49, 95% CI: [0.09, 2.67], p = 0.41) (Figure 4C). 3.6 Sensitivity Analysis After excluding each included RCT for FPG, 2hPG, HbA1c, and TC, sensitivity analyses showed no significant variation on WMD between before and after analysis. Yet, the after-removing analysis by Li et al. showed a noticeable shift in the pooled WMD of the TG, FINS. The changes in I 2 before and after excluding this study were also significant. Therefore, we took into account the heterogeneity of this study. Supplementary Table 1 displayed detailed information on the studies that were included. Furthermore, publication bias was demonstrated by funnel plots. Supplementary figure 4 showed asymmetry, which may indicate publishing bias. Important content should not be published without statistical significance. 4 Discussion Obesity (BMI above 25 kg/m 2 ) is strongly associated with an increased incidence of T2DM and the vast majority of people with diabetes are overweight or obese [40]. BMI is associated with increased risk for mortality. When BMI was treated as a continuous variable, the risk of developing cardiometabolic diseases, such as diabetes, stroke and coronary artery disease, increases with increasing BMI [8, 41]. Our analysis of 14 RCTs including 1605 obese type 2 diabetics showed that liraglutide and acarbose combination therapy resulted in a significant reduction in BMI levels, consistent with those reported in the previous meta-analysis [42]. It is important to note that the treatment regimen we studied reduces BMI without additional gastrointestinal adverse effects. Acarbose is one of the most studied and prescribed alpha-glucosidase inhibitors; it decreases postprandial plasma glucose excursions by slowing the absorption of carbohydrates from the small intestine and is an effective first-line therapy. Clinical research, however, have demonstrated that acarbose typically causes adverse symptoms, such as nausea, flatulence, diarrhea, and stomach distention [43] . Liraglutide was approved by Food and Drug Administration (FDA)- as one of the safe and effective drugs for weight loss [44]. Liraglutide has been reported to control obesity by controlling appetite and thus eating less. The mechanism is to activate the GLP-1 receptor in the brain, which produces anorexia [45], regulating gut flora and delaying gastric emptying to increase satiety [46]. In addition, it may reduce body weight by inducing browning of white adipose tissue through soluble guanosine cyclase dependent pathway, activating adenylate cyclase pathway, and ameliorating obesity[47]. Analysis of clinical data indicates that liraglutide is independent of its hypoglycemic effect in controlling obesity and has therapeutic effects in both diabetic and non-diabetic patients [24]. Dyslipidemia is increased fasting level of TC, LDL cholesterol (LDL-C), and TG, along with decreased levels of HDL cholesterol (HDL-C). As we all know, dyslipidemia is one of the most common metabolic diseases associated with obesity [48]. It has been shown that dyslipidemia is a major risk factor for cardiovascular disease (CVD) [49] and hyperuricemia (HUA) [50]. Given the increasing prevalence of diabetes worldwide, treating lipid abnormalities in obese patients may reduce their risk of cardiovascular disease (CVD) and other diseases [51]. Liraglutide promotes the reversal of cholesterol transport, resulting in a considerable reduction in blood glucose, serum TC, TG, and LDL-C, and an improvement in lipid metabolism and liver fat buildup in mice given a high-fat diet (HFD) [52, 53]. Studies have shown that acarbose monotherapy in non-diabetic overweight and obese patients can reduce TG levels in obese or overweight patients, although the difference is not statistically significant [54]. Liraglutide and acarbose combination therapy can not only reduce blood lipid level, but also significantly reduce BMI value, and has a very good regulatory effect on blood sugar and insulin resistance related indicators, which is better than acarbose monotherapy. To the best of our knowledge, this is the first meta-analysis centered on RCTs assessing the effectiveness and safety of liraglutide and acarbose combination therapy versus acarbose monotherapy in obese patients with T2DM. Other studies have shown that liraglutide dramatically lowers waist circumference, BMI, and HbA1c [55] in patients with and without T2DM for coronary heart disease.In addition, liraglutide and other GLP-1RA including semaglutide and exenatide were associated with reducing risk of hospitalization and all-cause mortality [56] from cardiovascular death, non-fatal stroke, heart failure, and heart failure. To provide rational and effective drug treatment strategies, physicians should consider the characteristics of the patient and the efficacy and safety of different treatment options. We suggest that liraglutide and acarbose combination therapy should be considered in the treatment of obese T2DM. 5 Limitations It is important to recognize the limitations of the study. First of all, the 14 literatures we included were all in Chinese and the patients were all Chinese, so the situation of other regions was not considered. This is because the action mechanism of acarbose makes it more beneficial to the hypoglycemic research of Chinese people. Secondly, there is a risk of bias in some studies, which could compromise the true effect of most of the results. Due to constraints, more center randomized controlled trials and large sample randomized double-blinding controlled studies are required. We suggest that more studies on GLP-1RA alone or in combination therapy should be carried out in order to achieve better therapeutic effects in clinical application. 6 Conclusion This study revealed that compared with acarbose alone, liraglutide and acarbose combination therapy is more helpful in reducing BMI and blood lipids. Our data also confirmed that combination therapy can improve patients’ blood glucose and insulin resistance without increasing the incidence of adverse reactions. For obese individuals with T2DM, liraglutide and acarbose combination therapy is often an effectiveness course of treatment. Author Contributions Concept and design: Yong Liu, Lili Jiang Acquisition, analysis, or interpretation of data: Ying Wang, Wenxuan Fan, Lili Jiang, Yong Liu Writing-original draft: Ying Wang Investigation: Ying Wang, Wenxuan Fan, Shuang Li Methodology: Ying Wang, Wenxuan Fan, Shuang Li, Zhen Wang, Jiaqi Liang, Jie Sun, Shichao Xiao, Lili Jiang, Yong Liu Project administration: Yong Liu, Lili Jiang Writing-review & editing: Yong Liu, Lili Jiang Acknowledgements This study was financially supported by the National Natural Science Foundation of China (82274006). Conflict of interest The authors declare that there is no conflict of interests regarding the publication of this article. Funding: National Natural Science Foundation of China (82274006). Data availability All data included in this study are available upon request by contact with the corresponding authors (Yong Liu, [email protected] ). References 1. Wu Y, Ding Y, Tanaka Y, Zhang W. 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Table 1 Characteristics of the included studies T C T C T C T C Chen 2021 RCT Random number table method Type 2 diabetes mellitus and obesity 100 100 58.63±6.45 58.65±6.47 64/36 66/34 4.86±0.57 4.87±0.58 3 months Gao 2020 RCT Random number table method Type 2 diabetes mellitus and obesity 75 75 57.54±4.87 57.48±4.85 39/36 40/35 6.61±1.30 6.53±1.28 4 weeks Han 2017 RCT Random number table method Type 2 diabetes mellitus and obesity 40 40 54.3 ±10.7 55.8±10.6 22/18 26/14 6.16 ±1.28 6.18±1.28 16 weeks Han 2020 RCT Random number table method Type 2 diabetes mellitus and obesity 43 43 55.18 ± 7.21 56.51 ± 7.46 23/20 24/19 8.96 ± 2.54 8.24 ± 2. 38 4 months Li 2014 RCT Random number table method Type 2 diabetes mellitus and obesity 49 49 49.6±4.1 50.7±4.3 29/20 26/23 2.1±1.3 2.9±1.5 12 weeks Li 2020 RCT Random Type 2 diabetes mellitus and obesity 36 35 48.61±5.12 47.65±5.11 20/16 20/15 2.09±1.02 2.06±1.01 - Lin 2018 RCT Random based on admission number Type 2 diabetes mellitus and obesity 25 25 64.45±4.46 63.49±4.09 16/14 12 13 - - 1 year Liu 2022 RCT Random number table method Type 2 diabetes mellitus and obesity 44 43 56.84±5.21 56.86±5.23 20/24 22/21 3.24±0.21 3.27±0.22 90 day Yang 2015 RCT Random Type 2 diabetes mellitus and obesity 38 38 - - - - - - 24 weeks Yang 2019 RCT Random computer numbering Type 2 diabetes mellitus and obesity 50 50 50.00±3.15 50.01±3.21 27/23 28/22 6.21±1.25 6.20±1.21 16 weeks Zhong 2019 RCT Random number table method Type 2 diabetes mellitus and obesity 48 47 59.10±9.40 58.30±9.31 20/28 20/27 - - 2 months Fan 2020 RCT Random number table method Type 2 diabetes mellitus and obesity 46 46 52.74±4.95 52.66±4.99 28/18 29/17 7.05±1.28 7.09±1.25 4 months Shen 2020 RCT Random number table method Type 2 diabetes mellitus and obesity 30 30 50.05±3.18 50.03±3.24 14/16 13/17 6.23±1.27 6.22±1.23 1 months Shi 2018 RCT Random Type 2 diabetes mellitus and obesity 80 80 46.54±5.81 46.87±5.79 37/43 38/42 6.27±1.40 6.32±1.34 16 weeks Figure legends Figure 1 Flow diagram of study screening and selection process. Figure 2 Forest plot for meta-analyses comparing the effects of liraglutide and acarbose combination therapy and acarbose monotherapy in BMI. CI, confidence interval. Figure 3 Forest plot for meta-analyses comparing the effects of liraglutide and acarbose combination therapy and acarbose monotherapy in TC (A), TG (B). CI, confidence interval. Figure 4 Forest plot for meta-analyses comparing the effects of liraglutide and acarbose combination therapy and acarbose monotherapy in adverse reactions: Gastrointestinal adverse reactions (A), hypoglycemia (B), pruritus (C). CI, confidence interval. Figure 1 Figure 2 Figure 3 Figure 4 Information & Authors Information Version history V1 Version 1 03 May 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords diabetes endocrinology meta-analysis public health statistics and study design Authors Affiliations Ying Wang Dalian University of Technology View all articles by this author Wenxuan Fan Dalian University of Technology View all articles by this author Shuang Li Dalian University of Technology View all articles by this author Zhen Wang Dalian University of Technology View all articles by this author Jiaqi Liang Dalian University of Technology View all articles by this author Jie Sun Dalian University of Technology View all articles by this author Shichao Xiao Dalian University of Technology View all articles by this author Lili Jiang Dalian University of Technology View all articles by this author Yong Liu 0000-0002-6173-8186 [email protected] Dalian University of Technology View all articles by this author Metrics & Citations Metrics Article Usage 387 views 143 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Ying Wang, Wenxuan Fan, Shuang Li, et al. 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