Efficacy, safety and impact on β

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1 J Endocrinol Invest (2016) 39: DOI /s ORIGINAL ARTICLE Efficacy, safety and impact on β cell function of dipeptidyl peptidase 4 inhibitors plus metformin combination therapy in patients with type 2 diabetes and the difference between Asians and Caucasians: a meta analysis W. Gao 1 Q. Wang 2 S. Yu 2 Received: 1 December 2015 / Accepted: 1 April 2016 / Published online: 12 April 2016 Italian Society of Endocrinology (SIE) 2016 Abstract Background To assess the efficacy, safety and impact on β-cell function of DPP-4 inhibitors plus metformin in T2DM patients and their difference between Asians and Caucasians. Methods We conducted a literature search (from 1 January 2000 to 14 April 2015) for s of DPP-4 inhibitors plus metformin combination therapy in T2DM. Results A total of 27 s were included. Compared with metformin, DPP-4 inhibitor plus metformin therapy was associated with higher reduction in HbA1c [ 0.61 %, 0.69 to 0.52], FPG [ 1.10 mmol/l, 1.29 to 0.92], TC [ 0.11 mmol/l, 0.20 to 0.02], TG [ 0.21 mmol/l, 0.33 to 0.10], HOMA-IR [ 0.19, 0.36 to 0.02], gastrointestinal adverse events [OR 0.86, ] and higher increment in HOMA-β [10.21, ]. Comparison of HbA1c, FPG, body weight and HOMA-IR changes between Asian and Caucasian patients did not show a significant between-group difference of 0.05 % ( 0.30, 0.20; P = 0.69), 0.17 mmol/l ( 0.52, 0.85; P = 0.62), 0.15 kg ( 0.64, 0.35; P = 0.53) and 0.27 ( 0.98, 1.53; P = 0.64) compared with metformin. Comparisons of HOMA-β between Asian and Caucasian Electronic supplementary material The online version of this article (doi: /s ) contains supplementary material, which is available to authorized users. * S. Yu xingbi3@hotmail.com; yushuwen@sdu.edu.cn 1 2 School of Pharmaceutical Science, Shandong University, 44 Wenhua Xi Road, Jinan , Shandong, China Shandong University Affiliated Jinan Central Hospital, 105 Jie Fang Road, Jinan , Shandong, China patients showed a significant between-group difference of 7.68 ( 14.95, 0.42; P = 0.04). Conclusion DPP-4 inhibitors and metformin therapy was effective and safe for T2DM patients. The glucose-lowering efficacy of DPP-4 inhibitors was same in Asian and Caucasian patients, although the effect on HOMA-β was inferior in Asian patients. The effect of DPP-4 inhibitors on HOMA-IR and body weight in Asian patients was comparable with that observed in Caucasian patients. Keywords Dipeptidyl peptidase-4 inhibitors Metformin Type 2 diabetes mellitus Asian Caucasian Introduction Diabetes is one of the most common epidemics worldwide and has become a serious global health issue. It is estimated by the International Diabetes Federation (IDF) that approximately 6.6 % of the world s population aged between 20 and 79 years had diabetes in 2010; by 2030 the figure will rise to 7.8 % [1], with type 2 diabetes mellitus (T2DM) accounting for approximately % of all cases [2]. Current clinical treatment recommendations for T2DM generally include life style modification, medical nutritional therapy and exercise, followed by the addition of metformin monotherapy if haemoglobin A1c (HbA1c) levels rise above the target of 7.0 % [3]. These pharmacologic therapies are often initially effective, but fail as time goes so that additional oral agents are added [4]. Incretin therapies which focus on increasing levels of the incretin hormone glucagon-like peptide-1 (GLP-1) have provided a novel therapeutic alternative for patients with T2DM [5, 6] in recent years. GLP-1 can elicit glucosedependent stimulation of insulin secretion and inhibition

2 1062 J Endocrinol Invest (2016) 39: of glucagon secretion [7]. However, the half-life period of GLP-1 is very short (2 min) and is rapidly inactivated by the enzyme dipeptidylpeptidase-4 (DPP-4) [8]. DPP-4 inhibitors work by enhancing endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), which are hormones released in response to food intake, and prevent inactivation of endogenous GLP-1 through competitive inhibition of the DPP-4 enzyme responsible for GLP-1 degradation [9]. The enhancement leads to the increase of insulin, reduction of glucagon secretion and liver glucose production. DPP-4 inhibitors have been examined in and used both in monotherapy and as combination therapy with metformin and sulphonylurea [10 12]. A main clinical use is as add-on therapy to metformin when metformin alone is insufficient for maintaining adequate glycemic control [13]. Several meta-analyses have been published on DPP-4 inhibitors; however, previous studies mainly summarized the efficacy and safety of sitagliptin and vildagliptin [11, 14]. Since 2009, more DPP-4 inhibitors have been approved by the FDA and more studies have appeared, including some that assessed the effects of saxagliptin, linagliptin and alogliptin. Thus it was necessary to provide an up-to-date comprehensive picture of the clinical efficacy and safety of the DPP-4 inhibitors. Patient groups on several different background therapies for T2DM were studied [11, 15], making it difficult to compare findings in uniform patient groups. More importantly, these studies did not differentiate outcomes in different ethnic groups. Recent evidence suggested that both anthropometric characteristics and clinical characteristics might be different in Asian and Caucasian T2DM patients [16, 17]. Thus, we guess that an ethnic difference in response to treatment with DPP-4 inhibitors and metformin exists between Asian and Caucasian T2DM patients. This meta-analysis compares the efficacy, safety and impact on β-cell function of DPP-4 inhibitors plus metformin combination therapy with metformin monotherapy and also assesses the difference of clinical efficacy between Asians and Caucasians. Methods Search strategy and inclusion criteria A Pubmed search for type 2 diabetes or T2DM metformin dipeptidyl peptidase-4 inhibitor or DPP-4 inhibitor or sitagliptin or saxagliptin or linagliptin or alogliptin or vildagliptin was performed for trials from 1 January 2000 to 14 April Electronic searching results were imported in a reference management software (EndNote X6). After deleting the duplicate results, two reviewers independently screened all titles and abstracts and investigated full texts for eligible studies. Clinical trials were included if they met the following criteria: (1) published in the English language; (2) comparing DPP-4 inhibitors plus metformin with metformin monotherapy; (3) included patients with T2DM at least 18 years of age; (4) duration of treatment 12 weeks; (5) at least one baseline and post-treatment efficacy and/or safety outcome of interest and (6) reports of a dispersion measure [standard deviation, standard error of the mean or confidence interval (CI)], for both treatment arms of the study. We also searched completed, but unpublished, trials at relevant web sites ( and reference lists from the articles to ensure completeness. We independently screened all abstracts generated by the search for inclusion and exclusion criteria. Full-text potentially relevant articles were reviewed independently to determine eligibility. Data extraction Two authors extracted data independently and any discrepancies were resolved by consensus. From the publications we extracted study characteristics and participants baseline characteristics [author identification, year of publication, sample size for each group, age, sex, ethnic, duration of intervention, body mass index (BMI)]. Our primary outcome was glycemic control as measured by the change in HbA1C from baseline to end of study. Secondary efficacy outcomes included changes in body weight, fasting plasma glucose (FPG), insulin resistance index (HOMA- IR), homeostatic model assessment for β-cell function (HOMA-β) and lipid parameters (total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride (TG) levels. To evaluate the safety data, information about hypoglycemia and gastrointestinal adverse events was extracted. Quality assessment The quality of studies was assessed by two independent reviewers using modified Jadad score [19]. Among them, randomizations, concealment of allocation and double blinding accounted for two scores, respectively, Withdrawals and dropouts accounted for one score. Therefore, the modified Jadad score had a total score of seven points (a high score indicating high quality, 1 3 scores considered as low quality, 4 7 scores considered as high quality). The specific details of the Jadad score could be seen in the supplementary material (Table S1). Data analysis Meta-analysis was conducted with the Review Manager (Revman Version 5.3, Copenhagen, Denmark). For efficacy measures, mean changes in HbA1c, FPG, body weight,

3 J Endocrinol Invest (2016) 39: lipid parameters, HOMA-IR and HOMA-β as continuous variables were assessed. For these continuous variables, weighted mean differences (MD) and 95 % confidence interval (CI) for changes from baseline were calculated. For safety measures, the dichotomous variables such as hypoglycaemia and gastrointestinal AEs were assessed using odds ratio (OR) with 95 % CI. Heterogeneity was assessed by using the Q statistic and I 2 tests among trials [18]. Significance of the Q statistic test (P < 0.05) indicates a substantial level of heterogeneity [19]. The I 2 statistic describes the percentage of the variability in effect estimates that is the result of heterogeneity rather than sampling error (chance), where I 2 values of 50 % or more indicate a substantial level of heterogeneity. If the I 2 statistics showed that significant heterogeneity existed between study results, a random effect model was selected. Results Study characteristics A total of 492 potentially relevant articles were identified in electronic database. Based on a review of these abstracts, 45 were retrieved for detailed evaluation, and 25 studies met all of the inclusion criteria [20 28, 30 32, 34 46]. One additional article indentified from reference list in relevant papers [29] and one article from clinicaltrials.gov were 1063 also found [33]. There were four trials in Asian patients [25, 31, 35, 44] and 23 trials in Caucasian patients [20 24, 26 30, 32 34, 36 43, 45, 46]. Search results are summarized in Fig. 1. A total of 10,089 patients were included. Participants baseline characteristics of the included studies were extracted and are summarized in Table 1. All included articles were of high quality (all had a score 4) and the results of modified Jadad score are shown in Table 2S. Glycemic control All 27 trials reported change in HbA1c from baseline to end of study period. We performed a random effects meta-analysis that included 5394 participants assigned to DPP-4 inhibitor + metformin groups and 4373 patients assigned to the metformin groups. The reduction in HbA1c was larger for patients in DPP-4 inhibitor + metformin groups than those in the metformin groups ( 0.61 %, 95 % CI 0.69 to 0.52, P < ), but with a substantial amount of heterogeneity (I 2 = 78 %, Fig. 2). Subgroup analyses showed an HbA1c reduction in trials assessing sitagliptin ( 0.69 %, 0.78 to 0.60, I 2 = 41 %, P < ), saxagliptin ( 0.41 %, 0.56 to 0.26, I 2 = 75 %, P < ), vildagliptin ( 0.69 %, 0.94 to 0.44, I 2 = 81 %, P < ), linagliptin ( 0.58 %, 0.81 to 0.35, I 2 = 78 %, P < ) and alogliptin ( 0.65 %, 0.85 to 0.44, I 2 = 76 %, P < ). Twenty-five studies reported change of FPG. Random Fig. 1 Flow chart demonstrating process of study selection

4 1064 J Endocrinol Invest (2016) 39: Table 1 Basic characteristics of included studies Study reference (NCT number) Study design Participants (N) M/F Ethnic Age (years) Duration of T2DM (years) BMI (kg/m 2 ) Baseline HbA1c Treatment dose (mg) Duration (weeks) Sitagliptin Goldstein et al. [20] Double-blind /105 Caucasian 53.3 ± 9.6 NA NA 8.8 ± 1.0 I: Met (NCT ) / ± 9.6 NA NA 8.7 ± 0.9 C: PLB + Met 2000 Derosa et al. [21] Double-blind 91 42/49 Caucasian 55.9 ± ± ± ± 0.8 I: Met 2500 ± / ± ± ± ± 0.7 C: PLB + Met 2500 ± 500 Raz et al. [22] Double-blind 96 49/47 Caucasian NA 8.4 ± ± ± 0.9 I: Met (NCT ) 94 39/55 NA 7.3 ± ± ± 0.8 C: PLB + Met 1500 Scott et al. [23] Double-blind 94 52/42 Caucasian 55.2 ± ± ± ± 1.0 I: Met (NCT ) 92 54/ ± ± ± ± 0.9 C: PLB + Met NA Caucasian NA NA NA 8.0 ± 0.8 I: Met Charbonnel et al. [24] Double-blind (NCT ) 224 NA NA NA NA 8.0 ± 0.8 C: PLB + Met 1500 Yang et al. [25] Double-blind /105 Asian 54.1 ± ± ± ± 0.9 I: Met 1000 or (NCT ) / ± ± ± ± 0.9 C: PLB + Met 1000 or 1700 Reasner et al. [26] Double-blind /272 Caucasian 49.4 ± ± ± ± 1.8 I: Met (NCT ) 6256/ ± ± ± ± 1.8 C: Met /194 Caucasian 55.5 ± ± 5.2 NA NA I: Met Lavalle-Gonzalez et al. [27] Double-blind (NCT ) / ± ± 5.3 NA NA C: PLB + Met 2500 Saxagliptin Fonseca et al. [28] Double-blind /81 Caucasian 55.2 ± ± ± ± 0.9 I: 5 + Met (NCT ) / ± ± ± ± 0.9 C: Met 2000 Hermans et al. [29] Double-blind /59 Caucasian 58.7 ± ± ± ± 0.9 I: 5 + Met (NCT ) / ± ± ± ± 0.8 C: Met 2000 Jadzinsky et al. [30] Double-blind /155 Caucasian 52.0 ± ± ± ± 1.3 I: 5 + Met (NCT ) / ± ± ± ± 1.3 C: Met 2000 Yang et al. [31] Double-blind /147 Asian 53.8 ± ± ± ± 0.8 I: 5 + Met

5 J Endocrinol Invest (2016) 39: Table 1 continued Study reference (NCT number) Study design Participants (N) M/F Ethnic Age (years) Duration of T2DM (years) BMI (kg/m 2 ) Baseline HbA1c Treatment dose (mg) Duration (weeks) (NCT ) / ± ± ± ± 0.8 C: PLB + Met 1500 Defronzo et al. [32] Double-blind /88 Caucasian 54.7 ± 9.6 NA 31.2 ± ± 0.8 I: 5 + Met (NCT ) / ± 10.2 NA 31.6 ± ± 0.9 C: PLB + Met NCT [33] Double-blind 74 40/34 Caucasian 53.9 ± ± ± ± 1.0 I: 5 + Met / ± ± ± ± 0.8 C: PLB + Met 1855 Vildagliptin Bosi et al. [34] Double-blind 185 NA Caucasian 53.9 ± ± ± ± 1.0 I: Met (NCT ) 182 NA 54.5 ± ± ± ± 0.9 C: PLB + Met 2102 Pan et al. [35] Double-blind /73 Asian 54.2 ± ± ± ± 0.9 I: Met / ± ± ± ± 0.8 C: PLB + Met 1500 Goodman et al [36] Double-blind /59 Caucasian 54.7 ± 10.3 NA 31.7 ± ± 1.0 I: Met / ± 9.7 NA 31.7 ± ± 1.1 C: PLB + Met 1932 Bosi et al. [37] Double-blind /124 Caucasian 52.8 ± ± ± ± 1.0 I: Met / ± ± ± ± 0.9 C: Met 2000 Ahren [38] Double-blind 56 39/17 Caucasian 57.9 ± ± ± ± 0.6 I: Met / ± ± ± ± 0.7 C: PLB + Met Linagliptin Ross et al. [39] Double-blind /103 Caucasian 58.4 ± 10.6 NA 29.6 ± ± 0.7 I: 5 + Met (NCT ) 44 21/ ± 10.7 NA 28.7 ± ± 0.7 C: PLB + Met 1500 Haak et al. [40] Double-blind /105 Caucasian 56.4 ± 10.7 NA 28.6 ± ± 1.0 I: 5 + Met (NCT ) / ± 10.6 NA 29.5 ± ± 0.9 C: Met 2000 Taskinen et al. [41] Double-blind /49 Caucasian 56.5 ± 10.1 NA 29.9 ± ± 0.9 I: 5 + Met (NCT ) / ± 10.9 NA 30.1 ± ± 0.9 C: PLB + Met 1500 Forst et al. [42] Double-blind 66 49/47 Caucasian 59.6 ± ± ± ± 0.9 I: 5 + Met (NCT ) 79/ ± ± ± ± 0.7 C: PLB + Met 1500

6 1066 J Endocrinol Invest (2016) 39: Table 1 continued Treatment dose (mg) Duration (weeks) BMI (kg/m 2 ) Baseline HbA1c Study design Participants (N) M/F Ethnic Age (years) Duration of T2DM (years) Study reference (NCT number) Alogliptin Nauck et al. [43] Double-blind /42 Caucasian 54.0 ± 11.0 NA 32.0 ± 5.0 NA I:25 + Met (NCT ) / ± 11.0 NA 32.0 ± 6.0 NA C: PLB + Met 1500 Seino et al. [44] Double-blind 96 NA Asian 52.3 ± ± ± ± 0.7 I: 25 + Met 500 or (NCT ) 100 NA 52.1 ± ± ± ± 0.9 C: PLB + Met 500 or 750 Pratley et al. [45] Double-blind /105 Caucasian 54.6 ± ± ± 5.4 NA I: 25 + Met (NCT ) / ± ± ± 5.0 NA C: Met 2000 Defronzo et al. [46] Double-blind /272 Caucasian 53.7 ± ± ± ± 0.7 I: 25 + Met (NCT ) / ± ± ± ± 0.6 C: PLB + Met 1937 Data presented as mean ± standard deviation HbA1c glycosylated haemoglobin, BMI body mass index (calculated as weight in kg divided by height in m 2 ), I, DPP-4 inhibitor plus metformin, C metformin, NA not applicable, M/F male/ female effects meta-analysis showed that there was a significant difference for reduction in FPG between patients in DPP-4 inhibitor + metformin groups and metformin groups ( 1.10 mmol/l, 95 % CI 1.29 to 0.92, P < ), but with a substantial amount of heterogeneity (I 2 = 74 %, Fig. 3). Subgroup analyses also showed an obvious difference in FPG reduction in trials assessing sitagliptin ( 1.27 mmol/l, 1.51 to 1.02, I 2 = 50 %, P < ), saxagliptin ( 0.63 mmol/l, 0.98 to 0.28, I 2 = 76 %, P = ), vildagliptin ( 1.53 mmol/l, 2.37 to 0.68, I 2 = 87 %, P = ), linagliptin ( 1.21 mmol/l, 1.57 to 0.85, I 2 = 51 %, P < ) and alogliptin ( 1.12 mmol/l, 1.38 to 0.86, I 2 = 0 %, P < ). Body weight In the 14 trials that reported data on body weight changes, DPP-4 inhibitors + metformin showed a slight weight gain compared with metformin (mean difference 0.11 kg, 95 % CI 0.03 to 0.26, I 2 = 1 %), but the difference was not significant (P = 0.13) (Fig. 1S). Increment of weight compared to metformin was found for each of the DPP-4 inhibitors + metformin: sitagliptin (0.17 kg, 0.20 to 0.55, I 2 = 0, P = 0.37), saxagliptin (0.37 kg, 0.61 to 1.34, I 2 = 89 %, P = 0.46), vildagliptin (0.22 kg, 0.15 to 0.59, I 2 = 0, P = 0.24, linagliptin (0.16 kg, 0.36 to 0.68, I 2 = 0, P = 0.55) and alogliptin (0.04 kg, 0.24 to 0.32, I 2 = 0, P = 0.76). HOMA β and HOMA IR Fifteen trials reported HOMA-β. Random effects metaanalysis showed a significant increase in HOMA-β between patients in DPP-4 inhibitor + metformin groups and metformin groups (10.21, 95 % CI 7.73 to 12.69, I 2 = 50 %, P < , Fig. 4). Twelve trials reported HOMA- IR. DPP-4 inhibitors + metformin combination therapy remarkably decreased the HOMA-IR compared with metformin ( 0.19, 95 % CI 0.36 to 0.02, I 2 = 31 %, P = 0.03, Fig. 5). Summary of β-cell effects from included studies are shown in Table S3. Lipid Mean difference for HDL and LDL were 0.00 mmol/l ( 0.02 to 0.03, I 2 = 0 %, P = 0.86) and 0.02 mmol/l ( 0.04 to 0.08, I 2 = 39 %, P = 0.55), respectively. Random effects meta-analysis show significant difference in reduction in TC and TG between the two groups: mean difference for TC and TG were 0.11 mmol/l ( 0.20 to 0.02, I 2 = 78 %, P = 0.02) and 0.21 mmol/l ( 0.33 to 0.10, I 2 = 78 %, P = ), respectively. Summary of lipid parameters from included studies are shown in Table S3.

7 J Endocrinol Invest (2016) 39: Fig. 2 Weighted mean difference in change in HbA1c for DPP-4 inhibitors plus metformin vs metformin. DPP-4i dipeptidyl peptidase 4 inhibitor, MET metformin Adverse events Data on hypoglycemic episodes were retrieved in 19 of 27 trials. To better observe the adverse events, we included all of the different doses of DPP-4 inhibitors and metformin, so the sample sizes were higher than those reported in Table 1. DPP-4 inhibitors + metformin decreased the risk of hypoglycemic compared with metformin (OR 0.85, 95 % CI , I 2 = 0), but the decrease was not significantly different (P = 0.38). Fixed effects meta-analysis showed that there was a significant reduction in gastrointestinal AEs risk between patients in DPP-4 inhibitor + metformin

8 1068 J Endocrinol Invest (2016) 39: Fig. 3 Weighted mean difference in change in FPG for DPP-4 inhibitors plus metformin vs metformin groups and metformin groups (OR 0.86, 95 % CI , I 2 = 10 %, P = 0.01, Fig. 6). Subgroup analyses showed an obvious difference in trials assessing add-on therapy (OR 0.78, 95 % CI , I 2 = 0, P = 0.009), but there were no significant difference in initial combination therapy between the two groups (OR 0.92, 95 % CI , I 2 = 36 %, P = 0.25). Summary of adverse events from included studies are shown in Table S4.

9 J Endocrinol Invest (2016) 39: Fig. 4 Weighted mean difference in change in HOMA-β for DPP-4 inhibitors plus metformin vs metformin Comparison the efficacy of DPP 4 inhibitor and metformin combination therapy in Asian and Caucasian patients The difference in HbA1c and FPG reduction with DPP-4 inhibitors plus metformin combination therapy compared with metformin monotherapy between Asian and Caucasian patients was not statistically significant: ( 0.05 %, 95 % CI 0.30 to 0.20, P = 0.69) and (0.17 mmol/l, 95 % CI 0.52 to 0.85, P = 0.62). However, the between-group difference in HOMA-β change from baseline had significant difference ( 7.68, 95 % CI to 0.42, P = 0.04) compared with metformin. Asian and Caucasian patients experienced comparable improvement in HOMA-IR (0.27, 95 % CI, 0.98 to 1.53, P = 0.64) and comparable changes in body weight ( 0.15 kg, 95 % CI, 0.64 to 0.35; P = 0.53) with DPP-4 inhibitor plus metformin combination therapy compared with metformin (Table 2).

10 1070 J Endocrinol Invest (2016) 39: Fig. 5 Weighted mean difference in change in HOMA-IR for DPP-4 inhibitors plus metformin vs metformin Discussion DPP-4 inhibitors are a relatively new therapeutic class of oral antihyperglycemic drugs for the management of T2DM. This meta-analysis investigated the clinical efficacy of DPP-4 inhibitors plus metformin combination therapy and their effect on β-cell function, insulin resistance, body weight and lipid level. In terms of clinical efficacy, DPP-4 inhibitors plus metformin lowered HbA1c by %, FPG by mmol/ml than metformin. The improvement in HbA1c and FPG were found to have no significant difference in Asian patients and Caucasian patients. However, the result was not consistent with findings from previous meta-analyses of DPP-4 inhibitors in Asian patients compared with placebo, which reported greater HbA1c reductions than in Caucasian. This may be due to the different research background and also the less included studies in Asian patients. So the effectiveness of incretin-based therapies in various races should be further investigated as more evidence becomes available. Obesity is a major factor in the pathogenesis of T2DM. A 1-kg weight gain has been shown to increase the risk of diabetes by %, whereas an 11 % weight loss decreases the risk of cardiovascular disease and diabetes mortality by 25 % [47]. The majority of patients with T2DM face vital challenges in terms of achieving and maintaining glycemic and weight loss targets. In our assay, almost DPP-4 inhibitor (except Bosi [34] and Fonseca [28]) plus metformin combination therapy decreased the body weight in different degrees and did not show remarkably weight gain compared with metformin monotherapy. The overall weight neutrality observed with DPP-4 inhibitors appears to be a class effect, as has been demonstrated by previous studies either as monotherapy or add-on therapy, without significant changes in body weight [18]. T2DM is characterized by increased insulin resistance, and deteriorating β-cell function, resulting in chronic hyperglycaemia. DPP-4 inhibitors induced the increase of GLP-1 levels resulted in enhanced sensitivity of β-cells to glucose and improved glucose-dependent insulin secretion. Improvements

11 J Endocrinol Invest (2016) 39: Fig. 6 Meta-analysis of gastrointestinal adverse events between DPP-4 inhibitors plus metformin vs metformin

12 1072 J Endocrinol Invest (2016) 39: Table 2 Comparison of DPP-4 inhibitor + metformin efficacy versus metformin in Asian and Caucasian T2DM patients Asian, WMD change from baseline (95 % CI, P value) Size (DPP-4i + Met versus Met) Caucasian, WMD change from baseline (95 % CI, P value) Size (DPP-4i + Met versus Met) Difference estimate (95 % CI, P value) DPP-4i + Met versus Met HbA1c (%) 0.66 ( 0.91, 0.41, < ) FPG (mmol/l) 0.96 ( 1.42, 0.49, <0.0001) 707/ ( 0.68, 0.51, < ) 565/ ( 1.33, 0.92, < ) 4687/ ( 0.30, 0.20, 0.69) 4585/ ( 0.52, 0.85, 0.62) Weight (kg) 0.01 ( 0.24, 0.21, 0.974/ (0.01, 0.40, 0.05) 2527/ ( 0.64, 0.35, 0.53) HOMA-β 6.08 (2.88, 9.29, ) 520/ (8.76, 14.98, < ) HOMA-IR 0.09 ( 0.49, 0.31, 0.66) 270/ ( 0.39, 0.02, 0.03) 2411/ ( 14.95, 0.42, 0.04) 2077/ ( 0.98, 1.53, 0.64) CI confidence interval, DPP-4i dipeptidyl peptidase-4 inhibitor, FPG fasting plasma glucose, HbA1c glycosylated haemoglobin, HOMA-β homeostatic model of assessment for β-call function, HOMA-IR homeostatic model of assessment for insulin resistance, T2DM type 2 diabetes mellitus, WMD weighted mean difference in HOMA-β were found to be greater in patients with DPP-4 inhibitor plus metformin treatment compared with metformin in this meta-analysis. However, improvements in HOMA-β were found to be significantly less in Asian patients than in Caucasian patients (P = 0.01). It has been suggested that in leaner Asian patients with T2DM, loss of glycemic control may be attributed to insulin deficiency rather than insulin resistance [48]. Thus, the promotion of insulin secretion by DPP-4 inhibitors though improvement in HOMA-β may be specially relevant for Caucasian patients. T2DM is also associated with lipid metabolic disorder, thus promoting the formation and development of atherosclerosis [49]. DPP-4 inhibitor plus metformin combination therapy yield a better efficacy in reducing TG and TC compared with metformin monotherapy. DPP-4 inhibitors as a new type of hypoglycemic drugs also have a certain role in regulation blood lipids. The studies of DPP-4 inhibitors on lipid metabolism were mainly concentrated on TG. DPP-4 inhibitors could increase the level of endogenous GLP-1 and the increase of GLP-1 may be an endocrine signal affecting the metabolism of lipoprotein in the intestine [50]. On the one hand, GLP-1 could prevent the breakdown of the fatty acids, thereby reducing the level of free fatty acids, which were positively correlated with the level apob48 [51]. The decrease of apob48 slowed down the exogenous pathway of lipid metabolism, which helped to reduce the production of intestinal lipoprotein [51]. One the other hand, GLP-1 could delay the gastric emptying, reduce the absorption of TG, thus lower the level of TG [52]. DPP-4 inhibitors also had a certain effect on lowering TC, while had no obvious regulation effect on LDL and HDL. The mechanism of the effect on TC, LDL and HDL needed more basic research and clinical follow-up observation to further clarify. Monotherapy targeting a single pathway may be effective in improving glycemic control in short term but often inadequate to control the multiple defects associated with T2DM [53]. Although metformin monotherapy is the cornerstone of T2D treatment, high doses are associated with an increased incidence of gastrointestinal AEs. Overall, compared with metformin monotherapy, DPP-4 inhibitors plus metformin combination therapy were well tolerated with lower gastrointestinal AEs. This was not consistent with the conclusion of Wu s research [18]. So we performed a subgroup analysis of the initial combination therapy [20, 26, 30, 37, 40, 41, 45] and add-on therapy [23 25, 27 29, 31, 32, 34 36, 42 44, 46] (Fig. 2S). Subgroup analyses showed an obvious difference in trials assessing addon therapy (P = 0.02), but there was no significant difference in initial combination therapy between the two groups (P = 0.25). So the difference may be due to the reduced dose of metformin in DPP-4 inhibitor and metformin combination group in add-on therapy [29, 34, 36, 46]. Moreover, the combination therapy almost did not increase the risk of hypoglycaemia, whatever was the initial combination therapy or add-on therapy. In view of the greater incidence of hypoglycaemia and even severe hypoglycaemia in elderly patients with T2DM [54], DPP-4 inhibitors are promising new therapies because of their overall safety profile, especially the negligible risk of hypoglycaemia [55]. This meta-analysis assessed the efficacy, safety and impact on-β function of DPP-4 inhibitors and metformin combination therapy in 27 randomized controlled trials, drawing comparisons between Asian and Caucasian patients. However, the study has several limitations. Despite the s being all high quality, statistical heterogeneity still existed. This heterogeneity may have been the result of differences in design, patient characteristics,

13 J Endocrinol Invest (2016) 39: duration of diabetes, and control drug therapy. The number of studies included in Asian patients was less, so the findings should be interpreted cautiously. Study duration was less than one year for the majority of studies included in this meta-analysis, limiting the assessment of the longterm clinical outcomes. Further investigations are needed to examine the long-term effects of these agents on cardiovascular events and death. Compliance with ethical standards Conflict of interest The authors do not declare any conflict of interest relevant to this manuscript. Ethical approval For this type of study formal consent is not required. Informed consent For this type of study, informed consent is not required. References 1. Shaw JE, Sicree RA, Zimmet PZ (2010) Global estimates of the prevalence of diabetes for 2010 and Diabetes Res Clin Pract 87(1): American Diabetes Association (2014) Diagnosis and classification of diabetes mellitus. 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