Glucagon-like peptide-1 receptor agonists (GLP-1 RA) versus insulin    in inadequately controlled patients with type 2 dia...
AbstractAims To compare the effect and safety of GLP-1 receptor agonists (GLP-1 RA) withinsulin therapy on type 2 diabetes...
hypoglycemia (M-H OR 0.65 [0.29,1.45]; P=0.29). A significantly higher number ofgastrointestinal adverse events were repor...
SU Sulfonylurea drugsTZD ThiazolidinedioneHbA1c Haemoglobin A1cFDA Food and Drug AdministrationMesh Medical subject headin...
glycemic control, which is largely attributed to progressive dysfunction of beta-cellsthat occurs irrespective of whether ...
the structure of native GLP-1 with minor amino acid substitution and attachment.Data from large, controlled, clinical stud...
Research design and methodsData Sources and SearchesWe searched the MEDLINE database for articles dated from October 1990 ...
human adults and published in English; (ii) included were nonpregnant adults at least18 years of age with T2DM for at leas...
trial. Secondary outcomes included weight loss from baseline to end of the trial.Furthermore, data on FPG, PPG, adverse ev...
calculated for change from baseline in the GLP-1 RA or insulin groups. Fordichotomous variables (eg. percentages with hypo...
We used the I2 statistic to evaluate statistical heterogeneity in each meta-analysis.The I2 statistic describes the percen...
Results     932 articles identified from Medline, Embase and Cochrane were screened, fromwhich 825 were excluded based on ...
corresponding 95% CIs for outcomes from each individual trial and pooled data areshown in the following figures respective...
deviations in FPG results. The mean reductions in FPG from baseline in the twogroups of that study was 1.55 and 1.79mmol/l...
after-breakfast (-0.91 [-1.39 to -0.43]mmol/l; P<0.002) and after-dinner (-1.41[-1.89to 0.93]mmol/l; P<0001) in the exenat...
Severe hypoglycemia (requiring third-party medical assistance) was rare withGLP-1 RA, reported in only 10 out of 1130 pati...
Discussion     The introduction of GLP-1 RA over the past few years as new therapeutic agentshas led to a novel choice of ...
comparatively high, treatment with GLP-1 RA was not very effective [16]. In anotherpilot study of patients with longer dia...
observed in subjects who did not experience side effects [29].  A low number of hypoglycemia events seen in all studies co...
RA therapy could not be fully assessed due to limited data. Finally, most studies didnot use a true intention-to-treat (IT...
Combination therapy with GLP-1 RA and insulin is currently not approved by theFDA. However, it may be a promising therapeu...
AcknowledgmentsThis work was supported by research grants from the National Natural Science Foundation ofChina (30871199, ...
References1. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction  to the pathophysiology o...
Diabetologia 2004; 47:357-3667. Barnett A. Exenatide. Expert Opin Pharmacother 2007; 8: 2593–2608.8. Edavalath M, Stephens...
16. Bergenstal R, Lewin A, Bailey T et al. Efficacy and safety of biphasic insulin   aspart 70/30 versus exenatide in subj...
Diabetologia 2007; 50: 259-267.22. Russell-Jones D, Vaag A, Schmitz O et al. Liraglutide vs insulin glargine and    placeb...
28. Henry RR, Ratner RE, Stonehouse AH et al. Exenatide maintained glycemic   control with associated weight reduction ove...
35. Tzefos M, Olin JL. Glucagon-like Peptide-1 analogue and insulin combination   therapy in the management of adults with...
Figure legendsFigure 1. Flowchart of search strategy and results                                         29
932   articles screened.Medline (n=407)Embase     (n-508)Cochrane (n=17)                  825   excluded ased on abstract ...
Figure 2. Forest plot illustrating the change in HbA1c levels following treatment withGLP-1 RA or insulin. IV= inverse var...
Figure 3. Forest plot illustrating the change in fasting plasma glucose levels followingtreatment with GLP-1 RA or insulin...
Figure 4. Forest plot illustrating the change in body weight from baseline to endpointfollowing treatment with GLP-1 RA or...
Figure 5. Forest plot illustrating the overall incidence of hypoglycemia followingtreatment with GLP-1 RA or insulin. M-H=...
Conflict of interest details: Design: Ling Li, Gangyi YangConduct/data collection:Yisu Wang, Mengliu YangAnalysis: Yisu Wa...
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INSULINA X GLP-1 AGONISTAS

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INSULINA X GLP-1 AGONISTAS

  1. 1. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) versus insulin in inadequately controlled patients with type 2 diabetes mellitus: a meta-analysis of clinical trialsRunning title: GLP-1 RA vs insulin: a meta-analysis of clinical trials Yisu Wang1, Ling Li 2, Mengliu Yang1, Hua Liu3, Guenther Boden4, Gangyi Yang1 1 Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China2 The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, Chongqing Medical University, 400016 Chongqing, China 3 Department of Pediatrics, University of Mississippi Medical Center, 2500 North State Street, Jackson, Mississippi, MS 39216-4505, USA 4 The Division of Endocrinology/Diabetes/Metabolism and the Clinical Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA Corresponding author: Gangyi Yang, Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, ChinaTel: +86-23-68485216 / Fax: +86-23-68486115e-mail: gangyiyang@yahoo.com.cn This is an Accepted Article that has been peer-reviewed and approved for publication in the Diabetes,Obesity and Metabolism, but has yet to undergo copy-editing and proof correction. Please cite thisarticle as an "Accepted Article"; doi: 10.1111/j.1463-1326.2011.01436.x 1
  2. 2. AbstractAims To compare the effect and safety of GLP-1 receptor agonists (GLP-1 RA) withinsulin therapy on type 2 diabetes mellitus (T2DM) patients inadequately controlledwith metformin (MET) and/or sulfonylurea (SU).Methods A systematic literature search on Medline, Embase and Cochrane forrandomized controlled trials (RCTs) was conducted using specific search terms“GLP-1 insulin type2 diabetes clinical trials” and 8 eligible studies were retrieved.Data on mean change in Haemoglobin A1c (HbA1C), weight loss, fasting plasmaglucose (FPG), incidence of hypoglycemia and gastrointestinal adverse events wereextracted from each study and pooled in meta-analysis. Data on postprandial plasmaglucose (PPG) and adverse events were also described or tabulated.Results Data from 8 RCTs enrolling 2782 patients were pooled using a random-effectsmodel. The mean net change(95% confidence interval(CIs)) for HbA1c, weight lossand FPG for patients treated with GLP-1 RA as compared with insulin was -0.14%(-2mmol/mol)[(-0.27, -0.02)%; 95%CI; P=0.03]; -4.40kg [(-5.23,-3.56)kg; 95%CI;P<0.01]; 1.18mmol/l[(0.43, 1.93) mmol/l; 95%CI; P<0.01], respectively, withnegative values favoring GLP-1 and positive values favoring insulin. The GLP-1group was associated with a greater reduction in PPG than the insulin group. Overall,hypoglycemia was reported less in the GLP-1 group (M-H OR 0.45[0.27, 0.76];P<0.01) while there was no significant difference in occurrence of severe 2
  3. 3. hypoglycemia (M-H OR 0.65 [0.29,1.45]; P=0.29). A significantly higher number ofgastrointestinal adverse events were reported with GLP-1 group (M-H OR 15.00[5.44,41.35] P<0.01).Conclusions GLP-1 RA are promising new agents compared with insulin. Furtherprospective clinical trials are expected to fully evaluate the long-term effectivenessand safety of these therapies within the T2DM treatment paradigm.Keywords GLP-1, insulin, type 2 diabetes mellitus, clinical trials.AbbreviationsT2DM type 2 diabetes mellitusDPP-IV Dipeptidyl peptidase 4GLP-1 RA Glucagon-like peptide-1 receptor agonistFPG fasting plasma glucosePPG postprandial plasma glucoseITT intention-to-treatRCT randomized controlled trialsM-H OR Mantel-Haenszel odds ratioADA American Diabetes AssociationEASD The European Association for the Study of DiabetesUKPDS United Kingdom Prospective Diabetes StudyMET Metformin 3
  4. 4. SU Sulfonylurea drugsTZD ThiazolidinedioneHbA1c Haemoglobin A1cFDA Food and Drug AdministrationMesh Medical subject headingsCIs Confidence intervalsBIAsp Biphasic insulin aspartTTT Treat-to-Target algorithmIntroduction Type 2 diabetes mellitus (T2DM) is characterized by two core defects in mostcases, progressive beta-cell dysfunction against a background of obesity-relatedinsulin resistance [1], making it difficult for patients to maintain glycemic control.Recently, it has been reported that impairments in the secretion levels and/or theactivity of incretin hormones may also play an important role in the development andprogression of hyperglycemia in T2DM [2]. According to 2009 American Diabetes Association (ADA)/ The EuropeanAssociation for the Study of Diabetes (EASD) consensus [3], standard therapy isinitiated by lifestyle changes and glucose-lowering agents, often followed by insulintreatment. Data from UK Prospective Diabetes Study (UKPDS) shows that long-termeffectiveness of these drugs can be unsatisfactory, leading to progressively worsening 4
  5. 5. glycemic control, which is largely attributed to progressive dysfunction of beta-cellsthat occurs irrespective of whether metformin (MET), sulfonylureas (SU), or insulinare used[4]. On the other hand, except for a few oral agents like dipeptidylpeptidase-IV(DPP-IV) inhibitors and acarbose, most of the current treatments areaccompanied by weight gain---a contributing factor to insulin resistance and theelevated fasting plasma glucose (FPG) and postprandial plasma glucose (PPG)concentrations[5], which still worsens glycemic control. Thus, a novel agent thatprotects the beta-cells and causes no weight gain and hypoglycemia is needed.. Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from endocrineK and L cells in response to nutrient ingestion, and is responsible for up to 70% of theinsulin response following a meal [6]. However, native GLP-1 has a short plasmahalf-life of only 1-2 min; as it is rapidly degraded by the enzyme DPP-IV, it is notproperly suitable to intermittent administration. Thus, research efforts directed atpotentiation of incretin action have focused on a glucagon-like peptide-1 receptoragonist (GLP-1 RA), which is degradation-resistant. Exenatide and Liraglutide arerepresentatives of GLP-1 RA that offer potential benefits over traditional therapies.Exenatide( Exendin-4), which shares 53% sequence homology with human GLP-1,has been proven to produce glucose-dependent enhancement of insulin secretion,suppression of inappropriately elevated postprandial glucagon secretion, slowing ofgastric emptying, and a reduction of food intake [7], and has been approved by Foodand Drug Administration (FDA) for use as monotherapy along with lifestyle changesin T2DM patients since November, 2009. Liraglutide is a GLP-1 analogue based on 5
  6. 6. the structure of native GLP-1 with minor amino acid substitution and attachment.Data from large, controlled, clinical studies have confirmed its therapeutic profilewith robust reductions in glycosylated hemoglobin (HbA1c), low risk ofhypoglycemia and clinically relevant reductions in body weight and systolic bloodpressure [8]. Since January 2010, Liraglutide has been licensed for the treatment forT2DM in conjunction with diet and exercise. However, in the position statement developed by experts from the ADA andEASD[3], GLP-1 RA are considered a possible albeit less well validated alternative toinsulin initiation after failure of lifestyle changes and MET, with or without a SU.Both insulin and GLP-1 RA have shown to be effective for inadequately controlledT2DM. Nevertheless, limited data is available from clinical trials with respect tohead-to-head comparisons of efficacy and safety between these two drugs. Thus, the purpose of our study was to assess the efficacy and safety of these twodrugs by using all available data in eligible clinical trials, when added to treatmentregimens of patients whose glucose levels were inadequately controlled with oralagents alone. 6
  7. 7. Research design and methodsData Sources and SearchesWe searched the MEDLINE database for articles dated from October 1990 to October2010, as well as the Cochrane Library Central Registry of Controlled Trials during thesame period of time. A further search was performed on EMBASE database forarticles dated from 1990 to 2011 for relevant publications, all using the followingmedical subject headings (MeSH) “diabetes mellitus”, “Type 2”, “insulin”, “insulinisophane”, “glucagon-like peptide 1”, “clinical trial”. The search was restricted topublications in English and in humans. Completed but unpublished trials wereidentified through a search of www.clinicaltrials.gov website. A manual search ofreferences cited in the published studies and relevant review articles was alsoperformed to identify additional studies suitable for our purpose. For unpublished andpublished trials which were not exhaustively disclosed, an attempt was made (throughe-mail) to contact principal investigators in order to retrieve missing data. Finally,known experts in the area were contacted to ensure that all relevant data werecaptured.Study Selection The identification of relevant abstracts and the selection of studies based on thecriteria described below were performed independently by two of the authors (WangY and Li L), and any discrepancy was resolved by a third investigator. Clinical trials were included if they met the following criteria: (i) randomizedcontrolled trials (RCT) using either crossover or parallel designs, conducted in 7
  8. 8. human adults and published in English; (ii) included were nonpregnant adults at least18 years of age with T2DM for at least three months, suboptimally controlled withoral agents(e.g. MET and/or SU) with HbA1c levels between 7-11%(53-97mmol/mol);(iii) use of subcutaneous injection as the only administration route; (iv) theintervention duration was at least 16 weeks; (v) comparisons of GLP-1 RA (exenatideor liraglutide) with insulin, e.g. glargine or biphasic insulin aspart (BIAsp); (vi) use ofHbA1c as the primary outcome in a manner that allowed data analysis, and data onweight changes, FPG, PPG, hypoglycemia, adverse effect from baseline to end oftrial. We excluded the following trials: Those on type 1 diabetes or with ages less than18 years, those that used a GLP-1 RA as monotherapy or, adjunctive therapy toinsulin, and those with integrated analysis, post hoc analysis or open-label extensionsof the original ones.Data extraction and Quality AssessmentThe following variables in each study were extracted: 1) Title, primary author’s name,year and source of publication. 2) Patient demographics, study design (cross over,parallel, factorial, or Latin square), treatment allocation procedures, blinding (open,single or double-blind) and interventions. 3) Inclusion and exclusion criteria for eachindividual study, diabetes history including duration of diabetes, mean HbA1c, FPGand body weight. 4) Description of the study medication exposure, study completionstatus, definition and assessment of diagnosis and outcome of diabetes. The primaryclinical outcome of interest was the effect of a GLP-1 RA on HbA1c at the end of the 8
  9. 9. trial. Secondary outcomes included weight loss from baseline to end of the trial.Furthermore, data on FPG, PPG, adverse events and incidence of hypoglycemia(number of patients with at least one event) were extracted in the form of net changevalues with confidential intervals (CIs), standard error or P-value. Any case of life threatening adverse events were considered severe and weretabulated specially, together with death for any cause. If data concerning the outcomewere missing from an article, an effort was made to contact the primary author inorder to obtain the missing data. The methodological quality of the included randomized clinical trials wasassessed based on criteria suggested by Jadad et al [9]. It awards a maximum of 5points to each study based on three main criteria: study randomization (1–2 pts),double-blinding of the study (1–2 pts), and a description of withdrawals or dropouts(1 pt). Any disagreement regarding study quality was resolved by discussion amongthe authors.Data Synthesis and Analysis This meta-analysis was carried out according to the QUOROM guidelines for theconducting and reporting of meta-analyses of RCTs [10].Statistical analyses wereperformed using the Review Manager (RevMan) version 5.0 for Windowssoftware(The Nordic Cochrane Centre, Copenhagen). Outcome variables (e.g. changes in HbA1c, FPG or body weight from baseline toend of trial) were converted to standard units (percentage and mmol/mol, mmol/l orkg). For continuous variables (HbA1c, FPG, weight), WMD with 95% CIs was 9
  10. 10. calculated for change from baseline in the GLP-1 RA or insulin groups. Fordichotomous variables (eg. percentages with hypoglycemia), Mantel-Haenszel oddsratio (M-H OR) with 95% CIs was calculated. Mean net change values werecalculated as the difference (GLP-1 RA minus insulin glargine) of the changes(baseline minus follow-up) of the mean values. Each study was weighted of itsvariance in order to pool the data for overall effect size. The variances were calculatedusing CIs, P-values, t-statistics or individual variances for the two treatment groups.For trials that reported no standardized difference for the changes of the twointervention groups, it was presented as reductions from baseline separately. We usedthe method of Follmann et al., in which a correlation coefficient of 0.5 between initialand final values is assumed [11]. All tests were two-sided with statistical significancewhen P<0.05, if not otherwise specified. If data from more than two trials wereavailable, we combined data within a class (insulin glargine or BIAsp ; exenatide orliraglutide) by type of group, duration of intervention, and available formulationwithin each class and explored heterogeneity. For PPG, we did not perform ameta-analysis because of the diverse methods used to assess outcomes and/or becauseof insufficiently reported data. Definitions and units for hypoglycemia differed substantially from one trial toanother. The most consistently reported measure of hypoglycemia was the percentageof participants experiencing an episode of a specific type (symptomatic,asymptomatic, nocturnal and severe). Therefore, the first measure was meta-analyzedwith the description of the rest two trials presented as event/patient/year [20, 21]. 10
  11. 11. We used the I2 statistic to evaluate statistical heterogeneity in each meta-analysis.The I2 statistic describes the percentage of the variability that is due to heterogeneityrather than sampling error. The Cochrane handbook suggests that a value greater than50% may be considered substantial heterogeneity. Possible sources of heterogeneitywere assessed through pre-stated subgroup analyses by intervention regimens. Asstatistical heterogeneity were presented, possibly related to different demographiccharacteristics and study intervention measurements, we utilized aDerSimonian-Laird’s random effects methodology throughout to calculate the pooledeffect size [12]. We examined each study for potential selection, attrition, and detection bias [13].In order to verify possible bias associated with inadequate allocation concealment orrandomization procedure, study quality characteristics were tabulated and evaluated.A funnel plot of primary end point outcomes or important secondary outcomes wasexamined to assess the potential publication bias by constructing it with varianceplotted against the corresponding effect sizes. In addition, the association betweenvariance and effect size was analyzed by the Begg adjusted rank correlation test,based on the Kendall’s tau [14]. 11
  12. 12. Results 932 articles identified from Medline, Embase and Cochrane were screened, fromwhich 825 were excluded based on title and abstract. After detailed evaluation ofpotential eligible reports, 8 reports [15-22] met all of the inclusion criteria and wereretrieved for meta-analysis. The trial flowchart is summarized in Figure 1. Characteristics of the studies included in the meta-analysis are presented inTable 1. In total, data from 2782 participants in 8 trials were included. Of those, themean values were: age 57.4 years, BMI 31.6 kg/m2, duration of diabetes 8.9 years,HbA1c 8.6%(70mmol/mol) and FPG 10.4 mmol/l. The average length of studies was30.2 weeks, with a range from 16 to 52 weeks, the average study size was 332participants with a range from 69 to 549 participants. The average insulin dose in theinsulin group was 37.6 IU/d. All 8 trials included were parallel, open-label trials. Twotrials in the insulin group used BIAsp, while the rest used glargine. In the GLP-1 RAgroup, one trial used liraglutide while the others used exenatide (including long-actingexenatide). Basic treatment protocols were slightly different in all trials: some trials[16,17,19-22] followed a fixed algorithm for titration of insulin [23] based on fastingconcentration of blood glucose while others [15,18] followed a treat-to-targetprinciple [24]. Both exenatide and liraglutide were used with a strict titration principleexcept for the trial of Bunck et al. [17], where exenatide was titrated to a maximumdose of 20 μg if necessary. All but 2 trials had only a 30-week or slightly longerduration, thus, long-term efficacy and safety could not be evaluated. Selected study design characteristics are shown in Table 2. Mean net changes and 12
  13. 13. corresponding 95% CIs for outcomes from each individual trial and pooled data areshown in the following figures respectively.1. Changes in HbA1c We included a total of 2782 patients for whom complete HbA1c measurementswere available with individual treatment arm size ranging from 36 to 282 patients.Study duration was at least 16 weeks in all cases, allowing sufficient time for changesin glycemic control to be reflected in changes in HbA1c. When combining all available trials, data showed a comparative differences inHbA1c decline from baseline favoring GLP-1 RA therapy[WMD-0.14(-0.27, -0.02)%,(-1.5mmol/mol); 95%CI; P=0.03](Figure 2). Exclusion of trials [15,18,22] whereinsulin was titrated following Treat-to-Target algorithm (TTT) [24] revealed slightlysignificant decrease in HbA1c [WMD-0.19(-0.34, -0.03)% (-2mmol/mol); 95%CI;P=0.02]. No significant differences were found between the exenatide BID and theinsulin groups [WMD-0.12(-0.30, 0.06) % (-1.3mmol/mol); 95%CI; P=0.19], norbetween the GLP-1 and glargine subgroups [WMD-0.08(-0.19, 0.03) %(-0.9mmol/mol); 95%CI; P=0.14]. There appeared to be a trend towards greaterHbA1c reductions in populations with higher compared to lower baseline HbA1c (r =-0.837, P<0.001).2. Changes in FPG FPG was reduced in both groups but more so in the insulin group (WMD 1.18(0.43,1.93) mmol/l; 95%CI; P<0.01) (Figure 3). The trial of liraglutide versus insulinglargine by Russell-Jones et al [22] was not included due to lack of standard 13
  14. 14. deviations in FPG results. The mean reductions in FPG from baseline in the twogroups of that study was 1.55 and 1.79mmol/l, respectively.3. Changes in bodyweight In the trials that reported data on changes in bodyweight, there was a statisticallysignificant net weight loss observed in the GLP-1 RA compared with the insulingroups (WMD -4.40(-5.23,-3.56) kg; 95%CI; P<0.01)(Figure 4). Net weight loss wasgreater comparing exenatide and insulin groups when BIAsp was used (WMD-5.51(-6.01,-5.01) kg; 95%CI; P<0.01) than when insulin glargine was used (WMD-3.95(-4.83,-3.07) kg; 95%CI; P<0.01).4. Changes in PPG A statistical comparison with GLP-1 RA and insulin on effect of PPG was notpossible since in the seven out of eight trials where PPG was mentioned, specific dataof PPG changes were only given in three. The trial by Davies et al. [18] did notmention PPG. However, even without a valid meta-analysis, we can describe theresults of several studies that came to similar conclusions. For instance, a cross overstudy [15] reported that exenatide was associated with significant lower PPGconcentrations compared with insulin glargine (mean [SEM] -1.5 [0.3] ( -2.1 to-0.9)mmol/l;95%CI, P<0.001), as 2-hour PPG excursions were lower with exenatide in themorning (mean[SEM] -2.2[0.3]( -2.8 to-1.7) mmol/l; 95%CI, P<0.001), atmidday(mean [SEM] -0.5[0.2]( -0.9 to-0.1)mmol/l; P=0.016), and in theevening(mean [SEM] -2.1[0.3]( -2.7 to-1.5)mmol/l; P<0.001). A study by Heine et al.[20] comparing exenatide and insulin glargine suggested a greater PPG reduction 14
  15. 15. after-breakfast (-0.91 [-1.39 to -0.43]mmol/l; P<0.002) and after-dinner (-1.41[-1.89to 0.93]mmol/l; P<0001) in the exenatide group. A similar reduction in PPG frombaseline was reported by Russell-Jones et al[22]in the liraglutide group(1.81mmol/l)and insulin glargine group(1.61mmol/l). Three trials [17,19,21] described a significantreduction of blood glucose after breakfast and dinner in the exenatide group, but nospecific data were shown. Results from the trial by Bengenstal et al.[16] were notconsistent with the rest, suggesting the reductions in the blood glucose values wassignificantly greater for BIAsp 30 BID than for exenatide at all time points of the8-point SMBG profile.5. Risk of hypoglycemic events Hypoglycemia was reported in the form of patient-reported incidence ofsymptomatic hypoglycemia in six studies, and frequency of hypoglycaemic episodes(event/patient/year) in another two studies [20, 21]. Of the data retrieved from thesestudies, hypoglycemic episodes were reported by 509 patients, 200 out of 877 in theGLP-1 RA group and 309 out of 855 in the insulin group. Based on the randomeffects pooling, there was a statistically significant decrease in risk of hypoglycemiaassociated with use of GLP-1 RA (M-H OR 0.45(0.27, 0.76); 95%CI; P<0.01)(Figure 5). The trial by Heine et al. [20] found no statistical difference in the overallincidence of hypoglycemic episodes (events/patient/year) between exenatide andinsulin glargine (n=549; 1.1[-1.3 to 3.4]). The trial by Nauck et al. [21] also showedsimilar rates at endpoint (Mean [SEM]: exenatide 4.7 [0.7], premixed insulin 5.6 [0.7];WMD -0.90 (-1.02 to -0.78); P<0.01) 15
  16. 16. Severe hypoglycemia (requiring third-party medical assistance) was rare withGLP-1 RA, reported in only 10 out of 1130 patients treated with exenatide comparedwith 15 out of 1103 patients treated with insulin. No statistically significant increasein risk of severe hypoglycemia was demonstrated with GLP-1 RA (M-H OR 0.65(0.29,1.45); 95%CI; P=0.29). When all data were combined, nocturnal hypoglycemia wasless commonly reported in the GLP-1 RA group than in the insulin group.6. Adverse effects Data of diverse adverse effects were available for quantitative evaluation in 5clinical trials [18-22]. The most commonly reported adverse effects, potentiallyrelated to GLP-1 RA, were gastrointestinal disorders of mild to moderate severity,such as nausea, diarrhea or vomiting, with a significantly increased risk ratio whencompared with insulin (M-H OR 15.00(5.44,41.35); 95%CI; P<0.01) (Figure 6).Life-threatening adverse events were rarely reported. Individual cases are presented inTable 3. 16
  17. 17. Discussion The introduction of GLP-1 RA over the past few years as new therapeutic agentshas led to a novel choice of treatment strategy in T2DM inadequately controlled byMET and/or SU. Recent studies have suggested that GLP-1 RA may better controlglycemia, inducing weight loss and causing less hypoglycemia compared to insulintherapy. Our current meta-analysis that involved 2782 T2DM patients confirmed thesefindings. The slightly larger reduction in HbA1c by GLP-1 RA compared with insulin wasnot surprising, as the physiologic role of GLP-1 RA is to augment glucose-stimulatedinsulin secretion. However, insulin was still more effective in reducing FPG. The twoagents lowered HbA1c through different mechanisms: GLP-1 RA primarily affectedPPG excursions with a modest effect on fasting glucose, whereas insulinpredominantly reduced FPG without influencing PPG levels [17]. This can explain themore significant reduction of FPG with insulin therapy and the lower PPGconcentrations with GLP-1 RA therapy. Within a certain range, the reduction ofHbA1c with GLP-1 RA therapy was dependent on the baseline HbA1c, so that greaterreductions were seen in groups with higher baseline HbA1c. The smaller reductions inHbA1c in these trials may be also attributed, at least in part, to the relatively lowbaseline HbA1c (8.6%, or 70mmol/mol) compared with earlier trials with othertherapies where baseline HbA1c was higher, often in the 9-10% (75-86mmol/mol)range. However, GLP-1 RA may be more suitable in early disease during which thereis more residual beta-cell function. For patients whose baseline HbA1c were 17
  18. 18. comparatively high, treatment with GLP-1 RA was not very effective [16]. In anotherpilot study of patients with longer diabetes duration and taking high doses of insulinsubstituting exenatide for insulin was not associated with a favorable outcome [25]. Incomparison, insulin therapy is independent of residual pancreatic activity and istherefore effective at all stages of the disease. These results suggest that the choice oftherapy should depend on HbA1c levels, the stage of disease (percentage of remainingbeta cells), and the target glucose level for each individual. In contrast to the weight gain commonly observed with insulin treatment, there wasa substantial and progressive decrease in body weight associated with the use ofGLP-1 RA. Weight loss was found in one study to be associated with long-termimprovements in CV risk factors, decreased lipids and BP levels, as well as a reducedneed for antihypertensive medication [26]. It has been shown that a 5-kg weight gainin individual can increase coronary heart disease risk as much as 30% [27]. Thus, theaverage 4.4kg weight loss could be important in T2DM patients. The difference inweight change was especially large in patients treated with GLP-1 RA compared tobiphasic insulin aspart, partly because higher daily doses of insulin were used in thebiphasic insulin aspart groups (insulin dose reached 96.1U/d in one trial [16]),compared to the other trials where insulin doses remained at about 30U/d. It wasreported that weight loss was continuous and continued when HbA1c was not furtherreduced [20]. Moreover, data from open-label extension trials indicated that weightloss with exenatide remained progressive for up to 2 years [28]. Weight loss appearedto be independent of gastro-intestinal side effects, as similar weight reductions were 18
  19. 19. observed in subjects who did not experience side effects [29]. A low number of hypoglycemia events seen in all studies confirmed theglucose-dependent action of GLP-1 RA. The low risk of hypoglycemia offersadvantages over other therapies, as hypoglycemia is a major problem for medicationadherence [30]. However, hypoglycemia can still occur when GLP-1 RA therapy iscombined with an insulin secretagogue such as a sulfonylurea [15,19,21]. Therefore,the dose of an insulin secretagogue should be adjusted when it is combined withGLP-1 RA[31]. GLP-1 RA can also cause transient and rarely serious, gastrointestinalside effects which are less pronounced with exenatide LAR and liraglutide[31]. Some limitations of this study need to be considered. First, the limited number ofrandomized trials available does not allow us to draw any definitive conclusion aboutthe efficacy and safety of these two therapies in patients failing on oral agents. Second,none of the trials that we identified in this study were double-blinded. Most of themwere open-label studies due to a requirement of dose adjustments to ensure optimaltherapeutic effects. Third, only two types of insulin (glargine/BIAsp) were included inthe analysis. In addition, patients with HbA1c>11% (97mmol/mol) were not includedand long-term data for the efficacy and safety of GLP-1 RA were not available. Thesetrials exhibited a wide variation in study duration (from 16 weeks to 52 weeks) andwere accompanied by differences in baseline data and diagnostic threshold fordetecting and reporting outcomes. Unfortunately, the limited data do not allowadjustment for these confounders. Fourth, most studies included predominantlyCaucasian participants; therefore, differential effects of race or ethnicity on GLP-1 19
  20. 20. RA therapy could not be fully assessed due to limited data. Finally, most studies didnot use a true intention-to-treat (ITT) analysis. This may have resulted inoverestimation of the glycemic efficacy, especially given the relatively high dropoutrate. Further trials should be performed to test whether the effects of GLP-1 RA aredurable and whether, in the long term, they could modify the natural course of T2DM. These results can not apply to all incretin-based therapy. Only two trials usingGLP-1 RA were not exenatide-related (one using liraglutide [21] and another usingexenatide LAR [18]). Recent data have shown that once-daily liraglutide and onceweekly exenatide LAR had a greater impact on HbA1c than exenatide and produced asubstantial reduction of FPG and weight loss [32-33]. A new study [34] has shownthat GLP-1 RA treatment was well tolerated and reduced HbA1c and body weightmore than DDP-IV inhibitors in patients inadequately controlled with metformin.However, further studies are needed to address the long-term effects of these drugs. Preliminary results of combination therapy with GLP-1 RA and insulin arepromising [35]. A study presented by Richard Bergenstal at the 46th EASD annualmeeting demonstrated that exenatide plus insulin resulted in greater improvement inHbA1c glucose profile (with no increase in hypoglycemia), and in a modest weightloss compared to the control group treated with insulin alone. Another prospectivestudy [36] has also shown that exenatide plus insulin therapy in obese patients withT2DM was associated with significant reductions in body weight and insulin doses. Inaddition, a proof-of-concept study [37] has shown improvement in PPG with additionof a GLP-1 receptor agonist to combination therapy with insulin glargine and MET. 20
  21. 21. Combination therapy with GLP-1 RA and insulin is currently not approved by theFDA. However, it may be a promising therapeutic strategy for those patients withinsulin resistance and poor glycaemic control due to obesity. Additionalwell-designed clinical trials will be required to test this hypothesis. In summary, GLP-1 RA, such as exenatide and liraglutide have modest butbeneficial effects on glycemic control compared to insulin (insulin glargine or BIAsp)and are associated with significant weight loss. They are also relatively safe in regardto the adverse events studied. However, GLP-1 RA is not a substitute for insulin.Further prospective clinical trials are needed to fully evaluate their long-termeffectiveness and safety and their place in the treatment of T2DM. 21
  22. 22. AcknowledgmentsThis work was supported by research grants from the National Natural Science Foundation ofChina (30871199, 81070640, 30971388, 30771037) and Doctoral Fund of Ministry of Educationof China(20105503110002).Declaration of InterestsThis article has no declaration of competing interests to report. 22
  23. 23. References1. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 2003; 46:3–19.2. Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med 2009; 122(6 Suppl): S37-50.3. Nathan DM, Buse JB, Davidson MB et al; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009; 32: 193-203.4. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study(UKPDS) Group. JAMA 1999; 281: 2005-2012.5. Maggio CA, Pi-Sunyer FX. The prevention and treatment of obesity, application to type 2 diabetes. Diabetes Care 1997; 20:1744-1766.6. Vilsbøll T, Holst JJ. Incretins, insulin secretion and Type 2 diabetes mellitus. 23
  24. 24. Diabetologia 2004; 47:357-3667. Barnett A. Exenatide. Expert Opin Pharmacother 2007; 8: 2593–2608.8. Edavalath M, Stephens JW. Liraglutide in the treatment of type 2 diabetes mellitus: clinical utility and patient perspectives. Patient Prefer Adherence 2010; 4: 61-68.9. Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12.10. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomized controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999; 354: 1896-1900.11. Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol 1992; 45 : 769–773.12. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–88.13. Feinstein AR. Clinical Epidemiology. The Architecture of Clinical Research. Philadelphia, Pa: WB Saunders Co; 1985.14. Begg C. Publication bias. In: Cooper H, Hughes L, eds. The Handbook of Research Synthesis. New York, NY: Russell Sage Foundation;1994: 22: 399-409.15. Barnett AH, Burger J, Johns D et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: A multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther 2007; 29: 2333-2348. 24
  25. 25. 16. Bergenstal R, Lewin A, Bailey T et al. Efficacy and safety of biphasic insulin aspart 70/30 versus exenatide in subjects with type 2 diabetes failing to achieve glycemic control with metformin and a sulfonylurea. Curr med Res Opin 2009 ; 25: 65-75.17. Bunck MC, Diamant M, Corner A et al. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. Diabetes Care 2009; 32:762-768.18. Davies M, Donnelly R, Barnett AH, Jones S, Nicolay C, Kilcoyne A. Exenatide compared with long-acting insulin to achieve glycemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study. Diabetes Obes Metab 2009;11: 1153-1162.19. Diamant M, Van Gaal L, Stranks S et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes( DURATION-3): an open-label randomized trial. Lancet 2010; 375: 2234-2243.20. Heine RJ, Van Gaal LF, Johns D et al. Exenacide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2005; 143: 559-569.21. Nauck.MA, Duran S, Kim D et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. 25
  26. 26. Diabetologia 2007; 50: 259-267.22. Russell-Jones D, Vaag A, Schmitz O et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met +SU): A randomised controlled trial. Diabetologia 2009; 52: 2046-2055.23. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The Treat-to-Target Trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetes patients. Diabetes Care 2003; 26: 3080–3086.24. Yki-Jarvinen H, Juurinen L, Alvarsson M et al. Initiate Insulin by Aggressive Titration and Education (INITIATE): a randomized study to compare initiation of insulin combination therapy in type 2 diabetic patients individually and in groups. Diabetes Care 2007; 30: 1364-1369.25. Davis SN, Johns D, Maggs D, Xu H, Northrup JH, Brodows RG. Exploring the substitution of exenatide for insulin in patients with type 2 diabetes treated with insulin in combination with oral antidiabetes agents. Diabetes Care 2007; 30: 2767-2772.26. Dixon JB, O’Brien PE. Health outcomes of severely obese type 2 diabetic subjects 1 year after laparoscopic adjustable gastric banding. Diabetes Care 2002; 25: 358-363.27. Anderson JW, Kendall CW, Jenkins DJ. Importance of weight management in type 2 diabetes: review with meta-analysis of clinical studies. J Am Coll Nutr 2003; 22: 331–339. 26
  27. 27. 28. Henry RR, Ratner RE, Stonehouse AH et al. Exenatide maintained glycemic control with associated weight reduction over two years in patients with type 2 diabetes. Diabetes 2006; 55:A11629. van Genugten RE, van Raalte DH, Diamant M. Does glucagon-like peptide-1 receptor agonist therapy add value in the treatment of type 2 diabetes? Focus on exenatide. Diabetes Res Clin Pract 2009; 86:S26-34.30. Hauber AB, Mohamed AF, Johnson FR, Falvey H. Treatment preferences and medication adherence of people with Type 2 diabetes using oral glucose-lowering agents. Diabet Med 2009; 26:416-424.31. Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med 2009; 122: S37-S50.32. Pinkney J, Fox T, Ranganath L. Selecting GLP-1 agonists in the management of type 2 diabetes : differential pharmacology and therapeutic benefits of liraglutide and exenatide. Ther Clin Risk Manag 2010; 6:401-411.33. Raskin P, Mohan A. Comparison of once-weekly with twice-daily exenatide in the treatment of type 2 diabetes (DURATION-1 trial). Expert Opin Pharmacother 2010; 11: 2269-2271.34. Pratley RE, Nauck M, Bailey T et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycemic control with metformin: a 26-week, randomized, parallel-group, open-label trial. Lancet 2010; 375: 1447-1456. 27
  28. 28. 35. Tzefos M, Olin JL. Glucagon-like Peptide-1 analogue and insulin combination therapy in the management of adults with type2 diabetes mellitus. Ann Pharmacother 2010; 44:1294-1300.36. Nayak UA, Govindan J, Baskar V, Kalupahana D, Singh BM. Exenatide therapy in insulin-treated type 2 diabetes and obesity. QJM 2010; 103: 687-69437. Arnolds S, Dellweg S, Clair J et al. Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study. Diabetes Care 2010; 33: 1509-1515. Corresponding author: Gangyi Yang, Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China Tel: +86-23-68485216 / Fax: +86-23-68486115 e-mail: gangyiyang@yahoo.com.cn 28
  29. 29. Figure legendsFigure 1. Flowchart of search strategy and results 29
  30. 30. 932 articles screened.Medline (n=407)Embase (n-508)Cochrane (n=17) 825 excluded ased on abstract review: 392 duplicate publications from different database 67 abstracts or letters only 123 reviews 243 unrelated themes 107 full-text manuscript or conference abstract retrieved for detailed evaluation 88 Excluded: 39 No T2DM patients 35 No comparable insulin interventions or adjunctive to insulin 3 Means of administration(1 inhaled; 2 intravenous) 11 Study durations<16 weeks 19 potential eligible reports. 11 excluded: 6 not reporting HbA1c as first outcome: 1 glycemic variability; 1 PPG excursions; 4 cost-effectiveness evaluations 2 secondary analysis based on original trials: 1 patient-report outcomes; 1 pooled post-hoc study 2 not RCTs: 1 cohort study; 1 matched study 1 GLP-1 RA substitution of insulin 8 RCTs included[14-21] 30
  31. 31. Figure 2. Forest plot illustrating the change in HbA1c levels following treatment withGLP-1 RA or insulin. IV= inverse variance. GLP-1 insulin Std. Mean Difference Std. Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI 2.1.1 exenatide vs insulin Barnett et al.2007 -1.36 1.03 136 -1.36 1.01 127 17.3% 0.00 [-0.24, 0.24] Bergenstal et al.2009 -2.67 1.79 124 -1.75 1.57 124 16.8% -0.54 [-0.80, -0.29] Bunck et al.2009 -0.8 0.6 36 -0.7 1.15 33 9.1% -0.11 [-0.58, 0.36] Davies et al.2009 -1.25 0.89 98 -1.26 0.9 102 15.7% 0.01 [-0.27, 0.29] Heine et al 2005 -1 1 275 -1.05 0.97 260 20.7% 0.05 [-0.12, 0.22] Nauck et al.2007 -1.04 1.11 253 -0.89 0.94 248 20.4% -0.15 [-0.32, 0.03] Subtotal (95% CI) 922 894 100.0% -0.12 [-0.30, 0.06] Heterogeneity: Tau² = 0.03; Chi² = 16.39, df = 5 (P = 0.006); I² = 69% Test for overall effect: Z = 1.31 (P = 0.19) 2.1.2 glp-1 vs glargine Barnett et al.2007 -1.36 1.03 136 -1.36 1.01 127 14.9% 0.00 [-0.24, 0.24] Bunck et al.2009 -0.8 0.6 36 -0.7 1.15 33 4.8% -0.11 [-0.58, 0.36] Davies et al.2009 -1.25 0.89 98 -1.26 0.9 102 12.1% 0.01 [-0.27, 0.29] Diamante et al.2010 -1.5 0.76 228 -1.3 0.92 220 21.7% -0.24 [-0.42, -0.05] Heine et al 2005 -1 1 275 -1.05 0.97 260 24.3% 0.05 [-0.12, 0.22] Russell-jones et al.2009 -1.33 1.37 232 -1.09 1.38 234 22.3% -0.17 [-0.36, 0.01] Subtotal (95% CI) 1005 976 100.0% -0.08 [-0.19, 0.03] Heterogeneity: Tau² = 0.00; Chi² = 6.90, df = 5 (P = 0.23); I² = 28% Test for overall effect: Z = 1.49 (P = 0.14) 2.1.3 GLP-1 vs non-TTT insulin Bergenstal et al.2009 -2.67 1.79 124 -1.75 1.57 124 15.2% -0.54 [-0.80, -0.29] Bunck et al.2009 -0.8 0.6 36 -0.7 1.15 33 7.5% -0.11 [-0.58, 0.36] Diamante et al.2010 -1.5 0.76 228 -1.3 0.92 220 18.9% -0.24 [-0.42, -0.05] Heine et al 2005 -1 1 275 -1.05 0.97 260 19.8% 0.05 [-0.12, 0.22] Nauck et al.2007 -1.04 1.11 253 -0.89 0.94 248 19.5% -0.15 [-0.32, 0.03] Russell-jones et al.2009 -1.33 1.37 232 -1.09 1.38 234 19.1% -0.17 [-0.36, 0.01] Subtotal (95% CI) 1148 1119 100.0% -0.19 [-0.34, -0.03] Heterogeneity: Tau² = 0.02; Chi² = 15.52, df = 5 (P = 0.008); I² = 68% Test for overall effect: Z = 2.40 (P = 0.02) 2.1.4 total Barnett et al.2007 -1.36 1.03 136 -1.36 1.01 127 12.1% 0.00 [-0.24, 0.24] Bergenstal et al.2009 -2.67 1.79 124 -1.75 1.57 124 11.6% -0.54 [-0.80, -0.29] Bunck et al.2009 -0.8 0.6 36 -0.7 1.15 33 5.4% -0.11 [-0.58, 0.36] Davies et al.2009 -1.25 0.89 98 -1.26 0.9 102 10.6% 0.01 [-0.27, 0.29] Diamante et al.2010 -1.5 0.76 228 -1.3 0.92 220 14.7% -0.24 [-0.42, -0.05] Heine et al 2005 -1 1 275 -1.05 0.97 260 15.5% 0.05 [-0.12, 0.22] Nauck et al.2007 -1.04 1.11 253 -0.89 0.94 248 15.2% -0.15 [-0.32, 0.03] Russell-jones et al.2009 -1.33 1.37 232 -1.09 1.38 234 14.9% -0.17 [-0.36, 0.01] Subtotal (95% CI) 1382 1348 100.0% -0.14 [-0.27, -0.02] Heterogeneity: Tau² = 0.02; Chi² = 18.26, df = 7 (P = 0.01); I² = 62% Test for overall effect: Z = 2.20 (P = 0.03) -0.5 -0.25 0 0.25 0.5 Favours GLP-1 Favours insulin 31
  32. 32. Figure 3. Forest plot illustrating the change in fasting plasma glucose levels followingtreatment with GLP-1 RA or insulin. IV= inverse variance. GLP-1 insulin Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Barnett et al.2007 -2.9 2.33 136 -4.1 2.25 127 14.4% 1.20 [0.65, 1.75] Bergenstal et al.2009 -1.2 0.3 124 -3.5 0.3 124 15.6% 2.30 [2.23, 2.37] Bunck et al.2009 -1.6 1.8 36 -2.9 2.3 33 12.3% 1.30 [0.32, 2.28] Davies et al.2009 -2.12 2.54 103 -3.61 2.51 101 13.8% 1.49 [0.80, 2.18] Diamante et al.2010 -2.1 2.9 214 -2.8 2.9 207 14.4% 0.70 [0.15, 1.25] Heine et al 2005 -1.25 2.18 282 -2.56 2.16 267 15.1% 1.31 [0.95, 1.67] Nauck et al.2007 -1.8 3.2 253 -1.7 3.15 248 14.4% -0.10 [-0.66, 0.46] Total (95% CI) 1148 1107 100.0% 1.18 [0.43, 1.93] Heterogeneity: Tau² = 0.93; Chi² = 142.75, df = 6 (P < 0.00001); I² = 96% -2 -1 0 1 2 Test for overall effect: Z = 3.10 (P = 0.002) Favours GLP-1 Favours insulin 32
  33. 33. Figure 4. Forest plot illustrating the change in body weight from baseline to endpointfollowing treatment with GLP-1 RA or insulin. IV=inverse variance. GLP-1 insulin Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI 4.1.1 exenatide vs insulin Barnett et al.2007 -1.6 3.5 136 0.6 3.38 127 17.5% -2.20 [-3.03, -1.37] Bergenstal et al.2009 -1.9 3.8 124 4.1 5.4 124 16.0% -6.00 [-7.16, -4.84] Bunck et al.2009 -3.6 3.6 36 1 4.6 33 12.2% -4.60 [-6.56, -2.64] Davies et al.2009 -2.73 3.1 100 2.98 3.16 104 17.4% -5.71 [-6.57, -4.85] Heine et al 2005 -2.32 3.19 231 1.75 3.28 244 18.4% -4.07 [-4.65, -3.49] Nauck et al.2007 -2.5 3.2 253 2.9 3.1 248 18.5% -5.40 [-5.95, -4.85] Subtotal (95% CI) 880 880 100.0% -4.65 [-5.78, -3.52] Heterogeneity: Tau² = 1.71; Chi² = 55.24, df = 5 (P < 0.00001); I² = 91% Test for overall effect: Z = 8.08 (P < 0.00001) 4.1.2 exenatide vs biphasic insulin Bergenstal et al.2009 -1.9 3.8 124 4.1 5.4 124 18.4% -6.00 [-7.16, -4.84] Nauck et al.2007 -2.5 3.2 253 2.9 3.1 248 81.6% -5.40 [-5.95, -4.85] Subtotal (95% CI) 377 372 100.0% -5.51 [-6.01, -5.01] Heterogeneity: Tau² = 0.00; Chi² = 0.84, df = 1 (P = 0.36); I² = 0% Test for overall effect: Z = 21.67 (P < 0.00001) 4.1.3 GLP-1 vs glargine Barnett et al.2007 -1.6 3.5 136 0.6 3.38 127 17.5% -2.20 [-3.03, -1.37] Bunck et al.2009 -3.6 3.6 36 1 4.6 33 10.2% -4.60 [-6.56, -2.64] Davies et al.2009 -2.73 3.1 100 2.98 3.16 104 17.3% -5.71 [-6.57, -4.85] Diamante et al.2010 -2.6 3.1 233 1.4 3 223 19.1% -4.00 [-4.56, -3.44] Heine et al 2005 -2.32 3.19 231 1.75 3.28 244 19.0% -4.07 [-4.65, -3.49] Russell-jones et al.2009 -1.8 5 230 1.6 5.03 232 16.9% -3.40 [-4.31, -2.49] Subtotal (95% CI) 966 963 100.0% -3.95 [-4.83, -3.07] Heterogeneity: Tau² = 0.97; Chi² = 35.13, df = 5 (P < 0.00001); I² = 86% Test for overall effect: Z = 8.81 (P < 0.00001) 4.1.4 total Barnett et al.2007 -1.6 3.5 136 0.6 3.38 127 13.0% -2.20 [-3.03, -1.37] Bergenstal et al.2009 -1.9 3.8 124 4.1 5.4 124 11.6% -6.00 [-7.16, -4.84] Bunck et al.2009 -3.6 3.6 36 1 4.6 33 8.2% -4.60 [-6.56, -2.64] Davies et al.2009 -2.73 3.1 100 2.98 3.16 104 12.9% -5.71 [-6.57, -4.85] Diamante et al.2010 -2.6 3.1 233 1.4 3 223 13.9% -4.00 [-4.56, -3.44] Heine et al 2005 -2.32 3.19 231 1.75 3.28 244 13.9% -4.07 [-4.65, -3.49] Nauck et al.2007 -2.5 3.2 253 2.9 3.1 248 14.0% -5.40 [-5.95, -4.85] Russell-jones et al.2009 -1.8 5 230 1.6 5.03 232 12.6% -3.40 [-4.31, -2.49] Subtotal (95% CI) 1343 1335 100.0% -4.40 [-5.23, -3.56] Heterogeneity: Tau² = 1.23; Chi² = 63.52, df = 7 (P < 0.00001); I² = 89% Test for overall effect: Z = 10.28 (P < 0.00001) -4 -2 0 2 4 Favours GLP-1 Favours insulin 33
  34. 34. Figure 5. Forest plot illustrating the overall incidence of hypoglycemia followingtreatment with GLP-1 RA or insulin. M-H= Mantel-Haenszel. GLP-1 insulin Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI Barnett et al.2007 20 136 32 127 17.1% 0.51 [0.28, 0.95] Bergenstal et al.2009 36 124 76 124 18.3% 0.26 [0.15, 0.44] Bunck et al.2009 3 36 8 33 8.3% 0.28 [0.07, 1.18] Davies et al.2009 59 118 68 116 18.5% 0.71 [0.42, 1.18] Diamante et al.2010 19 233 58 223 18.0% 0.25 [0.14, 0.44] Russell-jones et al.2009 63 230 67 232 19.9% 0.93 [0.62, 1.39] Total (95% CI) 877 855 100.0% 0.45 [0.27, 0.76] Total events 200 309 Heterogeneity: Tau² = 0.30; Chi² = 23.03, df = 5 (P = 0.0003); I² = 78% 0.1 0.2 0.5 1 2 5 10 Test for overall effect: Z = 3.03 (P = 0.002) Favours GLP-1 Favours insulinFigure 6. Forest plot illustrating the overall incidence of adverse events followingtreatment with GLP-1 RA or insulin. M-H= Mantel-Haenszel. GLP-1 insulin Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI Davies et al.2009 83 118 25 116 20.0% 8.63 [4.77, 15.62] Diamante et al.2010 72 233 22 223 20.3% 4.09 [2.43, 6.88] Heine et al 2005 263 282 43 267 20.1% 72.11 [40.84, 127.32] Nauck et al.2007 153 253 14 248 20.0% 25.57 [14.10, 46.38] Russell-jones et al.2009 85 230 11 232 19.7% 11.78 [6.07, 22.83] Total (95% CI) 1116 1086 100.0% 15.00 [5.44, 41.35] Total events 656 115 Heterogeneity: Tau² = 1.25; Chi² = 60.15, df = 4 (P < 0.00001); I² = 93% 0.01 0.1 1 10 100 Test for overall effect: Z = 5.23 (P < 0.00001) Favours GLP-1 Favours insulin 34
  35. 35. Conflict of interest details: Design: Ling Li, Gangyi YangConduct/data collection:Yisu Wang, Mengliu YangAnalysis: Yisu Wang,Ling LiWriting manuscript and revise: Yisu Wang, Hua Liu, Guenther Boden, Gangyi YangAuthorship details: This article has no declaration of competinginterests to report. The authors also denied any affiliation to anyorganization or entity which is relevant to the work reported. 35

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