ORIGINAL RESEARCH

Effect of Dipeptidyl Peptidase4 Inhibitors Usedin Combination with Insulin Treatment in Patientswith Type2 Diabetes: A Systematic Review and Meta-analysis

Jin Yang . Qing Tian . Yuexin Tang . Arvind K. Shah .

Ruya Zhang . Guojuan Chen . Ye Zhang . Swapnil Rajpathak .

Tianpei Hong

Received: July 26, 2020 / Published online: September 2, 2020� The Author(s) 2020

ABSTRACT

Introduction: To evaluate the efficacy andsafety of dipeptidyl peptidase 4 inhibitors(DPP4i) used in combination with insulin inpatients with type 2 diabetes mellitus (T2DM).Methods: We searched the MEDLINE, Embase,and Cochrane library databases for randomizedcontrolled trials (RCTs) published through June2018. Studies with at least a 12-week treatmentperiod were included to compare the additionof DPP4i to insulin with insulin control ther-apy. Meanwhile, groups on a stable insulindosage (insulin-stable subgroup) or titrating

insulin dosage (insulin-flexible subgroup) wereanalyzed separately.Results: Twenty-one RCTs with 3697 patientsrandomized to a DPP4i/insulin treatment armand 3538 to an insulin control arm were inclu-ded. DPP4i, when added to insulin therapy, ledto a significantly greater reduction in HbA1c(- 0.57%, 95% CI - 0.66, - 0.48) and providedsignificantly greater odds of achieving theHbA1c target\7% (OR 3.45; 95% CI 2.58,4.63). These effects were achieved in the contextof a decrease in the daily insulin requirement,without increases in hypoglycemia risk andbody weight, compared with the control treat-ment. Subgroup analysis showed control-ad-justed reductions in HbA1c from baseline in theinsulin-stable subgroup (- 0.64%; 95% CI- 0.74, - 0.53) and the insulin-flexible sub-group (- 0.43%; 95% CI - 0.56, - 0.30). Otherresults occurred similarly in both subgroups.Conclusions: The addition of DPP4i to insulinis associated with a statistically significantreduction in glycemic control as measured byHbA1c, fasting plasma glucose, and 2-h post-prandial glucose, without increasing the risk ofhypoglycemia and weight gain. These conclu-sions were also observed in both stable-dose andflexible-dose insulin subgroups.

Keywords: Dipeptidyl peptidase 4 inhibitor;Insulin; Type 2 diabetes

Jin Yang and Qing Tian contributed equally to this work.

Digital Features To view digital features for this articlego to https://doi.org/10.6084/m9.figshare.12788354.

Electronic supplementary material The onlineversion of this article (https://doi.org/10.1007/s13300-020-00914-x) contains supplementary material, which isavailable to authorized users.

J. Yang � Q. Tian � T. HongDepartment of Endocrinology and Metabolism,Peking University Third Hospital, Beijing, China

Y. Tang � A. K. Shah � S. Rajpathak (&)MRL, Merck & Co., Inc., Kenilworth, NJ, USAe-mail: swapnil.rajpathak@merck.com

R. Zhang � G. Chen � Y. ZhangMedical Affairs, MSD China Holding Co., Ltd.,Shanghai, China

Diabetes Ther (2020) 11:2371–2382

https://doi.org/10.1007/s13300-020-00914-x

Key Summary Points

Why carry out this study?

Effect of DPP4i used in combination withinsulin treatment in patients with T2DMremains unclear in real-world clinicalpractice.

In this meta-analysis, 21 RCTs with 3697patients randomized to a DPP4i/insulintreatment arm and 3538 to an insulincontrol arm were included.

What was learned from the study?

The addition of DPP4i to insulin isassociated with a statistically significantreduction in glycemic control as measuredby HbA1c, FPG, and PPG-2h, withoutincreasing the risk of hypoglycemia andweight gain.

These data allowed us to truly evaluate theefficacy and safety of DPP4i as add-ontherapy to insulin in real-world clinicalpractice.

DIGITAL FEATURES

This article is published with digital features tofacilitate understanding of the article. You canaccess the digital features on the article’s asso-ciated Figshare page. To view digital features forthis article go to https://doi.org/10.6084/m9.figshare.12788354.

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a serioushealth problem that affects people around theworld. The latest estimates showed a globaldiabetes prevalence of 9.3% (463 million) of theworld population in 2019, and the prevalence isexpected to further increase to 10.2% (578 mil-lion) by the year 2030 [1]. The diabetes preva-lence has been rising more rapidly in middle-

and low-income countries. However, in somecountries like China only a small proportion ofpatients with T2DM reach the target level ofhemoglobin A1c (HbA1c) [2]. Poor glycemiccontrol can lead to a variety of serious compli-cations of T2DM, including cardiovascular dis-ease and diabetic nephropathy, which are majorcauses of mortality [3]. Therefore, achieving thetargeted glycemic control is a key element ofdiabetes management.

The T2DM treatment guidelines suggest earlyinitiation of insulin and treatment intensifica-tion for patients who are not achieving gly-cemic goals [3]. On the other hand, with theprogression of disease, insulin monotherapysometimes fails to provide good glycemicresults, or up-titration of insulin is required toachieve or maintain adequate glycemic control.Some concerns about insulin initiation havetherefore been raised, such as the risk of hypo-glycemia, weight gain, and barriers to insulinself-titration [4, 5]. Thus, the use of the combi-nation of insulin treatment with oral antidia-betic drugs (OADs) is recommended tominimize side effects and obtain optimal gly-cemic control [6].

Dipeptide peptidase 4 enzyme inhibitors(DPP4i) are a class of OADs that prevent thedegradation of gastrointestinal incretins gluca-gon-like peptide 1 (GLP-1) and glucose-depen-dent insulinotropic polypeptide (GIP), resultingin glycemic improvement [6]. Both randomizedclinical trials (RCTs) and pooled studies havedemonstrated that DPP4i offer an ideal thera-peutic option, as they improve glycemic controlwith a low risk of hypoglycemia and neutraleffect on body weight [7, 8]. DPP4i have beenlisted as a strategic option to minimize hypo-glycemia for individuals with HbA1c abovetarget [3]. A number of RCTs have evaluated theefficacy and safety of DPP4i as add-on therapyto insulin in patients with T2DM [9–11]. How-ever, the results are inconsistent, which may bedue to variations in study design, patient pop-ulations, and insulin regimens.

Four previous meta-analyses evaluated theefficacy and safety of the addition of a DPP4i toinsulin therapy in patients with T2DM [12–15].However, these studies (1) mixed active controlsand placebo as comparators, which made the

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interpretation of the pooled results difficult; (2)only included patients who were on a stable in-sulin dose, which was not applicable to clinicalpractice, because combined therapy is oftenindicated in patients who do not achieve opti-mal glycemic control by insulin therapy andinsulin dose titration is needed in thesepatients; or (3) only included patients on insu-lin monotherapy or insulin plus metformin,which may not be representative of the generalpopulation. Therefore, an updated systematicreview and meta-analysis is needed to evaluatethe efficacy and safety of DPP4i used in combi-nation with insulin in patients with T2DMcompared with insulin control treatment.

This meta-analysis evaluated the efficacy andsafety of DPP4i used in combination withinsulin in patients with T2DM and separatelyanalyzed subgroups on a stable insulin dosageversus a titrating insulin dosage.

METHODS

Data Sources and Search Strategies

Studies were identified by a literature search ofMEDLINE (PubMed), Embase, and the Cochranelibrary through June 2018. The search termswere (DPP-4 OR DPP-4 OR ‘‘dipeptidyl pepti-dase-4 inhibitors’’ OR sitagliptin OR vildagliptinOR linagliptin OR saxagliptin OR alogliptin ORdutogliptin OR gemigliptin OR anagliptin ORgosogliptin OR teneligliptin OR trelagliptin ORomarigliptin) AND (‘‘insulin’’ OR ‘‘basal insulin’’OR ‘‘premix insulin’’ OR ‘‘CSII’’ OR ‘‘short-act-ing’’ OR ‘‘basal–bolus’’ OR ‘‘basal bolus’’ ORglargine OR detemir OR degludec OR NPH ORlispro OR aspart OR rapid insulin OR insulinanalogue) AND (T2DM OR ‘‘type 2 diabetesmellitus’’ OR ‘‘type 2 diabetes’’) AND (randomOR randomly OR randomized). The searchedstudies were limited to clinical trials in human.

Eligibility and Exclusion Criteria for StudySelection

The eligibility criteria were (1) RCTs in adultpatients with T2DM; (2) compared the addition

of DPP4i to insulin therapy (either with regi-mens of basal insulin, basal and premeal bolusof insulin, or premixed insulin) with insulincontrols, with or without background therapywith other OADs; (3) study duration at least12 weeks; and (4) reported at least one clinicaloutcome of interest. Non-RCTs, studies inpatients with type 1 diabetes, and duplicatedresults were excluded.

Data Extraction

Data were extracted by two independent inves-tigators. The following data from each studywere recorded: publication data (title, firstauthor, year of publication), study design,baseline characteristics of the study population,drug regimen, treatment duration, efficacyoutcomes [HbA1c, fasting plasma glucose (FPG),2-hour postprandial glucose (PPG-2h), totaldaily insulin dose; the number of participantsachieving the target HbA1c\7%)] and safetyoutcomes (body weight and incidence ofhypoglycemia). Disagreements were resolved byconsensus with a third investigator.

Assessment of Quality of Included Studies

Two independent investigators assessed thequality of the included studies by using theCochrane risk of bias tool in terms of selectionbias, performance bias, detection bias, attritionbias, reporting bias, and other biases [16]. Plotanalysis and Egger’s test were used for assess-ment of publication bias.

Statistical Analysis

For the continuous variables, including thechange in HbA1c, FPG, PPG-2h, body weight,and daily dosage of insulin from baseline, effectsizes were estimated using meta-analysis asweighted mean differences (WMDs) with 95%confidence intervals (95% CIs). For categoricaloutcomes such as the number of participantsachieving the HbA1c goal and those havinghypoglycemia, pooled odds ratios (ORs) werecalculated by meta-analysis. For all meta-anal-yses, a random effects model with inverse-

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variance weights and DerSimonian-Laird mea-sure for estimating heterogeneity (the between-study variance) were used. The I2 statistic wasused to calculate the extent of heterogeneityacross the selected studies. The meta-analysiswas conducted using the R software. A p valueless than 0.05 was considered statisticallysignificant.

Compliance with Ethics Guidelines

Ethical approval was unnecessary in this studybecause it was a systematic review and meta-analysis of existing published articles andtherefore does not contain any studies withhuman participants or animals performed byany of the authors.

RESULTS

Description of Enrolled Studies

A total of 2630 published articles were retrieved,among which 21 RCTs with 3697 patients ran-domized to a DPP4i/insulin treatment arm and3538 patients randomized to an insulin controlarm were finally included for the meta-analysis[9–11, 17–34]. The study selection process issummarized in Fig. 1. The characteristics of theincluded studies are shown in SupplementaryTable 1.

Quality of Included Studies and Riskof Publication Bias

There were 12 studies not clearly describing themethods of random sequence generation and/or allocation concealment (selection bias). Twotrials showed a high risk of performance anddetection bias. Also, risk of performance anddetection bias was unclear in four trials, and therisk was judged to be low for the other studies.Two, one, and two studies were considered tohave an unclear risk for incomplete outcomedata, selective reporting, and other bias,respectively, and the risks were considered lowfor the others. The risk of bias analysis is sum-marized in Supplementary Fig. 1.

The funnel plot did not show an asymmetrywith the non-significant result of Egger’s test forthe outcomes assessed, including change inHbA1c (p = 0.2501), FPG (p = 0.4435), PPG-2h(p = 0.4732), and body weight (p = 0.1022), andOR for incidences of overall hypoglycemia(p = 0.3704), symptomatic hypoglycemia (p =0.6073), and severe hypoglycemia (p = 0.5744).However, there was evidence of publication biasfor change in daily insulin dose (p = 0.0002)and for HbA1c goal attainment (p\ 0.0001).The results of the funnel plot analysis aredepicted in Supplementary Fig. 2.

Efficacy OutcomesChange in HbA1c All enrolled studies involv-ing 6851 patients with T2DM assessed thechange in HbA1c levels. The combinationtherapy of insulin and a DDP4i led to a greaterreduction in HbA1c level as compared with thecontrol (WMD = - 0.57%; 95% CI - 0.66,- 0.48; p\0.0001). A significant heterogeneityamong studies was detected (I2 = 82%,p\0.01). Subgroup analysis showed that con-trol-adjusted reductions in HbA1c from baselinewere observed in both the insulin-stable sub-group (WMD = - 0.64%; 95% CI - 0.74,- 0.53) and insulin-flexible subgroup (WMD =- 0.43%; 95% CI - 0.56, - 0.30) (Fig. 2).

Achievement of HbA1c Target Goal Eighteenstudies assessed the proportion of patientsachieving the target HbA1c (\ 7%). The com-bination therapy of DPP4i and insulin wasassociated a higher likelihood of achieving thisgoal (OR 3.45; 95% CI 2.58, 4.63; p\ 0.0001).Significant heterogeneity among studies wasdetected (I2 = 62%, p\ 0.01). In subgroupanalysis, the combination therapy of DPP4i andinsulin demonstrated a greater chance toachieve the target HbA1c goal in comparisonwith the control treatment in both the insulin-stable subgroup (OR 4.33; 95% CI 2.90, 6.48)and insulin-flexible subgroup (OR 2.43; 95% CI1.71, 3.46) (Fig. 3).

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Change in FPG Pooled analysis of 16 studiesassessed the change in FPG. The FPG changefrom baseline was significant between theDPP4i/insulin and control groups(WMD = - 0.53 mmol/L; 95% CI - 0.72,- 0.34; p\ 0.0001). The heterogeneity amongstudies was not significant (I2 = 37%, p = 0.07).Subgroup analysis revealed that the differencein the adjusted change from baseline for theDPP4i/insulin group compared with the controlwas - 0.64 mmol/L (95% CI - 0.84, - 0.44) inthe insulin-stable subgroup and - 0.27 mmol/L(95% CI - 0.66, 0.11) in the insulin-flexiblesubgroup (Supplementary Fig. 3).

Change in PPG-2h Seven studies were used forthe analysis of the PPG-2h change from base-line, which was significant between DPP4i/

insulin and control groups (WMD = - 1.91mmol/L; 95% CI - 2.24, - 1.58; p\ 0.0001).The heterogeneity among studies was not sig-nificant (I2 = 5%, p = 0.39). Subgroup analysisshowed that the control-adjusted mean changein PPG-2h from baseline was - 1.85 mmol/L(95% CI - 2.18, - 1.53) and - 2.55 mmol/L(95% CI - 3.67, - 1.43) in the insulin-stable and insulin-flexible subgroups, respec-tively (Supplementary Fig. 4).

Change in Daily Dosage of Insulin Use For thechange in daily insulin dose from baseline, 11studies were included for the analysis, of whichseven studies examined patients on stable in-sulin dose regimens while the other four studiesexamined patients with insulin dose titration.DPP4i/insulin treatment led to a greater

Fig. 1 Flow chart for the selection of studies

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decrease in daily insulin dose as compared withthe control treatment (WMD = - 1.94 IU/day;95% CI - 2.75, - 1.12; p\ 0.0001). Theheterogeneity among studies was significant(I2 = 93%, p\ 0.01).

In studies adopting a stable insulin dosage,insulin doses were maintained stable through-out the study, except if the insulin dose wasadjusted for glycemic rescue. Thus, the adjustedmean change in total daily insulin dose wasrelatively small (- 1.69 IU/day; 95% CI - 2.87,- 0.51). In contrast, among studies with atitrating insulin dosage, a larger adjustedreduction in daily insulin dose (- 4.70 IU/day;95% CI - 8.18, - 1.22) was observed, due to amore flexible regimen that allowed up-titration

of insulin in the control arm (SupplementaryFig. 5).

Safety OutcomesIncidence of Hypoglycemia Pooled analysis of18 studies with 6209 patients was performed toexamine the incidence rate of overall hypo-glycemia. Despite the lack of a universal defi-nition for hypoglycemia across the includedstudies, the risk of developing overall hypo-glycemia was similar between the DPP4i/insulinand control groups (OR 0.92; 95% CI 0.76, 1.12;p = 0.4310; significant heterogeneity amongstudies with I2 = 49%, p\ 0.01) (Fig. 4). We alsoanalyzed the risks of symptomatic hypo-glycemia and severe hypoglycemia, which did

Fig. 2 Results assessed by forest plots for the change in HbA1c from baseline (%)

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not differ between treatment with DPP4i/in-sulin and control (symptomatic hypoglycemia,OR 1.08, 95% CI 0.69, 1.68, p = 0.7484; signifi-cant heterogeneity among studies withI2 = 79%, p\0.01; and severe hypoglycemia,OR 1.00, 95% CI 0.66, 1.52, p = 0.9863; non-significant heterogeneity among studies withI2 = 0%, p = 0.98) (Supplementary Figs. 6 and7).

Among studies with a stable insulin dosage,DPP4i/insulin treatment caused an increasedrisk of symptomatic hypoglycemia (OR 1.64;95% CI 1.20, 2.25; p\0.05) compared with thecontrol. For studies with flexible insulin dosing,DPP4i/insulin did not increase the likelihood ofsymptomatic hypoglycemia (OR 0.71; 95% CI0.45, 1.14; p[0.05) (Supplementary Fig. 6).

Irrespective of the subgroup, the risk of devel-oping severe hypoglycemia was not signifi-cantly different with DPP4i/insulin relative tothe control treatment (Supplementary Fig. 7).

Change in Body Weight The change in bodyweight from baseline did not differ significantlybetween patients receiving DPP4i/insulin andcontrol treatment (WMD = 0.02 kg; 95% CI- 0.30, 0.34; p = 0.8931). The heterogeneityamong studies was significant (I2 = 77%,p\0.01). Subgroup analysis revealed that theadjusted mean change in body weight frombaseline was 0.02 kg (95% CI - 0.16, 0.19) inthe insulin-stable group and - 0.33 kg (95% CI- 1.51, 0.85) in the insulin-flexible group(Supplementary Fig. 8).

Fig. 3 Results assessed by forest plots for odds ratio (OR) in terms of achieving HbA1c\ 7.0%

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DISCUSSION

The resulting data revealed that the combina-tion therapy of a DPP4i and insulin yieldsimproved glycemic control and decreased dailyinsulin requirement, without increasing the riskof hypoglycemia and body weight, comparedwith the insulin control group. This was seen inpatients with or without concomitant use ofother OADs, such as metformin. Unlike previ-ous meta-analysis, this study evaluated theefficacy and safety of DPP4i in combinationwith insulin therapy in studies adopting flexibleor stable insulin regimens separately. In studiesthat were designed to flexibly up- or down-ti-trate the dose of insulin in a fashion mimicking

normal clinical practice, the DPP4i and insulincombination treatment provided glycemicbenefits and a clear insulin-sparing effect as wellas potentially reduced risks of hypoglycemia.These data allowed us to truly evaluate theefficacy and safety of DPP4i as add-on therapyto insulin.

DPP4i have been reported to lower HbA1clevels when used alone and in combinationtherapy [35, 36]. In a meta-analysis involving 43RCTs and 19,101 participants, all DPP4i resultedin a greater proportion of patients reaching theHbA1c target of less than 7% than did placebo,regardless of the type of combined antidiabeticdrugs [37]. In this study, DPP4i, when added toinsulin therapy, led to a greater reduction in

Fig. 4 Results assessed by forest plots for odds ratio (OR) in terms of developing overall hypoglycemia

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HbA1c and achievement of HbA1c target\7%.Also, the addition of DPP4i to ongoing insulintherapy provided significant reductions in FPGand PPG-2h relative to the control, demon-strating that DPP4i in combination with insulintherapy can improve fasting and postprandialglycemic control. In particular, DPP4i areeffective at decreasing postprandial plasmaglucose excursion [36, 38], whereas treatmentregimens with basal or premixed insulinpreparations may not adequately control gly-cemic excursions in the postprandial state.Therefore, a beneficial effect can be produced bythe complementary action of insulin combinedwith DPP4i.

In most included studies, the insulin dosewas designed to remain stable throughout thestudy period, unless the insulin dose needed tobe adjusted because of hypoglycemia or hyper-glycemia rescue, which is unlikely to be a truereflection of real-world clinical practice wherethe clinician would choose between add-ontherapy and titration of insulin dosage forpatients with poorly controlled T2DM. There-fore, we performed an insulin-flexible subgroupanalysis to explore which, insulin up-titrationversus addition of a DPP4i, would be more effi-cacious and safer. DPP4i, when added to insulintitration therapy, led to significantly greaterreductions in HbA1c of - 0.43% (- 0.56;- 0.30), FPG of - 0.27 mmol/L (- 0.66; 0.11),and 2-h PPG of - 2.55 mmol/L (95% CI - 3.67,- 1.43) and provided significantly greater oddsfor achieving the HbA1c target of less than 7%(OR 2.43; 95% CI 1.71, 3.46) relative to thecontrol treatment. Additionally, an adjustedreduction in daily insulin dose (- 4.70 IU/day;95% CI - 8.18, - 1.22) was observed in theinsulin-flexible subgroup. The incidence rates ofhypoglycemia varied across the studies inclu-ded. In this meta-analysis, we observed similarrates of overall hypoglycemia between theDPP4i/insulin and control groups in spite of thegreater blood glucose-lowering effect withDPP4i as evidenced by a control-adjustedreduction in HbA1c of 0.57%. These findingsare consistent with the known mechanism ofaction of DPP4i, which enhance insulin secre-tion by b-cells and/or decrease glucagon releaseby a-cells in a glucose-dependent manner [6].

Thus, the use of DPP4i in combination withinsulin may improve glycemic control withoutincreasing the risk of hypoglycemia.

Several studies evaluated the impact of theaddition of a DPP4i to insulin versus active up-titration of insulin on efficacy and safety end-points. In a study by Hong et al., compared to a25% increase in insulin dose, adding sitagliptinto an insulin-based regimen was more effectiveat lowering HbA1c and associated with lesshypoglycemia and weight gain over 24 weeks[19]. The similar results were found by Mathieuet al. [27]. In addition, insulin dose titrationwould likely carry a greater risk of hypoglycemiathat should be weighed against any glycemicbenefit. In this regard, the benefits of adding aDPP4i to insulin therapy could be even greaterwhen compared to intensified insulin therapy,especially for those particular patients who areconcerned about weight gain and/or those moreprone to hypoglycemia. In our study, DPP4i/insulin treatment did not increase the likeli-hood of hypoglycemia in comparison with up-titration of the insulin regime. In fact, the ORvalues for overall hypoglycemia and symp-tomatic hypoglycemia were less than 1 in theinsulin-flexible group (0.74 and 0.71, respec-tively), which indicated a decreased likelihoodof developing these hypoglycemia events,although the differences were not significant.

This study has several limitations. First, thepresent meta-analysis comprised studies withvarious types of insulin regimens and back-ground OADs used, which might introducesome bias. Also, evidence of publication bias forthe change in daily insulin dose and for HbA1cgoal attainment was observed. The results musttherefore be interpreted with caution. Second,algorithms for adjustment of insulin doses werenot consistent in the studies included, whichmight affect the insulin dosage used and therate of hypoglycemia among studies. Third, thenumbers of participants in some treatmentgroups differed greatly, which might limit thestatistical power. For T2DM management,besides glucose management, it is also impor-tant to control other cardiovascular risk factors,such as dyslipidemia, excess adiposity, andhypertension.

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CONCLUSION

The findings of the present study indicate thatthe addition of DPP4i to insulin is associatedwith a statistically significant reduction in gly-cemic control as measured by HbA1c, FPG, andPPG-2h, without increasing the risk of hypo-glycemia and weigh gain. Similar conclusionswere also observed in both stable-dose andflexible-dose insulin subgroups.

ACKNOWLEDGEMENTS

Funding. The study and the journal’s rapidservice fee were funded by MSD China.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Authorship Contributions. AKS and THperformed analyses. RZ collected and assembledthe data, wrote sections of the initial draft. JY,QT, YT, AKS, RZ, YZ, SR and TH interpreted theresults. All authors conceived and designedresearch, provided substantive suggestions forrevision, reviewed and approved final version ofthe paper, and for all aspects of the work inensuring that questions related to the accuracy.

Medical Writing and Editorial Assis-tance. Medical writing and editorial assistancewas provided by Medjaden Bioscience Limitedand was funded by MSD China. Shangyu Chaiof MSD China Holding Co., Ltd., Shanghai,China, reviewed and provided inputs on draftsof the manuscript. Administrative assistancewas provided by Louie Liang of MSD ChinaHolding Co., Ltd., Shanghai, China.

Disclosures. Swapnil Rajpathak, YuexinTang and Arvind K. Shah are employees ofMerck & Co., Inc., Ruya Zhang and Ye Zhangare employees of MSD China Holding Co., Ltd.,Guojuan Chen is ex-employee of MSD China

Holding Co., Ltd. Jin Yang, Qing Tian andTianpei Hong have nothing to disclose.

Compliance with Ethics Guidelines. Ethicalapproval was unnecessary in this study becauseit was a systematic review and meta-analysis ofexisting published articles and therefore doesnot contain any studies with human partici-pants or animals performed by any of theauthors.

Data Availability. All data relevant to thestudy are included in the article and uploadedas supplementary information.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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