Efficacy and Safety of Short- andLong-Acting Glucagon-LikePeptide 1 Receptor Agonists on aBackground of Basal Insulin inType 2 Diabetes: A Meta-analysisDiabetes Care 2020;43:2303–2312 | https://doi.org/10.2337/dc20-0498

PURPOSE

To compare the efficacy and safety of short- and long-acting glucagon-like peptide1 receptor agonists (GLP-1 RAs), both used in combination with basal insulin, inpatients with type 2 diabetes.

DATA SOURCES AND STUDY SELECTION

Randomized controlled trials comparing the coadministration of short- or long-acting GLP-1 RAs and basal insulin with basal insulin 6 placebo were identified(PubMed search). Of 974 identified publications, 14 clinical trials were included.Eight trials examined short-acting and six long-acting GLP-1 RAs.

DATA EXTRACTION AND DATA SYNTHESIS

Differences inHbA1c, fasting plasma glucose, bodyweight, and adverse eventswerecomparedbetween studies using short- or long-acting GLP-1 RAs by random-effectsmeta-analysis.

LIMITATIONS

There were relatively small numbers of available publications, some heterogeneityregarding protocols, and differences in the GLP-1 RA compound used.

CONCLUSIONS

Long-acting GLP-1 RAs more effectively reduced HbA1c (Δ 26 mmol/mol [95%CI210;22], P5 0.007), fasting plasma glucose (Δ20.7 mmol/L [21.2;20.3], P50.007), and body weight (Δ 21.4 kg [22.2; 20.6], P 5 0.002) and raised theproportion of patients achieving an HbA1c target <7.0% (<53mmol/mol) (P5 0.03)more than the short-acting ones. Patients reporting symptomatic (P 5 0.048) butnot severe (P50.96) hypoglycemiawere fewerwith long- versus short-actingGLP-1RAs added to insulin. A lower proportion of patients reported nausea (252%, P <

0.0001) or vomiting (236%, P5 0.0002) with long-acting GLP-1 RAs. Overall, GLP-1RAs improved HbA1c, fasting plasma glucose, and bodyweight when added to basalinsulin. However, long-acting GLP-1 RAs were significantly more effective forglycemic and bodyweight control and displayed better gastrointestinal tolerability.

Diabetes Division, Katholisches Klinikum Bo-chum, St. Josef-Hospital, Ruhr-University Bo-chum, Bochum, Germany

Corresponding author: Michael A. Nauck, mi-chael.nauck@rub.de

Received 12 March 2020 and accepted 3 May2020

This article contains supplementary material onlineat https://doi.org/10.2337/figshare.12272840.

© 2020 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered. More infor-mation is availableathttps://www.diabetesjournals.org/content/license.

Jessica A. Huthmacher, Juris J. Meier, and

Michael A. Nauck

Diabetes Care Volume 43, September 2020 2303

META

-ANALYSIS

Glucagon-like peptide 1 receptor agonists(GLP-1 RAs) are used not only on a back-ground of oral glucose-lowering medica-tions but also in conjunction with basalinsulin therapy (1,2). On the basis of theirpharmacokinetic properties, short-actingGLP-1RAsat their recommendedinjectionregimens lead to intermittent exposure,changing between short-lived peaks withtroughs characterized by negligible drugconcentrations in between (3). Long-acting GLP-1 RAs are characterized by asteadier exposure, with relatively smallfluctuations in plasma drug concentra-tions over a 24-h period (3). The resultingcontinuous exposure of GLP-1 receptorsleads to tachyphylaxis for the decelerationof gastric emptying with prolonged use ofGLP-1 RAs (4–7). Since postmeal glycemicexcursions are determined by the velocityof gastric emptying (8,9), long-acting GLP-1RAs in the long runhave less of an effect onpostprandial glucose increments (3,6,7),while short-acting GLP-1 RAs retain theability to slow gastric emptying and tocause rather flat postmeal glycemic ex-cursions, even with prolonged treat-ment (3,6,7).On a background of oral glucose-lowering

agents, long-acting GLP-1 RAs are moreeffective in controlling HbA1c, mainlythrough their better ability to lower fastingglucose (3,6,10), directly related to over-night exposure to higher drug concentra-tions compared with short-acting GLP-1RAs (11). Combinations of basal insulinand GLP-1 RAs have been proposed to actin a synergisticmanner, assuming that thebasal insulin component will mainly con-trol fasting plasma glucose, while theGLP-1 RA is thought to limit postmeal glycemicincrements. Suchcombinationshavebeenshown to provide an overall glycemiccontrol similar to more complex basal-bolus regimens (12). On the basis oftheoretical considerations, it has beenassumedthat insuchcombinationtherapyregimens, short-actingagents shouldhavethe advantage of more profoundly affect-ing postprandial glycemic increments be-cause of their retained action on gastricemptying after long-term exposure. How-ever,whilenumerous studieshaveproventhe effectiveness of GLP-1 RAs on a back-ground of basal insulin therapy (13–26),none have directly compared a short-with a long-acting compound.In the absence of head-to-head com-

parisons, we aimed to compare short-and long-acting GLP-1 RAs when used in

conjunctionwith basal insulin. Therefore, ameta-analysis of published clinical trialscomparing combinations of GLP-1 RAson a background of basal insulin therapywith basal insulin 6 placebo was per-formed, focusing on differences betweenshort- and long-actingcompounds regard-ing their effects on HbA1c, fasting plasmaglucose, and body weight.

METHODS

Search Strategy and Study SelectionFor the present analysis, articles report-ing clinical trials that compared a com-bination of GLP-1 RA and basal insulintherapywithbasal insulin6placebowereidentified through a systematic PubMedsearch. The search terms are displayed inSupplementary Table 1. Studies were in-cluded if published before 31 December2018. Of 1,306 records identified initially,14 publications could be used (13–26),with 8 reporting on a combination ofshort-acting GLP-1RAs (13–20) and 6 re-porting on long-acting GLP-1 RAs plusbasal insulin (21–26). Exclusion criteriaare described in Supplementary Fig. 1according to the Preferred ReportingItems for Systematic Reviews andMeta-Analyses statement (27). Open-label andblinded randomized prospective studieswere eligible if they studied free or fixed-dose combinations ofGLP-1RAs andbasalinsulin in patients with type 2 diabetes.We selected studies reporting baselineand end-of-study HbA1c, fasting plasmaglucose, and body weight as well asadverse events, prevalence of hypoglyce-mia, and proportion of patients prema-turely discontinuing drug treatment. Theminimum duration was 6 weeks. Twostudies reporting on GLP-1 RAs on abackground of premixed insulin prepa-rations in a small subgroup were alsoincluded (14,15). We registered our pro-tocol with PROSPERO (https://www.crd.york.ac.uk/prospero; identification No.CRD42019126069).

Design of the AnalysisReductions in HbA1c, fasting plasma glu-cose, and body weight (study end vs.baseline)were comparedbetweenGLP-1RA plus basal insulin and basal insulin6placebo. These differences were sub-jected to a random-effects meta-analysis,with subgroups defined using short- orlong-acting GLP-1 RAs (ComprehensiveMeta-Analysis version 3; https://www.meta-analysis.com). Changes in HbA1c

were defined as the primary end point.Changes in HbA1c target achievement(,7.0% and #6.5%), fasting plasma glu-cose, and body weight were secondaryend points. Safety end points includedadverse events, hypoglycemia, and pre-mature discontinuation.

Quality AssessmentStudyqualitywasassessedbyapplyingtheJadad score (28) (Supplementary Table 2)and the Risk of Bias tool (https://www.riskofbias.info) (29) (Supplementary Fig.2). All publications were suitable for ouranalysis.

Data ExtractionRelevant data were extracted into pre-structured paper forms listing variablesof interest (SupplementaryMaterial). Datawere extracted by J.A.H. In case of ques-tions, M.A.N. was consulted. In case ofdifferences that could not be resolved,J.J.M. had the final decision. The wayhow gastrointestinal adverse events havebeen captured has systematically beencategorized as shown in SupplementaryTable 3.

Data Synthesis and Meta-analysisFor the main end points (HbA1c, fastingplasma glucose, body weight reduction),the differences between study end andbaseline with their 95% CIs were ana-lyzed. Differences resulting from treat-ment with the combination of GLP-1 RAsandbasal insulin and thoseobtainedwithbasal insulin 6 placebo were subjectedto random-effects meta-analysis. Sub-groups were studies using short- orlong-acting GLP-1 RAs. Output variableswere differences in means (to insulin 6placebo). The subgroups were furthercompared by calculating their differenceas well as pooled SD (30,31) from whichthe 95% CIs were derived and P valuescalculated by unpaired Student t tests(common SD) or by Welch t test (sub-stantially different SDs) (32). Z values, Pvalues, and theweight of single studies inthe overall analysis were obtained foreach study as well as for the subgroupsand all GLP-1 RAs pooled. Heterogeneitywas reported as Q value, I2, and t2. Re-portingbiaseswereassessedusingafunnelplot and further analyzed with Egger re-gression intercept (33)andthetrim-and-fillmethodofDuval andTweedie (34).Graphsderived from the meta-analysis were re-drawn using GraphPad Prism version 8.0.0

2304 Short- and Long-Acting GLP-1 RAs With Insulin Diabetes Care Volume 43, September 2020

software (https://www.graphpad.com) toallow the use of various colors.

Sensitivity AnalysesTo test for robustnessandpotential causesof heterogeneity, the following sensitivityanalyses were performed: Main resultswere recalculated for studies either titrat-ing insulin during the study or not, forstudies with a duration of ,28 weeksand $28 weeks, with different sizes ofpatient numbers (small [n 5 259–323],intermediate [n 5 398–495], large [n 5731–1,246]), and for studies using free orfixed-dose combinations. P values for in-teraction were calculated for each com-parison. In addition,we systematically stud-ied all major efficacy and safety results forrobustness by repeating all analyses withone study after the other eliminated fromthe calculations.

Regression AnalysesA linear regression analysis was per-formed relating changes in fasting plasmaglucose andHbA1c aswell as reductions inpostmeal glycemic excursions and HbA1cto test for an association in improvingglycemic control. Postmeal glycemic ex-cursions were derived from self-monitoringof plasma glucose profiles. Differencesbetween premeal and postmeal meas-urements were averaged across the threemain meals of the day.

Statistical AnalysisBaseline patient characteristics and re-sults at studyendare reportedasmean6SDor counts (percentages). PooledmeanvaluesandSDs for all studiesbelonging tothe subgroups using short- and long-acting GLP-1 RAs were calculated usingstandard equations. Results of the meta-analysis are reported as differencesbetween baseline and study end andbetween GLP-1 RA plus basal insulintreatment and basal insulin 6 placeboand their 95% CIs. Significances of differ-ences were tested by using unpaired Stu-dent andWelch t test. P, 0.05 was takento indicate significant differences.

RESULTS

Selection of PublicationsEight publications used in the presentanalysis regardedshort-actingGLP-1RAs,and six concerned long-acting GLP-1 RAs.Relatively more studies on lixisenatideand fixed-dose combination of lixisena-tide and insulin glargine (iGlarLixi) were

available than those for any of the long-actingGLP-1 RAs (Supplementary Table 1and Supplementary Fig. 1).

Quality AssessmentThe quality of the studies assessed bythe Jadad score (28) (SupplementaryTable 2) and the Risk of Bias tool (29)(Supplementary Fig. 2) was found to besufficient for the inclusion of all re-trieved publications.

Study CharacteristicsTable 1 informs about the individualdesign of studies used in the presentmeta-analysis.

Baseline CharacteristicsBaseline patient characteristics of all stud-ies analyzed are shown in SupplementaryTables 4–7. Further study protocol de-tails are shown in Supplementary Tables8 and 9.

Primary End PointAll studies analyzed indicated a signifi-cant reduction in HbA1c with GLP-1 RAsplus basal insulin versus basal insulin 6placebo (Fig. 1A). This resulted in overallsignificant differences when looking notonly at all GLP-1 RAs (Δ 20.7% [95% CI21.2; 20.2], 28 mmol/mol [213; 22],P 5 0.006) but also for the subgroups ofshort-acting (Δ 20.5% [20.7; 20.3], 25mmol/mol [27; 23], P , 0.0001) andlong-acting (Δ 21.0% [21.2; 20.8],211 mmol/mol [213; 28], P , 0.0001)GLP-1 RAs (Fig. 1A).

Secondary End Points

HbA1c Target Achievement

The difference in proportions of patientsachieving an HbA1c ,7.0% (,53 mmol/mol) (Fig. 1B) or#6.5% (,48mmol/mol)(Supplementary Fig. 3) was significantlygreater for long-acting GLP-1 RAs.

Fasting Plasma Glucose

Nearly all studies using long-acting GLP-1RAs reported a significant reduction infasting plasma glucose compared withadministration of basal insulin 6 pla-cebo, while for most short-acting GLP-1 RAs, no significant reduction was ob-served (Fig. 1C). This resulted in overallinsignificant differences when looking atall GLP-1 RAs (Δ 20.5 mmol/L [95%CI21.2; 0.2], P5 0.18) and short-actingGLP-1 RAs (Δ 20.1 mmol/L [20.4; 0.2],P 5 0.35) but in a highly significantdifference for the long-acting GLP-1

RAs (Δ 20.9 mmol/L [21.2; 20.5], P ,0.0001) (Fig. 1C).

Body Weight

Body weight was almost uniformly re-duced in most studies except for oneusing lixisenatide (Fig. 1C). The effect forall GLP-1 RAs was significant (Δ 22.0 kg[95% CI23.4;20.6], P5 0.005), as wasthe effect in both subgroups represent-ing short-acting (Δ21.3 kg [21.7;20.8],P , 0.0001) and long-acting (Δ 22.7 kg[23.3; 22.1], P , 0.0001) GLP-1 RAs.Semaglutide had the largest effect onbody weight, again explaining some ofthe observed heterogeneity.

Association inReductionofHbA1cWithChanges in Fasting and PostmealPlasma GlucoseAs depicted in Supplementary Fig. 4A,there was a significant association of thereduction in fasting plasma glucose andHbA1c reduction for all GLP-1 RAs, whichfell almost on the same regression line(P 5 0.94 and P 5 0.99 for potentialdifferences in the slope and y-axis in-tercept of the regression lines). Short-acting GLP-1 RA studies resulted insmaller reductions in both fasting plasmaglucose and HbA1c compared with long-acting GLP-1 RAs.

The association between reductions inpostmeal glycemic excursions and HbA1cwas different. While the distribution ofpostprandial glucose increment reductionwas similar for short- and long-actingGLP-1 RAs, its impact on HbA1c reduction wasconsiderably stronger in the case of long-acting GLP-1 RAs, as indicated by a sig-nificant difference in the y-axis intercept(P 5 0.0033) (Supplementary Fig. 4B).

Differences Among SubgroupsLong-acting GLP-1 RAs had significantlygreater effects on HbA1c reduction(Δ 20.5% [95% CI 20.9; 20.2], 25.8-mmol/mol [29.6;22.0], P5 0.007) (Fig.2A), fasting plasma glucose reduction(Δ 20.7 mmol/L [21.2; 20.3], P 50.007) (Fig. 2C), and body weight reduc-tion (Δ21.4 kg [22.2;20.6], P5 0.002)(Fig. 2D), all compared with insulin 6placebo, versus short-acting GLP-1 RAs.They were also more effective in theachievement of HbA1c targets (,7.0%[53mmol/mol]:Δ18.6 [10.6;231.7],P50.03 [Fig. 2D]; #6.5% [48 mmol/mol]: Δ21.2 [10.6; 31.7], P 5 0.001 [Fig. 2B andSupplementary Fig. 3]).

care.diabetesjournals.org Huthmacher, Meier, and Nauck 2305

Table

1—Ove

rview

oftheindividualdes

ignofstudiesuse

dfortheprese

ntmeta-analysisco

mparingtheeffica

cyandsa

fety

ofsh

ort-andlong-actingGLP-1

RAsin

combination

withbasa

linsu

lin

Study

Publication

year

Trialduration

(weeks)

GLP-1

RA

Basal

insulin

Use

of

placebo

CombinationofGLP-1

RA

andbasal

insulin

Studydesign

Titrationof

basal

insulin

during

trial

Target

dose

of

GLP-1

RA

Short-actingGLP-1

RAs

added

tobasal

insulin

Buse

etal.(13)

2011

30Exen

atide(twiceaday)

Insulin

glargine

Yes

Free

Double

blind

Yes

20mg/day

Seinoet

al.(14)

2012

24Lixisenatide

Basal

insulin

aYes

Free

Double

blind

No

20mg/day

Riddle

etal.(15)

2013

24Lixisenatide

Basal

insulin

aYes

Free

Double

blind

No

20mg/day

Riddle

etal.(16)

2013

24Lixisenatide

Insulin

glargine

Yes

Free

Double

blind

Yes

20mg/day

Yanget

al.(17)

2018

24Lixisenatide

Basal

insulin

aYes

Free

Double

blind

No

20mg/day

Arodaet

al.(18)

2016

30Lixisenatide

Insulin

glargine

No

Fixed(iGlarLixi)

Open

label

Yes

5–20

mg/day

b

Rosenstock

etal.(19)

2016

30Lixisenatide

Insulin

glargine

No

Fixed(iGlarLixi)

Open

label

Yes

5–20

mg/day

b

Rosenstock

etal.(20)

2016

24Lixisenatide

Insulin

glargine

No

Fixed(iGlarLixi)

Open

label

Yes

5–20

mg/day

b

Long-actingGLP-1

RAs

added

tobasal

insulin

Ahmannet

al.(21)

2015

26Liraglutide

Basal

insulin

aYes

Free

Double

blind

No

1.8mg/day

Gujaet

al.(22)

2018

28Exen

atide(once

aweek)

Insulin

glargine

Yes

Free

Double

blind

Yes

2.0mg/week

Pozzilliet

al.(23)

2017

28Dulaglutide

Insulin

glargine

Yes

Free

Double

blind

Yes

1.5mg/week

Rodbardet

al.(24)

2018

30Semaglutide

Basal

insulin

aYes

Free

Double

blind

No

1.0mg/week

Buse

etal.(25)

2014

26Liraglutide

Insulin

degludec

No

Fixed(iDegLira)

Double

blind

Yes

0.6–1.8mg/

day

b

Gou

ghet

al.(26)

2014

26Liraglutide

Insulin

degludec

No

Fixed(iDegLira)

Open

label

Yes

0.36–1.8mg/

day

b

aDifferentcompoundsofbasal

insulin

wereused;adetailedpresentationisgivenin

Supplem

entary

Tables6and8.

bAsper

resultofthetitrationprocess.

2306 Short- and Long-Acting GLP-1 RAs With Insulin Diabetes Care Volume 43, September 2020

Insulin DosesIn combinationwithGLP-1 RAs, the insulindose at the endof titrationwas lower thanwith basal insulin alone (SupplementaryTable 5). This differencewasmoremarkedand significant in the case of long-actingGLP-1 RAs. In studies using fixed-dosecombinations, such differences wereless apparent, probably related to pro-tocol-related maximum limits for in-sulin doses (Supplementary Table 6).

Adverse EventsNausea, vomiting, and diarrhea werereported in a small proportion of thosetreated with insulin 6 placebo but oc-curred with greater prevalence in thosetreated by GLP-1 RAs with basal insulin(Table 2). Among patients treated withGLP-1 RAs and basal insulin, the pro-portion with nausea was approximatelytwofold higher in the case of short-actingGLP-1 RAs (P , 0.0001). Vomiting wasobserved more frequently (57%) withshort-acting GLP-1 RAs (P , 0.0001) aswell. There were no major differencesregarding diarrhea (Table 2).

HypoglycemiaThe proportion of patients reportingsymptomatic hypoglycemia was higherin patients treated with GLP-1 RAs andbasal insulin than in those treated withbasal insulin 6 placebo (P 5 0.020)(SupplementaryTable10).Patients treatedin studies using short-actingGLP-1RAs andbasal insulinhadslightlyhigherproportionsreporting symptomatic hypoglycemic epi-sodes compared with those using long-acting GLP-1 RAs (27.3 vs. 24.4%, P 50.048) (Supplementary Table 10). Propor-tions of patients reporting severe epi-sodes of hypoglycemia were low andnotsignificantlydifferentbetweenstudiesusing short- and long-acting GLP-1 RAs(Supplementary Table 10).

Sensitivity AnalysesResults regarding differences in HbA1c,fasting plasma glucose, and body weightreductionaswell as achievementofHbA1ctarget remained consistent with varioussensitivity analyses (Supplementary Fig.5A–D). Only one comparison related tofasting plasma glucose showed a signifi-cant P value for interaction betweenstudies with active insulin titration ver-sus constant insulin doses. In line with apreviousmeta-analysis (35), there wasno significant or substantial difference

between free and fixed-dose combina-tions of GLP-1 RAs and basal insulin. If thesubgroups are again divided into sub-groups and an analysis is performedseparately, thedifferencebetween short-and long-acting GLP-1 RAs stays signifi-cant for the main end points when onlythe free combinations are compared,but there is no significant differencewhen short- and long-acting GLP-1 RAsare compared as components of fixed-dose combinations (insulin glargine andlixisenatide [iGlarLixi] vs. insulin degludecand liraglutide [iDegLira]) (Supplemen-tary Table 11). Systematically eliminatingstudies from the analysis did not at allchange the interpretation regarding allefficacy parameters. Likewise, for nausea,vomiting, and symptomatic hypoglycemiaas main adverse events, our conclusionswere fully confirmed. Regarding diarrheaand severe hypoglycemia, differences be-tween short- and long-acting GLP-1 RAsremained nonsignificant like in the fullanalysis (Supplementary Tables 12–15).

Publication BiasThe funnel plot and the Egger regres-sion intercept (33) (P5 0.005) indicatesome degree of publication bias, butusing themethod ofDuval and Tweedie(34), only one study is trimmed withvery small and insignificant effects (P50.75) (Supplementary Fig. 6). So, evenif there had been publication bias, itshould not have had a great impact onthe overall results regarding our mainend point.

DISCUSSION

The present meta-analysis comparingshort- and long-acting GLP-1 RAs on abackground of basal insulin therapy wasdriven by the hypothesis that a morepronounced effect on preventing post-meal glycemic excursions of short-actingGLP-1 RAs might potentially outweigh agreatereffect on fastingplasmaglucoseoflong-actingGLP-1RAs (3,7,11).Our resultsclearly indicate that in combination withbasal insulin, long-acting GLP-1 RAs re-sulted in greater reductions in HbA1c,fasting plasma glucose, and bodyweight(Fig. 1). This is novel information notavailable from previous meta-analyses(35–37) and provides meaningful guid-ance for the choice of GLP-1 RAs to beused in combination with basal insulin.

The results regarding HbA1c and fast-ing plasma glucose reduction resemble

previous findings in clinical trials compar-ing short- with long-acting GLP-1 RAs on abackgroundoforalglucose-loweringmed-ications (6,38,39). The explanation for thegreater efficacy of long-acting GLP-1 RAshas been the greater exposure to drugconcentrations during the overnight pe-riod with an associated greater reductionin overnight and early morning fastingplasma glucose concentrations (3).

The selection of studies on a combina-tion of short-acting GLP-1 RAs and basalinsulin was such that only one study withexenatide twice a day contrastswith sevenstudiesusing lixisenatide.Exenatidetwiceaday seems to be particularly different in itsability to reduce body weight (Fig. 1D).Overall, our results regarding short-actingGLP-1 RAs combined with basal insulinmainly inform about lixisenatide.

Previous meta-analyses have under-scored the efficacy of a combination ofGLP-1 RAs and basal insulin (37) withoutdifferentiating the effects of short- ver-sus long-acting compounds within theGLP-1 RA class. For example, free combi-nations of a GLP-1 RA with basal insulinhave been compared with fixed-dosecombinations (35), andnoessential differ-ences in effectiveness on HbA1c or bodyweight reduction were found (35). Like inour analysis (Supplementary Fig. 5 andSupplementary Table 11), no significantdifferences in the efficacy regarding ab-solute HbA1c or body weight reductionsbetween iGlarLixi and iDegLira were de-scribed in a previous publication (36).

A novel aspect of the present analysisis that this effect on fasting plasmaglucose is observed in studies allowingbasal insulin use (and in some studies,titration) in the comparator group. Thisindicates that there is an additionallowering of overnight and earlymorningfasting plasma glucose with long-actingGLP-1 RAs, even on top of basal insulin.Thus, the fasting plasma glucose levelreached was not significantly differentbetween patients treated with short-acting GLP-1 RAs plus basal insulin com-pared with basal insulin 6 placebo,while there was a significant differencefor long-acting GLP-1 RAs (Fig. 1 andSupplementary Table 5). As indicated bythe regression analysis, the additionalreduction in fasting plasma glucose con-centrations induced by long-acting GLP-1RAs seems to have an important role inmediating the improvement in overallglycemic control (Supplementary Fig. 4A).

care.diabetesjournals.org Huthmacher, Meier, and Nauck 2307

Figure1—Forestplotof reductions inHbA1c (A), theproportionofpatientsachievinganHbA1c target,7.0%(B), and reductions in fastingplasmaglucose(C) andbodyweight (D) in patientswith type2diabetes treatedwith short- or long-actingGLP-1RAs in combinationwithbasal insulin. Forest plots showthedifference inmeans (A,C, andD) and the riskdifference (B) between the interventionarm(GLP-1RA1basal insulin) andcomparatorarm(placebo1basal insulin or basal insulin alone). Color codes for the various GLP-1 RAs are shown in panel A. Filled circles indicate the results for individual studies,while rhombuses indicate results of themeta-analysis.Measuresofheterogeneity arealso shown inall panels (Q, I2,t2, and relatedPvalues) for allGLP-1RAs.Adetailedpresentationof theheterogeneity statistics for the subgroupsof short- and long-actingGLP-1RAs is provided in Supplementary Table17.

2308 Short- and Long-Acting GLP-1 RAs With Insulin Diabetes Care Volume 43, September 2020

The lack of HbA1c differences in favorof short-acting GLP-1 RAs versus long-acting GLP-1 RAs in combination withbasal insulin (Supplementary Fig. 4B) maybe explained by the finding that differ-ences in postmeal increments in plasmaglucose concentrations between patientstreated with GLP-1 RAs plus basal insulinand those treated with basal insulin onlywere relatively small (;0.5 mmol/L atpeak and only representative for limitedperiods after meals) (Supplementary Fig.4B). Furthermore, this reduction in post-prandial glycemic rises only applies tolimited meals, before a short-actingGLP-1 RA has been injected. This mayexplain why the postprandial effects ofshort-acting GLP-1 RAs do not quanti-tatively impact much on HbA1c reduc-tions, while the reduction in fastingplasma glucose following long-actingGLP-1 RA treatment (;0.65 mmol/L)(Supplementary Fig. 4A) is of greatermagnitude and can be assumed to bemaintained for a much longer periodduring the night and in the morning.Additional reasons may include theability of basal insulin treatment itselfto reduce postprandial increments inglucose concentrations, especiallywhennear-normal targets for fasting plasmaglucose are reached (40).The greater reduction in body weight

foundwith long- rather than short-actingGLP-1 RAs used on background of basalinsulin is at variance with studies usingGLP-1 RAs together with oral glucose-loweringmedications (6,38,39). Previouspublications have not described a differ-ence between short- and long-actingGLP-1 RAs in this respect (6,38,39,41).Thus, concomitant insulin therapy seems

to modify weight-reducing effects ofGLP-1 RAs, perhaps related to its effecton glucosuria (42). The differences ininsulin doses reached after titrating basalinsulin alone or in combinationwith GLP-1 RAs (Supplementary Tables 8 and 9)most likely has affected the results re-garding body weight (Figs. 1 and 2) andhypoglycemic episodes (SupplementaryTable 10).

The reduction of gastrointestinal ad-verse events for studies using long-acting compared with short-actingGLP-1 RAs (Table 2) is in line with pre-vious meta-analyses compiling tolera-bility data for various GLP-1 RAs on avariety of background glucose-loweringmedications, including basal insulin(43). As underscored by the differentways of capturing gastrointestinal ad-verse events (Supplementary Table 3),there is the possibility of heterogeneityacross trials with respect to trial-specificdefinitions and data capture methods,trial time frame, location of trial sites,and other influences. The trend towardmore symptomatic hypoglycemic epi-sodes with the combination of GLP-1RAs and basal insulin versus basal in-sulin 6 placebo probably representsthe better glycemic control in thosetreated with the combination. This differ-ence was slightly smaller with long-actingGLP-1 RAs (Supplementary Table 10) andmay be related to significantly lower in-sulindoseswhenusing thecombination inthe case of long-acting, but not short-acting, GLP-1 RAs (Supplementary Tables6 and 7).

There are some important differencesbetween using free versus fixed-dosecombinations of GLP-1 RAs and basal

insulin. In the case of fixed-dose combi-nations, there may be a maximum insulindose-limiting titration (because other-wise, the GLP-1 RA dose would rise aboveapproveddose ranges [18–20,25,26]),andoften, such considerations have had animpact on selection criteria for patientsparticipating in such studies (to excludethose with a high insulin requirement).Also, since not all patients on fixed-dosecombinations reach the maximum dose,theirexposure toGLP-1RAs,onaverage, islowerthanwith freecombinations.Other-wise, the differences in the primary out-come were significant when comparingfree combinations of short- and long-acting GLP-1 RAs, while this was not thecase for fixed-dose combinations, whichis in line with a previous meta-analysis(36). The main reason probably is thesmaller number of studies with fixed-dose combinations. Nevertheless, we findsimilar differences between basal insulinalone or in combination with GLP-1 RAs,regardless of the use of free or fixed-dosecombinations (Supplementary Table 11).Nonsignificant interaction P values sug-gest that the overall results apply to freeand fixed-dose combinations.

Limitations of our study are the rel-atively small number of publicationsavailable, some heterogeneity regard-ing protocols, and probably most im-portantly, differences in the GLP-1 RAcompoundused (pharmacokinetic prop-erties, known clinical effectiveness, freevs. fixed-dose combination affecting thetitration process and the final dose usedduring the core trial period, etc.) (44).Nevertheless, our study had an unequiv-ocal result, and the conclusions seemto be robust, as indicated by various

Figure 2—Differences in reductions in HbA1c (A), the proportion of patients achieving an HbA1c target ,7.0% (B), and reductions in fasting plasmaglucose (C) and body weight (D) relative to placebo/insulin only between short- and long-acting GLP-1 RAs added to basal insulin therapy. Meandifferences and their 95% CIs are shown. P values were calculated on the basis of the comparison of subgroups (short- vs. long-acting GLP-1 RAs) thatwas based on the meta-analysis as depicted in Fig. 1.

care.diabetesjournals.org Huthmacher, Meier, and Nauck 2309

Table

2—Ove

rview

ofadve

rseeve

nts

andwithdrawals

from

studiesuse

dfortheprese

ntmeta-analysisco

mparingtheeffica

cyandsa

fety

ofsh

ort-andlong-actingGLP-1

RAsin

combinationwithbasa

linsu

lin

Patien

ts,n

Nausea,

n(%

)Vomiting,

n(%

)Diarrhea,n(%

)

Withdrawalsbecause

ofadverseeven

ts,

n(%

)Withdrawalsbecause

ofany

reason,n(%

)

Study,

publicationyear

GLP-1

RA

Placeb

oGLP-1

RA

Placeb

oGLP-1

RA

Placeb

oGLP-1

RA

Placeb

oGLP-1

RA

Placeb

oGLP-1

RA

Placeb

o

Short-actingGLP-1

RAsadded

tobasal

insulin

Buse

etal.(13),20

1113

712

256

(40.9)

10(8.2)

25(18.2)

5(4.1)

25(18.2)

10(8.2)

13(9.5)

1(0.8)

26(19.0)

22(18.0)

Seinoet

al.(14),20

1215

415

761

(39.6)

7(4.5)

28(18.2)

3(1.9)

10(6.5)

4(2.5)

14(9.1)

5(3.2)

21(13.6)

13(8.3)

Riddle

etal.(15),2013

328

167

86(26.2)

14(8.4)

27(8.2)

1(0.6)

24(7.3)

9(5.4)

26(7.9)

4(2.4)

53(16.2)

20(12.0)

Riddle

etal.(16),2013

223

223

61(27.4)

11(4.9)

21(9.4)

3(1.3)

15(6.7)

7(3.1)

19(8.5)

9(4.0)

29(13.0)

12(5.4)

Yanget

al.(17),20

1822

322

351

(22.9)

12(5.4)

25(11.2)

2(0.9)

NA

NA

8(3.6)

4(1.8)

32(14.3)

18(8.1)

Arodaet

al.(18),20

1636

636

538

(10.4)

2(0.5)

13(3.6)

2(0.5)

16(4.4)

10(2.7)

12(3.3)

3(0.8)

29(7.9)

10(2.7)

Rosenstock

etal.(19),20

1646

846

645

(9.6)

17(3.6)

15(3.2)

7(1.5)

42(9.0)

20(4.3)

12(2.6)

9(1.9)

29(6.2)

27(5.8)

Rosenstock

etal.(20),20

1616

116

212

(7.5)

0(0.0)

4(2.5)

1(0.6)

5(3.1)

6(3.7)

6(3.7)

0(0.0)

11(6.8)

3(1.9)

Allshort-actingGLP-1

RA

2,060

1,88

541

0(19.9)

73(3.9)

158(7.7)

24(1.3)

137(7.5)

66(4.0)

110(5.3)

35(1.9)

230(11.2)

125(6.6)

Long-actingGLP-1

RAsadded

tobasal

insulin

Ahmannet

al.(21),20

1522

522

550

(22.2)

7(3.1)

20(8.9)

2(0.9)

24(10.7)

11(4.9)

12(5.3)

3(1.3)

35(15.6)

51(22.7)

Gujaet

al.(22),20

1823

123

012

(5.2)

9(3.9)

1(0.4)

3(1.3)

11(4.8)

8(3.5)

7(3.0)

5(2.2)

19(8.2)

23(10.0)

Pozzilliet

al.(23),20

1715

015

018

(12.0)

2(1.3)

9(6.0)

0(0.0)

17(11.3)

6(4.0)

6(4.0)

2(1.3)

12(8.0)

16(10.7)

Rodbardet

al.(24),20

1813

113

322

(16.8)

6(4.5)

15(11.5)

4(3.0)

9(6.9)

2(1.5)

10(7.6)

1(0.8)

16(12.2)

13(9.8)

Buse

etal.(25),20

1419

919

913

(6.5)

7(3.5)

NA

NA

13(6.5)

7(3.5)

1(0.5)

3(1.5)

32(16.1)

35(17.6)

Gou

ghet

al.(26),20

1483

341

373

(8.8)

15(3.6)

32(3.8)

6(1.5)

66(7.9)

19(4.6)

10(1.2)

8(1.9)

90(10.8)

47(11.4)

Alllong-actingGLP-1

RAs

1,769

1,350

170(9.6)*

46(3.4)

77(4.9)†

15(1.3)

130(7.3)¶

53(3.9)

46(2.6)**

22(1.6)

204(11.5)‡

185(13.7)

NA,notavailable.*Oddsratio0.43

(95%

CI0.18;0.52),P,0.0001

.†Oddsratio0.55

(95%

CI0.41;0.72

),P,0.00

01.¶P5

0.41.**O

ddsratio0.43

(95%

CI0.34;0.67),P,0.00

01.‡Oddsratio1.04

(95%

CI0.85;1.26

),P5

0.72;however,w

ithplacebo,theoddsratiowas

2.24

(1.76;2.83),P,

0.0001

,and

the95

%CIsforverum

andplacebostudiesdidnotoverlap,indicatingasignificantdifference

(P,

0.05)betweenshort-and

long-actingGLP-1

RAsrelative

toplacebo.

2310 Short- and Long-Acting GLP-1 RAs With Insulin Diabetes Care Volume 43, September 2020

sensitivity analyses. However, our con-clusions cannot be generalized beyondthe inclusion/exclusion criteria of themeta-analyzed trials.In conclusion, the results of our meta-

analysis indicate that long-acting GLP-1RAs should preferentially be combinedwith basal insulin, since this combinationresults in not only better overall glycemiccontrol (HbA1c) but also improved fastingplasmaglucoseconcentrationsand lowerbody weight. This combination also hasadvantages regarding gastrointestinaladverse events.

Acknowledgments. The authors acknowledgehelp with retrieving literature by Laura Kupfer.Duality of Interest. J.J.M. has received consul-ting and speaker honoraria from AstraZeneca,Bristol-Myers Squibb, Eli Lilly & Co., Merck Sharp& Dohme, Novo Nordisk, and Sanofi. He hasreceived research support from Eli Lilly & Co.,Boehringer Ingelheim, Merck Sharp & Dohme,Novo Nordisk, Novartis, and Sanofi. M.A.N. hasbeen a member on advisory boards or has con-sultedwithAstraZeneca,Boehringer Ingelheim,EliLilly & Co., Fractyl, GlaxoSmithKline, Menarini/Berlin-Chemie, Merck Sharp & Dohme, and NovoNordisk. He has received grant support fromAstraZeneca, Eli Lilly & Co., Menarini/Berlin-Chemie, Merck Sharp & Dohme, No-vartis Pharma, and Novo Nordisk. He has alsoserved on the speakers’ bureau of AstraZeneca,Boehringer Ingelheim, Eli Lilly & Co., Menarini/Berlin-Chemie, Merck Sharp & Dohme, and NovoNordisk. No other potential conflicts of interestrelevant to this article were reported.AuthorContributions. J.A.H., J.J.M., andM.A.N.designed the study, analyzed the data, per-formed the statistical analysis, and wrote themanuscript. All authors saw and approved thefinal draft of this manuscript and decided tosubmit it for publication.M.A.N. is the guarantorof this work and, as such, had full access to all thedata in the study and takes responsibility for theintegrity of the data and the accuracy of the dataanalysis.

References1. Drucker DJ, Nauck MA. The incretin system:glucagon-like peptide-1 receptor agonists anddipeptidyl peptidase-4 inhibitors in type 2 di-abetes. Lancet 2006;368:1696–17052. Nauck M. Incretin therapies: highlightingcommon features and differences in the modesof action of glucagon-like peptide-1 receptoragonists and dipeptidyl peptidase-4 inhibitors.Diabetes Obes Metab 2016;18:203–2163. Meier JJ. GLP-1 receptor agonists for individ-ualized treatment of type 2 diabetes mellitus.Nat Rev Endocrinol 2012;8:728–7424. Nauck MA, Kemmeries G, Holst JJ, Meier JJ.Rapid tachyphylaxis of the glucagon-like peptide1-induced deceleration of gastric emptying inhumans. Diabetes 2011;60:1561–15655. UmapathysivamMM, Lee MY, Jones KL, et al.Comparative effects of prolonged and intermittent

stimulation of the glucagon-like peptide 1 receptoron gastric emptying and glycemia. Diabetes 2014;63:785–7906. DruckerDJ, Buse JB, Taylor K, et al.; DURATION-1Study Group. Exenatide once weekly versustwice daily for the treatment of type 2 diabetes:a randomised, open-label, non-inferiority study.Lancet 2008;372:1240–12507. Meier JJ, Rosenstock J, Hincelin-Mery A, et al.Contrasting effects of lixisenatide and liraglutideon postprandial glycemic control, gastric emp-tying, and safety parameters in patients withtype2diabetesonoptimized insulinglarginewithor withoutmetformin: a randomized, open-labeltrial. Diabetes Care 2015;38:1263–12738. Horowitz M, Edelbroek MA, Wishart JM,Straathof JW. Relationship between oral glucosetolerance and gastric emptying in normal healthysubjects. Diabetologia 1993;36:857–8629. Jones KL, HorowitzM,WishartMJ,MaddoxAF,Harding PE, Chatterton BE. Relationships betweengastric emptying, intragastric meal distributionand blood glucose concentrations in diabetesmellitus. J Nucl Med 1995;36:2220–222810. Meier JJ, Schenker N, Kahle M, Schliess F,Kapitza C, Menge BA. Impact of insulin glargineand lixisenatide on b-cell function in patientswith type 2 diabetes mellitus: a randomizedopen-label study. Diabetes Obes Metab 2017;19:1625–162911. Nauck MA, Meier JJ. Individualised incretin-based treatment for type 2 diabetes. Lancet2010;376:393–39412. Diamant M, Nauck MA, Shaginian R, et al.; 4BStudy Group. Glucagon-like peptide 1 receptor ag-onist or bolus insulin with optimized basal insulin intype 2 diabetes. Diabetes Care 2014;37:2763–277313. Buse JB, Bergenstal RM, Glass LC, et al. Use oftwice-daily exenatide in Basal insulin-treated pa-tients with type 2 diabetes: a randomized, con-trolled trial. Ann Intern Med 2011;154:103–11214. Seino Y, Min KW, Niemoeller E, Takami A;EFC10887 GETGOAL-L Asia Study Investigators.Randomized, double-blind, placebo-controlledtrial of the once-daily GLP-1 receptor agonistlixisenatide in Asian patients with type 2 di-abetes insufficiently controlled on basal insulinwith orwithout a sulfonylurea (GetGoal-L-Asia).Diabetes Obes Metab 2012;14:910–91715. Riddle MC, Aronson R, Home P, et al.Adding once-daily lixisenatide for type 2 di-abetes inadequately controlled by establishedbasal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L). DiabetesCare 2013;36:2489–249616. Riddle MC, Forst T, Aronson R, et al. Addingonce-daily lixisenatide for type 2 diabetes in-adequately controlled with newly initiated andcontinuously titrated basal insulin glargine:a 24-week, randomized, placebo-controlledstudy (GetGoal-Duo 1). Diabetes Care 2013;36:2497–250317. Yang W, Min K, Zhou Z, et al. Efficacy andsafety of lixisenatide in a predominantly Asianpopulation with type 2 diabetes insufficientlycontrolled with basal insulin: the GetGoal-L-Crandomized trial. Diabetes ObesMetab 2018;20:335–34318. Aroda VR, Rosenstock J, Wysham C, et al.;LixiLan-L Trial Investigators. Efficacy and safetyof LixiLan, a titratable fixed-ratio combinationof insulin glargine plus lixisenatide in type 2

diabetes inadequately controlled onbasal insulinand metformin: the LixiLan-L Randomized Trial.Diabetes Care 2016;39:1972–198019. Rosenstock J, Aronson R, Grunberger G,et al.; LixiLan-O Trial Investigators. Benefits ofLixiLan, a titratable fixed-ratio combination ofinsulin glargine plus lixisenatide, versus insulinglargine and lixisenatide monocomponents intype 2 diabetes inadequately controlled on oralagents: the LixiLan-O randomized trial. DiabetesCare 2016;39:2026–203520. Rosenstock J, Diamant M, Aroda VR, et al.;LixiLan PoC Study Group. Efficacy and safety ofLixiLan, a titratable fixed-ratio combination oflixisenatide and insulin glargine, versus insulinglargine in type 2 diabetes inadequately con-trolled on metformin monotherapy: the LixiLanproof-of-concept randomized trial. DiabetesCare 2016;39:1579–158621. AhmannA, RodbardHW,Rosenstock J, et al.;NN2211-3917StudyGroup. Efficacy and safety ofliraglutide versus placebo added to basal insulinanalogues (with or without metformin) in pa-tients with type 2 diabetes: a randomized, pla-cebo-controlled trial. Diabetes Obes Metab2015;17:1056–106422. Guja C, Frıas JP, Somogyi A, et al. Effect ofexenatide QWor placebo, both added to titratedinsulin glargine, in uncontrolled type 2 diabetes:the DURATION-7 randomized study. DiabetesObes Metab 2018;20:1602–161423. Pozzilli P, Norwood P, Jodar E, et al. Placebo-controlled, randomized trial of the addition ofonce-weekly glucagon-like peptide-1 receptoragonist dulaglutide to titrated daily insulin glar-gine in patients with type 2 diabetes (AWARD-9).Diabetes Obes Metab 2017;19:1024–103124. Rodbard HW, Lingvay I, Reed J, et al. Sem-aglutide added to basal insulin in type 2 diabetes(SUSTAIN5): a randomized, controlled trial. J ClinEndocrinol Metab 2018;103:2291–230125. Buse JB, Vilsbøll T, Thurman J, et al.;NN9068-3912 (DUAL-II) Trial Investigators. Contributionof liraglutide in the fixed-ratio combination ofinsulin degludec and liraglutide (IDegLira). Di-abetes Care 2014;37:2926–293326. Gough SCL, Bode B, Woo V, et al.; NN9068-3697 (DUAL-I) trial investigators. Efficacy andsafety of a fixed-ratio combination of insulindegludec and liraglutide (IDegLira) comparedwith its components given alone: results of aphase3,open-label, randomised,26-week, treat-to-target trial in insulin-naivepatientswith type2diabetes. Lancet Diabetes Endocrinol 2014;2:885–89327. Moher D, Liberati A, Tetzlaff J, Altman DG;PRISMA Group. Preferred reporting items forsystematic reviews and meta-analyses: thePRISMA statement. BMJ 2009;339:b253528. Jadad AR, Moore RA, Carroll D, et al. Assess-ing the quality of reports of randomized clinicaltrials: is blinding necessary? Control Clin Trials1996;17:1–1229. Higgins JPT, Altman DG, Gøtzsche PC, et al.;Cochrane Bias Methods Group; Cochrane Sta-tistical Methods Group. The Cochrane Collabo-ration’s tool for assessing risk of bias inrandomised trials. BMJ 2011;343:d592830. Cumming G, Calin-Jageman R. Introductionto the New Statistics: Estimation, Open Science,andBeyond. NewYork, London, RoutledgeTaylor&Francis Group, 2017

care.diabetesjournals.org Huthmacher, Meier, and Nauck 2311

31. GranicherWHH.Messungbeendet -wasnun?:Einfuhrung und Nachschlagewerk fur die Planungund Auswertung von Messungen. Zurich, Switzer-land, vdf Hochschul-Verl. an der ETH Zurich, 199632. Osborne JW. Best Practices in QuantitativeMethods. Los Angeles, CA, Sage Publ, 2008, p.332–33333. Egger M, Davey Smith G, Schneider M,Minder C. Bias in meta-analysis detected by asimple, graphical test. BMJ 1997;315:629–63434. Duval S, Tweedie R. Trim and fill: a simplefunnel-plot-based method of testing and adjust-ing for publication bias in meta-analysis. Bio-metrics 2000;56:455–46335. Maiorino MI, Chiodini P, Bellastella G, et al.Free and fixed-ratio combinations of basal insulinand GLP-1 receptor agonists versus basal insulinintensification in type 2 diabetes: a systematicreviewandmeta-analysisofrandomizedcontrolledtrials. Diabetes Obes Metab 2018;20:2309–231336. Cai X, Gao X, Yang W, Ji L. Comparisonbetween insulin degludec/liraglutide treatmentand insulin glargine/lixisenatide treatment intype 2 diabetes: a systematic review and meta-

analysis. Expert Opin Pharmacother 2017;18:1789–179837. Eng C, Kramer CK, Zinman B, Retnakaran R.Glucagon-like peptide-1 receptor agonist andbasal insulin combination treatment for themanagement of type 2 diabetes: a systematicreview and meta-analysis. Lancet 2014;384:2228–223438. Buse JB, Rosenstock J, Sesti G, et al.; LEAD-6Study Group. Liraglutide once a day versusexenatide twice a day for type 2 diabetes: a26-week randomised, parallel-group, multina-tional, open-label trial (LEAD-6). Lancet 2009;374:39–4739. NauckM,RizzoM, JohnsonA, Bosch-TrabergH, Madsen J, Cariou B. Once-daily liraglutideversus lixisenatide as add-on to metformin intype 2 diabetes: a 26-week randomized con-trolledclinical trial.DiabetesCare2016;39:1501–150940. BuchholzC,Kahle-StephanM,Meier J,NauckMA. Clinical predictors of the need for furthertreatment escalation in patients with type 2diabetesonbasal insulin therapy -a retrospective

observational study. Exp Clin Endocrinol Diabe-tes, 2019;127:663–67141. Abd El AzizMS, KahleM,Meier JJ, NauckMA.A meta-analysis comparing clinical effects ofshort- or long-acting GLP-1 receptor agonistsversus insulin treatment from head-to-headstudies in type 2 diabetic patients. DiabetesObes Metab 2017;19:216–22742. Makimattila S, Nikkila K, Yki-Jarvinen H.Causes of weight gain during insulin therapywith and without metformin in patients withType II diabetes mellitus. Diabetologia 1999;42:406–41243. Bettge K, Kahle M, Abd El Aziz MS, Meier JJ,Nauck MA. Occurrence of nausea, vomiting anddiarrhoea reported as adverse events in clinicaltrials studying glucagon-like peptide-1 receptoragonists: a systematic analysis of publishedclinical trials. Diabetes Obes Metab 2017;19:336–34744. Nauck MA, Meier JJ. Management of endo-crine disease: are all GLP-1 agonists equal in thetreatment of type 2 diabetes? Eur J Endocrinol2019;181:R211–R234

2312 Short- and Long-Acting GLP-1 RAs With Insulin Diabetes Care Volume 43, September 2020