Safety and Efficacy of ExenatideOnce Weekly Plus DapagliflozinOnce Daily Versus Exenatide orDapagliflozin Alone in PatientsWithType2Diabetes InadequatelyControlled With MetforminMonotherapy: 52-Week Results ofthe DURATION-8 RandomizedControlled TrialDiabetes Care 2018;41:2136–2146 | https://doi.org/10.2337/dc18-0680

OBJECTIVE

Among patients with type 2 diabetes uncontrolled with metformin, exenatideonce weekly (QW) plus dapagliflozin combination produced greater reductions inglycemia, weight, and systolic blood pressure (SBP) at 28 weeks than exenatideQW or dapagliflozin alone (DURATION-8). Here, we investigated the safety andmaintenance of efficacy at 52 weeks, after a 24-week extension.

RESEARCH DESIGN AND METHODS

This phase 3, multicenter, double-blind study randomized adults with type 2diabetes (with glycated hemoglobin [HbA1c] 8.0–12.0% [64–108 mmol/mol]and on metformin ‡1,500 mg/day) to exenatide QW (2-mg subcutaneous injection)plus once-daily dapagliflozin (10-mg oral tablet), exenatide QW plus oral placebo,or dapagliflozin plus injected placebo. Extension-period P values were nominal.

RESULTS

Of 1,375 patients screened, 695 were randomized (mean baseline HbA1c 9.3%[78 mmol/mol]); 81.2% completed the study, and 75.3% completed treatment.At 52 weeks, HbA1c reductions were greater with exenatide QW plus dapagliflozin(least squares mean change 21.75% [219.1 mmol/mol]) versus exenatide QW(21.38% [215.1 mmol/mol]; P = 0.006) or dapagliflozin (21.23% [213.4 mmol/mol];P < 0.001); mean HbA1c values were 6.9% (52 mmol/mol), 7.2% (55 mmol/mol),and 7.4% (57 mmol/mol), respectively. Weight and SBP reductions were greaterwith exenatide QW plus dapagliflozin (23.31 kg and 24.5 mmHg) versus exena-tide QW (21.51 kg and 20.7 mmHg; both P < 0.001) but similar to those withdapagliflozin (22.28 kg and22.7 mmHg; P = 0.057 and P = 0.100, respectively). Theexenatide QW plus dapagliflozin regimen was well tolerated with no unexpectedsafety findings; more patients treated with exenatide QW experienced gastro-intestinal and injection site–related adverse events. No major hypoglycemiaoccurred.

CONCLUSIONS

Among patients with type 2 diabetes uncontrolled with metformin, exenatide QWplus dapagliflozin provided sustained improvements in glycemia, weight, and SBPover 52 weeks, with no unexpected safety findings.

1Jefferson Medical College of Thomas JeffersonUniversity, Philadelphia, PA2National Research Institute, Los Angeles, CA3AstraZeneca, Gaithersburg, MD4Apex Medical Research, Chicago, IL5“Carol Davila” University of Medicine and Phar-macy, Bucharest, Romania6“N. Paulescu” National Institute of Diabetes,Nutrition and Metabolic Diseases, Bucharest,Romania

Corresponding author: Serge A. Jabbour,serge.jabbour@jefferson.edu.

Received 28 March 2018 and accepted 9 July2018.

Clinical trial reg no. NCT02229396, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-0680/-/DC1.

© 2018 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered. More infor-mation is available at http://www.diabetesjournals.org/content/license.

Serge A. Jabbour,1 Juan P. Frıas,2

Elise Hardy,3 Azazuddin Ahmed,4

Hui Wang,3 Peter Ohman,3 and

Cristian Guja5,6

2136 Diabetes Care Volume 41, October 2018

EMER

GINGTH

ERAPIES:

DRUGSANDREG

IMEN

S

The choice of therapeutic combinationsthat maximize glycemic control and min-imize adverse events (AEs), such as weightgain or hypoglycemia, is critical and im-portant to both health care providersand patients when selecting therapy toachieve glycemic targets in patients withtype 2 diabetes (1). In addition, it isessential to choose therapies shown tohave durability of effect and safety overtime. Professional guidelines (2–4) furthersupport this aim by recommending thecombination of glucose-lowering thera-pies with different modes of action toachieve glycemic targets.Two major classes of glucose-lowering

drugs, glucagon-like peptide 1 receptoragonists (GLP-1RAs) and sodium–glucosecotransporter 2 (SGLT2) inhibitors, havebeen launched in the last decade for thetreatment of type 2 diabetes. GLP-1RAsincrease insulin secretion, decrease glu-cagon secretion, slow gastric emptying,and increase satiety (5), whereas SGLT2inhibitors increase caloric loss via urinaryglucose excretion (6). Despite their differ-ent effects on glucose metabolism, thesetwo classes of glucose-lowering drugs bothreduce blood glucose levels with a minimalrisk of hypoglycemia, produce sustainedreductions in weight, and reduce systolicblood pressure (SBP), which may contrib-ute to reduced cardiovascular risk (7,8).In addition, SGLT2 inhibition appears toimprove incretin sensitivity of pancreaticb-cells, providing a further rationale forthe glycemic efficacy of the GLP-1RA/SGLT2 inhibitor combination (9).Despite the potential benefits of com-

bining a GLP-1RA and an SGLT2 inhibitor,the combination was not formally in-vestigated in patients with type 2 di-abetes until the DURATION-8 study.DURATION-8 was a multicenter, double-blind, randomized, active-controlledphase 3 trial that evaluated the effectsof adding a combination of once-weeklyexenatide (an extended-release formu-lation of the GLP-1RA exenatide that isencapsulated in biodegradable micro-spheres and administered by subcutane-ous injection) and dapagliflozin (an SGLT2inhibitor administered orally daily) in695 patients with type 2 diabetes andpoor glycemic control who are receivingmetformin monotherapy (10). The resultsof the initial 28-week treatment period,which have been published previously,demonstrated that concomitant useof exenatide once weekly (QW) and

dapagliflozin resulted in significantly su-perior clinical improvements in glycemiccontrol, weight, and SBP compared withexenatide QW or dapagliflozin alone, withno unexpected safety findings (10). Here,we present results from the first 24-weekextension of DURATION-8, which investi-gated the durability of the response forthe efficacy and safety of this combina-tion over 52 weeks (a further 52-weekextension, period 2, is ongoing).

RESEARCH DESIGN AND METHODS

Study Design and ParticipantsThe design of the DURATION-8 study(clinical trial reg. no. NCT02229396,ClinicalTrials.gov) has been previouslypublished (10). Briefly, DURATION-8enrolled adults ($18 years of age)with type 2 diabetes and inadequateglycemic control (glycated hemoglobin[HbA1c] 8.0–12.0% [64–108 mmol/mol])despite stable metformin monotherapy($1,500mg/day). Patients were random-ized to receive exenatide 2mg QWby sub-cutaneous injection plus dapagliflozin10-mg oral tablets daily, exenatide QWwith dapagliflozin-matched oral placebodaily, or dapagliflozin daily with exena-tide QW–matched placebo injections.After week 28, patients continued intoa 24-week double-blind extension periodwhere they continued to receive theirrandomized treatment (extension period1 [Supplementary Fig. 1]). From weeks8 to 36, patients with inadequate gly-cemic control based on progressivelystricter fasting plasma glucose (FPG)criteria (.15.0 mmol/L from weeks 8 to12, .13.2 mmol/L from weeks 12 to 20,and .11.1 mmol/L from weeks 20 to 36)remained in the study and receivedopen-label rescue therapy with basalinsulin (Supplementary Table 1). Fromweeks 36 to 52, patients received res-cue therapy if HbA1c level was .8.0%(.64 mmol/mol). The study protocolwas approved at each study site bythe appropriate institutional reviewboard, and the study was conductedin accordance with the principles de-scribed in the Declaration of Helsinkiand a common clinical protocol. Patientsprovided written informed consent be-fore any study procedure.

OutcomesThe primary end point of the DURATION-8study was the change in HbA1c frombaseline to week 28. All end points at

52 weeks were considered exploratoryand included the change from baselinein glycemic parameters (HbA1c, FPG, 2-hpostprandial glucose [PPG] during astandardized liquid meal test (10), andchange in six-point self-monitored bloodglucose), the proportion of patients achiev-ing glycemic targets (HbA1c ,7.0% or#6.5% [,53 or #48 mmol/mol]), thechange from baseline in selected car-diovascular risk factors (including weight,SBP, diastolic blood pressure [DBP], waistcircumference, and fasting lipids [totalcholesterol, LDL cholesterol, HDL choles-terol, non-HDL cholesterol, and trigly-cerides]), and the proportion of patientswith weight loss of $5%.

Safety and tolerability over the52-week study were also assessed. Aspreviously described (10), safety wasassessed using spontaneously reportedAEs, laboratory tests, and vital signs.Hypoglycemic episodes were also re-corded and were classified as major,minor, or other. Major hypoglycemiawas defined as loss of consciousness,seizure, or coma resolving after glucagonor glucose administration, or any eventrequiring third-party assistance to re-solve because of severe impairment inconsciousness or behavior with a glucoseconcentration of ,3.0 mmol/L. Minorhypoglycemia was defined as a nonma-jor hypoglycemia event with symptomsconsistent with hypoglycemia and a glu-cose concentration of ,3.0 mmol/L be-fore treatment of the episode. If ahypoglycemia event did not meet thecriteria for a major or minor event, as de-scribed above, it was classified as “other”hypoglycemia.

Statistical AnalysisAll efficacy variables were assessed in theintention-to-treat population, which wasdefined as all randomly assigned patientswho received at least one dose of studydrug with at least one postbaseline HbA1cassessment. All safety variables were an-alyzed in the safety analysis set, definedas all randomly assigned patients whoreceived at least one dose of study drug.

Because all end points at 52 weekswere exploratory, only nominal P valueswere calculated. Changes in continuousvariables were analyzed with a mixed-effects model for repeated-measuresanalyses (HbA1c, FPG, weight, SBP, DBP,waist circumference, and self-monitoredblood glucose level) or an ANCOVA model

care.diabetesjournals.org Jabbour and Associates 2137

(2-h PPG and fasting lipids). Categoricalresponse variables (proportions achiev-ing glycemic or weight targets) wereanalyzed using stratified Cochran-Mantel-Haenszel tests; missing 52-week data wereimputed by the last observation carriedforward (LOCF) method.Data collected after the initiation of

glycemic rescue therapy, or at the post-treatment follow-up visits after a pre-mature treatment discontinuation, wereexcluded from the analyses of glycemicvariables and weight. However, suppor-tive analyses were also conducted includ-ing data after the initiation of rescuetherapy for changes in HbA1c, FPG, andweight over time and are shown inSupplementary Fig. 2.All analyses were conducted using SAS

version 9.2 or higher (SAS Institute, Inc.,Cary, NC).

RESULTS

PatientsOf the 695 patients enrolled and ran-domized, 564 (81.2%) completed the52-week study period and 523 (75.3%)completed 52 weeks of treatment (Fig. 1).The most common reasons for treatmentdiscontinuation or study withdrawal werewithdrawals by patients, AEs, or lost tofollow-up. Over the 52 weeks of treat-ment, adherence to treatment was high(Supplementary Table 2).Baseline characteristics and demo-

graphics of patients included in theDURATION-8 study have been reportedpreviously (10). Briefly, patients (meanage 54.2 years; 47.9% male) had a meanbaseline HbA1c of 9.3% (78 mmol/mol)and a mean diabetes duration of 7.4years, and were mostly obese (meanBMI 32.7 kg/m2), with a low incidenceof moderate renal dysfunction (3.6%with an estimated glomerular filtrationrate [eGFR] of $30 to ,60 mL/min/1.73 m2 and 96.4% with an eGFR of$60 mL/min/1.73 m2). Demographicand baseline characteristics were similaracross treatment groups, with the ex-ception of fewer women in the exenatideQW group and fewer Hispanic patients inthe dapagliflozin group (SupplementaryTable 3).

EfficacyTreatment with exenatide QW plus dap-agliflozin resulted in significantly greatermean reductions in HbA1c from base-line to week 28 (Fig. 2A), which were

maintained through week 52 (leastsquares mean [LSM] change from base-line 21.75% [219.1 mmol/mol]) com-pared with exenatide QW plus placebo(21.38% [215.1 mmol/mol]; P = 0.006)or dapagliflozin plus placebo (21.23%[213.4mmol/mol];P,0.001) (Table1).At week 52, mean HbA1c was 6.87%(52 mmol/mol) with exenatide QW plusdapagliflozin, 7.21% (55mmol/mol) withexenatide QW plus placebo, and 7.36%(57 mmol/mol) with dapagliflozin plusplacebo. The proportions of patientswho achieved glycemic goals with ex-enatide QW plus dapagliflozin weregenerally similar at 28 and 52 weeks(Fig. 2B). At 52 weeks, more patientsachieved an HbA1c level of ,7.0% or#6.5% (,53 or #48 mmol/mol), respec-tively, with exenatide QW plus dapagli-flozin (37.7% and 26.3%) than withexenatide QW plus placebo (30.0%and 17.2%) or dapagliflozin plus placebo(16.5% and 8.7%) (Fig. 2B and Table 1).

Patients who received exenatide QWplus dapagliflozin achieved significantlygreater mean reductions in FPG frombaseline to week 28 (Fig. 2C), whichweremaintained throughweek 52 (LSMchange from baseline 23.50 mmol/L)compared with patients who received ex-enatide QW plus placebo (22.52 mmol/L;P , 0.001) or dapagliflozin plus placebo(22.21 mmol/L; P , 0.001) (Table 1).Furthermore, mean reductions in 2-hPPG at 28 weeks were significantlygreater with exenatide QW plus dapa-gliflozin (Fig. 2D), which were main-tained through week 52 (LSM changefrom baseline 24.58 mmol/L) com-pared with exenatide QW plus placebo(23.56 mmol/L; P = 0.004) or dapagli-flozin plus placebo (23.31 mmol/L; P ,0.001) (Fig. 2DandTable 1). Similar resultswere also observed for mean averagesix-point self-monitored blood glucoseconcentrations: reductions at 28 weekswere significantly greater with exena-tide QWplusdapagliflozin (SupplementaryTable 4), which were maintained throughweek 52 (LSM change from baseline22.85 mmol/L) compared with exena-tide QW plus placebo (22.36 mmol/L;P = 0.011) or dapagliflozin plus placebo(22.18mmol/L;P,0.001)(SupplementaryTable 4).

Treatment with exenatide QW plusdapagliflozin resulted in significantlygreater mean reductions in weightfrom baseline to week 28 compared

with exenatide QW plus placebo ordapagliflozin plus placebo (Fig. 2E), andthese differences between treatmentgroups were maintained at 52 weeks(Fig. 2E and Table 1). A significantlygreater proportion of patients who re-ceived exenatide QW plus dapagliflozinachieved a weight loss of $5% at 28weeks (Table 1), which was maintainedthrough week 52 (30.7%) comparedwith exenatide QW plus placebo (14.1%;P , 0.001) or dapagliflozin plus placebo(21.3%; P = 0.022) (Table 1).

Patients who received exenatide QWplus dapagliflozin achieved significantlygreater mean reductions in SBP frombaseline to week 28 compared withpatients who received exenatide QWplus placebo or dapagliflozin plus placebo(Fig. 2F), which were maintainedthrough week 52 (LSM change frombaseline 24.5 mmHg), compared withpatients who received exenatide QWplus placebo (20.7 mmHg; P , 0.001) ordapagliflozin plus placebo (22.7 mmHg;P = 0.100) (Fig. 2F and Table 1). Asobserved in the 28-week analysis, nointergroup differences were noted forthe changes inwaist circumference, DBP,or fasting cholesterol measures atweek 52 (Supplementary Table 4). Al-though nominal P values for treatmentdifferences were$0.05, themagnitude ofreduction in mean triglyceride concen-trations was numerically greater withexenatide QW plus dapagliflozin (20.22mmol/L, an ;10% reduction from base-line) compared with that observed withexenatide QW plus placebo (20.06mmol/L) or dapagliflozin plus placebo(0.01 mmol/L).

The proportions of patients who ini-tiated rescue therapy by week 52 were26.8%, 32.2%, and 37.8% in the exenatideQW plus dapagliflozin, exenatide QWplus placebo, and dapagliflozin plus pla-cebo groups, respectively. These propor-tions were greater than those observedduring the 28-week treatment period(3.9%, 4.4%, and 7.4%, respectively),mainly as a result of the change in rescuecriteria from confirmed FPG thresholdsto a singleHbA1cmeasurement of.8.0%(.64 mmol/mol) that commenced at36 weeks (Supplementary Table 1). Be-tween baseline and week 36, low num-bers of patients were rescued for lackof glycemic control; after week 36, theproportion of patients rescued increased(Supplementary Fig. 3). This inflection

2138 Exenatide Plus Dapagliflozin: One-Year Outcomes Diabetes Care Volume 41, October 2018

point follows the change in rescue cri-teria to HbA1c .8.0% (.64 mmol/mol).The results of treatment efficacy as-

sessed at 52 weeks in a patient popula-tion that included data after the initiationof rescue therapy (Supplementary Fig. 2)were very similar to those in which dataobtained after the initiation of rescuetherapy were excluded (Fig. 2 and Table 1).

Safety and TolerabilityExenatide QW plus dapagliflozin was welltolerated; similar proportions of patientsexperienced an AE over 52 weeks acrossall treatment groups (Table 2). The mostcommon AEs reported with exenatideQW plus dapagliflozin were injection-site nodule, urinary tract infection, head-ache, and nausea. Most AEs were mild

or moderate in intensity. Patients whoreceived exenatide QW plus dapagliflo-zin and exenatide QW plus placeboexperienced more gastrointestinal orinjection site–related AEs than thosewho received dapagliflozin plus placebo(Table 2).

Five patients died during the study;all deaths occurred in the first 28-week

Figure 1—Patient disposition. *Indicates those participants discontinuing therapy with exanatide QW (ExQW); numbers discontinuing dapagliflozin(DAPA) within the ExQW plus DAPA arm were 23 (withdrawals by patient), 15 (for other reasons), 9 (had AEs), and 5 (missing data). ITT, intention-to-treat; wk, week.

care.diabetesjournals.org Jabbour and Associates 2139

Figure 2—A: LSM (SE) change in HbA1c over time. B: Proportion of patients achieving an HbA1c ,7.0 or #6.5% (,53 or #48 mmol/mol) atweeks 28 and 52. C: LSM (SE) changes in FPG over time. D: LSM (SE) change in 2-h PPG at weeks 28 and 52. E: LSM (SE) changes in weight overtime. F: LSM (SE) change in SBP over time. Error bars show SEs or 95% CIs. To convert FPG or 2-h PPG from mmol/L to mg/dL, divide by0.0555. DAPA, dapagliflozin; ExQW, exenatide QW; PBO, placebo. *P , 0.05, **P , 0.01, ***P , 0.001 vs. ExQW + DAPA (P values at week 52are nominal).

2140 Exenatide Plus Dapagliflozin: One-Year Outcomes Diabetes Care Volume 41, October 2018

Table

1—Primary

andse

condary

effica

cyendpoints

atweeks28and52in

theintention-to-treatpatientpopulation

Exen

atideQW

+dapagliflozin

(n=22

8)Exen

atideQW

+placebo

(n=22

7)Dapagliflozin+placebo

(n=23

0)

Between-groupdifference

(95%

CI)

Exen

atideQW

+dapagliflozinvs.

exen

atideQW

+placebo

Exen

atideQW

+dapagliflozinvs.

dapagliflozin+placebo

HbA1c,%

Baseline

9.34

(1.07)

9.30

(1.06)

9.30

(1.03)

Week28

7.24

(1.28)

7.58

(1.30)

7.74

(1.13)

Change

atweek28

21.98

(0.09)

21.60

(0.10)

21.39

(0.09)

20.38

(20.63

to20.13);P=0.003

20.59

(20.84

to20.34);P,

0.00

1Week52

6.87

(0.78)

7.21

(1.04)

7.36

(0.86)

Change

atweek52

21.75

(0.10)

21.38

(0.10)

21.23

(0.10)

20.37

(20.64

to20.11);P=0.006

20.52

(20.79

to20.26);P,

0.00

1

HbA1c,mmol/mol

Baseline

79(11.7)

78(11.6)

78(11.3)

Week28

56(14.0)

59(14.2)

61(12.4)

Change

atweek28

221

.6(1.0)

217

.5(1.1)

215

.2(1.0)

24.2(2

6.9to

21.4);P=0.003

26.4(2

9.2to

23.7);P,

0.001

Week52

52(8.5)

55(11.4)

57(9.4)

Change

atweek52

219

.1(1.1)

215

.1(1.1)

213

.4(1.1)

24.0(2

7.0to

21.2);P=0.006

25.7(2

8.6to

22.8);P,

0.001

HbA1c,7.0%

*Week28

108(47.4;

40.9–53

.9)

70(30.8;

24.8–36

.8)

46(20.0;

14.8–25

.2)

16.5;P,

0.001

27.4;P,

0.00

1Week52

86(37.7;

31.4–44

.0)

68(30.0;

24.0–35

.9)

38(16.5;

11.7–21

.3)

7.8;

P=0.079

21.2;P,

0.00

1

HbA1c#6.5%

†

Week28

72(31.6;

25.6–37

.6)

48(21.1;

15.8–26

.5)

25(10.9;

6.9–14

.9)

10.4;P=0.011

20.7;P,

0.00

1Week52

60(26.3;

20.6–32

.0)

39(17.2;

12.3–22

.1)

20(8.7;5.1–12

.3)

9.1;

P=0.018

17.6;P,

0.00

1

FPG,mmol/L

Baseline

11.01(3.01)

10.66(2.80)

10.58(2.63)

Week28

7.17

(1.90)

8.21

(2.75)

7.89

(1.93)

Change

atweek28

23.66

(0.16)

22.54

(0.17)

22.73

(0.16)

21.12

(21.55

to20.68);P,

0.001

20.92

(21.36

to20.49);P,

0.00

1Week52

6.66

(1.55)

7.48

(1.93)

7.78

(1.92)

Change

atweek52

23.50

(0.16)

22.52

(0.17)

22.21

(0.17)

20.98

(21.42

to20.54);P,

0.001

21.29

(21.73

to20.85);P,

0.00

1

2-hPP

G,mmol/L

Baseline

15.04(3.69)

14.96(3.70)

14.58(3.38)

Week28

9.84

(2.65)

11.38(3.38)

11.23(3.02)

Change

atweek28

24.88

(0.23)

23.34

(0.24)

23.39

(0.23)

21.54

(22.10

to20.98);P,

0.001

21.49

(22.04

to20.93);P,

0.00

1Week52

9.98

(2.84)

11.03(3.39)

11.14(3.02)

Change

atweek52

24.58

(0.27)

23.56

(0.28)

23.31

(0.28)

21.02

(21.70

to20.34);P=0.004

21.26

(21.94

to20.59);P,

0.00

1

Weight,kg

Baseline

91.79(22.24

)89

.77(20.22

)91

.06(19.71

)Week28

88.35(20.57

)87

.62(18.05

)88

.64(18.89

)Change

atweek28

23.55

(0.29)

21.56

(0.29)

22.22

(0.28)

22.00

(22.79

to21.20);P,

0.001

21.33

(22.12

to20.55);P,

0.00

1Week52

89.44(20.99

)89

.69(18.00

)89

.49(16.85

)Change

atweek52

23.31

(0.38)

21.51

(0.40)

22.28

(0.39)

21.80

(22.87

to20.73);P,

0.001

21.02

(22.08

to0.03);P=0.057

Weightloss

$5%

Week28

77(33.8;

27.6–39

.9)

36(15.9;

11.1–20

.6)

49(21.3;

16.0–26

.6)

17.9;P,

0.001

12.5;P=0.003

Week52

70(30.7;

24.7–36

.7)

32(14.1;

9.6–18

.6)

49(21.3;

16.0–26

.6)

16.6;P,

0.001

9.4;

P=0.022

Con

tinu

edon

p.21

42

care.diabetesjournals.org Jabbour and Associates 2141

treatment period and were discussed indetail previously (10). Serious AEs werereported in 4.8% of patients who re-ceived exenatide QW plus dapagliflozinand in 5.2% who received exenatide QWplus placebo or dapagliflozin plus pla-cebo. Most of these events occurredduring the first 28-week treatment pe-riod. During the 24-week extension pe-riod, serious AEs were reported by sevenpatients who did not report serious AEsduring the primary 28-week treatmentperiod (exenatide QW plus dapagliflozinn = 1, exenatide QW plus placebo n = 4,and dapagliflozin plus placebo n = 2).A similar proportion of patients discon-tinued treatment because of an AEacross all groups (Table 2).

Potential cardiovascular and hepaticAEs were adjudicated (Table 2). Overall,0.4%, 1.3%, and 1.3% of patients whoreceived exenatide QW plus dapagliflo-zin, exenatide QW plus placebo, anddapagliflozin plus placebo, respectively,experienced a cardiovascular event. Twoof these events occurred in the 24-weekextension period: one case of anginapectoris in a patient who received ex-enatide QW plus placebo and one caseof acute myocardial infarction in a pa-tient who received dapagliflozin plusplacebo. Hepatic events were reportedin one patient in the exenatide QWplus placebo group (raised levels ofalanine aminotransferase, aspartateaminotransferase, g-glutamyltransferase,and total bilirubin) and one patientin the dapagliflozin plus placebo group(levels of alanine aminotransferase in-creased). Both occurred during theoriginal 28-week treatment period,and both were adjudicated as unlikelyto be related to study drugs (Table 2). Ofnote, patients with clinically significantcardiovascular disease occurring with-in 3 months of screening or significanthepatic disease were excluded from thestudy.

No episodes of major hypoglycemiawere reported (Table 2). Episodes ofminor hypoglycemia occurred amongthree patients (1.3%) in the exenatideQW plus dapagliflozin group and onepatient (0.4%) in the dapagliflozin plusplacebo group; all of these events oc-curred during the extension period(none during the 28-week randomizedtreatment period). The patient in thedapagliflozin plus placebo group was re-ceiving rescue therapy with basal insulin

at the time of the event. More patientsin the exenatide QW plus dapagliflozingroup had episodes of “other” hypogly-cemia during the study (5.2% vs. 3.0%and 1.7% in the exenatide QW plusplacebo and dapagliflozin plus placebogroups, respectively) (Table 2). During the24-week extension period, overall eventsof hypoglycemia were reported by 10patients who did not report hypoglyce-mia episodes during the primary 28-weektreatment period (exenatideQWplus dapa-gliflozin n = 4 [other hypoglycemia n = 1;other hypoglycemia and minor hypogly-cemia n = 3], exenatide QW plus placebon = 4 [other hypoglycemia], and dapagli-flozin plus placebo n = 2 [other hypogly-cemia n = 1; minor hypoglycemia n = 1]).

Incidences of pancreatitis, volumedepletion–related AEs, marked abnor-malities of hematocrit, and acute renaldisorders were low and similar betweengroups (Table 2). None of the volumedepletion–related or acute renal failure–related events were severe or consideredas serious AEs; most events were tran-sient and reversible. The mean eGFRinitially decreased in the dapagliflozin-containing groups, recovering to near-baseline levels by 52 weeks (SupplementaryFig. 4A).

Patients in the dapagliflozin-containinggroups had an increase in hematocritfrom baseline to week 28, and this wasmaintained at week 52 (SupplementaryFig. 4B). Patients in the exenatide QW–

containing groups had small increasesin heart rate at 28 weeks, which weremaintained at 52 weeks (1.9 and 0.8 beatsper minute at 52 weeks vs. baseline inthe exenatide QW plus dapagliflozin andexenatide QW plus placebo groups, re-spectively [Supplementary Fig. 4C]). Incontrast, the heart rates among patientswho received dapagliflozin plus placeboremained unchanged.

At week 52, 45.8% of patients (82of 179 patients) and 49.1% of patients(78 of 159 patients) treated with exena-tide QW plus dapagliflozin and exena-tide QW plus placebo, respectively,had positive anti-exenatide antibodies.Over 52 weeks, 75.4% of patients (169of 224 patients) and 76.4% of patients(172 of 225 patients) who receivedexenatide QW plus dapagliflozin andexenatide QW plus placebo, respec-tively, developed anti-exenatide anti-bodies at some point (Table 2), withoutaffecting HbA1c response. The mean

Table

1—Continued

Exen

atideQW

+dapagliflozin

(n=22

8)Exen

atideQW

+placebo

(n=22

7)Dapagliflozin+placebo

(n=23

0)

Between-groupdifference

(95%

CI)

Exen

atideQW

+dapagliflozinvs.

exen

atideQW

+placebo

Exen

atideQW

+dapagliflozinvs.

dapagliflozin+placebo

SBP,

mmHg

Baseline

130.1(12.7)

129.1(13.1)

130.0(12.9)

Week28

126.5(13.0)

129.2(12.6)

128.4(13.7)

Change

atweek28

24.3(0.8)

21.2(0.8)

21.8(0.8)

23.0(2

5.2to

20.9);P=0.005

22.4(2

4.5to

20.4);P=0.022

Week52

126.5(12.6)

130.2(12.9)

127.8(14.0)

Change

atweek52

24.5(0.8)

20.7(0.9)

22.7(0.8)

23.9(2

6.1to

21.7);P,

0.001

21.8(2

3.9to

0.3);P=0.100

Dataexcludemeasuremen

tsaftertheinitiationofrescuetherapywiththeexceptionofSBP.

ForHbA1c(%

),HbA1c(m

mol/mol),FPG(m

mol/L),2-hPP

G(m

mol/L),weight(kg),andSBP(m

mHg),baseline,

week28

,andweek52

dataaremean(SD),change

atweek28

andweek52

dataareLSM

(SE),anddifference

dataareLSM

(95%

CI).ForHbA1c,7%

,HbA1c#6.5%

,andweightloss

$5%

,week28

andweek52

dataaren(%

;binomialCIs),anddifference

dataarepercent.To

convert

FPGor2-hPP

Gfrom

mmol/Lto

mg/dL,divideby0.0555

.*,

53mmol/mol.†,48

mmol/mol.

2142 Exenatide Plus Dapagliflozin: One-Year Outcomes Diabetes Care Volume 41, October 2018

changes from baseline in HbA1c amongpatients who were antibody nega-tive were 21.98% (221.6 mmol/mol)and 22.03% (222.2 mmol/mol) in theexenatide QW plus dapagliflozin andexenatide QW plus placebo groups,

respectively. Corresponding mean changesin HbA1c among patients with any pos-itive anti-exenatide antibodies were22.35% (225.7 mmol/mol) and21.78%(219.5 mmol/mol) in the exenatideQW plus dapagliflozin and exenatide

QW plus placebo groups, respectively.Injection site–relatedAEsweremore com-mon among patients with any positiveanti-exenatide antibodies (12.6% and10.4% in the exenatide QW plus dapagli-flozin and exenatide QW plus placebo

Table 2—AEs in the safety population

Exenatide QW + dapagliflozin(n = 231)

Exenatide QW + placebo(n = 230)

Dapagliflozin + placebo(n = 233)

Any AE 153 (66.2) 143 (62.2) 144 (61.8)

Any SAE 11 (4.8) 12 (5.2) 12 (5.2)Deaths 3 (1.3) 1 (0.4) 1 (0.4)

AE leading to discontinuation 10 (4.3) 12 (5.2) 8 (3.4)

AEs occurring in $5% of patientsInjection site nodule 20 (8.7) 14 (6.1) 13 (5.6)Nausea 13 (5.6) 22 (9.6) 9 (3.9)Urinary tract infection 16 (6.9) 13 (5.7) 14 (6.0)Diarrhea 11 (4.8) 15 (6.5) 9 (3.9)Upper respiratory tract infection 8 (3.5) 14 (6.1) 13 (5.6)Headache 14 (6.1) 8 (3.5) 10 (4.3)

AEs of special interestVolume depletion–related AEs 2 (0.9) 1 (0.4) 4 (1.7)Dehydration 2 (0.9) 0 1 (0.4)Hypotension 0 1 (0.4) 2 (0.9)Syncope 0 0 1 (0.4)

Hematocrit .55% 5 (2.2) 0 5 (2.1)Pancreatitis 2 (0.9) 1 (0.4) 0Acute renal disorders 0 2 (0.9) 2 (0.9)Acute kidney injury 0 1 (0.4) 1 (0.4)Renal failure 0 1 (0.4) 1 (0.4)

Gastrointestinal AEs 41 (17.7) 45 (19.6) 33 (14.2)Genital infection AEs 11 (4.8) 4 (1.7) 12 (5.2)Injection site–related AEs 32 (13.9) 27 (11.7) 17 (7.3)Nodule 20 (8.7) 14 (6.1) 13 (5.6)Induration 5 (2.2) 6 (2.6) 2 (0.9)Bruising 4 (1.7) 4 (1.7) 2 (0.9)Pruritus 2 (0.9) 2 (0.9) 2 (0.9)Injection site mass 0 2 (0.9) 2 (0.9)Injection site reaction 3 (1.3) 0 0Erythema 0 3 (1.3) 1 (0.4)Inflammation 2 (0.9) 0 0Dermatitis 0 0 1 (0.4)Hemorrhage 1 (0.4) 0 0Hypersensitivity 0 1 (0.4) 0

Adjudicated cardiovascular AEs 1 (0.4) 3 (1.3) 3 (1.3)Adjudicated hepatic AEs 0 1 (0.4) 1 (0.4)Hypoglycemia 12 (5.2) 7 (3.0) 5 (2.1)Major 0 0 0Minor 3 (1.3) 0 1 (0.4)Other 12 (5.2) 7 (3.0) 4 (1.7)

Highest anti-exenatide antibody levels overstudy period

Negative 55 (24.6) 53 (23.6)High positive ($625) 94 (42.0) 64 (28.4)Low positive (,625) 75 (33.5) 108 (48.0)Any positive 169 (75.4) 172 (76.4)

Injection site–related AEs by anti-exenatideantibody levels

Negative 3 (1.3) 3 (1.3)High positive ($625) 18 (7.8) 10 (4.3)Low positive (,625) 11 (4.8) 14 (6.1)Any positive 29 (12.6) 24 (10.4)

Data are n (%). SAE, serious adverse event.

care.diabetesjournals.org Jabbour and Associates 2143

groups, respectively) compared with pa-tientswhowere antibody negative (1.3%in both the exenatide QW plus dapa-gliflozin and exenatide QW plus placebogroups) (Table 2).

CONCLUSIONS

Over the last decade, medications for thetreatment of type 2 diabetes have beendeveloped that improve glycemic controlwithout significant risk of hypoglycemia,as well as provide additional benefitssuch as weight loss, reduced blood pres-sure, and an improved lipid profile. TheDURATION-8 study aimed to investigatethe metabolic effects of using the com-bination of a GLP-1RA (exenatide QW)and an SGLT2 inhibitor (dapagliflozin)compared with each individual drug inpatients with type 2 diabetes inadequatelycontrolled with metformin. Previouslyreported results of this combinationshowed significant improvements in gly-cemic control, weight, and SBP after28 weeks, with no unexpected safetyfindings (10). This 24-week extension ofDURATION-8, inwhich patients continuedto receive their randomized therapy, dem-onstrated that the initial efficacy andsafety of the combination of exenatideQW and dapagliflozin were maintainedover a 52-week treatment period.Glycemic responses with the combi-

nation of exenatide QW plus dapagliflo-zin were less than additive comparedwith either individual drug, as expectedbased on changes at 28 weeks (10) andas typically observed with combinationsof glucose-lowering therapies. Less thanadditive glycemic responses with com-bination therapy may result from a de-pendency on baseline glycemic control.The reduction in weight at 52 weeks withtreatment with exenatide QW plus dap-agliflozin was slightly less than additive,whereas reductions in SBP and triglycer-ides with combination treatment weremore than additive. These additive andnear-additive results suggest the pres-ence of independent mechanisms forchanges in weight, SBP, and triglyceridesthat did not trigger compensatory coun-teracting responses.The maintenance of effect observed in

this analysis was not unexpected giventhe profile of the individual drugs. Long-term studies of treatment with exenatideQW have demonstrated sustained gly-cemic improvement, weight reduction,and improved markers of cardiovascular

risk (11,12), even after 6 years of treat-ment (13). Similar durability has beenobserved in long-term studies (14–18) ofdapagliflozin in patients with type 2 di-abetes. In DURATION-8, the proportionof patients (33.8%) who achieved anHbA1c level of ,7.0% (,53 mmol/mol)with exenatide QW plus dapagliflozinat 52 weeks was lower than in some ofthe aforementioned long-term studiesof exenatide QW, whereas the propor-tion rescued as a result of inadequateglycemic control (26.8%) with exenatideQW plus dapagliflozin was higher than insome of the long-term studies of exena-tide QW. These differences are likely dueto the high baseline HbA1c inclusion cri-terion and differences in rescue criteriain DURATION-8; thus, direct comparisonscannot be made.

Safety and tolerability for the combi-nation therapy of exenatide QW plusdapagliflozin were in line with expecta-tions for the individual drugs. Treatmentswith exenatide QW plus dapagliflozin andexenatide QW plus placebo were asso-ciated with more gastrointestinal or in-jection site–related AEs than treatmentwith dapagliflozin plus placebo, as ex-pected for the GLP-1RA class. At week52, the frequency of anti-exenatide anti-bodies in the exenatide QW plus dapa-gliflozin (46%) and exenatide QW plusplacebo (49%) groups was lower thanpreviously reported in an analysis offour 24- to 30-week clinical trials of ex-enatide QW (57%) (19). In addition, therates of antibody-positive patients atany time during 52 weeks in DURATION-8 did not change from those reportedduring the primary 28-week study pe-riod, in which the number of patientspositive for anti-exenatide antibodiespeaked at 12 weeks and subsequentlydeclined (10).

Although the literature on the com-bination of a GLP-1RA and an SGLT2inhibitor is limited (20), previous studieshave established the feasibility of com-bining GLP-1RAs and SGLT2 inhibitors.A post hoc subgroup analysis of theCanagliflozin Cardiovascular Assess-ment Study (CANVAS) showed reduc-tions in HbA1c, weight, and BPwhen theSGLT2 inhibitor canagliflozin was addedto GLP-1RA therapy (21). A randomized,placebo-controlled study combiningexenatide QW and dapagliflozin in par-ticipants who were obese without di-abetes reported significant weight loss,

BP reduction, and glucose normalizationwithout unexpected AEs (22). Findingsfrom real-world observational and ret-rospective analyses further support theuse of these two drug classes in com-bination (23–28). Although having adifferent design to DURATION-8, therecent Assessment of Weekly Admin-istration of LY2189265 (dulaglutide) inDiabetes-10 (AWARD-10) trial among pa-tients with inadequately controlled type2 diabetes receiving an SGLT2 inhibitorwith or without metformin demonstratedimproved glycemic control with add-ondulaglutide therapy versus placebo (29).

Dual therapy with exenatide QW plusdapagliflozin may have advantages overother combinations for patients withpoor HbA1c control. Although dipeptidylpeptidase 4 inhibitors and SGLT2 inhib-itors are orally administered, greater re-ductions in HbA1c, weight, and BP havegenerally been observed with a GLP-1RAthan with a dipeptidyl peptidase 4 inhib-itor (30,31). Combination therapies withGLP-1RAs and insulins are also available,but greater hypoglycemia risk and at-tenuated weight loss would be expectedwith this combination (32).

In 2018, the American Diabetes Asso-ciation updated the Standards of Med-ical Care in Diabetes (4), indicating that aone-size-fits-all approach to treating un-controlled hyperglycemia is not appropri-ate. Instead, they recommend balancingthe benefits of glycemic control withits potential risks, particularly the riskof hypoglycemia associated with certaintreatments in elderly patients or patientswith comorbid conditions. This is furthersupported by a recent consensus state-ment from the American Association ofClinical Endocrinologists and AmericanCollege of Endocrinology (3), which sup-ports the individualization of glycemicgoals and a nuanced approach to treat-ing hyperglycemia that balances age,comorbidities, and hypoglycemia risk.The combination of GLP-1RAs and SGLT2inhibitors, drug classes with complemen-tary mechanisms of action that are as-sociated with a low risk of hypoglycemia,positive effects on a number of cardio-vascular risk markers (including weightand blood pressure), and some individ-ual molecules with proven cardiovascu-lar benefits (33–35) adds to the range oftherapeutic options available in theera of individualized type 2 diabetestreatment.

2144 Exenatide Plus Dapagliflozin: One-Year Outcomes Diabetes Care Volume 41, October 2018

There are some limitations to thisanalysis. First, all analyses at 52 weekswere exploratory, with only nominalP values calculated. Second, the studyexcluded patients with eGFR valuesof ,60 mL/min/1.73 m2, so the resultscannot be generalized to this populationof patients with type 2 diabetes. Therate of study discontinuation representsanother potential limitation, as ;19%did not complete the 52-week study.Finally, this study was not designed totest the relative benefits of GLP-1RA/SGLT2 inhibitor dual therapy versus se-quential add-on therapy, so this clinicalquestion remains unanswered. Althoughthe use of rescue therapy with insulin,which could affect weight and hypogly-cemia results, could be viewed as a studylimitation, we think that this may also beviewed as a strength, as the study designrepresents the real-life clinical scenarioencountered by many patients with type2 diabetes.In conclusion, the metabolic effects

of combined administration of exenatideQW plus dapagliflozin appear to be sub-stantial and durable. Among patientswith type 2 diabetes inadequately con-trolled with metformin, this combinationprovided sustained improvements inglycemic control, weight, and SBP over52 weeks. Treatment with exenatideQW plus dapagliflozin was well tolerated,with no unexpected safety findings.

Duality of Interest. The study was supported byAstraZeneca. Exenatide and dapagliflozin are pro-prietary compounds of AstraZeneca. All authorsinterpreted the data and wrote the manuscripttogether with the sponsor’s medical writingservices; Simone Boniface and Julian Martinsof inScience Communications, Springer Health-care, provided medical writing support thatwas funded by AstraZeneca. AstraZeneca wasinvolved in the study design and protocol de-velopment, provided logistical support, and ob-tained the data, which were evaluated jointly bythe authors and the sponsor. S.A.J. has receivedhonoraria for consultancy from AstraZeneca, EliLilly, and Janssen. J.P.F. has received researchsupport from AbbVie, Allergan, AstraZeneca,Boehringer Ingelheim, Bristol-Myers Squibb,Elcelyx Therapeutics, Inc., Eli Lilly, Genentech,IONIS, Janssen, Johnson & Johnson, Lexicon,Ligand, Madrigal Pharmaceuticals, Inc., Merck,Mylan, Myovant Sciences, Novartis, NovoNordisk, Ogeda, Pfizer, Sanofi, TaiwanJ Phar-maceuticals Co Ltd., Theracos, Inc., and Vik-ing Therapeutics and has received honorariafor consultancy and participation in advisoryboards from AstraZeneca, Bristol-Myers Squibb,Echosens, Elcelyx Therapeutics, Inc., Johnson &

Johnson, Ligand, Novo Nordisk, and Sanofi. E.H.,H.W., and P.O. are employees and shareholdersofAstraZeneca. A.A. has received researchgrantsfrom AbbVie, AstraZeneca, Kowa Pharma-ceuticals, Novo Nordisk, and Sanofi. C.G. par-ticipated in scientific advisory boards for andreceived consulting/lecturing fees from AlfaWasserman, AstraZeneca, Bayer AG, BoehringerIngelheim, Eli Lilly, Merck KGaA, Merck Sharp &Dohme, Novo Nordisk, and Sanofi. No otherpotential conflicts of interest relevant to thisarticle were reported.Author Contributions. S.A.J. assisted in thedesign of the study, was the international co-ordinating investigator, oversaw the conduct ofthe study, contributed to the acquisition andinterpretation of the data, and provided criticalrevisions to themanuscript. J.P.F. was a principalinvestigator in the study, contributed to theacquisition and interpretation of the data, andprovided critical revisions to the manuscript. E.H.and P.O. participated in study design, data in-terpretation, and manuscript writing. A.A. con-tributed to the acquisition and interpretation ofthe data and provided critical revisions to themanuscript. H.W. was responsible for statisti-cal analysis and interpretation of the data andprovided critical revisions to the manuscript. C.G.was a principal investigator in the study, con-tributed to the acquisition and interpretation ofthe data, and provided critical revisions to themanuscript. S.A.J., J.P.F., E.H., A.A., H.W., P.O.,and C.G. are the guarantors of this work and, assuch, had full access to all the data in the studyand take responsibility for the integrity of thedata and the accuracy of the data analysis.Prior Presentation. Parts of this study werepresented in abstract form at the 77th ScientificSessions of the American Diabetes Association,San Diego, CA, 9–13 June 2017, and at the 53rdAnnual Meeting of the European Association forthe Study of Diabetes, Lisbon, Portugal, 11–15September 2017.

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2146 Exenatide Plus Dapagliflozin: One-Year Outcomes Diabetes Care Volume 41, October 2018