Assessment of Saxagliptin Efficacy: Meta-Analysis of 14 Phase 2 and 3 Clinical Trials

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1 Diabetes Ther (2017) 8: DOI /s ORIGINAL RESEARCH Assessmet of Saxaglipti Efficacy: Meta-Aalysis of 14 Phase 2 ad 3 Cliical Trials Mikaela Sjöstrad. Cheryl Wei. William Cook. Kristia Johsso. Pia S. Pollack. Christia Stahre. Boaz Hirshberg Received: Jauary 11, 2017 / Published olie: April 21, 2017 Ó The Author(s) This article is a ope access publicatio ABSTRACT Itroductio: This meta-aalysis of data from 14 phase 2 ad 3, double-blid, radomized, cotrolled 12- ad 24-week studies (N = 4632) summarizes saxaglipti efficacy i patiets with type 2 diabetes (T2D) across treatmet regimes. Methods: Patiets received saxaglipti 5 mg/d or cotrol as either mootherapy ( = 1196 vs placebo), add-o therapy ( = 2139 vs placebo ad = 514 vs uptitrated sulfoylurea), or iitial combiatio therapy ( = 619 vs cotrol mootherapy). Patiets with real impairmet received saxaglipti 2.5 mg/d or placebo ( = 164). Ehaced cotet To view ehaced cotet for this article go to F B3CC. Electroic supplemetary material The olie versio of this article (doi: /s ) cotais supplemetary material, which is available to authorized users. M. Sjöstrad (&) K. Johsso C. Stahre AstraZeeca, Gotheburg, Swede mikaela.sjostrad@astrazeeca.com C. Wei P. S. Pollack AstraZeeca, Gaithersburg, MD, USA W. Cook B. Hirshberg MedImmue, Gaithersburg, MD, USA Results: Mea baselie glycated hemoglobi (A1C) raged from 8.07% to 9.43% for the saxaglipti ad cotrol groups across treatmet regimes. A1C reductio from baselie was greater with saxaglipti versus cotrol for all studies combied (mea treatmet differece [95% CI]: 0.55% [ 0.63%, 0.47%]) ad whe used as mootherapy ( 0.52% [ 0.63, 0.40%]), add-o ( 0.55% [ 0.69%, 0.40%] vs placebo; 0.72% [ 0.88%, 0.56%] vs uptitrated sulfoylurea), iitial combiatio therapy ( 0.54% [ 0.73%, 0.35%] vs cotrol mootherapy), ad i patiets with real impairmet ( 0.42% [ 0.75%, 0.09%]). Similar reductios i A1C versus cotrol were oted for patiets\65 years ( 0.55% [ 0.67%, 0.43%]) ad C65 years ( 0.54% [ 0.69%, 0.38%]) ad for me ( 0.54% [ 0.69%, 0.40%]) ad wome ( 0.55% [ 0.64%, 0.47%]) across treatmet regimes. More patiets achieved A1C \7% (39% vs 23%) ad A1C B6.5% (24% vs 14%) with saxaglipti tha with placebo or active-cotrol treatmet. Saxaglipti versus cotrol was associated with a reductio i glucago area uder the curve (AUC) from baselie ad icreases i isuli AUC, C-peptide AUC, ad the homeostasis model assessmet of b-cell fuctio. Coclusio: Results of this meta-aalysis demostrate the cosistecy of saxaglipti efficacy i differet subgroups of patiets with T2D across treatmet regimes. Fudig: AstraZeeca.

2 588 Diabetes Ther (2017) 8: Keywords: Dipeptidyl peptidase-4 (DPP-4) ihibitor; Icreti ehacer; Meta-aalysis; Saxaglipti; Type 2 diabetes INTRODUCTION Diabetes is a global health problem, ad although recet US treds suggest that the prevalece of diabetes has stabilized [1], global projectios idicate that the umber of idividuals with diabetes is set to grow substatially i the comig years [2]. Globally, i 2015, 415 millio adults aged years had diabetes, ad by 2040 that umber is expected to icrease to 642 millio [3]. Regioal icreases i diabetes prevalece of 19 to 141% are expected amog adults i Europe (19%), North America ad the Caribbea (37%), the Wester Pacific (41%), South ad Cetral America (65%), South-East Asia (79%), the Middle East ad North Africa (104%), ad Africa (141%) [3]. The prevalece of diabetes is expected to icrease across all icome levels ad age groups [2]. The progressive ature of type 2 diabetes (T2D) [4] ecessitates the use of more tha oe glucose-lowerig aget i may idividuals with diabetes i order to achieve glycemic cotrol [5]. Curret diabetes treatmet guidelies recommed a idividualized stepwise approach with sequetial additio of sigle oral glucose-lowerig agets for patiets who do ot achieve their glycemic goal withi 3 moths [3, 5, 6]. The selectio of a glucose-lowerig aget should take ito cosideratio umerous factors such as efficacy, potetial side effects, weight profile, hypoglycemia risk, cost, patiet preferece, ad comorbidities [5, 6]. Of these factors, comorbidities associated with diabetes such as hypercholesterolemia, hypertesio, ad obesity are associated with marked morbidity ad mortality amog patiets [7]. Amog patiets with T2D, the prevalece is C60% for each of elevated low-desity lipoprotei (LDL), hypertesio, ad obesity [7]. I additio to icreased cardiovascular(cv) morbidity, CV disease (CVD) is a leadig cause of deathipatietswithdiabetesadaccoutsfor [50%ofdeathsipatietswithT2D[8]. Mortality from heart disease is 2 4 times greater for patiets with T2D compared to patiets without diabetes [7]. The cosequeces of diabetes comorbidities are grave, yet the achievemet of glycemic, blood pressure, ad lipid treatmet goals remais suboptimalipatietswitht2d,especiallyisome miority groups (e.g., Mexica Americas ad o-hispaic blacks) [9]. Itesive glucose cotrol early i the course of T2D has bee associated with reductios i microvascular complicatios [10, 11], ad, over the log-term, risk reductios i some macrovascular complicatios have also bee reported [11, 12]. The results of large CV outcomes trials for ewer classes of glucose-lowerig agets have show a CV beefit (empagliflozi [13], a sodium-glucose cotrasporter-2 ihibitor; liraglutide [14] ad semaglutide [15], glucago-like peptide-1 (GLP-1) receptor agoists) or o icreased CV risk (lixiseatide [16], a GLP-1 receptor agoist; aloglipti [17], sitaglipti [18], ad saxaglipti [19], dipeptidyl peptidase-4 (DPP-4) ihibitors). Although o evidece of icreased CV harm (eutral results for composite ed poits of major CV evets ad exteded major CV evets, icludig hospitalizatio for heart failure) has bee observed, a icrease i hospitalizatio for heart failure was observed i the CV outcomes trial for saxaglipti (the Saxaglipti Assessmet of Vascular Outcomes Recorded i Patiets with Diabetes-Mellitus-Thombolysis i Myocardial Ifarctio 53 (SAVOR-TIMI 53) trial [19]) ad i patiets without a history of heart failure i a separate post hoc subaalysis of the CV outcomes trial for aloglipti (Examiatio of CV Outcomes With Aloglipti Versus Stadard Care [17, 20]). Therapies that have favorable or eutral metabolic effects i additio to glucose-lowerig properties are eeded. Saxaglipti is a orally active, selective, ad competitive DPP-4 ihibitor idicated for the treatmet of T2D as a adjuct to diet ad exercise to improve glycemic cotrol [21]. Ihibitio of DPP-4 prevets the degradatio of GLP-1 ad glucose-depedet isuliotropic polypeptide (GIP), two gastroitestial-derived hormoes that play major roles i blood glucose cotrol [22]. I idividual trials, saxaglipti has demostrated efficacy ad safety as a mootherapy ad a add-o combiatio therapy i patiets with T2D [23 29]. Additioally, saxaglipti demostrated a

3 Diabetes Ther (2017) 8: favorable safety ad tolerability profile i patiets with T2D C65 years of age whe saxaglipti was used as a mootherapy or add-o therapy [30 33]. A pooled aalysis of 20 radomized cotrolled studies demostrated the safety ad tolerability of saxaglipti whe used as a mootherapy or add-o therapy; however, this pooled aalysis did ot examie efficacy [34]. The preset paper reports a meta-aalysis of data from 14 phase 2 ad 3, double-blid, radomized, cotrolled trials that evaluated the efficacy of saxaglipti i relatio to glycemic ad metabolic ed poits i patiets with T2D across treatmet regimes. METHODS Study Desig This aalysis icluded data from 14 phase 2 ad 3, 12- ad 24-week, double-blid, radomized, cotrolled studies (N = 4632) examiig saxaglipti 5 mg/d (or 2.5 mg/d i idividuals with moderate [creatiie clearace 30 to \50 ml/ mi], severe [creatiie clearace \30 ml/mi, ot receivig dialysis], or ed-stage [hemodialysis-depedet] real impairmet) for the treatmet of patiets with T2D ad iadequate glycemic cotrol (Table 1) [23, 24, 26 28, 35 43]. This aalysis icluded 13 studies from the previously published pooled safety aalysis [34] ad oe more recet study. Seve studies used i the pooled safety aalysis were excluded from our meta-aalysis because they were either less tha 12 weeks i duratio, used a active comparator, or they used uptitratio of metformi as a cotrol. I the studies icluded i this meta-aalysis, all procedures followed were i accordace with the ethical stadards of the resposible committee o huma experimetatio (istitutioal ad atioal) ad with the Declaratio of Helsiki (1964). Iformed coset was obtaied from all patiets before they were icluded i the studies. Outcome Measures The pricipal glycemic efficacy ed poits were mea chage i glycated hemoglobi (A1C) from baselie ad the percetage of patiets achievig A1C targets of \7% ad B6.5%. Other glycemic ed poits that were assessed icluded mea chage from baselie i fastig plasma glucose (FPG), isuli, C-peptide, ad glucago plasma cocetratios; area uder the curve (AUC) durig a oral glucose test for postpradial glucose (PPG), isuli, C-peptide, ad glucago; ad mea chage from baselie i homeostasis model assessmet of b-cell fuctio (HOMA-2%b) ad HOMA-2 isuli resistace (IR). Metabolic efficacy ed poits that were assessed icluded mea chage from baselie i body weight, waist circumferece, ad body mass idex (BMI); mea chage from baselie i systolic ad diastolic blood pressure; ad mea percet chage from baselie i fastig lipids (total cholesterol, LDL cholesterol, high-desity lipoprotei [HDL] cholesterol, triglycerides, ad free fatty acids). Statistical Aalysis Baselie was defied as the last assessmet o or before the date of the first dose of the double-blid study medicatio. The differece betwee saxaglipti ad the comparator i chage or percetage chage from baselie mea (95% CI) for each study was determied usig a aalysis of covariace (ANCOVA) model with treatmet group as a effect ad baselie value as the covariate. The aalyses were performed o the full aalysis set, cosistig of all radomized patiets who had both a baselie ad at least oe postradomizatio measuremet icluded i the aalysis. If o ed-of-study measuremet was available, the last available earlier postbaselie measuremet (last observatio carried forward, LOCF) method was applied. For patiets who started rescue medicatio before the ed of the study, their last postbaselie measuremet take before the date of the first dose of rescue medicatio was used (prior to rescue). Whe studies were pooled, the chage from baselie mea (95% CI) differece betwee saxaglipti ad cotrol for all cotiuous data glycemic ad metabolic ed poits was determied usig Review Maager 5.3 software (RevMa, Cochrae, Lodo, UK). For dichotomous data, the treatmet differeces i the proportios of patiets achievig A1C targets

4 590 Diabetes Ther (2017) 8: Table 1 Trial characteristics Study idetifier Desig a A1C iclusio criteria, % Patiets i aalysis, CV [35] Mootherapy, treatmet-aive b CV [24] Mootherapy, treatmet-aive CV [23] Mootherapy, treatmet-aive CV [36] Mootherapy, treatmet-aive CV [37] Mootherapy, treatmet-aive CV [38] Add-o to INS?MET CV [39] Add-o to MET CV [40] Add-o to MET b,c CV [41] Add-o to MET CV [26] Add-o to MET?SU CV [27] Add-o to TZD CV [42] Add-o to SU vs SU CV [28] Iitial combiatio therapy vs mootherapy CV [43] Real impairmet, add-o to existig therapy b,d Total umber of patiets, N 4638 A1C glycated hemoglobi, BID twice daily, INS isuli, MET metformi, SU sulfoylurea, TZD thiazolidiedioe a All trials were 24 weeks i duratio ad the dose of saxaglipti dose was 5 mg/d uless otherwise oted b Trial duratio was 12 weeks c Saxaglipti dose was 2.5 mg BID d Saxaglipti dose was 2.5 mg/d of \7 ad B6.5% (expressed as percetages) for saxaglipti ad cotrol were determied usig RevMa. Betwee-treatmet differeces i study edpoits were aalyzed usig a radom effects method where the weight assiged to each study was the iverse of the variace of the effect estimate. Thus, i geeral, larger studies were give more weight tha smaller studies. RESULTS Study Characteristics This aalysis icluded 14 phase 2 or 3 studies (Table 1) that evaluated saxaglipti 5 mg/d or cotrol as either mootherapy ( = 1196; 5 studies), add-o therapy ( = 2139 vs placebo ad = 514 vs uptitrated sulfoylurea; 6 studies ad 1 study, respectively), or iitial combiatio therapy ( = 619 vs cotrol mootherapy; 1 study); or, for patiets with real impairmet, saxaglipti 2.5 mg/d or placebo ( = 164; 1 study). All studies were 12 or 24 weeks i duratio. Data from all 14 trials were icluded i the aalysis of chage from baselie i A1C; availability of data per study varied for all other ed poits. Mea (SD) baselie A1C levels for saxaglipti ad cotrol were 8.12% (0.9%) ad 8.07% (0.9%) for mootherapy versus placebo, 8.26% (1.0%) ad 8.15% (0.9%) for add-o versus placebo, 8.26% (0.8%) ad 8.15% (0.9%) for add-o versus uptitrated sulfoylurea, 9.41%

5 Diabetes Ther (2017) 8: (1.3%) ad 9.43% (1.3%) for iitial combiatio therapy versus cotrol mootherapy, ad 8.45% (1.2%) ad 8.09% (1.1%) for saxaglipti versus placebo i patiets with real impairmet (Fig. 1). Glycemic Outcomes For all 14 studies combied, the reductio from baselie i A1C was greater with saxaglipti versus cotrol (mea treatmet differece [95% CI] 0.55% [ 0.63%, 0.47%]; Fig. 1). Large reductios i A1C were observed whether saxaglipti was used as a mootherapy versus placebo ( 0.52% [ 0.63%, 0.40%]; 5 studies) or as a add-o versus placebo ( 0.55% [ 0.69%, 0.40%]; 6 studies). Marked reductios i A1C from baselie were also observed whether saxaglipti was used as a add-o versus uptitrated sulfoylurea ( 0.72% [ 0.88%, 0.56%]; 1 study) or as a iitial combiatio therapy versus cotrol mootherapy ( 0.54% [ 0.73%, 0.35%]; 1 study). Large reductios i A1C with saxaglipti versus placebo were also oted i patiets with real impairmet ( 0.42% [ 0.75%, 0.09%]; 1 study). Similar treatmet effects were observed across subgroups of age, sex, ad geographical regio (Figs. S1 S3 i the Electroic supplemetary material, ESM). Reductios from baselie i A1C favored saxaglipti versus cotrol for patiets \65 years of age ( 0.55% [ 0.67%, 0.43%]; 9 studies), patiets C65 years of age (0.54% [ 0.69% [ 0.69%, 0.38%]; 10 studies), me ( 0.54% [ 0.69%, 0.40%]; 10 studies), ad wome ( 0.55% [ 0.64%, 0.47%]; 10 studies). The A1C reductio from baselie was geerally similar across geographical regios of North America, Europe, Lati America, ad Asia. A smaller reductio from baselie i A1C was observed Fig. 1 Mea treatmet differece i chage i A1C from baselie across treatmet regimes. A1C glycated hemoglobi, CTL cotrol, INS isuli, IV iverse variace, MET metformi, SAXA saxaglipti, SU sulfoylurea, TZD thiazolidiedioe

6 592 Diabetes Ther (2017) 8: A B Fig. 2 Percetages of patiets who achieved a A1C\7% ad b A1C B6.5%. CTL cotrol, INS isuli, IV iverse variace, MET metformi, SAXA saxaglipti, SU sulfoylurea, TZD thiazolidiedioe for Africa; however, data were limited to a sigle add-o to isuli trial. Across the combied studies, patiets treated with saxaglipti were more likely to achieve A1C \7% (39% vs 23%; treatmet differece [95% CI] 0.16 [0.13, 0.19]; 13 studies) ad A1C B6.5% (24% vs 14%; treatmet differece [95% CI] 0.10 [0.07, 0.13]; 10 studies) versus cotrol, with similar effects obtaied whe saxaglipti was used as a mootherapy or add-o therapy (Fig. 2a, b). The percetage of patiets achievig A1C \7% was greater with saxaglipti whether it was used as a mootherapy versus placebo (40% vs 25%), a add-o versus placebo (36% vs 21%), a add-o versus uptitrated sulfoylurea (23% vs 9.1%), or as iitial combiatio therapy versus cotrol mootherapy (60% vs 41%). Similarly, the percetage of patiets achievig A1C B6.5% was greater with saxaglipti mootherapy versus placebo (22% vs 14%), add-o versus placebo (22% vs 10%), add-o versus uptitrated sulfoylurea (10% vs 4.5%), ad iitial combiatio therapy versus cotrol mootherapy (45% vs 29%).

7 Diabetes Ther (2017) 8: Table 2 Effect estimates for mea treatmet differeces i glycemic efficacy ed-poit chages from baselie for saxaglipti versus cotrol i adults with T2D Outcome Baselie saxaglipti Saxaglipti, Baselie cotrol Cotrol, Studies, Mea treatmet differece a IV, radom 95% CI FPG, mg/dl , 9.97 PPG AUC, 46, , , 3.30 g mi/dl Fastig isuli, uu/ml Isuli AUC, mu mi/ml Fastig C-peptide, g/ml C-peptide AUC, g mi/ml , , , , Glucago, pg/ml , 0.52 Glucago AUC, 14, , , 0.58 g mi/ml HOMA-2%b, % , 9.78 HOMA-2 IR, % , 0.04 AUC area uder the curve, FPG fastig plasma glucose, HOMA homeostasis model assessmet of b-cell fuctio, IR isuli resistace, IV iverse variace, PPG postpradial glucose; T2D type 2 diabetes a Mea treatmet differece i chage from baselie for saxaglipti versus cotrol The reductio from baselie i FPG was greater with saxaglipti versus cotrol across the combied studies (mea treatmet differece [95% CI] mg/dl [ 15.82, 9.97]; 13 studies, Table 2). Likewise, a greater reductio from baselie i PPG AUC was observed with saxaglipti versus cotrol across 10 studies (mea treatmet differece [95% CI] 4.67 g mi/dl [ 6.03, 3.30]; Table 2). No differece was observed for chage from baselie i fastig isuli betwee saxaglipti versus cotrol (mea treatmet differece [95% CI] 0.15 lu/ml [ 0.65, 0.35]; 11 studies), whereas there was a modest icrease from baselie i isuli AUC with saxaglipti versus cotrol (mea treatmet differece [95% CI] 1.14 mu mi/ml [0.65, 1.63]; 8 studies, Table 2). Results for C-peptide paralleled those observed for isuli, with o cliically meaigful differeces observed for chage from baselie i fastig C-peptide ad a icrease from baselie i C-peptide AUC with saxaglipti versus cotrol. The reductio from baselie i fastig glucago was greater with saxaglipti versus placebo across 10 studies combied (mea treatmet differece [95% CI] 2.22 pg/ml [ 3.92, 0.52]). Similarly, a greater reductio from baselie i glucago AUC was observed with saxaglipti versus cotrol across eight studies (mea treatmet differece [95% CI] 0.93 g mi/ml [ 1.28, 0.58], Table 2). b-cell fuctio, calculated via the chage from baselie i HOMA-2%b, improved with saxaglipti versus cotrol (mea treatmet differece [95% CI] 7.55% [5.32%, 9.78%]; 10 studies). The chage from baselie i HOMA-2 IR idicated a slight reductio i isuli

8 594 Diabetes Ther (2017) 8: Table 3 Total effect estimates for mea treatmet differeces i weight ad blood pressure ed-poit chages from baselie for saxaglipti versus cotrol i adults with T2D Parameter Baselie saxaglipti Saxaglipti, Baselie cotrol Cotrol, Studies, Mea treatmet differece a IV, radom 95% CI Body weight, kg , 0.64 Waist circumferece, cm , 0.69 BMI, kg/m , 0.28 Blood pressure Systolic, mmhg , 0.68 Diastolic, mmhg , 0.64 IV iverse variace, T2D type 2 diabetes a Mea treatmet differece i chage from baselie for saxaglipti versus cotrol Table 4 Total effect estimates for mea treatmet differeces i lipid ed-poit percetage chages from baselie for saxaglipti versus cotrol i adults with T2D Parameter Total cholesterol, mg/dl LDL cholesterol, mg/dl HDL cholesterol, mg/dl Fastig triglycerides, mg/dl Free fatty acids, mg/dl Baselie saxaglipti Saxaglipti, Baselie cotrol Cotrol, Studies, Mea treatmet differece a IV, radom 95% CI , , , , , 3.13 HDL high-desity lipoprotei, IV iverse variace, LDL low-desity lipoprotei, T2D type-2 diabetes a Mea treatmet differece i percetage chage from baselie for saxaglipti versus cotrol

9 Diabetes Ther (2017) 8: resistace with saxaglipti versus cotrol (mea treatmet differece [95% CI] 0.14% [ 0.24%, 0.04%]; 7 studies, Table 2). Metabolic (Weight, Blood Pressure, ad Lipid) Outcomes No cliically meaigful effects were observed for chage from baselie i body weight (mea treatmet differece [95% CI] 0.39 [0.14, 0.64] kg; 12 studies), waist circumferece (0.31 [ 0.06, 0.69] cm; 11 studies), or BMI (0.17 [0.06, 0.28] kg/m 2 ; 11 studies) with saxaglipti versus cotrol (Table 3). Chages from baselie i systolic (mea treatmet differece [95% CI] 0.19 [ 1.07, 0.68] mmhg; 14 studies) ad diastolic (0.09 [ 0.45, 0.64] mmhg; 14 studies) blood pressure were similar with saxaglipti ad cotrol (Table 3). Modest reductios i percetage chage from baselie i total cholesterol (mea treatmet differece [95% CI] 1.47% [ 2.62%, 0.33%]; 10 studies), HDL cholesterol ( 1.74%, 2.92%, 0.57%]; 10 studies), ad fastig triglycerides ( 4.08% [ 7.30% to 0.85%]; 10 studies) were observed, alog with tedecies for small reductios i LDL cholesterol ( 0.73% [ 2.75% to 1.29%]; 10 studies) ad free fatty acid ( 2.53% [ 8.19% to 3.13%]; 7 studies) with saxaglipti versus cotrol (Table 4). DISCUSSION These aalyses demostrate that the efficacy of saxaglipti is cosistet, whether give as a mootherapy, add-o therapy, or iitial combiatio therapy. The effects are likewise cosistet i patiets with real impairmet, regardless of age ad sex, ad i differet geographic regios. Patiets with T2D were more likely to achieve therapeutic glycemic goals of either A1C\7% or B6.5% with saxaglipti tha with cotrols. Patiets experieced greater mea reductios i A1C, FPG, PPG, ad glucago, as well as greater mea icreases i postpradial isuli secretio ad C-peptide levels. There were improvemets i b-cell fuctio as assessed by HOMA-2%b. Saxaglipti prevets the degradatio of icretis by ihibitig DPP-4. Icretis play a major role i glucose cotrol, with as much as 70% of postpradial isuli secretio mediated by the icretis GIP ad GLP-1 [44]. After eatig, patiets experiece a rapid ad trasiet icrease i GIP ad GLP-1, with degradatio by DPP-4 withi miutes of secretio [45 47]. Saxaglipti at doses of mg ihibits plasma DPP-4 activity by 50 79% at 24 h [48]. Cosequetly, at the recommeded dose of 5 mg/d i patiets with T2D, GIP ad GLP-1 cocetratios are at least twofold more tha baselie [48, 49]. The icreti effects of saxaglipti have bee demostrated as improvemets i FPG, PPG, ad glucose disposal through a combiatio of icreased fastig ad postpradial isuli secretio ad a reductio i postpradial glucago secretio i patiets with T2D [49]. Our aalysis demostrated a icrease i isuli AUC ad C-peptide AUC ad reductios i fastig ad postpradial glucago secretio. Although we did ot see a icrease i fastig isuli or fastig C-peptide, treatmet with saxaglipti was associated with sigificat reductios i both FPG ad PPG. I additio to improvig glucoregulatory hormoal secretio, DPP-4 ihibitio may also be associated with protective ad/or restorative effects o b-cell fuctio. Precliical studies usig a high-fat diet-fed, streptozotoci-iduced mouse model of diabetes have show that saxaglipti has beeficial effects o b-cell mass ad islet cell morphology [50], with cliical studies also demostratig small positive effects o b-cell fuctio. After a media 2-year follow-up, treatmet with saxaglipti was associated with preservatio of b-cell fuctio, assessed by HOMA-2%b, whereas treatmet with placebo was associated with a declie i b-cell fuctio i patiets with a history of T2D ad CVD who participated i the SAVOR-TIMI 53 trial (N = 16,492) [19, 51]. These positive effects o pacreatic b-cells may explai the small improvemets i HOMA-2%b observed i this study. The results preseted here are similar to a meta-aalysis of 16 radomized, cotrolled studies C12 weeks i duratio that examied the efficacy of DPP-4 ihibitors, icludig

10 596 Diabetes Ther (2017) 8: saxaglipti, compared with placebo i adults with T2D [52]. The reductio from baselie i A1C was greater with DPP-4 ihibitors versus placebo (weighted mea differece [95% CI] 0.74% [ 0.85%, 0.62%]; 16 studies), with similar efficacies observed whe used as a mootherapy or add-o therapy [52]. The magitude of A1C reductio i the curret aalysis with saxaglipti ( 0.55% [ 0.63%, 0.47%]) was slightly lower tha that obtaied with either vildaglipti ( 0.73% [ 0.94%, 0.52%]; 9 studies) or sitaglipti ( 0.74% [ 0.84%, 0.63%]; 7 studies), but this may be explaied by differeces i cliical study desig, such as baselie A1C, T2D duratio, cocomitat glucose-lowerig agets, study duratio, ru-i period, ad washout [52]. Similar to the aalyses reported here for saxaglipti, a greater percetage of patiets achieved A1C \7% (43% vs 17%; 9 studies) ad there was a greater reductio i FPG (weighted mea differece, 18 [ 22, 14] mg/dl; 15 studies) with DPP-4 ihibitors versus placebo. Neutral effects of DPP-4 ihibitors versus placebo o oglycemic parameters such as body weight ad lipids were also observed [52]. These eutral effects o weight ad lipids are cosistet with our meta-aalysis. Weight eutrality is a desirable attribute for a glucose-lowerig aget, give the associatio of obesity with CVD morbidity ad mortality. I additio to efficacy, the safety ad risk beefit profiles of glucose-lowerig agets are importat cosideratios whe selectig appropriate therapies for patiets. This report does ot iclude a safety aalysis because a previously published pooled aalysis of 20 radomized cotrolled studies, icludig 13 of the studies i the curret meta-aalysis, demostrated the safety ad tolerability of saxaglipti whe used as a mootherapy or add-o therapy [34]. Aalysis of these 20 studies foud that the icidece rates (per 100 patiet-years) of serious adverse evets (saxaglipti, 7.3; cotrol, 7.2) ad discotiuatios due to adverse evets (saxaglipti, 4.2; cotrol, 3.9) with saxiglipti were similar to those obtaied with the cotrol, ad were cosistet irrespective of age ad sex. Compared with the cotrols, premature discotiuatio rates with saxaglipti were similar i eight studies, higher i three studies, ad lower i ie studies [34]. The limitatios of our aalyses are the small umber of studies i some treatmet regimes ad the iclusio of oly a sigle study for some treatmet regime categories. Because these aalyses were limited to studies 12 or 24 weeks i duratio, the durability of the efficacy of saxaglipti could ot be evaluated. However, the log-term efficacy of saxaglipti was demostrated previously [53]. Although we recogize these limitatios, our study has several stregths. Its large size is represetative of a heterogeeous patiet populatio, ad the icluded studies were radomized, double-blid, placebo- or active-cotrolled studies. The iclusio of a broad patiet populatio allowed for subgroup aalysis, which demostrated the efficacy of saxaglipti across subgroups defied by age, sex, or geographical locatio. CONCLUSION Improvig glycemic cotrol is of the utmost importace whe attemptig to slow the progressio of T2D ad prevet microvascular complicatios. Thus, glucose-lowerig agets such as saxaglipti with glycemic efficacy, a low risk for hypoglycemia, ad eutral effects o metabolic ed poits are advatageous. The cosistecy of saxaglipti efficacy i differet patiet subgroups with T2D ad across treatmet regimes, as show here, demostrates its usefuless i a broad rage of treatmet settigs. ACKNOWLEDGEMENTS Sposorship for this study ad article processig charges were fuded by AstraZeeca. All amed authors meet the Iteratioal Committee of Medical Joural Editors (ICMJE) criteria for authorship of this mauscript ad gave fial approval to the versio to be published. All

11 Diabetes Ther (2017) 8: authors had full access to all of the data i this study ad take complete resposibility for the itegrity of the data ad accuracy of the data aalysis. Medical writig support for the preparatio of this mauscript was provided by Laure D Agelo, PhD, ad Jaet Matsuura, PhD, from Complete Healthcare Commuicatios, LLC (Chadds Ford, PA, USA), with fudig from AstraZeeca. Disclosures. Mikaela Sjöstrad is a employee of AstraZeeca. Cheryl Wei is a employee of AstraZeeca. William Cook is a employee of MedImmue, a subsidiary of AstraZeeca. Kristia Johsso is a employee of AstraZeeca. Pia S. Pollack was a employee of AstraZeeca at the time this research was coducted ad ows AstraZeeca stock. Christia Stahre is a employee of AstraZeeca. Boaz Hirshberg is a employee of MedImmue, a subsidiary of AstraZeeca. Compliace with Ethics Guidelies. This article does ot cotai ay ew studies with huma subjects performed by ay of the authors. I the studies icluded i this meta-aalysis, all procedures followed were i accordace with the ethical stadards of the resposible committee o huma experimetatio (istitutioal ad atioal) ad with the Declaratio of Helsiki (1964). Iformed coset was obtaied from all patiets before they were icluded i the studies. Data Availability. The datasets geerated ad/or aalyzed durig the curret study are available from the correspodig author o reasoable request. Ope Access. This article is distributed uder the terms of the Creative Commos Attributio-NoCommercial 4.0 Iteratioal Licese ( by-c/4.0/), which permits ay ocommercial use, distributio, ad reproductio i ay medium, provided you give appropriate credit to the origial author(s) ad the source, provide a lik to the Creative Commos licese, ad idicate if chages were made. REFERENCES 1. Meke A, Casagrade S, Geiss L, Cowie CC. Prevalece of ad treds i diabetes amog adults i the Uited States, JAMA. 2015;314: Guariguata L, Whitig DR, Hambleto I, Beagley J, Liekamp U, Shaw JE. Global estimates of diabetes prevalece for 2013 ad projectios for Diabetes Res Cli Pract. 2014;103: Iteratioal Diabetes Federatio. IDF diabetes atlas, sixth editio [cited 2016 September 27]. Available from: 5e/the-global-burde. 4. Foseca VA. Defiig ad characterizig the progressio of type 2 diabetes. Diabetes Care. 2009;32:S America Diabetes Associatio. Approaches to glycemic treatmet. Diabetes Care. 2016;39:S Garber AJ, Abrahamso MJ, Barzilay JI, et al. Cosesus statemet by the America Associatio of Cliical Edocriologists ad America College of Edocriology o the comprehesive type 2 diabetes maagemet algorithm 2016 executive summary. Edocr Pract. 2016;22: Mozaffaria D, Bejami EJ, Go AS, et al. Heart disease ad stroke statistics 2016 update: a report from the America Heart Associatio. Circulatio. 2016;133:e Morrish NJ, Wag SL, Steves LK, Fuller JH, Kee H. Mortality ad causes of death i the WHO Multiatioal Study of Vascular Disease i Diabetes. Diabetologia. 2001;44:S Stark Casagrade S, Fradki JE, Saydah SH, Rust KF, Cowie CC. The prevalece of meetig A1C, blood pressure, ad LDL goals amog people with diabetes, Diabetes Care. 2013;36: UK Prospective Diabetes Study (UKPDS) Group. Itesive blood-glucose cotrol with sulphoylureas or isuli compared with covetioal treatmet ad risk of complicatios i patiets with type 2 diabetes. Lacet. 1998;352: Holma RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-Year follow-up of itesive glucose cotrol i type 2 diabetes. N Egl J Med. 2008;359: Hayward RA, Reave PD, Wiitala WL, et al. Follow-up of glycemic cotrol ad cardiovascular outcomes i type 2 diabetes. N Egl J Med. 2015;372:

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