Until recently, only two drugs available for type 2. Weight Beneficial Treatments for Type 2 Diabetes

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1 SPECIAL FEATURE Weight Beneficil Tretments for Type 2 Dietes Review L. F. Meneghini, D. Orozco-Beltrn, K. Khunti, S. Cputo, T. Dmçi, A. Liel, nd S. A. Ross Dietes Reserch Institute (L.F.M.), University of Mimi Miller School of Medicine, Mimi, Florid 33136; Cthedr of Fmily Medicine (D.O.-B.), Clinicl Medicine Deprtment, University Miguel Hernndez, Sn Jun de Alicnte, Spin; Deprtment of Helth Sciences (K.K.), University of Leicester, Leicester LE1 7RH, United Kingdom; Servizio di Dietologi (S.C.), Policlinico Gemelli, Università Cttolic, Rome, Itly; Istnul University (T.D.), Cerrhps Medicl Fculty, Deprtment of Endocrinology, Dietes nd Metolism, Istnul, Turkey; Center for Dietes nd Metolism (A.L.), Fchklinik Bd Heilrunn, Germny; nd University of Clgry (S.R.), Alert, Cnd AB T2N 1N4 Context: Thecloselinketweentype2dietesndexcessodyweighthighlightstheneedtoconsider the weight effects of different tretment regimens. We exmine the impct of weight-friendly type 2 dietes phrmcotherpies nd suggest tretment strtegies tht mitigte weight gin. Evidence Acquisition: Evidence ws identified vi PuMed serch y clss nd gent nd in iliogrphies of review rticles, with finl rticles for inclusion selected y uthor consensus. Evidence Synthesis: Sustntil evidence confirms the weight enefits of metformin nd shows tht, of the newer ville gents, glucgon-like peptide-1 (GLP-1) gonists nd mylin nlogs promote weight loss. Dipeptidyl peptidse-4 (DPP-4) inhiitors nd ile cid sequestrnts re weight-neutrl. Lirglutide nd exentide pper to hve similr effects on weight; however, recent reserch suggests potentilly greter effect of lirglutide on glycemic control compred to exentide, when used s second-line therpy. Mounting evidence suggests tht insulin detemir my provide the most fvorle weight enefits of ville insulins. Conclusions: Weight-eneficil gents should e considered in ptients, prticulrly oese ptients, who fil to rech glycemic trgets on metformin therpy. We propose the following tretment choices sed on potentil weight enefit nd lood glucose increment: long-cting GLP-1 gonists (lirglutide), DPP-4 inhiitors, ile cid sequestrnts, mylin nlogs, nd sl insulin for ptients with elevted fsting plsm glucose; nd short-cting (exentide) or long-cting GLP-1 gonists, mylin nlogs, DPP-4 inhiitors, crose, nd ile cid sequestrnts for ptients with elevted postprndil glucose. The weight-spring effects of insulin detemir, notly in ptients with high ody mss index, should lso e considered when inititing insulin therpy. (J Clin Endocrinol Met 96: , 2011) Until recently, only two drugs ville for type 2 dietes (T2D) tretment could e considered weight-neutrl: metformin nd crose (1). Although weight is modifile risk fctor nd n integrl prt of T2D mngement, weight control is prticulrly chllenging when tretments such s sulfonylures (SU), thizolidinediones (TZD), nd/or insulin re introduced to chieve glycemic trgets. In ddition, oth ISSN Print X ISSN Online Printed in U.S.A. Copyright 2011 y The Endocrine Society doi: /jc Received Mrch 23, Accepted August 10, First Pulished Online Septemer 7, 2011 weight gin nd weight loss cn e self-perpetuting. Beyond the psychologicl implictions, weight gin increses insulin resistnce, which in turn leds to esclting insulin requirements nd eventul intensifiction of therpy (2). Becuse these effects could e reversile with dequte weight reduction (3), tretment decisions should idelly incorporte weight-friendly strtegies in the mngement pln. Arevitions: BMI, Body mss index; CI, confidence intervl; DPP-4, dipeptidyl peptidse-4; FPG, fsting plsm glucose; GLP-1, glucgon-like peptide-1; HA1c, hemogloin A1c; OAD, orl ntidietic gent; PPG, postprndil glucose; RCT, rndomized control tril; SU, sulfonylure; T2D, type 2 dietes; TZD, thizolidinedione. J Clin Endocrinol Met, Novemer 2011, 96(11): jcem.endojournls.org 3337

2 3338 Meneghini et l. Weight Beneficil Tretments for Type 2 Dietes J Clin Endocrinol Met, Novemer 2011, 96(11): An incresing numer of ntidietic gents tht re not ssocited with weight gin hve ecome ville in recent yers. Some gents, such s the glucgon-like peptide-1 (GLP-1) gonists (exentide, lirglutide), metformin, nd mylin nlogs (prmlintide), re ssocited with weight loss. Other gents, including dipeptidyl peptidse-4 (DPP-4) inhiitors (sitgliptin, sxgliptin, vildgliptin), ile cid sequestrnts (colesevelm), nd -glucosidse (crohydrte) inhiitors (crose, miglitol, vogliose), re weight-neutrl. In ddition, sl insulin nlogs, such s insulin detemir nd glrgine, pper to hve differentil effects on weight gin reltive to humn insulin preprtions, iphsic, nd prndil insulin regimens. In this focused review rticle, we exmine the effects of weight-friendly phrmcotherpies in the tretment cscde of T2D nd suggest glucose-lowering strtegies tht mitigte weight gin nd its potentil negtive impct on glycemic control, crdiovsculr disese, nd other helth outcomes. Methods This review includes comprehensive selection of representtive clinicl trils covering ll gents with dt ville to report weight chnge in T2D. The literture serch for rticles to include in this review strted with the iliogrphies of severl relevnt review rticles (4 6) for reports of T2D clinicl trils reporting weight s n outcome. Articles deemed pproprite were included, nd dditionl references were identified using the relted cittions serch option on PuMed. This ws judged y the uthors to e preferle pproch to strting the literture review with term serch on PuMed. In prticulr, the uthors were concerned tht using the serch term weight might produce results only for gents showing consistent weight enefits, which could led to ised results. Alterntively, excluding the serch term weight would hve likely produced n unworkly lrge numer of rticles, with only minor proportion of relevnt trils for inclusion in this pper. Additionl PuMedsercheswereperformedyclssorgentusingthefollowing serch terms ( All fields ): incretin, DPP4 inhiitor, igunide, mylin nlog, ile cid sequestrnt, glucosidse inhiitors, colesevelm, crose, or insulin, limited to clinicl trils in type 2 dietes [MeSH term]. At ech stge of the serch, ech uthor provided expert opinion on which rticles to include or exclude; this ws done to prevent is. Generlly, rticles summrizing nonrndomized studies were excluded in cses where insulin ws evluted in comintion with regimens no longer commonly prescried; these decisions were mde sed on uthor expert opinion regrding clinicl relevnce. The finl selection of studies considered suitle for inclusion ws sed on uthor consensus. Results Phrmcologicl tretments in T2D providing weight enefit: clinicl trils Metformin monotherpy nd comintion therpy The igunide insulin-sensitizing gent, metformin, is thought to decrese heptic glucose production nd enhnce peripherl tissue sensitivity to insulin. Metformin, long with lifestyle intervention, typiclly chieves reduction in hemogloin A1c (HA1c) of pproximtely 1.0% (7) nd is the recommended first-line tretment of T2D in ll current mngement guidelines (8 10). Metformin is weight-neutrl, or ssocited with modest weight loss, prticulrly in oese ptients (11). The weight enefits of metformin monotherpy hve een demonstrted in severl trils reporting 0.6- to 2.9-kg weight reduction in tretment-nive ptients followed for 6 months to 5 yr; most of this weight loss occurred within the first yer (12 15). Often, this outcome ws compred with weight increses in the comprtor groups in these trils: rosiglitzone ( 4.8 kg), glyuride ( 1.6 kg) (13), nd pioglitzone ( 1.9 kg) (14). In ddition, switching previously diet- nd glyuride-treted ptients to metformin resulted in 3.8-kg weight loss, wheres ptients continuing glyuride monotherpy did not experience ny significnt weight chnge (12). Reserch lso indictes tht comintion tretment with metformin ppers to mitigte, to some degree, the weight gin ssocited with SU nd TZD therpy (12, 15). A met-nlysis ws recently pulished tht comprises rndomized controlled trils (RCT) of noninsulin ntidietic therpies dded to metformin in T2D ptients with indequte response to mximized metformin therpy (16). The met-nlysis reports sttisticlly significnt weight gin in ptients dding SU ( 2.1 kg), glinides ( 1.8 kg), nd TZD ( 2.1 kg) to metformin. Only the ddition of GLP-1 nlogs resulted in further significnt weight loss ( 1.7 kg), wheres DPP-4 nd -glucosidse inhiitors were weight-neutrl. GLP-1 nlogs were ssocited with the lrgest simultneous reductions in HA1c ( 0.97%), compred with -glucosidse inhiitors ( 0.64%), glinides ( 0.65%), DPP-4 inhiitors ( 0.78%), SU ( 0.79%), nd TZD ( 0.85%). Thus, lthough numer of trils investigting the effects of comintion therpy with metformin report weight enefits (17 21), the only second-line gents ssocited with dditionl weight loss in ptients lredy receiving mximlly tolerted metformin doses were the GLP-1 nlogs. Weight reduction with GLP-1 nlogs hs lso een shown to e sustinle in the long term. In n 82-wk extension tril, exentide ddition to metformin resulted in finl HA1c reduction of 1.3% nd men weight loss of 5.3 kg in the 92 of 150 (61%) completers (18). In n open-lel single-rm extension study of exentide, glycemic control nd weight enefits were sustined for up to 3.5 yr (22). Weight reduction hs lso een demonstrted for ptients dding GLP-1 nlogs s third-line gents, oth for ptients previously treted with metformin/su comin-

3 J Clin Endocrinol Met, Novemer 2011, 96(11): jcem.endojournls.org 3339 tion therpy (22 26) nd those treted with metformin/ TZD comintion therpy (27). A single tril compring the ddition of the two ville GLP-1 nlogs, lirglutide or exentide, to existing tretment with metformin nd/or SU showed tht lirglutide chieved greter HA1c reduction (HA1c, 1.12 vs. 0.79%, respectively) with similr weight enefits ( 3.2 vs. 2.9 kg) reltive to exentide (23). When compred with insulin glrgine, lirglutide in comintion with metformin nd SU chieved improved glycemic control (HA1c, 1.33 vs. 1.09%) nd weight enefit ( 1.8 vs. 1.6 kg) (28). Wist circumference lso decresed with lirglutide ( 1.50 cm) compred with n increse with insulin glrgine ( 0.89 cm). Other studies compring exentide with insulin support the forementioned GLP-1 weight enefits nd report comprle HA1c reductions, lthough it is importnt to note tht insulin dosing in most studies compring GLP-1 gonists to insulin replcement might hve een suoptiml (25, 28 30). The study y Brnett et l. (29) compred insulin glrgine with exentide in ptients with T2D receiving single dditionl orl ntidietic gent. After 16 wk, oth groups chieved similr HA1c reductions ( 1.36%), ut ptients receiving exentide lost weight (men, 4.2 kg), wheres ptients receiving insulin glrgine gined weight (men, 3.3 kg). In 26-wk study compring exentide nd glrgine in ptients (n 551) with indequtely controlled T2D, Heine et l. (30) oserved ody weight increses of 1.8 kg in the insulin glrgine group compred with 2.3-kg decrese in the exentide group ( difference of 4.1 kg), in ssocition with similr reductions in HA1c ( 1.11%). Lstly, Nuck et l. (25) compred exentide vs. iphsic insulin sprt in 52-wk, open-lel study. Agin, oth tretments were ssocited with similr HA1c reductions (exentide, 1.04%; iphsic insulin sprt, 0.89%), nd ptients tking exentide experienced weight loss compred with weight gin in the insulin group (etween-group difference, 5.1 kg). Of note is tht, in ll of these studies compring GLP-1 gonist to insulin therpy, the finl insulin doses were pproximtely 0.25 U/kg d, which is n mount tht is sustntilly lower thn wht hs een oserved in prior insulin tretto-trget studies. This ws likely due to concerns out hypoglycemi nd weight gin often ssocited with insulin use. If ptients receiving insulin in these studies hd een given higher doses, HA1c outcomes in the insulin group my hve een improved. However, higher doses of insulin, for exmple, in the Vetern Affirs Dietes Tril, hve een ssocited with incresed weight gin s well s hypoglycemi, predictor of crdiovsculr mortlity nd mcrovsculr outcomes (31, 32). A slightly higher, ut not intensive, dose of insulin my result in improved HA1c with fewer complictions; however, the expected ccompnying increse in weight gin or crdiovsculr risk is unknown. Comintion therpy with metformin hs lso een employed to reduce the degree of weight gin ssocited with insulin. A met-nlysis (33) ssessing three clinicl trils using NPH insulin (34, 35) or insulin glrgine (36) indicted tht ddition of metformin to sl or sl/ olus insulin resulted in sttisticlly significntly less weight gin compred with insulin monotherpy. Similr results hve een reported elsewhere (37). Individul RCT hve demonstrted tht, in comintion with metformin, oth insulin glrgine nd insulin detemir re ssocited with less weight gin reltive to NPH insulin ( 2.6 vs. 3.5 kg, nd 0.4 vs. 1.9 kg, respectively) (38, 39) Furthermore, initition with sl insulin is generlly ssocited with less weight gin reltive to insulin regimens comprising prndil insulin coverge (40 43). However, comining metformin with rpid-cting insulin preprtion cn still provide significnt weight enefit. Lund et l. (44) demonstrted tht metformin comined with iphsic insulin sprt resulted in significntly less weight gin compred with repglinide plus the sme insulin regimen (2.2 vs. 4.7 kg, respectively). Other non-insulin monotherpy nd comintion therpy GLP-1 receptor gonists. Exentide, sed on the reptilin GLP-1 homolog exendin-4, is dministered sc, twice dily, 0 to 60 min efore mels (45). Administered s monotherpy, exentide is ssocited with weight loss of pproximtely 3 kg over 24 wk of tretment, with H1Ac reductions of 0.7 to 0.9% (46). When dded to SU, exentide chieved dose-dependent weight loss (up to 1.6 kg) nd HA1c reductions (up to 0.86%) (47). In ddition, recent met-nlysis y Fkhoury et l. (48) confirmed positive ssocition etween exentide nd weight loss. Lirglutide is humn GLP-1 nlog with high homology to ntive humn GLP-1 (97 vs. 53% for exentide), long hlf-life (up to 13 h vs. 2 to 4 h for exentide) (49), nd low immunogenicity (23, 27, 28, 50, 51). In recent T2D trils, lirglutide monotherpy showed weight loss, compred with weight gin seen with the SU glimepiride (50) nd glienclmide (52). Lirglutide monotherpy (1.2- nd 1.8-mg doses) ws ssocited with dose-dependent reductions in men ody weight ( 1.9 nd 2.3 kg, respectively) compred with men weight gin of pproximtely 1.0 kg in ptients treted with glimepiride (50). Similrly, lirglutide (0.9-mg dose) chieved weight loss of 0.9 kg compred with weight gin of 1.0 kg

4 3340 Meneghini et l. Weight Beneficil Tretments for Type 2 Dietes J Clin Endocrinol Met, Novemer 2011, 96(11): with glienclmide (P ) in Jpnese sujects (52). Additionlly, met-nlysis of 38 RCT compring incretin therpies for T2D to plceo found tht lirglutide hd the gretest HA1c-reducing effect ( 1.03%), compred with exentide ( 0.75%), sitgliptin ( 0.79%), nd vildgliptin ( 0.67%) (48). In comintion with SU, lirglutide hs demonstrted greter improvements in HA1c nd weight control thn dd-on rosiglitzone or plceo (51). In ddition, lirglutide in comintion with metformin nd SU hs demonstrted superior HA1c reductions (estimted tretment difference, 0.33%) nd greter weight reductions ( 3.24 vs kg) reltive to exentide (23) (Tle 1). Interestingly, lthough overll improvement in HA1c ws greter in the group receiving lirglutide, there were significnt differences in fsting plsm glucose (FPG) nd postprndil glucose (PPG) in the two groups. Wheres ptients receiving lirglutide chieved significntly reduced FPG levels compred with those receiving exentide ( 29 vs. 11 mg/dl; P ), ptients receiving exentide chieved significntly reduced rekfst nd dinner PPG increments compred with those receiving lirglutide (estimted tretment difference of 24 mg/dl fter rekfst, P ; nd 18 mg/dl fter dinner, P ) (23). DPP-4 inhiitors. Sxgliptin nd sitgliptin monotherpy hve demonstrted reductions in HA1c of %, respectively, nd weight chnges not significntly different from plceo (20, 53, 54). In comintion with pioglitzone, sitgliptin significntly reduced HA1c compred with plceo ( 0.9 vs. 0.2%, respectively), without significnt weight gin (55). In comintion with TZD (either pioglitzone or rosiglitzone), sxgliptin (2.5 nd 5 mg) significntly reduced HA1c compred with TZD lone ( 0.66, 0.94 vs. 0.3%, respectively), with smll weight increses in ll study groups (56). In comintion with glimepiride or glimepiride plus metformin, sitgliptin produced significnt reductions in HA1c vs. either tretment lone ( 0.45 vs. 0.28%, respectively), lthough weight gin, while moderte, ws significntly higher with sitgliptin ( 0.8 kg for sitgliptin vs. 0.4 kg for plceo; P 0.001) (57). In comintion with glyuride, sxgliptin (2.5 nd 5 mg) significntly reduced HA1c vs. glyuride up-titrtion lone ( 0.54, 0.64, vs. 0.08%, respectively). In this study, men ody weight incresed in ll groups ut ws highest in ptients receiving sxgliptin (0.7 to 0.8 kg for sxgliptin vs. 0.3 kg for up-titrted glyuride lone) (58). Study investigtors speculted tht the modest weight gin oserved with DPP-4 inhiitors in comintion therpy scenrios might hve een due to decresed glucosuri (58) or ckground tretment with n SU or TZD (56, 57). -Glucosidse inhiitors. Systemtic review nd metnlyses hve shown tht crose is weight-neutrl (1, 59). Results from 16 RCT showed weighted men solute difference in ody weight etween crose nd plceo of 0.1 kg (1). Similrly, met-nlysis of 41 RCT of -glucosidse inhiitors (crose, 30; miglitol, seven; vogliose, one; nd vrious, three) confirmed tht these gents hd no sttisticlly significnt effect on ody weight. Both crose nd miglitol were ssocited with significnt reductions in HA1c of etween 0.7 nd 0.8% reltive to plceo (59). Severl clinicl trils hve demonstrted n dditive effect of crose in ptients treted with SU, resulting in significnt reductions in HA1c of etween 0.5 nd 1.3% (60). Bile cid sequestrnts. The ile cid sequestrnt colesevelm hs demonstrted significnt plceo-corrected reductions in HA1c (rnge, 0.32 to 0.41%) in comintion with metformin (61), SU (62), or insulin (63) in 1018 sujects with seline HA1c of 7.5 to 9.5% (64). In 26-wk tril in sujects lredy receiving metformin with or without other orl ntidietic gents (OAD), the ddition of colesevelm chieved weight loss similr to plceo ( 0.5 vs. 0.3 kg) (61). In comintion with SU, ody weight ws unchnged with colesevelm, compred with reduction of 0.4 kg with plceo (62). In ptients lredy treted with insulin with or without OAD, ody weight incresed y 0.6 kg with colesevelm nd 0.2 kg with plceo (63). Amylin nlogs. Most pulished trils of mylin nlogs hve investigted the ddition of prmlintide to existing insulin tretment. A dose-finding study with prmlintide dded to vriety of insulin regimens showed weight loss ( 1.4 kg) cross the ctive tretment groups (65), with HA1c reductions of 0.62 to 0.68% in the 120- g dose group. No weight gin ws seen when prmlintide ws dded to the sl insulins glrgine or detemir. Additionlly, prmlintide lowered FPG similrly to rpid-cting insulin nlogs, without the weight gin ssocited with insulin (66). A single phse 2 study investigting the use of prmlintide in oese sujects reported plceo-corrected men weight reduction of 3.6 kg (67). Prmlintide is currently pproved only for use in ptients lredy tking prndil insulin. Insulin Insulin remins the most effective gent to control serum glucose, especilly in the setting of decresed endog-

5 J Clin Endocrinol Met, Novemer 2011, 96(11): jcem.endojournls.org 3341 TABLE 1. Weight chnge in clinicl trils in ptients with T2D: ntidietic gents ssocited with weight loss or neutrlity Study design Regimen y rm n Metformin-sed therpy Monotherpy 29-wk R, PG, DB, MC, controlled (12) 32-wk R, DB, MC, PG (15) 4-yr (medin) R, DB, MC, controlled (13) 1-yr R, DB, PG (14) MET ( mg/d) initil phrmcotherpy vs. PLA MET ( mg/d) fter GLY vs. MET GLY vs. GLY MET ( mg/d) s initil phrmcotherpy or fter OAD vs. MET ROS MET (500 mg/d to 1000 mg BID) initil phrmcotherpy vs. ROS vs. GLY MET (850 mg up to TID) initil phrmcotherpy vs. PIO Men BMI (kg/m 2 ) % HA1c, decrese from seline Men weight (kg) Weight P NS c Increse 0.14/yr 2.9 over 5 yr GLP-gonists MET 30-wk triple-lind, PC, MC In ptients filing MET, (17) exentide 5 g BID MET Exentide 10 g BID MET wk MC, extension study In ptients filing MET, 150 (92) c (18) to DeFronzo, 2005 (17) exentide 5 g BID MET for 4 wk, then 10 g BID MET 24-wk R, OL, PG, MC; Exentide, 5 g BID for 4 wk NR n 372 (26) nd 10 g BID therefter in ptients filing MET/SU vs. BIAsp 30 QD SU/MET vs. BIAsp 30 BID SU/MET 30-wk PC, DB, MC (24) In ptients filing MET/SU, exentide (5 g BID) MET/SU Exentide (5 g, then 10 g 241 (199) BID) MET/SU 52-wk OL, MC, noninferiority Exentide (5 g BID for 4 wk, tril (25) then 10 g BID) MET/ SU, vs. BIAsp 30-wk R, MC, noninferiority Exentide (long-cting relese NS, BID vs. QD study (104) formultion, 2 mg QW) Exentide, 10 g BID, in drug-nive or ptients on one or more MET, SU, TZD 22-wk comprtor-controlled, OL, MC, extension (105) to Drucker et l., 2008 Exentide (long-cting relese formultion, 2 mg QW) Ptients continuing on exentide NS vs. switch (104) (52 wk totl) 2mgQW Ptients switching from exentide BID to 2 mg QW 26-wk R, DB, doule-dummy, Lirglutide 1.8 mg QD MET Approximtely ctive-control, PG, MC, suset nlysis (106) Lirglutide 1.8 mg QD GLI Approximtely wk R, OL, DB, ctivecontrol, Lirglutide 1.8 mg QD MET 221 (218) PG, MC (107) Lirglutide 1.2 mg QD MET 225 (221) Sitgliptin 100 mg QD MET 219 (219) DPP-4 inhiitors MET 24-wk R, DB, PC, PG, MC (20) Sitgliptin (50 mg) MET to 1.3 c 24-wk R, DB, PC, MC (21) Sxgliptin (2.5, 5, nd 10 mg) MET to 0.53 NR (Continued)

6 3342 Meneghini et l. Weight Beneficil Tretments for Type 2 Dietes J Clin Endocrinol Met, Novemer 2011, 96(11): TABLE 1. Continued % HA1c, decrese from seline Study design Regimen y rm n Men BMI (kg/m 2 ) Men weight (kg) Weight P Insulin MET 9-month R, OL, PG, MC tril MET glrgine NS vs. comprtor (38) MET NPH wk R, OL, PG, MC; MET glrgine n 315 (41) 24-wk R, OL, PG, MC; MET prndil lispro, TID n 315 (41) 0.73, 14-wk MC, R, 2 2 fctoril tril of OL insulin glrgine nd PC MET; n 500 (37) MET glrgine HA1c ner normlized 32-wk MC, R, OL, MET glrgine, then iphsic prospective, crossover (108) insulin lispro MET iphsic insulin lispro then glrgine 32-wk MC, OL, crossover MET glrgine then NPH/lispro study (40) MET NPH/lispro 75/2, twice dily, then glrgine 26-wk R, MC, ctive-control MET detemir sprt tril (39) MET NPH sprt wk R, MC, OL, PG (109) MET SU lispro 70/30, BID NS vs. comprtor MET SU glrgine month R, DB, douledummy, PG, single center; n 101 (44) MET iphsic insulin sprt, BID wk R, PG; n 200 (110) GLP-1 gonists Exentide 24-wk R, DB, PC, PG, MC (46) 26-wk R, OL, PG, MC (23) 30-wk triple-lind, PC, MC (47) 3-yr MC extension study (22) to 3 PC trils (17, 24, 47) Lirglutide 14-wk R, DB, PC, PG, MC (111) 52-wk R, DB, doule-dummy, ctive-control, PG, MC tril (50) 26-wk R, DB, doule-dummy, ctive-control, PG, MC tril (51) 26-wk R, PG, PC, OL, MC (28) 26-wk DB, PC, PG tril (27) 26-wk R, OL, PG, ctive-control, MC (23) MET PIO iphsic insulin sprt, BID As initil phrmcotherpy: Exentide 5 g BID Exentide 10 g BID In ptients filing MET, SU, or NS vs. comprtor oth, exentide 10 g BID MET or SU or oth, vs. lirglutide In ptients filing SU, exentide NS vs. plceo 5 g BID SU vs. SU/PLA Exentide 5, then 10 g BID SU vs. SU/PLA In ptients filing MET nd/or c SU, exentide 5 g BID for 4 wk, then 10 g BID MET nd/or SU Lirglutide fter diet or OAD: mg/d NS 0.3 mg/d Mximum, 0.6 mg/d Mximum, 0.9 mg/d Lirglutide s initil phrmcotherpy vs. GLI: 1.2 mg QD , e 3.24 f 1.8 mg QD 247 (246) , e 3.39 f Lirglutide (0.6, 1.2, or 1.8 mg (dose QD) GLI vs. rosiglitzone dependent) Lirglutide (1.8 mg QD) MET/ GLI vs. insulin glrgine MET/GLI vs. plceo Lirglutide (1.2 or 1.8 mg QD) MET/TZD In ptients filing MET, SU, or oth, lirglutide 1.8 mg QD MET or SU or oth vs. exentide 0.2 to 0.7 (weight gin seen t lower doses) 232 (230) , to NS vs. comprtor, (Continued)

7 J Clin Endocrinol Met, Novemer 2011, 96(11): jcem.endojournls.org 3343 TABLE 1. Continued Study design Regimen y rm n DPP-4 inhiitors Sitgliptin 24-wk DB, PC, R, MC (53) Sxgliptin 24-wk DB, PC, R, PG, MC (54) Men BMI (kg/m 2 ) % HA1c, decrese from seline Men weight (kg) Weight P Sitgliptin 100 mg QD 238 NR 0.61 d mg QD 250 NR 0.76 d 0.1 Sxgliptin 2.5 mg QD mg QD mg QD Bile cid sequestrnts Colesevelm 26-wk R, DB, PC, PG, MC (61) Colesevelm (3.75 g/d) MET NR or MET/OAD 26-wk R, DB, PC, PG, MC (62) Colesevelm (3.75 g/d) SU NR 16-wk R, DB, PC, PG, MC (63) Colesevelm (3.75 g/d) insulin NS vs. seline (vrious) with or without OAD Amylin nlogs 24-wk R, OL, PG, MC study; Glrgine or detemir, once or d 0.0 n 113 (66) twice dily, with or without OAD meltime prmlintide 52-wk R, DB, PC, PG, MC; Prmlintide (90 g BID) insulin n 656 (65) regimen (ny) Prmlintide (120 g BID) insulin regimen (ny) Endpoint nlysis ws crried out on intent to tret (ITT) popultion unless otherwise indicted. Where two n vlues re presented, ITT vlues re followed y the nlysis set (numers exposed or numers completed). BID, Twice dily; DB, doule lind; GLI, glimepiride; MC, multicenter; MET, metformin; NS, not significnt; OL, open lel; PG, prllel group; PLA, plceo; PIO, pioglitzone; QD, once dily; R, rndomized; TID, three times dily; PC, plceo controlled; QW, once weekly; GLY, glyuride; BIAsp, iphsic insulin sprt; NR, not reported. P 0.05 vs. plceo. P 0.05 vs. comprtor. c P 0.05 vs. seline. d Lest squres men vlues. e No or 7 d nuse. f 7 d nuse. enous insulin secretion, with reductions in HA1c of 1.5 to 3.5% chievle with insulin lone (68). However, multiple lrge studies typiclly show weight gin ssocited with insulin use, either s monotherpy or in comintion with OAD (Tle 2). Fctors implicted in insulin-ssocited weight gin include interctions etween improved glycemic control nd decresed glycosuri (69), suppression of heptic glucose production (70, 71), nolic effects incresing ft deposition (3), nd incresed food intke from defensive sncking to preempt hypoglycemi. Ptients most t risk for insulin-ssocited weight gin re those with high seline glycemi; it hs een suggested tht this weight gin my e eneficil to some degree ecuse it my e relted to reduced sl metolic rte nd glucosuri. However, ptients on oth metformin nd insulin my experience similr enefit with decresed glucose, without excessive dditionl weight gin (72). Some weight enefits hve een seen with the sl insulin nlogs, reltive to iphsic nd prndil insulin nlog regimens. The 1-yr results from the 4-T tril in ptients receiving metformin/su compred the initition of sl insulin detemir (twice dily if required) to tht of iphsic insulin sprt twice dily or prndil insulin sprt three times dily. Bsl insulinusewsssocitedwiththelestweightgin( 1.9vs. 4.7 vs. 5.7 kg, detemir vs. iphsic vs. prndil, respectively) (42). After 3 yr, nd despite intensifiction to full sl nd prndil insulin in ll three regimens, ptients originlly inititing sl insulin detemir hd sustined weight dvntge over ptients treted with iphsic or prndil insulin regimens (43). Notly, insulin detemir hs lso consistently een shown to result in reduced weight gin in comprison to NPH insulin. Monmi et l. (73) conducted met-nlysis of 14 RCT of insulin glrgine (11 trils) nd insulin detemir (three trils). In this nlysis, significnt reductions in weight gin reltive to NPH were reported in two of three trils involving insulin detemir (74 76) nd in only one of 11 trils of insulin glrgine (77). Pooled nlysis of two 22- to 24-wk trils ssessing sl detemir vs.

8 3344 Meneghini et l. Weight Beneficil Tretments for Type 2 Dietes J Clin Endocrinol Met, Novemer 2011, 96(11): TABLE 2. Weight chnge in insulin clinicl trils in ptients with T2D Regimen nd insulin type y rm Men BMI (kg/m 2 ) HA1c %, decrese from seline Men weight (kg) Study design n weight P Insulin detemir 20-wk cse series; Detemir, prior therpy NPH P 0.22 n 20 (79) 22-wk MC, OL, Detemir/sprt P (vs. symmetriclly R, NPH/humn PG tril; insulin n 395 (78) NPH/humn insulin wk R, MC, OL, Detemir/sprt P (vs. PG tril; NPH/sprt) n 505 (75) NPH/sprt Detemir/OAD 20-wk R, OAD (25% MET; 75% MET NS controlled, OL, OAD) detemir QD FPG trget, MC, PG (80) mmol/liter OAD (25% MET; 75% MET NS OAD) detemir QD FPG trget, mmol/liter 20-wk R, OL, 3-rm, PG, MC (83) 26-wk R, MC, OL, PG tril; n 476 (76) 1-yr dt, R, controlled, MC, OL tril (42) OAD detemir, QD prerekfst dose 168 (165) P (for evening detemir vs. NPH) OAD detemir, QD evening dose 170 (169) OAD NPH, evening dose 166 (164) OAD detemir P (detemir vs. NPH) OAD NPH OAD detemir QD or BID P (overll nd for ll group comprisons) OAD iphsic sprt BID OAD prndil sprt TID wk R (112) OAD detemir BID P (vs. glrgine) OAD glrgine QD Glrgine 28-wk MC, OL, R tril; n 518 (113) 14-wk MC, R, 2 2 fctoril tril of OL insulin glrgine; n 500 (37) Glrgine, prior therpy NPH P (vs. NPH) NPH insulin Glrgine ( 50% no prior drug therpy) P 0.04 vs. seline (Continued)

9 J Clin Endocrinol Met, Novemer 2011, 96(11): jcem.endojournls.org 3345 TABLE 2. Continued Study design Glrgine OAD 24-wk MC, R, OL, PG; n 217 (114) 24-wk R, PG, MC, 4-rm, OL study (115) 24-wk R, OL, PG, MC (116) 12-month OL, R, MC; n 570 (117) 28-month MC, extension study (118) to Mssi Benedetti et l., 2003 (117) 44-wk MC, PG, OL; n 418 (119) 24-wk initition phse R, MC, OL, PG study; n 2091 (120) 52-wk R, MC tril (36) 24-wk MC, PG, controlled, OL, R tril (121) Sunlysis 24-wk MC, OL, R tril (122) Sunlysis 24-wk MC, OL, R tril (82) 24-wk OL, R, PG, MC, noninferiority study; n 448 (123) 24-wk MC, OL, R, controlled, PG study; n 695 (124) Regimen nd insulin type y rm n Men BMI (kg/m 2 ) HA1c %, decrese from seline Men weight (kg) weight P MET/SU glrgine P 0.02 (glrgine vs. dd-on rosiglitzone) OAD glrgine ccording to 4 titrtion protocols to to 2.0 P (vs. seline) OAD glrgine NS OAD NPH OAD glrgine evening P 0.58 OAD NPH evening OAD glrgine evening P (vs. seline) OAD glrgine P 0.23 (etweengroup difference) OAD glrgine P (vs. lispro) OAD edtime glrgine NS OAD edtime NPH OAD glrgine, titrted t every to to 1.3 P (vs. visit or every 3 d (72% of seline) ptients previously treted with insulin) Glrgine, s ove; ptients in primry nd secondry cre 819 NR 0.51 to to 1.2 P 0.05 (vs. seline) Glrgine, s ove; nonoese Oese P 0.67 (oese vs. nonoese GLI glrgine BMI NS (NPH vs. glrgine) GLI NPH BMI GLI glrgine morning 237 (236) NS (tretment group comprison) GLI glrgine evening 229 (227) GLI NPH 234 (232) (Continued)

10 3346 Meneghini et l. Weight Beneficil Tretments for Type 2 Dietes J Clin Endocrinol Met, Novemer 2011, 96(11): TABLE 2. Continued Regimen nd insulin type y rm Study design Detemir vs. glrgine 52-wk MC, R, OL, PG, noninferiority tril; n 582 (85) 26-wk R, OL, PG, MC, noninferiority study; n 385, 20% insulin nive (86) 52-wk MC, OL, PG, noninferiority (125) Lispro or sprt (prndil/iphsic) 52-wk R, MC, OL, Prndil insulin sprt premix noninferiority BID MET SU tril; n 506 (25) Exentide 5 g BID/4 wk; 10 g 44-wk R, MC, PG, OL; n 418 (119) 16-wk MC, R, OL, PG; n 308 (126) 12-month singlecenter, R, DB, doule-dummy, PG; n 102 (44) 24-wk MC, R, OL tril; n 372 (26) 24-wk MC, initition phse R, OL, PG study; n 2091 (120) 24-wk R, OL, PG, MC study; n 113 (66) n Men BMI (kg/m 2 ) HA1c %, decrese from seline Men weight (kg) weight P OAD detemir QD P 0.01 (vs. glrgine) OAD glrgine OAD detemir/sprt P (vs. glrgine) OAD glrgine/sprt OAD detemir P 0.05 OAD glrgine P (vs. exentide); P 0.01 (vs. seline) therefter Prndil insulin lispro TID OAD P 0.23 (glrgine vs. lispro) Insulin glrgine once dily OAD Prndil iphsic insulin sprt TID P (vs. seline) Prndil iphsic insulin sprt BID MET REP iphsic insulin sprt, BID P (MET insulin vs. REP insulin) MET iphsic insulin sprt, BID Prndil insulin sprt, QD dded to MET or SU Prndil insulin sprt, BID dded to MET or SU OAD prndil iphsic lispro, BID Not reported P (lispro vs. glrgine) OAD glrgine (once dily) Glrgine or detemir, once or twice dily prndil nlog with or without OAD Prmlintide glrgine or detemir, with or without OAD P (insulin vs. prmlintide) Endpoint nlysis ws crried out on intent to tret (ITT) popultion unless otherwise indicted. Where two n vlues re presented, ITT vlues re followed y the nlysis set (numers exposed or numers completed). Selection of representtive studies for inclusion ws sed on uthor consensus. BID, Twice dily; DB, doule lind; GLI, glimepiride; MC, multicenter; MET, metformin; NS, not significnt; OL, open lel; PG, prllel group; PIO, pioglitzone; QD, once dily; R, rndomized; REP, repglinide; TID, three times dily.

11 J Clin Endocrinol Met, Novemer 2011, 96(11): jcem.endojournls.org 3347 NPH insulin found reltionship etween higher seline ody mss index (BMI) nd the enhnced weight-spring effect of insulin detemir (78). Specificlly, ptients with higher seline BMI levels ( 35 kg/m 2 ) lost n verge of 0.5 kg, wheres those with BMI levels elow 35 kg/m 2 tended to gin etween 0.4 nd 0.6 kg. This finding hs lso een reported in susequent RCT nd oservtionl trils (79 81). Conversely, post hoc sugroup nlysis of lrge rndomized tril compring two lgorithms for initition nd titrtion of insulin glrgine showed tht, t 24 wk, weight gin with insulin glrgine ws independent of seline BMI (weight gin of 1.21 vs kg for nonoese vs. oese individuls, respectively) (82). In line with results seen when insulin is used in comintion with metformin lone, comintion studies with insulin nlogs nd OAD confirm tht the weight effects of sl insulins re not uniform. In prticulr, trils of insulin detemir show similr glycemic control, ut less weight gin not only vs. NPH (39, 76, 83) ut lso vs. insulin glrgine (76, 83 86). An indirect comprison of five trils in ptients currently receiving OAD showed tht evening insulin detemir ws ssocited with less weight gin vs. evening insulin glrgine (undjusted weighted men difference, 1.2 kg in fvor of detemir) (87). Additionlly, pooled nlysis of dt from 22 RCT found tht wheres weight gin per HA1c chnge ws similr for glrgine nd detemir, tretment with glrgine resulted in higher solute weight gin of orderline significnce ( 2.5 vs. 1.7 kg with detemir, P 0.049). However, weight chnges per 1% reduction of HA1c were not sttisticlly different for glrgine vs. detemir (1.8 vs. 1.2 kg; P 0.05) (88). These oservtions hve fueled investigtion into the comintion of insulin detemir with weight-eneficil gents such s the weight-neutrl DPP-4 inhiitor sitgliptin (89) nd weight-reducing comintion therpy with lirglutide nd metformin. A study y Buse et l. (90) investigted the ddition of exentide or plceo to regimens of insulin glrgine lone or in comintion with metformin or pioglitzone or oth, in dult T2D ptients with HA1c of 7.1 to 10.5%. HA1c levels decresed y 1.74% in the exentide group nd y 1.04% in the plceo group [etween-group difference, 0.69%; 95% confidence intervl (CI), 0.93 to 0.46%; P 0.001]. However, weight decresed y 1.8 kg in the exentide group ut incresed y 1.0 kg in the plceo group (etween-group difference, 2.7 kg; 95% CI, 3.7 to 1.7). Averge increses in insulin dosge were 13 nd 20 U/d in the exentide nd plceo groups, respectively (90). In the TRANSITION study, insulin-nive ptients on regimen of metformin with or without second OAD experienced significntly greter HA1c reductions when trnsitioned to insulin detemir nd sitgliptin thn sujects receiving sitgliptin with or without SU. Notly however, smll decreses in weight were seen in oth groups (91). Prcticl recommendtions for intensifying therpy Tle 3 shows summry of men HA1c reductions nd impct on FPG, PPG, nd weight chnge ssocited with the ntidietic gents presented. For ptients who do not rech glycemic gols on metformin lone, we recommend considering tretment choices y weight enefit s well s glycemic enefit, prticulrly in ptients who re oese. This might e prticulrly relevnt in ptients whose HA1c levels re close (within 1 to 1.5%) to recommended glycemic trgets. Although reltive risk reduction for microvsculr disese is pproximtely 20 30% TABLE 3. Summry of tretment effects on HA1c, weight, PPG, nd FPG (1, 49, 68, 103) Expected reduction in HA1c with monotherpy (%) Expected weight over 6 months (kg) Impct on PPG Impct on FPG -Glucosidse inhiitors Weight neutrl (crose) Amylin nlogs Weight neutrl or loss 0 to to 1.5 kg Bsl insulin Detemir Weight neutrl or gin 0 to to 1.5 kg Glrgine Weight gin up to 4 kg to GLP-1 nlogs Weight loss 1.0 to to to 3.0 kg DPP-4 inhiitors Weight neutrl Metformin Weight neutrl or loss 0 to 1.5 kg SU Weight gin 1 to 5 kg TZD Weight gin: 3 kg

12 3348 Meneghini et l. Weight Beneficil Tretments for Type 2 Dietes J Clin Endocrinol Met, Novemer 2011, 96(11): for every 1% fll in HA1c (92 94), the solute risk reduction tends to decrese s HA1c pproches nondietic levels. A few reports nd comments in the literture seem to point to n HA1c of round 8% s threshold for sustntil increse in the risk for microluminuri (95 97). A Kiser Permnente study lso found significntly incresed risk of complictions or mortlity for HA1c of 8% or higher in ptients 60 yr or older (98). There is lso cler reltionship etween disese durtion nd risk of vsculr complictions. Given this informtion, for ptients with n HA1c pproching trget, the preference might e given to therpies tht promote weight loss (or minimize weight gin), which coincidentlly re lso ssocited with low hypoglycemi risk. Additionlly, in ptients tht re more vulnerle to hypoglycemi, hve long disese durtion, lredy hve dvnced vsculr complictions, or hve significnt resistnce to using insulin due to weight concerns, n pproch tht minimizes weight gin t the expense of smller expected reduction in HA1c might e pproprite. On the other hnd, in individuls with very poor glycemic control (HA1c vlues over 8 8.5%), priority should clerly e given to improving glycemi nd secondrily mitigting weight gin (99). Either therpeutic strtegy would need to e reevluted ccording to the individul ptients response to tretment nd ptient concerns out weight gin nd the impct tht weight loss my hve on ptient qulity of life ( ). The current tretment pproch in T2D, s outlined y the Americn Dietes Assocition/Europen Assocition for the Study of Dietes (ADA/EASD) tretment lgorithm, encourges flexiility nd clinicl judgment ut is cutious in recommending the use of newer gents. In line with current guidelines, the decision to intensify therpy is sed on HA1c trgets of no more thn 7% (68). Interventions cn e further tilored y using self-monitoring of lood glucose to identify whether the predominnt glycemic urden is elevted FPG or elevted PPG. A weightconscious pproch to glycemic mngement might strtify weight-friendly tretment choices sed on two generl prmeters: 1) overll glycemic reduction; or 2) specific effects on fsting nd postprndil glycemi identified through ptient self-monitoring of lood glucose. Antiglycemic gents hve vrying effects on fsting nd postprndil glycemi (103) nd should llow for tiloring of therpy to specific ptient needs. For metformin-treted ptients who fil to chieve ADA/EASD trgets for FPG of 70 to 130 mg/dl (3.9 to7.2 mmol/liter) (9), second-line tretment choices in order of weight enefit first nd FPG reduction second would e: GLP-1 gonists [long-cting (i.e. lirglutide) fvored over short-cting (i.e. exentide) GLP-1 preprtions], DPP-4 inhiitors, ile cid sequestrnts, nd mylin nlogs. If insulin tretment is indicted, sl insulin supplementtion should e considered (insulin detemir fvored over insulin glrgine or NPH with respect to weight effects). The current ADA/EASD trgets for PPG re elow 180 mg/dl ( 10.0 mmol/liter) (9). For ptients who fil to chieve this trget on metformin therpy, the tretment choices in order of weight enefit first nd PPG reduction second would e: GLP-1 gonists (short-cting fvored over long-cting GLP-1 preprtions), mylin nlogs, DPP-4 inhiitors, crose, nd ile cid sequestrnts. Shortcting GLP-1 gonists re recommended over long-cting GLP-1 gonists in this sitution ecuse the LEAD-6 tril, which compred lirglutide nd exentide, found tht ptients receiving exentide chieved significntly reduced PPG increments compred with lirglutide (23). Discussion Normliztion of glycemi remins the cornerstone of dietes mngement in ptients of ll ody weights, nd insulin use is often key to meeting glycemic trgets. However, the close link etween excess ody weight, T2D disese progression, nd the development of lte complictions highlights the need for physicins to consider weight mngement s well. Optimizing weight should e priority in T2D, nd physicins should consider weight issues t every stge of the disese through the use of pproprite therpy. Lifestyle modifiction should e encourged t ll stges of dietes mngement; however, this is seldom sufficient to chieve stringent glycemic control or dequte weight control, nd s T2D progresses, therpeutic intervention will e required. Although trditionl therpies such s humn insulin nd some older OAD re ssocited with weight gin, newer therpies hve more eneficil effect on weight. This review reffirms the weight enefits of metformin, lone nd in comintion with other noninsulin nd insulin therpies, nd highlights the weight effects of certin newer gents. The GLP-1 gonists nd mylin nlogs promote weight loss, wheres the DPP-4 inhiitors, ile cid sequestrnts, nd crohydrte inhiitors tend to e weight-neutrl. In light of the dt presented in this review, erlier nd preferentil introduction of weight-eneficil gents such s GLP-1 gonists should e considered, prticulrly in oese ptients. In severely uncontrolled dietes, lifestyle intervention plus insulin remins key strtegy. Initition of insulin erly in tretment lgorithm, fter metformin nd GLP-1 nlogs, might e n effective strtegy. Of the insulin preprtions, insulin detemir provides the most

13 J Clin Endocrinol Met, Novemer 2011, 96(11): jcem.endojournls.org 3349 fvorle weight profile, especilly in ptients with high seline BMI, ecuse these ptients cn lest fford to incur further weight gin. Acknowledgments Writing nd editoril support ws provided y Jnet Stephenson, Dn Booth, nd Citlin Rothermel of Bioscript Stirling Ltd., with funding from Novo Nordisk. Address ll correspondence nd requests for reprints to: Luigi F. Meneghini, M.D., MBA, Dietes Reserch Institute, University of Mimi Miller School of Medicine, 1450 N.W. 10th Avenue, Mimi, Florid E-mil: LMeneghi@ med.mimi.edu. L.F.M., D.O.-B., K.K., S.C., T.D., A.L., nd S.R. provided sustntil contriutions to literture review conception nd design, drfting nd criticlly revising the mnuscript for intellectul content, nd giving finl pprovl of the mnuscript efore puliction. Disclosure Summry: A.L. is ord memer nd/or speker for Astr Zenec, Eli Lilly, MSD, Novo Nordisk, nd Roche. D.O.-B. is ord memer for Eli Lilly, Novo Nordisk nd Snofi Aventis, speker for MSD nd Snofi Aventis, nd hs received reserch funding from MSD. K.K. is ord memer for Bristol Meyers Squi, MSD, Novo Nordisk, nd Roche; nd speker for Eli Lilly, MSD, Novrtis, Novo Nordisk nd Snofi Aventis. L.F.M. hs received consultncy nd/or speker ureu fees from Eli Lilly, Novo Nordisk nd Snofi Aventis. S.C. is ord memer for MSD nd Novo Nordisk nd hs dditionlly received speker ureu fees from Eli Lilly, Merck, Snofi Aventis nd Tked. S.R. hs received consulting fees from Novo Nordisk nd dditionlly hs received lecture fees nd reserch grnts from Eli Lilly. T.D. is ord memer nd consults for Astr Zenec, Bristol Meyers Squi, Eli Lilly, MSD, Novo Nordisk, nd Snofi Aventis. References 1. Bolen S, Feldmn L, Vssy J, Wilson L, Yeh HC, Mrinopoulos S, Wiley C, Selvin E, Wilson R, Bss EB, Brncti FL 2007 Systemtic review: comprtive effectiveness nd sfety of orl medictions for type 2 dietes mellitus. 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