Science Journal of Clinical Medicine

2012; 1(1) : 4-9 Published online December 30, 2012 (http:// doi: 10!11$4%/#!s#cm!20120101!12 !sciencepublishin""roup!com/#/s#cm)

Recombinant insulin in type 2 diabetes treatment: where are we now?

Giuseppina T. Russo, Provvidenza Villari, Elisabetta L Romeo, Annalisa Giandalia, Domenico Cucinotta*
Dep&rtment o' (linic&l &nd )*periment&l +edicine, ,ni-ersit. o' +essin&, /t&l.

Email address
domenico!cucinott&0unime!it (D! (ucinott&)

To cite t!is article

1iuseppin& 2! 3usso, Pro--iden4& 5ill&ri, )lis&bett& 6 3omeo, 7nn&lis& 1i&nd&li&, Domenico (ucinott&! 3ecombin&nt /nsulin in 2.pe 2 Di&betes 2re&tment: 8here 7re 8e 9o :! Science Journal of Clinical Medicine! 5ol! 1, 9o! 1, 2012, pp! 4-9! doi: 10!11$4%/#!s#cm!20120101!12

Abstract ;e-er&l insulin 'ormul&tions &re currentl. &-&il&ble 'or clinic&l use, includin" hum&n re"ul&r &nd prot&min&ted
insulins, r&pid- &nd lon"- &ctin" &n&lo"s &nd premi*ed combin&tions, hich c&n be used in di''erent re"imens! <o e-er, there is no consensus on hich &re the insulin 'ormul&tion &nd the insulin re"imen o' choice, especi&ll. in t.pe 2 di&betes! =-er&ll, insulin &n&lo"s &re pre'erred 'or their better ph&rm&colo"ic&l properties ith & minor h.po"l.c&emic ris>, here&s their superiorit. in reducin" <b71c le-els is still deb&ted! Despite the impressi-e steps undert&>en so '&r, insulin ther&p. is still too comple* &nd burdensome, &nd e-en ith &n intensi'ied re"imen, onl. & modest percent&"e o' sub#ects re&ches <b71c "o&ls! 9e insulin 'ormul&tions &nd de-ices &re currentl. & &ited to better 'ul'ill the still unmet needs o' insulin ther&p.!

"e#$ords /nsulin 7n&lo"s, 2.pe 2 Di&betes, <.po"l.c&emi&, <b&1c

%. Recombinant &uman 'nsulins

;ince 1922, hen substituti-e ther&p. ith insulin e*tr&cted 'rom &nim&l p&ncre&s &s initi&ted, medic&l rese&rch h&s m&de & "re&t e''ort to reproduce the ph.siolo"ic&l insulin pro'ile, i!e!, & b&s&l insulin secretion to control hep&tic "lucose output &nd insulin pe&>s to o-ercome postpr&ndi&l "lucose (PP1) e*cursions! /n most countries, t o 'ormul&tions o' hum&n insulin, s.nthesi4ed b. recombin&nt D97 techni?ue, &re into the m&r>et, n&mel. 3e"ul&r <um&n /nsulin (3</) &nd the intermedi&te-&ctin" 9eutr&l Prot&mine <&"edorn (9P<)! 3</ is & molecul&r he*&mer, hich must bre&> do n into monomers to be &bsorbed b. subcut&neous (s!c!) tissue! /ts slo onset &nd rel&ti-el. lon" dur&tion o' &ction &nd the need to t&>e in#ections 30@4A minutes prior to me&l represent import&nt limit&tions to its use B1, 2C! Durthermore, 3</ pe&> concentr&tions m&. not occur until 2@4 hours &'ter in#ection, e*posin" the p&tient to postpr&ndi&l h.per"l.cemi& &nd the ris> o' subse?uent h.po"l.c&emi& B1, 2C! 9P< insulin c&n be used to repl&ce or supplement b&s&l insulin, but its pro'ile sho s & distinct pe&> &nd & limited dur&tion o' &ction, th&t does not mirror the 'l&t ph.siolo"ic&l b&s&l insulin secretion B1,2C!

(. Rapid) Actin* 'nsulin Analo*s

/nsulin &n&lo"s, i!e! modi'ied recombin&nt hum&n insulins, ere de-eloped to o-ercome the ph&rm&co>inetic (PE) &nd ph&rm&codin&mic (PD) limit&tions o' 3</ &nd 9P< (2&ble 1) B1,2C! /nsulin lispro, &sp&rt, &nd "lulisine &re the three currentl. &-&il&ble r&pid &ctin" &n&lo"s (377s) B3C! 6ispro, the 'irst to "et the m&r>et, h&s been obt&ined b. e*ch&n"in" proline &t position F2% ith l.sine &t position F29 (6.sF2%, ProF29) in insulin ch&in B4C; in insulin &sp&rt (7spF2%) proline F2% is substituted ith &sp&rtic &cid BAC, &nd "lulisine h&s t o &mino &cids substitutions, i!e! F3 l.sine inste&d o' &sp&r&"ine &nd F29 "lut&mic &cid 'or l.sine B$C! 2h&n>s to these structur&l modi'ic&tions &t cruci&l sites o' the insulin molecule, &ll 377s &re ch&r&cteri4ed b. reduced tendenc. 'or sel'-&ssoci&tion, '&ster &bsorption, hi"her pe&> serum le-els, &nd shorter dur&tion o' &ction, hen comp&red ith 3</! <o e-er, despite their ph&rm&colo".c&l superiorit., comp&r&ti-e clinic&l d&t& ith 3</ .ielded con'lictin" results! 7 met&-&n&l.sis b. Pl&n> et &l! BGC, includin" 42 r&ndomi4ed controlled tri&ls (3(2s) ith o-er G900 p&tients ith t.pe 1 (21D+), t.pe 2 (22D+) or "est&tion&l di&betes, demonstr&ted & sm&ll but si"ni'ic&nt impro-ement o' <b71c onl. in 21D+, but no di''erences in 22D+ p&tients! (on-

;cience Hourn&l o' (linic&l +edicine 2012, 1(1): 4-9

-ersel., &nother met&-&n&l.sis B%C, &n&l.4in" d&t& 'rom 13 3(2s on 22D+, sho ed th&t 377s pro-ided & better control o' <b71c &nd postpr&ndi&l "lucose (PP1) o-er 3</, ithout &n. si"ni'ic&nt di''erence in the o-er&ll r&te o' se-ere h.po"l.c&emi&, thus con'irmin" -&rious reports on the

&d-&nt&"es o' 377s on me&l time "lucose e*cursions B9C! 3esults b. Pl&n> et &l! ere &lso con'irmed b. & more recent met&-&n&l.sis b. 3.s et &l! on insulin &sp&rt (/7sp) B10C, not sho in" & si"ni'ic&nt e''ect on <b71c &nd PP1 in 22D+ sub#ects!

Table 1. Current available insulin analogs. +olecule ,Trade compan#Rapid)actin* 6ispro ()li 6ill.) 6.s (F2%) Pro (F29) Fe"innin" 10-1A min Pe&> 1-3 hours Dur&tion 3-4 hours Fe"innin" 10-1A min Pe&> 1-3 hours Dur&tion 3-4 hours Fe"innin" 0 @ 1A min Pe&> 0!A @ 1!A hours Dur&tion 3 @ 4 hours Fe"innin" 2 - 4 hours Pe&> A - $ hours Dur&tion 1A - 1G hours Fe"innin" 2 hours 9o pe&> Dur&tion &bout 20 hours Fe"innin" 1-2 hours 9o pe&> Dur&tion &bout 24 hours Fe"innin" 1A min Pe&> 0!A - 1!2 hours Dur&tion 13 - 1$ hours 'nsulin t#pe and structure Dru* .inetics

7sp&rt (9o-o 9ordis> )

7sp (F2%)

1lulis.ne (;&no'i 7-entis ) /ntermedi&te-&ctin" 6ispro prot&min ()li 6ill. ) 6on"-&ctin" Detemir (9o-o9ordis> )

6.s (F3) 1lu (F29)

6.s (F2%) Pro (F29) plus prot&mine

6.s F29 (9-tetr&dec&no.l) des (F30)

1l&r"ine (;&no'i7-entis ) Premi*ed Di''erent mi*tures &-&il&ble

1li (721) 7r" (F31) 7r" (F32)

Premi*ed r&pid-&ctin" &nd prot&mine-bound &n&lo"ues

2he results o' these met&-&n&l.ses m&. be rele-&nt hen e-&lu&tin" the economic costs &ssoci&ted ith recombin&nt technolo"ies, &lthou"h the possible lon"-term bene'its o' 377s, includin" the potenti&l c&rdio-&scul&r &d-&nt&"e o' speci'ic&ll. t&r"etin" PP1 e*cursions B11C, should &lso be t&>en into &ccount! =-er&ll, di''erent 377s h&-e sho n & simil&r e''ic&c. in reducin" PP1 e*cursions &nd the r&te o' h.po"l.c&emi& &nd their mito"enic &cti-it. is comp&r&ble to th&t o' hum&n insulin B3, 12C! ;ome di''erences e*ist 'or the use o' di''erent 377s in pre"n&nc.: insulin &sp&rt h&s been speci'ic&ll. tested in se-er&l 3(2s &nd it h&s recei-ed re"istr&tion 'or this indic&tion; insulin lispro h&s been sho n to be s&'e in se-er&l obser-&tion&l studies, here&s no published d&t& on the use o' "lulisine in pre"n&nt omen &re &-&il&ble .et B1%-20C!

/. Lon*)Actin* 'nsulin Analo*s

2he shorter dur&tion o' &ction o' 377s ith respect to 3</ h&s un-eiled the need o' lon"-&ctin" pe&>-less insulin prep&r&tions to "u&r&ntee b&s&l insulini4&tion &nd to &-oid pre-pr&ndi&l "lucose incre&se, especi&ll. in insulin-de'icient indi-idu&ls B1$C! 2 o lon"-&ctin" &n&lo"s (677s) &re currentl. &-&il&ble 'or clinic&l use (t&ble 1)! /nsulin "l&r"ine results 'rom the

&ddition o' t o &r"inine residues in the F ch&in, &nd the substitution o' &sp&r&"ine ith "l.cine &t the 721 residue (7211l., F317r", F327r")! 2hese modi'ic&tions m&>e "l&r"ine less soluble &t ph.siolo"ic&l p< le-els, &nd le&d to the deposition o' microprecipit&tes in the s!c! tissue, thus del&.in" its &bsorption &nd prolon"in" its dur&tion o' &ction B1G, 1%C! Detemir is & structur&ll. modi'ied insulin b. me&ns o' & deletion o' treonine on F-ch&in &nd &c.l&tion o' lisine F29 ith miristic &cid! Detemir is soluble &t & neutr&l p<, tends to sel'-&ssoci&tion &nd re-ersibl. binds to &lbumin, hich is responsible 'or its slo &bsorption &nd protr&cted dur&tion o' &ction hen comp&red to 9P<! Durthermore, since detemir rem&ins soluble once in#ected in s!c! tissue, this seems to reduce insulin inter- &nd intr&p&tient -&ri&bilit. B1G, 19C! 9umerous l&r"e, multicenter 3(2s h&-e comp&red 9P< insulin ith either insulin "l&r"ine or detemir! 7 met&-&n&l.sis B20C sho ed th&t 677s &re &s e''ecti-e &s 9P< in terms o' "lucose control in 22D+ p&tients, &lthou"h more p&tients in the "l&r"ine or detemir "roups &chie-ed "lucose t&r"ets ithout nocturn&l h.po"l.c&emi&, &nd ith hi"her tre&tment s&tis'&ction scores B21, 22C! 3ecentl., the ;=65) stud., the l&r"est multicenter obser-&tion&l tri&l on insulin ther&p. in 22D+, demonstr&ted th&t insulin detemir &s e''ecti-e &nd s&'e &lso in the Ire&l li'eJ settin" o' p&tients th&t &re not usu&ll. included in the re"istr&tion tri&ls, i!e!, those ho st&rt insulin ther&p. l&te, hen h.po"l.cemic ris>

Domenico (ucinott& et al. : 3ecombin&nt insulin in t.pe 2 di&betes tre&tment: here &re e no :

is hi"her bec&use o' &n older &"e &nd concomit&nt lon"-term complic&tions B23C! PE &nd PD properties o' 9P< &nd the t o &-&il&ble 677s ere recentl. comp&red in 1% 22D+ sub#ects, ho under ent repe&tedl. eu"l.c&emic cl&mps! /n this stud., insulin "l&r"ine pro-ided & "re&ter met&bolic &cti-it. &nd superior "lucose control 'or up 32 h, ith & me&n 1/30-32 h, & surro"&te me&sure o' insulin met&bolic &cti-it., th&t &s 31K "re&ter th&n 9P< &nd 42K hi"her th&n insulin detemir B24C! <o e-er, se-er&l he&d-to-he&d studies th&t h&-e comp&red the e''ic&c. &nd s&'et. o' insulin "l&r"ine &nd detemir sho ed no si"ni'ic&nt di''erences ith respect to "l.cemic control &nd both nocturn&l &nd se-ere h.po"l.cemi& B2AC! 9ot&bl., insulin detemir &s &ssoci&ted ith more 're?uent t ice-&-d&. need o' use, &n hi"her insulin dose re?uirement &nd lesser ei"ht "&in, hen comp&red to "l&r"ine B2$-29C! 2he re&sons 'or the lo er ei"ht "&in ith insulin detemir &re not completel. understood, &lthou"h the. m&. be rel&ted to & reduced ener". int&>e in-ol-in" hormones re"ul&tin" s&tiet. B30C! 2o d&te, there is no speci'ic in'orm&tion on the use o' 677s in pre"n&nc., &lthou"h both 677s &re usu&ll. prescribed o''-l&bel, &nd l&r"e sur-e.s sho ed th&t the. &re s&'e &nd ell toler&ted comp&red ith hum&n insulin B13-1AC! ;ome concern h&s been recentl. r&ised re"&rdin" & m&#or s&'et. issue ith the use o' insulin "l&r"ine, i!e! th&t o' & potenti&ll. incre&sed c&ncer ris>! 2his concern comes 'rom some obser-&tion&l, m&inl. retrospecti-e studies &nd it is especi&ll. rel&ted ith the incidence o' bre&st c&ncer; ho e-er, subse?uent d&t& did not report &n. disp&rit. in c&ncer incidence bet een p&rticip&nts tre&ted ith insulin "l&r"ine &nd those tre&ted ith other t.pes o' insulin B31, 32C! Durthermore, the 7meric&n Di&betes 7ssoci&tion &nd the 7meric&n (&ncer ;ociet. recentl. published & #oint consensus report th&t did not le&d to 'irm conclusions on insulin ther&p. &nd c&ncer ris> B33C!

p&tients ho need & simpli'ied &ppro&ch, the in&bilit. to sep&r&tel. titr&te the shorter- &nd the lon"er-&ctin" component o' these 'ormul&tions m&>es it & poorl. 'le*ible &ppro&ch &nd "re&tl. limits its use!

2. 3ovel 'nsulins
Despite the pro"ress in insulin ther&p. m&de so '&r, the se&rch o' no-el insulins ith & better PD/PE pro'ile, &llo in" & more con-enient timin" or &. o' &dministr&tion is still on"oin", &nd se-er&l ne products &re close to re&ch the m&r>et! 7mon" these ne 'ormul&tions, there &re '&ster insulins, such &s 5/7#ect (Fiodel /nc! D&nbur., (2), ith & more r&pid onset o' &ction, potenti&ll. e-en '&ster th&n the currentl. &-&il&ble 377s, &nd others, hich &re &imed to &melior&te current 677sL properties, such &s F/=D-7d#ust&ble F&s&l (Fiodel /nc! D&nbur., (2), &nd F/=D-;m&rt F&s&l, includin" "l&r"ine in their molecules B3G-39C! 2he 'irst to be &-&il&ble 'or use ill be insulin de"ludec (9o-o 9ordis>), & ph&se 3 677 hich ret&ins the hum&n insulin &mino &cid se?uence e*cept 'or the deletion o' 2hrF30 &nd the &ddition o' & 1$-c&rbon '&tt. di&cid &tt&ched to 6.sF29 -i& & "lut&mic &cid sp&cer! /t h&s &n ultr&-lon" (up to 9$ hrs) li'e-time, deri-ed 'rom the soluble multi-he*&mers 'orm&tion, resultin" in & continuous slo &nd st&ble rele&se o' insulin monomers 'rom s!c! tissue B3G,39,40C! (omp&red to b&s&l insulin "l&r"ine, de"ludec h&s sho n simil&r "l.cemic control &nd r&te o' h.po"lic&emi&, dependin" on the re"imen used B4%-A1C! 2he F)1/9, F&s&l-Folus 2.pe 2, studies sho ed th&t insulin de"ludec &s non-in'erior to "l&r"ine in terms o' "lucose control, hen both ere &dministr&ted once & d&. in & b&s&l bolus re"imen, &nd it &s &ssoci&ted ith & lo er ris> o' h.po"l.cemi& B41C!

4. E1pert 5pinion
+&n. 22D+ sub#ects ill e-entu&ll. need insulin ther&p. bec&use o' the pro"ressi-e loss o' bet&-cell 'unction o-er time! 2he &im o' insulin tre&tment is to recre&te insulin le-els &nd mode o' &ction &s close &s possible to the ph.siolo"ic&l pro'ile, in order to &chie-e & ti"ht "lucose control, to reduce the ris> o' h.po"l.c&emi& &nd to impro-e ?u&lit. o' p&tientsL li'e! 8hile in 21D+ it is &n obli"&te choice, prescribin" insulin ther&p. in 22D+ p&tients is still problem&tic! Despite the potenti&l bene'its o' e&rl. insulini4&tion to preser-e bet&-cell 'unction, insulin ther&p. is o'ten del&.ed bec&use o' numerous b&rriers in both p&tients &nd c&re-"i-ers, includin" the 'e&r o' h.po"l.c&emi& &nd ei"ht "&in, di''iculties in insulin titr&tion, &nd the necessit. o' multiple d&il. "lucose controls! /nsulin &n&lo"s, either &lone or in premi*ed 'ormul&tions, h&-e simpli'ied se-er&l o' these points! <o e-er, there is no consensus on hich re"imen should be pre'erred to st&rt insulin ther&p. in these p&tients! 7ctu&ll., once d&il. b&s&l insulin, &dded to the pre-iousl. used or&l &"ents, is the most popul&r re"imen, &nd it is &ble to

0. Premi1ed 'nsulin Analo*s

7nother, more con-enient &nd l&r"el. used &ppro&ch to insulin ther&p. is th&t b&sed on Ipremi*edJ insulins, consistin" o' & 'i*ed combin&tion o' 9P< &nd 3</ or 377, in di''erent r&tios! 2hese biph&sic insulins &re usu&ll. &dministered t ice d&il., be'ore mornin" &nd e-enin" me&ls! /n 22D+, &"&inst b&s&l insulins once d&il., biph&sic insulin &n&lo"s t ice d&il. seem to per'orm better in &chie-in" the "lucose t&r"ets &nd, e-en hen comp&red ith the more comple* b&s&l-bolus re"imens, these premi*ed insulins &re &t le&st non-in'erior! 7 recent s.stem&tic re-ie , in-esti"&tin" the role o' di''erent insulin &n&lo"s in &chie-in" optim&l <b71c t&r"ets in 22D+, sho ed th&t biph&sic insulins r&n>ed second, &'ter the b&s&l@bolus scheme B34C! ,su&ll., side e''ects &re no more 're?uent th&n ith other insulins; more h.po"l.cemic episodes o' lo se-erit. h&-e been sometimes reported, but onl. in comp&rison ith b&s&l insulin B3A, 3$C! 7lthou"h premi*ed insulin &n&lo"s m&. represent & more con-enient insulin re"imen, especi&ll. 'or

;cience Hourn&l o' (linic&l +edicine 2012, 1(1): 4-9

&melior&te "lucose control in the m&#orit. o' 22D+ p&tients, &s demonstr&ted b. the Itre&t to t&r"etJ tri&ls B21,22,2%,29C! 2 ice & d&. premi*ed insulins B42C or & b&s&l-plus scheme ith & r&pid-&ctin" insulin &t the me&n me&l B43C represent -&lid &ltern&ti-es! Din&ll., & b&s&l-bolus re"imen m&. &lso be used in 22D+, hen the more simpli'ied ones &re no lon"er e''ecti-e B44C! /n this conte*t, Pontiroli et &l B4AC recentl. &n&l.4ed the e''ect o' di''erent insulin re"imens &nd insulin &n&lo"s in 22D+ durin" the 'irst .e&r o' insulin tre&tment! 2his met&-&n&l.sis 'ound th&t both "lucose control &nd the ris> o' h.po"l.c&emi& ere prim&ril. &ssoci&ted ith the intensit. o' tre&tment, ith 'in&l <b71c th&t &s hi"her ith b&s&l th&n ith t ice-&-d&. or pr&ndi&l re"imen, &nd ith opposite 'i"ures 'or h.po"l.c&emi&! 8ithin b&s&l re"imens, detemir &nd "l&r"ine ere simil&r to 9P< in <b71c lo erin", ith less h.po"l.c&emi&, here&s ithin pr&ndi&l re"imens, 377s ere more e''ecti-e th&n 3</ on <b71c, &nd induced less h.po"l.c&emi&! /n & l&r"e met&-&n&l.sis in-ol-in" M32,000 p&tients, 1iu"li&no et &l 'ound th&t insulin &n&lo"s resulted in di''erent success r&te in &chie-in" <b71c t&r"ets in 22D+ B34C! <o e-er, e-en ith the best &ppro&ch to insulin ther&p., i!e!, b&s&l-bolus re"imen, there ere & consider&ble percent&"e o' sub#ects not re&chin" <b71c "o&ls B23C, &lthou"h the &ppropri&teness o' &n intensi-e "lucose control in &ll 22D+ sub#ects is tod&. & hi"hl. deb&ted issue, especi&ll. in the li"ht o' reducin" c&rdio-&scul&r ris> B4$,4GC! Durthermore, se-er&l tri&ls in-esti"&ted the Idur&bilit.J o' "lucose control ith di''erent st&rter insulin re"imens! 2he D,37F6) tri&l demonstr&ted & modestl. lon"er m&inten&nce o' <b71c le-els NGK in 22D+ p&tients tre&ted ith t ice d&il. premi*ed lispro 'ormul&tions th&n ith once d&il. "l&r"ine plus or&l &"ents (43K -s! 3AK), ith &n o-er&ll lon"er dur&tion o' "lucose control in p&tients ith lo er <b71c &t b&seline B4%C! 2his stud. 'urther demonstr&ted the bene'its o' e&rl. initi&tion o' insulin ther&p. &nd, &s reported in the 2re&tin" to 2&r"et in 2.pe 2 Di&betes 2ri&l (4-2), the rel&ti-el. short dur&tion o' control in 22D+, in spite o' &n. insulin re"imen B49C! /n the l&st dec&des, insulin ther&p. h&s m&de se-er&l steps 'or &rd &nd recombin&nt D97 technolo". h&s m&de &-&il&ble di''erent 'ormul&tions 'or clinic&l use, st&rtin" 'rom hum&n insulins (3</ &nd 9P<) &nd comin" to the current &n&lo"s, &nd to no-el insulins th&t &re re&d. to be introduced into the m&r>et! /nsulin &n&lo"s h&-e &melior&ted se-er&l critic&l points o' insulin ther&p., i!e!, timin" o' insulin &dministr&tion, 'l&t b&s&l pro'ile, &nd h.po"l.cemic ris>! =-er&ll, both 377s &nd 677s seem to better per'orm in b&s&l-bolus schemes, representin" the insulins o' choice in 21D+! /n 22D+, di''erent schemes, either ith recombin&nt insulin or insulin &n&lo"s seem to be e''ic&cious in t&r"etin" <b71c, &lthou"h &n&lo"s should be pre'erred hen considerin" h.po"l.cemic ris> &nd the opportunit. to t&ilor tre&tment on p&tientsL li'est.le! 9e-ertheless, m&n. problems persist: &lthou"h impro-ed,

the possibilit. to &chie-e &n optim&l pl&sm& "lucose control hile &-oidin" h.po"l.c&emi& is still '&r 'rom bein" obt&ined in m&n. p&tients; 'urthermore, the selection o' hich insulin re"imen ill better 'it p&tientsL needs is still ch&llen"in", not to mention the uncom'ort&ble route o' &dministr&tion! Dor these re&sons, ne insulin 'ormul&tions &nd de-ices &re under intensi-e rese&rch &nd it is li>el. th&t in & rel&ti-el. short period o' time insulin ther&p. ill be enriched b. these ne opportunities, th&t hope'ull. ill represent & pro"ress on the lon" &. to m&tch & s.stem th&t is per'ectl. re"ul&ted in n&ture, i!e! the ph.siolo"ic&l insulin secretion &nd &ction!

Re6erences
B1C De8itt D), <irsch /F! =utp&tient insulin ther&p. in t.pe 1 &nd t.pe 2 di&betes mellitus: scienti'ic re-ie ! H7+7! 2003;2%9:22A4-$4! 1erich H)! 9o-el insulins: e*p&ndin" options in di&betes m&n&"ement! 7m H +ed 2002;113:30%@31$! Fode F8! (omp&rison o' ph&rm&co>inetic properties, ph.sicochemic&l st&bilit., &nd pump comp&tibilit. o' 3 r&pid-&ctin" insulin &n&lo"ues - &sp&rt, lispro, &nd "lulisine! )ndocr Pr&ct! 2011;1G:2G1-%0! <o e. D(, Fo sher 33, Frunelle 36, et &l! B6.s(F2%),Pro(F29)C- hum&n insulin! 7 r&pidl. &bsorbed &n&lo"ue o' hum&n insulin! Di&betes 1994;43:39$@402! 5&#o O, D& cett H, Duc> orth 8(! 3ecombin&nt D97 technolo". in the tre&tment o' di&betes: insulin &n&lo"s! )ndocr 3e-! 2001;22:G0$-1G! ,lrich <, ;n.de F, ;&tish E1! (ombinin" insulins 'or optim&l blood "lucose control in t.pe 1 &nd 2 di&betes: Docus on insulin "lulisine!5&scul <e&lth 7nd 3is> +&n&"ement 200G;3:24A-2A4! Pl&n> H, ;iebenho'er 7, Fer"hold 7, et &l! ;.stem&tic re-ie &nd met&-&n&l.sis o' short-&ctin" insulin &n&lo"ues in p&tients ith di&betes mellitus! 7rch /ntern +ed 200A;1$A:133G-44! +&nnucci ), +on&mi +, +&rchionni 9! ;hort-&ctin" insulin &n&lo"ues -s! re"ul&r hum&n insulin in t.pe 2 di&betes: & met&-&n&l.sis! Di&betes =bes +et&b 2009;11:A3-9! Perriello 1, P&mp&nelli ;, Porcell&ti D, et &l! /nsulin &sp&rt impro-es me&l time "l.c&emic control in p&tients ith 2.pe 2di&betes: & r&ndomi4ed, str&ti'ied, double-blind &nd cross-o-er tri&l! Di&bet +ed 200A;22:$0$-11!

B2C B3C

B4C

BAC

B$C

BGC

B%C

B9C

B10C 3.s P, P&n>ie ic4 =, P&ch E, et &l!)''ic&c. &nd s&'et. comp&rison o' r&pid-&ctin" insulin &sp&rt &nd re"ul&r hum&n insulin in the tre&tment o' t.pe 1 &nd t.pe 2 di&betes mellitus: & s.stem&tic re-ie ! Di&betes +et&b 2011;3G:190-200! B11C Fl&&> )), 7ntoine H+, Fenton D, et &l! /mp&ct o' postpr&ndi&l "l.c&emi& on he&lth &nd pre-ention o' dise&se! =bes 3e2012! doi: 10!1111/#!14$G-G%9Q!2012!01011!*! B12C <ome PD! 2he ph&rm&co>inetics &nd ph&rm&cod.n&mics o' r&pid-&ctin" insulin &n&lo"ues &nd their clinic&l conse-

Domenico (ucinott& et al. : 3ecombin&nt insulin in t.pe 2 di&betes tre&tment: here &re e no :

?uences! Di&betes =bes +et&b 2012;14:G%0-%! B13C 2orlone ), Di (i&nni 1, +&nnino D, et &l! /nsulin &n&lo"s &nd pre"n&nc.: &n upd&te! 7ct& Di&betol 2009;4$:1$3-G2! B14C Durn &ld (P, 6&ndon +F! /nsulin &n&lo"ues in the m&n&"ement o' the pre"n&nc. complic&ted b. di&betes mellitus! (urr Di&b 3ep 2011;11:2%-34! B1AC de 5&l> <8, 5isser 1<! /nsulin durin" pre"n&nc., l&bour &nd deli-er.! Fest Pr&ct 3es (lin =bstet 1.n&ecol 2011;2A:$A-G$! B1$C 1!F! Folli, 3! D! Di +&rchi, 1! D! P&r>, et &l! /nsulin &n&lo"ues &nd their potenti&l in the m&n&"ement o' di&betes mellitus Di&betolo"i& 1999;42:11A1-11$G! B1GC +&>& ;, <edrin"ton +D, 6inds&. Pulli&m F; et &l! F&s&l insulin tre&tment in t.pe 2 di&betes! Di&betes technolo". R ther&peutics 2011;13:;uppl 1 (; 33-42)! B1%C ;&no'i-7-entis! 6&ntus! Prescribin" /n'orm&tion! 3e-ised 200G http://products!s&no'i-&-entis!us/l&ntus/l&ntus!pd'! B19C 6e-emirS (insulin detemir BrD97 ori"inC in#ection) Bprescribin" in'orm&tionC! Princeton, 9H: 9o-o 9ordis> /nc 2010! B20C +on&mi +, +&rchionni 9, +&nnucci )! 6on"-&ctin" insulin &n&lo"ues -ersus 9P< hum&n insulin in t.pe 2 di&betes: & met&-&n&l.sis! Di&betes 3es (lin Pr&ct 200%;%1:1%4-9! B21C 3iddle +(, 3osenstoc> H, 1erich H! /nsulin 1l&r"ine 4002 ;tud. /n-esti"&tors! 2he tre&t-to-t&r"et tri&l: r&ndomi4ed &ddition o' "l&r"ine or hum&n 9P< insulin to or&l ther&p. o' t.pe 2 di&betic p&tients! Di&betes (&re 2003;2$:30%0-$! B22C <erm&nsen E, D&-ies +, Dere4ins>i 2, et &l! 7 2$- ee>, r&ndomi4ed, p&r&llel, tre&t-to-t&r"et tri&l comp&rin" insulin detemir ith 9P< insulin &s &dd-on ther&p. to or&l "lucose-lo erin" dru"s in insulin-n&i-e people ith t.pe 2 di&betes! Di&betes (&re 200$;29:12$9-G4! B23C Ehunti E, D&mci 2, +ene"hini 6, et &l! ;=65) ;tud. 1roup! ;tud. o' =nce D&il. 6e-emir (;=65)T): insi"hts into the timin" o' insulin initi&tion in people ith poorl. controlled t.pe 2 di&betes in routine clinic&l pr&ctice! Di&betes =bes +et&b 2012;14:$A4-$1! B24C 6ucidi P, Porcell&ti D, 3ossetti P, et &l! Ph&rm&co>inetics &nd ph&rm&cod.n&mics o' ther&peutic doses o' b&s&l insulins 9P<, "l&r"ine, &nd detemir &'ter 1 ee> o' d&il. &dministr&tion &t bedtime in t.pe 2 di&betic sub#ects: & r&ndomi4ed cross-o-er stud.! Di&betes (&re 2011;34:1312-4! B2AC ; innen ;1, ;imon 7(, <ollem&n D, et &l! /nsulin detemir -ersus insulin "l&r"ine 'or t.pe 2 di&betes mellitus! (ochr&ne D&t&b&se o' ;.stem&tic 3e-ie s 2011;G:(D00$3%3! D=/: 10!1002/14$A1%A%! (D00$3%3!pub!2 B2$C 2$! 3&s>in P, 1.l-in 2, 8en" 8, et &l! (omp&rison o' insulin detemir &nd insulin "l&r"ine usin" & b&s&l-bolus re"imen in & r&ndomi4ed, controlled clinic&l stud. in p&tients ith t.pe 2 di&betes! Di&betes +et&b 3es 3e- 2009;2A:A42@A4%! B2GC <oll&nder P, (ooper H, Fre"nhU# H, et &l! 7 A2- ee>, multin&tion&l, open-l&bel, p&r&llel-"roup, nonin'eriorit., tre&t-to-t&r"et tri&l comp&rin" insulin detemir ith insulin "l&r"ine in & b&s&l-bolus re"imen ith me&ltime insulin &sp&rt in p&tients ith t.pe 2 di&betes! (lin 2her 200%;30:19G$@19%G!

B2%C 3osenstoc> H, D&-ies +, <ome PD, et &l! 7 r&ndomised, A2- ee>, tre&t-to-t&r"et tri&l comp&rin" insulin detemir ith insulin "l&r"ine hen &dministered &s &dd-on to "lucose-lo erin" dru"s in insulin n&i-e people ith t.pe 2 di&betes! Di&betolo"i& 200%;A1: 40%@41$! B29C ; innen ;1, D&in +P, 7ronson 3, et &l! 7 24- ee>, r&ndomi4ed, tre&t-to-t&r"et tri&l comp&rin" initi&tion o' insulin "l&r"ine once-d&il. ith insulin detemir t ice-d&il. in p&tients ith t.pe 2 di&betes in&de?u&tel. controlled on or&l "lucose-lo erin" dru"s! Di&betes (&re 2010;33:11G$@11G%! B30C O&ch&ri&h ;, ;heldon F, ;ho#&ee-+or&die D, et &l! /nsulin detemir reduces ei"ht "&in &s & result o' reduced 'ood int&>e in p&tients ith t.pe 1 di&betes! Di&betes c&re 2011;34:14%G-1491! B31C (&ll 3, 1rimsle. +, (&d &ll&der 6, et &l! /nsulin--c&rcino"en or mito"en: Preclinic&l &nd clinic&l e-idence 'rom prost&te, bre&st, p&ncre&tic, &nd colorect&l c&ncer rese&rch! Post"r&d +ed 2010;122:1A%-$A! B32C <ome PD, 6&"&renne P! (ombined r&ndomised controlled tri&l e*perience o' m&li"n&ncies in studies usin" insulin "l&r"ine! Di&betolo"i& 2009;A2:2499-A0$! B33C 1io-&nnucci ), <&rl&n D+, 7rcher +(, et &l! Di&betes &nd c&ncer: & consensus report! (7 (&ncer H (lin 2010;$0:20G-21! B34C 1iu"li&no D, +&iorino +/, Fell&stell& 1, et &l! +ultiple <b71c t&r"ets &nd insulin &n&lo"ues in t.pe 2 di&betes: & s.stem&tic re-ie ! H Di&betes (omplic&tions 2011;2A:2GA-%1! B3AC (ucinott& D, 3usso 1! Fiph&sic insulin &sp&rt in the tre&tment o' t.pe 2 di&betes mellitus! )*pert =pin Ph&rm&cother 2009;10:290A-11! B3$C D&-idson H, 5e*i&u P, (ucinott& D, et &l! 3! Fiph&sic insulin &sp&rt 30: liter&ture re-ie o' &d-erse e-ents &ssoci&ted ith tre&tment! (lin 2her! 200A;2G ;uppl F:;GA-%%! B3GC D&nne 2, Folinder H! 9e insulins &nd insulin ther&p.! /nt H (lin Pr&ct ;uppl 2011;1G0:2$-30! B3%C ;teiner ;, <ompesch +, Pohl 3, et &l! 7 no-el insulin 'ormul&tion ith & more r&pid onset o' &ction! Di&betolo"i&! 200%;A1:1$02-$! B39C ;imon 7(, De5ries H<! 2he 'uture o' b&s&l insulin supplement&tion! Di&betes 2echnol 2her 2011;13 ;uppl 1:;103-%! B40C E&lr& ;, ,nni>rishn&n 71, F&ru&h +, et &l! De"ludec insulin: 7 no-el b&s&l insulin! H )ndocrinol +et&b 2011;1A:;12-$! B41C 1&rber 7H, Ein" 7F, Del Pr&to ;, et &l! 9912A0-3A%2 (F)1/9 FF 22D) 2ri&l /n-esti"&tors! /nsulin de"ludec, &n ultr&-lon"-&ctin" b&s&l insulin, -ersus insulin "l&r"ine in b&s&l-bolus tre&tment ith me&ltime insulin &sp&rt in t.pe 2 di&betes (F)1/9 F&s&l-Folus 2.pe 2): & ph&se 3, r&ndomised, open-l&bel, tre&t-to-t&r"et non-in'eriorit. tri&l! 6&ncet 2012;3G9: 149%-A0G! B42C 6&sserson D;, 1l&s4iou P, Perer& 3, et &l! =ptim&l insulin re"imens in t.pe 2 di&betes mellitus: s.stem&tic re-ie &nd met&-&n&l.ses! Di&betolo"i& 2009;A2:1990-2000! B43C 9icolucci 7, Del Pr&to ;, 5esp&si&ni 1; )6)=9=3 ;tud. 1roup! =ptimi4in" insulin "l&r"ine plus one in#ection o' insulin "lulisine in t.pe 2 di&betes in the )6)=9=3 stud.:

;cience Hourn&l o' (linic&l +edicine 2012, 1(1): 4-9

simil&r e''ects o' telec&re &nd con-ention&l sel'-monitorin" o' blood "lucose on p&tient 'unction&l he&lth st&tus &nd tre&tment s&tis'&ction! Di&betes (&re 2011;34:2A24-$! B44C +&n&"ement o' <.per"l.cemi& in 2.pe 2 Di&betes: 7 P&tient-(entered 7ppro&ch! Position ;t&tement o' the 7meric&n Di&betes 7ssoci&tion (7D7) &nd the )urope&n 7ssoci&tion 'or the ;tud. o' Di&betes ()7;D)! Di&betes (&re, published online 7pril 19, 2012! B4AC Pontiroli 7), +iele 6, +or&bito 7! +et&bolic control &nd ris> o' h.po"l.c&emi& durin" the 'irst .e&r o' intensi-e insulin tre&tment in t.pe 2 di&betes: s.stem&tic re-ie &nd met&-&n&l.sis! Di&betes =bes +et&b 2012;14:433-4$! B4$C (urrie (H, Peters H3, 2.n&n 7, )-&ns +, et &l! ;ur-i-&l &s & 'unction o' <b7(1c) in people ith t.pe 2 di&betes: & re-

trospecti-e cohort stud.! 6&ncet 2010;3GA:4%1-9! B4GC Vud>in H;, 3ichter F, 1&le )7! /ntensi'ied "lucose lo erin" in t.pe 2 di&betes: time 'or & re&ppr&is&l! Di&betolo"i& 2010;A3:20G9-%A! B4%C Fuse HF, 8ol''enbuttel F<, <erm&n 8<, et &l! 2he D,37bilit. o' F&s&l -ersus 6ispro mi* GA/2A insulin )''ic&c. (D,37F6)) tri&l:comp&rin" the dur&bilit. o' lispro mi* GA/2A &nd "l&r"ine! Di&betes (&re 2011;34:249-AA! B49C <olm&n 33, D&rmer 7H, D&-ies +H, et &l! 4-2 ;tud. 1roup! 2hree-.e&r e''ic&c. o' comple* insulin re"imens in t.pe 2 di&betes! 9 )n"l H +ed 2009;3$1:1G3$-4G!