review article

Diabesity: therapeutic options

S. Colagiuri
Boden Institute of Obesity, Nutrition and Exercise, University of Sydney, Sydney, NSW, ustralia
Diabetes, Obesity and Metabolism !"# $%& '$(&, ")!).
")!) Blac*well +ublis,ing -td
.at,ogenic relations,i. exists between ty.e " diabetes and obesity. Over t,e last decade, t,e escalation in diabetes cases ,as .aralleled t,e
ra.id increase in obesity rates, constituting a global ,ealt, crisis. Environ/ental ris* factors attributed to t,e global increase in obesity include
t,e consu/.tion of ,ig,0calorie, ,ig,0fat foods and inade1uate .,ysical activity. Obese individuals /ay also ,ave a genetic .redis.osition for
obesity. Bot, diabetes and obesity confer an elevated ris* of develo.ing a range of co/.lications and co/orbidities, including cardiovascular
disease, ,y.ertension and stro*e, w,ic, can co/.licate disease /anage/ent. 2,is review exa/ines t,e aetiology of t,e lin*ages between
diabetes and obesity and t,e range of available t,era.ies. 3ecent clinical evidence substantiating t,e ef4cacy and safety of incretin0based
antidiabetic t,era.ies is analysed, in addition to data on antiobesity t,era.eutic strategies, suc, as antiobesity agents, be,aviour /odi4cation
and bariatric surgery. 5lucose control is often acco/.anied by weig,t0neutral or /odest weig,t reduction effects wit, 6++0$ in,ibitor
treat/ent 7sitagli.tin, vildagli.tin, saxagli.tin8 and weig,t loss wit, 5-+0! rece.tor agonist t,era.y 7exenatide, liraglutide8. Studies of
antiobesity agents including orlistat, sibutra/ine and ri/onabant ,ave s,own attrition rates of &) ' $)9, and t,e long0ter/ effects of
t,ese agents re/ain un*nown. Bariatric surgical .rocedures co//only .erfor/ed are la.arosco.ic ad:ustable banding of t,e sto/ac, and
t,e 3oux0en0; gastric by.ass, and ,ave .roduced ty.e " diabetes re/ission rates of u. to (&9. 2,era.eutic strategies t,at integrate
glycae/ic control and weig,t loss will assu/e greater i/.ortance as t,e .revalence of diabetes and obesity increase.
Keywords: 6++0$, exenatide, 5-+0! analogue, ,u/an, incretin, liraglutide, once0daily, ty.e " diabetes
/ellitus
Date submitted 2 June 2009; date of first decision 2 November 2009; date of final acceptance 4 November 2009
Introduction
2,e ter/ <diabesity=, coined by Si/s and colleagues >!? in
t,e !@()s, describes t,e strong lin* between ty.e " diabetes
and obesity >!,"?. s evidence of t,is .at,ogenic
interrelations,i. continues to accu/ulate, so does t,e
a..earance of t,e ter/ in t,e clinical literature. large body
of clinical evidence attests to t,e relations,i. between being
overweig,t or obese and being at an elevated ris* for
develo./ent of ty.e " diabetes >& ' (?. 2,e ris* escalates
wit, t,e degree of excess weig,t, increasing t,reefold wit, a
body /ass index 7BAI8 of "B.) ' "@.@ *gC/
"
and ")0fold
wit, a BAI over &) *gC/
"
>$?. In .articular, abdo/inal fat
accu/ulation exacerbates insulin resistance and confers a
strong, inde.endent ris* of develo.ing diabetes >D?. 5lobal
diabetes .revalence is esti/ated at !(! /illion and is
.ro:ected to /ore t,an double, to &%% /illion, by ")&) >@?.
Countries wit, t,e ,ig,est nu/bers of diabetes cases
include India, C,ina, US, Indonesia and Ea.an >@ ' !!?.
2,e greatest relative increases in diabetes incidence rates are
.redicted to occur in India, sub0Sa,aran frica and t,e
Aiddle East >@?. If current trends continue, a..roxi/ately
one fift, of diabetes cases globally will be in t,e Indian
subcontinent by ")&).
2y.e " diabetes is associated wit, an elevated ris* for a
nu/ber of serious, indeed life0t,reatening /icrovascular and
/acrovascular co/.lications. Incidence figures co/.iled by
Corres.ondence to# +rof. S. Colagiuri, 6e.art/ent of Aetabolic Fealt,, Boden Institute of
Obesity, Nutrition and Exercise, University of Sydney, Sydney, NSW, ustralia.
E0/ail# scolagiuriGusyd.edu.au
t,e /erican 6iabetes ssociation indicate t,at, every day
in US, %% .eo.le lose t,eir eyesig,t because of diabetesH
!!" .eo.le begin treat/ent for end0stage renal diseaseH ""B
a/.utations are .erfor/ed because of diabetesH and BD$
.eo.le die fro/ diabetes and its co/.lications, /ost often
as a result of cardiovascular disease or stro*e >!"?. Si/ilar
rates of incidence and .revalence of diabetes0related
/icrovascular and /acrovascular co/.lications ,ave been
re.orted fro/ Euro.e and elsew,ere. n analysis of United
Iingdo/ +ros.ective 6iabetes Study 7UI+6S8 data found
a "9 .er annu/ .rogression fro/ nor/o0 to /icro0
albu/inuria, as well as an additional "9 .er annu/
.rogression fro/ /icro0 albu/inuria to .roteinuria >!&?. n
Italian study of t,e recurrence of cardiovascular events in
.eo.le wit, ty.e " diabetes re.orted a (".( .er !)))
.atient0years incidence of a recurrent event in /en wit,
cardiovascular disease at ti/e of enrol/ent and a &".B
incidence in wo/en >!$?.
Over t,e last decade, t,ere ,as been a ra.id escalation in
t,e .revalence of obesity, one t,at .arallels t,e e1ually ra.id
increase in ty.e " diabetes >!B?. 2,e World Fealt,
OrganiJation 7WFO8 considers obesity to be a global
e.ide/ic >!%?. 2,e /ost recent WFO data indicate t,at
!.% billion adults worldwide are overweig,t 7BAI "B.) '
"@.@ *gC/
"
8
and $)) /illion are obese 7BAI &) *gC/
"
8 >!%?. By
")!B,
".& billion adults will be overweig,t and /ore t,an ())
/illion will be obese, according to WFO .ro:ections >!%?.
2,e consu/.tion of ,ig,0calorie, ,ig,0fat foods and
insufficient .,ysical activity ,ave been cited as causative
re
vie
w
ar
tic
le
factors in t,e
Kolu/e !" No. % Eune ")!) doi#!).!!!!C:.!$%&0!&"%."))@.)!!D".x &
review article DIABETES, OBESITY AD !ETABO"IS!
increase in obesity >!(?. 2,ose environ/ental ris* factors
are also cited as reasons for t,e increases in obesity a/ong
c,ildren and adults in develo.ing countries >!D,!@?. Based on
t,e findings of observational studies in develo.ing countries,
it ,as also been ,y.ot,esiJed t,at .oor fetal nutrition is a ris*
factor for obesity and ty.e " diabetes in later adult life >")?.
Lunda/entally, obesity results fro/ an i/balance between
energy inta*e and energy ex.enditure. W,ile a sedentary
lifestyle cou.led wit, excessive food consu/.tion are
regarded as c,ief causes of obesity, t,ere are ot,er less
co//on ris* factors, including ,y.ot,yroidis/, Cus,ing=s
syndro/e and abnor/alities in le.tin action and
regulation and in t,e AC3$ rece.tor >"! ' "&?. Individuals
/ay ,ave a genetic .redis.osition for obesity, as
evidenced by studies describing .oly/or.,is/s in t,e
&
0
adrenergic rece.tor in +i/a Indians and ot,er .o.ulations
>"$,"B?. 2,e <t,rifty= genoty.e ,y.ot,esis s.eculates t,at a
need for increased /etabolic efficiency and fat storage
during fluctuations between feast and fa/ine in t,e
+alaeolit,ic .eriod /ay ,ave resulted in a genetic
.redis.osition to obesity and diabetes in .o.ulations newly
introduced to Western diets of calorie0dense foods. 2,ose
sa/e .o.ulations, in recent decades, ,ave also de/onstrated
a /ar*ed decrease in daily .,ysical activity >"% ' "D?.
2,e coexistence of ty.e " diabetes and obesity .resents a
co/.lex t,era.eutic c,allenge. 2y.e " diabetes confers an
elevated ris* of develo.ing a broad range of co/.lications,
including /acrovascular disorders 7e.g. cardiovascular
disease, stro*e8 and /icrovascular disease 7e.g. retino.at,y,
neuro.at,y and ne.,ro.at,y8 >!"?. -i*ewise, obesity
increases t,e ris* of a /yriad of c,ronic diseases,
including ty.e " diabetes, coronary ,eart disease,
,y.ertension, ,y.erli.idae/ia, stro*e and certain cancers
>$,"@ ' &!?. Obesity is lin*ed to t,e develo./ent of
additional co/orbidities t,at can furt,er co/.licate disease
/anage/ent, including /obility .roble/s associated wit,
osteoart,ritis, obstructive slee. a.nea and clinical
de.ression. 2reat/ent of co/orbid ,y.ertension /ay
confound antidiabetic treat/ent. Siegel and Swisloc*i ,ave
suggested an association between t,iaJide diuretic t,era.y
for ,y.ertension and weig,t gain and glucose
dysregulation, including elevated levels of fasting .las/a
glucose >&"?. 0bloc*er t,era.y ,as been associated wit,
weig,t gain, alt,oug, t,e effect /ay be relatively s/all.
/eta0analysis of 0bloc*er use in ,y.ertension re.orted
a weig,t gain of between !.) ' &.B *g >&&,&$?.
ntide.ressant agents, .articularly tricyclics, are also
associated wit, weig,t gain >&B?. 5iven t,e .revalence of
co/orbid de.ressive and anxiety disorders in .eo.le wit,
diabetes, t,e use of tricyclics /ay confound antidiabetic
treat/ent >&%,&(?. 2,e /erican 6iabetes ssociation
reco//ends a BAI "B *gC/
"
>&D?, but individuals /ay
find t,ey are unable to ac,ieve or /aintain t,is benc,/ar*
because of t,e difficulties associated wit, t,eir t,era.eutic
regi/en. Aany conventional antidiabetic agents, including
t,iaJolidinediones 72M6s8, insulin, sul.,onylureas and
/eglitinides, are associated wit, weig,t gainH an exce.tion is
/etfor/in, w,ic, ,as been associated wit, weig,t neutrality
or /odest weig,t reduction >&@ ' $$?. s furt,er
discussed below, t,e newer basal for/ulation insulin
dete/ir ex,ibits li/ited weig,t gain in co/.arison to
neutral .rota/ine
review article
4 Colagiuri Kolu/e !" No. % Eune ")!)
DIABETES, OBESITY AD !ETABO"IS!
Fagedorn 7N+F8 insulin >$B,$%? and dete/ir, N+F
insulin and insulin glargine ,ave de/onstrated /odest
weig,t reductions in co/bination wit, oral antidiabetic
drugs 7O6s8 in a real0 world setting >$(?. Nevert,eless,
a vicious circle /ay ensue wit, antidiabetic agents, wit,
increases in weig,t resulting in a secondary increase in
insulin resistance, w,ic, subse1uently necessitates an
increase in /edication re1uire/ents to /aintain glucose
,o/eostasis. Weig,t gain wit, antidiabetic agents can
.ose a significant .syc,ological barrier to t,e initiation
or intensification of treat/ent, leading to .atient non0
co/.liance >$D?.
5iven t,e strong association between excess weig,t
and ty.e " diabetes, t,e .revention of weig,t gain in
.eo.le wit, diabetes, as well as in individuals wit,
i/.aired glucose tolerance 7I528, s,ould be a cardinal
focus in treat/ent strategies. In t,is review, t,e
/ultifactorial and .rogressive nature of ty.e " diabetes
is discussed wit, a view to understanding t,e aetiology
and treat/ent of diabetes and associated obesity,
leading to an exa/ination of t,e range of antidiabetic
t,era.eutics available to treat it. In addition to
.,ar/aceutical0based strategies, antiobesity t,era.eutic
strategies, including lifestyle /odification and bariatric
surgery, will be exa/ined.
Clinical
+at,o.,ysiology
2y.e " diabetes is a .rogressive, /ultifactorial /etabolic
disease. 2,e ,y.erglycae/ia, w,ic, is t,e ,all/ar* of
t,is disease, is caused by a nu/ber of /etabolic
derange/ents, including di/inis,ed insulin secretion,
increased insulin resistance, excessive .roduction of
glucagon and deterioration of 0cell /ass and function >$@ '
B!?.
Diminis!ed "irst#$!ase %nsulin &ecretion' Lirst0.,ase insulin
secretion is t,e nor/al res.onse to glucose elevations following
a /eal. Lirst0.,ase res.onse is reduced by a..roxi/ately "(9
in individuals wit, I52, and continues to worsen as ty.e "
diabetes .rogresses >B!?. Uncontrolled ,y.erglycae/ia leads
to .ancreatic 0cell destruction, glucose intolerance and fran*
diabetes >B"?. By t,e ti/e of diagnosis, B)9 of a .atient=s 0cell
ca.acity is ty.ically lost >B&?.
(lunted %ncretin )ffect' Insulin release is sti/ulated /ainly
t,roug, t,e direct action of glucose on and in cells. 2wo
gut0 derived .e.tide ,or/ones, glucagon0li*e .e.tide0!
75-+0!8 and glucose0de.endent insulinotro.ic .oly.e.tide
75I+8, also .lay a role in sti/ulating insulin secretion >B$?.
5-+0! and 5I+ function in an additive /anner, lowering
blood glucose levels following t,e ingestion of a /eal by
sti/ulating insulin synt,esis and secretion in a glucose0
de.endent fas,ion w,ile su..ressing glucagon secretion >B$?.
In ,ealt,y individuals, glucose ad/inistered orally
sti/ulates greater 0cell insulin secretion t,an if t,e
sa/e a/ount of glucose is given intravenously. 2,is
difference is called t,e <incretin effect=, because
intravenous glucose does not sti/ulate t,e release of t,e
incretin ,or/ones, .articularly 5-+0! >BB?. 2,is effect
/ay be res.onsible for u. to two t,irds of t,e insulin
secreted following a /eal >B"?. In ty.e " diabetes, t,e
incretin effect is blunted considerably >B%?. In
addition it ,as been ,y.ot,esiJed t,at i/.air/ent of 5-+0
! and 5I+ secretion andCor activity /ig,t .lay a role in
t,e .at,ogenesis of ty.e " diabetes. Fowever, t,is re/ains
controversial, as studies in first0degree relatives of .eo.le
wit, ty.e " diabetes and in individuals wit, I52 ,ave
de/onstrated an incretin res.onse si/ilar to t,at observed
in nor/al sub:ects >B(,BD?.
*diposity, +ipoto,icity and -ype 2 Diabetes' Increased levels
of adi.osity, .articularly visceral adi.osity, ,ave been
associated wit, insulin resistance and develo./ent or
worsening of ty.e " diabetes. 2,e overflow ,y.ot,esis .osits
t,at, as t,e ca.acity of adi.ocytes to store fat is exceeded,
li.ids overflow into ot,er tissues, .articularly t,e liver and
/uscle >B@?. Increasing levels of ecto.ic li.id infiltration
correlate wit, insulin resistance and increase ris* of ty.e "
diabetes >%),%!?. Elevated free fatty acid levels, and t,e
conversion of free fatty acids to long c,ain acyl Co
derivatives, results in reduced insulin signalling and glucose
trans.ort, as well as furt,er insulin resistance in liver and
/uscle >%",%&?. 2,ese free fatty acid0sti/ulated c,anges
lead to a condition *nown as <li.otoxicity=, and t,e resulting
oxidative stress /ay be a factor in t,e decline in 0cell /ass
associated wit, t,e .at,ogenesis and .at,o.,ysiology of ty.e
" diabetes >B@?. Obesity0associated c,anges in circulating
le.tin and cyto*ine levels ,ave also been s,own to
contribute to 0 cell destruction >%$?. di.onectin, an
adi.ocyto*ine associated wit, insulin sensitiJation and
vascular .rotection, is .resent in reduced .las/a
concentrations in bot, t,e obese and t,e insulin resistant
>%B,%%?. Elevated levels of circulating resistin ,ave been
correlated wit, adi.osity, infla//atory /ar*ers and
increased ris* for ty.e " diabetes >%(?. In su/, t,e
contributions of elevated adi.osity to li.id overflow, elevated
levels of free fatty acids, and .at,ogenic .atterns of
adi.ocyto*ine secretion
' .articularly in t,e context of clinical trial evidence t,at
/oderate weig,t reduction will in,ibit conversion to ty.e "
diabetes in /any at0ris* sub:ects ' suggest t,at in /any
res.ects ty.e " diabetes is a disease of obesity >%D,%@?.
Conventional ntidiabetic 2,era.eutics# I/.act on
Weig,t
Conventional antidiabetic treat/ents include insulin, insulin
sensitiJers 7e.g. 2M6s8, insulin secretagogues 7e.g. sul.,o0
nylureas8 and /odulators of ,e.atic glucose .roduction
7/etfor/in8. Aetfor/in, a biguinide and co//only reco/0
/ended as initial .,ar/acot,era.y in ty.e " diabetes,
in,ibits ,e.atic gluconeogenesis w,ile increasing tissue
sensitivity to insulin0/ediated glucose trans.ort >&@,()?.
Sul.,onylureas 7SU8 are glucose0inde.endent insulin
secretagogues w,ic, bind to t,e SU rece.tor on t,e 0cell
t,ereby sti/ulating insulin release >(!?. Aodulation of t,e
.eroxiso/e .roliferator acti0 vated rece.tor0. by 2M6s
7rosiglitaJone, .ioglitaJone8 results in t,e transcri.tion of a
nu/ber of genes involved in glucose and li.id utiliJation.
2,e result is i/.roved insulin sensitivity of adi.ose, liver and
/uscle tissue >("?. W,ile eac, of t,ese classes of agents can
be effective initially in controlling ,y.erglycae/ia and
lowering glycated ,ae/oglobin 7Fb!c8 by ).B ' !.B9,
t,eir efficacy .rogressively attenuates as insulin resistance
increases and 0cell function declines >$! ' $$?. Weig,t gain,
,y.oglycae/ia and ot,er treat/ent0associated adverse
effects can also under/ine t,era.eutic benefits. In
.articular, weig,t gain is .roble/atic for .eo.le wit,
ty.e " diabetes, as even a /odest increase in weig,t can
increase insulin resistance.
2,e .roble/ of weig,t gain for .eo.le undergoing treat/ent
wit, insulin t,era.y is well recogniJed. 2,e UI+6S
found t,at individuals began gaining weig,t soon after
t,e initiation of insulin t,era.y >(&?. Weig,t gain can be a
.syc,ological barrier to .,ar/acot,era.y, as suggested
by t,e 6iabetes ttitudes, Wis,es, and Needs study,
w,ic, found t,at /ore t,an B)9 of .eo.le wit, ty.e "
diabetes were worried about starting insulin because of
concerns about weig,t gain and t,at &&9 of .,ysicians
.ost.one insulin treat/ent until it is absolutely essential
>($,(B?. So0called <defensive snac*ing=, because of t,e
.erceived ris* of ,y.oglycae/ia, /ay be res.onsible for
weig,t gain during insulin t,era.yH ot,er .ossible
reasons include a reduction of t,e /etabolic rate because
of decreased glucose out.ut and caloric retention
ste//ing fro/ reduced urinary excretion of glucose
cou.led wit, a reduction in energy ex.enditure >(%?.
Clinical trial data suggest t,at weig,t gain associated
wit, insulin t,era.y /ay vary according to
for/ulationH newer basal insulin analogues, for exa/.le,
/ay ex,ibit so/ew,at less weig,t gain t,an N+F >((?.
Since t,ese trials were not blinded and not s.ecifically
geared toward exa/ining effects on weig,t, t,e clinical
significance of t,e observed differences cannot be
establis,ed. "$0wee* study of $(% .eo.le wit, ty.e "
diabetes titrated to twice daily insulin dete/ir vs. N+F
insulin re.orted a /ean weig,t increase of !." *g for insulin
dete/ir vs. a /ean weig,t increase of ".D *g for N+F.
d:ust/ent for c,ange in Fb!c did not affect t,e finding
>(D?. In a subgrou. analysis of t,e +3E6IC2IKE study
evaluating individuals in a clinical .ractice setting w,o
transferred fro/ an O60only regi/en to an O6 .lus
insulin dete/ir, N+F insulin or insulin glargine, all
subgrou.s co/bined lost an average of
).@ *g of body weig,t 7. )')))!8
>$(?.
2,e clinical efficacy of rosiglitaJone and .ioglitaJone
as /onot,era.y or co/bination t,era.y wit, insulin,
sul.,onylureas or /etfor/in is well establis,ed >(@ ' D!?.
class effect of 2M6s, ,owever, is treat/ent0associated
weig,t gain and large, longitudinal studies suc, as 6O+2,
63EA and +3Oactive ,ave s,own t,at t,ese agents can
cause a..reciable weig,t gain of u. to $ ' B *g
>$!,$",$$?. 2M6s are also associated wit, oede/a and ris*
of congestive ,eart failure exacerbation. .ossible
association between cardiovascular adverse effects and
rosiglitaJone ,ave been suggested by /eta0analysis >D"?.
3esults fro/ t,e 3ECO36 73osiglitaJone Evaluated for
Cardiac Outco/es and 3egulation of 5lycae/ia in 6iabetes8
trial found t,at rosiglitaJone, /etfor/in and sulfonylureas
7its co/.arators8 were associated wit, si/ilar ris* for
cardiovascular ,os.italiJation rates and cardiovascular
/ortality, but t,at rosiglitaJone was associated wit,
significantly greater ris* of ,eart failure >D&?. 2wo recent
/eta0analyses of .ioglitaJone suggest t,at it is associated
wit, a significantly reduced ris* of deat,, AI and stro*eH
,owever, ris* of serious ,eart failure /ay be increased wit,
.ioglitaJone >D$,DB?.
#i$ure %& 2,e /ulti.le direct effects of 5-+0! on ,u/an .,ysiology.
5I, gastrointestinalH 5-+0!, glucagon0li*e .e.tide0!.
Incretin 2,era.eutics# 5-+0! 3ece.tor gonists
and 6++0$ In,ibitors
2,e recognition t,at i/.air/ents in t,e incretin res.onse,
and .articularly in 5-+0! activity, /ay contribute to
dysregulation of insulin and glucagon secretion ,as
resulted in t,e develo./ent of an incretin fa/ily of
t,era.eutic agents.
In clinical studies, ad/inistration of 5-+0! ,as been
s,own to nor/aliJe 0cell res.onsiveness to glucose and
restore first0.,ase insulin res.onse, w,ile su..ressing
glucagon levels in .eo.le wit, ty.e " diabetes. 5-+0! /ay
also ,ave extra0glycae/ic effects, including satiety
induction and cardio.rotection >D%,D(? 7figure !8. Fowever,
native 5-+0
! is ra.idly degraded and /etaboliJed by t,e enJy/e
di.e.tidyl .e.tidase0$ 76++0$8. 2wo strategies ,ave been
used to overco/e t,is. 5-+0! rece.tor agonists ,ave been
develo.ed t,at are resistant to t,e action of 6++0$, t,ereby
.,ar/acologically increasing t,e activity of t,ese agonists.
2,e second strategy, 6++0$ in,ibition, e/.loys agents to
delay inactivation of endogenous 5-+0! and 5I+ by bloc*ing
6++0$ activity.
/+$#0 1eceptor *2onists' 5-+0! rece.tor agonists ,ave
different structures fro/ endogenous 5-+0!, allowing for
longer ,alf0lives. 5-+0! rece.tor agonists reduce blood
glucose dose0de.endently as bot, /onot,era.y and in
co/bination wit, ot,er agents. 2,ey slow gastric e/.tying
and increase satiety, /ec,anis/s t,at are in .art
res.onsible for t,e weig,t loss associated wit, t,is class
>B$,DD,D@?. 2,ere is also recent clinical evidence
de/onstrating t,at treat/ent wit, 5-+0! rece.tor agonists
reduces systolic blood .ressure and triglyceride levels, and
exerts beneficial effects on cardiovascular ris* factors >@) '
@&?.
),enatide' Exenatide is t,e first incretin /i/etic to receive
a..roval in US as ad:unctive t,era.y for t,e treat/ent
of .eo.le wit, ty.e " diabetes. Exenatide is a synt,etic, &@0
a/ino acid .e.tide identical to t,e exendin0$ /olecule
first isolated fro/ t,e salivary gland secretions of t,e 5ila
/onster and is B&9 ,o/ologous to ,u/an 5-+0! >@$,@B?. It
is ad/inistered twice daily wit,in %) /in before /orning
and evening /eals >@$?. In t,ree double0blind, .lacebo0
controlled, &)0wee* trials involving .eo.le wit, ty.e "
diabetes w,o were inade1uately controlled wit,
/etfor/in andCor sul.,onylureas, exenatide treat/ent
.roduced i/.rove/ents
in glycae/ic control 7).D9 reductions in Fb!c wit,
t,e
!) g twice daily8 acco/.anied by significant
reductions in body weig,t co/.ared wit, .lacebo
7/ean reduction# ".D to !.% vs. ).@ to +).& *g8 >@%
' @D?. n interi/ analysis of
data fro/ t,e o.en0label, uncontrolled extension of t,ese
t,ree trials found t,at exenatide was associated wit, a
significant
reduction in /ean body weig,t fro/ baseline 7"'! )'"
*g8,
wit, .rogressive reductions after " years 7$'( )'& *g8
>@@?. Exenatide a..ears to elicit an i//une res.onse,
as "( ' $@9
of individuals treated develo.ed antibodies >@% ' @D?. In
a s/all subset w,ere antibody for/ation occurred at ,ig,
titres
7!C%"B8, anti0exenatide antibodies could i/.air t,e
ability
of exenatide to establis, ade1uate i/.rove/ent in
glycae/ic control >@$,!))?.
Exenatide ,as been associated wit, gastrointestinal
adverse events, /ost co//only nausea. Exenatide is also
contraindi0 cated in .eo.le wit, severe renal insufficiency
or end0state renal disease >@$?. ..roxi/ately &) cases of
.ancreatitis ,ave been re.orted to t,e US Lood and 6rug
d/inistration 7L68 since t,e a..roval of exenatide.
2,e L6 ,as t,erefore re1uired a new warning label
citing a strong te/.oral association between exenatide
and .ancreatitis >@$,!)!?. It s,ould be noted t,at
.eo.le wit, ty.e " diabetes ,ave nearly a t,reefold
greater incidence of .ancreatitis t,an t,e general
.o.ulation >!)"?. 6uring exenatide clinical develo./ent,
incidence of .ancreati0 tis was lower in t,e treat/ent grou.
t,an in eit,er t,e .lacebo or insulin co,orts >!)&?.
),enatide +*1' long0acting, once0wee*ly for/ulation of
exenatide 7exenatide -38 is currently in clinical
develo./ent. In a !B0wee*, .,ase " trial, sub:ects wit,
ty.e " diabetes receiving exenatide -3 ".) /g
ex.erienced reductions in
weig,t 7&'D !'$ *gH . )')B8 co/.ared wit, .lacebo,
alt,oug, body weig,t re/ained unc,anged in t,ose receiving
exenatide -3 ).D /g. Exenatide -3 ).D and ".) /g
reduced
/ean Fb!c by !.$ ).& and !.( ).&9 res.ectively, wit, &%
and D%9 of sub:ects ac,ieving Fb!c (9. 2,e incidence
of treat/ent0associated nausea wit, exenatide -3 was
relatively
,ig,, u. to "(9 >!)$?. In a recent non0inferiority study
co/.aring exenatide once wee*ly to exenatide twice daily,
($9 of sub:ects in t,e once0wee*ly grou. develo.ed anti0
exenatide antibodies and "$9 develo.ed ,ig, titre
antibodies, w,ic, reduced t,e glucose lowering effect >!))?.
+ira2lutide' -iraglutide, a once0daily, ,u/an 5-+0! ana0
logue, is a..roved in t,e United States and t,e Euro.ean
Union as bot, initial t,era.y and as ad:unctive t,era.y in
co/bina0 tion wit, oral antidiabetics. -iraglutide is @(9
,o/ologous to ,u/an 5-+0!, wit, only a single a/ino acid
substitution and a gluta/ate0s.aced fatty acid c,ain to
distinguis, it fro/ t,e native .e.tide >!)B?. 2,ese
/odifications slow t,e degradation of liraglutide by 6++0$,
t,ereby extending .las/a ,alf0life to !& , >!)% ' !)@?.
-iraglutide .roduces clinically /eaningful reductions in
Fb!c and body weig,t relative to .lacebo >@!,@",!!) '
!!"?.
In a double0blind, .lacebocontrolled, B"0wee* study
evaluating t,e effects of liraglutide or gli/e.iride as first0line
/onot,era.y in ($% .eo.le wit, ty.e " diabetes, body
weig,t was reduced by "')B $'$) and "'$B $'&( *g in t,e
liraglutide !." and
!.D /g co,orts res.ectively, co/.ared wit, weig,t gain of
!'!" $'"$ *g in t,ose receiving gli/e.iride D /g 7p
)')))! for bot, vs. gli/e.iride8. -iraglutide also .roduced
greater reductions in Fb!c co/.ared wit, gli/e.iride
7).D$ and !.!$9 for liraglutide !." and !.D /g res.ectively,
vs. ).B!9 for
gli/e.iride D /gH p )'))!8 >!!!?. In a .,ase "
/onot,era.y trial, liraglutide reduced body weig,t in all
treat/ent grou.s, wit, a significant reduction of &.) *g in
t,e !.@ /g grou. after !$ wee*s of treat/ent 7. = )')&@8
>!!&?. -iraglutide
!.@ /g reduced Fb!c by !.($9 co/.ared wit, .lacebo
7. )')))!8 >!!&?.
-iraglutide co/bination t,era.y is also associated wit,
reductions in body weig,t and Fb!c >@",!!"?. In two "%0
wee* studies, dose0de.endent reductions in body weig,t
ranging fro/ !.D! ' ".D *g were re.orted in sub:ects
receiving liraglutide co/bination t,era.y wit, /etfor/in or
wit, /etfor/in and a sul.,onylurea co/.ared wit,
weig,t increases ranging
fro/ !.) ' !.%" wit, co/.arator t,era.ies 7sul.,onylurea +
/etfor/inH insulin glargine + /etfor/in and gli/e.irideH
p )')))!8 >@",!!"?. In a subgrou. of sub:ects wit, a
BAI &B *gC/
"
, t,e liraglutide0based regi/en resulted in
dose0de.endent weig,t reductions of u. to $.$ *gC/
"
>@&?.
In a ,ead0to0,ead trial co/.aring liraglutide !.D /g once
daily wit, exenatide !) g twice daily in sub:ects wit, ty.e "
diabetes inade1uately controlled on /etfor/in andCor
sul.,onylurea, liraglutide de/onstrated slig,tly greater
weig,t reductions 7".D! to $.)D *g8 t,an exenatide
7".%D to &.)B *g8 7. = )'""&B8 >!!$?. -iraglutide
.roduced significantly greater reductions fro/ baseline in
Fb!c 7!.!" vs. ).(@98 and fasting .las/a glucose
7!.%! //olC- vs. ).%) //olC-8 co/.ared wit,
exenatide 7. )')))! for bot,8.
In addition to weig,t reduction, liraglutide /ay i/.rove
ot,er /ar*ers of /etabolic ris* suc, as visceral adi.osity and
waist circu/ference. substudy of a .,ase & trial co/.aring
liraglutide + /etfor/in vs. /etfor/in /onot,era.y or
/etfor/in + gli/e.iride re.orted a significant reduction
7. )')B8 of subcutaneous fat wit, t,e liraglutide +
/etfor/in co/bination. co/.uted to/ogra.,y analysis
of visceral fat revealed a !& ' !(9 reduction fro/
baseline in t,e liraglutide + /etfor/in co,ort >!!B?. "%0
wee* trial co/.aring liraglutide in co/bination wit,
/etfor/in and gli/e.iride vs. .lacebo and insulin glargine
in co/bination wit, /etfor/in and gli/e.iride found t,at
in addition to a significant weig,t reduction vs. insulin
glargine 7&.$& *gH . )')))!8, liraglutide t,era.y was
also associated wit, a significant reduction in waist
circu/ference 7!.B c/, liraglutide vs. +).D@ c/, insulin
glargineH . )')))!8 >@"?.
Nausea ,as been t,e /ost co//on adverse event noted in
treat/ent wit, liraglutide. Because of its transient nature, t,e
nausea associated wit, liraglutide is not li*ely to be t,e cause
of weig,t loss observed wit, t,is agent. In a B"0wee*
/onot,era.y study of liraglutide !." and !.D /g vs. gli/e.iride,
to deter/ine if .ersistent nausea was a factor in weig,t loss,
.artici.ants were analysed by t,e nu/ber of days t,ey ,ad
nausea 73( days or
( days8. +artici.ants w,o ,ad nausea for /ore t,an (
days ,ad a /ean weig,t c,ange of &."$, &.&@ and !.$&
*g, co/.ared wit, !.DB, "."% and +!."" *g
res.ectively, for
t,ose wit, no nausea or u. to ( days of nausea. 2,e
differences were not significant for any treat/ent grou.
>!!!?.
D$$#4 %n!ibitors' W,ile 5-+0! rece.tor agonists
directly sti/ulate t,e incretin syste/, 6++0$ in,ibitors
indirectly en,ance endogenous incretin levels by
.reventing t,e degradation of endogenous 5-+0! and
5I+. 6++0$ in,ibitors reduce seru/ 6++0$ activity by
a..roxi/ately D)9, an effect t,at is acco/.anied by a
rise in .ost.randial levels of 5-+0! >!!%?. In contrast to
5-+0! rece.tor agonists, 6++0$ in,ibitors are not
associated wit, decelerated gastric e/.tying or increased
satiety. 2reat/ent wit, 6++0$ in,ibitors tends to ,ave
weig,t0neutral effects.
&ita2liptin' Sitagli.tin is a..roved in bot, US and t,e
Euro.ean Union and /any ot,er countriesH indications
include its use as /onot,era.y and in co/bination
t,era.y wit, /etfor/in, a sul.,onylurea or 2M6 in
.eo.le wit, ty.e " diabetes. In a "$0wee* study,
sitagli.tin cot,era.y
led to significant reductions in bot, Fb!c 7).%B98
and
fasting glucose levels 7!.$ //olC-8 in sub:ects
inade1uately controlled on /etfor/in alone >!!(?.
Weig,t reduction was
not different in t,e active or .lacebo grou.s 7a /ean
decrease of ).% *g co/.ared wit, ).( for .lacebo8 >!!(?.
Si/ilarly, sitagli.tin /onot,era.y 7!)) /gH ")) /g8
.ro0 duced significant reductions in Fb!c 7).(@ and
).@$9
res.ectively8, but did not result in clinically /eaningful
weig,t loss 7c,ange fro/ baseline )'" )'" and )'!
)'" *g
res.ectively8 >!!D?.
,ead0to0,ead co/.arison of sitagli.tin, /etfor/in and
co/bined sitagli.tin and /etfor/in t,era.y revealed t,at
co/bination t,era.y led to significantly greater i/.rove0
/ents in Fb!c t,an eit,er agent alone. ll treat/ent
grou.s ex.erienced s/all but significant reductions in body
weig,t 7).% to !.& *g8, exce.t t,ose receiving sitagli.tin
/onot,era.y, in w,o/ no c,ange in weig,t 7).) *g8 was
observed >!!@?.
4ilda2liptin' Kildagli.tin ,as been a..roved for use in t,e
Euro.ean Union. In a "$0wee* study involving &B$ .eo.le
wit, ty.e " diabetes, vildagli.tin /onot,era.y 7B) /g once
daily, B) /g twice daily or !)) /g once daily8 i/.roved
glycae/ic control but did not .roduce significant body
weig,t c,ange.
Weig,t reduction relative to baseline was ).$ *g in eac,
treat/ent grou., w,ereas .lacebo was associated wit, a
weig,t reduction of !.$ *g >!")?.
W,ile t,e available clinical data suggest t,at vildagli.tin
/onot,era.y significantly lowers Fb!c, it was not as effective
as /etfor/in alone 7!.) vs. !.$ for vildagli.tin and
/etfor/in, res.ectively8 >!"!?. Co/.ared wit, vildagli.tin,
/etfor/in /onot,era.y .roduced statistically significant
reductions in weig,t 7!'@ )'& *gH . )'))!8 >!"!?.
&a,a2liptin' Saxagli.tin is a 6++0$ in,ibitor recently
a..roved for use by t,e US L6. In co/bination wit,
/etfor/in, saxagli.tin at doses of ".B, B and !) /g reduced
Fb!c by ).B@, ).%@ and ).BD9 res.ectively. Saxagli.tin
t,era.y was associated wit, a s/all reduction in weig,t,
).B to
!.B *g >!""?.
2,e c,ronic conse1uences of in,ibiting 6++0$ re/ain
un*nown at .resent. Since 6++0$, a ubi1uitous cell0
/e/brane .rotein, is ex.ressed in /any tissues including
ly/.,ocytes, concerns ,ave been raised about t,e long0ter/
effects of 6++0 $ in,ibitors on i//une function >B$,!!%?.
Aeta0analysis data derived fro/ clinical trials s,ow t,at
6++0$ in,ibitors confer an increased ris* of urinary tract
infection and naso.,aryngitis. 2,e weig,t loss, or weig,t
neutrality, seen wit, various incretin agents confers
considerable .otential benefits on /etabolic and
cardiovascular .ara/eters in .eo.le wit, ty.e
" diabetes. Lurt,er/ore, t,e beneficial effects of incretins
/ay extend beyond glucose control and weig,t reduction to
include clinically significant reductions in blood .ressure and
i/.rove/ents in ot,er cardiovascular ris* factors, including
visceral adi.osity and li.id levels >@D,!!&,!"&?. 2,e
observation t,at 5-+0! rece.tor agonists /ay i/.rove li.id
.rofiles and /yocardial function in .eo.le wit, ty.e "
diabetes ,ig,lig,ts t,e need for /ore long0ter/ trials,
es.ecially given t,e increased ris* of cardiovascular
/orbidity and /ortality in t,is .o.ulation >!!B?.
Ot,er ntiobesity 2,era.eutic Strategies
+ifestyle Modification' 2,e US 6iabetes +revention +rogra/
76++8 de/onstrated t,at intensive lifestyle /anage/ent
involving weig,t reduction of (9 of baseline body weig,t,
dietary c,anges e/.,asiJing low0calorie, low0fat foods and
/oderate .,ysical activity significantly 7. )'))!8 reduced
ris* of .rogression in individuals at ris* for develo./ent
of ty.e " diabetes >%D,!"$?. In .atients wit, ty.e " diabetes
enrolled in t,e -oo* FE6 7ction for Fealt, in 6iabetes8
trial, intensive lifestyle /anage/ent vs. usual care was
associated wit, an D.%9 reduction in body weig,t at year
! co/.ared wit, a ).(9 reduction in t,e usual care co,ort.
5reater weig,t loss fro/ baseline correlated wit, a
significant
reduction in Fb!c# ).%$ vs. ).!$9 7. )'))! fro/
baseline8 >!"B?. 2,ese results, ,owever, are often difficult to
sustain, .articularly in real0world clinical settings. Weig,t
loss as a result of non0.,ar/acologic interventions is often a
te/.orary .,eno/enon, and as weig,t is regained, glycae/ic
and cardiovascular benefits associated wit, weig,t reduction
tend to di/inis, >!"%,!"(?.
*ntiobesity *2ents' Only two agents, sibutra/ine and
orlistat, are currently a..roved for long0ter/ use in t,e
treat/ent of obesityH bot, agents can be used in individuals
wit, a BAI "( wit, co/orbidities or 3&) wit,out
co/orbidities >!"D?.
Orlistat, a gastrointestinal li.ase in,ibitor, reduces weig,t
by a..roxi/ately & *g on average, i/.roves cardiovascular
ris* factors and decreases .rogression to diabetes in ,ig,0ris*
individuals >!"@?. Orlistat is available over t,e counter and
by .rescri.tion. In a $0year, double0blind, .lacebo0controlled,
rando/iJed study of &&)B Swedis, obese sub:ects, orlistat
reduced weig,t by ".( *g and decreased t,e incidence of ty.e
" diabetes by %." vs. @.)9 for .lacebo >!&)?. ttrition rates were
,ig,, averaging &&9 >!&!?. Aa:or treat/ent0related adverse
effects are gastrointestinal# fatty and oily stool, fecal
urgency and oily s.otting occurred in !B ' &)9 of
orlistat0treated sub:ects vs. " ' (9 wit, .lacebo >!"@?.
Sibutra/ine is a /onoa/ine' reu.ta*e in,ibitor
wit, weig,t loss effects associated wit, increases in
satiety >!"@?. In a /eta0analysis of eig,t .lacebo0
controlled, double0 blind, rando/iJed trials in .eo.le
wit, ty.e " diabetes, sibutra/ine .roduced statistically
significant reductions fro/ baseline in Fb!c cou.led
wit, significant decreases in body
weig,t co/.ared wit, controls 7B'B )'" vs. )'@
)'" *g
res.ectively8 >!&"?. dverse effects include inso/nia,
nausea and consti.ation >!"@?. Sibutra/ine is associated
wit, s/all increases in blood .ressure and .ulse rate in
t,ose w,o are nor/otensive, but it a..ears to reduce
blood .ressure in t,ose wit, ,y.ertension >!&&?.
Currently, a large study of cardiovascular outco/es
7t,e Sibutra/ine Cardiovascular Outco/es >SCOU2?
trial8 is underway >!"@?.
3i/onabant was a..roved in Euro.e for t,e
treat/ent of overweig,t or obese adults wit, ty.e "
diabetes >!&$? but ,as recently been wit,drawn because
of concerns about side effects, .articularly de.ression
and anxiety. It was t,e first of a new class of drugs t,at
act to su..ress a..etite by selectively in,ibiting CB0!, an
endocannabinoid rece.tor in t,e brain and adi.ose tissue.
3i/onabant treat/ent significantly decreased t,e
.revalence of /etabolic syndro/e co/.ared wit, .lacebo
in obese or overweig,t .eo.le after " years of treat/ent
>!&B?. It resulted in significantly greater reductions
fro/ baseline in body weig,t co/.ared wit, .lacebo
7B.& vs. !.$ *g8 and significantly greater reductions in
waist circu/ference, Fb!c and triglyceride concentrations
vs. .lacebo in t,ose wit, ty.e " diabetes >!&%?. Studies of all
antiobesity agents ,ave s,own ,ig, attrition rates of &) '
$)9, and t,e long0ter/ effects of t,ese agents are not
*nown >!"@?.
(ariatric &ur2ery' Since t,e benefits of weig,t loss on
/etabolic and cardiovascular .ara/eters are well *nown,
.eo.le wit, ty.e " diabetes /ay elect to .ursue /ore
invasive interventions to lose weig,t. Aore t,an !)) )))
bariatric surgery .rocedures were .erfor/ed in US in
"))& >!&(?. 2,e .rocedure ,as en:oyed co/.arable growt,
elsew,ereH a .o.ulation0based analysis in Western
ustralia, for exa/.le, re.orted t,at t,e rate of bariatric
surgeries .er !)) ))) .erson0years increased fro/ !." in
!@@D to "$." in "))$ >!&D?. 2,e two /ost co//on
.rocedures are la.arosco.ic ad:ustable banding of t,e
sto/ac, and t,e 3oux0en0; gastric by.ass. 2,e ty.e of
o.eration co//only .erfor/ed varies by countryH in US,
for exa/.le, t,e gastric by.ass .rocedure is /ore co//on
w,ilst in ustralia gastric banding is .referred.
2,ere ,ave been a nu/ber of recent studies s,owing t,at
bariatric surgery .roduces a "B9 reduction in /ortality.
In t,e Swedis, Obese Study !)0year follow u. of $)$(
obese sub:ects, t,ere were !"@ deat,s in t,e control grou.
and !)! deat,s a/ong surgery .atients >!&(?. Si/ilarly, in
a retros.ective co,ort study co/.aring !D0year deat, rates
a/ong severely obese sub:ects w,o ,ad undergone bariatric
surgery wit, /atc,ed controls, long0ter/ /ortality fro/ any
cause decreased by $)9 in t,e surgical grou. co/.ared
wit, severely obese sub:ects w,o ,ad not undergone bariatric
surgery. /ong sub:ects w,o ,ad undergone bariatric
surgery,
t,ere was a @"9 reduction in /ortality for diabetes and
B@9 reduction for coronary artery disease co/.ared wit,
controls >!&@?.
6ixon and colleagues recently re.orted "0year outco/e
results of t,e first rando/iJed, controlled clinical trial of
la.arosco.ic ad:ustable gastric banding in recently diagnosed
.eo.le wit, ty.e " diabetes. /ong t,ose w,o ,ad under0
gone bariatric surgery, (&9 ac,ieved re/ission of ty.e "
diabetes co/.ared wit, only !&9 in t,e conventional t,era.y
grou. >!$)?.
'onclusion
5iven t,e current scale of t,e ty.e " diabetes and
obesity e.ide/ics worldwide, diabetes and associated obesity
constitutes a /a:or global ,ealt, .roble/ wit, critical
i/.lications for .ublic ,ealt, .olicy.
W,ile weig,t gain is associated wit, t,e develo./ent of
ty.e " diabetes, weig,t loss can i/.rove insulin sensitivity
and 0cell function in bot, ,ealt,y individuals and in t,ose
wit, ty.e " diabetes >!"$,!$!,!$"?. Notably, a /odest weig,t
loss of only B ' (9 reduced t,e ris* of develo.ing
diabetes by u. to BD9 in large, land/ar* studies suc, as
t,e Linnis, and US 6iabetes +revention studies >!"$?. In t,e
US 6iabetes +revention +rogra/, weig,t loss was t,e
do/inant .redictor of reduced diabetes incidence. Lor every
*ilogra/ of weig,t loss, t,ere was a !%9 reduction in ris*,
ad:usted for c,anges in diet and activity >!$&?. In anot,er
study, weig,t loss of !B ' ")9 in t,e first year after ty.e "
diabetes diagnosis reversed t,e excess /ortality associated
wit, overweig,t >!$$?.
Effective interventions for weig,t /anage/ent s,ould
co//ence as soon as diabetes is diagnosed. Effective obesity
/anage/ent /ust incor.orate an integrated .rogra/ of
caloric and fat restriction in co/bination wit, increased
activity and exercise, be,aviour /odification and considering
antidiabetic t,era.y wit, a /ore favourable effect on body
weig,t. Incretin0 based t,era.ies offer considerable .ro/ise
in t,e /anage/ent of diabetes and associated obesity, and its
effects on glycae/ic control, weig,t and blood .ressure
suggest t,ey /ay be able to address t,e un/et needs
associated wit, /any conventional antidiabetic treat/ents,
including weig,t loss and reduction of cardio/etabolic ris*
factors.
Ac(nowled$e)ents
ssistance wit, /anuscri.t .re.aration was .rovided by
3ebecca 6onner and del.,iEden Fealt, Co//unications
su..orted by Novo Nordis*.
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