P ima y Ca e Diabe es 17 (2023) 366–372
A ailable online 23 May 2023
1751-9918/© 2023 The Au ho s. Published by Else ie L d on behal o P ima y Ca e Diabe es Eu ope. This is an open access a icle unde he CC BY license
(h p://c ea i ecommons.o g/licenses/by/4.0/).
Di e ences in weigh loss and sa e y be ween he glucagon-like pep ide-1
ecep o agonis s: A non- andomized mul icen e s udy om he
i a ion phase
Jos´
e Seijas-Amigo
a
,
b
,
c
,
d
,
*
, ´
Angel Salgado-Ba ei a
e
,
,
g
, Rosana Cas elo-Dominguez
h
,
Ma ía Te esa P´
e ez-´
Al a ez
i
, Bel´
en Ponce-Pi˜
n´
on
j
, Ma l´
en Fe n´
andez-Sil a
k
,
Ma a Rod íguez-Ba ei o
l
, Me cedes Pe ei a-Pía
m
, Jose Manuel Iglesias-Mo eno
n
,
Ma Gago-Ga cía
o
, Raquel Mon ´
ans-Ga cía
p
, Agus ina Fe nandez-Pe ez
q
,
Dolo es F agaGayoso
, Mon se Fe nandez-Mon eneg o
s
, Bea iz Ri ei o-Ba ciela
,
Na alia Rilla-Villa
u
, Albe o Co de o
c
,
,
w
, Mois´
es Rod íguezMa˜
ne o
a
,
c
,
Jos´
e R. Gonz´
alez-Juana ey
a
,
c
a
Ca diology Depa men . Complejo Hospi ala io Uni e sidad de San iago de Compos ela, San iago de Compos ela, Spain
b
Fundaci´
on Ins i u o de In es igaci´
on Sani a ia de San iago de Compos ela (FIDIS), Spain
c
Cen o de In es igaci´
on Biom´
edica en Red de En e medades Ca dio ascula es (CIBERCV), Mad id, Spain
d
Uni e sidade de San iago de Compos ela
e
Depa men o P e en i e Medicine and Public Heal h, Uni e si y o San iago de Compos ela, San iago de Compos ela, Spain
Heal h Resea ch Ins i u e o San iago de Compos ela (IDIS), San iago de Compos ela, Spain
g
Conso ium o Biomedical Resea ch in Epidemiology and Public Heal h (CIBER en Epidemiología y Salud PúblicaCIBERESP), Ca los III Heal h Ins i u e, Mad id, Spain
h
Cen o de Salud, Ribei a, A Co u˜
na, Spain
i
Cen o de Salud de Culle edo, A Co u˜
na, Spain
j
Cen o de Salud de Fene, A Co u˜
na, Spain
k
Cen o de Salud O Ven o illo, A Co u˜
na, Spain
l
Cen o de Salud. Vi xe Pe eg ina, Pon e ed a, Spain
m
Cen o de Salud de San Roque, Lugo, Spain
n
Cen o de Salud de Val Mi˜
no , Nig ´
an, Pon e ed a, Spain
o
Cen o de Salud de Ribadeo, Lugo, Spain
p
Cen o de Salud de Cee, A Co u˜
na, Spain
q
Cen o de Salud Vilalba, Lugo, Spain
Cen o de Salud de Sa ia, Lugo, Spain
s
Cen o de Salud de O Ca balli˜
no, Ou ense, Spain
Cen o de Salud O Temple, A Co u˜
na, Spain
u
Cen o de Salud de A iondas, As u ias, Spain
Ca diology Depa men . Hospi al Uni e si a io de San Juan, Alican e, Spain
w
Unidad de In es igaci´
on en Ca diología. Fundaci´
on pa a el Fomen o de la In es igaci´
on Sani a ia y Biom´
edica de la Comuni a Valenciana (FISABIO), Spain
ARTICLE INFO
Keywo ds:
Obesi y
Weigh change
Glucagon-like pep ide 1
Sa e y
Adhe ence
Glycemic con ol
Type 2 diabe es
ABSTRACT
In oduc ion: Obesi y inc eases he isk o ype 2 diabe es melli us and ca dio ascula disease (CVD). Weigh loss
(≥5 %) educes he isk o CVD. Glucagon-like pep ide-1 ecep o agonis s (GLP1 RA) ha e shown clinically
weigh loss. Objec i es: 1) To assess di e ences in he e icacy o weigh loss and HbA1c; 2) o e alua e he sa e y
and adhe ence du ing he i a ion phase.
Me hods: I is a mul icen e , p ospec i e, and obse a ional s udy on GLP1 RA naï e pa ien s. The p ima y end
poin was he weigh loss (≥5 %). Changes in weigh , BMI and HbA1c we e also calcula ed as co-p ima y
endpoin s. Seconda y endpoin s we e sa e y, adhe ence, and ole ance.
Resul s: Among 94 subjec s, 42.4 % ecei ed dulaglu ide, 29,3 % subcu aneous semaglu ide, 22,8 % o al sem-
aglu ide. 45 % emale and he mean age was 62. Baseline cha ac e is ics we e body weigh 99.3 kg, BMI 36.7 kg/
* Co espondence o: Hospi al Clinico de San iago de Compos ela, Ca diology Depa men , Spain.
E-mail add esses: [email p o ec ed], [email p o ec ed] (J. Seijas-Amigo).
Con en s lis s a ailable a ScienceDi ec
P ima y Ca e Diabe es
jou nal homepage: www.jou nals.else ie .com/p ima y-ca e-diabe es
h ps://doi.o g/10.1016/j.pcd.2023.05.004
Recei ed 13 Feb ua y 2023; Recei ed in e ised o m 18 Ap il 2023; Accep ed 11 May 2023
P ima y Ca e Diabe es 17 (2023) 366–372
367
m
2
and Hba1c 8.2 %. O al semaglu ide achie ed he highes educ ion: 61.1 % o pa ien s achie ing ≥5 %,
subcu aneous semaglu ide 45.8 % and dulaglu ide 40.6 %. GLP1 RA signi ican ly educed body weigh (−4.95
kg, p <0.001) and BMI (−1.86 kg/m
2
, p <0.001), wi hou signi ican di e ences be ween g oups. Gas oin-
es inal diso de s we e he mos equen ly epo ed e en s (74.5 %). 62 % o pa ien s on dulaglu ide, 25 % on
o al semaglu ide and 22 % on subcu aneous semaglu ide.
Conclusions: O al semaglu ide achie ed he highes p opo ion o pa ien s ha los ≥5 %. GLP1 RA signi ican ly
educed BMI and HbA1c. Mos o he epo ed ad e se e en s we e gas oin es inal diso de s and hey we e
epo ed in a majo equency in he dulaglu ide g oup. O al semaglu ide would be a easonable swi ch in case o
u u e sho ages.
1. In oduc ion
1.1. Backg ound
The In e na ional Diabe es Fede a ion Diabe es A las es ima es ha 510
million people ha e diabe es a ound he wo ld in 2021, 91 % o whom
ha e ype 2 diabe es melli us (T2DM) [1]. The p esence o diabe es
nea ly doubles he isk o ca dio ascula disease (CVD) [2], and dia-
be es is also associa ed wi h o he po en ially a al condi ions, including
cance and li e- h ea ening in ec ions [3]. On he o he hand, i is es i-
ma ed ha abou 2 billion adul s p esen o e weigh and 600 million
ha e obesi y [4]. Obesi y inc eases he isk o T2DM and CVD, in pa
ela ed o gene ic and li es yle- ela ed causes [5] leading o high
heal h-ca e cos s a ibu able o obesi y ela ed diseases [6]. I is also
known ha mode a e weigh loss (5–7 % o body weigh ) imp o es he
con ol o blood glucose and educes he isk o de eloping CVD [7].
We ha e cu en ly a high a ailable numbe o d ugs o he man-
agemen o T2DM, including o al and injec able d ugs. Cu en guide-
lines om he Ame ican Diabe es Associa ion ecommend a glucagon-like
pep ide-1 ecep o agonis s (GLP1 RA) as i s line he apy in pa ien s
wi h T2DM and high ca dio ascula isk o es ablished CVD. They also
ecommend s a ing p io o insulin when an injec able d ug is necessa y
and in he o e weigh popula ion [8]. Se e al andomized ials wi h
GLP1 RA ha e showed e icacy by educing HbA1c and majo ca dio-
ascula e en s (MACE) jus as hey ha e also showed clinically weigh
loss e sus placebo bu e en wi h ac i e compa a o s, including o he
GLP1 RA [9–13]. Consis en wi h his, wo ecen me a-analyses ha e
also demons a ed long- e m ca dio ascula and enal bene i s wi h
GLP1 RA [14,15]. Howe e , he e is a pauci y o clinical ial e idence
compa ing he e icacy and ad e se e ec s o he di e en GLP1 RA
ea men s wi h each o he . In addi ion, clinical ials o en exceed he
eal-wo ld e ec i eness, due in pa o lowe adhe ence and discon in-
ua ion he apy in eal-wo ld, as well as he lack o ep esen a i eness
among clinical ial pa icipan s. Fu he mo e, GLP1 RA a e known o
cause gas oin es inal e en s, and while hese e ec s may educe a e
ini ial use, hey ha e been shown o nega i ely impac adhe ence [16].
The use o GLP1 RA in Spain is limi ed o indi iduals wi h T2DM and
a body mass index o e 30 kg/m2 who canno achie e hei glycaemic
con ol goals. The demand o weekly adminis a ion p esen a ions o
dulaglu ide and semaglu ide has ecen ly inc eased signi ican ly, ac-
coun ing o 82 % o all aGLP-1 p esc ip ions. Due o supply chain
p oblems in Eu ope, he Agencia Espa˜
nola de Medicamen os y P oduc os
Sani a ios (AEMPS) has issued ecommenda ions o he use o hese
d ugs in 2023 [17]. AEMPS ecommends p io i izing he use o hese
ea men s o pa ien s wi h T2DM, a oiding s a ing new ea men s
wi h GLP1RA un il he supply issue is esol ed. I is also ecommended
o eplace he ea men wi h one om he same he apeu ic g oup i he
d ug is una ailable.
1.2. Objec i es
Fo all hese easons, we designed a mul icen e , p ospec i e,
obse a ional s udy, aimed o: 1) To assess he ini ial di e ences in he
e icacy o weigh loss and HbA1c educ ion be ween he di e en GLP1
RA in eal wo ld; 2) o e alua e he sa e y and adhe ence du ing he
i a ion phase; and as addi ional objec i e, and as a esul o a cu en
impo an issue in he supply chain o hese d ugs, o selec he po en ial
u u e swi ches due o he AEMPS es ic ions and ecommenda ions.
2. Me hods
2.1. S udy design
This s udy is a mul icen e , p ospec i e, and obse a ional ial
including hose pa ien s ha s a ed ea men wi h GLP1 RA in ou ine
clinical p ac ice ac oss 13 p ima y ca e pha macis consul a ions ha a e
pa o he Spanish na ional heal h sys em. This p ima y analysis is
enclosed in o a la ge p o ocol (SEVERAL) al eady published [18] and
egis e ed in clinical ial.go (NCT05136287). The p o ocol was
app o ed by he e hics commi ee (CEIm) and by he AEMPS in ea ly
2022.
2.2. Se ing and popula ion
The pa icipan s we e ec ui ed om 13 heal h ins i u ions in Spain
om Feb ua y 2022 o July 2022, and hey we e ollowed o 3 mon hs.
The inclusion c i e ia we e people o e 18 yea s old wi h T2DM, BMI >
30 Kg/m
2
and a i s GLP1 RA p esc ip ion: semaglu ide, li aglu ide,
exena ide, dilaglu ide o lixisena ide. Exclusion c i e ia consis ed o he
condi ions speci ied in he echnical speci ica ions, as well as unwill-
ingness o inabili y (e.g. physical o cogni i e) o comply wi h s udy
p ocedu es. All he subjec s p o ided w i en in o med consen . In-
es iga o s we e he p ima y ca e pha macis s om he pa icipa ing
si es, and he pa icipan s we e ec ui ed once hey ecei ed he i s
au ho ized p esc ip ion.Pa ien s ecei ed GLP1 RA p esc ip ions om
hei physicians du ing no mal clinical p ac ice, and pha macis s
included hem in he homologa ion p ocess a e wa d. The inclusion o
pa ien s is o ally sepa a ed om he ini ial p esc ip ions o GLP1 RA.
2.3. End poin s
The p ima y end poin was he weigh loss achie emen , de ined as a
weigh loss ≥5 % o pa ien ´s baseline weigh [19]. Weigh was
measu ed and eco ded on baseline isi and a ollow-up (3 mon hs)
wi hin a one-week window. I no he weigh closes o he ollow-up
da e was used. We also calcula ed he change o weigh loss in kg and
he change o BMI om he baseline isi o he ollow-up (3 mon hs).
Ano he co-p ima y endpoin was he change in HbA1c (% uni ) a 3
mon hs. HbA1c was measu ed and eco ded on baseline isi and a
ollow-up (3 mon hs) wi hin a window o 3 mon hs o he baseline isi ,
i no he HbA1c closes o he ollow-up da e was used.
As a seconda y endpoin , sa e y was assessed by moni o ing ad e se
e en s epo ed by he in es iga o s on he elec onic clinical epo
o m (e-CRF). Da a collec ed a he baseline included in o ma ion on
p esc ibing physicians and pa ien demog aphics and clinical cha ac-
e is ics. Da a ela ed o sa e y ou comes we e collec ed a ollow-up
isi s (week 4, week 8 and week 12). This in o ma ion was collec ed
h ough he elec onic medical epo s (ou heal h sys em includes
J. Seijas-Amigo e al.
P ima y Ca e Diabe es 17 (2023) 366–372
368
ad e se e en s epo s om he p ima y ca e sys em o hospi al spe-
cialis s) and i was also collec ed h ough di ec in e iew calls wi h he
pa ien s.
The assessmen o adhe ence was based on he p opo ion o days
co e ed (PDC) [20]. PDC is de ined as he numbe o days co e ed by a
GLP-1 RA p esc ip ion di ided by he numbe o days du ing he mea-
su emen pe iod. Pa ien s we e classi ied as adhe en i he PDC was ≥
0.80 a hese ime poin s. Discon inua ions and change o doses, due o
ad e se e en s, we e also collec ed by he in es iga o s h ough he
p e iously desc ibed me hods.
2.4. S a is ical analysis
A desc ip i e analysis exp essing he con inuous a iables in mean
and s anda d de ia ion (SD) and quali a i e a iables in absolu e and
ela i e equencies we e pe o med.
To e alua e di e ences in weigh , BMIand HbA1c educ ion be ween
baseline and ollow-up we used S uden ´s es o pai ed samples, and o
Table 1
Demog aphic and baseline cha ac e is ics.
All GLP1 (n =94) GLP1 RA (n)
s.c. semaglu ide [40] o al semaglu ide
[28]
dulaglu ide
[21]
O he
[5]
Sex (male); n(%) 51 (55.4) 16 (59.3) 13 (61.9) 20 (51.3) 2 (40.0)
Yea s; mean (SD) 61.9 (10.9) 62.0 (10.6) 62.3 (10.2) 61.4 (11.8) 63.8 (11.6)
Medical his o y; n (%)
Diabe ic neu opa hy 5 (5.4) 0 (0.0) 1 (4.8) 3 (7.7) 1 (20.0)
Diabe ic e inopa hy 7 (7.6) 2 (7.4) 3 (14.3) 2 (5.1) 0 (0.0)
Bilia y disease 8 (8.7) 0 (0.0) 2 (9.5) 6 (15.4) 0 (0.0)
Panc ea i is 2 (2.2) 1 (3.7) 0 (0.0) 1 (2.6) 0 (0.0)
Familia hy oids 10 (11.0) 2 (7.4) 2 (9.5) 4 (10.5) 2 (40.0)
Hype ension 71 (77.2) 24 (88.9) 16 (76.2) 28 (71.8) 3 (60.0)
Dyslipidemia 73 (79.3) 22 (81.5) 16 (76.2) 30 (76.9) 5 (100.0)
ACS 19 (20.9) 8 (30.8) 6 (28.6) 4 (10.3) 1 (20.0)
S oke 6 (6.5) 1 (3.7) 1 (4.8) 3 (7.7) 1 (20.0)
HF 12 (13.0) 6 (22.2) 3 (14.3) 3 (7.7) 0 (0.0)
OSAHS 16 (17.4) 3 (11.1) 5 (23.8) 7 (17.9) 1 (20.0)
As hma o COPD 13 (14.1) 2 (7.4) 4 (19.0) 5 (12.8) 2 (40.0)
*s.c.: subcu aneous. ACS: Acu e Co ona y Synd ome. HF: Hea Failu e. OSAHS: Obs uc i e Sleep Apnea Hypopnea Synd ome. COPD: Ch onic Obs uc i e Pulmona y
Disease.
Table 2
P ima y endpoin : change in body weigh . Change in HbA1c.
To al Medica ion p- alue
s.c. semaglu ide o al semaglu ide dulaglu ide O he
Weigh Loss ≥5%;
n (%)
37/77 (48.1%) 11/24 (45.8%) 11/18 (61.1%) 13/32 (40.6%) 2/3 (66.7%) 0.494
Body Weigh Change (-kg); Mean (95%CI) -4.9 (−6.2; −3.6) -4.7 (−7.5; −1.9) -4.9 (−7.9; −1.9) -5.0 (−6.8; −3.3) -6.1 (−22.4; 10.2) 0.982
BMI (-kg/m
2
);
Mean (95%CI)
-1.87 (−2.36; −1.37) -1.87 (−2.95; −0.81) -1.82 (−2.95; −0.69) -1.82 (−2.50; −1.15) -2.47 (−9.91; 4.97) 0.971
HbA1c (-%);
Mean (95%CI)
-1.36 (−1.76; −0.95) -0.91 (−1.41; −0.41) -1.36 (−2.46; −0.27) -1.74 (−2.46; −1.03) -1.40 (no da a) 0.383
*s.c.: subcu aneous. BMI: Body Mass Index.
Fig. 1. Tole ance and discon inua ions om GLP1 RA ea men s.
J. Seijas-Amigo e al.
P ima y Ca e Diabe es 17 (2023) 366–372
369
de ec di e ences be ween di e en GLP1 RA we ca ied ou one- ac o
analysis o a iance (ANOVA). The analyses we e pe o med wi h he
so wa e SPSS e sion 19.
As i was no easible o include he comple e es ima ed sample in he
ini ial p o ocol, s a is ical powe analysis was conduc ed using G*Powe
so wa e o de e mine he main endpoin de e mina ions. Fo compa ing
weigh , BMI, and Hba1c a ia ions be ween he ini ial and inal pe iod
o he en i e sample, he s a is ical powe was abo e 95 % o all
compa isons. Howe e , o g oup compa isons, he powe a ied om
16 % and 20 % o weigh and BMI compa isons o 83.9 % o he Hba1c
compa ison. Rega ding ad e se e en s (AEs) compa isons be ween he s.
c. semaglu ide, o al semaglu ide, and dulaglu ide g oups, he s a is ical
powe o gas ic abno mali ies was o e 80 %, while o o he abno -
mali ies, i was 7 %.
3. Resul s
3.1. S udy pa icipan s
A o al o 94 pa ien s me he inclusion c i e ia and we e included in
he s udy. Weigh measu emen s we e a ailable o 77 pa ien s a 3
mon hs. Among he 94 pa ien s ini ia ing a GLP-1 RA, 42,4 % ecei ed
dulaglu ide, 29,3 % subcu aneous semaglu ide, 22,8 % o al semaglu ide and
5,4 % o he GLP1 RA.
3.2. Demog aphics and baseline cha ac e is ics
The h ee main ea men g oups had simila demog aphics and
baseline cha ac e is ics (Table 1). Among he pa icipan s, 45 % we e
emale and he mean age was 62 yea s. The mean (SD) body weigh ,
BMI, and wais ci cum e ence we e 99.3 (19.2) kg, 36.7 (5.9) kg/m2,
and 118.6 (14.0) cm, espec i ely. A baseline, he mean (SD) Hba1c and
se um glucose we e 8.2 % (1.3) and 173.1 mg/dL (53.3), espec i ely.
The majo i y o pa ien s had hype ension and dyslipidaemia, and some
had a his o y o ACS o hea ailu e. A subse o pa ien s also had o he
T2DM complica ions o ela ed pa hologies (see Table 1).
3.3. P ima y end poin : change in body weigh
Among pa ien s who had weigh de e mina ions a 3 mon hs, nea ly
50 % o all pa ien s los ≥5 % o hei baseline weigh . O al semaglu ide
achie ed he highes educ ion wi h 61,1 % o pa ien s achie ing ≥5 %.
Subcu aneous semaglu ide 45,8 % and dulaglu ide 40,6 %. GLP1 RA
signi ican ly educed body weigh (MD −4.95 kg; CI (−6.2; −3.6) p <
0.001). The change in body weigh om baseline o mon h 3 we e −5.0
kg in he dulaglu ide g oup, −4.9 kg in he o al semaglu ide g oup and −
Fig. 2. Weigh loss ≥5% by dose o ole ance.
Fig. 3. Sa e y: ad e se e en s. Gas oin es inal e en s and o he e en s.
J. Seijas-Amigo e al.
P ima y Ca e Diabe es 17 (2023) 366–372
370
4.7 kg in he subcu aneous semaglu ide g oup, he e we e no s a is ically
signi ican di e ences be ween g oups (p =0.982). GLP1 RA signi i-
can ly educed BMI (MD −1.86 kg/m
2
; CI (−2.36; −1.37) p <0.001).
BMI was educed om baseline o ollow-up isi by −1.87 kg/m
2
in he
subcu aneous semaglu ide and by −1.82 kg/m
2
in o he bo h g oups
(dulaglu ide and o al semaglu ide), bu no s a is ically signi ican di e -
ences we e ound among he 3 ea men g oups (p =0.971). (Table 2).
3.4. Change in HbA1c
Among pa ien s who had HbA1c, and se um glucose measu ed a 3
mon hs (N =60; N =69), GLP1 RA signi ican ly educed HbA1c (MD
−1.4 %; CI (−1.76; −0.95) p <0.001) and glucose (MD −48.7 mg/dL, p
<0.001). The e we e no s a is ically signi ican di e ences be ween
g oups o bo h pa ame e s (p =0.383) (Table 2).
3.5. Seconda y end poin s: adhe ence and sa e y
All he pa ien s adhe ed o he ea men egimen, and none o hem
sco ed a PDC≤80. The o e all p opo ion o pa ien s who discon inued
GLP1 RA he apy was 4 % a 3 mon hs, whe eas 52 % o all pa ien s
eached he maximum dose a mon h 3; 24 % o all pa ien s did no
achie e he maximum goal dose objec i e due o in ole ance, bu 20 %
o he pa ien s did no i a e up o he highes dose despi e adequa e
ole ance; 55,8 % o pa ien s ha ecei ing maximum dose o GLP1RA
los ≥5 % o hei baseline weigh whe eas only 37,5 % o pa ien s ha
did no achie e he maximum dose o GLP1RA los ≥5 % o hei
baseline weigh (Fig. 1 and Fig. 2).
Rega ding he ad e se e en s (AEs), 47 e en s we e epo ed.
Gas oin es inal diso de s (nausea, dia hoea, cons ipa ion, dyspepsia,
e c.) we e he mos equen ly epo ed e en s (N =35; 74,5 %) and
occu ed in mo e pa icipan s ecei ing dulaglu ide han hose ecei ing
o al semaglu ide and subcu aneous semaglu ide (62 % s. 25 % s. 22 %).
O he mild e en s (N =11) we e epo ed in mino p opo ion (head-
ache, nauseas, o injec ion eac ion), 14 % in pa icipan s ecei ing
dulaglu ide, 10 % subcu aneous semaglu ide and 11 % o al semaglu ide. One
pa ien unde dulaglu ide p esen ed a ca dio ascula dea h. (Fig. 3).
4. Discussion
In his mul icen e p ospec i e s udy, we ound ha du ing he ini ial
i a ion phase, 3 o he GLP1 RA e alua ed we e associa ed wi h a
signi ican weigh loss al hough wi h some di e ences be ween hese
h ee d ugs. O e all, i can be said ha almos 50 % o he pa ien s
achie ed a weigh loss ≥5 %. Mo eo e , all GLP1 RA signi ican ly
educed HbA1c wi hou di e ences among g oups. Howe e , i need o
be highligh ed ha 20 % o he sample did no each he maximum dose
a mon h 3 despi e adequa e ole ance. Finally, dulaglu ide p esen ed a
signi ican ly highe a e o gas oin es inal diso de s han o al and sub-
cu aneous semaglu ide. F om ou poin o iew, hese esul s could be
ele an no only a he ime o GLP1 RA p esc ip ions bu also a he
ime o ca dio ascula e en s educ ion shown in he pi o al s udies.
Ou popula ion sha es demog aphics and baseline cha ac e is ics
wi h he main pi o al s udies wi h GLP1 RA. Hype ension was epo ed
by 77,2 % o all pa ien s, 79,3 % had dyslipidaemia, 20,9 % p e ious
acu e co ona y synd ome (ACS) and 13,0 % hea ailu e. Conside ing
he CV high isk o his popula ion, we could sugges ini ia ing hese
d ugs ea lie han hey a e being p esc ibed. Mo eo e , he pa ien s
included had a mean (SD) body weigh o 99.3 (19.2) kg, a mean (SD)
BMI 36.7 (5.9) kg/m
2
, a mean (SD) wais ci cum e ence 118.6 (14.0)
cm, a mean (SD) Hba1c 8.2 % (1.3) and a mean (SD) se um glucose
173.1 mg/dL (53.3) which shows ha we a e ini ia ing GLP1 RA in
pa ien s wi h e y ad anced obesi y and T2DM. Fo his eason, we
opine ha GLP1 RA migh be p esc ibed oo ea lie han hey a e, and
pa ien s wi h hese cha ac e is ics could bene i om an ea lie s a . On
he o he hand, only 7,6 % o all pa ien s p esen ed diabe ic e inopa hy,
8,7 % p esen ed p e ious his o y o bilia y disease, 2,2 % panc ea i is
and 11,0 % p e ious amilia hy oids disease, which shows a high
adhe ence o he summa y o p oduc cha ac e is ics.
Subcu aneous semaglu ide has been in es iga ed in he SUSTAIN ials
[9–13], which showed signi ican educ ions in HbA1c, and body weigh
compa ed o placebo and o he GLP1 RA. Subcu aneous semaglu ide
educed body weigh om −2.50 kg o −4.15 kg. O he clinical ials
ha e examined he e icacy and sa e y o o al semaglu ide in e ms o
educing HbA1c and body weigh in indi iduals wi h T2DM as epo ed
by he PIONEER s udies [21–24]. O al semaglu ide educed body weigh
om −0.53 kg o −3.18 kg. Mo eo e , 14.0 mg o al semaglu ide was
supe io o ano he GLP1 RA compa a o in educing body weigh by −
2.42 kg. The LEADER [25] was a clinical ial wi h li aglu ide whe e he
di e ence be ween li aglu ide and placebo in weigh loss was 2.3 kg.
Dulaglu ide showed changes in weigh in he AWARD-11 ial [26]. Fo
he e icacy, pa ien s whose dulaglu ide dose was inc eased om 1.5 mg
o he 3.0 mg and 4.5 mg doses had g ea e educ ions in body weigh
compa ed o hose s ayed on dulaglu ide 1.5 mg om 12 weeks, wi h
supe io weigh loss o 3.0 mg (−4.0 kg) and 4.5 mg (−4.7 kg). An
analysis o he e ec s o exena ide [27] o e 82 weeks epo ed ha
pa ien s aking exena ide in dual he apy wi h me o min expe ienced
weigh loss. Reduc ion in body weigh was p og essi e, wi h a change
om baseline o −4.4 kg a week 82. Howe e , he e is a pauci y o
clinical ial e idence compa ing he e icacy and ad e se e ec s o
di e en GLP1 RA ea men s wi h each o he . Also, al hough andom-
ized ials o GLP-1 RA ha e demons a ed clinically signi ican weigh
loss, weigh loss has no been widely cha ac e ized using eal-wo ld da a
in pa ien s naï e o GLP-1 RA he apy. A ecen s udy in pa ien s wi h
ype 2 diabe es ini ia ing GLP1 RA in he UK showed ha a mino i y o
pa ien s ini ia ing GLP1 RA achie ed ≥5 % weigh loss (34 % o all
pa ien s a mon h 12), sugges ing he eal-wo ld bene i o hese agen s
on weigh loss may be lowe han ha obse ed in clinical ials [14]. In
ou s udy, nea ly 50 % o pa ien s achie ed ≥5 %weigh loss. One o he
easons could be ha in ou egion hese p esc ip ions equi e app o al
by pha macis s and hese pa ien s ecei e close ollow-up, and as a
esul , he adhe ence and discon inua ions we e lowe han epo ed in
he abo e-men ioned s udies. On he o he hand, ou s udy had a sho e
ollow-up (3 mon hs), one o he limi a ions o he analysis. Howe e , i
we compa e ou s udy wi h he STEP s udy [28], we ound ha e en
hough bo h popula ions had simila demog aphics and baseline cha -
ac e is ics, in he STEP ial, 86 % o he pa ien s achie ed ≥5 % weigh
loss du ing he 68 weeks o ollow-up, highe han hose seen in ou
s udy despi e good adhe ence and ewe discon inua ions. One po en ial
explana ion could be ha pa icipan s o clinical ials end o be mo e
mo i a ed o comply wi h he ea men egimens assigned by he in-
es iga o s. In con as , in he pi o al clinical ials, in ou en i onmen ,
20 % o pa ien s a e no aking maximum doses despi e good ole ance,
in sha p con as wha was epo ed in STEP [28] and LEADER [25] o
ins ance, by he me e ac o being included in he ials.
A sys ema ic e iew and ne wo k me a-analysis ecen ly published
(n =27,000 pa ien s) epo ed ha semaglu ide (subcu aneous and o al)
and li aglu ide we e he mos e icacious GLP1 RA o weigh loss a 12
weeks o ollow-up [29]. These esul s a e in line wi h ou s udy. The
second ele an me a-analysis (n =7000 pa ien s) showed ha he e
we e no s a is ically signi ican di e ences be ween semaglu ide (sub-
cu aneous and o al) and li aglu ide [30], simila o ou s udy, bu his
me a-analysis p esen ed he limi a ion ha hey included e ospec i e
s udies, and hey did no epo he pe cen age o pa ien s achie ing ≥5
% weigh loss. F om ou poin o iew, because ha weigh loss be ween
5 % and 7 % o body weigh is known o imp o e me abolic con ol and
educe he isk o de eloping ca dio ascula disease [7], we used his
a iable as an endpoin. Rele an ly, o al semaglu ide had a highe p o-
po ion o pa ien s achie ing ≥5 % o weigh loss han subcu aneous
semaglu ide and dulaglu ide (61,1 % s. 45,8 % s. 40,6 % espec i ely).
Rega ding he weigh loss in kg and changes o BMI we did no ind
s a is ically signi ican di e ences be ween di e en GLP1 RA, possibly
J. Seijas-Amigo e al.
P ima y Ca e Diabe es 17 (2023) 366–372
371
due o he small sample size and a sho e ollow up. We ound a sig-
ni ican body weigh educ ion (MD −4.95 kg, p <0.001) and a sig-
ni ican BMI educ ion (MD −1.86, p <0.001), highe han hose
epo ed in he SUSTAIN [9–13] and PIONEER [21–24] ial and
me a-analysis bu lowe han in he STEP [26] ial.
The o e all educ ion in HbA1c and se um glucose a 3 mon hs we e
also s a is ically signi ican : HbA1c (MD −1.4 %, p <0.001) and glucose
(MD −48.7 mg/dL, p <0.001), and hey we e e y simila o hose in he
pi o al clinical ials and e en highe wi h o al semaglu ide. This ea ly
a ge in he glycaemic con ol could be he eason ha 20 % o he
pa ien s we e no aking maximum doses o GLP1 RA. One possible
eason could be he sa u a ion o he p ima y heal h ca e sys em, whe e
he pa ien s do no ecei e mon hly ollow-up as equi ed by he i a-
ion. Ano he po en ial eason could be ela ed o he glycaemic con ol
alone and no he deg ee o weigh loss. Impo an ly, he impo ance o
inc easing doses is shown in ou esul s: 56 % o pa ien s aking
maximum doses achie ed ≥5 % o weigh loss whe eas 37 % o pa ien s
wi h good ole ance and aking medium doses did no achie e ≥5 % o
weigh loss. Only 4 % o he pa ien s discon inued he ea men bu his
could be explained by he sho ollow-up (3 mon hs). In ou s udy, he
adhe ence o he ea men s among he emaining pa ien s anged om
80 % o 100 % acco ding o he PDC o mula [20]. This is in sha p
con as wi h p e ious obse a ional s udies ha showed an adhe ence
o 65 % [16]. Mo eo e , 24 % o he pa ien s did no each he maximum
doses due o in ole ance. High adhe ence o hese d ugs in Spain can be
explained by hei compliance wi h sani a y app o al. Pa ien s who a e
sui able o GLP1RA a e closely moni o ed, and adhe ence o ea men
is one o he p esc ip ion c i e ia. In es iga o s could ob ain da a by
e iewing elec onic medical eco ds. An en y wi h he da e and ime in
he medical eco d can be checked o de e mine when pa ien s ob ained
medica ion om pha macies.
Gas oin es inal diso de s we e he mos equen ly epo ed e en s
(74,5 %). Acco ding o ea men s, 62 % o he pa ien s ecei ing
dulaglu ide expe ienced some so o gas oin es inal ad e se e en , 25 %
o hose ecei ing o al semaglu ide and 22 % o subcu aneous semaglu ide.
O he mild e en s (N =11) we e epo ed in mino p opo ion (head-
ache, nauseas, o injec ion eac ion), 14 % in pa icipan s ecei ing
dulaglu ide, 11 % on o al semaglu ide and 10 % on subcu aneous sem-
aglu ide. These indings do no align well wi h he esul s o Kia Vosoughi
e al. [29], pe haps due o he small ollow-up, bu mo e in he di ec ion
o he REALISE-DM S udy [31] whe e au ho s epo ed a smalle num-
be o ad e se e en s. Taking in o accoun he esul s o he
REALISE-DM S udy ha indica es ha swi ching o subcu aneous sem-
aglu ide om li aglu ide o dulaglu ide is associa ed wi h u he e-
duc ions in HbA1c, weigh , and BMI in pa ien s wi h T2DM and also ha
his swi ch may help o imp o e pa ien adhe ence i he swi ch is om
daily subcu aneous GLP1 RA injec ions and based on ou esul s whe e
we ob ained a highe e icacy and sa e y wi h o al semaglu ide, a
easonable op ion could be o swi ch o o al semaglu ide.
We acknowledge ha ou s udy has se e al limi a ions. One limi a-
ion o ou s udy is ha we did no ake in o accoun o he an idiabe ic
d ugs. We minimized his bias by he Spanish unding c i e ia o GLP1
RA, which equi e he concomi an use o me o min, and we assumed
ha o he an idiabe ic d ugs did no a ec weigh loss ( he p ima y
ou come). Rega ding li es yle in e en ions, all pa ien s ecei ed die a y
and exe cise ad ice a each s udy isi . Ano he limi a ion o his s udy
was he low numbe o p esc ip ions o o he GLP1 RA (including li -
aglu ide), which we e only i e cases. Howe e , his e lec s he eali y o
a eal-wo ld s udy and shows he clinical p ac ice accu a ely. The s udy
has he inhe en limi a ions o a non andomized s udy wi h a small
numbe o pa ien s, u he mo e he ini ial calcula ion es ima ed he
inclusion o 360 pa ien s in he s udy, bu due o supply p oblems wi h
hese medica ions in ou egion, he inclusion a e was a ec ed, and we
we e only able o include 94 subjec s who me he inclusion c i e ia
du ing he s udy pe iod, u he mo e, he pa ien coun o each analysis
a ied as a esul o some indi iduals being los o ollow-up, which is an
inhe en cha ac e is ic o eal-wo ld s udies As limi a ions, due o he
s udy design whe e we ocused only on he i a ion phase, he ollow-up
is sho e han o he s udies and we analysed a small sample size,
he e o e u he in es iga ions in his di ec ion a e needed, including
new analogues wi h dual glucose-s imula ed insulino opic pep ide
agonis , i zepa ide, which showed a mean pe cen age change in weigh
a week 72 by −15.0 %, wi h 5-mg weekly doses o i zepa ide; by −
19.5 % wi h 10-mg doses; and by −20.9 % wi h 15-mg doses [32].
5. Conclusions
To ou knowledge, his s udy is one o he i s p ospec i e eal-wo ld
s udies in pa ien s wi h T2DM and obesi y who achie ed clinically sig-
ni ican weigh loss (≥5 %) besides clinically signi ican changes in
weigh (kg) and HbA1c (%). O al semaglu ide achie ed he highes p o-
po ion o pa ien s ha los ≥5 %. A small g oup o pa ien s (4 %)
discon inued he ea men , a qua e o pa ien s we e unable o i a e
doses due o ad e se e en s bu 20 % o pa ien s did no each maximum
doses despi e good ole ance, his g oup o pa ien s could bene i om
highe i a ion doses. Mos o he epo ed ad e se e en s we e
gas oin es inal diso de s and hey occu ed mo e equen ly in he
dulaglu ide g oup. O al semaglu ide would be a easonable swi ch in case
o u u e sho ages.
Au ho s a emen
All named au ho s mee he In e na ional Commi ee o Medical
Jou nal Edi o s (ICMJE) c i e ia o au ho ship o his a icle, ake e-
sponsibili y o he in eg i y o he wo k as a whole, and ha e gi en hei
app o al o his e sion o be published.
Decla a ion o Compe ing In e es
Au ho s decla e ha he e a e no con lic s o in e es ela ed o he
esul s o his s udy. Jose Seijas Amigo epo s consul ing ees om As a
Zeneca. All au ho s accep he ules o he announcemen .
Acknowledgemen s
In es iga o s ecei ed he suppo o he Fundaci´
on Ins i u o de
In es igaci´
on Sani a iade San iago de Compos ela (FIDIS) and he web
applica ion REDCap; Fa mac´
eu icos de A enci´
on P ima ia de Galicia
(FAPsGAL) and Na ional Ne wo k o BiomedicalCa dio ascula
Resea ch o Ca dio ascula Disease (CIBERCV, Cen o de In es-
igaci´
onBiom´
edica en Red de En e medades Ca dio ascula es). Bonni
Dye con ibu ed o he English w i ing assis ance.
Appendix 1
See Tables 1 and 2.
Appendix 2
See Figs. 1–3.
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