Ponencia en Congreso ASCARICA (Tenerife 23 feb 18) sobre Riesgo CV DM2 y GLP1. Aplicaciones clínicas practicas derivadas de los estudios de seguridad CV de los fármacos para la DM2
13. ME ENGORDA EL AGUA
“TENGO UN POCO DE AZUCAR”
“Pero de la buena”
FUMO LO NORMAL
NO SOY HIPERTENSO, TOMO
2 PASTILLAS PA LA TENSION
NO PUEDO TENER
COLESTEROL ME TOMO
DANACOL DIARIO
@cristob.morales
DE LA DIA-BESIDAD AL …OBESI-CARDIO-BETICO
23. Pancreas
Liver
Adapted from Baggio & Drucker. Gastroenterol 2007;132;2131–57
Intestine
Glucose production
Glucose-dependent
insulin secretion
Insulin synthesis
Glucose-dependent glucagon
secretion
β
β
β
α
α
GLP-1
L-cells secrete GLP-1
→ degraded by DPP-4
EFECTO GLP1 EN CONTROL GLUCEMICO
victoryThe
@Cristob_Morales
24. GLP-1: Beyond glucose metabolism
Brain
Neuroprotection
Neurogenesis
Memory
Heart
Myocardial contractility
Heart rate
Myocardial glucose
uptake
Ischaemia-induced
myocardial damage
Kidney
Natriuresis
GLP-1
DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1
Adapted from Meier JJ et al. Nat Rev Endocrinol 2012;8:728–42
His Ala Thr Thr SerPheGlu Gly Asp
Val
Ser
SerTyrLeuGluGlyAlaAla GlnLys
Phe
Glu
Ile Ala Trp Leu GlyVal Gly ArgLys
Fat cells
Glucose uptake
Lipolysis
Liver
Glycogen storage
Skeletal muscle
Glucose uptake
Blood vessel
Endothelium-dependent
vasodilation
Pancreas
New β-cell formation
β-cell apoptosis
Insulin biosynthesis
DPP-4
GI tract
Motility
@Cristob_Morales
25. Incretins
Liraglutide clinical trial programme overview
BID, twice daily; H2H, head-to-head; Met, metformin; OAD, oral antidiabetes drug; SU, sulphonylurea; TZD, thiazolidinedione
Source: ClinicalTrials.gov
Drug naive Special populations
LIRA-RENAL™ (n=279)
vs placebo
Add-on to SOC
≥1 OAD
Insulin
combinations
LIRA-DETEMIR (n=323)
vs liraglutide plus IDet
Add-on to met
LIRA-ADD2BASAL™ (n=446)
vs placebo
Add-on to basal insulin ± met
ellipse™ (paediatric; n=150)
vs placebo
Add-on to met ± basal insulin
LIRA-LIXI™ (n=404)
vs lixisenatide
Add-on to met
LIRA-SWITCH™ (n=407)
vs sitagliptin
Add-on to met, switch from
sitagliptin
LIRA-Ramadan™ (n=320)
vs SU
Add-on to met, switch from SU
LEAD-3 (n=746)
vs SU
LEAD-4 (n=533)
vs placebo
Add-on to met + TZD
LEAD-2 (n=1091)
vs SU or placebo
Add-on to met
LEAD-1 (n=1041)
vs TZD or placebo
Add-on to SU
LEAD-5 (n=581)
vs insulin glargine or placebo
Add-on to met + SU
LEAD-6 (n=564)
vs exenatide BID
Add-on to met ± SU
LIRA-DPP-4 (n=665)
vs sitagliptin
Add-on to met
Completed
Ongoing
LIRA-DPP-4 CHINA™ (n=366)
vs sitagliptin
Add-on to met
LEADER (cardiovascular outcomes trial) SOC plus liraglutide 0.6 mg–1.8 mg vs SOC plus placebo (n=9,340)
Drug-naïve or add-on to ≥1 OAD or add-on to basal or premix insulin (alone or in combination with OADs)
LIRA-1.8 mg JAPAN (n=470)
vs Liraglutide 0.9 mg
Monotherapy
LIRA-PRIME (N=1994)
vs OADs
Add-on to met
26.
27. HbA1c effects in the LEAD programme
Significant *vs comparator; change in HbA1c from baseline for overall population (LEAD-4,-5, -6); add-on to diet and exercise failure (LEAD-3); add-on to previous OAD
monotherapy (LEAD-2,-1; LIRA-DPP-4).
BID, twice daily; HbA1c, glycosylated haemoglobin; MET, metformin; Sita, sitagliptin; OAD, oral anti-diabetic drug; SU, sulphonylurea; TZD, thiazolidinedione
Marre M et al. Diabet Med 2009;26;268–278 (LEAD-1); Nauck M et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber A et al. Lancet 2009;373:473–481
(LEAD-3); Zinman B et al. Diabetes Care 2009;32:1224–1230 (LEAD-4); Russell-Jones D et al. Diabetologia 2009;52:2046–2055 (LEAD-5); Buse JB et al. Lancet
2009;374:39–47 (LEAD-6); Pratley RE et al. Lancet 2010:375;1447–1456 (LIRA-DPP-4)
Baseline
HbA1c (%) 8.3 8.18.68.58.38.68.58.2 8.28.6 8.6 8.48.4 8.4 8.2 8.1
-1.2
-1.6
-0.9
-1.3 -1.3
-1.1
-1.4
-1.5
-0.8
-1.5 -1.5
-0.5
-1.3
-1.1 -1.1
-0.8
-1.2
-1.5
-0.9
-2
-1.5
-1
-0.5
0
SU add-on
LEAD-1
MET add-on
LEAD-2
MET + TZD
add-on
LEAD-4
MET + SU
add-on
LEAD-5
Monotherapy
LEAD-3
MET ± SU
add-on
LEAD-6
MET add-on
LIRA–DPP-4
8.4 8.4 8.5
Liraglutide 1.8 mgLiraglutide 1.2 mg Glimepiride
Rosiglitazone Glargine Placebo
Exenatide BID
Sitagliptin
*
*
*
* * *
*
*
*
*
ΔHbA1c(%)
28. Weight reduction with lira in people with T2DM
*Significant vs comparator
BID, twice daily; Met, metformin; SU, sulphonylurea; TZD, thiazolidinedione
Marre M et al. Diabet Med 2009;26:268–278 (LEAD-1); Nauck M et al. Diabetes Care 2009;32:84–90 (LEAD-2); Garber A et al. Lancet
2009;373:473–481 (LEAD-3); Zinman B et al. Diabetes Care 2009;32:1224–1230 (LEAD-4); Russell-Jones D et al. Diabetologia 2009;52:2046–
2055 (LEAD-5); Buse JB et al. Lancet 2009;374:39–47 (LEAD-6); Pratley RE et al. Lancet 2010;375:1447–56 (LIRA-DPP-4)
-2.1
-2.5
1.1
-2.6 -2.8
1.0
0.3
-0.2
2.1
-1.0
-2.0
0.6
-1.8
1.6
-3.2
-2.9 -2.9
-3.4
-1.0
-4
-3
-2
-1
0
1
2
3
SU add-on
LEAD-1
MET add-on
LEAD-2
MET + TZD
add-on
LEAD-4
MET + SU
add-on
LEAD-5
Monotherapy
LEAD-3
MET ± SU
add-on
LEAD-6
MET add-on
LIRA–DPP-4
Liraglutide 1.8 mgLiraglutide 1.2 mg Glimepiride
Rosiglitazone Glargine Placebo
Exenatide BID
Sitagliptin
*
* * *
*
*
*
* *
*
*
Changeinweight(kg)
29. 134
133
132
131
130
129
128
127
126
LeastsquaresmeansSBP(mmHg)
Liraglutide 1.2 mg
Liraglutide 1.8 mg
Placebo
0 2 4 8 12 14 16 18 20 22 24 26
Weeks
6 10
Liraglutide reduced systolic blood pressure
in LEAD 1–6
SBP, systolic blood pressure; ITT, intent-to-treat
Adapted from Fonseca VA et al. J Diabetes Complications 2014;28:399–405
Data are last observation
carried forward for the ITT
population and expressed as
least squares ± confidence
intervals
Mean SBP reductions after 26
weeks were 2.7 [0.8] mmHg
with liraglutide 1.2 mg, 2.9
[0.7 mmHg] with liraglutide
1.8 mg and 0.5 [0.9] mmHg
with placebo
30. Improvements in cardiovascular risk biomarkers
with liraglutide from the LEAD programme
LEAD 1–6: meta-analysis
*p<0.05; **p<0.01; ***p<0.0001; all vs baseline; † is used instead of * to indicate a significant increase from baseline
BNP, brain natriuretic peptide; hsCRP, high-sensitivity C-reactive protein; PAI-1, plasminogen activator inhibitor-1
Fonseca VA et al. International Diabetes Federation 21st World Diabetes Congress, 4–8 December 2011, Dubai, UAE
PAI-1 BNP hsCRP
***
***
***
**
†††
†
31. Liraglutide effect on fasting lipid levels
LEAD 1–6: meta-analysis
*p<0.05; **p<0.01; ***p<0.0001; all vs baseline; † is used instead of * to indicate a significant increase from baseline
LDL-C, low-density lipoprotein cholesterol; T2DM, type 2 diabetes
Fonseca VA et al. International Diabetes Federation 21st World Diabetes Congress, 4–8 December 2011, Dubai, UAE
***
***
**
***
††
††
LDL-CTotal cholesterol Triglyceride
**
32. Events/subject-year
1.9
0.0
0.5
1.0
1.5
2.0
2.5
Liraglutide 1.2 mg Liraglutide 1.8 mg
0.5
0.4
0.6
1.21.2
0.1
1.3
0.3
0.5
0.1
0.3
Rosiglitazone
0.2
Placebo
0.0
Exenatide
Glimepiride
Glimepiride
Glargine
3.0
2.0
2.6
0.2 0.2
0.1
SU add-on
(LEAD-1)
Met add-on
(LEAD-2)
Met + TZD
add-on
(LEAD-4)
Met + SU add-
on (LEAD-5)
Monotherapy
(LEAD-3)
Met ± SU
add-on (LEAD-6)
Met add-on
(Lira vs. sita)
Sitagliptin
Rates of minor hypoglycaemia throughout the
liraglutide clinical development programme
IDet, insulin detemir; lira, liraglutide; met, metformin; sita, sitagliptin; SU, sulphonylurea; TZD, thiazolidinedione
Marre M et al. Diabetic Med 2009;26;268–278 (LEAD-1); Nauck M et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber A et al. Lancet
2009;373:473–481 (LEAD-3); Zinman B et al. Diabetes Care 2009;32:1224–1230 (LEAD-4); Russell-Jones D et al. Diabetologia 2009;52:2046–
2055 (LEAD-5); Buse JB et al. Lancet 2009;374:39–47 (LEAD-6); Pratley RE et al. Lancet 2010;375:1447–1456 (LIRA-DPP-4); DeVries JH et al.
Diabetes Care 2012;35:1446–1454 (IDet add-on to Lira)
0.0
0.3
0.1
Met add-on
(IDet add-on
to Lira)
Lira1.8(control)
Lira1.8+IDet
Lira1.8(observational)
33. Nausea with liraglutide is generally transient
Garber A et al. Diabetes Obes Metab 2011;13:348–56 (LEAD-3 2-year extension); Novo Nordisk, data on file. www.novonordisk-trials.com.
Accessed March 2016
Liraglutide 1.8 mg Liraglutide 1.2 mg Glimepiride
34. Nueva escala de satisfacción del paciente con el
tratamiento y con su medico
Morales Cristobal et al (pendiente de aceptación para publicación)
39. 39
Liraglutida 3,0 mg: programa del ensayo clínico de fase IIIa
Liraglutida 3,0 mg para el tratamiento del peso:
Liraglutida 3,0 mg
n=180
Placebo
n=179
En individuos con apnea del sueño ‒ 3970
Efecto de liraglutida en
sujetos con obesidad y
AOS de moderada a
intensa
n=359
En una población obesa/prediabética ‒ 1839
Liraglutida 3,0 mg
n=2487
Placebo n=1244
Tratamiento del peso y
aparición tardía de la
diabetes
n=3731
Liraglutida 3,0 mg
n=423
Placebo
n=212
Liraglutida 1,8 mg
n=211
En población diabética ‒ 1922
Tratamiento del peso en
la diabetes tipo 2
n=846
Liraglutida 3,0 mg
n=212
Placebo
n=210
Ensayo de mantenimiento del peso ‒ 1923
Prevención de la
recuperación del peso
n=422
IMC, índice de masa corporal; AOS, apnea obstructiva del sueño; SCALE, Saciedad y adiposidad clínica - Evidencias de liraglutida en personas diabéticas y no
diabéticas
Liraglutida 1,8 mg no está aprobado para el control del peso
40. 40
6,2 %
Liraglutida 3,0 mg: resumen de la eficacia – reducción de peso
2,6 %
8,0 %
SCALE Obesidad y prediabetes1
56 semanas; n=3731
63,2 27,1
1,6 %
5,7 %
SCALE Apnea del sueño4
32 semanas; n=359
46,3 18,5
Liraglutida 3,0 mg Placebo
Reducción de peso al final del ensayo
% de sujetos que logran una reducción de peso ≥5 %
2,0 %
6,0 %
SCALE Diabetes3
56 semanas; n=846
49,9 13,8
0,2 %
6,2
%
SCALE Mantenimiento2
12 semanas de preinclusión,
56 semanas; n=422
50,5 21,8
Los datos corresponden a las medias observadas; LOCF al final del ensayo.
LOCF, imputación de la última observación realizada;SCALE, Saciedad y adiposidad clínica - Evidencias de liraglutida en personas diabéticas y no diabéticas
Bibliografía: 1. Pi-Sunyer X et al. N Engl J Med 2015; 373:11–22. 2. Wadden TA et al. Int J Obes (Lond) 2013; 37:1443–51. 3. Davies MJ et al. JAMA 2015;
314:687–99.
4. Blackman A et al. Int J Obes 2016; doi: 10.1038/ijo.2016.52 [Publicación en línea previa a la publicación impresa].
41. INTRO: DIABESIDAD
QUE HA SUPUESTO GLP1 EN DM2
LEADER:
ESTUDIO DE SEGURIDAD CV LIRA
GLP1 EN MI PRACTICA CLINICA
@Cristob_Morales
46. PRIMARY OUTCOME: MACE-3
HR 0.86
(95.02% CI 0.74, 0.99)
p=0.0382*
Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio.
* Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)
-14%
47. EMPA-REG OUTCOME®
Una nueva perspectiva
For internal use only. Strictly confidential. Do not copy or distribute externally.
*Defined as new onset of macroalbuminuria, doubling of serum creatinine (accompanied by eGFR [MDRD]
≤45 ml/min/1.73m2), initiation of renal replacement therapy or death due to renal disease; 3P-MACE, 3-
point major adverse cardiovascular events
1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Wanner C et al. N Engl J Med 2016 (submitted)
For internal use only. Strictly confidential. Do not copy or distribute externally.
↓ 3P-MACE1
14%
↓ CV death1
38%
↓ All-cause mortality1
32%
↓New or
worsening
nephropathy*,2
39%
↓ HF hospitalisations1
35%
60. Summary of efficacy results at 3 years - LEADER
• Mean change from baseline is to Month 36
BP: blood pressure; DBP: diastolic blood pressure; HbA1c: glycated hemoglobin; HDL-C: low-density lipoprotein cholesterol; LDL-C: low-density lipoprotein
cholesterol;
SBP: systolic blood pressure; TG: triglycerides; TC: total cholesterol
Marso SP et al. N Engl J Med 2016;375:311–322; Presented at ADA 2016
63. LEADER: Composite renal outcome
Macroalbuminuria, doubling of serum creatinine,* ESRD, renal death (N=605)
*And eGFR ≤45 mL/min/1.73 m2 per MDRD. The cumulative incidences were estimated with the use of the Kaplan–Meier method and the hazard ratios with the use of the Cox proportional-hazard
regression model. The data analyses are truncated at 54 months because less than 10% of the patients had an observation time beyond 54 months
CI, confidence interval; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, hazard ratio; MDRD, modification of diet in renal disease
Mann JFE et al. N Engl J Med 2017;377:839–848
0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4
0
2
4
6
8
1 0
T im e s in c e ra n d o m is a tio n (m o n th s )
Subjectswithevent(%)
Liraglutide
Placebo
Patients with an event (%)
HR: 0.78
95% CI (0.67 ; 0.92)
p=0.003
No. at risk
Liraglutide
Placebo
4668
4672
4635
4643
4561
4540
4492
4428
4400
4316
4304
4196
4210
4094
4114
3990
1632
1613
454
433
Time since randomisation (months)
-22 %
64. New onset of persistent macroalbuminuria
Full analysis set. EAC-confirmed index events from randomisation to follow-up. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use
of the Cox proportional-hazards regression model. The data analyses are truncated at 54 months because less than 10% of the patients had an observation time beyond 54 months. Macroalbuminuria
was defined as urine albumin >300 mg/g creatinine
CI, confidence interval; EAC, event adjudication committee; HR, hazard ratio
Mann JFE et al. N Engl J Med 2017;377:839–848
Patients with an event (%)
0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4
0
2
4
6
8
1 0
No. at risk
Liraglutide
Placebo
4668
4672
4638
4646
4570
4551
4508
4455
4437
4359
4353
4252
4268
4162
4182
4073
1662
1642
461
442
Patients with an event (%)
Time since randomisation (months)
Liraglutide
Placebo
HR: 0.74
95% CI (0.60 ; 0.91)
p=0.004
-26 %
68. The proportions of patients with DFU events during the trial were 3.8% in the
liraglutide group (n=176) and 4.1% in the placebo group (n=191)
Cumulative incidence plot of time to first DFU event among all patients in
the LEADER trial
Aalen-Johansen plot, with death as a competing risk factor. This figure includes data from the first DFU events in 176 liraglutide-treated and 191 placebo-treated patients. HR estimated using Cox
proportional hazards model with treatment as factor
CI, confidence interval; DFU, diabetic foot ulcer; HR, hazard ratio
Dhatariya et al. 53rd Annual meeting of the European Association for the Study of Diabetes 2017; Poster 1005.
HR 0.92
(95% CI 0.75 ; 1.13)
p=0.41
0.00
0.02
0.04
0.06
0.08
0 4812 603624
Cumulative incidence
Time since randomisation (months)
Liraglutide
Placebo
110. Tengo DIABETES desde
hace 3 años, hace 1 mes
me cambiaron las
pastillas porque la tenia
muy alta
Me encanta comer
Trabajo de abogado con
mucho stress
Los Triglicéridos por las
nubes
JOSÉ
48 años
DM2 de 3 años de evolución.
Tras MET+DPP4
A1c:9,7% IMC:41,8 PA_ 159 /76
111.
112. DATOS INICIALES DATOS POST-INTERVENCIÓN
A1C (%) 9,7% 5,7%
PESO (Kg) / IMC (Kg/m2) 124,5kg IMC_41,8 117,9Kg
PA MMHG 159/76 138/90
COLESTEROL mg/dL / TOTAL/HDL/LDL LDL:41 HDL:25 LDL: 76 HDL:28
TRIGLICERIDOS mg/dL 1228 156
CREATININA mg/dL ? 1,04
ALBUMINURIA mcg/mg ? ?
FILTRADO GLOMERULAR ESTIMADO mL/min/
1,73m2
? 81
TABACO NO NO
OTROS DE INTERÉS GRAN STRESS
TRATAMIENTO ANTIDIABÉTICO MET+VILDA MET+LIRA