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PCSK9: De la ciencia a la práctica clínica, ¿qué representa para los pacientes con diabetes?
Dr. Francisco J. TinahonesJefe de Servicio de Endocrinología y Nutrición Hospitales Regional y Hospital Virgen de la Victoria.Málaga.
SUMARIO
• Diabetes y dislipemia.
• Resultados ALIROCUMAB en pacientes diabéticos.
• Resultados de alirocumab y tamaño de LDL.
• Seguridad en pacientes diabéticos
• Nuevos estudios de alirocumab en diabetes.
• Alirocumab en las nuevas guías.
SUMARIO
• Diabetes y dislipemia.
• Resultados ALIROCUMAB en pacientes diabéticos.
• Resultados de alirocumab y tamaño de LDL.
• Seguridad en pacientes diabéticos
• Nuevos estudios de alirocumab en diabetes.
• Alirocumab en las nuevas guías.
La diabetes se asocia a una importante pérdida de años de vida
Seshasai, et al. N EnglJ Med 2011;364:829–41
Mecanismos de la dislipemia aterogénica
FFA
VLDL
CETP
HDL
ECTriglicéridos
LDL pequeñas y densas
FFA: ácidos grasos libres; CETP: proteína transferidora de ésteres de colesterol; EC: ésteres de colesterol.
El control intensivo del colesterol en diabéticos disminuye un 35% los eventos cardiovasculares sufridos en 10 años
Wong ND, et al. Am J Cardiol. 2014;113:1356-61.
Cumplimiento de los objetivos de c-LDL en pacientes diabéticos (US NHANES)
US NHANES 1999-2010 (n = 2.403)• En el año 2009-2010, solo alrededor de la mitad de pacientes diabéticos alcanzan el objetivo de
c-LDL < 100 mg/dL.• La tasa de cumplimiento del objetivo de c-LDL fue más alta en los pacientes con ECV.
Wong ND, et al. Diab Vas Dis Res. 2013;10:505-13.
SUMARIO
• Diabetes y dislipemia.
• Resultados ALIROCUMAB en pacientes diabéticos.• Resultados de alirocumab y tamaño de LDL.
• Seguridad en pacientes diabéticos.
• Nuevos estudios de alirocumab en diabetes.
• Alirocumab en las nuevas guías.
D5 ESTUDIOS FASE IIIPacientes con Diabetes y sin Diabetes
• 3499 individuals with inadequately controlled hypercholesterolemia receiving stable
maximally tolerated statin ± other LLT 1051 with DM, 2448 without DM
Alirocumab 150 mg Q2W versus placebo
COMBO I, 52 weeks Alirocumab: n=94 of 209 with DM Placebo: n=42 of 107 with DM
FH I, 78 weeks
Alirocumab: n=31 of 323 with DMPlacebo: n=25 of 163 with DM
FH II, 78 weeks
Alirocumab: n=7 of 167 with DM Placebo: n=4 of 82 with DM
LONG TERM, 78 weeks
Alirocumab: n=555 of 1553 with DMPlacebo: n=278 of 788 with DM
HIGH FH, 78 weeks
Alirocumab: n=9 of 72 with DMPlacebo: n=6 of 35 with DM
Alirocumab 75 mg Q2W† versus placebo
Ginsberg HN, et al. AHA 2015.
% de Cambio de LDL-C LD
L-C
LS
mea
n (S
E) %
cha
nge
from
bas
elin
e
†75 mg Q2W increased to 150 mg Q2W at Week 12 if LDL-C levels at Week 8 were ≥70 mg/dL (1.81 mmol/L). ALI, alirocumab; mITT, modified intent-to-treat; PBO, placebo.
0 4 8 12 16 24 36 52 0 4 8 12 16 24 36 52
Placebo with DMAlirocumab with DM
Placebo without DMAlirocumab without DM
25.6% with and 36.5% without DMhad dose increase at Week 12
Alirocumab 150 mg Q2W
Week Week
Ginsberg HN, et al. AHA 2015.
Mea
n (S
E) %
cha
nge
from
bas
elin
e to
W
eek
24
†75 mg Q2W increased to 150 mg Q2W at Week 12 if LDL-C levels at Week 8 were ≥70 mg/dL (1.81 mmol/L).Non-HDL-C LS mean; Lp(a), adjusted mean.
DM DMNo DM No DM
Alirocumab 150 mg Q2W Alirocumab 75/150 mg Q2W† Placebo
AlirocumabN
on-H
DL-
CLp
(a)
No-HDL-C y Lp(a) Porcentaje de cambio con respecto a la basal
Ginsberg HN, et al. AHA 2015.
HDL-C y Triglicéridos Porcentaje de cambio con respecto a la basal
Mea
n (S
E) %
cha
nge
from
bas
elin
e to
W
eek
24
†75 mg Q2W increased to 150 mg Q2W at Week 12 if LDL-C levels at Week 8 were ≥70 mg/dL (1.81 mmol/L).HDL-C LS mean; TG adjusted mean.
DM DMNo DM No DM
Alirocumab 150 mg Q2W
Alirocumab 75/150 mg Q2W † Placebo
AlirocumabH
DL-
CTG
Ginsberg HN, et al. AHA 2015.
Eficacia y seguridad de alirocumab en pacientes con diabetes: análisis del ODYSSEY LONG TERM Study
Helen M. Colhoun,1 Henry N. Ginsberg,2 Lawrence A. Leiter,3 Umesh Chaudhari,4 Christelle Lorenzato,5 Robert Pordy,6 Jennifer G. Robinson7
1University of Dundee, Dundee, UK; 2Columbia University, New York, NY, USA; 3University of Toronto, Toronto, ON, Canada; 4Sanofi, Bridgewater, NY, USA; 5Sanofi, Chilly-Mazarin, France; 6Regeneron
Pharmaceuticals, Tarrytown, NY, USA; 7University of Iowa, Iowa City, IA, USA
Presentado en el 51st EASD Annual Meeting, Stockholm, Suecia, 14-18 de septiembre de 2015.
Diseño del estudioODYSSEY LONG TERM: DIABETES SUB-ANALYSIS
HeFH or high CV risk patients*
(n=2341, 838 with DM) on maximally tolerated statin ± other LLT and
LDL-C ≥70 mg/dL
Double-blind treatment (18 months)
n=1553
n=788R
Follow-up(8 weeks)
Alirocumab 150 mg Q2W SC(single 1 mL injection using prefilled syringe for self-administration)
Placebo Q2W SC
AssessmentsW0
W4W8
W12W16
W24W36
W52
Primary efficacy endpoint% change in LDL-C from baseline at Week 24, ITT analysis (all
LDL-C values whether on or off treatment)
W64 W78
*HbA1c >10% was an exclusion criterion.Q2W, every 2 weeks; R, randomisation; SC, subcutaneous; W, week.
Robinson JG, et al. N Engl J Med. 2015;372:1489-99.
Niveles de c-LDL calculado en pacientes con o sin DM (ITTm) Diseño del EstudioPacientes con Diabetes y sin Diabetes
Placebo with DM
Alirocumab with DM
Placebo without DM
Alirocumab without DMLS
mea
n (S
E) L
DL-
C le
vel,
mg/
dL
Colhoun HM, et al. EASD 2015.
Pacientes con c-LDL < 70 mg/dLen la semana 24 según estatus DM (ITT)
*Nominal p-values, not adjusted for multiplicity.Combined estimate for proportion of patients was obtained by analysed using multiple imputation followed by logistic regression.
Colhoun HM, et al. EASD 2015.
Análisis de seguridad (LONG TERM)MACE Adjudicados por DM Status
Colhoun HM, et al. EASD 2015.
SUMARIO
• Diabetes y dislipemia.
• Resultados ODYSSEY LONG TERM Study en pacientes diabéticos.
• Resultados de alirocumab y tamaño de LDL.• Seguridad en pacientes diabéticos.
• Nuevos estudios de alirocumab en diabetes.
• Alirocumab en las nuevas guías.
Los niveles de PCSK9 se asocian a los niveles de LDL pequeñas y densas
Zhang Y, et al. Nutr Metab Cardiovasc Dis. 2015;25:426-33.
Alirocumab y sus efectos sobre el tamaño de las lipoproteínas
Krauss RM, et al. AHA 2014.
SUMARIO
• Diabetes y dislipemia.
• Resultados ODYSSEY LONG TERM Study en pacientes diabéticos.
• Resultados de alirocumab y tamaño de LDL.
• Seguridad en pacientes diabéticos.• Nuevos estudios de alirocumab en diabetes.
• Alirocumab en las nuevas guías.
Resultados de seguridad de interés y TEAE en ≥ 5% de los pacientes en cualquier grupo†
Colhoun HM, et al. EASD 2015.
DIABETES SEGURIDADEN DIABETES
23
CAMBIOS EN EL CONTROL GLUCEMICO
APARICION DE NUEVOS CASO DE DIABETES
Cambios en HbA1c durante los estudios en fase III
Ginsberg HN, et al. AHA 2015.
Helen M Colhoun1, Henry N Ginsberg2, Jennifer G Robinson3, Lawrence A Leiter4, Dirk Müller-Wieland5, Robert R Henry6, Bertrand Cariou7, Marie T Baccara-Dinet8, Robert Pordy9, Laurence Merlet10, Robert H Eckel11
1University of Dundee, Dundee, UK; 2Columbia University, New York, NY, USA; 3University of Iowa, Iowa City, IA, USA; 4Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, ON, Canada; 5Asklepios Klinik St Georg, Medical Faculty of Semmelweis University, Hamburg, Germany; 6University of California San Diego School of Medicine, and Center for Metabolic Research, Veterans Affairs, San Diego Healthcare System, San Diego, CA, USA; 7Institut du Thorax, Nantes University Hospital, Nantes, France; 8Sanofi,Montpellier, France; 9Regeneron Pharmaceuticals, Tarrytown, NY, USA; 10Sanofi, Paris, France; 11University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
Effect on Glycemic Measures in Individuals without Diabetes at Baseline
Efecto en Prediabetes y Normoglucemia
CMQ, Custom Medical Dictionary for Regulatory Activities (MedDRA) Query; FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin A1
Diabetes excluded from further analysis
Pre-diabetes
Normoglycemia
Yes
Yes
No
No
− Specific terms reported in the medical history (CMQ “pre-diabetes”)
− OR baseline HbA1c ≥5.7%, − OR 2 values of FPG (at screening
and randomization)≥100 mg/dL
− Diabetes reported in the medical history (CMQ “diabetes”)
Colhoun HM, et al. AHA 2015.
Paso de Prediabetes a DiabetesPlacebo-controlled pool Ezetimibe-controlled pool
Placebo Alirocumab Ezetimibe Alirocumab
Analysis of transition from baseline pre-diabetes to new-onset diabetes (by AE or laboratory measurements)
n (%) 47 (10.4) 84 (9.3) 14 (5.5) 26 (7.2)
95% mid-p CI 7.8 to 13.4 7.5 to 11.3 3.2 to 8.9 4.9 to 10.3
Number of individuals with an event/100 patient years 7.7 6.9 7.2 8.4
95% CI 5.6 to 10.2 5.5 to 8.5 3.9 to 12.1 5.5 to 12.3
Hazard ratio versus control (95% CI) 0.90 (0.63 to 1.29) 1.10 (0.57 to 2.12)
CI, confidence interval; AE, adverse event Colhoun HM, et al. AHA 2015.
Alirocumab en pacientes con o sin DM
• ODYSSEY LONG TERM: blinded study of 2341 high CV risk patients on maximally tolerated statin with LDL-C >70 mg/dL randomised to alirocumab 150 mg or placebo SC Q2W for 78 weeks.
Fisher’s exact test and have not been adjusted for multiple testing. They are provided for descriptive purposes only; †Selection of preferred terms is based on the custom MedDRA query “diabetes,” including the High-Level Group Term “diabetes complications,” the High-Level Term “diabetes mellitus,” and the High-Level Term “carbohydrate tolerance analyses (including diabetes)” (excluding the preferred terms “blood glucose decreased” and “hyperglycemia”).
Robinson JG et al. N Eng J Med. 2015;372:1489-99.
SUMARIO
• Diabetes y dislipemia.
• Resultados ODYSSEY LONG TERM Study en pacientes diabéticos.
• Resultados de alirocumab y tamaño de LDL.
• Seguridad en pacientes diabéticos.
• Nuevos estudios de alirocumab en diabetes.
• Alirocumab en las nuevas guías.
Nuevos estudios de alirocumab en diabetes
Efficacy and safety of alirocumab versus placebo on top of maximally tolerated lipid lowering therapy in patients with hypercholesterolemia
who have type 1 or type 2 diabetes and are treated with insulin (ODYSSEY DM-Insulin)
Efficacy and safety of alirocumab versus usual care on top of maximally tolerated statin therapy in patients with type 2 diabetes and mixed
dyslipidemia (ODYSSEY DM-Dyslipidemia)ClinicalTrials.gov identifier: NCT02642159
ClinicalTrials.gov identifier: NCT02585778
Efficacy and safety of alirocumab versus usual care on top of maximally tolerated statin therapy in patients with type 2 diabetes and mixed dyslipidemia
(ODYSSEY DM-Dyslipidemia)
ClinicalTrials.gov identifier: NCT02642159
Objetivos del estudio
Primary objective
Secondary objective
• To demonstrate the reduction of LDL-C/non-HDL-C by alirocumab in comparison with usual care after 24 weeks of treatment in patients with diabetes and mixed dyslipidemia not adequately controlled with maximally tolerated statin therapy.
• To evaluate the effect of alirocumab on Apo B, TC, Lp(a), HDL-C, TG, Apo A-1, Apo C III.
• To evaluate the safety and tolerability of alirocumab.
ClinicalTrials.gov identifier: NCT02642159
Efficacy and safety of alirocumab versus placebo on top of maximally tolerated lipid
lowering therapy in patients with hypercholesterolemia who have type 1 or type 2
diabetes and are treated with insulin (ODYSSEY DM - Insulin)
ClinicalTrials.gov identifier: NCT02585778
Objetivos
Primary objective
Secondary objective
• To demonstrate the superiority of alirocumab in comparison with placebo in the reduction of calculated low-density lipoprotein cholesterol (LDL-C) in patients with diabetes treated with insulin and with hypercholesterolemia at high cardiovascular risk not adequately controlled on maximally tolerated LDL-C lowering therapy.
• To evaluate the safety and tolerability of alirocumab in patients with diabetes treated with insulin.
• To demonstrate that alirocumab is superior in comparison to placebo in its effects on other lipid parameters (ie, measured LDL-C, non-high-density lipoprotein cholesterol [non-HDL-C], apolipoprotein B [Apo B], total cholesterol [TC], lipoprotein a [Lp(a)]), high density lipoprotein cholesterol (HDL-C), triglyceride (TG) levels, triglyceride rich lipoproteins (TGRL), apolipoprotein A-1 (Apo A-1), apolipoprotein CIII (Apo C-III), and LDL particle number and size).
ClinicalTrials.gov identifier: NCT02585778
SUMARIO• Diabetes y dislipemia.
• Resultados ODYSSEY LONG TERM Study en pacientes diabéticos.
• Resultados de alirocumab y tamaño de LDL.
• Seguridad en pacientes diabéticos.
• Nuevos estudios de alirocumab en diabetes.
• Alirocumab en las nuevas guías.
Guías de la ADA 2016
• Statins and PCSK9 Inhibitors • Placebo-controlled trials evaluating the addition of the novel PCSK9 inhibitors, evolocumab and alirocumab, to
maximally tolerated doses of statin therapy in participants who were at high risk for ASCVD demonstrated an average reduction in LDL cholesterol ranging from 36% to 59%. These agents may therefore be considered as adjunctive therapy for patients with diabetes at high risk for ASCVD events who require additional lowering of LDL cholesterol or who require but are intolerant to high-intensity statin therapy. It is important to note that the effects of this novel class of agents on ASCVD outcomes are unknown as phase 4 studies are currently under way.
Guías de la AACE/ACE 2016
Garber AJ, et al. Endocr Pract. 2016;22:84-113.
Guías de la AACE/ACE 2016
Garber AJ, et al. Endocr Pract. 2016;22:84-113.
GRACIAS
SAES.ALI.16.06.0170 – Junio 2016