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