CONGRESO AHA 2018:

DESDE LA VISION DE UN ENDOCRINOLOGO

CHICAGO, 2018
Dr. Jorge Castillo – Internista Endocrinólogo
DIABETES TIPO 2

DISLIPIDEMIA
2078

Accepted Manuscript

2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA
Guideline on the Management of Blood Cholesterol: Executive Summary

Scott M. Grundy, MD, PhD, FAHA, Chair, Writing Committee, Neil J. Stone,
MD, FACC, FAHA, Vice Chair, Writing Committee, Alison L. Bailey, MD, FACC,
FAACVPR, Writing Committee Member, Craig Beam, CRE, Writing Committee
Member, Kim K. Birtcher, MS, PharmD, AACC, FNLA, Writing Committee Member,
Roger S. Blumenthal, MD, FACC, FAHA, FNLA, Writing Committee Member, Lynne
T. Braun, PhD, CNP, FAHA, FPCNA, FNLA, Writing Committee Member, Lynne T.
DISLIPIDEMIA
Braun, PhD, CNP, FAHA, FPCNA, FNLA, Writing Committee Member, Sarah de
Ferranti, MD, MPH, Writing Committee Member, Joseph Faiella-Tommasino, PhD,
PA-C, Writing Committee Member, Daniel E. Forman, MD, FAHA, Writing Committee
Member, Ronald Goldberg, MD, Writing Committee Member, Paul A. Heidenreich,
MD, MS, FACC, FAHA, Writing Committee Member, Mark A. Hlatky, MD, FACC,
Top 10 Take-Home Messages to Reduce Risk of Atherosclerotic
Cardiovascular Disease Through Cholesterol Management
1.
• 1. En todos los individuos, enfatice un estilo de vida
saludable para el corazón en todo el curso de la
vida. Un estilo de vida saludable reduce el riesgo
de enfermedad cardiovascular aterosclerótica
(ASCVD) en todas las edades.
• En todos los grupos de edad, la terapia de estilo de
vida es la intervención primaria para el síndrome
metabólico.
2.
• En pacientes con ASCVD clínico, se debe
reducir el colesterol de lipoproteínas de baja
densidad (LDL-C) con terapia de estatinas de
alta intensidad o terapia de estatinas de
máxima tolerancia.
• Cuanto más se reduzca el LDL-C con el
tratamiento con estatinas, mayor será la
reducción posterior del riesgo.
• Use una estatina de máxima tolerancia para
disminuir los niveles de LDL-C en ≥50%.
3. • En ASCVD de muy alto riesgo, use un umbral de LDL-C de 70
mg/dL para considerar la adición de no estatinas al tratamiento
con estatinas.
– Muy alto riesgo incluye un historial de múltiples eventos ASCVD
principales o 1 evento ASCVD principal y múltiples condiciones de
alto riesgo.
• Es razonable agregar ezetimiba al tratamiento con estatinas de
máxima tolerancia cuando el nivel de LDL-C permanece en ≥70
mg / dL.
• En pacientes con riesgo muy alto cuyo nivel de LDL-C
permanece en ≥70 mg / dL en el tratamiento con estatinas y
ezetimiba máximamente tolerado, agregar un inhibidor de
PCSK9 es razonable.
4.
• En pacientes con hipercolesterolemia primaria grave (nivel
de LDL-C ≥190 mg / dL), comenzar el tratamiento con
estatinas de alta intensidad sin calcular el riesgo de 10 años
de ASCVD.
• Si el nivel de LDL-C sigue siendo ≥100 mg / dL, es razonable
agregar ezetimibe.
• Si el nivel de LDL-C en estatinas más ezetimibe permanece
≥100 mg / dL y el paciente tiene múltiples factores que
aumentan el riesgo subsiguiente de eventos de ASCVD, se
puede considerar un inhibidor de PCSK9
5.
• En pacientes de 40 a 75 años de edad con
diabetes mellitus y LDL-C ≥70 mg / dL, iniciar el
tratamiento con estatinas de intensidad
moderada sin calcular el riesgo de ASCVD a 10
años.
• En pacientes con diabetes mellitus con mayor
riesgo, especialmente en aquellos con múltiples
factores de riesgo o de 50 a 75 años de edad, es
razonable usar una estatina de alta intensidad
para reducir el nivel de LDL-C en ≥50%.
6.
• En adultos de 40 a 75 años de edad evaluados para la
prevención primaria de ASCVD, tenga una discusión
de riesgo entre el médico y el paciente antes de
comenzar el tratamiento con estatinas.
• La discusión del riesgo debe incluir una revisión de los
principales factores de riesgo y riesgo calculado de 10
años de ASCVD); la presencia de factores que
aumentan el riesgo y las preferencias y valores de los
pacientes en la toma de decisiones compartida.
7.
• En adultos de 40 a 75 años de edad sin diabetes
mellitus y con niveles de LDL-C ≥70 mg / dL, con un
riesgo ASCVD a 10 años de ≥7.5%, comenzar una
estatina de intensidad moderada.
• Si el estado de riesgo es incierto, considere el uso de
calcio en la arteria coronaria (CAC) para mejorar la
especificidad.
• Si se indican las estatinas, reduzca los niveles de LDL-
C en ≥30%, y si el riesgo a 10 años es ≥20%, reduzca
los niveles de LDL-C en ≥50%.
8. • En adultos de 40 a 75 años de edad sin diabetes mellitus
y riesgo de 10 años de 7,5% a 19,9% (riesgo intermedio),
los factores que aumentan el riesgo favorecen el inicio del
tratamiento con estatinas son:

– LDL-C persistentemente elevados ≥160 mg / dL

– síndrome metabólico
– enfermedad renal crónica
– antecedentes de preeclampsia o menopausia prematura (edad
<40 años)
– trastornos inflamatorios crónicos (por ejemplo, artritis
reumatoide, psoriasis o VIH crónico)
– grupos étnicos de alto riesgo (por ejemplo, sur de Asia)
– elevaciones persistentes de triglicéridos ≥175 mg / dL
– indice tobillo-brazo (ABI) <0.9
9.
• En adultos de 40 a 75 años de edad sin diabetes mellitus
y con niveles de LDL-C ≥70 mg / dL a 189 mg / dL, con
un riesgo ASCVD a 10 años de ≥7.5% al 19,9%, si la
decisión sobre el tratamiento con estatinas es incierta,
considere la posibilidad de medir la CAC.
• Una puntuación CAC de 1 a 99 favorece el tratamiento
con estatinas, especialmente en los ≥55 años de edad.
• Para cualquier paciente, si la puntuación CAC es ≥100
unidades de Agatston o ≥75 percentil, se indica la
terapia con estatinas, a menos que el resultado de la
discusión de riesgo clínico-paciente sea diferido.
10.
• Evalúe la adherencia y el porcentaje
de respuesta a los medicamentos
que disminuyen la LDL-C y los
cambios en el estilo de vida con la
medición repetida de lípidos 4 a 12
semanas
Grundy SM, et al.
2018 Cholesterol Clinical Practice Guidelines: Executive Summary

Table 3. High-, Moderate-, and Low-Intensity Statin Therapy*

High Intensity Moderate Intensity Low Intensity

LDL-C ≥50% 30%–49% <30%
lowering†
Statins Atorvastatin (40 mg‡) 80 Atorvastatin 10 mg (20 mg) Simvastatin 10 mg

PT
mg Rosuvastatin (5 mg) 10 mg
Rosuvastatin 20 mg (40 mg Simvastatin 20–40 mg§
… Pravastatin 40 mg (80 mg) Pravastatin 10–20 mg
Lovastatin 40 mg (80 mg) Lovastatin 20 mg

RI
Fluvastatin XL 80 mg Fluvastatin 20–40 mg
Fluvastatin 40 mg BID
Pitavastatin 1–4 mg
*Percent reductions are estimates from data across large populations. Individual responses to statin therapy varied

C
in the RCTs and should be expected to vary in clinical practice (S3.1.1-2).
†LDL-C lowering that should occur with the dosage listed below each intensity.

US
‡Evidence from 1 RCT only: down titration if unable to tolerate atorvastatin 80 mg in the IDEAL (Incremental
Decrease through Aggressive Lipid Lowering) study (S3.1.1-18).
§Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not
2078 Figure 1. Secondary Prevention in Patients With Clinical ASCVD

T
IP
CR
US
AN
M
D
Colors correspond to Class of Recommendation in Table 2.
2078 Figure 2. Primary Prevention

PT
RI
U SC
AN
M
D
Colors correspond to Class of Recommendation in Table 2.
 (B-NR)

AN
4.3. Diabetes Mellitus in Adults

M
Recommendations for Patients With Diabetes Mellitus
Referenced studies that support recommendations are summarized in Online Data Supplements 11 and

Diabetes Mellitus
12.

D
COR LOE Recommendations
1. In adults 40 to 75 years of age with diabetes mellitus, regardless of

TE
I A estimated 10-year ASCVD risk, moderate-intensity statin therapy is
indicated (S4.3-1–S4.3-9).
2. In adults 40 to 75 years of age with diabetes mellitus and an LDL-C level of

EP
IIa B-NR 70 to 189 mg/dL (1.7 to 4.8 mmol/L), it is reasonable to assess the 10-year
risk of a first ASCVD event by using the race and sex-specific PCE to help
stratify ASCVD risk (S4.3-10, S4.3-11).
3. In adults with diabetes mellitus who have multiple ASCVD risk factors, it is

C
IIa B-R reasonable to prescribe high-intensity statin therapy with the aim to
reduce LDL-C levels by 50% or more (S4.3-12, S4.3-13).

AC
4. In adults older than 75 years of age with diabetes mellitus and who are
IIa B-NR already on statin therapy, it is reasonable to continue statin therapy (S4.3-
5, S4.3-8, S4.3-13).
5. In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher,
IIb C-LD it may be reasonable to add ezetimibe to maximally tolerated statin
ACCEPTED
therapy MANUSCRIPT
to reduce LDL-C levels by 50% or more (S4.3-14, S4.3-15).
Grundy SM, et al. 6. In adults older than 75 years with diabetes mellitus, it may be reasonable
2018
IIbCholesterol Clinical Practice
C-LD to Guidelines: Executive
initiate statin Summary
therapy after a clinician–patient discussion of potential
benefits and risks (S4.3-5, S4.3-8, S4.3-13).
7. In adults 20 to 39 years of age with diabetes mellitus that is either of long
duration (≥10 years of type 2 diabetes mellitus, ≥20 years of type 1
diabetes mellitus), Page 17
albuminuria (≥30 mcg of albumin/mg creatinine),
IIb C-LD
estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2,
retinopathy, neuropathy, or ABI (<0.9), it may be reasonable to initiate
statin therapy (S4.3-5, S4.3-6, S4.3-8, S4.3-16–S4.3-25).

T
 C
moderate-intensity statin therapy with patients who have had type 2 diabetes mellitus for at least
years or type 1 diabetes mellitus for at least 20 years and with patients with ≥1 major CVD risk factors
complications, such as diabetic retinopathy (S4.3-19), neuropathy (S4.3-16), nephropathy (eGFR <

US
mL/min/1.73 m2 or albuminuria ≥30 mcg albumin/mg creatinine) (S4.3-25), or an ABI of <0.9 (S4.3-2
Diabetes Mellitus
S4.3-24) (Table 5).

AN
Table 5. Diabetes-Specific Risk Enhancers That Are Independent of Other Risk Factors in Diabetes
Mellitus

Risk Enhancers

M
• Long duration (≥10 years for type 2 diabetes mellitus (S4.3-20) or ≥20 years for
type 1 diabetes mellitus (S4.3-6)
• Albuminuria ≥30 mcg of albumin/mg creatinine (S4.3-25)
2

D
• eGFR <60 mL/min/1.73 m (S4.3-25)
• Retinopathy (S4.3-19)
• Neuropathy (S4.3-16)

TE
• ABI <0.9 (S4.3-22, S4.3-24)
ABI indicates ankle-brachial index; and eGFR, estimated glomerular filtration rate.
EP
4.4. Primary Prevention
Primary prevention of ASCVD over the life span requires attention to prevention or management
1475

Table 6
Atherosclerotic Cardiovascular Disease Risk Categories and
Low-Density Lipoprotein Treatment Goals
Treatment goals
a b
Risk category Risk factors /10-year risk LDL-C Non-HDL-C Apo B
(mg/dL) (mg/dL) (mg/dL)
Extreme Risk – Progressive ASCVD including unstable angina in
patients after achieving an LDL-C <70 mg/dL
– Established clinical cardiovascular disease in patients <55 <80 <70
with DM, CKD 3/4, or HeFH
– History of premature ASCVD (<55 male, <65 female)
Very High Risk – Established or recent hospitalization for ACS,
coronary, carotid or peripheral vascular disease, 10-
year risk >20%
<70 <100 <80
– Diabetes or CKD 3/4 with 1 or more risk factor(s)
– HeFH
High Risk – ≥2 risk factors and 10-year risk 10%-20%
<100 <130 <90
– Diabetes or CKD 3/4 with no other risk factors
Moderate Risk ≤2 risk factors and 10-year risk <10% <100 <130 <90
Low Risk 0 risk factors <130 <160 NR
Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; DM, diabetes mellitus; HeFH,
heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; MESA, Multi-Ethnic Study of
Atherosclerosis; NR, not recommended; UKPDS, United Kingdom Prospective Diabetes Study.
a
Major independent risk factors are high LDL-C, polycystic ovary syndrome, cigarette smoking, hypertension (blood pressure
Endocrine Practice. April 2017, Vol. 23, No. Supplement 2, pp. 1-87.
≥140/90 mm Hg or on hypertensive medication), low HDL-C (<40 mg/dL), family history of coronary artery disease (in male,
first-degree relative younger than 55 years; in female, first-degree relative younger than 65 years), chronic renal disease (CKD)
2078
4.5.2. Hypertriglyceridemia

TE
Recommendations for Hypertriglyceridemia
Referenced studies that support recommendations are summarized in Online Data Supplement 30, 31,
and 32.

EP
COR LOE Recommendations
1. In adults 20 years of age or older with moderate hypertriglyceridemia
(fasting or nonfasting triglycerides 175-499 mg/dL [1.9-5.6 mmol/L]),

C
clinicians should address and treat lifestyle factors (obesity and metabolic
I B-NR
syndrome), secondary factors (diabetes mellitus, chronic liver or kidney

AC
disease and/or nephrotic syndrome, hypothyroidism), and medications
that increase triglycerides (S4.5.2-1).
2. In adults 40 to 75 years of age with moderate or severe
hypertriglyceridemia and ASCVD risk of 7.5% or higher, it is reasonable to
ACCEPTED MANUSCRIPT
reevaluate ASCVD risk after lifestyle and secondary factors are addressed
IIa B-R
Grundy SM, et al. and to consider a persistently elevated triglyceride level as a factor
2018 Cholesterol Clinical Practice Guidelines:
favoring Executive
initiation Summary
or intensification of statin therapy (see Section 4.4.2.)
(S4.5.2-2–S4.5.2-6).
3. In adults 40 to 75 years of age with severe hypertriglyceridemia (fasting
triglycerides ≥500 mg/dL [≥5.6 mmol/L])) and ASCVD risk of 7.5% or
IIa B-R
higher, it is reasonable to address reversible causes of high triglyceride
and to initiate statin therapy (S4.5.2-3-5, S4.5.2-7, S4.5.2–8).
Page 31
4. In adults with severe hypertriglyceridemia (fasting triglycerides ≥500
mg/dL [≥5.7 mmol/L], and especially fasting triglycerides ≥1000 mg/dL

T
[11.3 mmol/L]), it is reasonable to identify and address other causes of
hypertriglyceridemia), and if triglycerides are persistently elevated or

IP
IIa B-NR
increasing, to further reduce triglycerides by implementation of a very
low-fat diet, avoidance of refined carbohydrates and alcohol,

CR
consumption of omega-3 fatty acids, and, if necessary to prevent acute
pancreatitis, fibrate therapy (S4.5.2-7, S4.5.2-9).
2086
2086
Ezetimibe in Prevention of Cerebro- and Cardiovascular Events in Midd…tients With Elevated LDL-Cholesterol - American College of Cardiology 21/11/18 23'56

Ezetimibe in Prevention of Cerebro- and

Cardiovascular Events in Middle- to High-Risk,
Elderly (75 Years Old or Over) Patients With
Elevated LDL-Cholesterol - EWTOPIA 75
Nov 10, 2018

Se incluyeron 3.796 pacientes con niveles elevados de colesterol de

•
Author/Summarized by
Author:
lipoproteínas de baja densidad mayor a 140 mg/dl, que fueron
Dharam J. Kumbhani, MD, SM, FACC

Summary Reviewer:
aleatorizados a ezetimibe frente a placebo.
Deepak L. Bhatt, MD, MPH, FACC

Date Presented:
Date Published:
Date Updated:
Original Posted Date:
References
11/10/2018 • El descenlace final primario del estudio fue el combinado de muerte
11/10/2018
súbita, infarto de miocardio fatal y no fatal, revascularización
11/10/2018
coronaria y accidente cerebrovascular fatal y no fatal.
11/11/2018 • El uso de ezekmibe se asoció a una reducción relativa del riesgo de
44% del punto final primario, a expensas de reducción en eventos
cardiovasculares no fatales.

Contribution To Literature:

The EWTOPIA 75 trial showed that, compared with • dietaryLos resultados del estudio son promisorios y representan el primer
counseling alone, the
use of additional ezetimibe for primary prevention among estudio en sugerir que es posible la prevención primaria de eventos
elderly Japanese

cardiovasculares en forma segura en pacientes mayores de 75 años

patients with LDL ≥140 mg/dl and ≥1 high-risk feature reduced CV events,
primarily cardiac events, with no difference in all-cause mortality.

Description:
con ezetimibe.
https://www.acc.org/latest-in-cardiology/clinical-trials/2018/11/08/22/56/ewtopia75 Página 1 de 4
2082

The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Cardiovascular Risk Reduction with

Icosapent Ethyl for Hypertriglyceridemia
Deepak L. Bhatt, M.D., M.P.H., P. Gabriel Steg, M.D., Michael Miller, M.D.,
Eliot A. Brinton, M.D., Terry A. Jacobson, M.D., Steven B. Ketchum, Ph.D.,
Ralph T. Doyle, Jr., B.A., Rebecca A. Juliano, Ph.D., Lixia Jiao, Ph.D.,
Craig Granowitz, M.D., Ph.D., Jean-Claude Tardif, M.D., and
Christie M. Ballantyne, M.D., for the REDUCE-IT Investigators*

A BS T R AC T

BACKGROUND REDUCE-IT
Patients with elevated triglyceride levels are at increased risk for ischemic events. From Brigham and Women’s Hospital
Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride Heart and Vascular Center and Harvard
Medical School, Boston (D.L.B.); FACT
levels, but data are needed to determine its effects on ischemic events.
 2084
s of the writing committee
man, M.D., Marion Mafham,
endszus, M.Sc., Will Stevens,
na Buck, M.Sc., Jill Barton,
The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
Effects of n−3 Fatty Acid Supplements
in Diabetes Mellitus
The ASCEND Study Collaborative Group*
A BS T R AC T
BACKGROUND
Increased intake of n−3 fatty acids has been associated with a reduced risk of car-
diovascular disease in observational studies, but this finding has not been confirmed
in randomized trials. It remains unclear whether n−3 (also called NEJM 379;16
omega-3) fattyOctober 18, 2018
• Asignamos aleatoriamente a 15,480 pacientes con
diabetes, pero sin evidencia de enfermedad
cardiovascular ateroesclerótica para recibir cápsulas
de 1 g que contengan ácidos grasos n-3 (grupo de
ácidos grasos) o placebo (aceite de oliva) al día.
• El resultado primario fue un nuevo evento vascular (es
decir, infarto de miocardio no fatal o infarto de
miocardio, ataque isquémico transitorio o muerte
vascular, excluyendo hemorragia intracraneal
confirmada).
• El resultado secundario fue un primer evento vascular
grave o cualquier revascularización arterial.

NEJM 379;16 October 18, 2018

2084
A First Serious Vascular Event
100 15
90 Rate ratio, 0.97 (95% CI, 0.87–1.08)
P=0.55 Placebo
80 10

Patients with Event (%)

70 Fatty acids
60
5
50
40
30 0
0 1 2 3 4 5 6 7 8 9
20
10
0
0 1 2 3 4 5 6 7 8 9
Years of Follow-up
No. at Risk
Placebo 7740 7627 7503 7377 7222 7047 5792 3934 2224 1428
Fatty acids 7740 7646 7519 7369 7218 7050 5804 3922 2198 1430

Cumulative benefit per 1000 3±2 2±2 0±3 0±3 0±4 1±4 3±5 4±6 3±7
patients in fatty acid group

B First Serious Vascular Event, According to Year of Follow-up

Fatty Acids Placebo
Year of First Event (N=7740) (N=7740) Rate Ratio (95% CI) P Value
no. of patients with event (%)
<3 236 (3.0) 234 (3.0) NEJM 379;16
1.01 (0.84–1.21) October 18, 2018
3 to <5 181 (2.5) 186 (2.5) 0.97 (0.79–1.20)
943
Atherosclerosis 242 (2015) 357e366

Contents lists available at ScienceDirect

Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Review article

Biologic plausibility, cellular effects, and molecular mechanisms of

eicosapentaenoic acid (EPA) in atherosclerosis
Kenneth M. Borow a, *, John R. Nelson b, R. Preston Mason c
a
MediMergent, LLC and The National Medication Safety, Outcomes and Adherence Program, 407 Wyntre Lea Drive, Bryn Mawr, PA 19010, USA
b
UCSF School of Medicine, Fresno-Medicine Residency ProgrameVolunteer, 7061 N. Whitney Street, Suite 101, Fresno, CA 93720, USA
c
Harvard Medical School, 100 Cummings Center, Suite 135L, Beverly, MA 01915, USA

a r t i c l e i n f o a b s t r a c t

Article history: Residual cardiovascular (CV) risk remains in dyslipidemic patients despite intensive statin therapy,
Received 21 May 2015 underscoring the need for additional intervention. Eicosapentaenoic acid (EPA), an omega-3 poly-
Received in revised form unsaturated fatty acid, is incorporated into membrane phospholipids and atherosclerotic plaques and
6 July 2015
exerts beneficial effects on the pathophysiologic cascade from onset of plaque formation through
Accepted 20 July 2015
Available online 22 July 2015
rupture. Specific salutary actions have been reported relating to endothelial function, oxidative stress,
foam cell formation, inflammation, plaque formation/progression, platelet aggregation, thrombus for-
mation, and plaque rupture. EPA also improves atherogenic dyslipidemia characterized by reduction of
Keywords:
Acute coronary syndrome
triglycerides without raising low-density lipoprotein cholesterol. Other beneficial effects of EPA include
Atherosclerosis vasodilation, resulting in blood pressure reductions, as well as improved membrane fluidity. EPA's effects
Atherosclerotic plaque are at least additive to those of statins when given as adjunctive therapy. In this review, we present data
Eicosapentaenoic acid supporting the biologic plausibility of EPA as an anti-atherosclerotic agent with potential clinical benefit
Endothelial function for prevention of CV events, as well as its cellular effects and molecular mechanisms of action. REDUCE-IT
Icosapent ethyl is an ongoing, randomized, controlled study evaluating whether the high-purity ethyl ester of EPA
Inflammation (icosapent ethyl) at 4 g/day combined with statin therapy is superior to statin therapy alone for reducing
Thrombosis
CV events in high-risk patients with mixed dyslipidemia. The results from this study are expected to
clarify the role of EPA as adjunctive therapy to a statin for reduction of residual CV risk.
© 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-
ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Inflamación y
citokinas
1. The importance of biologic plausibility studies have demonstrated that causality can be ascribed to specific
pathways that may or may not directly correlate with changes in
Biologic plausibility has been defined as evidence that a surro- surrogates of interest [3,4].

Atherosclerosis 242 (2015) 357-366

gate biochemical, anatomic and/or morphologic, or pathophysio-
logic end point is on the causal pathway to the adverse outcome or
is a regular finding associated with that outcome and is plausibly
Over the past decade, multiple large, randomized, comparative
cardiovascular (CV) trials conducted in statin-treated patients have
had disappointing results, thereby raising questions about the
814 Articles

Dietary supplementation with n-3 polyunsaturated fatty acids and

vitamin E after myocardial infarction: results of the
GISSI-Prevenzione trial
Martínez-González J et al. Estatinas y ácidos grasos omega-3. Disminución

GISSI-Prevenzione Investigators* (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico)

Summary Introduction
1,00
The protective effects of foods rich in n-3 polyunsaturated
Background There is conflicting evidence on the benefits of
fatty acids (PUFA) derived from marine vertebrates, AGPI n-3
foods rich in vitamin E (α-tocopherol), n-3 polyunsaturated
vitamin E (α-tocopherol), and their pharmacological Control
n: 11.324
fatty acids (PUFA), and their pharmacological substitutes. We equivalents on0,99cardiovascular risk has been of interest for

Probabilidad de supervivencia
investigated the effects of these substances as supplements the past 20 years.1–4 Since a low rate of coronary heart
172 centros
in patients who had myocardial infarction.
Methods From October, 1993, to September, 1995, 11 324
disease was reported in the Eskimo population exposed
to a diet rich in fish oil,5 several studies have explored
3.5 años
patients surviving recent (!3 months) myocardial infarction
were randomly assigned supplements of n-3 PUFA (1 g daily,
and supported antiatherogenic, antithrombotic, and
antiarrhythmic 0,98
effects of n-3 PUFA.2–4 Although no
n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), consensus existed on the underlying mechanism of action,
or none (control, n=2828) for 3· 5 years. The primary focus was placed on the ability of triglycerides to lower
combined efficacy endpoint was death, non-fatal myocardial high-dose n-3 PUFA (registration approval was given for
infarction, and stroke. Intention-to-treat analyses were done this indication),0,97
and to modify membrane composition.2–4
according to a factorial design (two-way) and by treatment 0,59 (0,36-0,97)
A protective role in the secondary prevention of coronary
heart disease was seen for fatty fish in the Diet And
group (four-way).
Reinfarction Trial (DART).6 p = 0,037
Findings Treatment with n-3 PUFA, but not vitamin E, By contrast, large observational cohort studies7–10
significantly lowered the risk of the primary endpoint (relative- support the role 0,96
of vitamin E as an antioxidant against the 0,72 (0,54-0,96)
risk decrease 10% [95% CI 1–18] by two-way analysis, 15% proatherogenic and prothrombotic effects of LDL p = 0,027
[2–26] by four-way analysis). Benefit was attributable to a oxidation. 11–13
However, controlled trials testing this
decrease in the risk of death (14% [3–24] two-way, 20% hypothesis in populations with different background
cardiovascular risk produced controversial results. No
[6–33] four-way) and cardiovascular death (17% [3–29] two-
way, 30% [13–44] four-way). The effect of the combined
0,95
decrease in cardiovascular events was seen with low-dose
(50 mg daily) vitamin E supplementation in smokers;14 a
significant decrease in0non-fatal
30myocardial
60 infarction
90 and120 150 180 210 260 270 300 330 360
treatment was similar to that for n-3 PUFA for the primary
endpoint (14% [1–26]) and for fatal events (20% [5–33]).
an increase in fatal cardiovascular events was reported
Fig. 2. M
Interpretation Dietary supplementation with n-3 PUFA led to with a daily regimen of 400–800 mg vitamin E in patients Días SI-Preven
a clinically important and satistically significant benefit.
Vitamin E had no benefit. Its effects on fatal cardiovascular
with angiographically proven coronary atherosclerosis.15
A possible complementary role for these two dietary
ción de
events require further exploration. components has been purported: vitamin E could improve mente sig
THE LANCET • Vol 354 • August
Lancet 1999; 354: 447–55
7, 1999 447
the role of n-3 PUFA through protection from lipid
peroxidation, by acting independently on the same or closely Datos pro
See Commentary page ???
related atherogenic and thrombotic mechanisms, or both.4,16
We investigated in the Gruppo Italiano per lo Studio
20
Clinical Therapeutics/Volume 35, Number 1, 2013

Omega-3 Fatty Acids and Mortality Outcome in Patients With

and Without Type 2 Diabetes After Myocardial Infarction: A
Retrospective, Matched-Cohort Study
Chris D. Poole, PhD1; Julian P. Halcox, MD2; Sara Jenkins-Jones, MSc3;
Emma S.M. Carr, PhD4; Mathias G. Schifflers, MD4; Kausik K. Ray, MD, MPhil5; and
Craig J. Currie, PhD1 Clinical Therapeutics
1
Department of Primary Care and Public Health, School of Medicine, Cardiff University, The Pharma
Research Centre, Cardiff MediCentre, Cardiff, United Kingdom; 2Wales Heart Research Institute, Cardiff
Table II. 3Global
University, Heath Park, Cardiff, United Kingdom; Exposure to omega-3
Epidemiology, (n-3) fatty Cardiff
Pharmatelligence, acids and cardiovascular risk–modifying treatments after myocardial
MediCentre, Cardiff, United Kingdom; 4Abbott Products
infarction.
Operations AG, Allschwil, Switzerland; and
5
Cardiovascular Sciences Research Centre, St. George’s, University of London, London, United Kingdom
No Diabetes Previous Type 2 Diabetes
ABSTRACT Conclusion: After MI, early treatment with licensed
Background: There are conflicting dataDrug regarding
Class n-3 fatty acids was associated
Exposedwith improvement
Nonexposed in P Exposed Nonexposed P
the benefits of omega-3 (n-3) fatty acids, most recently all-cause mortality in patients with and without type 2
in patients with type 2 diabetes. Exposure within diabetes, against a background of contemporary
90 days
Objective: Our goal was to evaluate the impact of cardiovascular risk–modifying treatments. (Clin Ther.
Lipid-lowering
licensed, highly purified n-3 fatty acids on all-cause drugs, % 97.6 84.0
2013;35:40–51) © 2013 Elsevier HS Journals, Inc. All
"0.0001 96.2 82.8 "0.0001
mortality after myocardial infarction (MI). Antihypertensives, %
rights reserved. 98.5 86.6 "0.0001 98.1 87.9 "0.0001
Methods: This was a retrospective, matched-cohortAntiplatelets,Key % words: all-cause 98.3 84.9
mortality, n-3 fatty acids, "0.0001 97.8 83.2 "0.0001
study using data from the General Practice Research Da- omega-3 fatty acids, ORIGIN trial, type 2 diabetes.
tabase. Patients initiating treatment with 1 g Exposure
of n-3 fatty within 12
acids in the 90 days after first MI were identified and each
months
matched to 4 nonexposed patients. Progression to death INTRODUCTION
Lipid-lowering drugs, % 92.4 79.1 "0.0001 91.7 77.9 "0.0001
was compared using time-dependent Cox models to ac- Essential omega-3 (n-3) fatty acid supplementation is
count for potential differences in exposure to Antihypertensives,
other % 95.3 82.9 "0.0001 95.2 84.7 "0.0001
associated with improved endothelial and myocardial
cardiovascular risk–modifying treatments. Antiplatelets, % and with triglyceride-lowering,
function 94.2 79.6
anti-inflam- "0.0001 88.9 78.8 "0.0001
Results: A total of 2466 eligible subjects exposed to
matory, antithrombotic, and antiarrhythmogenic effects.
n-3 fatty acids were matched. The majority of patients
High dietary intake of oily fish, and thus marine-derived
had concurrent treatment with lipid-lowering thera-
n-3 fatty acids, is also associated with improved cardio-
pies, antihypertensives, and antiplateletsRESULTS
after first MI, tively, and for antiplatelet drugs, it was 98% versus
vascular disease (CVD) outcomes.1,2 Several large ran-
Clinical Therapeutics/Vol 35, No 1, 2013
with subjects exposed to n-3 fatty acids Patients
having and
greater likelihood of concurrent exposure. For those
a Baseline Characteristics
domized studies have shown significant improvements in 85% (P " 0.0001). Thus, it was necessary to account
Clinical Therapeutics

Table IV. Time-dependent Cox models of the hazard of all-cause mortality for patients exposed to omega-3 (n-3)
fatty acids initiated within 90 and 14 days of their first myocardial infarction (MI) versus matched,
nonexposed patients.

Initiation !90 Days Initiation !14 Days

Model Parameter HR 95% CI P HR 95% CI P

Time-dependent covariates
(quarterly periods)
n-3 fatty acid exposure, 1 g/d, 0.782 0.641–0.955 0.0159 0.680 0.481–0.961 0.0288
yes/no
Lipid-lowering drug exposure, 0.433 0.373–0.503 !0.0001 0.445 0.346–0.571 !0.0001
yes/no
Antihypertensive exposure, 0.416 0.358–0.483 !0.0001 0.425 0.331–0.546 !0.0001
yes/no
Antiplatelet exposure, yes/no 0.563 0.485–0.653 !0.0001 0.535 0.415–0.690 !0.0001
Time-fixed covariates (at first MI)
Age, y 1.069 1.064–1.074 !0.0001 1.060 1.051–1.068 !0.0001
Smoking status vs never
Ex-smoker 1.255
22%
1.112–1.417
!0.0001
0.0002 1.222
32%
1.003–1.488
0.0704
0.0469
Current smoker 1.454 1.255–1.684 !0.0001 1.273 1.002–1.617 0.0482
Socioeconomic status, IMD 0.0131 0.7815
quintile vs group 1
2082

The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Cardiovascular Risk Reduction with

Icosapent Ethyl for Hypertriglyceridemia
Deepak L. Bhatt, M.D., M.P.H., P. Gabriel Steg, M.D., Michael Miller, M.D.,
Eliot A. Brinton, M.D., Terry A. Jacobson, M.D., Steven B. Ketchum, Ph.D.,
Ralph T. Doyle, Jr., B.A., Rebecca A. Juliano, Ph.D., Lixia Jiao, Ph.D.,
Craig Granowitz, M.D., Ph.D., Jean-Claude Tardif, M.D., and
Christie M. Ballantyne, M.D., for the REDUCE-IT Investigators*

A BS T R AC T

BACKGROUND REDUCE-IT
Patients with elevated triglyceride levels are at increased risk for ischemic events. From Brigham and Women’s Hospital
Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride Heart and Vascular Center and Harvard
Medical School, Boston (D.L.B.); FACT
levels, but data are needed to determine its effects on ischemic events.
2082

The ne w e ngl a nd j o u r na l of m e dic i ne

• El estudio REDUCE IT aleatorizó 8.179
pacientes con enfermedad cardiovascular
Table 1. Characteristics of the Patients at Baseline.*

Characteristic Icosapent Ethyl (N = 4089) Placebo (N = 4090)

establecida o diabetes con otros factores

Age
Median (IQR) — yr 64.0 (57.0–69.0) 64.0 (57.0–69.0)
≥65 yr — no. (%) 1857 (45.4) 1906 (46.6)
Male sex — no. (%) 2927 (71.6) 2895 (70.8)

de riesgo, a recibir ácido etil-

White race — no. (%)† 3691 (90.3) 3688 (90.2)
Body-mass index‡
Median (IQR) 30.8 (27.8–34.5) 30.8 (27.9–34.7)
≥30 — no. (%) 2331 (57.0) 2362 (57.8)

eicosapentaenoico (EPA) dos veces por día

Geographic region — no. (%)§
United States, Canada, the Netherlands, Australia, New Zealand, 2906 (71.1) 2905 (71.0)
and South Africa
Eastern European 1053 (25.8) 1053 (25.7)

frente a placebo.
Asia–Pacific 130 (3.2) 132 (3.2)
Cardiovascular risk stratum — no. (%)
Secondary-prevention cohort 2892 (70.7) 2893 (70.7)
Primary-prevention cohort 1197 (29.3) 1197 (29.3)

• Todos los pacientes se encontraban en

Ezetimibe use — no. (%) 262 (6.4) 262 (6.4)
Statin intensity — no. (%)
Low 254 (6.2) 267 (6.5)
Moderate 2533 (61.9) 2575 (63.0)

tratamiento con estatinas y los niveles de

High 1290 (31.5) 1226 (30.0)
Data missing 12 (0.3) 22 (0.5)
Diabetes — no. (%)

triglicéridos estaban entre 151 y 499

Type 1 27 (0.7) 30 (0.7)
Type 2 2367 (57.9) 2363 (57.8)
No diabetes at baseline 1695 (41.5) 1694 (41.4)
Data missing 0 3 (0.1)

mg/dl; LDL > 40 mg/dl y ≤ 100 mg/dl.

Median high-sensitivity CRP level (IQR) — mg/liter 2.2 (1.1–4.5) 2.1 (1.1–4.5)
Median triglyceride level (IQR) — mg/dl 216.5 (176.5–272.0) 216.0 (175.5–274.0)
Median HDL cholesterol level (IQR) — mg/dl 40.0 (34.5–46.0) 40.0 (35.0–46.0)
Median LDL cholesterol level (IQR) — mg/dl 74.0 (61.5–88.0) 76.0 (63.0–89.0)
Distribution of triglyceride levels — no./total no. (%)

• Seguimiento medio de 4,9 años.

<150 mg/dl 412/4086 (10.1) 429/4089 (10.5)
≥150 to <200 mg/dl 1193/4086 (29.2) 1191/4089 (29.1)
≥200 mg/dl 2481/4086 (60.7) 2469/4089 (60.4)
Triglyceride level ≥200 mg/dl and HDL cholesterol level ≤35 mg/dl — no. (%) 823 (20.1) 794 (19.4)

• El criterio de valoración final primario se

Median eicosapentaenoic acid level (IQR) — µg/ml 26.1 (17.1–40.1) 26.1 (17.1–39.9)

* Median low-density lipoprotein (LDL) cholesterol level at baseline differed significantly between the trial groups (P = 0.03); there were no
other significant between-group differences in baseline characteristics. To convert the values for triglycerides to millimoles per liter, multiply
by 0.01129. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. In general, the baseline value was defined as

componía de muerte cardiovascular,

the last nonmissing measurement obtained before randomization. The baseline LDL cholesterol value as measured by means of preparative
ultracentrifugation was used in our analyses; however, if the preparative ultracentrifugation value was missing, the LDL cholesterol value
measured by another method was used in the following order of priority: the value obtained by means of direct measurement of LDL choles-
terol, the value derived with the use of the Friedewald equation (only for patients with a triglyceride level <400 mg per deciliter), and the val-
ue derived with the use of the calculation published by Johns Hopkins University investigators.22 At the first and second screening visits, the

infarto de miocardio no fatal, accidente

LDL cholesterol value obtained by direct measurement was used if at the same visit the triglyceride level was higher than 400 mg per decili-
ter. At all remaining visits, the LDL cholesterol value was obtained by means of direct measurement or preparative ultracentrifugation if at
the same visit the triglyceride level was higher than 400 mg per deciliter. For all other measures of lipid and lipoprotein markers, whenever
possible, the baseline value was derived as the arithmetic mean of the value obtained at visit 2 (day 0) and the value obtained at the preced-

cerebrovascular no fatal, revascularización

ing screening visit. If only one of these values was available, that single value was used as the baseline value. CRP denotes C-reactive pro-
tein, HDL high-density lipoprotein, and IQR interquartile range. Percentages may not total 100 because of rounding.
† Race was reported by the investigators.
‡ Body-mass index is the weight in kilograms divided by the square of the height in meters.
§ Eastern European region includes Poland, Romania, Russia, and Ukraine, and Asia–Pacific region includes India.

coronaria o angina inestable.

4 n engl j med nejm.org

The New England Journal of Medicine

Downloaded from nejm.org on November 10, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
 Cardiovascular
2084 Risk Reduction with Icosapent Ethyl
CV death, MI, stroke, coronary revascularization, or unstable angina
us and at least one additional
A Primary End Point
dian age of the patients was 100 30
ere female, and 38.5% were Hazard ratio, 0.75 (95% CI, 0.68–0.83)
90 P<0.001
ates. At baseline, the median Placebo
el was 75.0 mg per deciliter 80 20

Patients with an Event (%)

er), the median high-density 70
Icosapent ethyl
erol level was 40.0 mg per
25%
60 10
ol per liter), and the median 50
s 216.0 mg per deciliter (2.44 40 0
0 1 2 3 4 5
30

ects on Lipids 20

n of follow-up was 4.9 years 10

ars). The median change in 0
0 1 2 3 4 5
om baseline to 1 year was a
−39.0 mg per deciliter [−0.44 Years since Randomization

he icosapent ethyl group and No. at Risk

Placebo 4090 3743 3327 2807 2347 1358
% (4.5 mg per deciliter [0.05 Icosapent ethyl 4089 3787 3431 2951 2503 1430
the placebo group; the me-
m baseline (as estimated with B Key Secondary End Point
ges–Lehmann approach) was 100 30
Hazard ratio, 0.74 (95% CI, 0.65–0.83)
NEJM 379;16 October 18, 2018
e icosapent ethyl group than
0 mg per deciliter [−0.44
2084 ethyl group and
osapent No. at Risk
CV death, MI, or
5 mg per deciliter [0.05
Placebo stroke
4090 (key
3743 secondary
3327 2807endpoint)
2347 1358
Icosapent ethyl 4089 3787 3431 2951 2503 1430
placebo group; the me-
eline (as estimated with B Key Secondary End Point
Lehmann approach) was 100 30
Hazard ratio, 0.74 (95% CI, 0.65–0.83)
sapent ethyl group than 90 P<0.001
a 44.5 mg per deciliter 80 20

Patients with an Event (%)

ater reduction; P<0.001). Placebo
70
n LDL cholesterol level
ncrease of 3.1% (2.0 mg 60 10
Icosapent ethyl
26%
per liter]) in the icosa- 50

ncrease of 10.2% (7.0 mg 40 0

per liter]) in the placebo 30
0 1 2 3 4 5

per deciliter [0.13 mmol 20

with icosapent ethyl than
10
The results with respect
0
pid, lipoprotein, and in- 0 1 2 3 4 5
are provided in Table S4 Years since Randomization
ppendix.
No. at Risk
Placebo 4090 3837 3500 3002 2542 1487
Icosapent ethyl 4089 3861 3565 3115 2681 1562

ated primary end-point

mary end-point event oc- Figure 1. Cumulative Incidence of Cardiovascular Events. NEJM 379;16 October 18, 2018
2082 The n e w e ng l a n d j o u r na l of m e dic i n e

Icosapent Ethyl Placebo P Value for

End Point (N=4089) (N=4090) Hazard Ratio (95% CI) Interaction
no. of patients with event (%)
Primary composite 705 (17.2) 901 (22.0) 0.75 (0.68–0.83) <0.001
Key secondary composite 459 (11.2) 606 (14.8) 0.74 (0.65–0.83) <0.001
Cardiovascular death or nonfatal 392 (9.6) 507 (12.4) 0.75 (0.66–0.86) <0.001
myocardial infarction
Fatal or nonfatal myocardial infarction 250 (6.1) 355 (8.7) 0.69 (0.58–0.81) <0.001
Urgent or emergency revascularization 216 (5.3) 321 (7.8) 0.65 (0.55–0.78) <0.001
Cardiovascular death 174 (4.3) 213 (5.2) 0.80 (0.66–0.98) 0.03
Hospitalization for unstable angina 108 (2.6) 157 (3.8) 0.68 (0.53–0.87) 0.002
Fatal or nonfatal stroke 98 (2.4) 134 (3.3) 0.72 (0.55–0.93) 0.01
Death from any cause, nonfatal myocardial 549 (13.4) 690 (16.9) 0.77 (0.69–0.86) <0.001
infarction, or nonfatal stroke
Death from any cause 274 (6.7) 310 (7.6) 0.87 (0.74–1.02) —
0.4 0.6 0.8 1.0 1.2 1.4

Icosapent Ethyl Placebo

Better Better

Figure 4. Hierarchical Testing of End Points.

Shown is the prespecified plan for hierarchical testing of end points. The rates of all end points up to death from any cause were
significantly lower in the icosapent ethyl group than in the placebo group.
NEJM 379;16 October 18, 2018
2085

18/11/18 9:07 p.m.

www.medscape.com

REDUCE-IT: 'A New Era' in CVD Prevention With High-Dose EPA

Sue Hughes

November 10, 2018

CHICAGO — A high-dose purified form of the omega-3 oil, eicosapentaenoic acid (EPA), in patients with raised
triglycerides who had cardiovascular (CV) disease or diabetes and one additional risk factor has shown significant benefit,
final results of the REDUCE-IT trial show.

Reducción absoluta del riesgo del 4.4%

The findings show a "robust benefit that was extremely statistically significant," said lead author Deepak L. Bhatt, MD,
Brigham and Women's Hospital, Boston, Massachusetts.

Top-line results showing a 25%NNT: 21

relative risk reduction in major adverse cardiovascular events were announced a few
weeks ago by Amarin, manufacturer of the EPA product, icosapent ethyl (Vascepa), used in the study.

Today Bhatt presented more details from the trial at the American Heart Association (AHA) Scientific Sessions 2018. The
study was also simultaneously published online November 10 in the New England Journal of Medicine (NEJM).

"The 25% reduction in the primary endpoint revealed previously is itself very impressive, but now we are reporting detailed
results showing large consistent reductions on multiple endpoints and statistics which show that these results are
extremely statistically significant and robust," Bhatt told theheart.org | Medscape Cardiology.

"The primary endpoint had a P value of .00000001 — that is seven zeros. And the key secondary endpoint of hard events
2087

The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Marine n−3 Fatty Acids and Prevention

of Cardiovascular Disease and Cancer
JoAnn E. Manson, M.D., Dr.P.H., Nancy R. Cook, Sc.D., I-Min Lee, M.B., B.S., Sc.D.,
William Christen, Sc.D., Shari S. Bassuk, Sc.D., Samia Mora, M.D., M.H.S.,
Heike Gibson, Ph.D., Christine M. Albert, M.D., M.P.H., David Gordon, M.A.T.,
Trisha Copeland, M.S., R.D., Denise D’Agostino, B.S., Georgina Friedenberg, M.P.H.,
Claire Ridge, M.P.H., Vadim Bubes, Ph.D., Edward L. Giovannucci, M.D., Sc.D.,
Walter C. Willett, M.D., Dr.P.H., and Julie E. Buring, Sc.D.,
for the VITAL Research Group*

A BS T R AC T

BACKGROUND
Vital
Higher intake of marine n−3 (also called omega-3) fatty acids has been associated From the Department of Medicine,
with reduced risks of cardiovascular disease and cancer in several observational stud- Brigham and Women’s Hospital and
Harvard Medical School (J.E.M., N.R.C.,
ies. Whether supplementation with n−3 fatty acids has such effects in general popu- I-M.L., W.C., S.S.B., S.M., H.G., C.M.A.,
lations at usual risk for these end points is unclear. D.G., T.C., D.D., G.F., C.R., V.B., E.L.G.,
W.C.W., J.E.B.), and the Departments of
METHODS
Published on November 10, 2018, at NEJM.org.
We conducted a randomized, placebo-controlled trial, with a two-by-two factorial de-
Epidemiology (J.E.M., N.R.C., I.-M.L.,
W.C.W., J.E.B.) and Nutrition (E.L.G.,
sign, of vitamin D3 (at a dose of 2000 IU per day) and marine n−3 fatty acids (at a dose W.C.W.), Harvard T.H. Chan School of
 The n e w e ng l a n d j o u r na l of m e dic i n e
2087
Table 1. Characteristics of the Participants at Baseline, According to Randomized Assignment to Marine n−3 Fatty Acids or Placebo.*

Total n−3 Group Placebo Group

Characteristic (N = 25,871) (N = 12,933) (N = 12,938)
Age — yr 67.1±7.1 67.2±7.1 67.1±7.1
Female sex — no. (%) 13,085 (50.6) 6547 (50.6) 6538 (50.5)
Race or ethnic group — no./total no. (%)†
Non-Hispanic white 18,046/25,304 (71.3) 9044/12,653 (71.5) 9002/12,651 (71.2)
Black 5106/25,304 (20.2) 2549/12,653 (20.1) 2557/12,651 (20.2)
Nonblack Hispanic 1013/25,304 (4.0) 491/12,653 (3.9) 522/12,651 (4.1)
Asian or Pacific Islander 388/25,304 (1.5) 200/12,653 (1.6) 188/12,651 (1.5)
Native American 228/25,304 (0.9) 120/12,653 (0.9) 108/12,651 (0.9)
Other or unknown 523/25,304 (2.1) 249/12,653 (2.0) 274/12,651 (2.2)
Body-mass index‡ 28.1±5.7 28.1±5.7 28.1±5.8
Current smoking — no./total no. (%) 1836/25,485 (7.2) 920/12,739 (7.2) 916/12,746 (7.2)
Hypertension treated with medication — no./total no. (%) 12,791/25,698 (49.8) 6338/12,853 (49.3) 6453/12,845 (50.2)
Current use of cholesterol-lowering medication — no./total 9524/25,428 (37.5) 4788/12,707 (37.7) 4736/12,721 (37.2)
no. (%)
Diabetes — no./total no. (%) 3549/25,828 (13.7) 1799/12,912 (13.9) 1750/12,916 (13.5)

* Plus–minus values are means ±SD. There were no significant differences between the two groups with regard to the baseline characteristics.
Percentages may not total 100 because of rounding.
† Race and ethnic group were reported by the participant.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters. Data were available for 12,615 participants in
the n−3 group and for 12,639 in the placebo group.

Published on November 10, 2018, at NEJM.org.

ble 2). The results regarding stroke subtypes and variables for the primary end point of major car-
• Es un estudio aleatorizado, controlado con
placebo, con diseño factorial 2 x 2, que incluyó
25.871 individuos en prevención primaria de
enfermedad cardiovascular y cáncer.
• Se aleatorizó a los participantes a vitamina D3
(colecalciferol) 2.000 UI por día y 1 g de ácidos
grasos omega-3 por día.
• El objetivo primario del estudio fue evaluar si
colecalciferol/ácido graso omega-3 reducía el
riesgo de eventos cardiovasculares combinados
(infarto de miocardio, muerte cardiovascular o
accidente cerebrovascular) y cáncer invasivo.

Published on November 10, 2018, at NEJM.org.

2087
hazards analysis sugges
A Major Cardiovascular Events
Placebo
(P = 0.08). In analyses that
1.0 0.03 Hazard ratio, 0.92 (95% CI, 0.80–1.06) of follow-up, the hazard
0.9 P=0.24 n−3 group, as compared
0.8 0.02 was 1.13 (95% CI, 1.00

Cumulative Incidence
n–3 Fatty acids
0.7 ratio for death from ca
0.6
0.01 1.19) (Table 2).
0.5
In the subgroup anal
0.4
0.00 may have modified the
0.3
0 1 2 3 4 5 6 incidence (P = 0.02 for i
0.2
0.1
the Supplementary App
0.0
baseline may have mod
0 1 2 3 4 5 6 intervention on the incid
Years since Randomization cause (P = 0.02 for inter
No. at Risk Supplementary Appendi
Placebo 12,938 12,862 12,745 12,592 12,281 9825 775 significant interactions
n–3 Fatty acids 12,933 12,842 12,725 12,594 12,322 9878 765
points or death from an
B Invasive Cancer of Any Type
Adverse Events
1.0 0.06
The incidence of gastroi
Hazard ratio, 1.03 (95% CI, 0.93–1.13)
0.9 P=0.56
0.8
0.05
Published on November 10, 2018, at NEJM.org.
jor bleeding episodes, o
0.04 Placebo events did not differ si
ce
 significant interactions
n–3 Fatty acids 12,933 12,842 12,725 12,594 12,322 9878 765
2087 points or death from an
B Invasive Cancer of Any Type
Adverse Events
1.0 0.06 Hazard ratio, 1.03 (95% CI, 0.93–1.13) The incidence of gastroi
0.9 0.05 P=0.56
jor bleeding episodes, o
0.8 0.04 Placebo events did not differ si

Cumulative Incidence
0.7
0.6
0.03
n–3 Fatty acids n−3 group and the placeb
0.5
0.02 vided in Table S7 in the S
0.01
0.4
0.00
0.3
0 1 2 3 4 5 6 Discu
0.2
0.1 In this primary prevent
0.0 follow-up of 5.3 years, su
0 1 2 3 4 5 6 fatty acids at a dose of 1
Years since Randomization a significantly lower inci
No. at Risk points of major cardiova
Placebo 12,938 12,747 12,544 12,330 11,981 9543 756
n–3 Fatty acids 12,933 12,756 12,566 12,356 11,996 9557 734 ite of myocardial infarc
from cardiovascular ca
Figure 1. Cumulative Incidence Rates of Major Cardiovascular Events than placebo. Analyses o
and Invasive Cancer of Any Type, According to Year of Follow-up, primary composite cardi
in the n−3 Group and the Placebo Group. gested that the risk of m
Analyses were from Cox regression models that were controlled for age, sex, lower in the n−3 group t
and randomization group in Published on November
the vitamin D portion 10, 2018, at NEJM.org.
of the trial (intention-to-
and that there was no s
treat analyses). The insets show the same data on an enlarged y axis.
2087 Table 2. Hazard Ratios and 95% Confidence Intervals for the Primary, Secondary, and Other End Points,
According to Randomized Assignment to n−3 Fatty Acids or Placebo, in Intention-to-Treat Analyses.*

n−3 Group Placebo Group Hazard Ratio

End Point (N = 12,933) (N = 12,938) (95% CI)

no. of participants with event

Cardiovascular disease
Primary end point: major cardiovascular 386 419 0.92 (0.80–1.06)
event†
Cardiovascular event in expanded composite 527 567 0.93 (0.82–1.04)
end point‡
Total myocardial infarction 145 200 0.72 (0.59–0.90)
Total stroke 148 142 1.04 (0.83–1.31)

PCI 0.78 (0.63-0.95)

Death from cardiovascular causes 142 148 0.96 (0.76–1.21)
Other cardiovascular end point§
PCI 162 208 0.78 (0.63–0.95)
CABG
Total coronary heart disease¶
85
308
86
370
0.99 (0.73–1.33)
0.83 (0.71–0.97)
TCHD 0.83 (0.71-0.97)
Death IAM 0.50 (0.26-0.97)
Ischemic stroke 111 116 0.96 (0.74–1.24)
Hemorrhagic stroke 25 19 1.32 (0.72–2.39)
Death from coronary heart disease 37 49 0.76 (0.49–1.16)
Death from myocardial infarction
Death from stroke
13
22
26
20
0.50 (0.26–0.97)
1.10 (0.60–2.01)
Total IAM 0.72 (0.55-0.93)
Cancer
Primary end point: invasive cancer of any type 820 797 1.03 (0.93–1.13)
Breast cancer 117 129 0.90 (0.70–1.16)
Prostate cancer 219 192 1.15 (0.94–1.39)
Colorectal cancer 54 44 1.23 (0.83–1.83)
Death from cancer 168 173 0.97 (0.79–1.20)
Death from any cause 493 485 1.02 (0.90–1.15)
Analyses excluding the first 2 yr of follow-up
Major cardiovascular event 269 301 0.89 (0.76–1.05)
Total myocardial infarction 94 131 0.72 (0.55–0.93)
Invasive cancer of any type
Death from cancer
536
126
476
135
1.13 (1.00–1.28)
0.93 (0.73–1.19)
TCHD: Total Coronary Heart Disease
Death from any cause 371 381 0.97 (0.84–1.12)

* Analyses were from Cox regression models that were controlled for age, sex, and randomization group in the vitamin D
portion of the trial. The 95% confidence intervals were not adjusted for multiple comparisons.
† This end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes.
‡ This end point was a composite of myocardial infarction, stroke, death from cardiovascular causes, or coronary revas-
cularization (percutaneous coronary intervention [PCI] or coronary-artery bypass grafting [CABG]).
§ These events were not prespecified as primary or secondary end points.
¶ This end point was a composite of myocardial infarction, coronary revascularization (PCI or CABG), and death from
coronary heart disease.

Published on November 10, 2018, at NEJM.org.

5
2083

The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Vitamin D Supplements and Prevention

of Cancer and Cardiovascular Disease
JoAnn E. Manson, M.D., Dr.P.H., Nancy R. Cook, Sc.D., I-Min Lee, M.B., B.S., Sc.D.,
William Christen, Sc.D., Shari S. Bassuk, Sc.D., Samia Mora, M.D., M.H.S.,
Heike Gibson, Ph.D., David Gordon, M.A.T., Trisha Copeland, M.S., R.D.,
Denise D’Agostino, B.S., Georgina Friedenberg, M.P.H., Claire Ridge, M.P.H.,
Vadim Bubes, Ph.D., Edward L. Giovannucci, M.D., Sc.D., Walter C. Willett, M.D., Dr.P.H.,
and Julie E. Buring, Sc.D., for the VITAL Research Group*

A BS T R AC T

BACKGROUND
It is unclear whether supplementation with vitamin D reduces the risk of cancer From the Department of Medicine,
or cardiovascular disease, and data from randomized trials are limited. Brigham and Women’s Hospital and
Harvard Medical School (J.E.M., N.R.C.,
METHODS Published on November 10, 2018, at NEJM.org.
I.-M.L., W.C., S.S.B., S.M., H.G., D.G.,
T.C., D.D., G.F., C.R., V.B., E.L.G., W.C.W.,
We conducted a nationwide, randomized, placebo-controlled trial, with a two-by-two
J.E.B.), and the Departments of Epidemi-
 Vitamin D and Cancer and Cardiovascular Disease
2083
Table 1. Characteristics of the Participants at Baseline, According to Randomized Assignment to Vitamin D or Placebo.*

Total Vitamin D Group Placebo Group

Characteristic (N = 25,871) (N = 12,927) (N = 12,944)
Female sex — no. (%) 13,085 (50.6) 6547 (50.6) 6538 (50.5)
Age — yr 67.1±7.1 67.1±7.0 67.1±7.1
Race or ethnic group — no./total no. (%)†
Non-Hispanic white 18,046/25,304 (71.3) 9013/12,647 (71.3) 9033/12,657 (71.4)
Black 5106/25,304 (20.2) 2553/12,647 (20.2) 2553/12,657 (20.2)
Nonblack Hispanic 1013/25,304 (4.0) 516/12,647 (4.1) 497/12,657 (3.9)
Asian or Pacific Islander 388/25,304 (1.5) 188/12,647 (1.5) 200/12,657 (1.6)
Native American or Alaskan native 228/25,304 (0.9) 118/12,647 (0.9) 110/12,657 (0.9)
Other or unknown 523/25,304 (2.1) 259/12,647 (2.0) 264/12,657 (2.1)
Body-mass index‡ 28.1±5.7 28.1±5.7 28.1±5.8
Current smoking — no./total no. (%) 1836/25,485 (7.2) 921/12,729 (7.2) 915/12,756 (7.2)
Hypertension treated with medication — no./total no. 12,791/25,698 (49.8) 6352/12,834 (49.5) 6439/12,864 (50.1)
(%)
Current use of cholesterol-lowering medication — 9524/25,428 (37.5) 4822/12,700 (38.0) 4702/12,728 (36.9)
no./total no. (%)
Diabetes — no./total no. (%) 3549/25,828 (13.7) 1812/12,903 (14.0) 1737/12,925 (13.4)

* Plus–minus values are means ±SD. Percentages may not sum to 100 because of rounding. There were no significant differences between
the groups with regard to the baseline characteristics.
† Race and ethnic group were reported by the participants.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters. Data were missing for 2.4% of the partici-
pants.

Published on November 10, 2018, at NEJM.org.

line 25-hydroxyvitamin D levels varied according Cancer
 Vitamin
2083 D and Cancer and Cardiovascular Disease

3. The findings suggest that

A Invasive Cancer of Any Type
ified the effect of vitamin D Placebo
0.06 Hazard ratio, 0.96 (95% CI, 0.88–1.06)
1.0
0.05 P=0.47
0.9 Vitamin D
sease and All-Cause 0.04
0.8

Cumulative Incidence
0.7 0.03
here were 805 major cardio- 0.6 0.02
ocardial infarction, stroke, or 0.5 0.01
h), with events in 396 partici- 0.4
0.00
D group and 409 participants 0.3 0 1 2 3 4 5 6
p (hazard ratio, 0.97; 95% CI, 0.2
9) (Table 2). Supplementation 0.1
o did not affect the risk of 0.0
0 1 2 3 4 5 6
scular end points (Table 2).
Years since Randomization
icant differences between the
spect to the cumulative inci- No. at Risk
Placebo 12,944 12,765 12,567 12,345 11,985 9543 746
diovascular events (Fig. 2B) Vitamin D 12,927 12,738 12,543 12,341 11,992 9557 744
effect modification according
eristics or randomization to B Major Cardiovascular Events
intervention (Table 3) or ac- Placebo
al cardiovascular risk factors 1.0
0.06
Published on November 10, 2018, at NEJM.org.
Hazard ratio, 0.97 (95% CI, 0.85–1.12)
0.05 P=0.69
plementary Appendix). There 0.9 Vitamin D
 nt differences between the
ct 2083
to the cumulative inci- No. at Risk
Placebo 12,944 12,765 12,567 12,345 11,985 9543 746
vascular events (Fig. 2B) Vitamin D 12,927 12,738 12,543 12,341 11,992 9557 744
ct modification according
tics or randomization to B Major Cardiovascular Events
rvention (Table 3) or ac- Placebo
0.06
ardiovascular risk factors 1.0 Hazard ratio, 0.97 (95% CI, 0.85–1.12)
0.05 P=0.69
mentary Appendix). There 0.9 Vitamin D

any cause; the numbers of 0.8 0.04

Cumulative Incidence
ar in the vitamin D group 0.7 0.03

(485 and 493 deaths, re- 0.6 0.02

0.5
0.99; 95% CI, 0.87 to 1.12). 0.01
0.4
data for nonadherence did 0.00
0.3 0 1 2 3 4 5 6
e results. No meaningful
0.2
major cardiovascular events
0.1
e occurred after data from 0.0
follow-up were excluded 0 1 2 3 4 5 6
Years since Randomization
No. at Risk
Placebo 12,944 12,862 12,747 12,593 12,289 9841 766
Vitamin D 12,927 12,842 12,723 12,593 12,314 9862 774
nt differences between the
t to incident diagnoses of
Figure 2. Cumulative Incidence Rates of Invasive Cancer of Any Type
stones, or gastrointestinal
n the Supplementary Ap-
and Major Cardiovascular Events, According to Year of Follow-up,
in the Vitamin D Group and Placebo Group.
Published on November 10, 2018, at NEJM.org.
2080

The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Dapagliflozin and Cardiovascular Outcomes

in Type 2 Diabetes
S.D. Wiviott, I. Raz, M.P. Bonaca, O. Mosenzon, E.T. Kato, A. Cahn, M.G. Silverman,
T.A. Zelniker, J.F. Kuder, S.A. Murphy, D.L. Bhatt, L.A. Leiter, D.K. McGuire,
J.P.H. Wilding, C.T. Ruff, I.A.M. Gause-Nilsson, M. Fredriksson, P.A. Johansson,
A.-M. Langkilde, and M.S. Sabatine, for the DECLARE–TIMI 58 Investigators*

A BS T R AC T
BACKGROUND
The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium– The authors’ full names, academic de-
glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, grees, and affiliations are listed in the Ap-
pendix. Address reprint requests to Dr.
is undefined. Wiviott at the TIMI Study Group, Division
METHODS of Cardiovascular Medicine, Brigham
We randomly assigned patients with type 2 diabetes Published
who had or onwere November
at risk for ath- 10, 2018, at NEJM.org.
and Women’s Hospital, Hale Building for
Transformative Medicine, 60 Fenwood
erosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The pri- Rd., 7th Fl., Boston, MA 02115, or at
• The primary safety outcome was a composite of major
adverse cardiovascular events (MACE), defined as
cardiovascular death, myocardial infarction, or ischemic
stroke.
• The primary efficacy outcomes were MACE and a composite
of cardiovascular death or hospitalization for heart failure.
• Secondary efficacy outcomes were a renal composite (≥40%
decrease in estimated glomerular filtration rate to <60 ml, new
end-stage renal disease, or death from renal or
cardiovascular causes) and death from any cause.

Published on November 10, 2018, at NEJM.org.

 Dapagliflozin in Type 2 Diabetes

Table 1. Baseline Characteristics of the Patients.*

Dapagliflozin Placebo

• El estudio incluyó 17.160

Characteristic (N = 8582) (N = 8578)
Age — yr 63.9±6.8 64.0±6.8
Female sex — no. (%) 3171 (36.9) 3251 (37.9)

pacientes con diabetes

Race — no. (%)†
White 6843 (79.7) 6810 (79.4)
Black 295 (3.4) 308 (3.6)

(10.186 en prevención
Asian 1148 (13.4) 1155 (13.5)
Other 296 (3.4) 305 (3.6)
Region — no. (%)
North America 2737 (31.9) 2731 (31.8)

primaria y 6.974 con

Europe 3806 (44.3) 3823 (44.6)
Latin America 946 (11.0) 931 (10.9)
Asia–Pacific 1093 (12.7) 1093 (12.7)

enfermedad
Body-mass index‡ 32.1±6.0 32.0±6.1
Median duration of type 2 diabetes (IQR) — yr 11.0 (6.0–16.0) 10.0 (6.0–16.0)
Glycated hemoglobin — % 8.3±1.2 8.3±1.2

cardiovascular) a recibir
Systolic blood pressure — mm Hg 135.1±15.3 134.8±15.5
Estimated glomerular filtration rate — ml/min/1.73 m2 85.4±15.8 85.1±16.0
Established atherosclerotic cardiovascular disease — no. (%) 3474 (40.5) 3500 (40.8)
History of coronary artery disease — no. (%) 2824 (32.9) 2834 (33.0)

dapagliflozina 10 mg frente
History of peripheral artery disease — no. (%) 522 (6.1) 503 (5.9)
History of cerebrovascular disease — no. (%) 653 (7.6) 648 (7.6)
History of heart failure — no. (%) 852 (9.9) 872 (10.2)

a placebo durante un
Glucose-lowering therapies — no. (%)
Insulin 3567 (41.6) 3446 (40.2)
Metformin 7020 (81.8) 7048 (82.2)

seguimiento de 4,2 años.

Sulfonylurea 3615 (42.1) 3707 (43.2)
DPP-4 1418 (16.5) 1470 (17.1)
GLP-1 receptor agonist 397 (4.6) 353 (4.1)
Cardiovascular therapies — no. (%)
Antiplatelet agents 5245 (61.1) 5242 (61.1)
ACE inhibitor or ARB 6977 (81.3) 6973 (81.3)
Beta-blocker 4498 (52.4) 4532 (52.8)
Statin or ezetimibe 6432 (74.9) 6436 (75.0)
Diuretics 3488 (40.6) 3479 (40.6)

* Plus–minus values are means ±SD. There were no significant differences between the groups in the characteristics at
baseline. Percentages may not total 100 because of rounding. ACE denotes angiotensin-converting enzyme, ARB angio-
tensin-receptor blocker, DPP-4 dipeptidyl peptidase 4, GLP-1 glucagon-like peptide 1, and IQR interquartile range.
† Race was reported by the patient.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.

placebo group; hazard ratio, 0.83; 95% CI, 0.71 ratio, 0.84; 95% CI, 0.67 to 1.04; P = 0.99 for in-
to 0.98) and in the subgroup of patients with teraction) (Fig. 3). Dapagliflozin did not result in
2080

A Cardiovascular Death or Hospitalization for Heart Failure B MACE

100 6 Hazard ratio, 0.83 (95% CI, 0.73–0.95) 100 10 Hazard ra
90 P=0.005 for superiority 90 9 P=0.17 fo
5 Placebo 8

Cumulative Incidence (%)

Cumulative Incidence (%)

80 80
4 7
70 70 6
60 3 Dapagliflozin 60 5
4
17%40
50 2 50
3
40
1 2
30 30 1
20 0 20 0
0 180 360 540 720 900 1080 1260 1440 0 180 36
10 10
0 0
0 180 360 540 720 900 1080 1260 1440 0 180 360
Days
No. at Risk No. at Risk
Placebo 8578 8485 8387 8259 8127 8003 7880 7367 5362 Placebo 8578 8433 8281 8
Dapagliflozin 8582 8517 8415 8322 8224 8110 7970 7497 5445 Dapagliflozin 8582 8466 8303 8

C Renal Composite D Death from Any Cause

100 6 6 Hazard ra 100
90
Published on November 10, 2018, at NEJM.org.
Hazard ratio, 0.76 (95% CI, 0.67–0.87)
90
5 Placebo 5
)

)
2080 The n e w e ng l a n d j o u r na l of m e dic i n e

A Cardiovascular Death or Hospitalization for Heart Failure

P Value for
Subgroup Dapagliflozin Placebo Hazard Ratio (95% CI) Interaction
no. of events/no. of patients
Total cohort 417/8582 496/8578 0.83 (0.73–0.95)
Risk group 0.99
ASCVD 272/3474 325/3500 0.83 (0.71–0.98)
MRF 145/5108 171/5078 0.84 (0.67–1.04)
History of heart failure 0.60
Yes 142/852 172/872 0.79 (0.63–0.99)
No 275/7730 324/7706 0.84 (0.72–0.99)
eGFR 0.37
≥90 ml/min/1.73 m2 163/4137 163/4025 0.96 (0.77–1.19)
60 to <90 ml/min/1.73 m2 199/3838 252/3894 0.79 (0.66–0.95)
<60 ml/min/1.73 m2 55/606 81/659 0.78 (0.55–1.09)
0.30 0.50 1.0 1.5 2.0

Dapagliflozin Placebo
Better Better

B MACE
P Value for
Subgroup Dapagliflozin Placebo Hazard Ratio (95% CI) Interaction
no. of events/no. of patients
Total cohort 756/8582 803/8578 Published on November 10, 2018, at NEJM.org.
0.93 (0.84–1.03)
Risk group 0.25
 2080
talization for Heart Failure B MACE
ratio, 0.83 (95% CI, 0.73–0.95) 100 10 Hazard ratio, 0.93 (95% CI, 0.84–1.03)
for superiority 90 9 P=0.17 for superiority
Placebo 8 Placebo

Cumulative Incidence (%)

80
7
70 6
Dapagliflozin
Dapagliflozin 60 5
50 4
3
40
2
30 1
20 0
60 540 720 900 1080 1260 1440 0 180 360 540 720 900 1080 1260 1440
10
0
540 720 900 1080 1260 1440 0 180 360 540 720 900 1080 1260 1440
Days Days
No. at Risk
8259 8127 8003 7880 7367 5362 Placebo 8578 8433 8281 8129 7969 7805 7649 7137 5158
8322 8224 8110 7970 7497 5445 Dapagliflozin 8582 8466 8303 8166 8017 7873 7708 7237 5225

D Death from Any Cause

ratio, 0.76 (95% CI, 0.67–0.87) 100 6 Hazard ratio, 0.93 (95% CI, 0.82–1.04)
90
Placebo 5
Published on November 10, 2018, at NEJM.org.
ce (%)

80
70 4 Dapagliflozin
Placebo
 0.30 0.50 1.0 1.5 2.0
2080
Dapagliflozin Placebo
Better Better

B MACE
P Value for
Subgroup Dapagliflozin Placebo Hazard Ratio (95% CI) Interaction
no. of events/no. of patients
Total cohort 756/8582 803/8578 0.93 (0.84–1.03)
Risk group 0.25
ASCVD 483/3474 537/3500 0.90 (0.79–1.02)
MRF 273/5108 266/5078 1.01 (0.86–1.20)
History of heart failure 0.46
Yes 153/852 151/872 1.01 (0.81–1.27)
No 603/7730 652/7706 0.92 (0.82–1.02)
eGFR 0.99
≥90 ml/min/1.73 m2 304/4137 309/4025 0.94 (0.80–1.10)
60 to <90 ml/min/1.73 m2 367/3838 390/3894 0.95 (0.82–1.09)
<60 ml/min/1.73 m2 85/606 104/659 0.92 (0.69–1.23)
0.30 0.50 1.0 1.5 2.0

Dapagliflozin Placebo
Better Better

Figure 3. Major Subgroup Analyses of the Primary Efficacy Outcomes.

The two primary efficacy outcomes were a composite of cardiovascular death or hospitalization for heart failure and
MACE. ASCVD denotes atherosclerotic cardiovascular disease, and MRF multiple risk factors with no evidence of
ASCVD.
Published on November 10, 2018, at NEJM.org.
 Placebo 8578 8485 8387 8259 8127 8003 7880 7367 5362 Placebo 8578 8433 8281 812
2080 Dapagliflozin 8582 8517 8415 8322 8224 8110 7970 7497 5445 Dapagliflozin 8582 8466 8303 816

C Renal Composite D Death from Any Cause

100 6 Hazard ratio, 0.76 (95% CI, 0.67–0.87) 100 6 Hazard ratio,
90 90
5 Placebo 5

Cumulative Incidence (%)

Cumulative Incidence (%)

80 80
70 4 70 4

60 3 60 3
Dapagliflozin
50 50
40
2

1
24%
40
2

1
30 30
20 0 20 0
0 180 360 540 720 900 1080 1260 1440 0 180 360
10 10
0 0
0 180 360 540 720 900 1080 1260 1440 0 180 360 540
Days
No. at Risk No. at Risk
Placebo 8578 8508 8422 8326 8200 8056 7932 7409 5389 Placebo 8578 8542 8484 841
Dapagliflozin 8582 8533 8436 8347 8248 8136 8009 7534 5472 Dapagliflozin 8582 8554 8495 843

Figure 1. Major Cardiovascular and Renal Outcomes and Death from Any Cause.
Shown is the cumulative incidence of the two primary efficacy outcomes of cardiovascular death or hospi
Publishedevents
(Panel A) and major adverse cardiovascular on November
(MACE), defined10, 2018, at NEJM.org.
as cardiovascular death, myocardial
(Panel B). Dapagliflozin was noninferior to placebo with respect to the primary safety outcome of MACE
 No. at Risk
8259
20808127 8003 7880 7367 5362 Placebo 8578 8433 8281 8129 7969 7805 7649 7137 5158
8322 8224 8110 7970 7497 5445 Dapagliflozin 8582 8466 8303 8166 8017 7873 7708 7237 5225

D Death from Any Cause

d ratio, 0.76 (95% CI, 0.67–0.87) 100 6 Hazard ratio, 0.93 (95% CI, 0.82–1.04)
90
Placebo 5

Cumulative Incidence (%)

80
70 4 Dapagliflozin
Placebo
60 3
Dapagliflozin
50 2
40
1
30
20 0
360 540 720 900 1080 1260 1440 0 180 360 540 720 900 1080 1260 1440
10
0
540 720 900 1080 1260 1440 0 180 360 540 720 900 1080 1260 1440
Days Days
No. at Risk
8326 8200 8056 7932 7409 5389 Placebo 8578 8542 8484 8414 8337 8258 8184 7741 5715
8347 8248 8136 8009 7534 5472 Dapagliflozin 8582 8554 8495 8437 8369 8305 8207 7763 5715

r and Renal Outcomes and Death from Any Cause.

dence of the two primary efficacy outcomes of cardiovascular death or hospitalization for heart failure
cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke
Published
noninferior to placebo with respect to the primary safety outcome of MACE on November
(upper boundary 10, 2018, at NEJM.org.
of the 95% CI,
ty). Also shown is the cumulative incidence of the secondary efficacy outcomes of a renal composite
 Dapagliflozin in Type 2 Diabetes
2080

Dapagliflozin Placebo
Outcome (N=8582) (N=8578) Hazard Ratio (95% CI) P Value
rate/1000 rate/1000
no. (%) patient-yr no. (%) patient-yr
Cardiovascular death or hospitalization 417 (4.9) 12.2 496 (5.8) 14.7 0.83 (0.73−0.95) 0.005
for heart failure
MACE 756 (8.8) 22.6 803 (9.4) 24.2 0.93 (0.84−1.03) 0.17
≥40% decrease in eGFR 370 (4.3) 10.8 480 (5.6) 14.1 0.76 (0.67−0.87)
to <60 ml/min/1.73 m2,
ESRD, or death from renal
or cardiovascular cause
Death from any cause 529 (6.2) 15.1 570 (6.6) 16.4 0.93 (0.82−1.04)
Hospitalization for heart failure 212 (2.5) 6.2 286 (3.3) 8.5 0.73 (0.61−0.88)
Myocardial infarction 393 (4.6) 11.7 441 (5.1) 13.2 0.89 (0.77−1.01)
Ischemic stroke 235 (2.7) 6.9 231 (2.7) 6.8 1.01 (0.84−1.21)
Death from cardiovascular cause 245 (2.9) 7.0 249 (2.9) 7.1 0.98 (0.82−1.17)
Death from noncardiovascular cause 211 (2.5) 6.0 238 (2.8) 6.8 0.88 (0.73−1.06)
≥40% decrease in eGFR 127 (1.5) 3.7 238 (2.8) 7.0 0.53 (0.43−0.66)
to <60 ml/min/1.73 m2,
ESRD, or death from
renal cause
0.40 0.50 1.0 1.5

Dapagliflozin Placebo
Better Better

Figure 2. Key Efficacy Outcomes and Their Components.

Two-sided P values are shown for the two primary efficacy outcomes of cardiovascular death or hospitalization for heart failure and
MACE. The abbreviation eGFR denotes estimated glomerular filtration rate, and ESRD end-stage renal disease.
Published on November 10, 2018, at NEJM.org.
2080
Table 2. Safety Events.*

Dapagliflozin Placebo Hazard Ratio

Event (N = 8574) (N = 8569) (95% CI) P Value

no. (%)
Serious adverse event 2925 (34.1) 3100 (36.2) 0.91 (0.87–0.96) <0.001
Adverse event leading to discontinuation 693 (8.1) 592 (6.9) 1.15 (1.03–1.28) 0.01
of trial regimen
Major hypoglycemic event 58 (0.7) 83 (1.0) 0.68 (0.49–0.95) 0.02
Diabetic ketoacidosis 27 (0.3) 12 (0.1) 2.18 (1.10–4.30) 0.02
Amputation 123 (1.4) 113 (1.3) 1.09 (0.84–1.40) 0.53
Fracture 457 (5.3) 440 (5.1) 1.04 (0.91–1.18) 0.59
Symptoms of volume depletion 213 (2.5) 207 (2.4) 1.00 (0.83–1.21) 0.99
Acute kidney injury 125 (1.5) 175 (2.0) 0.69 (0.55–0.87) 0.002
Genital infection 76 (0.9) 9 (0.1) 8.36 (4.19–16.68) <0.001
Urinary tract infection 127 (1.5) 133 (1.6) 0.93 (0.73–1.18) 0.54
Cancer 481 (5.6) 486 (5.7) 0.99 (0.87–1.12) 0.83
Bladder cancer 26 (0.3) 45 (0.5) 0.57 (0.35–0.93) 0.02
Breast cancer 36 (0.4) 35 (0.4) 1.02 (0.64–1.63) 0.92
Hypersensitivity 32 (0.4) 36 (0.4) 0.87 (0.54–1.40) 0.57
Hepatic event 82 (1.0) 87 (1.0) 0.92 (0.68–1.25) 0.60

* Additional details, data sources, and a complete list of serious adverse events are provided in the Supplementary
Appendix. P values and 95% confidence intervals have not been adjusted for multiple comparisons.

Published on November 10, 2018, at NEJM.org.

efficacy outcome (the composite of cardiovascu- use of SGLT2 inhibitors in patients with athero-
lar death or hospitalization for heart failure), sclerotic cardiovascular disease. These new data
 DECLARE – TIMI 58
Multicenter Trial to Evaluate the Effect of
Dapagliflozin on the Incidence of Cardiovascular Events
Discussant

Javed Butler, MD, MPH, MBA

Patrick H. Lehan Chair in Cardiovascular Research
Chairman, Department of Medicine
Professor of Medicine and Physiology
University of Mississippi
Please specifically note RWI relevant to the management of diabetes
Astra Zeneca, Boehringer Ingelheim, Janssen, Sanofi, Novo Nordisk and Merck
 Type 2 Diabetes Mellitus - Facts
• High-risk for mortality
• CV mortality - number 1 cause of death
• Risk for “macrovascular” complications
– MI, PVD, and Stroke
• Risk for “microvascular” complications
– Retinopathy, Neuropathy, and Nephropathy
• Risk for heart failure
• Worse outcomes with these complication
• PREVENTION and TREATMENT of these complications
central to T2DM management
 DECLARE – TIMI 58
• Well conducted trial
• Highest proportion of patients with risk factor
but without ASCVD
• Confirm and replicate data from other studies
with SGLT2i
– Safety
– HbA1c
– Blood pressure
– Weight
SGLT2i and T2DM

Subodh Verma et al. Lancet 2018

 Interpretation
• SGLT2i data cannot be taken in isolation from other
T2DM trials and therapies
• All CV complications are all important
• Microvascular and macrovascular designation
– Arbitrary
– Biologically overlapping
– Not distinct concepts
• Macrovascular does not include heart failure
• CKD in T2DM should not be group in “microvascular”
diseases with neuropathy and retinopathy
 Treatment - T2DM
• ‘Micro’ and ‘macro’ vascular disease is an obsolete concept
• ‘Primary’ and ‘secondary’ prevention cohort for one disease may or may not
apply to a different disease
• For patients similar to those studied in the SGLT2i trials – these drugs should
be used for HF risk reduction irrespective of their effect on MACE outcomes
• For patients not studied adequately e.g. T2DM with no risk factors or with
manifest HF – further data are needed
2088

Review

Heart failure in diabetes: effects of anti-hyperglycaemic

drug therapy
Richard E Gilbert, Henry Krum

Individuals with diabetes are not only at high risk of developing heart failure but are also at increased risk of dying Lancet 2015; 385: 2107–17
from it. Fortunately, antiheart failure therapies such as angiotensin-converting-enzyme inhibitors, β blockers and Division of Endocrinology,
mineralocorticoid-receptor antagonists work similarly well in individuals with diabetes as in individuals without the St Michael’s Hospital,
University of Toronto, On,
disease. Response to intensive glycaemic control and the various classes of antihyperglycaemic agent therapy is
Canada (Prof R E Gilbert MBBS);
substantially less well understood. Insulin, for example, induces sodium retention and thiazolidinediones increase and Centre of Cardiovascular
the risk of heart failure. The need for new glucose-lowering drugs to show cardiovascular safety has led to the Research and Education in
unexpected finding of an increase in the risk of admission to hospital for heart failure in patients treated with the Therapeutics, Monash
University, Melbourne, VIC,
dipeptidylpeptidase-4 (DPP4) inhibitor, saxagliptin, compared with placebo. Here we review the relation between
Australia (Prof H Krum MBBS)
glycaemic control and heart failure risk, focusing on the state of knowledge for the various types of antihyperglycaemic
Correspondence to:
drugs that are used at present. Prof Richard E Gilbert, Division of
Endocrinology, St Michael’s
Introduction emphasis on heart failure in diabetes education seems to Hospital, 61 Queen Street East,
Toronto, Ontario Canada
Not fitting neatly into the microvascular or macrovascular justify Bell’s labelling of it as “the frequent, forgotten, and
categories, heart failure, despite its frequency, morbidity, Lancet 2015; 385: 2107–17
often fatal complication of diabetes”.9
M5C 2T2
richard.gilbert@utoronto.ca
and high mortality rate has been relegated to an inferior From a cardiology perspective, although diabetes is a
position in the hierarchy of diabetes complications. This noted comorbidity in roughly a third of patients that carry
2088
400 Diabetic individuals Glycaemic control
Non-diabetic individuals Observational studies exa
350 control suggest a positive
300
of heart failure. In the U
with newly diagnosed

Prevalence rate per 1000

250 between heart-failure risk
200
was evident such that a 1
(HbA1c ) was associated w
150 development of heart failu
Although observational
100
glycaemic control might
50 failure in at-risk individ
seem to be the case.
0
<45 45–54 55–64 65–74 75–84 85–94 ACCORD, ADVANCE, an
Age at baseline (years) intensive glycaemic cont
when combined with th
Figure 1: Age-associated prevalence of heart failure in diabetic and
non-diabetic individuals show a statistically sign
Reproduced from Nichols and colleagues 4 infarction in individuals
than standard glycaemic c
Heart failure Lancet 2015; 385: owing2107–17
to the importance
10
pathogenesis of heart fail