does hypoglycemia increase the risk of cardiovascular events?karolinska institutet, stockholm county...

Linda G Mellbin

Lars Rydén, Matthew Riddle, Jeffrey Probstfield,

Julio Rosenstock, Rafael Díaz, Salim Yusuf, Hertzel Gerstein

on behalf of

The ORIGIN Trial Investigators

Does Hypoglycemia Increase the Risk

of Cardiovascular Events? A report from

Research grants

Swedish Heart-Lung Foundation, Swedish Diabetes Association,

Swedish Cardiac Society,

Karolinska Institutet, Stockholm County Council

MSD, Sanofi

Lecture fees MSD, Sanofi, Novartis, Bayer AG, AstraZeneca, Lilly, Roche

Consulting fees/Clinical trials Roche, GSK, Sanofi, AstraZeneca

Linda G Mellbin Declaration of interest

Hypoglycemia in focus when managing people with diabetes

Diabetes Care 2013; 36: 1384

From current gaps in knowledge

➸ “Hypoglycemia continues to cause considerable

morbidity and even mortality…”

➸ “The impact of hypoglycemia on such outcomes need

to be better defined and mechanisms understood…”

Study objectives

➸ To assess the relationship between hypoglycemia

and cardiovascular events in people with

dysglycaemia at high cardiovascular risk

➸ To analyse whether any such relationship differs in

people allocated to glucose lowering with basal

insulin glargine versus standard glycaemic care with

oral agents

Glargine Standard Care

Omega 3 FA Glargine + Omega 3 Omega 3

Placebo Glargine + Placebo Placebo

In high risk people with IFG, IGT or early diabetes,

does insulin replacement therapy targeting fasting

normoglycemia (< 5.3 mM or 95 mg/dl) with insulin

glargine, reduce CV outcomes more than standard

approaches to dysglycemia?

ORIGIN Design

ORIGIN Patient population

Spain

Norway

PortugalTurkey

Ukraine

Greece

Ireland

Greenland

Iceland

United States

Canada

MexicoThe Bahamas

Cuba

Panama

El Salvador Nicaragua

Costa Rica

JamaicaHaiti

Dom. Rep.

Argentina

Bolivia

Colombia

Venezuela

Peru

Brazil

Guyana

Chile

Ecuador

Kenya

Ethiopia

EritreaSudan

Egypt

Niger

MauritaniaMali

Nigeria

Somalia

Namibia

Libya

Chad

TanzaniaDem. Rep.

Of Congo

Angola

Algeria

Madagascar

Zambia

Gabon

Tunisia

Morocco

Swaziland

Lesotho

Liberia

Sierra Leone

Guinea

Gambia

Congo

Senegal

Guinea Bissau

IsraelLebanon

GeorgiaKyrgyzstan

Yemen

IraqIran

Oman

Saudi Arabia

Russia

India

China

Kazakhstan

Nepal

Vietnam

Sri Lanka

Papua

New

Guinea

Brunei

Philippines

Malaysia

Indonesia

Japan

Mongolia

S. KoreaN. Korea

Australia

New Zealand

United Kingdom

Fiji

ZimbabweVanuatu

Uzbekistan

Uruguay

U.A.E.

Uganda

Turkmenistan

Togo

Thailand

Tajikistan

Syria

Sweden

Suriname

South Africa

Antarctica

Solomon Islands

Sao Tome & Principe

Rwanda

Qatar

Poland

Paraguay

Pakistan

Neth.

Mozambique

Laos

Kuwait

Honduras

Guatemala

Ghana

Germany

French Guiana

France

Finland

Equatorial Guinea

Dijbouti

Denmark

Cyprus

Cote

d'Ivoire Central African Republic

Cape Verde

Cameroon

Cambodia

Burundi

Burkina Faso

Bulgaria

Botswana

Bhutan

Benin

Belize

Bangla-

desh

Azerb.

Afghanistan

Western Sahara

(Occupied by Morocco)

Timor Leste (East Timor)

Myanmar

(Burma)

ATLANTIC

PACIFIC

PACIFIC

INDIAN

OCEAN

OCEAN

OCEAN

OCEAN

Bel.Belarus

HungaryRomania

Switz.Italy

Jordan

n=12537 from 573 sites in 40 countries

Mean Age = 63.5 yrs; Females = 35%

Diabetes 82%; IFG or IGT 12%

ORIGIN Glycemic control – FPG

6,9

5,2 5 5 5,1 5,1 5,2 5,2 5,3

6,9

6,6 6,8

4,0

4,5

5,0

5,5

6,0

6,5

7,0

7,5

8,0

0 1 2 3 4 5 6 7 End

FP

G (

mm

ol/L)

Follow up (years)

Glargine

Standard

IQR 4.4 – 5.8

IQR 5.7 – 7.9

F

PG

(m

mo

l/l)

Main outcome Cardiovascular death, myocardial Infarction or stroke

(Gerstein et al. NEJM 2012;367:319)

Adjusted Hazard Ratio 1.02 (0.94-1.11)

P=0.63 by log rank test

Standard care

Insulin glargine

Pro

port

ion

with e

vents

Follow up (years)

➸ Non-severe hypoglycemia symptoms confirmed by a glucose ≤3.0 mmol/l [≤54 mg/dl]

➸ Severe hypoglycemia symptomatic hypoglycemia with need for assistance and

either

a) prompt recovery with oral carbohydrate, intravenous

glucose, or glucagon

and/or

b) documented glucose ≤2.0 mmol/l [≤36 mg/dl]

Hypoglycemia Definitions

➸ The primary composite outcome

cardiovascular death or nonfatal myocardial

infarction or stroke

➸ Mortality

➸ Cardiovascular mortality

➸ Arrhythmic death

sudden unexpected death, death from

documented arrhythmia, unwitnessed death

and resuscitated cardiac arrest

Outcome measures Definitions

Scores were developed for hypoglycemic episodes including the following independent variables

➸ Demographics age, gender, ethnicity, education, DM, prior CV event, hypertension, depression, current smoking, alcohol >2/wk

➸ Pharmacological treatment metformin, SU, statin, ACE/ARB, beta-blocker, thiazides, antiplatelets

➸ Measurements BMI, WHR, HbA1c, FPG, HDL, LDL, TG, sCr,

ACR ≥30 mg/g, MMSE

Statistical considerations Propensity scores

➸ Any episode of hypoglycemia

glargine 2 614

standard 904

Hypoglycemic episodes Total number = 3 518

➸ Severe hypoglycemia

glargine 359

standard 113

Glargine (n = 6264)

Standard (n = 6273)

P

Episode % /100py % /100py

Non severe

≥ 1 episode 42 10 14 3 <0.001 No episode 58 86 <0.001

Severe

≥1 episode 6 1.0 2 0.3 <0.001

Hypoglycemia during the trial Prevalence by glucose lowering treatment

Non-severe hypoglycemia

CV death or nonfatal MI or stroke

Mortality

Cardiovascular death

Arrhythmic death

Severe hypoglycemia


Total mortality


Arrhythmic death

p

0.115

<0.001

0.049

0.091

<0.001

<0.001

<0.001

<0.001

HR (95% CI)

1.10 (0.98-1.23)

1.21 (1.08-1.35)

1.16 (1.00-1.34)

1.19 (0.97-1.47)

1.77 (1.39-2.25)

2.05 (1.65-2.55)

2.02 (1.52-2.69)

2.14 (1.43-3.18)

0.5 1 1.5 2 2.5 3 3.5

Risk for an outcome comparing

patients with and without hypoglycemia

Nonsevere hypoglycemia

Severe hypoglycemia

Unadjusted data

0.5 1 1.5 2 2.5 3 3.5

Non-severe hypoglycemia


Mortality


Arrhythmic death

Severe hypoglycemia


Total mortality


Arrhythmic death

p

0.938

0.069

0.701

0.402

<0.001

<0.001

<0.001

0.007

HR (95% CI)

1.00 (0.88-1.12)

1.12 (0.99-1.26)

1.03 (0.88-1.20)

1.10 (0.88-1.36)

1.59 (1.24-2.03)

1.75 (1.39-2.19)

1.71 (1.27-2.30)

1.77 (1.17-2.68)

Nonsevere hypoglycemia

Severe hypoglycemia

Risk for an outcome comparing

patients with and without hypoglycemia

Adjusted (propensity score)

Outcome Nonsevere Severe

Composite

Glargine 1.01 (0.88-1.17) 1.38 (1.03-1.86)

Standard Care 0.95 (0.76-1.18) 2.39 (1.55-3.70)

Standard vs. Glargine 0.93 (0.72-1.20) 1.70 (1.01-2.87)

Mortality

Glargine 1.09 (0.94-1.26) 1.34 (1.00-1.79)

Standard Care 1.18 (0.97-1.45) 3.13 (2.20-4.46)


Hypoglycemia and outcomes Impact of glucose lowering therapy (adjusted)

Outcome Nonsevere Severe

CV Death

Glargine 1.08 (0.90-1.31) 1.38 (0.94-2.01)

Standard Care 0.95 (0.72-1.25) 2.89 (1.80-4.65)


Arrhythmic Death

Glargine 1.18 (0.91-1.53) 1.24 (0.71-2.17)

Standard Care 0.97 (0.66-1.43) 3.66 (1.99-6.76)


Hypoglycemia and outcomes Impact of glucose lowering therapy (adjusted)

30

20

10

0 Primary

outcome

Arrhythmic

mortality

Total

mortality

Cardiovascular

mortality

Glargine none

Standard ≥ 1

Glargine ≥ 1

Standard none

Severe hypoglycemia and outcomes Proportion of participants with an outcome by treatment

% Number of severe

hypoglycaemic episodes

Conclusion

➸ There is a relationship between severe hypoglycaemia & CV outcomes in people with dysglycaemia at high CV risk

➸ This relationship was 2-3 times lower in the insulin-glargine compared to the standard group

➸ In light of more frequent severe hypoglycemia in the insulin group, hypoglycemia caused by insulin-glargine mediated glucose lowering is unlikely to be the cause of CV outcomes

➸ The relationship between severe hypoglycaemia & CV outcomes is likely due to confounding by unmeasured riskfactors for CV outcomes

does hypoglycemia increase the risk of cardiovascular events?karolinska institutet, stockholm county...

Documents