does hypoglycemia increase the risk of cardiovascular events?karolinska institutet, stockholm county...
TRANSCRIPT
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
CV death or nonfatal MI or stroke
Total mortality
Cardiovascular death
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
CV death or nonfatal MI or stroke
Mortality
Cardiovascular death
Arrhythmic death
Severe hypoglycemia
CV death or nonfatal MI or stroke
Total mortality
Cardiovascular death
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)
Standard vs. Glargine 1.10 (0.87-1.40) 2.31 (1.47-3.64)
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)
Standard vs. Glargine 0.89 (0.65-1.22) 2.09 (1.15-3.82)
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)
Standard vs. Glargine 0.86 (0.55-1.35) 2.94 (1.29-6.69)
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