Myocardial Infarction Subtypes in Patients With Type

2 Diabetes Mellitus and the Effect of Liraglutide

Therapy (from the LEADER Trial)
Steven P. Marso, MDa,*, Michael A. Nauck, MDb, Tea Monk Fries, MD PhDc, Søren Rasmussen, PhDc,
Marianne Bach Treppendahl, MD PhDc, and John B. Buse, MD PhDd the LEADER Publication
Committee on behalf of the LEADER Trial Investigators

Diabetes mellitus (DM) is a known risk factor for myocardial infarction (MI); however,
data regarding MI subtypes in people with diabetes are limited. In the Liraglutide Effect
and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial
(n = 9,340), liraglutide significantly reduced the risk of major adverse cardiovascular (CV)
events (composite of CV death, nonfatal MI, or nonfatal stroke) versus placebo in patients
with type 2 DM and high CV risk. Liraglutide also reduced risk of first MI (292 events
with liraglutide vs 339 with placebo). This post hoc analysis characterized MIs (first and
recurrent) occurring in LEADER, by treatment arm and regarding incidence, outcome,
subtype, and troponin levels. A total of 780 MIs (first and recurrent) were reported, with
fewer in the liraglutide-treatment group than in the placebo-treatment group (359 vs 421,
p = 0.022). Numerically fewer MIs were associated with CV death with liraglutide than
with placebo (17 vs 28 fatal MIs, p = 0.28). Symptomatic MIs in both arms were mainly
non–ST-segment elevation MI (555/641) and spontaneous MI (518/641). Numerically greater
proportions of symptomatic MIs were associated with troponin levels ≤5× or ≤10× the
upper reference limit with liraglutide versus placebo (p = 0.16 and p = 0.42, respectively).
At baseline, more liraglutide-treated patients than placebo-treated patients with MI during
the trial had a history of coronary artery bypass graft (p = 0.008), and fewer had periph-
eral arterial disease in the lower extremities (p = 0.005) and >50% stenosis of the coronary
artery, the carotid artery, or other arteries (p = 0.044). In conclusion, this analysis showed
that liraglutide reduces the incidence of MIs in patients with type 2 DM at high CV
risk and may impact the clinical outcomes of MI. © 2018 The Author(s). Published by
Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/). (Am J Cardiol 2018;121:1467–1470)

Diabetes mellitus (DM) is an established risk factor for
coronary heart disease and is associated with an approxi-
mately twofold increase in the risk of myocardial infarction
(MI).1 However, there are limited data regarding the distri-
bution of MI subtypes in people with diabetes. Liraglutide, a
a
HCA Midwest Health Heart & Vascular Institute, Kansas City,
Missouri; bDiabetes Center Bochum-Hattingen, St. Josef Hospital, Ruhr-
University Bochum, Bochum, Germany; cNovo Nordisk A/S, Søborg,
Denmark; and dDepartment of Medicine, University of North Carolina School
of Medicine, Chapel Hill, North Carolina. Manuscript received December
13, 2017; revised manuscript received and accepted February 20, 2018.
The LEADER trial was conducted at 410 sites in 32 countries. A full
list of the investigators in the LEADER trial and their institutions is avail-
able within the Supplementary Appendix of the primary results publication
(Marso et al. New Engl J Med 2016;375:311–322), available at NEJM.org.
This study was supported by Novo Nordisk A/S (Bagsværd, Denmark),
which had a role in the review of the manuscript for scientific accuracy.
Medical writing and editing assistance was provided by Watermeadow
Medical, an Ashfield Company, part of UDG Healthcare plc, funded by Novo
Nordisk A/S, in accordance with Good Publication Practice (GPP3) guide-
lines (http://www.ismpp.org/gpp3).
See page 1470 for disclosure information.
*Corresponding author: Tel: +1 816 276 4800; fax: + 1 816 276 4800.
E-mail address: s.marso@gmail.com (S.P. Marso).
human glucagon-like peptide-1 (GLP-1) analog, is approved
for the treatment of adults with type 2 DM.2,3 The long-term
effects of liraglutide have been assessed in the Liraglutide Effect
and Action in Diabetes: Evaluation of Cardiovascular Outcome
Results (LEADER) cardiovascular (CV) outcomes trial, and
liraglutide has been shown to reduce the risk of major CV
events (CV death, nonfatal MI, or nonfatal stroke) by 13%
versus placebo, both in addition to standard of care.4 Post hoc
analysis of LEADER has also shown that a lower proportion
of patients experienced any MI with liraglutide versus placebo.4
The aim of the present post hoc analysis was to characterize
the MI subtypes in LEADER and to examine differences in
the subtypes observed with liraglutide versus placebo.
Methods
LEADER (NCT01179048) was a double-blind, random-
ized controlled trial including 9,340 patients with type 2 DM
at high risk of CV events, assigned to liraglutide 1.8 mg/
day (or maximum tolerated dose) (n = 4,668) or placebo
(n = 4,672), both in addition to standard of care, with a follow-
up period of 3.5 to 5.0 years.4 Institutional review board or
ethics committee approval was obtained from all participat-
ing centers, and all patients provided written informed consent
before participation.4 There was a comprehensive strategy to

0002-9149/$ - see front matter © 2018 The Author(s). Published by Elsevier Inc. This is an www.ajconline.org
open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.amjcard.2018.02.030
1468 The American Journal of Cardiology (www.ajconline.org)

identify potential MIs, including silent MIs. Strategies in-
cluded investigator-reported adverse events, central
electrocardiogram readings, and blinded sponsor-conducted
Medical Dictionary for Regulatory Activities searches of
adverse events reported throughout the trial. Potential acute
coronary syndromes, including MIs, along with all deaths and
cerebrovascular events and other prespecified end points, were
adjudicated by an external, independent, and blinded event
adjudication committee that, together with the clinical re-
search organization, could report further MI events identified
during the review of medical documents for reported events.
Confirmed MI events were categorized to be either fatal
or nonfatal—by correlation or no correlation with CV death,
as determined by the event adjudication committee—and, by
analysis of the timing of events, to be either first or recur-
rent. MI types were categorized into symptomatic or silent.
Symptomatic MIs were described as ST-segment elevation
myocardial infarction (STEMI) or non-STEMI, by type (type
1: spontaneous MI; type 2: MI secondary to ischemia, due
to an imbalance between oxygen supply and demand; type
3: sudden cardiac death due to suspected MI; type 4a: MI as-
sociated with percutaneous coronary intervention; type 4b:
MI associated with stent thrombosis; and type 5: MI asso-
ciated with coronary artery bypass graft) and, if available, by
quantitative evaluation of biomarkers increased relative to
normal values.4
In this post hoc analysis of MI data from LEADER, the
incidence and outcome of all MIs, and the incidence and clas-
sification of symptomatic MIs according to subtype and
troponin levels, were examined in the liraglutide and placebo
arms. Between-group differences in baseline characteris-
tics, including CV history at screening, were also assessed.
Differences between treatment arms were tested using Poisson
regression adjusted for individual trial observation time (to
compare observed rates for all MIs), chi-squared test (to
compare CV history at screening for patients who experienced
≥1 MI during the trial), and Fisher’s exact test (to compare
the proportions of nonfatal and fatal MIs; STEMI and
non-STEMI events; type 1 and types 2 to 5 [combined] symp-
tomatic MI subtypes; and symptomatic MIs associated with
troponin levels ≤5× upper reference limit [URL] vs >5× URL
or troponin levels ≤10× URL or >10× URL). A p value of
<0.05 was considered statistically significant.
Results
A total of 780 MIs (first and recurrent) were reported during
the trial by 631 patients (liraglutide n = 292, placebo n = 339),
with a significantly lower incidence in the liraglutide-
treatment versus the placebo-treatment group (Table 1). First
MIs represented 81% of all MIs in both liraglutide-treated
and placebo-treated patients, and 19% of all MIs were re-
current events (Table 1). Of the liraglutide-treated patients
who experienced an MI (n = 292), 84% had only 1 MI, 11%
had 2 MIs, and 4% had >2 MIs. Correspondingly, of the
placebo-treated patients who experienced an MI (n = 339),
proportions were 83% (1 MI), 13% (2 MIs), and 4% (>2 MIs).
There was a trend toward a lower proportion of fatal MIs (out
of all MIs) in the liraglutide-treatment than in the placebo-
treatment group, but this difference was without statistical
significance (Table 1).
At baseline, more liraglutide-treated patients with MI during
the trial had a history of coronary artery bypass graft (31%
vs 22%), whereas fewer had peripheral arterial disease in the

Table 1
All myocardial infarctions and symptomatic myocardial infarctions according to subtype
Variable Liraglutide, events Placebo, events p-value

All myocardial infarctions 359 (100%) 421 (100%) 0.022*

First 292 (81%) 339 (81%) –
Recurrent 67 (19%) 82 (19%) –
Symptomatic myocardial infarction 297 (83%) 344 (82%) –
Silent myocardial infarction 62 (17%) 77 (18%) –
Outcome
Nonfatal / fatal 342 (95%) / 17 (5%) 393 (93%) / 28 (7%) 0.28†
Symptomatic myocardial infarctions 297 (100%) 344 (100%)
ST-segment elevation myocardial infarction / non–ST-segment elevation myocardial infarction 48 (16%) / 249 (84%) 38 (11%) / 306 (89%) 0.06†
Type‡
1 / 2–5 241 (81%) / 56 (19%) 277 (81%) / 67 (19%) 0.92†
2 43 (14%) 43 (13%) –
3 5 (2%) 10 (3%) –
4a 4 (1%) 7 (2%) –
4b 4 (1%) 7 (2%) –
5 0 (0%) 0 (0%) –
Troponin available§ 229 (100%) 282 (100%)
≤5x upper reference limit / > 5x upper reference limit 90 (39%) / 139 (61%) 93 (33%) / 189 (67%) 0.16†
≤10x upper reference limit / > 10x upper reference limit 111 (48%) / 118 (52%) 126 (45%) / 156 (55%) 0.42†

* Poisson regression adjusted for individual trial observation time.

†
Fisher’s exact test.
‡
Type 1, spontaneous myocardial infarction; type 2, myocardial infarction secondary to ischemia, due to an imbalance between oxygen supply and demand;
type 3, sudden cardiac death due to suspected myocardial infarction; type 4a, myocardial infarction associated with percutaneous coronary intervention;
type 4b, myocardial infarction associated with stent thrombosis; type 5, myocardial infarction associated with coronary artery bypass graft.
§
Includes patients within each treatment arm with troponin levels available.
 Coronary Artery Disease/Myocardial Infarction Subtypes in LEADER 1469

Table 2
Cardiovascular history at screening
Variable Liraglutide Placebo p-value: liraglutide versus
placebo myocardial
Total cohort Myocardial Total cohort Myocardial
infarction cohort
(n = 4668) infarction cohort (n = 4672) infarction cohort
(n = 292) (n = 339)
With information for cardiovascular history* 4,588 (98%) 287 (98%) 4,603 (99%) 338 (100%) –
Myocardial infarction 1,434 (31%) 136 (47%) 1,373 (29%) 155 (46%) 0.83
Arrhythmia 718 (15%) 52 (18%) 721 (15%) 65 (19%) 0.66
Heart failure 835 (18%) 58 (20%) 832 (18%) 76 (22%) 0.43
(New York Heart Association class I–III)
Ischemic heart disease 2,542 (54%) 206 (71%) 2,517 (54%) 236 (70%) 0.80
Percutaneous coronary intervention performed 1,302 (28%) 139 (48%) 1,266 (27%) 137 (40%) 0.07
Coronary artery bypass graft performed 782 (17%) 90 (31%) 749 (16%) 73 (22%) 0.008
Left ventricular systolic dysfunction 521 (11%) 49 (17%) 478 (10%) 52 (15%) 0.62
Left ventricular diastolic dysfunction 782 (17%) 39 (13%) 799 (17%) 64 (19%) 0.06
Hypertension 4,261 (91%) 266 (91%) 4,250 (91%) 315 (93%) 0.40
Ischemic stroke 512 (11%) 31 (11%) 526 (11%) 38 (11%) 0.81
Transient ischemic attack 257 (6%) 22 (8%) 310 (7%) 31 (9%) 0.47
Hemorrhagic stroke 53 (1%) 1 (0%) 50 (1%) 5 (1%) 0.14
Intracranial artery stenosis 64 (1%) 7 (2%) 46 (1%) 5 (1%) 0.40
Carotid artery stenosis 367 (8%) 32 (11%) 332 (7.1%) 34 (10%) 0.70
Peripheral arterial disease in lower extremities 567 (12%) 29 (10%) 600 (13%) 60 (18%) 0.005
>50% stenosis of coronary, carotid or other arteries 1,187 (25%) 97 (33%) 1,191 (25%) 139 (41%) 0.044

* Based on medical history as reported by the trial investigator for each patient.

lower extremities (10% vs 18%) and >50% stenosis of coro-
nary, carotid, or other arteries (33% vs 41%) compared with
placebo-treated patients with MI during the trial (p <0.05 for
all, Table 2). Between-group comparisons for other aspects
of CV history at baseline were not statistically significant
(Table 2), and there were no between-group differences in
other baseline characteristics (data not shown).
The majority (82%, 641/780) of all MIs across treatment
groups were symptomatic, and of these, 87% (555/641) were
non-STEMI versus 13% (86/641) STEMI (Table 1). There
was a trend toward a higher incidence of STEMI events in
the liraglutide group versus the placebo group, but the dif-
ference was not statistically significant (proportion of events
between treatment arms, p = 0.06; Table 1). The incidence
of symptomatic type 1 (spontaneous) MIs was higher than
other symptomatic MIs (types 2 to 5) within both treatment
groups (Table 1). Additionally, a nonsignificant trend toward
a greater incidence of MIs associated with troponin levels ≤5×
URL was observed in the liraglutide-treatment group (39%)
than in the placebo-treatment group (33%) (proportion of
events ≤5× URL vs >5× URL between treatment groups,
p = 0.16; Table 1). A similar, nonsignificant trend of the same
direction was observed when the proportions of MIs associ-
ated with troponin levels ≤10× URL were analyzed (Table 1).
Discussion
The incidence of all MIs observed in patients receiving
liraglutide was significantly lower than that in patients re-
ceiving placebo. However, there were no significant differences
in the distribution of the MI subtypes analyzed between
liraglutide- and placebo-treated patients.
Among patients who experienced MI during the trial, dif-
ferences were detected for the proportions of patients receiving
liraglutide versus placebo who had a history of coronary artery
bypass graft, peripheral arterial disease in the lower extremi-
ties, or >50% stenosis of the coronary artery, the carotid artery,
or other arteries at baseline. Because of the relatively low
number of patients affected by each individual CV compli-
cation at baseline and the multiple comparisons made, these
CV history data should be interpreted with caution.
Most symptomatic MIs in both treatment groups were non-
STEMI and type 1 (spontaneous), but no significant differences
between the treatment groups were identified for any of the
MI subtypes analyzed, including MIs with nonfatal or fatal
outcome, STEMI and non-STEMI, type 1 and types 2 to 5
MIs, or MIs with high or low troponin levels. However, there
were some numeric differences in MI subtypes between the
treatment groups, and the lack of power in our study to examine
MI subtypes may obscure genuine differences (a type II error).
The mechanisms underlying the CV benefits of liraglutide
shown in the LEADER trial have not been fully elucidated,
but because of the effects on a composite end point of ath-
erosclerotic events, it has been suggested that it could be due
to an antiatherogenic effect.5 Several mechanistic hypoth-
eses for such an effect have been proposed, including the
favorable effects of liraglutide on weight, lipid profiles, sys-
tolic blood pressure, and anti-inflammatory effects.5,6 A direct
effect of liraglutide on the myocardium has also been
observed.5 Pretreatment with liraglutide before experimen-
tally induced MI was associated with robust cardioprotective
effects versus saline in both wild-type and transgenic mice
with induced inactivation of cardiomyocyte GLP-1 receptor
expression, suggesting cardioprotective actions indepen-
dent of the cardiomyocyte GLP-1 receptor.7 Periprocedural
administration of GLP-1 or liraglutide in humans has also been
shown to have cardioprotective effects for patients with acute
MI and coronary artery disease. 8–13 In line with these
1470 The American Journal of Cardiology (www.ajconline.org)
findings, in liraglutide-treated patients in our analyses, trends
toward a lower proportion of fatal MIs (out of all MIs) and
lower troponin levels (symptomatic MIs) may be sugges-
tive of reduced infarct severity.14
Our analyses were not adjusted for competing risk, which
may have influenced the distribution of the MI subtypes. For
example, in the event of a severe MI leading to CV death,
the occurrence of CV death would supersede the severe MI
in the analyses. For this reason, an intervention that reduces
the number of fatal MIs could be associated with a shift toward
more severe MI subtypes.
In summary, the present post hoc analysis showed that
liraglutide reduces the total number of MI events in patients
with type 2 DM at high risk, but no significant differences
in subtype distribution were found between treatment groups.
However, numeric differences in some subtypes between treat-
ment groups suggest that liraglutide may also impact the
clinical outcomes of MI.
Acknowledgment: The authors thank the participants, in-
vestigators, trial-site staff, and the leadership, employees, and
contractors of the sponsor who were involved in the conduct
of the trial.
Disclosures
The data presented in this article are part of the LEADER
trial dataset, which is confidential and the property of Novo
Nordisk. Novo Nordisk will consider requests for access to
LEADER trial data on a case-by-case basis. The LEADER
trial (NCT01179048) and this analysis were supported by Novo
Nordisk. Author disclosures are provided as Supplementary
Data.
Supplementary Data
Supplementary data associated with this article can be
found, in the online version, at https://doi.org/10.1016/
j.amjcard.2018.02.030.
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