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Myocardial Infarction Subtypes in Patients With Type 2 Diabetes Mellitus and the Effect of Liraglutide Therapy (from the LEADER Trial)

Open AccessPublished:March 15, 2018DOI:https://doi.org/10.1016/j.amjcard.2018.02.030
      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 peripheral 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.
      Diabetes mellitus (DM) is an established risk factor for coronary heart disease and is associated with an approximately twofold increase in the risk of myocardial infarction (MI).
      • Sarwar N.
      • Gao P.
      • Seshasai S.R.
      • Gobin R.
      • Kaptoge S.
      • Di Angelantonio E.
      • Ingelsson E.
      • Lawlor D.A.
      • Selvin E.
      • Stampfer M.
      • Stehouwer C.D.
      • Lewington S.
      • Pennells L.
      • Thompson A.
      • Sattar N.
      • White I.R.
      • Ray K.K.
      • Danesh J.
      Emerging Risk Factors Collaboration
      Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.
      However, there are limited data regarding the distribution of MI subtypes in people with diabetes. Liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, is approved for the treatment of adults with type 2 DM.
      • Novo Nordisk Inc
      Victoza (liraglutide) Highlights of prescribing information.
      • Novo Nordisk A/S
      Victoza (liraglutide) Summary of Product Characteristics.
      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.
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.
      • Nauck M.A.
      • Nissen S.E.
      • Pocock S.
      • Poulter N.R.
      • Ravn L.S.
      • Steinberg W.M.
      • Stockner M.
      • Zinman B.
      • Bergenstal R.M.
      • Buse J.B.
      • LEADER Steering Committee
      • LEADER Trial Investigators
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      Post hoc analysis of LEADER has also shown that a lower proportion of patients experienced any MI with liraglutide versus placebo.
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.
      • Nauck M.A.
      • Nissen S.E.
      • Pocock S.
      • Poulter N.R.
      • Ravn L.S.
      • Steinberg W.M.
      • Stockner M.
      • Zinman B.
      • Bergenstal R.M.
      • Buse J.B.
      • LEADER Steering Committee
      • LEADER Trial Investigators
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      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, randomized 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.
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.
      • Nauck M.A.
      • Nissen S.E.
      • Pocock S.
      • Poulter N.R.
      • Ravn L.S.
      • Steinberg W.M.
      • Stockner M.
      • Zinman B.
      • Bergenstal R.M.
      • Buse J.B.
      • LEADER Steering Committee
      • LEADER Trial Investigators
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      Institutional review board or ethics committee approval was obtained from all participating centers, and all patients provided written informed consent before participation.
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.
      • Nauck M.A.
      • Nissen S.E.
      • Pocock S.
      • Poulter N.R.
      • Ravn L.S.
      • Steinberg W.M.
      • Stockner M.
      • Zinman B.
      • Bergenstal R.M.
      • Buse J.B.
      • LEADER Steering Committee
      • LEADER Trial Investigators
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      There was a comprehensive strategy to identify potential MIs, including silent MIs. Strategies included 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 research 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 recurrent. 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 associated with percutaneous coronary intervention; type 4b: MI associated with stent thrombosis; and type 5: MI associated with coronary artery bypass graft) and, if available, by quantitative evaluation of biomarkers increased relative to normal values.
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.
      • Nauck M.A.
      • Nissen S.E.
      • Pocock S.
      • Poulter N.R.
      • Ravn L.S.
      • Steinberg W.M.
      • Stockner M.
      • Zinman B.
      • Bergenstal R.M.
      • Buse J.B.
      • LEADER Steering Committee
      • LEADER Trial Investigators
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      In this post hoc analysis of MI data from LEADER, the incidence and outcome of all MIs, and the incidence and classification of symptomatic MIs according to subtype and troponin levels, were examined in the liraglutide and placebo arms. Between-group differences in baseline characteristics, 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] symptomatic 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 recurrent 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).
      Table 1All myocardial infarctions and symptomatic myocardial infarctions according to subtype
      VariableLiraglutide, eventsPlacebo, eventsp-value
      All myocardial infarctions359 (100%)421 (100%)0.022
      Poisson regression adjusted for individual trial observation time.
      First292 (81%)339 (81%)
      Recurrent67 (19%)82 (19%)
      Symptomatic myocardial infarction297 (83%)344 (82%)
      Silent myocardial infarction62 (17%)77 (18%)
      Outcome
       Nonfatal / fatal342 (95%) / 17 (5%)393 (93%) / 28 (7%)0.28
      Fisher's exact test.
      Symptomatic myocardial infarctions297 (100%)344 (100%)
       ST-segment elevation myocardial infarction / non–ST-segment elevation myocardial infarction48 (16%) / 249 (84%)38 (11%) / 306 (89%)0.06
      Fisher's exact test.
      Type
      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.
       1 / 2–5241 (81%) / 56 (19%)277 (81%) / 67 (19%)0.92
      Fisher's exact test.
        243 (14%)43 (13%)
        35 (2%)10 (3%)
        4a4 (1%)7 (2%)
        4b4 (1%)7 (2%)
        50 (0%)0 (0%)
      Troponin available
      Includes patients within each treatment arm with troponin levels available.
      229 (100%)282 (100%)
       ≤5x upper reference limit / > 5x upper reference limit90 (39%) / 139 (61%)93 (33%) / 189 (67%)0.16
      Fisher's exact test.
       ≤10x upper reference limit / > 10x upper reference limit111 (48%) / 118 (52%)126 (45%) / 156 (55%)0.42
      Fisher's exact test.
      * 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.
      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 lower extremities (10% vs 18%) and >50% stenosis of coronary, 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).
      Table 2Cardiovascular history at screening
      VariableLiraglutidePlacebop-value: liraglutide versus placebo myocardial infarction cohort
      Total cohort (n = 4668)Myocardial infarction cohort (n = 292)Total cohort (n = 4672)Myocardial infarction cohort (n = 339)
      With information for cardiovascular history
      Based on medical history as reported by the trial investigator for each patient.
      4,588 (98%)287 (98%)4,603 (99%)338 (100%)
      Myocardial infarction1,434 (31%)136 (47%)1,373 (29%)155 (46%)0.83
      Arrhythmia718 (15%)52 (18%)721 (15%)65 (19%)0.66
      Heart failure (New York Heart Association class I–III)835 (18%)58 (20%)832 (18%)76 (22%)0.43
      Ischemic heart disease2,542 (54%)206 (71%)2,517 (54%)236 (70%)0.80
      Percutaneous coronary intervention performed1,302 (28%)139 (48%)1,266 (27%)137 (40%)0.07
      Coronary artery bypass graft performed782 (17%)90 (31%)749 (16%)73 (22%)0.008
      Left ventricular systolic dysfunction521 (11%)49 (17%)478 (10%)52 (15%)0.62
      Left ventricular diastolic dysfunction782 (17%)39 (13%)799 (17%)64 (19%)0.06
      Hypertension4,261 (91%)266 (91%)4,250 (91%)315 (93%)0.40
      Ischemic stroke512 (11%)31 (11%)526 (11%)38 (11%)0.81
      Transient ischemic attack257 (6%)22 (8%)310 (7%)31 (9%)0.47
      Hemorrhagic stroke53 (1%)1 (0%)50 (1%)5 (1%)0.14
      Intracranial artery stenosis64 (1%)7 (2%)46 (1%)5 (1%)0.40
      Carotid artery stenosis367 (8%)32 (11%)332 (7.1%)34 (10%)0.70
      Peripheral arterial disease in lower extremities567 (12%)29 (10%)600 (13%)60 (18%)0.005
      >50% stenosis of coronary, carotid or other arteries1,187 (25%)97 (33%)1,191 (25%)139 (41%)0.044
      * Based on medical history as reported by the trial investigator for each patient.
      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 difference 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 associated 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 receiving 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, differences 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 extremities, 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 complication 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 atherosclerotic events, it has been suggested that it could be due to an antiatherogenic effect.
      • Verges B.
      • Charbonnel B.
      After the LEADER trial and SUSTAIN-6, how do we explain the cardiovascular benefits of some GLP-1 receptor agonists?.
      Several mechanistic hypotheses for such an effect have been proposed, including the favorable effects of liraglutide on weight, lipid profiles, systolic blood pressure, and anti-inflammatory effects.
      • Verges B.
      • Charbonnel B.
      After the LEADER trial and SUSTAIN-6, how do we explain the cardiovascular benefits of some GLP-1 receptor agonists?.
      • Drucker D.J.
      The cardiovascular biology of glucagon-like peptide-1.
      A direct effect of liraglutide on the myocardium has also been observed.
      • Verges B.
      • Charbonnel B.
      After the LEADER trial and SUSTAIN-6, how do we explain the cardiovascular benefits of some GLP-1 receptor agonists?.
      Pretreatment with liraglutide before experimentally 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 independent of the cardiomyocyte GLP-1 receptor.
      • Ussher J.R.
      • Baggio L.L.
      • Campbell J.E.
      • Mulvihill E.E.
      • Kim M.
      • Kabir M.G.
      • Cao X.
      • Baranek B.M.
      • Stoffers D.A.
      • Seeley R.J.
      • Drucker D.J.
      Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection.
      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.
      • Nikolaidis L.A.
      • Mankad S.
      • Sokos G.G.
      • Miske G.
      • Shah A.
      • Elahi D.
      • Shannon R.P.
      Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion.
      • Read P.A.
      • Hoole S.P.
      • White P.A.
      • Khan F.Z.
      • O'Sullivan M.
      • West N.E.
      • Dutka D.P.
      A pilot study to assess whether glucagon-like peptide-1 protects the heart from ischemic dysfunction and attenuates stunning after coronary balloon occlusion in humans.
      • Read P.A.
      • Khan F.Z.
      • Dutka D.P.
      Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease.
      • Chen W.R.
      • Hu S.Y.
      • Chen Y.D.
      • Zhang Y.
      • Qian G.
      • Wang J.
      • Yang J.J.
      • Wang Z.F.
      • Tian F.
      • Ning Q.X.
      Effects of liraglutide on left ventricular function in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.
      • Chen W.R.
      • Tian F.
      • Chen Y.D.
      • Wang J.
      • Yang J.J.
      • Wang Z.F.
      • Da Wang J.
      • Ning Q.X.
      Effects of liraglutide on no-reflow in patients with acute ST-segment elevation myocardial infarction.
      • Chen W.R.
      • Chen Y.D.
      • Tian F.
      • Yang N.
      • Cheng L.Q.
      • Hu S.Y.
      • Wang J.
      • Yang J.J.
      • Wang S.F.
      • Gu X.F.
      Effects of liraglutide on reperfusion injury in patients with ST-segment-elevation myocardial infarction.
      In line with these 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 suggestive of reduced infarct severity.
      • Hallen J.
      Troponin for the estimation of infarct size: what have we learned?.
      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 treatment groups suggest that liraglutide may also impact the clinical outcomes of MI.

      Acknowledgment

      The authors thank the participants, investigators, 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

      The following is the supplementary data to this article:

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