Diabetes in special situations: Glucagon-like peptide-1 receptor agonist use in acute myocardial infarction
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a commonly used class of glucose-lowering medications which have proven cardiovascular (CV) safety and benefit. While their use in persons with asymptomatic and stable coronary artery disease is encouraged, there is no clarity as to whether these medications can be used in patients with acute myocardial infarction (AMI). This article, based on prescribing information, evidence from clinical and CV outcome trials (CVOTs), and good clinical sense, discusses the pragmatic usage of GLP-1 RAs in AMI.
GLP-1 RAs are an injectable class of incretin-based glucose-lowering medications, which include a wide variety of preparations and combinations (Box 1) [1, 2].
|Box 1. Classification of GLP-1 RAs|
|GLP-1 RA monotherapy|
|GLP-1 RA + insulin coformulation|
|GLP-1 RA=glucagon-like peptide-1 receptor agonist|
Cardiovascular outcome trials
As a class, GLP-1 RAs possess multiple pleiotropic effects which offer distinct CV advantages. Recent CVOTs have demonstrated the CV safety of lixisenatide (ELIXA ) and once-weekly exenatide (EXSCEL ), and the CV benefit of liraglutide (LEADER ). Liraglutide is indicated for reducing the risk of CV events.
There is a clear cut agreement regarding the advantages of GLP-1 RAs in type 2 diabetes, with or without stable coronary artery disease. However, no consensus has developed regarding the use of GLP-1 RAs in patients with acute coronary syndrome (ACS). Only two CVOTs (EXAMINE  AND ELIXA ) have recruited post-ACS patients for study. EXAMINE studied the effect of the dipeptidyl peptidase 4 inhibitor alogliptin on participants who were 90 days post-ACS . In ELIXA, eligible patients had type 2 diabetes and had experienced an acute coronary event in the 180 days prior to screening . Major exclusion criteria included percutaneous coronary intervention in the 15 days prior to screening, coronary-artery bypass graft surgery for the qualifying event, and planned coronary revascularization procedure in the 90 days following screening .
Cardioprotection in acute settings
Exenatide has been shown to have cardioprotective effects in persons with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Exenatide reduces reperfusion injury and reduces infarct size [7, 8], but the benefit is only achieved in persons with ischemia of short duration . However, other researchers have reported additional exenatide treatment in patients with AMI to have no benefit [10, 11]. It should be noted that all these studies have used intravenous exenatide infusion.
Liraglutide has also been studied in the setting of STEMI. A 7-day course of subcutaneous liraglutide in patients with STEMI treated with PPCI improves myocardial salvage and infarct size after STEMI, perhaps by reducing reperfusion injury . Other authors have reported that similar treatment reduces no-reflow rates , corrects stress hyperglycemia, improves inflammatory markers and endothelial function, and improves left ventricular ejection fraction at 3 months . A reduction in ventricular remodeling may explain these benefits .
However, one must be aware that in patients with chronic heart failure, treatment with liraglutide for 24 weeks has been shown to significantly increase heart rate . While an increase in heart rate correlated positively with liraglutide dose, no association between heart rate increase and adverse events was found .
Such data encourage the use of GLP-1 RAs during and after an AMI. However, a blanket statement promoting GLP-1 RA use in an AMI setting is not possible. Appropriate caution must be exercised, especially in situations where heart failure exists or may be precipitated . Multiple glycemic, hemodynamic, renal, and other medical factors influence clinical decision making regarding the management of hyperglycemia in AMI. These should be taken into account while prescribing GLP-1 RAs in AMI (Box 2).
|Box 2. Factors to be considered while prescribing GLP-1 RAs in acute myocardial infarction|
|GLP-1 RAs=glucagon-like peptide-1 receptor agonists|
Below, I suggest a working framework upon which to base such decisions (see Box 3). This pragmatic guidance is based on the prescribing information for GLP-1 RAs and good clinical sense.
|Box 3. Rational use of GLP-1 RAs during acute myocardial infarction|
GLP-1 RA-naïve patients
Current GLP-1 RA users
In all patients
|ACS=acute coronary syndrome; AMI=acute myocardial infarction; GLP-1 RA=glucagon-like peptide-1 receptor agonist|
- Kalra S. Choosing appropriate glucagon-like peptide 1 receptor agonists: A patient-centered approach. Diabetes Therapy 2014; 5: 333–340.
- Kalra S, Gupta Y. Injectable coformulations in diabetology. Diabetes Therapy 2015; 6: 101–111.
- Pfeffer MA, Claggett B, Diaz R et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Eng J Med 2015; 373: 2247–2257.
- Holman RR, Bethel MA, Mentz RJ et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Eng J Med 2017; 377: 1228–1239.
- Marso SP, Daniels GH, Brown-Frandsen K et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375: 311-22.
- White WB, Bakris GL, Bergenstal RM et al. EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J 2011; 162: 620–626.e1.
- Lønborg J, Vejlstrup N, Kelbæk H et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2011; 33: 1491–1499.
- Woo JS, Kim W, Ha SJ et al. Cardioprotective Effects of Exenatide in Patients With ST-Segment–Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. Arterioscler Thromb Vasc Biol 2013; 33: 2252–2260.
- Lønborg J, Kelbæk H, Vejlstrup N et al. Exenatide reduces final infarct size in patients with ST-segment–elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv 2012; 5: 288–295.
- Bernink FJ, Timmers L, Diamant M et al. Effect of additional treatment with EXenatide in patients with an Acute Myocardial Infarction: the EXAMI study. Int J Cardiol 2013; 167: 289–290.
- Lønborg J, Vejlstrup N, Kelbæk H et al. Impact of acute hyperglycemia on myocardial infarct size, area at risk, and salvage in patients with STEMI and the association with exenatide treatment: results from a randomized study. Diabetes 2014; 63: 2474–2485.
- Chen WR, Chen YD, Tian F et al. Effects of liraglutide on reperfusion injury in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Imaging 2016; 9: e005146.
- Chen WR, Tian F, Dai Chen Y et al. Effects of liraglutide on no-reflow in patients with acute ST-segment elevation myocardial infarction. Int J Cardiol 2016; 208: 109–114.
- Chen WR, Hu SY, Dai Chen Y et al. Effects of liraglutide on left ventricular function in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am Heart J 2015; 170: 845–854.
- Nozue T, Yamada M, Tsunoda T et al. Effects of liraglutide, a glucagon-like peptide-1 analog, on left ventricular remodeling assessed by cardiac magnetic resonance imaging in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Heart Vessels 2016; 31: 1239–1246.
- Tougaard RS, Jorsal A, Tarnow L et al. The glucagon-like peptide 1 agonist liraglutide increases heart rate in heart failure patients. Eur Heart J 2017; 38: A247 (Abstract).
- Komajda M. Liraglutide in heart failure: caution is needed. Eur J Heart Fail 2017; 19: 78–79.