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10-23-2017 | Cardiovascular disorders | Editorial | Article

Diabetes in special situations: Glucagon-like peptide-1 receptor agonist use in acute myocardial infarction

Author:
Sanjay Kalra

Disclosures

Introduction

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.

Classification

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
  • Short acting
    • Exenatide
    • Lixisenatide
  • Intermediate acting
    • Liraglutide
  • Long acting
    • Dulaglutide
    • Once-weekly exenatide
GLP-1 RA + insulin coformulation
  • Lixisenatide + glargine
  • Liraglutide + degludec
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 [3]) and once-weekly exenatide (EXSCEL [4]), and the CV benefit of liraglutide (LEADER [5]). 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 [6] AND ELIXA [3]) 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 [6]. In ELIXA, eligible patients had type 2 diabetes and had experienced an acute coronary event in the 180 days prior to screening [3]. 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 [3].

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 [9]. 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 [12]. Other authors have reported that similar treatment reduces no-reflow rates [13], corrects stress hyperglycemia, improves inflammatory markers and endothelial function, and improves left ventricular ejection fraction at 3 months [14]. A reduction in ventricular remodeling may explain these benefits [15].

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 [16]. While an increase in heart rate correlated positively with liraglutide dose, no association between heart rate increase and adverse events was found [16].

Real-world extrapolation

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 [17]. 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
  • Insulin is the medication of choice for the management of hyperglycemia in hospitalized patients.
  • GLP-1 RAs should be viewed as an adjunct to, rather than an alternative to, insulin.
  • Routine caveats and contraindications must be respected while prescribing GLP-1 RAs.
  • GLP-1 RAs can only be prescribed if hemodynamic, renal, and gastrointestinal functions support their use.
GLP-1 RAs=glucagon-like peptide-1 receptor agonists

Working framework

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
During admission

GLP-1 RA-naïve patients

  • In GLP-1 RA-naïve patients who develop AMI, there may be a role for short-acting or intermediate-acting GLP-1 RA therapy.
  • Exenatide or liraglutide can be used to provide glycemic control and cardiovascular benefit during admission for AMI.
  • Subcutaneous liraglutide should be considered the medication of choice in AMI settings as randomized controlled trial data are available.
  • Once-weekly GLP-1 RA therapy may not be preferable in AMI settings as they take a longer time to achieve steady state.
  • GLP-1 RA therapy should be initiated only if hemodynamic, renal, gastrointestinal, and cognitive functions allow so.

Current GLP-1 RA users

  • Patients on GLP-1 RA therapy who develop ACS should not:
    • ­discontinue GLP-1 RA therapy; or
    • change GLP-1 RA preparation.
  • Patients on long-acting (once-weekly) GLP-1 RA therapy who develop ACS may postpone their dose by up to 3 days. In such cases, the next dose must be taken on the scheduled day.
  • GLP-1 RA therapy may be temporarily discontinued in patients with:
    • ­hemodynamic instability, which compromises absorption of the medication from subcutaneous site;
    • renal dysfunction;
    • gastroinstestinal dysfunction, which prevents regular/adequate oral intake; or
    • cognitive dysfunction.

In all patients

  • Regular monitoring for adverse effects and contraindications of GLP-1 RA therapy must be done.
  • The clinical decision to continue/discontinue/reinstitute GLP-1 RA therapy should be reviewed daily.
Upon discharge
  • GLP-1 RA therapy may be instituted upon discharge as part of a comprehensive glucose-lowering therapeutic plan.
  • All contraindications, caveats, and precautions for GLP-1 RA must be respected.
  • Patients and caregivers must be counseled regarding possible adverse effects.
Upon follow-up
  • In such cases, the potential utility and safety of GLP-1 RA therapy should be reevaluated at first outpatient follow up.
  • The need to institute or to continue GLP-1 RA therapy should be monitored at each outpatient visit based on routine protocol.
  • Regular monitoring of GLP-1 RA therapy must be done.
ACS=acute coronary syndrome; AMI=acute myocardial infarction; GLP-1 RA=glucagon-like peptide-1 receptor agonist
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