Pharmacologically relevant drug interactions of Glucagon-like peptide-1 receptor agonists

Abstract

Glucagon-like peptide-1 receptor agonists are incretin mimetics and they help to manage the blood glucose of patients with type 2 diabetes mellitus. The gastric emptying is delayed by the administration of Glucagon-like peptide-1 receptor agonists and hence the absorption of orally administered medications such as Acetaminophen, Digoxin, Warfarin, Oral contraceptive pills, Metformin, Statins, Angiotensin Converting Enzyme Inhibitors and Griseofulvin delayed by their concomitant use. It has been observed that the pharmacokinetics of all these drugs did not get altered by the concurrent administration of Glucagon-like peptide-1 receptor agonists. Moreover, the delay in absorption of interacting drugs could be avoided by taking 1 hour before the administration of Glucagon-like peptide-1 receptor agonists.

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Introduction
Glucagon-like peptide-1 (GLP-1) receptor agonists are incretin
mimetics and they are useful in the treatment of type 2 diabetes
mellitus (Type 2 DM). The drugs such as Exenatide, Liraglutide,
Lixisenatide, Albiglutide, Dulaglutide and Semaglutide are approved
as GLP-1 agonists and administered subcutaneously to manage fasting
and postprandial blood glucose.1 The antidiabetic effect of GLP-
1 agonists occurs through many mechanisms including increased
glucose-dependent insulin secretion, suppressed glucagon levels,
delayed gastric emptying and reduced food intake.2
Diabetes affects millions of people around the world and it is one
of the leading causes of cardiovascular diseases, blindness, kidney
failure, amputations, and others. International Diabetes Federation
(IDF) estimated that approximately 5 million global deaths and 850
billion US dollars of healthcare costs were attributed to diabetes in the
year of 2017.3 The patients with diabetes are more prone to develop
comorbidities such as cardiovascular diseases, hepatic diseases,
renal problems, depression, and others and they may take several
medications to manage them all that may result in Polypharmacy.4
The rate of drug interactions is enhanced by inappropriate use
of multiple medications.5 Modication of effects of one drug by
other drug(s), supplements, food, smoking or alcohol consumption,
is termed as Drug interaction.6 And the drug interaction resulting in
elevated risk of adverse effects or decreased therapeutic efcacy is
termed Adverse Drug Interaction.7 GLP-1 agonists may slow down
the absorption of certain orally administered medications through
delayed gastric emptying.
Acetaminophen (paracetamol)
Acetaminophen has a high permeability and high solubility
and hence it is preferably employed to study gastric emptying
properties of drugs.8 The absorption of Acetaminophen was delayed
by the concomitant administration of Exenatide,9 Liraglutide10 or
Lixisenatide.11 The interaction between Acetaminophen and GLP-1
agonists is minimal and clinically insignicant and no management
required. Delayed absorption of Acetaminophen could be avoided by
1 hour prior to the GLP-1 agonists’ administration.
Digoxin
Digoxin is a glycoside isolated from Digitalis and it is used as a
cardio tonic to treat congestive heart failure and as an antiarrhythmic
drug to treat atrial utter and atrial brillation.12 Concurrent use of
Digoxin and Exenatide,13 Liraglutide,14 Lixisenatide,15 Albiglutide,16
Dulaglutide17 or Semaglutide18 resulted in a little delay in the tmax
of Digoxin which was clinically insignicant and do not require any
dose adjustments.
Warfarin
Warfarin is widely used as an oral anticoagulant and it helps to
manage the conditions such as chronic atrial brillation, coronary
artery disease and others through the prevention of thromboembolic
events.19 The International Normalized Ratio (INR) of patients
taking Exenatide,20 Liraglutide,21,22 Lixisenatide,15 Albiglutide,16
Dulaglutide,17 or Semaglutide18 along with Warfarin did not get
affected signicantly though there was a delay observed in the
absorption of Warfarin. Nevertheless, the INR of patients taking
GLP-1 agonists and Warfarin concurrently required to be monitored
frequently as Warfarin is a drug with narrow therapeutic index.
Oral contraceptive pills
The peak concentrations of Oral contraceptives were delayed
insignicantly by the coadministration of Exenatide,23 Liraglutide,24
Lixisenatide,15 Albiglutide,16 Dulaglutide17 or Semaglutide.25 Though
this interaction is not clinically signicant, it is recommended to take
oral contraceptives at least 1 hour before the administration of GLP-1
agonists.26
Metformin
Metformin is a biguanide and it helps to manage many conditions
such as Type 2 diabetes mellitus, Gestational diabetes mellitus
(GDM), Prediabetes, Obesity, Polycystic Ovarian Syndrome (PCOS),
J Anal Pharm Res. 2019;8(2):51‒53. 51
© 2019 Maideen. This is an open access article distributed under the terms of the Creative Commons Attribution License, which
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Pharmacologically relevant drug interactions of
Glucagon-like peptide-1 receptor agonists
Volume 8 Issue 2 - 2019
Naina Mohamed Pakkir Maideen
Pharmacologist, Dubai Health Authority, UAE
Correspondence: Naina Mohamed Pakkir Maideen,
Pharmacologist, Dubai Health Authority, PB No: 4545, Dubai,
UAE, Tel +97142164952, +971505769833, Fax +97142244302,
Email
Received: March 01, 2019 | Published: March 22, 2019
Abstract
Glucagon-like peptide-1 receptor agonists are incretin mimetics and they help
to manage the blood glucose of patients with type 2 diabetes mellitus. The gastric
emptying is delayed by the administration of Glucagon-like peptide-1 receptor agonists
and hence the absorption of orally administered medications such as Acetaminophen,
Digoxin, Warfarin, Oral contraceptive pills, Metformin, Statins, Angiotensin
Converting Enzyme Inhibitors and Griseofulvin delayed by their concomitant use. It
has been observed that the pharmacokinetics of all these drugs did not get altered by
the concurrent administration of Glucagon-like peptide-1 receptor agonists. Moreover,
the delay in absorption of interacting drugs could be avoided by taking 1 hour before
the administration of Glucagon-like peptide-1 receptor agonists.
Keywords: drug interactions, glucagon-like peptide-1 receptor agonists, exenatide,
liraglutide, lixisenatide
Journal of Analytical & Pharmaceutical Research
Review Article Open Access

Pharmacologically relevant drug interactions of Glucagon-like peptide-1 receptor agonists 52
Copyright:
©2019 Maideen
Citation: Maideen NMP. Pharmacologically relevant drug interactions of Glucagon-like peptide-1 receptor agonists. J Anal Pharm Res. 2019;8(2):51‒53.
DOI: 10.15406/japlr.2019.08.00311
Cancer, and others.27 Concomitant use of Metformin and Semaglutide
did not result in clinically signicant changes in the pharmacokinetics
of Metformin.18 Moreover the coadministration of Metformin with
Exenatide28 or Lixisenatide29 lead to improved glycemic control
and with Liraglutide produced synergistic anti-tumor effect on
the pancreatic cancer cells30 and synergistic protective effects on
endothelial function.31
Sulfonylureas
Sulfonylureas are oral hypoglycemic agents employed in the
treatment of type 2 diabetes mellitus and they include the drugs such
as Glibenclamide, Gliclazide, Glipizide and others.32,33 The risk of
hypoglycemia was observed higher in patients taking Liraglutide
along with sulfonylurea.34 The dose of sulfonylurea is recommended
to be halved when a GLP-1 agonist is initiated in a patient receiving
Sulfonylurea to avoid hypoglycemic episodes.35
Insulins
Signicant glycemic control and body weight reduction were
achieved by the addition of Insulin in patients receiving Exenatide36
or Liraglutide.37 To avoid hypoglycemia, the dosage adjustments
of Insulin are recommended in patients taking this combination of
drugs.35
Statins
Statins are the drugs inhibiting cholesterol biosynthesis through
the blockade of rate limiting-enzyme 3-hydroxy-methylglutaryl
Coenzyme A (HMG CoA) reductase.38 The bioavailability of
Lovastatin slightly changed by the coadministration of Exenatide
and did not require a dosage adjustment of Lovastatin.39 Concomitant
use of Atorvastatin and Liraglutide,14 Lixisenatide,15 Dulaglutide17 or
Semaglutide18 resulted in insignicant delay in tmax of Atorvastatin.
ACE Inhibitors
Angiotensin converting enzyme (ACE) inhibitors are preferred
as the rst line antihypertensive agents to treat patients with
Hypertension and Diabetes.40 The tmax of Lisinopril was delayed by
concomitant use of Liraglutide,14 while Lixisenatide15 was delaying
the tmax of Ramipril insignicantly. However, dosage adjustments for
ACE inhibitors is not required.
Hydrocortisone
The administration of Exenatide in a diabetic patient with
panhypopituitarism taking hydrocortisone delayed the absorption
of hydrocortisone resulting in general fatigue and appetite loss with
hypotension.41
Griseofulvin
Griseofulvin is an antifungal drug and it shows antifungal activity
against dermatophytes.42 There was a delay in the initial absorption of
Griseofulvin when it was coadministered with Liraglutide43 and this
interaction was found clinically insignicant.
Conclusion
GLP-1 agonists delay the gastric emptying through which they
interfere with the absorption of interacting drugs. Nonetheless, they
do not signicantly alter the pharmacokinetics of interacting drugs
such as Acetaminophen, Digoxin, Warfarin, Oral contraceptive pills,
Metformin, Statins, ACE Inhibitors and Griseofulvin and hence
do not require any dosage adjustments. However, GLP-1 agonists
may increase the risk of hypoglycemia when coadministered with
Sulfonylureas or Insulins and their dose should be adjusted to
prevent hypoglycemic episodes. In addition, the delay in absorption
of interacting drugs could be avoided by taking 1 hour before the
administration of GLP-1 agonists.
Funding
Nil
Acknowledgments
None.
Conicts of interest
The author declares that there is no conicts of interest.
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