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



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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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 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 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
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):5153. 51
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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,
Received: March 01, 2019 | Published: March 22, 2019
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
©2019 Maideen
Citation: Maideen NMP. Pharmacologically relevant drug interactions of Glucagon-like peptide-1 receptor agonists. J Anal Pharm Res. 2019;8(2):5153.
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 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
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
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.
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
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.
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.
Conicts of interest
The author declares that there is no conicts of interest.
1. Romera I, Cebrián–Cuenca A, Álvarez–Guisasola F, et al. A Review
of Practical Issues on the Use of Glucagon–Like Peptide–1 Receptor
Agonists for the Management of Type 2 Diabetes. Diabetes Ther.
2. Kalra S, Baruah MP, Sahay RK, et al. Glucagon–like peptide–1 receptor
agonists in the treatment of type 2 diabetes: past, present, and future.
Indian J Endocrinol Metab. 2016;20(2):254–267.
3. Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: Global
estimates of diabetes prevalence for 2017 and projections for 2045.
Diabetes Res Clin Pract. 2018;138:271–281.
4. Ibrahim IA, Kang E, Dansky KH. Polypharmacy and possible drug–drug
interactions among diabetic patients receiving home health care services.
Home Health Care Serv Q. 2005;24(1–2):87–99.
5. Mohamed N, Maideen P. Thiazolidinediones and their Drug Interactions
involving CYP enzymes. American Journal of Physiology, Biochemistry
and Pharmacology. 2018;8(2):47–54.
6. Pakkir Maideen NM, Manavalan G, Balasubramanian K. Drug
interactions of meglitinide antidiabetics involving CYP enzymes and
OATP1B1 transporter. Therapeutic advances in endocrinology and
metabolism. 2018;9(8):259–268.
7. Maideen NM. Tobacco smoking and its drug interactions with
comedications involving CYP and UGT enzymes and nicotine. World
Journal of Pharmacology. 2019;8(2):14–25.
8. Ayalasomayajula S, Meyers D, Koo P, et al. Assessment of pharmacokinetic
drug–drug interaction between pradigastat and acetaminophen in healthy
subjects. Eur J Clin Pharmacol. 2015;71(4):425–432.
9. Blase E, Taylor K, Gao HY, et al. Pharmacokinetics of an oral drug
(acetaminophen) administered at various times in relation to subcutaneous
injection of exenatide (exendin4) in healthy subjects. J Clin Pharmacol.
10. Kapitza C, Zdravkovic M, Hindsberger C, et al. The effect of the
once–daily human glucagon–like peptide 1 analog liraglutide on the
pharmacokinetics of acetaminophen. Adv Ther. 2011;28(8):650–660.
11. McCarty D, Coleman M, Boland CL. Lixisenatide: a new daily GLP–1
agonist for type 2 diabetes management. Annals of Pharmacotherapy.
12. Gheorghiade M, Adams KF, Colucci WS. Digoxin in the management of
cardiovascular disorders. Circulation. 2004;109(24):2959–2964.
13. Kothare PA, Soon DK, Linnebjerg H, et al. Effect of exenatide on
the steadystate pharmacokinetics of digoxin. J Clin Pharmacol.
Pharmacologically relevant drug interactions of Glucagon-like peptide-1 receptor agonists 53
©2019 Maideen
Citation: Maideen NMP. Pharmacologically relevant drug interactions of Glucagon-like peptide-1 receptor agonists. J Anal Pharm Res. 2019;8(2):5153.
DOI: 10.15406/japlr.2019.08.00311
14. Malm–Erjefält M, Ekblom M, Vouis J, et al. Effect on the gastrointestinal
absorption of drugs from different classes in the biopharmaceutics
classication system, when treating with liraglutide. Molecular
Pharmaceutics. 2015;12(11):4166–4173.
15. Petersen AB, Knop FK, Christensen M. Lixisenatide for the treatment of
type 2 diabetes. Drugs Today (Barc). 2013;49(9):537–553.
16. Bush M, Scott R, Watanalumlerd P, et al. Effects of multiple doses of
albiglutide on the pharmacokinetics, pharmacodynamics, and safety
of digoxin, warfarin, or a low–dose oral contraceptive. Postgrad Med.
17. de la Peña A, Cui X, Geiser J, et al. No Dose Adjustment is Recommended
for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive
When Coadministered with Dulaglutide. Clin Pharmacokinet.
18. Hausner H, Karsbøl JD, Holst AG, et al. Effect of semaglutide on the
pharmacokinetics of metformin, warfarin, atorvastatin and digoxin in
healthy subjects. Clin Pharmacokinet. 2017;56(11):1391–1401.
19. Tadros R, Shakib S. Warfarin: Indications, risks and drug interactions.
Aust Fam Physician. 2010;39(7):476–479.
20. Soon D, Kothare PA, Linnebjerg H, et al. Effect of exenatide on the
pharmacokinetics and pharmacodynamics of warfarin in healthy Asian
men. J Clin Pharmacol. 2006;46(10):1179–1187.
21. Gough SC. Liraglutide: from clinical trials to clinical practice. Diabetes,
Obesity and Metabolism. 2012;14:33–40.
22. Peterson GE, Pollom RD. Liraglutide in clinical practice: dosing, safety
and efcacy. Int J Clin Pract Suppl. 2010;167:35–43.
23. Kothare PA, Seger ME, Northrup J, et al. Effect of exenatide on the
pharmacokinetics of a combination oral contraceptive in healthy women:
an open–label, randomised, crossover trial. BMC Clin Pharmacol.
24. Jacobsen LV, Vouis J, Hindsberger C, et al. Treatment With Liraglutide—a
OnceDaily GLP1 Analog—Does Not Reduce the Bioavailability
of Ethinyl Estradiol/Levonorgestrel Taken as an Oral Combination
Contraceptive Drug. J Clin Pharmacol. 2011;51(12):1696–703.
25. Kapitza C, Nosek L, Jensen L, et al. Semaglutide, a onceweekly human
GLP1 analog, does not reduce the bioavailability of the combined
oral contraceptive, ethinylestradiol/levonorgestrel. J Clin Pharmacol.
26. Freeman JS. Optimizing outcomes for GLP–1 agonists. The Journal of
the American Osteopathic Association. 2011;111(2_suppl_1):eS15–S20.
27. Maideen NM, Jumale A, Balasubramaniam R. Drug interactions
of metformin involving drug transporter proteins. Adv Pharm Bull.
28. Bergenstal RM, Wysham C, MacConell L, et al. DURATION–2 Study
Group. Efcacy and safety of exenatide once weekly versus sitagliptin or
pioglitazone as an adjunct to metformin for treatment of type 2 diabetes
(DURATION–2): a randomised trial. Lancet. 2010;376(9739):431–439.
29. Ratner RE, Rosenstock J, Boka G. DRI6012 Study Investigators. Dose
dependent effects of the oncedaily GLP1 receptor agonist lixisenatide
in patients with Type 2 diabetes inadequately controlled with metformin:
a randomized, doubleblind, placebocontrolled trial. Diabet Med.
30. Lu R, Yang J, Wei R, et al. Synergistic anti–tumor effects of liraglutide with
metformin on pancreatic cancer cells. PloS one. 2018;13(6):e0198938.
31. Ke J, Liu Y, Yang J, et al. Synergistic effects of metformin with
liraglutide against endothelial dysfunction through GLP–1 receptor and
PKA signalling pathway. Sci Rep. 2017;7:41085.
32. Maideen NM, Balasubramaniam R. Pharmacologically relevant drug
interactions of sulfonylurea antidiabetics with common herbs. Journal of
Herbmed Pharmacology. 2018;7(3):200–210.
33. Maideen NM. Pharmacokinetic and Pharmacodynamic Interactions
of Sulfonylurea Antidiabetics. European Journal of Medicine.
34. Jackson SH, Martin TS, Jones JD, et al. Liraglutide (victoza): the
rst once–daily incretin mimetic injection for type–2 diabetes. P T.
35. Filippatos TD, Panagiotopoulou TV, Elisaf MS. Adverse effects of GLP–
1 receptor agonists. Rev Diabet Stud. 2014;11(3):202.
36. Shefeld C, Kane M, Busch R, et al. Safety and efcacy of exenatide
in combination with insulin in patients with type 2 diabetes mellitus.
Endocr Pract. 2008;14(3):285–292.
37. Morrow L, Hompesch M, Guthrie H, et al. Coadministration of
liraglutide with insulin detemir demonstrates additive pharmacodynamic
effects with no pharmacokinetic interaction. Diabetes Obes Metab.
38. Oliveira EF, Santos–Martins D, Ribeiro AM, et al. HMG–CoA Reductase
inhibitors: an updated review of patents of novel compounds and
formulations (2011–2015). Expert Opin Ther Pat. 2016;26(11):1257–
39. Kothare PA, Linnebjerg H, Skrivanek Z, et al. Exenatide effects on
statin pharmacokinetics and lipid response. Int J Clin Pharmacol Ther.
40. Wu HY, Huang JW, Lin HJ, et al. Comparative effectiveness of renin–
angiotensin system blockers and other antihypertensive drugs in patients
with diabetes: systematic review and bayesian network meta–analysis.
BMJ. 2013;347:f6008.
41. Fujita Y, Kitamura T, Otsuki M, et al. Exenatide alters absorption of
hydrocortisone in a diabetic patient with panhypopituitarism: iatrogenic
adrenal insufciency. Diabetes care. 2013;36(1):e8.
42. Winston JA, Miller JL. Treatment of onychomycosis in diabetic patients.
Clinical Diabetes. 2006;24(4):160–166.
43. Jacobsen LV, Flint A, Olsen AK, et al. Liraglutide in type 2 diabetes
mellitus: clinical pharmacokinetics and pharmacodynamics. Clin
Pharmacokinet. 2016;55(6):657–672.
... Digoxin is a cardiotonic drug, which is obtained from digitalis, and it helps to manage cardiac conditions such as congestive heart failure (CHF), atrial flutter or atrial fibrillation [24,25]. The renal tubular secretion of Digoxin could be reduced by the administration of Potassium-sparing diuretics, which may result in increased Digoxin concentrations [26]. ...
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Potassium-sparing diuretics are useful in the treatment of resistant hypertension and salt sensitive forms of hypertension common in black, obese, diabetic and elderly patients and they include Spironolactone, Eplerenone, Amiloride and Triamterene. Potassium-sparing diuretics interact pharmacodynamically with the drugs such as ACE inhibitors, angiotensin receptor blockers, direct renin inhibitor, potassium supplements, trimethoprim and cyclosporine and elevate the risk of hyperkalemia. To predict and prevent the adverse drug interactions, the prescribers and the pharmacists are needed to be aware of the possible drug interactions of Potassium-sparing diuretics.
... Digoxin is a digitalis glycoside and is indicated in the management of patients with conditions such as congestive heart failure, atrial flutter (AFL), or atrial fibrillation (AF) [14,15]. The combined therapy of thiazide diuretics and digoxin results in more than three-fold increase in the risk of hospitalization for digoxin intoxication. ...
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Thiazide diuretics are used as one of the first-line agents to treat hypertension. However, the treated patients may have to receive multiple medications to treat comorbidities ensuing in drug-induced side effects. The present review was conducted using keywords such as drug interactions, pharmacodynamic drug interactions, thiazide diuretics, hydrochlorothiazide, chlorthalidone, and indapamide. The abovementioned words were searched in databases such as Medline, PubMed, PubMed Central (PMC), Google Scholar, ScienceDirect, Cochrane Library, and reference lists. Thiazides are diuretics, known to interact with drugs such as digoxin, flecainide, and dofeti-lide pharmacodynamically through thiazide-induced hypokalemia, hyponatremia, and hypovolemia respectively. The pharmacological interaction of thiazide diuretics with drugs such as lithium, angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs, antidiabetic, and Vitamin D has been reported. Herbs such as licorice and ginkgo were also studied for their interactivity with thiazides. Doctors and pharmacists are required to be well aware of drug-induced side effects of thiazide. This step is crucial for preventing adverse side effects.
Background An 81-year-old woman with type 2 diabetes, residing in a long-term care facility, has experienced a fall after medication changes, and a few days of irregular eating. Assessment This patient may be experiencing one or more common potential adverse events related to her diabetes medications. There is a need to create individualized treatment goals in this case. Outcome After a revision of treatment goals for hypertension and diabetes, and adjustments to the medication regimen, there have been no subsequent falls and this patient reports that she feels better. Conclusion As the person with diabetes ages, quality of life should be considered when setting treatment goals. Older people can be more at risk for adverse effects of medications to treat diabetes, so a clinician should be vigilant in the identification, management, and prevention of such adverse events. Inter-professional communication is key to the safe and effective treatment of diabetes.
Background Loop diuretics help to manage the patients with edema associated with congestive heart failure, liver cirrhosis, and renal disease and hypertension. The patients taking loop diuretics may receive other medications to treat comorbidities leading to drug interactions. Methodology The literature was searched in databases such as Medline/PMC/PubMed, Google Scholar, Cochrane Library, Science Direct, EMBASE, Web of science, Ebsco, Directory of open access journals (DOAJ) and reference lists to spot relevant articles using the keywords Drug interactions, Pharmacodynamic interactions, Loop diuretics, Bumetanide, Ethacrynic acid, Furosemide, and Torsemide. Results Loop diuretics are associated with hypokalemia, ototoxicity and other adverse effects. The drugs affected by hypokalemia, and having the potential of inducing ototoxicity could interact with loop diuretics pharmacodynamically. Loop diuretics can interact with drugs such as amphotericin B, digoxin, angiotensin-converting enzyme inhibitors (ACE inhibitors), antidiabetic drugs, antifungal agents, dobutamine, gossypoland sotalol due to diuretic associated hypokalemia. In addition, the risk of ototoxicity could be enhanced by the concomitant use of loop diuretics and cisplatin, aminoglycoside antibiotics or phosphodiesterase 5 (PDE 5) inhibitors. Loop diuretics may also interact pharmacodynamically with drugs like cephalosporins, ceritinib, levothyroxine, pixantrone, probenecid, lithium, non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas and herbal drugs. Conclusion Clinicians, pharmacists and other health care providers should take responsibility for the safe use of medications. In addition, they are required to be aware of the drugs interacting with loop diuretics, to prevent adverse drug interactions.
Obesity is a major public health issue with an increasing prevalence worldwide. Excess body fat is associated with various comorbidities, as well as increased overall mortality risk. The benefits of weight loss are evident by the reductions in morbidity and mortality. The foundation for most weight loss programs involves strict lifestyle modification, including dietary change and exercise. Unfortunately, many individuals struggle with weight loss and chronic weight management due to difficulty adhering to long-term lifestyle modification and the metabolic adaptations that promote weight regain. The use of adjunctive pharmacotherapy has been employed to help patients not only achieve greater weight loss than lifestyle modification alone but also to assist with long-term weight management. Historically, antiobesity drugs have produced only modest weight loss and required at least once daily administration. Glucagon-like peptide-1 (GLP-1), a hormone with significant effects on glycemic control and weight regulation, has been explored for use as adjunctive pharmacotherapy for weight loss. Semaglutide, a GLP-1 receptor agonist, was recently approved by the Food and Drug Administration for chronic weight management in adults with obesity or who are overweight. The approval came after the publication of the Semaglutide Treatment Effect in People with Obesity clinical trials. In these 68-week trials, semaglutide 2.4 mg was associated with significantly greater weight loss compared to placebo. Semaglutide differs from other GLP-1 receptor agonists by having a longer half-life and producing greater weight loss. This article provides an overview of the discovery and mechanism of action of semaglutide 2.4 mg, and the clinical trials that led to its approval.
Background Diabetic nephropathy (DN) has been the major contributor to chronic kidney disease (CKD), end stage renal disease (ESRD), and cardiovascular risks. Incretin pathway modulators (GLP-1 analogs, GLP-1R agonist, GLP-1 secretagogues and DPP-IV inhibitors) and SGLT2 inhibitors are presently the favourable outlooks among the numerous therapeutic approaches and efforts considered for DN beyond RAAS modulation. Purpose The current state of art is an attempt to mine and demonstrate extant knowledge of plausible plant source of SGLT2 inhibitors, GLP-1 secretagogues and DPP-IV inhibitors towards mitigation of DN. Methods Scientific search engines PubMed, Google Scholar, Scopus, and SciFinder are accessed towards collecting literatures on pathophysiology of DN, treatment regimens, herbs for DN, and available literatures regarding plant sources of SGLT2 inhibitors and incretin modulators. Results This literature review has comprehensively collated, critically analyzed, and documented the state of art phyto-preparations and phytocompounds based strategies for management of DN. GLP-1 secretagogues activity, DPP-IV and SGLT2 inhibitory activity elicited from plant -based compounds have been extensively reviewed. The literature on mechanism of action, dose and principles of the treatments, and the degree of evidence for plant derived formulations have been rigorously examined and critiqued. Consequently, the review has brought into focus that the bioactive principle of many of the effective investigated phyto-preparations with potential against DN are yet to be discovered. It is also revealed the need of toxicological safety assessment and effectiveness in vivo investigation for many of the plant preparations and plant compound demonstrating in vitro potential against DN towards availing effective, safer and economically sound alternatives to synthetic incretin modulators and SGLT2 inhibitors. Conclusion The extant literature reviewed in the present article provides a good scope to further investigate in-depth mechanistic aspects of phytomedicine reported for DN management. The reviewed literatures suggest that in vivo investigations can be made with toxicologically safe phytomedicine and plant derived incretin modulators, and SGLT2 inhibitors having excellent therapeutic potential against DN. Further, this review endeavors to bolster research into plant based alternatives that are comparatively safe and less costly, to augment extant state of art incretin modulators and SGLT2 inhibitors.
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Tobacco smoking is a global public health threat causing several illnesses including cardiovascular disease (Myocardial infarction), cerebrovascular disease (Stroke), peripheral vascular disease (Claudication), chronic obstructive pulmonary disease, asthma, reduced female infertility, sexual dysfunction in men, different types of cancer and many other diseases. It has been estimated in 2015 that approximately 1.3 billion people smoke, around the globe. Use of medications among smokers is more common, nowadays. This review is aimed to identify the medications affected by smoking, involving Cytochrome P450 (CYP) and uridine diphosphate-glucuronosyltransferases (UGTs) enzymes and Nicotine. Polycyclic aromatic hydrocarbons (PAHs) of tobacco smoke have been associated with the induction of CYP enzymes such as CYP1A1, CYP1A2 and possibly CYP2E1 and UGT enzymes. The drugs metabolized by CYP1A1, CYP1A2, CYP2E1 and UGT enzymes might be affected by tobacco smoking and the smokers taking medications metabolized by those enzymes, may need higher doses due to decreased plasma concentrations through enhanced induction by PAHs of tobacco smoke. The prescribers and the pharmacists are required to be aware of medications affected by tobacco smoking to prevent the toxicity-associated complications during smoking cessation.
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Background: Thiazolidinediones (TZDs) include pioglitazone and rosiglitazone and they are indicated in the treatment of type 2 diabetes mellitus. They are insulin sensitizers and are metabolized primarily by the CYP2C8 enzyme. The drugs inhibiting or inducing CYP2C8 enzyme may result in pharmacokinetic drug interactions of TZDs. The probability of drug interactions is higher in type 2 diabetic patients as they administer many medications to manage blood glucose and to treat other diseases. Clinically significant drug interactions of TZDs are discussed in this review. Methods: The literature review was done in databases like Medline/PubMed/PMC, Science Direct, Google Scholar, Directory of Open Access Journals, and reference lists to identify relevant articles. Results: The drugs inhibiting the CYP2C8 enzyme such as gemfibrozil, clopidogrel, trimethoprim, ketoconazole, and rifampicin have been identified to affect the pharmacokinetics of TZDs. Conclusion: The clinicians need to be aware of adverse drug interactions of TZDs to prevent negative outcomes.
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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well established as effective treatments for patients with type 2 diabetes. GLP-1 RAs augment insulin secretion and suppress glucagon release via the stimulation of GLP-1 receptors. Although all GLP-1 RAs share the same underlying mechanism of action, they differ in terms of formulations, administration, injection devices and dosages. With six GLP-1 RAs currently available in Europe (namely, immediate-release exenatide, lixisenatide, liraglutide; prolonged-release exenatide, dulaglutide and semaglutide), each with its own characteristics and administration requirements, physicians caring for patients in their routine practice face the challenge of being cognizant of all this information so they are able to select the agent that is most suitable for their patient and use it in an efficient and optimal way. The objective of this review is to bring together practical information on the use of these GLP-1 RAs that reflects their approved use. Funding: Eli Lilly and Company. Plain Language Summary: Plain language summary available for this article.
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Sulfonylureas are useful to treat type 2 diabetes patients. Apart from sulfonylureas, the patients with diabetes may use many other medications to treat various concomitant illnesses such as high blood pressure, higher lipids, infections, pain, etc. The probability of interactions increases with the number of drugs used concomitantly. Most of the adverse drug interactions of sulfonylureas result in hypoglycemia, which can be life threatening. Sulfonylureas are primarily metabolized by CYP2C9 enzyme, which paves the way for most of their pharmacokinetic drug interactions. Drugs inhibiting CYP2C9 enzyme are expected to elevate the plasma concentrations of sulfonylureas and subsequent hypoglycemic complications. Some drugs potentiate the hypoglycemic activity of sulfonylureas pharmacodynamically too. The prescribers and pharmacists must be aware of the adverse drug interactions of sulfonylureas to prevent hypoglycemic episodes.
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Introduction: Sulfonylurea antidiabetics are insulin secretogogues useful in the treatment of type 2 diabetic patients. The probability of adverse drug interactions is high in patients taking sulfonylureas and other drugs including herbal medicines. The present review is aimed to present the herbal drugs having interacting potentials with sulfonylurea antidiabetics. Methods: The databases such as PubMed, Google Scholar, Science Direct, Directory of open access journals (DOAJ) and reference lists were searched using the keywords drug interactions, Sulfonylureas, pharmacodynamic interactions, antidiabetic herbs, pharmacokinetic interactions and CYP2C9. Results: Sulfonylureas are primarily metabolized by CYP2C9 enzyme and the herbs like St. John’s wort and Ginkgo biloba induce CYP2C9-mediated metabolism of sulfonylureas while fruit juices like Pomegranate juice and Pineapple juice inhibit their metabolism. In addition, the antidiabetic herbal supplements such as Bitter melon, Fenugreek, Cinnamon, Gymnema, Ginseng, Ginger, Garlic, Aloe vera, Sesame, Andrographis paniculata and Neem potentiate the hypoglycemic activity of sulfonylureas, pharmacodynamically. Conclusion: Some herbal supplements are capable of interacting pharmacokinetically and pharmacodynamically with sulfonylurea antidiabetics
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Either metformin or liraglutide has been reported to have anti-tumor effects on pancreatic cancer cells. However, it is not clear whether their combined treatment has additive or synergistic anti-tumor effects on pancreatic cancer cells. In this study, the human pancreatic cancer cell line MiaPaca-2 was incubated with liraglutide and/or metformin. The cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and wound-healing and transwell migration assays were used to detect cell viability, clonogenic survival, cell cycle and cell migration, respectively. RT-PCR and western blot analyses were used to determine the mRNA and protein levels of related molecules. Results showed that combination treatment with liraglutide (100 nmol/L) and metformin (0.75 mmol/L) significantly decreased cell viability and colony formation, caused cell cycle arrest, upregulated the level of pro-apoptotic proteins Bax and cleaved caspase-3, and inhibited cell migration in the cells, although their single treatment did not exhibit such effects. Combination index value for cell viability indicated a synergistic interaction of liraglutide and metformin. Moreover, the combined treatment with liraglutide and metformin could activate the phosphorylation of AMP-activated protein kinase (AMPK) more potently than their single treatment in the cells. These results suggest that liraglutide in combination with metformin has a synergistic anti-tumor effect on the pancreatic cancer cells, which may be at least partly due to activation of AMPK signaling. Our study provides new insights into the treatment of patients with type 2 diabetes and pancreatic cancer.
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Meglitinides such as repaglinide and nateglinide are useful to treat type 2 diabetes patients who follow a flexible lifestyle. They are short-acting insulin secretagogues and are associated with less risk of hypoglycemia, weight gain and chronic hyperinsulinemia compared with sulfonylureas. Meglitinides are the substrates of cytochrome P450 (CYP) enzymes and organic anion transporting polypeptide 1B1 (OATP1B1 transporter) and the coadministration of the drugs affecting them will result in pharmacokinetic drug interactions. This article focuses on the drug interactions of meglitinides involving CYP enzymes and OATP1B1 transporter. To prevent the risk of hypoglycemic episodes, prescribers and pharmacists must be aware of the adverse drug interactions of meglitinides.
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Metformin is a most widely used medication all around the world to treat Type 2 diabetes mellitus. It is also found to be effective against various conditions including, Prediabetes, Gestational diabetes mellitus (GDM), Polycystic Ovarian Syndrome (PCOS), Obesity, Cancer, etc. It is a cationic drug and it depends Organic Cation Transporters (OCTs) and Multidrug and Toxin Extruders (MATEs) mostly for its pharmacokinetics movement. The probability of drug interaction increases with the number of concomitant medications. This article focuses the drug interactions of metformin and most of them are linked to the inhibition of OCTs and MATEs leading to increased plasma metformin concentrations and subsequent elevation of risk of Metformin Associated Lactic Acidosis (MALA). By identifying the drugs inhibiting OCTs and MATEs, the healthcare professionals can predict the drug interactions of metformin.
Objective To evaluate the 1-year efficacy and safety of treatment with exenatide in combination with insulin (a use not approved by the US Food and Drug Administration). Methods Electronic medical records of 3 private-practice endocrinologists were reviewed to identify patients with type 2 diabetes mellitus (T2DM) receiving insulin who subsequently began exenatide therapy. Patients’ baseline hemoglobin A1c (A1C) levels, weights, lipid profiles, blood pressures, and medication utilization were compared with corresponding data obtained after a minimal duration of 12 months. Results We identified 134 patients with T2DM initiating exenatide therapy in combination with insulin between April 2005 and April 2006. One-year follow-up information was available for 124 patients. Exenatide use resulted in a significant 0.87% reduction in A1C (P < .001), despite a 45% discontinuation of premeal insulin use (P < .001), a 9-U reduction in mean premeal insulin doses (P = .0066), a reduction in the median number of daily insulin injections from 2 to 1 (P = .0053), and a 59% discontinuation rate of sulfonylurea use (P = .0088). Exenatide use was associated with a mean weight loss of 5.2 kg (P < .001), with 72% of evaluable patients losing weight. Forty-eight patients (36%) discontinued exenatide therapy during the first year, primarily attributable to gastrointestinal intolerance. Fourteen patients (10%) experienced hypoglycemia, most of which was mild. Conclusion Exenatide in combination with insulin in patients with T2DM was associated with significant reductions in A1C and weight after 1 year of therapy. This was offset, however, by an exenatide discontinuation rate of 36%, primarily due to adverse gastrointestinal effects. (Endocr Pract. 2008;14:285-292)
Introduction: Since the year 2000, IDF has been measuring the prevalence of diabetes nationally, regionally and globally. Aim: To produce estimates of the global burden of diabetes and its impact for 2017 and projections for 2045. Methods: A systematic literature review was conducted to identify published studies on the prevalence of diabetes, impaired glucose tolerance and hyperglycaemia in pregnancy in the period from 1990 to 2016. The highest quality studies on diabetes prevalence were selected for each country. A logistic regression model was used to generate age-specific prevalence estimates or each country. Estimates for countries without data were extrapolated from similar countries. Results: It was estimated that in 2017 there are 451 million (age 18-99 years) people with diabetes worldwide. These figures were expected to increase to 693 million) by 2045. It was estimated that almost half of all people (49.7%) living with diabetes are undiagnosed. Moreover, there was an estimated 374 million people with impaired glucose tolerance (IGT) and it was projected that almost 21.3 million live births to women were affected by some form of hyperglycaemia in pregnancy. In 2017, approximately 5 million deaths worldwide were attributable to diabetes in the 20-99 years age range. The global healthcare expenditure on people with diabetes was estimated to be USD 850 billion in 2017. Conclusion: The new estimates of diabetes prevalence, deaths attributable to diabetes and healthcare expenditure due to diabetes present a large social, financial and health system burden across the world.