Drug/Small Molecule:
glimepiride

last updated 08/10/2011

Dutch Pharmacogenetics Working Group Guideline for glimepiride and CYP2C9

Summary

There are currently no dosing recommendations for glimepiride based on CYP2C9 genotype.

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for glimepiride based on CYP2C9 genotype (PMID:21412232). They conclude that there are no recommendations at this time.

Genotype Therapeutic Dose Recommendation Level of Evidence Clinical Relevance
CYP2C9 *1/*2 None Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (NS) Kinetic effect (NS)
CYP2C9 *2/*2 None Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (NS) Kinetic effect (NS)
CYP2C9 *1/*3 None Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (NS)
CYP2C9 *2/*3 None Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea
CYP2C9 *3/*3 None Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea
  • *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
  • S: statistically significant difference.

PharmGKB gathers information regarding PGx on FDA drug labels from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", and from FDA-approved FDA and EMA-approved (European Medicines Agency) EMA labels brought to our attention. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.

Please note that some drugs may have been removed from or added to the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" without our knowledge. We periodically check the table for additions to this table and update PharmGKB accordingly.

There is currently no such list for European drug labels - we are working with the EMA to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information. We are constructing this list by initially searching for drugs for which we have PGx-containing FDA drug labels - of these 44 EMA EPARs were identified and are being curated for pgx information.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA or other Medicine Agencies around the world - please contact feedback.



last updated 12/17/2013

FDA Label for glimepiride and G6PD

This label is on the FDA Biomarker List
Actionable PGx

Summary

The FDA-approved drug label for glimepiride (AMARYL) states that caution should be used in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency due to the risk for hemolytic anemia, and that a non-sulfonylurea alternative should be considered in this subset of patients. G6PD deficiency is a condition caused by variants in the G6PD gene which can be determined by enzymatic or genetic tests, however the drug label does not specifically mention testing.

Annotation

Glimepiride (AMARYL) is a blood-glucose-lowering drug indicated for use in adults with type 2 diabetes mellitus as an adjunct to diet and exercise.

Excerpt from the glimepiride (AMARYL) drug label:

Hemolytic Anemia: Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because AMARYL is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the glimepiride drug label.

*Disclaimer: The contents of this page are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Diabetes Mellitus
    • Indications & usage section, Contraindications section, Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Diabetes Mellitus, Type 2
    • Contraindications section, Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Hypoglycemia
    • Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • CYP2C9
    • Drug interactions section, Clinical pharmacology section, metabolism/PK
    • source: FDA Label
  • G6PD
    • Adverse reactions section, Warnings and precautions section, toxicity
    • source: FDA Label

last updated 05/09/2014

European Medicines Agency (EMA) Label for glimepiride and G6PD

Actionable PGx

Summary

The EMA European Public Assessment Report (EPAR) for pioglitazone and glimepiride (Tandemact) states that caution should be taken in patients with G6PD deficiency as glimepiride is a sulfonylurea agent and a non-sulfonylurea alternative should be considered.

Annotation

Pioglitazone and glimepiride (Tandemact) is indicated in patients with Type 2 Diabetes in patients in whom metformin is contraindicated or not tolerated. G6PD deficiency results from variants with the G6PD gene and confers an increased risk of hemolytic anemia induced by various substances, including sulfonylurea agents.

Excerpt from the Pioglitazone and glimepiride (Tandemact) EPAR:

Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since glimepiride belongs to the chemical class of sulfonylurea medicinal products, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the pioglitazone and glimepiride (Tandemact) EMA drug label.

*Disclaimer: The contents of this page have not been endorsed by the EMA and are the sole responsibility of PharmGKB.

Genes and/or phenotypes found in this label

  • CYP2C8
    • Drug interactions section, Pharmacokinetics section, Warnings and precautions section, metabolism/PK
    • source: European Medicines Agency (EMA) Label
  • CYP2C9
    • Pharmacokinetics section, metabolism/PK
    • source: European Medicines Agency (EMA) Label
  • G6PD
    • Warnings and precautions section, toxicity
    • source: European Medicines Agency (EMA) Label

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

Gene ? Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No VIP available VA CYP2C9 *1 N/A N/A N/A
No VIP available No VIP available VA CYP2C9 *2 N/A N/A N/A
No VIP available No VIP available VA CYP2C9 *3 N/A N/A N/A
No VIP available No Clinical Annotations available VA
rs1057910 1075A>C, 47545517A>C, 47639A>C, 96741053A>C, CYP2C9*3, CYP2C9*3:Ile359Leu, CYP2C9: I359L, CYP2C9:359Ile>Leu, CYP2C9:Ile359Leu, Ile359Leu, mRNA 11A>C
A > C
Missense
Ile359Leu
No VIP available No Clinical Annotations available VA
rs1799853 430C>T, 47506511C>T, 8633C>T, 96702047C>T, Arg144Cys, CYP2C9*2, CYP2C9:144Arg>Cys, CYP2C9:Arg144Cys, mRNA 455C>T
C > T
Missense
Arg144Cys
No VIP available No Clinical Annotations available VA
rs5215 1009G>A, 17348630C>T, 17408630C>T, 6577G>A, 748G>A, Val250Ile, Val337Ile
C > T
Missense
Val250Ile
No VIP available No Clinical Annotations available VA
rs5219 -16-179A>G, 17349572T>C, 17409572T>C, 5635A>G, 67A>G, E23K, KCNJ11: Lys23Glu, KCNJ11:67A>G, KCNJ11:E23K, Lys23Glu
T > C
Intronic
Lys23Glu
No VIP available No Clinical Annotations available VA
rs757110 17358477C>A, 17418477C>A, 4105G>T, 84973G>T, Ala1369Ser
C > A
Missense
Ala1369Ser
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • Glimepirid
  • Glimepirida
  • Glimepiridum
  • Glimepride
Trade Names
  • Amarel
  • Amaryl
  • Avaglim
  • Endial
  • Novo-glimepiride
  • PMS-glimepiride
  • Ratio-glimepiride
  • Sandoz glimepiride
Brand Mixture Names
  • Avandaryl (glimepiride + rosiglitazone maleate)

PharmGKB Accession Id:
PA449761

Description

Glimepiride is the first III generation sulphonyl urea it is a very potent sulphonyl urea with long duration of action.

Source: Drug Bank

Indication

For concomitant use with insulin for the treatment of noninsulin-dependent (type 2) diabetes mellitus.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

The mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells, and increasing sensitivity of peripheral tissues to insulin. Glimepiride likely binds to ATP-sensitive potassium channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Membrane depolarization stimulates calcium ion influx through voltage-sensitive calcium channels. This increase in intracellular calcium ion concentration induces the secretion of insulin.

Source: Drug Bank

Pharmacology

Glimepiride, like glyburide and glipizide, is a "second-generation" sulfonylurea agents. Glimepiride is used with diet to lower blood glucose by increasing the secretion of insulin from pancreas and increasing the sensitivity of peripheral tissues to insulin.

Source: Drug Bank

Food Interaction

Even though food reduces product absorption, the manufacturer recommends taking the product with the first meal of the day.|Avoid alcohol.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic. Following either an intravenous or oral dose, glimepiride is completely metabolized by oxidative biotransformation to a major metabolite, cyclohexyl hydroxymethyl derivative (M1), via the hepatic cytochrome P450 II C9 subsystem. M1 is further metabolized to the carboxyl derivative (M2) by one or several cytosolic enzymes. M1, but not M2, possessed approximately one third of the pharmacologic activity of its parent in an animal model. However, whether the glucose-lowering effect of M1 is clinically significant is not clear.

Source: Drug Bank

Protein Binding

Over 99.5% bound to plasma protein.

Source: Drug Bank

Absorption

Completely (100%) absorbed following oral administration.

Source: Drug Bank

Half-Life

Approximately 5 hours following single dose.

Source: Drug Bank

Toxicity

Severe hypoglycemic reactions with coma, seizure, or other neurological impairment.

Source: Drug Bank

Volume of Distribution

Source: Drug Bank

Chemical Properties

Chemical Formula

C24H34N4O5S

Source: Drug Bank

Isomeric SMILES

CCC1=C(CN(C1=O)C(=O)NCCC2=CC=C(C=C2)S(=O)(=O)NC(=O)N[C@H]3CC[C@@H](CC3)C)C

Source: Drug Bank

CCC1=C(C)CN(C(=O)NCCC2=CC=C(C=C2)S(=O)(=O)NC(=O)NC2CCC(C)CC2)C1=O

Source: Drug Bank

Canonical SMILES

CCC1=C(C)CN(C(=O)NCCC2=CC=C(C=C2)S(=O)(=O)NC(=O)NC2CCC(C)CC2)C1=O

Source: Drug Bank

Average Molecular Weight

490.616

Source: Drug Bank

Monoisotopic Molecular Weight

490.224990908

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Targets

Gene Description
ABCC8 (source: Drug Bank)
KCNJ1 (source: Drug Bank)
KCNJ11 (source: Drug Bank)

Drug Interactions

Drug Description
glimepiride The sulfonylurea increases the effect of cyclosporine (source: Drug Bank)
glimepiride The sulfonylurea increases the effect of cyclosporine (source: Drug Bank)
cyclosporine The sulfonylurea increases the effect of cyclosporine (source: Drug Bank)
cyclosporine The sulfonylurea increases the effect of cyclosporine (source: Drug Bank)
gemfibrozil Gemfibrozil increases the effect and toxicity of rosiglitazone/pioglitazone (source: Drug Bank)
gemfibrozil Gemfibrozil increases the effect and toxicity of rosiglitazone/pioglitazone (source: Drug Bank)
glucosamine Possible hyperglycemia (source: Drug Bank)
ketoconazole Ketoconazole increases the effect of rosiglitazone (source: Drug Bank)
ketoconazole Ketoconazole increases the effect of rosiglitazone (source: Drug Bank)
pregabalin Increased risk of edema (source: Drug Bank)
repaglinide Similar mode of action - questionable association (source: Drug Bank)
rifampin Rifampin reduces levels and efficacy of rosiglitazone, rifampin decreases the effect of sulfonylurea (source: Drug Bank)
rifampin Rifampin reduces levels and efficacy of rosiglitazone, rifampin decreases the effect of sulfonylurea (source: Drug Bank)
somatropin recombinant Somatropin may antagonize the hypoglycemic effect of glimepiride. Monitor for changes in fasting and postprandial blood sugars. (source: Drug Bank)
glimepiride Similar mode of action - questionable association (source: Drug Bank)
glimepiride Rifampin decreases the effect of sulfonylurea (source: Drug Bank)
glimepiride Rifampin decreases the effect of sulfonylurea (source: Drug Bank)
glimepiride Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Glimepiride. Consider alternate therapy or monitor for changes in Glimepiride therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed. (source: Drug Bank)
glimepiride Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Glimepiride. Consider alternate therapy or monitor for changes in Glimepiride therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed. (source: Drug Bank)

Curated Information ?

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to glimepiride: 18

No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
CYP2C9, KCNJ11 and ABCC8 polymorphisms and the response to sulphonylurea treatment in type 2 diabetes patients. European journal of clinical pharmacology. 2014. Klen Jasna, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
The Ser1369Ala variant of ABCC8 and the risk for severe sulfonylurea-induced hypoglycemia in German patients with Type 2 diabetes. Pharmacogenomics. 2012. Holstein Judith Dina, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genetic risk factors for type 2 diabetes mellitus and response to sulfonylurea treatment. Pharmacogenetics and genomics. 2011. Swen Jesse J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
ABCC8 polymorphism (Ser1369Ala): influence on severe hypoglycemia due to sulfonylureas. Pharmacogenomics. 2010. Sato Ryosuke, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Effect of CYP2C9 polymorphisms on prescribed dose and time-to-stable dose of sulfonylureas in primary care patients with Type 2 diabetes mellitus. Pharmacogenomics. 2010. Swen Jesse J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Cytochrome P450 2C9-CYP2C9. Pharmacogenetics and genomics. 2010. Van Booven Derek, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: a Go-DARTS study. Clinical pharmacology and therapeutics. 2010. Zhou K, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Presence of CYP2C9*3 allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas. Pharmacogenomics. 2009. Ragia Georgia, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Substrate-dependent functional alterations of seven CYP2C9 variants found in Japanese subjects. Drug metabolism and disposition: the biological fate of chemicals. 2009. Maekawa Keiko, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Machine learning methods and docking for predicting human pregnane X receptor activation. Chemical research in toxicology. 2008. Khandelwal Akash, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetics of glucose-lowering drug treatment: a systematic review. Molecular diagnosis & therapy. 2007. Bozkurt Ozlem, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Effect of CYP2C9 genetic polymorphisms on the efficacy and pharmacokinetics of glimepiride in subjects with type 2 diabetes. Diabetes research and clinical practice. 2006. Suzuki Kazuko, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacokinetics of glimepiride and cytochrome P450 2C9 genetic polymorphisms. Clinical pharmacology and therapeutics. 2005. Wang Rui, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Sulfonylurea stimulation of insulin secretion. Diabetes. 2002. Proks Peter, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Differential selectivity of insulin secretagogues: mechanisms, clinical implications, and drug interactions. Journal of diabetes and its complications. 2003. Gribble Fiona M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clinical pharmacology and therapeutics. 2002. Niemi Mikko, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clinical pharmacology and therapeutics. 2002. Kirchheiner Julia, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Sulfonylurea sensitivity of adenosine triphosphate-sensitive potassium channels from beta cells and extrapancreatic tissues. Metabolism: clinical and experimental. 2000. Gribble F M, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
61442-115-01
DrugBank:
DB00222
ChEBI:
5383
KEGG Compound:
C07669
KEGG Drug:
D00593
PubChem Compound:
3476
PubChem Substance:
193913
46508842
Drugs Product Database (DPD):
2245274
ChemSpider:
3357
Therapeutic Targets Database:
DAP000132
FDA Drug Label at DailyMed:
72d88c6d-2f0a-4bf8-aa7f-1e1811794187

Clinical Trials

These are trials that mention glimepiride and are related to either pharmacogenetics or pharmacogenomics.

Common Searches

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.