Glimepiride and CYP2C9

The drug glimepiride (Amaryl®) is used to treat type 2 diabetes. In a healthy person, the body releases insulin from the pancreas when you eat. This keeps blood sugar from rising too high. In a patient with type 2 diabetes, the body is not able to use the insulin as well as it should and begins to make and release less insulin over time. Glimepiride helps the pancreas to release more insulin and allows the body to use the insulin better to help control blood sugar. One way to think about how glimepiride works is to imagine the pancreas as a sponge filled with insulin. A little bit of insulin might be dripping off, but then the glimepiride comes and squeezes that sponge (the pancreas) to allow more insulin to be released and used by the body.

Because glimepiride is releasing more insulin from the pancreas, the biggest side effect it can cause is low blood sugar.1 This can make patients feel confused, shaky, sweaty, angry, nervous, or tired. They may also get a bad headache or feel their heart beating faster than normal. If you feel these symptoms or know that you your blood sugar is lower than normal, drink half a cup of juice or soda or eat hard candies, like lifesavers. Because glimepiride causes you to release more insulin, it should be taken with food to prevent your blood sugar from dropping too low. If you skip a meal, make sure you also skip your dose of glimepiride.

A gene in the body makes the CYP2C9 (pronounced “sip two see nine”) enzyme, which is responsible for breaking down many drugs, including glimepiride. This makes the drug inactive so the body can get rid of it and to keep the drug from building up in the body. There are many different types of the CYP2C9 enzyme. Different types of the enzyme make you break down drugs faster, slower, or somewhere in between. Depending on which type of the CYP2C9 enzyme a patient has, he or she may need more or less of the drug in order for it to work.

If a patient has the CYP2C9*3 (pronounced “sip two see nine star three”) version of the gene, his or her body will break down glimepiride slower than other types of the gene. This causes the drug to stay in the body longer. Because of this, patients may be more likely to have low blood sugar after taking glimepiride, especially if they are older. At this point in time, there are no recommendations to decrease the amount of glimepiride a patient is taking if he or she has the CYP2C9*3 version of the gene.

Samuel, a 46-year-old white male, was recently diagnosed with type 2 diabetes mellitus (T2DM). His endocrinologist decided to start him on glimepiride 2 mg once daily. When Samuel returns for his next checkup 4 weeks later, he tells his doctor he has been experiencing increased fatigue, lightheadedness, and also unusually dry lips. Samuel had taken his dose of glimepiride earlier in the morning, and he was currently experiencing severe lightheadedness. Concerned for the possibility of low blood sugar, the endocrinologist decides to take labs. Samuel’s blood sugar ends up being 62 mg/dL, which is low.

Samuel actually has his full genotype information available as a result of previous testing for a genetic disorder that runs in his family. The endocrinologist looks at his information, and notices that CYP2C9, the enzyme responsible for glimepiride metabolism, is the CYP2C9*3 variant. This variant is known to lead to decreased CYP2C9 function, which would lead to increased levels of glimepiride in the body. Increased glimepiride levels will decrease blood sugar, which could explain the symptoms Samuel has been experiencing. As a result of this, the endocrinologist decides to switch Samuel to metformin, a T2DM medication that is not metabolized by CYP2C9.

The links below provide access to important articles and information relative to glimepiride. The links are to external websites and will be checked regularly for consistency.

• Glimepiride Prescribing Information
• Glimepiride Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Glimepiride

Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Clinical Drug Information Inc. c1978-2017. Glimepiride; [updated 2017 Jan 1; cited 2017 Feb 1]; [about 16 screens]. Available from: http://0-online.lexi.com.polar.onu.edu/lco/action/doc/retrieve/docid/patch_f/6980

Triplitt CL, Repas T, Alvarez C. Pharmacotherapy: a pathophysiologic approach [Internet]. 9th ed. New York: McGraw-Hill; 2014. Chapter 57, Diabetes Mellitus; [cited 2017 Feb 1]; [about 10 screens]. Available from: http://0-accesspharmacy.mhmedical.com.polar.onu.edu/content.aspx?bookid=689§ionid=45310509

Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012 Oct;92(4):414-7.