Metformin pharmacogenetics: The most up to date evidence does not support clinical use

Metformin pharmacogenetics: The most up to date evidence does not support clinical use

The most up to date evidence does not support the use of SLC47A2 variants to predict glycemic response to metformin in diabetes

Type 2 diabetes

Type 2 diabetes is a chronic condition that affects the way the body metabolizes glucose (sugar) and is characterized by high levels of glucose in the blood that occurs when the body doesn’t produce enough insulin or doesn’t use insulin properly. Insulin is a hormone that controls the amount of glucose in the blood. Initially, the body may try to correct this by increasing the production of insulin, but over time the body is less able to meet this demand and the level of glucose in the blood remains high.
Some people may experience a combination of tiredness, frequent urination (peeing), unusual feelings of thirst, or unexpected weight loss. Having high levels of glucose in the blood can lead to complications such as damage to the heart, eyes, and kidneys. The goal of treatment is to lower the level of sugar in the blood and thereby prevent complications.

Metformin as first-line therapy for type 2 diabetes

Metformin is a very common medication that is used as first-line therapy for type 2 diabetes. Clinically, we can measure response to metformin in diabetes by monitoring for a reduction in HbA1c, which may be dependent on several factors, including genetics. Even in those who are at risk of a decreased response to metformin, we would still use it as a first line medication due to its long history of safety and effectiveness in treating diabetes and preventing long-term complications. In addition, all other diabetes drugs are indicated to be used in combination with metformin if the target HbA1c is not reached with metformin monotherapy, especially since metformin can mediate weight gain caused by other medications. Initial metformin monotherapy, followed by combination with additional antidiabetic medications, is currently the standard of care and supported by all the treatment guidelines.

SLC47A2 gene variants showed no significant effect on metformin response

Metformin response has been linked to variants in metformin transporter genes, including the SLC47A2 gene (rs12943590 variant) which is rated as level 2B evidence on PharmGKB. However, the established role of cation-selective transporters in metformin pharmacokinetics does not translate into real clinical outcomes and polymorphisms in these transporters showed no significant impact on glycemic response to metformin.
A recent meta-analysis (PMID: 27859023) by the Metformin Genetics Consortium showed that the most up to date evidence does not support the use of the SLC47A2 variant to predict glycemic response (HbA1c reduction) to metformin in diabetes. This meta-analysis examined variants in five metformin transporter genes (including SLC47A2 mentioned above) across 10 international cohorts. None of the variants were significantly associated with glycemic response to metformin in an analysis of close to 8000 people with type 2 diabetes, including approximately 6000 participants on metformin monotherapy and 1800 participants on dual therapy with metformin plus a sulfonylurea

TreatGxPlus is an evidence-based pharmacogenetic service that provides safe, effective, and personalized prescribing options. Since the best available evidence does not support a causal relationship between known genetic variants and metformin response, a pharmacogenetic test for metformin is not included on TreatGxPlus. As more evidence becomes available, this may be updated in the future.

In Canada, TreatGxPlus is brought to you in partnership with LifeLabs

For more information on metformin pharmacogenetics, the Metformin Genetics Consortium website includes contact information as well as recent publications and ongoing projects.

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