By: Jack (Hongkai) Bao, PharmD Candidate 2018
Metformin is an oral anti-hyperglycemic agent of the biguanide class and is FDA-indicated to treat type 2 diabetes or non-insulin-dependent diabetes mellitus (NIDDM).1 Metformin works by decreasing hepatic glucose production and simultaneously increasing peripheral tissue sensitivity to insulin. Unlike other oral anti-hyperglycemic agents such as the sulfonylureas, metformin does not stimulate insulin production in the body.1 Additionally, metformin does not cause weight gain or hypoglycemia as side effects.1 Because of these advantages, metformin has been the standard for monotherapy or combination therapy for type 2 diabetes.
Elimination of metformin from the body occurs mainly through the kidneys with approximately 40% to 60% of the drug being recovered unchanged in the urine.2 Because of this, metformin’s elimination half-life has a strong correlation to creatinine clearance and kidney function. In a patient with normal kidney function (as represented by a high creatinine clearance), metformin will have a short elimination half-life and will be removed from the body rapidly. Generally, it is beneficial for the patient when a drug acts quickly and is eliminated quickly. On the other hand, a patient with poor kidney function (low creatinine clearance) will observe a longer elimination half-life and higher than normal metformin levels in the body. Not surprisingly, the development of lactic acidosis, a serious adverse effect that results from metformin accumulation in the body, is especially prevalent when metformin is used in patients with renal dysfunction.1 Metformin is able to accumulate to toxic levels in the body when the kidneys fail to eliminate it. For this reason, the FDA advises extreme caution when using metformin in elderly patients, as they are more likely to have impaired renal function.1
Based on past FDA recommendations, contraindications in metformin use were solely based on serum creatinine levels, which measure the amount of creatinine in the body.2 Creatinine is the byproduct of muscle breakdown which can vary depending on a patient’s muscle mass.
However, only focusing on serum creatinine levels does not accurately measure a patient’s renal function. Renal function is an accumulation of different factors such as age, gender, race, and weight. Merely selecting one parameter, serum creatinine, as a basis for metformin eligibility led to physicians not accurately prescribing metformin. Certain patients may have been denied metformin simply because they did not meet the serum creatinine cut-off when their renal function was adequate. Conversely, other patients may have been inaccurately prescribed metformin even though their kidney function was poor. These recommendations by the FDA were strict and limited the use of metformin to a handful of patients and neglected those who would likely benefit from it.
This was changed in April 2016 when the FDA issued a statement requiring manufacturers to revise their labeling. It was changed to a parameter that provided a more accurate estimate of a renal function: eGFR or estimated glomerular filtration rate based on the Modification of Diet in Renal Disease-4 (MDRD-4) equation.3 The reason for this change is that eGFR takes into account a patient’s serum creatinine but also their age, race, gender and/or weight. These other factors can all influence a patient’s renal function and factoring them into eGFR provides a more accurate determination of how well their kidneys are working.
Utilizing the MDRD-4 equation to calculate eGFR is crucial because it takes into account body surface area. As mentioned previously, creatinine is a byproduct of muscle breakdown and those with less muscle mass will expectedly have a lower serum creatinine level. On the other hand, patients with more muscle mass will be expected to have a high level. By adjusting eGFR for body surface area, we can more accurately estimate renal function and metformin eligibility.
With this labeling change, we can hope that more patients will receive the benefits of metformin use. The critical aspect of this change is, as mentioned before, using a more accurate estimate of renal function: eGFR. Now, physicians will be able to prescribe metformin on a much more appropriate basis. In the past, physicians may have prescribed patients metformin on the basis that their serum creatinine levels met the criteria but in reality, their actual renal function did not. Likewise, it is possible that patients have been denied metformin by being under the serum creatinine cut-off yet their kidneys were functioning properly.
Now physicians can more accurately gauge if a patient is eligible for metformin. With these changes, we can hope to see fewer side effects from patients. This is especially important in this patient population as many are elderly and have poor renal function. Being careful when deciding to initiate or discontinue metformin therapy is crucial in promoting safety and efficacy.
- Metformin Hydrochloride Extended-Release Tablets USP, 500 mg and 1000 mg [package insert]. Baltimore, Maryland; Lupin Pharmaceuticals, Inc.; Revised 01/30/2012.
- FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. U.S. Food and Drug Administration. Updated 4/08/2016.
- Stevens L, Levey A. Frequently asked questions about GFR estimates. National Kidney Foundation. Published 01/01/2007.
- PL Detail-Document, Clinical use of metformin in special populations. Pharmacist’s Letter/Prescriber’s Letter. Published 03/01/2015. Updated 05/01/2016.