Metformin Appears To Be Safe And Effective In Stage 3 Chronic Kidney Disease

A study published in the Diabetes Care attempted to define the appropriate dose of metformin for type 2 diabetes patients suffering from stages 3 and 4 chronic kidney disease (CKD). The antidiabetes drug metformin was previously not recommended for type 2 diabetes patients with moderate-to-severe chronic kidney disease since it is excreted unchanged by the kidneys, and can therefore accumulate in the body, subsequently resulting in a dangerous complication called lactic acidosis.

Taking into consideration that the risk of lactic acidosis is overstated, in 2016, the European Medicines Agency and the U.S. Food and Drug Administration

(FDA) allowed the use of metformin in CKD stages 3A and 3B with glomerular filtration rates in the ranges of 59–45 and 44–30 mL/min/1.73 m², respectively. The approval, however, was not based on any clinical study, and prospective studies evaluating the effects and safety of the drug in this population are not available.

Scientists conducted three sub-studies in an attempt to fill in the missing data:

In the first study, patients with CKD stages 1 to 5 were administered increasing doses of metformin, and the concentration of metformin in the blood was evaluated in the week following an increase in the dose. The scientists found that the likely appropriate doses were:

• 0.5 g in the morning and 1 g in the evening for CKD3A patients
• 0.5 g in the morning and 0.5 g in the evening for CKD3B patients
• 0.5 g in the morning for CKD4 patients

The second study validated the above doses for moderate-to-severe CKD cases (stages 3 and 4) over a period of 4 months with monthly monitoring of the blood metformin lactate, and HbA1c concentrations. The HbA1c concentration indicates the control of blood glucose levels over the previous few weeks. The scientists found that:

• The metformin concentrations were stable and did not exceed the generally accepted safe upper limit of 5.0 mg/L
• High lactate levels of more than 5 mmol/L (which qualifies for true hyperlactatemia) were not noted, except in one patient with a heart attack. (The high lactate levels in the patient could be due to the heart attack). Some patients did record a lactate level of 2.5 mmol/L, which is above the usual normal levels
• The HbA1c levels did not change towards the end of the treatment, which indicates the lower than usual dose was effective in these patients

In the third study, the way the body processed the medication (in terms of the amount of drug absorbed from the gut, the distribution in the body, the blood levels of the free drug, and the excretion of the drug) were determined following the administration of a single dose of metformin in steady-state CKD3A, 3B, and 4. No significant differences in these parameters were noted among the patients from different groups.

The scientists thus concluded that with dosage adjustments, metformin can be a good option in terms of efficacy as well as safety in patients with moderate-to-severe CKD. The regular monitoring of blood metformin levels is not needed, which is in itself a costly procedure and not easily available. Further studies in larger number of patients and for a longer duration, along with measurement of blood bicarbonate levels to assess the acid-base status, and comparison of the lactate levels with patients with a lesser severe form of CKD will be able to throw more light on the benefits of metformin in these patients, especially in those with CKD4, for which metformin has yet to receive approval.

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The scientists suggest that if metformin is used for CKD3, the eGFR (estimated glomerular filtration rate) for kidney function should be assessed every 6 months. The medication should be stopped in the presence of acute kidney injury. Monitoring of the lactate levels is advised in fragile patients, especially in the presence of an additional illness. Metformin should be stopped if two consecutive lactate readings are more than 2.5 mmol/L or a single reading is more than 5 mmol/L.

About Metformin

Metformin is a drug commonly used for the treatment of type 2 diabetes. It normalizes blood glucose levels by improving the sensitivity of tissues to insulin, in addition to reducing the glucose production by the liver and its absorption from the intestine. The treatment with metformin is usually begun at a dose of 500 mg twice a day or 850 mg once a day, which is later increased as per the patient’s requirement to a maximum of 2550 mg in adults. While many old treatments fade in the background when new ones are discovered, metformin has withstood the test of time, and is still among the frontline drugs used for the treatment of type 2 diabetes.

Reference:

1. Lalau J et al. Metformin Treatment in Patients with Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4. Diabetes Care 2018. https://doi.org/10.2337/dc17-2231

Source-Medindia