Safety and Efficacy of Metformin in Severe CKD

Study confirms recent guideline changes on metformin use in moderate-to-severe chronic kidney disease.

Use of metformin for CKD has been a topic of long debates. While it was previously contraindicated in individuals with increased serum creatinine above a certain point due to a risk of accumulation and, in turn, lactic acidosis, new guidelines have established updated information on dosing and adjustments based on renal dysfunction. Changes in the guidelines were made lacking studies that tracked the use of metformin in individuals with renal impairment. Hence, an investigation was needed to determine the safety and effective dosing schedule of metformin in individuals with CKD stages 3A, 3B, and 4. Three subsequent, open-label, single-center studies were performed to determine the appropriate dose adjustments, levels of metformin in chronically treated patients, and on the pharmacokinetics changes seen in CKD individuals.

The first study sought to determine a metformin dosing schedule; patients with CKD stages 1 to 5 were enrolled if their HbA1c level was above 6.5%. Patients with liver failure, pregnancy, and heart failure were excluded from participation. 69 enrolled patients were given metformin 500 mg for 1 week, after which they underwent a washout period. The following week, the metformin dose was increased to 1000 mg, followed by another week of washout period; the cycle was repeated for the third time, with increased doses of metformin to 2,000 mg daily. Lactate concentrations, plasma levels, and erythrocyte metformin levels were measured. Treatment with metformin was discontinued in subjects who had one plasma lactate value greater than 5 mmol/L, two lactate levels greater than 2.5 mmol/L, or if metformin levels were above 5 mg/L.  The goal of the second study was to detect any changes in metformin levels when it is given chronically to subjects with renal impairment. A total of 46 individuals with DM and CKD stages 3A, 3B, and 4 were given fixed metformin doses of 1500 mg, 1000 mg, and 500 mg per day, respectively. At the conclusion of each month, lactate and metformin levels were recorded. The last study enrolled patients in hopes of estimating noncompartmental pharmacokinetic analyses in CKD stages 3A to 4, based on changes in metformin plasma and erythrocyte concentrations.

To achieve the necessary blood levels, patients were given a monthlong therapy with metformin twice daily; a dose of 500 mg was given in the morning, while the evening dose depended on CKD stage. Blood levels of metformin, Cmax, time to Cmax, and through concentrations at 24 hours were measured.

During the first week of the study, only one subject receiving 500 mg of metformin had increased plasma levels above 2.5 mg/L. As the doses increased, more patients were seen to have higher metformin plasma levels as well. There were a total of six individuals during the 1000mg/day week, and 19 individuals during 2000 mg/day week who had plasma concentrations >2.5 mg/L.

Regardless of the increased plasma concentrations, only one patient in the trial experienced two consecutive readings of lactate to be above 2 mmol/L, and no participants had dangerously increased levels. Each of the dosing cycles proved to have an inversely proportional relationship between metformin concentration 12 hours post last dose of the week and estimated GFR.

Based on the curves of the slopes, researchers selected a metformin dosing schedule of 1500 mg daily for CKD stage 3A, 1000 mg daily for stage 3B, and 500 mg every evening for stage 4.

Patients who completed the second trial had stable A1c levels, plasma and metformin erythrocyte levels despite chronic metformin concentrations. Lactate levels were determined not to be affected by stable metformin concentrations. Lastly, the PK study did not find statistically significant differences in the pharmacokinetic parameters between three different CKD stages.

Three studies presented in this article validate the recent changes in guidelines for metformin use in patients with CKD and diabetes. Although the study showed metformin to be safely used in CKD stage 4, the authors concluded that its use should be limited with severe renal dysfunction, calling for larger, prospective studies to be completed to evaluate its true safety with later stages of chronic kidney disease. Most importantly, the studies proved the risk of metformin-induced lactic acidosis in renal impairment to be insignificant, as no patients had developed dangerously high lactic acid levels even when receiving doses substantially higher than recommended.

Practice Pearls:

• Metformin is safe and efficacious to use in CKD stages 3A and 3B when the dose is adjusted according to renal function.
• Patients with CKD stage 3A and 3B should receive 1500 mg and 1000 mg of metformin daily, respectively.
• Lactate levels should routinely be measured in frail patients; if lactate levels are seen to rise above 5 mmol/L, metformin should be promptly discontinued.

Reference:

Jean-Daniel Lalau, Farshad Kajbaf, Youssef Bennis.  “Metformin Treatment in Patients with Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, Or 4”. Diabetes Care. 2018.  https://care.diabetesjournals.org/content/early/2018/01/02/dc17-2231. Accessed on Jan 2018.

Lamija Zimic, PharmD(c), University of South Florida, College of Pharmacy