Non-steroidal anti-inflammatory drugs and metformin: a cause for concern?

Abstract

Patients with type 2 diabetes who are treated with metformin are at risk of metformin-associated lactic acidosis if they develop renal failure. Impairment of renal function in diabetes may be a consequence of diabetic nephropathy, or secondary to metabolic, immunological, or drug factors. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed and are known to cause renal failure. We describe a case of severe lactic acidosis in a patient with type 2 diabetes mellitus on long-term metformin therapy, who developed acute renal failure after recent treatment with a NSAID. A 57-year-old Asian woman with type 2 diabetes mellitus who had been treated with metformin (500 mg twice daily) for 15 years was admitted with general malaise, abdominal pain, nausea, and vomiting. 2 months before admission indomethacin (50 mg four times daily) was prescribed for severe backache. There was no history of analgesic abuse or previous renal disease. On admission, she was clinically euvolaemic but oliguric with a blood pressure (BP) of 180/90 mm Hg. There was no evidence of loin tenderness. Fundoscopy showed no signs of diabetic retinopathy. Initial biochemistry confirmed acute renal failure and severe metabolic acidosis with sodium 131 mmol/L, potassium 4·6 mmol/L, urea 28 mmol/L, creatinine 480 mol/L, pH 6·82, standard bicarbonate 1·2 mmol/L, glucose 13·6 mmol/L, and corrected calcium 2·1 mmol/L. Lactate was greatly raised at 21·1 mmol/L (normal range 0–1·2 mmol/L). Plasma alcohol was not detected. No immunological cause of glomerulonephritis was identified. Urinalysis showed no ketones or protein. Electrocardiogram revealed no evidence of acute myocardial ischaemia. Normal size kidneys without obstruction were confirmed by ultrasound scan. Subsequent management in the intensive care unit included intravenous fluids, and inotrope and insulin infusion. Both metformin and indomethacin were discontinued. Her condition gradually improved and she was discharged with stable impaired renal function (urea 17·6 mmol/L and creatinine 220 mol/L), BP 100/70 mm Hg, and diabetes requiring only dietary control. Although diabetic nephropathy is a potential cause of renal failure in all diabetic patients, the absence of diabetic retinopathy and proteinuria would suggest a non-diabetic cause in this case. The cause of the acute renal failure in this patient was most likely due to the NSAID which is known to reduce glomerular filtration rate with subsequent impairment of renal function. Metformin is excreted by the kidneys and may accumulate in the presence of acute renal insufficiency, contributing to the development of lactic acidosis. It is highly likely that considerable numbers of patients with diabetes have received this drug combination. However, to date there have been only three cases of metformin-associated lactic acidosis with concurrent NSAID therapy (two of whom had renal failure) reported to the Committee on Safety of Medicines in the UK. The manufacturers’ data sheets for both drugs do not have a warning of potential hazard for this combination. Drugs which may precipitate renal failure, including NSAIDs, should be used with caution in type 2 diabetic patients treated with metformin.