Hemodialysis International 2014; 18:522–561
Lactic acidosis induced by metformin in a chronic hemodialysis patient with diabetes mellitus type 2* Eda ALTUN,1 Bülent KAYA,1 Saime PAYDAS ¸ ,1 Barıs ¸ SARIAKÇALI,2 ˙I brahim KARAYAYLALI1 1
Department of Nephrology, Faculty of Medicine, Cukurova University, Adana, Turkey; 2Department of Endocrinology, Faculty of Medicine, Cukurova University, Adana, Turkey
Abstract Metformin is a biguanide group oral antidiabetic drug used for the treatment of type 2 diabetes mellitus. Nausea, vomiting, diarrhea, abdominal pain, and anorexia are the most common adverse effects encountered during treatment. Lactic acidosis is a serious side effect seen with metformin use, and while the incidence of lactic acidosis is similar to other oral antidiabetics, metformin is not recommended to patients with certain risk factors, such as cardiovascular, pulmonary, and renal and liver failure. We describe a chronic hemodialysis patient treated with metformin, presenting to the nephrology department with altered mental status. Key words: Hemodialysis, lactic acidosis, metformin, type 2 diabetes mellitus
INTRODUCTION Metformin is the first-line, widely used oral antidiabetic agent for the management of type 2 diabetes. An extremely rare, but potentially life-threatening adverse effect of metformin is lactic acidosis; therefore, its use is traditionally contraindicated if the glomerular filtrate rate is below 30 mL/min. We describe a chronic hemodialysis patient treated with metformin, presenting to the nephrology department with altered mental status.
Correspondence to: Eda Altun, Department of Nephrology, Faculty of Medicine, Cukurova University, Adana 01130, Turkey. E-mail: [email protected] Conflict of interest: No conflict of interest was declared by the authors. Funding: None. *Corrections added on 5 February 2014, after first online publication: The following revisions were made to the title: 1.) “by” was inserted between “induced” and “metformin”; 2.) “tip” was changed to “type.” “Tip 2” in the key words and in the Case section were corrected to “type 2.”
Metformin-induced lactic acidosis was diagnosed and he was treated with hemodialysis.
CASE A 76-year-old male with impaired consciousness was admitted to our clinic. His medical history included chronic renal failure, undergoing hemodialysis three times a week, hypertension, and diabetes mellitus type 2. He was treated with metformin 2 g/day for the last 4 weeks. The patient had been hospitalized in another center for consciousness 10 days ago. At that time, the result of blood gas analysis was pH 6.84, pCO2 14.4 mmHg, HCO3 2.5 mEq/L, and lactat level was measured. Upon admission, his respiratory rate was 22 per minute while his other vital signs were within normal range. However, sepsis, diarrhea, dehydration was not found. Laboratory test results were as follow: blood glucose 208 mg/dL, blood urea nitrogen 54 mg/dL, creatinine 6.54 mg/dL, sodium 135 mmol/L, potassium 4.9 mmol/L. Computerized brain tomography was found normal. Blood gas analyses showed pH: 7.07, pCO2: 32 mmHg, HCO3:
© 2013 International Society for Hemodialysis DOI:10.1111/hdi.12109
529
Case Reports
Table 1 Laboratory findings
Baseline 1. 2. 3.
pH
pCO2 (mmHg)
HCO3 (mEq/L)
Lactate (mEq/L)
7.07 7.32 7.36 7.41
32 33 35 34
13 14.3 21.1 24
7 5.5 3.5 1.05
1, 2, and 3 indicates following daily hemodialysis session.
13 mEq/L. Blood lactate level was 7 mEq/L. Metformininduced lactic acidosis was diagnosed and he was treated with intermittent hemodialysis with a bicarbonate buffer solution for 6 hours, during 3 days. After hospitalization, metformin was stopped. He was treated with a single dose of insulin glargine to regulate blood glucose levels (Table 1).
DISCUSSION Metformin is commonly used as a first-line agent in the treatment of diabetes mellitus type 2. In addition to controlling blood sugar, it has been shown to reduce the long-term complications of diabetes, including macrovascular disease. Metformin is not metabolized and mainly (90%) excreted by kidneys. Glomerular filtration and tubular secretion are considered the major routes of metformin elimination. The blood elimination half-life is around 6.5 hours in patients with a normal renal function. It is prolonged in patients with renal impairment. Reduction in creatinine clearance is proportional to reduction in metformin clearance.1,2 Metformin-associated lactic acidosis (MALA) is defined as a syndrome of elevated blood lactate level with acidemia in patients treated with metformin, after excluding other causes of lactic acidosis. It can develop under pharmacologic or toxic doses of metformin. The incidence of MALA is not clearly documented in the literature with estimated 3 and 9 cases per 100,000 patient years.3–6 Clinically significant lactic acid accumulation almost always occurs in the presence of comorbid conditions, such as renal insufficiency (serum creatinine concentration above 1.4 mg/dL [124 μmol/L] in women and 1.5 mg/dL [132 μmol/L] in men), or low creatinine clearance, concurrent liver disease or alcohol abuse, heart failure, history of lactic acidosis, decreased tissue perfusion or hemodynamic instability, hypoxic states or serious acute illness.7 In our case, predisposing factor for MALA
530
were chronic renal failure, advanced age, history of hypertension. Similar risk factors and advanced age >65 years were reported by other authors.3,5 Chun Wing Yeung et al. reported that hypertension was the commonest associated medical problem with MALA as in our case.7,8 Although the incidence of MALA is relatively low, its mortality is extremely high and estimated to be over 50%.8,9 The treatment involves repairing acid-base balance, removing causes of lactic acidosis, and supportive therapy. Hemodialysis with bicarbonate replacement fluid has been used successfully in the treatment of lactic acidosis due to metformin use. Hemodialysis not only corrects the acidosis, but also efficiently removes metformin from plasma, preventing further lactate overproduction and removes lactate.2 Following 6 hours of hemodialysis, impairment of consciousness improved, and lactic acidosis regressed as monitored by blood levels in our patient. Metformin prescription in patients with renal impairment is limited by concerns relating to the theoretical risk of lactic acidosis—a fear perpetuated by numerous case reports in which it is implicated. Current National Institute for Health and Clinical Excellence guidelines recommend that the dose of metformin should be reviewed if the estimated glomerular filtration rate (eGFR) is
Lactic acidosis induced by metformin in a chronic hemodialysis patient with diabetes mellitus type 2* Eda ALTUN,1 Bülent KAYA,1 Saime PAYDAS ¸ ,1 Barıs ¸ SARIAKÇALI,2 ˙I brahim KARAYAYLALI1 1
Department of Nephrology, Faculty of Medicine, Cukurova University, Adana, Turkey; 2Department of Endocrinology, Faculty of Medicine, Cukurova University, Adana, Turkey
Abstract Metformin is a biguanide group oral antidiabetic drug used for the treatment of type 2 diabetes mellitus. Nausea, vomiting, diarrhea, abdominal pain, and anorexia are the most common adverse effects encountered during treatment. Lactic acidosis is a serious side effect seen with metformin use, and while the incidence of lactic acidosis is similar to other oral antidiabetics, metformin is not recommended to patients with certain risk factors, such as cardiovascular, pulmonary, and renal and liver failure. We describe a chronic hemodialysis patient treated with metformin, presenting to the nephrology department with altered mental status. Key words: Hemodialysis, lactic acidosis, metformin, type 2 diabetes mellitus
INTRODUCTION Metformin is the first-line, widely used oral antidiabetic agent for the management of type 2 diabetes. An extremely rare, but potentially life-threatening adverse effect of metformin is lactic acidosis; therefore, its use is traditionally contraindicated if the glomerular filtrate rate is below 30 mL/min. We describe a chronic hemodialysis patient treated with metformin, presenting to the nephrology department with altered mental status.
Correspondence to: Eda Altun, Department of Nephrology, Faculty of Medicine, Cukurova University, Adana 01130, Turkey. E-mail: [email protected] Conflict of interest: No conflict of interest was declared by the authors. Funding: None. *Corrections added on 5 February 2014, after first online publication: The following revisions were made to the title: 1.) “by” was inserted between “induced” and “metformin”; 2.) “tip” was changed to “type.” “Tip 2” in the key words and in the Case section were corrected to “type 2.”
Metformin-induced lactic acidosis was diagnosed and he was treated with hemodialysis.
CASE A 76-year-old male with impaired consciousness was admitted to our clinic. His medical history included chronic renal failure, undergoing hemodialysis three times a week, hypertension, and diabetes mellitus type 2. He was treated with metformin 2 g/day for the last 4 weeks. The patient had been hospitalized in another center for consciousness 10 days ago. At that time, the result of blood gas analysis was pH 6.84, pCO2 14.4 mmHg, HCO3 2.5 mEq/L, and lactat level was measured. Upon admission, his respiratory rate was 22 per minute while his other vital signs were within normal range. However, sepsis, diarrhea, dehydration was not found. Laboratory test results were as follow: blood glucose 208 mg/dL, blood urea nitrogen 54 mg/dL, creatinine 6.54 mg/dL, sodium 135 mmol/L, potassium 4.9 mmol/L. Computerized brain tomography was found normal. Blood gas analyses showed pH: 7.07, pCO2: 32 mmHg, HCO3:
© 2013 International Society for Hemodialysis DOI:10.1111/hdi.12109
529
Case Reports
Table 1 Laboratory findings
Baseline 1. 2. 3.
pH
pCO2 (mmHg)
HCO3 (mEq/L)
Lactate (mEq/L)
7.07 7.32 7.36 7.41
32 33 35 34
13 14.3 21.1 24
7 5.5 3.5 1.05
1, 2, and 3 indicates following daily hemodialysis session.
13 mEq/L. Blood lactate level was 7 mEq/L. Metformininduced lactic acidosis was diagnosed and he was treated with intermittent hemodialysis with a bicarbonate buffer solution for 6 hours, during 3 days. After hospitalization, metformin was stopped. He was treated with a single dose of insulin glargine to regulate blood glucose levels (Table 1).
DISCUSSION Metformin is commonly used as a first-line agent in the treatment of diabetes mellitus type 2. In addition to controlling blood sugar, it has been shown to reduce the long-term complications of diabetes, including macrovascular disease. Metformin is not metabolized and mainly (90%) excreted by kidneys. Glomerular filtration and tubular secretion are considered the major routes of metformin elimination. The blood elimination half-life is around 6.5 hours in patients with a normal renal function. It is prolonged in patients with renal impairment. Reduction in creatinine clearance is proportional to reduction in metformin clearance.1,2 Metformin-associated lactic acidosis (MALA) is defined as a syndrome of elevated blood lactate level with acidemia in patients treated with metformin, after excluding other causes of lactic acidosis. It can develop under pharmacologic or toxic doses of metformin. The incidence of MALA is not clearly documented in the literature with estimated 3 and 9 cases per 100,000 patient years.3–6 Clinically significant lactic acid accumulation almost always occurs in the presence of comorbid conditions, such as renal insufficiency (serum creatinine concentration above 1.4 mg/dL [124 μmol/L] in women and 1.5 mg/dL [132 μmol/L] in men), or low creatinine clearance, concurrent liver disease or alcohol abuse, heart failure, history of lactic acidosis, decreased tissue perfusion or hemodynamic instability, hypoxic states or serious acute illness.7 In our case, predisposing factor for MALA
530
were chronic renal failure, advanced age, history of hypertension. Similar risk factors and advanced age >65 years were reported by other authors.3,5 Chun Wing Yeung et al. reported that hypertension was the commonest associated medical problem with MALA as in our case.7,8 Although the incidence of MALA is relatively low, its mortality is extremely high and estimated to be over 50%.8,9 The treatment involves repairing acid-base balance, removing causes of lactic acidosis, and supportive therapy. Hemodialysis with bicarbonate replacement fluid has been used successfully in the treatment of lactic acidosis due to metformin use. Hemodialysis not only corrects the acidosis, but also efficiently removes metformin from plasma, preventing further lactate overproduction and removes lactate.2 Following 6 hours of hemodialysis, impairment of consciousness improved, and lactic acidosis regressed as monitored by blood levels in our patient. Metformin prescription in patients with renal impairment is limited by concerns relating to the theoretical risk of lactic acidosis—a fear perpetuated by numerous case reports in which it is implicated. Current National Institute for Health and Clinical Excellence guidelines recommend that the dose of metformin should be reviewed if the estimated glomerular filtration rate (eGFR) is
