Metformin in patients with chronic kidney disease: strengths and weaknesses

REVIEW JNEPHROL 2013; 26 ( 01 ) : 55- 60 DOI: 10.5301/jn.5000166 Metformin in patients with chronic kidney disease: strengths and weaknesses Ana Roc...
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REVIEW

JNEPHROL 2013; 26 ( 01 ) : 55- 60 DOI: 10.5301/jn.5000166

Metformin in patients with chronic kidney disease: strengths and weaknesses Ana Rocha 1, Marta Almeida 2, Josefina Santos 1, André Carvalho 2

Introduction

Abstract A wide array of benefits has been attributed to metformin. These include attenuation of abnormal glucose metabolism (diabetes treatment and prevention), weight neutrality or weight loss, improvement in the pathophysiologic components of metabolic syndrome (insulin resistance, subclinical inflammation, and endothelial dysfunction), lipid-lowering properties, cardiovascular protection, and antineoplastic potential. Metformin itself is not a nephrotoxic drug. Initially appointed as the safest hypoglycemic agent in chronic kidney disease, its use has been limited in these patients because of the perceived risk of lactic acidosis. A fear perpetuated by numerous case reports in which it is implicated. Current guidelines stipulate that it must be used with caution in estimated glomerular filtration rates (eGFRs) of less than 60 mL/minute and not at all in eGFRs of less than 30 mL/minute. Identified risk factors for metformin-associated lactic acidosis include acute kidney injury, hypoxemia, sepsis, alcohol abuse, liver failure, myocardial infarction, and shock. Treatment may include supportive care and dialysis techniques. On the other hand, it is likely that the use of metformin would be beneficial in many with chronic kidney disease according to the advantages associated with attenuation of metabolic syndrome and cardiovascular protection. The reality of severe metformin-induced lactic acidosis in the absence of chronic renal impairment raises the question of limitation of its use in these patients. Key words: Diabetes, Lactic acidosis, Metformin, Renal

failure

Nephrology Department, Centro Hospitalar do Porto, Porto - Portugal 2 Endocrinology Department, Centro Hospitalar do Porto, Porto - Portugal 1

Metformin is an insulin-sensitizing biguanide widely used to treat patients with type-2 diabetes mellitus. The efficacy of metformin in reducing hyperglycemia is well established, but there is emerging evidence of several other beneficial effects. However, metformin therapy has been associated with lactic acidosis. During 2010, patients admitted to Hospital de Santo António, in Portugal, with lactic acidosis associated with metformin were analyzed. A literature search was performed with a review of practical approach to these patients. The role of metformin was analyzed by the endocrinologist and nephrologist.

The patients We reviewed the chart of all patients admitted to our hospital between January 1 and December 30, 2010, with lactic acidosis attributed to metformin. Clinical data were recorded. Admission serum lactate and creatinine level, pH, as well as renal replacement therapy, length of stay, and outcomes were reviewed. Seven patients were included. Clinical and analytical characteristics are represented in Table I. The patients were elderly, mostly women, with at least two comorbidities. Daily metformin dose was 2600 mg. All patients developed an acute kidney injury but renal function prognosis was good.

Metformin-associated lactic acidosis Lactic acidosis is a recognized complication of metformin, that is, metformin-associated lactic acidosis (MALA),

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Rocha et al: Metformin: two opinions, one conclusion

Table I Clinical and analytical characteristics of the patients All patients (n=7) Age Sex (M/F) (%) Cocomitant conditions (%)  Hypertension   Chronic heart disease   Liver Disease   Chronic respiratory disease   Infection eGFR > 60 mL/min/1.73 m2 (%) Hemoglobin A1C mean value (%) Metformin dosage (mg) Other treatments (%)   Antihypertensive drugs   RAAS blockers    ACE inhibitors    ARB   Diuretics   β-blocker   Other antidiabetic agents    DPP-4 inhibitors    Sulfonylureas   Thiazolidinediones   Insulin Laboratory values at diagnosis   Creatinine (mg/dL)  pH   Lactate (mmol/L)   Bicarbonate (mmol/L)   Anion gap Gastrointestinal symptoms (%) Outcomes (%)   RRT requirement   Renal recovery

75.78±6.44 71.4/28.6 100 57.2 14.3 57.2 57.2 100 8.14 2571

57.2 28.6 85.7 57.2 42.8 14.3 14.3 42.8 5.7 7.062 13.9 8 31.2 71.4 85.7 100

Mean ± standard deviation for quantitative variables; percentages for qualitative variables. Estimated glomerular filtration rate (eGFR) calculated according to the MDRD equation. RAAS = renin-angiotensin-aldosterone system; ACE = angiotensin-converting enzyme; ARB = aldosterone-receptor blockers; DPP-4 = Dipeptidyl peptidase-4; RRT = renal replacement therapy. 56

defined as a syndrome of elevated blood lactate level with acidemia in patients taking metformin (after other causes of lactic acidosis have been excluded). It can occur under pharmacologic doses or intoxication. Although increased lactic acid production may be induced by hemodynamic instability and/or tissue hypoxia associated with severe metformin overdose or any underlying unstable cardiovascular or respiratory condition, lactic acidosis is predominantly because of a lack of lactate clearance rather than increased production (1, 2). It could be that metformin accumulates in the intestine and increases the production of lactate, which lowers the pH within the liver and decreases lactate metabolism by suppressing pyruvate carboxylase. It is a rare but serious complication, with a frequency of 3 per 1000 patient-years but with mortality as high as 42% to 50%. No deaths were recorded in our series. A possible explanation is a more timely presentation to the emergency service because of gastrointestinal symptoms, frequently reported in our patients. Lalau and Race, in 2001, proposed a classification of lactic acidosis in metformin therapy into three main types: 1) unrelated to metformin; 2) metformin-associated, which refers to metformin and concurrent pathologies as co-precipitating factors; 3) metformin-induced, precipitated only by metformin without apparent associated pathology (1). Identified risk factors for MALA include acute kidney injury, hypoxemia, sepsis, alcohol abuse, liver failure, myocardial infarction, and shock. Medications that interfere with renal hemodynamic autoregulation (that is, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and non-steroidal anti-inflammatory drugs) and volume depletion because of gastrointestinal losses are frequently implicated in generating acute kidney injury leading to MALA. Therefore, we can classify all of our cases as metforminassociated lactic acidosis. In many series of case reports of MALA, as in ours, patients present gastrointestinal symptoms, leading to the question of whether the symptoms are side effects of metformin or the first signs of lactic acidosis. On the other hand, this adds the confounding factor of volume depletion which might have contributed to the severity of metabolic acidosis and acute renal failure. Since the symptomatology is nonspecific and the clinic onset subtle a high level of suspicion is required to establish an early diagnosis (3). MALA incidence drops when the contra-indications and correct rules of prescription are respected. The stated contraindications to metformin include: hypoxic conditions (respiratory failure and heart failure), impaired lactate clearance (liver failure), and impaired metformin clearance (renal failure) (4, 5).

© 2012 Società Italiana di Nefrologia - ISSN 1121-8428

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Van Berlo-van de Laar et al, in a study to estimate the incidence of MALA by means of metformin serum concentration measurements and investigate its correlation with clinical outcome, reported that 11 of the 16 MALA cases (69%) had risk factors for lactic acidosis in their medical history (6). The mainstay of MALA therapy is supportive care. Particular attention should be paid to eliminating offending medication and normalizing the acid-base imbalance. Renal replacement therapies have been successfully employed for both isovolemic correction of the metabolic acidosis as well as removal of metformin and lactate, treating concomitant disease. In our sample, seven patients with oligoanuric acute renal failure have undergone dialysis. These were patients with GFR > 60 mL/min and therefore without prior vascular access, which requires considering the risk/benefit of placing a central venous catheter for dialysis. Intravenous sodium bicarbonate can also be used to correct blood pH, but it is not free of risks such as hypernatremia, hyperosmolarity and volume overload, and decreased myocardial contractility (3). The management of metformin-associated lactic acidosis (MALA) is controversial. The literature is sparse and consists of case reports and case series. It is suggested that prolonged dialysis is indicated in patients with severe metformin overdose, particularly those with renal failure, whose cardiovascular status so permits (7, 8). A cumulative HD duration of 15 hours was associated with the return of metformin level to the normal therapeutic range.

Endocrinologist opinion Metformin has been available in Europe since 1957 but in the United States (US) the US Food and Drug Administration only approved its use in 1995 (9). This delay was in part due to the fact that metformin is a biguanide related to phenformin, removed from the market in 1977 because of several cases of fatal lactic acidosis (10-12). However, they are molecules with different structures and pharmacokinetics. Biguanide drugs mainly exert their therapeutic effect by impairing hepatocyte mitochondrial respiration with anaerobic lactate generation associated with metabolic acidosis. Phenformin limits gluconeogenesis binding to mitochondrial membranes and inhibiting oxidative phosphorylation and the formation of high-energy adenosine triphosphate necessary to reverse the glycolytic pathway (12, 13). However, metformin does not bind to mitochondrial membranes as efficiently as phenformin. Salpeter et al, in a recent Cochrane database analysis concluded that metformin is associated with a decreased risk of lactic acidosis compared to other anti-hyperglycemic

treatments (4 per 100 000 patients-year vs. 5 per 100 000 patients-year, respectively) (13). In the same review, metformin therapy was associated with lactic acidosis only when there was an underlying condition. The cases reported in which metformin has caused lactic acidosis in an isolated form are rare (the authors only found three cases published by Bruijstens et al in 2008). The increasing recognition that individuals with type 2 diabetes may benefit from metformin treatment despite the presence of chronic kidney disease and cardiovascular disease has led many to reconsider its use in this high-risk population. In the United Kingdom Perspective Diabetes Study, metformin-treated patients had a risk reduction in diabetes-related death, incident myocardial infarction, fatal and non-fatal strokes, as well as heart failure (9, 14-17). This cardiovascular benefit is expanded by means of the effect on attenuation of metabolic syndrome. The efficacy of metformin in reducing hyperglycemia is well established but additional antiglycemic benefits relate to its ability to prevent the occurrence of diabetes in patients with impaired fasting glucose or impaired glucose tolerance. In the Diabetes Prevention Program, metformin was associated with a 31% reduction in the risk of occurrence of diabetes over a three-year period of follow-up (15). While many glucose-lowering pharmacotherapy agents increase weight, metformin results in no weight change or modest weight loss (18). Carter et al demonstrated a significant reduction in C-reactive protein in overweight patients with type 2 diabetes mellitus given metformin over a 24-week period (19). Decreasing subclinical inflammation may attenuate the development of the metabolic syndrome. Metformin is also associated with modest improvements in lipid profile regardless of any glucose-lowering effect (15). The anticancer effects of metformin are associated with both hypoglycemic-independent and hypoglycemic-dependent actions of the drug. The indirect effects of metformin are mediated by the ability to induce AMP-activated protein kinase which inhibits the transcription of key gluconeogenesis genes in the liver and stimulates glucose uptake in muscle, thus reducing fasting blood glucose and insulin. The glucose-lowering effects of metformin may play a major role in its anticancer activity since insulin has mitogenic and prosurvival effects and tumor cells often express high levels of the insulin receptor, indicating a potential sensitivity to the growth promoting effects of the hormone (20). Over time, metformin has proven to have a number of benefits and an excellent safety profile. There is no clear rationale to deny the clinical benefits attributed to metformin therapy in the absence of definitive contraindications.

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Nephrology opinion Metformin is the most commonly prescribed oral antiglycemic agent in the world and is established as a first-line agent in the pharmacologic management of type 2 DM. The latest Standards of Care from the American Diabetes Association recommend metformin as the first-line agent of use in type 2 diabetics not adequately diet controlled (21). Metformin also remains the only glucose-lowering agent with clear cardio-protective benefits (22), which can be particularly good for the 20% to 40% of patients with diabetes who ultimately develop diabetic nephropathy. As a result of the combination of chronic kidney disease, diabetes and, in most cases, other traditional risk factors, these patients are at a particularly high risk of cardiovascular events (14). However, while metformin is recommended as the antiglycemic agent of choice in the general population, guidelines on chronic renal disease do not endorse metformin with equal importance. Insulin has been the mainstay of treatment (23), mainly insulin glargine, which has a 24-h time-action profile without a pronounced peak, resulting in enhanced stabilization of glycemic control and reduced chance of hypoglycemia (24, 25). 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