Nephrology Hypertension

Pharmacology and Toxicology: Treatment of Poisons - Metformin Intoxication

Does this patient have metformin intoxication?

Description of the problem

Since its introduction to the US market in 1995, the biguinide, metformin has become one of the most prescribed oral hypoglycemics. It is now considered the first line agent to treat type 2 diabetes. Because of its similarity to the drug another biguinide, phenformin, there was concern that it might increase the risk of lactic acidosis as was seen in phenformin. This delayed its release in the United States and led to a number of safety studies in the 1990’s.

One such study compared the incidence of lactic acidosis in patients treated with metformin and found that among the 7,227 patients followed on metformin, there were no incidents of lactic acidosis reported. Following its introduction, there have been a number of comparative studies with other oral agents for diabetes showing that metformin has a superior safety profile and excellent efficacy.

As per the manufacturer, metformin is contraindicated in patients with chronic kidney disease. This is defined as a creatinine ≥ 1.4 mg/dL in women and ≥ 1.5 mg/dL in men. There have been a number of studies in patients with diabetes and chronic kidney disease that show that metformin remains a very safe medication and a number of authors have argued that its use should no longer be restricted in chronic kidney disease. Other authors have argued that for consistency sake alone, metformin should be restricted by a creatinine clearance estimate as it is with most medications whose clearance depends on renal function rather than a serum creatinine. For the time being, this author recommends following the restricted use of metformin as described by the manufacturer unless it is changed.

Although it has been shown to be a very safe medication, metformin’s increased use has led to an increased incidence of intoxications both accidental and as a suicide attempt. In 2009, there were 7,128 toxic exposures and 7 deaths reported to NPDS which is a 0.098% mortality rate (Figure 1). This is a 2 fold increase in reported metformin intoxications over the past 5 years. The risk of toxicity increases with decreasing kidney function in chronic kidney disease or acute kidney injury and impaired liver function in liver disease.

Figure 1.

Exposures and fatalities that are substantially removable by extracorporeal techniques.

The major intoxication syndrome related to metformin use is lactic acidosis. There is still some controversy regarding whether or not the metformin use is responsible for the majority of cases of lactic acidosis occurring in patients on metformin. There is also some uncertainty in the literature regarding therapy for patients who develop lactic acidosis while on metformin.

Pharmacokinetics of metformin

Metformin exists as a hydrophilic cation at physiologic pH. It has only partial absorption which varies from subject to subject with the population mean is around 55%.

Metformin elimination is almost entirely by the kidney.

Clinical and laboratory findings in metformin intoxication – Lactic acidosis

A recent study looked at the incidence of lactic acidosis in patients on metformin and compared it to that seen in patients on sulfonylureas. The estimation was found to be 3.3 cases per 100,000 patient years with metformin use and 4.8 per 100,00 those patient years on a sulfonylurea. Also of note, no incident of lactic acidosis was found during initial clinical trials of metformin that included 70,000 patient years. This suggests that with careful patient selection, lactic acidosis due to metformin use is very unlikely.

The clearance of metformin by the kidney is significantly higher than creatinine clearance and can be estimated at approximately 10 times creatinine clearance. This is likely due to significant secretion of the drug at the tubule. Factors that decrease kidney function such as chronic kidney disease, acute kidney injury and age can increase metformin levels. For this reason, the product information for metformin contains the statement that it should not be prescribed for patients with a glomerular filtration rate (GFR) below 60 ml/min.It is mostly absorbed in the small intestine and it reaches a peak serum concentration in 2 to 3 hours. It is not bound to plasma proteins and has a low molecular weight (130 D), but it has a very large Vd (12 – 28 L/kg).

The volume of distribution has been reported to be much lower (1 – 4 L/Kg) in studies of initial dosing but increases with chronic use to up to 10 times that volume. This is likely due to distribution of metformin out of plasma and into other tissues including erythrocytes. With chronic use, metformin distributes into other tissues such as kidneys, pancreas and liver. The concentration becomes much higher in these organs as compared to that in plasma. This delayed distribution also leads to a variability in the elimination half –life of the drug.

How should patients with metformin intoxication be managed?

Emergency management

Supportive care for metformin intoxication includes prevention of further absorption and methods to increase renal excretion. Activated charcoal can be effective in preventing intestinal absorption and should be used in intentional overdoses if presenting early. Since metformin is poorly absorbed from the gut, activated charcoal may be helpful even in late presentation of ingestions. Since metformin is cleared solely by the kidney, all efforts should be made to preserve renal function. The hypotensive patient should be given fluid and pressor support to maintain cardiac output. It remains unclear if large volume infusion of bicarbonate containing solutions are beneficial.

There is some concern that bicarbonate infusion may worsen lactic acidosis in metformin intoxication. The large sodium load may also be detrimental in these patients by causing volume overload or hypernatremia. Hemodialysis with a bicarbonate based solution remains the best way to correct the acid base disturbance in metformin intoxication.

Treatment

Hemodialysis for metformin intoxication

Indications

There remains some uncertainty regarding the indications for dialysis in metformin intoxication.

Although metformin is cleared with hemodialysis, the large volume of distribution (Vd) of the drug requires prolonged treatment times for effective removal. The estimated volume of distribution of metformin depends on the chronicity of its use. With acute intoxication, the Vd is likely close to 500 L but with chronic use, this volume may increase to 1000 - 2000 L. Clearances with dialysis have been reported to be close to 200 cc/min. Given the large Vd, the required time on dialysis will be prolonged.

An estimate of the half life of elimination of metformin with dialysis could be calculated using the fomula:

C1/C0=e -kt/v

If we solve for the time on dialysis:

t(min) = - ln (C1/C0) x Vd (L) / k (L/min).

Finally, we can calculate the half-life on dialysis by using:

C1/C0 = 1/2 and - ln (C1/C0) = 0.69 and we are left with the equation:

t (half-life) = 0.69 x Vd / k.

With a Vd = 1000 L and a k = 0.2 L/min the half life of metformin on dialysis = 3500 minutes or 57.5 hours.

We can also calculate the dialysis time for an acute intoxication where the patient has not been on the medication before the ingestion. In this case the volume of distribution may be closer to 400 L and the time on dialysis would be 23 hours.

To determine if dialysis will substantially improve clearance, we can compare the clearance constant for dialysis with the renal clearance. The renal clearance of metformin can be estimated using the formula that the clearance of metformin is 10 times creatinine clearance or 10 x 100 cc/min = 1 L/min in normal renal function.

In the case of a patient with a creatine clearance of 20 cc/min, estimated renal clearance of metformin would be 20 cc/min x 10 = 0.2 L/min. Using the rule that dialysis should be considered when it can add 30% to the clearance of the drug, we can conclude that dialysis will significantly contribute to the clearance when renal clearance is less than 0.2/30% = .67 L/min. This would correspond to a renal function around 60 – 70 cc/min. Therefore, most patients with metformin toxicity and acute kidney injury or CKD (stage 3 or worse) will benefit from hemodialysis to increase clearance of the drug.

It should be noted once again that for dialysis to contribute to intrinsic clearance of metformin, it needs to be prolonged. Dialysis may also help with treatment of the severe acidosis and may be considered for this indication even when it may not significantly contribute to the clearance of metformin.

Prescription

The dialysis prescription should maximize filter size, dialysate flow and blood flow to improve clearance rates. There continues to be some controversy regarding an endpoint for dialysis in metformin intoxication. Because of the difficulty in getting rapid metformin levels, many authors argue that the endpoint for dialysis should be resolution of the lactic acidosis. As described above, the dialysis treatment will need to be prolonged to remove a significant amount of the medication.

Because of the large volume of distribution and the high intracellular stores of metformin, especially in chronic ingestion, rebound in metformin levels can be a risk once dialysis has been completed. Lactate levels and acid base status should be monitored closely following cessation of dialysis. Dialysis should be restarted in the case of worsening clinical status or increasing lactate levels suggesting rebound of the serum level as the drug moves out of cellular compartments into the serum. This is of greatest concern in patients who have been on metformin for a prolonged period.

Modality

It has been proposed that patients with metformin intoxication may be better treated with a continuous dialysis modality. The argument has been that these patients are too unstable to receive conventional dialysis and that the clearances are comparable with either modality. There are now a number of studies that show that even the most unstable patients can tolerate conventional hemodialysis. It is also clear that the clearance of metformin is substantially higher with conventional hemodialysis as compared to most forms of continuous dialysis. A standard therapy with continuous dialysis would include replacement solution at 2 – 3 L/hr and an estimated urea clearance of 30 to 50 cc/min. This is one quarter of the estimated clearance with a high flux membrane in conventional dialysis.

As long as the conventional dialysis can be prolonged, metformin clearances will be substantially higher with this modality. In centers where logistics preclude extended hemodialysis, continuous dialysis may be superior to short and infrequent dialysis sessions. Continuous dialysis may also have a role in treating patients who are experiencing a rebound in metformin levels following hemodialysis due to chronic use and large intracellular stores. In these cases, hemodialysis should be continued until lactic acidosis resolves and then the modality can be switched to continuous dialysis if the patient is likely to have a rebound in their metformin level leading to another bout of lactic acidosis.

What happens to patients with metformin intoxication?

There remains considerable controversy regarding the potential for metformin to cause lactic acidosis. Although it is clear that metformin use rarely causes lactic acidosis, it is a potential consequence with inappropriate patient selection and with intentional overdose.

Metformin causes type B lactic acidosis due to its blockage of the metabolism of lactate and alanine to pyruvate. Patients present with a high anion-gap metabolic acidosis, related to high serum lactate levels. The lactate acidosis can be severe with serum pH < 7, bicarbonate concentration < 10 mEq/L and lactate concentration > 20 mmol/L. Patient’s symptoms often include malaise, somnolence, abdominal pain and respiratory distress. Many patients also have hypotension, respiratory failure requiring mechanical ventilation, decreased cognition and circulatory collapse. Hypoglycemia is uncommon in metformin toxicity.

What is the evidence?

Bennett, WL, Maruthur, NM, Singh, S, Segal, JB, Wilson, LM, Chatterjee, R, Marinopoulos, SS, Puhan, MA, Ranasinghe, P, Block, L, Nicholson, WK, Hutfless, S.

Bass, EB, Bolen, S. "Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations". Annals of Internal Medicine. vol. 154. 2011. pp. 602-613.

Seidowsky, A, Nseir, S, Houdret, N, Fourrier, F. "Metformin-associated lactic acidosis: a prognostic and therapeutic study". Critical Care Medicine. vol. 37. 2009. pp. 2191-2196.

Lalau, J-D. "Lactic acidosis induced by metformin: incidence, management and prevention". Drug Safety. vol. 33. 2010. pp. 727-740.

Dell'Aglio, DM, Perino, LJ, Kazzi, Z, Abramson, J, Schwartz, MD, Morgan, BW. "Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature". Annals of Emergency Medicine. vol. 54. 2009. pp. 818-823.

Salpeter, SR, Greyber, E, Pasternak, GA, Salpeter, EE. "Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus". Cochrane Database of Systematic Reviews: CD002967. 2010.

Bronstein, AC, Spyker, DA, Cantilena, LR, Green, J, Rumack, BH, Heard, SE. "2009 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS)". Clin Toxicol (Phila). vol. 45. 2009. pp. 815-917.

Eurich, DT, Weir, DL, Majumdar, SR, Tsuyuki, RT, Johnson, JA, Tjosvold, L, Vanderloo, SE, McAlister, FA. "Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circulation". Heart Failure. vol. 6. 2013. pp. 395-402.

This is a good review of the data supporting the argument that metformin use is safe in chronic kidney disease as well as heart failure.

Vecchio, S, Giampreti, A, Petrolini, VM. "Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy". Clin Tox. vol. 52. 2014. pp. 129-35.

An excellent recent case series of patients with high metformin levels and lactic acidosis. The authors do find a correlation between the metformin level and the degree of renal dysfunction and the lactate level but not the severity of the illness.
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