Metformin Toxicity

Author: Ryan Walsh, MD
Editor: Nicole Anthony, MD

THE CASE

A 33-year-old woman with unspecified developmental delay is brought to the ED after her friend called EMS for a wellness check and for poor living conditions. There is no collateral information available and the friend (the patient’s only listed contact) is unreachable. 

On arrival to the ED, the vital signs are notable for blood pressure 104/45 mm Hg, heart rate of 123/minute, temperature 96.9 F, respiratory rate 43/minute and oxygen saturation of 100% on room air. Her fingerstick glucose is 83 mg/dL. The patient is tachypneic with dry mucous membranes and poor skin turgor. EMS reports that the patient is at her baseline mental status according the patient’s friend. 

While in the ED, she has one episode of watery diarrhea and one episode of urinary incontinence. Her ECG shows sinus tachycardia with peaked T waves.

Figure 1. Sinus tachycardia and peaked T waves.

The patient is promptly placed on a monitor and given a 2-liter bolus of crystalloid. The venous blood gas (VBG) results are:

pH: < 7.00
pCO2: 24
pO2: 47
Potassium: 8.1
HCO3: 4
Lactate: > 17
Cr: 4.88 (previously 0.9)

The patient is treated medically for severe hyperkalemia medications, and the remaining workup (including urinalysis, chest x-ray, CT chest/abdomen/pelvis) are unrevealing. Repeat labs remain unchanged. 

DIFFERENTIAL DIAGNOSIS

An elevated lactate should prompt consideration for shock states as well as sepsis, severe congestive heart failure, and ischemia of the limb or gut. In the case of extremely elevated lactate (with an otherwise normal workup), however, toxicologic etiologies should rise to the top of the differential. Specifically, toxicities due to aspirin, cyanide, carbon monoxide, toxic alcohols, and metformin are well known to cause an extremely elevated lactate. 

BACKGROUND AND BIOCHEM

As of 2019, metformin is the fourth most prescribed generic drug in the United States. Unlike most modern drugs (designed with a specific target in mind), metformin was derived from the medieval-era herb galegine (Galega officinalis aka French lilac). It was established as a safe and effective treatment for glycemic control before its exact mechanism was even known.[1] While it remains unclear exactly how metformin affects glucose levels, the best evidence suggests that it does so by acting on targets in the small intestine and liver. 

In gut enterocytes, metformin is thought to increase glucose uptake and subsequent glycolysis. In hepatocytes, it inhibits gluconeogenesis. The cumulative effect is decreased glucose absorption, decreased glucose production, and increased lactate production.[2] Metformin has also been shown to inhibit the electron transport chain within mitochondria. In patients with functioning electron transport chains, the protons generated through lactate production are later consumed during the oxidative phosphorylation process. These series of reactions are a key part of regulating our pH. Metformin’s inhibition of the electron transport chain and subsequent net production of H+ ions is ultimately what links lactate production to an actual acidosis.

Figure 2. The path of pyruvate through glycolysis [source – Tox and The Hound – Whence the Protons of Lactic Acidosis?] 

Figure 3. Metabolic derangements in metformin toxicity. [source – IBCC Metformin Toxicity]

Instances of extreme metformin toxicity are rare and are mainly limited to small case series and case reports. When it does occur, symptoms are often vague, typically including GI upset (nausea, vomiting, diarrhea) and, less commonly, confusion. Although mortality is reported to be approximately 30 to 50 percent, the degree of acidemia and lactate elevation have not been shown to be a predictor of mortality.[3,4] A 10-year retrospective analysis found a significant association between a patient’s comorbid conditions and mortality, with an elevated PT/INR (a marker of hepatic synthetic dysfunction) being the most accurate predictor of death.[5] 

Recently, cases of toxicity have been classified according to the MILA-MALA-MULA spectrum:

Figure 4. MILA-MALA-MULA. [source – IBCC Metformin Toxicity]

In cases of MILA, the patient may be well-appearing initially but rapidly decompensate as the endless loop of metformin-induced renal failure followed by increasing metformin accumulation begins. Acidemia and lactate will typically not respond to basic resuscitative measures. 

MULA, on the other hand, will have little or no associated renal failure. As mentioned earlier, the clinical picture will strongly suggest an alternate primary diagnosis, such as sepsis, heart failure, etc. In MULA, the lactic acidosis should improve rapidly with appropriate resuscitative measures. 

MANAGEMENT

Now that we have a basic understanding of the biochemistry of metformin toxicity, how does this help us treat the extremely ill patient in front of us? A quick internet search on management strategies for metformin overdoses reveal vague recommendations of “aggressive supportive care.” For some, supportive care means flooding the patient with 8 liters of normal saline, and for others, it means giving aliquots of 200 ccs. What is the best way to correct the acidosis? Is there evidence to support these recommendations? Is gastrointestinal decontamination an effective strategy and should activated charcoal be a consideration? Which supportive measures exactly should be prioritized?

FLUIDS

Most patients presenting with metformin toxicity will develop significant vomiting and diarrhea, leading to hypovolemia. Although these patients should receive fluids to address their subsequent hypovolemia, fluids are UNLIKELY to correct the underlying lactic acidosis and thus, the correction thereof should not drive resuscitation. Clinical reassessment and bedside markers of fluid status should drive resuscitation instead. 

Which fluid is best? There is little to no solid evidence to guide us here, but a review of the properties of different crystalloid fluids is helpful. 

Normal Saline (NS): Large-volume resuscitation with normal saline can lead to hyperchloremic metabolic acidosis and should probably be avoided.[6] 

Lactated Ringers (LR): While the actual lactate content of LR is small, patients with significant metformin toxicity have essentially lost their ability to metabolize lactate.[7] Probably should avoid.

D5 ½ NS: There is no evidence to support or condemn its use.

Isotonic bicarb (150 meq NaHCO3 in 1L of D5W): There is no evidence to suggest that bicarbonate, given in any form, will improve acidosis from lactate. More on this next. 

ACIDOSIS

In general, the evidence for the use of bicarbonate in the treatment of any type of acidosis is poor and has not been shown to be helpful in lactic acidosis. In fact, there is some evidence suggesting that bicarbonate may worsen the underlying pathology of metformin through a few different mechanisms. Recall the bicarbonate equilibrium equation:

1. Intravenous bicarbonate is almost immediately metabolized into water and carbon dioxide, which readily crosses the cellular membrane, leading to a worsening of intracellular acidosis.[8]

2. Bicarbonate may also lead to increased metformin uptake by increasing lipid membrane permeability.

3. There is evidence to show that bicarbonate also stimulates glycolysis, further encouraging lactate production.[9]

4. The rate of bicarbonate infusion may actually be outpaced by lactate production in severe cases. 

Despite the lack of evidence to support its use, bicarbonate is generally given in settings of pH < 7 or HCO3– < 5 to theoretically provide some buffering capacity to patients who may otherwise have none. 

INSULIN

There is very scant evidence to support the use of high-dose insulin protocols in metformin toxicity and the evidence that does exist is mainly derived from animal models of phenformin toxicity. To date, there is only one case series (4 patients receiving an insulin protocol of 0.5 U/kg/hr) suggesting some benefit in treating pH and lactate abnormalities.[10] The case series did not have a control group, and all patients were concurrently receiving dialysis. 

RENAL REPLACEMENT THERAPY

At the end of the day, coordinating renal replacement therapy should be the top priority in cases of severe metformin toxicity. Dialysis is the only therapy that can reliably correct acidemia and severe electrolyte derangements quickly. Additionally, due to its small molecular size and complete lack of plasma protein binding, metformin is an easily dialyzable drug. The Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) has established guidelines for dialysis criteria in these patients.[11] 

Figure 5. EXTRIP guidelines for MALA treatment. [source – Calello et al 2015 cited in IBCC Metformin Toxicity]

Continuous venovenous hemodialysis (CVVHD)  is also an option in patients with hemodynamic instability, but correction of metformin levels and acidemia will take significantly longer (often more than 24 hours). 

The patient from the above case had a resolution of renal failure and acidosis after two rounds of hemodialysis.

TAKE HOME POINTS

– Dialysis is the mainstay of treatment in critically ill patients with MALA, so consult nephrology early. Everything else is supportive care to bridge patients to dialysis.
– Very little evidence exists to direct supportive therapy. Studies are heterogenous and often include the whole spectrum of MILA-MALA-MULA patients with various secondary pathologies.
– D5 ½ NS is reasonable as a fluid of choice. Though some suggest using isotonic bicarbonate, it is unlikely to be helpful unless the patient is extremely acidemic.
– Most patients have a secondary pathology contributing to the disease process, and it can be very difficult to clinically distinguish MILA from MALA. Metformin is rarely the sole culprit.

REFERENCES

1. Spiller HA. Toxicology of oral antidiabetic medications. American Journal of Health-System Pharmacy. 2006;63(10). doi:10.2146/ajhp050500

2. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9). doi:10.1007/s00125-017-4342-z

3. Peters N, Jay N, Barraud D, et al. Metformin-associated lactic acidosis in an intensive care unit. Critical Care. 2008;12(6). doi:10.1186/cc7137

4. Blumenberg A, Benabbas R, Sinert R, Jeng A, Wiener SW. Do Patients Die with or from Metformin-Associated Lactic Acidosis (MALA)? Systematic Review and Meta-analysis of pH and Lactate as Predictors of Mortality in MALA. Journal of Medical Toxicology. 2020;16(2). doi:10.1007/s13181-019-00755-6

5. Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin-associated lactic acidosis: a prognostic and therapeutic study. Crit Care Med. 2009;37(7):2191-2196. doi:10.1097/CCM.0b013e3181a0249

6. Yunos N, Bellomo R, Story D, Kellum J. Bench-to-bedside review: Chloride in critical illness. Critical Care. 2010;14(4). doi:10.1186/cc9052

7. Wardi G, Brice J, Correia M, Liu D, Self M, Tainter C. Demystifying Lactate in the Emergency Department. Annals of Emergency Medicine. 2020;75(2). doi:10.1016/j.annemergmed.2019.06.027

8. Forsythe SM, Schmidt GA. Sodium Bicarbonate for the Treatment of Lactic Acidosis. Chest. 2000;117(1). doi:10.1378/chest.117.1.260

9. Lopes-Silva JP, da Silva Santos JF, Artioli GG, Loturco I, Abbiss C, Franchini E. Sodium bicarbonate ingestion increases glycolytic contribution and improves performance during simulated taekwondo combat. European Journal of Sport Science. 2018;18(3). doi:10.1080/17461391.2018.1424942]

10. Young T, Cevallos J, Napier J, Martin-Lazaro J. Metformin poisoning treated with high dose insulin dextrose therapy: a case series. Acta medica Lituanica. 2019;26(1). doi:10.6001/actamedica.v26i1.3958

11.Calello DP, Liu KD, Wiegand TJ, et al. Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations From the Extracorporeal Treatments in Poisoning Workgroup. Crit Care Med. 2015;43(8):1716-1730. doi:10.1097/CCM.0000000000001002

12. van Berlo-van de Laar IRF, Vermeij CG, van den Elsen-Hutten M, de Meijer A, Taxis K, Jansman FGA. Extracorporeal treatment of metformin associated lactic acidosis in clinical practice: a retrospective cohort study. European Journal of Clinical Pharmacology. 2020;76(6). doi:10.1007/s00228-020-02857-5

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• Metformin Toxicity - March 9, 2023