Metformin-Associated Lactic Acidosis in an Older Adult: A Case Report and Review

Metformin is a widely prescribed medication for the management of type 2 diabetes. It is known to have a high safety index; however, it can cause serious adverse effects such as lactic acidosis, particularly in patients with chronic kidney disease. Elderly patients are at higher risk of developing metformin-associated lactic acidosis (MALA) due to aging kidneys. We present an 82-year-old male with a past medical history of diabetes, stage 2 chronic kidney disease, atrial fibrillation on apixaban, stroke, and chronic stage 4 sacral decubitus ulcer who was sent to the emergency department (ED) for altered mental status. He was admitted to the intensive care unit for the management of septic shock, pulseless electrical activity (PEA) cardiac arrest, and acute hypoxemic respiratory failure requiring intubation. Laboratory tests showed lactic acidosis and anion gap metabolic acidosis in the absence of an infectious source. The patient had chronic kidney disease with acute renal failure on metformin. He was diagnosed with MALA. This case highlights the potential risks associated with metformin use in older adults with chronic kidney disease and acute kidney injury from infections, dehydration, and decreasing oral intake due to acute illness, aging, or dementia. There are expected physiological changes in the aging kidney, including cellular dysfunction and nephrosclerosis, that can cause unexpected kidney injury in older adults, causing their estimated glomerular filtration rate (eGFR) to drop acutely. Age-related changes in renal function and decreased clearance of drugs place elderly patients at higher risk of developing MALA. Guidelines for reducing or deprescribing metformin can be considered in older adults. This could prevent morbidity, mortality, and adverse outcomes in frail older adults with diabetes.


Introduction
Metformin has emerged as one of the most widely prescribed oral hypoglycemic agents for managing type 2 diabetes mellitus.The use of biguanides, such as metformin, has shown a significant increase over the years, surging from 8.3% in 1998 to 54.3% in 2010 [1].Research has demonstrated that metformin can reduce the postprandial glycemic index by 20-30% and can prevent the occurrence of both small and large blood vessel diseases [2][3][4][5].Additionally, it leads to a substantial decrease in overall mortality of 36%, as well as a 32% decrease in diabetes-related complications and a remarkable 47% decline in diabetes-related deaths [6].Furthermore, metformin has shown various other impacts, including the amelioration of non-alcoholic steatohepatitis [7].Metformin's effectiveness in improving blood sugar control, affordability, and favorable side effect profile have made it popular among healthcare professionals and patients alike.Despite the numerous benefits it offers, certain vulnerable groups, particularly individuals with renal disease and reduced estimated glomerular filtration rates (eGFR) less than 45 ml/min, may experience tissue accumulation of metformin.This accumulation can lead to a potentially life-threatening complication known as metformin-associated lactic acidosis (MALA) [8].
We present a case report of an older adult with diabetes, chronic kidney disease (CKD), and a stage 4 decubitus ulcer who experienced an acute episode of altered mental status.Further investigation revealed that the underlying cause of the anion gap metabolic acidosis was renal failure with metformin toxicity contributing to the development of lactic acidosis.There are expected physiological changes in the aging kidney, including cellular dysfunction and nephrosclerosis that can cause unexpected kidney injury in older adults [9].This can result in a sudden drop in eGFR and a longer recovery time in older adults compared to younger adults.Guidelines for early reduction or deprescribing metformin can be considered, which could

Case Presentation
An 82-year-old male with a past medical history of diabetes, stage 2 CKD, atrial fibrillation on apixaban, stroke, and chronic stage 4 sacral decubitus ulcer was sent to the emergency department (ED) for altered mental status and admitted for bacteremia due to sacral ulcer.He was started on oral amoxicillin/clavulanic acid for six months and was discharged.At the rehab nursing facility, he was noticed to have poor oral intake, low blood glucose levels ranging from 80 to 90 mg/dL (normal 70-130 mg/dL), and eGFR of 43 (normal >60), so his long-acting sulfonylurea was discontinued and metformin was decreased from 1000 mg twice a day to 500 mg twice a day.Glucose levels remained within an acceptable range between 100 and 150 mg/dL for his eGFR.
Three months later, he was readmitted from the nursing facility for an abnormally elevated white blood cell (WBC) count of 22 K/UL (normal 4.5-11.0microliter).The stool test was positive for Norovirus, enterotoxigenic E. coli, and Clostridium difficile infection.He was given intravenous fluids and oral vancomycin to finish the 10-day course.He was placed back on oral amoxicillin and clavulanic acid for his sacral ulcer and discharged back to the nursing facility.
One month later, the patient was noted to be lethargic.He was sent to the ED, where labs showed he was acidotic with a pH of 6.5 (normal 7.35-7.45)and a bicarbonate level of 2 (normal 22-29 mEq/L) and lactic acid levels were 15 (normal <2 mmol).His eGFR was found to be 18.More laboratory values can be seen in Table 1.He was admitted to the intensive care unit for the management of possible septic shock, pulseless electrical activity (PEA) cardiac arrest, and acute hypoxemic respiratory failure requiring intubation.Differentials included septic shock from an unclear source.He was empirically started on intravenous meropenem and vancomycin.The infectious source was initially thought to be from his known sacral decubitus ulcer although he had already been on oral antibiotics for this for a few months.He received dialysis for acute renal failure and acidosis.The patient was seen by infectious disease consultants, and his chronic sacral wound was deemed to be an unlikely source of infection as he was recently treated for it, he was on long-term oral antibiotics, and the wound appeared clean.Due to low suspicion for infection leading to septic shock and cardiac arrest, he was diagnosed with anion gap metabolic acidosis secondary to renal failure and MALA from metformin toxicity.A metformin level was not ordered as he had already received dialysis and his levels would not have been accurate.He was stabilized and discharged back to the nursing home.MALA is characterized by the buildup of lactate in the bloodstream due to impaired lactate clearance, leading to a decrease in pH and bicarbonate levels.This metabolic disturbance can result in severe clinical manifestations and pose significant risks to the patient's health and well-being [10].It is crucial to promptly recognize and diagnose MALA, as delayed treatment can have grave consequences for those affected.Five patients were <65 years old and five patients were >65 years of age, with the youngest being 48 years old with a female predominance.Whether CKD was preexistent or not, the majority of the cases presented with acute vomiting and diarrhea, which caused pre-renal acute kidney injury (AKI) and precipitated the development of MALA.One hundred percent of the cases were discharged from the hospital, but discharge destinations are unavailable for four cases, as is data on rehospitalizations or follow-up.One patient was a nursing home resident.Five patients were discharged home, and of the four with unknown destinations, two of them were over age 70.Around 41% of patients never return home after discharge from the hospital to a nursing facility, in part due to physical debility and permanent cognitive deficits after acute illness [18].It is important to recognize the risk factors of MALA in the outpatient and nursing home setting and prevent hospitalizations as some patients might become permanently debilitated from a long hospitalization.

Normal lab values
This case highlights the potential risks associated with metformin use in older adults with or without CKD.More importantly, it highlights the fact that sudden development of AKI from infections, dehydration, or decreasing oral intake due to acute illness, aging, or dementia is a huge risk factor for developing MALA.A study has shown nephrosclerosis in 2.7% of patients less than 30 years old, 58% in the age group of 60-69 years old, and 73% in those over 70 years old [9].Cellular dysfunction and nephrosclerosis are expected physiological changes in the aging kidney that can cause sudden kidney injury in older adults causing their eGFR to drop acutely [19].Age-related changes in renal function and decreased clearance of drugs place older adults at higher risk of developing MALA.
It is of importance to carefully monitor kidney function in patients taking metformin and either deprescribe or discontinue it completely based on eGFR since metformin is renally cleared and can accumulate if there is decreased renal clearance.Patients also need to be counselled on discontinuing or reducing metformin in acute illness.While there are guidelines on eGFR contraindications to metformin, there are no guidelines on metformin reduction or deprescribing in elderly patients who are at high risk of sudden AKI from sudden acute illness.

Conclusions
Metformin use in older adults poses a risk whether preexistent CKD exists or not.Any AKI that adults are susceptible to very quickly as evidenced by the various case reports and discussion can precipitate MALA from regular metformin use.Anticipated physiological changes in the aging kidney, including cellular dysfunction and nephrosclerosis, can lead to AKI in older adults, causing a sudden drop in their eGFR.AKI causes decreased drug clearance placing older adults at a higher risk of developing MALA.Patients taking metformin can be counselled on reducing or discontinuing metformin during acute illness or states in which they have poor oral intake; however, no guidelines are available currently.More research is required to come up with guidelines on whether reducing or deprescribing metformin earlier would prevent morbidity, mortality, and adverse outcomes in older patients with diabetes.
potassium of 7.4 mmol/L.ABG showed a pH of 6.57.ECG: No p waves, irregular broad complexes, and tall T waves consistent with hyperkalemia.pH of 6.80, lactic acid of >15 mmol/L, and PCO2 of 14 mmHg.ECG: tachycardia with a wide QRS.Echocardiography showed a diffuse reduction of left ventricular wall motion, and the LVEF was 23.of 6.94, PO2 of 151 mmHg, PCO2 of 14 mmHg, bicarbonate of 3 mmol/L, anion gap of 48 mmol/L, and lactate level of

Table 2
summarizes case reports of MALA across different geographic regions of the world with patients of varying ethnicities and races.