Metformin susceptibility factors

The main susceptibility factor for lactic acidosis due to metformin is renal insufficiency (49). In patients taking phenformin, poor oxidative metabolism may contribute (73). 

All patients admitted to a hospital during 6 months who had taken at least one dose of metformin were retrospectively evaluated for susceptibility factors for metformin-associated lactic acidosis (8). There were 263 hospitalizations in 204 patients. In 71 admissions there was at least one contraindication, such as renal or liver disease, renal dysfunction, congestive cardiac failure, metabolic acidosis, or an intravenous iodinated contrast medium given within 48 hours of metformin. In 29 (41%) metformin was continued despite the contraindication. The most frequent contraindication was a raised serum creatinine, but in only eight of the 32 admissions was metformin withdrawn. Of nine patients using metformin who died (not necessarily directly related to metformin), six had an absolute contraindication. In two patients who died and in one who survived, blood lactate was increased and this was temporally related to the use of metformin. 

In another review it was suggested that the risk of lactic acidosis when metformin is used as recommended is close to zero (84). The author discussed the COSMIC study, which compared metformin treatment for 1 year (n = 7227) with usual care with other antidiabetic agents (n = 1505). There were no cases of lactic acidosis. The findings in controlled trials contrast with case reports of lactic acidosis. About one million patients have received metformin in the USA and the FDA has received 47 reports of lactic acidosis (20 fatal). Of these, 43 patients had renal insufficiency or susceptibility factors for lactic acidosis, such as congestive cardiac failure. Only four cases appeared to have no other susceptibility factors, one of which may have been precipitated by urinary sepsis none of these four died. 

Six experts in intensive care or metabolic disease reviewed all case reports of lactic acidosis from 1957 to 1999—37 articles reporting 80 cases (85). To be assessed the reports had to meet strict criteria, including a diagnosis of type 2 diabetes, metformin therapy before lactic acidosis, a pH of 7.35 or less, or a plasma bicarbonate concentration below 22 mmol/1 and a lactic acid concentration of at least 5 mmol/1. Because of lack of information, 33 cases were excluded. There were other susceptibility factors for lactic acidosis besides metformin in 46 of 47 cases. Only 13 of the 47 cases were classified as probably due to metformin by at least three experts. The authors suggested a rethink about the relation between lactic acidosis and metformin. However, they still recommended withdrawing therapy in acute renal insufficiency and when contrast dyes are used for radiological investigation. 

In a review of reports to the Australian Adverse Drugs Reactions Advisory Committee between 1985 and 2001 there were 48 cases of lactic acidosis with metformin (86). In 35 of the 48 cases known susceptibility factors were identified. The estimated frequency was one case of lactic acidosis in 30 000 patients taking metformin. The authors... 

The most important susceptibility factors are pre-existing chronic kidney disease (CKD eGFR below 60 mVmin) and chronic kidney disease associated with diabetes [15]. Other factors include age over 70 years, the presence of congestive heart failure, nephrotoxic drugs (loop diuretics, metformin, nonsteroidal anti-inflammatory agents), volume depletion, and repeated exposure within short periods of time (under 72 hours). 

Urinary tract Contrast-induced nephrotoxicity has been reviewed in successive volumes of SEDA [SEDA-29, 575 SEDA-30, 535 SEDA-31, 731 SEDA-32, 846]. The EIDOS and DoTS descriptions of this reaction are shown in Figure 2. Susceptibility factors include age (over 70 years), drugs (nephrotoxic drugs, such as non-steroidal anti-inflammatory drugs metformin mannitol, and diuretics, particularly loop diuretics multiple repeat exposures to contrast media within 72 hours), and diseases (pre-existing renal insufflciency, particularly if it is associated with diabetes melli-tus, congestive heart failure, dehydration). There is also an increased risk in organ transplant recipients. 

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