Metformin is the most prescribed drug used in the treatment of type 2 diabetes and is one of the top 10 drugs prescribed in the world. This drug has an excellent safety record, however, there remains debate about its association with the potentially fatal condition lactic acidosis.
As metformin is excreted by the kidneys it has been widely accepted that this drug should be stopped during illnesses that may increase the risk of acute kidney injury (AKI). For example, the current NHS England ‘Think Kidneys’ initiative recommends this. However, there has been no systematic population based study of this association and the only evidence of this relationship is based upon limited case reports and retrospective case series.
This aim of this study was to comprehensively investigate the association between AKI, lactate concentrations and the risk of lactic acidosis in those exposed to metformin.
A population-based case-control study of lactic acidosis in 1,746 participants with type 2 diabetes and 846 individuals without diabetes with clinically measured lactates with and without AKI between 1994-2014 was undertaken. This utilised the Genetics of Diabetes Audit and Research Tayside (GoDARTs) cohort. This is a Health Informatics Centre (HIC) managed cohort that links clinical records by a patient-specific identifier, the Community Health Index (CHI) number, allowing the creation and maintenance of a sophisticated regional health informatics resource of approximately 18,000 cases and controls.
Due to this unique resource provided by HIC we obtained over 10 years of follow up of people in this cohort with and without diabetes and captured all biochemistry tests they had taken. Our main finding is that acute kidney injury increases lactate levels and risk of lactic acidosis. In addition, however, metformin use interacts with stage of AKI to further increase lactate concentrations; this effect is seen in both those with and without chronic kidney disease; and metformin use is independently associated with a doubling in the risk of lactic acidosis.
Importantly, access to this biochemistry data allowed us to demonstrate that GP “READ codes” (that are often used in large scale population studies) have very low sensitivity and specificity compared to biochemically determined lactic acidosis, meaning that most studies under report this relationship.
A clear association was found between metformin, lactate accumulation and the development of lactic acidosis. These results provide for the first time robust evidence to support current recommendations that patients should be instructed to temporarily stop taking metformin during illnesses associated with acute renal impairment.