Usage of metformin in patients with type 2 diabetes mellitus

Metformin is an old drug which is widely prescribed for the treatment of type 2 diabetes mellitus (T2DM). It is recommended as the first line oral anti-hyperglycaemic agent in Australia, United States and most European countries. It reduces haemoglobin A1c (HbA1c) by 10-20 mmol/mol (approximately 1-2%), and does not cause weight gain or hypoglycaemia. Metformin is well tolerated in most patients and has potential clinical advantages in patients with cardiovascular disease. The clinical conundrum facing practitioners while prescribing metformin is the potential risk of lactic acidosis, which although rare is often fatal. The current official product information recommends that metformin should be avoided or the dosages adjusted in patients with coexisting conditions that are likely to increase the risk of lactic acidosis. The safe use of metformin is still under debate, which may confuse practitioners when prescribing. Thus we aimed to provide more evidence regarding the current prescribing pattern and usage of metformin in Australia, and to explore the safety of metformin, especially its association with lactic acidosis. To achieve this aim, a number of complementary studies were conducted. We evaluated the prescribing pattern of metformin in patients who were admitted to a local hospital. The main finding of this study was that metformin was often being prescribed ‘inappropriately’ with regards to the restrictions listed in the official product information, in terms of usage with contraindications and in higher than recommended dosages. Similar results were observed when we reviewed the use of metformin in patients who lived in the community or aged care facilities receiving either Home Medicines Reviews or Residential Medication Management Reviews respectively. This study included more than 6,000 patients living across Australia. Our findings were consistent with those conducted in other countries. To evaluate the potential association between the use of metformin and lactic acidosis, we reviewed all the potential adverse drug reaction cases of metformin which were reported to the Therapeutic Goods Administration (TGA) of Australia from 1971 October 2014. A total of 152 potential cases of lactic acidosis associated with metformin were reported to the TGA. Approximately 75% of these cases had at least one clinical condition which itself might cause acidosis. The incidence of metformin-associated lactic acidosis (MALA) was estimated to be 2.3 (95%CI, 1.5-3.1) cases per 100,000 patient-years between 1997 and 2011. This relatively low incidence of MALA may be explained by the nature of spontaneous reports to the TGA. In addition, we reviewed the cases of patients who were admitted to a local hospital with lactic acidosis. Over a four-year period, 139 patients were identified using the digital medical record; only 23 patients had T2DM and 11 patients had been taking metformin. To further verify the low incidence of lactic acidosis in metformin users, we conducted a literature review on regular tested lactate level among metformin users. Limited studies have reported the lactate levels with continued metformin usage. Few studies reported that the lactate level in metformin users did not alter after the initiation of metformin. However, compared to the lactate level of patients without being treated with metformin, the level in metformin-treated patients was, on average, higher; but, remained within the normal range. The findings of studies contained in this thesis indicate that it is generally safe to use metformin in most patients with T2DM. Recently, therapeutic guidelines in Australia have modified the prescribing recommendations for metformin, with less restrictions in patients with so-called “contraindications”. It is necessary to update the official product information for metformin, which will give a clearer recommendation to prescribers in practice.