ISSN 1849-9031 (Online)

ISSN 1849-8922    (Print)

Metabolic acidosis: expected and fatal adverse effects of metformin and empagliflozin: a case series and literature review.
Miriam Čupić, Jelena Dumančić, Ines Potočnjak, Iva Klobučar, Matias Trbušić, Vesna Degoricija.


Metformin, a well-known first-line diabetes therapy, and the recently developed sodium- glucose co-transporter 2 (SGLT2) inhibitor empagliflozin are widely used oral antihyperglycemic drugs in the long-term treatment of type 2 diabetes mellitus (T2DM). Metabolic acidosis is a potentially fatal adverse effect (AE) of these drugs with a high mortality rate. However, the reported incidence of metabolic acidosis in clinical practice has been proven to be very low. Nevertheless, it should be considered that the event rates are based on confounded data and spontaneous case reports.

Metformin increases plasma lactate levels by inhibiting mitochondrial respiration, which, accompanied by elevated plasma metformin concentrations (in renal impairment) and a secondary event that further disrupts lactate production (e.g., hypoperfusion, sepsis), typically leads to metformin-associated lactic acidosis (MALA).

At the same time, SGLT2 inhibitors are thought to promote ketogenesis and precipitate ketoacidosis by their extra-pancreatic glucuretic mode of action.

The present article describes 3 patients suffering from severe metabolic acidosis caused by metformin or empagliflozin, presents similar cases reported in the literature, and assesses the possible etiopathogenesis of the metabolic derangement. Diabetic patients should be educated about the importance of regular fluid and food intake as well as regular blood and urine glucose and ketone self-checkups, whereas physicians should be more aware that the key to an effective use of all glucose-lowering medication is appropriate patient selection, counseling, and follow-up. It is a good clinical sense which will ensure that physicians are able to translate pharmaceutical advances into clinical benefits for patients with T2DM.

Patient consent: The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, verbal and written informed consent has been obtained from the participants involved.