SGLT2 inhibitors and metformin: Dual antihyperglycemic therapy and the risk of metabolic acidosis in type 2 diabetes

Abstract

The prevalence of type 2 diabetes mellitus (T2D) has risen in the United States and worldwide, with an increase in global prevalence from 4.7% to 8.5% between 1980 and 2014. A variety of antidiabetic drugs are available with different mechanisms of action, and multiple drugs are often used concomitantly to improve glycemic control. One of the newest classes of oral antihyperglycemic agents is the sodium glucose cotransporter-2 (SGLT2) inhibitors or "flozins". Recent clinical guidelines have suggested the use of SGLT2 inhibitors as add-on therapy in patients for whom metformin alone does not achieve glycemic targets, or as initial dual therapy with metformin in patients who present with higher glycated hemoglobin (HbA1c) levels. The FDA has approved fixed-dose combination (FDC) tablets with each of the three available SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) and metformin. Both drug classes are associated with the rare but serious life-threatening complications that result from metabolic acidosis, including lactic acidosis (with metformin) and euglycemic diabetic ketoacidosis (with SGLT2 inhibitors). This review summarizes the current literature on the pharmacokinetics and the molecular targets of metformin and SGLT2 inhibitors. It also addresses the common adverse effects and highlights the molecular mechanisms by which this dual antihyperglycemic therapy contributes to high anion gap metabolic acidosis. In conclusion, while the combination of metformin and SGLT2 inhibitors would be a better option in improving glycemic control with a low risk of hypoglycemia, an increase in the risk of metabolic acidosis during combination therapy may be borne in mind.

Keywords: Hepatic gluconeogenesis; High anion gap metabolic acidosis; Metformin; Renal tubular glucose reabsorption; Sodium glucose cotransporter-2 Inhibitors.

Fig. 1.

Molecular targets of metformin and SGLT2 inhibitors. A) After its uptake through Oct1 in hepatocytes, metformin inhibits gluconeogenesis (and thereby glucose output) through inhibition of complex I or mGPD, a decrease in ATP/ADP ratio, inhibition of AC by AMP, and activation of AMPK. B) SGLT2 inhibitors inhibit SGLT2-mediated reabsorption of glucose in the S1 segment of renal proximal tubule. I, II, III, IV, complexes I through IV; ADP, adenosine diphosphate; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; cAMP, cyclic AMP; cGPD, cytosolic glycerophosphate dehydrogenase; DHAP, dihydroxyacetone phosphate; GLUT1, glucose transporter-1; GLUT2, glucose transporter-2; G3P, glycerol-3-phosphate; mGPD, mitochondrial glycerophosphate dehydrogenase; Oct1, organic cation transporter-1; PKA, protein kinase A; SGLT1, sodium glucose co-transporter-1; SGLT2, sodium glucose co-transporter-2; ⊥, inhibition; ↑, increase; ↓ decrease.

Fig. 2.

Molecular mechanisms that contribute to enhanced blood lactate and ketone body levels. A) Increase in blood lactate level (and thereby lactic acidosis) in hypoxic or metformin-treated conditions. A decrease in microcirculatory perfusion in target tissues (e.g., skeletal muscle) would result in tissue hypoxia. An increase in anaerobic glycolysis under hypoxic conditions would lead to enhanced lactate formation/release into the systemic circulation. In addition, lactate accumulation may result from its impaired hepatic clearance due to high concentration of plasma metformin, which would inhibit utilization of lactate toward hepatic gluconeogenesis. B) Synthesis of ketone bodies (e.g., βOHB, AcAc, and acetone) in DKA. A decrease in systemic insulin-to-glucagon ratio would promote lipolysis in adipose tissue to enhance FFA release and its uptake by the liver. In the hepatic mitochondria, HMGCS2 catalyzes the condensation reaction between AcAc-CoA and Acetyl-CoA (derived from β-oxidation of fatty acids) to form HMG-CoA. Subsequently, HMGCL cleaves HMG-CoA to generate AcAc. In the presence of increased NADH/NAD⁺ ratio, BDH1 catalyzes the conversion of AcAc to βOHB. In addition, AcAc undergoes nonenzymatic decarboxylation to form acetone. AcAc, acetoacetate; AcAc-CoA, acetoacetyl-CoA; BDH1, mitochondrial βOHB dehydrogenase; FFA, free fatty acids; HMG-CoA, 3-hydroxymethylglutaryl-CoA; HMGCL, HMG-CoA lyase; HMGCS2, mitochondrial HMG-CoA synthase.