Reduced lactic acidosis risk with Imeglimin: Comparison with Metformin

Abstract

The global prevalence of type 2 diabetes (T2D) is expected to exceed 642 million people by 2040. Metformin is a widely used biguanide T2D therapy, associated with rare but serious events of lactic acidosis, in particular with predisposing conditions (e.g., renal failure or major surgery). Imeglimin, a recently approved drug, is the first in a new class (novel mode of action) of T2D medicines. Although not a biguanide, Imeglimin shares a chemical moiety with Metformin and also modulates mitochondrial complex I activity, a potential mechanism for Metformin‐mediated lactate accumulation. We interrogated the potential for Imeglimin to induce lacticacidosis in relevant animal models and further assessed differences in key mechanisms known for Metformin's effects. In a dog model of major surgery, Metformin or Imeglimin (30–1000 mg/kg) was acutely administered, only Metformin‐induced lactate accumulation and pH decrease leading to lactic acidosis with fatality at the highest dose. Rats with gentamycin‐induced renal insufficiency received Metformin or Imeglimin (50–100 mg/kg/h), only Metformin increased lactatemia and H+ concentrations with mortality at higher doses. Plasma levels of Metformin and Imeglimin were similar in both models. Mice were chronically treated with Metformin or Imeglimin 200 mg/kg bid. Only Metformin produced hyperlactatemia after acute intraperitoneal glucose loading. Ex vivo measurements revealed higher mitochondrial complex I inhibition with Metformin versus slight effects with Imeglimin. Another mechanism implicated in Metformin's effects on lactate production was assessed: in isolated rat, liver mitochondria exposed to Imeglimin or Metformin, only Metformin (50–250 µM) inhibited the mitochondrial glycerol‐3‐phosphate dehydrogenase (mGPDH). In liver samples from chronically treated mice, measured mGPDH activity was lower with Metformin versus Imeglimin. These data indicate that the risk of lactic acidosis with Imeglimin treatment may be lower than with Metformin and confirm that the underlying mechanisms of action are distinct, supporting its potential utility for patients with predisposing conditions.

Phase 2 trial with imeglimin in patients with Type 2 diabetes indicates effects on insulin secretion and sensitivity

“…Metformin acts principally to reduce hepatic glucose overproduction ‐ an insulin‐like effect. Although it is widely used, metformin can be associated with GI tolerability issues and residual risk of lactic acidosis, especially in the context of impaired renal function 5 . SGLT2 inhibitors are a recent and valuable class due to demonstrated cardio‐renal benefits; however, these agents have no specific‐direct effects on either β‐cell function or insulin action 39 .…”

“…Although it is widely used, metformin can be associated with GI tolerability issues and residual risk of lactic acidosis, especially in the context of impaired renal function. 5 SGLT2 inhibitors are a recent and valuable class due to demonstrated cardio-renal benefits; however, these agents have no specific-direct effects on either β-cell function or insulin action. 39 In contrast, F I G U R E 4 Effect of imeglimin on insulin secretion in response to glucose a substantial body of data supports the dual effects of imeglimin -to both reverse β-cell dysfunction (augmenting GSIS) and to enhance insulin action (in both liver and muscle).…”

“…Imeglimin is the first in a new class of tetrahydrotriazine‐based family of oral antidiabetics: the glimins (World Health Organization: ATC 5th level ‐ A10BX15 imeglimin), targeting mitochondrial dysfunction. In this context, imeglimin has demonstrated a positive effect on mitochondrial function in diabetic mice through mild and competitive inhibition of complex I and rescue of complex III activity/protein content, and inhibition of reactive oxygen species production 5–7 …”

“…In this context, imeglimin has demonstrated a positive effect on mitochondrial function in diabetic mice through mild and competitive inhibition of complex I and rescue of complex III activity/protein content, and inhibition of reactive oxygen species production. [5][6][7] Several lines of evidence have shown the beneficial effects of imeglimin on pancreatic β-cell mass and function. Preclinical studies showed that imeglimin improved hyperglycaemia and enhanced glucose-stimulated insulin secretion (GSIS) using multiple rodent models of T2D (isolated islets and intact animals), including models characterized by a primary defect in β-cell mass and function.…”

Ursolic acid regulates gut microbiota and corrects the imbalance of Th17/Treg cells in T1DM rats

“…Compared to MET, UA exhibits poor oral bioavailability, low solubility, and intestinal permeability [ 38 ]. However, metformin is associated with rare but serious events of lactic acidosis and gastrointestinal side effects [ 39 , 40 ], whereas UA did not exhibit any significant toxicity in human THP-1 cells [ 41 ]. Moreover, a long-term toxicity study showed that oral dosing with UA for 90 consecutive days did not lead to toxic effects at any dose.…”