What is imeglimin's role in treating type 2 diabetes?

Imeglimin: A Novel Oral Antidiabetic Agent for Type 2 Diabetes

Imeglimin is the first drug in a new class of tetrahydrotriazine-containing oral hypoglycemic agents called "glimins" that works through a unique dual mechanism of action targeting mitochondrial function to improve both insulin secretion and insulin sensitivity in type 2 diabetes. 1, 2

Mechanism of Action

• Imeglimin has a dual mechanism of action that differs from existing antidiabetic medications:

  • Enhances glucose-stimulated insulin secretion (GSIS) and preserves β-cell mass 2
  • Improves insulin sensitivity in peripheral tissues, particularly liver and skeletal muscle 2, 3

• At the cellular level, imeglimin modulates mitochondrial function by:

  • Rebalancing respiratory chain activity (partial inhibition of Complex I and correction of deficient Complex III activity) 2
  • Reducing reactive oxygen species formation, thereby decreasing oxidative stress 2
  • Preventing mitochondrial permeability transition pore opening, which helps prevent cell death 2
  • Enhancing glucose-stimulated ATP generation and inducing NAD+ synthesis via the 'salvage pathway' 2, 3

Clinical Efficacy

• In clinical trials, imeglimin has demonstrated:
  • Similar efficacy to metformin in reducing HbA1c, fasting plasma glucose (FPG), and postprandial glucose 4
  • Significant improvement in mean glucose levels (from 159.0 ± 27.5 mg/dL to 141.7 ± 22.1 mg/dL) 5
  • Increased time in range (TIR) from 67.9% to 79.5% as measured by continuous glucose monitoring 5
  • Decreased time above range (TAR) from 29.4% to 17.9% 5
  • Particularly effective in patients with low insulin secretory capacity, a common phenotype in East-Asian patients with type 2 diabetes 5

Safety Profile and Tolerability

• Imeglimin exhibits a favorable safety and tolerability profile:
  • No severe hypoglycemia when used as monotherapy 2
  • Generally well-tolerated compared to metformin 4
  • Main adverse effects are gastrointestinal disorders 5
  • Increased risk of hypoglycemia when combined with insulin or glinide agents 5

Pharmacokinetics

• The drug is well absorbed with a Tmax of approximately 4 hours 1
• Half-life of 5-6 hours 1
• Primarily excreted through the kidneys 1
• No clinically significant interactions with metformin or sitagliptin 1

Position in Diabetes Treatment Algorithm

• While imeglimin shows promise as a novel agent, it is not yet included in major diabetes treatment guidelines 6
• Current guidelines still recommend metformin as the preferred initial pharmacologic agent for type 2 diabetes 6
• For patients requiring additional glycemic control, guidelines recommend SGLT2 inhibitors or GLP-1 receptor agonists due to their proven cardiovascular and renal benefits 6

Potential Clinical Applications

• May be suitable for combination therapy with other antidiabetic agents due to its unique mechanism of action 1
• Could be particularly beneficial for patients who cannot tolerate metformin or other first-line agents 4
• Shows promise for patients with low insulin secretory capacity 5
• May offer an alternative option for patients with varying pathophysiologies of type 2 diabetes 3

Limitations and Considerations

• As a newer agent, long-term safety and efficacy data are limited compared to established medications like metformin, SGLT2 inhibitors, and GLP-1 receptor agonists 6
• Not yet widely approved globally (first approved in Japan) 3
• Current guidelines still prioritize medications with established cardiovascular and renal benefits (SGLT2 inhibitors and GLP-1 receptor agonists) for most patients with type 2 diabetes 6