What is imeglimin, its mechanism of action, and its indication for type 2 diabetes (T2D) treatment?

Imeglimin: A Novel Antidiabetic Agent

Imeglimin is the first-in-class "glimin" drug with a unique dual mechanism of action that targets mitochondrial function to improve both insulin secretion and insulin sensitivity in type 2 diabetes mellitus (T2DM). 1

Mechanism of Action

Imeglimin works through a distinctive dual mechanism that differentiates it from other antidiabetic medications:

1. Mitochondrial Effects:

   • Rebalances respiratory chain activity by partially inhibiting Complex I while correcting deficient Complex III activity 1
   • Reduces reactive oxygen species formation, decreasing oxidative stress 1
   • Prevents mitochondrial permeability transition pore opening, protecting cells from death 1
   • Enhances glucose-stimulated ATP generation 1
   • Induces synthesis of nicotinamide adenine dinucleotide (NAD+) via the 'salvage pathway' 2

2. Pancreatic Effects:

   • Amplifies glucose-stimulated insulin secretion (GSIS) in a glucose-dependent manner 2
   • Preserves β-cell mass in rodent models 1
   • Increases intracellular calcium mobilization through NAD+ metabolites 2

3. Extrapancreatic Effects:

   • Enhances insulin sensitivity 2
   • Decreases hepatic glucose production 3
   • Increases muscle glucose uptake 3
   • May promote increased fatty acid oxidation 3
   • Decreases hepatic lipid accumulation (shown in rodent models) 3

Indications

Imeglimin is indicated for the treatment of type 2 diabetes mellitus:

• Approved in Japan (under the brand name TWYMEEG® Tablets) as the first country worldwide 2
• Can be used as monotherapy or in combination therapy with other antidiabetic agents 2
• Particularly useful for patients who need improvement in both insulin secretion and insulin sensitivity 4

Clinical Efficacy

• Achieves statistically significant glucose lowering with peak effect on fasting plasma glucose (FPG) and HbA1c after 16 weeks of treatment 4
• Shows comparable efficacy to established agents like metformin and sitagliptin 3
• Demonstrates increased efficacy when used in combination with either metformin or sitagliptin 3
• Provides a generally favorable safety and tolerability profile, including lack of severe hypoglycemia 1, 2

Pharmacokinetics

• Well absorbed with Tmax of approximately 4 hours 5
• Half-life of 5-6 hours 5
• Primarily excreted through the kidneys 5
• No clinically significant interactions with metformin or sitagliptin 5

Unique Advantages

• Novel mechanism of action targeting a key root cause of T2DM: defective cellular energy metabolism 1
• Glucose-dependent insulin secretion (reducing hypoglycemia risk) without the mechanism of GLP-1 receptor agonists 5
• Potential application in patients with chronic kidney disease due to favorable safety profile 3
• Early preclinical studies suggest potential improvements in cardiac and renal function in metabolic syndrome models 3

Position in Treatment Algorithm

While imeglimin is not yet mentioned in major diabetes guidelines like the 2019 ESC guidelines 6 or the 2017 ADA standards 6, its unique mechanism of action suggests it could be positioned as:

• An alternative oral agent for patients who cannot tolerate or have contraindications to first-line agents like metformin
• An add-on therapy to existing regimens, particularly with agents like metformin or DPP-4 inhibitors 5
• A potential option for patients with renal impairment, pending further clinical validation 3

Important Considerations

• Differs mechanistically from established drug classes including biguanides, sulfonylureas, GLP-1 receptor agonists, SGLT-2 inhibitors, and thiazolidinediones 1, 5
• May offer advantages in specific patient populations, though more comparative outcome studies are needed
• Long-term cardiovascular and mortality outcomes have not yet been established, unlike some SGLT-2 inhibitors and GLP-1 RAs that have demonstrated cardiovascular benefits 6

Imeglimin represents an innovative approach to T2DM management by addressing mitochondrial dysfunction, which is increasingly recognized as a fundamental aspect of diabetes pathophysiology.