A New Diabetes Drug Class

Imeglimin, a new, first-in-class blood-glucose-lowering agent, proves to be safe and efficient as monotherapy and adjunctive therapy to lower A1C in patients with type 2 diabetes. 

A systematic review and meta-analysis published in the British Journal of Diabetes presented promising data for Imeglimin, a medication to treat diabetes using a novel mechanism of action. This drug is currently in phase 3 trials of human studies and is likely to continue in the approval process based on currently available data. 

Imeglimin is a new medication in a class of glucose-lowering agents called “glimins.” Studies in animal models show that its likely mechanism of action is “via a mitochondrial mechanism to increase glucose uptake by skeletal muscle, decrease hepatic glucose output, and increase glucose-dependent insulin secretion.” It may also protect endothelial cells from damage caused by glucotoxicity and have beneficial cardiovascular effects.   

This study identified 45 articles that discussed the use of this new medication, five of which were RCT’s and were included in the systematic review, three of those showing data usable in the meta-analysis. Data, synthesized through a random-effects analysis of 180 total patients, provided the meta-analysis’s primary outcomes. Baseline patient characteristics were similar, with ages ranging from 18-75 years old, depending on the trial. The average baseline HbA1c and fasting plasma glucose (FPG) in the three included trials were 8.2±0.6% (66±7 mmol/mol) and 10.3±1.9 mmol/L, respectively.  

The primary outcomes analyzed were HbA1C and FPG after treatment with Imeglimin. Secondary outcomes looked at adverse reactions and hypoglycemic events to assess whether Imeglimin is safe and well tolerated. The researchers studied Imeglimin’s efficacy as monotherapy or adjunct therapy with metformin or sitagliptin compared to either placebo or treatment with monotherapy metformin or sitagliptin (dependent upon the study). The two other studies used in the systemic review “were not included in the meta-analysis due to their use of placebo-subtracted values rather than mean and SD for the individual arms.” 

Patients treated with Imeglimin 1500mg twice daily showed reductions of HbA1c by −0.63% (95% CI −0.84 to −0.42) (−6.6 mmol/mol, 95% CI −8.8 to −4.4) and decreases in FPG by −0.52 mmol/L (95% CI −0.80 to −0.24) compared with placebo. The other two studies not included in this data also demonstrated statistically significant diminution in HbA1C and FPG. The first highlighted a reduction in HbA1C by 1% and -1.4 mmol/L of FPG in 299 patients randomized to monotherapy with Imeglimin or placebo (p<0.001). The second showed a 0.87% reduction in HbA1C and 1.1 mmol/L decrease in FPG in 213 patients treated with either Imeglimin monotherapy or placebo (p<0.001). Four of the five studies used a dose of 1500mg of Imeglimin two times daily, while the last study mentioned dosed the medication at 1000mg twice daily.  

The secondary outcomes were also very positive through all of these studies. Two of the three in the meta-analysis had less treatment-related adverse events compared to the placebo arms. The third study saw an increase in adverse events by 3.9%. None of the adverse effects seen were deemed severe. The most common side effects seen were gastrointestinal (noted in <6% of patients taking Imeglimin). Four patients experienced hypoglycemia in one of the studies before the initiation of Imeglimin treatment, but none had extremely low blood sugar once the trials began Imeglimin therapy. One also mentioned a “slight decrease” in weight in patients taking metformin with Imeglimin compared to those just taking metformin. 

This data is very promising for Imeglimin as it seeks market approval, but more studies are warranted as there are many limitations to consider when looking at these RCT’s. A more consistent trial-type with a uniform comparator (i.e., just placebo, metformin) would be beneficial for interpreting efficacy. Also, more extensive trials with a more diverse patient population (more comorbidities, ethnicities) would help prove safety, efficacy, and generalizability. Longer trials would be beneficial, too, as the most extended trial here was only 24 weeks. Overall, though, this current data consistently demonstrates reductions in HbA1C and FPG and that Imeglimin is generally safe and well-tolerated. 

Practice Pearls: 

• Imeglimin is the first in a new class of medications with a unique mechanism of action that utilizes mitochondrial mechanisms to lower blood sugars.  
• Through 3 trials in a meta-analysis, it consistently, significantly demonstrated efficacy in lowering HbA1C and FPG while showing few issues for patient safety. 
• Further research is needed with more extensive trials to prove its benefit before the drug moves to the market. 

Crabtree, Thomas Sj, et al. “Imeglimin, a Novel, First–in-Class, Blood Glucose-Lowering Agent: a Systematic Review and Meta-Analysis of Clinical Evidence.“ British Journal of Diabetes, vol. 20, no. 1, May 2020, pp. 28–31., doi:10.15277/bjd.2020.247. 

Jacob Roberts, 2021 PharmD. Candidate, University of Colorado Denver Skaggs School of Pharmacy and Pharmaceutical Sciences 

See more about Imeglimin.