IMEGLIMIN-A NOVEL ANTIDIABETIC

1. IMEGLIMIN 500 & 1000 mg

2. DYSFUNCTIONAL
MITOCHONDRIAARE
PATHOLOGICAL
BASIS FOR DIABETES

3. MITOCHONDRIAAND DIABETES
• Mitochondria are important for adenosine triphosphate (ATP) production, which is vital for
all living organisms.
• Mitochondria are also the key regulator of glucose-stimulated insulin secretion in the
pancreatic β-cells.
• During the past two decades, evidence has shown that mitochondrial function is closely
related to various facets of diabetes – pancreatic β-cell dysfunction, insulin resistance,
obesity and vascular complications of diabetes.
J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00047.x, 2010

4. MITOCHONDIRAAND DIABETES
The three major functions of mitochondria in regard to
energy metabolism include:
(i) Adenosine triphosphate (ATP) production;
(ii) Generation of reactive oxygen species (ROS); and
(iii)Apoptosis.
J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00047.x, 2010

5. PATHOPHYSIOLOGY OF MITOCHONDRIAL DYSFUNCTION IN
DIABETES
J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00047.x, 2010

6. MITOCHONDRIAL DYSFUNCTION IN T2DM

7. Diabetes Obes Metab. 2021;23:664–673

9. IMEGLIMIN
 Imeglimin is a novel and promising anti-hyperglycaemic agent.
 First drug of the "glimin" group.
 Glimin is a new group of hypoglycaemic drugs for the treatment of patients with type 2
diabetes mellitus (T2DM).

10. IMEGLIMIN
 Imeglimin hydrochloride
(TWYMEEG; hereafter referred to
as imeglimin) is an orally
administered, first-in-class glimin
being developed by Poxel &
Sumitomo Dainippon Pharma for
the treatment of type 2 diabetes
(T2D).

11. A New Promising and Effective
Weapon in the Treatment of Type 2 Diabetes
 In June 2021, imeglimin received its first approval
for use in T2D in Japan.
 Imeglimin has been shown to have a beneficial
effect on 3 key pathogenetic elements of T2DM,
✓ Increased gluconeogenesis
✓ Inadequate glucose-induced insulin secretion by
beta cells
✓ Peripheral insulin resistance.
https://doi.org/10.1155/2020/8768954

12. https://doi.org/10.1371/journal.pone.0241651
A New Promising and Effective
Weapon in the Treatment of Type 2 Diabetes

13. MECHANISM OF ACTION
1. Imeglimin's mechanism of action involves dual effects:
(a) Amplification of glucose-stimulated insulin secretion (GSIS) and preservation of ß-
cell mass
(b) Enhanced insulin action
2. Correction of mitochondrial dysfunction, a common underlying element of T2D
pathogenesis.
3. Reduce reactive oxygen species production and increase mitochondrial DNA
synthesis

15. HOW IT DIFFERS FROM CURRENT
TREATMENT OPTIONS?
The current portfolio of available oral drugs to treat T2D is targeting the different
elements of the disease pathogenesis :
• by reducing hepatic gluconeogenesis,
• indirectly and directly promoting insulin secretion,
• promoting renal glucose excretion, and
• improving peripheral insulin resistance.
Imeglimin stands out by exhibiting a dual effect on both glucose-stimulated insulin
secretion highlighted in preclinical and in T2D patients, and insulin sensitivity in muscle
and liver in preclinical models, associated with a preclinical cardiorenal benefit.
Endocrinol Diab Metab. 2022;00:e371.

16. Diabetes Obes Metab. 2021;23:664–673

18. IMEGLIMIN-MITOCHONDRIA TARGETED DRUG
FOR DIABETES
• IMEGLIMIN improves glucose tolerance due to a variety of mechanisms, including
decreased hepatic lipids, improved insulin signaling in the liver and muscle, and
ameliorated β-cell function.
• Protective for end organ (kidney and heart)- IMEGLIMIN prevents endothelial
death by decreasing the size of the mitochondrial permeability transition pore, which
plays a pivotal role in cell death, without inhibiting mitochondrial
respiration.(contrast to METFORMIN)

22. PK-PD
• Oral drug (500 mg and 1000 mg)
• Twice daily dosing
• Very low protein binding (1%-8%)
• Very low hepatic metabolism
• Urinary excretion in unchanged form
• NO drug drug interaction with sitagliptin, metformin and cimetidine
• No food effect

23. IMEGLIMN- BEYOND ANTI-DIABETIC
• IMEGLIMIN exerts a Reno protective
effect by improving mitochondrial
function in the kidneys. IMEGLIMIN
has been reported to improve
mitochondrial density and function.
• In vivo studies claimed that IMEGLIMIN
decreases in albuminuria and
interstitial fibrosis.

24. WHAT IS THE ADVANTAGE FOR KIDNEY?
Drug Recommendation based on eGFR
Metformin Not recommended when the eGFR is <30 mL/min/1.73
m2
Gliclazide Recommended upto eGFR upto 30 ml/min/1.73 m2
Glibenclamide Not recommended if eGFR < 60 mL/min/1.73 m2
Alpha glucosidase
inhibitors
No data
Sitagliptin Recommended upto eGFR 30 ml/min/1.73 m2
Dapagliflozin Not recommended when the eGFR is <45 mL/min/1.73
m2
Imeglimin Can be used upto eGFR <15 ml/min/1.73 m2 (PK data)

25. DOSAGE
500 mg twice daily (b.i.d.) for patients with
eGFR 15-45 ml/min/1.73 m2 , and 500 mg
with a longer dosing interval was suggested
for those with eGFR less than 15
Clin Transl Sci. 2022 Apr;15(4)

26. WHAT IS THE ADVANTAGE FOR HEART?
Key question: Is there any CV efficacy?
In rat models, imeglimin improved cardiac diastolic and vascular dysfunction, as
well as myocardial and kidney structure.
In mouse models of heart failure with preserved ejection fraction (HFpEF),
imeglimin showed positive effects on cardiac abnormalities.
Endocrinol Diab Metab. 2022;00:e371

27. The risk of lactic acidosis with Imeglimin
lower than with Metformin
Lactate acidosis is a common finding in diabetic ketoacidosis (DKA). Lactate acidosis in DKA is
multifactorial in aetiology- elevated lactate levels.
BMJ Case Rep. 2014; Physiol Rep. 2022 Mar
Research Statement –
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.

28. CLINICAL DATA

29. Diabetes Obes Metab. 2021;23:800–810

37. KEY POINTS FROM CLINICAL DATA
• Statistically significant reductions in glycated haemoglobin(HbA1c) & fasting
plasma glucose (FPG)
• Suitable as a monotherapy or in combination with other classes of antidiabetic
agents.(TIME 2 AND 3 STUDY)
• While Imeglimin has structural similarity and Mech of action similarity with
Metformin, but Imeglimin is truly unique and this can also be added safely to
Metformin and achieve further reduction in HbA1c .
• No significant increase in hypoglycaemic events , lactic acidosis.

38. TO SUMMARIZE….
• Imeglimin acts on root cause of diabetes by correcting mitochondrial dysfunction
• It does not affect mitochondrial respiration unlike metformin
• Add on to any oral antidiabetics/insulin
• It has effects beyond diabetes- ROS reduction and cardiorenal protection
• Less lactic acidosis compared to metformin