Newer OHA, pharmacology and its role in treatment of Type II Diabetes mellitus

1. Imeglimin
Novel Approachfor Diabetes Management

2. Diabetes Mellitus:GlobalBurden
North America
and Caribbean
51 million
South & Central
America
32 million
Africa
24 million
Middle east &
North Africa
73 million
South East
Asia
90 million
Europe
61 million
Western Pacific
206 million
IDF Diabetes Atlas, 10th edn. Brussels, Belgium: 2021. https://www.diabetesatlas.org
• 537 million adults (20-79 years) are living with diabetes - 1 in 10.
• This number is predicted to rise to 643 million by 2030 and 783 million by 2045.

3. IndianPerspective
IDF Diabetes Atlas, 10th edn. Brussels, Belgium: 2021. https://www.diabetesatlas.org accessed on 21-03-2022
74.2 million people are
suffering from Diabetes
mellitus in India
39.4 million (53.1%) adults in
India are underdiagnosed
1 in 12 adults in India is suffering
from Diabetes

4. LimitationswithCurrentTherapiesinT2DM
1) Chemical Reviews 2015 115 (11), 4719-4743
2) 2019 AACE/ACE T2D Management,
4
Class of
Therapy
MOA Examples Limitations
Biguanides ↓Hepatic glucose
production
Metformin GI side effects, lactic acidosis, vitamin B12
deficiency
Sulfonylurea ↑insulin
secretion
Glimepiride Risk of hypoglycemia, Weight gain
AGIs ↓ GI glucose
absorption
Voglibose GI disturbance, including diarrhea, abdominal
cramping, and flatulence
Glinides ↑insulin
secretion
Repaglinide Risk of hypoglycemia, Weight gain
DPP4
inhibitors
↑incretin effect Vildagliptin,
Sitagliptin,
Linagliptin
Nasopharyngitis and upper respiratory tract
related infection, possible association with
acute pancreatitis
TZD ↓ Insulin
resistance,
↑ glucose
utilization
Pioglitazone Hepatotoxicity, edema, congestive heart
failure, weight gain, bone fractures, possible
increased risk of ischemic heart disease,
bladder cancer
SGLT2 ↑ Renal glucose
excretion
Empagliflozin,
dapagliflozin
Genitourinary tract infections

5. Need of the hour
5
Treatments that have action on insulin
secretion, beta cell apoptosis, hepatic glucose
production and peripheral glucose uptake
Atreatmentoption
Action on
insulin
secretion &
insulin
resistance
↓Hepatic
glucose
production
↑Peripheral
glucose
uptake
↓ β cell
apoptosis
Favourable
safety &
tolerability
profile
Correcting
mitochondrial
dysfunction

6. WhatareMitochondria?
• Mitochondrion is an intracellular
organelle present in most of the
eukaryotic cells.
• Mitochondria are important for
adenosine triphosphate (ATP)
production, which is vital for all
living organisms.
Structure of mitochondria
• A mitochondrion is structurally divided into four compartments:
Outer membrane
Intermembranous
space
Inner membrane Matrix

7. Majorfunctionsofmitochondriaw.r.t.energymetabolism
Journal of Diabetes Investigation Volume 1 Issue 5 October 2010

8. RelationshipbetweenmitochondrialdysfunctionandT2DM
Journal of Diabetes Investigation Volume 1 Issue 5 October 2010

9. LossofGSISduetoMitochondrialDysfunction
• There is a fine process of entry of glucose into the cell, energy
generation, calcium influx and insulin secretion our of beta cells
• Mitochondrial dysfunction leads to impairing of GSIS.

10. Imeglimin

11. Introduction
Imeglimin is an OAD
Innovator Brand name: Twymeeg (Poxel & Sumitomo Dainippon
Pharma)
First in “Glimins” class molecule
11

12. • Imeglimin has a mechanism of action that differs from that of
other major classes of antidiabetic agents,
• Improving mitochondrial bioenergetics
• Targeting multiple organ systems affected by T2D pathology
(E.g. Excessive hepatic gluconeogenesis, inadequate insulin
secretion and reduced skeletal muscle glucose uptake)
Mechanismofaction

13. Imeglimin improves mitochondrial bioenergetics
• Imeglimin leads to Increased fatty acid oxidation
• It leads to production of acetyl-CoA, which enters the tricarboxylic acid (TCA)
cycle
• This increases flux through complex II (CII) and complex III (CIII).
• Reverse electron transfer (RET) from CII to complex I (CI) is decreased, which
results in a decrease in reactive oxygen species (ROS) production
ROS: Reactive oxygen species
RET: Reverse Electron Transport
HAD: 3-hydroxyacylcoenzyme A (CoA) dehydrogenase
(HAD), pointing to increased fatty acid oxidation.

14. MechanismofImeglimin…
…addressesbothInsulinSensitivityandSecretoryDefect

18. Imegliminactions
• Better insulin release in both the
phases of insulin secretion
Phase-1 (110%)
Phase-2 (29%)
• Improved β-cell glucose sensitivity
(by 36%)
Chronic Imeglimin treatment was
shown to increase
• Pancreatic β-cell mass
• Enhance β-cell proliferation
• Suppress β-cell apoptosis
Drugs volume 81, pages185–190 (2021)

20. IndicationandDosage
T2DM
Dose: 1000mg BID
If you miss a dose of Imeglimin Tablets, take it as soon as possible. However, if it is
almost time for your next dose, skip the missed dose and go back to your regular
schedule. Do not double the dose

21. Pharmacokinetics
• Peak plasma concentrations reached 3.5 h after administration;
• Apparent half-life 13 h;
• Low potential for clinically relevant metabolism-dependent drug-
drug interactions
Adverse events
Hypoglycaemia, gastrointestinal disorders – nausea, diarrhoea, constipation
(less than 1–5%)

22. Useinspecialpopulations
•Should not be used in patients
with renal dysfunction with
eGFR < 45 mL / min / 1.73 m 2
Renal dysfunction
•Clinical trials have not been
conducted in patients with severe
(Child-Pugh classification C) liver
dysfunction.
Hepatic dysfunction
Carefully administer while
observing the patient's
condition. In general,
physiological function is often
reduced.
Elderly
Patients with renal dysfunction, it is recommended to perform renal function check regularly, as the excretion of this
drug may be delayed and the blood concentration of this drug may increase.
•Contraindicated in pregnant or
women who may be pregnant
•Excreted in breast milk in
animals
Pregnancy &
Breastfeeding

23. Clinical Studies
23

24. Imeglimin:MajorPublishedPhaseIIITrials
24
Sr.
no.
Parameter TIMES 1* TIMES 2# TIMES 3**
1 Phase Phase III Phase III Phase III
2 Design RCT RCT RCT
3 Dose 1000 mg twice 1000 mg twice 1000 mg twice
4 Duration 24 wks 52 wks 52 (16+36) wks
5 Subjects 213 714 215
6 HbA1c (%, ) -0.72% (monotherapy) -0.46% (addon) -0.6% (addon)
* in Treatment-naïve cases (70%) or uncontrolled (30%)
#Background therapy with SU vs. -0.46% as Monotherapy
**Patients with Inadequate glycemic control and background therapy with Insulin

25. Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in
JapanesePatientsWithType2Diabetes(TIMES1)
Diabetes Care 2021;44:952–959
Aim To investigate the efficacy and safety of imeglimin, in Japanese patients
with type 2 diabetes
Study type double-blind, randomized, parallel-group, placebo-controlled phase 3
trial
Patients 213 patients aged >=20 years with T2DM treated with diet and exercise,
stable for ≥12 weeks prior to screening, and whose HbA1c was 7.0–
10.0%
Treatment
groups
oral imeglimin (1,000 mg twice daily)
Placebo
Duration 24 weeks
Primary
endpoint
Change in mean HbA1c from baseline to week 24
Secondary
end point
Percentage of responders at week 24

26. Results
At week 24, HbA1c had significantly decreased by 0.72% with imeglimin
versus a non significant increase of 0.15% with placebo
HbA1c reduction with imeglimin compared with placebo. Mean HbA1c after 24
weeks (A), change in mean HbA1c by week (B).

27. Results
• At week 24, HbA1c <7% (53 mmol/mol) was achieved by significantly more patients in the
imeglimin group (n=38 of 106 patients; 35.8%) compared with the placebo group (n = 8 of
106 patients [7.5%]; P <0.0001).
• At week 24, a relative decrease of >=7% from baseline HbA1c was achieved by significantly
more patients in the imeglimin group (n = 61 of 106 patients; 57.5%) compared with the
placebo group (n = 12 of 106 patients [11.3%]; P , 0.0001).
• The HbA1c decrease was consistent across age-groups
Safety
• No deaths were reported in any of the groups. The proportion of participants reporting any
adverse events was similar between groups
• Imeglimin monotherapy in Japanese individuals with type 2 diabetes was
associated with substantial improvements in glycemic control that were superior to
placebo.
• These results confirm the efficacy, safety, and tolerability of imeglimin
monotherapy in Japanese patients with type 2 diabetes.
Conclusion

28. Long-termsafetyandefficacyofimegliminasmonotherapyorincombinationwith
existingantidiabeticagentsinJapanesepatientswithtype2diabetes(TIMES2)
Diabetes Obes Metab. 2022;24:609–619.
Aim To evaluate the safety and efficacy of imeglimin for 52 weeks as
monotherapy or combination therapy with existing antidiabetic agents
in Japanese patients with type 2 diabetes.
Study type Open-label, multicentre phase 3 trial
Patients 714
Method Patients received the following treatments: imeglimin monotherapy
(n = 134), combination with an α-glucosidase inhibitor (n = 64),
biguanide (n = 64), dipeptidyl peptidase-4 inhibitor (DPP4-I; n = 63),
glinide (n = 64), glucagonlike peptide-1 receptor agonist (GLP1-RA; n =
70), sodium-glucose co-transporter-2 inhibitor (n = 63), sulphonylurea (n
= 127), or thiazolidinedione (n = 65).
Duration 52 week
Primary
endpoint
Safety (adverse events, laboratory results, ECG).
Secondary
end point
Changes from baseline in HbA1c and fasting plasma glucose at week 52.

29. Results
Safety
• The percentage of patients experiencing at least one treatment
emergent adverse event (TEAE) was 75.5%
• Most of these events were mild or moderate in intensity.
• Serious TEAEs,(none of them related to the study drug), occurred
in 5.6% of all patients.
• No clinically significant changes in ECG, vital signs, physical
examination, or laboratory tests were noted in any groups

30. AdjustedmeanchangefrombaselineinHbA1catweek52
• At week 52, HbA1c decreased by 0.46% with imeglimin monotherapy, by 0.56%-0.92% with
imeglimin as oral combination therapy, and by 0.12% with injectable GLP1-RA combination
therapy.
• The greatest net HbA1c reduction (0.92%) occurred in patients receiving a DPP4-I in
combination with imeglimin.
StudyConclusion
Imeglimin monotherapy and, in combination with oral antidiabetic drugs in Japanese
individuals with type 2 diabetes, was well tolerated and led to clinically meaningful
and sustained improvements in glycaemic control.
DPP4i

31. Efficacyandsafetyofimegliminadd-ontoinsulinmonotherapyin
Japanesepatientswithtype2diabetes(TIMES3)
Diabetes Obes Metab. 2022;24:838–848.
Aim To evaluate the efficacy and safety of imeglimin for up to 52 weeks as
combination therapy with insulin in Japanese patients with type 2 diabetes
Study type double-blind, randomized, parallel-group phase 3 trial
Patients 215
Method Patients were randomly assigned (1:1) to either imeglimin (1000 mg twice daily)
or matched placebo, in combination with insulin, for 16 weeks
In a subsequent 36-week, open-label extension period, all patients received
imeglimin 1000 mg twice daily
Duration 52 week
Primary
endpoint
Change in mean glycated haemoglobin (HbA1c) from baseline to week 16
Secondary
end point
Percentage of responders

32. Results
At Week 16, HbA1c had significantly
decreased by 0.63% with imeglimin
versus a decrease of 0.03% with
placebo: estimated treatment
difference versus placebo 0.60%
This decrease was sustained up to
52 weeks with a mean decrease of
0.64% (95% CI 0.82 to 0.46) versus
baseline.
Significantly more patients in Imeglimin group
Achieved HbA1c conc. < 7.0% Relative HbA1c decrease of at least 7% from baseline
A clinically meaningful HbA1c decrease versus placebo was evident across all age
subgroups with a reduction of 0.46% in patients younger than 65 years and a
reduction of 0.77% in patients aged 65 years or older at Week 16 for patients in the
imeglimin group

33. Time course of glycated haemoglobin (HbA1c) over the 52-week study period
according to treatment groups.
• The HbA1c decrease was sustained through to Week 52 for patients in the
IME/IME group
• Switching from placebo to imeglimin at Week 16 was also associated with a
reduction of 0.54% in HbA1c (PLA/IME group) after 36 weeks of added imeglimin
treatment

34. Safety
• The incidence of patients experiencing adverse events and serious
adverse events was similar in the two treatment groups.
• The number of patients experiencing hypoglycaemia was similar in the
two treatment groups.
• In patients receiving imeglimin, all hypoglycaemic events were mild in
severity; no episodes required assistance
• Imeglimin 1000 mg twice daily as add-on to insulin therapy for 52 weeks was well
tolerated and was associated with clinically meaningful and sustained reductions in
HbA1c
• Imeglimin could potentially be used to augment basal insulin use by enhancing
glycaemic control during and after meals.
• The net efficacy and safety profile of Imeglimin when used in conjunction with
insulin in patients with advancing age and renal dysfunction also appears to be
favourable
Conclusion

35. Efficacyandsafetyofimeglimin:Asystematicreviewandmeta-analysis
ofRCT Eight studies comprising 1555 patients with T2DM
HbA1c
• Low dose imeglimin 500mg was superior to placebo fig. 2(a).
• Regarding high doses (1000,1500 mg), the overall effect estimate favored
imeglimin group over control group (p<0.00001)
• Subgroup analysis showed that imeglimin monotherapy and dual therapy were
superior to control group

36. FPG
Imeglimin Addresses both HbA1c and FPG in Treatment-
naïve or Uncontrolled cases
Low dose imeglimin 500mgwas superior to placebo for FPG reduction
• Regarding high doses (1000, 1500 mg), the overall effect estimate favored
imeglimin group over control group (p<0.00001)
• Subgroup analysis showed that imeglimin monotherapy and dual therapy were
superior to control group

37. Imeglimin vs Metformin

38. ImegliminVsMetformin
• Imeglimin contains a biguanide substructure bearing similarity and
cyclopentane ring (differences) with metformin
Drug Dev Res. 2020 Jun;81(4):390-401
Parameter Imeglimin Metformin
On ETC
C- I
competitive/partial
inhibition
Restores c-III
function
C- I non
competitive
inhibition
Mitochondrial
respiration
Facilitates Decreases
Reduction in ROS ✓ less
Insulin secretion ✓ ✗
Insulin resistance ✓ ✓
Hepatic Glucose
production
✓ ✓
Diabetes Obes Metab. 2021; 23: 664-673

39. Imeglimin's mode of actionVs Metformin1
Imeglimin Metformin
Clinical Findings
↑Glucose-stimulated insulin secretion (hyperglycaemic clamp) No reported effect on insulin secretion
Evidence of insulin sensitivity – Insulin/Proinsulin ration change,
QUICKI
No clear increase in insulin sensitivity
Pre-Clinical Findings
↑Glucose disposal; ↑insulin sensitivity; ↑insulin signalling ± Insulin sensitization
Cell and organ
↑GSIS No effect on GSIS
Islet β-cell protection; preserved β-cell mass β-cell protection; no known effects on β-cell
mass
↑Muscle glucose uptake ± ↑Muscle glucose uptake
↓Gluconeogenesis (hepatocytes) ↓Gluconeogenesis (hepatocytes)
Intracellular
Competitive/partial mitochondrial Complex I inhibition; no decrease
in mitochondrial respiration; decreased ROS formation
Uncompetitive mitochondrial Complex I
inhibition; decreased respiration; decreased
ROS formation
No effect on mitochondrial glycerophosphate ↓Mitochondrial glycerophosphate
dehydrogenase
Increased NAD
+
synthesis; potentially via NAMPT; increased glucose-
responsive intracellular Ca
++
None
a Poxel, unpublished data. b Reactive oxygen species. c Nicotinamide phosphoribosyltransferase.
Abbreviations: GTT, glucose tolerance test; NAD+, nicotinamide adenine dinucleotide;
NAMPT, nicotinamide phosphoribosyltransferase; ROS, reactive oxygen species. 1. Diabetes Obes Metab. 2021; 23: 664-673

41. ComparisonofImegliminwithothermajortherapeuticclass

43. Targeting1st linetreatmentinJapan

44. Place in therapy
Initiation Interchange Intensification
• Other drugs are
contraindicated or
have averse risk
benefit ratio Eg
• Elderly
• Renal insufficiency
• Isolated fasting
hyperglycaemia
Other drugs are not
well tolerated
• GI side effects
• Risk of lactic
acidosis
• Weight gain
• Hypoglycemia
If other drugs are
insufficient in
achieving glycaemic
goals
Kalra S. Indian journal of clinical practice, vol 33, no 5,Oct 22

45. Summary
First in class treatment for T2DM with
potential differentiated benefits
Differentiated mechanism of action that
works at the level of mitochondria
Improves insulin secretion and resistance
Preserves beta cell function and improves
endothelial dysfunction
Efficacious as monotherapy as well as
combination therapy
Safe tolerable, comparable efficacy with most
OADs

46. Thank you!