Ueda2016 symposium - glimepiride journey in management of type 2 dm - megahed abuel magd

1. GLIMEPIRIDE JOURNEY
IN MANAGEMENT OF
TYPE 2 DM

2. Estimated Global Prevalence Of Diabetes
2000 2014 2035
151 million 387 million 592 million
International Diabetes Federation. IDF Diabetes Atlas, 2014

3. Chan JCN, et al. Diabetes Care 2009;32:227-233.
3.6%
49.0%
64.4%
33.2%
19.2%
36.4%
Triglycerides <150 mg/dL
HDL cholesterol >40 mg/dL
LDL cholesterol <100 mg/dL
Blood Pressure <130/80 mmHg
HbA1c <7%
0% 20% 40% 60%
% Patients (with available
data)
Reached HbA1c,
blood pressure, and
LDL cholesterol
recommended
targets
Only 36% of T2D patients were at glycemic target
(HbA1c <7%) across regions

4. Importance of tight glycemic control

5. HbA1C(%)
UKPDS: Long-term follow-up
Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242–247.
Holman RR, et al. N Engl J Med 2008; 359:1577–1589.
Differences in mean glycated
hemoglobin levels between the
intensive therapy group and the
conventional-therapy group
were lost by 1 year, with similar
glycated hemoglobin
improvements thereafter in all
groups (p= not significant)
P=0.71
Glucose similar
BUT CV
events now
better
Metformin group 21% 33% 27%

6. A new paradigm
Del Prato S. Diabetologia 2009; 52:1219–1226.Del Prato S. Diabetologia 2009; 52:1219–1226.

7. Glycemic Goals
Parameter Normal
ADA
Goals
ACE/AACE
Goals
Fasting plasma glucose
(mg/dL)
< 100 90-130 < 110
Postprandial plasma glucose
(mg/dL)
< 120 < 180* < 140**
A1C (%) 4-6 < 7*** ≤ 6.5
*1-2 hours post-meal
**2 hours post-meal
***as close to normal as possible without undue risk of hypoglycemia

8. Sulfonylurea & Guidelines

9. LIFESTYLE MEASURES
Then at each step, if not to target (generally HbA1c <7.0%)
IDF Treatment algorithm for people with type 2 diabetes
or
oror
Metformin
Sulfonylurea or
α-Glucosidase inhibitor
Sulfonylurea
α-Glucosidase inhibitor
or DPP-4 inhibitor
or Thiazolidinedione
Basal insulin or
Pre-mix insulin
GLP-1 agonist
Basal + meal-time insulin
Metformin
(if not first line)
α-Glucosidase inhibitor
or DPP-4 inhibitor
or Thiazolidinedione
Basal insulin or
Pre-mix insulin
(later basal + meal-time)
Alternative approachUsual approach
Consider
first line
Consider
second line
Consider
third line
Consider
fourth line

12. Management of Hyperglycemia in
Type 2 Diabetes, 2015:
A Patient-Centered Approach
Update to a PositionStatementof the AmericanDiabetesAssociation(ADA)
and the European Associationfor the Study of Diabetes(EASD)
Diabetes Care 2015;38:140–149
Diabetologia 2015;58:429–442

13. ANTI-HYPERGLYCEMIC THERAPY
• Glycemic targets
- HbA1c < 7.0% (mean PG 150-160mg/dl [8.3-8.9 mmol/l])
- Pre-prandial PG <130mg/dl (7.2 mmol/l)
- Post-prandial PG <180mg/dl (10.0mmol/l)
- Individualization is key:
 Tighter targets (6.0 - 6.5%) - younger, healthier
 Looser targets (7.5 - 8.0%+) - older, comorbidities,
hypoglycemia prone, etc.
- Avoidance of hypoglycemia
PG = plasma glucose
ADA-EASD Position Statement Update:
Management of Hyperglycemia in T2DM, 2015
Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

14. more
stringent
less
stringent
Patient attitude and
expected treatment efforts highly motivated, adherent,
excellent self-care capacities
less motivated, non-adherent,
poor self-care capacities
Risks potentially associated
with hypoglycemia and
other drug adverse effects
low high
Disease duration
newly diagnosed long-standing
Life expectancy
long short
Important comorbidities
absent severefew / mild
Established vascular
complications absent severefew / mild
Readily available limited
Usually not
modifiable
Potentially
modifiable
HbA1c
7%
PATIENT / DISEASE FEATURES
Approach to the management
of hyperglycemia
Resources and support
system
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
Figure 1. Modulation of the
intensiveness of glucose
lowering therapy in T2DM

15. Healthy eating, weight control, increased physical activity & diabetes education
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
high
low risk
gain
edema, HF, fxs
low
Thiazolidine-
dione
intermediate
low risk
neutral
rare
high
DPP-4
inhibitor
highest
high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-
dione
+
SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-ior
or
or GLP-1-RA
high
low risk
loss
GI
high
GLP-1 receptor
agonist
Sulfonylurea
high
moderate risk
gain
hypoglycemia
low
SGLT2
inhibitor
intermediate
low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor
agonist
+
SGLT-2
Inhibitor
+
SU
TZD
Insulin§
Metformin
+
Metformin
+
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono-
therapy
Efficacy*
Hypo risk
Weight
Side effects
Costs
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Triple
therapy
or
or
DPP-4
Inhibitor
+
SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable
therapy‡
GLP-1-RAMealtime Insulin
Insulin (basal)
+
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442
HbA1c
≥9%
Metformin
intolerance or
contraindication
Uncontrolled
hyperglycemia
(catabolic features,
BG ≥300-350 mg/dl,
HbA1c ≥10-12%)

16. Oral Class Mechanism Advantages Disadvantages Cost
Biguanides • Ac vates AMP-
kinase (?other)
• ¯ Hepa c glucose
produc on
• Extensive experience
• No hypoglycemia
• Weight neutral
• ? ¯ CVD
• Gastrointes nal
• Lac c acidosis (rare)
• B-12 defici e ncy
• Contraindica ons
Low
Sulfonylureas • Closes KATP channels
• - Insulin secre on
• Extensive experience
• ¯ Microvascular risk
• Hypoglycemia
• - Weight
• Low durability
• ? Blunts ischemic
precondi oning
Low
Megli nides • Closes KATP channels
• - Insulin secre on
• ¯ Postprandial glucose
• Dosing flexibility
• Hypoglycemia
• - Weight
• ? Blunts ischemic
precondi oning
• Dosing frequency
Mod.
TZDs • PPAR-g ac vator
• - Insulin sensi vity
• No hypoglycemia
• Durability
• ¯ TGs (pio)
• - HDL-C
• - Weight
• Edema/heart failure
• Bone fractures
• - LDL-C (rosi)
Low
Extensive experience and efficacy for supporting
SU vs. new comers class

17. DPP-IV inhibitors and the debate of increase
the HF ?!
Death from CV causes, non-fatal MI or non-fatal stroke Death from CV causes, MI or ischemic stroke

18. Comparison :
Glimepiride vs DPP4 Inhibitors
*from Baseline in Premarketing trials
†2-6 mg Glimepiride vs Maximum DPP4 Inhibitors
‡Severe, Rare with both
#MI in UKPDS, ADOPT, ADVANCE,BARI trials[Diabetes Care,2015;38(1):166]
¶ Increased CHF [Clin Ther,2014;36(12):20729,CurrTreatOptionsCardiovascMed,2014;16(12):353]
Glimepiride DPP4 Inhibitors
Efficacy:∆A1c(minus) 25-30%* 8-12%*
Efficacy:∆A1c(minus) More or equal† Less or equal†
Cost Less More
Cost Efficacy More Less
Hypoglycemia ++++ ++
CVD Decreased# No Change¶

19. Injectabl
e
Class
Mechanism Advantages Disadvantages Cost
Amylin
mimetics
• Activates amylin
receptor
•  glucagon
•  gastric emptying
•  satiety
•  Weight
•  Postprandial
glucose
• Gastrointestinal
• Modest  A1c
• Injectable
• Hypo if insulin dose
not reduced
• Dosing frequency
• Training
requirements
High
GLP-1
receptor
agonists
• Activates GLP-1 R
•  Insulin, 
glucagon
•  gastric emptying
•  satiety
•  Weight
• No hypoglycemia
•  Postprandial
glucose
•  Some CV risk
factors
• Gastrointestinal
• ? Pancreatitis
•  Heart rate
• Medullary ca
(rodents)
• Injectable
• Training
requirements
High
Insulin • Activates insulin
receptor
• Myriad
• Universally effective
• Unlimited efficacy
•  Microvascular risk
• Hypoglycemia
• Weight gain
• ? Mitogenicity
Variabl
e
Table 1. Properties of anti-hyperglycemic agents
Diabetes Care 2015;38:140-149;
Diabetologia 2015;58:429-442

20. SU management in T2DM

21. Mechanism of action
Bind to the sulfonylurea receptor on the surface of the
β-cell
Closes KATP channels → Inhibit potassium efflux
(depolarizing the β-cells)
↑ Insulin secretion

22. GLIMEPIRIDE

23. K+
K+
GlimepirideGlibenclamide
Solubilisation
Glibenclamide Glimepiride
65 kDa
140 kDa
65 kDa
140 kDa
 cell membrane
Sulfonylurea
receptor
Potassium channels
Glimepiride binds to the 65 kDa subunit of the sulfonylurea receptor;
glibenclamide binds to the 140 kDa subunit
Kramer W et al., Biochim Biophys Acta 1994;1191: 278-290
Hypothetical Model of Sulfonylurea Receptor in -cells

24. 0 10 20 30 40 50 60 70 80 90 minutes
3Hsulphonylureabound(%)
Glimepiride dissociates from its binding protein
8-9 times faster than glibenclamide
Glimepiride Glibenclamide
Müller G et al., Biochim Biophys Acta 1994;1191: 267-277.
80
60
40
20
100
1.5x106 RINm5F cells
were incubated
(4°C for 45 mins)
with 2 nM [3H]
Glimepiride or [3H]
glibenclamide. At
time zero,
dissociation was
induced by addition
of unlabeled
sulfonylurea (final
conc 2µM). Specific
binding is given as a
percentage of
specific binding at
time zero (100%).
Sulfonylurea Receptor Binding Affinity
Dissociation kinetics of 3H sulfonylurea binding to RINm5F cells

25. Acting on Both Phases of Insulin Secretion
Glimepiride: The only sulfonylurea to treat
fasting and postprandial hyperglycemia
First Phase Second Phase
Insulin secretion
Before treatment After Glimepiride treatment
Incrementalplasmainsulin
(pmol/L)
0
50
100
p=0.04
First and second phase insulin secretion
before and after treatment with Glimepiride
p=0.02
+Glimepiride
+Glimepiride
Korytkowski M et al. Diabetes Care 2002; 25(9):1607-11.
Euglycemic and
hyperglycemic
clamp studies in 11
obese patients with
T2DM with good
glycemic control
before and after 4
months treatment
with Glimepiride to
assess effect of
Glimepiride on insulin
secretion

26. Glimepiride Controls Glycemia with Less Insulin Secretion
For an equivalent glycemic effect, Glimepiride induces a
lower secretion of insulin
Mean variation of insulin and
glycemia over a 36-h period
Mean ratio between increased level
of insulin and reduced glycemia
5
10
15
0
1
2
3
Glimepiride Glibenclamide Gliclazide Glipizide
20
0
Glycemic
variation(%)
Insulinemia
(U/mL)
Glimepi
ride
Glibenclamide Glipizide Gliclazide
0.00
0.05
0.10
0.15
0.20
n=16
n=13
n=14
n=16
Ratio
Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37
Sulfonylureas tested in
fasted male beagle
dogs to determine
ratios of mean plasma
insulin release/ blood
glucose decrease

27. Glimepiride reduces Insulin Resistance
Inukai K, et al. Diabetes Res Clin Pract 2005; 68: 250-257
0
1
2
3
4
5
HOMA-IR
6
6.5
7
7.5
8
HbA1c (%)
Baseline 6 months
Gliclazide or
glibenclamide
(n=52)
all patients BMI ≥ 25 BMI < 25
Glimepiride
(n=120)
all patients BMI ≥ 25 BMI < 25
Glimepiride
(n=120)
*
* *
Mean homeostasis model of insulin resistance (HOMA-IR) and
HbA1c (%) levels at baseline and after 6 months of treatment
*p< 0.05 vs baseline
Glimepiride maintains glycemic control and improves insulin sensitivity in
patients switching from gliclazide or glibenclamide
Gliclazide or
glibenclamide
(n=52)
Multicentre study in 172
Japanese patients in
whom glycemia was
inadequately controlled
(HbA1c ≥7%) by
gliclazide or
glibenclamide. Patients
were randomly assigned
to continue their usual
sulfonylurea or switch to
Glimepiride and were
followed for 6 months.
Baseline HbA1c: 7.5%
gliclazide/glibenclamide
; 7.6% Glimepiride

28. EFFICACY

29. Effectiveness of Antidiabetic Agent
DPP-4 = dipeptidyl peptidase 4; TZD = thiazolidinedione.
Nathan DM. N Engl J Med. 2007;356(5):437-440.
1.5 1.5 1.0-1.5 0.5-0.9 0.8-1.0
≥2.5
SUs
Biguanides
(metformin) Glinides
DPP-4
inhibitors TZDs Insulin
0.0
0.5
1.0
1.5
2.0
2.5
3.0
HbA1cReduction(%)
Efficacy as
monother
apy
Antidiab
etic
agents

30. Glimepiride Efficacy Proven in Monotherapy
Tight glycemic control (HbA1c<7.2%) was
achieved in 69% of Glimepiride patients
and 32% of placebo patients
Schade DS et al. J Clin Pharmacol 1998;38:636-51
ΔinmedianHbA1c(%)
6.7%
Change from baseline to week 22
in median HbA1c
9.1%
7.9%
-1%
8.9%
Baseline HbA1c
-4
-3
-2
-1
0
HbA1c at Endpoint
-2.4%#
Glimepiride decreased FPG by 46 mg/dL
more and 2-hour PPG by 72 mg/dL more
than placebo (p<0.001)
Change from baseline to week 22 in
median FPG and 2-hour PPG
n=117 n=118 n=108 n=101
Δinglucoseconcentration(mg/dL)
FPG PPG
-59*
-117*
-13
-31
-140
-120
-100
-80
-60
-40
-20
0
Glimepiride Placebo
*p<0.001 vs placebo
Prospective,
randomized, double-
blind, placebo-
controlled, dose-
titration study. T2DM
patients received
Glimepiride (n=123) or
placebo (n=126) for a
10-week dose-titration
period and then the
optimal dose (1 to 8
mg) for 12 weeks. 54%
of patients on active
treatment received <4
mg/day Glimepiride

31. Modest efficacy of gliptins in meta-analyses1-3
1Amori et al. JAMA 2007;298:194-206.
2Richter et al. Cochrane Database Syst Rev 2008;Apr 16;(2):CD006739.
3Richter et al. Vasc Health Risk Manag 2008;4:753-68.
28994Gliptins vs. active control
419016Gliptins vs. placebo
30959Duration 12-24 wk vs. placebo
10957Duration 12 wk vs. placebo
17869Vildagliptin vs. placebo
24047Sitagliptin vs. placebo
No. of
patients
No. of
studies
-1.0 0 1.0
Favors gliptins Favors control
Weighted mean
difference, % (95% CI)
-0.74 (-0.85 to -0.62)
-0.70 (-0.83 to -0.58)
-0.78 (-1.00 to -0.56)
-0.73 (-0.94 to -0.52)
-0.74 (-0.84 to -0.63)
0.21 (0.02 to 0.39)
0.5-0.5-1.5
Weighted mean difference in change in HbA1C (%)
for gliptins vs. control in adults with type-2 diabetes1

32. A multicenter, 52-week, randomized, double-blind study in patients with type-2
diabetes inadequately controlled on metformin therapy
Vildagliptin, less effective than glimepiride?
1Ferranini et al. Diabetes Obes Metab 2009;11:157-66.
2Haute Autorité de Santé. 10 December 2008.
http://www.has-sante.fr/portail/upload/docs/application/pdf/2010-11/galvus_ct_5731.pdf.
100
0
36.5%
43.4%
Patients(%)
Target HbA1C ≤6.5%
at Week 522
50
Glimepiride
(n=1014)
Vildagliptin
(n=1043)
p=0.001

33. A multicenter, 30-week, randomized, double-blind study in patients with type-2
diabetes inadequately controlled on metformin therapy
Sitagliptin, less effective than glimepiride?
Goldstein et al. EASD 2010.
100
0
21.2%
27.5%
Patients(%)
Target HbA1C ≤6.5%
at Week 30
50
Glimepiride
(n=436)
Sitagliptin
(n=443)
Odds ratio (95% CI):
0.67 (0.47 to 0.95)

34. Additional Benefits for the Patient
Beyond Blood Glucose Control

35. Reductions metabolic parameters after 12 months of
treatment with Glimepiride
Glimepiride Beneficial Effect on Cardiovascular Risk Factors
Glimepiride significantly reduces cardiovascular risk markers
De Rosa, et al. Clin Ther 2003; 25(2); 472-484
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
Lp(a)
mg/dL
PAI-1
(ng/mL)
Hcy
(mol/L)
Changefrombaseline
-39.7*
mg/dL
-21.4†
ng/mL
-40.1*
mol/L
*p<0.01; †p<0.05 vs baseline
Lp(a) = Lipoprotein A
PAI-1 = plasminogen activator inhibitor-1
Hcy = homocysteine
Randomized, double-
blind study in which
patients with type 2
diabetes were treated
with Glimepiride
(n=62)or repaglinide
(n=62) for 12 months.

36. Glimepiride Beneficial Effect on Adiponectin Levels
Glimepiride increases plasma adiponectin levels
whilst achieving control of glycemia
Tsunekawa T, et al. Diabetes Care 2003; 26(2); 285-289
11
10
9
8
7
6
5
9
8
7
6
Baseline 4 weeks 8 weeks 12 weeks
Plasma adiponectin HbA1c (%)
Plasmaadiponectin
concentration(g/mL)
HbA1c(%)
8.4
8.2
6.5
7.5
6.96.6
10.2
Evolution of adiponectin and HbA1c levels during 12
weeks of Glimepiride treatment
A study in 17 elderly
patients with type 2
diabetes who were
treated with
Glimepiride for 12
weeks.

37. Change from baseline in lipid and lipoprotein
concentrations
Glimepiride Beneficial Effects on Lipid and
Lipoprotein Parameters
Glimepiride significantly improves lipid and lipoprotein parameters in
patients with metabolic syndrome vs rosiglitazone
Derosa G, et al. Diabetes Obes Metab 2006; 8: 197-205
TC LDL-C HDL-C TG Apo-AI Apo B
-60
-40
-20
0
20
* * *
*p<0.05 vs rosiglitazone + metformin
Glimepiride + metformin Rosiglitazone + metformin
Concentration(mg/dL)
Double-blind study
in which 95 patients
with metabolic
syndrome (T2DM,
triglycerides ≥150
mg/dL, BP ≥130/85
mmHg) were
randomized to
Glimepiride +
metformin or
rosiglitazone +
metformin for 12
months

38. Safety Profile of Glimepiride
Hypoglycemic Events
Impact on Weight
Cardiovascular Effects

39. Incidence of severe* hypoglycemic events
according to treatment
*Defined as requiring IV glucose or glucagon
Significantly lower incidence of severe hypoglycemic events with
Glimepiride vs glibenclamide (0.86 vs 5.6/1000 person-years)
Holstein A et al. Diabetes Met Res Rev 2001; 17:467-73
0.86
5.6
GlibenclamideGlimepiride
#Episodes/1000person-years
0
2
4
6
Prospective, population-
based, 4-year study to
compare frequency of
severe hypoglycemia in
patients with T2DM
treated with Glimepiride
(estimated n=1768)
versus glibenclamide
(estimated n=1721)
Safety: Hypoglycemia vs Glibenclamide
6.5x
less
risk of
hypo

40. Weitgasser R et al. Diabetes Res Clin Pract 2003; 61: 13-19
Mean intra-individual changes from baseline in body
weight and HbA1c
Months of treatment
Reduction in glycemia with Glimepiride is accompanied by
significant and stable weight loss
Changefrombaseline
*p<0.0001; †p<0.05; ‡p<0.005 vs baseline
4 12
- 1
- 2
- 3
18
0
Safety: Weight
-1.9*
-2.9†
-3.0‡
-1.4* -1.5*
-1.7*
Body weight (kg) HbA1c (%)
Open, uncontrolled,
observational study.
1770 T2DM patients
were enrolled and
284 were followed-up
for 1.5 years. Patients
received 0.5 to > 4
mg Glimepiride once
daily. Baseline HbA1c:
8.4%; body weight:
79.8kg

41. Safety: All-Cause Mortality
Retrospective,
observational cohort
study in T2D
outpatients. A total of
696 patients received
insulin secretagogues
in combination with
biguanides. A
Kaplan-Meier survival
analysis was
conducted in
patients treated with
metformin in
combination with
glibenclamide,
gliclazide,
repaglinide or
Glimepiride.
Monami M, et al. Diabetes Metab Res Rev 2006; 22(6): 477-482
Kaplan-Meier survival analysis
In combination with metformin, Glimepiride is associated with lower all-cause mortality
than other sulfonylureas with less selectivity for β-cell receptors
Glimepiride or gliclazide
Repaglinide
Glibenclamide
Time (months)
Cumulativesurvival
1.0
0.9
0.8
0.7
0.6
0 10.0 20.0 30.0 40.0
Glimepiride
Gliclazide
Repaglinide
Glibenclamide
Yearly mortality
0.4%
2.1%*
3.1%*
8.7%**
* P < 0.05 vs Glimepiride
**P <0.01 vs all comparators

42. Take Home Message

43. Take Home Message
• DM is a complex disease with multiple etiologies.
• Glycemic control in important to reduce the risk of
microvascular complications of DM & glucose
control in the early years of DM may reduce the risk
of macrovascular disease.
• Various guidelines insists on the importance of
lifestyle modification & metformin as initial treatment
of T2DM.
• ADA-EASD 2015 position statement introduce the
concept of individualization of target & treatment of
DM.
• SU is a cornerstone in management of T2DM..

44. Glimepiride : Take Home Message
Unique dual mode of action
• Improves 1st and 2nd phases of insulin secretion
• Improves peripheral insulin resistance (extrapancreatic effects)
Fast and sustained blood glucose lowering effect in monotherapy
Suitable for combination with insulin and/or other oral antidiabetic
agents
Benefits beyond blood glucose-lowering
Suitable for use in all type 2 diabetes patients
Clinically proven safety profile
• Low incidence of hypoglycemic events
• No weight gain
• Lower risk of cardiovascular complications
Convenient, once-daily dosing resulting in excellent compliance

45. THANK YOU