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Sulphonylurea

A Golden Therapy For


Diabetes
By
Eman Rushdy
Prof. Internal Medicine
Cairo University

The shoes story

Many years ago two salesmen were sent


by a British shoe manufacturer to Africa to
investigate and report back on market
potential.
The first salesman reported back, "There is
no potential here - nobody wears shoes."
The second salesman reported back,
"There is massive potential here - nobody
wears shoes."

What is your concern about oral


?!hypoglycemic drug

B cell exhaution.
Less effective
Hypoglycemia
Expensive

The normal beta-cell


Pancreas consists of
1 million islets of
Langerhans
Start to develop from
week 9-11 gestation

10 m
~ 10,000
granules

Micrograph: Lelio Orci, Geneva

Presented by Pr Philippe Halban


at the 1st Amsterdam Diabetes Meeting, March 30-April 1,
2006

Half-life of ~30 days


Apoptosis is the major mechanism of death

normal

apoptotic
New beta-cells by:
*Replication
*Neogenesis

-cell mass (%)

~65%

Modified from Butler AE, et al. Diabetes 2003;52:10210.

Factors for progressive loss of Bcell function & mass


Glucotoxicity

Lipotoxicity

Amyloid deposition

Inflamatory
Cytokines& ROS

l
Insulin
Secretion

Prentki M et al. Diabetes. 2002;51(suppl 3):s405-s413.

Apoptosis

B-cell Exhaustion
- A physical depletion of B-cell insulin stores
secondary to prolonged chronic stimulation
with glucose on non-glucose secretagogues.
- No defect in insulin synthesis.
- The B-cell function fully recovers as it rests.

Exhaustion is reversible

Glucotoxicity
Non physiological and potentially
irreversible B-cell damage caused by chronic
exposure to supra-physiological glucose
concentration with characteristic decreases in
insulin synthesis and secretion caused by
decreases insulin gene expression.

Glucotoxicity is irreversible

Interplay between B-cell exhaustion & glucotoxicity


Hyperglycemia
Excess insulin secretion
Prolonged hyperglycemia

Treatment

Insulin depletion from B-cell (Exhaustion)


More, prolonged hyperglycemia
ER Stress

ROS

Ca++

Cytokines

Irreversible B-cell damage


& apoptosis (Glucotoxicity)

Frequently prescribed
oral hypoglycemic
?medications

Factors to Consider when


Choosing Pharmacological
Agent(s) for Diabetes

Current A1C

Duration of diabetes

Body weight (BMI, abdominal


obesity)

Effectiveness

Co-morbidities

Cradiovascular risk

Cost of medication

Compliance.

ADA/EASD:
Considerations for the Guidelines
1.

Use of information from clinical trials that address the efficacy


and safety of different modalities of treatment ( Evidence based)

2.

Clinical judgment of the panel participants ( Recognize that beta


cell failure is progressive)

3.

Extrapolation of UKPDS data that glucose lowering of drugs


(metformin, sulfonylureas, insulin) predicted decrease in
complications.

4.

Nonglycemic effects of medication , such as effect on CV risk,


lipids, hypertension or insulin resistance

5.

Safety, side effects, ease of use and expense

AACE/ ACE Criteria

Attempts to provide a place and recommendation


for all FDA approved drugs
Greater emphasis on hypoglycemia avoidance
Recognizes that people may want choices, so
allows a wide variety of choices and combinations
for individual situations

ADA/EASD Management Algorithm


Lifestyle intervention and metformin
If HbA1c 7%*
Add basal insulin
(most effective)

Add sulfonylurea
(least expensive)

Add TZD

If HbA1c 7%
Intensify
insulin***

Add TZD

Add basal
insulin***

Add
sulfonylurea

If HbA1c 7%

Intensive insulin + metformin +/ TZD**

Add basal or
intensify insulin

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.


Nathan DM et al. Diabetologia 2008;51(1):8-11.

ADA/EASD Consensus Algorithm for


Management of Diabetes
Diabetes Care. 2009, 32:193-203 Tier

At diagnosis:
Lifestyle
+
Metformin

Lifestyle+Metformin
+
Basal Insulin

1: Well-validated core therapies

Lifestyle+Metformin
+
Intensive insulin

Lifestyle+Metformin
+

Sulfonylurea
Step 1
Tier 2: less well-validated
therapies
*Useful when
hypoglycemia is to be
avoided

Amylin agonists, Glinides


DPP-4 inhibitors may be
appropriate in selected
patients

Step 3

Step 2
Lifestyle+Metformin
+
Pioglitazone
(No hypoglycemia, edema,
CHF, bone loss)

Lifestyle+Metformin
+
GLP1
(No hypoglycemia, wt loss,
Nausea/vomiting)

Lifestyle+Metformin
+
Pioglitazone
+
Sulfonylurea
Lifestyle+Metformin
+
Basal Insulin

Life style modification

AACE consensus
Algorithm (2009)

18

Trends in Use of Different Therapeutic Drug


Classes to Treat Diabetes, 1994-2007

Big
SU

Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094.

Leading Diabetes Medications


by Treatment Class

SU
+M
et

SU

Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094.

Sulfonylureas - Drug
Profile
Advantages

Disadvantages

Concomitant use with


other drugs

Potent glucose lowering


effect
Favorable adverse effect
profile
*Hypoglycemia, less with
Glimipride
*Weight gain, less with
Glimipride
Can be used as
monotherapy and with all
classes including insulin

Sulfonylureas

Divided into First, Second, and Third


Generation

First Generation: rarely used today


Second Generation: glipizide, Gliclazide
Third Generation: glimepiride
The duration of action depends on the
affinity to SUR and which part of it , the
rate of metabolism, activity of
metabolites and rate of excretion

Modes of action:
Most Sulphonylureas K+
Glimepiride
Glimepiride

140
kDa

- cell
membrane

65
kDa

Sulphonylurea
KATP channel

Receptor

K+

The duration of action depends on the affinity to SUR,


rate of metabolism, activity of metabolites and rate of
excretion

So What ??

Pharmakokinetics of
:sulphonylurea
*Glimepiride has a lower affinity to the cell
membrane than others
*The metabolites of glibenclamide are
active while those of glimipride and
gliclazide are inactive.

Glimepiride Controls Glycemia


with Less Insulin Secretion
Mean ratio between increased
level of insulin and reduced
glycemia
3
2
1
0
0
5
10
15
20

Sulfonylureas
tested in fasted
male beagle
dogs to
determine ratios
of mean plasma
insulin release/
blood glucose
decrease

Ratio
0.20

n=16

0.15
0.10
0.05

n=13
n=14
n=16

0.00

Glibenclami Glipizid Gliclazide Glimepirid


e
de
e

Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37

Hypoglycemia vs
Glibenclamide
Significantly lower incidence of severe hypoglycemic events with

Glimepiride vs glibenclamide (0.86 vs 5.6/1000 person-years)

6.5x
less
risk
of
hypo

# Episodes/1000 personyears

5.6

0.86

Glimepirid

Glibenclamide

e
*Defined
requiring
IV glucose
glucagon
Holstein
A et al.as
Diabetes
Met
Res Rev or
2001;
17:467-73

Prospective,
population-based, 4year study to compare
frequency of severe
hypoglycemia in
patients with T2DM
treated with Amaryl
(estimated n=1768)
versus glibenclamide
(estimated n=1721)

:Less weight gain


Weight gain is seen with all
agents, glimepride has been
reported to be the most weightneutral sulphonylurea

Insulin Resistance
The extrapancreatic effect of Glimipride

Translocation of
GLUT4 transporters
from low-density
microsomes to
plasma membrane
of insulin-resistant
fat and muscle cells

Mller G, Wied S. Diabetes. 1993;42: 1852-1867

Glimepiride Increases Plasma


Adiponectin
Hyperinsulinemic-euglycemic clamp study elderly T2 diabetic patients 12
weeks treatment

+ 54%

Tsunekawa et al, Plasma Adiponectin Plays an Important Role in Improving Insulin Resistance With Glimepiride
in Elderly Type 2 Diabetic Subjects Diabetes Care 26:285289, 2003

Glimepiride Dual
Mechanism for Dual
Problem

INSULIN
RESISTANCE

FPG / PPG
HbA1C

INSULIN
SECRETION
Normal

IGT

Type 2

Graphic interpretation based on: Type 2 Diabetes BASICS. Minneapolis, MN: International Diabetes Center; 2000
Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37; Massi-Benedetti M. Clin Ther 2003; 25(3): 799-816

Expected HbA1c reduction


according
to intervention
(%) Expected in HbA
Intervention

1c

Lifestyle interventions

1 to

2%

Metformin

1 to

2%

Sulfonylureas

1 to

2%

Insulin

1.5 to

3.5%

Glinides

1 to

1.5%1

Thiazolidinediones

0.5 to

1.4%

-Glucosidase inhibitors
GLP-1 agonist

0.5 to

0.8%

0.5 to

1.0%

Pramlintide

0.5 to

1.0%

DPP-IV inhibitors

0.5 to

0.8%

1. Repaglinide is more effective than nateglinide


Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.

UKPDS: legacy effect of

UKPDS
Active

Median HbA1c (%)

10
9

UKPDS
Follow-up

Conventional
Biochemical
data no
longer
collected

Intensive

7
6
0
1977

10

15

5
1997

10
2007

Relative risk reduction (%)

Intervention
ends

An
re y d
la ia
te b
d et
M end espo
di icro
se v
as as int
e cu
la
M
r
y
in oc
fa ar
rc d
tio ial
n
Al
m l-ca
or u
ta se
lit
y

earlier SU/insulin therapy

0
5
9%

10 P = 0.040

13%
15%

P = 0.007
P = 0.014

15
20
24%

25

P = 0.001

30

Years from randomization

Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242247.


Holman RR, et al. N Engl J Med 2008; 359:15771589.
Copyright 2008. Reprinted by permission of SAGE.

Glycemic
Control
In Monotherapy

Glimepiride Efficacy Proven in


Monotherapy

HbA1c<7.2% was achieved in 69% of


Glimepiride patients and 32% of placebo
patients

Glimepiride decreased FPG by 46


mg/dL more and 2-hour PPG by 86
mg/dL more than placebo (p<0.001)

-1

9.1%

FPG

8.9%

-1%

n=117

-20

-2.4%#

PPG

n=118

n=108 n=101

-13
-31

-40

-2

-60

7.9%

-3
-4

in glucose concentration
(mg/dL)

in median HbA1c (%)

Baseline HbA1c

-59*

-80

-100

6.7%

HbA1c at Endpoint

-120

*p<0.001 vs placebo

Glimepiride

-140

Placebo

Schade DS et al. J Clin Pharmacol 1998;38:636-51

-117*

Suitable for
Combination
Therapy
Efficacy of Glimepiride + Metformin
Efficacy of Glimepiride + Gliptins
Efficacy of Glimepiride + Insulins

Glimepiride + Metformin Combination


Reduces Insulin Resistance More than
Metformin Monotherapy
Percent change in homeostasis model assessment
for insulin resistance (HOMAIR) at week 10
0

7.8

11.7

6.4

Baseline HOMAIR values

in HOMAIR (%)

-10
Metformin
+ diet & exercise
(n=29)

-20
-30

Metformin + Glimepiride
+ diet & exercise
(n=21)

-40
-50
-60
-70

-46.9
-52.4

Diet & exercise


(n=9)

-65.3*
*p<0.01 vs metformin and vs diet and exercise alone
Bermdez-Pirela VJ, et al. Am J Therapeutics 2007; 14: 194-202

Efficacy: Glimepiride +
Gliptin Combination

Baseline HbA1c
8.4%

8.3%

in HbA1c (%)

0
-0.1
-0.2
Glimepiride + sitagliptin
-0.3
-0.4
Glimepiride +
metformin +
-0.57*
-0.5
sitagliptin
-0.6
-0.7
-0.89*
-0.8
-0.9
-1
*p<0.001 vs placebo 1Hermansen K, et al. Diabetes Obes Metab 2007; 9: 733-745

The EUs Committee for Medicinal Products for Humans (CHMP) recently recommended that sitagliptin be
pproved for use in combination with a sulfonylurea and for triple therapy in combination with metformin +
sulfonylurea2

European Medicines Agency, 15 Nov 2007: Available at


http://emea.europa.eu/pdfs/human/opinion/Januvia_53120907en.pdf
2

Efficacy: Glimepiride + Insulin


Combination

Reduced insulin requirement and faster


glycemic control

Mean insulin dosage required to


restore glycemic control

Evolution of mean FPG over time

300

Units/day

75

* * *

50

-38%

49 U/day

25
0

78 U/day

12
16
Weeks

* p<0.001; p<0.05 vs Glimepiride

20

24

Mean FPG (mg/dL)

100

250

*
*

200
150
100
0

12
Weeks

Placebo + Insulin (n=62) Glimepiride + Insulin (n=70)


Riddle et al. Diabetes Care 1998;21:1052-1057

16

20

24

Additionnal
Benefits for the
Patient Beyond
Blood Glucose
Control

Mode of action: Different


SURs in different tissues

Pancreatic beta-cell
SUR1/Kir6.2
Cardiac and skeletal muscle
SUR2A/Kir6.2
Vascular smooth muscle
SUR2B/Kir6.1
Non-vascular smooth muscle
SUR2B/Kir6.2
Brain
SUR1-2B/Kir6.2

Proks P et al., Diabetes 2002; 51: S368-S376.

Glimepride Efficient in reducing CV risk


markers
Lp(a), PAI-I and Hcy
Lp (a)

PAI - I

Hcy

Lp (a)

PAI - I

months 12
Hcy

Glimepiride accompanied by a better CV risk marker


Lp (a) = lipoprotein (a) ; PAI-I = plasminogen activator inhibitor I ; Hcy =
homocysteine

Glimepiride does not block the beneficial cardioprotective


effect of ischemic preconditioning

p = 0.049

p = 0.01

p = NS

% change in mean ST
shift

100

50

0
Placebo
(n=15)

Glimepiride
(n=15)
Baseline

Glibenclamide
(n=15)

After drug
administration

Mean ST segment depression during


balloon occlusion according to treatment

Klepzig et al. Eur Heart J 1999;20:439-446

Sulfonylureas

More efficacy ( more reduction in HbA1c)

Have an established long-term benefit with regard to


decreased risk
of micro and macro cardiovascular diabetes-related
complications (UKPDS),

You can lower risk of hypoglycemia in the case of


second-generation sulfonylureas, such as glimepiride.

Necessitate almost no precautions for use in patients


with impaired renal function

Have no detrimental effect on ischemic


preconditioning,

Have a favorable cost/efficacy/safety ratio.

1
2

Nathan et al. Diabetes Care 2009;32:193-203.


Briscoe et al. Expert Opin Drug Metab 2010;6:225-235.

Advantages of Glimepiride

Single daily dosing

Comparable hypoglycaemic side effect profile


to other SU
Safer in the presence of cardiac disease
Peripheral action conserves endogenous
insulin

Safer to use in the physically active

Review
Annals of Internal Medicine

Systematic Review: Comparative Effectiveness and


Safety of Oral Medications for Type 2 Diabetes
Mellitus
Shari Bolen, MD, MPH; Leonard Feldman, MD; Jason Vassy, MD, MPH; Lisa Wilson, BS, ScM; Hsin-Chieh Yeh, PhD;
Spyridon Marinopoulos, MD, MBA; Crystal Wiley, MD, MPH; Elizabeth Selvin, PhD; Renee Wilson, MS; Eric B. Bass,
MD, MPH; and Frederick L. Brancati, MD, MHS

Conclusions: Compared with newer, more expensive agents older


agents (second-generation sulfonylureas and metformin) have
similar or superior effects on glycemic control, lipids, and other
intermediate end points. Large, long-term comparative studies
are needed to determine the comparative effects of oral
diabetes agents on hard clinical end points.
Ann Intern Med. 2007;147:386-399