Download Sulphonylurea A Golden Therapy For Diabetes

Sulphonylurea
A Golden Therapy For
Diabetes
By
Eman Rushdy
Prof. Internal Medicine
Cairo University
The shoes story

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
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 µm
~ 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 (%)
150
~65%
100
50
0
Lean
(non-diabetic)
Obese
(non-diabetic)
T2DM
Modified from Butler AE, et al. Diabetes 2003;52:102–10.
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
At diagnosis:
Lifestyle
+
Metformin
Tier 1: Well-validated core therapies
Lifestyle+Metformin
+
Basal Insulin
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
Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094.
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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
140
Glimepiride kDa
 - cell
membrane
65
kDa
Sulphonylurea
Receptor
KATP channel
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
n=13
n=14
0.05
n=16
0.00
Glibenclamid Glipizide Gliclazide
e
Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37
Glimepiride
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 person-years
6
4
5.6
2
0.86
0
Glimepiride
Glibenclamide
*Defined
requiring
IV glucose
glucagon
Holstein
A et al.as
Diabetes
Met
Res Rev or
2001;
17:467-73
Prospective, populationbased, 4-year 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 weight-neutral 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
Müller G, Wied S. Diabetes. 1993;42: 1852-1867
Glimepiride Increases Plasma Adiponectin
Hyperinsulinemic-euglycemic clamp study elderly T2 diabetic patients 12 weeks treatment
Plasma concentration (µg/dl)
Baseline
4 weeks
11
+ 54%
10
9
8 weeks
10.2
8.2
8
7
6.6
6
5
Tsunekawa et al, Plasma Adiponectin Plays an Important Role in Improving Insulin Resistance With Glimepiride in Elderly Type 2 Diabetic
Subjects Diabetes Care 26:285–289, 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 HbA1c (%)
Intervention
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
0.5 to
0.8%
GLP-1 agonist
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 earlier
SU/insulin therapy
UKPDS
Active
Median HbA1c (%)
10
9
UKPDS
Follow-up
Conventional
Biochemical
data no
longer
collected
8
Intensive
7
6
0
1977
5
10
15
5
1997
10
2007
Relative risk reduction (%)
Intervention
ends
0
–5
9%
–10 P = 0.040
13%
15%
–15
P = 0.007
P = 0.014
–20
24%
–25
P = 0.001
–30
Years from randomization
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.
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)
Baseline HbA1c
0
-1
9.1%
FPG
8.9%
-1%
-2.4%#
-2
7.9%
-3
-4
6.7%
HbA1c at Endpoint
*p<0.001 vs placebo
Glimepiride
Δ in glucose concentration (mg/dL)
Δ in median HbA1c (%)

0
n=117
-20
PPG
n=118
n=108
-13
-31
-40
-60
n=101
-59*
-80
-100
-120
-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
Δ 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
Bermúdez-Pirela VJ, et al. Am J Therapeutics 2007; 14: 194-202
Efficacy: Glimepiride + Gliptin
Combination
Baseline HbA1c
∆ in HbA1c (%)
0
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.8
-0.9
-1
*p<0.001 vs placebo
8.4%
8.3%
Glimepiride + sitagliptin
Glimepiride +
metformin + sitagliptin
-0.57*
-0.89*
1Hermansen
K, et al. Diabetes Obes Metab 2007; 9: 733-745
The EU’s Committee for Medicinal Products for Humans (CHMP) recently –
recommended that sitagliptin be approved for use in combination with a
ulfonylurea and for triple therapy in combination with metformin + sulfonylurea2
2European
Medicines Agency, 15 Nov 2007: Available at
http://emea.europa.eu/pdfs/human/opinion/Januvia_53120907en.pdf
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
100
*
*
*
50
-38%
†
49 U/day
25
0
78 U/day
0
4
8
12
16
Weeks
* p<0.001; † p<0.05 vs Glimepiride
20
24
Placebo + Insulin (n=62)
Mean FPG (mg/dL)
Units/day
75
* * *
*
250
*
200
150
100
0
4
8
12
Weeks
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
Cardiac and skeletal muscle
Vascular smooth muscle
Non-vascular smooth muscle
Brain
Proks P et al., Diabetes 2002; 51: S368-S376.
SUR1/Kir6.2
SUR2A/Kir6.2
SUR2B/Kir6.1
SUR2B/Kir6.2
SUR1-2B/Kir6.2
Glimepride Efficient in reducing CV risk markers
Lp(a), PAI-I and Hcy
12 months
Reduction (%)
repaglinide
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
Lp (a)
PAI - I
Hcy
glimepiride
Lp (a)
-20.5
PAI - I
Hcy
-21.4
-23.7
-27.9
-39.7
-40.1
Glimepiride accompanied by a better CV risk marker
Lp (a) = lipoprotein (a) ; PAI-I = plasminogen activator inhibitor – I ; Hcy = homocysteine
% change in mean ST shift
Glimepiride does not block the beneficial cardioprotective effect
of ischemic preconditioning
p = 0.049
p = 0.01
p = NS
Placebo
(n=15)
Glimepiride
(n=15)
Glibenclamide
(n=15)
100
50
0
Baseline
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.
1Nathan
et al. Diabetes Care 2009;32:193-203.
et al. Expert Opin Drug Metab 2010;6:225-235.
2Briscoe
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