SulphonylureaSulphonylureaA Golden Therapy For A Golden Therapy For
DiabetesDiabetes
ByByEman RushdyEman Rushdy
Prof. Internal MedicineProf. Internal MedicineCairo UniversityCairo University
The shoes storyThe shoes story
Many years ago two salesmen were sent Many years ago two salesmen were sent by a British shoe manufacturer to Africa by a British shoe manufacturer to Africa to investigate and report back on market to investigate and report back on market potential.potential.
The first salesman reported back, "There The first salesman reported back, "There is no potential here - nobody wears is no potential here - nobody wears shoes."shoes."
The second salesman reported back, The second salesman reported back, "There is massive potential here - nobody "There is massive potential here - nobody wears shoes."wears shoes."
What is your concern about oral What is your concern about oral hypoglycemic drughypoglycemic drug!? !?
B cell exhaution. B cell exhaution. Less effectiveLess effective HypoglycemiaHypoglycemia ExpensiveExpensive
10 µm~ 10,000granules
Micrograph: Lelio Orci, Geneva
The normal beta-cellThe normal beta-cell
Presented by Pr Philippe Halbanat the 1st Amsterdam Diabetes Meeting, March 30-April 1, 2006
Pancreas consists of 1 million islets of
Langerhans Start to develop from week 9-11 gestation
Half-life of ~30 daysHalf-life of ~30 days Apoptosis is the major mechanism of deathApoptosis is the major mechanism of death
normal apoptotic
New beta-cells by:New beta-cells by:*Replication*Replication
*Neogenesis*Neogenesis
0
50
100
150
Lean (non-diabetic)
Obese(non-diabetic)
T2DM
-ce
ll m
ass
(%)
~65%
Modified from Butler AE, et al. Diabetes 2003;52:102–10.
Factors for progressive loss of B- cell function & mass
Glucotoxicity Lipotoxicity
l
ApoptosisInsulinSecretion
Prentki M et al. Prentki M et al. Diabetes.Diabetes. 2002;51(suppl 3):s405-s413. 2002;51(suppl 3):s405-s413.
Amyloid depositionInflamatoryCytokines& ROS
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
Excess insulin secretion
Prolonged hyperglycemia
Insulin depletion from B-cell (Exhaustion)
Hyperglycemia
More, prolonged hyperglycemia
ER Stress ROS Ca++ Cytokines
Irreversible B-cell damage& apoptosis (Glucotoxicity)
Treatment
Frequently prescribed Frequently prescribed oral hypoglycemic oral hypoglycemic medicationsmedications??
Factors to Consider when Factors to Consider when Choosing Pharmacological Choosing Pharmacological Agent(s) for DiabetesAgent(s) for Diabetes
Current A1CCurrent A1C
Duration of diabetesDuration of diabetes
Body weight (BMI, abdominal Body weight (BMI, abdominal obesity)obesity)
EffectivenessEffectiveness
Co-morbiditiesCo-morbidities
Cradiovascular riskCradiovascular risk
Cost of medicationCost of medication
Compliance. Compliance.
ADA/EASD: ADA/EASD: Considerations for the GuidelinesConsiderations for the Guidelines
1.1. Use of information from Use of information from clinical trials that address the efficacy clinical trials that address the efficacy and safetyand safety of different modalities of treatment ( of different modalities of treatment (Evidence based)Evidence based)
2.2. Clinical judgment of the panel participants (Clinical judgment of the panel participants (Recognize that beta Recognize that beta cell failure is progressive)cell failure is progressive)
3.3. Extrapolation of Extrapolation of UKPDS dataUKPDS data that glucose lowering of drugs that glucose lowering of drugs (metformin, sulfonylureas, insulin) predicted decrease in (metformin, sulfonylureas, insulin) predicted decrease in complications. complications.
4.4. Nonglycemic effects of medicationNonglycemic effects of medication, such as effect on CV risk, , such as effect on CV risk, lipids, hypertension or insulin resistancelipids, hypertension or insulin resistance
5.5. Safety, side effects, ease of use and expenseSafety, side effects, ease of use and expense
AACE/ ACE CriteriaAACE/ ACE Criteria
Attempts to provide a place and recommendation Attempts to provide a place and recommendation for all FDA approved drugs for all FDA approved drugs
Greater emphasis on hypoglycemia avoidanceGreater emphasis on hypoglycemia avoidance Recognizes that people may want choices, so Recognizes that people may want choices, so
allows a wide variety of choices and combinations allows a wide variety of choices and combinations for individual situationsfor individual situations
Add basal or intensify insulin
Lifestyle intervention and metformin
Add sulfonylurea(least expensive)
Add basal insulin (most effective)
Add TZD
Add TZDAdd basal insulin***
Add sulfonylurea
If HbA1c ≥7%*
If HbA1c ≥7%
If HbA1c ≥7%
Intensive insulin + metformin +/− TZD**
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.Nathan DM et al. Diabetologia 2008;51(1):8-11.
Intensify insulin***
ADA/EASD Management AlgorithmADA/EASD Management Algorithm
ADA/EASD ConsensusADA/EASD Consensus Algorithm for Algorithm for Management of DiabetesManagement of DiabetesDiabetes Care. 2009, 32:193-203Diabetes Care. 2009, 32:193-203
At diagnosis:Lifestyle
+Metformin
Lifestyle+Metformin+
Pioglitazone(No hypoglycemia, edema,
CHF, bone loss)
Lifestyle+Metformin+
Sulfonylurea
Lifestyle+Metformin+
Intensive insulin
Lifestyle+Metformin+
Basal Insulin
Lifestyle+Metformin+
GLP1 (No hypoglycemia, wt loss,
Nausea/vomiting)
Lifestyle+Metformin+
Pioglitazone+
Sulfonylurea
Lifestyle+Metformin+
Basal Insulin
Tier 2: less well-validatedtherapies
Tier 1: Well-validated core therapies
Step 1Step 1 Step 2Step 2 Step 3Step 3
Amylin agonists, GlinidesDPP-4 inhibitors may be appropriate in selected patients
*Useful when hypoglycemia is to be avoided
18
Life style modification
AACE consensus AACE consensus Algorithm (2009)Algorithm (2009)
Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094.Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094.
Trends in Use of Different Therapeutic Drug Trends in Use of Different Therapeutic Drug Classes to Treat Diabetes, 1994-2007Classes to Treat Diabetes, 1994-2007
SU
Big
Leading Diabetes Medications Leading Diabetes Medications by Treatment Classby Treatment Class
Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094.Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094.
SU
SU+M
et
0.000
500.000
1,000.000
1,500.000
2,000.000
2,500.000
BIGUANIDE
SULPHONYLUREA
HUMAN INSULIN+Ana
GLITAZONE
GLINIDE
DPP-IV INHIBITOR
RX EGYPT 2010
RX EGYPT 2010
Sulfonylureas - Drug Sulfonylureas - Drug ProfileProfile
AdvantagesAdvantages
Potent glucose lowering Potent glucose lowering effecteffect
Favorable adverse effect Favorable adverse effect profileprofile
DisadvantagesDisadvantages
*Hypoglycemia, less with *Hypoglycemia, less with Glimipride Glimipride
*Weight gain, less with *Weight gain, less with GlimiprideGlimipride
Concomitant use with Concomitant use with other drugsother drugs
Can be used as Can be used as monotherapy and with all monotherapy and with all classes including insulinclasses including insulin
SulfonylureasSulfonylureas
Divided into First, Second, and Third Divided into First, Second, and Third GenerationGeneration– First Generation: rarely used todayFirst Generation: rarely used today– Second Generation: Second Generation: glipizide, Gliclazideglipizide, Gliclazide– Third Generation: Third Generation: glimepiride glimepiride
The duration of action depends on the The duration of action depends on the affinity to SUR and which part of it , the affinity to SUR and which part of it , the rate of metabolism, activity of rate of metabolism, activity of metabolites and rate of excretionmetabolites and rate of excretion
K+K+
140 kDa140 kDa
65 kDa65 kDa
- cell membrane - cell membrane
K+K+
KATP channelKATP channel
Modes of action:
Most Sulphonylureas Glimepiride
Sulphonylurea
Receptor
The duration of action depends on the affinity to SUR, rate of metabolism, activity of metabolites and rate of excretion
So What ??
Glimepiride
Pharmakokinetics of Pharmakokinetics of sulphonylureasulphonylurea::
*Glimepiride*Glimepiride has a lower affinity to the has a lower affinity to the --cell cell
membrane than othersmembrane than others
*The metabolites of *The metabolites of glibenclamide are glibenclamide are activeactive while those of while those of glimipride and glimipride and gliclazide are inactive.gliclazide are inactive.
Glimepiride Controls Glycemia Glimepiride Controls Glycemia with Less Insulin Secretionwith Less Insulin Secretion
Mean ratio between increased level of insulin and reduced
glycemia
5
10
15
0
1
2
3
20
0
Glimepiride
Glibenclamide
Glipizide
Gliclazide
0.00
0.05
0.10
0.15
0.20n=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
*Defined as requiring IV glucose or glucagon
Significantly lower incidence of severe hypoglycemic events withSignificantly lower incidence of severe hypoglycemic events with Glimepiride vs glibenclamide (0.86 vs 5.6/1000 person-years)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# Ep
isod
es/1
000
pers
on-y
ears
0
2
4
6
Prospective, population-based, 4-year study to compare frequency of severe hypoglycemia in patients with T2DM treated with Amaryl® (estimated n=1768)versus glibenclamide (estimated n=1721)
Hypoglycemia vs Hypoglycemia vs GlibenclamideGlibenclamide
6.5x less risk of hypo
Less weight gainLess weight gain::
Weight gain is seen with all Weight gain is seen with all agents, glimepride has been agents, glimepride has been reported to be the most weight-reported to be the most weight-neutral sulphonylurea neutral sulphonylurea
Müller G, Wied S. Diabetes. 1993;42: 1852-1867
Insulin ResistanceInsulin ResistanceThe extrapancreatic effect of GlimiprideThe extrapancreatic effect of Glimipride
– ↑ ↑ Translocation of Translocation of GLUT4 transporters GLUT4 transporters from low-density from low-density microsomes to microsomes to plasma membrane plasma membrane of insulin-resistant of insulin-resistant fat and muscle cellsfat and muscle cells
6.6
8.2
10.2
5
6
7
8
9
10
11
Baseline 4 weeks 8 weeks
Pla
sma
con
cen
trat
ion
(µ
g/d
l)
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 Increases Plasma Adiponectin
Hyperinsulinemic-euglycemic clamp study elderly T2 diabetic patients 12 weeks treatment
+ 54%
Normal IGT Type 2
INSULINRESISTANCE
FPG / PPG HbA1C
INSULINSECRETION
Glimepiride Dual Glimepiride Dual Mechanism for Dual Mechanism for Dual ProblemProblem
Graphic interpretation based on: Type 2 Diabetes BASICS. Minneapolis, MN: International Diabetes Center; 2000Muller 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 Expected HbA1c reduction accordingaccordingto interventionto intervention
InterventionInterventionExpected ↓ in HbAExpected ↓ in HbA1c1c (%)(%)
Lifestyle interventionsLifestyle interventions11toto2%2%
MetforminMetformin11toto2%2%
SulfonylureasSulfonylureas11toto2%2%
InsulinInsulin1.51.5 toto3.5%3.5%
GlinidesGlinides11 toto1.5%1.5%11
ThiazolidinedionesThiazolidinediones0.50.5toto1.4%1.4%
-Glucosidase inhibitors-Glucosidase inhibitors0.50.5 toto0.8%0.8%
GLP-1 agonistGLP-1 agonist0.50.5 toto1.0%1.0%
PramlintidePramlintide0.50.5 toto1.0%1.0%
DPP-IV inhibitorsDPP-IV inhibitors0.50.5 toto0.8%0.8%
1. Repaglinide is more effective than nateglinideAdapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
–30
–25
–20
–15
–10
–5
0
Rel
ativ
e ri
sk r
edu
ctio
n (
%)
All-
caus
e
mor
talit
y
Any
dia
bete
s-
rela
ted
end
poin
tM
yoca
rdia
l
infa
rctio
n
Mic
rova
scul
ar
dise
ase
9%
24%
15%
13%P = 0.040
P = 0.001
P = 0.014 P = 0.007
UKPDS: legacy effect of UKPDS: legacy effect of earlier SU/insulin therapyearlier SU/insulin therapy
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.
10
9
8
7
6
0 5 10 15 5 10 1977 1997 2007 Years from randomization
UKPDS
Active
Conventional
Intensive
Intervention ends UKPDS
Follow-up
Med
ian
Hb
A1c
(%)
Biochemical data no longer
collected
Copyright © 2008. Reprinted by permission of SAGE.
Glycemic Glycemic ControlControl
In MonotherapyIn Monotherapy
Glimepiride Efficacy Proven in Glimepiride Efficacy Proven in MonotherapyMonotherapy
Schade DS et al. J Clin Pharmacol 1998;38:636-51
Δ in
med
ian
Hb
A1c (
%)
6.7%
9.1%
HbAHbA1c1c<<7.2% was achieved in 69% of 7.2% was achieved in 69% of Glimepiride patients and 32% of Glimepiride patients and 32% of
placebo patientsplacebo patients
7.9%
-1%
8.9%
Baseline HbA1c
-4
-3
-2
-1
0
HbA1c at Endpoint
-2.4%#
Glimepiride decreased FPG by 46 Glimepiride decreased FPG by 46 mg/dL more and 2-hour PPG by 86 mg/dL more and 2-hour PPG by 86
mg/dL more than placebo (p<0.001)mg/dL more than placebo (p<0.001)
n=117 n=118 n=108 n=101
Δ in
glu
cose c
on
cen
trati
on
(m
g/d
L)
FPG PPG
-59*
-117*
-13
-31
-140
-120
-100
-80
-60
-40
-20
0
Glimepiride Placebo
*p<0.001 vs placebo
Suitable for Suitable for Combination Combination TherapyTherapy
Efficacy of Glimepiride + MetforminEfficacy of Glimepiride + Metformin
Efficacy of Glimepiride + GliptinsEfficacy of Glimepiride + Gliptins
Efficacy of Glimepiride + InsulinsEfficacy of Glimepiride + Insulins
Glimepiride + Metformin Combination Glimepiride + Metformin Combination Reduces Insulin Resistance More than Reduces Insulin Resistance More than Metformin MonotherapyMetformin Monotherapy
Bermúdez-Pirela VJ, et al. Am J Therapeutics 2007; 14: 194-202
-52.4
-65.3*
-46.9
-70
-60
-50
-40
-30
-20
-10
0
Metformin+ diet & exercise(n=29)
Metformin + Glimepiride+ diet & exercise(n=21)
Diet & exercise(n=9)
Δ in
HO
MA
IR (
%)
Percent change in homeostasis model assessment for insulin resistance (HOMAIR) at week 10
*p<0.01 vs metformin and vs diet and exercise alone
7.8 11.7 6.4 Baseline HOMAIR values
Efficacy: Glimepiride + Efficacy: Glimepiride + Gliptin CombinationGliptin Combination
1Hermansen K, et al. Diabetes Obes Metab 2007; 9: 733-745
–The EU’s Committee for Medicinal Products for Humans (CHMP) recently recommended that The EU’s Committee for Medicinal Products for Humans (CHMP) recently recommended that sitagliptin sitagliptin be approved for use in combination with a sulfonylurea and for triple therapy in combination with be approved for use in combination with a sulfonylurea and for triple therapy in combination with
metformin + sulfonylureametformin + sulfonylurea22
2European Medicines Agency, 15 Nov 2007: Available at http://emea.europa.eu/pdfs/human/opinion/Januvia_53120907en.pdf
∆ in
Hb
A1c (%
)
-1
-0.9-0.8
-0.7
-0.6-0.5
-0.4
-0.3
-0.2-0.1
0
-0.57*
-0.89*
Glimepiride + sitagliptin
Glimepiride + metformin + sitagliptin
*p<0.001 vs placebo
Baseline HbA1c
8.4% 8.3%
Efficacy: Glimepiride + Insulin Efficacy: Glimepiride + Insulin CombinationCombination Reduced insulin requirement and faster Reduced insulin requirement and faster
glycemic control glycemic control
Riddle et al. Diabetes Care 1998;21:1052-1057
* p<0.001; † p<0.05 vs GlimepiridePlacebo + Insulin (n=62)Glimepiride + Insulin (n=70)
Un
its/d
ay
Weeks
0
25
50
75
100
0 4 8 12 16 20 24
†
**
* * * *78 U/day
49 U/day
-38%
Mean insulin dosage required to restore glycemic control
Weeks
Mean
FP
G (
mg
/dL)
100
150
200
250
300
0 4 8 12 16 20 24
*
*
Evolution of mean FPG over time
Additionnal Additionnal Benefits for the Benefits for the Patient Patient Beyond Beyond Blood Glucose Blood Glucose
ControlControl
Mode of action:Mode of action: Different Different SURs in different tissuesSURs in different tissues
Pancreatic beta-cellPancreatic beta-cell SUR1/Kir6.2SUR1/Kir6.2 Cardiac and skeletal muscle Cardiac and skeletal muscle SUR2A/Kir6.2SUR2A/Kir6.2 Vascular smooth muscleVascular smooth muscle SUR2B/Kir6.1SUR2B/Kir6.1 Non-vascular smooth muscle Non-vascular smooth muscle SUR2B/Kir6.2SUR2B/Kir6.2 BrainBrain SUR1-2B/Kir6.2SUR1-2B/Kir6.2
Proks P et al., Diabetes 2002; 51: S368-S376.
Glimepiride accompanied by a better CV risk markerGlimepiride accompanied by a better CV risk marker
-27.9
-39.7
-20.5 -21.4-23.7
-40.1-45
-40
-35
-30
-25
-20
-15
-10
-5
0
repaglinide glimepiride
Red
uct
ion
(%
)Glimepride Efficient in reducing CV risk
markers
Lp(a), PAI-I and Hcy
Lp (a) = lipoprotein (a) ; PAI-I = plasminogen activator inhibitor – I ; Hcy = homocysteine
Lp (a) Lp (a)PAI - I PAI - I HcyHcy
12 months
%
ch
an
ge in
mean
ST
sh
ift
Baseline After drug administration
Mean ST segment depression duringballoon occlusion according to treatment
Klepzig et al. Eur Heart J 1999;20:439-446
Glimepiride does not block the beneficial cardioprotective Glimepiride does not block the beneficial cardioprotective effect of ischemic preconditioningeffect of ischemic preconditioning
50
100
Placebo(n=15)
Glimepiride(n=15)
Glibenclamide (n=15)
p = 0.01 p = NSp = 0.049
0
More efficacy ( more reduction in HbA1c)More efficacy ( more reduction in HbA1c) Have an established long-term benefit with regard to Have an established long-term benefit with regard to
decreased risk decreased risk of micro and macro cardiovascular diabetes-related of micro and macro cardiovascular diabetes-related complications (UKPDS), complications (UKPDS),
You can lower risk of hypoglycemia in the case of You can lower risk of hypoglycemia in the case of second-generation sulfonylureas, such as glimepiride.second-generation sulfonylureas, such as glimepiride.
Necessitate almost no precautions for use in patients Necessitate almost no precautions for use in patients with iwith impaired renal function mpaired renal function
Have no detrimental effect on ischemic Have no detrimental effect on ischemic preconditioning,preconditioning,
Have a favorable cost/efficacy/safety ratio.Have a favorable cost/efficacy/safety ratio.
Sulfonylureas
1Nathan et al. Diabetes Care 2009;32:193-203.2Briscoe et al. Expert Opin Drug Metab 2010;6:225-235.
Advantages of GlimepirideAdvantages of Glimepiride
Single daily dosingSingle daily dosing
Comparable hypoglycaemic side effect profile Comparable hypoglycaemic side effect profile to other SUto other SU
Safer in the presence of cardiac diseaseSafer in the presence of cardiac disease Peripheral action conserves endogenous Peripheral action conserves endogenous
insulininsulin
Safer to use in the physically activeSafer to use in the physically active
Review
Annals of Internal Medicine
Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes MellitusShari 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