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