Presentation on Sulfonylureas by Dr Shahjada Selim.

1. SULFONYLUREA IN THESULFONYLUREA IN THE
MANAGEMENT OF DIABETESMANAGEMENT OF DIABETES
Dr Shahjada Selim
Endocrinologist
ShSMCH, Dhaka
Email:selimshahjada@gmail.com

2. SULFONYLUREA
Mode of action:
• Sulfonylureas act directly on the β-cells of
the islets of Langerhans to stimulate insulin
secretion.
• They enter into the β–cell and bind to the
cytosolic surface of the sulfonylurea receptor
1.
• Binding of a sulfonylurea closes the K+ATP
channel, reducing the efflux of potassium
enabling membrane depolarization.

3. SULFONYLUREA
Mode of action:
• Localized membrane depolarization opens
adjacent voltage-dependent L - type calcium
channels.
• Increasing calcium influx and raising the
cytosolic free calcium concentration
• Mediate the exocytotic release of insulin
granules.

5. Classification
• Divided into first and second generation
agents
• In general, the second-generation agents
– Are more potent
– Have fewer adverse effects and drug-drug
interactions

6. Extended release preparations
These are long acting/once daily using drugs.
Extended-release/long acting glipizide and
glimepiride are preferred agents in some
situations as
- they can be given once daily
- involve a relatively low risk of hypoglycemia
- low weight gain

7. ……Modified release preparations
• A “modified release” (MR) formulation of
gliclazide has been introduced for once - daily
dosing.
• Interestingly, the 30 mg preparation of
gliclazide MR gives similar efficacy to 80 mg
of unmodified gliclazide and reduces risk of
severe hypoglycemia.

8. Different Sulfonylureas

9. Now, which SU to beNow, which SU to be
chosen-chosen-
gliclazide80, glimepiride?gliclazide80, glimepiride?
EvidencesEvidences
?

10. Gliclazide (Gliclazide (DIAMICRON MR60)DIAMICRON MR60) versus
conventional ggliclazide80liclazide80
Points to consider:
01. Compliance
02. Efficacy
03. Vascular benefit

11.  Compliance with treatment is crucial to
the optimal management of any chronic
disease
 Non-compliance with OHA increases
risk of micro & macro-vascular
complications
 Compliance is a therapeutic objective
 Frequency of administration is an
important factor affecting compliance
Treat Endocrinol 2005;4(3):167-175Treat Endocrinol 2005;4(3):167-175
COMPLIANC
COMPLIANC
EE
Once daily vs. Multiple administrationOnce daily vs. Multiple administration

12. DIAMICRON MR60provides bettercompliance and therefore
ensures superiorglycemic control compared to gliclazide80
Treat Endocrinol 2005;4(3):167-175Treat Endocrinol 2005;4(3):167-175

13. Diabetologia Praktyczna. 2003.
 Total number of patients: 769
(316 men and 453 women)
 Switched from gliclazide 80 to
once-daily MR formulation
 On tablet-to-tablet basis
 Duration: 27 weeks (6 months)
EFFICAC
EFFICAC
YY
DIAMICRON MR60 vs. gliclazide 80DIAMICRON MR60 vs. gliclazide 80

14. DIAMICRON MR60provides additional around -1.0%
HbA1c reduction while switched fromgliclazide 80
Diabetologia Praktyczna. 2003.

15. BMJ. 2000;321:405-412
According to the UKPDS (United KingdomProspective
Diabetes Study) -1.0% HbA1c reduction resulted into life
saving benefits

16. DIAMICRON MR60DIAMICRON MR60 versus conventional glimepirideglimepiride
01. Efficacy & tolerability
02. Vascular benefit
03. Beta cell preservation
04. W.H.O. recommendation

17.  Head to head comparing study
 GUIDE study: GlUcose control
in type 2 dIabetes: Diamicron MR
versus glimEpiride
 Total number of patients: 845
 Duration: 27 weeks (6
months)
Eur J Clin Invest. 2004.Eur J Clin Invest. 2004.
EFFICACY &
EFFICACY &
TOLERABILITY
TOLERABILITY
Gliclazide MRGliclazide MR (DIAMICRON MR60) vs.(DIAMICRON MR60) vs.
glimepirideglimepiride

18. DIAMICRON MR60provides betterglycemic control
with -50% less hypoglycemia compared to glimepiride
Eur J Clin Invest. 2004.Eur J Clin Invest. 2004.

19. Int J Clin Pract. 2011;65:1132-1140.Int J Clin Pract. 2011;65:1132-1140.
 Aims: To compare hypoglycemia in
patients treated with DPP4-inhibitor
or Sulfonylurea during Ramadan
 Total no. of patients: 1021
 507 on DPP4-inhibitor & 514 on SU
 SU includes DIAMICRON MR60,
glimepiride & glibenclamide
TOLERABILIT
TOLERABILIT
YY
DIAMICRON MR60 vs. DPP-4DIAMICRON MR60 vs. DPP-4
inhibitor and glimepirideinhibitor and glimepiride

20. Int J Clin Pract. 2011;65:1132-1140.Int J Clin Pract. 2011;65:1132-1140.
Hypoglycemia is -50% less with the new
DIAMICRON MR60compared to glimepiride
DIAMICRON MR60 provides better tolerability than DPP4
inhibitor!!

21.  Aim: Compare hypo in patients
treated with DPP4-inhibitor or SU in
Ramadan
 Total no. of patients: 848
 421 on DPP4-inhibitor and 427 on
SU
Curr Med Res Opin 2012; 28:1–8
TOLERABILIT
TOLERABILIT
YY
DIAMICRON MR60 vs. DPP-4DIAMICRON MR60 vs. DPP-4
inhibitor and glimepirideinhibitor and glimepiride

22. Curr Med Res Opin 2012; 28:1–8
Hypoglycemia is 5 times less with the new
DIAMICRON MR60compared to glimepiride
DIAMICRON MR60 provides better tolerability than DPP4
inhibitor!!

23.  New data, published in 2014
 Meta-analysis of 25 trials
 Incidence of hypoglycemia
observed
Diabetes Metab Res Rev 2014; 30: 11–22.
DIAMICRON MR60 vs. glimepirideDIAMICRON MR60 vs. glimepiride
TOLERABILIT
TOLERABILIT
YY

24. Diabetes Metab Res Rev 2014; 30: 11–22.
Hypoglycemia is 11 times less with the new
DIAMICRON MR60compared to glimepiride

25.  Nationwide Study conducted in
Denmark
 Impact of insulin secretagouges on
mortality & CV risk compared with
metformin
 Total: 107,806 patients
 9607 had previous MI
 Duration: 9yrs (1997-2006) [Mean:
Eur Heart J. 2011 Aug;32(15):1900-8.
CARDIOVASCULAR OUTCOMECARDIOVASCULAR OUTCOME
VASCULA
VASCULA
RR
BENEFIT
BENEFIT
SS

26. Compared to metformin DIAMICRON MR60reduces CV death
by -13%, while glimepiride increases by +35%
Eur Heart J. 2011 Aug;32(15):1900-8.

27. Among the SUs, only DIAMICRON MR60based intensive
treatment reduces CV mortality in type 2 diabetes
Diabetologia. 2009;52:2288-2298.
CV death increased in ACCORD & VADT trial, using
glimepiride!!

28. IDF recommends SU as first line as well asIDF recommends SU as first line as well as
first option just aftermetforminfirst option just aftermetformin
IDF global guideline for the management of type 2 diabetes 2012IDF global guideline for the management of type 2 diabetes 2012

29. 3/28/2013 29

30. Hot Topics in Diabetes: 19 September 2014Hot Topics in Diabetes: 19 September 2014
15- 19 September15- 19 September

32. -65%
After10 years treatment with DIAMICRON MR60
End Stage Renal Diseases reduces by - 46%
Therefore, DIAMICRON MR60 protects patients’ life and
money
due to less dialysis & less transplantation for over 10 years!!

33.  SU is considered to cause -β cell
apoptosis
 It is unclear how this occurs & is
there any difference among various
sulfonylureas
 This research work examined effects
of SUs & insulin secretagouge on
pancreatic -β cell
Metabolism Clinical and Experimental 57 (2008) 1038–1045
BETA CELL
BETA CELL
PRESERVATI
PRESERVATI
ONON
EFFECT OF SU ON PANCREATICEFFECT OF SU ON PANCREATIC ββ--
CELLCELL

34. DIAMICRON MR60does not produce free radical-
ROS (Reactive Oxygen Species) in the beta cell
Control Glibenclami
de
Glimepiri
de
Diamicron MR
60
Nateglinid
e
0
50
100
150
200
250
300
StimulatoryeffectonROSproductioninbeta
cell
Metabolism Clinical and Experimental 57 (2008) 1038–1045

35. Metabolism Clinical and Experimental 57 (2008) 1038–1045
DIAMICRON MR60is the only secretagouge
that reduces beta cell apoptosis
0
50
100
150
200
250
300
350
Control Glibenclami
de
Glimepiri
de
Diamicron MR
60
Nateglinid
e
Effectofapoptosisonbeta
cell

36. J Diabetes Complications. 2000;14:201-206.
Because, DIAMICRON MR60is the only SU
that possesses unique antioxidant properties

37. Diabetes Res Clin Pract. 2005;70:291-297.
As a result, DIAMICRON MR60prolongs insulin free period
up to 14.5 years while maintaining HbA1c ≤7%

38. Essential MedicinesEssential Medicines
List of WorldList of World
Health OrganizationHealth Organization
W.H.O.
W.H.O.
RECOMMENDATIO
RECOMMENDATIO
NN

39. What is Essential Medicines List of WHO?
# Core list of minimum medicines needs for basic
health care system. The most‐ efficacious, safe & cost‐
effective medicines for priority conditions.
# Priority conditions are selected on the basis of
current & estimated future public health relevance;
potential for safe & cost effective treatment.‐

40. List of Essential Medicines forDiabetes
Not glimepiride, but the new DIAMICRON MR60 is
recommended!!

41.  IDF global guideline recommends SU as first
line
 ADA recommends SU just after metformin
 But all sulfonylureas are not same!!
 Therefore, selection of SU is a challenge for
the clinicians
CONCLUSION

42. MR60 provides
- better compliance, which ensures superior glycemic
control
- superior glycemic control resulted in to vascular
protection
 Compared to glimepiride, new DIAMICRON MR60 provides
- better glycemic control with 11 times less
hypoglycemia
- reduces ESRD & cardiovascular mortality up to 10
years
- preserves β-cell function & prolongs insulin free
CONCLUSION

43. THANK YOU