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Presentation on Sulfonylureas by Dr Shahjada Selim.
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SULFONYLUREA IN THESULFONYLUREA IN THEMANAGEMENT OF DIABETESMANAGEMENT OF DIABETES
Dr Shahjada Selim Endocrinologist ShSMCH, Dhaka
Email:[email protected]
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.
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.
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
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
……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.
Different Sulfonylureas
Now, which SU to be Now, which SU to be chosen-chosen-gliclazide80, glimepir ide?gliclazide80, glimepir ide?
EvidencesEvidences
?
Gliclazide (Gliclazide (DIAMICRON MR60)DIAMICRON MR60) versusconventional ggliclazide80liclazide80
Points to consider:
01. Compliance
02. Efficacy
03. Vascular benefit
Compliance with treatment is crucial to
the optimal management of any chronic
disease
Non-compliance with OHA increases
r isk of micro & macro-vascular
complications
Compliance is a therapeutic objective
Frequency of administration is an
important factor affecting compliance
with treatmentTreat Endocrinol 2005;4(3):167-175Treat Endocrinol 2005;4(3):167-175
COMPLIANCCOMPLIANC
E E Once daily vs. Multiple administrationOnce daily vs. Multiple administration
DIAMICRON MR60 provides better compliance and therefore ensures superior glycemic control compared to gliclazide80
Treat Endocrinol 2005;4(3):167-175Treat Endocrinol 2005;4(3):167-175
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)
EFFICACEFFICAC
YYDIAMICRON MR60 vs. gliclazide 80DIAMICRON MR60 vs. gliclazide 80
DIAMICRON MR60 provides additional around -1.0%HbA1c reduction while switched from gliclazide 80
Diabetologia Praktyczna. 2003.
BMJ. 2000;321:405-412
According to the UKPDS (United Kingdom Prospective Diabetes Study) -1.0% HbA1c reduction resulted into life
saving benefits
DIAMICRON MR60DIAMICRON MR60 versus conventional glimepir ideglimepir ide
01. Efficacy & tolerability
02. Vascular benefit
03. Beta cell preservation
04. W.H.O. recommendation
Head to head comparing study
GUIDE study: GlUcose control
in type 2 dIabetes: Diamicron MR
versus glimEpir ide
Total number of patients: 845
Duration: 27 weeks (6
months)Eur J Clin Invest. 2004.Eur J Clin Invest. 2004.
EFFICACY & EFFICACY &
TOLERABILITYTOLERABILITY
Gliclazide MR Gliclazide MR (DIAMICRON MR60) vs. (DIAMICRON MR60) vs. glimepirideglimepiride
DIAMICRON MR60 provides better glycemic controlwith -50% less hypoglycemia compared to glimepiride
Eur J Clin Invest. 2004.Eur J Clin Invest. 2004.
Int J Clin Pract. 2011;65:1132-1140.Int J Clin Pract. 2011;65:1132-1140.
A ims: 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,
glimepir ide & glibenclamide
TOLERABILITTOLERABILIT
YYDIAMICRON MR60 vs. DPP-4DIAMICRON MR60 vs. DPP-4
inhibitor and glimepirideinhibitor and glimepiride
Int J Clin Pract. 2011;65:1132-1140.Int J Clin Pract. 2011;65:1132-1140.
Hypoglycemia is -50% less with the newDIAMICRON MR60 compared to glimepiride
DIAMICRON MR60 provides better tolerability than DPP4 inhibitor!!
A im: 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
TOLERABILITTOLERABILIT
YY
DIAMICRON MR60 vs. DPP-4DIAMICRON MR60 vs. DPP-4inhibitor and glimepirideinhibitor and glimepiride
Curr Med Res Opin 2012; 28:1–8
Hypoglycemia is 5 times less with the newDIAMICRON MR60 compared to glimepiride
DIAMICRON MR60 provides better tolerability than DPP4 inhibitor!!
New data, published in 2014
Meta-analysis of 25 tr ials
Incidence of hypoglycemia
observed
Diabetes Metab Res Rev 2014; 30: 11–22.
DIAMICRON MR60 vs. glimepirideDIAMICRON MR60 vs. glimepiride
TOLERABILITTOLERABILIT
YY
Diabetes Metab Res Rev 2014; 30: 11–22.
Hypoglycemia is 11 times less with the newDIAMICRON MR60 compared to glimepiride
Nationwide Study conducted in
Denmark
Impact of insulin secretagouges on
mortality & CV r isk compared with
metformin
Total: 107,806 patients
9607 had previous MI
Duration: 9yrs (1997-2006) [Mean:
3.3yrs]Eur Heart J. 2011 Aug;32(15):1900-8.
CARDIOVASCULAR OUTCOMECARDIOVASCULAR OUTCOME
VASCULAVASCULA
R R
BENEFITBENEFIT
SS
Compared to metformin DIAMICRON MR60 reduces CV deathby -13%, while glimepiride increases by +35%
Eur Heart J. 2011 Aug;32(15):1900-8.
Among the SUs, only DIAMICRON MR60 based intensivetreatment reduces CV mortality in type 2 diabetes
Diabetologia. 2009;52:2288-2298.
CV death increased in ACCORD & VADT tr ial, using glimepir ide!!
IDF recommends SU as first line as well asIDF recommends SU as first line as well asfirst option just after metforminfirst option just after metformin
IDF global guideline for the management of type 2 diabetes 2012IDF global guideline for the management of type 2 diabetes 2012
3/28/2013 29
Hot Topics in Diabetes: 19 September 2014Hot Topics in Diabetes: 19 September 2014
15- 19 September 15- 19 September
-65%
After 10 years treatment with DIAMICRON MR60End Stage Renal Diseases reduces by - 46%
Therefore, DIAMICRON MR60 protects patients’ life and money
due to less dialysis & less transplantation for over 10 years!!
SU is considered to cause -β cell
apoptosis
It is unclear how this occurs & is
there any difference among var ious
sulfonylureas
This research work examined effects
of SUs & insulin secretagouge on
pancreatic -β cellMetabolism Clinical and Experimental 57 (2008) 1038–1045
BETA CELL BETA CELL
PRESERVATIPRESERVATI
ONONEFFECT OF SU ON PANCREATIC EFFECT OF SU ON PANCREATIC ββ --
CELLCELL
DIAMICRON MR60 does not produce free radical-
ROS (Reactive Oxygen Species) in the beta cell
Control Glibenclamide
Glimepir ide
Diamicron MR 60
Nateglinide
0
50
100
150
200
250
300
Stim
ulat
ory
effe
ct o
n R
OS p
rodu
ctio
n in
bet
a ce
ll
Metabolism Clinical and Experimental 57 (2008) 1038–1045
Metabolism Clinical and Experimental 57 (2008) 1038–1045
DIAMICRON MR60 is the only secretagouge
that reduces beta cell apoptosis
0
50
100
150
200
250
300
350
Control Glibenclamide
Glimepir ide
Diamicron MR 60
Nateglinide
Effe
ct o
f ap
opto
sis
on b
eta
cell
J Diabetes Complications. 2000;14:201-206.
Because, DIAMICRON MR60 is the only SU
that possesses unique antioxidant properties
Diabetes Res Clin Pract. 2005;70:291-297.
As a result, DIAMICRON MR60 prolongs insulin free period
up to 14.5 years while maintaining HbA1c ≤7%
Essential Medicines Essential Medicines List of World List of World Health OrganizationHealth Organization
W.H.O. W.H.O.
RECOMMENDATIO
RECOMMENDATIO
NN
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 pr ior ity conditions.
# Pr ior ity conditions are selected on the basis of current & estimated future public health relevance; potential for safe & cost effective treatment.‐
List of Essential Medicines for Diabetes
Not glimepir ide, but the new DIAMICRON MR60 is recommended!!
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
Compared to conventional gliclazide80, new DIAMICRON
MR60 provides
- better compliance, which ensures superior glycemic
control
- super ior glycemic control resulted in to vascular
protection
Compared to glimepir ide, 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
per iod
- that is why, recommended by W.H.O. as essential
medicine
CONCLUSION
THANK YOU
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