1. Better control,Better Life
Ko Ko Taunggyi MMA 15.2.13
UM 2

2. What new in 2013
BP 140/80 rather than 130/80
Patient centre apporoach

3. Conclusions from recent trials
Tight control
-early on has long term benefit on CVD
-later in the disease has little impact on CVD
-later in the disease may CVD risk
Severe Hypo may be dangerous
BP <120/80 no better than <140/80
Multifactorial management saves lives
Early combination Therapy
Therapeutic Inertia

5. Do we need better control?
YES

6. Are we achieving good control?Are we achieving good control?

7. Are We getting better control?
• Why?
• Diet and exercise(Life long)
• Therapeutic Inertia (Target not achieved)
• Not using better drugs,better combination,sup-optimal dose
• Poor compliance,Poor monitoring
• Not giving drug according to pathogenesis
• Secondary drug failure---Need insulin
• Stress,Infection,MI,
• Steroid
No

8. Treatment Strategies for Diabetes:Treatment Strategies for Diabetes:
Are Patients Achieving Good Control?Are Patients Achieving Good Control?
Controlled
Uncontrolle
d
Hypertension Hyperlipidemia Diabetes
59%
41%
Harris MI et al. Diabetes Care. 2000;23:754
BP <140/90 mm Hg LDL-C <130 mg/dL A1C <7.0
59%
41%
58%
42%

9. Need SMBG 3 times per day in Type 1
Type 2—depend on c ontrol,3,5,7 days/week
SMBG is associated with a better glycemic control in
type 2 diabetes

10. - The pain: the ends of fingers are rich in nervous terminations (sensitivity +++)
- Certain professions or certain leisures require a frequent use of the fingers:
musicians (guitarists, pianists…), health workforces, plumbers, users of computer,
hairdressers…
Obstacles with the self-monitoring at the end
of the fingers

11. Self-monitoring Blood Glucose (SMBG)
American Diabetes Association Recommendations
SMBG 3 or more times per day for type 1 diabetes
No specific frequency is recommended for type 2
diabetes
Standards of medical care in diabetes. Diabetes Care 2008

12. Measures to improve drug-complianceMeasures to improve drug-compliance
• Patient’s educationPatient’s education
• Promoting patient’s involvement in managementPromoting patient’s involvement in management
• Reducing pill load (Reducing pill load (long acting drugs eg.metforminlong acting drugs eg.metformin
XR,Gliclazide MR)XR,Gliclazide MR)
• Encouraging family involvement in patient’s careEncouraging family involvement in patient’s care

13. DRUGSDRUGS
• Correct DrugsCorrect Drugs
• Correct DosesCorrect Doses
• Correct TimingCorrect Timing
• Correct CombinationCorrect Combination
• ComplianceCompliance
• ?steroid?steroid

14. Correct DrugsCorrect Drugs
• InsulinInsulin
Type(1)DM/Type 2 DM with Stress/OHA FailureType(1)DM/Type 2 DM with Stress/OHA Failure
• TZD/MetforminTZD/Metformin
Insulin ResistanceInsulin Resistance
• Postprandial HyperglycemiaPostprandial Hyperglycemia
Glinites/Acarbose/voglibose/Soluble insulinGlinites/Acarbose/voglibose/Soluble insulin
• Insulin DeficiencyInsulin Deficiency
SU/GliniteSU/Glinite
• Beta cell PreservationBeta cell Preservation
TZDTZD

15. Correct Drugs
Insulin
Resistance
Postprandial Hyperglycemic Insulin Deficiency
• Glinides
• Acarbose
• Voglibos
• Solube Insulin
• Thiazolidine
diones
• Metformin
• Insulin Secretogogues
• Sulphonylurea Glinides

16. Correct CombinationCorrect Combination
• SU+MFMSU+MFM
• SU + AcarboseSU + Acarbose
• SU + ThiazolidinedionesSU + Thiazolidinediones
• MFM + ThiazolidinedionesMFM + Thiazolidinediones
• MFM + AcarboseMFM + Acarbose
• SU + MFM + AcarboseSU + MFM + Acarbose
• SUSU ++MFM + INSULATARDMFM + INSULATARD

19. 901301802007
Optimal Glycaemic Control
 Is important to prevent death ,disability &
complications of DM
 -FBS - 90-130mg%
 -2HPP - <180mg%
 -RBS - <200mg%
 -Bed time - 110-150mg%
 -HbA1c - <7%

20. How Can we get good control of DM?How Can we get good control of DM?
?

23. Diabetes food pyramidDiabetes food pyramid
Cereals, wholeCereals, whole
grains and starch:grains and starch:
6-11 servings6-11 servings
Fruits: 1-Fruits: 1-
2 servings2 servings
Vegetables:Vegetables:
3-4 servings3-4 servings
Low fat milk and milkLow fat milk and milk
products: 2-3 servingsproducts: 2-3 servings
Lean meat, fish,Lean meat, fish,
poultry, pulses:poultry, pulses:
1-2 servings1-2 servings
Fats, oils, sugars, refined foods,Fats, oils, sugars, refined foods,
fatty foods: eat sparinglyfatty foods: eat sparingly
Exercise for at least 30 minutes every dayExercise for at least 30 minutes every day
Therapeutic Lifestyle change
Fats, oils, sugars, refined foods,Fats, oils, sugars, refined foods,
fatty foods: eat sparinglyfatty foods: eat sparingly
Vegetables:Vegetables:
3-4 servings3-4 servings
Low fat milk and milkLow fat milk and milk
products: 2-3 servingsproducts: 2-3 servings
Fats, oils, sugars, refined foods,Fats, oils, sugars, refined foods,
fatty foods: eat sparinglyfatty foods: eat sparingly
Cereals, wholeCereals, whole
grains and starch:grains and starch:
6-11 servings6-11 servings
Vegetables:Vegetables:
3-4 servings3-4 servings
Low fat milk and milkLow fat milk and milk
products: 2-3 servingsproducts: 2-3 servings
Fats, oils, sugars, refined foods,Fats, oils, sugars, refined foods,
fatty foods: eat sparinglyfatty foods: eat sparingly

24. Plate modelPlate model
Vegetable
Milk/yoghurt
Fruit
Vegetable
Protein
Starch/cereal

25. Physical activityPhysical activity
RecommendationsRecommendations
• People with diabetes should be advised to performPeople with diabetes should be advised to perform atat
least 150 min/weekleast 150 min/week of moderate-intensity aerobicof moderate-intensity aerobic
physical activityphysical activity (50 – 70% of maximum heart rate).(50 – 70% of maximum heart rate). (A)(A)
• In the absence of contraindications, people with type 2In the absence of contraindications, people with type 2
diabetes should be encouraged to perform resistancediabetes should be encouraged to perform resistance
training three times per week. (A)training three times per week. (A)
Standard of Medical Care in Diabetes 2010

26. Diabetes And Glycemic Control: A Rational Approach
• As low as possible
• As early as possible
• For as long as possible
• As safely as possible
• And as rationally as possible
Lifestyle +
MET + TZD + SU
HbA1c < 6%

27. MedicationMedication RouteRoute YearYear
Efficacy as monotherapy: %Efficacy as monotherapy: % ↓↓ inin
HgbA1cHgbA1c
Insulin s.c. 1921 ≥2.5
Sulfonylureas Oral 1946 1.5 -2
Glinides Oral 1997 1.0-1.5
Metformin Oral 1995 1.5-2
α-glucosidase inhibitors OralOral 19951995 0.5-0.80.5-0.8
TZDs OralOral 19991999 0.8-1.00.8-1.0
GLP analogue s.c.s.c. 20052005 0.60.6
DPP-IV Inhibitors OralOral 20062006 0.5-0.80.5-0.8
Amylin analogue s.c.s.c. 20052005 0.60.6
Colesevelam OralOral 20082008 0.50.5
Bromocriptine mesylate OralOral 20092009 0.2-0.40.2-0.4
Type 2 Diabetes Medication ChoicesType 2 Diabetes Medication Choices
Experience and PotencyExperience and Potency

28. Mechanisms of Action of Pharmacologic AgentsMechanisms of Action of Pharmacologic Agents
for Diabetesfor Diabetes
Improving Outcomes in Patients With Type 2 Diabetes Mellitus: Practical Solutions for Clinical Challenges
James R. Gavin, III, MD, PhD; Mark W. Stolar, MD; Jeffrey S. Freeman, DO; Craig W. Spellman, DO, PhD
JAOA • Vol 110 • No 5suppl6 • May 2010 • 2-14

29. Basic Steps in the Management of Type 2 DiabetesBasic Steps in the Management of Type 2 Diabetes
+ +
diet &exercise
Oral
monotherapy
insulin
+
Oral
combination
Oral plus
Insulin

30. • Fast onset of action
• To stimulate insulin secretion (including first phase)
• Decrease fasting and post prandial blood glucose
• Preservation of the beta cells
• Decrease insulin resistance
• Prevent complications
• Long duration of action (once daily administration)
An Ideal OHA should have…

31. • Control FPG & PPG effectively
• Lowest risk of hypoglycemia
• Should not produce hyperinsulinemia & weight gain
• Less drug interactions
An Ideal OHA should have…

32. No Single Class of Oral Antihyperglycemic
Monotherapy Targets All Key Pathophysiologies
Alpha-Alpha-
GlucosidaseGlucosidase
InhibitorsInhibitors1,21,2
MeglitinideMeglitinide
ss33 SUsSUs4,54,5
TZDsTZDs6,76,7
MetformiMetformi
nn88
DPP-4DPP-4
InhibitorsInhibitors
Insulin
deficiency
Insulin
resistance
Excess
hepatic
glucose
output
MajorPathophysiologies
1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.
3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007.
5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.
7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.
8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.
  
 
  
Intestinal
glucose
absorption


33. Early combination approach

34. When you saw a patient with DM
• Glucose control?(glucose level)
• Monitoring?
• Compliance
• Comobidities
• Drugs
• Stress –infection?MI,Pregnancy
• Diet,exercise,body weight
• Renal ,cardiac,liver
• Economic status
• Set the Target ----HbA1C,FBS,PPG

35. Glycaemic Indices : Present andGlycaemic Indices : Present and
FutureFuture

37. HbA1C 7% in general
HbA1C Target
<7% General
8% elderly
HbA1C Target
<7% General
8% elderly

39. Effect SU and NSU Metformin TZA AGI
Mechanism Increase in
insulin secretion
Decrease in HGO
plus increases
muscle sensitivity
Decrease in HGO
plus increases
muscle sensitivity
Decrease in
glucose
absorption
Decrease in
FPG
60-70 mg% 60-70 mg% 35-40 mg% 20-30 mg%
Decrease in
HbA
1.5-2.0% 1.5-2.0% 1.0-1.2% 0.7-1.0%
TG level No effect Decrease Decrease No effect
HDL level No effect Slight increase Increase No effect
LDL level No effect Decrease Increase No effect
Body weight Increase Decrease Increase No effect
Insulin level Increase Decrease Decrease No effect
Adverse
effects
Hypoglycemia GI disturbances Anemia, hepatic GI disturbances

40. Initial Therapy with OHAs
Initial Add Add
Thin/normal Wt SU Metformin Insulin
Obese Metformin SU TZD/Insulin
Obese not tolerating MET TZD SU
MET contraindicated TZD SU
Severe IR Metformin TZD SU
Elderly SU Insulin
PPHG prominent MEG/AGI
PPHG prominent in Sec
Failure
AGI/Exenatid
e

41. Combination Therapy with OHAs
• Drug combinations should be based on
A. Therapeutic efficacy (“fire power”)
B. Complementary mechanisms of action
C. Ancillary benefits (CVD risk factors)
D. Safety and tolerability
E. ? Compliance with multiple dosing regimens

42. Estimated Improvements with Combination Rx
Combination AIC% reduction FPG reduction
SU + MET 1.7% 65 mg/dl
SU + ROS 1.4% 60 mg/dl
SU + PIO 1.2% 50 mg/dl
SU + ACAR 1.3% 40 mg/dl
REP + MET 1.4% 40 mg/dl
MET + ROS/PIO 0.7-0.8% 40 mg/dl
INS + OHA Open to targets Open to targets
De Fronzo, NEJM 1995
Horton, Diabetes Care 1998
Coniff, Diabetes Care 1995
Moses, Diabetes Care 1999
Schneider, Diabetes 1999
Egan, Diabetes 1999
Fonseca, Diabetes 1999

43. Strategies for Antidiabetic Treatment
Oral Triple Combination
Therapy plus Basal Insulin or
plus
Oral Monotherapy
Oral Dual Combination
Therapy
Oral Triple Combination
Therapy
NPG, Glargine, Levemir
Metformin + Sulfonylureas + TZDs
Metformin + Sulfonylureas+DPP-4-
Inhib.
Metformin
DPP-4 Inhibitors
Glinides
TZDs
Sulfonylureas
α-Glucosidase-Inhibitors
Metformin + DPP-4-Inhibitors
Sulfonylureas + DPP-4-Inhibitors
Metformin + Sulfonylureas
Sulfonylureas + TZDs
Metformin + TZDs
Exenatide, Liraglutide

44. Master Decision PathMaster Decision Path
Type 2 Diabetes Glycemic ControlType 2 Diabetes Glycemic Control
Medical Nutrition TherapyMedical Nutrition Therapy
&& Activity PlanActivity Plan
start monotherapystart monotherapy
Medical Nutrition TherapyMedical Nutrition Therapy
&& Activity PlanActivity Plan
start monotherapystart monotherapy
Oral combination treatment 2 drugsOral combination treatment 2 drugs
If target not reached after maximumIf target not reached after maximum
dose for 4 - 8 weeks - - start oral agentdose for 4 - 8 weeks - - start oral agent
Oral combination treatment 2 drugsOral combination treatment 2 drugs
If target not reached after maximumIf target not reached after maximum
dose for 4 - 8 weeks - - start oral agentdose for 4 - 8 weeks - - start oral agent
Insulin TherapyInsulin TherapyInsulin TherapyInsulin Therapy Oral Agent(s) + InsulinOral Agent(s) + InsulinOral Agent(s) + InsulinOral Agent(s) + Insulin
Oral Combination Rx 3 drugsOral Combination Rx 3 drugs
If target not reached after maximumIf target not reached after maximum
doses for 4 - 8 weeks -- start insulindoses for 4 - 8 weeks -- start insulin
Oral Combination Rx 3 drugsOral Combination Rx 3 drugs
If target not reached after maximumIf target not reached after maximum
doses for 4 - 8 weeks -- start insulindoses for 4 - 8 weeks -- start insulin
FPG < 200FPG < 200
Casual < 250Casual < 250
FPG < 200FPG < 200
Casual < 250Casual < 250
FPG 200-300FPG 200-300
Casual 250-350Casual 250-350
FPG 200-300FPG 200-300
Casual 250-350Casual 250-350
FPG > 350FPG > 350
Casual > 400Casual > 400
FPG > 350FPG > 350
Casual > 400Casual > 400
At Diagnosis
(mg/dl)
Targets forTargets for
Glycemic ControGlycemic Contro
HbA1c <7%HbA1c <7%
Targets forTargets for
Glycemic ControGlycemic Contro
HbA1c <7%HbA1c <7%
FPG > 300-350FPG > 300-350
Casual > 350-400Casual > 350-400
with severe symptomwith severe symptom
FPG > 300-350FPG > 300-350
Casual > 350-400Casual > 350-400
with severe symptomwith severe symptom
KK/ESSENTIAL
DRUG/3.4.11/tAUNGGHU

45. Practice GuidelinesPractice Guidelines

46. A1C 6.5 – 7.5%**
Monotherapy
MET +
GLP-1 or DPP4
1
TZD 2
Glinide or SU 5
TZD + GLP-1 or DPP4 1
MET +
Colesevelam
AGI
3
2 - 3 Mos.***
2 - 3 Mos.***
2 - 3 Mos.***
Dual Therapy
MET +
GLP-1 or
DPP4 1
+
TZD 2
Glinide or SU 4,7
A1C > 9.0%
No Symptoms
Drug Naive Under Treatment
INSULIN
± Other
Agent(s) 6
Symptoms
INSULIN
± Other
Agent(s) 6
INSULIN
± Other
Agent(s) 6
Triple Therapy
AACE/ACE Algorithm for Glycemic
Control Committee
Cochairpersons:
Helena W. Rodbard, MD, FACP, MACE
Paul S. Jellinger, MD, MACE
Zachary T. Bloomgarden, MD, FACE
Jaime A. Davidson, MD, FACP, MACE
Daniel Einhorn, MD, FACP, FACE
Alan J. Garber, MD, PhD, FACE
James R. Gavin III, MD, PhD
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Edward S. Horton, MD, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, MACE
Etie S. Moghissi, MD, FACP, FACE
Stanley S. Schwartz, MD, FACE
* May not be appropriate for all patients
** For patients with diabetes and A1C < 6.5%,
pharmacologic Rx may be considered
*** If A1C goal not achieved safely
† Preferred initial agent
1 DPP4 if ↑ PPG and ↑ FPG or GLP-1 if ↑↑ PPG
2 TZD if metabolic syndrome and/or
nonalcoholic fatty liver disease (NAFLD)
3 AGI if ↑ PPG
4 Glinide if ↑ PPG or SU if ↑ FPG
5 Low-dose secretagogue recommended
6 a) Discontinue insulin secretagogue
with multidose insulin
b) Can use pramlintide with prandial insulin
7 Decrease secretagogue by 50% when added
to GLP-1 or DPP-4
8 If A1C < 8.5%, combination Rx with agents
that cause hypoglycemia should be used with
caution
9 If A1C > 8.5%, in patients on Dual Therapy,
insulin should be considered
MET +
GLP-1
or DPP4 1
± SU 7
TZD 2
GLP-1
or DPP4 1 ± TZD 2
A1C 7.6 – 9.0%
Dual Therapy 8
2 - 3 Mos.***
2 - 3 Mos.***
Triple Therapy 9
INSULIN
± Other
Agent(s) 6
MET +
GLP-1 or DPP4
1
or TZD 2
SU or Glinide 4,5
MET +
GLP-1
or DPP4 1 + TZD 2
GLP-1
or DPP4 1
+ SU 7
TZD 2
MET †
DPP4 1 GLP-1 TZD 2
AGI 3
Available at www.aace.com/pub
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

47. Mean Plasma Glucose (mg/dl)Mean Plasma Glucose (mg/dl) A1C %A1C %
135135 66
170170 77
205205 88
240240 99
275275 1010
310310 1111
345345 1212
Correlation between A1c level & mean plasmaCorrelation between A1c level & mean plasma
glucose level on multiple testing over 2-3glucose level on multiple testing over 2-3
months (Based on DCCT)months (Based on DCCT)
ADA 2010 Guidelines on Diagnosing diabetesADA 2010 Guidelines on Diagnosing diabetes

48. 2. Juliana C. n. Chan; Vasanti Malik: Weiping Jia; et al. JAMA. 2009; 301 (20);2129-2140 (doi:10.1001/jama.2009.726)
SU – Sulphonylurea,SU – Sulphonylurea,
MET – Metformin,MET – Metformin,
TZD - ThiazolidinedioneTZD - Thiazolidinedione
HbA1c ≥6.5% after lifestyle interventionHbA1c ≥6.5% after lifestyle intervention
MET+ SUMET+ SU
HbA1c ≥7.5%HbA1c ≥7.5%
MetforminMetformin
HbA1c ≥6.5%HbA1c ≥6.5%
Insulin + MET + SUInsulin + MET + SU
HbA1c ≥7.5%HbA1c ≥7.5%
Increase InsulinIncrease Insulin
DoseDose
(or)(or)
Insulin + PioglitazoneInsulin + Pioglitazone
SU (DIAMICRON MR)SU (DIAMICRON MR)
- Not overweightNot overweight
- MET not tolerated orMET not tolerated or
is contraindicatedis contraindicated
- Rapid therapeutic response- Rapid therapeutic response
HbA1c ≥6.5%HbA1c ≥6.5%
If MET is contraindicated or notIf MET is contraindicated or not
toleratedtolerated
SU + DPP4 inhibitor or TZDSU + DPP4 inhibitor or TZD
If SU contraindicated orIf SU contraindicated or
not toleratednot tolerated
MET + DPP4 inhibitorMET + DPP4 inhibitor
or TZDor TZD
HbA1c ≥7.5%HbA1c ≥7.5%
Start InsulinStart Insulin
HbA1c ≥7.5%HbA1c ≥7.5%
If insulin is unacceptableIf insulin is unacceptable
MET + SU + SitagliptinMET + SU + Sitagliptin
(or)(or)
MET + SU + TZDMET + SU + TZD
(or)(or)
MET + SU + ExenatideMET + SU + Exenatide
HbA1c ≥7.5%HbA1c ≥7.5%
NICE guideline forNICE guideline for
Type 2 Diabetic Management,Type 2 Diabetic Management,
May 09May 09

49. 1st
line option in addition to lifestyle measures; start ONE OF
METMET SUSU (if intolerate of metformin or
if weight loss/ osmotic symptoms)
1st
line option in addition to lifestyle measures; start ONE OF
METMET SUSU (if intolerate of metformin or
if weight loss/ osmotic symptoms)
2nd
line options
SUSU
(Usual approach)
SUSU
(Usual approach)
AlternativeAlternative
TZD or DPP-4 InhibitorTZD or DPP-4 Inhibitor
AlternativeAlternative
TZD or DPP-4 InhibitorTZD or DPP-4 Inhibitor
OralOral
MET/ SU + TZD (if no HF)MET/ SU + TZD (if no HF)
OralOral
MET/ SU + TZD (if no HF)MET/ SU + TZD (if no HF)
InjectableInjectable
MET/ SU + Insulin (before bed)MET/ SU + Insulin (before bed)
(or)(or)
MET/ SU + GLP -1 agonistsMET/ SU + GLP -1 agonists
InjectableInjectable
MET/ SU + Insulin (before bed)MET/ SU + Insulin (before bed)
(or)(or)
MET/ SU + GLP -1 agonistsMET/ SU + GLP -1 agonists
Review & if not reaching target move to 2nd
line
Review & if not reaching target move to 3rd
line
3rd
line options

50. ADA/EASD Consensus Algorithm for the Initiation and Adjustment of
Therapy Diabetes Care 2009; 32:193–203

52. 1. Patient-Centered Approach
“...providing care that is respectful of and
responsive to individual patient preferences,
needs, and values ensuring that patient values
guide all clinical decisions.”
• Gauge patient’s preferred level of involvement.
• Explore, where possible, therapeutic choices.
• Utilize decision aids.
•Shared decision making – final decisions re:
lifestyle choices ultimately lies with the patient.
Diabetes Care,Diabetes Care, Diabetologia.Diabetologia. 1919 April 2012 [Epub ahead ofApril 2012 [Epub ahead of
ADA-EASD Position Statement:
Management of Hyperglycemia in T2DM: A Patient-Centered
Approach

53. T2DM Anti-hyperglycemic Therapy: General Recommendations
Diabetes Care, Diabetologia. 19 April 2012
[Epub ahead of print]

54. Adapted Recommendations: When Goal is to Avoid Hypoglycemia
Diabetes Care, Diabetologia. 19 April 201
[Epub ahead of print]

55. Adapted Recommendations: When Goal is to Minimize Costs
Diabetes Care, Diabetologia. 19 April 201
[Epub ahead of print]

56. Patient Preference: EfficacyPatient Preference: Efficacy
metformin
sulfonylurea
TZD
glinide
DPP4
inhibitor
α
-glucosidase
inhibitors

57. Patient Preference: CostPatient Preference: Cost
metformin sulfonylurea
α-
glucosidase
inhibitor
TZD
DPP4
inhibitor

58. Patient Preference: WeightPatient Preference: Weight
metformin
DPP4
inhibitor
α
-glucosidase
inhibitor
TZD
sulfonylurea

59. Patient Preference:Patient Preference:
Hypoglycemia AvoidanceHypoglycemia Avoidance
metformin
DPP4
inhibitor
TZD
α
-glucosidase
inhibitor
sulfonylurea
glinide

61. CASE 1
• 56 year male ,newly diagnosed DM,
• BMI 35
• RBS 350mg%
• BP 150/90
• Creatinine 100 mg%
• Total Cholesterol-250mg%
• ECG
Treatment
?

62. Proplems
• DM,obese,hyperglycemia,IHD,increased cholesterol and
TG,H/T
• Treatment
• Metformin 500mg BD
• Gliclazide MR 60 mg 1 od
• Aspirin 1 od
• Atovastatin 10 mg
• Metoprolol 25 mg BD
• Ramipril 5 mg od
• Orlistat 120 mg 3 times
• Diet and exercise

63. Why I choose
Metformin?

64. Metformin
• Obese
• Cardiac safe
• Reduced mortality
• First line drug in every guidelines
• Widely available
• Cheap-cost effective
• Powerful glucose lowering efffect
• 80% of Type 2 DM is due to Insulin Resistance
• Cannot use in advanced liver, renal and cardiac failure
because of lactic acidosis

65. Metformin: Crucial Part ofMetformin: Crucial Part of
TherapyTherapy Metformin Effects on Risk
Factors
Hundal RS, Inzucchi SE. Metformin New Understandings, New Uses.
Drugs 2003; 63(18): 1879-1894
Dose – 500 to 3000 mg
CI - serum creatinine >1.5 mg%, Advanced Heart Failure
SE - Reduce appetite, nausea, vomiting, diarrhoea

66. 12 studies; ≥ 52 weeks; at least 1 CVD event
CVD outcomes:
- fatal / non-fatal MI or stroke
- PVD
- other CVD death

67. Effect of Metformin on CVD Events

68. Why I choose
Gliclazide (Diamicron MR 60 ) ?

69. Rationale of Use of SU in T2DM
“Sulfonylureas are a rational choice to
begin pharmacological intervention
because almost all patients with NIDDM
[type 2 diabetes] are relatively insulin
deficient.”
ADA Consensus Statement 1996-1997

70. SulfonylureasSulfonylureas
• Which ?
• When?
• Why?
1st
line in underwt/normal wt type 2 patients
Along with insulin sensitizers: metformin or
glitazones
Along with insulin to facilitate
reduction/frequency of insulin dosing
1st
line in underwt/normal wt type 2 patients
Along with insulin sensitizers: metformin or
glitazones
Along with insulin to facilitate
reduction/frequency of insulin dosing
All have same MOA
Require some viable β cell mass to work
Do not work in type 1 and after sec failure sets in type 2
Differential effects amongs SUs
All have same MOA
Require some viable β cell mass to work
Do not work in type 1 and after sec failure sets in type 2
Differential effects amongs SUs
• Can use in heart failure, renal failure
• SE - Weight gain, hypoglycemia
• Choice of SU – Newer SU to prevent cardiac side effect, prolong
hypoglycemia

71. Sulfonylureas: How to Choose?
• Cardiac patients: Glimepiride/GLICLAZIDE
• Elderly patients: Glimepiride/GLICLAZIDE
• Economy: Glibenclamide
• Mild renal insufficiency: Glimepiride
• Severe Renal : Gliclazide and glipizide
• Require high potency: Glibenclamide
• Relatively younger patients: Glibenclamide

72. Glucose control therapy- Rationale

73. Mean
HbA1c at
final visit
Standard:
7.3%
Intensive:
6.5%
The ADVANCE Study
ADVANCE Collaborative Group. NEJM 2008

74. Combined primary outcomes
Major macro or microvascular event
Follow-up (months)
Cumulativeincidence(%)
25
20
15
10
5
0
0 6 12 18 24 30 36 42 48 54 60 66
Standard
Intensive
Relative risk reduction
10%: 95% CI: 2 to 18%
p=0.013
ADVANCE Collaborative Group. NEJM 2008

75. Any prevention of β cell dysfunction
and failure (i.e. loss of β cell mass)
 Initially correct glucotoxicity, lipotoxicity
some SU claims for reduction of ROS
 Some literature said :
SU can even increase ROS  ↑ apoptosis
 Esp in Glipizide,glimepride,glibenclamide
 ↓ROS  *Gliclazide

76. Beta-cell apoptosis in islets:
gliclazide vs glibenclamide
Islets pre-exposed for 5 days to
- NG (5.5 mmol/L)
- HG (alternating 5.5 & 16.7 mmol/L)
Groups differed significantly (p<0.01) by ANOVA: *p<0.05 vs NG;
**p<0.005 vs HG and HG + glib after Bonferroni correction
S Del Guerra et al. Diabet Metab Res Rev 2007;23:234-8
HG +
gliclazide
HG +
glib
NG
HG

77. Effect of SU on MI
Patients
Glipizide ,gliclazide and glimepiride
are safer than glibenclamide b/c of
more selective effect on pancreatic
SU receptor

80. Relative risk of 1st
-time MI according to OHA
0
0.5
1
1.5
2
2.5
C Glib Tolb Glicl Glimp
C
Glib
Tolb
Glicl
Glimp
(Johnsen SP, et al. Am J Ther. 2006;13:134-140
OR 2.08
[1.77-2.45]
OR 2.32
[1.48-2.64]
OR 1.37
[0.84-2.22]
OR 1.36
[0.93-1.99]

81. 30-day post MI mortality according to OHA30-day post MI mortality according to OHA
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Controls Glib/Tolb Glic/Glim
Controls
Glib/Tolb
Glic/Glim
(Johnsen SP, et al. Am J Ther. 2006;13:134-140
OR 1.29
[1.00-1.67]
OR 1.0
[0.53-1.90]

82. Use of Sulfonylureas and mortalityUse of Sulfonylureas and mortality
after MI in diabetic patients:after MI in diabetic patients:
Danish nationwide population-based studyDanish nationwide population-based study
Thisted H,Thisted H, et alet al. EASD 2006. EASD 2006
old SHN
new SHN
1.08
0.81
0
0.4
0.8
1.2
old Sus new Sus
-25%

84. • Total mortality – Gliclazide - 67% (p<0.01),Total mortality – Gliclazide - 67% (p<0.01),
Glimepiride - 40% (p<0.01)Glimepiride - 40% (p<0.01)
• CVD mortality – Gliclazide -71% (p<0.001)CVD mortality – Gliclazide -71% (p<0.001)

85. Cardiovascular death 253 289 12% (-4 to 26)
All deaths 498 533 7% (-6 to 17)
Non-cardiovascular death 245 244 0% (-20 to 16)
Number of patients with event
Intensive Standard
(n=5,571) (n=5,569)
Relative risk
reduction (95%CI)
Favours
Intensive
Favours
Standard
Hazard ratio
0.5 1.0 2.0
ADVANCE study - trend to reduction in CV death with
gliclazide MR based intensive control regimen
ADVANCE Collaborative Group. NEJM 2008

86.  ADVANCE is the only study to show a trend in favor of a reduction in
cardiovascular death.
Control Group; Turnbull FM, Abraira C, Anderson RJ, et al. Diabetologia. 2009;52(11):2288-2298.

87. 0.5 1.0 2.0
End stage kidney disease
Percent of patients with event
Intensive Standard
(n=5,571) (n=5,569)
Relative risk
reduction (95% CI)
Favours
Intensive
Favours
Standard
New microalbuminuria 23.7% 25.7%
Total renal events 26.9% 30.0%
9% (2 to 15)‡
11% (5 to 17)†
New macroalbuminuria 2.9% 4.1% 30% (15 to 43)†
New / worsening nephropathy 4.1% 5.2% 21% (7 to 34)***
Hazard ratio
† P=<0.001
‡ P=0.02
*** P=0.006
*P=0.09
36% (-8 to 62)*0.4% 0.6%
ADVANCE Collaborative Group. NEJM 2008
ADVANCE: Reduction of Renal events
Less risk of dialysis, kidney transplantation
and most of all death

88. Renal outcomes of the main morbidity-mortality trials in diabetesRenal outcomes of the main morbidity-mortality trials in diabetes
1. UKPDS Group (33). Lancet. 1998;352(9131):837-853. 2. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. N Engl J Med.
2009;360(2):129-139. 3. Ismail-Beigi F, Craven T, Banerji MA, et al; ACCORD trial group. Lancet. 2010;376(9739):419-430. 4. Zoungas S, Lambers
Heerspink HJ, Chalmers J, et al. Diabetologia. 2011;54(suppl 1):S23. 5. The ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et
al. N Engl J Med. 2008;358(24):2560-2572. * new or worsening nephropathy
*

89. ADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication
20 mg/l200 mg/l
albuminuria
Macroalbuminuria
Normal range of
albuminuria
Majority of
these patients
*versus standard treatment group
Microalbuminuria
20% more patients regressed to
normal range vs standard treatment
(P=0.0002)
ADVANCE: New renal results EASD 2010

90.  ADVANCE is currently the only trial demonstrating protection of type 2
diabetic patients from end-stage kidney disease
Coca SG, Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Arch Intern Med. 2012;172(10):761-769.

91. ACCORD2
ADVANCE3
Intensive Control
Standard Control
Patientsexperiencingatleastone
severehypoglycemicevent(%)
0
5
10
15
20
25
VADT1
2.7% 1.5%
16.2%
5.1%
21.2%
9.9%
P<0.001 P<0.001 HR=1.86
(95% CI 1.40-2.40)
% HbA1c at study end 7.36.46.9
% change from baseline -0.2-1.7-2.5
8.4
-1.0
7.5
-0.6
6.5
-1.0
Comparison of severe hypoglycemia in
morbimortality trials in diabetes
1. VADT Investigators. N Engl J Med. 2009;360:129-139. 2. Bonds DE, et al, BMJ. 2010;340:b4909.
3. ADVANCE Study Group. N Engl J Med. 2008;358(24):2560-2572.

92. • 1066 fasting patients
• Comparing incidence of hypos
between SUs vs Sitagliptin
• Sponsored by MSD
Hypoglycemia in Ramadan: Sitagliptin vs SU
S. Al Sifri et al. Int J Clin Prac, Nov 2011;65,11: 1132–40

93. Hypoglycemia in Ramadan: Sitagliptin vs SU
S. Al Sifri et al. Int J Clin Prac, Nov 2011;65,11: 1132–40

94. 0%
2%
4%
6%
8%
10%
Glimepiride Glibenclamide Gliclazide MR
(%)ofpatientswith>onesymptomatichypoglycemia
Patient fasting Ramadan
2012
comparison
Patients’ Safety
9.1%
5.2%
1.8%

95. Hypoglycaemia with different
Sulfonylureas
*<50 mg/dL.
Tayek J. Diabetes Obes Metab. 2008; 10:
0
5
10
15
20
25
30
Gliclazide
0.85
Glipizide
8.70
Glimepiride
0.86
Tolbutamide
3.50
Chlorpropamide
16.00
Glyburide
16.00
Severe hypoglycemia*
n/1000 person years
RelativeRisk(%)
SAFETY

96. Hypoglycemia in SU
OHA
Risk of
hypoglycemia
Glinide +
Gliclazide ++
Gliclazide MR +
Glimepride ++
Glibenclamide +++
All SU can give rise to hypoglycemia

97. HYPOGLYCEMIAHYPOGLYCEMIA
Gliclazide MR vs Glimepiride

98. Gliclazide
M
R
n=157
Gliclazide
M
R
n=226
Hypoglycaemia (blood glucose < 3.0 mmol/L)
according to Creatinine Clearance (CCl)
Glim
epiride
n=25
Gliclazide
M
R
n=17
0
6
12
18
24
50-80 ml/min
0
6
12
18
24
0
6
12
18
24
Numberofpatients
Glim
epiride
n=182
Glim
epiride
n=232
CCl > 80ml/minCCl < 50 ml/min
0% 12% 3.2% 12.6 % 4.4% 5.6%
(GUIDE-Study: Schernthaner G et al. Eur.J.Clin.Invest. 2004; 34:535-542)

99. 50 year Male DM 12 years
on Metformin 500mg 2 TDS
gliclazide MR 60 2 od
Pioglitazone 45 mg od
HbA1C 8%,FBG-200,2hpp 350mg%
Next Treatment?
CASE 2

100. Uncontrolled DM
 Check Diet
 Check Steroid
 Check Compliance
 Check Infection and Stress
3 drugs ,maximum dose for 3 months
Drug Failure,Beta cell failure
Need INSULIN
3 drugs ,maximum dose for 3 months
Drug Failure,Beta cell failure
Need INSULIN

101. Insulin Regimen for Type 2 Diabetes
Mellitus
Guidelines for initiating insulin
0.15 units /kg /body wt /day
C h a r t G u i d e l i n e s f o r S t a r t i n g I n s u l i n T h e r a p y
( A s ia P a c if ic T y p e 2 D ia b e t e s P o lic y g r o u p )
M o r n i n g 2 / 3
P r e - M i x - 3 0 / 7 0
E v e n i n g 1 / 3
P r e - M i x - 3 0 / 7 0
P r e - m i x e d i n s u l i n 3 0 / 7 0
> 3 0 - 4 0 i u - - s t o p p i n g O A D
T e s t F P G / A d j u s t 3 - 4 d a y s
O A D + 1 0 i u N P H i n s u l i n ( B e d t i m e )

102. TWO basic INSULINTWO basic INSULIN
REGIMENSREGIMENS
SupplementarySupplementarySupplementarySupplementary SubstitutionSubstitutionSubstitutionSubstitution
(OHD +Bed time insulin) ( No OHD +Only insulin)
Premixed/split mixedPremixed/split mixedPremixed/split mixedPremixed/split mixed Basal bolus insulinBasal bolus insulinBasal bolus insulinBasal bolus insulin

103. Insulin Regimen for Type 2 Diabetes
Mellitus
Guidelines for Starting insulin therapy
(Asia Pacific Type 2 Diabetes Policy group)
In normal person = 0.5 units /kg /BW /Day
Pre-mixed insulin 30/70Pre-mixed insulin 30/70
Morning 2/3
Pre-Mix 30/70
Morning 2/3
Pre-Mix 30/70
SubstitutionSubstitution
Evening 1/3
Pre-Mix 30/70
Evening 1/3
Pre-Mix 30/70

104. 60
0
20
40
Insulin
PREMIX 30/70 PREMIX 30/70
6 AM 6 PM12 AM 12 PM
Insulin Regimen for Type 2 Diabetes
Mellitus
PREMIXPREMIX

105. Basal Bolus Regimen (Substitution)Basal Bolus Regimen (Substitution)
106
• Mimics physiological insulin profile: starting dose
- 40% daily dose as basal insulin
(Intermediate-acting insulin- Insulatard or Humulin N)
- 60% as short acting insulin (Actrapid or Humulin R)
divided into
20% at breakfast
20% at lunch
20% at dinner
• Insulin dose adjusted if needed
• Requires highly motivated patients with constant monitoring

106. •
Cardiac
•Lipid Management
•Smoking cessation
•Vaccines
•Transfer and
discharge
Blood sugar control
•Patient education
•Nutrition counseling
•Medication
•Physical activity
•Foot care
•Retinopathy

108. Take Home Messages:Take Home Messages:
Place of Sulfonylureas in T2DMPlace of Sulfonylureas in T2DM
• Are effective
• Proven in OUTCOME trials → ↓ Complications
• ADVANCE (Gliclazide MR)
– weight gain NOT a given
– hypoglycaemia can be minimised
– effective irrespective of age, BMI or
duration of DM
– ↓ renal failure / worsening of nephropathy
• Not ALL Sulfonylureas are the same

109. CASE B
• 65 male with DM 10 years,IHD,Hypertension
,,Stroke
• HbAIC Target?
• A. 7%
• B.8%
• C.6.5%

110. CASE c
• 45 female DM 3 year Thin ,RBS 230 ,creatinine
140,pedal oedema +
• Start with
• A.Metformin
• B.Metformin with Gliclazide MR
• C.Gliclazide MR
• D.Pioglitazone

111. CASE c
• 48 female DM 6 year ,RBS 350 ,
• Start with
• A.Metformin
• B.Gliclazide MR
• C.Metformin +Gliclazide MR

112. f RBS is >500mg%
Poorly controlled DM
DKA
HHS(HONK)
Admisssion is needed in patient with stressful conditions such as
Infection
Stroke
Myocardial infact.
If there is no stressful condition
Can be managed as OPD patient

113. Don't let theDon't let the
situationsituation
confuseconfuse
you...you...

114. Thank you 