2. better control, better life dr. ko ko

Better control,Better LifeKo Ko Taunggyi MMA 15.2.13

UM 2

What new in 2013

BP 140/80 rather than 130/80Patient centre apporoach

Conclusions from recent trialsTight 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

Do we need better control?YES

Are we achieving good control?Are we achieving good control?Are we achieving good control?Are we achieving good control?

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

Treatment Strategies for Diabetes:Treatment Strategies for Diabetes:Are Patients Achieving Good Control?Are Patients Achieving Good Control?

Controlled

Uncontrolled

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%

Need SMBG 3 times per day in Type 1Type 2—depend on c ontrol,3,5,7 days/week

SMBG is associated with a better glycemic control in type 2 diabetes

- 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

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

Measures to improve drug-Measures to improve drug-compliancecompliance

• 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.metformin long acting drugs eg.metformin XR,Gliclazide MR)XR,Gliclazide MR)

• Encouraging family involvement in patient’s careEncouraging family involvement in patient’s care

DRUGSDRUGS

• Correct DrugsCorrect Drugs

• Correct DosesCorrect Doses

• Correct TimingCorrect Timing

• Correct CombinationCorrect Combination

• ComplianceCompliance

• ?steroid?steroid

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

Correct Drugs

Insulin Resistance

Postprandial Hyperglycemic Insulin Deficiency

• Glinides

• Acarbose

• Voglibos

• Solube Insulin

• Thiazolidine diones

• Metformin

• Insulin Secretogogues

• Sulphonylurea Glinides

Correct CombinationCorrect Combination

• SU+MFMSU+MFM

• SU + AcarboseSU + Acarbose

• SU + ThiazolidinedionesSU + Thiazolidinediones

• MFM + ThiazolidinedionesMFM + Thiazolidinediones

• MFM + AcarboseMFM + Acarbose

• SU + MFM + AcarboseSU + MFM + Acarbose

• SU SU ++MFM + INSULATARDMFM + INSULATARD

• Clinical Inertia

901301802007Optimal Glycaemic Control

Is important to prevent death ,disability & complications of DM

-FBS -90-130mg% -2HPP -<180mg% -RBS -<200mg% -Bed time -110-150mg% -HbA1c -<7%

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

?

Diabetes food pyramidDiabetes food pyramid

Cereals, whole Cereals, whole grains and starch: grains and starch:

6-11 servings6-11 servings

Fruits: 1- 2 Fruits: 1- 2 servingsservings

Vegetables:Vegetables:3-4 servings3-4 servings

Low fat milk and milkLow fat milk and milkproducts: 2-3 servingsproducts: 2-3 servings

Lean meat, fish, Lean meat, fish, poultry, pulses: poultry, pulses:


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





Cereals, whole Cereals, whole grains and starch: grains and starch:





Plate modelPlate model

Vegetable

Milk/yoghurt

Fruit

Vegetable

Protein

Starch/cereal

Physical activityPhysical activity

RecommendationsRecommendations

• People with diabetes should be advised to perform People with diabetes should be advised to perform at at

least 150 min/weekleast 150 min/week of moderate-intensity aerobic of moderate-intensity aerobic

physical activity physical activity (50 – 70% of maximum heart rate).(50 – 70% of maximum heart rate). (A) (A)

• In the absence of contraindications, people with type 2 In the absence of contraindications, people with type 2

diabetes should be encouraged to perform resistance diabetes should be encouraged to perform resistance

training three times per week. (A)training three times per week. (A)

Standard of Medical Care in Diabetes 2010Standard of Medical Care in Diabetes 2010

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%

MedicationMedication RouteRoute YearYear Efficacy as monotherapy: % Efficacy as monotherapy: % in in 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

-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 ChoicesExperience and PotencyExperience and Potency

Mechanisms of Action of Pharmacologic Mechanisms of Action of Pharmacologic Agents for Diabetes Agents for Diabetes

Improving Outcomes in Patients With Type 2 Diabetes Mellitus: Practical Solutions for Clinical ChallengesJames R. Gavin, III, MD, PhD; Mark W. Stolar, MD; Jeffrey S. Freeman, DO; Craig W. Spellman, DO, PhDJAOA • Vol 110 • No 5suppl6 • May 2010 • 2-14

Basic Steps in the Management of Type 2 DiabetesBasic Steps in the Management of Type 2 Diabetes

+ +

diet &exercise

Oral monotherapy

insulin

+

Oralcombination

Oral plusInsulin

• 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…

• Control FPG & PPG effectively

• Lowest risk of hypoglycemia

• Should not produce hyperinsulinemia & weight gain

• Less drug interactions

An Ideal OHA should have…

No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies

Alpha-Alpha-Glucosidase Glucosidase InhibitorsInhibitors1,21,2

MeglitinideMeglitinidess33 SUsSUs4,54,5 TZDsTZDs6,76,7

MetformiMetforminn88

DPP-4 DPP-4 InhibitorsInhibitors

Insulin deficiency Insulin resistance Excess hepatic glucose outputM

ajor

Pat

hoph

ysio

logi

es

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

Early combination approach

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

Glycaemic Indices : Present and Glycaemic Indices : Present and FutureFuture

HbA1C 7% in general HbA1C 7% in general

HbA1C Target <7% General

8% elderly6.5 to 7% in Young DM

HbA1C Target <7% General

8% elderly6.5 to 7% in Young DM

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

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/Exenatide

Combination Therapy with OHAs

• Drug combinations should be based on A. Therapeutic efficacy (“fire power”)B. Complementary mechanisms of actionC. Ancillary benefits (CVD risk factors)D. Safety and tolerabilityE. ? Compliance with multiple dosing regimens

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 1995Horton, Diabetes Care 1998Coniff, Diabetes Care 1995Moses, Diabetes Care 1999Schneider, Diabetes 1999Egan, Diabetes 1999Fonseca, Diabetes 1999

Strategies for Antidiabetic Treatment

Oral Triple Combination Therapy plus Basal Insulin or plus GLP-1-Mimeticum

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

-Glucosidase-Inhibitors

Metformin + DPP-4-InhibitorsSulfonylureas + DPP-4-Inhibitors

Metformin + Sulfonylureas

Sulfonylureas + TZDsMetformin + TZDs

Exenatide, Liraglutide

Master Decision Path Master Decision Path Type 2 Diabetes Glycemic ControlType 2 Diabetes Glycemic Control

Medical Nutrition TherapyMedical Nutrition Therapy&& Activity Plan Activity Plan start monotherapystart monotherapy

Medical Nutrition TherapyMedical Nutrition Therapy&& Activity Plan Activity Plan start monotherapystart monotherapy

Oral combination treatment 2 drugsOral combination treatment 2 drugsIf 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 drugsIf 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 drugsIf target not reached after maximum If 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 drugsIf target not reached after maximum If target not reached after maximum doses for 4 - 8 weeks -- start insulindoses for 4 - 8 weeks -- start insulin

FPG < 200FPG < 200Casual < 250Casual < 250

FPG < 200FPG < 200Casual < 250Casual < 250

FPG 200-300FPG 200-300Casual 250-350Casual 250-350

FPG 200-300FPG 200-300Casual 250-350Casual 250-350

FPG > 350FPG > 350Casual > 400Casual > 400

FPG > 350FPG > 350Casual > 400Casual > 400

At Diagnosis(mg/dl)

Targets for Targets for Glycemic ControlGlycemic Control

HbA1c <7%HbA1c <7%

Targets for Targets for Glycemic ControlGlycemic Control

HbA1c <7%HbA1c <7%

FPG > 300-350FPG > 300-350Casual > 350-400Casual > 350-400

with severe symptomwith severe symptom

FPG > 300-350FPG > 300-350Casual > 350-400Casual > 350-400

with severe symptomwith severe symptom

KK/ESSENTIAL DRUG/3.4.11/tAUNGGHU

Practice GuidelinesPractice Guidelines

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, MACEPaul S. Jellinger, MD, MACE

Zachary T. Bloomgarden, MD, FACEJaime A. Davidson, MD, FACP, MACEDaniel Einhorn, MD, FACP, FACEAlan J. Garber, MD, PhD, FACEJames R. Gavin III, MD, PhDGeorge Grunberger, MD, FACP, FACEYehuda Handelsman, MD, FACP, FACEEdward S. Horton, MD, FACEHarold Lebovitz, MD, FACEPhilip Levy, MD, MACEEtie S. Moghissi, MD, FACP, FACEStanley 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 secretagoguewith 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

Mean Plasma Glucose Mean Plasma Glucose (mg/dl)(mg/dl)

A1C %A1C %

135135 66

170170 77

205205 88

240240 99

275275 1010

310310 1111

345345 1212

Correlation between A1c level & mean Correlation between A1c level & mean plasma glucose level on multiple testing plasma glucose level on multiple testing

over 2-3 months (Based on DCCT)over 2-3 months (Based on DCCT)

ADA 2010 Guidelines on Diagnosing diabetesADA 2010 Guidelines on Diagnosing diabetes

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 InsulinDoseDose(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 If MET is contraindicated or not toleratednot toleratedSU + DPP4 inhibitor or TZDSU + DPP4 inhibitor or TZD

If SU contraindicated If SU contraindicated or not toleratedor not toleratedMET + DPP4 inhibitorMET + DPP4 inhibitoror TZDor TZD

HbA1c ≥7.5%HbA1c ≥7.5%

Start InsulinStart Insulin

HbA1c ≥7.5%HbA1c ≥7.5%

If insulin is unacceptableIf insulin is unacceptableMET + 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 for NICE guideline for Type 2 Diabetic Management, Type 2 Diabetic Management,

May 09May 09

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 options2nd 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 2nd line

Review & if not reaching target move to 3rd line Review & if not reaching target move to 3rd line

3rd line options3rd line options

ADA/EASD Consensus Algorithm for the Initiation and Adjustment of

Therapy Diabetes Care 2009; 32:193–203

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 of April 2012 [Epub ahead of print]print]

Diabetes Care,Diabetes Care, Diabetologia. Diabetologia. 1919 April 2012 [Epub ahead of April 2012 [Epub ahead of print]print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM: A Patient-

Centered Approach

T2DM Anti-hyperglycemic Therapy: General Recommendations

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Adapted Recommendations: When Goal is to Avoid Hypoglycemia

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Adapted Recommendations: When Goal is to Minimize CostsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Patient Preference: EfficacyPatient Preference: Efficacy

metformin

sulfonylurea

TZD

glinide

DPP4 inhibitor

α -glucosidase inhibitors

Patient Preference: CostPatient Preference: Cost

metformin sulfonylurea

α-glucosidase

inhibitor

TZD

DPP4 inhibitor

Patient Preference: WeightPatient Preference: Weight

metforminDPP4

inhibitor

α -glucosidase inhibitor

TZD

sulfonylurea

Patient Preference: Patient Preference: Hypoglycemia AvoidanceHypoglycemia Avoidance

metformin

DPP4 inhibitor

TZD

α -glucosidase inhibitor

sulfonylurea

glinide

CASE 1

• 56 year male ,newly diagnosed DM,

• BMI 35

• RBS 350mg%

• BP 150/90

• Creatinine 100 mg%

• Total Cholesterol-250mg%

• ECG

Treatment?

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

Why I choose Metformin?

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

Metformin: Crucial Part of Metformin: 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 mgCI - serum creatinine >1.5 mg%, Advanced Heart FailureSE - Reduce appetite, nausea, vomiting, diarrhoea

12 studies; ≥ 52 weeks; at least 1 CVD event

CVD outcomes: - fatal / non-fatal MI or stroke- PVD - other CVD death

Effect of Metformin on CVD Events

Why I choose Gliclazide (Diamicron MR 60 )

?

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

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

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

Glucose control therapy- Rationale

Mean HbA1c at final visit

Standard: 7.3%

Intensive: 6.5%

The ADVANCE Study

ADVANCE Collaborative Group. NEJM 2008

Combined primary outcomesMajor macro or microvascular event

Follow-up (months)

Cu

mu

lat i

ve i

nci

de

nce

(%

)

25

20

15

10

5

0

0 6 12 18 24 30 36 42 48 54 60 66

Standard

Intensive

Relative risk reduction10%: 95% CI: 2 to 18%

p=0.013


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

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

Effect of SU on MI Patients

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

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]

30-day post MI mortality according to 30-day post MI mortality according to OHAOHA

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]

Use of Sulfonylureas and mortality Use 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%

• Total mortality – Gliclazide - 67% (p<0.01), Total mortality – Gliclazide - 67% (p<0.01), Glimepiride - 40% Glimepiride - 40%

(p<0.01)(p<0.01)• CVD mortality – Gliclazide -71% (p<0.001)CVD mortality – Gliclazide -71% (p<0.001)

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 riskreduction (95%CI)

FavoursIntensive

FavoursStandard

Hazard ratio0.5 1.0 2.0

ADVANCE study - trend to reduction in CV death with gliclazide MR based intensive control regimen

ADVANCE study - trend to reduction in CV death with gliclazide MR based intensive control regimen


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.

0.5 1.0 2.0

End stage kidney disease

Percent of patients with eventIntensive Standard(n=5,571) (n=5,569)

Relative riskreduction (95% CI)

FavoursIntensive

FavoursStandard

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: Reduction of Renal events

Less risk of dialysis, kidney transplantationand most of all death

Renal outcomes of the main morbidity-mortality trials in Renal outcomes of the main morbidity-mortality trials in diabetesdiabetes

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

*

ADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication

20 mg/l200 mg/lalbuminuria

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

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.

ACCORD2

ADVANCE3

Intensive Control

Standard Control

Pat

ien

ts e

xper

ien

cin

g a

t le

ast

on

e se

vere

hyp

og

lyce

mic

eve

nt

(%)

0

5

10

15

20

25

VADT1

2.7%2.7% 1.5%1.5%

16.2%16.2%

5.1%5.1%

21.2%21.2%

9.9%9.9%

P<0.001 P<0.001 P<0.001 P<0.001 HR=1.86(95% CI 1.40-2.40)

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.

• 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

Hypoglycemia in Ramadan: Sitagliptin vs SU

S. Al Sifri et al. Int J Clin Prac, Nov 2011;65,11: 1132–40

0%

2%

4%

6%

8%

10%

Glimepiride Glibenclamide Gliclazide MR

(%)

of

pati

ents

wit

h >

one s

ym

pto

mati

c hypogly

cem

ia

Patient fasting Ramadan

2012 comparison

Patients’ Safety

9.1%9.1%

5.2%5.2%

1.8%1.8%

Hypoglycaemia with different Sulfonylureas

*<50 mg/dL. Tayek J. Diabetes Obes Metab. 2008;

10: 1128–1130.

0

5

10

15

20

25

30

Gliclazide0.85

Gliclazide0.85

Glipizide8.70

Glipizide8.70

Glimepiride0.86

Glimepiride0.86

Tolbutamide3.50

Tolbutamide3.50

Chlorpropamide

16.00

Chlorpropamide

16.00

Glyburide

16.00

Glyburide

16.00

Severe hypoglycemia*n/1000 person years

Severe hypoglycemia*n/1000 person years

Rela

tive R

isk (

%)

Rela

tive R

isk (

%)

SAFETY

Hypoglycemia in SU

OHARisk of

hypoglycemia

Glinide +

Gliclazide ++

Gliclazide MR +

Glimepride ++

Glibenclamide +++

All SU can give rise to hypoglycemia

HYPOGLYCEMIAHYPOGLYCEMIAGliclazide MR vs Glimepiride

Gliclazide MR

n=157

Gliclazide MR

n=226

Hypoglycaemia (blood glucose < 3.0 mmol/L) according to Creatinine Clearance (CCl)

Glimepiriden=25

Gliclazide MRn=17

0

6

12

18

24

50-80 ml/min

0

6

12

18

24

0

6

12

18

24

Num

ber o

f pati

ents

Glimepiriden=182

Glimepiriden=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)

50 year Male DM 12 yearson Metformin 500mg 2 TDSgliclazide MR 60 2 odPioglitazone 45 mg odHbA1C 8%,FBG-200,2hpp 350mg%Next Treatment?

CASE 2CASE 2

Uncontrolled DM

Check Diet Check Steroid Check Compliance Check Infection and Stress

3 drugs ,maximum dose for 3 monthsDrug Failure,Beta cell failure

Need INSULIN

3 drugs ,maximum dose for 3 monthsDrug Failure,Beta cell failure

Need INSULIN

Insulin Regimen for Type 2 Diabetes MellitusGuidelines for initiating insulin

0.15 units /kg /body wt /day

Chart G uidelines for Starting Insulin T herapy(Asia Pacific Type 2 D iabetes Policy group)

M orning 2 /3Pre-M ix-30/70

Evening 1 /3Pre-M ix-30/70

Pre-m ixed insulin 30/70

>30-40 iu --stopping OAD

T est FPG /Adjust 3-4 days

OAD + 10 iu NPH insulin (Bedtim e)

TWO basic INSULIN TWO basic INSULIN REGIMENSREGIMENS

SupplementarySupplementarySupplementarySupplementary SubstitutionSubstitutionSubstitutionSubstitution

(OHD +Bed time insulin)(OHD +Bed time insulin) ( No OHD +Only insulin)( No OHD +Only insulin)

Premixed/split mixedPremixed/split mixedPremixed/split mixedPremixed/split mixedBasal bolus insulinBasal bolus insulinBasal bolus insulinBasal bolus insulin

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

SubstitutionSubstitutionSubstitutionSubstitution

Evening 1/3

Pre-Mix 30/70

Evening 1/3

Pre-Mix 30/70

60

0

20

40

Insu

lin

PREMIX 30/70 PREMIX 30/706 AM 6 PM12 AM 12 PM

Insulin Regimen for Type 2 Diabetes Mellitus

PREMIXPREMIXPREMIXPREMIX

Basal Bolus Regimen Basal Bolus Regimen (Substitution)(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

•Cardiac •Lipid Management•Smoking cessation •Vaccines •Transfer and

discharge

Cardiac •Lipid Management•Smoking cessation •Vaccines •Transfer and

discharge

Blood sugar control •Patient education •Nutrition counseling •Medication •Physical activity •Foot care •Retinopathy

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

CASE B

• 65 male with DM 10 years,IHD,Hypertension ,,Stroke

• HbAIC Target?• A. 7%• B.8%• C.6.5%

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

CASE c

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

If 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

Don't let the Don't let the situation situation confuse confuse you...you...

Thank you

2. better control, better life dr. ko ko

Health & Medicine

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