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Management of Type 2 Diabetic
patients in Daily Clinical Practice
KO KONOGH,UM(2)
The majority of diabetic patients (greater than 90 percent) receive their care from primary care physician.
generalist and the specialist
A large observational study (the Medical Outcomes Study) found
little advantage for patients under the care of endocrinologists,
when compared with family practitioners,
except for improved foot care and lower infection risk [77,78] .
Overall functional status at four years and mortality at seven years were similar.
• A 40 years old lady is found to have A 40 years old lady is found to have hyperglycaemia at your clinics. Her hyperglycaemia at your clinics. Her RBS isRBS is 220 mg/dl.220 mg/dl.
Is she diabetic?Is she diabetic?
• Diagnosis of DM should not be made by Diagnosis of DM should not be made by single single measurement of blood sugar alone.measurement of blood sugar alone.
• It is important to assessIt is important to assessHyperosmolar symptoms(polyuria,polydipsia)Hyperosmolar symptoms(polyuria,polydipsia)Weight lossWeight lossPrevious history of poor wound healingPrevious history of poor wound healingFamily history of DMFamily history of DMSigns of DM complicationsSigns of DM complications
(e.g. diabetic shin spots, retinopathy)(e.g. diabetic shin spots, retinopathy)
AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (Suppl 1) 2007
ADA 2012 Guidelines on ADA 2012 Guidelines on Diagnosing diabetesDiagnosing diabetes
Prediabetes: IFG, IGT, Increased A1CPrediabetes: IFG, IGT, Increased A1C
Categories of increased risk for diabetes (Prediabetes)*
FPG 100-125 mg/dl (5.6-6.9 mmol/l): IFGor
2-h plasma glucose in the 75-g OGTT140-199 mg/dl (7.8-11.0 mmol/l): IGT
or
A1C 5.7-6.4%
*For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater at higher ends of the range.
ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S13. Table 3.
Definition of DiabetesDefinition of Diabetes
IndicatorIndicator AmericanAmerican(mg/dL)(mg/dL)
SISI(mmo/L)(mmo/L)
Glucose – FastingNormalNormal 65 - 9965 - 99 3.6 – 5.53.6 – 5.5
DMDM >> 126 126 >> 7.0 7.0
Random (with symptoms) DMDM >> 200 200 > > 11.111.1
GTT (2 hr.) DMDM >> 200 200 > > 11.111.1
HbA1c DMDM >> 6.5% 6.5%
Number of People with Diabetes Number of People with Diabetes by Age Group, 2010 and 2030by Age Group, 2010 and 2030
Mill
ions
Mill
ions
Number of People with Impaired Glucose Number of People with Impaired Glucose Tolerance by Age Group, 2010 and 2030Tolerance by Age Group, 2010 and 2030
Mill
ions
Mill
ions
CHALLENGESCHALLENGES
• PrediabetesPrediabetes
SOLUTIONSSOLUTIONS
• Early diagnosis &Early diagnosis &• Life style changesLife style changes
PREDIABETES DIABETES
Early diagnosisLife style changes
Criteria for Testing for Diabetes in Criteria for Testing for Diabetes in Asymptomatic Adult Individuals (1)Asymptomatic Adult Individuals (1)
•Physical inactivity
•First-degree relative with diabetes
•High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander)
•Women who delivered a baby weighing >9 lb or were diagnosed with GDM
•Hypertension (≥140/90 mmHg or on therapy for hypertension)
• HDL cholesterol level<35 mg/dl (0.90 mmol/l) and/or a triglyceride level >250 mg/dl (2.82 mmol/l)
• Women with polycystic ovarian syndrome (PCOS)
• A1C ≥5.7%, IGT, or IFG on previous testing
• Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)
• History of CVD
*At-risk BMI may be lower in some ethnic groups.
1. Testing should be considered in all adults who are overweight (BMI ≥25 kg/m2*) and have additional risk factors:
ADA. Testing in Asymptomatic Patients. Diabetes Care 2011;34(suppl 1):S14. Table 4.
2. In the absence of criteria (risk factors on previous slide), testing for diabetes should begin at age 45 years
3. If results are normal, testing should be repeated at least at 3-year intervals, with consideration of more frequent testing depending on initial results and risk status
ADA. Testing in Asymptomatic Patients. Diabetes Care 2011;34(suppl 1):S14. Table 4.
Criteria for Testing for Diabetes in Criteria for Testing for Diabetes in Asymptomatic Adult Individuals (2)Asymptomatic Adult Individuals (2)
• The lady is tested again the next The lady is tested again the next day. Her FBS isday. Her FBS is 170mg/dl170mg/dl. So DM is . So DM is diagnosed.diagnosed.
What should I do What should I do next?next?
Doctors should doDoctors should do
What a Doctor should do for medical care of What a Doctor should do for medical care of patient with DM?patient with DM?
• DiagnosisDiagnosis• ScreeningScreening• Evaluation of diabetes complications-macro and microvascularEvaluation of diabetes complications-macro and microvascular• Detection of comobiditiesDetection of comobidities• Reducting the risk of microvascular complicationsReducting the risk of microvascular complications
Glycemic controlGlycemic control• Reducting the risk of Macrovascular complicationsReducting the risk of Macrovascular complications
smoking cessationsmoking cessationcontrol of control of BP,Lipid,asprinBP,Lipid,asprin
• Monitoring of complicationsMonitoring of complications• Prevention of DiabetesPrevention of Diabetes• DSME (Diabetes self management education)DSME (Diabetes self management education)
• Diabetes never come aloneDiabetes never come alone
• It come in hand with It come in hand with ObesityObesityHypertensionHypertensiondyslipidemiadyslipidemiaComplications (Microvascular & Complications (Microvascular &
Macrovascular)Macrovascular)
So look for them!So look for them!
•Diabetes•Hypertension•IHD•Increased Lipid•Stroke
Patient Education in Diabetes Mellitus:Patient Education in Diabetes Mellitus:10 Content Areas10 Content Areas
Diabetes Self-Management
Education
Diabetes Disease Process
Physical Activity
UtilizingMedicationMonitoring
Blood Glucose
Preventing,Detecting & Treating Acute Complications
Preventing,Detecting & Treating
Chronic Complications
Goal setting forHealth &
Daily Living
IntegratingPsychosocial Adjustment
To Daily Living
Promoting Care prior to and during
Pregnancy
Nutritional Management
Funnell et. al. Diabetes Care 2010:33 (Suppl1) S89-96
ATP III : General features of the ATP III : General features of the Metabolic SyndromeMetabolic Syndrome
• Abdominal obesityAbdominal obesity(waist circumference)(waist circumference)
MenMen > 102cm (>40inches)> 102cm (>40inches)WomenWomen >88cm (>35inches)>88cm (>35inches)
• Elevated triglyceridesElevated triglycerides > or = 150mg/dl> or = 150mg/dl• Low HDL cholesterolLow HDL cholesterol
MenMen < 40mg/dl< 40mg/dlWomenWomen <50mg/dl<50mg/dl
• Raised blood pressureRaised blood pressure > or = 130/85mmHg> or = 130/85mmHg• FBSFBS > or = 110mg/dl> or = 110mg/dl
The Metabolic Syndrome
Low HDL cholesterol Borderline
triglycerides Central obesity Prehypertension Impaired fasting
glucose
ComplicationsComplications
• MicrovascularMicrovascular Retinopathy (Fundoscopy)Retinopathy (Fundoscopy) Nephropathy (microalbuminuria, Urine RE, Urea, Cr)Nephropathy (microalbuminuria, Urine RE, Urea, Cr) NeuropathyNeuropathy
• MacrovascularMacrovascular Stroke, TIAStroke, TIA IHD (ECG)IHD (ECG) Peripherial vascular diseasePeripherial vascular disease
(pulse examination & claudication pain)(pulse examination & claudication pain)
• Examination and investigations of the Examination and investigations of the lady showedlady showedBMIBMI 3232Waist circumference Waist circumference 90cm90cmBPBP 150/90mmHg150/90mmHgTotal cholesterolTotal cholesterol 250mg/dl250mg/dlLDLLDL 160mg/dl160mg/dlHDLHDL 30mg/dl30mg/dlTriglycerideTriglyceride 300mg/dl300mg/dl
How would I manage How would I manage her?her?
ProblemsProblems
1.1. Newly diagnosed Type (2)DMNewly diagnosed Type (2)DM
2.2. Obesity(BMI 32)Obesity(BMI 32)
3.3. HypertensionHypertension
4.4. HyperlipidaemiaHyperlipidaemia
0
10
20
30
40
50
%of deaths
Ischemicheart
disease
Otherheart
disease
DiabetesCancer Stroke Infection Other
Geiss LS et al. In: Diabetes in America. 2nd ed. 1995; chap 11.
Mortality in People With Diabetes:Causes of Death
©2006. American College of Physicians. All Rights Reserved.
Evidence level of the recommendationsEvidence level of the recommendations
In type 2 DM managementIn type 2 DM management
Strategy Strategy Evidence-based benefit Evidence-based benefit Quality of evidenceQuality of evidence
Glycemic Glycemic 30% decrease in microvascular30% decrease in microvascular IIControlControl complications/1% fall in HbA1ccomplications/1% fall in HbA1c
BP controlBP control 35-58% decrease in macro & 35-58% decrease in macro & IIMicro vascular complicationsMicro vascular complicationsdeathdeath
Lipid controlLipid control 19-55% decrease in CHD events19-55% decrease in CHD events II-1II-1
Aspirin useAspirin use 28-61% decrease in AMI 28-61% decrease in AMI II15-18% decrease in CVD15-18% decrease in CVD
Treatment of Type 2 DiabetesTreatment of Type 2 Diabetes
Combination Therapy - Oral Drug with InsulinCombination Therapy - Oral Drug with Insulin
DiagnosisDiagnosis
Therapeutic Lifestyle ChangeTherapeutic Lifestyle Change
Combination Therapy - Oral Drugs OnlyCombination Therapy - Oral Drugs Only
MonotherapyMonotherapy
Do we need to get good glycemic control?
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%
Glycemic Recommendations for Non-Glycemic Recommendations for Non-Pregnant Adults with Diabetes (1)Pregnant Adults with Diabetes (1)
A1C <7.0%*
Preprandial capillary plasma glucose
70–130 mg/dl* (3.9–7.2 mol/l)
Peak postprandial capillary plasma glucose†
<180 mg/dl* (<10.0 mmol/l)
*Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes.
ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S21. Table 10.
Recommendations:Recommendations:Glycemic Goals in Adults (2)Glycemic Goals in Adults (2)
ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S19.
• Additional analysis from several randomized trials suggest a small but incremental benefit in microvascular outcomes with A1C values closer to normal
• Providers might reasonably suggest more stringent A1C goals for selected individual patients, if this can be achieved without significant hypoglycemia or other adverse effects of treatment
– Such patients might include those with short duration of diabetes, long life expectancy, and no significant cardiovascular disease (B)
Recommendations:Recommendations:Glycemic Goals in Adults (3)Glycemic Goals in Adults (3)
ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S19.
• Conversely, less stringent A1C goals may be appropriate for patients with– History of severe hypoglycemia, limited life
expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions
– Those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose lowering agents including insulin (C)
How Can we get good control of How Can we get good control of DM?DM?
How Can we get good control of How Can we get good control of DM?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:
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
Plate modelPlate model
Vegetable
Milk/yoghurt
Fruit
Vegetable
Protein
Starch/cereal
Rate Your PlateRate Your Plate
Slides current until 2008
Physical activityPhysical activity
RecommendationsRecommendations
• People with diabetes should be advised to perform People with diabetes should be advised to perform
at least 150 min/weekat least 150 min/week of moderate-intensity of moderate-intensity
aerobic physical activity aerobic physical activity (50 – 70% of maximum (50 – 70% of maximum
heart rate).heart rate). (A) (A)
• In the absence of contraindications, people with In the absence of contraindications, people with
type 2 diabetes should be encouraged to perform type 2 diabetes should be encouraged to perform
resistance training three times per week. (A)resistance training three times per week. (A)
Standard of Medical Care in Diabetes 2010Standard of Medical Care in Diabetes 2010
Medical Nutrition Therapy and Physical
Activity
Prevent
Diabetes
Pharmacological Pharmacological treatmenttreatment
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%
Basic Steps in the Management of Basic Steps in the Management of Type 2 DiabetesType 2 Diabetes
+ +
diet &exercise
Oral monotherapy
insulin
+
Oralcombination
Oral plusInsulin
MedicationMedication RouteRoute YearYear Efficacy as monotherapy: % Efficacy as monotherapy: % in HgbA1cin HgbA1c
Insulin s.c. 1921 2.5
Sulfonylureas Oral 1946 1.5
Glinides Oral 1997 1.0-1.5
Metformin Oral 1995 1.5
-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
NEWNEW IDF IDF20112011
Early combination approach
MonitoringMonitoring
• SMBGSMBG• HbA1CHbA1C
52
Glycemic controlGlycemic controlRecommendations for A1CRecommendations for A1C• Perform the A1C test at least Perform the A1C test at least two times two times a year in patients who a year in patients who
are meeting treatment goals (and who have stable glycemic are meeting treatment goals (and who have stable glycemic control) (E)control) (E)
• Perform the A1C test Perform the A1C test quarterlyquarterly in patients whose therapy has in patients whose therapy has changed or who are not meeting glycemic goals. (E)changed or who are not meeting glycemic goals. (E)
• Use of point-of-care testing for A1C allows for timely decisions Use of point-of-care testing for A1C allows for timely decisions on therapy changes, when needed. (E)on therapy changes, when needed. (E)
Standard of Medical Care in Diabetes 2010Standard of Medical Care in Diabetes 2010
Self-monitoring of Blood Glucose Self-monitoring of Blood Glucose (SMBG)(SMBG)
• SMBG should be carried out SMBG should be carried out three or more times daily three or more times daily for for
patients using multiple insulin injections or insulin pump therapy.patients using multiple insulin injections or insulin pump therapy.
• For patients using less frequent insulin injections, noninsulin For patients using less frequent insulin injections, noninsulin
therapies, or medical nutrition therapy (MNT) alone, therapies, or medical nutrition therapy (MNT) alone, SMBG may SMBG may
be useful in achieving glycaemic goals.be useful in achieving glycaemic goals.
• To achieve postprandial glucose targets, To achieve postprandial glucose targets, postprandial SMBGpostprandial SMBG may may
be appropriate.be appropriate.
54
Which one is important?Which one is important?
• FPG ------basal for microvascular FPG ------basal for microvascular complicationcomplication
• 2HPG ----for macrovascular 2HPG ----for macrovascular complication(mainly CVS)complication(mainly CVS)
Both are importantBoth are important
55
What Do We Look For In Anti-diabetic What Do We Look For In Anti-diabetic Drug?Drug?• Effectiveness in lowering glucose
• Extra-glycemic Effects
• Long-term complications
• ? Effect on β cell mass
• Tolerability and Safety
• Easy of Use
• Expense
Body WtLipids
BP
Body WtLipids
BP
Obviously no such agent available, nor likely to be available in near or medium-term future
Unwise to anticipate “golden” Rx; rather, would be preferable to learn how to better use available pharmacologic tools
Obviously no such agent available, nor likely to be available in near or medium-term future
Unwise to anticipate “golden” Rx; rather, would be preferable to learn how to better use available pharmacologic tools
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…
Sulfonylureas
Non-Sulfonylureas
Biguanides
Thiozolidinediones (Glitazones)
Alpha Glucosidase enzyme inhibitors
Newer Antidiabetic drugs (ADA)
▪ GLP-1 (Incretin Mimetics )-exenatide-liraglutide
▪ DPP-IV inhibitor (Incretin enhancer) -Sitagliptin
-Vildagliptin-Saxagliptin
ADA (antidiabetic drugs)
SU/Non-SU
Metformin/Glitazones
α-glucosidase inhibitors
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
Anti-hyperglycemic agents in T2DMAnti-hyperglycemic agents in T2DM
Class AIC reduction
Fasting versus PPG
Hypoglycemia
Weight change
Dosing
MET 1.5 Fasting No Neutral 1-3
INS-LA 1.5-2.5 Fasting Yes Gain 1
INS-RA 1.5-2.5 PPG Yes Gain 1-4
SU 1.5 Fasting Yes Gain 1-3
GLIT 0.5-1.4 Fasting No Gain 1
GLIN 1-1.5 Both Yes Gain 3
AGI 0.5-0.8 PPG No Neutral 3
PRAM 0.5-0.8 PPG No Loss 3
EXE 0.5-1 PPG No Loss 2
DPP-IV 0.5-0.8 PPG No Neutral 1
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
Metformin - Drug ProfileMetformin - Drug Profile
Advantages
No hypoglycemiaNo hypoglycemia
Weight lossWeight loss
Cardiovascular benefitCardiovascular benefit
Reduces LDL-C (approx 10 mg/dL), Reduces LDL-C (approx 10 mg/dL), reduces TGreduces TG
Disadvantages
Diarrhea is commonDiarrhea is common
Contraindicated in renal impairment, Contraindicated in renal impairment, liver failure, advanced cardiac failureliver failure, advanced cardiac failure
Risk of lactic acidosis not increased Risk of lactic acidosis not increased in meta-analyses and systematic in meta-analyses and systematic reviewsreviews
Concomitant use with other drugs Can be used as monotherapy and Can be used as monotherapy and with all classes including insulinwith all classes including insulin
Sulfonylureas - Drug ProfileSulfonylureas - Drug Profile
AdvantagesPotent glucose lowering effect
Favorable adverse effect profile
Disadvantages
Hypoglycemia, more with Glyburide
Glyburide contraindicated in renal impairment
?Glyburide impairs ischemic preconditioning in heart (UKPDS did not reveal increased cardiac risk)
Concomitant use with other drugsCan be used as monotherapy and with all classes including insulin
Repaglinide and Nateglinide: Drug Profiles Repaglinide and Nateglinide: Drug Profiles
Advantages
Less hypoglycemia than sulfonylureas
Favorable adverse effect profile
Disadvantages
Less potent than sulfonylureas; target mainly post-prandial glucose
Nateglinide less potent than Repaglinide
Concomitant use with other drugs
Can be used with all classes including insulin
TZDs - Drug ProfileTZDs - Drug Profile
Advantages
No hypoglycemia
May be useful in nonalcoholic fatty liver disease
Disadvantages
Increased fracture risk
Weight gain
Edema and exacerbation of CHF Rosiglitazone increases LDL-C (10mg/dL), TG (15-50mg/dL) and possible increase in MI
?? Bladder Ca
Concomitant use with other drugs
Can be used with other classes including insulin!. Increased fluid retention and weight gain with insulin
Alpha Glucosidase Inhibitor (AGI) - Alpha Glucosidase Inhibitor (AGI) - Drug ProfileDrug Profile
AdvantagesNo hypoglycemiaNo hypoglycemia
Weight neutralWeight neutral
Disadvantages
Targets only postprandial Targets only postprandial glucoseglucose
GI side effectsGI side effects
Concomitant use with other drugs
Can be used as Can be used as monotherapy and with all monotherapy and with all classes including insulinclasses including insulin
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
ADA/EASD Consensus Algorithm for the Initiation and Adjustment of
Therapy Diabetes Care 2009; 32:193–203
Master Decision Path Master Decision Path Type 2 Diabetes Glycemic ControlType 2 Diabetes Glycemic Control
Medical Nutrition TherapyMedical Nutrition Therapy&& Activity Plan Activity Plan If target not reached within 3 If target not reached within 3 months --months --start oral agent start oral agent
Medical Nutrition TherapyMedical Nutrition Therapy&& Activity Plan Activity Plan If target not reached within 3 If target not reached within 3 months --months --start oral agent start oral agent
Oral Agent-Monotherapy Oral Agent-Monotherapy 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 Agent-Monotherapy Oral Agent-Monotherapy 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 RxOral Combination RxIf 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 RxOral Combination RxIf 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 > 350Casual > 350
FPG > 350FPG > 350Casual > 350Casual > 350
At Diagnosis(mg/dl)
Targets for Targets for Glycemic ControlGlycemic Control
HbA1c <7%HbA1c <7%SMBG 80-140SMBG 80-140
Targets for Targets for Glycemic ControlGlycemic Control
HbA1c <7%HbA1c <7%SMBG 80-140SMBG 80-140
FPG > 300FPG > 300Casual > 350Casual > 350
with severe symptomwith severe symptom
FPG > 300FPG > 300Casual > 350Casual > 350
with severe symptomwith severe symptom
KK/ESSENTIAL DRUG/3.4.11/tAUNGGHU
GlitazonesGlitazones
• Monotherapy if • MET contraindicated• Intolerant to MET
• Combination Rx• SU• MET (high IR)• Insulin (Bbox in US)
• Disadvantages• Wt gain• Fluid retention ? CHF• Possibly hepatotoxicity• Fracture risk in
• ROS/PIO• PPAR-γ agonists• Insulin action at muscle/fat cells (?
liver)• Pleiotropic effects• Beta cell preservation
Pioglitazone – 15 – 45 mg ODRosiglitazone – 2- 8 mg OD
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
Comparison between 3 generations of Sulphonylureas
Drug Duration of action
Range of dosage
Relative potency
Doses per day
1st generation Tolbutamide 6-12 hrs 500-3000 mg 1 2-3
Tolazamide 14-16 hrs 100-1000 mg 3 1-2
Chlorpropamide 24-72 hrs 100-500 mg 6 1-22nd generation Glipizide 12-24 hrs 2.5-40 mg 75 1-2
Glipizide-ER 24 hrs (lesser fluctuations compared to
regular Glipizide)
2.5-20 mg 150 1
Glyburide (Glibenclamide)
18-24 hrs 1.25-20 mg 150 1-2
Micronized Glyburide
24 hrs 3-12 mg 250 1-2
3rd generation Glimepiride 24 hrs 1-8 mg 350 1
Drugdex Evaluations; Vol.133,2007
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
Metformin: Crucial Part of TherapyMetformin: Crucial Part of Therapy
Metformin Effects on Risk FactorsMetformin 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
No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies
Alpha-Alpha-Glucosidase Glucosidase InhibitorsInhibitors1,21,2
MeglitinidesMeglitinides33 SUsSUs4,54,5 TZDsTZDs6,76,7 MetforminMetformin88
DPP-4 DPP-4 InhibitorsInhibitors
Insulin deficiency
Insulin resistance
Excess hepatic glucose output
Maj
or P
atho
phys
iolo
gies
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
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)
0.15 units /kg /BW /Day
OAD + 10 iu NDP insulin (Bedtime)OAD + 10 iu NDP insulin (Bedtime)
Test FPG/ Adjust 3-4 daysTest FPG/ Adjust 3-4 days
>30-40 iu – stopping OAD>30-40 iu – stopping OAD
SupplementarySupplementarySupplementarySupplementary
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)
85
• 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
Total Mealtime Insulin (lispro, aspart or regular) = 60% of
TDI
eg: 60% x 30 units = 18 units
Total Basal insulin (NPH, glargine, ultralente) =
40 % of TDI
eg: 40% x 30 units = 12 units
Breakfast dose = 1/3 of
mealtime insulin
eg: 1/3 x 18 units = 6 units
Lunch dose = 1/3 of mealtime
insulin
eg: 1/3 x 18 units = 6 units
Dinner dose = 1/3 of
mealtimeinsulin
eg: 1/3 x 18 units = 6 units
Bed-time dose = total basal
insulin
eg: 40% x 30 units = 12 units
Calculate Total Daily Insulin (TDI) =
0.5 units x weight (kg) OR (sum of current doses)
eg: if weight is 60 kg, TDI = 30 units
Initiation of Basal Bolus insulin regimen
“ Small Steps. Big Rewards.
Prevent type 2 Diabetes”
Diabetes Prevention
• Yes. We can
Can we prevent Diabetes Mellitus?
0 1 2 3 4
0
10
20
30
40Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )
Percent developing diabetes
All participants
All participants
Years from randomization
Cum
ulat
ive
inci
denc
e (%
)
Placebo (n=1082)
Metformin (n=1073, p<0.001 vs. Placebo)
Lifestyle (n=1079, p<0.001 vs. Metformin , p<0.001 vs. Placebo)
Incidence of Diabetes Incidence of Diabetes
Risk reductionRisk reduction31% by metformin31% by metformin58% by lifestyle58% by lifestyle
The DPP Research Group, NEJM 346:393-403, 2002
Standards of Medical Care in Diabetes—2011
PREVENTION/DELAY OF TYPE 2 DIABETES
Recommendations ● Patients with IGT (A), IFG (E), or an A1C of 5.7–6.4% (E) should be
referred to an effective ongoing support program targeting weight loss of 7% of body weight and increasing physical activity to at least 150 min/week of moderate activity such as walking.
● Metformin therapy for prevention of type 2 diabetes may be considered in
those at the highest risk for developing diabetes, such as those with multiple risk factors, especially if they demonstrate
progression of hyperglycemia
(e.g., A1C 6%) despite lifestyle interventions. (B)
Are we achieving good control?Are we achieving good control?Are we achieving good control?Are we achieving good control?
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%
If RBS control is difficultIf RBS control is difficult• Always ask about other medicationsAlways ask about other medications
SteroidsSteroids ThiazideThiazide Beta-blockersBeta-blockers
• Always check dietsAlways check diets
• Always check sepsisAlways check sepsis Skin – carbuncle, abscess, gangreneSkin – carbuncle, abscess, gangrene Foot – ulcerFoot – ulcer Lungs – TB, PneumoniaLungs – TB, Pneumonia Renal – UTI, pylonephritisRenal – UTI, pylonephritis
Compliance of drugsCompliance of drugs
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 (longacting drugs eg.metformin longacting drugs eg.metformin XR)XR)
• 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 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
Correct Drugs
Insulin Resistance
Postprandial Hyperglycemic Insulin Deficiency
• Glinides
• Acarbose
• Voglibos
• Solube Insulin
• Thiazolidine diones
• Metformin
• Insulin Secretogogues
• Sulphonylurea Glinides
JNC 7 and ADA recommendations JNC 7 and ADA recommendations • Hypertension blood pressure: Hypertension blood pressure: ≥≥140/90mmHg 140/90mmHg
• Target blood pressure goal in diabetes: Target blood pressure goal in diabetes: 130/80mmHg130/80mmHg
• 125/ 75 mmHg in Diabetes Nephropathy125/ 75 mmHg in Diabetes Nephropathy
• Many people require Many people require three or more drugsthree or more drugs to achieve the to achieve the recommended target recommended target
ADA 2004, JNC7
Blood Pressure ManagementBlood Pressure Management
ACE inhibitor or ARB should be first choice If not controlled add diuretic (thiazide if
GFR>50ml, or loop diuretic if GFR≤) If ACE inhibitor, ARB, or diuretics are used- kidney
function & serum potassium levels – closely monitor
In pregnant patients BP goals 110-129/65-79mmHg
ACE inhibitor, ARB are contraindicated. Amlodipine,beta blocker
99
ESH/ESC Guidelines recommend initiating a ESH/ESC Guidelines recommend initiating a
two-drug combination in high risk patientstwo-drug combination in high risk patients
ESH/ESC Guidelines recommend initiating a ESH/ESC Guidelines recommend initiating a
two-drug combination in high risk patientstwo-drug combination in high risk patients
Treat as a function of total CV risk
High Risk patients: diabetes, cardio renal disease
A combination is preferred as first step treatment for patients at risk
Mancia, De Backer et al. J Hypertens 2007: 25 1105-1187
High risk patient:Eg Diabetes
Management of DyslipidiaemiaManagement of Dyslipidiaemia
• Main predictors of CVD mortalityMain predictors of CVD mortalityLDL and HDL cholesterolLDL and HDL cholesterol
• Lipid profile in type 2 diabetesLipid profile in type 2 diabetesraised triglyceridesraised triglycerideslow HDLlow HDLraised small dense LDL particlesraised small dense LDL particles
Target for lipidsTarget for lipids
• HDLHDL >50 mg/dl>50 mg/dl
• LDLLDL <100 mg/dl<100 mg/dl
• TGTG <150 mg/dl<150 mg/dl
• TCTC <200 mg/dl<200 mg/dl
Treatment and goalTreatment and goal
• Increased physical activityIncreased physical activity• Reduction of saturated fat and cholesterolReduction of saturated fat and cholesterol• Statin therapy should be added to life-style therapy, Statin therapy should be added to life-style therapy,
regardless of baseline lipid levels, for regardless of baseline lipid levels, for Diabetes patients ± CVD, > 40yrs of ageDiabetes patients ± CVD, > 40yrs of age
• Statin therapy in addition to life style – LDL Statin therapy in addition to life style – LDL >100mg/dl>100mg/dl
• In overt CVD < 70mg/dl is goal.In overt CVD < 70mg/dl is goal.• TG <150mg/dl, HDL>40mg/dl in men, HDL>50mg/dl TG <150mg/dl, HDL>40mg/dl in men, HDL>50mg/dl
in women.in women.• Statin is contraindicated in pregnancy.Statin is contraindicated in pregnancy.
103
Dyslipidemia ManagementDyslipidemia ManagementDyslipidemia ManagementDyslipidemia Management
• Lifestyle modifications are essential. Lifestyle modifications are essential. (Grade D)(Grade D)
• Statins are the pharmacologic treatment of choice. Statins are the pharmacologic treatment of choice.
(Grade A)(Grade A)
• Exetimibe in patients who are intolerant of statins Exetimibe in patients who are intolerant of statins
or in combination therapy and other lipid modifying or in combination therapy and other lipid modifying
agent. agent. (Grade B)(Grade B)
• Use Use Fibrates as primary therapy if TG level > 400 Fibrates as primary therapy if TG level > 400
mg/dl mg/dl (Grade C)(Grade C)
• Use low dose aspirin prophylaxis Use low dose aspirin prophylaxis (Grade A)(Grade A)
AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (Suppl 1) 2007
Dyslipidemia ManagementDyslipidemia ManagementDyslipidemia ManagementDyslipidemia Management
• Combination therapy in patients who Combination therapy in patients who
have not achieved the desired goals have not achieved the desired goals
with monotherapy. with monotherapy. (Grade C)(Grade C)• Statin + FibrateStatin + Fibrate
• Statin + niacinStatin + niacin
• Statin + ezetimibeStatin + ezetimibe
• Statin + bile-acid sequestrantStatin + bile-acid sequestrant
• Statin + omega-3 fatty acidsStatin + omega-3 fatty acids
AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (Suppl 1) 2007
Diabetes UK recommends that aspirin should be offered to people with diabetes who already have a history of CVD.
107
Antiplatelet AgentsAntiplatelet Agents
• Use aspirin therapy (75-162 mg/day) as a Use aspirin therapy (75-162 mg/day) as a secondary secondary
prevention strategyprevention strategy in diabetic individuals with a in diabetic individuals with a
history of CVD.history of CVD.
• Use aspirin therapy (75-162 mg/day) as a Use aspirin therapy (75-162 mg/day) as a primary primary
prevention strategyprevention strategy in those with type 1 or type 2 in those with type 1 or type 2
diabetes diabetes at increased cardiovascular riskat increased cardiovascular risk, including , including
those who are those who are >40 years of age>40 years of age or who or who have additional have additional
risk factorsrisk factors (family history of CVD, hypertension, (family history of CVD, hypertension,
smoking, dyslipidemia, or albuminuria).smoking, dyslipidemia, or albuminuria).
108
• Aspirin therapy is Aspirin therapy is not recommended in people under 30 not recommended in people under 30
yearsyears of age, due to lack of evidence of benefit, and is of age, due to lack of evidence of benefit, and is
contraindicated in patients under the age of 21 yearscontraindicated in patients under the age of 21 years
because of the associated risk of Reye's syndrome.because of the associated risk of Reye's syndrome.
• Combination therapy using other antiplatelet agents Combination therapy using other antiplatelet agents
such as such as clopidogrel in addition to aspirin should be used clopidogrel in addition to aspirin should be used
in patients with severe and progressive CVD.in patients with severe and progressive CVD.
Antiplatelet AgentsAntiplatelet Agents
Is it necessary to hospitalize the Is it necessary to hospitalize the patient?patient?
• High blood sugar alone is not an High blood sugar alone is not an indication for hospitalizationindication for hospitalization
• When to refer to hospitalWhen to refer to hospitalDKA, HONKDKA, HONKDM with sever sepsisDM with sever sepsisDM with pregnancyDM with pregnancyDifficult - to - control DMDifficult - to - control DM
Indications for insulin therapy in Indications for insulin therapy in Type 2 DMType 2 DM
• Failure to achieve glycemic control with diet, exercise and Failure to achieve glycemic control with diet, exercise and oral medicationsoral medications
• Before and during pregnancyBefore and during pregnancy• During surgeryDuring surgery• Poor Diabetic control in any medical illness (e.g. septicaemia, Poor Diabetic control in any medical illness (e.g. septicaemia,
TB, diabetic foot)TB, diabetic foot)• Critically ill patient in ICUCritically ill patient in ICU• Glucose toxicityGlucose toxicity
Take Home MessageTake Home Message
Glycemic controlGlycemic control: HbA1c <7% ADA, <6.5% AACE : HbA1c <7% ADA, <6.5% AACE
(ADVANCE)(ADVANCE)
Blood pressure Blood pressure <130/ 80 mmHg<130/ 80 mmHg
Lipid controlLipid control
LDL-C: <100 mg/dl (<70 mg/dl in very high risk)LDL-C: <100 mg/dl (<70 mg/dl in very high risk)
HDL-C: men >45 mg/dl; women >55 mg/dlHDL-C: men >45 mg/dl; women >55 mg/dl
Triglycerides: <150 mg/dlTriglycerides: <150 mg/dl
Prothrombotic stateProthrombotic state: : ASA Rx (75 - 162 mg/day)ASA Rx (75 - 162 mg/day)
People with DM + CVDPeople with DM + CVD
> 40 years of age with DM + >1 other CV risk > 40 years of age with DM + >1 other CV risk
factorfactor
Cigarette smokingCigarette smoking: : CessationCessation
Diabetes Care. 2005; Supplement 1.
The Pill BurgerThe Pill Burger
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%
Need for global treatment to reduce complications
Hypertension
Dyslipidemia
Obesity
Smoking
Hyperglycem
ia
Exercise
Diabetes And Glycemic Control: A Rational Approach
A = Advice – Diet, Exercise, Stop smoking B = BP – 130/80 mm Hg C = Cholesterol – LDL 70 mg/dl D = Diabetes – FBG, PP BG, HbA1c E = Eye checkup regularly F = Foot examination daily G = Guardian Drugs – Aspirin, Statin, ACE-I
Avoid bad habits...Avoid bad habits...
118
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Don’t worryI will take care of DMSave big Money
Don’t worryI will take care of DMSave big Money
Thank you
Confused?
But
The end is here
Thank You for Kind Attention
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