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8/14/2019 Updates in the Management of Diabetes Type 2
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Updates in thepdates in theManagementanagementof Type 2 Diabetesf Type 2 Diabetes
Abdullah M. Kharbosh, B.Sc. Pharm
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Disorders of insulin action & secretion
It is characterized by symptomatic glucose intolerance as well asalterations in lipid & protein metabolism
Type 2 diabetes is the most common form of diabetes (90%)
What ?Typ
e 2 Introduction
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Type 2 diabetes is frequently undiagnosed for many yearsbecause hyperglycemia develops gradually & at earlier stages
It is often not severe enough for the patient to notice any of theclassic symptoms of diabetes
Nevertheless, such patients are at increased risk of developingMacro & Micro-vascular complications
What ?e 2
Introduction, contd
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What ?he
Red Zone
WHO report (2000)
More prevalenceLess population
Less prevalenceMore population
Genetic:Ethnicity Family history
Nutritional:Diet changeCalorie intake
Cultural:Physical activity
50% of the total Diabetic patients (~ 100 millions)50% of the total Diabetic patients (~ 100 millions)
0
5
10
15
20
25
W est co u n tries E ast co u n tries
Type 2 DM Prevalence
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Diseases Distribution in KSA - 2000
What ?e 2
High Prevalence in KSA
Diabetes is the leadingdisease that put a greatpressure on the health
system
0 5 10 15 20 25 30
Epilepsy
Tuberculosis
Hepatitis
Duodenal Ulcer
Asthma
Hypertension
Hyperlipidemia
Diabetes
%
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Obesity in KSA
What ?e 2
High Prevalence in KSA
44%32%
24%
NormalOver-weightObese
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Prevalence of Microvascular complications: Comparing dataComparing datafrom Arab countries with data of the highest & lowestfrom Arab countries with data of the highest & lowestprevalence world wide in the year 2000prevalence world wide in the year 2000
What ?e 2 High Prevalence in KSA
0
10
20
30
40
50
M w x i c
S a u d
i A r a U S A J a p a n S u d a n
S a u d
i A r a S p a i n T h a i l a n
S a u d
i A r a E g y p F r a n c
WHO report (2000)
Nephropathy
NeuropathyRetinopathy
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Homeostatic mechanisms maintain plasma glucoseconc. between 55 - 140 mg/dL (3.1 to 7.8 mmol/L)
A minimum concentration of 40 - 60 mg/dL(2.2 to 3.3 mmol/L) is required to provideadequate fuel for (CNS), which uses glucose as itsprimary energy source.
What ?boh ydrate Metabolism
CNS: Central Nervous System
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Blood glucose conc. exceed the re-absorptive capacityof the kidneys( 180 mg/dL ), glucose spills into theurine resulting in a loss of calories & water
Muscle & fat use glucose as major source of
energy, but these tissues require insulin for glucose uptake
If glucose is unavailable, these tissues are able to useamino acids & fatty acids for fuel
What ?boh ydrate Metabolism
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Postprandial Glucose Metabolism in Nondiabetics
What ?boh ydrate Metabolism
AA: Amino Acids; FFAs: Free Fatty Acids; TGs: Triglycerides
In muscle , insulin promotes the uptake of glucose& its storage as glycogen
It also stimulate the uptake of AA & their conversion toprotein
In adipose tissue , glucose is converted to FFAs &stored as TGs
Insulin prevents a breakdown of these TGs to FFAs
The liver doesn't require insulin for glucosetransport, but insulin facilitates the conversion of glucose to glycogen & FFAs
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Fasting Glucose Metabolism in Nondiabetics
What ?boh ydrate Metabolism
Epi:Epinephrine; GH:Growth Hormone; GCs:Glucocorticoides
As blood glucose conc. drop toward normal during thefasting state, insulin release is inhibited
A number of counter regulatory hormones that promotean increase in blood sugar are released (e.g.,glucagon, Epi, GH, GCs )
Several processes maintain a minimum bloodglucose conc. for the CNS
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Fasting Glucose Metabolism in Nondiabetics Contd
What ?boh ydrate Metabolism
AA: Amino Acids; FFAs: Free Fatty Acids; TGs: Triglycerides
Glycogen: in the liver glucose
AAs: transported from muscle liver glucose
Uptake of glucose by insulin dependent tissuesis diminished to conserve glucose for the brain
TGs are broken down into FFAs used as alternativefuel sources
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What ?yp e 2 Pathogenesis
(5) Excess glucose accumulationin the circulation
(2) Resistance to action of insulin
(6) HyperglycemiaStimulates thepancreasto produce more
insulin
(4) Glucoseoutput
(3) Glucoseutilization
(1) impaired Insulinsecretion
Hepatic Peripheral
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What ?Typ e 2 Risk Factors
Overweight/Obesity - Inactivity
HTN
A first degree relative with DM
Previous Gestational DM
Coronary Heart Disease
Dyslipidemia
Previously identified impaired fasting glucose (IFG) OR
Impaired glucose tolerance (IGT)
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What ?ype 2 Complications
Microvascular Microvascular Macrovascular Macrovascular Diabetic Retinopathy & CataractsLeading cause of 12.5% blindnesscases in working-age adults
Stroke2.5 fold increase in stroke
Diabetic NephropathyLeading cause of 42% of ESRD cases
Cardiovascular disease2 - 4 in HTN & CV Mortality25% of cardiac surgeries75% diabetics die from CV events
Erectile Dysfunction Peripheral Vascular Disease
Peripheral Neuropathy Diabetic FootLeading cause of 50% of all non-traumatic lower extremity amputations
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What ? Ty pe 2 Diagnosis
American Diabetes Association 2009
Diagnostic Criteria Of Type 2 DM
FPG 126 mg/dl (7 mmol/l). Fasting is defined as no caloric intakefor at least 8 h OR
A casual (random) plasma glucose 200 mg/dl (11.1 mmol/l) &symptoms of hyperglycemia OR
Results of a 2-hour 75- g OGTT > 200 mg/dl (11.1 mmol/l)
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What ? Ty pe 2 Screening
Screening of Asymptomatic Individuals
Screening of asymptomatic individuals at high risk for Type 2 DM should be carried out on an opportunistic basis
Screening should begin at age 40 years, & be considered at anearlier age (e.g. 30 years) if risk factors for DM are present
Screening should be carried out every 3 years for those withnormal glucose tolerance & annually for those with impairedfasting glucose (IFG) or impaired glucose tolerance (IGT)
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MANAGEMENT OF TYPE 2 DMCurrent Recommendations
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What ?Ma nagement Goals
Adapted from Applied Therapeutics, 2005
Biochemical IndexBiochemical Index GoalGoal
Pre-prandialPre-prandial GlucoseGlucose 9090 130130 mg/dlmg/dl
Blood Glucose EquivalentBlood Glucose Equivalent 8080 120120 mg/dlmg/dl
AverageAverage 22 -h-h PostprandialPostprandial PGPG
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What ?Ma nagement Goals
Adapted from Applied Therapeutics, 2005
Blood PressureBlood Pressure > 5050 >> 1.41.4LDL: Low Density LipoproteinHDL: High Density Lipoprotein
TG: Triglycerides
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What ?en t Old Stepped Care Approach
Lifestyle changes: Diet, Exercise, Smoking, LipidsLifestyle changes: Diet, Exercise, Smoking, Lipids
Single Oral AgentSingle Oral Agent
Combination Oral TherapyCombination Oral Therapy
Oral Therapy Plus InsulinOral Therapy Plus Insulin
InsulinInsulin
Insulin Plus Thiazolidinediones, Metformin, or SUInsulin Plus Thiazolidinediones, Metformin, or SU
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What ?ana gement Outcome
Diabetes is a reversiblepathological conditionthat can be done with:
ExerciseDietDrugs
Cumulative incidence of DM type 2 with:
placebo, metformin and lifestyle intervention
N Engl J Med 2002; 346: 393-403.
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What ?en t New Stepped Care Approach
Lifestyle Mod: Diet, Exercise, Smoking, LipidsLifestyle Mod: Diet, Exercise, Smoking, Lipids Single Oral AgentSingle Oral Agent
Combination Oral TherapyCombination Oral Therapy
Oral Therapy Plus InsulinOral Therapy Plus Insulin
InsulinInsulin
Insulin Plus Thiazolidinediones, Metformin, or SUInsulin Plus Thiazolidinediones, Metformin, or SU
PLUSPLUS
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What ?ent Medical Nutrition Therapy
Lifestyle ModificationLifestyle modification is a cornerstone of DM management &comprises the following: Medical Nutrition Therapy
Physical activity and exerciseAvoidance of smoking and alcoholic beverages
MNT & exercise prescription should be the initial therapy in:Obese (BMI > 30.0 ) &Overweight (BMI > 25.0 ) type 2 diabetic patients UNLESS they are:SYMPTOMATIC or SEVERELY HYPERGLYCEMIC
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What ?
MNT should be individualizedSaturated fat intake should not exceed 10%, with CHO 50-60% &Proteins 15-20% of total calorie intake
Diet should include foods from each of the basic food groups
An EXERCISE PROGRAM TAILORED to suit the individualsage, fitness, aptitude and interest should be prescribed
A PRE-EXERCISE EVALUATION to identify Macro-, Micro-
vascular & neurological complications is recommendedAn essential component of MNT is to avoid Smoking & Alcohol
What ?ent Medical Nutrition Therapy
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What ?em ent Antidiabetic Agents
- G l u c o s i d a s
e
I n h i b i t o r s
A c a r b o s e
M i g l i t o l
SulfonylureasGlibenclamideGliclazideGlipizide
Glimepiride
I n c r e t i n M i m
e t i c s
E x e n a t i d e
T h i a z o l i d i n e d i o n e s R o s i g l i t a z o n e P i o g l i t a z o n e
D P P - 4 I n h i b i t o r S i t a g l i p t i n
Am y l i n An a l o g P r a m l i n t i d e
G l i n i d e s
R e p a g l i n i d e
N a t e g l i n i d e
BiguanidesMetformin
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GLUCOSE ABSORPTION
GLUCOSE PRODUCTION
MUSCLE
PERIPHERAL GLUCOSE UPTAKE
PANCREAS
INSULIN SECRETION
ADIPOSE TISSUELIVER
Alpha-glucosidase inhibitors
INTESTINE
SU, Repaglinide, Nateglinide
Thiazolidinediones, MetforminThiazolidinediones, Metformin
iabetics Sites of Action
Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998; 7:551-5.
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HypoglycemiaHypoglycemia WtWt EdemaEdema GIGI L. AcidosisL. Acidosis HepaticHepaticGlibenclamideGlibenclamide 4+ + 0 0
GliclazideGliclazide 2+ + 0 0
GlimepirideGlimepiride 2+ + 0 0
RepaglinideRepaglinide 1+ + 0 0 0 0NateglinideNateglinide 1+ ? 0 0 0 0
MetforminMetformin 0 0 0 2+ + 0
AcarboseAcarbose 0 0 0 3+ 0
RosiglitazoneRosiglitazone** 0 + + 0 0
PioglitazonePioglitazone** 0 + + 0 0 *
* Liver Enzyme Monitoring Recommended In Product Monographs
be tics Adverse Reactions
Adapted from Lebovitz H: Endocrinol & Metab Clinics of NA; 30 (4)909-933
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A1CA1C%% Wt (kgWt (kg)) DisadvantagesDisadvantages Other AdvantagesOther AdvantagesMetforminMetformin 1.5 Lactic acidosis TG 10-20% -
TC 5-10%Not Expensive
SUSU 1.5 2 Wt gain Not Expensive
RepaglinideRepaglinide 1.5 Wt gain Short Duration
AcarboseAcarbose 0.5-0.8 Expensive, TID dose Wt Neutral
TZDsTZDs 0.5-1.4 Expensive, Wt gain Improve lipid profile
ExenatideExenatide 0.5 1 2-3 Injections,Expensive,L
ittle experience
Weight loss
PramlintidePramlintide 0.5 0.7 1-1.5
idia betics Comparison
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Consider Consider AvoidAvoid
Renal FunctionRenal Function Glipizide, Glimepiride, Insulin, TZDs,Repaglinides
Acarbose, Metformin
Liver FunctionLiver Function Insulin, Repaglinide, Miglitol Acarbose, Metformin, TZDs
HyperlipidemiaHyperlipidemia Metformin, TZDs --------------------ObesityObesity Acarbose, Miglitol, Metformin Insulin, SU, Repaglanide
Hypoglycemia dueHypoglycemia dueto irregular eatingto irregular eatingpatternspatterns
Metformin, Acarbose, Repaglinide,TZDs
Insulin, Long acting SU
tics Use in Special Situations
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Step 1Step 1 Step 2Step 2 Step 3Step 3
1:Well-Validated
1:Well-Validated Lifestyle + Metformin
At diagnosis:Lifestyle
+Metformin
+Basal insulin
Lifestyle + Metformin+
Sulfonylurea
Lifestyle + Metformin+
Intensive insulin
Lifestyle + Metformin+
Pioglitazone
Lifestyle + Metformin+
GLP-1 Agonist
No hypoglycemiaOedema/CHF/Bone loss
No hypoglycemiaWt loss/Nausea/Vomiting
Lifestyle + Metformin+ Pioglitazone
Sulfonylurea +
Lifestyle + Metformin+ Basal insulinGLP-1: Glucagon-like
peptide-1 (Exenatide)
Diabetes Care 2008 (Dec);31:1-11.
ment Stepwise Approach
2:Less Well-Validated
2:Less Well-Validated
In the last guideline try firstLSM if failed add meds.
Currently, Start LSM + medsat the diagnosis
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Diabetes Care 2008 (Dec);31:1-11.
ent Titration of Metformin
Begin with low dose (500 mg) OD or BID with meals or 850 mg OD
After 5-7 days, if no GI SEs, dose to 850 mg, or two 500 mg tablet, BID(before breakfast &/or dinner )
If GI SEs appear as doses advanced, to previous lower dose & try toadvance the dose at a later time
Max. effective dose can be up to 1 gm BID but is often 850 mg BIDModestly greater effectiveness has been observed with doses up toabout 2.5 gm/day. GI SEs may limit the dose that can be used
A longer acting formulations is available & can be given OD
1
2
3
4
5
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Start with HS intermediate acting or HS or AM LA insulin (can initiate with 10 U or 0.2 U/kg)
Check FG (usually daily) and dose, typically by 2 U Q3D until FG levels are consistently in target
range (3.9-7.2 mmol/l [70-130 mg/dl]). Can dose in larger increments, e.g., by 4 U Q3D, if FG is >10 mmol/l (180 mg/dl)
If hypoglycemia occurs, or FG level
Recommended