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Updates in the

Management
of Type 2 Diabetes
Abdullah M. Kharbosh, B.Sc. Pharm
Type 2
What… ? Introduction

Disorders of insulin action & secretion


It is characterized by symptomatic glucose intolerance as well as
alterations in lipid & protein metabolism
Type 2 diabetes is the most common form of diabetes (90%)
pe 2 What…
Introduction,
? cont’d

Type 2 diabetes is frequently undiagnosed for many years


because hyperglycemia develops gradually & at earlier stages
It is often not severe enough for the patient to notice any of the
classic symptoms of diabetes
Nevertheless, such patients are at increased risk of developing
Macro & Micro-vascular complications
TheWhat…
Red ? Zone
50% of the total Diabetic patients (~ 100 millions)

More prevalence Less prevalence


Less population More population

Genetic: 25 Type 2 DM Prevalence


Ethnicity
Family history 20
Nutritional:
15
Diet change
Calorie intake
10
Cultural:
Physical activity 5

0
W est co u n tries E ast co u n tries

WHO report (2000)


pe 2What…
High?Prevalence in KSA
Diseases Distribution in KSA - 2000

Diabetes

Hyperlipidemia

Hypertension Diabetes is the leading


disease that put a great
Asthma
pressure on the health
Duodenal Ulcer system
Hepatitis

Tuberculosis

Epilepsy

0 5 10 15 20 25 30 %
pe 2What…
High?Prevalence in KSA

Normal
Obesity in KSA
Over-weight
Obese
24%

32% 44%
pe 2What…
High?Prevalence in KSA

Prevalence of Microvascular complications: Comparing data


from Arab countries with data of the highest & lowest
prevalence world wide in the year 2000
50

40 Retinopathy Neuropathy

30
Nephropathy
20

10

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WHO report (2000)


rbohydrate
What… ? Metabolism

Homeostatic mechanisms maintain plasma glucose


conc. 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 provide
adequate fuel for (CNS), which uses glucose as its
primary energy source.

CNS: Central Nervous System


rbohydrate
What… ? Metabolism

Blood glucose conc. exceed the re-absorptive capacity


of the kidneys( 180 mg/dL ), glucose spills into the
urine 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 use
amino acids & fatty acids for fuel
rbohydrate
What… ? Metabolism

Postprandial Glucose Metabolism in Nondiabetics


In muscle, insulin promotes the uptake of glucose
& its storage as glycogen
It also stimulate the uptake of AA & their conversion to
protein
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 glucose
transport, but insulin facilitates the conversion of
glucose to glycogen & FFAs

AA: Amino Acids; FFAs: Free Fatty Acids; TGs: Triglycerides


rbohydrate
What… ? Metabolism

Fasting Glucose Metabolism in Nondiabetics


As blood glucose conc. drop toward normal during the
fasting state, insulin release is inhibited
A number of counter regulatory hormones that promote
an increase in blood sugar are released (e.g.,
glucagon, Epi, GH, GCs)
Several processes maintain a minimum blood
glucose conc. for the CNS

Epi:Epinephrine; GH:Growth Hormone; GCs:Glucocorticoides


rbohydrate
What… ? Metabolism

Fasting Glucose Metabolism in Nondiabetics – Cont’d


Glycogen: in the liver  glucose
AAs: transported from muscle  liver  glucose
Uptake of glucose by insulin dependent tissues
is diminished to conserve glucose for the brain
TGs are broken down into FFAs  used as alternative
fuel sources

AA: Amino Acids; FFAs: Free Fatty Acids; TGs: Triglycerides


Type 2
What… ?Pathogenesis
(1) impaired Insulin
secretion
(6) Hyperglycemia
Stimulates the
pancreas
to produce more
insulin

(5) Excess glucose accumulation


in the circulation

(2) Resistance to action of insulin


(4)↑ Glucose (3) ↓ Glucose
output utilization
Hepatic Peripheral
Type 2
What… ? 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)
TypeWhat…
2 ?Complications
Microvascular Macrovascular
Diabetic Retinopathy & Cataracts Stroke
Leading cause of 12.5% blindness 2.5 fold increase in stroke
cases in working-age adults
Diabetic Nephropathy Cardiovascular disease
Leading cause of 42% of ESRD cases 2 - 4 ↑ in HTN & CV Mortality
25% of cardiac surgeries
75% diabetics die from CV events
Erectile Dysfunction Peripheral Vascular Disease
Peripheral Neuropathy Diabetic Foot
Leading cause of 50% of all non-
traumatic lower extremity amputations
M Type 2 ? Diagnosis
What…
Clinical Presentation Of Hyperglycemia: S & S
M Type 2 ? Diagnosis
What…

Diagnostic Criteria Of Type 2 DM


FPG ≥ 126 mg/dl (7 mmol/l). Fasting is defined as no caloric intake
for 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)

American Diabetes Association 2009


M Type 2 ? Screening
What…

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 an
earlier age (e.g. 30 years) if risk factors for DM are present
Screening should be carried out every 3 years for those with
normal glucose tolerance & annually for those with impaired
fasting glucose (IFG) or impaired glucose tolerance (IGT)
MANAGEMENT OF TYPE 2 DM
Current Recommendations
Management
What… ? Goals
Glycemic Goals

Biochemical Index Goal


Pre-prandial Glucose 90 – 130 mg/dl
Blood Glucose Equivalent 80 – 120 mg/dl
Average 2-h Postprandial PG < 180 mg/dl
Blood Glucose Equivalent < 160 mg/dl
Average Bedtime Glucose 110 – 150 mg/dl
A1C (%) <7%

Adapted from Applied Therapeutics, 2005


Management
What… ? Goals

Blood Pressure < 130/80 mm Hg


Index Goal
Mg/dl mMol/L
LDL < 100 < 2.6
TG < 150 < 1.7
HDL - Men > 40 > 1.1
HDL - Women > 50 > 1.4
LDL: Low Density Lipoprotein
HDL: High Density Lipoprotein
TG: Triglycerides

Adapted from Applied Therapeutics, 2005


ment
What… ?
Old Stepped Care Approach

Insulin Plus Thiazolidinediones, Metformin, or SU


Insulin
Oral Therapy Plus Insulin
Combination Oral Therapy
Single Oral Agent
Lifestyle changes: Diet, Exercise, Smoking, Lipids
Management
What… ? Outcome
Cumulative incidence of DM type 2 with:
placebo, metformin and lifestyle intervention

Diabetes is a reversible
pathological condition
that can be done with:

Exercise
Diet
Drugs

N Engl J Med 2002; 346: 393-403.


mentWhat…
New ?
Stepped Care Approach

Insulin Plus Thiazolidinediones, Metformin, or SU


Insulin
Oral Therapy Plus Insulin
Combination Oral Therapy
Lifestyle Mod: Diet, Exercise, Smoking, Lipids PLUS Single Oral Agent
ment What…
Medical
? Nutrition Therapy

Lifestyle Modification
Lifestyle modification is a cornerstone of DM management &
comprises the following:
Medical Nutrition Therapy
Physical activity and exercise
Avoidance 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
ment What…
Medical
? Nutrition Therapy

MNT should be individualized


Saturated 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 individual’s


age, fitness, aptitude and interest should be prescribed

A PRE-EXERCISE EVALUATION to identify Macro-, Micro-


vascular & neurological complications is recommended

An essential component of MNT is to avoid Smoking & Alcohol


gement
What… ?
Antidiabetic Agents

Thiaz Biguanides id es
olidi G lin
Rosig nediones Metformin
e pa
de
glini
litazo R inide
Piogl ne t egl
itazon Na
e

Sulfonylureas
Glibenclamide
osi dase Gliclazide Amy
uc lin
α-Gl ibitors Glipizide Pram Analo
Inh se Glimepiride lintid g
bo e
Acar itol
Migl
DPP
im etics -4
tin M Sita Inhib
Incre enatide glip it
tin or
Ex
diabetics Sites of Action

LIVER ADIPOSE TISSUE MUSCLE

↓ GLUCOSE PRODUCTION ↑ PERIPHERAL GLUCOSE UPTAKE


Thiazolidinediones, Metformin Thiazolidinediones, Metformin

INTESTINE PANCREAS

↓ GLUCOSE ABSORPTION
↑INSULIN SECRETION
Alpha-glucosidase inhibitors
SU, Repaglinide, Nateglinide

Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998; 7:551-5.


abetics Adverse Reactions

Hypoglycemia ↑ Wt Edema GI L. Acidosis Hepatic


Glibenclamide +4 + 0 ± 0 ±
Gliclazide +2 + 0 ± 0 ±
Glimepiride +2 + 0 ± 0 ±
Repaglinide +1 + 0 0 0 0
Nateglinide +1 ? 0 0 0 0
Metformin 0 0 0 +2 + 0
Acarbose 0 0 0 +3 0 ±
*Rosiglitazone 0 + + 0 0 ±
* Pioglitazone 0 + + 0 0 *±

*
Liver Enzyme Monitoring Recommended In Product Monographs

Adapted from Lebovitz H: Endocrinol & Metab Clinics of NA; 30 (4)909-933


tidiabetics Comparison

%A1C )Wt (kg Disadvantages Other Advantages


Metformin  1.5  Lactic acidosis  TG 10-20% -
 TC 5-10%
Not Expensive
SU  1.5  2 Wt gain Not Expensive
Repaglinide  1.5  Wt gain Short Duration
Acarbose  0.5-0.8  Expensive, TID dose Wt Neutral
TZD’s  0.5-1.4  Expensive, Wt gain Improve lipid profile
Exenatide  0.5 –1  2-3 Injections,Expensive,L Weight loss
Pramlintide  0.5 – 0.7  1-1.5 ittle experience
etics Use in Special Situations

Consider Avoid
 Renal Function Glipizide, Glimepiride, Insulin, TZD’s, Acarbose, Metformin
Repaglinides

 Liver Function Insulin, Repaglinide, Miglitol Acarbose, Metformin, TZD’s

Hyperlipidemia Metformin, TZD’s --------------------

Obesity Acarbose, Miglitol, Metformin Insulin, SU, Repaglanide

Hypoglycemia due Metformin, Acarbose, Repaglinide, Insulin, Long acting SU


to irregular eating TZD’s
patterns
In the last guideline try first
ement Stepwise Approach
.LSM if failed add meds
Currently, Start LSM + meds
at the diagnosis

Lifestyle + Metformin Lifestyle + Metformin


1:Well-Validated

+ +
At diagnosis: Basal insulin Intensive insulin
Lifestyle
+
Metformin Lifestyle + Metformin
+
Sulfonylurea

Step 1 Step 2 Step 3


2: Less Well-Validated

Lifestyle + Metformin
+ Lifestyle + Metformin
Pioglitazone + Pioglitazone
No hypoglycemia + Sulfonylurea
Oedema/CHF/Bone loss

Lifestyle + Metformin
+ Lifestyle + Metformin
GLP-1 Agonist + Basal insulin
GLP-1: Glucagon-like No hypoglycemia
peptide-1 (Exenatide) Wt loss/Nausea/Vomiting

Diabetes Care 2008 (Dec);31:1-


11.
ment Titration of Metformin

1 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
2 )(before breakfast &/or dinner

If GI SEs appear as doses advanced, ↓ to previous lower dose & try to


3 advance the dose at a later time

Max. effective dose can be up to 1 gm BID but is often 850 mg BID


4 Modestly greater effectiveness has been observed with doses up to
about 2.5 gm/day. GI SEs may limit the dose that can be used

5 A longer acting formulations is available & can be given OD

Diabetes Care 2008 (Dec);31:1-


11.
ment Titration of Metformin
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 < A1c ≥ 7% after 2-3 months


3.9 mmol/l (70 mg/dl), ↓ HS dose by 4 If FG is in target range (3.9-7.2 mmol/l
units or 10% whichever is greater [70-130 mg/dl]), check BG before lunch,
YES dinner, & bed. Depending on BG results,
add 2nd Inj as below. Can usually begin
with 4 U & adjust by 2 U Q3D until B.glu is
NO in range

Continue regimen check A1c Q3M

NO Pre-lunch B.glu out Pre-bed B.glu out


of range. Add rapid of range. Add rapid
acting insulin at acting insulin at
breakfast dinner
Recheck pre-meal B.glu levels & if out
of range, may need to add another Pre-dinner B.glu out
YES of range. Add NPH
Injection. If A1c continues to be out of
or rapid acting
range, check 2 hr Postprandial levels insulin at breakfast
& adjust Preprandial rapid acting A1c ≥ 7% after 2-3 months
insulin
Knowing is not enough Willing is not enough
we must APPLY ! We must DO!
What… ?

THANK U