Diabetes basics.ppt

Diabetes Mellitus: Introduction
Diabetes - Greek
Meaning – “To Siphon”
– The most obvious sign of
diabetes is excessive
urination.
– As if water were being
siphoned from the mouth
through the urinary system out
of the body.
Mellitus - Latin
Means – “sweet like honey”
– The urine of a person with
diabetes contains extra sugar.
– In 1679, a physician tasted the
urine of a person with diabetes
& described it as sweet like
honey.

The Indian Scenario
India is the diabetes capital of the world
with 51 million Indians having diabetes
Every fifth diabetic in the world is an
Indian.
It also leads in prevalence of metabolic
syndrome as well as obesity.
Joshi SR, Parikh RM. India--diabetes capital of the world: now heading towards hypertension.J Assoc Physicians India. 2007 May;55:323-4.

TOP 10
Number of people with diabetes (20-79 years), 2010
and 2030
IDF atlas 2009

AT A GLANCE
World
IDF atlas 2009

IDF Regions and global projections for the number of
people with diabetes (20-79 years), 2010-2030
IDF atlas 2009

Diabetes Mellitus
Types of Diabetes
Type 1 Diabetes
Type 2 Diabetes
Gestational Diabetes

TYPE I + TYPE II
Type I Diabetes Type II Diabetes
GLUCOSE
GLUCOSE
INSULIN
CELL
CELL

Natural History of Type 2 Diabetes
Genetic background
for:
– Insulin sensitivity
– Insulin secretion
– Complications
Environmental
factors:
– Nutrition
– Obesity
– Physical inactivity
Age 0-15+ 15-40+ 15-60+ 25-70+
– Insulin resistance
– Hyperinsulinemia
– ↓ HDL cholesterol
– ↑ Triglycerides
– Hypertension
– Accelerated
atherosclerosis
IGT
Postprandial
hyperglycemia
Fasting
hyperglycemia
Death
– Pseudo-normal
insulin
– Retinopathy
– Nephropathy
– Neuropathy
– Hypoinsulinemia
– Blindness
– Renal failure
– Amputation
– IHD
– Stroke
Microvascular complications
Macrovascular complications
Disability
Disability

Type 2 Diabetes: Key Concepts
Dual impairment:
– ß-cell function: insulin secretion
– insulin action: insulin resistance
“Glucose toxicity” aggravates both
impairments
Multiple mechanisms to correct
hyperglycemia

Pathogenesis
Insulin Resistance and beta cell failure
– Both insulin resistance and insulin deficiency must be present in
order for someone to develop type 2 diabetes.
– Insulin resistance develops early in predisposed individuals.
– Dietary and lifestyle factors, can also contribute to insulin
resistance.

Type 2 diabetes
Years from
diagnosis
0 5
-10 -5 10 15
Pre-diabetes
Onset Diagnosis
Insulin secretion
Insulin resistance
Postprandial glucose
Macrovascular complications
Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789;
Nathan DM. N Engl J Med. 2002;347:1342-1349
Fasting glucose Microvascular complications
Natural History of Type 2 Diabetes

β-Cell mass in Type 2 diabetes
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
ND IFG T2DM ND T2DM
b
-Cell
volume
(%)
Obese Lean
-50%
-63%
Butler et al. Diabetes. 2003
ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus

IDF Diabetes Atlas 4th edition, © International Diabetes Federation, 2009

Diabetic
Retinopathy
Leading cause
of blindness
in adults1,2
Diabetic
Nephropathy
Leading cause of
end-stage renal disease3,4
Cardiovascular
Disease
Stroke
2- to 4-fold increase in
cardiovascular
mortality and stroke5
Diabetic
Neuropathy
Leading cause of
non-traumatic lower
extremity amputations7,8
8/10 individuals with
diabetes die from CV
events6
Type 2 diabetes is associated with
serious complications
1UK Prospective Diabetes Study Group. Diabetes Res 1990; 13:1–11. 2Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 3The Hypertension in Diabetes
Study Group. J Hypertens 1993; 11:309–317. 4Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 5Kannel WB, et al. Am Heart J 1990; 120:672–676.
6Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences. 7King’s Fund. Counting the cost.
The real impact of non-insulin dependent diabetes. London: British Diabetic Association, 1996. 8Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.

Diagnosis of Diabetes
 Polyuria – Increased micturition
 Polydipsia – Increased thirst
 Polyphagia – Increased hunger
 Fatigue
 Skin infections
 Impotence
 Tingling, numbness

Diagnosis of diabetes
symptoms + elevated blood glucose level
OR
elevated blood glucose levels on two occasions

Diagnostic criteria for type 2 diabetes
Any one of the following criteria confirms diagnosis of
type 2 diabetes:
 Fasting plasma glucose >/=126 mg/dL (7.0 mmol/L)
 2-hr postload 75-g glucose level >/=200 mg/dL (11.1 mmol/L)
 Random plasma glucose level >/=200 mg/dL (11.1 mmol/L)
associated with symptoms (polyuria, polydipsia, weight loss)

Using HbA1c%
Chronically elevated glucose levels will
combine with Hemoglobin to give
Glycoslated Hb
It gives an average value of 3 months of
glucose levels
Levels >= 6.5% is now considered a
diagnostic criteria for DM

High chronically elevated glucose binds to the hemoglobin in the RBC and
thus gives glycoslated Hb. This is used to measure long term average
control of glucose levels in the blood.

Screening vs. Diagnosing
• Diagnostic testing: Is performed when
an individual exhibits symptoms or signs of
the disease
• Screening: Is performed to identify
asymptomatic individuals who are likely to
have diabetes or pre-diabetes
• A positive screening test leads to a
diagnostic test
American Diabetes Association. Diabetes Care 2007;30(Suppl 1):S4-S41.

Considerations:
• Type 2 diabetes is frequently not diagnosed until
complications appear
•  1/3 of all people with type 2 diabetes may be
undiagnosed
• Screening for diabetes is essentially testing for
(diagnosing) diabetes
Should We Screen for Type 2
Diabetes?
Recommendation: Screen high-risk individuals
for diabetes and pre-diabetes

Criteria for Screening Type 2
Diabetes (Patients Aged ≥45 Years)
• Consider screening in all individuals aged ≥45,
particularly in:
– Individuals with a BMI ≥25 kg/m2 (BMI may not
be correct for all ethnic groups)
• If test is normal, repeat every 3 years

• Consider screening in individuals aged <45,
if they are overweight and have another risk factor
for diabetes, e.g.:
– Habitual physical inactivity
– First-degree relative with diabetes
– Delivered a baby weighing >9 lb or diagnosed with
gestational diabetes
– Presence of hyperlipidemia or hypertension
• If test is normal, repeat every 3 years
Criteria for Screening Type 2
Diabetes (Patients Aged <45 Years)

Criteria for Screening
Type 2 Diabetes (Children)
• Consider screening in children at age 10 or
onset of puberty (if earlier) if they are overweight
and have another risk factor for diabetes, e.g.:
– First-degree relative with diabetes
– Member of a high-risk ethnic population
– Signs of insulin resistance or conditions associated
with insulin resistance
– Maternal history of diabetes or gestational diabetes
• If test is normal, repeat every 2-3 years

Screening Methods
• FPG and 2-hr PG test are both appropriate
• FPG is recommended as initial screening for
non-pregnant adults because it is:
– More convenient to patients
– More reproducible
2-hr PG:
– Identifies people with IGT
– May be considered in patients with IFG to better
determine presence of diabetes
– Less costly
– Easier to administer

Lifestyle Modifications Recommended
for the Prevention of Diabetes
• Weight loss
• Regular physical activity
• Dietary changes to promote weight loss
- More fiber, fruits, and vegetables
- Less “processed” food
- Smaller portions
- Fewer high-caloric/high-dense foods

Making the Diagnosis
The Importance of
Diagnosing Early

Diabetes per se
offers higher risk of
mortality and
morbidity than non-
diabetics across
many diseases.
Thus getting
glucose to as close
to normal is vital
At the same time
minimizing
hypoglycemia
Nejm March 3 2011

ADA Diagnostic Criteria
1. Classic symptoms + casual plasma
glucose ≥200 mg/dL (11.1 mmol/l)
2. FPG ≥126 mg/dL (7.0 mmol/l)
3. 2-hr plasma glucose ≥200 mg/dL
(11.1 mmol/l) during an OGTT
4. HbA1c% >=6.5%
FPG, fasting prandial glucose; OGTT, oral glucose tolerance test

Considerations When Diagnosing
• FPG is the preferred method due to ease of use,
acceptability to patients, and lower cost
• OGTT is more sensitive and modestly more specific
than FPG, but poorly reproducible and rarely
performed in clinical practice
NOTE: The vast majority of patients who meet diagnostic
criteria for diabetes by OGTT but not FPG will have
HbA1c <7%
Use of HbA1c is not recommended for diagnosis
FPG, fasting prandial glucose; OGTT, oral glucose tolerance test

Recommended Glycemic Targets
• Goal: To achieve an HbA1C as close to normal
as possible without hypoglycemia
• Targets:
– In general: HbA1c <7%
– In the individual patient: HbA1c <6% without significant
hypoglycemia
In DCCT (type 1 diabetes) and UKPDS (type 2 diabetes),
reducing average HbA1C to ~7% reduced the risk of long-
term complications…

Glycemic Goals, cont’d
• Less stringent goals may be
appropriate for:
– Patients with a history of severe
hypoglycemia
– Patients with limited life expectancies
– Very young children or older adults
– Individuals with comorbid conditions

Why Not Aim for Lower HbA1c?
• Normal HbA1C levels are difficult to
achieve with present therapies
• Intensive therapy increases the risk of
weight gain and hypoglycemia
• The absolute risks and benefits are
largely unknown…
– The ACCORD and the ADVANCE studies threw
up controversial results

Why Test HbA1C?
• To assess the patient’s control over the
preceding 2-3 months
• To check on the accuracy of patients’
self-reported results and adequacy of
SMBG testing schedule
Regular performance of HbA1C tests
permits detection of departures from
target in a timely fashion

Method and Frequency
• Use a combination of HbA1c results and
patient’s self-monitoring results
• At initial assessment, document the degree
of glycemic control
• Frequency of follow-up should be based on
the clinical situation, treatment regimen, and
judgment of the clinician
– For patients meeting targets: ≥ twice a year
– For patients not meeting targets or whose treatment has
changed: 4 times a year

Point-of-Care HbA1C Testing
• Involves having the HbA1C results
available at the time the patient is seen
• Allows for timely decisions on therapy
changes when needed
• Has been reported to increase the
frequency of intensification of therapy and
improvement in glycemic control

Glycemic Goals
Table 1.
Parameter Normal
ADA
Goals
ACE/AACE
Goals
Fasting plasma glucose (mg/dL) < 100 90-130 < 110
Postprandial plasma glucose
(mg/dL)
< 120 < 180* < 140**
A1C (%) 4-6 < 7*** ≤ 6.5
*1-2 hours post-meal
**2 hours post-meal
***as close to normal as possible without undue risk of hypoglycemia

Microvascular
complications
Myocardial infarction
HbA1c
37%
14%
Lowering HbA1c reduces the risk of
complications
Deaths related to
diabetes
21%
1%
Stratton IM, et al. BMJ 2000; 321:405–412.

MANAGEMENT STRATEGIES
SELF
MEDICATIONS
MONITORING
EDUCATION

Selecting an Intervention
The overarching principle:
Choose a treatment plan that will
allow patients to achieve and
maintain glycemic goals
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

HbA1c Goals
• Targets:
– In general: HbA1c <7%
– In the individual patient: HbA1c as close to 6% as possible
without significant hypoglycemia
• NOTE: HbA1c < 7% will not be appropriate or
practical for some patients
An HbA1c of ≥ 7% should serve as a call to action to initiate
or change therapy

Factors to Consider when Choosing an
Antihyperglycemic Agent
• Effectiveness in lowering glucose
• Extraglycemic effects that may reduce
long-term complications
• Safety profile
• Tolerability
• Expense

Recommended Modifications
• Medical Nutrition Therapy
– Patients with diabetes and patients with
pre-diabetes should consult a registered dietitian
– Monitoring carbohydrates remains key to glycemic
control

Benefits of Dietary Modification Are
Apparent Within Weeks to Months
Effect of Intensive Dietary Management on Weight and FBG
Hadden DR et al. Br Med J 1975;3:276-8.
Weight
Fasting
blood glucose
82
80
78
76
74
72
70
68
12
10
8
6
Initial 1 2 3 4 5 6
Kg
mmol/L
Months

• Weight loss in overweight and obese
patients
– Via a structured, sustainable program that includes
healthy eating (e.g., reduced fat intake), exercise,
and behaviour modification
– Low-carb diets not recommended for weight loss
– Weight loss medication not currently recommended
as primary therapy for diabetes
Recommended Modifications, cont’d

Benefits of Weight Loss Demonstrated by
High Rates of Recovery from Diabetes in
Patients Undergoing Bariatric Surgery
Sjostrom L. N Engl J Med 2004;351(26):2683-93.
0
10
20
30
40
50
60
70
80
Year 2 Year 10
Patients
recovering
from
diabetes
(%)
Surgery
Control
21%
72%
13%
36%
p<0.001
p=0.001
n=342 n=248 n=118 n=84

Recommended Modifications, cont’d
Physical Activity
• 150 min/week of moderate-intensity aerobic physical activity (50-
70% of maximum heart rate)
• or 90 min/week of vigorous aerobic exercise (>70% of maximum
heart rate)
– Distributed over at least 3 days/week with no more than 2 consecutive
days without physical activity
• For patients already exercising, consider intensifying
• In the absence of contraindications, resistance exercise 3x/week
Exercise plan may require modification for certain patients
with complications

Pooled Meta-Analysis of 14 Exercise Trials:
Exercise Significantly Reduces HbA1c
Boulé NG et al. JAMA 2001;286:1218-27.
-0.66%
-0.7%
-0.6%
-0.5%
-0.4%
-0.3%
-0.2%
-0.1%
0.0%
0.1%
0.2%
Exercise
Non-exercise
Control
Change
in
HbA
1c
from
baseline
to
postintervention
(weighted
mean
difference)
p<0.001
Effect was
weight-independent
0.08%

Meta-Analysis of 9 RCT: More Intense Exercise
Linked to Greater Reduction in HbA1c
Boulé NG et al. Diabetologia 2003;46:1071-81.
1.0
0.5
0
-0.5
-1.0
-1.5
-2.0
50 55 60 65 70 75 80
Change
in
HbA
1c
(weighted
mean)
Intensity (% maximum oxygen uptake)
r=-0.91
p=0.002

Optimal glycemic control is not
achieved in clinical practice
Percentage of people with diabetes by HbA1c level in
Asia in 1998
Adapted from: Chuang LM et al. Diabet Med 2002;19:978−985
Overall
region
Philippines
China
India
Vietnam
Thailand
Sri
Lanka
Malaysia
Taiwan
Korea
Indonesia
Bangladesh
%
people
with
diabetes
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
Of the patients with HbA1c measurements, the majority (55%) had values exceeding 8%.
Chuang LM. Diabet Med 2002;19:978−985

The Available Antihyperglycemic
Agents

Glycemic Control & Treatment Options
Oral Antidiabetic Drugs
– Insulin Secretagogues
Sulfonylureas. Meglitinides
– Sensitizers
Biguanides, Thiazolidinediones
– Alpha-glucosidase inhibitors
Acarbose, Voglibose
– Glucagon-like Peptide (GLP) analogs and agonists
Exenatide, Liraglutide
– Dipeptidyl peptidase-4 (DPP-4) inhibitors
Sitagliptin, Vildagliptin, Saxagliptin

Primary Sites of Action of Oral
Antidiabetic Drugs (OADs)
 Glucose
output
 Insulin resistance
Biguanides
 Insulin
secretion
Sulfonylureas/
Meglitinides
 Carbohydrate
breakdown/
absorption
-glucosidase
inhibitors
 Insulin
resistance
Thiazolidinediones
Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1): S32–S40.
Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13: 309–329.

Sulfonylureas
Sulfonylureas increase endogenous insulin secretion
Efficacy
– Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)
– Reduce A1C by 1.0-2.0%
Other Effects
– Hypoglycemia
– Weight gain
– No specific effect on plasma lipids or blood pressure
– Generally the least expensive class of medication
Medications in this Class:
– First generation : chlorpropamide , tolazamide, acetohexamide ,
tolbutamide
– Second generation : glyburide , glimepiride , glipizide

Biguanides
Biguanides ↓ hepatic glucose production and increase
insulin-mediated peripheral glucose uptake.
Efficacy
– Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)
– Reduce A1C 1.0-2.0%
Other Effects
– Diarrhea and abdominal discomfort
– Lactic acidosis if improperly prescribed
– Cause small decrease in LDL cholesterol level and triglycerides
– No specific effect on blood pressure
– No weight gain, with possible modest weight loss
– Contraindicated in patients with impaired renal function
– metformin (Glucophage), metformin hydrochloride extended release
(Glucophage XR)

Meglitinides
Stimulate insulin secretion (rapidly and for a short duration) in the
presence of glucose.
Efficacy
– ↓ peak postprandial glucose
– ↓ plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)
– ↓ HbA1C 1.0-2.0%
Other Effects
– Hypoglycemia (may be less than with sulfonylureas if patient has a
variable eating schedule)
– Weight gain
– No significant effect on plasma lipid levels
– Safe at higher levels of serum Cr than sulfonylureas
– repaglinide , nateglinide

Thiazolidinediones
↓ insulin resistance by making muscle and adipose cells more
sensitive to insulin. They also suppress hepatic glucose production.
Efficacy
– ↓ fasting plasma glucose ~1.9-2.2 mmol/L
– Reduce A1C ~0.5-1.0%
– 6 weeks for maximum effect
Other Effects
– Weight gain, oedema
– Hypoglycemia (if taken with insulin or agents that stimulate insulin release)
– Contraindicated in patients with abnormal LFT or CHF
– Improves HDL cholesterol and plasma triglycerides; usually LDL neutral
– pioglitazone (Actos), rosiglitazone (Avandia)

Alpha-glucosidase Inhibitors
Alpha-glucosidase inhibitors block the enzymes that digest
starches in the small intestine
Efficacy
– ↓ peak postprandial glucose 2.2-2.8 mmol/L
– ↓ fasting plasma glucose 1.4-1.7 mmol/L
– Decrease A1C 0.5-1.0%
Other Effects
– Flatulence or abdominal discomfort
– No specific effect on lipids or blood pressure
– No weight gain
– Contraindicated in patients with inflammatory bowel disease or
cirrhosis
– acarbose, miglitol

Glucagon - like peptide (GLP) analogs & agonists14
– Glucagon-like peptide (GLP-1) is an incretin hormone released by gut cells in
response to food intake, promoting insulin release.
– The incretin effect, defined by a significantly greater insulin stimulatory effect
evoked after an oral glucose load than that evoked from an intravenous glucose
infusion was first described in the 1960’s.
– Although other hormones may take part in the incretin effect, the majority of the
effect is thought to be due to glucose-dependent insulinotropic peptide (GIP) and
glucagon like peptide-1 (GLP-1).
– GLP-1 concentrations are reduced in patients with type 2 diabetes in response to
a meal.
– Not orally available and must be injected.
14) Oral Pharmacological agents for type 2 diabetes. Accessed from URL: http://www.endotext.org/diabetes/diabetes16/diabetes16.htm.
Accessed on 28/04/2010 at 11.30 am

Dipeptidyl Peptidase IV (DPP-IV) Inhibitors15
– Inhibition of dipeptidyl peptidase 4 (DPP-4) is a novel treatment
for type-2 diabetes. Several DPP-4 inhibitors are in clinical
development.
– Most experience so far has been with sitagliptin and vildagliptin.
– Mechanism
DPP-4 inhibition prevents the inactivation of glucagon-like peptide 1
(GLP-1), which increases levels of active GLP-1.
Normally GLP-1 gets degraded very quickly due to enzyme DPP-4,
these drugs prevent this rapid degradation.
This increases insulin secretion and reduces glucagon secretion,
thereby lowering glucose levels.
– Efficacy
A reduction in HbA1c of approximately 0.5-0.8% in clinical studies.
15) Ahren B. DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab. 2007 Dec;21(4):517-33.

Dipeptidyl Peptidase IV (DPP-IV) Inhibitors15
– Side Effects
Common are: common cold features, nausea.
The risk of hypoglycaemia is minimal, and
DPP-4 inhibition is body-weight neutral
– Place in Therapy
Sitagliptin, vildagliptin and saxagliptin improve metabolic control in
type-2 diabetes, both in monotherapy and in combination with
metformin, sulfonylureas and thiazolidinediones.
Only vildagliptin is approved for use in combination with insulin.
Costly with not so much Hba1c% reduction.
Though these are wonderful drugs, long term studies regarding
their safety are awaited.
Watch for Pancreatitis and Cancers.

Overview of the mechanism of action of antidiabetic drugs
14) Oral Pharmacological agents for type 2 diabetes. Accessed from URL: http://www.endotext.org/diabetes/diabetes16/diabetes16.htm.
Accessed on 28/04/2010 at 11.30 am

Comparison of the Effects of Major
OADs on Glycaemic Control
Fonseca V. Current Medical Res Opin 2003; 19: 635–641.
Acarbose Glitazones
(PPAR 
agonists)
Metformin SUs Glinides
↓ HbA1c
(%)
0.5-1.0 0.3-1.0 1.4 1.0-2.0 1.1
↓ FPG
(mg/dL)
20-30 20-55 53 43-74 31-49
↓ PPG
(mg/dL)
49-61 No
effect
No
effect
63-94 22-99
19
Abbreviations: OADs – oral antidiabetic drugs: PPAR-γ – peroxisome proliferator-activated receptor- γ ; SUs – sulfonylureas;
HbA1c – glycosylated haemoglobin:FPG – fasting plasma glucose; PPG – postprandial plasma glucose

Choosing Antidiabetic Agents: Efficacy
= reduced levels = increased levels = no significant effect
20
Insulin
secretagogues
Metformin TZDs*
Effect on FPG/HbA1c
1,5
Effect on plasma
insulin1,2,5 –
Effect on insulin
resistance3 –
Effect on insulin
secretion4,5
EFFICACY Insulin
ANTIDIABETIC AGENTS
α-glucosidase
inhibitors
*TZDs = thiazolidinediones; GLP = glucagon-like peptide; DPP = dipeptidyl peptidase
–
GLP*
analogues
DPP IV*
inhibitors
1DeFronzo RA. Ann Intern Med 1999; 131: 281–303. 2Lebovitz HE. Endocrinol Metab Clin North Am 2001; 30: 909–933.
3Matthaei S, et al. Endocrine Rev 2000; 21: 585–618. 4Raptis SA & Dimitriadis GD. J Exp Clin Endocrinol 2001; 109
(Suppl 2): S265–S287. 5Amori RE, et al. JAMA 2007; 298: 194-206.

Choosing Antidiabetic Agents:
Safety and Tolerability
= not commonly seen in monotherapy
= treatment-related adverse event
21
Insulin
secretagogues
Metformin TZDs*
SAFETY AND
TOLERABILITY
Insulin
ANTIDIABETIC AGENTS
α-glucosidase
inhibitors
Risk of
hypoglycemia1,2,4
Weight gain1,2,4
Gastrointestinal
side effects1,4
Lactic acidosis1
Edema3
GLP*
analogues
DPP IV*
inhibitors
*TZDs = thiazolidinediones; GLP = glucagon-like peptide; DPP = dipeptidyl peptidase. ** Weight loss
**
1DeFronzo RA. Ann Intern Med 1999; 131: 281–303. 2UKPDS. Lancet 1998; 352: 837–853.
3Nesto RW, et al. Circulation 2003; 108: 2941–2948. 4Amori RE, et al. JAMA 2007; 298: 194-206.

An Ideal OAD
Suitable for use in all T2DM patients
Dual mode of action
Significant change in HbA1c in monotherapy
Rapid and sustained blood glucose lowering effect in monotherapy
Safe and effective when combined with insulin and/or other hypoglycaemic
agents
Clinically proven safety profile
– Lower incidence of hypoglycaemic events
– No weight gain
– Lower risk of cardiovascular complications
Single dose should confer 24-h blood glucose control
Convenient, once daily dosing resulting in good compliance
22

Predictors of response to therapy
Baseline glycemia
Duration of diabetes
Efficacy of interventional drug
Previous therapy
Life style (Sedentary Vs Active)

Contribution of fasting hyperglycaemia to overall glycaemia
increases with worsening diabetes
ADA=American Diabetes Association; OHA=oral hypoglycaemic agent; PG=plasma glucose.
Adapted from Monnier L, et al. Diabetes Care 2003;26:881―5.
290 patients with T2DM treated with diet or OHAs
Baseline (normal) PG defined as 6.1 mmol/l (110 mg/dl) ― threshold defined by
ADA as the upper limit of normal PG at fasting or preprandial times
100
0
50
Relative
contribution
(%)
<7.3 7.3―8.4 8.5―9.2 9.3―10.2 >10.2
HbA1c (%) quintiles
70%
30%
Fasting

HbA1c and diurnal glucose
variation
If fasting and preprandial glucose levels between
70-130 mg/dl: HbA1c 7-7.5%
Despite normal preprandial levels, HbA1c >7.5%
: assess postprandial levels

Antidiabetic Interventions
Intervention % Decrease
in A1c
Advantages Disadvantages
Lifestyle
intervention
1-2 Low cost, many benefits Fails for most in 1st
year
Metformin 1.5 Weight neutral, inexpensive GI side effects, lactic
acidosis
Insulin 1.5-2.5 No dose limit, improved lipid
Profile
Injections,monitoring,
hypoglycemia, weight gain
Sulfonylureas 1.5 Inexpensive Weight gain, hypoglycemia
TZDs 0.5-1.4 Improved lipids Fluid retention, weight gain
Other Medications
α-Glucosidase
inhibitors
0.5-0.8 Weight neutral GI side effects
Exenatide 0.5-1.0 Weight loss Injections, GI, expense
Glinides 1-1.5 Short duration 3x day dose, expense
Pramlintide 0.5-1.0 Weight loss Injections, expense, GI side
effects
Adapted from: Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy:
a consensus statement from the American Diabetes Association and the Europwan Association for the Study of Diabetes. Diabetes care August 2006

LSM
One
OHA
Two
OHA
Insulin
+
OHA
MSI
+
Sensitizers
Duration Of DM
Approach to treatment

+ +
+
Stepwise Management of T2 DM
Biggest Clinical Hurdle???
Adapted from Williams G. Lancet 1994; 343: 95-100.

Fasting hyperglycemia Post-prandial
hyperglycemia
-Increased hepatic glucose -Impaired insulin secretion
output
-Hepatic insulin resistance -Decreased tissue glucose
uptake
Modalities Modalities
Metformin -Sulfonylurea
Intermediate/Long acting -Glitazones
insulin -Glinides
- glucosidase inhibitors
-GLP-1 analogues
-Insulin

Efficacy of various interventions as
Monotherapy
Intervention Efficacy to decrease A1c
Life style modification 1-2%
Metformin 1.5%
Sulfonylurea 1.5%
Glitazones 0.5-1.4%
 glucosidase inhibitors 0.5-0.8%
Glinides 0.5-1.5%
GLP-1 analogues 0.5-1%
Insulin 1.5-2.5%

Efficacy as a combination therapy
Regimen HbA1c FPG
Metformin+SU ~1.7% ~65mg/dl
Metformin+Rosi ~1.2% ~50mg/dl
Metformin+Pio ~0.7% ~40mg/dl
SU + Rosi ~1.4% ~60mg/dl
SU + Pio ~1.2% ~50mg/dl
Diabetes 1999:48(Supple 1): A100-117
NEJM 1995; 333; 541-9

100
75
50
25
0
-10 -6 -2 2
0 6 10 14
-12
Years From Diagnosis
b-Cell
Function
(% b)
Stages of Type 2 Diabetes:
Type 2
Diabetes
Phase I
MonoTherapy
Type 2
Diabetes
Phase II
Combination Oral
Therapy
Phase III
Insulin
Criteria for Advancing to next stage?
HbA1C Not at target: < 7.0%
Based on data of UKPDS 16: Diabetes. 1995.

Call to action
How to choose an agent
Normal
HbA1c < 6%
ADD AGENT
Less potential to lower
glycemia and/or with a
slower onset of action
ADD AGENT
Greater glucose-lowering
effects or earlier initiation
of combination therapy
Uncontrolled type 2
< 7.5% > 8.5%
Nathan DM, et al. Diabetologia 2006;49:1711–21; Diabetes Care, Volume 29, Number 8, August 2006 (1963-72)

Combination Therapy
for Type 2 Diabetes
Biguanides
Insulin
Sulfonylureas
Alpha-glucosidase
Inhibitors
Meglitinide Thiazolidinediones

Why Algorithms?
Choice of medications
Order of recommendations
Usefulness of combinations
Addition of Insulin at appropriate time
Time schedule to achieve target HbA1c
Non-glycemic targets

ADA Consensus Algorithm for
the Metabolic Management of
Type 2 Diabetes

The ADA Algorithm
• Takes into account characteristics of
individual interventions, synergies, and
expenses
• Goal:
– To achieve and maintain glycemic levels as
close to non-diabetic range as possible
– To change interventions at as rapid a pace as
titration of medication allows

Medications Not Included in
the Management Algorithm
• Lower overall glucose-lowering effectiveness
• Limited clinical data
• And/or relative expense
Pramlintide, alpha-glucosidase inhibitors, glinides,
DPP-IV inhibitors are not included due to their:
However, they may be appropriate
choices in selected patients

ADA: Physical Activity/Exercise
Recommendations for Patients With
Type 2 Diabetes
Patients with type 2 diabetes should be evaluated prior to
initiation of any exercise program beyond brisk walking
Exercise program (absent contraindications) should include:
– ≥ 150 min/week moderate-intensity (50-70% max heart rate)
aerobic activity, and/or
– ≥ 90 min/week vigorous (>70% max heart rate) aerobic activity
– Resistance exercise 3 times/week targeting all major muscle
groups
Distribute physical activity over ≥ 3 days/week with no more
than 2 consecutive days without physical activity.
Sigal RJ et al. Diabetes Care 2006-29:1433-1438

ADA/EASD: Titration of Metformin
(cont’d)
The maximum effective dose can be up to 1,000 mg
twice daily but is often 850 mg twice daily. Modestly
greater effectiveness has been observed with doses
up to ~2,500 mg/d. Gastrointestinal side effects may
limit the dose that can be used.
Based on cost considerations, generic metformin is
the first choice of therapy. A longer-acting
formulation is available in some countries and can be
given once daily.
Nathan DM et al. Diabetes care. 2008;31. Epub ahead of publication

ADA/EASD: Metabolic Management of Type 2
Diabetes
a Rosiglitazone is not recommended.
b Sylfonylureas other than glybenclamide
(glyburide) or chlopropamide.
c Insufficient clinical use to be confident
regarding safety.
CHF=congestive heart failure;
GLP-1=glucagon-like peptide-1
Lifestyle + Metformin
+ GLP-1 agonistc
(exenatide)
No hypoglycemia
Weight loss
Nausea/Vomiting
+
Basal insulin
+
Pioglitazonea
+
Sulfonylureab
+
Pioglitazonea
No hypoglycemia
Edema/CHF
Bone loss
+
Sulfonylureab
+
Basal insulin
STEP 2
+
Intensive insulin
At diagnosis:
Lifestyle
+
Metformin
STEP 3
STEP 1
Tier 1:
Well
validated
core
therapies
Tier 2:
Less well
validated
therapies

ADA/EASD: Glucose-Lowering Interventions as
Monotherapy—
Tier 1: Well-Validated Core
Intervention Expected decrease in
A1C with Monotherapy
(%)
Step 1: initial
therapy
Lifestyle to decrease
weight and increase
activity
Metformin
1.0-2.0
1.0-2.0
Broad benefits
Weight neutral
Insufficient for most
within first year
GI side effects,
contraindicated with
renal insufficiency
Step 2: additional
therapy
Insulin
Sulfonylurea
1.5-3.5
1.0-2.0
No dose limit rapidly
effective, improved
lipid profile
Rapidly effective
One to four injections
daily, monitoring, weight
gain, hypoglycaemia,
analogues are
expensive
Weight gain,
hypoglycaemia
(especially with
glibenclamide or
chlorpropamide)
CHF, congestive heart failure; GI, gastrointestinal; MI, myocardial infarction

Monotherapy—
Tier 2: Less Well-Validated Therapies
Intervention
Expected
Decreased in
A1C with
Monotherapy (%)
TZDs 0.5-1.4 Improved lipid
profile
(pioglitazone),
potential decrease
in MI (pioglitazone)
Fluid retention, CHF,
weight gain, bone
fractures, expensive,
potential increase in MI
(rosiglitazone)
GLP-1 agonist 0.5 – 1.0 Weight loss 2 injections daily, frequent
GI side effects, long-term
safety not established,
expensive
CHF=congestive heart failure; GI=gastrointenstinal; GLP-1=glucagon-like peptide-1;
MI=myocardial infarction; TZD=thiazolidinediones.

Monotherapy—
Other therapy
Intervention Expected decrease in
A1C with Monotherapy
(%)
α-Glucosidase
inhibitor
0.5–0.8 Weight neutral Frequent GI side effects,
three times/day dosing,
expensive
Glinide 0.5–1.5a Rapidly effective Weight gain, three
times/day dosing,
hypoglycaemia,
expensive
Pramlintide 0.5–1.0 Weight loss Three injections daily,
frequent GI side effects,
long-term safety not
established, expensive
DPP-4 inhibitor 0.5–0.8 Weight neutral Long-term safety not
established, expensive
a Repaglinide more effective in lowering HbA1c than nateglinide
CHF, congestive heart failure; GI, gastrointestinal; MI, myocardial infarction

The ADA Recommendations on the
Use of Insulin in Type 2 Diabetes

Physiology of Insulin secretion
Normally, glucose induces a biphasic pattern of insulin release.
– 1st phase insulin release occurs within the first few minutes after
exposure to an elevated glucose level
Rapid release possible as insulin is pre stored in B cells during
periods of fasting, waiting to get released quickly on the arrival of
glucose.
– 2nd Phase release is prolonged
Insulin has to be synthesized, processed, and secreted for the
duration of the increase of blood glucose.
Beta cells also have to regenerate the stores of insulin initially
depleted in the fast response phase.
– Important to observe that 1st phase secretion is lost early in type 2
diabetes.
These patients experience hyperglycemic periods after meals.

Adapted from McCall AL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc; 2002:193-222.
Normal Plasma Insulin Profile
Breakfast Dinner
Lunch
Plasma
levels
Endogenous insulin
Time of day

Adapted from McCall AL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc; 2002:193-222.
Bolli GB et al. Diabetologia. 1999;42:1151-1167.
Normal Plasma Insulin Profile
Breakfast Dinner
Lunch
Plasma
levels
Bolus insulin
Basal insulin
Endogenous insulin
Time of day

The Use of Insulin
in Type 2 Diabetes

Post-prandial
hyperglycaemia
Post-prandial
hyperglycaemia
contributes HbA1c ~1%
B=breakfast; L=lunch; D=dinner.
Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.
Plasma
glucose
(mg/dL)
300
200
100
0
Time of day (h)
6 12 18 24 6
Uncontrolled Diabetes HbA1c 8%
Fasting
hyperglycaemia
Basal hyperglycaemia
contributes ~2%

B

L

D
Normal
HbA1c ~5%
Basal Hyperglycaemia Contributes
More to Increased HbA1c Levels Than Does
Post-prandial Hyperglycaemia

Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (P<0.001).
Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
Time of day (h)
400
300
200
100
0
6 6
10 14 18 22 2
Plasma
glucose
(mg/dL)
Diabetic (untreated)
Normal
Meal Meal Meal
20
15
10
5
0
Plasma
glucose
(mmol/L)
Treating Basal Hyperglycaemia Lowers the
Entire 24-Hour Plasma Glucose Curve

Diabetic
(after treatment)
Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.
200
100
Time of day (h)
400
300
0
6 6
10 14 18 22 2
Normal
Meal Meal Meal
Plasma
glucose
(mg/dL)
20
15
10
5
0
Treating Basal Hyperglycaemia Lowers the
Entire 24-Hour Plasma Glucose Curve
Plasma
glucose
(mmol/L)

Types of Insulin
1. Rapid-acting
2. Short-acting
3. Intermediate-acting
4. Premixed
5. Long-acting
6. Extended long-acting

Rapid Acting
(e.g., aspart, lispro,
glulisine)
Short Acting
(e.g., regular insulin)
Onset 10-15 mins 30-60 mins
Peak 60-90 mins 2-4 hrs
Duration 4-5 hrs 5-8 hrs
Types of Insulin

Intermediate Acting
(e.g., NPH, lente)
Premixed
(e.g., 75% NPL / 25%
lispro,
70% APS / 30% aspart,
70% NPH / 30%
regular/NPH)
Onset 1-3 hr(s)
One vial or cartridge
with a fixed ratio of
rapid- or short-acting
to intermediate-acting
insulin
Peak 5-8 hrs
Duration Up to 18 hrs
Types of Insulin

Long Acting
(e.g., ultralente)
Long-Acting Analogues
(glargine, detemir)
Onset 3-4 hrs 1.5-3 hrs
Peak 8-15 hrs No peak with glargine,
dose-dependent peak
with detemir
Duration 22-26 hrs 9-24 hrs (detemir);
20-24 hrs (glargine)
Types of Insulin

Advantages of Insulin Therapy
• Oldest of the currently available
medications, has the most clinical
experience
• Most effective of the diabetes
medications in lowering glycemia
– Can decrease any level of elevated HbA1c
– No maximum dose of insulin beyond which
a therapeutic effect will not occur
• Beneficial effects on triglyceride and
HDL cholesterol levels

Effect of Insulin on Triglyceride
and HDL-C Levels
Adapted from Nathan DM et al. Ann Int Med 1988;108:334-40.
1
1.1
1.2
1.3
1.4
1.5
Baseline Month 9
1
1.2
1.4
1.6
1.8
2
Baseline Month 9
Tryglyceride
level
(mmol/l)
HDL-C
(mmol/L)
0.22 mmol/l
(19.4mg/dl)
p=0.07
n=15
1.85
1.17
1.51
1.39
HDL-C
Triglycerides
0.34 mmol/l
(30mg/dl)
p=0.07
n=15

Disadvantages of Insulin Therapy
• Weight gain ~ 2-4 kg
– May adversely affect cardiovascular health
Hypoglycemia
– However, rates of severe hypoglycemia in
patients with type 2 diabetes are low…
 Type 1 DM: 61 events per 100 patient-years
 Type 2 DM: 1-3 events per 100 patient-years

Balancing Good Glycemic Control with
a Low Risk of Hypoglycemia…
Hypoglycemia
Glycemic
control

Choosing an Insulin with a
Lower Risk of Hypoglycemia
• Insulin analogues with longer, non-peaking
profiles may decrease the risk of
hypoglycemia…

Action Profiles of Insulin Analogues
Plasma
insulin
level
Regular, 6-8 h
NPH, 13-16 h
Ultralente, 18-24 h
Time (h)
Glargine, 24 h
Aspart, lispro, glulisine, 2-5 h
2 4 6 8 10 12 14 16 18 20 22 24
0
NPH=neutral protamine Hagedorn.

Elevated FPG
Normal FPG
Higher the Fasting - Higher the Post Prandial

Glucose Infusion Profiles
in Type 1 Diabetes
Adapted from Lepore M et al. Diabetes 2000;49:2142-8.
0 4 8 12 16 20 24
Glucose
infusion
rate
(mg/kg/min)
4
Time (hr)
3
2
1
0
(n=20)
Ultralente 0.3 U/kg
Glargine 0.3 U/kg
NPH 0.3 U/kg
Peak 4-6 hrs Peak 8-14 hrs

Rates of Hypoglycemia
for Premixed vs. Long-Acting Insulin
Adapted from Raskin P et al. Diabetes Care 2005;28(2):260-5.
0
0.5
1
1.5
2
2.5
3
3.5
BIAsp 70/30
(n=117)
0
5
10
15
20
25
30
35
40
45
Glargine
(n=116)
BIAsp 70/30
(n=117)
Glargine
(n=116)
Episodes
per
patient-year
%
of
subjects
p<0.05 p<0.05
3.4
0.7
43
16

HbA1c 7% Without Hypoglycemia (Composite
Endpoint) in Two Treat-to-Target Studies
Hypoglycemia definition: glucose levels
≤4 mmol/L (72 mg/dL) or requiring assistance 1. Riddle M et al. Diabetes Care 2003;26:3080-6.
2. Hermansen K et al. Diabetes Care 2006;29:1269-74.
0
5
10
15
20
25
30
35
Once-daily dosing1
Twice-daily dosing2
p<0.05
Percentage
of
patients
achieving
HbA
1c
7%
33.2
26.7
Insulin
glargine
NPH NPH
Insulin
detemir
0
5
10
15
20
25
30
35
Percentage
of
patients
achieving
HbA
1c
7%
p=0.008
26.0
16.0

Rates of Hypoglycemia for Premixed
vs. Long-Acting Insulin + OAD
Adapted from Janka et al. Diabetes Care 2005;28:254-9.
Mean number of confirmed hypoglycemic events
per patient-year in a 28-week study
0
1
2
3
4
5
6
Symptomatic Nocturnal Severe
Premixed insulin
Insulin glargine + OADs
5.73
2.62
1.04
0.51
0.05 0.00
Events
per
patient-year
p=0.0009
p=0.0449 p=0.0702

Rates of Hypoglycemia for Premixed
vs. Long-Acting Insulin + OAD in Elderly Patients
Adapted from Janka HU et al. J Am Geriatr Soc 2007;55(2):182-8.
Rate
of
event
per
patient-year
p=0.01
p=0.008
p=0.06
0
2
4
6
8
10
12
Premixed (n=63)
Glargine + OAD (n=69)
All episodes of
hypoglycemia
All confirmed
episodes of
hypoglycemia
Confirmed
symptomatic
hypoglycemia

Rates of Nocturnal Hypoglycemia for NPH
vs. Long-Acting Insulin
Adapted from Rosenstock J et al. Diabetes Care 2001;24(4):631-6.
HbA1c and rates of nocturnal hypoglycemia at Week 28
NPH (n=259)
Insulin glargine (n=259)
4
3
2
1
0
-1
-2
40
30
20
10
0
Adjusted
mean
change
from
baseline
Patients
(%)
p<0.01 for both
treatments vs.
baseline
p<0.02
glargine
vs. NPH
HbA1c (%) Nocturnal
hypoglycemia
(Month 2 to
endpoint)

The ADA Treatment
Algorithm for the Initiation
and Adjustment of Insulin

Initiating and Adjusting Insulin
Continue regimen; check
HbA1c every 3 months
If fasting BG in target range, check BG before lunch, dinner, and bed.
Depending on BG results, add second injection
(can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range)
Recheck pre-meal BG levels and if out of range, may need to add another
injection; if HbA1c continues to be out of range, check 2-hr postprandial levels
and adjust preprandial rapid-acting insulin
If HbA1c ≤7%...
Bedtime intermediate-acting insulin, or
bedtime or morning long-acting insulin
(initiate with 10 units or 0.2 units per kg)
Check FG and increase dose until in target range.
If HbA1c 7%...
Hypoglycemia
or FG >3.89 mmol/l (70 mg/dl):
Reduce bedtime dose by ≥4 units
(or 10% if dose >60 units)
Pre-lunch BG out of range: add
rapid-acting insulin at breakfast
Pre-dinner BG out of range: add NPH insulin at
breakfast or rapid-acting insulin at lunch
Pre-bed BG out of range: add
rapid-acting insulin at dinner
Target range:
3.89-7.22 mmol/L
(70-130 mg/dL)
Nathan DM et al. Diabetes Care. 2006;29(8):1963-72.
If HbA1c ≤7%... If HbA1c 7%...

Step One…
If HbA1c ≤7%...
If HbA1c 7%...
Hypoglycemia
Target range:
3.89-7.22 mmol/L
(70-130 mg/dL)
If HbA1c ≤7%... If HbA1c 7%...

Step One: Initiating Insulin
• Start with either…
– Bedtime intermediate-acting insulin or
– Bedtime or morning long-acting insulin
Insulin regimens should be designed taking
lifestyle and meal schedules into account

Step One: Initiating Insulin, cont’d
• Check fasting glucose and increase dose
until in target range
– Target range: 3.89-7.22 mmol/l (70-130 mg/dl)
– Typical dose increase is 2 units every 3 days,
but if fasting glucose >10 mmol/l (>180 mg/dl),
can increase by large increments (e.g., 4 units
every 3 days)

• If hypoglycemia occurs or if fasting
glucose >3.89 mmol/l (70 mg/dl)…
– Reduce bedtime dose by ≥4 units or 10%
if dose >60 units
Step One: Initiating Insulin, cont’d

• If HbA1c is <7%...
– Continue regimen and check HbA1c every
3 months
• If HbA1c is ≥7%...
– Move to Step Two…
After 2-3 Months…

If HbA1c ≤7%...
If HbA1c 7%...
Hypoglycemia
Target range:
3.89-7.22 mmol/L
(70-130 mg/dL)
If HbA1c ≤7%... If HbA1c 7%...
Step Two…

Step Two: Intensifying Insulin
If fasting blood glucose levels are in target range
but HbA1c ≥7%, check blood glucose before
lunch, dinner, and bed and add a second
injection:
• If pre-lunch blood glucose is out of range, add rapid-
acting insulin at breakfast
• If pre-dinner blood glucose is out of range, add NPH
insulin at breakfast or rapid-acting insulin at lunch
• If pre-bed blood glucose is out of range, add rapid-
acting insulin at dinner

Making Adjustments
• Can usually begin with ~4 units and
adjust by 2 units every 3 days until blood
glucose is in range

• If HbA1c is <7%...
– Continue regimen and check HbA1c every
3 months
• If HbA1c is ≥7%...
– Move to Step Three…
After 2-3 Months…

If HbA1c ≤7%...
If HbA1c 7%...
Hypoglycemia
Target range:
3.89-7.22 mmol/L
(70-130 mg/dL)
If HbA1c ≤7%... If HbA1c 7%...
Step Three…

Step Three:
Further Intensifying Insulin
• Recheck pre-meal blood glucose and if
out of range, may need to add a third
injection
• If HbA1c is still ≥ 7%
– Check 2-hr postprandial levels
– Adjust preprandial rapid-acting insulin

Premixed Insulin
• Not recommended during dose
adjustment
• Can be used before breakfast and/or
dinner if the proportion of rapid- and
intermediate-acting insulin is similar
to the fixed proportions available

Key Take-Home Messages
• Insulin is the oldest, most studied, and most effective
antihyperglycemic agent, but can cause weight gain
(2-4 kg) and hypoglycemia
• Insulin analogues with longer, non-peaking profiles may
decrease the risk of hypoglycemia compared with NPH
insulin
• Published studies have not demonstrated whether
inhaled insulin can lower HbA1c to ≤7%...
• Premixed insulin is not recommended during dose
adjustment

Key Take-Home Messages, cont’d
• When initiating insulin, start with bedtime intermediate-
acting insulin, or bedtime or morning long-acting
insulin
• After 2-3 months, if FBG levels are in target range but
HbA1c ≥7%, check BG before lunch, dinner, and bed,
and, depending on the results, add 2nd injection
• After 2-3 months, if pre-meal BG out of range, may
need to add a 3rd injection; if HbA1c is still ≥7% check
2-hr postprandial levels and adjust preprandial
rapid-acting insulin

Conclusions
Treatment of diabetes is individualized and tailor
made
Dose titration should be faster and target HbA1c
should be achieved at the earliest possible (3 –
6 months)
Insulin should be added if target HbA1c is not
achieved with submaximal doses of two drugs
Triple OHA therapy is inferior to intensive insulin
therapy

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