August 13, 2012

Management of
Hyperglycemia in Type 2
DM
I.
II.

III.
IV.

increase in hepatic glucose production, which

leads to an increase in blood glucose.
It is known that in DM type two, there are
bigger and more Alpha cells and they are not
suppressing glucagon as well as normal
individuals. In normal individuals, after a meal,
blood sugar level goes up and glucagon should
be suppressed. Insulin will be released so that
your liver will stop from gluconeogenesis and
glycogenolysis. In DM type 2, there is
decreased
insulin
and
improper
suppression of glucagon. Hence, the two
reasons for increased glucose release of liver
which leads to hyperglycemia, both in fasting
and postprandial states.
With decreased secretion of insulin, less
glucose is taken up by muscle, adipose
tissue, and liver. This leads to post meal
hyperglycemia.
There are other systems which are being
looked into like kidney, brain and the gut but
the most basic is this.

Outline
Review: Major Pathophysiologic Defects in T2DM
Management of Hyperglycemia in T2DM
o
UKPDS Prospective Diabetes Study
o
Steno-2 Study
o
ADA-EASD Position Statement: A PatientCentered Approach
1. Patient-Centered Approach
2. Background
- Epidemiology and healthcare impact
- Relationship of Glycemic Control Outcomes
- Overview of the Pathogenesis of Type 2 Diabetes
3. Antihyperglycemic Therapy
Oral agents and non-insulin injectables
(biguanides, SU, TZD, a-glucosidase inhib,
DPP-4-I, GLP-1-RA)
Insulin
Implementation therapy in type 2 DM
Sequential insulin strategies in type 2 DM
Variations in antihyperglycemic therapy
(avoid weight gain, minimize cost, guidelines
for glycemic, BP and lipid control)
4. Other considerations
5. Future directions/ Research Needs
Key points
Samplex review

{Editors note: Please go back to the outline if you feel lost in this
trans. We revised the flow of the discussion a bit to make it easier to
follow. FOCUS ON THE ADA-EASD position statement since it is the bulk
of the lecture. Thank you! }

REVIEW
MAJOR PATHOPHYSIOLOGIC DEFECTS IN
TYPE 2 DIABETES

Major defects: insulin resistance and islet

cell dysfunction. In the islet cells of
Langerhans there are two cells that are
involved in the generation of hyperglycemia: 1.
Beta Cell (insulin); 2. Alpha cells (glucagon).
Insulin resistance is increased and insulin
secretion is impaired.
Most
patients
have
insulin
resistance.
Pancreatic cells increase insulin secretion to
compensate for insulin resistance. When -cell
function is impaired, hyperglycemia develops.
By the time diabetes is diagnosed, -cell
function has already decreased substantially
and continues to decline over time.
Once insulin secretion is impaired, an
imbalance between insulin and glucagon can
develop. Elevated glucagon levels lead to an
Belisario, Bernabe, Bringas | Bautista XJV

{Editor: Not explained by Dr. Panelo but this picture just

illustrates 2 points in the pathophysiology mentioned
earlier. The graph on the upper part demonstrates that
both postprandial and fasting hyperglycemia is present in
uncontrolled diabetes. The lower graph shows that by
time of diagnosis of DM, -cell function has already
decreased substantially and continues to decline over
time.}

MANAGEMENT OF HYPERGLYCEMIA IN TYPE

2 DIABETES
UK PROSPECTIVE DIABETES STUDY
(UKPDS)

UK Prospective Diabetes Study (UKPDS) was a

prospective observational study to determine the
relation between exposure to hyperglycemia over
time
and
the
risk
of
macrovascular
or
microvascular complications in patients with type 2
diabetes who were participants in the UKPDS.
3,642 White, Asian Indian and Afro-Caribbean
UKPDS patients who had HbA 1c measured three
months after their diabetes diagnosis and with
complete data for potential confounders were
included in the sub-analysis of relative risk.
Page 1 of 13

Reductions in the risk of microvascular and

macrovascular complications that might be
achieved by lowering HbA 1c by 1% were
estimated.
UKPDS: Reduced micro- and macrovascular
complications for a 1% decrease in HbA1c
Any diabetes-related
21 % (P<0.0001)
endpoint
Diabetes-related death
21% (P<0.0001)
All cause mortality
14% (P<0.0001)
Myocardial Infarction
14% (P<0.0001)
Stroke
12% (P=0.035)
Peripheral Vascular Disease
43% (P<0.0001)
Microvascular Disease
37% (P<0.0001)
Cataract extraction
19% (P<0.0001
*NOTE: The conversion factor for blood glucose mg/dl to
mmol/l = x 0.0555.

This is showing the importance of decreasing

blood sugar level manifested by HBA1c that
for every 1% decrease you get these
advantage.
The incidence of clinical complications was
found to be significantly associated with
hyperglycemia. While any reduction in HbA1c is
likely to reduce the risk of complications, the
lowest risk was observed in those with HbA 1c
values in the normal range (< 6.0%). A 1%
decrease in HbA1c was
estimated to
correspond with significant reductions in any
diabetes-related endpoint, diabetes-related
death, all cause mortality,
myocardial
infarction, stroke, peripheral vascular disease,
microvascular disease and cataract extraction.

STENO-2 DIABETES STUDY

Effect
of
Intensive
Vs.
Conventional
Treatment on Cardiovascular Complications

prescribed medications, and was given

patient education only
o Intensive therapy same therapy, patient
education and care but patients were
followed up more closely: checking up
NOT ONLY the blood sugar level but also
the cholesterol, triglyceride, systolic and
diastolic BP
After 48 months, there was already a
significant
difference
with
regards
to
cardiovascular complications Patients in the
intensive group have LESS cardiovascular
group than those in the conventional group.
And at the end of the 96 months, there was a
50%
reduction
in
cardiovascular
and
microvascular complications in the intensive
group.
Long-term targeted, intensive intervention
involving multiple risk factors reduces the risk
of cardiovascular complications in patients
with type 2 diabetes and microalbuminuria
treat not only the hyperglycemia; be wary of
BP and serum cholesterol and triglycerides
If patients in the intensive group were unable
to maintain an HbA1c of < 6.5% by means of
diet and increased physical activity alone after
3 months, an oral hypoglycaemic agent was
started
(either
metformin
and/or
a
sulphonylurea). If the HbA1c exceeded 7%,
despite maximum doses of oral hypoglycaemic
agents,
the
addition
of
insulin
was
recommended.
The primary composite endpoint of this open,
parallel trial was a composite of death from
cardiovascular causes, non-fatal MI, non-fatal
stroke, revascularisation and amputation.
Subjects receiving intensive therapy were
much more likely to reach their total
cholesterol goal (< 175 mg/dl) (72% versus
22%, p< 0.001) and systolic BP goal (< 130
mmHg) (46% versus 19%, p = 0.001). The
difference between intensive and conventional
therapy for achieving HbA1c goal of < 6.5%
was 15% versus 3%, p = 0.06.

Efficacy of Multiple Risk Factor

Intervention in High-risk Subjects*

Patients were randomly assigned to receive

either conventional treatment in accordance
with
national
guidelines,
or
intensive
treatment, with a stepwise implementation of
behavior modification and pharmacological
therapy
that
targeted
hyperglycaemia,
hypertension,
dyslipidemia
and
microalbuminuria,
along
with
secondary
prevention of CVD with aspirin.
o Conventional therapy patients were
followed up in their regular clinic,

Belisario, Bernabe, Bringas | Bautista XJV

Page

*High-risk subject is defined as having type 2 diabetes

with microalbuminuria

The Steno-2 study showed the effect of a

multiple risk factor intervention strategy in
160 subjects with type 2 diabetes with
microalbuminuria. Although all these subjects
had type 2 diabetes, the results suggest that
multiple risk factor intervention may also be
highly beneficial in subjects with the metabolic
syndrome.
Subjects in the intensive therapy group were
to follow a reduced-fat diet and exercise
regularly, were offered smoking cessation
counselling, were prescribed an ACE inhibitor
or ARB regardless of blood pressure, and
received vitamin supplementation and aspirin;
stepwise antiglycaemic and antihypertension
medications were also prescribed as well as
lipid-modifying therapy with a statin and/or
fibrate.
Subjects receiving intensive therapy were
much more likely to reach their total
cholesterol goal (< 175 mg/dl) and systolic
blood pressure goal (< 130 mmHg) and to
routinely use ACE inhibitors or ARBs (data not
shown). Note that it was much more difficult
to achieve systolic blood pressure goal than
diastolic blood pressure goal. The difference
between intensive and conventional therapy
for HbA1c (glycosylated haemoglobin) was only
0.6%.

ADA-EASD POSITION STATEMENT: A PATIENTCENTERED APPROACH

I.
II.
III.
IV.
V.

Patient-Centered Approach
Background
Antihyperglycemic Therapy
Other considerations
Future directions/ Research Needs

values guide all clinical decisions. So we

cannot just dictate everything to the patient.
Remember that this is a chronic disease and
needs lifelong care: COMPLIANCE is a major
issue in chronic disease like diabetes. And you
will see when you practice that patients
develop TREATMENT FATIGUE (will stop seeing
you and will be absent for months or years
until they become symptomatic again). The
ADA and the EAS, they feel that if they are
involved in the decision making of what to do
with them, then maybe the compliance will be
better.
So in the implementation of the use of
antihyperglycemic therapy, you have this
initial drug therapy advancing to dual
combination therapy, advancing to triple
combination therapy, and transition to and
titrations of insulin. THIS should be the
norm to all DM patients knowing the natural
history of type 2 diabetes (Note review on
page 1). Knowing this, you cannot keep on
maintaining your patient with the initial drug
therapy. So if you started on 1 medication for
the 1st visit, you cannot maintain the patient
on that medication for a lifetime. You will soon
find out the blood sugar is continually going
up even if patient is compliant. Treatment
modality must be upgraded (initial dual
triple insulin). {If we can remember this, Dr.
Panelo will be very happy with the outcome of this
lecture }

II. BACKGROUND
Epidemiology and health care impact

I. PATIENT-CENTERED APPROACH

Gauge
patients
preferred
level
of
involvement.
o When we treat, we set targets but they
are
NOT
GENERIC;
MUST
BE
INDIVIDUALIZED. Most young patients who
do not have complications yet should
benefit from very strict glycemic control
(6-6.5). The older ones may need a higher
target level than 6.5 or even 7.
Explore, where possible, therapeutic choices.
o Options would include: lifestyle change,
use of oral anti-diabetic agents, noninsulin injectables, and insulin.
Utilize decision aids.
Shared decision making final decisions
regarding lifestyle choices ultimately lies
with the patient.
...providing care that is respectful of and
responsive to individual patient preferences,
needs, and values - ensuring that patient

Belisario, Bernabe, Bringas | Bautista XJV

Figure: The Diabetes Epidemic: Global

Projections 2010-2030
Figures given are: number of people with
diabetes in 2011 and predicted number of
people that will have diabetes in 2030
according to IDF estimates. Percentage is the
increase in diabetes from 2011 to 2030.
World box acts as the legend.
The burden of diabetes is one of the greatest
challenges of the 21st century,as seen in the
global incidence and projections of diabetes
epidemic worldwide.
Page

longer in the intensive treatment group,

there was a significant reduction in CV
disease as well. But after another ten
years even when patient was no longer in
the study, the original group showed
significant reduction in CV disease and
mortality.

366 million people have diabetes in 2011 and

this is predicted to rise to 552 million by 2030.
Diabetes caused at least $465 billion in
healthcare expenditure in 2011 11% of the
total expenditure, and is expected to exceed
$595 billion by 2030.

Relationship of Glycemic Control Outcomes

2.

This was also shown in another study, the

DCCT/ EDIC (Diabetes Control and Complications
Trial/ Epidemiology of Diabetes Intervention and
Complications). In the UKPDS, they did not give

a new name to the extension of the study. In

the DCCT, this was among type 1 diabetics
and was done in the US and Canada, the
extension of the study, after another 10 years
(extension of the study) was called EDIC.
Same findings as UKPDS. There is long
term legacy in good metabolic control. If only
for this, then we should opt to be able to
detect patients early and treat them
aggressively in the early stages of the
disease.
Figure: Impact of Intensive Therapy for
Diabetes: Summary of Major Clinical
Trials. Overview of the microvascular,
macrovascular and mortality outcomes from
large T2DM
and T1DM randomized clinical trials that
focused on the relationship between glycemic
control and complications.

3.

ACCORD (Action to Control Cardiovascular Risk in

Diabetes) study is different: patients recruited
were not newly diagnosed have been
diabetic for more than 10 years, and have
some cardiovascular diseases already. They
opted to lower HBA1c more aggressively
(<6%) but it did not show decrease in CVD
instead there was increase in mortality.
One of the reasons why this study showed an
increase in mortality is due to the sudden
reduction
in
level
of
blood
sugar
(hypoglycemia) which was very rapid. Many
are questioning the hypoglycemic effect and
mortality but in the meantime, the ACCORD
study contributed to the change in
targets of critically-ill patients.

4.

In the ADVANCE STUDY

SIMILARITY with Accord: Recruited same
kind of patients in the plus some patients
that have impaired glucose tolerance, or
prediabetic and some are diabetics. They
already have good control when they were
recruited into the study.
DIFFERENCE:
o The objective is to target HbA1c
of <6.5
o Reduction in sugar level was
slowly done
o Medication used: sulfonylurea
(gliclazide)
FINDING:
Only
microvascular
complications
showed
significant
reduction.

5.

In VADT (Veterans Affairs Diabetes Trial) study,

they used veterans in US targeted lower

{Please refer to this figure for the discussion below}

1.

According to UKPDS:

There
is
significant
decrease
in
microvascular complications during the
first 10 years of the study. Then after
another 10 years, the same patients went
back to the same attending physicians
who had the liberty to change medication
of patients. If patients were first on
conventional treatment, the attending
physicians may now opt to change to
intensive. And those who are on intensive
treatment may choose to change to
conventional. After another 10 years (the
blue), those who are exposed on intensive
therapy had a greater microvascular
complications than those who are not. So
there is a legacy of good metabolic
control. If you catch the patient EARLY
and treat them aggressively during the
first 10 years, the chances of being able to
maintain that advantage is kept even after
another ten years, and even if the control
is not as aggressive as during the first 10
years.

During the first ten years, during the

official conduct of study, UKPDS did not
show any change in cardiovascular
disease, but after another 10 years, when
patient were sent back to their doctors,
they were no longer in the study, no

Belisario, Bernabe, Bringas | Bautista XJV

Page

HBA1c with a lot of hypoglycemic events,

which people blamed for the increased
mortality in the intensive treatment group.

Overview of the Pathogenesis of Type 2

Diabetes

A. GLYCEMIC TARGETS
o
o
o

{Already mentioned in review on page 1 but was repeated by Dr.

Panelo here with emphasis on the ones with asterisk}

Insulin secretory dysfunction

Insulin resistance (muscle, fat, liver): causes
decreased peripheral glucose uptake
Increased endogenous glucose production
*Deranged adipocyte biology: increased
lipolysis will make the hepatic cell increase its
glucose production and increase glucagon
secretion
*Decreased incretin effect: if you decrease
your incretin you will have increased glucagon
secretion and decreased insulin secretion
because incretin increases insulin secretion
and suppresses glucagon; explains why
there are new medications that work on
incretin
Brain and kidneys are being looked into for
causing DM but still under study. There is
gluconeogenesis in your kidneys when you
have polyuria, you cause lowering of glucose
levels as well. So if you can increase
glucosuria, then you can help lower blood
sugar level (principle of glucosuria is
applied in new agents).

III. ANTIHYPERGLYCEMIC THERAPY

[Harrisons]

The goals of therapy for type 2 DM are to: 1)

eliminate symptoms related to hyperglycemia, 2)
reduce or eliminate long-term microvascular
complications of DM, and 3) allow the patient to
achieve a normal lifestyle.

The care of an individual with DM requires a

multidisciplinary team approach. Central to this
success are the patients participation, input, and
enthusiasm.
Members of the health care team
include the patients primary care provider,
endocrinologist, certified diabetes educator, and
nutritionist. It is important for the patient to receive
diabetes and nutrition information.

HbA1c < 7.0% to be able to get these:

Pre-prandial PG <130 mg/dl (7.2 mmol/l)
Post-prandial PG <180 mg/dl (10.0 mmol/l)
Mean PG 150-160 mg/dl [8.3-8.9 mmol/l

INDIVIDUALIZATION is key:
o Tighter targets (6.0 - 6.5%) younger,
healthier, no CV disease
o Looser targets (7.5 - 8.0%) 65 or 70
and older; regardless of age, persons with
comorbidities, hypoglycemia prone, etc.

Avoidance of hypoglycemia is as important as

reaching the target

B. LIFESTYLE CHANGE

Weight optimization through a healthy diet

o

Nutritional recommendations for adults with

diabetes [Harrisons]
Fat: 20-35% of caloric intake; saturated fat
<7% of total calories; <200 mg/day of
dietary cholesterol; 2 or more servings of
fish/week for omega 3 polyunsaturated
fatty acids; minimal trans fat consumption
Carbohydrate: 45-65% of total caloric
intake
(low
carb
diets
are
not
recommended)
Protein: 10-35% of total caloric intake (high
protein diets are not recommended)

Increased activity level

Oral Agents & Non-insulin Injectables

I.
II.

III.
IV.
V.

[Pharma 2014A trans] You may review these transes

from Pharmacology
Biguanides: Metformin
Insulin secretagogues

Sulfonylureas

Meglitinides (not discussed here)

D-phenylalanine derivative (not discussed here)

Thiazolidinediones
Alpha-glucosidase inhibitors
Incretin-based therapies

GLP-1 mimetics

DPP-IV inhibitors
(Older to newer drug: SUs Biguanide alphaglucosidae inhib TZD)

Not available in the Philippines, hence wont be

discussed and asked in the exams:
VI. Bile acid sequestrants
VII. Dopamine-2 agonists
VIII. Amylinmimetics
I. BIGUANIDE METFORMIN

This is approach is used because it is noted that DMspecific complications may be present in up to 2050% of individuals with newly diagnosed type 2 DM.

Belisario, Bernabe, Bringas | Bautista XJV

is the most preferred first line treatment

because of extensive experience.
Advantages:
a. not much hypoglycemia (because it
does
not
increase
insulin
release)
hypoglycemia is not in the official level of
hypoglycemia which is 54mg. metformin
patients
have
some
tremulousness,
sweating, feeling of hunger but it does not
lower sugar levels under 70. it may just be
clinical hypoglycemia.
Page

does not produce weight gain. Side

effect is loss of appetite, hence patients
love this.
c. in some very small studies, it decreases
cardiovascular disease.
Side effect: some patients cannot tolerate
even the smallest dose (500mg) because of
gastrointestinal effects (diarrhea or GI
irritation). Generic formulations may produce
more produce GI irritation more than others.
Try changing the brand first. Some companies
have reformulated their tablets, made
extended release or slow release formulations
to lessen such SE.

Remember which 2nd gen Dr. Valera loves? Evidencebased love; not love without reason. }

[Our Pharma trans]

Dosage: 500mg OD to max of 2.5g per day in 3

divided doses before meals (but Dr. Valera said,
after meals)

Contraindication:
Withhold
in
conditions
predisposing to renal insufficiency and/or hypoxia
(CV collapse, acute MI or acute CHF, severe
infection, use of IV iodinated contrast material [can
lead to contrast nephropathy], major surgical
procedures)

Should not be prescribed for patients with: renal

dysfunction, liver dysfunction, history of alcohol
abuse/binge drinking, acute or chronic metabolic
acidosis, chronic hypoxic lung disease

[Our Pharma trans]

Pioglitazone is the most friendly TZD no CV
toxicity, no hepatotoxicity; although use with OCP
requires additional contraception due to hepatic
metabolism

Dose: 15-30mg (45mg) OD, after meal

Contraindication: pregnancy, lactation, significant

hepatic dysfunction, CHF, cardiac disease

b.

II.

SULFONYLUREAS (SU)
Oldest antidiabetic agent
A secretagogue
Pros: decreases microvascular risk in the
Advance study
Cons: hypoglycemia, weight gain (makes
you hungry, so you eat more), low durability
(means that patients cannot be kept in control
for a long time)

[Our Pharma trans]

Contraindications:
Type
1
DM,
ketoacidosis,
azotemia, renal and hepatic impairment, pregnancy
and lactation

Dosage:

III. THIAZOLIDINEDIONES (TZD)

Relatively newer compared to two above

No hypoglycemia; with durability of

effect prevent beta-cell death (longer
control for longer periods of time)

Weight gain, edema/ heart failure,

bone fractures: most commonly reported SE;
questionable SE of bladder cancer

One of the best effect is on reduction of

fatty infiltration of liver (fatty liver is even
seen earlier than diabetes)

IV. a-GLUCOSIDASE INHIBITORS

No hypoglycaemia, Good for postprandial

hyperglycemia,
Decreased
CV
events:
decreased myocardial infarction and BP
GI irritation, flatulence
NO big reduction in HbA1c (around 0.5) an
add-on mostly
[Our Pharma trans]

MOA: Inhibit alpha-glucosidase in intestinal brush

border (does NOT break down glucose) leading to
delayed CHO absorption

Acarbose: 50-100mg OD-TID, after 1st spoonful of

meal

Voglibose: 0.2-0.3mg TID, before meals

Contraindication: IBD, Chronic intestinal disease with

markedly impaired digestion and absorption;
Caution in renal and hepatic impairment

V. DPP-4 INHIBITORS (DPP-4-i)

Incretin-based

Inhibits DPP-4 allows native GLP-1 to stay

in blood for a longer period (normally,
active GLP-1 stays for 1.5-2 minutes)

No hypoglycaemia, Well tolerated

Up to 1% reduction in HbA1c

Questionable SE: URTI

[Our Pharma trans]

Dose: Sitaglipin 25-200mg OD; Vildagliptin

50mg OD; Saxagliptin 5mg OD (2.5mg OD in
renal insufficiency)

Incretin: enteric hormone that augment glucosedependent insulin secretion when glucose is
taken orally unlike you SUs that will release insulin
as long as it is bounded in the receptor.

Effects of GLP-1:

{Note: ALL drugs starting with G are second

Generation SUs (more potent; less SE; more rapid onset).
Belisario, Bernabe, Bringas | Bautista XJV

Page

Inhibits aglucosidas
e

a-GIs

VI.

DPP4
inhibi
tors
GLP1
recep
tor
agoni
sts

GLP-1 RECEPTOR AGONISTS

Incretin-based, like DPP-4 inhibitor
Non-insulin injectable
NOT broken down by enzyme DPP-4
higher active GLP-1 (in type 2 DM GLP-1 is
decreased) causes increased insulin,
decreased glucagon, decreased emptying
time, increased satiety weight loss
without hypoglycemia
Good development: Being looked for its ability
to possibly regenerate beta-cells

Amyli
nmim
etics

Dopa
mine2
agoni
sts

*NOTE: In UKPDS, all of the regimen shows

that there was an increase in HBA1c which
was not due to the medication but because of the
rapidly declining function of beta cell. So you
cannot just maintain on initial drug continue
adding on then UPGRADE, UPGRADE, UPGRADE.
THIS!)
Class

Bigua
nides

SUs /
Megli
tinid
es

TZDs

Mechanis
m

Advantages

Disadvantag
es

Activates
AMPkinase
Hepatic
glucose
production

Extensive
experience
No
hypoglycemia
Weight
neutral
?CVD
Extensive
experience
Microvasc.
risk

GI
Lactic acidosis
B-12
deficiency
Contraindicati
ons

No
hypoglycemia
Durability
TGs, HDL-C
?CVD

Weight gain
Edema/ heart
failure
Bone
fractures
MI (rosi)
?Bladder ca
(pio)

Closes
KATP
channels
Insulin
secretion
PPAR-g
activator
insulin
sensitivity

Belisario, Bernabe, Bringas | Bautista XJV

Hypoglycemia
Weight gain
Low durability
Ischemic
preconditioni
ng

Activates
amylin
receptor
glucagon
gastric
emptying
satiety
Bind bile
acids
Hepatic
glucose
production

Bile
acid
seque
strant
s

[Our Pharma trans]

Exenatide (Byetta) subcutaneous injection; 510 mcg BID, 60 minutes before meals

SUMMARY IN TABULAR FORM: (STUDY

Slows
carbohydr
ate
absorption
Inhibits
DPP-4
Increases
GLP-1, GIP
Activates
GLP-1 R

Insulin,
glucagon

gastric
emptying

satiety

Activates
DA receptor
Modulates
hypothalami
c control of
metabolism
insulin
sensitivity

No
hypoglycemia
Nonsystemic
Postprandial
glucose
CVD events

Gastrointestin
al
Dosing
frequency
ModestA1c
Flatulence

No
hypoglycemia
Well
tolerated
Weight loss
No
hypoglycemi
a
? Beta cell
mass
? CV
protection

ModestA1c
? Pancreatitis
Urticaria

High

GI
? Pancreatitis
Medullary ca
Injectable

High

GI
ModestA1c
Injectable
Hypo w/ insulin
Dosing
frequency

High

GI
ModestA1c
Dosing
frequency

High

Weight loss
PPG

No

hypoglycemia
Nonsystemic

Post-prandial
glucose
CVD events
No hypoglyemia
? CVD events

ModestA1c
Dizziness/
syncope
Nausea
Fatigue

Mod.

High

REMEMBER!! (based on table & discussion)

NO hypoglycemia: ALL except
sulfonylureas

NO weight gain/weight neutral:

Cost
biguanides; GLP-1 agonist
Durable: TZD
Decreased CVD: a-glucosidase inhibitor
(others are questionable)
Low
Decreased microvascular complications:
SUs
LOW cost: SUS, biguanides

Insulin
Low
Class

High

Insuli
n

Mechani
sm

Activate
s insulin
receptor

peripher
al
glucose
uptake

Advantages

Disadvanta
ges

Universally
effective
Unlimited

efficacy
Microvasc
ular risk

Hypoglyce
mia
Weight gain
?
Mitogenicit
y
Injectable
Training

Cost

Variabl
e

Page

requiremen
ts
Stigma

Insulin has been used for a long time. If you

remember the natural history of T2 DM, at
time of diagnosis only 50% are left of your
beta-cell, so that after several years, you no
longer have a beta cell that will produce
insulin. Hence, you need insulin.
It is now being advocated to use insulin
EARLIER in the disease process.
Indicated for patients who are not well
controlled with oral medications.
Different kinds of insulin:
o Neutral protamine hagedorn (NPH)
o
o
o
o

Regular insulin
Basal analogues (glargine, detemir)
Rapid analogues (lispro, aspart, glulisine)
Pre-mixed varieties

Pharmacokinetic properties of various

insulin formulations.

Three basal insulin (very long DOA, flat

peak)
o Glargine no peak
o Human insulin almost same DOA but
higher peak than detimir; are genetically
modified from E. coli to become the same
as the native human insulin.
o Detimir
Studies show that in the end, all of them
have the same effect but again it was
emphasized that treating type 2 DM should be
patient-centered choose agents based on
capacity to buy also of the patients.

PHYSICAL AND CHEMICAL PROPERTIES [Our Pharma

trans]
INSULIN BRAND
APPE
ROUTE
pH
NOTES
TYPES
IN PHILS
ARANC
E
RAPID-ACTING
Lispro
Humalog
Clear
SC
Neutra
Used in
l
CSII
pumps
Aspart
Novorapi
Clear
SC, IV
Neutra
d
l
Glulisin
Apidra
Clear
SC
Neutra
e
l
SHORT-ACTING
Regular
MANY
Clear
SC, IM,
Neutra
IV
l
INTERMEDIATE
NPH
MANY
Clou
SC
Neutra
Redy
l
suspen
d!
LONG-ACTING
Glargine Lantus
Clear
SC
4.0
Cant
(acidi
be
c)
mixed
w/
Detemir
Levemir
Clear
SC
Neutra
other
l
insulin
s
PRE-MIXED

Take note of ONSET, PEAK and DURATION OF ACTION.

[Our Pharma trans]
Peak
Duration(
Appearanc
Insulin
Onset (hr)
(hr)
hr)
e
Lispro
W/in 15 min
-1
3-5
Clear
Aspart
W/in 15 min
1-3
3-5
Clear
Glulisi
0.25 - 0.5
0.5 1
4
Clear
ne
Regula
-1
2-4
5-8
Clear
r
NPH
1-2
4-10
14+
Cloudy
Detem
3-4
6-8
6-23
Clear
ir
Glargi
1.5
Flat
24
Clear
ne

Short acting insulin peaks earlier than

intermediate acting insulin
Rapid acting insulin mimics the first/early
insulin release and the first to be lost in type 2
diabetics use before meals to prevent
increase in blood sugar levels after eating.

Belisario, Bernabe, Bringas | Bautista XJV

Page

IMPLEMENTATION THERAPY IN T2 DM

Initial therapy
Advancing to dual combination therapy
Advancing to triple combination therapy
Transitions to & titrations of insulin

H e a l th y e a ti n g , w e i g h t c o n tr o l, i n c r e a s e d p h y s i c a l a c ti v ity

In iti a l d r u g
m o n o th e r a p y

M e tfo r m in

E ffi c a c y ( H b A 1 c )
H y p o g ly c e m ia
W e ig h t
S i d e e ff e c t s
C o s ts

h ig h
lo w r is k
n e u tr a l/lo s s
G I / l a c ti c a c id o s is
lo w
I f n e e d e d to r e a c h in d iv id u a liz e d H b A 1 c ta r g e t a fte r ~ 3 m o n th s , p r o c e e d to 2 - d r u g c o m b in a tio n
( o r d e r n o t m e a n t to d e n o te a n y s p e c if ic p r e f e r e n c e ) :

M e tf o r m in

T w o d ru g
c o m b in a tio n s *
E ffi c a c y ( H b A 1 c )
H y p o g ly c e m ia
W e ig h t
M a j o r s i d e e ff e c t ( s )
C o s ts

M e tfo r m in

M e tfo r m in

S u lfo n y lu r e a
h ig h
m o d e r a te r is k
g a in
h y p o g ly c e m ia
lo w

M e tf o r m in

M e tf o r m in

T h ia z o lid in e d io n e

D P P -4
In h ib ito r

G L P -1 r e c e p to r
a g o n is t

In s u l in (u s u a l ly
b a s a l)

h ig h
lo w r is k
g a in
e d e m a , H F , fx s
h ig h

i n te r m e d ia te
lo w r is k
n e u tr a l
ra re
h ig h

h ig h
lo w r is k
lo s s
G I
h ig h

h ig h e s t
h ig h r is k
g a in
h y p o g ly c e m ia
v a r ia b le

I f n e e d e d to r e a c h in d iv id u a liz e d H b A 1 c ta r g e t a fte r ~ 3 m o n th s , p r o c e e d to 3 - d r u g c o m b in a tio n

( o r d e r n o t m e a n t to d e n o te a n y s p e c if ic p r e f e r e n c e ) :

M e tf o r m in

T h re e d ru g
c o m b in a tio n s

M e tf o r m in

M e tfo r m in

S u lfo n y lu r e a

T h ia z o lid in e d io n e

TZD

S U

M e tfo r m in

D P P -4
In h ib ito r

G L P -1 r e c e p to r
a g o n is t
SU

or

D P P -4 -i

or

D P P -4 -i

or

TZD

or

G L P -1 -R A

or

G L P -1 -R A

or

In s u lin

or

In s u lin

or

In s u lin

M e tfo r m in

S U

or

TZD

or

In s u lin

In s u l in (u s u a l ly
b a s a l)

TZD

or

D P P -4 -i

or

G L P -1 -R A

I f c o m b in a tio n th e r a p y th a t in c l u d e s b a s a l in s u lin h a s fa ile d to a c h ie v e H b A 1 c ta r g e t a f te r 3 - 6 m o n th s ,

p r o c e e d to a m o r e c o m p le x in s u lin s tr a te g y , u s u a lly in c o m b in a tio n w ith 1 - 2 n o n - in s u lin a g e n ts :

M o r e c o m p le x
in s u lin s tr a te g i e s

In s u lin #
( m u lt ip le d a ily d o s e s )

Note: Source of figure above is Diabetes Care, Diabetologia, 19 April 2012

{Please look at Figure above for the succeeding explanations}

Moving from the top to the bottom of the figure, potential sequences of anti-hyperglycemic therapy. In
most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis
(unless there are explicit contraindications).

A.

BEGIN WITH LIFESTYLE CHANGES: Healthy

eating, weight control, increased physical
activity, cessation of smoking.
B. NEXT, ADD INITIAL DRUG MONOTHERAPY:
Metformin is the first line of treatment
o Why metformin?
High efficacy
Low risk for hypoglycemia
Weight neutral/ Weight loss
Side effects: GI/ lactic acidosis
Low cost
*If needed to reach individualized HbA1c
target after ~3 months, proceed to
C. TWO-DRUG COMBINATIONS
o Consider one of the 5 treatment options
(Metformin PLUS any of the ff:) a
Belisario, Bernabe, Bringas | Bautista XJV

sulfonylurea, TZD, DPP-4 inhibitor, GLP-1

receptor agonist or basal insulin.
Note that the order in the chart is
determined by historical introduction and
route of administration and is not meant to
denote any specific preference.
Choice is based on patient and drug
characteristics, with the over-riding goal of
improving
glycemic
control
while
minimizing side effects. Shared decisionmaking with the patient may help in the
selection of therapeutic options.
Rapid-acting secretagogues (meglitinides)
may be used in place of sulfonylureas.
Consider in patients with irregular meal
schedules
or
who
develop
late
postprandial
hypoglycemia
on
sulfonylureas. Other drugs not shown (Page

glucosidase
inhibitors,
colesevelam,
dopamine agonists, pramlintide) may be
used where available in selected patients
but have modest efficacy and/or limiting
side effects.
In patients intolerant of, or with
contraindications for, metformin, select
initial drug from other classes depicted,
and proceed accordingly.
Consider
starting
with
2-drug
combinations in patients with very
high HbA1c (e.g. 9%).

D. THREE-DRUG COMBINATIONS
o Further
progression
to
3-drug
combinations is reasonable if 2-drug
combinations do not achieve target.
If metformin contraindicated or not
tolerated, while published trials are
generally lacking, it is reasonable to
consider 3-drug combinations other than
metformin.
o Insulin is likely to be more effective
than most other agents as a third-line
therapy, especially when HbA1c is very
high (e.g. 9.0%). The therapeutic
regimen should include some basal
insulin before moving to more complex
insulin
strategies
{next
part
of
discussion}.
o Ultimately,
more
intensive
insulin
regimens may be required {next part of
discussion}.
o Dashed arrow line on the left-hand
side of the figure denotes the option of
a more rapid progression from a 2-drug
combination directly to multiple daily
insulin doses, in those patients with
severe hyperglycaemia (e.g. HbA1c
10.0-12.0%).
o Consider beginning with insulin if
patient
presents
with
severe
hyperglycemia
(300-350
mg/dl)
[16.7-19.4 mmol/L]; HbA1c 10.012.0%) with or without catabolic
features (weight loss, ketosis, etc).

SEQUENTIAL INSULIN STRATEGIES IN TYPE 2

DM

Belisario, Bernabe, Bringas | Bautista XJV

Basal insulin alone is usually the optimal initial

regimen, beginning at 0.1-0.2 U/kg body
weight, depending on the degree of
hyperglycemia. It is usually prescribed in
conjunction with 1-2 non-insulin agents. In
patients willing to take >1 injection and who
have higher A1c levels (9.0%), BID premixed insulin or a more advanced basal
plus mealtime insulin regimen could also
be considered (curved dashed arrow lines).
When basal insulin has been titrated to an
acceptable FPG but A1c remains above target,
consider proceeding to basal + meal-time
insulin, consisting of 1-3 injections of rapidacting analogues. A less studied alternative
progression from basal insulin to a twice daily
pre-mixed insulincould be also considered
(straight dashed arrow line); if this is
unsuccessful, move to basal + mealtime
insulin.
The figure also describes the number of
injections required at each stage, together
with the relative complexity and flexibility.
Once a strategy is initiated, titration of the
insulin
dose is
important,
with dose
adjustments made based on the prevailing
blood glucose levels as reported by the
patient.
Non-insulin agents may be continued,
although insulin secretagogues (sulfonylureas,
meglitinides) are typically stopped once more
complex regimens beyond basal insulin are
utilized.
Comprehensive education regarding selfmonitoring of blood glucose, diet, exercise,
and the avoidance of, and response to,
hypoglycemia are critical in any patient on
insulin therapy.

VARIATIONS OF ANTI-HYPERGLYCEMIC
THERAPY
What follows are variations of this figure to help
guide the clinician in choosing agents which may
be most appropriate under certain situations: to
avoid weight gain, to avoid hypoglycemia, and
to minimize costs.

1. TO AVOID WEIGHT GAIN

Page

available.
Two-drug combinations:
o Metformin PLUS Sulfonylurea
o Metformin PLUS Insulin (usually basal)

Three-drug combination: Metformin + SU +

Insulin

3. GUIDELINES FOR GLYCEMIC, BP AND

LIPID CONTROL

Avoiding
glucocentricity
is
key
in
the
comprehensive management of the patient with
Type 2 DM. Cardiovascular risk factor reduction
must incorporate blood pressure and lipid
control, and when indicated, anti-platelet
therapy.

This should be considered when the goal is to

avoid weight gain. Note that "hidden" agents may
obviously still be used when required, but
additional care is needed to avoid adverse events.
Here, the chances of weight gain when using the
hidden agents will be mitigated by more rigorous
adherence to dietary recommendations and
optimal dosing.

Two-drug combinations:
o Metformin PLUS Thiazolidinedione
o Metformin PLUS DPP-4 Inhibitor
o Metformin PLUS GLP-1 Receptor Agonist

Three-drug combinations:
o Metformin + TZD + DPP-4-i or GLP-1-RA
o Metformin + DPP-4-i + TZD
o Metformin + GLP-1-RA + TZD
2. TO MINIMIZE COSTS

HbA1c
Preprandial
glucose
Postprandial
glucose
Blood pressure
Lipids

< 7.0% (individualization)

70-130 mg/dL (3.9-7.2 mmol/L)
< 180 mg/dL
< 130/80 mmHg
LDL: < 100 mg/dL (2.59 mmol/L); < 70
mg/dL (1.81 mmol/L) with overt CVD
HDL: > 40 mg/dL (1.04 mmol/L) male; >
50 mg/dL (1.30 mmol/L) female
TG: < 150 mg/dL (1.69 mmol/L)

4. OTHER CONSIDERATIONS

Age: Older adults

Reduced life expectancy
Higher CVD burden
Reduced GFR
At risk for adverse events from polypharmacy
More likely to be compromised from
hypoglycemia
THEREFORE:

o
o
o

Less ambitious targets

HbA1c <7.5-8.0% if tighter targets not
easily achieved
Focus on drug safety

Weight
o Majority of T2DM patients are overweight /
obese
o Intensive lifestyle program
o Metformin
o GLP-1 receptor agonists
o ? Bariatric surgery
o Consider LADA (latent autoimmune diabetes
in adults) in lean type 2 DM patients

This should be considered when the goal is to

minimize costs. This reflects prevailing costs in the
North America and Europe in early 2012; costs of
certain drugs may vary considerably from country
to country and as generic formulations become
Belisario, Bernabe, Bringas | Bautista XJV

Sex/ racial/ ethnic/ genetic differences

o Little is known
o MODY (a monogenic form of diabetes that may
be due to a defect in glucokinase) & other
monogenic forms of diabetes
o Latinos: more insulin resistance
o East Asians: more beta cell dysfunction
o Gender may drive concerns about
adverse effects (e.g., bone loss from TZDs)
Page

Comorbidities
o Coronary artery disease
Metformin: CVD benefit (UKPDS)
Avoid hypoglycemia
? SUs and ischemic preconditioning
? Pioglitazone and decreased CVD events
? Effects of incretin-based therapies
o Heart failure
Metformin: may use unless condition is
unstable or severe
AVOID TZDs
? Effects if incretin-based therapies
o Chronic kidney disease / Renal disease
Increased risk of hypoglycemia
Metformin and lactic acidosis

US: Stop @SCr >1.5 (1.4 women)

UK: Decrease dose @GFR <45 and

stop @GFR <30
{SCr is serum creatinine; GFR is glomerular
filtration rate}

Caution with SUs (esp. glyburide)

DPP-4 inhibitors dose adjust for most
AVOID Exenatide if GFR <30
o Liver dysfunction
Most drugs not tested in advanced liver disease
Pioglitazone may help steatosis {fatty change of
liver}

Insulin best option if disease is severe

o Hypoglycemia
Emerging concerns regarding association
with increased mortality
Proper drug selection in the hypoglycemia
prone

5. FUTURE DIRECTIONS / RESEARCH NEEDS

Comparative effectiveness research: Focus on

important clinical outcomes
Contributions of genomic research
Perpetual need for clinical judgment!
KEYKEY POINTS
Glycemic targets & blood glucose-lowering
therapies must be individualized.
Diet, exercise, & education: foundation of any
Type 2 DM therapy program
Unless contraindicated, metformin = optimal
1st-line drug.
After
metformin,
data
are
limited.
Combination therapy with 1-2 other oral /
injectable agents is reasonable; minimize side
effects.
Ultimately, many patients will require insulin
therapy alone/ in combination with other
agents to maintain BG control.
All treatment decisions should be made in
conjunction with the patient (focus on
preferences, needs and values)
Comprehensive CV risk reduction a major
focus of therapy.

Belisario, Bernabe, Bringas | Bautista XJV

Remember diabetes is a life-long, chronic disease.

Therefore, it is important for the patient to follow up
consistently. Below are the guidelines for ongoing
medical care for patients with diabetes [Harrisons]

_____END_____
Sources: Dr. Panelos PPT and notes ~ Recording
~ Harrisons ~ Pharmacology 2014A transes

REVIEWER (c/o 2013 samplex)

{You may opt to not print this part
anymore :)}
1. A 30 y/o pregnant woman, LMP July 1, 2011 for your
opinion. Parents are both diabetic, prepregnancy weight
was 150 lbs, Ht 52. What will you do?
A. Ask the patient to get a glucose challenge test on the
24th week
B. Refer to dietitian
C. Request for an FBS
D. Do a Glucose challenge now
***high risk patients should be screened on the first
prenatal check up
For questions 2-4, refer to the following case: FP, a 28
year old pediatrician was referred by her obstetrician.
She weighs 130 lbs and is with a ht of 54. She has
previous history of 2 abortions. Her LMP is Aug. 10, 2010
her blood sugar is normal.
2. What will you suggest to the referring doctor?
A. FBS or 2hr 75 PGBS at 24 weeks AOG
B. 2 hour 75 OGTT at 24 weeks AOG
C. RBS, A1C
D. A and C are correct
***if sugar is normal now, screening is recommended at
24 weeks AOG with a 75gm 2hr OGTT.
3. If she turns out to be positive for Diabetes, she will be
classified as:
A. Type 1 DM
B. Type 2 DM
C. Gestational Diabetes Mellitus
D. Diabetes secondary to pregnancy
***Gestational DM is the appropriate diagnosis for
patient who develop diabetes during a pregnancy
4. Treatment of choice:
A. Insulin
B. Insulin and sulfonylureas
C. Sulfonylureas are now accepted in pregnant women
Page

D. Only diet and exercise can be used for pregnant

diabetics
***insulin is the main treatment for GDM. Sulfonylureas
are not as widely accepted yet.
5. Which among the following belongs to Categories of
Increased Risk of Diabetes?
A. FBS 120 mg, 2hr PGBS 180 mg/dl, A1C 5.9%
B. FBS 126 mg/dl, 2hr PGBS 140 mg/dl, A1C 6.5%
C. FBS 100 mg/dl, 2hr PGBS 140 mg/dl, A1C 6.7%
D. FBS 125 mg/dl, 2hr PGBS 130 mg/dl, A1C 6.0%
***categories include: FBS 100-125 mg/dl; 2 hr PGBS
140-180 mg/dl; A1C 5.7-6.4%
6. Which is true of A1C?
A. It is a potent mortality and CV risk marker
B. It varies from day to day because it is affected by
stress and illness
C. The test should be done using a method that is
certified by the NGSP and standardized to DCCT assay.
D. A and C are correct
***A1C reflects 3 months glycemia and does not vary
from day to day
7. Maturity onset diabetes in the young
A. May be due to a defect in the glucokinase genes
B. May be seen in patients with pheochromocytoma
C. Is due to chronic pancreatitis
D. Maybe due to the effect of rat poison in the beta cells.
***MODY is a monogenic form of diabetes that may be
due to a defect in glucokinase (MODY 2)
8. A 58 y/o teacher was diagnosed to have PTB at the
Quezon Institute after coughing out fresh blood. Blood
tests revealed fasting blood glucose of 400 mg/dl. The

Belisario, Bernabe, Bringas | Bautista XJV

patient was referred to you for diagnosis and

management. What will be the best antidiabetic agent to
use at the present?
A. Insulin
B. Combination insulin and metformin
C. Oral antidiabetic agents
D. Diet and exercise
***insulin is the treatment of choice for patients with
PTB. Diet and exercise are probably inadequate for the
patient.
9. A 20 y/o female medical student consults with the
following complaints: vaginal itchiness, frequent
urination, dryness of the mouth and blurring of vision. Ht
51, Wt 150 lbs. both parents are diabetic. RBS is 300
mg/dl. What should be her target HbA1C based on the
American Diabetes Association guideline?
A. <7%
B. 4 to 6%
C. 8%
D. 7.5%
*** ADA recommends target HbA1C <7% for most
patients.
10. DPP 4 inhibitors:
A. Delays the absorption of carbohydrate in the gut by
competing with d alpha glucosidase receptors
B. Enhances the effects of the native incretins by
blocking the latters breakdown
C. Stimulates secretion of insulin and suppresses
glucagon release depending on the ambient blood
glucose
D. B and C are correct
***A refers to a-glucosidase inhibitors

Page