Diabetes Mellitus
Grace Marie C. Alunan-Maclan, MS
March 21, 2021
Diabetes Mellitus
• Most common endocrine disorder
- also one of the most predominant non-communicable disease
• Chronic condition
- Usually could develop during early childhood particularly if
he/she has type 1 diabetes; for patients with type II this usually
starts in patients older than 40 years old
• A group of metabolic disease characterized by inappropriate
hyperglycemia resulting from defect in insulin secretion, insulin
action or both
§ Insulin
• a hormone that our body uses to control the glucose level
• particularly promotes cellular use or the cellular uptake of
glucose
• also used for the breakdown or in facilitating the conversion of
carbohydrates, proteins, and lipids
• Importance of discussion:
- one of the main reason why patients has hyperglycemia is
either because their (a) body is not able to produce insulin
therefore the carbohydrates and glucose are not being utilized
properly or it could also be because their (b) body is unable
to detect insulin thus there is now rejection of insulin or
insensitivity to insulin therefore it cannot promote the cellular
uptake of glucose
Epidemiology
• Diabetes mellitus it is the most common metabolic disorder
• In 2014, the World Health Organization has reported an estimate
of 422 million individuals who have been diagnosed with diabetes
• There are also 318 million individuals who are at risk to develop
diabetes because of their high glucose level in their blood
• In 2017, another study has been conduct and has found out 425
million people worldwide who have diabetes and they expect that
by the year 2045 there is going to be an increase by 48% of this
population to develop diabetes
- 98 million are geriatric patients from the age of 65-79
- 327 million are the majority from the age of 20-64
• we have to take note that there are still some patients who have
diabetes at a very young age, particularly those with type 1
diabetes
• during this time there are still a lot of people who have developed
diabetes particularly because of the unhealthy lifestyle that they
practice.
Classification
§ 1965 Classification
• Infantile or Childhood
• Young
• Adult
• Elderly
• Classification of diabetes action he started during this time
• Diabetes was classified based on the age range of the patient
wherein he or she has started to develop or started to experience
the symptoms of diabetes
§ 1985 Classification
• Insulin dependent diabetes mellitus(IDDM)
• Non-insulin dependent diabetes mellitus(NIDDM)
• Other types
• Based on the patient's dependency to insulin
§ 1999 Classification
• Type 1
• Type 2
• Based the classification on the etiology or pathophysiology of how
the patient would have diabetes mellitus
Belmonte, De Jesus, Fernandez, Martin, Sarto, Sultan, Sindayen, Tan
Clinical
Pharmacy II
PHA6132
Lecture
• In the earlier classification in the 1985 classification wherein
insulin-dependency was the basis of their classification, there are
some patients who are not dependent on insulin, which means
they are taking oral hypoglycemic but their blood sugar level is
not maintained thus there are days that they take insulin and
some days that they don’t.
• This was addressed by changing the classification and based it
now on the pathophysiology and how they acquire Diabetes
mellitus
§ Type 1
• Based on the production of insulin by the beta cells (beta-islet
cells) of the pancreas
• Destruction of the insulin producing pancreatic beta cell
• Associated with autoimmune disease
• Usually develops in children and young adult because the
immune system recognize beta islet cells as foreign, destroying it
• Associated with a faster onset of symptoms, leading to
dependency on extrinsic insulin for survival
- They need insulin supplementation because their body is no
longer able to produce insulin
§ Type 2
• More common
• Associated with lifestyle
• Occurs in adults older than 40
• Peaks onset between 60 and 70 years old
• Caused by a relative insulin deficiency and the body's inability to
effectively use insulin
• There are some patients with type 2 diabetes that would require
supplementation of insulin
• But type 2 diabetes is mainly because of the body’s ineffective
insulin receptors, meaning they no longer recognize insulin, thus
it does not produce the effect it has.
• Symptoms are slower in onset and less marked symptoms than
those of type 1
§ Gestational diabetes
• Experienced by pregnant patient
• If the diabetes is first detected during pregnancy, it belongs to this
classification
- but if the female patient is already diabetic prior to their
pregnancy, the classification of diabetes would be the one prior
to pregnancy and not gestational diabetes
• Patients with gestational diabetes would usually go back to their
normal glucose level after giving birth.
• Hyperglycemia that is first detected during pregnancy
• Hyperglycemia in pregnancy is associated with adverse
outcomes, including hypertension and foetal macrosomia
§ Nontypical diabetes
• Could be secondary (caused by the use of medications or other
conditions that could lead to increase in their blood glucose level)
• Latent autoimmune diabetes in adult (LADA)
- Somewhat similar to type 1 except the destruction of the beta
islet cells in the pancreas usually appears in adulthood
- Slow progressing disease
- Only during the adulthood wherein patient starts to have a
decrease in insulin production
• Maturity onset diabetes of the young (MODY)
- More of a type 2 diabetes
- Usually associated with genetics
- When a family member has a type 2 diabetes and there is a
change in the gene this could result in the development of
MODY
- At a very young age, usually during adolescent, patients starts
to develop symptoms of diabetes
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Clinical Pharmacy II: Diabetes Mellitus PHA6132 - Lecture
• Antiglutamic acid decarboxylase (GAD) antibodies • Ketosis is a result of breakdown of fats. Because there is no
- It causes an immune response insulin, glucose could not be converted into energy source. Thus,
- Basically, glutamic acid is converted to GABA which is the body would require other macronutrients for it to breakdown
responsible for insulin secretion. and will breakdown fats leaving to the production of ketose.
o Glutamic acid decarboxylase converts glutamic acid to • Antibodies
GABA. - Type 1:
o If there is an antiglutamic acid decarboxylase antibodies, o ICA positive these antibodies recognizes the islet cells
there will be an inhibition of the conversion of glutamic acid something foreign. Thus it would produce an immune
to GABA, thus inhibiting the insulin secretion. response to destroy the islet cells. Therefore, there will be no
production of insulin.
o Anti-Glutamic Acid Decarboxylase antibodies
o ICA 512 antibodies to be positive
- Type 2:
o All antibodies will be negative because T2DM it is not relate
to immunity or autoimmune disease
Pathophysiology

• Staging will be based on the glucose level of the patient.

• Whether you are type 1, type 2, or gestational diabetes, there are § Insulin
different stages of hyperglycemia. • Polypeptide hormone that regulates the metabolism of
• Normoglycemia or normal glucose tolerance– this is what we macronutrients (carbohydrates, proteins, fats).
want our patient to achieve. • Insulin is utilized for the conversion of glucose into energy, the
• Impaired glucose regulation – result of hyperglycemia ATP that we use. Can also be utilized in the liver, muscles, and
• Diabetes Mellitus – patients will not require insulin, or they would can also be stored in adipose tissues.
require insulin only for control in blood glucose level or for their
survival. • How is Insulin synthesize in our body?
• TYPE 1 is the only one that will require insulin for survival. The
other three may or may not require insulin for survival.
• Common cause
- Type 1 is autoimmune or idiopathic
- Type 2 will be predominantly resistance of power receptor to
recognize insulin or a defect in insulin secretion.
- Gestational diabetes
Table 1. Differentiation between Type 1 and Type 2 Diabetes
Mellitus, especially in younger individuals
Characteristics Type 1 DM Type 2 DM
Onset Acute-symptomatic Slow-often-
asymptomatic
Clinical Picture Weight loss, polyuria, If symptomatic, similar
polydipsia, picture as T1 DM –
polyphagia weight loss, polyuria,
polydipsia - Glucose enters in the cells through GLUT2 channel.
- Obese - Glucose will undergo both aerobic and anerobic metabolism,
- Strong family history of producing ATP.
T2DM - The ATP will bind to K+ channel, thus closing the K+ channel.
- Polycystic ovary
syndrome (PCOS)
Therefore, there is going to be an activation of K+ voltage-gated
Ketosis Almost always Usually absent channels ( ↑K+ activates VGCa+ channels).
present - It allows the Ca+ to go into the cells to stimulate secretory
C-Peptide Low/absent Normal/elevated vessels with insulin.
Antibodies - ICA positive - ICA negative - Aside from glucose levels inside the blood that allows the
- Anti-GAD positive - Anti-GAD negative production of insulin, another method of insulin to be produced
- ICA 512 positive - ICA 512 negative is through the Glutamic acid conversion.
Therapy Insulin Lifestyle, oral anti-
- Glutamic acid is converted via Glutamic acid decarboxylase into
diabetic agents, insulin
Associated auto- Yes No
GABA, which stimulates the production of Insulin.
immune diseases
Adapted from Alberti Diab Care, 2004.8
ICA – islet cell antibodies; Anti-GAD – glutamic acid decarboxylase antibodies

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Clinical Pharmacy II: Diabetes Mellitus
§ Counterregulatory hormones
• Counteracts the effect of insulin. Once increases in the
bloodstream, it will antagonize the effect of insulin.
• The pancreas produces the insulin. Insulin stimulates the uptake
of glucose into the tissue, therefore ↓glucoseà ↓blood sugar level.
• On the other hand, insulin can also be utilized to stimulate the
formation of glycogen (glucoseàglycogen). Glycogen can be
stored in muscle tissues and liver.
• Glucagon – counteracts the effect of insulin because glucagon
stimulates the breakdown of insulin; glucagon comes from
glucose. Breakdown of glycogenà ↑glucoseà ↑blood sugar level.
• Glucagon is actually a response if there is a low blood sugar level.
Aside from glucagon, other counterregulatory hormones are GH
(growth hormones), cortisol, and catecholamines, which are
released in response to low blood glucose level.
§ Incretin Hormones
• Ingested glucose promotes a more rapid release of insulin from
the pancreas
- This occurs because the incretin hormones, gastric inhibitory
peptide (GIP) and glucagon-like peptide-1 (GLP-1) are
secreted by the intestines in response to glucose ingestion,
before the glucose is absorbed
• Glucagon-like peptide (GLP-1): postprandial secretion is
diminished in patients with diabetes mellitus
- increases glucose-dependent insulin secretion
- inhibits inappropriate glucagon secretion
- increases β-cell growth/replication
- slows gastric emptying
- suppresses appetite
• Gastric inhibitory peptide (GIP): postprandial secretion is
normal or increased in patients with diabetes mellitus
§ Amylin
• Hormone that is cosecreted with insulin from pancreatic β-cells
• Little to no amylin is produced in patients with T1DM
• Amylin is produced but insufficient in patients with T2DM
• Lowers the postprandial glucose level by the following actions:
- Prolongs gastric emptying time
o Makes the food stay longer in the digestive system
- Decrease post-prandial glucagon secretion leading to the
inhibition of the raising of blood glucose level
- Suppresses appetite
§ T1DM
• Genetics: Human leukocyte antigen (HLAs) DQA and DQB
appear to code for either disease susceptibility or resistance
- Antigens recognized in rheumatoid arthritis, systemic lupus
erythematosus
• Environment: viral, chemical, or dietary
• Autoimmunity
- Anti-insulin, anti-beta cell antibodies
o Immune system recognize insulin, beta cells as something
foreign, leading to the production of antibodies, thus the body
will not be able to utilized insulin and the beta cells will not
be able to produce insulin
- Antibodies to glutamic acid decarboxylase
o Inhibits the formation of GABA (stimulates insulin release)
PHA6132 - Lecture
• Beta cells are being presented by antigen presenting cells
• (1) APC will present it to the lymph node and the (2) lymph node
will recognize this as foreign that will activate other immune cells
(T cells) to (3) go to the site and to (4) destroy the cells that have
this antigen (beta cells)
• Destruction of beta cells will result to decreased formation of
insulin
§ T2DM
• Familial
• Genetics: >90% concordance rate in identical twins if one has
T2DM
- Patients with family history of type 2 has a higher chance of
passing it to the next generation compare to type 1
• Beta cell dysfunction
• Peripheral site defect: Post-receptor binding or a decreased
number of insulin receptor can lead to hyperglycemia
- Insulin receptor does not recognize insulin, therefore, glucose
will not be transported inside the cell (would remain in the
bloodstream) -> high blood glucose
Risk Factors
§ Demographic and Clinical Risk Factors for type 2 DM
• Testing should be considered in all adults >40 yo
• Consider earlier testing if with at least one other risk factor as
follows:
- History of impaired glucose tolerance (IGT) or impaired fasting
glucose (IFG)
o Fasting glucose above the normal
- History of gestational diabetes (GDM) or delivery of a baby
weighing 8 lbs or above
- Polycystic ovary syndrome (PCOS)
o Patients with PCOS are usually insulin-resistant
- Overweight: Body Mass Index (BMI)2 of >23 kg/m2 or Obese:
BMI of >25 kg/m2, or
- Waist circumference >80 cm (females) and >90 cm (males), or
Waist-hip ratio (WHR) of >1 for males and >0.85 for females
- First degree relative with Type 2 diabetes
- Sedentary lifestyle
- Hypertension (BP >140/90 mmHg)
- Diagnosis or history of any vascular disease including stroke,
peripheral arterial occlusive disease, coronary artery disease
- Acanthosis nigricans
o Dark discoloration in the body folds and creases, such as in
the nape area
- Schizophrenia
- Serum HDL <35 mg/dL (0.9 mmol/L) and/or
- Serum Triglycerides >250 mg/dL (2.82 mmol/L)
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Clinical Pharmacy II: Diabetes Mellitus PHA6132 - Lecture

§ American Diabetes Association Risk Test Symptoms of Diabetes

Clinical Manifestation
§ 4 signs that is usually manifested by patients with diabetes:
1) Weight loss
• Unexplained weight loss is one of the manifestations of diabetes.
• How come the patient that has diabetes has weight loss?
- The uptake of glucose is impaired; therefore the body will result
into utilizing other source of energy, particularly fats and
proteins.
- It would be breaking down fats and proteins (↑ lipolysis and ↑
proteolysis).
- These fats and proteins are stored in the muscles and adipose
tissues. If the body utilizes these fats and proteins, our patients
will have weight loss.
- Polyphagia
o Because there is weight loss and utilization of fats and
proteins, your patients start to feel hungry all the time.
2-3) Glucosuria and Polyuria
• There is sugar in the urine of the patient.
• "Where glucose goes, water would follow."
- If there is glucose in the urine, there is also going to be an
increase in urination of your patient, thus your patient would
have polyuria.
4) ↓ Blood volume
• If there is increased amount of water in the urine, there is going
to be a decrease in blood volume because the blood went with
the urine, along with glucose. (↑ water in urine = ↓ blood volume)
• So if there is a decrease in the blood volume, that will increase
the concentration of glucose in the blood resulting to
hyperosmosis.
- Because there is hyperosmosis, you need to increase water
intake, thus it results to having polydipsia.
- Because the concentration of glucose in the bloodstream is
high so we have to regulate it so you're going to drink lots of
water, thus resulting to polydipsia.
• Systemic weight loss
• Sexual problems
• Always tired
- Because there is no glucose, no energy, the energy is coming
from fats
• Frequent urination
• Always hungry
• Wounds that won't heal
- If there is hyperglycemia, the immunity is affected. So the
process of chemotaxis is impaired, thereby the immune
system does not recognize the site of infection and it would not
be able to produce the immune response that it has to do,
resulting to poor wound healing
• Blurry vision
- One of the complications of diabetes is affecting the vision or
retinopathy
o Retinopathy is a condition wherein the vessels of the retina
are affected by the high glucose concentration. So there is a
blockage in the retina of the eyes, so it would not be able to
supply sufficient amount of blood into the retina, causing the
patients to have blurry vision
o Why is there a blockage?
§ If we have an increase in the glucose concentration, this
glucose actually conjugates with proteins and lipids, which
cause an inflammatory mechanism.
§ If there is an inflammatory mechanism or if there is
damage in the blood vessel, it causes low-density
lipoprotein (LDL) to get inside the lumen of the tissues or
the blood vessels causing atherosclerosis and/or
hyaline arteriolosclerosis.
§ If there is an inflammatory mechanism, there is going to
be rush in immune cells and LDL present in the blood
stream. This LDL is now able to go inside of the damaged
vessel, and they could accumulate in that particular area.
§ This is the same as how atherosclerosis block is being
formed in Coronary Artery Disease (CAD).
§ It develops into an atherosclerosis leading in decrease in
the blood supply of your patient in the different tissues and
areas.
§ It means that complications of diabetes could be stroke, it
could be myocardial infarction. Retinopathy is one
because it's actually blocking smaller blood vessels
particularly in the eyes, causing blurry vision.
§ Also because of the high concentration of glucose level in
the body, it now becomes more prone to infection.
Patients become more prone, not only to bacteria, but also
to fungal infection because glucose is a good medium for
bacterial and fungal growth
• Vaginal infections
• Always thirsty
• Numbness or tingling in hands or feet
Diagnosis and Assessment
Table 2. Blood Glucose Level
Test Value
Fasting Blood Glucose Level >126 mg/dL
Random Blood Glucose Level >200mg/dL
Oral Glucose Tolerance Test >200 mg/dL
Hemoglobin A1c > 6.5%
• Fasting blood glucose level
- Patients fast a period of hour (10 hours of fasting) before the
glucose level is tested
• Hemoglobin A1c
- One of the major testing
- Determines the average glucose level for the past 3 months

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Clinical Pharmacy II: Diabetes Mellitus
§ Testing for Asymptomatic Individuals
• Physical activity
• First degree relative with diabetes, particularly to diabetes type 2
• High risk ethnicity (African Americans, Latino, Native American,
Asian American, Pacific Islander)
• Women who delivered a baby weighing >9lbs or were diagnosed
with Gestational diabetes mellitus
• Hypertension (>140 / 90 mmHg or on therapy for HTN)
• HDL level < 35 mg/dL and/or triglyceride level >250mg/dL
• Women with polycystic ovary
• Previous testing indicative of prediabetes
• Clinical conditions associated with insulin resistance
• History of cardiovascular disease
Complications
• If there is an increase in glucose level, it promotes the conjugation
of proteins and lipids resulting to inflammatory molecules.
- The inflammatory molecule could lead to LDL accumulation in
that particular area or in the area where there is inflammatory
response causing atherosclerosis or it could also lead to
hyaline arteriolosclerosis
• Hyaline arteriolosclerosis can occur in the glomeruli
- There is a blockage in the glomeruli or the filtering portion of
the kidney
• Atherosclerosis does not only happens in cardiac muscle but it
could be in the peripheral vessel
- If it is in the heart, it can cause heart attack, myocardial
infarction
- If the atherosclerosis is in the brain, it could to a stroke
- If it is found in the peripheral muscle, peripheral artery
disease
• Hyaline arteriolosclerosis could lead to diabetic nephropathy
• Diabetic foot is one of the complications because there are
patients who no longer have sensation on their lower extremities,
particularly to peripheral nephropathy
- There is already a damage in their neurons that it no longer
passes any sensation to the brain so there is a destruction in
the neurons
- That is why patients who suddenly bumps their foot, they do
not feel any pain. They do not know that there is injury in the
particular area. That injury causes a nonhealing wound, which
could lead to diabetic foot
- Diabetic foot could lead to amputation because the non-healing
wound would release gangrenes and because patients does
not have any sensation, they do not feel any pain in their lower
extremities.
• Eyes are one of the organs usually damage by diabetes
- Diabetic retinopathy: there is microaneurysm - small vessel
starts to rupture in the blood vessel, which causes a blurry
vision
- There is cataract formation and it could lead to glaucoma
PHA6132 - Lecture
Management Part 1
• Illustration derived from the American Diabetes Association 2020
guidelines
• This figure tells us the different steps that we must do for us to be
able to manage our patient’s diabetes or glycemic problem with
the therapeutic goal of preventing complications that could arise
with diabetes as well as to optimize our patient's quality of life
• Just like in pharmaceutical care, the first thing do is to assess the
patient
- What are the characteristics of our patient that makes them
more vulnerable to different complications that could arise with
their condition?
• We must consider the different risk factors that a patient must
have for us to be able to identify the best drug to be used for the
management of the patient's condition
• Remember: creating therapeutic plan for a patient is a shared
decision between the patient and the pharmacist
- no matter how good the therapeutic plan is, if the patient does
not approve or does not agree with therapeutic plan created by
the pharmacist, there is no use because that would only be a
source of noncompliance or nonadherence of our patient
• Once the plan is already agreed upon, we must now specify the
goals for our patient
- Remember that the goals should be specific
- The goals must be measurable so that we could always
quantify if we have already achieved those goals
- The goals that we must stick in our plan should be achievable,
realistic for our patient and also time-limited
• After creating a plan, it must be implemented.
- Remember: the duty or responsibility of a pharmacist does not
stop when our patients are already undergoing the plan, there
should always be a follow up to the plan so that we will know if
the patient is improving with regards to the created plan
• We must continuously monitor our patient and consequently,
review whether the plan created for our patients are actually
beneficial for them or see if there are problems that they might
have encountered when they implementing the plan
Goals of Care
• Prevent complications
• Optimize quality of life
§ Assess Key Patient Characteristics
• Current lifestyle
• Comorbidities, i.e., ASCVD, CKD, HF
• Clinical characteristics, i.e., age, HbA1c , weight
• Issues such as motivation and depression
• Cultural and socioeconomic context
§ Consider Specific Factors that Impact Choice of Treatment
• Individualized HbA1c target
• Impact on weight and hypoglycemia
• Side effect profile of medication
• Complexity of regimen, i.e., frequency, mode of administration
• Choose regimen to optimize adherence and persistence
• Access, cost, and availability of medication
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Clinical Pharmacy II: Diabetes Mellitus PHA6132 - Lecture

§ Shared Decision Making to create a Management Plan § MOA

• Involves an educated and informed patient (and their family/ • Stimulates hepatic glycogen synthesis
caregiver) - Insulin helps in the conversion of glucose into glycogen and
• Seeks patient preferences store this glycogen in the liver, muscles, and adipose cells
• Effective consultation includes motivational interviewing, goal • Increased protein synthesis
setting and shared decision making - Diabetic patient has lesser insulin so proteins are being broken
• Empowers the patient down, the muscles which utilizes this protein weakens due to
• Ensures access to DSMES the proteolysis (breaking down of proteins.)
- One of the manifestations of diabetes is having a decrease in
§ Agree on Management Plan the weight of the patient
• Specify SMART goals • Facilitates triglyceride synthesis and storage by adipocytes
- Specific • Inhibits lipolysis
- Measurable - Diabetic patient has lesser insulin so lipolysis (breaking down
- Achievable of lipids) takes place that is why there is an unexplained
- Realistic increase in weight loss. The fats that they have are broken
- Time-limited down and being used as source of energy thus there is a
decrease in weight
§ Implement Management Plan - One of the manifestation is ketosis because of the breakdown
• Patients not meeting goals generally should be seen at least
of fat, forming ketones.
every 3 months as long as progress is being made; more frequent
contact initially is often desirable for DSMES • Stimulates peripheral uptake of glucose
Table 3. Types of Insulin
§ Ongoing Monitoring and Support including: Onset Peak Duration
• Emotional well-being of of Action
• Check tolerability of medication Action
• Monitor glycemic status Humalog < 15 min 60-90 3-5 hrs • Inject 10-15 min
or Lispro min before mealtime
• Biofeedback including SMBG, weight, step count, HbA1c, blood Novolog < 15 min 60- 3-5 hrs • Typically used in
pressure, lipids RAPID or Aspart 120 conjunction with
min longer-acting
§ Review and Agree on Management Plan Apidra or < 15 min 60-90 1-2.5 hrs insulin
Glusiline min
• Review management plan Regular ® 30-60 2-5 6-8 hrs
• Mutual agreement on changes Humulin, min hrs
• Inject at least 20-
• Ensure agreed modification of therapy is implemented in a timely SHORT
Actrapid
30 minutes
or Novolin
fashion to avoid clinical inertia before mealtime
Velosulin 30-60 2-3 2-3 hrs
• Decision cycle undertaken regularly (at least once/ twice a year) min hrs
NPH (N) 1-2 hrs 4-12 18-24 • Commonly used
Pharmacologic Treatment of Diabetes Mellitus hrs hrs twice daily
Insulin Lente (L) 1-2.5 3-10 18-24 • Often combined
INTER
hrs hrs hrs with rapid- or
MEDIATE
• Polypeptide hormone produce through recombinant DNA coming short-acting
from bacteria or yeast insulin
• Subcutaneous preparation Ultralente 30 min- 10-20 20-36 • Covers insulin
- Polypeptide is susceptible to GI degradation that is why it is not (U) 3hrs hrs hrs needs for 24 hrs
recommended as oral preparation Lantus or 1-1.5 No 20-24 • If needed, often
LONG
Glargine hrs Peak hrs combined with
• Hormone that regulates the metabolism of carbohydrates, Levemir or 1-2 hrs 6-8 Up to 24 rapid- or short-
proteins, and lipids Detemir hrs hrs acting insulin
• Promotes cellular reuptake of plasma glucose Humulin 30 min 2-4 14-24
70/30 hrs hrs
- Glucose is absorb in the tissue thus lowering the glucose found Novolin 30 min 2-12 Up to 24 • Combination of
in the blood 70/30 hrs hrs intermediate –
• Glucose –stimulates the conversion of glucose into glycogen Novolog 10-20 1-4 Up to 24 and short-acting
PRE- 70/30 min hrs hrs insulin
- Glycogen: stored in the liver, tissues and adipose cells MIXED Humulin 30 min 2-5 18-24hrs • Commonly used
50/50 hrs twice daily before
§ Indications Humalog 15 min 30 16-20 mealtime
• Required for glycemic management in individuals with T1DM 75/25 min- hrs
- In Type 1 Diabetes Mellitus, the pancreatic cells (beta islet 2.5
hrs
cells) are not able to produce sufficient amount of insulin, thus
there is a deficiency of insulin in the body leading to an increase
in the glucose that is present on the blood
• May be used in combination with oral agent or amylin agonist
- Amylin: is a hormone that is cosecreted with insulin, which
cause to lower the postprandial (increase of blood glucose after
meals) blood glucose
o After sometime this could accumulate in the intracellular
spaces which could cause amylin deposition leading to beta
cell destruction.
o Therefore if the body produces insulin, it also produces
amylin
o Accumulation of amylin can cause the destruction of beta
islet cells leading to a decrease in the insulin level that is
being produce by the patient
• May also be initial or adjunctive agent for individual with T2DM

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Clinical Pharmacy II: Diabetes Mellitus PHA6132 - Lecture
• Insulin likes to bind together. § Agent
• Insulin would usually be in the form of hexamer. • Pramlintide
- Hexamer is too large to be absorbed in the body. - Allows to lower the dose of insulin
- There are scientist who altered the sequencing of amino acids
of this insulin resulting to it being less aggregated. That is why § Indication
we have insulins that have different onset of action and different • Enhance post prandial control in individual with T1DM or T2DM
duration of action.
• Rapid acting Insulin
§ Contraindication
• Gastric motility disorder, such as gastroparesis
- It is formulated to be less aggregated so that they can penetrate
the cells and tissues faster. They have faster onset of action. § MOA
- Lispro/Humalog, Novolog/Aspart, and Apidra/Glulizine • Slow gastric emptying time
- Elicit their effect in less than 15 minutes. Lowering their blood • Decreases postprandial glucagon secretion
glucose levels (usually starts at 5 minutes and slowly • Suppresses appetite
increases).
- Peak of blood glucose lowering effect can be seen between 60- § Side effects
120 minutes. • Nausea
- Their duration of action lasts for more or less 5 hours. • Modest weight loss
• Short acting Insulin Incretin Mimetics (GLP-1 agonists)
- Longer onset of action compared to the rapid acting. They • Incretin is a group of metabolic hormones that is produced by
produce effects slower compared to the rapid acting. GUT
- Their peaks are reached between 2 to 5 hours. - Stimulates pancreas to produce more insulin
- Duration of action is usually (Humulin or Regular Insulin) would - Has two types: glucagon like peptide 1 (GLP-1) and glucose-
be around 6 to 8 hours. dependent insulinotropic polypeptide (GIP)
- We give short acting insulin 20 to 30 minutes before meals so o GLP-1 and GIP stimulates the release of insulin and inhibits
that the patient eats their meal, after finishing their meal that is the release of glucagon -> lowering the blood sugar level
the time that the onset of action of this regular insulin would • Increase concentration is beneficial to the patient
already take place. • Has a very limited action because it is easily deactivated by
- There is no increase or not high level of insulin would be dipeptidyl peptidase-IV (DPP4)
reached after the patient has taken their meal or the
postprandial glucose would not reached a very high level. § Agents
• Intermediate acting Insulin • Exenatide
- NPH (Isophane) and Lente. • Liraglutide
- Duration of Action 18 to 24 hours. • These 2 medications are resistant to DPP 4 -> more pronounced
o Incorporation of Zinc and Protamine. action
§ These two makes insulin less soluble. it would take some
time for it to be absorb that is why there is a delay in the § Indication
absorption and at the same time it would have a longer • Management of T2DM
duration of action because the insulin is slowly absorbed § Contraindications
by the body. • Individuals with severe GI motility disease (e.g., gastroparesis)
• Long acting Insulin • Pancreatitis or a history of pancreatitis
- Lantus or Glargine • Severe renal impairment or hepatic impairment
o No peak- it steadily delivers the insulin.
• Liraglutide is contraindicated in individuals with a history or family
§ It is caused by modification of the insulin so that the insulin
history of medullary carcinoma (MTC) and individuals with
is slowly released into the bloodstream.
multiple endocrine neoplasia syndrome type 2 (MEN2). It may be
o Low solubility at neutral pH because at neutral pH it actually
used in individuals with other thyroid disorders, including
causes the formation of precipitate that contributes to the
hypothyroidism or hyperthyroidism
slow release of insulin to the bloodstream.
- Levemir or Detemir § MOA
o Long duration of action due to addition of fatty acid side • Increase glucose dependent insulin secretion
chain which allows insulin to bind with proteins, such as • Decrease hepatic glucose output
albumin, so it slowly releases insulin into the bloodstream. • Increases ß-cell growth and replication
But because it is actually bound to albumin, it could cause - Can cause pancreatitis because there is a continuous increase
some problems or drug interactions because of protein in the number of ß-cells
binding. • Slows gastric emptying time
Amylin Receptor Agonist • Enhances satiety
• Amylin - Results to weight loss because they always feel full with the
- Hormone that is co-secreted together with insulin. medication
- How does it regulate the blood glucose level? Dipeptidyl Peptidase-IV (DPP-IV) Inhibitors
o Amylin causes a delay in the gastric emptying time. Thus, it • DPP-IV is the enzyme the inactivates the incretin
suppresses the post prandial glucagon secretion. Because • Inhibiting DPP-IV -> enhances incretin hormones promoting GLP-
there is a delay in gastric emptying time, therefore the food is 1 and GIP
not fully digested/converted into glucose so the body would
not produce/secrete glucagon all at once. § Agents
- Glucagon is released in response to low blood sugar level. If we • Sitagliptin
suppress the gastric emptying time, there will be slow release of • Saxagliptin
food or slow conversion of nutrients/sugar. • Linagliptin
- We actually maintain a plateau in the blood glucose level. At the § Indication
same time, it also promotes satiety (fullness), the patient would
• Patients with T2DM with normal or impaired hepatic and renal
not feel that he needs to eat because of the delay in metabolism function
or gastric emptying time

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Clinical Pharmacy II: Diabetes Mellitus PHA6132 - Lecture

§ Contraindications B. Meglitinide (Repaglinide) and Phenylalanine derivative

• Pancreatitis: use cautiously in an individual with a past medical (Netaglinide)
history of pancreatitis and discontinue use if an individual § Indication
develops pancreatitis while on a DPP-IV inhibitor • Management for T2DM
• T1DM: DPP-IV inhibitors provide a glucose-dependent insulin • Targets post prandial control.
secretion and thus are not appropriate for individuals with T1DM
§ MOA
§ MOA • Stimulates secretion of insulin from pancreatic, reduces hepatic
• Prevents the inactivation of incretin hormones by the enzyme glucose output.
DPP-IV during hyperglycemia - Repaglinide and Netaglinide stimulates insulin secretion by
• Inhibiting the breakdown of GLP-1 would allow for increased binding also to the ATP-sensitive potassium channels, but in
insulin secretion and decreased hepatic glucose production different site and kinetics than that of sulfonylureas.
- Because of the difference in kinetics these glinides have more
§ Side Effects rapid onset of action and shorter duration of action.
• Nasopharyngitis - Good choice for patients with postprandial hyperglycemia.
• Headache
• Weight loss: has a similar action with incretin mimetics § Contraindications
Insulin Secretagogues • Severe renal and hepatic dysfunction
• Used in caution in elderly due to increased risk of fall.
A. Sulfonylureas
• Targets fasting blood glucose levels § Side Effects
• Binds to and inhibit the activity of ATP-sensitive potassium • Hypoglycemia
channel • weight gain.
- Even without the presence of glucose inside the cell, there will Biguanides
be an inhibition of influx of calcium, depolarization, and release
in the insulin § Agent
- This mechanism allows the sensitivity of ß-cell to glucose • Metformin: the only available biguanide
• Reduces hepatic glucose production
• Highly protein bound - many drugs may interact with sulfonylureas
§ Indication
• Used for the glycemic control for management of T1DM or T2DM.
producing protein binding displacement or cause changes with
regards to distribution of drug - First line of treatment for patients when they are newly
diagnosed with type II diabetes.
• 1st Generation
• Targets fasting blood glucose.
- No longer being utilized because they have more pronounced
side effect compare to second generation § Contraindications
- Typically note prescribed since 2nd gen has fewer ADR • Renal disease: Contraindicated due to its potential for lactic
- Associated with thrombocytopenia, agranulocytosis, hemolytic acidosis
anemia, hyponatremia, SIADH, disulfiram like reaction • Hepatic impairment
- Tolbutamide, Tolazamide, Chlorpropamide • Heart failure
• 2nd Generation
- Glyburide § MOA
- Glipizide • Inhibits hepatic glucose output, thus exerting beneficial effects on
- Glimepiride fasting blood glucose level.
• Promotes glucose uptake by fat and muscles improving insulin
§ Side Effects sensitivity increasing insulin sensitivity.
• Major side effect is hypoglycemia due to the increased sensitivity • Minor role in decreasing intestinal absorption of glucose.
of beta cells - Slows down intestinal absorption of glucose while increasing
- Due to more influx of glucose inside the cells insulin sensitivity which enhances the peripheral glucose
• Known side effect is weight gain uptake.
Review: pathophysiology on how glucose allows the releases § Side Effects
of insulin • GI side effects: diarrhea, vomiting, weight loss
• Glucose goes into the cell thru the • Patients taking Metformin has a higher risk for lactic acidosis.
Glut2 receptors
• Because of this, the glucose is Thiazolidinediones
converted into ATP (major energy § Agents
that is utilized by the body) • Pioglitazone
• The ATP binds to ATP sensitive • Rosiglitazone
potassium channel
• Once they bind, they inhibit the entry of potassium § Indication
• Because of the inhibition of potassium channels, there will be a • Glycemic control in T2DM and primarily affects fasting blood
depolarization in the cell membrane, thus activating the voltage glucose level
gated calcium channel
§ Contraindications
• Upon the activation of the gated calcium channel, calcium would
• Hepatic dysfunction
be allowed to enter
• Class III/IV heart failures: TZDs may cause fluid retention, which
• The increase amount of calcium inside the cell would allow the can exacerbate or lead to heart failure
production and secretion of insulin from inside the blood
• Anemia: TZDs may cause plasma volume expansion. This may
result in a small decrease in hemoglobin and hematocrit
• Fracture risk: typically in the distal upper or lower limbs of females

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Clinical Pharmacy II: Diabetes Mellitus
§ MOA
• Promote glucose uptake by fat and muscles and inhibit hepatic
glucose output by stimulation of peroxisome-proliferator-activated
receptor-gamma (PPAR-γ)
- It selectively activates nuclear receptor called peroxisome-
proliferator-activated receptor gamma (PPAR- γ)
o Once that they activated this receptor, it binds to a DNA then
triggers the expression and repression of specific gene-
encoding proteins that regulates lipids as well as glucose
metabolism.
- At the same time, it signals insulin transduction. Once
activated, there is an increase in insulin sensitivity in the
adipose tissues, in the skeletal muscles, as well as in the liver.
- It also inhibits the hepatic glucose production, and the
activation of the PPAR- γ also promotes fatty acid uptake and
the utilization of adipocytes.
§ Side Effects
• Changes in the cholesterol or lipoprotein levels of the patients
because of the uptake and utilization of fats
• ↑ HDL level
• Weight gain
• Edema
• Hepatotoxicity
Alpha Glucosidase Inhibitor
§ Agents
• Acarbose
• Miglitol
§ Indication
• Management of postprandial blood glucose
§ Contraindications
• Inflammatory bowel disease, colonic ulceration, or obstructive
bowel disorders
• Acarbose is not recommended in patients with serum creatinine
of >2.0mg/dL or creatinine clearance of <25mL/min
• Acarbose is contraindicated in patients with hepatic impairment
• Side effects: more on GI
§ MOA
• Competitive inhibition of alpha-glucosidase in the intestinal
brush border, which leads to a slower absorption of complex
carbohydrates
• Alpha glucosidase
- An enzyme located in the intestinal brush border
- Responsible for breaking down carbohydrates into simple
sugar, particularly glucose
- If we inhibit alpha glucosidase, there is going to be a delay in
the glucose absorption and because of that, there is also going
to be a decrease in the postprandial glucose level because
there is no alpha glucosidase that would break down this
carbohydrate into simple sugar
Sodium Glucose Cotransporter Inhibitor
• New class of oral hypoglycemic agent
§ Agents
• Canagliflozin, Dapagliflozin, and Empagliflozin
§ MOA
• Selectively and reversibly inhibits the sodium glucose co
transporter which is selectively expressed in the proximal renal
tubule
• It inhibits the reabsorption of glucose into the bloodstream so
there is going to be a lesser amount of glucose.
• This group of medication is also seen to have beneficial effects
with regards to cardiovascular and patients with chronic kidney
disease.
- So if a patient has diabetes and are at risk for developing or
already has CKD or cardiovascular complications then this is
actually one of the group of medications that we used for them
PHA6132 - Lecture
Management Part 2
• For patients with diabetes, our main goal is for us to be able to
prevent complications that could arise from the progression of
diabetes as well as to improve our patient's quality of life.
• Remember that we need to reassess our patients every now and
then
• We do not want the patient's medication to be stagnant, we need
to reassess every three to six months to determine the effectivity
of the medications
• Dose adjustment must be done so that our patients would reach
the target glucose goal.
Type 1 Diabetes Mellitus: Refer to Table 3 (Types of Insulin)
• Type 1 diabetes is attributed to an autoimmune condition which
destroys the pancreatic beta cells that leads to a deficiency in the
insulin level.
• That is why for the management of patients with type 1 diabetes
mellitus - Insulin therapy is prescribed
- It is important that the insulin therapy given to the patients
mimics the natural release of insulin in our body.
• In the metabolic state we have 2 states - Absorption state and
Post absorption state.
• In the absorption state, hormone insulin predominates.
- Every time we eat. The state wherein our body takes in
nutrients.
• In the Post absorption state, glucagon predominates.
- The time wherein our body tries to utilize the food that we have
eaten so that it would produce the glucose that is needed by
the body for its metabolism.
• In patients with diabetes, since there is a deficiency of insulin,
there is a surge in the amount of glucose even at the time where
the body should be in its absorption state.
• So what insulin management does is that we actually want to
mimic our bodies release of insulin
• So what we do is we time the release of insulin to the time that it
is supposed to be released by the body.
§ Physiological Timeline
• The body state during the time of:
- 3 to 6 AM: Post Absorption
state
- 6 to 9 AM: Absorption state.
- 9 to 12 noon: Post absorption Basal level
state
- 12 to 3 PM: Absorption state
- 3 to 6 PM: Post absorption
- 6 to 9 PM: Absorption
- 9 to 12 PM: Post Absorption
• During the time of absorption, normally our body would release
insulin while during the time of post absorption, glucagon is being
released
• For patients with diabetes they do not have enough insulin for
them to be able to store nutrients therefore, we need to give our
patients an exogenous dose of insulin to compensate for the
amount the body requires. Thus, basal bolus strategy is
utilized.
§ Basal-Bolus Strategy
• Long-acting insulin analog and at the same time, rapid or short
acting insulin
• As seen in the illustration, the insulin level does not go to zero:
basal level
• For the patient to have insulin in their body, we give them a dose.
That basal dose is LA Insulin (duration action of 20-36 hrs, 24 hrs,
and for intermediate acting - 18-24 hrs)
- The longer the duration of action of insulin, the lesser the
frequency that it is to be administered to the patient.
• EXAMPLE: GLARGINE
- Duration of action: 20-24 hrs
- If this is to be administered before bedtime- there will be an
increase in insulin level of our patient and remember that there
is no peak up to the next day.
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Clinical Pharmacy II: Diabetes Mellitus
• During the absorption state there should be a higher level of
insulin.
- During this time we will give the rapid or short acting insulin.
- Usually if we will give a rapid acting insulin, we inject it more or
less 15 mins before mealtime so that when we already have
the meal, the insulin level will increase. It will decrease with the
post absorptive and before the next meal, we give another dose
and another dose before the next meal.
- Therefore, we are actually mimicking the natural release of
insulin of our body.
§ Own Notes
• Premixed Insulin (Combination of Intermediate and Short
Acting Insulin)
- Giving this, there will be lesser frequency of the administration
of insulin to the patients
- Instead of injecting it 5 times a day (2 basal using intermediate
and 3 bolus), it would be reduced to twice a day that is to be
given before mealtime
• Using the basal bolus strategy, 50% of the total insulin of the body
should be coming from the basal dose and another 50% from the
bolus doses based on American Diabetes Association Guidelines
of 2020
• With regards to the insulin, the usual dose given to a patient using
insulin would depend on their body weight.
- Usual dose: 0.5 units/kg up to 1unit/kg body weight.
• So, between 0.4-1 unit/kg body weight, what is the most
recommended?
- For metabolically stable patients: starting dose of 0.5 unit/kg
body weight but 0.4-1 unit/kg is still acceptable
§ Patient Education
• One of the things that we must consider if the patient is on insulin
therapy, whether type I or II diabetes, it is very important that we
educate them on how to properly administer the medication.
- Remember that your insulin is to be administered
subcutaneously and there would be different absorption if this
medication is given intramuscularly.
- So, we must instruct our patient, demonstrate to our patient
how to properly administer and what are the different areas
where they could administer insulin.
• Usual sites of insulin administration would be:
- Abdomen
- Buttocks
- Thighs
- Upper arms
PHA6132 - Lecture
Glucose-Lowering Medication in Type 2 Diabetes: Overall
Approach
Refer to the figure on page 15
• FIRST-LINE Therapy is Metformin and Comprehensive Lifestyle
(including weight management and physical activity)
§ Metformin
• First line therapy, unless there is a contraindication or patient
cannot tolerate.
• There should be comprehensive lifestyle (including weight
management and physical activity)
• To avoid therapeutic inertia, reassess and modify treatment
regularly (3-6 months)
o therapeutic inertia: therapeutic being stagnant or not titrated
Legend: For numbers in parenthesis and red
(1). Proven CVD benefit means it has label indication of reducing
CVD events
(2). Be aware that SGLT2i labelling varies by region and individual
agent with regard to indicated level of eGFR for initiation and
continued use
(3). Empagliflozin, canagliflozin, and dapagliflozin have shown
reduction in HF and to reduce CKD progression in CVOTs.
Canagliflozin has primary renal outcome data from CREDENCE.
Dapagliflozin has primary heart failure outcome data from DAPA-
HF
(4). Degludec or U100 glargine have demonstrated CVD safety
(5). Low dose may be better tolerated through less well studied for
CVD effects.
(6). Choose later generation SU to lower risk of hypoglycemia.
Glimepiride has shown similar CV safety to DPP-4i
(7). Degludec/glargine U300 < glargine U100/detemir < NPH insulin
(8). Semaglutide > Liraglutide > dulaglutide > exenatide >
lixisenatide
(9). If no specific comorbidities (i.e. no established CVD, low risk of
hypoglycemia and lower priority to avoid weight gain or no weight-
related comorbidities)
(10). Consider country- and region- specific cost of drugs. In some
counties TZDs relatively more expensive and DPP-4i relatively
cheaper.
§ ASCVD Predominates
• Patient is already in Metformin
• Established ASCVD
• Indicators of high ASCVD risk (age ≥55 years with coronary,
carotid or lower extremity artery stenosis >50%, or LVH)
• PREFERABLY: Metformin +
- GLP-1 RA with proven CVD Benefit (1):
o Liraglutide
o Dulaglutide
o Senaglutide
- or SGLT2i with proven CVD benefit(1) if eGFR adequate(2):
o Empagliflozin
o Canagliflozin
o Dapagliflozin
• If A1C above target
- If further intensification is required or patient is now unable to
tolerate GLP-1 RA and/or SGLT2i, choose agents
demonstrating CV safety:
o For patients on a GLP-1 RA, consider adding SGLT2i with
proven CVD benefit(1)
o DPP-4i if not on GLP-1 RA
§ Take note: If patient is on GLP-1 RA, do not give DPP-4i
because they both act on incretin hormones.
§ If patient is on SGLT2i then you can give DPP-4i
§ If still not worked then add basal insulin.
o Basal insulin(4)
§ Take note: In adding basal insulin, we give first Degludec or
U100 glargine because these two have demonstrated safety
regarding CVD.
o TZD(5) - Thiazolidinediones
o SU(6) – Sulfonylureas
§ Last line, should be 2nd generation.
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Clinical Pharmacy II: Diabetes Mellitus
§ HF or CKD Predominates
• For patients who are at risk or who had risk for Heart Failure or
CKD.
• Particularly Heart Failure Reduce Ejection Fraction or HFrEF
(LVEF <45%)
• CKD: Specifically eGFR 30-60 mL/min/1.73 m2 or
UACR>30mg/g, particularly UACR>300mg/g
• PREFERABLY:
- SGLT2i with evidence of reducing HF and/or CKD progression
in CVOTs if eGFR adequate(3).
- If FGLT2i not tolerated or less contraindicated or if eGFR less
than adequate add GLP-1 RA with proven CVD benefit(1)
- Notes:
o The first medication that we are going to add with Metformin
would be Sodium Glucose Co-transporter inhibitors because
they have been proven to have beneficial effect for patients
with CKD and HF.
o If this medications could not be tolerated by the patients then
we could add GLP-1 Receptor Agonist which have also been
proven to have benefits for patients with cardiovascular
diseases.
o With the combination therapy patient would still have
elevated A1C level that is above the target. Would proceed
to quadruple therapy
• If A1C above target
- Avoid TZD in setting of HF
- Choose agents demonstrating CV safety:
o For patients on a SGLT2i, consider adding GLP-1 RA with
proven CVD benefit(1)
o DPP-4i (not saxagliptin) in the setting of HF (if not on GLP-1
RA)
o Basal insulin(4)
o SU(6)
- Notes:
o Patients on SGLT2i + GLP-1RA* (triple therapy),
§ *take note to not give DPP-41 because they have almost
the same MoA.
o If DPP-4i is given, saxagliptin is not recommended.
§ Compelling Need to Minimize Hypoglycemia
• For patients with no complication with ASCVD, HF or CKD but is
concerned by hypoglycemic effect of the medication.
• These medications are actually medications that have a lesser
potential to cause hypoglycemic effect to our patient.
• In case with triple therapy of metformin, DPP-4i, or SGLT2i and
there is no improvement or slight improvement with A1C level of
the patient and it has not been achieved then we continue with
addition of another agent.
• A1C is the average blood glucose level for 3 months therefore this
changes in the medication is actually done as part of re-
assessment. Every 3 months you re-assess your patient add or
remove the medication if needed.
• If A1C is still above the target: consider the addition of SU(6) OR
basal insulin(7)
§ Compelling Need to Minimize Weight Gain or Promote
Weight Loss
• If the patient is concerned about weight gain or you want them to
lose weight together with the management with his/her diabetes
you could either choose your:
- GLP-1 RA which has a good efficacy for weight loss(8)
- SGLT2i(2)
• If the target A1C still not met, then you could combine the two
medication.
• And if still the A1C target has not been met, we are going to have
quadruple therapy of Metformin, SGLT2i, GLP-1 RA
• We could choose another oral hypoglycemic that has a neutral
effect on the weight of the patient.
- If the patient is not on GLP-1 RA, we could give our patient
DPP-4i which has a neutral effect on the patient’s weight.
• If the patient is in DPP-4i and is not well tolerated we could give
SU(6), TZD(5), and Basal Insulin.
PHA6132 - Lecture
§ Cost is a Major Issue
• Second line of medication will be your SU or TZD.
NOTE
• If the medication still have no beneficial effect even after
reassessment, triple or quadruple therapy, insulin therapy is
suggested
• Target HBA1C based on American Diabetes Association, but it
is better if our prescriber has a more stringent HBA1C level that
they want their patients to have
- Non-pregnant: <7.0% (53 mmol/mol)
Intensifying to Injectable Therapies
Refer to the figure on page 16
• If the patient is already on GLP-1 RA in most prior to insulin and
the patient still did not achieve the target HBA1c, consider basal
insulin
• Before adding new medication, we first titrate the dose to see if
there is no improvement
- After we initiate a therapy, we start with the lower dose then we
titrate it until we achieve the maximum dose. If there is still no
beneficial effect, that’s the time we’re going to add new
medication
§ Basal Insulin
• Start 10 IU a day or
• 0.1-0.2 IU/kg a day
• Slowly titrate this dose to see if the patient would have any
improvement with regards to the dose of the insulin that is given
• Intermediate-acting insulin and long-acting insulin
§ For Patient on GLP-1 RA and Basal Insulin
• Consider fixed-ratio combination of GLP-1 RA and insulin
- iDeglira: combination of Degludec (100U) and Liraglutide
(3.3U)
- iGlarLixi: combination of glargine (100U) and lixisenatide (33
mcg/mL)
• Initiation:
- 10-16 dose (iDegLira)
- 10-15 units (iGlarLixi)
• In titration, it is important to monitor the blood glucose level of
the patient
- If the HBA1C of the patient is above the target, increase the
dose
- If it achieves the target, there is no need to give an additional
dose of the medication/maintain the dose
- Depends on the dosing instruction of the physician
§ Initiation for Prandial
• If the patient still does not respond (above the HBA1C target)
even with triple therapy + administration of basal insulin, initiate
prandial insulin (short-acting insulin)
• Start with 4 IU per day or 10% basal insulin dose
• Usually, one dose with the largest meal or meal with greatest PPG
excursion
• Titrate by increasing 1-2 units or 10-15% 2x weekly
• For hypoglycemia, determine cause, if no clear reason lower the
corresponding dose by 10-20%
- Example: if we are giving the patient a prandial insulin dose of
2U, then the patient experiences hypoglycemia without known
cause, reduce the dose to 10-20%
o 2U – 10% = 1.8U
§ Initiation of Stepwise Prandial
• If the patient still does not achieve the HBA1C target even with
addition of prandial insulin after the biggest meal, initiate stepwise
additional injections of prandial insulin (two, then three additional
injections)
• Oral hypoglycemic effect
§ Full Basal Bolus Regimen
• If the patient still does not respond, give full basal bolus regimen,
i.e., basal insulin and prandial insulin with each meal
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Clinical Pharmacy II: Diabetes Mellitus PHA6132 - Lecture
Glycemic Control Algorithm - Example: If on Wednesday the patients Fasting blood glucose
Refer to the figure on page 17 level is 150mg/dL, we need to add 10% of the total daily dose
• Just like ADA guidelines, start with life style modification but in of insulin. If the patient’s dose is 7.5 x 10% therefore, the dose
this case, they actual stated the HbA1c goals that they want for the of the patient that we are going to give is 8.25 units.
patient • If hypoglycemia, reduce the dose depending on patient’s blood
• < 6.5% for patients without concurrent serious illness and at low glucose level
hypoglycemia risk - BG <70 mg/dL: 10%-20%
• > 6.5% but if possible, not exceeding 7.5, for patients with - BG <40 mg/dL: 20%-40%
concurrent serious illness and at risk of hypoglycemia
§ Glycemic Control Not at Goal
§ Lifestyle therapy • If the patient’s glucose level or glycemic control is still not
• First line of therapy achieved, then we need to intensify by giving our patients the
• Non pharmacologic therapy prandial insulin dose.
• Add GLP1 receptor agonist, SGLT2 inhibitor, or DPP4i
§ Entry A1C less than 7.5%
• If the patient has less than 7.5 HbA1c, start with monotherapy § Add prandial insulin.
• Can either choose from metformin, GLP1 receptor agonist, or • Basal insulin plus 1, 2, 3 prandial insulin dose.
SGLT2, DDP4i. - Begin with prandial insulin before the largest meal.
• Any of the four medications could be used. - If not at goal, progress to injections before 2 or 3 meals.
- Start 10 percent of basal dose of insulin or 5 units.
§ Entry A1C greater than 7.5% • If still does not respond to this management, the next thing is to
• Start with dual therapy have the basal bolus.
• Metformin + GLP1-RA/ SGLT2i/ DPP4i/ Colesevelam/ - 50% basal 50% prandial with a total daily dose of 0.3-0.5 units
Bromocriptine QR/ AGi /kg/day
• Usually start with SLT1 receptor agonist and SLGT2 inhibitor - Start 50% of total daily dose that is divided into 3 doses before
meals.
§ Triple Therapy
• If the patient does not respond or the goals are not met after 3 Philippine Guidelines
months
• Metformin plus combination
- Can combine SLGT1 with SGLT2 or SLGT1 plus EZi or SGLT2
plus DDP4i
§ Entry A1C greater than 9.0%
• If there no symptoms, proceed to dual therapy or triple therapy
• If there are persistence of symptoms of hyperglycemia that is
manifested by the patients, proceed with triple therapy
• With triple therapy, if patient still does not achieve individual goal,
add or intensify insulin
Algorithm for Adding / Intensifying Insulin
Refer to the figure on page 18
• Management with regards to insulin is more direct. They have
clear guidelines whether how much insulin is to be added to
patient’s daily dose unlike in ADA guidelines.
§ Start Basal (Long-Acting Insulin)
• If the patient’s HBA1C is less than 8% then the dose of the patient
Figure: Algorithm for initiation of anti-diabetic agents for newly-
insulin should be 0.1-0.2 U/kg/day.
diagnosed diabetics.
• If patients HBA1c is greater than 8% then we give our patient 0.2
• If the patient is newly diagnosed with T2DM
or 0.3 U/kg/day.
- HbA1c <9% and FBS <250, then you could start the patient
• We need to titrate the patients dose every 2-3 days for the patient
with monotherapy. Usually, the first line is still metformin.
to achieve their glycemic goals.
- HbA1c ≥9% and FBS ≥250, then you could start with
§ Insulin Titration Every 2-3 Days to Reach Glycemic Goal combination therapy.
• Fixed regimen: increase TDD by 2 U • This still goes with lifestyle modification.
- Based on patients fasting blood glucose level that means there • You still need to frequently re-asses your patient every 3 to 6
is monitoring that is to be done for us to be able to determine months to determine whether the medications that are being
how much of insulin is to be added to patient’s dose. given to your patient is effective in achieving their HbA1c goals.
- Example: patient is 75 kg and we are going to start his dose
with 0.1 units, it means that we need to give the patient 7.5
U/day.
o If we are going to follow the fixed dose regimen that means
every 2-3 days, we are going to add 2 units to the patient’s
insulin dose. Today (Sunday), we start with 7.5 then on
Wednesday we are going to increase patient’s dose by 2
units so the patient’s dose would be 9.5. By Saturday we
adjust again the dose of the patient by adding 2 units so it
would be 11.5 units.
• Adjusted regimen: For the adjusted regiment, we are going to
base it on patient’s fasting blood glucose level.
- FBG > 180 mg/dL: add 20% of TDD
- FBG 140-180 mg/dL: add 10% of TDD
- FBG 110-139 mg/dL: add 1 unit

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Clinical Pharmacy II: Diabetes Mellitus PHA6132 - Lecture
• Self-care education to patients with diabetes (especially on how
to properly take insulin preparations)
- Based on the ADA guidelines, there is a new type of insulin that
is no longer injected, these are the inhalational insulin, but they
it is not yet available in the Philippines.
• Optimal nutrition and protein intake
- Less carbohydrates, more of the proteins
- Smoking and alcohol intake should be managed
• Regular exercise (to control the patient’s body weight)
End of Diabetes Mellitus

Figure: Sequential Insulin Strategies in T2DM

Note: Basal insulin is typically started at a dose of 0.2 units/kg per
day (e.g., 50 kg x 0.2 units/kg = 10 units starting dose once a day).
[Similar to AACE guidelines]
Source: Diabetes Care, Diabetologia. 19 April 2012.
• If the patient has type 2 diabetes and the patient has HbA1c of
≥9% and the FBS ≥250 and the patient already has non-insulin
regimen but still the goal is not achieved, then we start our patient
with basal insulin.
• Start with basal insulin + 1 meal-time (prandial insulin), if the
patient still does not respond to this medication and HbA1c is still
not controlled, then we give 2 prandial doses of rapid-acting
insulin or
• Premixed insulin twice daily.
c. For the patient on insulin, should the patient adjust his
insulin? If so, when and how?
INSULIN SHOULD NOT BE STOPPED. There are no hard and fast
rules regarding insulin dosage as response depends on the
individual patient's metabolism and the type of insulin he is taking.
Sick-day rules should follow those agreed with
consultants/specialist units at the time of initiation of insulin or follow
local guidelines.
• Metabolism: There is no really strict dosage for insulin level, it
would always be based on the patient weight and blood glucose
level because there are individual factors that we must consider
just like how fast the metabolism of a patient is.
The following rule of thumb may also be followed:
• Blood glucose less than 13 mmol/L (or less than 230 mg/dL) -
continue with current dosage
• Blood glucose 13-22 mmol/L (or 230 to 390 mg/dL) - patient
should increase his insulin by 2 units per injection, even if unable
to eat
• Blood glucose greater than 22 mmol/L (or 390 mg/dL) - patient
should increase his insulin by 4 units per injection, even if unable
to eat
• Return dose to normal when blood glucose returns to normal
Non-Pharmacologic Intervention
• Optimize glycemic control to reduce risk of CKD, diabetic
retinopathy and other complication
• Optimize blood pressure and serum lipid control to reduce risk or
progression of diabetic retinopathy
• Patient must assessed for diabetic peripheral neuropathy starting
at diagnosis (with yearly assessment)
• Perform comprehensive foot evaluation at least annually to
identify risk for ulcers
- How to care for their foot?
- This is one area where patients will usually have complications,
diabetic foot ulcerations, and it is very important that patients
know how to properly clean these ulcerations so that it would
not progress rapidly because this may lead to amputation.
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TABLE 4: Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes

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Glucose-lowering medication in type 2 diabetes: overall approach.

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Intensifying to injectable therapies

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Glycemic Control Algorithm

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Algorithm for Adding/Intensifying Insulin

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