Endocrinology

Diabetes Mellitus

Endocrinology
Pharmacotherapy 4

1
 Diabetes Mellitus (DM)

• A clinical syndrome characterized by hyperglycemia, due to the deficiency

or diminished effectiveness of insulin.

• DM is the most common endocrine disorders.

• Insulin plays a key role in regulation of carbohydrate, fat and protein

metabolism.

• Patients with DM have an inability to take up and use glucose from the
blood, and, as a result, the glucose level in the blood rises.

• On the basis of aetiology two main categories of diabetes are recognised,

namely primary and secondary diabetes.

2
 Prevalence in Emirates

• 19.6 % in UAE

• 24% in the citizen group, while in the

expatriates it is 17.4%

• 40% in the age group 60 and above

3
 Diabetes Mellitus

• The great majority of cases seen belong to primary diabetes, which

consists of two main clinical types:
1. Insulin-Dependent Diabetes Mellitus - IDDM (Type I) primarily a
disease of the young mostly under 15 years old and rapidly fatal
without treatment of insulin.

2. Non-Insulin-Dependent Diabetes Mellitus - NIDDM (Type II)

occurring mainly in the middle-aged and elderly.
The following table shows the distinguishing features between Type I
and Type II DM.

• A minority of cases of diabetes occur as a result of a recognisable

pathological process or secondary to the treatment of some other
condition.
4
• In secondary diabetes, diseases such as:
o Pancreatitis, haemochromatosis (excessive absorption and storage
of iron) and carcinoma cause destruction of the pancreas and lead
to impaired secretion and release of insulin.

o Growth hormone antagonises insulin (30% of patients with

acromegaly are diabetic)

o Adrenocortical hormones, such as cortisol, raise the concentration

of glucose in the body by increasing gluconeogenesis (synthesis of
glucose) and by inhibiting utilisation of glucose by peripheral
tissues.

o Therefore, many patients with Cushing's syndrome show impaired

carbohydrate tolerance and diabetes may be precipitated by ACTH
(adrenocorticotrophic hormone) or corticosteroid therapy (the
stress of physical injury may operate in this way). 5
 Types of Diabetes Mellitus

Type 1 Type 2
• Autoimmune disease • Reduced insulin production
• Islet cells are destroyed • Insulin resistance
• Insulin dependence • 90-95% of all diagnosed DM
patients

Gestational Diabetes
• High BGL first diagnosed
between the 24th and 28th WEEK
in pregnancy
• Affects about 1% to 3% % of all
pregnant women

6
 Difference Between Type 1 and Type 2
Type II (NIDDM) Type I (IDDM)
2-5% 0.5% Prevalence
Gradual and after age of 35 Sudden and usually during childhood Onset
Possibly none, usually Polyphagia, polydipsia and polyuria. Often Symptoms
overweight underweight

Frequently positive Not usually positive Family history

Tissues unresponsive to insulin Deficiency of pancreatic B-cell secretion. Primary cause
(insulin resistance) in some Secretion may become totally absent in the
patients and often there is later stage of diabetes
inadequate secretion to keep
with ordinary requirement

Variations in blood glucose are Wide variation in blood glucose occur with Stability
less marked. Ketosis is small change in insulin dose. Exercise and
uncommon except when there is infection have a marked effect on diabetic
severe stress or sepsis control. Ketosis may occur frequently,
especially if regimen is insufficient in food or
insulin

unknown Unknown. Possible factors are autoimmune Aetiology

disease, viral infections and inheritance
7
 Complications
Dental cavities, gingivitis and periodental Mouth
disease
•Numerous infections and lesions, pruritis. Skin

Retinopathy, glaucoma, cataract formation and Eye

visual disturbance
Blood vessel disease (atherosclerosis) and Vascular system
microangiopathy (e.g. foot ischaemia)

Motor, autonomic and sensory neuropathy Nervous system

Higher incidence of cystitis, skin infection, Infections

tuberculosis, moniliasis
Stillbirth, large babies, miscarriages, neonatal Pregnancy
death and congenital defects
8
 Insulin Release
An increase in blood glucose (as occurs after a meal) will stimulate the release
of insulin and inhibit the release of glucagon.
Human insulin consists of 51 AA in two chains connected by 2 disulfide
bridges. Bovine insulin differs by 3 AAs, pork insulin differs by 1 AA.
Insulin binds to specific high affinity membrane receptors with tyrosine
kinase activity.
Beta cells comprise 70% to 90% of islet cells. Beta cells secrete insulin,
proinsulin, C-peptide (protein C), and amylin.

The cleaved polypeptide remnant is termed protein C. Normal individuals secrete

both insulin and much less pro-insulin.
Type 2 patients are found to secrete high levels of the inactive pro-insulin.
Measuring the level of C-protein is a more accurate estimation of normal insulin
secretion in type 2. 9
 Islets of Langerhans
β-cell of Pancreas

The major target tissues for insulin and glucagon are liver, skeletal muscle and fat.
Glucagon: Alpha cells
Insulin: Beta cells
Somatostatin: Delta 10
 Insulin Release: Normal Levels
• Approximately 200 units of insulin in the pancreas of a normal
adult
• Daily secretion in humans: 30 - 50 IUnit
• Basal plasma insulin: 8.2 mlU/ml
• Postprandial insulin: up to 90 mIU/ml
• One international unit of insulin (1 IU) is defined as the
"biological equivalent" of 34.7 mcg pure crystalline insulin.
120
Meal
Glucose, mg/dl

100
80

Insulin, U/ml
60
80
40
Basal 20
11
Minutes 0 30 60 90 120
 Microvascular and Macrovascular Complications

They are a significant cause of morbidity. Persistent hyperglycemia is major cause for
the microvascular complications which are highly specific for diabetes.
retinopathy with potential loss of vision
nephropathy leading to kidney failure
peripheral neuropathy leading to pain, foot ulcers, and limb amputation
autonomic neuropathy causing gastrointestinal, genitourinary, cardiovascular
symptoms and sexual dysfunction

• Macrovascular complications:
They are main cause of mortality and may contribute with the associated
conditions (hypertension, dyslipidemia, smoking) for most of the burden of the
macrovascular complications:
coronary heart disease which is the major cause of death for patients with diabetes
peripheral vascular disease
cerebrovascular disease

Unfortunately, many patients remain asymptomatic for long periods, so that the
first presentation of the disease is frequently a chronic complication. Indeed, about
50% of newly diagnosed type 2 will already have developed a vascular complication. 12
 Diabetic Ketoacidosis
Early symptoms:
In the early stages, the main signs of diabetic ketoacidosis are:
• Passing large amounts of urine
• Severe thirst
• Feeling sick
• Tiredness
• Abdominal (tummy) pain 
• Shortness of breath
Other symptoms may also develop like of dehydration, such as a dry mouth.
Monitoring of blood sugar and/or ketone levels are higher than normal.
Advanced symptoms:
Left untreated, more advanced symptoms can develop, such as:
• Tachycardia , Rapid breathing, where breathe in more oxygen than body actually
needs (hyperventilate) , Vomiting , Dizziness
• A smell of ketones on your breath, which can smell like pear drops or nail varnish
remover 
• Confusion, drowsiness or loss of consciousness (coma),
• In some cases, life-threatening complications of diabetic ketoacidosis can also
develop. 13
 Gestational Diabetes
• All expectant mothers will be tested for gestational diabetes at some point during their
pregnancy. Expecting mothers who are over the age of 35, over weight, or have a
family history of diabetes may be tested earlier and more frequently. The oral glucose
tolerance test (OGTT) is used to diagnose the condition.

• Checking pregnant if they have previously given birth to a baby who weighed more than
9 lb (4.1 kg) and younger than age 25 and were overweight before getting pregnant
14
• Pregnancy causes most women to urinate more often and to feel more
hungry. So having these symptoms doesn't always mean that a woman
has diabetes. These symptoms if experienced any time during pregnancy,
it should be monitored
• Gestational diabetes can be controlled by changing the way of eating and
by exercising regularly.

• These healthy choices can also help prevent gestational diabetes in future
pregnancies and type 2 diabetes later in life. Most often, gestational
diabetes goes away after the baby is born.

• Treatment for gestational diabetes also includes checking blood sugar level
at home and investigating it regularly.

• Diabetes medicine metformin or insulin shots is recommended to help

control blood sugar. This insulin adds to the insulin that body makes. 15
 Diagnosis

Fasting Plasma Glucose Oral Glucose Tolerance Test

Test (FPG) (OGTT)
Pre-diabetes: 100 -125 mg/dl Pre-diabetes: 140 -199 mg/dl
(4 to 5.5 mmol/l) (7.8 and 11 mmol/L)
Diabetes: ≥126 mg/dl Diabetes: ≥200 mg/dl
(≥ 7 mmol/l) (≥11.1 mmol/L)

16
 Fasting Blood Sugar

• A range of 4 to 5.5 mmol/l (70 to 99 mg/dl) before a meal is

normal.

• Continual fasting levels of 5.5 to 7 mmol/l (101–125 mg/dl) causes

concern of possible prediabetes and may be worth monitoring.

• 7 mmol/l (126 mg/dl) and above means a risk of diabetes.

• After a 12‑hour fast, a range of 3.9 to under 5.5 mmol/l (70.2 to

100 mg/dl) is normal; a level of 5.6 to under 7 mmol/l (100 to
126 mg/dl) is considered a sign of prediabetes

17
 Converting Glucose, Cholesterol, Triglyceride and
Creatinine Results between mmol/l and mg/dl
 To convert mmol/l of glucose to mg/dl, multiply by 18.
To convert mg/dl of glucose to mmol/l, divide by 18 or multiply by 0.055.

 These factors are specific for glucose, because they depend on the mass of
one molecule (the molecular weight). The conversion factors are different
for other substances (see below).

 To convert mmol/l of HDL or LDL cholesterol to mg/dl, multiply by 39.

To convert mg/dl of HDL or LDL cholesterol to mmol/l, divide by 39.

 To convert mmol/l of triglycerides to mg/dl, multiply by 89.

To convert mg/dl of triglycerides to mmol/l, divide by 89.

 To convert umol (micromoles) /l of creatinine to mg/dl, divide by 88.

To convert mg/dl of creatinine to umol/l, multiply by 88.
18
 Oral Glucose Tolerance Test (OGTT)

On the day of testing, the following steps will be done:

• A blood sample will be collected on arriving. This is fasting blood glucose
value. It provides a baseline for comparing other glucose values.

• Patient will be asked to drink a sweet liquid containing a measured

amount of glucose. It is best to drink the liquid quickly. For the standard
glucose tolerance test, drinking of 75 grams or 100 grams.

• Blood samples will be collected at timed intervals of 1, 2, and sometimes

3 hours after drinking the glucose. Blood samples may also be taken as
soon as 30 minutes to more than 3 hours after drinking the glucose.

19
 HbA1c Testing
• Blood sugar control can also be estimated with a blood test
called glycated hemoglobin, or A1c.

• The A1C blood test measures the average blood sugar level
during the past two to three months.

• The goal A1C for most people with type 2 diabetes is 7% or

less, which corresponds to an average blood sugar of 150
mg/dL (8.3 mmol/L).

• For some people, a higher HbA1c goal than this is safer and
leads to better health outcomes.

• A healthcare provider can help determine the A1C goal.

20
• Glycated hemoglobin's association with mortality in elderly non-diabetics is U-
shaped.

• Lowest and highest HgbA1c levels are associated with the highest mortality in
non-diabetics.

• A1c of 5.9–6.1% is associated with the lowest mortality in elderly non-diabetics.

• Several studies have shown that HgbA1C levels may be affected by levels of Hb
and nutritional factors associated with anemia, such as vitamin B12 and iron
deficiency.

• In diabetic and non diabetic subjects, a significant inverse relationship between

A1C) and serum 25(OH)D levels has been observed.

• Vitamin D may improve glucose-stimulated insulin secretion in pancreatic β-

cells, enhance glucose and lipid metabolism in skeletal ...
21
 That means your average blood sugar level during
the past two to three months was:
If your A1C level is If you live within the If you live outside the
(percent): United States, blood United States, blood
sugar is measured in sugar is measured in
milligrams/deciliter millimoles/liter
(mg/dL). (mmol/L).
5 97 5.4
6 126 7
7 154 8.6
8 183 10.2
9 212 11.8
10 240 13.3
11 269 15
12 298 16.5
13 326 18.1
14 355 19.7

22
 Treatment Goals

• HbA1c: <6.5% (AACE) or <7% (ADA)

• Blood pressure: <130/80 mm/Hg
• Lipid profile
LDL: <100 mg/dl.
HDL: >40 mg/dl men, >50mg/dL women
TG: <150 mg/dl.  
• Fasting plasma glucose: <100 mg/dl
• Postprandial glucose: A level of <140 mg/dl or
7.8 mmol/l 90 minutes after a meal is normal
23
 Who Could Benefit from Insulin Therapy?

• People with Type 1 diabetes are dependent on insulin

• People with Type 2 diabetes who:
o have inadequate blood glucose control on optimised oral
hypoglycaemic agents (NICE, 2003).
o with contraindications to oral hypoglycaemic agents.
o have recurrent symptoms of hyperglycaemia or unexplained weight
loss.
o are considering pregnancy or who are pregnant.
o are post acute MI.
o have acute illness or recurrent infection.
o have foot ulceration and/or infection.
o receiving parentral/enteral nutrition
o have pancreatitis diseases that ↓ beta cell function
o have diabetic ketoacidosis (KA)
o hyperosmolar hyperglycemic state (HHS)
o use of glucocorticoids and vasopressors
24
 History of Insulin Development

• Insulin was first isolated by Banting and Best in 1921. The first
injection of insulin was administered in 1922.

• Protamine Zinc insulin (PZI) was developed in1936.

• NPH insulin was introduced in 1946 and has been the most
commonly used insulin in the USA.

• Lente insulin series, suspensions of insulin with zinc but

containing no proteins, were developed in the early 1950's.

• Human insulin produced biosynthetically was first introduced

commercially in 1982.

• Insulin lispro was the first insulin analog introduced in 1994 25

 Timing and Frequency of Insulin Injections

The timing and frequency of insulin injections depend

upon a number of factors, including:
• Type of insulin,
• Amount and type of food eaten,
• Person's level of physical activity
• Preference of the person and the appropriateness to the
lifestyle.
• Other treatment options include insulin pumps, and
pancreas and islet-cell transplantation

26
 Admitted Patients
The timing and frequency of insulin injections depend upon a
number of factors, including:
• Type of insulin
• Amount and type of food eaten
• Person's level of physical activity
• Preference of the person and the appropriateness to the lifestyle.
• Other treatment options include insulin pumps, and pancreas and
islet-cell transplantation

Some recommended insulin regimens are listed below:

1. Short-acting mixed with intermediate-acting insulin - twice daily
before meals.
2. Intermediate-acting insulin - bedtime.
3. Short-acting insulin - three times daily before meals.
4. Long-acting insulin - at bedtime.

27
 Basal-bolus insulin Therapy
• Basal insulin, also known as background insulin, act to keep
blood glucose levels at consistent levels during periods of
fasting.
• Basal insulin is therefore needed to keep blood glucose
levels under control, and to allow the cells to take in glucose
for energy.

• A basal-bolus routine involves taking a longer acting form

of insulin to keep blood glucose levels stable through periods
of fasting and separate injections of shorter acting insulin to
prevent rises in blood glucose levels resulting from meals.

28
A basal-bolus injection regimen involves taking a number of injections
through the day

29
 Types of Insulin

They are classified by pharmacokinetics or how fast

they start to work and how long their effects last.
• Rapid acting
• Short acting
• Intermediate acting
• Long acting
• Pre-mixed

30
 Insulin Types & Brands

Long Intermediate Short Acting Rapid

Acting Acting Ultra Short
Acting
Glargine NPH Regular, Neutral, Lispro
(Lantos) Novolin N, Soluble (Actrapid, Humalog
Humulin N Humilin R, Novolin R)

Detemir Aspart
(Levemir) NovoRapid
Glulisine
Apidra

31
Insulin Types & Brands

32
 Insulin Coverage

Rapid/Short acting insulin

• Covers meal intake
• Used for elevated BG

Intermediate/Long acting insulin

• Used for basal insulin needs
• Not intended to cover meals

33
 Insulin Pens & Continuous Subcutaneous
Insulin Infusion
• Insulin pens are delivery devices which incorporate a cartridge vial of insulin
with a simple screw or lever action to deliver a predetermined volume of insulin.

• They are shaped like fountain pens and are convenient both to use and carry.

• Their use has been advocated as allowing greater freedom and flexibility, but
patients need to be highly motivated and prepared to test their own blood
glucose frequently.
• Continuous subcutaneous insulin infusion (CSII) via a battery operated portable
pump was introduced in 1977.

• It provides a continuous basal supply of unmodified, short-acting insulin

throughout 24 hours with supplementary boluses before meals, activated by the
user from the same pump.

• CSII can maintain blood glucose and glycosated haemoglobin concentrations at

near normal levels and lower serum lipid levels. 34
35
 Insulin Therapy
• The basal insulin component may be provided by once- or twice-daily
NPH or detemir, or once-daily insulin glargine.

• Carbohydrate counting is an effective tool for determining

the amount of insulin to be injected preprandially.

• Most type 1 DM patients require two injections of all insulins except

insulin glargine. All of the insulins (with the exception of insulin
glargine) have some degree of peak effect that must be considered in
planning meals and activity.

• Insulin glargine or insulin detemir is a feasible basal insulin

supplement for most patients.

• The bolus insulin component is given before meals with regular

insulin, insulin lispro, insulin aspart, or insulin glulisine. 36
37
• The rapid onset and short duration of rapid-acting insulin analogs more
closely replicate normal physiology than regular insulin, allowing the
self monitoring blood glucose (SMBG) level, upcoming activity level, and
anticipated carbohydrate intake.

• Most patients have a prescribed dose of insulin pre-prandially that they

vary based on an insulin algorithm.

• As an example, patients may begin on about 0.6 units/kg/day of insulin,

with basal insulin 50% of the total dose and prandial insulin 20% of the
total dose before breakfast, 15% before lunch, and 15% before dinner.

• Most patients require total daily doses between 0.5 and 1 unit/kg/day.

• Continuous subcutaneous insulin infusion (CSII) pump therapy (generally

using insulin lispro or aspart to diminish aggregation) is the most
sophisticated form of basal-bolus insulin delivery 38
 Human Regular Insulin (Humulin R®)
• Human soluble insulin with onset 30min–1 hour, peak 2-5
hours, duration 5-8 hours.
• It is used before meal. It covers insulin needs for meals eaten
within 30-60 minutes.

• It is beneficial to treat patients with coma, DKA, newly

diagnosed or unstable diabetics.

• In adult, loading dose of 0.15 units/kg (nonconcent regular

insulin) I.V. bolus, followed by continuous infusion of 0.1
unit/kg/hour until glucose level drops. Then administer SC.

• In children, 0.1 unit/kg I.V. bolus, then 0.1 unit/kg/hour

continuous I.V. infusion until serum glucose decreases to 250
mg/dl; then start S.C. insulin. When given iv, 50 u/ml is
diluted in 50 ml normal saline
39
• Dosage adjusting according to glucose level. Adjust in case of liver or
kidney disease. Follow medication, diet, and exercise routines very
closely.

• When the dose of human regular insulin is increased, the duration of

action is also prolonged, but not so with human lispro.

• The absorption of regular insulin varies depending on the site of

injection. It is slower from the deltoid and femoral regions compared to
the abdominal area, whereas the absorption rate of lispro is greater and
similar from all three sites
• Regular insulin effect peaked earlier when given im compared to when
given sc.
• Human insulin may help type 2 patients requiring intermittent or short-
term therapy (such as pregnancy, surgery, infection, or TPN therapy),
patients with insulin resistance, or those with lipoatrophy.
40
• Pregnancy risk is category B
41
 NPH ® Human Insulin
• NPH is Neutral Protamine Hagedorn was invented in 1936 from human
and pork by Hans Christian Hagedorn (Nordisk).

• NPH is cloudy insulin was created when formulated "isophane" porcine

insulin by adding neutral protamine to regular insulin

• Humulin N is a crystalline suspension of human insulin with protamine

and zinc providing an intermediate-acting insulin with a slower onset of
action and a longer duration of activity.

• Onset 1-2 hrs, peak 4-12 hrs, duration 10 – 16 hrs. It covers insulin needs
for about half the day or overnight.

• NPH is now prepared from synthetic 'human' insulin by adding synthetic

protamine. Danger of hypoglycaemia around midnight If given twice daily
and an adequate snack before bedtime.

• NPH may reduce A1c to target levels of 1.5% for 70% of patients in 52
weeks. 42
Insulin Pharmacokinetics

43
• NPH insulin is often combined with rapid- or short-acting insulin. NPH and
fast-acting insulin bind when mixed in the same syringe, so they should
not be combined until it is time to inject.

• Liver and kidney problems may affect NPH insulin dosage and the
changes in diet, exercise, or other medications, and overall health can
affect how much NPH insulin dosage.

• As with all insulin preparations, the duration of action of Humulin N is

dependent on dose, site of injection, blood supply, temperature, and
physical activity.

• Humulin N is a sterile suspension and is for SC injection only. It should not

be used iv or im.
• The basal insulin component may be provided by once- or twice-daily NPH
or detemir, or once-daily insulin glargine.
• The concentration of Humulin N is 100 units/ml (U–100).

44
 Insulin Analogues
(1) Lispro (Humalog®)
• Fast onset 10 - 20 min, peak1 hr, and shorter duration 3 -5 hrs compared
with regular.
• The rapid peak action should prevent postprandial hyperglycemia, and
the short duration of action should reduce postprandial hypoglycemia

• Thin, clear, and colorless human insulin analog. It is recommended to be

taken 5 minutes before meal in a dose of 0.1 u/kg and a standard lunch.

• In patients with type 1 diabetes, insulin lispro is always used with another
type of insulin, unless it is used in an external insulin pump. Humalog Mix
75/25 should be injected 15 minutes before a meal.

• In patients with type 2 diabetes, insulin lispro may be used with another
type of insulin or with oral medication for diabetes.

• Lispro is a short-acting, man-made version of human insulin. It works by

replacing the insulin that is normally produced by the body. It also stops
the liver from producing more sugar.
45
• Lispro when used with an insulin pump, it should not be mixed or diluted
with any other insulin.

• Insulin lispro comes in vials, cartridges that contain medication and dosing
pens that contain cartridges of medication. One unit of this insulin has the
same glucose-lowering effect as one unit of regular human insulin.

• The vial of diluted medication can be stored for 28 days in the refrigerator
or 14 days at room temperature. Store extra insulin lispro pens and
cartridges that are not in use in the refrigerator but do not freeze them.

• Store the pen and cartridge outside the refrigerator at room temperature
for up to 28 days. Store prefilled pens containing Humalog Mix ® 75/25
that is in use outside the refrigerator at room temperature for up to 10
days.

• Pregnancy risk is Category B, which is the same risk category as regular

insulin.

46
 (2) Aspart (NovoRapid ®)
• Fast onset 10 - 20 min, peak 1 hr, shorter duration 3 -5hrs compared with
regular.
• The rapid peak action should prevent postprandial hyperglycemia, and the
short duration of action should reduce postprandial hypoglycemia

• Thin, clear, and colorless human insulin analog. It is recommended to be

taken 5 minutes before meal in a dose of 0.1 u/kg and a standard lunch.

• In patients with type 1 diabetes, insulin aspart is always used with another
type of insulin, unless it is used in an external insulin pump. Novolog Mix
70/30 should be injected 15 minutes before a meal.

• In patients with type 2 diabetes, aspart may be used with another type of
insulin or with oral medication for diabetes.

• Aspart is a short-acting, man-made version of human insulin. It works by

replacing the insulin that is normally produced by the body. It also stops
the liver from producing more sugar.
47
• Aspart when use with an insulin pump, it should not be mixed or diluted
with any other insulin.

• Aspart comes in vials, cartridges that contain medication and dosing pens
that contain cartridges of medication. One unit of this insulin has the
same glucose-lowering effect as one unit of regular human insulin.

• The vial of diluted medication can be stored for 28 days in the refrigerator
or 14 days at room temperature. Store extra insulin aspart pens and
cartridges that are not in use in the refrigerator but do not freeze them.

• Store the pen and cartridge you are using outside the refrigerator at room
temperature for up to 28 days. Store prefilled pens containing aspart
Mix70/30 or Novolog Mix ® 70/30 that is in use outside the refrigerator
at room temperature for up to 10 days.

• Pregnancy risk is Category B, which is the same risk category as regular

insulin.

48
 (3) Glulisine (Apidra ®)

• Fast onset 10 - 20 min, peak 1 hr, shorter duration 3 -5hrs compared with
regular.
• The rapid peak action should prevent postprandial hyperglycemia, and the
short duration of action should reduce postprandial hypoglycemia

• Thin, clear, and colorless human insulin analog. It is recommended to be

taken 5 minutes before meal in a dose of 0.1 u/kg and a standard lunch.

• In patients with type 1 diabetes, insulin glulisine is always used with

another type of insulin, unless it is used in an external insulin pump.
Glulisine Mix 75/25 should be injected 15 minutes before a meal.

• In patients with type 2 diabetes, insulin glulisine may be used with

another type of insulin or with oral medication for diabetes.

• Glulisine is a short-acting, man-made version of human insulin. It works by

replacing the insulin that is normally produced by the body and by helping
move sugar from the blood into other body tissues where it is used for
energy. It also stops the liver from producing more sugar.
49
• Glulisine when use with an insulin pump, it should not be mixed or diluted with
any other insulin.
• Glulisine comes in vials, cartridges that contain medication and are to be placed in
dosing pens, and dosing pens that contain cartridges of medication. One unit of this
insulin has the same glucose-lowering effect as one unit of regular human insulin.

• The vial of diluted medication can be stored for 28 days in the refrigerator or 14
days at room temperature. Store extra insulin Glulisine pens and cartridges that are
not in use in the refrigerator but do not freeze them.

• Store the pen and cartridge you are using outside the refrigerator at room
temperature for up to 28 days. Store prefilled pens containing glulisine Mix75/25
that is in use outside the refrigerator at room temperature for up to 10 days.

• Pregnancy risk is Category C, which is not the same risk category as regular insulin
or lispro and aspart.

50
 Long Acting Insulins
(1) Glargine (Lantus®)

• Insulin glargine is a recombinant human insulin analogues. Onset 1-2 hrs, peak flat,
duration 24 hr. 1.7% mean A1C reduction at 24 weeks.

• It should be available as an option for patients with type1, it is not recommended for
routine use in type 2 patients who require insulin. IV short-acting regular insulin is the
preferred treatment for this condition.

 But it may be considered in type 2 for those:

o who require assistance with injecting their insulin
o whose lifestyle is significantly restricted by recurrent symptomatic hypoglycaemia or
o who would otherwise need twice-daily basal insulin injections in combination with oral
drugs

• Glargine is a clear solution with a pH of 4.0. This pH stabilizes the insulin hexamer and
results in a prolonged and predictable absorption from subcutaneous tissues.

• In clinical studies, insulin glargine results in less hypoglycemia, has a sustained "peakless"
absorption profile, and provides a better once-daily 24-hour insulin coverage than
ultralente or NPH insulin.

51
• Lantus® must not be diluted. Owing to acidic pH, it can not be mixed with any
other currently available short-acting insulin preparations (regular insulin, aspart,
or lispro) that are formulated at a neutral pH.

• It may be administered at any time during the day by only SC with equivalent
efficacy and no difference in the frequency of hypoglycemic episodes. But it is
preferred at bedtime.

• When given at bedtime, glargine was compared with NPH insulin (taken once or
twice a day), there was a significant reduction in the occurrence of severe and
nocturnal hypoglycemia with insulin glargine and with much lower weight gain.

• Glargine does not accumulate after several injections and can be combined with
various oral antihyperglycemic agents to effectively lower plasma glucose levels.

• Use of a long-acting basal insulin alone will not control postprandial glucose
elevations in insulin-deficient type 1 or type 2 DM.
52
• Unlike traditional insulin preparations the site of administration does not
influence the time-action profile of Glargine. Exercise does not influence
Glargine unique absorption kinetics, even when the insulin is injected into a
working limb.

• In case of type 2, a low insulin dose is prescribed at first, often 10 units once
daily at the same time every day, to see how well it helps lower blood sugar.
Then, over time, it might be increased, until getting the right dose.
• Lantus is contraindicated iv and attention to hypersensivity to any component of
insulin glargine.

• It is available in two form 100 units/ml (10 ml) vial injection, 3 ml cartridge and
disposable prefilled insulin pen.

• Each pen contains 300 units of insulin and is good for 28 days once it is in use.
• Category C in pregnancy and it is considered safe for usewhile breast feeding.
• Do NOT refrigerate pen once it is in use. Once use pen for the first time, it will last
up to 28 days when kept at room temperature (below 86º F).
53
 Long Acting Insulins
(2) Detemir (Levemir®)

• Human insulin analog is a clear insulin with onset 1-2 hrs, peak 3-9 hr, duration
17-23 hr. Once or twice daily dosing

• It was found that insulin detemir reduced A1c to target levels of 1.5% for 70% of
patients in 52 weeks, similar to human basal insulin NPH, but without the same
risk of hypoglycemia and with much lower weight gain.

• This insulin has a high affinity for serum albumin, increasing its duration of action.

• Use of a long-acting basal insulin alone will not control postprandial glucose
elevations in insulin-deficient type 1 or type 2 DM.

• Unlike traditional insulin preparations the site of administration does not

influence the time-action profile of detemir.
• Exercise does not influence detemir unique absorption kinetics, even when the
insulin is injected into a working limb.
54
• Detemir® must not be diluted or mixed with any other currently available short-acting insulin
preparations (regular insulin, aspart, or lispro) that are formulated at a neutral pH.
• Detemir is contraindicated intravenously and attention to hypersensivity to any component of
detemir.

• Do NOT refrigerate pen once it is in use. Once use pen for the first time, it will last up to 28 days
when kept at room temperature (below 86º F).

• Detemir does not accumulate after several injections and can be combined with various oral
antihyperglycemic agents to effectively lower plasma glucose levels.

• FDA pregnancy category B similar to NPH in pregnant women and safe in breast feeding as it does
not pass into breast milk.

• The basal insulin component may be provided by once daily at bedtime as insulin glargine in the
evening meal or may be used twice-daily such as NPH or detemir.

• Serious contraindication with Pramlintide (trade name Symlin) which is an injectable amylin analogue drug
for diabetes (both type 1 and 2), developed by Amylin Pharmaceuticals Pramlintide and they must be
adminstered seperately

• Detemir may either increase or decrease the blood glucose lowering effect of insulin . Alcohol
may decrease endogenous glucose production or worsen glycemic control by adding calories.
55
 Mixed Insulins
1- Novolin 70/30

• Premixed insulin mixes short-acting and intermediate-acting

insulin and is usually taken twice a day, just before meals, and is
used mainly for people who have difficulty mixing their own
insulin and reading instructions/dosages, etc.

• Novolin is a combination of specific proportions of intermediate-

acting and short-acting insulin in one bottle or insulin pen.

• The numbers following the brand name indicate the percentage

of each type of insulin.
• Onset 30 – 60 min, peak varies, duration 18 - 24 hrs.
• Cloudy insulin. Usually give BID
• Available OTC
• Not very effective for covering PPG
56
 2- Humalog 75/25
75% insulin lispro protamine suspension, 25% insulin lispro injection [rDNA origin])

o Onset 5 – 15 min, peak varies, duration varies

o Human insulin analog
o Given OD or BID
o Cloudy insulin
o Covers PPG

3- Humalog 50/50
o Onset 5 – 15 min, peak varies, duration varies
o Human insulin analog
o Intended for TID dosing
o Cloudy insulin
o Covers PPG
4- NovoLog 70/30
o Insulin aspart protamine suspension (intermediate-acting) and 30%
insulin aspart. The same thing but Given OD or BID
57
 Inhaled Insulins

• In 2015, an inhaled form of insulin became

available for clinical use.

• Inhaled insulins have not been shown to be

effective in reducing A1C levels to the goal of
less than 7 percent that is often recommended.

58
 Basal & Bolus Insulin
A basal-Bolus Insulin Regimen

• Basal insulin is insulin therapy that controls blood sugar

between meals and during sleep is called long-acting or basal
insulin.

• Bolus insulin is insulin therapy that controls blood sugar when

you eat is called fast-acting or bolus insulin.

• A basal-bolus insulin regimen involves a person with diabetes

taking both basal and bolus insulin throughout the day.

• It offers them a way to control their blood sugar levels. It helps

achieve levels similar to a person without diabetes.
59
I

N Pre-mixed insulin
S

U
10/90
L Post- prandial hyperglycemia
I
20/80
N

Pre-prandial hyperglycemia
I

N 30/70
J

C 40/60

O 50/50

Multiple Insulin Injection Therapy 60

60
 Drug interactions
1. Insulin and Steroids
• Glucocorticoids in therapeutic rather than replacement doses impair
glycaemic control in diabetic patients by provoking insulin resistance.

• Steroids decrease hepatic and peripheral tissue sensitivity to insulin,

thus allowing an inappropriately raised hepatic glucose output and
impaired uptake of glucose by muscle and fat.

• The hyperglycaemia results in a rise in pancreatic insulin secretion, but

the increase in circulating hormone level is insufficient to overcome
tissue insulin resistance.

• Administration of steroid to any diabetic subject requires prospective

adjustment of therapy and close monitoring of blood glucose
concentrations.
61
 2. Insulin and Thiazide

• Thiazide diuretics and, to a lesser extent, frusemide and

bumetanide are diabetogenic. This effect is due to inhibition of
insulin release and has led to episodes of ketoacidosis.

• In non-insulin-dependent diabetics, thiazides worsen glycaemic

control and may lead to the need for insulin therapy in a few
individuals.

• In insulin-dependent diabetes the addition of a thiazide diuretic

sometimes requires an increase in insulin dosage suggesting
that these drugs also provoke insulin resistance.

62
 3. Insulin and B-blockers
• Diabetic patients rely on sympathomimetic activation both to warn of,
and to counteract, hypoglycaemia.

• Beta-blockers mask many of the warning signs of hypoglycaemia such as

tremor and tachycardia, and patients can develop neuroglycopaenia
without warning.
• Neuroglycopenia is a medical term that refers to a shortage of glucose
(glycopenia) in the brain, usually due to hypoglycemia. Glycopenia affects
the function of neurons, and alters brain function and behavior.

• The worst offenders are the non­selective -blockers as these also inhibit
sympathetically mediated glycogenolysis. However, even selective -
blockers should be avoided in patients who suffer recurrent severe
hypoglycaemic episodes.
• Hypoglycaemia in patients receiving non-selective -blockers can cause
marked rises in blood pressure due to unopposed alpha-receptor
mediated vasoconstriction. 63
 Insulin and 4. Sympathomimetic Drugs

• Large intravenous doses of selective-receptor agonists (e.g. salbutamol and

terbutaline) have substantial effects on glycaemic control by increasing hepatic
glucose production.

• This effect is additive with that of the glucocorticoids which may be dangerous
when these agents are used together, e.g. in severe asthma and premature
labour.

• Many over-the­counter cold remedies contain sympathomimetics, e.g.

pseudoephedrine and phenylpropanolamine; these may be recommended to
diabetics provided that there are no other contra-indications such as
hypertension.
64
 5. Insulin and Oral Contraceptives

• The oral contraceptive pill can impair glucose tolerance.

The extent of impairment depends on steroid content
and dosage but is usually trivial.

• Nevertheless, the lowest possible dose of oestrogen

should be used in diabetic patients to reduce the risk of
thrombosis and vascular disease
Insulin and Alcohol
• As previously mentioned with sulphonylureas, alcohol
causes hypoglycaemic episodes in diabetics which are
due to inhibition of gluconeogenesis. 65
 Case Study
Practice Question on Insulin

Your patient’s blood glucose level is 215 mg/dL. The

patient is about to eat lunch. Per sliding scale, you
administer 4 units of Insulin Lispro (Humalog)
subcutaneously at 1130. As the pharmacist, you know
the patient is most at risk for hyperglycemia at what
time?
A. 1145
B. 1230
C. 1430
D. 1630
66
As you read the question, you want to start thinking about:
“What is a normal blood glucose level prior to eating?”
“What type of Insulin is Lispro? (rapid, short, intermediate, or long-
acting?)
“When is HYPOglycemia most likely to occur with Insulin medications?”
During the onset, peak, or duration?
“What are the onset, peak, and duration for Insulin Lispro?”

A normal blood sugar before meals should be 70-130 mg/dL. Therefore,

this patient’s blood glucose level is high, and they need insulin coverage
prior to eating because consuming a meal will increase the blood
glucose even further.

The physician has ordered Insulin Lispro (Humalog) to be given before

meals per sliding scale. So, you will be covering the patient with 4 units
of Lispro based on their blood glucose of 215 mg/dL.
What type of insulin is Lispro (Humalog)? It is RAPID-acting.  67
• To remember short-acting insulin onset, peak, duration times remember
this mnemonic:
• “15 minutes feels like an hour during 3 rapid responses.”
o Onset: 15 minutes
o Peak: 1 hour
o Duration: 3 hours

Therefore, for this medication (based on the time you gave the Lispro at
1130) it would be the following:
o Onset: 1145
o Peak: 1230
o Duration: 1430

• The answer is D. If you gave the Lispro at 1130, the patient is at most risk
for hyperglycemia 5 hour after administration, which is 1630.

68
 Case Study 2

• TR is taking 15 units of glargine at bedtime and 4 units of

Humalog before each meal. TR is experiencing at least one
episode of hypoglycemia a day, usually between meals. TR
checks glucose levels before each meal. Pre meal glucose
levels are 110mg/dl on average. What initial change in self-
management would you recommend?
A. decrease the glargine dose by 2 units
B. decrease the humalog by 1 unit each meal
C. ask TR to monitor 2 hour post-prandial glucose levels
D. ask TR to increase carbohydrate intake by 15 gms at each meal
69
 Case Study 3

• 22. KL is a 24 year old admitted in DKA.

Which of the following insulins may be used
intravenously to treat his hyperglycemia?
A. regular
B. lantus
C. NPH
D. a basal bolus combination

70
Diabetes Mellitus Type 2 Therapy
DMT2 Therapy

71
 Diabetes Mellitus Type 2: Management
• People with type 2 diabetes require regular monitoring and ongoing treatment to
maintain normal or near-normal blood sugar levels.

• Treatment includes lifestyle adjustments, self-care measures, and medicines, which

can minimize the risk of diabetes and cardiovascular (heart-related) complications.

• The goal of treatment in type 2 diabetes is to keep blood sugar levels at normal or
near-normal levels. Careful control of blood sugars can help prevent the long-term
effects of poorly controlled blood sugar (diabetic complications of the eye, kidney, and
cardiovascular system).

• In people with type 2 diabetes, home blood sugar testing might be recommended,
especially in those who take oral diabetes medicines or insulin. Home blood sugar
testing is not usually necessary for people who are diet-controlled.

• A normal fasting blood sugar is less than 100 mg/dL (5.6 mmol/L), although some
people will have a different goal. Doctor or pharmacist can help set blood sugar goal.

72
 Drug Treatment
• Drug treatment aims to initially relieve the immediate
symptoms of diabetes without causing hypoglycaemia and in
the long term, to prevent complications and reduce mortality.

• Oral antidiabetic (hypoglycaemic) drugs are used in Type II

diabetes; they should not be prescribed until patients have
been shown not to respond adequately to at least one month's
restriction of energy and carbohydrate intake.

• They should be used to augment the effect of diet and not to

replace it. A number of oral medicines (pills) or sc injections are
available to treat type 2 diabetes.

73
 Type 2 Hypoglycaemic Drugs

New Hypoglycaemic
- Glucagon-n-like peptide-e- 1(GLP-1)1 Analogues
- Dipeptidyl-l- peptidase-e- 4 (DPP-4) Inhibitors
- Antihyperglycemics: Pramlintide
- Amylinomimetics
- SGLT2Inhibitors
74
75
76
Drug Treatment

77
78
‘Type 2 diabetes in adults: management’, NICE guideline NG28. Published December 2015, last updated April 2017. © National Institute
79
for Health and Care Excellence 2015. All rights reserve
 (1) Metformin
• Glucophage is the first-line medication for the treatment of type 2. United Kingdom
Prospective Diabetes Study (UKPDS) reported that metformin decreases A1c by 1%
in 24 weeks and reduces MI by 39%.

• This is particularly true in people who are overweight. It is also used in the treatment
of polycystic ovary syndrome. Limited evidence suggests metformin may prevent the
cardiovascular disease and cancer complication of diabetes.
• It is not associated with weight gain. It is taken by mouth. Metformin is generally well
tolerated.

• It has a low risk of developing low blood sugar. High blood lactic acid levels is a
concern if prescribed inappropriately and in overdose (Lactic acidosis).

• It should not be used in those with liver disease or kidney problems. While there is no
clear harm if used during pregnancy as insulin is generally preferred for gestational
diabetes. 80
81
• Metformin is in the biguanide class. It works by decreasing glucose
production by the liver and increasing glucose use by body tissues.

• Most people who are newly diagnosed with type 2 will immediately
begin metformin which improves how body responds to insulin to
reduce high blood sugar levels.

• Metformin is a pill that is usually started with the evening meal; a second
dose may be added one to two weeks later (with breakfast).
• The dose may be increased every one to two weeks thereafter.

• Common side effects include nausea, diarrhea, and gas. These are usually
not severe, especially if taking metformin along with food.

• Patients with certain types of kidney, liver, and heart disease, and those
who drink alcohol excessively should not take metformin. 82
• Metformin should be stopped taking 48 hours before any test that uses iodine-based
contrast dye (like a computed tomography [CT] scan with contrast) (as it may cause a
condition called metabolic acidosis, or an unsafe change in your blood pH) and should be
stopped before any type of surgery to decrease the risk of a problem called lactic
acidosis

• The following are general recommendations:

o The most commonly recommended second medicine is a short acting sulfonylurea, such
as glipizide .

o Insulin shots might be recommended as the second medicine if A1C is higher than 8.5%.  

o If blood sugar levels is still high after two to three months, but A1C is close to the goal
(between 7 and 8.5%), a second oral medicine might be added.

o The “best” second medicine depends upon individual factors, including the person's
weight, other medical problems, and preferences regarding use of injections.
83
• The following are general recommendations:
o A thiazolidinedione, such as pioglitazone, is an alternative to sulfonylureas,
but only for people who are not at increased risk of heart failure or bone
fracture.

o A glucagon-like peptide (GLP) agonist, which requires injections, is an option

for patients who are overweight and who want to avoid developing low blood
sugar

o A meglitinide, such as repaglinide, is another option for people who cannot take a
sulfonylurea because of kidney failure.

o Addition of a second medicine might be recommended within the first two to

three months if blood sugar levels and glycated hemoglobin (A1C) are still higher
than the goal (6.5%).

• Which second medicine is best? It is based on patient factors.

84
 Metformin Summary
• Does not produce hypoglycemia when used alone
• Secondary beneficial effects on lipids
– Reduced triglycerides by 8% to 15%
– Reduced total cholesterol by 8% to 15%
– Reduced LDL by 8% to 15%
– Modestly increases HDL by 2%
• Weight loss, some reduction of blood pressure
• Appropriate for obese Type 2 diabetics.
• Excreted unchanged in the urine
• Half-life is approximately 2 hours and does not combined to plasma
protein
• It should not be used with renal or hepatic or cardiac dysfunction
• Also approved for prevention of Type 2 diabetes in high risk individuals
and it is used also for polycystic ovary syndrome: insulin resistance
with ovarian hyperandrogenism.
85
 Metformin Dose
•Metformin immediate-release:
It is usually initiated at 500 mg twice daily with the largest meals and increased by 500
mg weekly until glycemic goals or 2,000 mg/day is achieved.
•Metformin 850 mg can be dosed once daily and then increased every 1 to 2 weeks to a
maximum of 850 mg three times daily (2,550 mg/day).
•Titrate slowly to minimize GIT side effects. In general, significant responses are not
observed with doses less than 1500 mg/day
Metformin extended-release:
•Glucophage XR can be initiated with 500 mg with the evening meal and increased by
500 mg weekly to a maximum dose of 2,000 mg/day.
Administration two to three times a day may help minimize GI side effects and
improve glycemic control.
•The 750-mg tablets can be titrated weekly to the maximum dose of 2,250 mg/day.
•Comments: If glycemic control is not achieved with once a day administration of an
extended-release product, consider dividing doses.
•If higher doses are required, may switch to immediate-release product.

86
 (2) Sulphonylureas “SU”

• Sulphonylureas have been commercially available since the 1950s, but

their use continues to be associated with controversy.

• Although adverse cardiovascular outcomes in some observational studies

have raised concerns about SU, findings from relatively recent, robust,
and high-quality systematic reviews have indicated no increased risk of
all-cause mortality associated with SU compared with other active
treatments.

• Results from large, multicentre, randomised controlled trials such as the

UK Prospective Diabetes Study and ADVANCE have confirmed the
microvascular benefits of SU, a reduction in the incidence or worsening of
nephropathy and retinopathy, and no increase in all-cause mortality,
although whether these benefits were due to SU therapy and not an
overall glucose-lowering effect could not be confirmed. 87
• A comparison of SU and pioglitazone in the TOSCA.IT trial also confirmed
the efficacy and cardiovascular safety of SU.

• Investigators of randomized controlled trials have reported an increased

risk of hypoglycaemia and weight gain with SU, but data from
observational studies suggest that the incidence of severe
hypoglycaemia is lower in people taking SU than in people taking insulin,
and weight gain with SU has been relatively modest in large cohort
studies.

• 80% of people with diabetes live in low-to-middle income countries, so

the effectiveness, affordability, and safety of SU are particularly
important considerations when prescribing glucose-lowering therapy. 

• Results of ongoing head-to-head studies with new drugs, such as the

comparison of glimepiride with linagliptin in the CAROLINA study and
the comparison of various therapies (including SU) for glycaemic control
in the GRADE study, will determine the place of SU in glucose-lowering
88
therapy algorithms for patients with type 2 diabetes
 Sulphonylureas
• Sulphonylureas increase the sensitivity of pancreatic cells to glucose so
that the insulin response to glucose is augmented.

• To produce a hypoglycaemic effect, sulphonylureas require functioning

pancreatic tissue so they are ineffective in treating hyperglycaemia after
pancreatectomy or chronic pancreatitis.

• They act primarily by stimulating the pancreas to produce insulin and are
therefore anabolic in effect.

• The sulphonylureas are primarily metabolised by the liver (except for

chlorpropamide 20% excreted by the kidney).

• Hypoglycaemic activity is exhibited by some of these metabolites, which

are primarily renal excreted. 89
  
•It is these active metabolites that are probably responsible for the prolonged
hypoglycaemic effect even when the parent drug is absent from the plasma.

•This prolonged hypoglycaemic action is more dangerous in the elderly patient

whose renal function may be impaired. Usually the patient should be started
on a low dose, with gradual increases depending on the patient's blood glucose
levels.

•Some patients may never achieve good control on oral sulphonylureas, perhaps
due to a decrease in pancreatic cell activity or poor dietary compliance.

•Sulfonylureas have been used to treat type 2 for many years. They act by
increasing insulin release from the beta cells and can lower blood sugar levels
by approximately 20 %. However, they stop working over time.

90
• Weight gain is common; less common adverse effects include skin
rash, hemolytic anemia, GI upset, and cholestasis.

• The recommended starting doses should be reduced in elderly

patients who may have compromised renal or hepatic function.
Dosage can be titrated every 1 to 2 weeks to achieve glycemic goals.

• Sulfonylureas are generally used if metformin does not adequately

control blood sugar levels when taken alone. Sulfonylurea should not
be taken if allergic to sulfa drugs or in the setting of kidney failure.

• A number of sulfonylureas are available (Daonil, Diamicron,

Micronase, Menidiab, Amaryl), and the choice between them
depends mainly upon cost and availability; they work similarly.
91
• Sulfonylurea usage can develop low blood sugar (hypoglycemia). Low
blood sugar symptoms can include: Sweating, Shaking, Feeling hungry,
Feeling anxious and Feeling confused.
• Individuals at high risk include the elderly, those with renal
insufficiency or advanced liver disease, and those who skip meals,
exercise vigorously, or lose a substantial amount of weight.
• Low blood sugar must be treated quickly by eating 10 to 15 grams of
fast-acting carbohydrate (fruit juice, hard candy, glucose tablets). It is
possible to pass out if patient does not treat low blood sugar fast
enough.
• Sulfonylurea act by increasing endogenous insulin secretion not
indicated for Type 1.
• Most effective when ß cell function has not been severely
compromised. They Increase insulin secretion favors lipogenesis.
• Second generation poses fewer drug interactions than earlier.
• HAAD formulary includes: Glibenclamide, Gliclazide, Glipizide and
Glimepiride
92
 Sulphonylureas Side Effects
• Prolonged hypoglycaemia may occur with the sulphonylureas, particularly those
with a long half-life.

• This occurs more frequently in the elderly and therefore, for example,
chlorpropamide should be avoided in elderly patients as it has been associated
with fatal hypoglycaemia. Most sulphonylureas cause weight gain.
• Other minor side effects include gastrointestinal upsets, skin rashes and an
elevation of liver enzymes (mainly alkaline phosphatase).

• An antabuse effect will occur ir approximately 4% of patients, especially with

chlorpropamide. Hyponatraemia may occur with chlorpropamide and, less
commonly,"' glipizide and tolbutamide.

• Sulphonylureas cause hyponatraemia by enhancing the effect of ADH and the

incidence will increase if a diuretic is used as well.

• Recent evidence suggests that tolbutamide may have adverse effects on heart
muscle; however, it still has a place in the management of the elderly diabetic. 93
 Contra-indications
• Chlorpropamide is not recommended for use in the elderly and those with renal
disease as an appreciable proportion of the drug is excreted by the kidneys.

• As previously stated, it can also cause hyponatraemia by enhancing the effect of

ADH, which makes it unsuitable for use in patient with cardiac failure or other
oedematous conditions.

• Caution should be exercised in patients with concomitant renal disease the

hypoglycaemia produced by those sulphonylureas whose active metabolites are
excreted by the kidneys (acetohexamide and tolazamide) augmented.

• Concomitant liver disease enhances the hypoglycaemic effec all sulphonylureas

because of decreased metabolism and so caution should also be exercised.

• Contraindicatedv in pregnancy, surgery, severe infections, severe stress or trauma,

severe hepatic or renal failure, Insulin therapy should be used in all of these.

94
 Drug Interactions of Sulfonylureas
The sulphonylureas undergo extensive metabolism in the liver
which makes them susceptible to enzyme induction and, more
importantly, inhibition to other drugs.

Acute alcohol ingestion is responsible for a significant

proportion of hypoglycaemic episodes in diabetics.

Hypoglycaemia is caused by the alcohol inhibiting both

gluconeogenesis and the metabolism of sulphonylureas.

Monoamine oxidase inhibitors (MAOI's) have been reported to

cause profound and prolonged hypoglycaemia in patients
taking sulphonylurea possibly by potentiating the release of
insulin from the cells.
95
 Drug interactions of Sulphonylureas
Drug affected Drug interacting Effect

Sulphonylureas- Azapropazone, Potentiation

chlorpropamide, chloramphenicol,
tolbutamide, etc. cimetidine, clofibrate, co-
trimoxazole, miconazole,
fluconazole,
phenothiazines,
phenylbutazone,
sulphinpyrazone,
Chlorpropamide, bezafibrate
tolbutamide & Reduced
possibly Aminogluthemide, effect
other rifampicin Potentiation
sulphonylureas Reduced

96
 Conclusions

• Despite the great number of anti-diabetic agents currently available in

clinical practice, sulfonylureas are still frequently used: maybe this is due
to their lower cost, to the possibility of mono-dosing and to the presence
of an association with metformin in the same tablet.

• In patients suffering from inadequate glycemic control, sulfonylureas can

rapidly achieve significant improvement when added to metformin.

• According to recent guidelines, they can also be associated with

glitazones, GPL-1 analogues, DPP-4 inhibitors or long acting insulin when
the association with metformin alone fails to achieve the glycemic target.
• Considering adverse events, sulfonylureas, especially the older ones, are
linked to a greater prevalence of hypoglycemia, and cardiovascular risk;
in this respect, newer prolonged-release preparations of sulfonylureas
are undoubtedly safer, mainly due to reducing hypoglycemia, and for this
reason should be preferred. 97
• The European GUIDE study, for example, compared two sulfonylureas designed
for once-daily administration used under conditions of everyday clinical practice.
Patients were randomized to either gliclazide modified release (MR) 30–120 mg
daily or glimepiride 1–6 mg daily as monotherapy or in combination with their
current treatment for 27 weeks.

• Even if gliclazide MR and glimepiride were similarly effective in improving blood

glucose control, gliclazide MR gave approximately 50% fewer hypoglycemic
episodes in comparison with glimepiride.

• We can conclude that sulfonylureas should be used in relatively young patients

for a limited period of time, maybe 3–6 months, in order to rapidly achieve
adequate glycemic control.

• In this way we can avoid starting insulin, improving the patient's quality of life and
his/her compliance and reducing the cost of anti-diabetic therapy. After 3–6
months, if adequate glycemic control has not been achieved, we should start
insulin treatment. On the other hand, if we have reached a lower HbA 1c, we
should replace sulfonylureas with other oral anti-diabetic agents, according to the
98
guidelines.
 Choice of Sulfonylurea
Consider the following:
• Most appropriate in non or mildly obese.

• Duration of action, potency, metabolism, side effects

o The long acting Glibenclamide is associated with greater risk of
hypoglycaemia.
o Glicazide is short acting alternative. The number of severe hypoglycemic
episodes was extremely low, and gliclazide appears at least equally effective
compared to other glucose lowering agents.

In presence of renal dysfunction:

- Metabolized to inactive metabolites e.g. Glipizide
- Dual routes of elimination e.g. glimeperide in Initial: 1-2 mg PO after
breakfast or with first meal; may increase dose by 1-2 mg every 1-2 weeks;
not to exceed 8 mg/day
• Dosing Modifications in renal impairment: 1 mg PO qDay; titrate dose based
on fasting blood glucose levels
• Hepatic impairment: Not studied; not recommended in severe impairment;
99
initiate therapy with 1 mg PO qDay and titrate carefully
 (3) Thiazolidinediones (Glitazones)
Pioglitazone

•Glitazones do not increase insulin secretion and usually in combination

with other medicines such as metformin, a sulfonylurea, or insulin.
•These agents activate glitazone receptor, so pioglitazone enhances insulin
sensitivity in liver, skeletal muscle and adipose tissue.
•Insulin must be present in significant quantities for these actions to occur.
•They reduce hepatic glucose output.
•They improve lipid profiles.
•No evidence of drug-induced hepatotoxicity but it should not be used in
patients who experienced jaundice. It is ineffective and possibly harmful
in type1 and DKA
•Safety in pregnancy, lactation and breast feeding and safety in people
under 18 years is not established
100
 Pioglitazone

o Pioglitazone 15, 30 or maximum of 45mg tablet is taken by mouth once daily with
or without meals at around the same time every day. Low dose at 15 mg
pioglitazone is started and gradually increased

o When given for about 6 months, pioglitazone reduces A1C values by about 1.5%
and FPG levels by about 60 to 70 mg/dl at maximal doses.

o Maximal glycemic-lowering effects may not be seen until 2 to 3 months of therapy.

Monotherapy is often ineffective unless the drugs are given early in the disease
course when sufficient β-cell function and hyperinsulinemia are present
o Pioglitazone decreases plasma triglycerides by 10% to 20%, and does not cause
significant increases in LDL cholesterol.

o Fluid retention may occur (4% to 5%), perhaps as a result of peripheral

vasodilatation and/or improved insulin sensitization with a resultant increase in
renal sodium and water retention.
o A dilutional anemia may result, which does not require treatment. 101
oEdema is reported in 4% to 5% of patients and contraindicated in patients with
New York Heart Association Class III and IV heart failure and should be used
with great caution in patients with Class I or II heart failure or other underlying
cardiac disease.

oWeight gain is dose related, and an increase of 1.5 to 4 kg is not uncommon.

Rarely, rapid gain of a large amount of weight may necessitate discontinuation
of therapy. Weight gain positively predicts a larger A1C reduction but must be
balanced with the potential adverse effects of long term weight gain.

oContraindicated in acute liver diseases. Several case reports of hepatotoxicity

with pioglitazone have been reported, but improvement in alanine
aminotransferase (ALT) was consistently observed upon drug discontinuation.
oBaseline ALT should be obtained prior to therapy and then periodically
thereafter at the practitioner’s discretion. Neither drug should be started if the
baseline ALT exceeds 2.5 times the upper limit of normal. The drugs should be
discontinued if the ALT is more than 3 times the upper limit of normal.
102
oPioglitazone controls type 2 diabetes but does not cure it. It may take 2 weeks for
blood sugar to decrease and 2 to 3 months for the full effect of pioglitazone.
oWeight gain due to increase in subcutaneous adipose tissue and swelling of the
feet and ankles.

oA small but serious increased risk of developing or worsening heart failure. An early
sign of heart failure is swelling of the feet and ankles. People who take
thiazolidinediones should monitor for swelling.

oA small but serious increased risk of developing fluid retention at the back of the
eyes (macular edema).

oA small but serious increased risk of developing certain types of cancer (like bladder
cancer). A small increased risk of bone fractures.

oTherapy with increased risk for pregnancy in those taking oral contraception (failure
of contraceptive).
103
104
 Pioglitazone Drug Interactions

• Gemfibrozil, insulin, or oral antidiabetic medicines (eg, glipizide)

because the risk of low blood sugar may be increased

o Rifampin because it may decrease pioglitazone's effectiveness, resulting

in high blood sugar

o Anticoagulants (e.g, warfarin) because the risk of their side effects may
be increased or their effectiveness may be decreased by pioglitazone

• The concomitant use of clarithromycin tablets with certain

hypoglycemic drugs such as pioglitazone, inhibition of CYP3A enzyme
by clarithromycin may be involved and could cause hypoglycemia when
used concomitantly. Careful monitoring of glucose is recommended
105
 (4) Meglitinides
• Meglitinidesare Short-Acting Insulin Secretagogues include repaglinide (Prandin) and
nateglinide (Starlix). They are a second-line treatment because they are more
expensive than sulfonylureas and are short-acting, so they must be taken with each
meal.

• Similar to sulfonylure, they are taken in pill form, meglitinides lower glucose by
stimulating pancreatic insulin secretion, but insulin release is glucose dependent and
diminishes at low blood glucose concentrations.

• Hypoglycemic risk appears to be less with meglitinides than with sulfonylureas. The
average reduction in A1C is about 0.8% to 1%.
• These agents can be used to provide increased insulin secretion during meals (when it
is needed) in patients who are close to glycemic goals.
• They should be administered before each meal (up to 30 minutes prior) and if a meal is
skipped, the medication should also be skipped.
• Meglitinides seem to cause less weight gain and low blood sugar compared to
sulfonylureas 106
• Repaglinide (Prandin) is initiated at 0.5 to 2 mg with a maximum dose of 4
mg per meal (up to four meals per day or 16 mg/day).
• They work to lower blood sugar levels, similar to the sulfonylureas, and
might be recommended in people who are allergic to sulfa-based drugs.
Repaglinide can be used safely in patients with kidney failure

• Nateglinide (Starlix) dosing is 120 mg three times daily before each meal.
The dose may be lowered to 60 mg per meal in patients who are near
goal A1C when therapy is initiated.
• Nateglinide (Starlix), repaglinide (Prandin), and the combination medicine
repaglinide and metformin (Prandimet) help stop the rapid rise in blood
sugar levels that can occur immediately after a person with type 2
diabetes eats.
• Trouble breathing, Swelling of face, lips, tongue, or throat, Seizures,
Hives, Cold symptoms such as a cough, runny nose, stuffy nose, or sore
throat. Avoid in breast-feeding, or planning to get pregnant.
• Nateglinide and repaglinide may be involved in inhibition of CYP3A
enzyme by clarithromycin and could cause hypoglycemia when used
concomitantly. Careful monitoring of glucose is recommended  107
 (5) Alpha Glucosidase Inhibitors (AGI)
• These medicines, which include acarbose (Glucobay) and miglitol (Glyset), work by
interfering with the absorption of carbohydrates in the intestines.

• It is indicated for type 2 in patients inadequately controlled on diet alone, or on diet and
oral hypoglycaemic agents

• This helps to lower blood sugar levels, but not as well as metformin or the sulfonylureas.
They can be combined with other medicines if the first medicine does not lower blood
sugar levels enough.

• The main side effects of alpha-glucosidase inhibitors are gas (flatulence), diarrhea, and
abdominal pain; starting with a low dose may minimize these side effects.

• Used in gradual dose titration. The medicine is usually taken three times per day with the
first bite of each meal. It results in a reduction of fasting blood glucose and to modest
changes in levels of HbA1c
108
• Contraindicated for inflammatory and obstructive bowel disease, colonic ulcers
109
 (2) New Therapeutic Targets

five novel medication classes for DM

1. Glucagon-n-like peptide-e- 1(GLP-1)1 Analogues
Incretin mimetics (Exenatide)

2. Dipeptidyl-l- peptidase-e- 4 (DPP-4) Inhibitors Enzyme

Inhibitors (Sitagliptin)
3. Antihyperglycemics: Pramlintide
4. Amylinomimetics
5. SGLT2 Inhibitors
110
111
 (1) Glucagon like peptide1(GLP-1) Analogs

Exenatide
Liraglutide
Dulaglutide
Trulicity

Enhances
glucose- Reduces Delays
dependent glucagon secretion gastric emptying
insulin secretion

112
 GLP-1 Analogs (Incretin Analogues)

• The GLP agonists, exenatide (Byetta), liraglutide (Victoza), dulaglutide, albiglutide

(Tanzeum), and (Trulicity), are injectable medicines.
• They are not a first-line treatment, but might be considered for people whose
blood sugar is not controlled on the highest dose of one or two oral medicines.

• They may be especially helpful for overweight patients who are gaining weight on
oral medicine.
• GLP agonists do not usually cause low blood sugar similar to metformin.

• They promote weight loss, but side-effects, including nausea, vomiting, and
diarrhea. Pancreatitis has been reported rarely in patients taking GLP agonists, but
it is not known if the drugs caused the pancreatitis.

• Stop taking exenatide (byetta) or liraglutide (Victoza) if develop severe abdominal

pain. Exenatide should not be used in patients with abnormal kidney function.
113
 GLP-1 Analogs (Incretin Analogues)

• These drugs are more expensive than insulin. Because they are
relatively new drugs, long-term risks and benefits are not known

• Exenatide is an "incretin mimetic" that mimics the action of naturally

occurring hormones such as GLP-1 that regulate blood glucose by (1)
stimulating insulin-dependent glucose secretion, (2) inhibiting
glucagon secretion, and (3) slowing gastric emptying.

• Exenatide is commonly administered BID 60 minutes before meal. Not

substitutes for insulin and can lead to insulin release only in presence
of elevated glucose levels

• Low risk for hypoglycemia and they should not be used for type1
diabetes or diabetic ketoacidosis (DKA)

114
 Exenatidec (Byetta)

• There is efficacy and safety of Exenatide in addition to Metformin in type 2 DM as

an adjunct therapy and administered before morning and evening meals.
• Initial dose: 5 mcg sc twice daily for one month and it may be increased to 10 mcg
SC twice daily, within the 60 minutes before the first and last meal of the day

• A once-weekly injection has been approved as of January 27, 2012 under the
trademark Bydureon (Exenatide 2mg vial/syringe pen). Uses with insulin has not
been studied and is not recommended.

• Exenatide has a prolonged effect to (4) reduce appetite, (5)promote satiety via
hypothalamic receptors (different receptors than for amylin).

• Most people using exenatide slowly lose weight, and generally the greatest weight
loss is achieved by people who are the most overweight at the beginning of
exenatide therapy.
115
116
• Clinical trials have demonstrated the weight reducing effect continues at the same
rate through 2.25 years of continued use.

• When separated into weight loss quartiles, the highest 25% experience substantial
weight loss, and the lowest 25% experience no loss or small weight gain.

• - Average weight loss: 1.6 to 2.8 lbs

- Average change in HbA1C: -0.8%
- Hypoglycemia (25%)
• Exenatide should not be used in patients with abnormal kidney function and is not
recommended with CrCl < 30 ml/min.

• Diarrhea (13%), Nausea (44%) and vomiting and exenatide or liraglutide should be
stopped if develop severe abdominal pain.

• They are relatively new drugs, long-term risks and benefits are not known. Store in
refrigerator and may be kept at room temperature once in use.
117
(2) Dipeptidyl Peptidase 4 (DPP 4)
Inhibitors

118
 DPP-4Inhibitors
• The first dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin was approved
in 2006 as treatment for diabetes concurrently with lifestyle changes.

• A combined product of sitagliptin and glucophage was approved by the

U.S. FDA in 2007. The second DPP-4 inhibitor, saxagliptin (Onglyza), was
approved in the U.S.
• It was approved both as monotherapy as well as in combination with
metformin, sulfonylurea, or thiazolidinedione. Combination of sitagliptin
or vildagliptin with metformin should be taken twice a day just after meals
with food.

• Vildagliptin (Galvus) was approved in Europe and Latin America also as a

combination with metformin, sulfonylurea, or thiazolidinedione.
• Linagliptin (Tradjenta) and alogliptin are also available. The different DPP-4
inhibitors are distinctive in their metabolism, saxagliptin and vildagliptin
are metabolized in the liver and sitagliptin is not.
• The difference are also distinctive in their excretion, their recommended
dosage, and the daily dosage that is required for effective treatment. 119
• They lower blood sugar levels by increasing insulin release from the pancreas in
response to a meal.

• They are not a first-line treatment, but they can be given alone in patients who
can’t tolerate the first-line medicines (metformin, sulfonylureas), or they can
be given with other oral medicines if blood sugars are still higher than goal.

• They are all similar, however, when comparing their efficacy regarding lowering
HbA1c levels, safety profile, and patient tolerance.

• The influence of DPP-4 inhibitors on the blood levels of HbA1c as monotherapy

or in combination with other oral antidiabetes drugs was tested in multiple trials
lasting 12–52 weeks.

• Treatment with sitagliptin showed an average decrease in HbA1c levels of

approximately 0.7% to 1% at a dose of 100 mg/day.
120
121
• In a meta-analysis that included information regarding treatment of type
2 diabetes with sitagliptin and vildagliptin for ≥12 weeks compared with
placebo and other oral antidiabetic drugs,( Amori et al) showed a
reduction of 0.74% in HbA1c levels.

• This result proved DPP-4 inhibitors were only slightly less effective than
sulfonylureas and as effective as metformin and thiazolidinediones in
regard to reducing blood glucose.

• In studies with combination therapy of DPP-4 inhibitors and metformin in

one pill, the results were even better because of two possible causes.

• The drugs are well tolerated, weight neutral, and do not cause GI side
effects.
Mild hypoglycemia appears to be the only significant adverse effect, but
long-term safety data are limited. 122
Different DPP4Is Drugs Comparison

123
 DPP-4 Inhibitors Summary 

• The first DPP4 inhibitor on the market was sitagliptin (Januvia®) which is available in 3 dose
strengths: 100 mg, 50 mg (CrCl >30 to <50 ml/min), and 25 mg (CrCl < 30ml/min) including
patients on dialysis.

• They lower blood sugar levels by increasing insulin release from the pancreas in response
to a meal.

• In general, DPP4 inhibitors lower A1c levels by about 0.5% to 0.8%, so they are not big
blockbusters in terms of A1c reduction, but in certain patients more improvement is
achieved than in others. Therefore, the use of this class of drugs is individualized.

• These drugs do not cause hypoglycemia and they do not cause weight gain; they have
many good attributes.

• Sitagliptin compared to saxagliptin (Onglyza™), saxagliptin comes in 2 dose strengths,

which are adjusted based on the estimated CrCl. Linagliptin does not need dose
adjustment.
124
• Linagliptin is available in one dose strength; one size fits all in terms of renal
function. Thus, the real difference is not effectiveness or side effects.
• The difference is based on whether you need to reduce the drug dose based
on the patient's renal status.

• They are not a first-line treatment, but they can be given alone in patients
who can’t tolerate the first-line medicines (metformin, sulfonylureas), or
they can be given with other oral medicines if blood sugars are still higher.

• These medicines do not cause hypoglycemia or changes in body weight but

may cause some nausea and diarrhea.
• Rare reports of pancreatitis and skin reactions. DPP-4 inhibitors are
expensive, and the long-term risks and benefits are unknown.

• No head-to-head trials have compared these 3 DPP4 inhibitors. From a

clinical perspective, however, they all behave similarly 125
126
(3) Sodium Glucose Co-transporter 2 Inhibitors (SGLT2)
• SGLT-2 inhibitors work in the kidney to block the reabsorption of some glucose.
Normally, all glucose is reabsorbed back into the systemic circulation from the kidney at
normal glucose levels: about 10% through the SGLT-1 receptor, and 90% through the
SGLT-2 receptor

• Early data have shown approximately 50 to 80 g of glucose per day may be allowed to
pass into the urine with SGLT-2 inhibition. This lowers systemic glucose and allows
weight loss.

• Glucose levels may be lowered in both type 1 and type 2 DM by this mechanism of
action. It is used along with diet and exercise.

• The safety and efficacy of SGLT2 inhibitors to patients with type 1 diabetes have not
been established and dapagliflozin should not be used for treatment of patients with
type 1 diabetes.

• Limited data from clinical trials suggest that DKA occurs with common frequency when
patients with type 1 diabetes are treated with SGLT2 inhibitors.
• It is not recommended in DKA or in suspected bladder cancer or severe kidney
127
problems, or if patient on dialysis
128
129
• When the drug is used with insulin or other oral diabetes medicine (eg, repaglinide,
glipizide) be aware because the risk of low blood sugar may be increased

• It isn't recommended to be used with diuretics (furosemide, HCT, spironolactone)

because the risk of low blood pressure may be increased

• Safety data have shown a slightly higher rate of genitourinary yeast infections.

• SGLT-1 is involved with glucose absorption in the gut, and inhibition of SGLT-1 has
been historically thought to cause GI toxicity.

• Canagliflozin (Invokana) is currently the farthest in development, but several are

being developed. Dapagliflozin has been rejected by the FDA several times due to
concerns about cancer.

• SGLT2 inhibitors, dapagliflozin (Farxiga), canagliflozin (Invokana), and empagliflozin

(Jardiance), lower blood sugar by increasing the excretion of sugar in the urine (50
to 80 g of glucose per day).
130
  

• They are relatively weak anti diabetes drugs, similar in potency to the
DPP-4 inhibitors.

• They are not a first-line treatment. Although they can be combined with
other medications, including metformin, sulfonylureas, pioglitazone,
sitagliptin, and insulin, in patients with persistently elevated blood
sugars. We do not routinely use them because of the absence of long-
term efficacy and safety data.

• SGLT2 inhibitors do not cause hypoglycaemia. They promote modest

weight loss but can also cause bothersome side effects, including vaginal
yeast infections and urinary tract infections.

• The therapeutic indications of SGLT2 inhibitors in adults aged 18 years

and older with type 2 diabetes mellitus to improve glycaemic control as:
131
o It can be used as monotherapy when diet and exercise alone do not provide adequate
glycaemic control in patients for whom use of metformin is inappropriate due to
intolerance.

o Add-on combination therapy: In combination with other glucose-lowering medicinal

products including insulin, when these, together with diet and exercise, do not
provide adequate glycaemic control.

• Monotherapy and add-on combination therapy

• The recommended dose when using dapagliflozin is 10 mg once daily for
monotherapy and add-on combination therapy with other glucose-lowering
medicinal products including insulin.

• Used in combination with insulin or an insulin secretagogue, such as a sulphonylurea,

a lower dose of insulin or insulin secretagogue may be considered to reduce the risk
of hypoglycaemia.

• The efficacy of SGLT2 inhibitors are dependent on renal function, and efficacy is
reduced in patients who have moderate renal impairment and likely absent in
patients with severe renal impairment. 132
• Not recommended for use in patients with moderate to severe renal impairment
(CrCl < 60 ml/min).

• No dosage adjustment is indicated in patients with mild renal impairment and

no dosage adjustment is necessary with mild or moderate hepatic impairment.

• In severe hepatic impairment, a starting dose of 5 mg is recommended. If well

tolerated, the dose may be increased to 10 mg.

• Rare cases of DKA, including life-threatening cases, have been reported in clinical
trials and post-marketing in patients treated with SGLT2 inhibitors, including
dapagliflozin.

• In a number of cases, the presentation of the condition was atypical with only
moderately increased blood glucose values, below 14 mmol/l (250 mg/dl). It is
not known if DKA is more likely to occur with higher doses of dapagliflozin.

• The risk of diabetic ketoacidosis must be considered in the event of non-specific

symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst,
difficulty breathing, confusion, unusual fatigue or sleepiness.
133
The Work Group defined categories of decreased GFR as:
Mild (Stage 2: 60 to 89 mL/min/1.73 m2)
Moderate (Stage 3: 30 to 59 mL/min/1.73 m2)
Severe (Stage 4: 15 to 29 mL/min/1.73 m2)

134
• Patients should be assessed for ketoacidosis immediately if these symptoms occur,
regardless of blood glucose level. If DKA is suspected or diagnosed, treatment with
dapagliflozin should be discontinued immediately.

• Treatment should be interrupted in patients who are hospitalised for major surgical
procedures or acute serious medical illnesses.
• In both cases, treatment with SGLT 2 inhibitors may be restarted once the patient's
condition has stabilised.

• Before initiating SGLT 2 inhibitors, factors in the patient history that may predispose
to ketoacidosis should be considered

• In elderly, in general, no dosage adjustment is recommended based on elderly age.

Renal function and risk of volume depletion should be taken into account on
therapy.

• Due to the limited therapeutic experience in patients 75 years and older, initiation
of dapagliflozin therapy is not recommended . Caution of drop in blood pressure in
elderly could pose a risk of known cardiovascular disease or on anti-hypertensive
therapy with a history of hypotension. 135
136
• Higher proportion of subjects treated with dapagliflozin had ADRs related to renal
impairment or failure compared with placebo.

• The most commonly reported ADRs related to renal function was serum creatinine
increases, the majority of which were transient and reversible

• In subjects ≥ 65 years of age, a higher proportion of subjects treated with dapagliflozin had
ADRs is related to volume depletion.

• The safety and efficacy of SGLT-2 inhibitors in children aged 0 to < 18 years have not yet
been established. No data are available.

• SGLT-2 inhibitors such as dabagliflosin 5 or 10 mg film-coated tablets be taken orally once

daily at any time of day with or without food. Tablets are to be swallowed whole.
•
• Due to its mechanism of action, SGLT-2 inhibitors increases diuresis associated with a
modest decrease in blood pressure, which may be more pronounced in patients with
very high blood glucose concentrations.

• It is not recommended for use in patients receiving loop diuretics or who are volume
depleted, e.g. due to acute illness (such as GIT illness). 137
 Patients Using GLT2 inhibitors and at Higher Risk of
Diabetic Ketoacidosis Acidosis (KA)

• Patients who may be at higher risk of DKA include patients with a low
beta-cell function reserve (type 2 diabetes patients with low C-
peptide or latent autoimmune diabetes in adults (LADA) or patients
with a history of pancreatitis), patients with conditions that lead to
restricted food intake or severe dehydration, patients for whom
insulin doses are reduced and patients with increased insulin
requirements due to acute medical illness, surgery or alcohol abuse.
SGLT2 inhibitors should be used with caution in these patients.

• Restarting SGLT2 inhibitor treatment in patients with previous DKA

while on SGLT2 inhibitor treatment is not recommended, unless
another clear precipitating factor is identified and resolved.
138
• Urinary tract infections were more frequently reported for SGLT2
inhibitors compared to placebo in a pooled analysis up to 24 weeks.

• Pyelonephritis was uncommon and occurred at a similar frequency to

control. Urinary glucose excretion may be associated with an
increased risk of urinary tract infection; therefore, temporary
interruption of SGLT2 inhibitors should be considered when treating
pyelonephritis or urosepsis.

• While a causal relationship between SGLT2 inhibitors such as

dapagliflozin and bladder cancer is unlikely, as a precautionary
measure, dapagliflozin is not recommended for use in patients
concomitantly treated with pioglitazone.

• Available epidemiological data for pioglitazone suggest a small

increased risk of bladder cancer in diabetic patients treated with
pioglitazone.
139
• Haematocrit increase was observed with dapagliflozin treatment;
therefore, caution in patients with already elevated haematocrit is
warranted.

• Dapagliflozin has not been studied in combination with (GLP-1)

analogues.

• In urine laboratory assessments, due to its mechanism of action, patients

taking SGLT2 inhibitors will test positive for glucose in their urine.

140
 Interaction with other Medicinal Products

• SGLT2 inhibitors including emphagliflozin may add to the diuretic effect of

thiazide and loop diuretics and may increase the risk of dehydration and
hypotension.

• Insulin and insulin secretagogues, such as sulphonylureas, cause

hypoglycaemia. Therefore, a lower dose of insulin or an insulin
secretagogue may be required to reduce the risk of hypoglycaemia when
used in combination with SGLT2 inhibitors such as dapagliflozin

• The metabolism of dapagliflozin and canagliflosin are primarily via

glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9
(UGT1A9). In in vitro studies, dapagliflozin neither inhibited cytochrome
P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6,
CYP3A4, nor induced CYP1A2, CYP2B6 or CYP3A4.

• Therefore, dapagliflozin and canagliflosin are not expected to alter the

metabolic clearance of coadministered medicinal products that are
metabolised by these enzymes. 141
• Interaction studies conducted in healthy subjects, using mainly a single
dose design, suggest that the pharmacokinetics of SGLT2 inhibitors are
not altered by metformin, pioglitazone, sitagliptin, glimepiride,
voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin.

• Following coadministration of dapagliflozin with mefenamic acid (an

inhibitor of UGT1A9), a 55% increase in dapagliflozin systemic exposure
was seen, but with no clinically meaningful effect on 24-hour urinary
glucose excretion. No dose adjustment is recommended.

• Dapagliflozin did not alter the pharmacokinetics of metformin,

pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide,
valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C9
substrate), or the anticoagulatory effects of warfarin as measured by
INR.
• Combination of a single dose of dapagliflozin 20 mg and simvastatin (a
CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and
31% increase in AUC of simvastatin acid. The increase in simvastatin and
142
simvastatin acid exposures are not considered clinically relevant.
 (4) Inhaled Insulin
(a) Afrezza ®
• Afrezza is inhaled insulin, manufactured by Mannkind, was approved by
the FDA on June 28, 2014. Its attractive inhaler delivers a choice of 4u or
8u capsules of insulin powder.

• Capsules are prepared by loading insulin molecules onto pH-sensitive

carrier particles and then drying and placing the powder into plastic
capsules.
• The aerodynamic properties of the particles delivered by the device
scatters the insulin powder deep into the lungs when inhaled.
• Once these pH sensitive particles contact the neutral pH of the lungs,
they become a liquid and quickly absorb through the lung membranes.

• Mannkind’s Inhaled Insulin is faster increase in blood insulin level, can be

puffed right before eating rather than giving an injection 20 minutes early,
great for matching high GI food and large carbohydrate meals, fast drops
in high blood sugars, lower readings after meals 143
 Who May Benefit From Afrezza ® ?
• If Afrezza’s potency actually proves to be similar to injected insulin, capsule sizes
of 4 or 8 units may be too large for people who use less than 30 or 40 units of
insulin a day.

• Data reported that the dose of inhaled fast insulin needed to correct high
glucose levels is 4u capsule and it would lower the blood sugar about 120 mg/dl
(6.7 mmol) for someone whose average daily dose of insulin is 60 units a day.

• Someone on 30 units a day will drop about 240 mg/dl (13.3 mmol) with one
capsule and 480 mg/dl on an 8u capsule. This crude dosing might be contrasted
with that of an insulin pump where one twentieth of a unit delivered with
precision equates to 1.5 mg/dl and 3 mg/dl declines in the glucose, respectively.

• A major benefit of Afrezza is its ability to quickly raise blood insulin levels. In Type
2 diabetes a major defect is the loss of first phase insulin release that gets
quickly released from the pancreas after a meal and then reaches high levels in
the portal vein that goes directly to the liver.
144
• Afrezza ® obviously does not mimic this pathway when delivered through
the lungs to the peripheral circulation, but blood levels of insulin may rise
faster and further with inhaled insulin.

• The Dreamboat inhaler may encourage Type 2s who are hesitant to start
insulin to start sooner. There is competition in this area, of course, with
GLP-1 agonists, but Afrezza ® offers another alternative when a long-
acting insulin and oral agents cannot fully control postmeal glucose
levels.

• It may also find a nice as a tool to more rapidly lower high glucose levels,
and to cover large carbohydrate meals and high glycemic index foods. For
those already on insulin,

• The FDA warns that Afrezza ® should not be used with drugs that slow
digestion like Symlin or GLP-1 agonists (Byetta, Bydureon, Victoza) and
that it cannot replace long-acting insulins. The real question, though, is
whether Afrezza ® can replace fast-acting insulins.
145
• Once inhaled, the insulin level in the blood peak within 15 minutes and is
mostly gone after 90 to 120 minutes.

• Although the peak and duration of Afrezza ® are different from those of
Humalog, the total areas under the curve appear similar suggesting that an 8u
of Afrezza ® seems to be delivering the same amount of insulin as an 8u
injection of Humalog.

• It is important to know how Afrezza ® works and who can use it appropriately,
In head-to-head trials with Novalog, those who received Afrezza ® saw a
reduction in their A1c levels, while those who took mealtime injections of
Novolog showed a greater improvement in their A1c levels.

• The FDA is requiring post-marketing studies for Afrezza ®. These include

research on its pharmacokinetics and pharmacodynamics to better
characterize dose responses and to determine how its action varies from day
to day by a person using it.

• Afrezza’s speed may create a higher risk of hypoglycemia for some users
and not be appropriate for Type 1s on lower insulin doses a day. Capsule sizes
146
of 4 or 8 units may complicate dose accuracy.
 Afrezza ® Side Effects
• The most common side effects from Afrezza ® were hypoglycemia (low blood
sugar), cough, and throat pain or irritation.

• Afrezza ® may not eliminate the need for boluses or injections of a short-
acting insulin for many people on insulin. Its action appears to disappear too
quickly to prevent a late rise in BG after most meals.

• Smokers experience an even quicker rise in insulin and are advised against use.
Exercise increases insulin transport and the likelihood of lows.

• Small decreases in air flow, a measure of lung volume, have been noted in
research studies with both Afrezza ® and Exubera. People with asthma, COPD, and
certain lung conditions should not use Afrezza ® , due to a dangerous complication
called acute bronchospasm.

• Some concern remains about the long-term effects of inhaling a growth protein
into the lungs. Although the risk appears low, post-marketing studies will monitor
Afrezza ® users to see if there is any increase in lung cancer.
147
 (b) Exubera
• It was approved by FDA for those over 18 years of age with
diabetes, but realistically was only appropriate for those who
could handle large doses.

• Unfortunately, Exubera was removed from pharmacy shelves

in October 2007 after it failed to gain the acceptance of
patients and physicians. But the drug company Pfizer said it
was halting sales of the drug because of financial reasons .
• This failure occurred largely due to the bong-sized inhaler
that it required. The inhaler weighed about 4 ounces and was
about 12 inches long during delivery.

148
 (5) EXUBERA

• Inhaled insulin
• Rapid-acting
• Dry powder insulin
• Inhaled through the mouth
directly into the lungs
• A1c Lowering:
- EXUBERA monotherapy:
1.4% reduction
- EXUBERA + 2 oral agents:
1.9% reduction
149
 EXUBERA
Clinical Pharmacology

For the treatment of adults (18+yrs)

with DM to control hyperglycemia
It will be
Type 1
It is used for postprandial glucose load in combination with
a long-acting insulin ultralente or glargine for basal insulin.

Type 2
Monotherapy OR
Combination with oral agents OR with long-acting insulin

150
 Contraindications to EXUBERA
(Respiratory Exclusion Criteria)
• Smoking within 6 months of screening
• Poorly controlled asthma
• Clinically significant COPD
• FEV1 <70%
• Significant chest x-ray abnormality

Other Contraindication
• Hypoglycemia
• Chest discomfort
• Cough
• Dyspnea
151
152
153
154
155