CHAPTER 54 DRUGS FOR DIABETES MELLITUS

I. DIABETES MELLITUS: OVERVIEW OF THE DISEASE & ITS TREATMENT

Diabetes Mellitus – derived from the Greek word for fountain and the Latin
word for honey
- primarily a disorder of carbohydrate metabolism
- insulin is the key to unlocking cells to allow carbohydrates in for
energy production
- symptoms result from a deficiency of insulin or from resistance to
insulin’s actions
- principle sign is sustained hyperglycemia (too much sugar) which rapidly
causes polyuria (increased
urine output), polyphagia (increased hunger), polydipsia (increased
thirst), ketonuria, and weight
loss
- hyperglycemia can lead to hypertension, heart disease, renal failure,
blindness, neuropathy,
amputations, impotence and stroke
- most common endocrine disorder: 5th leading cause of death by disease
17 million have the disease, but only 11
million diagnosed

A. TYPES OF DIABETES MELLITUS

1. TYPE I DIABETES
- accounts for 5 – 10% of all cases
- was once called insulin dependent diabetes mellitus (IDDM) or
juvenile-onset diabetes mellitus
- MUST HAVE INSULIN OR DIE
- develops during childhood or adolescence with an onset that is
relatively abrupt
- primary defect is destruction of pancreatic beta cells (cells
responsible for insulin synthesis)
- insulin levels are reduced early in the disease and fall to zero
later

2. TYPE II DIABETES
- most prevalent form of diabetes
- was once called non-insulin dependent diabetes mellitus (NIDDM)
or adult onset diabetes
mellitus
- usually begins in middle age and progresses gradually and obesity
is almost always present
- carries little risk of ketoacidosis
- symptoms result from a combination of insulin resistance and
impaired insulin secretion
- insulin secretion is no longer tightly coupled to plasma glucose
content: release of insulin is
delayed and peak output is subnormal
 - target tissues of insulin (liver, muscle, adipose tissue) exhibit
insulin resistance
- resistance results from threes causes: reduced binding of
insulin to receptors
reduced receptor number
reduced receptor for
responsiveness
- hyperglycemia leads to destruction of pancreatic beta cells causing
insulin production and
secretion to eventually decline

TYPES OF DIABETES MELLITUS

CHARACTERISTICS TYPE I TYPE II
Alternative Insulin-dependent diabetes, Non-insulin dependent diabetes,
Names juvenile-onset diabetes, ketosis- adult-onset diabetes
prone diabetes
Age of Onset Usually childhood or Usually over 40
adolescence
Speed of Onset Abrupt Gradual
Family History Usually negative Frequently positive
Prevalence 5 – 10% of diabetics have Type I 90 – 95% of diabetics have Type
II
Etiology Autoimmune process Unknown – but there is strong
familial assoc., suggesting
heredity as the underlying cause
Primary Defect Loss of pancreatic beta cells Insulin resistance &
inappropriate insulin secretion
Insulin Levels Reduced early in the disease & Levels may be low (indicating
completely absent later deficiency), normal, or high
(indicating resistance)
Treatment Insulin replacement is Exercise & reduced-caloric diet
mandatory, along w/ strict may be sufficient; if not, an oral
dietary control, oral hypoglycemia agent &/or insulin
hypoglycemic drugs are not is required
effective
Blood Glucose Levels fluctuate widely in Levels are more stable than Type
response to infection, exercise, & I
changes in caloric intake &
insulin dose
Symptoms Polyuria, polydipsia, polyphagia, May be asymptomatic
weight loss
Body Usually thin & undernourished Frequently obese
Composition
Ketosis Common, especially if insulin Uncommon
dosage is insufficient

B. SHORT TERM COMPLICATIONS OF DIABETES

- principal concerns are hyperglycemia (insulin dosage is insufficient) and
hypoglycemia (insulin dosage
is excessive)
- ketoacidosis develops when hyperglycemia is allowed to persist and is a
potentially fatal acute
complication

C. LONG TERM COMPLICATIONS OF DIABETES

- Type I and Type II share the same long term complications
- takes years to develop
- deaths result from long-term complications, not from hypoglycemia or
ketoacidosis
- with rigorous control of blood glucose, development of long term
complications can be greatly reduced

1. Macrovascular Disease
- cardiovascular complications are leading cause of death among
diabetic patients
- increased risk of hypertension, heart disease and stroke
- pathology is due to atherosclerosis (develops earlier in diabetics
and progresses at an
accelerated rate)

2. Microvascular Disease - common

- basement membrane of capillaries thickens, causing blood flow in
the microvasculature to
decline
- destruction of small blood vessels leads to kidney damage and
blindness
- complications are directly related to the degree and duration of
hyperglycemia
- tight control of disease is important

a. Retinopathy - major cause of blindness among American adults

- visual loss results most commonly from damage to retinal
capillaries
- microaneurysms may occur, followed by scarring and
proliferation of new
vessels
- overgrowth of new retinal capillaries reduces visual
acuity
- capillary damage may also impair vision by causing
local ischemia which can
 kill retinal cells
- accelerated by hyperglycemia, hypertension, and smoking

b. Nephropathy – kidney damage

- characterized by proteinuria, reduced glomerular filtration
and increased arterial blood
pressure
- most common cause of end-stage renal disease (a condition
that requires dialysis or
kidney transplant for survival)
- primary cause of morbidity and mortality in patients with
Type I
- can be delayed and the extent of injury can be reduced with
tight glucose control

c. Neuropathy
- nerve degeneration often begins early in the course of
diabetes, but symptoms are
absent for years
- sensory and motor nerves may be affected
- symptoms include tingling sensation in the fingers and toes,
pain, suppression of
reflexes and loss of sensation (especially vibratory
sensation)
- nerve damage is directly related to sustained hyperglycemia
- tight glycemic control can reduce damage

d. Amputations - diabetes is responsible for more than 50% of lower

limb amputations
- results in part because of severe nerve damage

e. Impotence - combination of blood vessel injury and neuropathy can

cause impotence

f. Gastroparesis - manifestations include nausea, vomiting, delayed

gastric emptying, and
abdominal distention secondary to atony of the GI tract
- injury to autonomic nerves that control GI motility may be
the underlying cause

D. DIABETES & PREGNANCY

- placenta produces hormones that can antagonize insulin’s actions
- production of cortisol, a hormone that promotes hyperglycemia,
increases threefold during pregnancy
- since glucose can pass freely from the maternal circulation to the fetal
circulation, hyperglycemia in the
mother will stimulate secretion of fetal insulin, resulting in multiple
adverse effects on the developing fetus
 - successful management DEMANDS that proper glucose levels be
maintained in both the fetus and
mother

Gestational diabetes – diabetes that appears during pregnancy and

then subsides rapidly after delivery
- managed in the same manner as any other diabetic pregnancy =
BLOOD GLUCOSE
maintained in both the fetus and mother
- diabetic state disappears almost immediately after delivery,
permitting discontinuation
of insulin

E. DIAGNOSIS OF DIABETES
- patient must be tested on two separate days
- any combination of two tests can be used and both tests must be
positive

1. Fasting Plasma Glucose (FPG) TEST – preferred test used to diagnose

- blood is drawn at least 8 hours after the last meal
- normal glycemic individual levels are less than 110 mg/fl
- with FPG levels 126 mg/dl or higher, diabetes is indicated

2. Casual Plasma Glucose Test

- blood can be drawn at any time
- plasma glucose level that is 200 mg/ml or higher suggest diabetes
- to make diagnosis, patient must also display classic signs and
symptoms of diabetes (polyuria,
polyphagia, polydipsia, rapid weight loss)

3. Oral Glucose Tolerance Test (OGTT) – not used for routine screening
(used when diabetes is
suspected but can’t be confirmed by FPG or casual plasma glucose)
- performed by giving an oral glucose load (equal to 75 gm of
anhydrous glucose) and
measuring plasma glucose levels 2 hours later
- normal individual levels will be below 140 mg/dl
- levels of 200 mg/dl or higher suggest diabetes
- usual testing during pregnancy for gestational diabetes

F. TREATMENT OVERVIEW
1. Type I Diabetes
- goal of therapy is to maintain glucose levels within an acceptable
range in order to prevent
acute complications and reduce or prevent long-term
complications
- glycemic control is accomplished with an integrated program of
diet, self-monitoring of blood
 glucose (SMBG), exercise, and insulin replacement – oral
hypoglycemics are not used
- Proper diet, balanced by insulin replacement, is the cornerstone of
treatment
- Type I diabetics are usually thin, the dietary goal is to maintain
weight – not lose it
- total caloric intake should be spread evenly, w/ meals spaced 4 – 5
hrs apart
- ADA recommendations include foods that contain sucrose (table
sugar) – provided there is a
reduction of intake of other carbohydrates
- really important is the total amt of carbohydrates ingested –
not the type or the source
- regular exercise should be part of the management program
- strenuous exercise can produce hypoglycemia
- exercise should be avoided if glycemic control is unstable
- SURVIVAL REQUIRES DAILY ADMINISTRATION OF INSULIN

2. Type II Diabetes
- goal of therapy is to maintain blood glucose levels within an
acceptable range
- core of treatment is diet and exercise; insulin or oral hypoglycemic
agents are employed only
as adjuncts (oral, insulin, or combination of both)
- dietary goal is to promote weight loss and establishment of a
leaner body composition
- patients should be screened for hypertension, nephropathy,
retinopathy, and neuropathy

G. MONITORING TREATMENT
- goal is to determine whether glucose levels are being maintained in a
safe range

1. Self-Monitoring of Blood Glucose (SMBG)

- standard method for routine monitoring
- performed by placing a drop of blood on a treated strip, which is
read by a sm. machine
- test is rapid and can be performed in almost any setting
- Type I diabetics should do SMBG 3 or more times a day, especially
each time before
administration of medications
- Type II diabetics’ testing is dependent upon treatment
- target values for blood glucose are 80 – 120 mg/dl before meals
and 100 – 140 mg/dl at
bedtime

Drawbacks:
• more expensive than urine tests
• more difficult to perform than urine tests
 • machines require periodic calibration
• patients require education on how to apply test results
• not practical for patients with limited economic resources
• not practical for patients who are unable or unwilling to learn
how to use the device and apply the results

Advantages:
• superior to measuring glucose in urine
• hyperglycemia can be detected long before blood glucose
levels are high enough to cause spilling of glucose into urine
• can detect hypoglycemia, something that urinary
measurements simply can’t do

2. Urine Glucose Monitoring

- reserved method for patients who cannot or will not monitor their
blood glucose
- testing is inexpensive and easy
- testing has limited utility
• poor correlation between urine glucose concentration and
blood glucose levels
• negative test tells only that blood glucose is below 180 mg/dl
(the usual threshold for spilling glucose from blood to urine)
• negative test does not tell how much below the threshold the
glucose is
- patient could be hypoglycemic, normoglycemic or even
slightly hyperglycemic
- superior to no testing at all

3. Glycated Hemoglobin (Hemoglobin HbA1c) – blood test

- measured to assess long-term success
- provides an index of average blood glucose levels over the prior 2 –
3 months
- glucose interacts spontaneously with hemoglobin in red blood cells
to form glycated
derivatives
- most prevalent is hemoglobin A1c (HbA1c)
- prolonged hyperglycemic = levels of HbA1c gradually
increase
- levels of HbA1c reflect average glucose levels over an
extended time
- measurement every few months gives a picture of long-term
glycemic control
- should be measured at least twice a year for patients
who are meeting
treatment goals and have stable glycemic control
- should be measured 4 times a year for patients who
are not meeting glycemic
goals or whose therapy has changed
 - target value for HbA1c is 6.8% or less
- NOT a substitute for daily monitoring

II. INSULIN
- available in several forms which differ with respect to time course of
action, route of administration,
and source

A. TYPES OF INSULIN (See table on pg 602)

- seven types of insulin:“natural” insulin and six modified insulins
- when mixing insulins, draw up clear solution to cloudy solution

Prolonging Effects Processes:

• complexing natural insulin with a protein
• altering the physical state of natural insulin by mixing it with zinc
• altering the insulin molecule itself such that it has reduced solubility

Time Course Classifications:

• short acting
o rapid acting (lispro insulin and aspart insulin)
o slower acting (regular insulin)
• intermediate acting
• long acting

1. Regular (Natural) Insulin – unmodified crystalline insulin (trade name:

HumulinR, Novolin R)
- relatively rapid onset and short duration
- dispensed as a clear solution
- only form of insulin administered intravenously; however, usual
route is subcutaneous
- following SC injection, molecules form small aggregates
resulting in slightly delayed
absorption
- generally administered 30 to 60 minutes before meals
- insulin bottle in current use (usually a 2- to 4- week supply) does
not have to be kept cold,
although exposure to sunlight and extreme heat must be
avoided

2. Lispro Insulin – rapid acting analog of regular insulin (trade name:

Humalog)
- shorter duration of action
- can be administered immediately before eating and even after
eating
- should be used with an intermediate- or long-acting insulin
- available only by prescription
 3. Insulin Aspart – analog of human insulin with a rapid onset and short
duration (trade name:
Novolog)
- structurally identical to human insulin except that one amino acid
has been changed to
aspartic acid
- very similar to insulin lispro
- administration is SC
- should be injected immediately before meals or immediately after
- can be mixed with NPH insulin (provided mixing is done just before
administration)
- available only by prescription

4. Neutral Protamine Hagedorn (NPH) Insulin – prepared by conjugating

regular insulin with protamine
(a large protein)
- protamine decreases the solubility of NPH insulin and retards
absorption, resulting in delayed
onset of action and extended duration
- allergic reaction are possible
- intermediate duration

5. Lente Insulin and Ultralente Insulin – produced by complexing regular

insulin with zinc, which
changes physical state of insulin, reducing solubility
- consists of:
• semilente insulin – most rapid acting member of this series
- noncrystalline and present as particle of small size
- no longer available by itself
• ultralente insulin – present as large crystals that dissolve
slowly, giving a long duration
of action
• lente insulin – stable mixture composed of 70% ultralente and
30% semilente insulin
- intermediate duration of action
- no added proteins

6. Insulin Glargine – modified human insulin with a prolonged duration of

action (at least 24 hours)
- indicated for once-daily SC administration to treat adults and
children with Type I diabetes,
and adults with Type II diabetes
- subcutaneous injection should be made at bedtime, must not be
injected IV because doing
so could produce severe hypoglycemia owing to excessive
insulin levels in blood
- achieves blood levels that are relatively steady over 24 hours,
reducing risk of hypoglycemis
 (from excessive levels) or hyperglycemia (from insufficient
levels)
- supplied as a clear solution, but cannot be mixed with other
insulins
- stress correct preparation (not mixing) and administration (SC) to
patients; idea of clear
solution providing prolonged effects is new and needs
reinforcement

B. ADMINISTRATION AND STORAGE

1. Usual Routes of Administration – insulin is given by injection (not
activated by digestive system)
- all insulins may be injected subcutaneously
- only regular may also be given IV and IM
2. Preparing for Injection
- dispersion is accomplished by rolling the insulin vial between the
palms of the hands
- mixing must be gentle, because vigorous agitation will cause
frothing and render accurate
dosing impossible
- if granules or clumps remain after gentle agitation, the vial should
be discarded
- insulin suspensions are cloudy, whereas regular, lispro, glargine
insulins are dispersed as
clear, colorless solutions
- because these are solutions, preparations can be
administered without prior agitation
- if one of these preparations becomes cloudy or discolored, or
if a precipitate develops,
it should be discarded

3. Sites of Injection - most common sites of SC injection are the upper

arms, thighs, and abdomen

4. Mixing Insulins
- with the use of two different insulin preparations, it is usually
desirable to mix the preparations
rather than inject them separately, so as to eliminate the need
for additional shots
- mixing offers convenience, but can alter the time course of
the response
- only insulins that are compatible with each other should be
combined

5. Storage
- unopened vials should be stored under refrigeration (not frozen)
until needed and can be used
up to the expiration date on the vial
 - in current use vials can be kept at room temperature for up to 1
month without significant loss
of activity
- direct sunlight and extreme heat must be avoided
- partially filled vials should be discarded after several weeks if
left unused
- room temperature causes less pain than cold insulin
- insulin mixture vials are stable for 1 month at room temperature
and 3 months under
refrigeration
- prefilled insulin mixture syringes (plastic or glass) should be stored
under refrigeration where
they are stable for at least 1 week, perhaps 2
- syringes should be stored vertically with the needle pointing
up to avoid clogging
- prior to administration, the syringe should be agitated gently
to resuspend insulin

6. Alternative Methods of Insulin Delivery

a. Jet Injectors – devices that shoot insulin directly through the skin into
subcutaneous tissue
- no needle is used
- drawbacks: expensive
can be difficult to use
can cause stinging, burning, and pain
can cause bruising

b. Pen Injectors – look like a fountain pen but have a disposable needle
(where the writing tip
would be)
- disposable insulin-filled cartridge inside
- administration is accomplished by sticking the needle under
the skin and injecting the
insulin manually

c. Portable Insulin Pumps - computerized devices that deliver a basal

infusion of insulin (regular,
lispro, or aspart) plus bolus doses before each meal
- mealtime boluses are calculated to match caloric intake
- pumps are about the size of a call-pager, weigh only 4
ounces, and are worn on the
belt or in a pocket
- infusion set delivers insulin from the pump to a subcutaneous
needle, usually located
on the abdomen
- infusion set should be replace every 1 to 3 days, moving the
needle to a new site
- delivers short-acting insulin causing levels to drop quickly if
the pump is removed
 - drawbacks: expensive
underdelivery of insulin

d. Implantable Insulin Pumps – abdominal surgically implanted devices

that deliver insulin either
intraperitoneally or intravenously
- deliver basal insulin infusion plus bolus doses with meals
- delivery is adjusted by external telemetry
- produce superior glycemic control
- cause less hypoglycemia and weight gain
- improve quality of life
- drawback: impeded by formation of insulin microprecipitates
not yet available for general use

C. COMPLICATIONS OF INSULIN TREATMENT

1. Hypoglycemia – blood glucose <50 mg/dl; insulin levels exceed insulin
needs
- imbalance can result from: reduced intake of food
vomiting and diarrhea (reduces absorption of
nutrients)
excessive consumption of alcohol (promotes
hypoglycemia)
unaccustomed exercise (promotes glucose
uptake and
utilization)
parturition (reduces insulin requirements)

III. ORAL HYPOGLYCEMICS

- indicated for Type II diabetes only
- employed only after a program of diet modification and exercise has
failed to produce glycemic control

A. SULFONYLUREAS
- work by promoting insulin release from the pancreas
- may also increase cellular sensitivity to insulin
- major adverse effect is hypoglycemia

Groups:
• first generation agents
• second generation agents
- reduce glucose levels to the same extent
- principal difference is 2nd generation agents are more potent (produce
their effects at much lower
doses than do the 1st generation agents)
 - more important than potency are differences in duration of action,
since agents with longer
durations can be given once daily

1. Tolbutamide – 1st generation agent (trade name: Orinase)

- acts primarily by stimulating the release of insulin from pancreatic
islets
- may increase cellular sensitivity to insulin
- binds with and blocks ATP sensitive potassium channels in cell
membrane causing the
membrane to depolarize, permitting influx of calcium, causing
insulin release
- release is glucose dependent, and diminishes at low glucose levels
- readily absorbed following oral administration
- plasma levels peak within 3 – 5 hours
- undergoes extensive hepatic metabolism followed by urinary
excretion
- short half-life (about 6 hours) - must be administered 2 to 3
times a day
2. Glipizide – 2nd generation agent (trade name: Glucotrol)
- more potent than 1st generation

B. MEGLITINIDES
- work by promoting pancreatic insulin release

1. Repaglinide – blocks ATP sensitive potassium channels on pancreatic

beta cells to facilitate calcium
influx which leads to increased insulin release (trade name: Prandin)
- can lower HbA1c levels by about 1.7%
- undergoes rapid absorption followed by rapid elimination
- blood levels peak within 1 hour of oral administration & return to
baseline in about 4 hours
- elimination results from hepatic metabolism followed by biliary
excretion
- half-life is only 1 hour
- blood levels of insulin rise and fall in parallel with levels of drug

C. BIGUANIDES: METFORMIN - (trade name: Glucophage)

- frequently causes GI disturbances; lactic acidosis is rare – condition is
greatly increased by renal
impairment, which decreases metformin excretion and thereby
causing drug levels to rise
rapidly
- lowers blood glucose primarily by decreasing production of glucose in the
liver
- underlying mechanism appears to be suppression of gluconeogenesis
- enhances glucose uptake and utilization by muscle
- does not promote insulin release from pancreas and does not cause
hypoglycemia
 - administered by mouth
- absorbed slowly from small intestine
- excreted unchanged by the kidneys; hence, in the event of renal
insufficiency, metformin can
accumulate to toxic levels

Side Effects: decreased appetite

nausea
diarrhea

D. THIAZOLIDINEDIONES (“GLITZAONES”)
- also known as “glitazones”
- reduce glucose levels by decreasing insulin resistance
- can expand blood volume and cause edema, thereby posing a risk for
patients with heart failure

1. Rosiglitaone – (trade name: Avandia)

- acts primarily by decreasing insulin resistance (increases ability of
target cells to respond to
insulin)
- insulin must be present for drug to work - benefits take several
weeks to develop
- increases uptake of glucose by muscle and decreases glucose
production by liver
- approved for monotherapy and in combination with metformin, a
sulfonylurea, or insulin

Side Effects: fluid retention (can cause heart failure, can

exacerbate symptoms in existing)
edema
weight gain

E. ALPHA-GLUCOSIDASE INHIBITORS
- act in the intestine to delay absorption of carbohydrates
1. Acarbose – (trade name: Precose)
- delays absorption of dietary carbohydrates, reducing the rise in
blood glucose that occurs after
meals
- acarbose inhibits this enzyme, slowing digestion of carbohydrates,
hence reducing the
postprandial rise in blood glucose
- MUST be taken with every meal

Side Effects: - flatulence - borborygmus (rumbling

bowel sounds)
- cramps - diarrhea
- abdominal distention - decrease iron absorption

F. COMBINATION PRODUCTS
 1. Glyburide / Metformin – (trade name: Glucovance)
- combination of a sulfonamide (glyburide) and a biguanide
(metformin)
- glyburide acts primarily by increasing insulin secretion
- metformin acts primarily by decreasing hepatic glucose production,
partly by increasing
glucose uptake and utilization by muscle
- only advantage of combination is convenience

2. Glipizide / Metformin – (trade name: Metaglip)

- combination of a sulfonamide (glipizide) and a biguanide
(metformin)
- glipizide acts primarily by increasing insulin secretion
- metformin acts primarily by decreasing hepatic glucose production,
partly by increasing
glucose uptake and utilization by muscle
- only advantage of combination is convenience

3. Rosiglitazone / Metformin (trade name: Avandamet)

- combination of a thiazolidinedione (rosiglitazone) and a biguanide
(metformin)
- rosiglitazone acts by decreasing insulin resistance
- metformin acts primarily by decreasing hepatic glucose production,
partly by increasing
glucose uptake and utilization by muscle

IV. DIABETIC KETOACIDOSIS

- most severe manifestation of insulin deficiency; life-threatening
- characterized by hyperglycemia, production of ketoacids,
hemoconcentration, acidosis, and coma

TREATMENT
• Insulin Replacement – levels are restored with an initial IV bolus of regular
insulin followed by
continuous infusion
- when infusion is preferred to SC, insulin levels cannot be lowered
quickly in response to
excessive dosing; hence, avoiding hypoglycemia may be
difficult

• Bicarbonate for Acidosis – (blood pH 6.9 to 7.1)

- empiric therapy with bicarbonate
- potassium should be infused with bicarbonate unless hyperkalemia
is present

• Water & Sodium Replacement – dehydration and sodium loss are both
corrected with IV saline
- adults usually require between 8 and 10 L of fluid during the first
12 hours of treatment
 - central venous pressure should be monitored in elderly and
patients with heart disease
• Potassium Replacement – as a rule the serious problem of potassium loss
is corrected by IV
administration
- electrocardiographic monitoring is essential

Guideline: a) if plasma potassium is normal, no potassium until

levels decline in response
to insulin
b) if plasma potassium is low, potassium should be given
immediately (re-
administered if levels fall following insulin
administration)

• Normalization of Glucose Levels – if insulin therapy induces hypoglycemia,

plasma glucose can be restored by administering glucagons or glucose
itself

V. GLUCAGON
- “glucose is gone to the cell”
- used if there is an insulin overdose
- promotes breakdown of glycogen
- glucose level in blood stream increases
- administered parenterally – IV, IM, SC