Review of Medications Used in the

Treatment of Diabetes Mellitus

BRANDI K LALIBERTE AND JOSHUA J NEUMILLER

Objective: To review the pathophysiology of diabetes mellitus and outline currently available medications
used in its treatment.
Data Sources: A MEDLINE/PubMed search (1966–December 2009) was conducted for English-language
articles using the terms diabetes mellitus, pharmacotherapy, metformin, thiazolidinedione, sulfonylurea,
meglitinide, α-glucosidase inhibitor, DPP-4 inhibitor, colesevelam, bromocriptine, exenatide, pramlintide,
and insulin. Book chapters relevant to the pathophysiology and pharmacologic treatment of diabetes were
also searched.
Study Selection and Data Extraction: Articles and chapters pertinent to the pharmacologic management of
diabetes mellitus were reviewed.
Data Synthesis: Type 1 diabetes is characterized by an absolute lack of insulin production by the β-cells of the
pancreas, requiring insulin therapy. Type 2 diabetes is characterized by both insulin resistance and a relative
or absolute lack of insulin secretion. Because type 2 diabetes involves both insulin resistance and decreased
insulin production over time, people with type 2 diabetes can be treated with a variety of drugs currently on
the market. Therapies currently on the market include metformin, thiazolidinediones, sulfonylureas,
meglitinides, α-glucosidase inhibitors, DPP-4 inhibitors, colesevelam, bromocriptine, exenatide, pramlintide,
and insulin.
Conclusions: Given the multitude of medications available for the treatment of diabetes, it is important that
pharmacy technicians and pharmacists be aware of the various agents currently on the market. With a solid
foundation of knowledge regarding diabetes medications, a huge impact can be made on the quality of care
of the customers and patients the pharmacy serves.
J Pharm Technol 2010;26:136-46.
ACPE Universal Activity Number: 407-000-10-058-H01-T (Technicians)

Diabetes mellitus (DM) is the seventh leading cause of
death in the world.1 Approximately 8% of the global
population, or 23.6 million people, have diagnosed or
undiagnosed diabetes.1,2 Another 57 million people have
prediabetes or are currently without symptoms but have
a predisposition for the development of the disease.1,2 In
2007 alone, 1.6 million people over 20 years of age were
diagnosed with DM.1 The goal of managing DM is to
minimize symptoms of hyper- and hypoglycemia as well
as to prevent long-term complications associated with el-
evated blood glucose levels.3,4
Symptoms of hyperglycemia may not manifest for
years but can include fatigue, irritability, increased thirst
and hunger, frequent urination, unexplained weight loss,
and blurred vision.2,3 Chronic, or sustained, hyper-
glycemia can contribute to many health-related compli-
cations including kidney failure, blindness, amputation,
poor wound healing, and cardiac events.2,3
Hypoglycemia can be caused by increased levels of
circulating insulin without enough glucose available to
supply the cells at that time.3 Symptoms of hypo-
glycemia include shakiness, dizziness, sweating, hunger,
headache, sudden mood changes, and confusion.2,3 If hy-
poglycemia is not recognized and remedied by glucose
consumption or glucagon injection, seizures, coma, and
even death are possible.2 With the increasing number of
patients requiring treatment to manage DM, it is impor-
tant that technicians and other pharmacy staff be aware
of the wide range of medications dispensed by the phar-
macy. This article provides an overview of currently
available medications approved for the treatment of DM,
with a focus on enhancing the knowledge of pharmacy
technicians concerning the use of these medications by
their customers and clients.
Pathophysiology
DM is a disorder of carbohydrate metabolism and is
characteristically associated with hyperglycemia.3 Com-

BRANDI K LALIBERTE PharmD BS MS, Department of Pharmacotherapy, College of Pharmacy, Washington State University,
Spokane, WA; JOSHUA J NEUMILLER PharmD CDE CGP FASCP, Assistant Professor, Department of Pharmacotherapy, College
of Pharmacy, Washington State University/Elder Services. Reprints: Dr. Neumiller, Department of Pharmacotherapy, College of
Pharmacy, Washington State University/Elder Services, 5125 N. Market St., Spokane, WA 99217, fax 509/458-7459,
jneumiller@wsu.edu
Conflict of interest: Dr. Neumiller receives grant support from Merck, Johnson and Johnson, Amylin, and Novo Nordisk.

136 J PHARM TECHNOL I VOLUME 26 I MAY/JUNE 2010 JPHARMTECHNOL.COM

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plex carbohydrates, such as starch and fiber, as well as
simple carbohydrates, which include sugars such as su-
crose and fructose, are broken down during the digestive
process into glucose, which is subsequently absorbed
into the bloodstream.4 Before glucose can be utilized by
the body as an energy source, insulin must be released by
the pancreas to facilitate the uptake of glucose by cells
within the body.4
Insulin, which is a hormone, plays multiple roles in
the body to help process and use glucose.3 A primary
role of insulin is to activate glucose transporters. Glucose
transporters are located on the surface of many cells in
the body, including cells of the muscle, liver, and adipose
tissue, and essentially allow for glucose to be taken up by
these cells for use as energy.3,4 A secondary function of in-
sulin is to facilitate the conversion of glucose to glyco-
gen.3,4 Glycogen is stored in the body for later use as en-
ergy, such as during exercise. β-cells are cells in the
pancreas that produce and release insulin when glucose
levels rise after a meal.3,4 Insulin is produced and stored
within the β-cells until stimulated by glucose or other
signals (eg, medications) to release insulin into the blood-
stream.3,4
L crease cellular sensitivity to insulin, the result is reduced
A primary role of insulin is to
activate glucose transporters.
M L
While there are several types of diabetes, this article
will discuss the treatment of the 2 main types: type 1 dia-
betes mellitus (T1DM) and type 2 diabetes mellitus
(T2DM). T1DM is thought to result from either autoim-
mune disorders or genetic causes and is characterized by
an absolute lack of insulin production by the β-cells of the
pancreas. Because people with T1DM are not able to make
insulin, all those with T1DM require insulin supplementa-
tion to control their blood sugar. People with T2DM are of-
ten able to produce insulin, but the cells and tissues of
their bodies have an inability to efficiently utilize it.3-6 This
resistance to the effects of insulin creates a situation where
the cells of the body are less able to use glucose within the
bloodstream as energy. This deficiency can be due to sev-
eral factors, including impaired insulin receptors on the
surface of cells and/or decreased amounts of insulin being
produced by the pancreas over time. Unfortunately, be-
cause people with T2DM have insulin resistance, the β-
cells of the pancreas are forced to produce more insulin to
overcome the resistance and bring the blood glucose
down toward normal levels. Over time, this can overwork
the β-cells, leading to a decreased ability to produce in-
sulin as the disease progresses and the insulin resistance
persists. Because T2DM involves both insulin resistance
JPHARMTECHNOL.COM
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and decreased insulin production over time, people with
T2DM can be treated with more than just insulin. Medica-
tions are available to enhance the sensitivity of cells to in-
sulin and increase the production of insulin by pancreatic
β-cells. Generally, people with T2DM are started on oral
therapies, and as their disease progresses, they may re-
quire the addition of insulin to meet treatment goals. Some
patients with T2DM will even require intensive insulin
therapy after living with the disease for many years. Fig-
ure 1 provides a graphic representation of the mechanism
of select medications discussed throughout this article.
Key terms for pharmacy technicians to recognize are
shown in Appendix I.
Oral Medications
INSULIN SENSITIZERS
As mentioned previously, insulin resistance occurs as
cells lose the ability to respond to insulin, thus leading to
hyperglycemia.7 Two classes of oral antidiabetic medica-
tions, biguanides and thiazolidinediones (TZDs), in-
crease the sensitivity of cells to insulin and are known as
insulin sensitizers.3,4 By using these medications to in-
circulating blood glucose levels, increased glucose up-
take and use by cells, and decreased glucose release by
the liver.8 Table 1 provides adverse effect, dosing, and
other important information on noninsulin medications
discussed in this article.9
Biguanides and
thiazolidinediones increase the
sensitivity of cells to insulin.
M
Metformin
Metformin, which is currently available in several
generic and brand formulations (see Table 1), is the only
medication in the biguanide drug class currently avail-
able in the US. One of the ways metformin helps treat
T2DM is by increasing the sensitivity of cells to insulin to
overcome insulin resistance.3,4,8,10 While metformin does
enhance sensitivity to insulin, its primary function is to
prevent the liver from releasing glucose into the blood-
stream.4 One of the functions of liver cells is to store glu-
cose as glycogen. Glycogen is broken back down into
glucose when needed as an energy source.3 During a
fasting state, when a person has not eaten in some time,
pancreatic β-cells secrete glucagon. Glucagon stimulates
MAY/JUNE 2010 I VOLUME 26 I J PHARM TECHNOL 137
liver cells to convert glycogen to glucose and release glu-
cose into the bloodstream to keep the blood glucose lev-
els from becoming too low.3 After a person eats, glucagon
secretion is suppressed, insulin is released by β-cells, and
insulin signals the liver to stop breaking glucagon down
into glucose.3 When there is insulin resistance in the liver,
this “off” signal is not readily recognized, and glucose mo-
bilization from glycogen stores continues, thus further
causing the blood glucose levels to rise.8,10 Metformin is a
first-line treatment option for T2DM due to its multiple
mechanisms, low risk for causing hypoglycemia, and lack
of weight gain that can be seen with other medications
used to treat T2DM.11 Prescribing guidelines recommend
avoiding metformin in males with a serum creatinine (SCr)
of ≥1.5 mg/dL or in females with an SCr ≥1.4 mg/dL.12 Be-
cause metformin is eliminated by the kidneys, its use is rel-
atively contraindicated in patients with a creatinine clear-
ance (CrCl) of <60 mL/min.13 The most common adverse
effects of metformin are stomach upset, diarrhea, flatu-
lence, and abdominal pain. Many of these adverse effects
can be minimized by taking the medication with meals and
by slowly titrating the dose upward.3,4,10
Thiazolidinediones
Pioglitazone (Actos) and rosiglitazone (Avandia) are
the 2 currently approved TZD medications in the US.3,14
TZDs work by binding peroxisome proliferator-activated
receptor-gamma (PPAR-γ) receptors in fat and muscle
cells.3,4,8,10 By binding this receptor, TZDs are able to en-
hance cell sensitivity to insulin. These medica-
tions have a duration of action more than 24
hours, which allows for once-daily dosing.3
Common adverse effects of TZDs include
weight gain and fluid retention, which can lead
to serious complications, particularly in people
with heart failure.3,4

INSULIN SECRETAGOGUES

Another strategy for the treatment of T2DM

is to overcome insulin resistance by stimulating
the pancreas to release insulin. Several drug
classes work in this manner to help the cells

Figure 1. Mechanism of action of select medications in the treatment of type 2 diabetes. I. Glucose absorbed into the bloodstream is transported into
the β-cell by GLUT receptors (A). Through a series of cellular reactions, stored insulin is released (B) into the bloodstream. Sulfonylureas and megli-
tinide medications bind the SUR-1 receptor (C), and incretin mimetics bind the GLP-1 receptor (D) to stimulate insulin release. II. TZD medications
bind to PPAR-γ in the nucleus of muscle and fat cells and enhance insulin-mediated glucose uptake. Metformin assists the cells in overcoming insulin
resistance while increasing the ability of the cells to utilize glucose for energy. III. Metformin stimulates liver cells to increase glucose uptake and
storage in the form of glycogen. Metformin also decreases the breakdown of glycogen and mobilization of glucose from the liver. GLP-1 = glucagon-
like peptide-1; GLUT = glucose transporter; PPAR-γ = peroxisome proliferator-activated receptor-gamma; SUR-1 = sulfonylurea receptor; TZD = thi-
azolidinedione.

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 MEDICATIONS FOR THE TREATMENT OF DIABETES MELLITUS

Table 1. Currently Available Noninsulin Medications for the Treatment of Diabetes9

GENERIC BRAND COMMON ADVERSE
DRUG CLASS NAME NAME COMMON DOSE RANGE REACTIONS COMMENTS

Biguanide Metformin Glucophage, 500–2550 mg daily given 1–3 times GI upset, nausea, Take with food
Riomet daily (max 2550 mg/day) diarrhea, flatulence,
alterations in taste
Metformin XR Glucophage XR 500–2000 mg once daily given with
evening meal
Metformin XR Fortamet 500–2500 mg once daily given with
evening meal (max 2500 mg/day)
Metformin XR Glumetza 1000–2000 mg once daily given with
evening meal (max 2000 mg/day)
Thiazolinediones Pioglitazone Actosa 15–45 mg once daily (max 45 mg/day) Weight gain, fluid Take with or without
retention food
Rosiglitazone Avandiaa 4–8 mg daily given once or twice
daily (max 8 mg/day)
Sulfonylureas Glimepiride Amaryl 1–8 mg given once daily (max Weight gain, hypo- Take with meals
8 mg/day) glycemia, GI
upset
Glipizide Glucotrol 5–40 mg daily given once or twice
daily (max 40 mg/day)
Glipizide XL Glucotrol XL 5–20 mg daily given once daily (max
20 mg/day)
Glyburide Diabeta, 2.5–20 mg daily given once or twice
Micronase daily with first meal of the day
(max 20 mg/day)
Micronized Glynase 1.5–12 mg daily given once daily with
glyburide first meal of the day (max 12 mg/day)
Meglitinides Nateglinide Starlix 60–120 mg po tid before meals Weight gain, Take within 30 min of
(max 360 mg/day) hypoglycemia start of meal
Repaglinide Prandin 0.5–4 mg po 3–4 times daily before
meals (max 16 mg/day)
α-Glucosidase Acarbose Precose 25–100 mg po tid with meals (max GI upset, flatulence, Take with food
inhibitors 150 mg/day if ≤60 kg; max 300 mg/day weight loss
if >60 kg)
Miglitol Glyset 25–100 mg po tid with meals
(max 300 mg/day)
Dipeptidyl Sitagliptin Januviaa 25–100 mg daily given once daily Sinusitis, GI upset, Give in combination
peptidase-4 (max 100 mg/day) headache with other oral agents
inhibitor Saxagliptin Onglyza 2.5–5 mg daily given once daily
(DPP-4 inhibitor) (max 5 mg/day)
Bile acid Colesevelam Welchol 3750 mg daily given once or twice Hypoglycemia, Give in combination with
sequestrant daily with meals (max 3750 mg/day) constipation, other oral agents; take
weakness with food
Dopamine Bromocriptine Cycloset 0.8–4.8 mg daily given once daily Headache, dizziness, Starting dose of 0.8 mg
agonist (max 4.8 mg/day) constipation, nausea titrated up weekly
Incretin mimetic Exenatide Byettaa 5–10 μg sc bid (max 20 μg/ daily) Weight loss, GI upset, Doses given within 1 h
nausea/vomiting of meals; give in combi-
nation with other oral
agents
Store unopened pen in
refrigerator; may be
stored at room temper-
ature during use and
should be discarded
after 30 days or after the
expiration date, which-
ever comes first
Synthetic Amylin Pramlintide Symlin 15–120 μg sc immediately prior to Hypoglycemia, Only for use in DM
large meals (max 120 μg/ dose) GI upset patients using mealtime
insulin
Store unopened pens or
vials in refrigerator; may
be stored at room
temperature during use
and should be discarded
after 28 days or after the
expiration date, which-
ever comes first

DM = diabetes mellitus; GI = gastrointestinal; max = maximum.

a
Medication in the “Top 200.”

JPHARMTECHNOL.COM MAY/JUNE 2010 I VOLUME 26 I J PHARM TECHNOL 139

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take up glucose from the bloodstream in order to lower
blood glucose levels. Medications that stimulate insulin
release are insulin secretagogues.
Sulfonylureas
The most utilized class of medications that stimulate
insulin release from the pancreas is the sulfonylurea
class. This is the oldest drug class, other than insulin, cur-
rently in use in the US. The 3 most commonly used sul-
fonylureas are glimepiride (Amaryl), glipizide (Glu-
cotrol), and glyburide (Diabeta, Micronase), which are
available in immediate-release and/or extended-release
formulations (see Table 1).3,4 The primary mechanism of
these medications is to stimulate the release of presynthe-
sized insulin from the pancreas by binding to the β-cell
sulfonylurea receptor (SUR-1).3,4,10 Sulfonylureas initiate a
series of cellular reactions after binding to SUR-1, which
ultimately results in insulin release.10 The effects of sul-
fonylureas last from 12 to 24 hours and can stimulate in-
sulin release over longer periods of time.3,4 As a result,
the most common adverse effects of this class are hypo-
glycemia and weight gain.3 Since the durations of action
of these medications vary, care should be taken to differ-
entiate extended-release once-daily products from short-
er acting twice-daily products to prevent misfills that
could result in unnecessary hypoglycemic events.
Meglitinides
Nateglinide (Starlix) and repaglinide (Prandin) are
secretagogue medications that increase insulin release
from the pancreas.3,4 These drugs, like the SUs, bind to
SUR-1 on pancreatic β-cells.3,10 Nateglinide and repaglin-
ide are short-acting, with effects beginning within 15–30
minutes of taking the medication and lasting 4–6 hours.3
Due to their short duration of action, meglitinides should
be taken within 30 minutes of beginning each meal.3,10
Because these medications work similarly to sulfony-
lureas, their adverse effect profiles are similar, with hypo-
glycemia and weight gain being the most common.3
OTHER ORAL AGENTS
Aside from medications that primarily treat T2DM by
addressing insulin resistance and directly increasing insulin
secretion by the pancreas, there are a number of other oral
medications that work by different mechanisms. The fol-
lowing discussion outlines how these drugs work.
α-Glucosidase Inhibitors
Digestive enzymes in the small intestine break down
complex carbohydrates (such as those in grains, cereals,
fruits, and vegetables) into simple sugars, such as glucose,
that can be absorbed and used for energy. α-Glucosidase
inhibitors, namely acarbose (Precose) and miglitol (Gly-
set), bind to the enzyme α-glucosidase and slow the break-
140 J PHARM TECHNOL I VOLUME 26 I MAY/JUNE 2010
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down of complex sugars.3,4,10 By slowing the breakdown of
complex carbohydrates, the absorption of glucose is de-
layed, which causes less of a spike in blood glucose levels
immediately following a meal. To be effective, these medi-
cations must be taken with the first bite of every meal.3 Be-
cause of the way these drugs work, the delayed break-
down of carbohydrates commonly causes abdominal
pain, bloating, flatulence, and diarrhea.3,4,10 The gastroin-
testinal adverse effects associated with these medications
tend to limit acceptance of these medications by patients.
Dipeptidyl Peptidase-4 Inhibitors
In recent years, signals from the gastrointestinal tract
in response to a meal have been recognized as important
in stimulating insulin secretion from pancreatic β-cells.15
This signaling, known as the “incretin effect,” is due to
the release of hormones from the intestines that stimulate
insulin release from the pancreas following a meal. Peo-
ple with T2DM have been shown to have a “blunted” in-
cretin effect. Incretin hormones have a very short half-life
after they are released because they are inactivated in a
matter of minutes by an enzyme called dipeptidyl pepti-
dase-4 (DPP-4).16 One of the strategies used to take ad-
vantage of the incretin effect is to inhibit the DPP-4 en-
zyme so that incretin hormones can have a longer
duration of action.16 There are currently 2 DPP-4 in-
hibitors approved for use in the US: sitagliptin (Januvia)
and saxagliptin (Onglyza). In addition to increasing in-
sulin synthesis and release from β-cells of the pancreas,
DPP-4 inhibition also leads to decreases in glucagon pro-
duction.16 Desirable characteristics of DPP-4 inhibitors in-
clude once-daily dosing and a minimal risk of hypo-
glycemia. The most common adverse effects seen with
DPP-4 inhibitors include headache, upper respiratory
tract infections, and sinusitis.
Bile Acid Sequestrant
Colesevelam (Welchol) is a cholesterol-lowering agent
in the bile acid sequestrant drug class. Colesevelam was
recently approved for use as add-on therapy to other dia-
betes medications in people with T2DM.17,18 Colesevelam
therapy improves blood glucose control, lowers hemo-
globin A1c (A1C; a 3-month measure of control), and low-
ers low-density lipoprotein cholesterol in patients receiv-
ing other antidiabetic medications including metformin,
sulfonylureas, and insulin.17 The main theory as to cole-
sevelam’s mechanism in T2DM is that it decreases carbo-
hydrate absorption from the digestive system.19-21 Cole-
sevelam can be taken once- or twice-daily with meals.18
Adverse effects can include constipation, indigestion,
and nausea.3,18 Colesevelam can interact with many other
medications; therefore, to avoid potentially dangerous
drug interactions, accurate patient profile reviews and
diligent patient education about how to take this medica-
tion in relation to other drugs should be performed by
pharmacists.3
JPHARMTECHNOL.COM
 MEDICATIONS FOR THE TREATMENT OF DIABETES MELLITUS

Dopamine Agonist greater than 60% adherence by patients taking either

Bromocriptine is a dopamine agonist. Dopamine ago-
nists mimic the actions of dopamine within the body by
stimulating dopamine receptors. Bromocriptine is ap-
proved for use in Parkinson’s Disease, acromegaly, and hy-
perprolactinemia.3,4 In May of 2009, the Federal Drug Ad-
ministration (FDA) approved bromocriptine (Cycloset) for
the treatment of T2DM.22,23 Studies have shown reduced
fasting blood glucose and A1C levels in patients receiving
bromocriptine therapy.24 While the exact mechanism is un-
known, some researchers believe that bromocriptine resets
circadian rhythms (the normal cycle of biochemical and
physiological processes that fluctuate throughout the day)
in patients with T2DM, which somehow lowers blood glu-
cose.24 Cycloset should be administered with food within 2
hours of waking.22,23 While other doses and forms of
bromocriptine are available generically, the Cycloset prod-
uct that is approved for the treatment of T2DM is a differ-
ent dosage form available at a different dose. Generic
bromocriptine products should not be substituted for a pre-
scription for Cycloset. Common adverse effects of this
medication include hypotension, fainting, nausea, vomit-
ing, diarrhea, and constipation.22
COMBINATION ORAL MEDICATIONS
Current guidelines recommend metformin as initial
therapy for patients with T2DM.25,26 As the disease pro-
gresses, patients may benefit from the addition of other
antidiabetic agents.26 Combinations of medications with
different mechanisms of action can provide additive anti-
hyperglycemic effects.26 Although disease control may be
enhanced with the addition of a second agent, patient ad-
herence can decrease with the increased number of medi-
cations a person is prescribed.26 A 2-year study revealed
metformin or a sulfonylurea as monotherapy for T2DM.
Adherence subsequently decreased to 35% when pa-
tients were prescribed both medications.27 Another study
compared adherence rates in patients with T2DM who
were taking metformin and rosiglitazone as separate
tablets versus those who were taking the combination
product Avandamet.28 The study revealed 20% greater
adherence in those receiving the combination tablet.
Many combination products are available to ease the pill
burden and increase adherence in patients with DM.
Table 2 provides a listing of currently available oral com-
bination products.9
L
Combinations of medications
with different mechanisms of
action can provide additive
antihyperglycemic effects.
M
While combination products can be beneficial in im-
proving medication adherence, it is important to consid-
er cost as a limiting factor. Many combination products
are available in brand name only and can be cost pro-
hibitive for some patients, depending on their personal
finances and insurance coverage. It is sometimes the case
that patients receiving combination products are nonad-

Table 2. Currently Available Oral Combination Products for the Treatment of Type 2 Diabetes9
GENERIC BRAND COMMON
DRUG CLASS NAME NAME COMMON DOSE RANGE ADVERSE REACTIONS COMMENTS

Biguanide / Metformin / Metaglip 250–2000 mg/2.5–20 mg po bid GI upset, hypoglycemia Take with meals
sulfonylurea glipizide
Biguanide / Metformin / Glucovance 500–2000 mg/2.5–20 mg po bid GI upset, hypoglycemia Take with meals
sulfonylurea glyburide
Biguanide / Metformin / Actoplus Meta 500–2000 mg/15–45 mg po GI upset, fluid retention Take with evening
thiazolinedione pioglitazone daily meal
Biguanide / Metformin / Avandameta 500–2000 mg/2–8 mg po daily GI upset, fluid retention Take with food
thiazolinedione rosiglitazone or bid
Biguanide /DPP-4 Metformin / Janumeta 500–2000 mg/50–100 mg po bid GI upset Take with food
inhibitor sitagliptin with meals
Biguanide/ Metformin / PrandiMet 500 mg/1–2 mg po bid with meals GI upset, hypoglycemia Within 15 minutes
meglitinide repaglinide before meals
Thiazolinedione / Pioglitazone / Duetact 30 mg/2–4 mg po daily Weight gain, hypoglycemia Take with morning
sulfonylurea glimepiride meal
Thiazolinedione / Rosiglitazone / Avandaryl 4–8 mg/1–4 mg po daily Weight gain, hypoglycemia Take with morning
sulfonylurea glimepiride meal

DPP-4 = dipeptidyl peptidase-4; GI = gastrointestinal.

a
Medication in the “Top 200.”

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 Table 3. Currently Available Insulin Products for the Treatment of Diabetes9
142
AVAILABLE PRODUCTS
Rapid-acting insulin
Insulin aspart (NovoLog) Novolog Solution
Novolog FlexPen
NovoLog PenFill
J PHARM TECHNOL
Insulin lispro (Humalog)b Humalog Prefilled Pen
Humalog Cartridge
I
Humalog KwikPen
Humalog Suspension
Insulin glulisine (Apidra) Apidra Solution
Apidra SoloSTAR Prefilled
Pen
VOLUME 26
I
Short-acting insulin
Regular insulin (Humulin R, Humulin R Solution
Novolin R) Novolin R Solution
Novolin R Penfill
ReliOn R Solution
Intermediate-acting insulin
MAY/JUNE 2010
NPH insulinb Humulin N Suspension
Humulin N Prefilled Pen
Novolin N Suspension
Novolin N Penfill
ReliOn N Suspension
Long-acting insulin
Insulin glargine (Lantus) Lantus Solutionb
Lantus OptiClik Cartridge
Lantus SoloSTAR Prefilled
Penb
Insulin detemir (Levemir)b Levemir Solution
Levemir FlexPen
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Combination products
NPH / regular insulin Humulin 70/30 Suspension
(70/30)b Humulin 70/30 Pen
Suspension
Novolin 70/30 Suspension
Novolin 70/30 Pen Suspension
NPH / regular insulin (50/50) Humulin 50/50 Suspension
JPHARMTECHNOL.COM
STORAGE INSTRUCTIONSa
Unopened product should be stored in the refrigerator
Once opened or removed from the refrigerator, vials, cartridges, and pens must be discarded after 28 days
Vials may be stored in the refrigerator or at room temperature once opened
Insulin pens and cartridges should be stored at room temperature once opened
Unopened product should be stored in the refrigerator
Once opened or removed from the refrigerator, vials, cartridges, and pens must be discarded after 28 days
Vials may be stored in the refrigerator or at room temperature once opened
Insulin pens and cartridges should be stored at room temperature once opened
Unopened product should be stored in the refrigerator
Once opened or removed from the refrigerator, vials and pens must be discarded after 28 days
Vials may be stored in the refrigerator or at room temperature once opened
Insulin pens should be stored at room temperature once opened
Unopened product should be stored in the refrigerator
Vials should be discarded after the expiration date, and potency may be lost when opened for more than 1 mo; if changes in blood glucose
occur a new vial should be used
Vials may be stored in the refrigerator or at room temperature once opened to minimize local irritation
Insulin cartridges should be stored at room temperature once opened and discarded after 28 days
Unopened product should be stored in the refrigerator
Vials should be discarded after the expiration date, and potency may be lost when opened for more than 1 mo; if changes in blood glucose
occur a new vial should be used
Vials may be stored in the refrigerator or at room temperature once opened to minimize local irritation
Insulin cartridges should be stored at room temperature once opened and discarded after 14 days
Unopened product should be stored in the refrigerator
Once opened or removed from the refrigerator, vials and cartridges must be discarded after 28 days
Vials may be stored in the refrigerator or at room temperature once opened
Cartridges in use should be stored at room temperature
Unopened product should be stored in the refrigerator
Once opened or removed from the refrigerator, vials and cartridges must be discarded after 42 days
Insulin vials may be stored in the refrigerator or at room temperature once opened
Pens and cartridges should be stored at room temperature once opened
Unopened product should be stored in the refrigerator
Vials should be discarded after the expiration date, and potency may be lost when opened for more than 1 mo; if changes in blood glucose
occur a new vial should be used
Vials may be stored in the refrigerator or at room temperature once opened to minimize local irritation
Insulin cartridges should be stored at room temperature once opened and discarded after 10 days
Unopened product should be stored in the refrigerator
Vials should be discarded after the expiration date, and potency may be lost when opened for more than 1 mo; if changes in blood glucose
occur a new vial should be used
Vials may be stored in the refrigerator or at room temperature once opened to minimize local irritation
Insulin cartridges should be stored at room temperature once opened and discarded after 10 days
 MEDICATIONS FOR THE TREATMENT OF DIABETES MELLITUS

herent to therapy due to cost, in which case dispensing

the medications individually may financially allow for
patients to take both medications on a daily basis.

Injectable Medications
INCRETIN MIMETIC

Exenatide (Byetta) is the first agent in the incretin

mimetic drug class. As mentioned previously when the
Insulin pens and cartridges should be stored at room temperature once opened and discarded after 14 days

Insulin pens and cartridges should be stored at room temperature once opened and discarded after 10 days

Insulin pens and cartridges should be stored at room temperature once opened and discarded after 10 days
DPP-4 inhibitors were discussed, augmentation of the in-
Vials may be stored in the refrigerator or at room temperature once opened to minimize local irritation

cretin effect can have beneficial effects on glucose control in

people with T2DM.29 Exenatide, initially approved by the
Insulin cartridges should be stored at room temperature once opened and discarded after 10 days

FDA in April 2005 for the treatment of T2DM, is a struc-

tural analog of glucagon-like peptide-1 (GLP-1).29,30 Exena-
tide mimics the function of the natural GLP-1 incretin hor-
Once opened or removed from the refrigerator, vials must be discarded after 28 days

Once opened or removed from the refrigerator, vials must be discarded after 28 days

Once opened or removed from the refrigerator, vials must be discarded after 28 days

mone in the body but is modified in such a way that it is

resistant to being broken down by the DPP-4 enzyme. Ex-
enatide, administered as a twice-daily subcutaneous injec-
Vials may be stored in the refrigerator or at room temperature once opened

Vials may be stored in the refrigerator or at room temperature once opened

Vials may be stored in the refrigerator or at room temperature once opened

tion, is approved for use as add-on therapy for patients

with T2DM who are inadequately managed with met-
formin, a sulfonylurea, a TZD, or a combination of met-
formin plus a sulfonylurea or metformin plus a TZD.29,30
Exenatide was approved in 2009 as monotherapy with diet
and exercise to improve blood glucose control in people
Unopened product should be stored in the refrigerator

Unopened product should be stored in the refrigerator

Unopened product should be stored in the refrigerator

with T2DM.30 Exenatide is currently available in 60-dose

(30-day supply) prefilled pens. Exenatide improves blood
glucose control by increasing insulin secretion following a
meal, regulating glucagon secretion from the α-cells of the
pancreas, and delaying gastric emptying.31 Of additional
benefit, exenatide has effects in the brain that lessen peo-
ple’s hunger. Accordingly, exenatide has shown benefit in
both improved blood glucose control and weight loss in
some patients.31 The most common adverse effects associat-
ed with exenatide include nausea and vomiting, particular-
ly when starting therapy. It is important that the dose be in-
creased slowly to avoid serious adverse effects. Exenatide
All insulin products should be stored in the refrigerator prior to dispensing.

is eliminated primarily through the kidneys, and its use is

not recommended in patients with a CrCl of <30 mL/min.
However, no dose adjustment is required in those with a
CrCl >30 mL/min.32 The FDA recommended revised label-
Humalog Mix 75/25 KwikPen

Humalog Mix 50/50 KwikPen

ing for exenatide in November of 2009 due to reports of

NovoLog 70/30 Suspension

worsening kidney function in people using exenatide, and

NovoLog 70/30 Flexpen

patients should report any changes in their health while us-

Humalog Mix 75/25

Humalog Mix 50/50

ing this agent.33 Likewise, information regarding the risk of

acute pancreatitis was added to the US labeling for exena-
Suspension

Suspension

tide in 2007.30,34 The risk of pancreatitis with exenatide use

relative to other agents used for the treatment of T2DM is
currently under debate. Ultimately, sufficient counseling re-
garding proper use of the pen device, adverse effects to be
Medication in the “Top 200.”

aware of, and proper administration technique to avoid

NPH-like / insulin aspart

nausea is imperative to the successful use of exenatide.

NPH-like / insulin lispro

NPH-like /insulin lispro

AMYLINOMIMETIC

Pramlintide (Symlin) is another injectable medication

(70/30)b

(75/25)b

(50/50)

that is used in patients using mealtime insulin. Pramlin-

tide is an analog of a hormone that is cosecreted with in-
b
a

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sulin from the β-cells of the pancreas.35 Pramlintide is ap-
proved for use in patients with T1DM who are not
achieving adequate glycemic control on mealtime insulin
and for patients with T2DM who are not achieving ade-
quate glycemic control on mealtime insulin with or with-
out concomitant sulfonylurea and/or metformin thera-
py.35 Pramlintide works together with insulin to regulate
postmeal glucose levels and works by decreasing post-
meal glucagon secretion, slowing gastric emptying, and
working in the brain to suppress the appetite.31 Pramlin-
tide is given by subcutaneous injection immediately pri-
or to each large meal or snack and should never be
mixed with insulin or other injectable agents in the same
syringe.35 The biggest concern associated with pramlin-
tide use is the risk of severe hypoglycemia, particularly
in people just starting the medication.31 It is important
that patients receiving a new prescription for pramlintide
receive counseling from the pharmacist about how to use
pramlintide in combination with their insulin to mini-
mize their risk of low blood glucose. Patients must un-
derstand the importance of decreasing their mealtime in-
sulin doses under the supervision and instruction of their
health-care team when first starting pramlintide to avoid
a severe low blood glucose level.31
INSULIN
As discussed, insulin is the hormone produced by the
pancreas to facilitate glucose utilization by cells.4 Natu-
rally, β-cells release insulin at a constant, or basal, rate as
well as in response to increased levels of blood glucose
following a meal.4 Insulin binds to specific receptors on
muscle, liver, and fat cells. Patients with DM who have
insulin deficiency have decreased glucose uptake by
cells, decreased glucose storage, and increased glucose
production by the liver.6
Synthetic insulin products produced in laboratories
are the primary (and essential) treatment option for pa-
tients with T1DM, and many patients with T2DM re-
quire insulin therapy, particularly as their disease pro-
gresses and their β-cells lose the ability to produce
insulin. The main categories of insulin used are rapid-
and short-acting, intermediate-acting, long-acting, and
mixed-acting insulin. Table 3 provides an outline of cur-
rently available insulin products.9 Insulin products differ
in their onset of action and duration of action.3,4 Great
care should be taken when dispensing insulin products
to patients to ensure accurate prescription filling, suffi-
cient counseling, and adequate patient understanding.
Many of the products have similar names and are avail-
able in similar doses but have very different onsets and
durations of action.
Rapid-acting insulin, such as aspart (NovoLog), lispro
(Humalog), and glulisine (Apidra), can be administered
subcutaneously immediately prior to a meal. Rapid-act-
ing insulins serve to mimic natural insulin release by the
pancreas in response to increased blood glucose after a
meal.3,4 The onset of action is 15–30 minutes for the rapid-
144 J PHARM TECHNOL I VOLUME 26 I MAY/JUNE 2010
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acting insulin products, with peak insulin concentrations
between 1 and 2 hours after an injection. The duration of
action with these insulin products is up to 5 hours.3
These insulins can be used in insulin infusion pumps by
some patients with DM. These devices release a continu-
al basal amount of insulin and can also be programmed
to release bolus insulin doses just prior to eating to cover
glucose consumed with the meal.3,4 Currently, rapid-act-
ing insulin preparations are available in vials, prefilled
insulin pens, and prefilled cartridges for use in durable
insulin pens. All of these products should be clear in so-
lution, free of particulates, and stored appropriately giv-
en the manufacturer’s recommendation (see Table 3).9
L
Rapid-acting insulin can be
administered subcutaneously
immediately prior to a meal.
M
Regular insulin (Humulin R, Novolin R) is the short-
acting commercially available preparation. Regular in-
sulin is best administered 30–45 minutes prior to eating.3
The blood concentrations of regular insulin reach a peak
within 2–3 hours after injection, with a duration of action
of 3–6 hours.3 Many products are available as 100
units/mL solutions, but a more concentrated Humulin R
product is also available (500 units/mL solution).9 Ex-
treme caution should be used in patients using U-500 in-
sulin, as its use can lead to overdose when used with tra-
ditional insulin syringes.
The intermediate-acting insulin, NPH (Humulin N,
Novolin N), is formulated such that it is slowly absorbed,
compared to rapid- and fast-acting insulins.3 As a result,
NPH insulin is usually administered 2–3 times daily,
with an onset of action of 2–4 hours and a duration of ac-
tion of 8–12 hours.3 NPH is available as a suspension and
should remain visually cloudy with gentle rolling (in
contrast to some other insulin products that are clear).
While most insulin preparations cannot be mixed in the
same syringe, NPH is unique in that it can be mixed with
rapid- or short-acting insulins just prior to administra-
tion.3,4 Pre-mixed preparations of NPH and regular in-
sulin are stable and available commercially.
Two long-acting insulin products are available: insulin
glargine (Lantus) and insulin detemir (Levemir). Insulin
glargine is formulated in an acidic solution.3,36 Upon in-
jection into the body, which has a neutral pH, insulin
glargine precipitates out of solution to form a depot in
the subcutaneous tissue.3,4 As the depot begins to dis-
solve, a continuous level of insulin is absorbed into the
bloodstream.36 This mechanism lends to insulin glargine
JPHARMTECHNOL.COM

being an effective product for patients needing basal in-
sulin coverage. Insulin glargine maintains constant levels
within the circulation for approximately 24 hours36 and is
administered once- or twice-daily. Because insulin
glargine is acidic in solution, it should not be mixed with
other insulins in the same syringe. Insulin detemir is syn-
thesized to bind to albumin in both the subcutaneous tis-
sue and within the bloodstream. By binding to albumin, in-
sulin detemir is slowly absorbed, allowing for a prolonged
duration of action.36 Like insulin glargine, insulin detemir
should never be mixed with other insulin products in the
same syringe. Insulin detemir is administered once- or
twice-daily to provide a basal level of circulating insulin
lasting up to 24 hours; however, its duration of action is
dose dependent, which is why some patients require twice-
daily dosing.4,36 The long-acting insulin preparations do not
provide mealtime insulin coverage, but rather maintain a
constant level of circulating insulin to mimic the basal in-
sulin release of the pancreas in nondiabetic individuals.
In order to facilitate easier administration in some pa-
tients with DM, mixtures of rapid- or short-acting insulin
with intermediate-acting insulin are available. Regular
and NPH insulins are stable as a mixture and are avail-
able in varying concentrations to minimize the number
of daily injections some patients must take. NPH and
rapid-acting insulins are not stable for long periods of
time. While they can be mixed in a single syringe and ad-
ministered together, they cannot be prepared commer-
cially as a single mixed product due to this long-term
lack of stability. To overcome this instability, both lispro
and aspart have been modified to structurally mimic
NPH insulin to increase their duration of action.36 Mix-
tures of the intermediate-acting lispro or aspart with its
rapid-acting lispro or aspart counterpart are commercial-
ly available. These premixed products provide 2 phases
of insulin release to provide both mealtime and basal in-
sulin coverage.
Some patients with DM may be maintained on oral
antidiabetic medications as well as insulin. As the disease
progresses, loss of β-cell function can be overcome by
supplementing with insulin. Oral medications that im-
prove insulin resistance and thus assist cells in respond-
ing to insulin may continue to be utilized by patients re-
ceiving insulin injections.
Appendix I. Key Terms for Pharmacy Technicians to Recognize
β-cells: insulin-producing cells in the pancreas
Glucose: simple carbohydrate, or sugar, that is utilized by cells for energy
Glycogen: storage form of glucose produced in the liver and muscle
Hemoglobin A1C: blood glucose test that provides a value of average glucose level over the previous 3-4 months
Hyperglycemia: blood glucose levels that are above “normal”
Hypoglycemia: blood glucose levels that are less than “normal”
Insulin: hormone produced by β-cells of the pancreas that stimulates cellular uptake of glucose from the blood
Insulin resistance: condition where normal amounts of insulin are unable to produce a normal insulin response from fat, muscle, and liver cells
Pancreas: organ that synthesizes and releases insulin into the bloodstream in response to increased blood glucose levels
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MEDICATIONS FOR THE TREATMENT OF DIABETES MELLITUS
Given the multitude of medications available for the
treatment of both T1DM and T2DM, it is important that
pharmacy technicians and pharmacists be aware of the
various agents currently on the market. It is imperative
that pharmacy technicians be sensitive to the needs of
their customers to appropriately convey issues or con-
cerns to the pharmacist. The pharmacy is often the first
place to which patients will turn for advice, and pharma-
cy technicians and pharmacists who have a solid founda-
tion of knowledge regarding diabetes medications can
make a huge impact on the quality of care of customers
they serve on a daily basis.
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