Test Your Knowledge:

Diabetes
Continuing Pharmacy Education November 2010 Supplement to Pharmacy Today

Are you on the right path?

Before participating in the activity, test your knowledge by
answering the following questions. These questions will also
be a part of the CPE exam.
1. In the American Association of Clinical
Endocrinologists/American College of
Endocrinology algorithm for glycemic control
in type 2 diabetes, which of the following
regimens would be preferred for initial therapy
in a patient with an A1C level of 8.9%?
a. Metformin monotherapy.
b. Metformin + a sulfonylurea.
c. Metformin + a glucagon-like peptide-1 agonist.
d. Insulin alone or with other agents.
2. Tom Rogers has a current total daily insulin
dose of 250 units. His most recent A1C level
was 7.8%. Toms primary care provider wants
to switch him to U-500 insulin and calculates
an initial total dose of 200 units. If twice daily
dosing is desired, which U-100 syringe marking
should Tom use to measure each dose?
a. 20.
b. 25.
c. 40.
d. 50.
3. A patient with type 2 diabetes has a blood
pressure reading of 137/85 mm Hg. Which
of the following options represents a
recommended course of action?
a. Do nothingthis reading is below the goal of
140/90 mm Hg.
b. Initiate antihypertensive therapy with a thiazide
diuretic.
c. Initiate antihypertensive therapy with an
angiotensin-converting enzyme inhibitor.
d. Initiate antihypertensive therapy with a calciumchannel blocker.

Introduction

early 24 million adults in the United States have diabetes.1 Of

those, mostapproximately 90% to 95%have type 2 diabetes.2
Both environmental and genetic factors are believed to contribute
to the pathogenesis of type 2 diabetes.3
Type 2 diabetes is associated with substantial morbidity and mortality.
Poorly controlled diabetes often leads to serious long-term complications
that include both microvascular disease (e.g., retinopathy, neuropathy,
nephropathy) and macrovascular disease (e.g., coronary artery disease,
cerebrovascular disease, and peripheral arterial disease).3,4 In the United
States, diabetes is the most frequent cause of new cases of blindness
among adults 20 to 74 years of age, as well as the leading cause of endstage renal disease.1,4 More than 60% of nontraumatic lower-limb amputations are performed in people with diabetes.1 Atherosclerosis occurs at
an earlier age and with greater frequency among people with diabetes,
such that diabetes is counted as a coronary heart disease risk equivalent.3-5 Two out of three patients with diabetes die from some form of
cardiovascular disease (CVD).6,7 Overall, the risk for death among people
with diabetes is approximately twice that of people without diabetes of
similar age.1
The long-term complications of type 2 diabetes contribute to exceptionally high disease-related costs. In 2007 (the latest year for which data
are available), the direct medical costs and indirect costs (e.g., disability,
work loss, premature mortality) associated with diagnosed diabetes in
the United States totaled $174 billion.8 Nearly one in five hospitalizations in 2008 was related to diabetes, representing more than 7.7 million
stays and $83 billion in hospital costs23% of the total hospital costs
in the United States.9 Average medical expenditures among people with
diagnosed diabetes are estimated to be 2.3 times higher than what expenditures would be in the absence of diabetes.8
Because pharmacists have frequent contact with patients with type
2 diabetes, they are ideally positioned to make substantial contributions to diabetes care. This monograph employs case vignettes to explore common clinical scenarios and emerging problems encountered
by pharmacists. As is true in practice, the vignettes may not have a clear
resolution. When firm recommendations cannot be made, summaries
of the latest thinking about each situation are provided.

2010 by the American Pharmacists Association.

All rights reserved. Printed in U.S.A.

Provider: American Pharmacists Association

Target Audience: Pharmacists
Release Date: November 1, 2010
Expiration Date: November 1, 2013
Learning Level: 2

ACPE Number: 202-000-10-260-H01-P

CPE Credit: 2 hours (0.2 CEUs))
ACPE Activity Type: Application-based
Fee: There is no fee associated with this activity.

Learning Objectives

This publication was prepared by Cynthia Knapp Dlugosz,

BSPharm, of CKD Associates, LLC, on behalf of the American
Pharmacists Association.

At the completion of this activity, the pharmacist will be able to:

1. State key statistics regarding the impact of type 2 diabetes in the
United States.
2. Summarize the latest thinking about the pathogenesis of type
2 diabetes.
3. Recall treatment goals and options for patients with type
2 diabetes.
4. Compare and contrast current treatment recommendations for
glycemic control in type 2 diabetes.
5. Identify effective strategies for addressing patient concerns
about initiating insulin therapy.
6. Explain the appropriate use of U-500 insulin.
7. Discuss nonglycemic goals in comprehensive type 2 diabetes
management.

Advisory Board

Accreditation Information
The American Pharmacists Association is accredited by
the Accreditation Council for Pharmacy Education as a
provider of continuing pharmacy education (CPE). The
ACPE Universal Activity Number assigned to this activity
by the accredited provider is 202-000-10-260-H01-P.
To obtain 2 hours of CPE credit (0.2 CEUs) for this activity, complete the CPE exam and submit it online at www.pharmacist.com/
education. A Statement of Credit will be awarded for a passing
grade of 70% or better. You will have two opportunities to successfully complete the CPE exam. Pharmacists who successfully complete this activity before November 1, 2013, can receive credit.

Tommy Johnson, PharmD, BC-ADM, CDE, FAADE

Chair and Professor of Pharmacy Practice
Presbyterian College School of Pharmacy
Clinton, South Carolina

Your Statement of Credit will be available online immediately upon

successful completion of the CPE exam.

Karen Reed, RPh, FAPhA

Staff Pharmacist
Kmart Pharmacy
Beckley, West Virginia

This home-study CPE activity was developed by the American

Pharmacists Association.

Development

Disclosures
Tommy Johnson, PharmD, BC-ADM, CDE, FAADE, has served as
an advisory board member for Can-Am Care. He declares no other
conflicts of interest or financial interests in any product or service
mentioned in this activity, including grants, employment, gifts,
stock holdings, and honoraria.

Support
This activity is supported by an independent educational grant from
Merck.

Karen Reed, RPh, FAPhA, declares she has served on an advisory

board and received honoraria from GlaxoSmithKline and Eli Lilly
and Company. She declares that her spouse is a former employee
of GlaxoSmithKline. She declares no other conflicts of interest
or financial interests in any product or service mentioned in this
activity, including grants, employment, gifts, stock holdings, and
honoraria.
APhAs editorial staff declare no conflicts of interest or financial
interests in any product or service mentioned in this activity,
including grants, employment, gifts, stock holdings, and
honoraria.

American Pharmacists Association 2215 Constitution Avenue, NW Washington, DC 20037 800-237-APhA www.pharmacist.com

Mini-Review: Pathogenesis of Type 2

Diabetes
Type 2 diabetes is characterized by the dual defects of insulin
resistance (i.e., diminished liver, muscle, and adipose sensitivity
to insulin) and impaired pancreatic -cell secretory function (i.e.,
impaired insulin secretion).3 Insulin resistance is associated with a
decrease in the uptake and utilization of glucose by insulin-sensitive
tissues (primarily muscle and adipose tissue) as well as ineffective
suppression of hepatic glucose production.3,10 -Cells are able to
compensate for the decrease in insulin action (and resulting hyperglycemia) by increasing their production of insulin.3,11,12 However,
as the fasting plasma glucose concentration continues to rise, the
-cells become less and less able to sustain the necessary levels of insulin secretion. A cycle of diminished insulin secretion and worsening insulin resistance ensues; the -cells eventually fail altogether.
Because not everyone with insulin resistance goes on to develop
type 2 diabetes, there is growing speculation that -cell deteriorationreflecting both intrinsic secretion failure and reductions in
-cell massmay actually precede insulin resistance and even
contribute to its development.3,10,11 -Cell dysfunction is now known
to occur much earlier in the natural history of type 2 diabetes than
originally thought; the landmark United Kingdom Prospective
Diabetes Study (UKPDS) demonstrated that approximately 50% of
-cell function already has been lost by the time type 2 diabetes is
diagnosed, and some experts posit that as much as 80% of function
may be lost.12-14 Data from the Belfast Diet Study show that -cell
deterioration proceeds relatively slowly at firstat a rate of 1.7% per
year for as long as 15 to 17 yearsthen accelerates abruptly to more
than 18% per year between 3 and 5 years after diagnosis.11,15 -Cell
failure currently is considered to be more important than insulin
resistance in the natural history of type 2 diabetes.11,12,16
There also is growing appreciation of the role of etiologic mechanisms beyond -cell dysfunction and insulin resistance. Diabetes
expert Ralph DeFronzo, MD, refers to the multiple pathogenic mechanisms of type 2 diabetes as the ominous octet (Figure 1).12,13 In
addition to decreased insulin secretion and decreased uptake of glucose, these mechanisms include increased hepatic glucose produc-

Figure 1. Multiple Defects That Contribute

to the Progression of Type 2 Diabetes

HGP = hepatic glucose production.

Source: Reference 13. Reprinted with permission from the American Diabetes
Association.

tion, accelerated lipolysis in adipocytes (elevated plasma free fatty

acid levels), diminished incretin effect, hypersecretion of glucagon
by pancreatic -cells, enhanced renal glucose reabsorption, and
central nervous system insulin resistance resulting from neurotransmitter dysfunction.12,17

Mini-Review: Approach to Treatment

Abundant conclusive evidence from long-term, randomized clinical trials shows that maintaining hemoglobin A1C levels close to the
normal range reduces the incidence and progression of microvascular complications of type 2 diabetes.4,18-21 In general, every percentage
point drop in A1C (e.g., from 8.0% to 7.0%) decreases the risk of
microvascular complications by 40%.1 Early intervention to reduce
A1C levels also appears to contribute to a long-term reduction in the
risk of macrovascular disease.18
Accordingly, A1C has become the primary target for glycemic control. The American Diabetes Association (ADA) Standards of Medical
Care in Diabetes recommend an A1C goal of <7%.4 The American
College of Endocrinology (ACE) and the American Association of
Clinical Endocrinologists (AACE) recommend a more stringent A1C
goal of 6.5%.22,23 All of these organizations recognize that more or
less stringent A1C goals may be appropriate for certain patients, depending on the risk for hypoglycemia, comorbid conditions that limit life expectancy, and factors that may limit the safety of attempting
aggressive glucose control.4,18,22-24
A range of noninsulin oral and injectable antihyperglycemic
agents (Table 1) and insulins are used in the treatment of type 2
diabetes.3,17,25 All agents (other than insulin) are limited in their ability to lower A1C.26 In one recent systematic review and meta-analysis
of 61 double-blind, randomized controlled trials that met predefined
methodologic criteria, most oral antihyperglycemic agents were
found to decrease A1C levels by 0.5% to 1.25% (thiazolidinediones
and sulfonylureas lowered A1C levels by approximately 1.0% to
1.25%).27 An increase in dose yielded a further decrease in A1C initially, with most of the treatment effect evident by 3 to 6 months.
Higher baseline A1C levels were associated with greater declines in
A1C; every 1% higher pretreatment A1C level predicted a 0.5% greater
fall of A1C levels after 6 months of therapy. Disease duration had no
clear effect on treatment response.
Because of the progressive loss of -cell function in patients with
type 2 diabetes, most available antihyperglycemic therapies are unable to maintain glycemic control over time, and the majority of
patients eventually require combination therapy.3,24,28-31 The response
to antihyperglycemic agents (other than insulin) usually is more
pronounced in patients who are treatment nave than in those who
already are receiving therapy.28 This was demonstrated in a recent
mixed-treatment comparison meta-analysis by Phung and colleagues.32 The analysis evaluated the efficacy of antihyperglycemic
agents used as second-line therapy in patients experiencing an inadequate response to maximized and stable metformin therapy (4
weeks at 1,500 mg daily, or the maximally tolerated dose); it included 27 randomized clinical trials that enrolled more than 11,000
participants. The additional reductions in A1C provided by the different classes of drugs ranged from 0.64% to 0.97%.
Eventually, -cell function deteriorates to such a degree that
the secretory capacity of the cells is exceeded and exogenous insu-

Test Your
Your Knowledge:
Knowledge: Diabetes
Diabetes 33
Test

Table 1. Antihyperglycemic Agents

(Other Than Insulin) Available in the
United States
Drug Class

Available Agents
(Brand Name)

Route of
Administration

Agents That Augment the Supply of Insulin

Meglitinides
(glinides)

Nateglinide (Starlix)
Repaglinide (Prandin)

Oral

Sulfonylureas
(secretagogues)

First generation:
Acetohexamide (Dymelor)
Chlorpropamide
(Diabinese)
Tolazamide (Tolinase)
Tolbutamide (Orinase)

Oral

Second generation:
Glimepiride (Amaryl)
Glipizide (Glucotrol)
Glyburide (DiaBeta,
Micronase)

Case 1: Initiating Therapy in a Newly

Diagnosed Patient

Agents That Enhance the Effects of Insulin

-Glucosidase
inhibitors

Acarbose (Precose)
Miglitol (Glyset)

Oral

Biguanide

Metformin (Glucophage)

Oral

Thiazolidinediones
(glitazones)

Pioglitazone (Actos)
a
Rosiglitazone (Avandia)

Oral

Agents That Modify Noninsulin Hormonal Systems

Amylin analogs

Pramlintide (Symlin)

Injectable

Dipeptidyl
peptidase-4
(DPP-4)
inhibitors

Saxagliptin (Onglyza)
Sitagliptin (Januvia)

Oral

Glucagon-like
peptide-1 (GLP1) agonists
(incretin
mimetics)

Exenatide (Byetta)
Liraglutide (Victoza)

Injectable

Bile acid
sequestrant

Colesevelam (Welchol)

Oral

Dopamine
agonist

Bromocriptine mesylate
(Cycloset)

Oral

In response to data suggesting an elevated risk of cardiovascular events in patients treated with rosiglitazone, the
U.S. Food and Drug Administration has restricted the use of
rosiglitazone to patients who cannot control their diabetes on
other medications.

Source: References 3, 17, and 25.

lin replacement is required.3,23,24,29 Insulin remains the most potent

glucose-lowering agent available; when used in adequate doses, insulin is able to decrease any level of elevated A1C to, or close to, the
therapeutic goal.33 Most patients experience a 1% to 2% decrease in
A1C after insulin therapy is initiated.24,34
The surprising results of several recent large, long-term clinical
American Pharmacists Association

Dawn Jones is a 53-year-old white woman who

stopped by your diabetes screening station at a recent
health fair. She had eaten lunch 1 hour previously; her
blood glucose reading was 275 mg/dL. You encouraged Dawn to visit
her primary care provider for follow-up. The primary care provider
diagnosed type 2 diabetes.
Dawn is 5 5 tall and weighs 202 lb (body mass index [BMI]
~34). Her A1C level at diagnosis was 8.7%.
Dawn visits the pharmacy today with prescriptions for metformin
500 mg once daily (to be titrated to 500 mg twice daily) and a glucose monitor. She explains with some pride that she wont be needing the medication. I finally joined Weight Watchers yesterday,
she tells you. I just need to lose some of this weight. Then everything should be just fine.

Other Agents

trialswhich showed no significant reduction in cardiovascular

events with intensive glycemic control in patients with type 2 diabetesreinforced the importance of also controlling nonglycemic
risk factors, especially hypertension and dyslipidemias.4,16,18,35-37 According to estimates based on data from the Household Component
of the Medical Expenditure Panel Survey, approximately two thirds
(64.8%) of patients with diabetes have coexisting hypertension, and
more than half (52.8%) have coexisting hyperlipidemia.38 Aggressive
control of blood pressure and lipid levels in addition to glycemic
control yields multiple benefits1,4:
Treating blood pressure to specified targets reduces the risk of
CVD among patients with diabetes by 33% to 50% and the risk of
microvascular complications by approximately 33%.
In general, for every 10 mm Hg reduction in systolic blood
pressure, the risk for any diabetes-related complication
decreases by 12%.
Improved control of low-density lipoprotein (LDL) cholesterol
can reduce cardiovascular complications by 20% to 50%.

Test Your Knowledge: What constitutes

appropriate initial treatment for Dawn
Jones?

Lifestyle interventions that include medical nutrition therapy and

regular exercise (at least 150 minutes/week of moderate-intensity
aerobic physical activity) are considered to be the cornerstone of
management for type 2 diabetes.4,24 Given that approximately two
thirds of patients with type 2 diabetes are obese (BMI 30), with a
mean BMI of 34.2and one out of five patients is morbidly obese
(BMI 40)weight loss is a principal focus of lifestyle interventions.4,33,39 Weight loss has a beneficial effect on glycemic control:
in the ongoing Look AHEAD (Action for Health in Diabetes) study,
overweight and obese patients with type 2 diabetes randomized to an
intensive lifestyle intervention lost an average of 8.6% of their initial
weight during the first 12 months, with an associated increase from
46% to 73% in the percentage of participants who achieved an A1C
<7%.40 Weight loss also helps to reduce blood pressure and improve
the lipid profile in patients with type 2 diabetes.4,40,41
Although there is widespread agreement that lifestyle interventions should be included as part of a comprehensive diabetes man-

agement strategy, implementing and maintaining these changes

poses an exceedingly high hurdle for many patients.3,25,33 It is now
generally accepted that most patients with type 2 diabetes require
pharmacologic therapy superimposed on lifestyle interventions to
achieve desired glycemic targets.24,31,33
A consensus algorithm (Figure 2) developed jointly by the ADA
and the European Association for the Study of Diabetes (EASD) calls
for metformin to be initiated concurrently with lifestyle interventions at the time of diagnosis and titrated to its maximally effective
dose over a period of 1 to 2 months, as tolerated.4,33 Factors supporting this recommendation include the following33:
Metformin usually does not cause either hypoglycemia or
weight gain.
Metformin is associated with a generally low level of adverse
effects (primarily gastrointestinal).
The availability of generic versions of metformin contributes to
a generally low cost of therapy.
Metformin therapy is recommended for all newly diagnosed patients
unless specific contraindications (e.g., renal impairment, hepatic
dysfunction, heart failure) are present.26,33
A growing number of primary care providers are aware of the
ADA/EASD algorithm, so it is becoming increasingly common to see
newly diagnosed patients present with a prescription for metformin.
Clinicians may not be aware that the algorithm has been the subject
of much controversy; they also may not know that the algorithm
reflects the expert opinion of the authors rather than official ADA
position.13,17,42 Thus, it is not considered a universal guideline for

diabetes management.17
Other algorithms based on expert opinion are available. Notably, the AACE and ACE collaborated on Diabetes Road Maps and
a glycemic control algorithm that incorporate all major classes of
currently available antihyperglycemic therapies.22,23 The treatment
pathways in these documents are stratified by A1C level as well as
whether the patient is drug nave or already receiving treatment.23
The stated concerns in prioritizing choices of medications include23:
Minimizing the risk and severity of hypoglycemia.
Minimizing the risk and magnitude of weight gain.
Consideration of both fasting and postprandial glucose levels
as end points.
Anticipated degree of patient adherence.
The algorithm (Figure 3) emphasizes the appropriate use of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1
(GLP-1) agonists because of their effectiveness in reducing A1C
levels, lower risk of hypoglycemia, and beneficial effects on weight
(weight neutrality with DPP-4 inhibitors, weight loss with GLP-1 agonists). Sulfonylureas and meglitinides are assigned a lower priority
in the algorithm because they cause hypoglycemia and weight gain
and provide only short-term beneficial effects on glycemic control.
Although medication costs also were considered when prioritizing choices of medications in the AACE/ACE algorithm, safety and
efficacy were viewed as higher priorities than cost.23 The authors
reasoned that the cost of medications represents only a very small
portion (approximately 10%) of the total cost of care for patients
with diabetes; the majority of total cost is related to the treatment of

Figure 2. American Diabetes Association/European Association for the Study of Diabetes

Algorithm for the Treatment of Type 2 Diabetes

CHF = congestive heart failure; GLP-1 = glucagon-like peptide-1.

Source: Reference 33. Copyright 2009 American Diabetes Association from Diabetes Care, Vol. 32, 2009; 193-203. Reprinted with permission from the American Diabetes Association.

Test Your Knowledge: Diabetes 5

Figure 3. American Association of Clinical Endocrinologists/American College of

Endocrinology Algorithm for Glycemic Control

AGI = -glucosidase inhibitor; DPP4 = dipeptidyl peptidase-4 (DPP-4) inhibitor; FPG = fasting plasma glucose; GLP-1 = glucagon-like peptide-1
agonist; MET = metformin; PPG = postprandial glucose; SU = sulfonylurea; TZD = thiazolidinedione.
Source: Reference 23. Reprinted with permission from the American Association of Clinical Endocrinologists.

diabetes-associated complications and hospitalizations.23,43,44 Accordingly, it would be counterproductive to base treatment decisions
primarily on cost if those therapies might result in increased (and
more costly) complications, emergency department visits, and hospitalizations.43,44
As shown in Figure 3, monotherapy is recommended only for
patients with an A1C level of 6.5% to 7.5%.23 Metformin is recognized as the most appropriate initial choice for many patients in
this range, but DPP-4 inhibitors, GLP-1 agonists, thiazolidinediones,
and -glucosidase inhibitors also are possibilities, especially in
the specific situations described in the footnotes to the algorithm.
For example, DPP-4 inhibitors are suggested for patients who have
elevations in both fasting and postprandial glucose levels; GLP-1
inhibitors are suggested for patients who have greatly elevated postprandial glucose levels.
Combination therapy is recommended for all patients with an A1C
level 7.6% because no single agent is likely to produce the degree
of A1C lowering needed to achieve the target goal.23 Dual therapy is
recommended for patients with an A1C of 7.6% to 9.0%; the preferred
combination is metformin with either a GLP-1 agonist, a DPP-4 inhibitor, or a thiazolidinedione, in that order of preference. GLP-1
6

American Pharmacists Association

agonists are given the highest priority because of their somewhat

greater effect on reducing postprandial glucose excursions and their
potential for inducing weight loss.
Dual or triple drug therapy is recommended for asymptomatic,
drug-nave patients with an A1C level >9.0%.23 Symptomatic patients
and patients already receiving treatment are candidates for insulin
therapy, because even triple therapy is unlikely to achieve the target
A1C goal.
Although the ADA/EASD algorithm and the AACE/ACE algorithm
take different approaches, both focus on lowering the A1C level.
Some diabetes experts have called for a radical rethinking of this
focus, arguing that therapy for type 2 diabetes should be designed
to target the multiple pathogenic abnormalities known to promote
-cell failure.10-12,17 Both DeFronzo12,13 and Unger and Parkin17 have
advocated triple pharmacologic therapy consisting of metformin, a
thiazolidinedione, and a GLP-1 agonist (in addition to lifestyle interventions), initiated as early as possible during the course of type
2 diabetes. The complementary mechanisms of action of these drugs
would preserve -cell function (and may maintain -cell mass), increase insulin sensitivity in muscle and hepatic tissue, reduce hepatic gluconeogenesis, inhibit lipolysis, and decrease plasma free fatty

acid levels, as well as provide antiatherogenic effects and support

weight loss.10,12,13,17,31 Importantly, this combination would not cause
hypoglycemia.12,17 According to DeFronzo, this triple combination
approach offers the greatest likelihood of providing durable glucose
control through a blunting of disease progression.12 DPP-4 inhibitors could be an alternative to GLP-1 agonists in the combination
if they are shown to preserve -cell function on a long-term basis.12
(Pharmacists should note that the efficacy and safety of this strategy
have not been confirmed; a randomized clinical trial is planned.10)
As the treatment options for type 2 diabetes expand, the question of which medication or medications represents the best option
for initial therapy in a given patient increasingly will lack a clear,
evidence-based solution. The approach recommended to prescribers in the absence of evidence is to inform patients of all treatment
options, explain the benefits and risks of each, and engage patients
in the decision-making process.45 Initiating aggressive combination
therapy would be of little benefit if, for example, a patient chose to
fill only the least expensive prescription, thereby defaulting to an
approach that would fail to fulfill the treatment plan.25

Case 2: When to Adjust Therapy

Leroy Thomas is a 58-year-old African American man
who was diagnosed with type 2 diabetes approximately 3
years ago. He visits the pharmacy today with a prescription for metformin extended-release 2,000 mg daily. Leroy
is not new to your practice; dispensing records for the past 2 years
show periodic prescriptions for the same dosage of metformin. Based
on transfer notations and a brief discussion with Leroy about adherence, you suspect that he has been coupon chasingvisiting
other pharmacies to take advantage of the latest promotion. You also
are aware that Leroy receives most of his care from a busy group
practice and rarely sees the same provider twice in a row.
Leroy is 5 10 tall and weighs 218 lb (BMI ~31). You collect the
following additional information during todays visit:
A1C: 8.9%.
Blood pressure: 128/78 mm Hg.
In addition to metformin, Leroy Thomass other current medications include:
Hydrochlorothiazide 25 mg daily.
Lisinopril 20 mg daily.
Simvastatin 20 mg daily.
Aspirin 81 mg daily.

Test Your Knowledge: At what point should

Leroy Thomass antihyperglycemic regimen
ideally have been adjusted?

For decades, the paradigm for long-term management of type 2 diabetes involved a stepwise treat to failure approach.10,34,46 Therapy
was initiated with lifestyle modifications alone; medications were
added slowly and sequentially only when a trial of diet and exercise
proved to be inadequate for achieving glycemic control.28,34 A single
oral agent was titrated to its maximal recommended dose, followed
by a second oral agent added and titrated to its maximal dose, and
so on.10
As a result, prescribers often failed to adjust antihyperglycemic
therapy in a timely mannera problem referred to as clinical iner-

tia.17,23,46,47 Long delays were incurred between treatment steps, leaving

patients with uncontrolled hyperglycemia for extended periods.46,48
For example, in a study published in 2004, Brown and colleagues
found that patients remained on sulfonylurea monotherapy (the
usual initial treatment at the time of the study) for a mean of 35.1
17.8 months before a new or additional treatment was started.48
During that interval, the patients A1C level exceeded 8.0% (the recommended action threshold at the time of the study) for a mean
of 20.5 18.0 months. Patients who followed the usual treatment
progressionlifestyle intervention first, then oral monotherapy,
then oral combination therapy, and finally insulinwould have
spent approximately 10 years with an A1C level >7% and nearly
5 years with an A1C level >8%.
The current treatment paradigm calls for patients to be evaluated
frequently to monitor response to treatment, and for therapy to be
intensified rapidly if glycemic goals are not achieved.16,34,46 Yet clinical inertia persists in todays practice environment.10 This may be
attributed in part to the lack of direct evidence regarding the ideal
frequency of physician visits for patients with type 2 diabetes.24 The
2010 ADA Standards of Medical Care in Diabetes call for routine A1C
testing in all patients with diabetes, at the following recommended
intervals4 :
At least twice yearly in patients who are meeting treatment goals
and have stable glycemic control (A1C <7%).
Quarterly in patients whose therapy has changed or who are not
meeting glycemic goals.
Some clinicians schedule follow-up visits to coincide with these testing intervals (i.e., two to four visits per year). Anecdotal evidence
suggests that many patients are seen far less frequently, and that
A1C testing does not occur as recommended.23 The fault does not
necessarily lie entirely with health care providers; in some cases, patients may receive inadequate follow-up because they fail to return
for routine visits.25
Both the ADA/EASD and AACE/ACE algorithms challenge clinicians to monitor therapy closely and adjust the treatment plan every
2 to 3 months as needed until the goal for A1C has been achieved.23,33
Because the response from dose escalation usually is limited, adjusting the treatment plan generally means adding another agent.24
Pharmacists can help to combat clinical inertia by offering pointof-care A1C testing and intervening with prescribers as appropriate.
Several devices appropriate for use in pharmacies (e.g., Bayer A1C
Now+) have been granted waived status under the Clinical Laboratory Improvement Amendments. However, pharmacists should be
aware that the results obtained with these devices may be less sensitive and specific than laboratory testing.49

Case 3: How to Adjust Therapy

Martina Hernandez is a 48-year-old Hispanic woman
of Mexican descent who was diagnosed with type 2 diabetes approximately 2 years ago. Therapy was initiated
with metformin 500 mg twice daily and titrated to the current dose
of metformin 1,000 mg twice daily.
Martina is 5 1 tall and weighs 180 lb (BMI 34). Although she
has successfully lost weight (as much as 25 lb) on various diets in
the past, she regained all of the lost weight each time. She is better
able to adhere to her goal of taking a 30-minute walk on at least
5 days each week.
Test Your Knowledge: Diabetes 7

When Martina visited her primary care provider earlier this week,
her measured A1C level was 8.1%. She comes to the pharmacy today
with a prescription for glipizide 10 mg once daily in addition to a
metformin refill. She asks the pharmacy technician to make sure
that glipizide is on the list of medications that cost $4.

Test Your Knowledge: What constitutes

appropriate intensification of
antihyperglycemic therapy for Martina
Hernandez?

The care of patients with type 2 diabetes whose A1C level remains
above target despite metformin therapy and lifestyle modifications
is another area of clinical controversy. The ADA/EASD and AACE/
ACE algorithms provide strikingly different advice about escalating
antihyperglycemic therapy.
The ADA/EASD algorithm calls for a second agent to be added
to metformin monotherapy within 2 to 3 months if the maximum
tolerated dose of metformin fails to achieve or sustain the glycemic
goals (Figure 2).33 The preferred options for the second agent are
a sulfonylurea or insulin, with insulin therapy (basal therapy with
an intermediate- or long-acting formulation) recommended for
patients with an A1C level >8.5% or symptoms secondary to hyperglycemia.
The ADA/EASD algorithm also offers two tier 2 options for the
second agent: pioglitazone and a GLP-1 agonist.33 (Tier 2 represents less well-validated therapies.) Either agent may be considered
when the risk of hypoglycemia is especially undesirable (e.g., in patients who have hazardous jobs); a GLP-1 agonist may be considered
if weight loss is a major goal of therapy and the patients A1C level
is <8.0%.
As illustrated in Figure 2, the options for further escalation of
therapy depend on which second agent was added.33 Ultimately, a
combination of metformin and intensive insulin therapy (i.e., basal
therapy plus bolus injections of a short- or rapid-acting insulin before selected meals to reduce postprandial glucose excursions) is
recommended for all patients.
It is noteworthy that none of the other available antihyperglycemic agentsamylin agonists, -glucosidase inhibitors, meglitinides, or DPP-4 inhibitorsare included in the algorithm. The
authors state that these agents were omitted for one or more of the
following reasons33:
They have lower or equivalent overall glucose-lowering
effectiveness compared with the recommended agents.
Limited clinical data regarding their use are available.
They are relatively expensive compared with the
recommended agents.
The authors do note that these agents may be appropriate choices in
selected patients.
In clinical practice, the choice of a sulfonylurea for second-line
therapy is reinforced by the pricing policies of a growing number
of pharmacies, which offer select diabetes medicationstypically
generic versions of metformin and sulfonylureasto patients at low
(e.g., $4) or no cost. Combination therapy with metformin and a
sulfonylurea thus becomes the least expensive option by far. A key
criticism of the ADA/EASD algorithm is that neither metformin nor
the sulfonylureas have been shown to preserve -cell function.12,17
8

American Pharmacists Association

Sulfonylureas also are associated with a substantial risk of hypoglycemia and weight gain.17,23
In the AACE/ACE algorithm (Figure 3), metformin remains the
foundation of combination therapy for most patients because of its
safety and mechanism of action as an insulin sensitizer.23 For patients with an A1C level of 6.5% to 7.5%, the recommended second
component of dual therapy is a GLP-1 agonist, a DPP-4 inhibitor,
a thiazolidinedione, or a meglitinide or sulfonylurea, in that order
of preference. Again, GLP-1 agonists are given the highest priority
because of their somewhat greater effectiveness in reducing postprandial glucose excursions relative and their potential for inducing
weight loss. When triple therapy is indicated for patients with an A1C
level of 6.5% to 7.5%, six combinations are possible, based on the addition of a thiazolidinedione, meglitinide, or sulfonylurea:
1. Metformin + GLP-1 agonist + thiazolidinedione.
2. Metformin + GLP-1 agonist + meglitinide.
3. Metformin + GLP-1 agonist + sulfonylurea.
4. Metformin + DPP-4 inhibitor + thiazolidinedione.
5. Metformin + DPP-4 inhibitor + meglitinide.
6. Metformin + DPP-4 inhibitor + sulfonylurea.
A thiazolidinedione is preferred to minimize the risk of hypoglycemia.
Patients with an A1C level of 7.6% to 9.0% would have been started
on dual therapy (Figure 3).23 The preferred strategy for triple therapy
is to add a thiazolidinedione to the combination of either metformin
plus a GLP-1 agonist or metformin plus a DPP-4 inhibitor. The least
preferred combination is metformin, a thiazolidinedione, and a sulfonylurea because of the high risk of weight gain and hypoglycemia.
Meglitinides and -glucosidase inhibitors do not have sufficient
A1C-lowering potential to be considered for triple therapy.
The one place in the AACE/ACE algorithm where sulfonylureas are
preferred is in triple therapy for asymptomatic patients with an A1C
level >9.0% who were started on dual therapy.23 The recommendation is based on the somewhat greater efficacy and more rapid onset
of action of the sulfonylurea compared with a thiazolidinedione.
Nauck and colleagues recently speculated on the most likely future roles of the various incretin-based therapies in the treatment of
type 2 diabetes.50 One of the authors suggested that DPP-4 inhibitors
eventually will be ranked before GLP-1 agonists in treatment algorithms because of the greater acceptability of oral administration.
Ultimately, DPP-4 inhibitors may replace existing oral antihyperglycemic agents, while the GLP-1 agonists (which are administered
by subcutaneous injection) may be viewed as competitors for insulin
treatment.
As is the case when therapy for type 2 diabetes is initiated, prescribers seeking to intensify a patients treatment regimen are advised to inform the patients of all options available, explain the
benefits and risks of each, and include the patient in the decisionmaking process.45

Initiating Insulin Therapy

It is 4 years later. Martina Hernandez is now 52 years old. Her
current medication regimen includes:
Metformin 1,000 mg/sitagliptin 50 mg (administered as a
combination product).
Glipizide 10 mg once daily.
Martina visited her primary care provider earlier this week to assess
the current level of glycemic control after 11 months on this regi-

men. Her measured A1C was 9.2%.

Martina comes to the pharmacy today with a prescription for insulin glargine. As the pharmacy technician readies the product and
associated supplies for dispensing, you sit down with Martina to teach
her how to use and inject insulin. She begins to cry. I knew this
would happen, Martina says. Its all my fault because I couldnt lose
weight. My mother had to use insulin when I was a little girlIll
never forget what she went through, how painful it was.

Table 2. Pharmacist Responses to

Patient Concerns About Initiating
Insulin Therapy
Patient Belief

Pharmacist Response

Insulins are not

effective

Insulin analogs closely mimic

endogenous insulin secretion
Insulin reduces extremely high glucose
levels more effectively than any other
agent
Landmark trials and recent outcome
studies have proven that tight glycemic
control reduces microvascular and
potentially macrovascular complications

Insulin causes
hypoglycemia

Insulin analogs have a more predictable

timeaction profile than human insulins
and are associated with lower levels of
hypoglycemia
Rapid-acting analogs can be given just
before meals and so the patient can feel
more in control of his/her glucose levels

Insulin causes
weight gain

The basal insulin analogs, and insulin

detemir in particular, are associated with
considerably less weight gain than human
insulin
Because insulin analogs are less likely
to cause hypoglycemia than earlier
formulations, patients are less likely to
engage in defensive snacking
Diet and exercise can help improve
glycemic control and reduce weight

Insulin regimens
are complex

Basal insulin analogs usually need to be

given only once daily
Rapid-acting analogs can be given within
15 minutes of eating
Premixed insulin analogs combine two
types of insulin in one formulation and are
suitable for patients with regular eating
patterns
Self-adjusted insulin dose titration
algorithms provide a simple tool for
insulin titration
Pen delivery devices are discreet, easy to
use, and accurate
Modern needles are fine and typically
associated with less pain

Test Your Knowledge: What interventions

might help to overcome Martina
Hernandezs concerns about using insulin?

All current treatment algorithms for type 2 diabetes culminate

in the initiation of insulin therapy.23,33 Because most patients will
require insulin therapy at some point during the course of treatmentand because insulin is considered to have a greater potential
than other agents for preserving -cell functionearly initiation
of insulin is becoming more widely accepted.23,26,33 There is growing
consensus that insulin no longer should be considered a treatment
of last resort after other therapies have failed.51
Unfortunately, many patients who could benefit from insulin
therapy do not receive it in a timely manner, or may not receive it
at all.51 A retrospective cohort analysis by Rubino and colleagues involving more than 2,500 patients with type 2 diabetes illustrates this
point.52 In fully half of the patients, insulin initiation was delayed for
almost 5 years after combination therapy with oral agents failed to
maintain glycemic control, even in the presence of diabetes-related
complications.
Both patients and clinicians may be reluctant to initiate insulin
therapya phenomenon known as psychological insulin resistance.47,53-56 Table 2 provides examples of patient beliefs that may
present barriers to insulin therapy as well as possible pharmacist responses that address those issues.54 Some key concerns are discussed
in greater detail below.
Many patients cite anxiety about needles and the possibility of
pain on injection as the reason for avoiding insulin therapy.54,56,57
This anxiety may be a cover for other concernsfor example, that
insulin therapy will be disruptive and inconvenient, leading to a loss
of personal freedom and control.54,56 The use of insulin pens can help
to allay all of these fears and make patients feel more comfortable
with insulin therapy in general.26,54,56-59 Insulin pens offer many benefits: they do not resemble syringes, the needle is hidden, the injections are relatively painless, and patients usually find the devices to
be discreet and easy to use. Insulin pens also may be associated with
lower rates of hypoglycemia and greater patient adherence.57,59
As part of the cross-national Diabetes Attitudes, Wishes, and Needs
(DAWN) study, Peyrot and colleagues surveyed more than 2,000 patients in 13 countries in Asia, Australia, Europe, and North America
to examine attitudes toward insulin therapy.53 Patients in the United
States reported more self-blame for insulin therapyfor example,
Starting insulin would mean that I have not followed my treatment
recommendations properlythan patients from all other countries. They also were less likely than patients from all other countries
to believe that insulin would help them better manage their diabetes.
The DAWN study findings have the following implications for facilitating the initiation of insulin therapy53,54,56:

Source: Reprinted from reference 51.

Health care providers should never use insulin as a threat or

punishment for not adhering to lifestyle modifications or
medication therapy.
For each patient, health care providers should strive to identify
and address the specific attitudes and beliefs that underlie
reluctance to use insulin therapy.
The importance of the latter point was reinforced in a study by Nakar
and colleagues comparing the attitudes and beliefs of 92 patients
who were hesitant to start insulin therapy with those of 101 patients
who recently had begun insulin treatment.60 Prescribers interviewed
for the study assumed that the hesitant patients were primarily afraid
of the actual injections. In fact, the hesitant patients were far more
likely to perceive their illness as not very serious, have a fear of becoming addicted to insulin, or be worried about weight gain or
hypoglycemia.
Test Your Knowledge: Diabetes 9

Pharmacists can help to overcome psychological insulin resistance by discussing insulin therapy with patients from the time
they are first diagnosed with type 2 diabetes.51,54,56 Patients need to
understand both the progressive nature of their conditionand
the concomitant decrease in insulin productionand the very real
possibility that insulin replacement will be needed at some point,
through no fault of their own.34,57 Pharmacists should explain that
insulin is an effective means of improving glycemic control at any
time during the course of type 2 diabetes; it should not be perceived
as a last resort.47,56 Insulin pens should be considered for all appropriate patients.

Case 4: Insulin Therapy in Severe Insulin

Resistance
James Smith is a 67-year-old white man who was diagnosed with type 2 diabetes 10 years ago. He is 5 8 tall and
weighs 308 lb (BMI ~47). His current daily insulin regimen180 units of NPH insulin in the morning, 120 units of NPH
insulin in the evening, and 25 units of regular insulin before each
meal provides a total of 375 units. Despite this regimen, Jamess
A1C has not dropped below 8.9%. You know that he has struggled to
inject the appropriate volume each day because of the associated discomfort. He assumes that he is likely to die soon because he needs
to use so much insulin.
James visits the pharmacy today with a prescription that reads:
U-500 insulin regular
Inject 30 units SQ bid
James Smiths other current medications include:
Lisinopril 20 mg daily.
Simvastatin 20 mg daily.
Gabapentin 300 mg three times daily.
Omeprazole 20 mg daily.
Paroxetine 20 mg daily.

Test Your Knowledge: Is the prescription

for U-500 insulin a valid and appropriate
intervention for James Smith? What potential
problems (if any) are associated with the use of
U-500 insulin?

The typical patient with type 2 diabetes who uses insulin requires
a total daily dose of approximately 80 units.61 One of the consequences of the high prevalence of obesity among patients with type
2 diabetes is a growing number of patients with severe insulin resistance who require insulin doses in excess of 200 units per day to
achieve glycemic control.61,62
The treatment of patients with such large daily insulin requirements can be problematic.62,63 Injecting large volumes of insulin
(e.g., 2 mL with a dose of 200 units of U-100 insulin) may cause
considerable injection site discomfort.61,62 The volume of U-100 insulin needed often exceeds the capacity of the delivery device (1 mL
maximum for U-100 syringes; 60 to 80 units maximum for insulin
pens), necessitating multiple injections to deliver a single dose.61-63
Adherence inevitably suffers, resulting in poor glycemic control.62-64
U-500 insulina highly concentrated form of human regular
insulin containing 500 units per milliliter (i.e., five times more
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American Pharmacists Association

concentrated than U-100 insulin)represents an attractive alternative for patients with severe insulin resistance.65 It enables large
doses of insulin to be administered in small volumes (e.g., 0.4 mL
for a dose of 200 units).61,63 Although the cost per vial is considerably
higher than the cost for U-100 insulin, the cost per unit ends up
being substantially lower because of the smaller volumes required,
the possibility of fewer injections per day, use of fewer syringes and
supplies, and other savings.63,64,66 Patients who are switched from
standard insulin to U-500 typically experience reductions in A1C
of about 2% without significant hypoglycemia; the improvement in
glycemic control is attributed to increased patient satisfaction and
adherence.62-64,66
Diabetes expert Irl Hirsch, MD, has called U-500 insulin perhaps
the most important underused tool for the type 2 diabetes population.65 The underuse he refers to appears to be changing: use of
U-500 insulin increased by 137% from June 2007 to June 2009.62
Pharmacists who are not already seeing prescriptions for U-500
should anticipate encountering them.63
Although U-500 insulin is nonmodified regular insulin, its onset,
peak, and duration of action are similar to NPH insulin.63,64,66 The
dosing thus is similar to NPH, with up to four injections per day
(including a bedtime dose when needed).61,63,64,66 The actual dose of
U-500 insulin may be determined by adding up the total daily dose of
U-100 insulin and dividing by 5; an initial dose reduction of 10% to
20% has been recommended by some experts, especially for patients
with an A1C level <8%.62,64 The dose usually is titrated over the first
few days and weeks.64
Pharmacists have an important opportunity to help patients and
prescribers avoid errors with U-500 insulin. For example, ambiguity
in the dosage and administration instructions could result in a fivefold overdosage or underdosage.62-64 In the case vignette that introduces this section, does inject 30 units of U-500 insulin mean that
James Smith should draw up 30 actual units of U-500or should
he draw U-500 insulin up to the 30-unit mark on a U-100 syringe,
corresponding to an actual insulin dose of 150 units?62 The dose ideally should be expressed in both volume and total units (e.g., inject
0.3 mL (150 units) SQ twice daily).63 The dosing instructions can
be verified using a dose-equivalence chart such as the one presented
in Table 3.62
As implied in the preceding paragraph, syringes are another possible source of confusion and error. Standard insulin syringes are
marked for U-100 insulin, so the dose of U-500 insulin does not
correspond to the unit markings on the syringe.63,66 (U-500 insulin
is not available in insulin pens.) Most published guidance advises
using 0.3-mL, 0.5-mL, or tuberculin syringes instead of a 1-mL syringe.61,63,64,66 However, tuberculin syringes may not be readily available, and some insurers may not provide reimbursement for them
(tuberculin syringes may not be viewed as diabetes supplies).63,66 If
a U-100 syringe must be used, the pharmacist should take special
care to explain the amount to be taken in both dose and volume
terms, and preferably mark the appropriate level on the syringe.62,63,66
Pharmacists should teach all patients how to draw up the exact dose
required by first demonstrating the amount to be measured and then
having the patient practice drawing up the correct volume.63
The need for caution when using a highly concentrated insulin
product should be apparent to pharmacists, especially if there is

Table 3. Dosing Conversion Table

and Formulas for Dose and Syringe
Markingsa
U-500 Insulin
Dose (Actual
Units)

U-100 Syringe
(Unit Markings)

Volume for
Tuberculin
Syringe (mL)

25

0.05

50

10

0.10

75

15

0.15

100

20

0.20

125

25

0.25

150

30

0.30

175

35

0.35

200

40

0.40

225

45

0.45

250

50

0.50

275

55

0.55

300

60

0.60

325

65

0.65

350

70

0.70

375

75

0.75

400

80

0.80

425

85

0.85

450

90

0.90

475

95

0.95

500

100

1.00

aThe following dosing formulas also may be used: dose (actual

units) x 0.2 = unit markings in a U-100 insulin syringe; dose
(actual units) x 0.002 = volume (mL) in a tuberculin syringe.
Source: Reference 62. Originally published in Use of concentrated insulin human
regular (U-500) for patients with diabetes. Am J Health Syst Pharm. 2010;67:1526-35.
2010, American Society of Health-System Pharmacists, Inc. All rights reserved.
Reprinted with permission. (R1031).

any potential for patients to confuse it with U-100 regular insulin.65

Pharmacists should ensure that the patient, the patients family
members, and any caregivers are aware that U-500 insulin is five
times more concentrated than U-100 insulins.62,63 Patients should
be warned that small changes in a dose of U-500 insulin have the
potential to cause both greater shifts in blood glucose readings and
prolonged, severe hypoglycemia.61,62 Doses of U-500 insulin should be
adjusted only with the approval of the presciber.63
U-500 insulin is provided in 20-mL vials with the word concentrated marked on them.61,63 To avoid the possibility of drug administration errors, U-500 insulin should be stored separately from U-100
insulin.61-64 This is of critical importance if any family members
in the same household use U-100 insulin. Patients also should be
aware of the possibility for mix-ups during transitions between care
settings (e.g., when admitted to a hospital or long-term care facility); adding the use of U-500 insulin to medical alert identification
is one strategy for avoiding errors.62

Case 5: Controlling Nonglycemic Risk Factors

Gail Burton is a 53-year-old African American woman
who was diagnosed with type 2 diabetes 3 years ago. Her A1C
level is controlled to 6.7% on a combination of metformin
1,000 mg twice daily and exenatide 10 g twice daily.
Through dedicated adherence to lifestyle modifications (and
likely with assistance from the GLP-1 agonist), Gail has managed to
reduce her weight from 211 lb to 182 lb and maintain it at that level.
She is 5 7 tall (BMI ~29).
Gail visits the pharmacy to take advantage of a cholesterol and
blood pressure screening event you are offering in conjunction with
National Cholesterol Education Month. Results show her blood pressure to be 172/100 mm Hg and the following lipid levels:
Total cholesterol: 280 mg/dL.
Low-density lipoprotein cholesterol: 200 mg/dL.
High-density lipoprotein cholesterol: 35 mg/dL.
Triglycerides: 225 mg/dL.
Gail is surprised by these results. I feel really good, Ive lost
weight, I dont smoke, and Ive worked hard to get my diabetes under control, she says with frustration. Why am I having these other
problems? As you talk with Gail, you discover that her primary care
provider had prescribed both simvastatin and lisinopril at her last
visit approximately 10 months ago. Gail elected not to fill those prescriptions because, as she explains, Im not a really sick personI
dont need to be taking all these medications. You question Gail
about other aspects of care and find out that she has never been
vaccinated against either influenza or pneumococcal pneumonia.

Test Your Knowledge: What nonglycemic

elements of diabetes care are appropriate
and important for Gail Burton?

Patients such as Gail Burton must appreciate that the management of type 2 diabetes involves much more than controlling
hyperglycemia. Many pharmacists already are familiar with the
ABCs of diabetes, which correspond to goals for A1C, blood pressure (<130/80 mm Hg), and LDL cholesterol (<100 mg/dL).67 An
extended alphabet mnemonic (Table 4) can help pharmacists recall
additional elements of comprehensive diabetes management.67
Attainment of nonglycemic goals for diabetes management remains disappointingly low. Using National Health and Nutrition Examination Survey data from 1999 to 2006, Cheung and colleagues
found that only 57.1% of participants with diagnosed diabetes had
achieved the target A1C level <7%, 45.5% had achieved the target
blood pressure, and 46.5% had achieved the target LDL cholesterol
level.68 Only 12.2% of participantsone in eighthad attained all
three targets. In a recent analysis of Medical Expenditure Panel Survey data from 2005, more than 40% of the study population (2,003
adults with diagnosed diabetes) had not received a flu shot within
the previous year.69
Effective long-term blood pressure control may be the most important intervention for preventing complications in patients with
diabetes.24,70 The ADA Standards of Medical Care in Diabetes call for
blood pressure to be measured at every routine diabetes visit.4 When
hypertension is present, the treatment regimen should include either
an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) in addition to lifestyle modificaTest Your Knowledge: Diabetes 11

Table 4. Elements of Comprehensive

Diabetes Care
Letter

Element of Care

A1C

Blood pressure/microalbumin

Cholesterol/aspirin

Diabetes education

Eye examinations

Foot examinations

Glucose monitoring

Health maintenance (i.e., immunizations)

Indications for specialty care (i.e., referrals)

Source: Reference 67.

tions.4,71 If one class is not tolerated, the other should be substituted.

Combination therapy with at least two and possibly three or more
agents usually is required to achieve the target blood pressure goal;
the ADA standards recommend addition of a thiazide or loop diuretic
(depending on the patients renal status) when a second agent is
needed.4
Treating hypertension in patients with type 2 diabetes also is
important for reducing the risk and slowing the progression of nephropathy, which occurs in 20% to 40% of patients and is the single
leading cause of end-stage renal disease.4 Microalbuminuria is both
a marker for the development of nephropathy in patients with type
2 diabetes and a well-established marker of increased CVD risk. ACE
inhibitors and ARBs are more effective than other antihypertensive
agents in delaying the progression from microalbuminuria to macroalbuminuria and reducing the associated decline in glomerular
filtration rate.4,71 ACE inhibitors and ARBs also independently reduce
the loss of kidney function in patients with nephropathy, above and
beyond the effect attributable to a reduction in systemic blood pressure.4 The ongoing Veterans Affairs Nephropathy in Diabetes Study
(VA NEPHRON-D) is examining whether combination therapy with
an ACE inhibitor and an ARB (lisinopril plus losartan) is superior
to ARB monotherapy (losartan alone) for slowing the progression
of diabetic nephropathy in 1,850 patients with overt proteinuria.72
For most patients with type 2 diabetes, the primary goal of lipid
management is to lower LDL cholesterol.4 Statin therapy is indicated
for all patients with overt CVD, as well as all patients older than 40
years of age who have one or more cardiovascular risk factors (other
than diabetes).4,5 Niacin, fenofibrate, ezetimibe, or a bile acid sequestrant (e.g., colesevelam) may be added if needed to reach the LDL
goal.
Although aspirin therapy is recommended as a secondary prevention strategy for all patients with diabetes who have a history of CVD,
the role of aspirin for primary prevention in patients with diabetes is controversial.4 In the past, aspirin therapy was recommended
for primary prevention in all patients older than 40 years of age.
An updated expert consensus statement issued jointly by the ADA,
American Heart Association, and American College of Cardiology
Foundation in June 2010 recommends low-dose (75162 mg/day)
aspirin use only for patients who are at increased CVD risk (10-year
risk of CVD events >10%) and who are not at increased risk for bleed12

American Pharmacists Association

ing.73 According to the statement, patients at increased CVD risk include most men older than 50 years of age and women older than
60 years of age who have one or more of the following additional
major risk factors: smoking, hypertension, dyslipidemia, family history of premature CVD, and albuminuria. Aspirin therapy also may
be considered for primary prevention in patients at intermediate CVD
risk: younger patients with one or more risk factors, older patients
with no risk factors, or patients with a 10-year CVD risk of 5% to 10%.
Using the Atherosclerosis Risk in Communities (ARIC) Coronary
Heart Disease Risk Calculator (available at http://www.aricnews.
net/riskcalc/html/RC1.html), Gail Burton currently would fall into
the intermediate risk category (with a 10-year risk of approximately
7.5%). If Gail were to start taking the prescribed simvastatin and
lisinopril, it is likely that her risk would improve to the extent that
aspirin therapy would not be warranted.73
A daily medication regimen that includes antihyperglycemic
agents, antihypertensive agents, lipid-lowering agents, and perhaps other medications has the potential to pose adherence challenges for many patients.25 Factors that contribute to better adherence include a higher perceived need for the medication and better
knowledge about the medication.25,34,74 Pharmacists should make a
special effort to ensure that patients with type 2 diabetes know their
ABC goals and understand the importance of managing each of
them. A brochure from the National Diabetes Education Program
(available at http://ndep.nih.gov/media/ControlABC_broch_Eng.
pdf?redirect=true) may help to support this conversation. The
Web-based ADA Diabetes PHD (Personal Health Decisions) provides a more comprehensive assessment of patient risk; it is available at https://www.diabetesarchive.net/phd/profile/.
Influenza and pneumonia are more likely to be fatal in patients
with diabetes than in people who do not have diabetes.1 Both the
ADA standards and the Centers for Disease Control and Prevention
Advisory Committee on Immunization Practices recommend pneumococcal vaccine and annual influenza vaccine for all patients with
diabetes.4,75 As more and more people take advantage of pharmacybased immunization services, pharmacists are presented with a
unique opportunity to improve vaccination rates among patients
with diabetes.

Conclusion
Type 2 diabetes is a chronic, progressive disease that typically requires a combination of antihyperglycemic therapiesincluding
insulinto achieve glycemic control and forestall long-term complications. A host of nonglycemic risk factors also must be addressed.
Pharmacists are uniquely positioned to identify and address gaps in
the care of patients with diabetes and improve therapeutic outcomes
for every patient they see.

References
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2007. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf.
Accessed September 12, 2010.
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dm/pubs/statistics/index.htm. Accessed September 12, 2010.
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glycemic control. Endocr Pract. 2009;15:54059.
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antidiabetic agents on A1C levels: a systematic review and meta-analysis.
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9. Fraze T, Jiang J, Burgess J. Hospital stays for patients with diabetes, 2008.
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30. Campbell RK. Type 2 diabetes: where we are today: an overview of disease
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10. Del Prato S, Penno G, Miccoli R. Changing the treatment paradigm for
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31. Blonde L. Current antihyperglycemic treatment guidelines and algorithms

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11. Campbell RK. Fate of the beta-cell in the pathophysiology of type 2

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32. Phung OJ, Scholle JM, Talwar M, et al. Effect of noninsulin antidiabetic
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12. DeFronzo RA. Overview of newer agents: where treatment is going. Am J

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18. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the
prevention of cardiovascular events: implications of the ACCORD, ADVANCE,
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the progression of diabetic microvascular complications in Japanese
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33. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and
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57. LaSalle JR. Empowering patients during insulin initiation: a real-world

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40. Look AHEAD Research Group. Reduction in weight and cardiovascular

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59. McCoy EK, Wright BM. A review of insulin pen devices. Postgrad Med.
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58. Goldstein HH. Pen devices to improve patient adherence with insulin
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60. Nakar S, Yitzhaki G, Rosenberg R, et al. Transition to insulin in type 2

diabetes: family physicians misconception of patients fears contributes
to existing barriers. J Diabetes Complications. 2007;21:2206.
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regular (U-500) for patients with diabetes. Am J Health Syst Pharm.
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to use in clinical practice. Diabetes Metab Res Rev. 2007;23:2658.
65. Hirsch IB. Intensifying insulin therapy in patients with type 2 diabetes
mellitus. Am J Med. 2005;118(5A):21S6S.
66. Cochran E, Musso C, Gorden P. The use of U-500 in patients with extreme
insulin resistance. Diabetes Care. 2005;28:12404.
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46. Kuritzky L, Epstein BJ, Lavernia F. How to obtain appropriate type 2

diabetes control in the first 180 days of treatment initiation. Postgrad
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68. Cheung BMY, Ong KL, Cherny SS, et al. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med.
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47. Berger JE, Ahmann AJ, Balfour DC, et al. Treating to target: implementing
an effective diabetes care paradigm for managed care. Am J Manag Care.
2010;16(suppl treating):S435.

69. Wang J, Thomas J, Byrd D, et al. Status of diabetes care among community pharmacy patients with diabetes: analysis of the Medical Expenditure
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48. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2
diabetes. Diabetes Care. 2004; 27:153540.

70. Holman RR, Paul SK, Bethel MA, et al. 10-Year follow-up of intensive
glucose control in type 2 diabetes. N Engl J Med. 2008;359:157789.

49. Schwartz KL, Monsur J, Hammad A, et al. Comparison of point of care

and laboratory HbA1c analysis: a MetroNet study. J Am Board Fam Med.
2009;22:4613.

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50. Nauck MA, Vilsbll T, Gallwitz B, et al. Incretin-based therapies:

viewpoints on the way to consensus. Diabetes Care. 2009;32(suppl 2):
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the pharmacist in type 2 diabetes management. J Am Pharm Assoc.
2009;49:e15262.
52. Rubino A, McQuay LJ, Gough SC, et al. Delayed initiation of subcutaneous insulin therapy after failure of oral glucose-lowering agents in
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53. Peyrot M, Rubin RR, Lauritzen T, et al. Resistance to insulin therapy among
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14

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72. Fried LF, Duckworth W, Zhang JH, et al.; VA NEPHRON-D Investigators.

Design of combination angiotensin receptor blocker and angiotensinconverting enzyme inhibitor for treatment of diabetic nephropathy (VA
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Test Your
Knowledge:

Diabetes
CPE Exam

1. Approximately what percentage of adults in the

United States with diabetes has type 2 diabetes?
a. 30%.
c. 70%.
b. 50%.
d. 90%.
2. Cardiovascular disease is the cause of death in
what percentage of patients with type 2 diabetes?
c. 66%.
a. 33%.
d. 75%.
b. 50%.
3. Which of the following are considered to be the
dual defects that characterize type 2 diabetes?
a. Impaired -cell function and insulin resistance.
b. Glucagon hypersecretion and reduced incretin
secretion.
c. Peripheral and central insulin resistance.
d. Increased lipolysis and impaired -cell function.
4. What percentage of -cell function is lost by the
time type 2 diabetes is diagnosed?
a. 10%.
c. 35%.
b. 18%.
d. 50%.
5. The American Diabetes Association (ADA)
recommends an A1C goal of _____%, while
the American College of Endocrinology (ACE)
and the American Association of Clinical
Endocrinologists (AACE) recommend an A1C
goal of _____%.
a. <8.0; 7.0.
c. <6.5; 7.0.
b. <7.0; 6.5.
d. <6.0; 6.5.
6. In general, most oral antihyperglycemic agents are
able to decrease A1C levels by an average maximum
of:
c. 1.25%.
a. 0.5%.
d. 2.0%.
b. 1.0%.
7. Which of the following statements is true?
a. Patients with type 2 diabetes are unlikely to
require insulin therapy if they are adherent to oral
antihyperglycemic therapy.
b. Intensive glycemic control is an effective intervention
for reducing the risk of cardiovascular events.
c. Sulfonylureas are the most potent glucose-lowering
agents available.
d. Aggressive treatment of hypertension and dyslipidemias
is an important aspect of type 2 diabetes management.

Instructions: The assessment questions printed below allow

you to preview the online CPE exam. Please review all
of your answers to be sure you have marked the
proper letter on the online CPE exam. There is only
one correct answer to each question.
8. In the ADA/European Association for the Study of
Diabetes (EASD) algorithm, what is the preferred
initial therapy for newly diagnosed patients with
type 2 diabetes?
a. Lifestyle interventions alone.
b. Lifestyle interventions + metformin.
c. Lifestyle interventions + a sulfonylurea.
d. Lifestyle interventions + basal insulin.
9. In the AACE/ACE algorithm, which of the
following agents is not recommended for initial
antihyperglycemic therapy in a patient with an
A1C level of 7.2%?
a. Metformin.
b. A sulfonylurea.
c. A dipeptidyl peptidase-4 (DPP-4) inhibitor.
d. A thiazolidinedione.
10. In the AACE/ACE algorithm, which of the
following regimens would be preferred for
initial therapy in a patient with an A1C level of
8.9%?
a. Metformin monotherapy.
b. Metformin + a sulfonylurea.
c. Metformin + a glucagon-like peptide-1 (GLP-1)
agonist.
d. Insulin alone or with other agents.
11. Which of the following triple medication
regimens is advocated by DeFronzo for early
treatment of the pathogenic abnormalities of
type 2 diabetes?
a. Metformin, a thiazolidinedione, and a GLP-1 agonist.
b. Metformin, a thiazolidinedione, and a DPP-4 inhibitor.
c. Metformin, a sulfonylurea, and a thiazolidinedione.
d. Metformin, a sulfonylurea, and a GLP-1 agonist.
12. According to the ADA/EASD and AACE/ACE
algorithms, how frequently should the
therapeutic regimen for patients with type 2
diabetes be evaluated?
a. Every 2 to 3 months.
b. Every 6 months.
c. Annually.
d. Whenever the patient experiences symptoms of
hyperglycemia.

Test Your Knowledge: Diabetes 15

13. In the ADA/EASD algorithm, which of the

following options is recommended when
therapy needs to be intensified in a patient
with an A1C level >8.5%?
a. Increase the dose of metformin.
b. Add basal insulin to lifestyle interventions +
metformin.
c. Add a GLP-1 agonist to lifestyle interventions +
metformin.
d. Add a sulfonylurea to lifestyle interventions +
metformin.
14. A patient with type 2 diabetes has an A1C level
of 7.4% despite therapy consisting of lifestyle
modifications and metformin. In the AACE/
ACE algorithm, what is the preferred second
component of dual pharmacotherapy for this
patient?
c. A sulfonylurea.
a. A GLP-1 agonist.
d. A thiazolidinedione.
b. A meglitinide.
15. A man with type 2 diabetes needs to have insulin
added to the treatment regimen to improve
glycemic control. With some embarrassment, he
admits that he is afraid of needles. Which of the
following interventions is most likely to address
his concern effectively?
a. Ask him if a family member or friend could assist him
in administering the injections.
b. Assure him that insulin will improve his symptoms and
make him feel better.
c. Recommend a long-acting insulin that only needs to be
administered at bedtime.
d. Suggest that he try using an insulin pen device.
16. Pharmacists might help patients to overcome
psychological insulin resistance by:
a. Empowering patientsexplaining that they are
unlikely to need insulin if they make all of the
recommended lifestyle modifications.
b. Introducing the possibility of insulin use when
patients are first diagnosed with type 2 diabetes.
c. Reassuring patients that insulin therapy is introduced
only as a last resort and therefore would not be a
concern for many years.
d. Referring patients to a mental health professional.

17. Tom Rogers has a current total daily insulin

dose of 250 units. His most recent A1C level
was 7.8%. Toms primary care provider wants
to switch him to U-500 insulin and calculates
an initial total dose of 200 units. If twice daily
dosing is desired, which U-100 syringe marking
should Tom use to measure each dose?
a. 20.
c. 40.
b. 25.
d. 50.
18. Approximately what percentage of adults
with type 2 diabetes currently achieves the
recommended goals for A1C, blood pressure,
and cholesterol?
c. 33%.
a. 12%.
d. 45%.
b. 21%.
19. A patient with type 2 diabetes has a blood
pressure reading of 137/85 mm Hg. Which
of the following options represents a
recommended course of action?
a. Do nothingthis reading is below the goal of
140/90 mm Hg.
b. Initiate antihypertensive therapy with a thiazide
diuretic.
c. Initiate antihypertensive therapy with an angiotensinconverting enzyme inhibitor.
d. Initiate antihypertensive therapy with a calciumchannel blocker.
20. In addition to an annual influenza vaccine,
which of the following vaccines is recommended
for all patients with type 2 diabetes?
a. Hepatitis B.
b. Human papillomavirus.
c. Meningococcal.
d. Pneumococcal.

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