ominous octet for pharmacists

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Introduction

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

those, most—approximately 90% to 95%—have type 2 diabetes.2

Both environmental and genetic factors are believed to contributeto 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 complicationsthat 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 UnitedStates, diabetes is the most frequent cause of new cases of blindnessamong adults 20 to 74 years of age, as well as the leading cause of end-stage renal disease.1,4 More than 60% of nontraumatic lower-limb ampu-tations 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 equiva-lent.3-5 Two out of three patients with diabetes die from some form ofcardiovascular disease (CVD).6,7 Overall, the risk for death among people

with diabetes is approximately twice that of people without diabetes ofsimilar age.1

The long-term complications of type 2 diabetes contribute to excep-tionally high disease-related costs. In 2007 (the latest year for which dataare available), the direct medical costs and indirect costs (e.g., disability,

work loss, premature mortality) associated with diagnosed diabetes inthe United States totaled $174 billion.8 Nearly one in five hospitaliza-

tions in 2008 was related to diabetes, representing more than 7.7 millionstays and $83 billion in hospital costs—23% of the total hospital costsin the United States.9 Average medical expenditures among people withdiagnosed diabetes are estimated to be 2.3 times higher than what expen-ditures would be in the absence of diabetes.8

Because pharmacists have frequent contact with patients with type2 diabetes, they are ideally positioned to make substantial contribu-tions to diabetes care. This monograph employs case vignettes to ex-

plore common clinical scenarios and emerging problems encounteredby pharmacists. As is true in practice, the vignettes may not have a clearresolution. When firm recommendations cannot be made, summariesof the latest thinking about each situation are provided.

DiabetesTest Your Knowledge:

© 2010 by the American Pharmacists Association. All rights reserved. Printed in U.S.A.

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%. Tom’s 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 nothing—this 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 calcium-

channel blocker.

Continuing Pharmacy Education • November 2010 • Supplement to Pharmacy Today



Learning Objectives

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

Chair and Professor of Pharmacy Practice

Presbyterian College School of Pharmacy

Clinton, South Carolina

Karen Reed, RPh, FAPhA Staff Pharmacist

Kmart Pharmacy

Beckley, West Virginia

DisclosuresTommy 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.

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.

APhA’s edi torial 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.

This publication was prepared by Cynthia Knapp Dlugosz,

BSPharm, of CKD Associates, LLC, on behalf of the American

Pharmacists Association.

Accreditation InformationThe American Pharmacists Association is accredited by

the Accreditation Council for Pharmacy Education as a

provider of continuing pharmacy education (CPE). The

ACPE Universal Activi ty 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, com-

plete the CPE exam and submit i t 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 success-

fully complete the CPE exam. Pharmacists who successfully com-

plete this activ ity before November 1, 2013, can receive credit.

Your Statement of Credit will be available online immediately upon

successful completion of the CPE exam.

DevelopmentThis home-study CPE activity was developed by the AmericanPharmacists Association.

SupportThis activity is supported by an independent educational grant fromMerck.

Provider: American Pharmacists Association Target Audience: PharmacistsRelease Date: November 1, 2010Expiration Date: November 1, 2013Learning Level: 2

ACPE Number: 202-000-10-260-H01-PCPE Credit: 2 hours (0.2 CEUs))

ACPE Activity Type: Application-basedFee: There is no fee associated with this activity.

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


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Mini-Review: Pathogenesis of Type 2Diabetes

Type 2 diabetes is characterized by the dual defects of insulinresistance (i.e., diminished liver, muscle, and adipose sensitivityto insulin) and impaired pancreatic β-cell secretory function (i.e.,impaired insulin secretion).3 Insulin resistance is associated with adecrease in the uptake and utilization of glucose by insulin-sensitivetissues (primarily muscle and adipose tissue) as well as ineffective

suppression of hepatic glucose production.3,10 β-Cells are able tocompensate for the decrease in insulin action (and resulting hyper-glycemia) by increasing their production of insulin.3,11,12 However,as the fasting plasma glucose concentration continues to rise, theβ-cells become less and less able to sustain the necessary levels of in-sulin secretion. A cycle of diminished insulin secretion and worsen-ing insulin resistance ensues; the β-cells eventually fail altogether.

Because not everyone with insulin resistance goes on to developtype 2 diabetes, there is growing speculation that β-cell deteriora-tion—reflecting both intrinsic secretion failure and reductions inβ-cell mass—may actually precede insulin resistance and evencontribute to its development.3,10,11 β-Cell dysfunction is now knownto occur much earlier in the natural history of type 2 diabetes thanoriginally thought; the landmark United Kingdom ProspectiveDiabetes Study (UKPDS) demonstrated that approximately 50% ofβ-cell function already has been lost by the time type 2 diabetes isdiagnosed, and some experts posit that as much as 80% of functionmay be lost.12-14 Data from the Belfast Diet Study show that β-celldeterioration proceeds relatively slowly at first—at a rate of 1.7% per

year for as long as 15 to 17 years—then accelerates abruptly to morethan 18% per year between 3 and 5 years after diagnosis. 11,15 β-Cell

failure currently is considered to be more important than insulinresistance in the natural history of type 2 diabetes.11,12,16

There also is growing appreciation of the role of etiologic mecha-nisms beyond β-cell dysfunction and insulin resistance. Diabetesexpert Ralph DeFronzo, MD, refers to the multiple pathogenic mech-anisms of type 2 diabetes as the “ominous octet” (FIGURE 1).12,13 Inaddition to decreased insulin secretion and decreased uptake of glu-cose, these mechanisms include increased hepatic glucose produc-

tion, accelerated lipolysis in adipocytes (elevated plasma free fattyacid levels), diminished incretin effect, hypersecretion of glucagonby pancreatic α-cells, enhanced renal glucose reabsorption, andcentral nervous system insulin resistance resulting from neurotrans-mitter dysfunction.12,17

Mini-Review: Approach to Treatment Abundant conclusive evidence from long-term, randomized clini-

cal trials shows that maintaining hemoglobin A1C levels close to thenormal range reduces the incidence and progression of microvascu-lar 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 ofmicrovascular complications by 40%.1 Early intervention to reduce

A1C levels also appears to contribute to a long-term reduction in therisk of macrovascular disease.18

Accordingly, A1C has become the primary target for glycemic con-trol. The American Diabetes Association (ADA) Standards of MedicalCare in Diabetes recommend an A1C goal of <7%.4 The AmericanCollege of Endocrinology (ACE) and the American Association ofClinical Endocrinologists (AACE) recommend a more stringent A1Cgoal of ≤6.5%.22,23 All of these organizations recognize that more orless stringent A1C goals may be appropriate for certain patients, de-

pending on the risk for hypoglycemia, comorbid conditions that lim-it life expectancy, and factors that may limit the safety of attemptingaggressive glucose control.4,18,22-24

A range of noninsulin oral and injectable antihyperglycemicagents (T ABLE 1) and insulins are used in the treatment of type 2diabetes.3,17,25 All agents (other than insulin) are limited in their abil-ity to lower A1C.26 In one recent systematic review and meta-analysisof 61 double-blind, randomized controlled trials that met predefinedmethodologic criteria, most oral antihyperglycemic agents were

found to decrease A1C levels by 0.5% to 1.25% (thiazolidinedionesand sulfonylureas lowered A1C levels by approximately 1.0% to1.25%).27 An increase in dose yielded a further decrease in A1C ini-tially, 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 noclear effect on treatment response.

Because of the progressive loss of β-cell function in patients withtype 2 diabetes, most available antihyperglycemic therapies are un-able to maintain glycemic control over time, and the majority of

patients eventually require combination therapy.3,24,28-31 The responseto antihyperglycemic agents (other than insulin) usually is more

pronounced in patients who are treatment naïve than in those whoalready are receiving therapy.28 This was demonstrated in a recentmixed-treatment comparison meta-analysis by Phung and col-leagues.32 The analysis evaluated the efficacy of antihyperglycemicagents used as second-line therapy in patients experiencing an in-adequate response to maximized and stable metformin therapy (≥4

weeks at ≥1,500 mg daily, or the maximally tolerated dose); it in-cluded 27 randomized clinical trials that enrolled more than 11,000

participants. The additional reductions in A1C provided by the differ-ent classes of drugs ranged from 0.64% to 0.97%.

Eventually, β-cell function deteriorates to such a degree thatthe secretory capacity of the cells is exceeded and exogenous insu-

Figure 1. Multiple Defects That Contributeto the Progression of Type 2 Diabetes

HGP = hepatic glucose production.

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

Association.

Test Your Knowledge: Diabetes 3


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lin replacement is required.3,23,24,29 Insulin remains the most potentglucose-lowering agent available; when used in adequate doses, in-sulin 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

trials—which showed no significant reduction in cardiovascularevents with intensive glycemic control in patients with type 2 dia-betes—reinforced the importance of also controlling nonglycemicrisk factors, especially hypertension and dyslipidemias.4,16,18,35-37 Ac-cording to estimates based on data from the Household Componentof the Medical Expenditure Panel Survey, approximately two thirds(64.8%) of patients with diabetes have coexisting hypertension, andmore than half (52.8%) have coexisting hyperlipidemia.38 Aggressive

control of blood pressure and lipid levels in addition to glycemiccontrol 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 ofmicrovascular complications by approximately 33%.

• In general, for every 10 mm Hg reduction in systolic blood pressure, the risk for any diabetes-related complicationdecreases by 12%.

• Improved control of low-density lipoprotein (LDL) cholesterolcan reduce cardiovascular complications by 20% to 50%.

Case 1: Initiating Therapy in a NewlyDiagnosed Patient

Dawn Jones is a 53-year-old white woman whostopped by your diabetes screening station at a recenthealth fair. She had eaten lunch 1 hour previously; her

blood glucose reading was 275 mg/dL. You encouraged Dawn to visither primary care provider for follow-up. The primary care providerdiagnosed 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 metformin500 mg once daily (to be titrated to 500 mg twice daily) and a glu-

cose monitor. She explains with some pride that she won’t be need-ing the medication. “I finally joined Weight Watchers yesterday,”she tells you. “I just need to lose some of this weight. Then every-thing should be just fine.”

Lifestyle interventions that include medical nutrition therapy andregular exercise (at least 150 minutes/week of moderate-intensity

aerobic physical activity) are considered to be the cornerstone ofmanagement for type 2 diabetes.4,24 Given that approximately twothirds of patients with type 2 diabetes are obese (BMI ≥30), with amean BMI of 34.2—and one out of five patients is morbidly obese(BMI ≥40)—weight loss is a principal focus of lifestyle interven-tions.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 anintensive lifestyle intervention lost an average of 8.6% of their initial

weight during the first 12 months, with an associated increase from46% 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 interven-tions should be included as part of a comprehensive diabetes man-

Table 1. Antihyperglycemic Agents(Other Than Insulin) Available in theUnited States

Drug Class Available Agents(Brand Name)

Route ofAdministration

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)

Second generation:

Glimepiride (Amaryl)Glipizide (Glucotrol)Glyburide (DiaBeta,Micronase)

Oral

Agents That Enhance the Effects of Insulin

α -Glucosidaseinhibitors

Acarbose (Precose)Miglitol (Glyset)

Oral

Biguanide Metformin (Glucophage) Oral

Thiazoli-dinediones(“glitazones”)

Pioglitazone (Actos)Rosiglitazone (Avandia)

aOral

Agents That Modify Noninsulin Hormonal Systems

Amylin analogs Pramlintide (Symlin) Injectable

Dipeptidyl

peptidase-4(DPP-4)inhibitors

Saxagliptin (Onglyza)

Sitagliptin (Januvia)

Oral

Glucagon-likepeptide-1 (GLP-1) agonists(incretinmimetics)

Exenatide (Byetta)Liraglutide (Victoza)

Injectable

Other Agents

Bile acidsequestrant

Colesevelam (Welchol) Oral

Dopamineagonist

Bromocriptine mesylate(Cycloset)

Oral

a In response to data suggesting an elevated risk of cardio-

vascular 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.

Test Your Knowledge: What constitutesappropriate initial treatment for DawnJones??



diabetes-associated complications and hospitalizations.23,43,44 Accord-ingly, it would be “counterproductive” to base treatment decisions

primarily on cost if those therapies might result in increased (andmore costly) complications, emergency department visits, and hos-

pitalizations. 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 recog-nized as the most appropriate initial choice for many patients inthis range, but DPP-4 inhibitors, GLP-1 agonists, thiazolidinediones,and α-glucosidase inhibitors also are possibilities, especially inthe specific situations described in the footnotes to the algorithm.For example, DPP-4 inhibitors are suggested for patients who haveelevations in both fasting and postprandial glucose levels; GLP-1inhibitors are suggested for patients who have greatly elevated post-

prandial glucose levels.Combination therapy is recommended for all patients with an A1C

level ≥7.6% because no single agent is likely to produce the degreeof 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 preferredcombination is metformin with either a GLP-1 agonist, a DPP-4 in-hibitor, or a thiazolidinedione, in that order of preference. GLP-1

agonists are given the highest priority because of their somewhatgreater effect on reducing postprandial glucose excursions and their

potential for inducing weight loss.Dual or triple drug therapy is recommended for asymptomatic,

drug-naïve patients with an A1C level >9.0%.23 Symptomatic patientsand patients already receiving treatment are candidates for insulintherapy, 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 designedto target the multiple pathogenic abnormalities known to promoteβ-cell failure.10-12,17 Both DeFronzo12,13 and Unger and Parkin17 haveadvocated triple pharmacologic therapy consisting of metformin, athiazolidinedione, and a GLP-1 agonist (in addition to lifestyle in-terventions), initiated as early as possible during the course of type2 diabetes. The complementary mechanisms of action of these drugs

would preserve β-cell function (and may maintain β-cell mass), in-crease insulin sensitivity in muscle and hepatic tissue, reduce hepat-ic gluconeogenesis, inhibit lipolysis, and decrease plasma free fatty

Figure 3. American Association of Clinical Endocrinologists/American College ofEndocrinology Algorithm for Glycemic Control

AGI =α-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.



acid levels, as well as provide antiatherogenic effects and support weight loss.10,12,13,17,31 Importantly, this combination would not causehypoglycemia.12,17 According to DeFronzo, this triple combinationapproach offers the greatest likelihood of providing durable glucosecontrol through a blunting of disease progression. 12 DPP-4 inhibi-tors could be an alternative to GLP-1 agonists in the combinationif they are shown to preserve β-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 ques-tion 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 prescrib-ers in the absence of evidence is to inform patients of all treatmentoptions, explain the benefits and risks of each, and engage patientsin the decision-making process.45 Initiating aggressive combinationtherapy would be of little benefit if, for example, a patient chose tofill only the least expensive prescription, thereby defaulting to anapproach that would fail to fulfill the treatment plan.25

Case 2: When to Adjust TherapyLeroy 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 prescrip-tion for metformin extended-release 2,000 mg daily. Leroy

is not new to your practice; dispensing records for the past 2 yearsshow periodic prescriptions for the same dosage of metformin. Basedon transfer notations and a brief discussion with Leroy about ad-herence, you suspect that he has been “coupon chasing”—visitingother pharmacies to take advantage of the latest promotion. You alsoare 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 today’s vis it:• A1C: 8.9%.• Blood pressure: 128/78 mm Hg.

In addition to metformin, Leroy Thomas’s other current medica-tions include:

• Hydrochlorothiazide 25 mg daily.• Lisinopril 20 mg daily.• Simvastatin 20 mg daily.• Aspirin 81 mg daily.

For decades, the paradigm for long-term management of type 2 dia-betes involved a stepwise “treat to failure” approach.10,34,46 Therapy

was initiated with lifestyle modifications alone; medicat ions wereadded slowly and sequentially only when a trial of diet and exercise

proved to be inadequate for achieving glycemic control.28,34 A singleoral agent was titrated to its maximal recommended dose, followedby a second oral agent added and titrated to its maximal dose, and

so on.10

As a result, prescribers often failed to adjust antihyperglycemictherapy in a timely manner—a 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 (theusual 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 rec-ommended “action threshold” at the time of the study) for a mean

of 20.5 ± 18.0 months. Patients who followed the usual treatment progression—lifestyle intervention first, then oral monotherapy,then oral combination therapy, and finally insulin—would havespent approximately 10 years with an A1C level >7% and nearly5 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 beintensified rapidly if glycemic goals are not achieved. 16,34,46 Yet clini-cal inertia persists in today’s practice environment.10 This may beattributed in part to the lack of direct evidence regarding the ideal

frequency of physician visits for patients with type 2 diabetes.24 The2010 ADA Standards of Medical Care in Diabetes call for routine A1C

testing in all patients with diabetes, at the following recommendedintervals4 :

• At least twice yearly in patients who are meeting treatment goalsand have stable glycemic control (A1C <7%).

• Quarterly in patients whose therapy has changed or who are notmeeting glycemic goals.

Some clinicians schedule follow-up visits to coincide with these test-ing intervals (i.e., two to four visits per year). Anecdotal evidencesuggests that many patients are seen far less frequently, and that

A1C testing does not occur as recommended.23 The fault does notnecessarily lie entirely with health care providers; in some cases, pa-

tients may receive inadequate follow-up because they fail to return for routine vis its.25

Both the ADA/EASD and AACE/ACE algorithms challenge clini-cians to monitor therapy closely and adjust the treatment plan every2 to 3 months as needed until the goal for A1C has been achieved. 23,33 Because the response from dose escalation usually is limited, adjust-ing the treatment plan generally means adding another agent.24

Pharmacists can help to combat clinical inertia by offering point-of-care A1C testing and intervening with prescribers as appropriate.Several devices appropriate for use in pharmacies (e.g., Bayer A1CNow+) have been granted waived status under the Clinical Labo-ratory Improvement Amendments. However, pharmacists should be

aware that the results obtained with these devices may be less sensi-tive and specific than laboratory testing.49

Case 3: How to Adjust TherapyMartina Hernandez is a 48-year-old Hispanic woman

of Mexican descent who was diagnosed with type 2 dia-betes approximately 2 years ago. Therapy was initiated

with metformin 500 mg twice daily and titrated to the current doseof metformin 1,000 mg twice daily.

Martina is 5’ 1” tall and weighs 180 lb (BMI 34). Although shehas 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 betterable to adhere to her goal of taking a 30-minute walk on at least5 days each week.

Test Your Knowledge: At what point shouldLeroy Thomas’s antihyperglycemic regimenideally have been adjusted??



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 ametformin refill. She asks the pharmacy technician to make surethat glipizide is on the list of medications that cost $4.

The care of patients with type 2 diabetes whose A1C level remainsabove target despite metformin therapy and lifestyle modificationsis another area of clinical controversy. The ADA/EASD and AACE/

ACE algorithms provide strikingly different advice about escalatingantihyperglycemic therapy.

The ADA/EASD algorithm calls for a second agent to be addedto metformin monotherapy within 2 to 3 months if the maximumtolerated dose of metformin fails to achieve or sustain the glycemicgoals (FIGURE 2).33 The preferred options for the second agent are

a sulfonylurea or insulin, with insulin therapy (basal therapy withan intermediate- or long-acting formulation) recommended for

patients with an A1C level >8.5% or symptoms secondary to hyper-glycemia.

The ADA/EASD algorithm also offers two “tier 2” options for thesecond agent: pioglitazone and a GLP-1 agonist.33 (“Tier 2” repre-sents less well-validated therapies.) Either agent may be considered

when the risk of hypoglycemia is especially undesirable (e .g., in pa-tients who have hazardous jobs); a GLP-1 agonist may be consideredif weight loss is a major goal of therapy and the patient’s A1C levelis <8.0%.

As illustrated in FIGURE 2, the options for further escalation oftherapy depend on which second agent was added. 33 Ultimately, acombination of metformin and intensive insulin therapy (i.e., basaltherapy plus bolus injections of a short- or rapid-acting insulin be-

fore selected meals to reduce postprandial glucose excursions) isrecommended for all patients.

It is noteworthy that none of the other available antihypergly-cemic agents—amylin agonists, α-glucosidase inhibitors, megli-tinides, or DPP-4 inhibitors—are included in the algorithm. Theauthors 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 inselected patients.

In clinical practice, the choice of a sulfonylurea for second-linetherapy is reinforced by the pricing policies of a growing numberof pharmacies, which offer select diabetes medications—typicallygeneric versions of metformin and sulfonylureas—to 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 keycriticism of the ADA/EASD algorithm is that neither metformin northe sulfonylureas have been shown to preserve β-cell function.12,17

Sulfonylureas also are associated with a substantial risk of hypogly-cemia and weight gain.17,23

In the AACE/ACE algorithm (FIGURE 3), metformin remains the foundation of combination therapy for most patients because of itssafety and mechanism of action as an insulin sensitizer. 23 For pa-tients with an A1C level of 6.5% to 7.5%, the recommended secondcomponent 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 prioritybecause 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 wi th an A1Clevel of 6.5% to 7.5%, six combinations are possible, based on the ad-dition 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 therapyis 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 α-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 recommenda-tion is based on the somewhat greater efficacy and more rapid onsetof action of the sulfonylurea compared with a thiazolidinedione.

Nauck and colleagues recently speculated on the most likely fu-ture roles of the various incretin-based therapies in the treatment oftype 2 diabetes.50 One of the authors suggested that DPP-4 inhibitorseventually will be ranked before GLP-1 agonists in treatment algo-rithms because of the greater acceptability of oral administration.Ultimately, DPP-4 inhibitors may replace existing oral antihyper-glycemic agents, while the GLP-1 agonists (which are administeredby subcutaneous injection) may be viewed as competitors for insulintreatment.

As is the case when therapy for type 2 diabetes is initiated, pre-scribers seeking to intensify a patient’s treatment regimen are ad-

vised to inform the patients of all options available, explain thebenefits and risks of each, and include the patient in the decision-making process.45

Initiating Insulin TherapyIt 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 assessthe current level of glycemic control after 11 months on this regi-

Test Your Knowledge: What constitutesappropriate intensification ofantihyperglycemic therapy for MartinaHernandez?

?



men. Her measured A1C was 9.2%.Martina comes to the pharmacy today with a prescription for in-

sulin glargine. As the pharmacy technician readies the product andassociated supplies for dispensing, you sit down with Martina to teachher how to use and inject insulin. She begins to cry. “I knew this

would happen,” Martina says. “It’s all my fault because I couldn’t lose weight. My mother had to use insulin when I was a little girl—I’llnever forget what she went through, how painful it was.”

All current treatment algorithms for type 2 diabetes culminatein the initiation of insulin therapy.23,33 Because most patients willrequire insulin therapy at some point during the course of treat-ment—and because insulin is considered to have a greater potentialthan other agents for preserving β-cell function—early initiationof insulin is becoming more widely accepted.23,26,33 There is growingconsensus 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 insulintherapy do not receive it in a timely manner, or may not receive itat all.51 A retrospective cohort analysis by Rubino and colleagues in-

volving more than 2,500 patients with type 2 diabetes illustrates this point. 52 In fully half of the patients, insulin initiation was delayed foralmost 5 years after combination therapy with oral agents failed tomaintain glycemic control, even in the presence of diabetes-relatedcomplications.

Both patients and clinicians may be reluctant to initiate insulintherapy—a phenomenon known as “psychological insulin resis-

tance.”47,53-56

T ABLE 2 provides examples of patient beliefs that may present barriers to insulin therapy as well as possible pharmacist re-sponses that address those issues.54 Some key concerns are discussedin 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 concerns—for example, thatinsulin therapy will be disruptive and inconvenient, leading to a lossof personal freedom and control.54,56 The use of insulin pens can helpto allay all of these fears and make patients feel more comfortable

with insulin therapy in general. 26,54,56-59 Insulin pens offer many ben-efits: they do not resemble syringes, the needle is hidden, the injec-

tions are relatively painless, and patients usually find the devices tobe discreet and easy to use. Insulin pens also may be associated withlower 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 pa-tients in 13 countries in Asia, Australia, Europe, and North Americato examine attitudes toward insulin therapy.53 Patients in the UnitedStates reported more self-blame for insulin therapy—for example,“Starting insulin would mean that I have not followed my treatmentrecommendations properly”—than patients from all other coun-tries. 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 fa-

cilitating the initiation of insulin therapy 53,54,56:

• Health care providers should never use insulin as a threat or

punishment for not adhering to lifestyle modifications ormedication therapy.

• For each patient, health care providers should strive to identifyand address the specific attitudes and beliefs that underliereluctance to use insulin therapy.

The importance of the latter point was reinforced in a study by Nakarand 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 afraidof the actual injections. In fact, the hesitant patients were far more

likely to perceive their illness as not very serious, have a fear of be-coming “addicted” to insulin, or be worried about weight gain orhypoglycemia.

Table 2. Pharmacist Responses toPatient Concerns About InitiatingInsulin Therapy

Patient Belief Pharmacist Response

Insulins are noteffective

• Insulin analogs closely mimicendogenous insulin secretion

• Insulin reduces extremely high glucose

levels more effectively than any otheragent

• Landmark trials and recent outcomestudies have proven that tight glycemiccontrol reduces microvascular andpotentially macrovascular complications

Insulin causeshypoglycemia

• Insulin analogs have a more predictabletime–action profile than human insulinsand are associated with lower levels ofhypoglycemia

• Rapid-acting analogs can be given justbefore meals and so the patient can feelmore in control of his/her glucose levels

Insulin causesweight gain • The basal insulin analogs, and insulindetemir in particular, are associated withconsiderably less weight gain than humaninsulin

• Because insulin analogs are less likelyto cause hypoglycemia than earlierformulations, patients are less likely toengage in defensive snacking

• Diet and exercise can help improveglycemic control and reduce weight

Insulin regimensare complex

• Basal insulin analogs usually need to begiven only once daily

• Rapid-acting analogs can be given within15 minutes of eating

• Premixed insulin analogs combine twotypes of insulin in one formulation and aresuitable for patients with regular eatingpatterns

• Self-adjusted insulin dose titrationalgorithms provide a simple tool forinsulin titration

• Pen delivery devices are discreet, easy touse, and accurate

• Modern needles are fine and typicallyassociated with less pain

Source: Reprinted from reference 51.

Test Your Knowledge: What interventionsmight help to overcome MartinaHernandez’s concerns about using insulin??



any potential for patients to confuse it with U-100 regular insulin. 65 Pharmacists should ensure that the patient, the patient’s familymembers, and any caregivers are aware that U-500 insulin is five

times more concentrated than U-100 insulins.62,63

Patients shouldbe 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 beadjusted only with the approval of the presciber.63

U-500 insulin is provided in 20-mL vials with the word ‘‘concen-trated’’ marked on them.61,63 To avoid the possibility of drug adminis-tration errors, U-500 insulin should be stored separately from U-100insulin.61-64 This is of critical importance if any family membersin the same household use U-100 insulin. Patients also should beaware of the possibility for mix-ups during transitions between caresettings (e.g., when admitted to a hospital or long-term care facil-

ity); adding the use of U-500 insulin to medical alert identificationis one strategy for avoiding errors.62

Case 5: Controlling Nonglycemic Risk FactorsGail Burton is a 53-year-old African American woman

who was diagnosed with type 2 diabetes 3 years ago. Her A1Clevel is controlled to 6.7% on a combination of metformin1,000 mg twice daily and exenatide 10 µg twice daily.

Through dedicated adherence to lifestyle modifications (andlikely with assistance from the GLP-1 agonist), Gail has managed toreduce 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 andblood pressure screening event you are offering in conjunction withNational Cholesterol Education Month. Results show her blood pres-sure 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, I’ve lost

weight, I don’t smoke, and I’ve worked hard to get my diabetes un-der 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 pre-scriptions because, as she explains, “I’m not a really sick person—Idon’t need to be taking all these medications.” You question Gailabout other aspects of care and find out that she has never been

vaccinated against either influenza or pneumococcal pneumonia.

Patients such as Gail Burton must appreciate that the man-agement of type 2 diabetes involves much more than controllinghyperglycemia. Many pharmacists already are familiar with the“ABCs” of diabetes, which correspond to goals for A1C, blood pres-sure (<130/80 mm Hg), and LDL cholesterol (<100 mg/dL).67 Anextended alphabet mnemonic (T ABLE 4) can help pharmacists recalladditional elements of comprehensive diabetes management.67

Attainment of nonglycemic goals for diabetes management re-mains disappointingly low. Using National Health and Nutrition Ex-amination Survey data from 1999 to 2006, Cheung and colleagues

found that only 57.1% of participants with diagnosed diabetes hadachieved the target A1C level <7%, 45.5% had achieved the targetblood pressure, and 46.5% had achieved the target LDL cholesterollevel.68 Only 12.2% of participants—one in eight—had attained allthree targets. In a recent analysis of Medical Expenditure Panel Sur-

vey data from 2005, more than 40% of the study population (2,003adults with diagnosed diabetes) had not received a flu shot withinthe previous year.69

Effective long-term blood pressure control may be the most important intervention for preventing complications in patients withdiabetes.24,70 The ADA Standards of Medical Care in Diabetes call forblood pressure to be measured at every routine diabetes visit. 4 When

hypertension is present, the treatment regimen should include eitheran angiotensin-converting enzyme (ACE) inhibitor or an angio-tensin II receptor blocker (ARB) in addition to lifestyle modifica-

Table 3. Dosing Conversion Tableand Formulas for Dose and SyringeMarkingsa

U-500 InsulinDose (ActualUnits)

U-100 Syringe(Unit Markings)

Volume forTuberculinSyringe (mL)

25 5 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 1.00aThe 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).

Test Your Knowledge: What nonglycemicelements of diabetes care are appropriateand important for Gail Burton??



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51. Drab S. Translating clinical guidelines into clinical practice: role ofthe pharmacist in type 2 diabetes management. J Am Pharm Assoc.2009;49:e152–62.

52. Rubino A, McQuay LJ, Gough SC, et al. Delayed initiation of subcutane-ous insulin therapy after failure of oral glucose-lowering agents in

patients with type 2 diabetes: a population-based analysis in the UK. Diabet Med . 2007;24:1412–8.

53. Peyrot M, Rubin RR, Lauritzen T, et al. Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care . 2005;28:2673–9.

54. Peyrot M, Rubin RR, Khunti K. Addressing barriers to initiation of insulinin patients with type 2 diabetes. Prim Care Diabetes. 2010;4(suppl 1):S11–8.

55. Polonsky WH, Fisher L, Guzman S, et al. Psychological insulin resistancein patients with type 2 diabetes: the scope of the problem. Diabetes Care .2005;28:2543–5.

56. Davis SN, Renda SM. Psychological insulin resistance: overcomingbarriers to starting insulin therapy. Diabetes Educ. 2006;32(suppl 4):146S–52S.

57. LaSalle JR. Empowering patients during insulin initiation: a real-worldapproach. J Am Osteopath Assoc. 2010;110:69–78.

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60. Nakar S, Yitzhaki G, Rosenberg R, et al. Transition to insulin in type 2diabetes: family physicians’ misconception of patients’ fears contributesto existing barriers. J Diabetes Complications. 2007;21:220–6.

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65. Hirsch IB. Intensifying insulin therapy in patients with type 2 diabetes

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Accessed September 12, 2010.



Test YourKnowledge:

DiabetesCPE Exam

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.

1. Approximately what percentage of adults in theUnited States with diabetes has type 2 diabetes?

a. 30%.b. 50%.

2. Cardiovascular disease is the cause of death in what percentage of patients with type 2 diabetes?

a. 33%.b. 50%.

3. Which of the following are considered to be thedual defects that characterize type 2 diabetes?

a. Impaired β-cell function and insulin resistance.b. Glucagon hypersecretion and reduced incretinsecretion.

c. Peripheral and central insulin resistance.d. Increased lipolysis and impaired β-cell function.

4. What percentage of β-cell function is lost by the time type 2 diabetes is diagnosed?

a. 10%.b. 18%.

5. The American Diabetes Association (ADA)

recommends an A1C goal of _____%, while the American College of Endocrinology (ACE)and the American Association of ClinicalEndocrinologists (AACE) recommend an A1Cgoal of _____%.

a. <8.0; ≤7.0.b. <7.0; ≤6.5.

6. In general, most oral antihyperglycemic agents areable to decrease A1C levels by an average maximumof:

a. 0.5%.b. 1.0%.

7. Which of the following statements is true?

a. Patients with type 2 diabetes are unlikely torequire insulin therapy if they are adherent to oralantihyperglycemic therapy.

b. Intensive glycemic control is an effective intervention for reducing the risk of cardiovascular events.

c. Sulfonylureas are the most potent glucose-loweringagents available.

d. Aggressive treatment of hypertension and dyslipidemias

is an important aspect of type 2 diabetes management.

8. In the ADA/European Association for the Study ofDiabetes (EASD) algorithm, what is the preferredinitial 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 thefollowing agents is not recommended for initialantihyperglycemic 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 thefollowing regimens would be preferred forinitial therapy in a patient with an A1C level of8.9%?

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 medicationregimens 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/ACEalgorithms, how frequently should the

therapeutic regimen for patients with type 2diabetes be evaluated?

a. Every 2 to 3 months.b. Every 6 months.c. Annually.d. Whenever the patient experiences symptoms of

hyperglycemia.

c. 70%.d. 90%.

c. 66%.d. 75%.

c. 35%.d. 50%.

c. <6.5; ≤7.0.d. <6.0; ≤6.5.

c. 1.25%.d. 2.0%.



13. In the ADA/EASD algorithm, which of thefollowing 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 intervent ions +

metformin.d. Add a sulfonylurea to lifestyle interventions +

metformin.

14. A patient with type 2 diabetes has an A1C levelof 7.4% despite therapy consisting of lifestyle

modifications and metformin. In the AACE/ ACE algorithm, what is the preferred secondcomponent of dual pharmacotherapy for this

patient?

a. A GLP-1 agonist.

b. A meglitinide.15. A man with type 2 diabetes needs to have insulin

added to the treatment regimen to improveglycemic control. With some embarrassment, headmits that he is afraid of needles. Which of thefollowing interventions is most likely to addresshis concern effectively?

a. Ask him if a family member or friend could assist himin administering the injections.

b. Assure him that insulin will improve his symptoms andmake him feel better.

c. Recommend a long-acting insulin that only needs to beadministered 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 patients—explaining that they areunlikely to need insulin if they make all of therecommended 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 introducedonly as a last resort and therefore would not be aconcern for many years.

d. Referring patients to a mental health professional.

17. Tom Rogers has a current total daily insulindose of 250 units. His most recent A1C level

was 7.8%. Tom’s primary care provider wants to switch him to U-500 insulin and calculatesan initial total dose of 200 units. If twice dailydosing is desired, which U-100 syringe markingshould Tom use to measure each dose?

a. 20.

b. 25.

18. Approximately what percentage of adults with type 2 diabetes currently achieves therecommended goals for A1C, blood pressure,and cholesterol?

a. 12%.b. 21%.

19. A patient with type 2 diabetes has a blood pressure reading of 137/85 mm Hg. Whichof the following options represents a

recommended course of action?a. Do nothing—this 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 calcium-

channel blocker.

20. In addition to an annual influenza vaccine,

which of the following vaccines is recommendedfor all patients with type 2 diabetes?

a. Hepatitis B.b. Human papillomavirus.c. Meningococcal.d. Pneumococcal.

c. A sulfonylurea.

d. A thiazolidinedione.

c. 40.

d. 50.

c. 33%.d. 45%.

CPE Instructions

Completing a posttest at www.pharmacist.com/education is as easy as 1-2-3…1. Go to Online CPE Quick List and click on the title of this activity.2. Log in. APhA members enter your user name and password. Not an APhA member? Just click “Create one now” to open an account.

No fee is required to register.

3. Successfully complete the CPE exam and evaluation form to gain immediate access to your Statement of Credit.Live step-by-step assistance is available Monday through Friday, 8:30 AM to 5:00 PM ET from APhA Member Services at 800-237-APhA (2742)or e-mail [email protected].

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