Update DM

New Pharmacotherapies
for Type 2 Diabetes

By Brian Irons, Pharm.D., FCCP, BCACP, BCPS, BC-ADM
Reviewed by Charmaine Rochester, Pharm.D., BCPS, CDE; and Karen Whalen, Pharm.D., BCPS, CDE
Learning Objectives 2010 (CDC 2011). Regardless of the health care setting,
today’s clinical pharmacist is faced with many chal-
1. Compare and contrast the differences between the
lenges and responsibilities to minimize the impact of
drug therapy recommendations of several of the lat-
this disease on patients and health care resources. New
est and leading diabetes guidelines.
therapeutic agents, older drugs with new indications to
2. Assess the differences in incretin-based therapies for
treat hyperglycemia, changing therapeutic recommen-
the treatment of type 2 diabetes mellitus (T2DM)
dations, safety of existing diabetes drugs, and patient
and tell how they compare with other agents to
education are just a few of these challenges and respon-
treat hyperglycemia.
sibilities for pharmacists. This chapter focuses on the
3. Delineate the role and place in therapy of bromo-
treatment of hyperglycemia in patients with T2DM and
criptine and colesevelam in the treatment of T2DM.
how pharmacists can best develop and recommend safe
4. Convert a patient with T2DM with significant
and effective treatment options. The focus on hyper-
hyperglycemia to an insulin-only drug regimen.
glycemia does not negate the critical need to optimize
5. Evaluate the latest noncardiac precautions, con-
blood pressure and cholesterol control, the importance
traindications, or warnings with agents used in the
of lifestyle changes in diet and physical activity, or the
treatment of hyperglycemia.
treatment or prevention of disease complications.
Introduction
Clinical Guideline Updates in
The prevalence and incidence of type 2 diabetes mel-
litus (T2DM) continues to rise. It is estimated that Drug Therapy Management
8.3% of U.S. adults have diabetes and that about 1.9 mil- Given the volume of research and literature devoted
lion adults were newly given diagnoses of diabetes in to the management of hyperglycemia, it is very diffi-
Baseline Knowledge Statements

Readers of this chapter are presumed to be familiar with the following:
■■ General knowledge of the pathophysiology that leads to hyperglycemia in T2DM
■■ Fasting and postprandial glycemic goals defined by leading diabetes guidelines
■■ Drug knowledge of the oral pharmacologic agents used to treat T2DM
■■ Basic knowledge of the various parenteral diabetes agents used to treat hyperglycemia, including the onset and duration
of insulin formulations as well as the dosing and insulin requirements of pramlintide therapy
■■ The consequences of poor glycemic control including microvascular and macrovascular complications
Additional Readings
The following free resource is available for readers wishing additional background information on this topic.
American Diabetes Association. Standards of medical care in diabetes – 2012. Diabetes Care 2012;35(suppl1):
S11-S63.
PSAP 2013 • Cardiology/Endocrinology 5 New Pharmacotherapies for Type 2 Diabetes

and most patients will eventually require additional
Abbreviations in This Chapter therapy. The recommended options—once metformin
ADA American Diabetes fails to adequately control hyperglycemia—vary be-
Association tween guidelines (Table 1-1; Figure 1-1).
BAS Bile acid sequestrant
DPP-4 Dipeptidyl peptidase-4 ADA/European Association for
GIP Glucose-dependent the Study of Diabetes
insulinotropic peptide The ADA, in conjunction with the European
GLP-1 Glucagon-like peptide 1 Association for the Study of Diabetes, updated its drug
therapy recommendations for T2DM in early 2012
LDL Low-density lipoprotein
(Inzucchi 2012). The ADA 2009 drug management rec-
PPAR Peroxisome proliferator ommendations used an algorithm and tiered approach
activated receptor to therapeutic options and response to therapy based
T2DM Type 2 diabetes mellitus on the quality and quantity of data at the time. These
organizations now take a less prescriptive but more
patient-centered approach to drug therapy recommen-
cult for most clinicians to keep abreast of therapeutic dations. Metformin remains the initial treatment of
options for T2DM. Hence, clinical guidelines or con- choice (barring contraindications), though guidelines
sensus recommendations provide useful tools and suggest if patients are highly motivated and their A1C is
guidance to aid in T2DM management. There is a pleth- less than 7.5%, a 3- to 6-month trial of lifestyle modifica-
ora of diabetes guidelines and recommendations, with tions can be used before pharmacotherapy is initiated.
some more recognized than others. Some are updated The guidelines continue to recommend adding, rather
annually, whereas others are updated only after a suf- than changing to, additional agents when metformin no
ficient volume of new literature supports changes in longer provides adequate glycemic control or when A1C
recommendations. remains elevated after about a 3-month trial. Despite a
Optimizing physical activity and weight loss are goals failing metformin regimen, there may still be some clin-
of T2DM management. Diets should be low in fat, high ical benefit with its continued use. If the baseline A1C is
in fiber, and not excessive in total daily caloric intake. between 9.0% and 9.9%, the initial treatment regimen
Patients should be encouraged to exercise with a variety may contain an additional agent because metformin
of activities at least 150 minutes/week (ADA 2012). For alone is unlikely to attain glycemic targets. Insulin ther-
patients who are considerably overweight, bariatric sur- apy may be considered for initial therapy if a patient is
gery may be an option to significantly lose weight and symptomatic and/or has markedly elevated plasma glu-
has been associated with considerable improvements in cose concentrations (i.e., greater than 300 mg/dL) or
hyperglycemia in patients with T2DM. The American A1C (i.e., 10% or greater). If insulin is initiated early,
Diabetes Association (ADA) recommends consider- other T2DM medications may be added when improved
ation of bariatric surgery in adults with T2DM and glycemic control is achieved, and daily insulin require-
body mass indexes greater than 35 kg/m2 (ADA 2012). ments can be lowered.
With respect to drug therapy management of hyper- The choice of which agent(s) to add to metformin
glycemia, metformin is the drug of choice to initiate depends on the advantages and disadvantages of the
in patients newly given a diagnosis with T2DM or in other therapies such as cost; risk of hypoglycemia;
patients whose lifestyle modifications fail to attain gly- degree of hyperglycemia; other comorbidities; adverse
cemic control. This recommendation is in large part event profile, whether fasting, postprandial, or both are
because of this agent’s tolerability, low cost, effective- problematic; and patient injection preference. More
ness in hemoglobin A1C (A1C) reduction, low rate importantly, patient preferences and values must be
of hypoglycemia, potential for weight loss, cardio- considered, and the patient should take part in the deci-
vascular benefit in obese patients, and ability to be sion-making process. Another oral agent, basal insulin,
combined with most other medications used to treat or a glucagon-like peptide 1 (GLP-1) agonist is a poten-
T2DM. Metformin continues to be the most widely tial option to add to metformin; however, the lack of
used medication in T2DM, but with the emergence of long-term comparative studies limits any specific rec-
other treatment options and provider or patient prefer- ommendation. If dual therapy after about 3 months
ences, the drug remains underused in as many as 35% of fails to meet glycemic goals, a third agent may be added.
patients (Desai 2012). The guidelines state that adding insulin, if not already
Although metformin monotherapy is effective in the implemented, is the most likely choice to attain thera-
average patient with T2DM, the disease is progressive, peutic goals, especially if the A1C is 8.5% or greater.
New Pharmacotherapies for Type 2 Diabetes 6 PSAP 2013 • Cardiology/Endocrinology

Table 1-1. Comparison of T2DM Drug Therapy Recommendations
Guideline ADA/EASD ACCE/ACE NICE ACP
First-line
monotherapya Metformin Metformin Metformin Metformin
Dual therapy Other oral DM In order: GLP-1 Sulfonylurea No specific
(options to add to medication (e.g. agonist, DPP-4 DPP-4 inhibitor or recommendations
metformin) sulfonylurea, inhibitor, thiazolidinedione (if provided
thiazolidinedione, thiazolidinedione, high risk for
DPP-4 inhibitor) meglitinide, hypoglycemia)
GLP-1 agonist sulfonylurea GLP-1 agonist (if
Basal insulin BMI >35 kg/m 2)
Considerations Efficacy Degree of Risk of hypoglycemia No specific
based on: Adverse effect profile hyperglycemia based Problems with weight recommendations
on A1C. Risk of gain provided
Cost hypoglycemia and
Injection preference effects on weight
Glucose issue (fasting also considered
or prandial)
Triple therapy Same as for dual GLP-1 agonist plus DPP-4 inhibitor Not addressed
(options to add therapy thiazolidinedione or
to metformin) Insulin most likely to GLP-1 agonist plus thiazolidinedione or
obtain A1C goal meglitinide
GLP agonist
Strongly consider if GLP-1 agonist plus
or
A1C > 8.5% sulfonylurea
Insulin (with marked
DPP-4 inhibitor plus
hyperglycemia)
thiazolidinedione
meglitinide
sulfonylurea
When to initiate At diagnosis with Symptomatic patients A1C remains > 7.5% Not addressed
insulin symptoms and/or with A1C >9% despite other
glucose > 300 mg/ measures
dL or A1C >10%
a
Assumes no contraindications to metformin use.
ACCE = American College of Clinical Endocrinologists; ACE = American College of Endocrinology; ACP = American College of
Physicians; ADA = American Diabetes Association; BMI = body mass index; DPP-4 = dipeptidyl peptidase-4; EASD = European
Association for the Study of Diabetes; NICE = National Institute for Health and Clinical Excellence; T2DM = type 2 diabetes mellitus.
Information from: Inzucchi S, Bergenstal R, Buse J. Management of hyperglycemia in type 2 diabetes: a patient-centered approach.
Diabetes Care 2012;35:1364-79; Rodbard H, Jellinger P, Davidson J, et al. Statement by an American Association of Clinical
Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control.
Endocr Pract 2009;15:540-59; Qaseem A, Humphrey L, Sweet D, et al. Oral pharmacologic treatment of type 2 diabetes mellitus:
A clinical practice guideline from the American College of Physicians. Ann Intern Med 2012;156:218-31; and National Institute for
Health and Clinical Excellence. The Management of Type 2 Diabetes, NICE Clinical Guideline 87, 2009. Available at guidance.nice
.org/CG87/NICEGuidance/pdf/English. Accessed May 3, 2012.

Diagnosis of T2DM
A1C < 6.5%–7.0% A1C 7.1%–9.0% A1C 9.0%–9.9% A1C > 10%
Diet/exercise and Diet/exercise and Diet/exercise and Diet/exercise

consider low- initiate metformin initiate metformin Implement basal/
dose metformin therapy therapy and bolus or premixed
therapy consider insulin regimen
(especially if additional agent Upon improved
overweight) glycemic control,
No additional consider adding oral
therapy needed
agents (especially
metformin) and
Assess A1C reduce daily insulin
requirements
< 6.5%–7.0% Still elevated
No additional Add additional

therapy needed therapy
Cost is Primary glucose Primary glucose Both fasting Weight loss No aversion to
significant issue is prandial issue is fasting and prandial desired injections
issue problematic
Sulfonylurea GLP-1 agonist Thiazolidinedione Thiazolidinedione GLP-1 agonist GLP-1 agonist
NPH insulin DPP-4 inhibitor Basal insulin Sulfonylurea Insulin
Meglitinide Sulfonylurea Once-weekly
Glucosidase exenatide
inhibitor Bromocriptine
Rapid-acting Colesevelam
insulin
Pramlintidea
Figure 1-1. General approach to the management of type 2 diabetes mellitus.

a
Pramlintide should only be used in patients currently receiving bolus/prandial insulin therapy.
A1C = hemoglobin A1C; DPP-4 = dipeptidyl peptidase -4; GLP-1 = glucagon-like peptide 1; NPH = neutral protamine
Hagedorn; T2DM = type 2 diabetes mellitus.
Information from Inzucchi S, Bergenstal R, Buse J. Management of hyperglycemia in type 2 diabetes: a patient-centered
approach. Diabetes Care 2012;35:1364-79; and Rodbard H, Jellinger P, Davidson J, et al. Statement by an American Association
of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for
glycemic control. Endocr Pract 2009;15:540-59.

American Association of Clinical Endocrinologists/ min monotherapy, sulfonylurea therapy is regarded as
American College of Endocrinology second-line therapy. If the patient is at significant risk
The American Association of Clinical Endocrinol- of hypoglycemia and did not tolerate the sulfonylurea,
ogists/American College of Endocrinology recommen- or if the sulfonylurea is contraindicated, DPP-4 inhib-
dations and algorithm for managing hyperglycemia were itors or thiazolidinediones are considered alternatives.
last updated in 2009 (Rodbard 2009). Their 2011 guide- Adding a third agent depends on the choice of dual ther-
lines for developing diabetes comprehensive care plans apy, considering the consequences of further weight
continue to follow the 2009 recommendations. The gain, existing obesity, insulin resistance, and level of
approach to therapy is similar to the ADA’s newer recom- hyperglycemia.
mendations; however, initial and subsequent treatment
options are categorized more so by A1C and differ by
A1C range (i.e., 6.5%–7.5%, 7.6%–9.0%, or greater than Incretin-Based Therapies
9.0%). Their goal A1C is 6.5% or less, which is more Decreased insulin sensitivity and progressive loss of
stringent than the ADA goal of 7% or less. Monotherapy pancreatic beta-cell insulin secretion remain hallmarks
is recommended for those with an A1C of 7.5% or less; of the pathophysiology of T2DM. In addition, a signif-
this advances to dual and perhaps triple therapy, with or icant amount of research has focused on the incretin
without insulin, if the glycemic goal is not met after 2–3 system and its role in contributing to hyperglycemia.
months. Dual therapy is warranted early when the A1C The two main incretin hormones thought to maintain
is between 7.6% and 9.0%, again with progression to tri- euglycemia are GLP-1 and glucose-dependent insuli-
ple therapy or insulin as needed. If the patient presents notropic peptide (GIP). Both hormones are secreted
with an A1C of greater than 9% and without symptoms, because of carbohydrate and fat consumption, and both
triple therapy may be initiated; if the patient has an A1C result primarily in increased glucose-dependent insu-
of greater than 9% with symptoms, insulin should be lin secretion and decreased glucagon secretion. Both
considered. Recommended agents to add to metformin hormones are rapidly metabolized in the circulation by
are, in order, a GLP-1 agonist, a dipeptidyl peptidase-4 DPP-4. In patients with T2DM, the action of DPP-4 is
(DPP-4) inhibitor, thiazolidinedione, meglitinide, or maintained and GLP-1 is minimized, and the activity of
sulfonylurea. This selection sequence is based on over- GIP is almost completely lost. Even if exogenous GIP is
all efficacy, risk of hypoglycemia, and effects on weight. administered at supraphysiologic doses, GIP effects are
negligible. Therefore, most research into incretin-based
Practice Guideline from the American therapies has focused on preserving or enhancing the
College of Physicians effects of GLP-1.
In early 2012, the American College of Physicians
published a practice guideline specific to the oral DDP-4 Inhibitors
pharmacologic treatment of T2DM (Qaseem 2012). By competing for GLP-1 binding to DPP, DPP-4
Although the guideline is thorough in evaluating the inhibitors block the breakdown of naturally secreted
existing clinical data in this area, it provides few spe- GLP-1 and extend its duration of effect in the body.
cific recommendations. Metformin is recommended Five DPP-4 inhibitors are available on the international
as initial monotherapy for patients who do not achieve market: sitagliptin, saxagliptin, linagliptin, vildagliptin,
glycemic control through diet, physical activity, and and alogliptin. The first three are approved for use in
weight loss. The only additional recommendation re- the United States and are administered orally and once
garding glycemic control is to add a second agent to daily. Sitagliptin and saxagliptin require dosage adjust-
metformin if persistent hyperglycemia continues; the ment with kidney impairment, whereas linagliptin does
guideline finds no proven superiority of one combina- not (Table 1-2).
tion over another in reduced mortality, cardiovascular These agents appear to have a larger effect on reduc-
events, or microvascular complications. The place in ing postprandial than fasting glucose concentrations.
therapy of GLP-1 agonists or insulin therapies is not Many clinical studies of varying design are reported in
addressed, which limits the use of this guideline in clin- the literature, and each agent has not been studied to
ical practice. the same degree, particularly with respect to compar-
isons with other T2DM drugs. Meta-analyses suggest
National Institute for Health and Clinical Excellence that DPP-4 inhibitors, when used as monotherapy, do
The United Kingdom’s National Institute for Health not provide the same degree of glycemic control as
and Clinical Excellence (NICE) guidelines regarding metformin (Karagiannis 2012). In combination ther-
the therapeutic management of T2DM were last updated apy with metformin, DPP-4 inhibitors provide an A1C
in 2009 (NICE 2009). These guidelines are more pre- decrease slightly smaller than that with sulfonylureas,
scriptive than current ADA guidelines. For patients not about the same as that with pioglitazone, and signifi-
attaining adequate glycemic control despite metfor- cantly less than that with GLP-1 agonists. From a safety

Table 1-2. Comparison of Incretin-Based Therapies
Twice-Daily Once-Weekly
Sitagliptin Saxagliptin Linagliptin Exenatide Liraglutide Exenatide
Dosage 100 mg/day 2.5–5 mg/day 5 mg/day 5 mcg bid for 1 0.6 mg/day; increase 2 mg once weekly
month; then 10 weekly as tolerated
mcg bid if tolerated up to 1.8 mg/day
Dosage adjustment with kidney CrCl ≥ 30–49: CrCl < 50: Adjustment not Adjustment not Adjustment not Same as for
impairment 50 mg/day 2.5 mg/day needed needed, but use needed twice-daily
CrCl < 30: caution if CrCl is Use with caution in formulation
25 mg/day 30–50, and avoid patients with
if < 30 kidney impairment
New Pharmacotherapies for Type 2 Diabetes

Primary glycemic focus Postprandial Postprandial Postprandial Postprandial Postprandial Fasting and
Postprandial
Adverse effect profile Upper respiratory tract infection, urinary tract Nausea, vomiting, constipation, diarrhea, Injection site
infection, headache, hypoglycemia (when taken with hypoglycemia, case reports of acute kidney pruritus, nausea,
sulfonylurea), angioedema (rare), case reports of acute failure and pancreatitis vomiting,
10
kidney failure and pancreatitis diarrhea
Comparative efficacya
Monotherapy vs. placebo –0.79% –0.63 to 0.65% –0.69% –0.7% to 0.9% –1.65% NS
Monotherapy vs. metformin 0.145%–0.51% 0.24%–0.30% NS NS NS –0.05%
Monotherapy vs. pioglitazone 0.48% NS NS NS NS 0.10%
Monotherapy vs. GLP-1 agonist 0.38% NS NS NA NA NA
Monotherapy vs. DPP-4 inhibitor NA NA NA NS NS –0.38%
Monotherapy vs. sulfonylurea NS NS NS NS –0.81% NS
+ Metformin vs. placebo –0.65% –0.82% –0.64% to 0.73% –0.60% to 0.86% –1.1% NS
+ Metformin vs. sulfonylurea 0.035%–0.07% 0.06% NS NS 0.0% NS
+ Metformin vs. thiazolidinedione 0.06% NS NS NS NS –0.3%
+ Metformin vs. DPP-4 inhibitor NA NA NA NS –0.9% –0.6%
+ Metformin vs. GLP-1 agonist 0.9% NS NS NA NA NA
a
Efficacy denoted as between group difference in A1C change from baseline (positive difference suggests the comparator medication more effective).
bid = twice daily; CrCl = creatinine clearance (mL/minute); DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide 1; NA = not applicable; NS = not studied.
PSAP 2013 • Cardiology/Endocrinology

standpoint, DPP-4 inhibitors are very well tolerated. In comparisons of twice-daily exenatide with other oral
one comparative study, the incidence of hypoglycemia T2DM medications are lacking. Exenatide in combi-
with sitagliptin was low (4.9%), whereas that with the nation with basal insulin therapy provides additional
sulfonylurea glipizide was much higher (32%) (Nauck benefit in reducing A1C over either agent as mono-
2007). In contrast to sulfonylureas and pioglitazone, therapy.
both of which are associated with weight gain, DPP-4 Liraglutide monotherapy has been shown to reduce
inhibitors appear to be weight neutral. A concern with A1C significantly more than sulfonylurea monotherapy,
this class upon postmarketing surveillance is case –1.14% and –0.51%, respectively (Garber 2009). It also
reports of pancreatitis. This is discussed in more detail provided better improvements in fasting (–25.5 vs.
below. –5.2 mg/dL) and postprandial glucose (–37.5 vs. –24.5
The DPP-4 inhibitors provide a novel mechanism mg/dL) concentrations as well as a more favorable
of action that is a good complement when added to effect on weight and a lower risk of hypoglycemia (8%
metformin. There are no data from long-term compar- vs. 24%). For patients unable to respond adequately to
ative studies on whether one agent within the class is metformin monotherapy, adding liraglutide shows effi-
either more effective or safer than another. The overall cacy similar to adding a sulfonylurea as well as a greater
reduction in A1C is modest (0.6%–0.9%) and depen- reduction in A1C compared with adding a DPP-4 in-
dent on baseline A1C. Patients with high A1Cs are more hibitor. Liraglutide also shows a favorable effect on
likely to experience a greater reduction in A1C than glycemic control compared with placebo when added
those closer to goal. The DPP-4 inhibitors are a viable to the combination of metformin and thiazolidin-
option in patients with mildly elevated A1C despite edione. Liraglutide and exenatide have each shown
metformin therapy, especially when postprandial either similar or greater reductions in A1C compared
hyperglycemia is a predominant issue. The tolerabil- with insulin glargine when added to the regimen of
ity, route and frequency of administration, and weight patients taking metformin and a sulfonylurea (–1.11%
neutrality of DPP-4 inhibitors make them an attractive to 1.33% vs. 1.09% to 1.11%, respectively). However,
option compared with other T2DM agents. Limitations because these studies showed a very low rate of attain-
of their use include cost and the inability to continu- ing the a priori goal fasting glucose concentration in
ally dose adjust to optimize glycemic control. If DPP-4 the basal insulin treatment arms, any direct compari-
inhibitors are added to existing sulfonylurea therapy, son is difficult.
consider decreasing the dose of sulfonylurea by one-half Data from head-to-head comparisons suggest liraglu-
to reduce the risk of hypoglycemia. Linagliptin offers tide reduces A1C to a small (–0.33%) but greater degree
the advantage of not requiring a dose adjustment when than twice-daily exenatide in patients treated with
used in patients with kidney impairment. metformin, a sulfonylurea, or both (Buse 2009). When
switching from exenatide to liraglutide, an additional
GLP-1 Agonists reduction (–0.32%) in A1C reduction can be seen (Buse
Short-Acting GLP-1 Agonists 2010). Both agents show a beneficial, though modest,
Exenatide and Liraglutide effect on blood pressure (–2.0 to 2.5 mm Hg systolic,
Exenatide entered the world market in 2005 and was -1.0 to 2.0 diastolic) and lipids (–15 mg/dL to 17 mg/dL
the first GLP-1 agonist to receive U.S. Food and Drug in low-density lipoprotein [LDL] cholesterol). However,
Administration (FDA) label approval. Liraglutide fol- no prospective studies have specifically evaluated any
lowed, with FDA approval in 2010. As GLP-1 analogs, cardiovascular benefit of this class of agents. A sub-
these agents mimic endogenously secreted GLP-1 and stantial amount of research is addressing whether these
increase pancreatic insulin secretion, reduce glucagon agents preserve beta-cell function over time. Agents
secretion, slow gastric emptying, and promote satiety that stimulate insulin secretion (e.g., sulfonylureas) can
during meals. Liraglutide is more homologous to human hasten the loss of beta-cell insulin secretion. The GLP-1
GLP-1 than exenatide. Administration of exenatide agonists have shown improvements in beta-cell insulin
must be within 60 minutes of the morning and evening secretion; exenatide studies with up to 3 years of follow-
meals, whereas liraglutide can be administered once up show that insulin secretion does not significantly
daily without regard to meals. Exenatide can be titrated decrease and may actually increase (Klonoff 2008).
from initial to maximal daily dosage after 1 month if Overall, the incidence of serious adverse events is
tolerated (see Table 1-2). Liraglutide can be increased at very low in clinical trials. The GLP-1 agonists show
weekly intervals as tolerated. significant benefits in weight loss (–1.6% to 3.4%) com-
Exenatide significantly reduces A1C both as mono- pared with DPP-4 inhibitors, thiazolidinediones, sul-
therapy and when added to existing treatments with a fonylureas, and insulin. As previously mentioned, DPP-4
sulfonylurea, metformin, thiazolidinediones, the com- inhibitors are relatively weight neutral, whereas the lat-
bination of sulfonylurea and metformin, and the combi- ter three agents can increase patient weight. The inci-
nation of metformin and sitagliptin (see Table 1-2). Direct dence of hypoglycemia is lower than with sulfonylureas.

Dose-dependent nausea and vomiting are significant further lower the A1C to a small degree (–0.2%), but
with either exenatide or liraglutide, but the persistence the clinical relevance of this has not been evaluated. A
of these adverse effects appears to be less with liraglu- comparative study of drug-naive patients showed that
tide than with twice-daily exenatide (Buse 2009). These once-weekly exenatide provides a reduction in A1C
effects limit the use of these agents, although a toler- from baseline similar to that of metformin or piogli-
ance to nausea and vomiting may develop over time in tazone but greater than that of sitagliptin (Table 1-3)
some patients. Weight loss, although markedly higher (Russell-Jones 2012). When added to metformin, once-
in patients who experience significant nausea or vomit- weekly exenatide showed reductions in A1C similar
ing, is still seen in patients who do not experience these to those with pioglitazone and greater than those with
adverse effects. sitagliptin. If patients are currently receiving and then
Either exenatide or liraglutide should be considered switched from pioglitazone or sitagliptin to extended-
in patients with a suboptimal response to metformin, release exenatide, A1C reductions are maintained in
those with moderate hyperglycemia, those willing to patients receiving pioglitazone and further decreased
receive injections, or those seeking additional weight in those receiving sitagliptin (Wysham 2011). Studies
loss beyond what they might attain with metformin. comparing once-weekly exenatide with insulin glargine
In patients with significant gastroparesis, both agents in patients not under optimal control with other oral
should be avoided because they may aggravate this T2DM agents suggest that exenatide reduces A1C to
condition. Kidney function should be assessed before a slightly greater extent, is associated with weight loss
initiating either agent. If significant renal insufficiency versus weight gain, and has a lower incidence of hypo-
(creatinine clearance less than 30 mL/minute) exists, glycemia. However, the trial data must be considered
exenatide should be avoided. The manufacturer of lira- with caution because the insulin glargine arm of the
glutide states to use with caution but does not provide a study attained prespecified fasting glucose targets in
specific clearance cutoff. only about 20% of subjects, and the dropout rate was
higher in those receiving exenatide (Diamant 2010).
Long-Acting GLP-1 Agonists Unlike twice-daily exenatide, the extended-release for-
In June 2011, an extended-release formulation of mulation is not approved for use with insulin of any type
exenatide allowing once-weekly administration was because the combination has not been studied in clini-
approved in Europe. Petitions for approval in the cal trials.
United States were rejected pending additional safety The adverse effect profile of the once-weekly exenatide
data; however, in early 2012, extended-release exena- formulation appears to be similar to that of the twice-
tide received FDA approval. Incorporating exenatide daily formulation. No difference in weight loss between
into microspheres allows the extended-dosage interval. the two agents has been reported. The weight loss in
Previous treatment with the twice-daily formulation is drug-naive patients is similar between monotherapy
not a stipulation for initiation. The only available dos- with metformin and once-weekly exenatide and is more
age is 2 mg by subcutaneous injection once weekly. favorable than that observed with pioglitazone, sitag-
In contrast to the twice-daily formulation, extended- liptin, or insulin. The incidence of nausea and vomiting
release exenatide is administered without regard to is lower with once-weekly exenatide, but injection site
meal ingestion, and it requires no dose titration to min- pruritus is much higher. In preclinical rodent studies,
imize adverse effects (see Table 1-2). It normally takes exenatide showed a potential risk of thyroid carcinoma
6–10 weeks to see the maximal effect on plasma glu- similar to early studies with liraglutide. This has not
cose concentrations. The drug is supplied as a kit with been an issue with the twice-daily formulation. This
a powder vial that must be reconstituted by the patient topic is discussed in greater detail below.
immediately before injection. The supplied materials As with insulin, use of once-weekly exenatide is lim-
also include a prefilled syringe to deliver the diluent, ited because some patients may be averse to the parenteral
a vial connector for the two, and a custom needle for route of administration. Nor does the agent allow dose
the delivery system. A delivery pen that may lessen titration if glycemic goals are not met. Patients should
the administrative steps for patients is currently under be monitored for improvement in glycemic control
development. using A1C and both fasting and postprandial glucose
In clinical trials comparing the once-weekly and concentrations. Weight loss and gastrointestinal toler-
twice-daily formulations, the extended-release agent ability should be monitored.
provided a greater and statistically significant A1C Because of the potential for severe adverse events,
reduction (0.4%–0.7% between-group difference from once-weekly exenatide should not be considered first-
baseline) and a more profound impact on fasting glu- line therapy for patients with a contraindication to
cose concentrations (16–23 mg/dL between-group dif- metformin until a better understanding of its overall
ference) (Blevins 2011; Drucker 2008). Switching from risk can be assessed. The agent should be considered in
the twice-daily to the once-weekly formulation can patients who might benefit from a GLP-1 analog, in those

Table 1-3. Comparison of Therapies for T2DM Hyperglycemia Added to Metformin
Agent or Class Primary Glycemic Effect Benefits Limitations/Precautions
Sulfonylurea Fasting and prandial Efficacy Weight gain
Cost Hypoglycemia risk
Hastens beta-cell
dysfunction
Meglitinide Prandial Prandial focus Hypoglycemia risk
Use in kidney impairment Weight gain
Mealtime dosing
Pioglitazone Fasting and prandial Improves insulin sensitivity Weight gain and edema
Low risk of hypoglycemia Risk of heart failure
Possible cardiovascular benefit Risk of osteoporosis
Possible bladder cancer risk
a-Glucosidase inhibitor Prandial No systemic absorption GI adverse effect profile
Prandial focus Mealtime dosing
DPP-4 inhibitor Prandial Well tolerated Possible pancreatitis risk
Weight neutral Modest A1C effect
Cost
GLP-1 agonist Fasting and prandial Greater effect on prandial Nausea/vomiting
(once-weekly exenatide glucose Injection site effects
greater fasting effect) Weight loss Questionable pancreatitis or
Efficacy thyroid cancer risk
Cost
Colesevelam Prandial Lipid benefits Large pill size/burden
No systemic absorption GI adverse effect profile
Small decrease in A1C
Avoid with high triglycerides
Bromocriptine Fasting and prandial Low risk of hypoglycemia Small decrease in A1C
CNS adverse effects
Amylin agonist Prandial Modest weight loss High risk of hypoglycemia
Efficacy on postprandial Must be taken with insulin
glucose Frequent injections
Injection site effects
GI adverse effects
Insulin Basal – fasting Significant A1C reduction Hypoglycemia
Bolus – prandial Flexibility in dosing strategies Weight gain
and titration Injection site effects
CNS = central nervous system; DPP-4 = dipeptidyl peptidase-4; GI = gastrointestinal; GLP = glucagon-like peptide.
Information from: Inzucchi S, Bergenstal R, Buse J. Management of hyperglycemia in type 2 diabetes: a patient-centered approach.
Diabetes Care 2012;35:1364-79; and Rodbard H, Jellinger P, Davidson J, et al. Statement by an American Association of Clinical
Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control.
Endocr Pract 2009;15:540-59.

willing and able to reconstitute the dry powder, and Colesevelam
in those for whom once-weekly administration could Bile acid sequestrants (BASs) have been used in the
improve adherence. treatment of dyslipidemia for decades. In addition to
their ability to lower LDL cholesterol, they have been
Other Agents Now Approved shown to improve glycemic control in patients with
T2DM. Colesevelam was approved for dyslipidemia
for T2DM Hyperglycemia in 2000; in 2008, it was approved to control hypergly-
Bromocriptine cemia in adults with T2DM. Colesevelam remains the
The dopamine (D2) receptor agonist bromocriptine only BAS approved for such use in the United States,
has been used for Parkinson disease and various endo- even though colestimide is approved in Japan for the
crinologic disorders since its approval in the late 1970s. same indication.
Bromocriptine mesylate quick release was approved The exact mechanism of how colesevelam improves
in 2009 for use in T2DM to control hyperglycemia. glucose concentrations is unknown. It is proposed to
How bromocriptine lowers glucose concentrations is have an effect on farnesoid X receptor, a bile acid recep-
unknown. The mechanism is thought to include resetting tor, and activity in the gut and possibly in the liver. This
the body’s circadian clock by increasing dopaminer- is thought to eventually lead to reduced hepatic gluco-
gic and sympathetic tone within the central nervous neogenesis and perhaps affects GLP-1 and GIP as well
system to a time of day it normally peaks in healthy sub- (Handelsman 2011). The standard total daily dosage is
jects. This increased tone has been linked to an increase 3.75 g orally, given in one or two doses. Colesevelam is
in glucose tolerance and improved insulin sensitivity available as a pill or suspension.
and may affect lipid metabolism (DeFronzo 2011). In This agent has not been studied as monotherapy in
addition, bromocriptine has α 2-agonist, α1-antagonist, patients with T2DM, but it has been compared with
prolactin, and serotonin-like properties. placebo when added to metformin, sulfonylurea, and
The dosing strategy and formulation used for the insulin therapy. The ability of colesevelam to lower
treatment of T2DM differ from those employed for A1C is limited, with reductions from baseline of –0.3%
other disorders. The usual starting dose is 0.8 mg once to –0.5% (Handelsman 2011; Goldfine 2010). Limited
daily, taken with food to improve bioavailability and data exist to compare colesevelam with other diabetes
within 2 hours of awakening. The dose can be increased agents in their ability to lower A1C. In a small (n=169),
at weekly intervals as tolerated and to glycemic effect short (16 weeks) study, colesevelam 3.75 g/day was
by 0.8 mg/day to an effective dose of 1.6–4.8 mg/day. compared with rosiglitazone 4 mg/day and sitagliptin
Bromocriptine affects both fasting glucose (0–27 mg/ 100 mg/day (Rigby 2010). In each treatment group,
dL) and postprandial glucose (37 mg/dL) concentra- A1C was significantly reduced from baseline; coleseve-
tions. Clinical efficacy data are limited to small, short- lam reduced A1C by –0.3%, rosiglitazone by –0.6%, and
term studies of up to 24 weeks, and no comparisons sitagliptin by –0.4%. However, no statistical analysis
with other diabetes drugs have been published. When was performed between treatment groups.
added to other oral agents or insulin, bromocriptine Colesevelam is well tolerated, showing no impact on
lowers A1C from baseline by 0.1%–0.6%. weight and only a minimal risk of hypoglycemia. As with
Compared with placebo, the formulation of bro- all BAS agents, constipation, dyspepsia, and nausea are
mocriptine used for T2DM causes an increase in the most common adverse effects. The agent should be
nausea, vomiting, dizziness, headache, and diarrhea; it used with caution in patients with gastroparesis and not
also produces a lower rate of hypoglycemia and cardio- used at all in patients with triglyceride concentrations
vascular events and is weight neutral (Gaziano 2010). greater than 500 mg/dL, a history of bowel obstruction,
Bromocriptine should not be used during pregnancy or or previous hypertriglyceridemia-induced pancreatitis.
in patients with a history of syncopal migraines. Caution According to the manufacturer’s package insert, this
is warranted in patients with orthostatic hypotension or agent should also not be administered within 4 hours
psychosis because bromocriptine may exacerbate these of other drugs known to have reduced absorption or
conditions or limit the effectiveness of agents used in effect when coadministered with colesevelam (e.g.,
their treatment. phenytoin, warfarin, cyclosporine, levothyroxine).
Because there are no data comparing bromocriptine The precise place in therapy of colesevelam is un-
with other agents used to treat hyperglycemia, it is diffi- known. Given its limited efficacy, the agent may be
cult to determine the role of this agent in the treatment considered in patients with only mildly elevated A1C
of T2DM. In patients with mild hyperglycemia who who are inadequately controlled with a sulfonylurea,
have both fasting and postprandial glycemic problems, metformin, or insulin therapy with or without mild
bromocriptine may be considered in addition to other elevations in LDL cholesterol. The individual pills
oral agents or insulin therapy. are large, and six tablets are required to achieve the

recommended daily dose. Therefore, colesevelam may bolus estimates is 0.1 unit/kg before the biggest carbo-
not be an appropriate alternative for patients who have hydrate meal of the day (referred to as basal plus), with
difficulty swallowing; a suspension is available, which subsequent increases in frequency to other mealtimes as
may be a better substitute in such patients. needed (Ampudia-Blasco 2011). These initial bolus esti-
mates assume a fixed carbohydrate intake; therefore, if
Conversion from Oral DM Agents the patient eats very little at one meal and significantly
more at another, hypoglycemia or hyperglycemia can
to Insulin-Only Therapy occur. Eventually, it is best to provide a specific amount
Some patients, because of significant hyperglycemia, of bolus insulin based on total carbohydrate ingestion at
adverse effects, or contraindications to other T2DM each meal. This latter technique requires considerable
drugs, require an insulin-only regimen to control their patient education to estimate the carbohydrate quantity
hyperglycemia. Current ADA recommendations are to of meals but has the advantage of providing adequate
initiate insulin early in patients with significant base- mealtime insulin based on the patient’s specific diet.
line hyperglycemia (A1C of 10% or greater; glucose Advantages of using premixed insulin therapy
greater than 300 mg/dL) and in those with symptoms include fewer injections per day, less calculation by the
of hyperglycemia (e.g., polyuria, polydipsia, polypha- patient, lower costs with older insulin formulations, and
gia) (Inzucchi 2012). Monotherapy with a long-acting ease of use in patients incapable of or unwilling to deter-
basal insulin alone (e.g., glargine, detemir) in patients mine and manage their daily insulin needs. The primary
with T2DM will not provide control of hyperglycemic disadvantage of this therapy option is that dosage adjust-
excursions after meals. Therefore, the most common ment alters both administered insulins, and patients
insulin-only regimens include the use of twice-daily may not have issues with both fasting and postprandial
premixed insulin preparations or basal/bolus insulin glucose control. The risk of hypoglycemia using older,
therapy. The premixed option uses existing commercial less expensive insulin options is higher than with newer
insulin products containing more than one type of insu- insulin analogs. Patients also need to make sure they are
lin (e.g., 70% neutral protamine Hagedorn, 30% regular consistent in their food intake because increases in dos-
insulin), or has the patient draw two types of insulin age are not as flexible.
into the same syringe. Basal/bolus insulin therapy Advantages of basal/bolus therapy are that it is more
employs a long-acting insulin preparation either once or patient-specific given the insulin needs and can be
twice daily (basal therapy) and premeal injections with more easily adjusted to patient lifestyles. If a patient
a rapid-acting insulin (bolus therapy). The intent of the eats more carbohydrates at one meal, the bolus ther-
basal therapy is to mimic the natural insulin secretion apy can be increased accordingly. If the patient skips
that occurs throughout the day and night even while a meal, the bolus therapy can be skipped at that time.
fasting, whereas the bolus therapy controls for hyper- Disadvantages include a higher number of daily injec-
glycemic excursions after meals. tions than with premixed formulations because neither
Whether premixed or basal/bolus therapy is initiated, of the currently available basal insulins should be mixed
the first step in developing an insulin-only regimen is to with other insulins in the same syringe. Two 6-month
estimate the patient’s total daily insulin requirements. studies comparing basal/bolus therapy with premixed
Initial estimates vary by clinician and are most com- analog insulin therapy (either 50:50 or 70:30 prot-
monly weight-based. Estimates of 0.4–0.6 unit/kg/day amine/rapid-acting analog) showed greater, though
are common, and patients with T2DM often require small, improvements in A1C with basal/bolus ther-
considerably more insulin compared with patients apy (a 0.17%–0.33% difference between groups) (Liebl
with type 1 diabetes mellitus because of insulin resis- 2009; Rosenstock 2008). The incidence of significant
tance. Premixed insulin therapy administers two-thirds hypoglycemia was higher with basal/bolus therapy in
of the total daily insulin requirements before the one study, whereas the other study found no differences.
morning meal and the remaining one-third before Yet another study showed that basal/bolus therapy pro-
the evening meal. Administration time before meals vided a 0.47% improvement in A1C compared with a
depends on the specific short- or rapid-acting insulin premixed alternative; no difference in hypoglycemia
selected. Alterations in basal insulin dosage can then be was seen, and basal/bolus therapy was more cost-effec-
based on assessing glycemic control in the morning and tive per drop in A1C (Vora 2011; Fritsche 2010).
before the evening meal. Despite due diligence and patient adherence to in-
With basal/bolus therapy, one-half of the total daily sulin regimens and diet, hyperglycemic excursions still
insulin requirement is provided as basal insulin, with occur. When this happens, patient-specific plans to reduce
the other half used for premeal bolus dosing. The daily glucose concentrations must be in place. Historically,
bolus requirement is then equally divided for morning, sliding-scale insulin regimens have been used; how-
midday, and evening meals. An alternative to the initial ever, these regimens treat each patient the same, even

though insulin requirements vary with the individual. Updates in Noncardiac
Correctional dosing for hyperglycemic excursions pro- Diabetes Drug Safety
vides more patient-specific insulin regimens based on
total daily insulin needs. It is best to implement correc- GLP-1 Agonists and Thyroid Carcinoma
tional dosing after the basal insulin has been employed In their early stages of development, both liraglutide
and found to be accurate. The rule of 1800 provides and exenatide LAR showed an increased risk of thyroid
an estimate of a patient’s insulin sensitivity. This rule C-cell focal hyperplasia and medullary thyroid cancer
assists in estimating how much of a decrease in blood in rodent studies (Knudsen 2010). There are no such
glucose will occur with a specific amount of rapid-act- data suggesting that twice-daily exenatide formulation
ing insulin. When 1800 is divided by the patient’s total causes this same problem. This lower risk of cancer may
daily insulin needs (i.e., the sum of the patient’s current be because the other two GLP-1 formulations allow
or estimated bolus and basal insulin daily use), the quo- a more constant exposure to GLP-1 activity. Clinical
tient provides an estimate of the milligram-per-deciliter trial data in humans have not shown an increased risk
reduction in glucose that 1 unit of a rapid-acting insu- of such events with any of these agents, but the rarity of
lin might provide (Peters 2011). If using regular human this type of cancer means it cannot be completely ruled
insulin for bolus therapy, the numerator should be mod- out.
ified from 1800 to 1500. Because individual patient’s Serum calcitonin concentrations, a potential bio-
daily insulin requirements vary, correctional dosing is marker for medullary thyroid cancers, are no higher in
more patient-specific than sliding scales, which are more patients receiving liraglutide than in control patients in
“one size fits all.” The patient care scenario describes a studies lasting up to 2 years (Parks 2010). The potential
practical example of formulating a basal/bolus and cor- cause of this adverse effect in rodents is not understood.
rectional dosing regimen. Recent studies show that GLP-1 receptors are expressed
Patient Care Scenario

A male patient (weight 238 lb) with newly diagnosed Selections for basal insulin include insulin detemir
T2DM has an A1C today of 11.2%. You have been charged and glargine. Although NPH is an alternative, it carries
by the endocrinologist to develop an insulin-only med- a greater risk of hypoglycemia and does not mimic phys-
ication strategy to aid in the control of the patient’s iologic insulin secretion as well as the others. Selections
hyperglycemia using basal/bolus insulin. Calculate this for bolus insulin include the rapid-acting insulins aspart,
patient’s basal, bolus, and correctional insulin needs, and lispro, and glulisine. Regular insulin can be used, but it
design an appropriate initial regimen for him. has a slower onset and a longer duration than the rapid-
acting insulins. Hence, an appropriate insulin regimen for
Answer this patient could include 27 units of insulin glargine once
The first step is to estimate the patient’s total daily insu- daily and 9 units of insulin aspart administered 15 min-
lin needs. Estimates of total daily insulin needs vary, but utes before meals.
for this case, assume that 0.5 unit/kg/day is sufficient. After implementing the basal and bolus insulin regi-
Doses of both basal and bolus insulin can be quickly men, the correctional insulin needs can be estimated.
optimized after initiation on the basis of patient-attained Correction insulin needs for hyperglycemic excursions
glucose concentrations. This patient weighs 238 lb, or 108 commonly use the “rule of 1800.” The quotient of 1800/
kg. Total daily insulin requirements are thus estimated total daily insulin estimates the mg/dL decrease in blood
to be 54 units (0.5 × 108). The patient’s basal insulin glucose that 1 unit of rapid-acting insulin may achieve (in
requirements are one-half of the total daily needs esti- this case, 1800 ÷ 54 = 33 mg/dL). This can be rounded up
mate—in this case, 27 units (0.5 × 54). The other half of (35) or down (30) for simplicity. A patient-specific sliding
the total daily needs estimate is the bolus insulin require- scale can then be developed around this estimate. Assume
ments (again, 27 units); this is split among the daily meals. a goal of 100–130 mg/dL is the target to achieve after
Assuming the patient eats breakfast, lunch, and dinner, hyperglycemia is detected. One unit can be administered
premeal bolus requirements equal 9 units (27 ÷ 3). The if the blood glucose is between 130 mg/dL and 160 mg/
alternative method of 0.1 unit/kg before meals gives 10.8 dL, 2 units can be administered if it is 160–190 mg/dL,
units, which can be rounded up or down. and so on.
1. Peters K. Intensifying treatment of type 2 diabetes mellitus: adding insulin. Pharmacotherapy 2011;31(12 suppl):54S-64S.
2. Fritsche A, Larbig M, Owens D, et al. Comparison between a basal-bolus and a premixed insulin regimen in individuals with type 2
diabetes – results of the GINGER study. Diabetes Obes Metab 2010;12:115-23.

in C-cells of normal rodent thyroid tissue but not in nor- Pioglitazone and Bladder Cancer
mal human tissue. However, 27% of human medullary The potential association between pioglitazone and
thyroid carcinomas express GLP-1 receptors (Waser bladder cancer has been a matter of debate dating back
2011). As part of its Risk Evaluation and Mitigation to the drug’s U.S. approval in 1999. The concern was
Strategy, liraglutide’s manufacturer issued a reminder to increased after a cardiovascular secondary prevention
health care professionals in June 2011 to be more atten- study reported a higher rate of bladder neoplasm in
tive to this rare potential adverse effect to their patients. patients receiving pioglitazone than in those receiv-
The manufacturer of once-weekly exenatide is following placebo (0.5% vs. 0.2%, respectively) (Dormandy
ing the same strategy and is implementing a medullary 2005). The difference was not statistically significant.
thyroid carcinoma registry to monitor this risk. To Since then, several epidemiologic studies have provided
avoid potential risk, neither liraglutide nor once-weekly additional information regarding the risk of this adverse
exenatide should be used in patients with a personal or event. In April 2011, two cohort studies from a large
family history of medullary thyroid carcinoma. Routine health care provider data registry found no association
monitoring of serum calcitonin is of uncertain use and between pioglitazone use and bladder cancer (Ferrara
is not deemed necessary. 2011; Lewis 2011). However, one of these studies, a
planned midpoint analysis of a 10-year FDA-requested
Incretin-Based Therapies and Pancreatitis study, found a weak association with pioglitazone use
Patients with diabetes have an almost 3-fold higher greater than 24 months (hazard ratio 1.4; 95% confi-
rate of pancreatitis compared with patients without the dence interval [CI], 1.03–2.0) (Lewis 2011). A study
disease (Noel 2009). When GLP-1 agonists and DPP-4 using the FDA’s Adverse Event Reporting System cited
inhibitors entered the market, case reports of acute pan- a greater than 4-fold increased odds ratio for piogli-
creatitis began to emerge for both agent classes. The tazone use and bladder cancer compared with other
FDA issued its first warning on this phenomenon in diabetes agents, together with an odds ratio of 4.3 (95%
2007. Although this alarming potential adverse effect CI, 2.82–6.52) (Piccinni 2011). More recently, a cohort
has led to much speculation, neither the cause nor the study using the French national health system informa-
extent of risk has been discerned. This has prompted tion found that patients using pioglitazone had a 22%
meta-analyses and epidemiologic studies. adjusted relative increased risk of bladder cancer com-
A 5-year review of the FDA’s Adverse Event Re- pared with patients never exposed to the agent (crude
porting System found 6-fold higher odds of reported incidence per 100,000 person-years was 49.4 and 42.8,
pancreatitis for exenatide and sitagliptin than with respectively) (Neumann 2012). This study found that
other diabetes medications used as a control (Elashoff higher cumulative doses had a stronger link and con-
2011). However, meta-analyses of 19 clinical trials firmed the risk to be higher with pioglitazone use for
lasting 12–52 weeks and including more than 5500 more than 24 months.
patients suggest that exenatide is not associated with Given the three studies in the United States and
a higher risk of the adverse event than active compar- in review of the French data, the FDA in June 2011
ator drugs (MacConell 2012). Another meta-analysis required additional safety information to the labeling of
evaluated the six most-studied DPP-4 inhibitors in tri- pioglitazone, recommending against its use in patients
als lasting at least 24 weeks and found no increased risk with active bladder cancer and caution with its use in
compared with either placebo or active comparators those with a history of bladder cancer. Both France and
(Monami 2011). Recent large cohort studies evaluating Germany subsequently suspended pioglitazone use, and
medical and pharmacy claims data also suggest there both the FDA and European Medicines Agency con-
is no increased risk with the use of exenatide or sita- tinue to evaluate this issue.
gliptin. One such study found the risk of pancreatitis
to be 1.9, 5.6, 5.7, and 5.6 cases per 1000 patient-years Thiazolidinediones and Fracture Risk
for patients without diabetes, patients receiving other Type 2 diabetes mellitus is considered a risk factor for
diabetes drugs, exenatide, and sitagliptin, respectively osteoporotic fracture, particularly in women. Fractures
(Garg 2010). of the foot, arm, and hip are more common in patients
It is still unclear whether either class is truly associ- with T2DM, even in the presence of normal bone min-
ated with pancreatitis or whether an individual agent eral density. Thiazolidinediones may adversely affect
within each class may produce greater risk. There are bone homeostasis by reducing osteoblastic activity and
more reports associated with sitagliptin and exenatide, increasing urinary calcium excretion.
but these agents have also been on the market longer. The Data collected between 2006 and 2008 suggested that
FDA recommends that providers stay vigilant of this rosiglitazone, compared with metformin or a sulfonyl-
potential risk, monitor for possible signs and symptoms, urea, was associated with a higher incidence of fractures
and obtain further laboratory assessment if pancreatitis in women but not men (Kahn 2008). A meta-analysis of
is suspected. 10 randomized clinical trials confirmed a 45% increased

risk of fractures in patients who received either piogl- only allow once-daily administration, but some patients
itazone or rosiglitazone, but this risk was observed in may also be able to administer it only three times/week.
women, not in men (Loke 2009). Two other large epi- Several new therapeutic classes have shown prom-
demiologic studies using U.S. and Canadian medical ise in treating hyperglycemia and are in various stages
and pharmacy claims data suggested the risk is also of development. A novel new class, sodium-glucose
increased in men at least 50 years of age (15%–25% rela- cotransporter type 2 inhibitors, reduces the reabsorp-
tive risk), although the incidence is lower than in women tion of glucose in the proximal tubules of the kidney.
(34%–47% relative risk) (Aubert 2010; Dormuth 2009). The best-studied agent, dapagliflozin, reduces hyper-
The fracture rate per 100 patient-years in one study was glycemia when used as monotherapy or in addition to
estimated to be 1.7 in men and 2.9 in women for those metformin. Dapagliflozin also shows efficacy compa-
receiving treatment with a thiazolidinedione (Dormuth rable with the sulfonylurea glipizide when added to
2009). The more common fracture sites include the metformin (Anderson 2012). A pooled analysis of 19
foot/ankle, wrist/forearms, hand/fingers, and humerus clinical trials involving more than 5000 patients showed
(Aubert 2010). More recently, a cohort study using a a small (0.2%) occurrence of bladder cancer compared
with placebo and a small risk of breast cancer in women.
Dutch database compared the risk of fractures of thia-
The FDA has requested additional safety data and has
zolidinediones with other diabetes agents and found a
so far rejected dapagliflozin for approval. Another agent
25% increased risk of fractures; however, the risk was within this class, canagliflozin, has also been evaluated
only significant in women receiving thiazolidinediones in the treatment of T2DM, and its manufacturer filed
(Bazelier 2012). a new drug application with the FDA in the summer of
Although the overall risk of fractures appears to be 2012.
greater in women than in men, both sexes may be af- The interleukin-1 blocker diacerein is used for osteo-
fected. Caution is advised in the use of thiazolidinediones arthritis in some countries, although it is not approved
in patients with existing osteoporosis or osteopenia, par- in the United States. Diacerein has been shown to lower
ticularly women. glucose concentrations, but its mechanism is not known.
TAK-875 is a free fatty acid receptor agonist thought to
Newer Pharmacotherapies stimulate insulin secretion. When evaluated in a phase
II study, TAK-875 reduced A1C by up to 1.1%, with effi-
in the Pipeline cacy comparable with glimepiride (Burant 2012).
Several new agents within existing classes of T2DM Finally, the dual peroxisome proliferator activated
drugs are currently being evaluated in human clini- receptor (PPAR) (alpha and gamma) agonist aleglita-
cal trials. The DPP-4 inhibitor dutogliptin is currently zar also shows promise in treating T2DM. Having dual
in phase III studies. Alogliptin is currently available in properties combines the efficacy of both a fibrate-type
Japan and was submitted for FDA label approval; how- and thiazolidinedione-type agent. A phase III study is
ever, the FDA rejected the application in April 2012, currently evaluating aleglitazar’s efficacy and safety in
stating that more studies were needed before this agent patients with T2DM and cardiovascular disease. Of
could be approved in the United States. Several once- note, two other dual PPAR agonists have failed to gain
daily and once-weekly GLP-1 agonists are also in various approval because of adverse events, particularly cardio-
phases of development; these include taspoglutide, albi- vascular outcomes.
glutide, dulaglutide, and lixisenatide. A once-monthly
formulation of exenatide is being investigated. Patient Education
Novel insulin administration has been a goal of many The pharmacist should counsel patients receiving the
manufacturers for decades in an effort to do away with once-weekly formulation of exenatide regarding missed
subcutaneous administration. Inhaled insulin formula- doses. A missed dose can be administered as long as it
tions are still in development, although concerns about is at least 3 days before the next scheduled dose. If it is
lung damage have limited their ability to gain approval. within 1–2 days before, the dose should be skipped, and
The only approved inhaled insulin product was volun- the patient should resume the regular schedule. The day
tarily removed from the market in 2008 because of poor of the week it is administered can be switched as long as
sales and provider/patient acceptance.Oral formula- the last dose was at least 3 or more days before switching.
tions for insulin delivery are also being investigated. Patients should also be instructed on how to reconsti-
A new long-acting insulin, insulin degludec, has been tute the agent with the supplied diluents and syringes
evaluated in phase III studies. As with insulin detemir, and be warned not to use other types of syringes than
insulin degludec has a fatty acid moiety attached to what is supplied. The diluent is provided within the sup-
it, allowing a 24-hour half-life twice that of insulin plied syringe. An adapter is used to connect the syringe
glargine (Owens 2011). This extended half-life may not to a vial containing the dry powder formulation. The

diluent is injected into the vial, which the patient should mors (e.g., dyspnea, dysphagia, hoarseness, a lump in the
agitate thoroughly to reconstitute the drug. Once in neck). Patients receiving a DPP-4 inhibitor or GLP-1
solution, the formulation can be withdrawn back into agonist should be instructed to report any symptoms
the syringe, and air bubbles should be removed. Once consistent with pancreatitis, including severe abdom-
reconstituted and in the syringe, the once-weekly for- inal pain (especially if it radiates to the back), nausea,
mulation must be administered immediately. It is best or vomiting. If any of these occur, the patient should
to inject at a different injection site each week but to use discontinue the drug and contact a health care pro-
the same region of the body (e.g., arm, thigh, abdomen). fessional. Although the risk of bladder cancer with
Patients receiving either the once-weekly exenatide pioglitazone is a matter of debate and continued eval-
formulation or liraglutide should be counseled to report uation, patients should be educated to report blood in
any symptoms potentially associated with thyroid tu- the urine, urinary urgency, abdominal pain, or pain on
urination.
Both men and women, and particularly those with
Practice Points osteoporosis or osteopenia, should be warned of the pos-
Many challenges face the clinical pharmacist in their sible increased risk of bone fractures with pioglitazone
efforts to optimize pharmacotherapy for their patients use. Patients should be told of the more common fracture
with T2DM. New data continue to emerge regarding sites associated with its use, which mainly involve the
how to treat hyperglycemia associated with T2DM. As distal upper and lower limbs as previously described.
a result, guidelines/recommendations, new indications
for existing medications, new therapeutic entities, and
safety issues continue to evolve: References
Ampudia-Blasco FJ, Rossetti P, Ascaso JF. Basal plus basal-
■■ Th
e ADA recently updated its therapeutic bolus approach in type 2 diabetes. Diabetes Technol Ther
recommendations in the treatment of T2DM 2011;13(suppl 1):S75–S83.
hyperglycemia. It recommends a patient-centered PubMed Link
approach to care and a need to evaluate the advantages
and disadvantages of the various agents used to treat Anderson SL, Marrs JC. Dapagliflozin for the treatment of
type 2 diabetes. Ann Pharmacother 2012;46:590–8.
hyperglycemia when making therapeutic changes to
PubMed Link
patients.
■■ The various guidelines differ in their recommendations Aubert RE, Herrera V, Chen W, et al. Rosiglitazone and
in treating hyperglycemia, and the clinical pharmacist pioglitazone increase fracture risk in women and men with
should be aware of these differences. type 2 diabetes. Diabetes Obes Metab 2010;12:716–21.
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lam, rosiglitazone, or sitagliptin on glycemic control
and lipid profile in patients with type 2 diabetes mellitus

Self-Assessment Questions
Questions 1 and 2 pertain to the following case. averaged 165 mg/dL and been consistent after each
R.S., a 34-year-old man (weight 86 kg) with type 2 dia- meal of the day; and the A1C has been 6.9%. The
betes mellitus (T2DM) and an A1C of 10.2%, is being patient’s endocrinologist today switched the insu-
converted from oral diabetes drug therapy to basal/ lin regimen to insulin detemir and lispro. Which
bolus insulin with insulin glargine and insulin aspart. one of the following is the best patient counseling
His endocrinologist wants to start R.S.’s total daily point regarding this regimen change?
insulin at 0.5 unit/kg/day. A. It will provide a substantial reduction in A1C.
B. It will increase the number of daily insulin
1. Which one of the following is the most appropriate
injections.
initial dose estimate of rapid-acting insulin aspart
C. It will increase the frequency of nocturnal
before breakfast for R.S.?
hypoglycemia.
A. 2. D. It will improve the patient’s morning fasting
B. 4. glucose concentrations.
C. 7.
D. 14. 5. A 62-year-old man with T2DM for 8 years began
receiving metformin 1000 mg twice daily 2 years
2. After initiating and assessing the basal and bolus ago. His A1C today is 7.9% (personal goal less than
insulin regimen as accurate in this patient, which 7%). His fasting morning blood glucose readings
one of the following is the best estimate for how are consistently at goal (average 95 mg/dL). His
much 1 unit of insulin aspart would decrease R.S.’s after-meal glucose readings average 190–200 mg/
serum glucose concentration in the case of hyper- dL. Which one of the following would be most
glycemic excursions? appropriate for this patient?
A. 10. A. Add sitagliptin 100 mg once daily.
B. 20. B. Add insulin aspart 6 units once daily prior to
C. 40. the evening meal.
D. 80. C. Switch from metformin to insulin glargine
10 units once daily.
3. A patient with T2DM is currently receiving an D. Add bromocriptine 0.8 mg once daily.
insulin-only regimen of premixed insulin 70/30.
The morning dose is 20 units before breakfast, and 6. A 54-year-old woman with newly diagnosed T2DM
the evening dose is 10 units before dinner. The presents to the clinic today. She has an A1C of 10.4%
patient has frequent bouts of low blood glucose con- and a random glucose concentration of 330 mg/dL.
centrations between 1 a.m. and 3 a.m. The average The patient is not experiencing any symptoms of
morning fasting glucose concentration is 75 mg/ hyperglycemia. In addition to improvements in diet
dL, and the average after-dinner glucose concen- and physical activity, which one of the following is
tration is 250 mg/dL. Which one of the following the best initial treatment option for this patient?
would be the best option for this patient to optimize
glycemic control? A. Metformin.
B. Liraglutide.
A. Convert to insulin glargine and glulisine.
C. Insulin.
B. Increase the evening insulin 70/30 dose.
D. Bromocriptine.
C. Increase the morning insulin 70/30 dose.
D. Convert to insulin neutral protamine
7. You have been asked to provide an update in diabetes
Hagedorn and detemir.
guidelines to a group of family practice physicians.
4. A patient is currently receiving 43 units of insulin Which one of the following is the most important
70/30 in the morning and 20 units in the evening. message to convey regarding the current diabetes
The patient is experiencing hypoglycemic events guidelines/recommendations?
four or five times/week, primarily in the early morn- A. The American College of Physicians’
ing hours. During the past 2 weeks, the average recommendations are most prescriptive
fasting morning glucose concentration has been and recommend the use of several agents in
110 mg/dL; after-meal glucose concentrations have addition to metformin.

B. In the American Association of Clinical the patient states it has been this way for 6 months.
Endocrinologists recommendations, drug Which one of the following would be best to recom-
therapy is based on baseline weight. mend to improve this patient’s glycemic control?
C. The National Institute for Health and Clinical
A. Discontinue metformin and add another oral
Excellence recommendations promote the use
T2DM agent.
of incretin-based therapies as first line.
B. Discontinue bromocriptine and add another
D. The American Diabetes Association (ADA)
oral T2DM agent.
recommends weighing the therapeutic
C. Alter the timing of bromocriptine
advantages or disadvantages of T2DM agents
administration.
when adding to metformin.
D. Continue the current therapy; no changes are
necessary.
8. Which one of the following best characterizes the
differences in drug therapy management of T2DM
11. A 58-year-old man with a 10-year history of T2DM
hyperglycemia between the 2009 and 2012 ADA
and a history of not tolerating metformin has an
recommendations?
A1C of 7.4% (goal less than 7%). His current anti-
A. The 2012 recommendations provide an hyperglycemic regimen includes pioglitazone 45
algorithmic approach to treatment decisions. mg/day. SCr is 2.1 mg/dL, and his estimated CrCl
B. The 2009 recommendations are more is 28 mL/minute. Which one of the following
prescriptive in treatment decisions. would be most appropriate to add to this patient’s
C. The 2012 recommendations base treatment drug regimen?
decisions on the quality and quantity of A. Sitagliptin 100 mg/day.
clinical data. B. Liraglutide 0.6 mg/day.
D. The 2009 recommendations recommend C. Once-weekly exenatide 2 mg/day.
sulfonylureas as first-line agents. D. Linagliptin 5 mg/day.
9. A 56-year-old man with T2DM has been treated 12. Which one of the following agents, if coadministered
successfully with metformin for 5 years. Despite with exenatide, would be most likely to increase the
his adherence to pharmacotherapy, diet, and physi- risk of hypoglycemia?
cal activity, the last two A1Cs obtained have been
mildly elevated (7.3% and 7.4%, goal less than 7%). A. Glyburide.
The patient’s medical history includes depression, B. Metformin.
hypertension, and schizophrenia, for which he takes C. Pioglitazone.
sertraline, hydrochlorothiazide, and clozapine. Each D. Saxagliptin.
of these comorbidities is under good control. The
patient is initiated on bromocriptine for his dia- 13. A patient with T2DM is taking metformin 500
betes by his physician. Which one of the following mg twice daily for glycemic control. However,
would be of most concern given the change in this the patient has had consistent diarrhea since
patient’s regimen? starting the drug. Current laboratory values
include A1C 7.3% (goal less than 7%), LDL cho-
A. Bromocriptine will not likely get this patient
lesterol 111 mg/dL (goal less than 100 mg/dL),
to their goal A1C.
TG 155 mg/dL (goal less than 150 mg/dL), and
B. Bromocriptine may exacerbate the patient’s
SCr 0.5 mg/dL. The patient’s other drugs in-
schizophrenia.
clude atorvastatin 80 mg/day and aspirin 81 mg/
C. Bromocriptine should not be used due to the
day. Which one of the following would be best to
patient’s history of hypertension.
recommend for this patient?
D. Bromocriptine will increase the likelihood of
pituitary tumor in this patient. A. No change in therapy is necessary.
B. Add colesevelam 1,875 mg twice daily.
10. A patient new to your diabetes clinic has a history C. Add bromocriptine 0.8 mg once daily.
of T2DM, hypertension, and dyslipidemia. For 6 D. Switch metformin to acarbose 25 mg once daily.
months, his drug regimen has included metformin
1000 mg twice daily, bromocriptine 4.8 mg at bed- 14. A patient who started once-weekly exenatide in
time, lisinopril 10 mg at bedtime, and atorvastatin addition to metformin is suspected of having de-
40 mg at bedtime. He currently has no adverse veloped thyroid carcinoma. Which one of the fol-
effects from his drugs. His A1C today is 7.4%, and lowing is most appropriate for this patient?

A. Change exenatide to liraglutide as it has a lower of information regarding pioglitazone and bladder
risk of thyroid carcinoma. cancer, and her physician told her to discontinue the
B. Continue current therapy and refer the patient to drug. Which one of the following is the most appro-
an oncologist for further evaluation. priate response to these concerns?
C. Notify the exenatide manufacturer and the FDA
of the potential adverse event. A. There appears to be an increased risk of bladder
D. Obtain a serum calcitonin concentration and cancer, but the risk appears to be in rodents but
refer the patient to an endocrinologist. not in humans.
B. There appears to be an increased risk of bladder
15. Which one of the following is the most appropriate cancer, but the risk appears to be dependent on
education point for a patient with established osteo- the daily dosage.
porosis who is receiving pioglitazone therapy for C. There appears to be an increased risk of bladder
T2DM? cancer, but the risk appears to be dependent on
the duration of use.
A. Patients with T2DM are at increased risk of D. There appears to be an increased risk of bladder
osteoporosis, but in general all T2DM drugs cancer, but the risk appears to be dependent on
pose a further increased risk. the duration of diabetes since diagnosis.
B. There is a risk of bone fracture with pioglitazone,
but it appears to be greater in women than in
men. 19. During the past year, a patient has received twice-
C. There is a risk of bone fractures with daily exenatide in addition to metformin and has
pioglitazone, but it appears to be limited to experienced good glycemic control. Now he is con-
the spine and hip. cerned about news reports of pancreatitis with
D. Patients with T2DM are at decreased risk of exenatide and wants to switch to another incretin-
osteoporosis, but pioglitazone may increase the based agent. Which one of the following is the most
risk more than other T2DM drugs. appropriate counseling point to provide to this
patient?
16. A patient with a new diagnosis of T2DM understands
that metformin is usually the initial drug of choice but A. The risk of pancreatitis is derived mainly from
has heard news reports regarding the benefits of incre- epidemiologic studies, but no case reports have
tin-based therapies. Which one of the following been provided to the FDA.
education points is most important for this patient? B. There are case reports of pancreatitis with both
GLP-1 agonists and DPP-4 inhibitors, and meta-
A. Once-weekly exenatide offers greater reductions in analysis data from clinical trials support this
weight compared with metformin. risk.
B. Metformin offers greater reductions in A1C C. Patients with T2DM have an increased risk of
compared with once-weekly exenatide. pancreatitis, but the risk with GLP-1 agonists or
C. Sitagliptin is a more cost-effective initial DPP-4 inhibitors does not appear greater than
treatment than metformin. with other agents.
D. Sitagliptin is less effective in A1C reduction than D. Epidemiologic studies have shown a greater risk
metformin. of pancreatitis with DPP-4 inhibitors compared
with GLP-1 agonists.
17. Which one of the following statements best expresses
the comparison of twice-daily versus once-weekly
exenatide? 20. A patient with T2DM is receiving metformin 1000
mg twice daily. An A1C obtained today is 7.8%. The
A. Tolerability with one formulation is required patient has a known history of hypertension, pan-
before switching to the other. creatitis, dyslipidemia, and depression. The patient
B. The formulations are considered equally has low blood pressure with dizziness on a near-daily
effective in reducing A1C. basis. Which one of the following would best facilitate
C. Both formulations can be used with basal and glycemic control for this patient?
bolus insulin therapy.
D. The once-weekly formulation better reduces A. Liraglutide 0.6 mg once daily.
fasting glucose concentrations. B. Bromocriptine 0.8 mg once daily.
C. Linagliptin 5 mg once daily.
18. Six months ago, a patient was initiated on pioglita- D. Pioglitazone 15 mg once daily.
zone 15 mg/day and she has since experienced very
good glycemic control. She has recently heard a lot

Learner Chapter Evaluation: New Pharmacotherapies for Type 2 Diabetes.
As you take the posttest for this chapter, also evaluate the Use the 5-point scale to indicate whether this chapter pre-
material’s quality and usefulness, as well as the achievement pared you to accomplish the following learning objectives:
of learning objectives. Rate each item using this 5-point 12. Compare and contrast the differences between the
scale: drug therapy recommendations of several of the latest
and leading diabetes guidelines.
• Strongly agree 13. Assess the differences in incretin-based therapies for
• Agree the treatment of type 2 diabetes mellitus (T2DM)
• Neutral and tell how they compare with other agents to treat
• Disagree hyperglycemia.
• Strongly disagree 14. Delineate the role and place in therapy of bromocrip-
tine and colesevelam in the treatment of T2DM.
1.
The content of the chapter met my educational needs. 15. Convert a patient with T2DM with significant hyper-
2.
The content of the chapter satisfied my expectations. glycemia to an insulin-only drug regimen.
3.
The author presented the chapter content effectively. 16 Evaluate the latest noncardiac precautions, contraindi-
4.
The content of the chapter was relevant to my practice cations, or warnings with agents used in the treatment
and presented at the appropriate depth and scope. of hyperglycemia.
5. The content of the chapter was objective and 17. Please expand upon any of your above responses,
balanced. and/or provide any additional comments regarding
6. The content of the chapter was free of commercial this chapter:
bias.
7. The content of the chapter was useful to me.
8. The teaching and learning methods used in the chap-
ter were effective.
9. The active learning methods used in the chapter were
effective.
10. The learning assessment activities used in the chapter
were effective.
11. The chapter was effective overall.

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New Pharmacotherapies

for Type 2 Diabetes

Baseline Knowledge Statements

PSAP 2013 • Cardiology/Endocrinology 5 New Pharmacotherapies for Type 2 Diabetes

New Pharmacotherapies for Type 2 Diabetes 6 PSAP 2013 • Cardiology/Endocrinology

PSAP 2013 • Cardiology/Endocrinology 7 New Pharmacotherapies for Type 2 Diabetes

Diet/exercise and Diet/exercise and Diet/exercise and Diet/exercise

< 6.5%–7.0% Still elevated

No additional Add additional

Figure 1-1. General approach to the management of type 2 diabetes mellitus.

New Pharmacotherapies for Type 2 Diabetes 8 PSAP 2013 • Cardiology/Endocrinology

PSAP 2013 • Cardiology/Endocrinology 9 New Pharmacotherapies for Type 2 Diabetes

New Pharmacotherapies for Type 2 Diabetes

PSAP 2013 • Cardiology/Endocrinology

PSAP 2013 • Cardiology/Endocrinology 11 New Pharmacotherapies for Type 2 Diabetes

New Pharmacotherapies for Type 2 Diabetes 12 PSAP 2013 • Cardiology/Endocrinology

PSAP 2013 • Cardiology/Endocrinology 13 New Pharmacotherapies for Type 2 Diabetes

New Pharmacotherapies for Type 2 Diabetes 14 PSAP 2013 • Cardiology/Endocrinology

PSAP 2013 • Cardiology/Endocrinology 15 New Pharmacotherapies for Type 2 Diabetes

Patient Care Scenario

New Pharmacotherapies for Type 2 Diabetes 16 PSAP 2013 • Cardiology/Endocrinology

PSAP 2013 • Cardiology/Endocrinology 17 New Pharmacotherapies for Type 2 Diabetes

New Pharmacotherapies for Type 2 Diabetes 18 PSAP 2013 • Cardiology/Endocrinology

PSAP 2013 • Cardiology/Endocrinology 19 New Pharmacotherapies for Type 2 Diabetes

New Pharmacotherapies for Type 2 Diabetes 20 PSAP 2013 • Cardiology/Endocrinology

PSAP 2013 • Cardiology/Endocrinology 21 New Pharmacotherapies for Type 2 Diabetes

New Pharmacotherapies for Type 2 Diabetes 22 PSAP 2013 • Cardiology/Endocrinology

PSAP 2013 • Cardiology/Endocrinology 23 New Pharmacotherapies for Type 2 Diabetes

New Pharmacotherapies for Type 2 Diabetes 24 PSAP 2013 • Cardiology/Endocrinology

PSAP 2013 • Cardiology/Endocrinology 25 New Pharmacotherapies for Type 2 Diabetes

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