Diabetes Management: Pharmacotherapy Options for Diabetes

Mellitus
Dhiren Patel, PharmD, CDE, BC-ADM, BCACP

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Diabetes Management:
Pharmacotherapy Options for Diabetes Mellitus

By

Dhiren Patel, PharmD, CDE, BC-ADM, BCACP

Upon successful completion of this course, continuing education hours

will be awarded as follows:
Pharmacists: 3 Contact Hours

ABOUT THE AUTHOR

Dhiren K. Patel, PharmD, CDE, BC-ADM, BCACP, is an associate professor of
pharmacy practice in the School of Pharmacy Boston at MCPHS University
(formerly Massachusetts College of Pharmacy and Health Sciences). He also
maintains a clinical practice site with the VA Boston Healthcare System, where he
functions as a mid-level provider for a variety of chronic diseases such as diabetes,
hypertension, dyslipidemia, and obesity. He earned his PharmD from MCPHS
University and received his postdoctoral residency training at the VA Boston
Healthcare System. He is also board-certified in advanced diabetes management
(BC-ADM), as an ambulatory care pharmacist (BCACP), and as a diabetes educator
(CDE). Dr. Patel is one of the co-authors of the Obesity and Diabetes chapters in
Koda-Kimble and Youngs Applied Therapeutics: The Clinical Use of Drugs, the first
clinical pharmacy textbook to be based on patient case histories. This book is now
in its 11th edition, has been translated into many languages, and is widely used in
the United States and internationally. Dr. Patel has also been published in
numerous peer-reviewed journals and has delivered numerous presentations and
lectures on obesity.
Dhiren K. Patel has disclosed that he is on the Speakers Bureau for
Sanofi, Novo Nordisk, and Merck, and that he is on the Advisory Board for
Sanofi, Novo Nordisk, and AstraZeneca. He has agreed to present content
that is current, evidence-based, and without bias.
ABOUT THE PEER REVIEWER
Justinne Guyton, PharmD, BCACP, is an assistant professor of pharmacy practice
at St. Louis College of Pharmacy. She received her bachelor of arts degree in
chemistry from Westminster College and her doctor of pharmacy degree from
Southern Illinois University Edwardsville in 2011. She completed postgraduate
training accredited by the American Society of Health-System Pharmacists at the
University of Mississippi Medical Center, followed by a second-year ambulatory care
specialty residency at the University of North Carolina Hospitals and Clinics. Dr.
Guytons practice site is at the St. Louis County Department of Health, where she
provides clinical pharmacy services for atherosclerotic cardiovascular disease riskreduction, diabetes, hypertension, smoking cessation, and chronic anticoagulation
through Medication Therapy Services. She has facilitated several courses within the
Doctor of Pharmacy program and is the Director of the Postgraduate Year One
Pharmacy Residency at the St. Louis County Department of Public Health.
Justinne Guyton has disclosed that she has no significant financial or
other conflicts of interest pertaining to this course book.
Pharmacy Planner: Cheryl Durand, PharmD
The planner who worked on this continuing education activity has disclosed
that she has no significant financial or other conflicts of interest pertaining to
this course book.
Copy Editor: Diane Hinckley
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PRETEST
Begin this course by completing the pretest. Compare your answers to
the answer key at the end of the pretest. Make note of the questions you
missed so that you can focus on those areas as you proceed to read the
entire course. To review the pretest questions you answered incorrectly,
you may also use your ebook readers search function to search the text
for a word or phrase from the correct answer (a, b, c, or d).

Note: Choose the one option that BEST answers each question.

1. Diabetes increases the risk for developing which of the following disease states?
a. New-onset chronic obstructive pulmonary disease (COPD)
b. Neuropathy
c. Amyotrophic lateral sclerosis (ALS)
d. Schizophrenia

2. According to American Association of Clinical Endocrinologists (AACE)

guidelines, what is an appropriate A1c goal for most adult patients with
diabetes?
a. < 6%
b. < 6.5%
c. < 7%
d. < 8%

3. Which of the following is a long-acting insulin?

a. Insulin aspart
b. Regular insulin
c. Insulin glulisine
d. Insulin degludec

4. Which of the following is a major adverse effect of sulfonylureas?

a. Weight gain
b. Urinary tract infections
c. Flatulence
d. Persistent cough

5. Which of the following medications is contraindicated in patients with a family

history of pancreatitis?
a. Acarbose
b. Bromocriptine
c. Canagliflozin
d. Liraglutide

PRETEST KEY
1. b
2. b
3. d
4. a
5. d

INTRODUCTION

COURSE OBJECTIVES
After completing this course, the learner will be able to:
1. Recognize complications and comorbid conditions associated with
diabetes.
2. Identify appropriate treatment goals for a patient with diabetes.
3. Recognize the time-action profiles and usual uses of insulin formulations.
4. Compare and contrast the safety and efficacy of pharmacotherapies used
in the management of diabetes.
5. Identify adverse events that patients may experience while using
pharmacotherapy for diabetes management and contraindications to
therapy.

ccording to the Centers for Disease Control and Prevention (CDC; 2014),
9.3% of the U.S. population had diabetes in 2014. This is a significantly
higher percentage than in 2007, when 7.8% of the U.S. population had
diabetes (CDC, 2008). Additionally, 37% of adults aged 20 years or older had
prediabetes in 2014. Diabetes was the seventh leading cause of death in the U.S. in
2010, and it is thought that the number of deaths related to diabetes is
underreported. The total costs associated with diabetes in 2012 added up to $245
billion (CDC, 2014). As these striking figures make clear, diabetes is a national
health concern, and the numbers of patients with diabetes are rapidly growing.
Diabetes is a chronic disease state with no known cure. For this reason,
diabetes management is intended to prevent complications and improve the
patients quality of life. If diabetes is left untreated or is poorly managed, the
patients disease may progress more rapidly or precipitate a hyperglycemic crisis, or
the patient may experience treatment-related adverse events, such as
hypoglycemia. As diabetes progresses, patients may develop diabetes
complications or comorbid conditions, such as hypertension, hypercholesterolemia,
cardiovascular disease, retinopathy, diabetic kidney disease, neuropathy, nonalcoholic fatty liver disease, gum disease, hearing loss, erectile dysfunction, and
depression (CDC, 2014).
As a result of its high incidence and economic burden, diabetes management is
an area of tremendous research. Many new pharmacotherapies have become
available in recent years. The variety of options is ideal for patients with diabetes,
but this vast array of choices may make treating diabetes daunting for healthcare
providers. In addition, new guidelines for the treatment of diabetes have been
released by both the American Diabetes Association (ADA) and the American
Association of Clinical Endocrinologists (AACE). In order to effectively manage
patients with diabetes, it is important to stay current with the standard of care for

treatment of diabetes and the therapeutic options available. It is the aim of this
course to review the current treatment guidelines for diabetes management and the
pharmacotherapies, both new and time-tested, available on the market today.

DIABETES MANAGEMENT:
PHARMACOTHERAPY OPTIONS FOR
DIABETES MELLITUS
CURRENT TREATMENT GUIDELINES

uidelines for the treatment of diabetes were released by the ADA and
AACE at the beginning of 2016. These guidelines are similar in many ways,
but do vary in some key aspects. This section will provide a brief overview
of these two guidelines.
With regard to diagnosis of diabetes, both guidelines recommend the same
criteria. There are four diagnostic tests that may be used to confirm a diagnosis of
diabetes. Satisfaction of any of these four criteria is sufficient for a diagnosis.
Results from any but the fourth criterion should be confirmed by repeat testing. The
four criteria are as follows:
1. A1c 6.5%,
2. fasting plasma glucose 126 mg/dL,
3. oral glucose tolerance test with plasma glucose 200 mg/dL 2 hours after
ingesting 75 grams of anhydrous glucose, and
4. random plasma glucose 200 mg/dL with classic symptoms of hyperglycemia
(e.g., polyuria, polydipsia).
With regard to treatment goals, the guidelines vary somewhat. The ADA
recommends setting a treatment goal of A1c <7% for most patients. A more
stringent goal of A1c <6.5% may be reasonable for some patients (e.g., those with
short duration of diabetes, long life expectancy, or no significant cardiovascular
disease). A less stringent goal may be reasonable for patients with a history of
severe hypoglycemia, limited life expectancy, or advanced complications. The A1c
goal may even be as high as <8.5% for older adults with a limited life expectancy.
The guidelines also recommend a target fasting plasma glucose of 80 mg/dL to 130
mg/dL and a target 2-hour postprandial plasma glucose of <180 mg/dL (ADA, 2016).
The AACE recommends setting a treatment goal of A1c <6.5% for most patients.
They recommend setting a goal above 6.5% for patients with concurrent serious
illness and those at risk for hypoglycemia. They also recommend a target fasting
plasma glucose of <110 mg/dL and a target 2-hour postprandial plasma glucose of
<140 mg/dL (Garber et al., 2016).

Both guidelines indicate that lifestyle modification is a necessary part of a

diabetes treatment strategy. These modifications must be individualized, but should
include a healthy diet (e.g., with reduced sodium and alcohol consumption), weight
loss (if the patient is obese), and at least 150 minutes of moderate-intensity exercise
(e.g., brisk walking) per week (ADA, 2016; Garber et al., 2016). The recent ADA
guidelines now include a comprehensive section about weight management. The
guidelines recommend lifestyle modifications with or without long-term
pharmacotherapy to achieve a weight loss of 5%, possibly greater for certain
individuals (ADA, 2016).
Both guidelines recommend metformin as the ideal first-line agent in patients
with type 2 diabetes, if tolerated. If metformin in combination with lifestyle
modification is not enough to achieve glycemic targets, then additional non-insulin or
insulin agents may be added to the treatment regimen (ADA, 2016; Garber et al.,
2016). The guidelines differ when ranking preference of available agents. The
following sections will review available treatment options and their place in the ADA
and AACE treatment guidelines. The choice of pharmacotherapy should be based
on guideline recommendations, the expected A1c reduction, the patients preference
and comorbidities, and typical adverse effects and contraindications of the
medication.

PHARMACOTHERAPY
Insulin Pharmacotherapy

All patients with type 1 diabetes will require insulin therapy upon diagnosis.
Additionally, disease progression may cause many patients with type 2 diabetes to
require insulin therapy (Garber et al., 2016). Insulin is an endogenous hormone that
plays a key role in blood glucose regulation. Insulin works by stimulating glucose
uptake by both skeletal muscle and adipose tissue and by inhibiting hepatic
gluconeogenesis (Eli Lilly and Company, 2015f). According to their package inserts,
adverse effects associated with all injectable insulin preparations include
hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, weight
gain, rash, and pruritus. Additionally, all insulin preparations are contraindicated
during episodes of hypoglycemia and in patients with hypersensitivity to each
respective product. Insulin therapy is considered first-line therapy for type 1
diabetes, and in the absence of symptomatic hyperglycemia, it is second-line
therapy for type 2 diabetes in both the ADA and AACE treatment guidelines (ADA,
2016; Garber et al., 2016). Please refer to Table 1 for specific time-action profile
data of available insulins, as well as other helpful information.

Long-Acting Insulins
Available long-acting insulins, otherwise known as basal insulins, include insulin
glargine, insulin detemir, and insulin degludec. Because of the simplicity of basal
insulin regimens, the ADA recommends that a long-acting insulin preparation be
initiated as the first step in building a patient-specific insulin regimen (ADA, 2016).
For a long time, insulin glargine and insulin detemir U-100 formulations were the
only long-acting insulins on the market, but recently the U.S. Food and Drug
Administration (FDA) has approved insulin degludec (available as U-100 and U-200
preparations) and a U-300 formulation of insulin glargine. In general, these new
insulins are slow-onset, long-duration (24 hours) preparations. All are approved
only for subcutaneous administration (Sanofi-Aventis, 2015b, 2015c; Novo Nordisk,
2015a, 2015e). Insulin detemir and U-100 insulin glargine are both available as vials
for use with insulin syringes, as well as in pre-filled insulin pen devices (Novo

Nordisk, 2015a; Sanofi-Aventis, 2015b). Insulin degludec and U-300 insulin glargine
are available only in pre-filled insulin pen devices (Novo Nordisk, 2015e; SanofiAventis, 2015c). The ADA recommends initiating basal insulin at a dose of 10
units/day or 0.1 to 0.2 units/kg/day and increasing the dose by 10% to 15% or 2 to 4
units once or twice weekly until the fasting blood glucose target has been achieved
(ADA, 2016).
Rapid-Acting Insulins
Rapid-acting insulins, otherwise known as meal-time insulins, include insulin
aspart, insulin lispro, and insulin glulisine. All are available as U-100 formulations,
and insulin lispro is also available as a U-200 formulation. In general, these insulins
have a rapid onset (15 minutes) with short duration (5 hours). All are typically
administered by subcutaneous injection within about 5 to 15 minutes before a meal.
These insulins are available in vials for use with insulin syringes or in pre-filled
insulin pen devices. Other potential routes of administration are via continuous
subcutaneous infusion pump or intravenous infusion (Eli Lilly and Company, 2016;
Novo Nordisk, 2015b; Sanofi-Aventis, 2015a). The ADA recommends starting any of
these agents as add-on therapy to a basal insulin regimen if postprandial blood
glucose remains elevated after the fasting blood glucose target has been achieved.
The recommended starting dose is a bolus of 4 units, 0.1 units/kg, or 10% of the
current basal insulin dose before the largest meal of the day, increasing the dose by
1 to 2 units or 10% to 15% once or twice weekly until the blood glucose is
maintained within the target range. Additional bolus doses may be added before the
patients other daily meals as necessary (ADA, 2016).
Short-Acting Insulins
Short-acting insulin is also called regular insulin. It is available as U-100
injectable formulations, a U-500 injectable formulation, and as a cartridge for
inhalation. In general, these drugs have a more delayed onset than rapid-acting
insulin (30 minutes) and a longer duration of action. Insulin for inhalation has a timeaction profile similar to rapid-acting insulins, and U-500 has a time-action profile
similar to intermediate-acting insulin (Eli Lilly and Company, 2015e 2015f; MannKind
Corporation, 2015). The U-100 preparation is approved for subcutaneous,
intramuscular, or intravenous administration, while U-500 insulin is approved only
for subcutaneous administration (Eli Lilly and Company, 2015f; Novo Nordisk,
2016). Because of their less desirable pharmacokinetic profile, the use of shortacting insulins has been significantly reduced since the introduction of rapid-acting
insulins (ADA, 2016).
Regular insulin U-100 is generally given three times daily, 30 minutes before
meals (Eli Lilly and Company, 2015f; Novo Nordisk, 2016). Despite its long duration
of action, insulin U-500 may be given two or three times daily, 30 minutes before
meals. This insulin may be administered using a tuberculin syringe, measured in
milliliters, to avoid confusion with the unit markings on a U-100 insulin syringe (Eli
Lilly and Company, 2015e). Insulin for inhalation should be used at the beginning of
a meal. It is available in 4-, 8-, and 12-unit cartridges. Insulin-nave individuals
should start with 4 units at each meal. Injectable mealtime insulin may be converted
to insulin inhalation at a 1:1 ratio, rounding up to the nearest cartridge strength
(MannKind Corporation, 2015). Insulin for inhalation is subject to a Risk Evaluation
and Mitigation Strategy (REMS) program to inform healthcare providers about the
risks of acute bronchospasm in patients with lung disease, the need to evaluate all

patients for lung disease before starting the medication, and the contraindications
for use of this medication in patients with chronic lung disease. Before initiation of
insulin for inhalation, providers must perform a detailed medical history, physical
examination, and spirometry (Sanofi US, n.d.).
Intermediate-Acting Insulins
Intermediate-acting insulins are also called insulin isophane or insulin NPH.
These preparations have a time-action profile between those of rapid- and longacting insulins. These preparations appear milky or cloudy and should be gently
rolled between the palms of the hands to ensure that the suspension is uniformly
mixed before each injection (Eli Lilly and Company, 2015d; Novo Nordisk, 2015b).
The ADA guidelines consider these preparations long-acting and as such they
follow the same dosing recommendations found in the section on long-acting
insulins in this course (ADA, 2016).
Pre-Mixed Insulins
There are several types of pre-mixed insulins currently available. All are
approved for subcutaneous administration only. In general, these formulations have
a rapid onset of action with a long duration of action. The intermediate-acting/rapidacting mixtures consist of insulin NPH mixed with either insulin aspart or insulin
lispro. The NPH/aspart mixture is available as a 70/30 mixture in a vial or a pre-filled
pen device (Novo Nordisk, 2015c). The NPH/lispro mixture is available as either a
75/25 mixture or a 50/50 mixture. Both mixtures are available in vials or pre-filled
pen devices (Eli Lilly and Company, 2015a, 2015b). The intermediate-acting/shortacting mixtures consist of insulin NPH mixed with regular insulin. These medications
are available as a 70/30 mixture in vials or pre-filled pen devices (Eli Lilly and
Company, 2015c; Novo Nordisk, 2013). The only long-acting/rapid-acting mixture on
the market consists of insulin degludec combined with insulin aspart in a 70/30
mixture. It is available only in a pre-filled pen device (Novo Nordisk, 2015d). The
ADA recommends considering a trial of premixed insulin twice daily if basal insulin
plus one mealtime dose of rapid-acting insulin is not enough to control the blood
glucose. Premixed insulin is initiated by dividing the current basal dose into either
two thirds as a morning dose and one third as an evening dose or one half as a
morning dose and one half as an evening dose. The dose may then be increased by
1 to 2 units, or 10% to 15%, twice weekly until blood glucose targets are achieved
(ADA, 2016).

Non-Insulin Pharmacotherapy

Non-insulin pharmacotherapy is generally targeted at treatment of type 2

diabetes. It is vital to pay close attention to the contraindications for these drugs, as
some are specifically contraindicated in patients with type 1 diabetes. In general,
when choosing pharmacotherapy for a specific patient, it is important to consider the
medications place in the treatment guidelines (ADA and/or AACE), the expected
A1c reduction, potential adverse effects, and contraindications.
Biguanides
As stated previously, metformin is the preferred first-line pharmacotherapeutic
option for type 2 diabetes in both the ADA and AACE guidelines (ADA, 2016;
Garber et al., 2016). Metformin is the only agent with positive data showing a
reduction in all-cause mortality, as well as vascular complications, independent of its
effect on glycemia (UK Prospective Diabetes Study Group, 1998). Metformin works
primarily to reduce blood glucose concentrations by decreasing hepatic
gluconeogenesis and increasing glucose uptake by muscle and adipose tissue
(Pharmacists Letter, 2015). These actions result in an A1c reduction of 1.0% to
1.3% (George, Brujin, Will, & Howard-Thompson, 2015). Metformin use has the
added benefit of reducing cholesterol and triglyceride levels and may even increase
HDL-C levels (Bristol-Myers Squibb Company, 2009).
In order to minimize side effects, metformin is generally initiated at either 500 mg
twice daily or 850 mg once daily, to be taken with food (Bristol-Myers Squibb
Company, 2009). The usual maintenance dose is 500 mg to 1,000 mg twice daily
(George et al., 2015). The dose of metformin should be reduced in patients with
reduced renal function. A recent review recommends that patients with an estimated
glomerular filtration rate (eGFR) < 45mL/min/1.73m2 be limited to a maximum of
1,000 mg per day and that metformin be discontinued in patients with eGFR < 30
mL/min/1.73m2 or those at increased risk for acute kidney injury (e.g., a patient
undergoing a procedure that requires the use of radiocontrast dye; Lipska, Bailey, &
Inzucchi, 2011). In the metformin prescribing information, renal dysfunction is
defined as a serum creatinine level 1.4 mg/dL in women and 1.5 mg/dL in men
(Bristol-Myers Squibb Company, 2009).
Common adverse effects associated with metformin use include diarrhea,
nausea, abdominal discomfort, metallic taste, flatulence, and anorexia. These
adverse effects are usually mild, transient, and reversible after dose reduction or
discontinuation of the drug. Diarrhea is the most common complaint and may be
alleviated by switching to an extended-release formulation (Bristol-Myers Squibb
Company, 2009). Metformin has also long been associated with a risk of lactic
acidosis, though a Cochrane review of 347 studies found no difference in risk
between metformin therapy and either placebo or non-biguanide therapies
(Salpeter, Greyber, Pasternak, & Salpeter, 2010). Metformin is contraindicated in
patients with renal disease or dysfunction, known hypersensitivity to metformin, or
acute or chronic metabolic acidosis, including diabetic ketoacidosis (Bristol-Myers
Squibb Company, 2009).
Sulfonylureas
The sulfonylureas are divided into first- and second-generation agents. The
second-generation agents are used almost exclusively and include glyburide,
glimepiride, and glipizide. The ADA guidelines recommend these drugs for secondline therapy, usually as an add-on to metformin therapy (ADA, 2016). Because of

the side-effect profile of these medications, the AACE guidelines give them low
preference as first-line agents and recommend caution when considering their use
(Garber et al., 2016). Sulfonylureas act directly on the beta-cells of the pancreas to
promote the release of insulin and enhance beta-cell sensitivity to glucose. They
also appear to help normalize hepatic glucose production and improve peripheral
glucose disposal, and reduce glucagon levels (Nolte, 2009). Sulfonylureas reduce
the A1c by 0.4% to 1.2%. As pancreatic beta-cell function decreases, these
medications become less effective (George et al., 2015).
Generally speaking, sulfonylureas are initiated at a low dose and slowly titrated
upward based on effect and tolerability. These medications should be administered
with meals. Glimepiride is typically dosed at 1 to 8 mg daily. Glipizide is typically
dosed at 5 to 15 mg daily. Glyburide is typically dosed at 1.25 to 20 mg daily
(George et al., 2015). All of these medications may be divided into two daily doses
as necessary.
The most common adverse effects associated with sulfonylureas are
hypoglycemia and weight gain (George et al., 2015; Pharmacists Letter, 2015). All
of the sulfonylureas are contraindicated in patients with diabetic ketoacidosis or
hypersensitivity to the product (Pfizer, 2013, 2015; Sanofi-Aventis, 2013).
Additionally, glyburide is contraindicated in patients with type 1 diabetes (Pfizer,
2015).
Thiazolidinediones
Medications in the thiazolidinedione (TZD) class include pioglitazone and
rosiglitazone. The ADA guidelines categorize these medications as second-line
agents (ADA, 2016). The AACE guidelines list TZDs as first-line agents, but give
them low preference and recommend caution when considering their use (Garber et
al., 2016). The TZDs work by sensitizing adipose and muscle tissues to the action of
insulin, thereby increasing glucose uptake by these cells. This process is primarily
facilitated by interaction of TZDs with the PPAR- receptor (Yki-Jarvinen, 2004) and
results in an A1c reduction of 0.5% to 1.4% (George et al., 2015).
Pioglitazone is typically dosed at 15 to 45 mg daily, and rosiglitazone is typically
dosed at 4 to 8 mg daily (George et al., 2015). The most commonly reported
adverse effects associated with TZD therapy are weight gain and edema (George et
al., 2015; Pharmacists Letter, 2015; Yki-Jarvinen, 2004). Although rosiglitazone had
also been associated with an increased risk of myocardial infarction, resulting in
restricted dispensing under a risk evaluation and mitigation strategy (REMS),
subsequent study has confirmed that there is no increased risk of myocardial
infarction with rosiglitazone use and dispensing is no longer restricted (Mahaffey et
al., 2013; Rosiglitazone REMS Program, 2014). Although pioglitazone has been
associated with an increased risk of bladder cancer, a recent analysis found that the
increased risk was not statistically significant. This same study did find that patients
on pioglitazone therapy were possibly at an increased risk of pancreatic and
prostate cancer (Lewis et al., 2015). TZDs are contraindicated in patients with New
York Heart Association (NYHA) class III or IV heart failure or hypersensitivity to the
product (GlaxoSmithKline, 2014; Takeda Pharmaceuticals, 2013a).

Dipeptidyl Peptidase-4 Inhibitors

Available dipeptyl peptidase-4 (DPP-4) inhibitors include sitagliptin, saxagliptin,
linagliptin, and alogliptin. The ADA guidelines recommend that these medications be
considered as second-line therapy (ADA, 2016). The AACE guidelines recommend
DPP-4 inhibitors as first-line agents and ranks them fourth in order of preference
(Garber et al., 2016). These agents work by inhibiting the DPP-4 enzyme, an
enzyme responsible for the degradation of the endogenous incretins GIP and
GLP-1. These hormones act to increase insulin secretion, decrease glucagon
secretion, slow gastric emptying, and increase satiety (Drucker & Nauck, 2006;
Pharmacists Letter, 2015). These actions result in a reduction in A1c of 0.5% to
0.9% (George et al., 2015).
Sitagliptin is typically dosed at 50 to 100 mg daily. Saxagliptin is typically dosed
at 2.5 to 5 mg daily. Linagliptin is typically dosed at 5 mg daily. Alogliptin is typically
dosed at 25 mg daily (George et al., 2015). Linagliptin is the only medication in this
class that does not require dose adjustment in renal impairment (Boehringer
Ingelheim International GmbH, 2015b). The dose of sitagliptin should be reduced to
50 mg daily in patients with CrCl 30 to 50 mL/min and 25 mg in patients with CrCl
<30 mL/min (Merck, 2015). Saxagliptin should be dosed at 2.5 mg daily in patients
with CrCl <50 mL/min (AstraZeneca, 2015d). Alogliptin should be dosed at 12.5 mg
daily in patients with CrCl 30 to 60 mL/min and 6.25 mg daily in patients with CrCl
>30 mL/min (Takeda Pharmaceuticals, 2013b).
These agents are generally well tolerated, but side effects may include
headache, nasopharyngitis, and hypoglycemia, though the risk of hypoglycemia is
relatively low with these medications. These agents are weight neutral
(AstraZeneca, 2015d; Boehringer Ingelheim International GmbH, 2015b; Merck,
2015; Takeda Pharmaceuticals, 2013b; George et al., 2015). There have been
some reports of pancreatitis associated with the use of DPP-4 inhibitors, but
causality has not been demonstrated (George et al., 2015). The only
contraindication to use of DPP-4 inhibitors is hypersensitivity to the product
(Boehringer Ingelheim International GmbH, 2015b; Merck, 2015; Takeda
Pharmaceuticals, 2013b).
Glucagon-Like Peptide-1 Receptor Agonists
Available glucagon-like peptide-1 receptor agonists (GLP-1 RAs) include
exenatide, albiglutide, liraglutide, and dulaglutide. All of these agents are
administered by subcutaneous injection. Exenatide (not the extended-release
formulation) is the only agent in this class approved for monotherapy (AstraZeneca,
2015b). ADA guidelines recommend these to be second-line agents (ADA, 2016).
The AACE guidelines list GLP-1 RAs as first-line agents, and they are superseded
in preference only by metformin (Garber et al., 2016). They work by activating the
same receptors that are activated by the endogenous incretin GLP-1. As stated
earlier, this activation results in increased insulin secretion, reduced glucagon
secretion, slowed gastric emptying, and increased satiety (Pharmacists Letter,
2015). This process results in a reduction in the A1c of 0.8% to 2% (George et al.,
2015). Medications in this class are also associated with weight loss, which is
helpful for patients with overweight and obesity (AstraZeneca, 2015a, 2015b; Eli
Lilly and Company, 2015g; GlaxoSmithKline, 2015; Novo Nordisk, 2015f).

Exenatide is available in two formulations: regular and extended-release. The

regular formulation is dosed at 5 mcg to 10 mcg twice daily, to be injected 30 to 60
minutes prior to a meal (AstraZeneca, 2015b). The extended-release formulation is
dosed at 2 mg once weekly (AstraZeneca, 2015a). Exenatide should not be used in
patients with CrCl <30 mL/min (AstraZeneca, 2015b). Albiglutide is dosed at 30 mg
to 50 mg once weekly (GlaxoSmithKline, 2015). Liraglutide is initiated at 0.6 mg
once weekly for the first week, to minimize gastric discomfort, and increased to 1.2
mg once weekly thereafter. It may be increased to a maximum dose of 1.8 mg once
weekly (Novo Nordisk, 2015f). Dulaglutide is dosed at 0.75 mg to 1.5 mg once
weekly (Eli Lilly and Company, 2015g). Dulaglutide and albiglutide should be used
with caution in patients with renal impairment.
The most common side effects associated with GLP-1 RAs are nausea,
diarrhea, and headache (Pharmacists Letter, 2015). Additionally, these agents may
be associated with the development of pancreatitis and for this reason should be
used cautiously in patients with a history of pancreatitis. All GLP-1 RAs are
contraindicated in patients with hypersensitivity to the product or a personal or
family history of medullary thyroid carcinoma, as these medications have been
shown to cause these carcinomas in rats (AstraZeneca, 2015a, 2015b; Eli Lilly and
Company, 2015g; GlaxoSmithKline, 2015; Novo Nordisk, 2015f).
Sodium-Glucose Transporter 2 Inhibitors
Available sodium-glucose transporter 2 (SGLT2) inhibitors include dapagliflozin,
canagliflozin, and empagliflozin. The ADA guidelines consider them second-line
agents (ADA, 2016). The AACE guidelines list SGLT2 inhibitors as first-line agents,
categorizing them as third in order of preference (Garber et al., 2016). They work by
reducing reabsorption of glucose in the kidney, which results in greater urinary
excretion of glucose (Lajara, 2014). These agents reduce the A1c by 0.5% to 0.9%
(George et al., 2015). Medications in this class have also been shown to reduce
blood pressure and may promote weight loss, which is helpful for patients with
hypertension or obesity (AstraZeneca, 2015c; Boehringer Ingelheim International
GmbH, 2015a; Janssen Pharmaceuticals, 2015).
Dapagliflozin is typically dosed at 5 mg to 10 mg daily and should not be used in
patients with eGFR <60 mL/min/1.73m2 (AstraZeneca, 2015c). Canagliflozin is
typically dosed at 100 mg to 300 mg daily, but the dose should be limited to 100 mg
daily in patients with eGFR 45 to 60 mL/min/1.73m2 and discontinued in patients
with eGFR <45 mL/min/1.73m2 (Janssen Pharmaceuticals, 2015). Empagliflozin is
typically dosed at 10 mg to 25 mg daily and should be discontinued in patients with
eGFR <45 mL/min/1.73m2 (Boehringer Ingelheim International GmbH, 2015a).
The most commonly reported adverse effects associated with SGLT2 inhibitors
are urinary tract infections and female genital mycotic infections. These drugs are
contraindicated for use in patients with hypersensitivity to the product or severe
renal impairment, end stage renal disease, or dialysis (AstraZeneca, 2015c;
Boehringer Ingelheim International GmbH, 2015a; Janssen Pharmaceuticals, 2015).
Other Agents
There are several other medications that may be used to treat type 2 diabetes in
selected patients. A brief overview of these agents is given here. None of these
agents are included in the ADA guidelines treatment algorithm (ADA, 2016). Only
colesevelam, bromocriptine, and the alpha-glucosidase inhibitors are included in the

AACE guidelines treatment algorithm. The alpha-glucosidase inhibitors are listed as

first-line agents with low preference, and colesevelam and bromocriptine are listed
as second-line agents with low preference (Garber et al., 2016).
Colesevelam is a bile acid sequestrant that is thought to work by reducing
hepatic glucose production, increasing incretin levels, and decreasing glucose
absorption in the GI tract (Pharmacists Letter, 2015). It lowers that A1c by 0.5% to
1% (Inzucchi et al., 2012). It is dosed at 3.75 gm once daily or in two divided doses.
The most common adverse effects are constipation, nausea, and increased
triglycerides. Colesevelam is weight neutral (Pharmacists Letter, 2015). It is
contraindicated in patients with a history of bowel obstruction, serum triglycerides
>500 mg/dL, or history of hypertriglyceridemia-induced pancreatitis (Daiichi Sankyo,
Inc., 2014).
Bromocriptine is a dopamine agonist that is thought to act centrally to regulate
metabolism and increase insulin sensitivity (Pharmacists Letter, 2015). It lowers
A1c by 0.5% to 1% (Inzucchi et al., 2012). It is initiated at 0.8 mg daily and titrated
up to a typical dose of 1.6 mg to 4.8 mg daily in the morning (Drugs.com, 2015). The
most common adverse effects are dizziness, syncope, and nausea. Bromocriptine is
weight neutral (Pharmacists Letter, 2015). Bromocriptine is contraindicated in
patients with hypersensitivity to the product or syncopal migraines, and in women
who are nursing (Drugs.com, 2015).
Alpha glucosidase inhibitors include acarbose and miglitol. They work by
inhibiting glucosidase, an enzyme in the small intestine responsible for breaking
down polysaccharides into absorbable glucose (Bayer HealthCare Pharmaceuticals
Inc., 2011). They reduce the A1c by 0.5% to 0.8%. Both are dosed at 25 to 100 mg
three times daily with meals (George et al., 2015). The most common adverse
effects are flatulence, diarrhea, and abdominal bloating. These agents are weight
neutral (George et al., 2015; Pharmacists Letter, 2015). Both agents are
contraindicated in patients with hypersensitivity to the product, diabetic ketoacidosis,
inflammatory bowel disease or other chronic intestinal diseases affecting digestion
or absorption, or conditions that may deteriorate due to gas formation in the
intestine (Bayer HealthCare Pharmaceuticals Inc., 2011; Pfizer, 2012).
Non-sulfonylurea insulin secretagogues, or meglitinides, include repaglinide and
nateglinide. These medications work by stimulating insulin secretion from beta-cells
of the pancreas. They have a more rapid onset of action and shorter duration than
sulfonylureas (Nolte, 2009). Meglitinides lower the A1c by 0.5% to 1% (George et
al., 2015). Nateglinide is dosed at 120 mg three times daily with meals, and
repaglinide is dosed at 0.5 mg to 4 mg three times daily with meals (George et al.,
2015; Nolte, 2009). The most common adverse effects are hypoglycemia and
weight gain (Pharmacists Letter, 2015). These agents are contraindicated for use in
patients with type 1 diabetes, diabetic ketoacidosis, or hypersensitivity to the
product (Novo Nordisk, 2011; Novartis, 2013). Additionally, repaglinide is
contraindicated for coadministration with gemfibrozil (Novo Nordisk, 2011).
The amylin receptor agonist pramlintide works by slowing gastric emptying,
suppressing glucagon secretion, and promoting satiety (AstraZeneca, 2015e).
Pramlintide reduces A1c by 0.2% to 0.4% when used to augment insulin therapy
(Lee, Norris, & Thakurta, 2010; Singh-Franco, Perez, & Harrington, 2011). The dose
in type 1 diabetes is 15 to 60 mcg before meals, and in type 2 diabetes it is 60 to
120 mcg before meals. The most common side effects are nausea and vomiting.
Pramlintide may promote weight loss. Pramlintide is contraindicated in patients with
hypersensitivity to the product, hypoglycemia unawareness, and gastroparesis
(AstraZeneca, 2015e). Pramlintide is distributed under a REMS program to inform

healthcare providers of the risk of hypoglycemia, especially if insulin dose is not

reduced upon initiation (PDR.net, 2015).

CASE STUDY

.L. is a 43-year-old man who has been newly diagnosed with type 2
diabetes mellitus. His A1c is 7.8%. His typical diet is as follows: for
breakfast several eggs, bacon, an English muffin, and a tall glass of
orange juice; for lunch a salami or ham sandwich and a bag of chips; for dinner
usually meat and potatoes, sometimes canned beef stew or fish and chips; snacks
frequently snacks on salty foods throughout the day and has a sweet tooth. The
patient does not like to exercise because it is too much work. The patients other
conditions include hypertension, depression, and obesity. The patients current
medication list includes amlodipine 5 mg daily, citalopram 20 mg daily, and a
multivitamin every morning. The patients clinical care team has decided to initiate
metformin therapy at 1,000 mg twice daily.

Questions
1. According to AACE guidelines, what would be an appropriate A1c goal for this
patient? What is the A1c goal according to ADA guidelines?
2. Is the prescribed metformin dose appropriate for this patient?
3. What lifestyle changes could this patient make to help control his diabetes?
4. Would a sulfonylurea be appropriate add-on therapy for this patient if lifestyle
modifications and metformin therapy alone are not enough for him to reach
the goal A1c?
5. Which non-insulin medications may benefit this patient, considering his
obesity?
6. If insulin is initiated, which insulin formulation and dose would you choose?
When would you have the patient test his blood glucose in order to modify
this insulin regimen?

Discussion
1. Since this patient is young, otherwise healthy, and has a short duration of
diabetes, an A1c goal of <6.5% is recommended by AACE guidelines.
According to ADA guidelines, a goal of <7% would be acceptable, but the
patient may also be a candidate for a more stringent goal, e.g., <6.5%.
2. The prescribed dose of metformin is too high. Metformin should be initiated at
a lower dose (e.g., 500 mg twice daily or 850 mg once daily) in order to
minimize gastrointestinal side effects, especially diarrhea. The dose can then
be titrated up as tolerated.
3. This patient has a diet that is high in sodium (cured meats, soups, salty
snacks). He would benefit from reducing his sodium intake. For example, he
could replace his lunchtime chips with an apple. He also admits to snacking
frequently and having a sweet tooth. Reducing his intake of sweets and
replacing his unhealthy snacks with healthier options would benefit the

patient. Finally, the patient does not currently exercise. It would be worthwhile
to talk to the patient about simple exercises he can work into his daily routine.
The patient may be under the impression that exercise means going to the
gym multiple times per week, whereas simple brisk walking for half an hour a
day may be feasible and would be of benefit.
4. A sulfonylurea would not be ideal for this patient. Sulfonylureas are
associated with significant weight gain. Since this patient is already obese,
this medication could exacerbate this comorbid condition.
5. Any non-insulin medication that is weight neutral or that induces weight loss
may be a good option for this patient, barring any applicable
contraindications. These medications could include metformin, DPP-4
inhibitors, GLP-1 RAs, SGLT2 inhibitors, alpha-glucosidase inhibitors, and
pramlintide.
6. The ADA recommends initiating insulin therapy with a long-acting insulin
administered at bedtime. The initiation dose should be 10 units/day or 0.1
units/kg to 0.2 units/kg. Thus, a reasonable option would be insulin glargine,
injecting 10 units subcutaneously every night at bedtime. The patient should
monitor his blood sugar in the morning before eating breakfast, to get a
fasting plasma glucose reading. According to ADA guidelines, the target
reading should be 80 mg/dL to 130 mg/dL. If the fasting plasma glucose
readings remain high, the insulin dose may be increased by 2 to 4 units or
10% to 15% twice weekly until the target has been achieved.

SUMMARY

iabetes is a disease characterized by elevated plasma glucose levels. Once

diagnosed, a diabetes management plan should be designed to include
realistic glycemic targets, comprehensive lifestyle management, and
pharmacotherapy. Appropriate glycemic targets may be as low as <6.5% for some
patients or much higher (e.g., <8%) for patients with significant comorbidities or a
history of hypoglycemia (ADA, 2016; Garber et al., 2016).
There are a number of pharmacotherapeutic agents currently on the market to
help patients manage their diabetes. These include both insulin and non-insulin
agents. All patients with type 2 diabetes should receive metformin therapy, if
tolerated. Additional insulin or non-insulin agents may be added on as necessary to
achieve the patients individualized glycemic targets. All patients with type 1
diabetes should receive insulin therapy. Insulin therapy should be initiated with a
long-acting insulin, with meal-time insulin added as necessary (ADA, 2016; Garber
et al., 2016).
Since diabetes is a chronic disease, the primary goal of diabetes management is
to prevent complications and improve the patients quality of life. With that in mind,
medication management should be chosen based on the patients comorbidities and
medication preferences, as well as the contraindications and potential adverse
effects of the medication and the A1c lowering desired. With an appropriate,
individualized care plan in place, patients can have a good quality of life without fear
of being limited by their diabetes.

EXAM QUESTIONS
DIABETES MANAGEMENT:
PHARMACOTHERAPY OPTIONS FOR
DIABETES MELLITUS
This is for your reference only. To complete the exam, login to your
account at http://www.westernschools.com

Questions 110
Note: Choose the one option that BEST answers each question.

1. Which of the following is a complication of diabetes?

a. Cystic fibrosis
b. Asthma
c. Migraine headaches
d. Retinopathy

2. According to ADA guidelines, what is an appropriate A1c goal for most adult
patients with diabetes?
a. <6%
b. <6.5%
c. <7%
d. <8%

3. According to ADA guidelines, what is an appropriate fasting plasma glucose

target
for most adult patients with diabetes?
a. 70 mg/dL to 130 mg/dL
b. <110 mg/dL
c. 80 mg/dL to 130 mg/dL
d. <140 mg/dL

4. What is the duration of action of insulin degludec?

a. Up to 5 hours

b. Up to 16 hours
c. Up to 24 hours
d. Up to 42 hours

5. Which of the following insulin preparations may be safely administered

intravenously in a clinical setting under proper medical supervision?
a. Regular insulin U-500
b. Insulin aspart
c. Insulin detemir
d. Insulin isophane

6. Which of the following insulins is considered short-acting?

a. Regular insulin
b. Insulin lispro
c. Insulin glargine
d. Insulin isophane

7. Which of the following is a major adverse effect of metformin therapy?

a. Edema
b. Hypoglycemia
c. Diarrhea
d. Urinary tract infections

8. Which of the following medications is contraindicated in patients with New York

Heart Association (NYHA) class III and IV heart failure?
a. Pioglitazone
b. Metformin
c. Empagliflozin
d. Linagliptin

9. Which of the following is a major adverse effect of SGLT2 inhibitors?

a. Urinary tract infections
b. Weight gain
c. Diarrhea
d. Pancreatitis

10. Which of the following agents should not be used in a patient with inflammatory
bowel disease?

a. Glipizide
b. Acarbose
c. Sitagliptin
d. Insulin

This concludes the final examination. To complete the exam, login to

your account at http://www.westernschools.com

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