and adverse drug reactions
in older patients
Joshua S. Coren, DO, MBA
Kevin J. Overbeck, DO
Frank A. Filipetto, DO
As the U.S. population
ages there will be
in the number of older adults
who have type 2 diabetes mellitus.
Older adults with diabetes often
will be taking many other medications.
Health care professionals who coordinate
care for older patients with diabetes must
not only be able to treat hyperglycemia to target
individualized goals of care but also anticipate and
recognize the adverse effects of various pharmacologic
May 2011 DOs Against DIABETES
AOA Health Watch
Prescriber knowledge about drug
pharmacodynamics and pharmacokinetics
and their interaction with normally
aging physiology is critical in treating
the elderly patient with diabetes.
This knowledge is needed to minimize
and even avoid the potentially adverse
effects of hypoglycemia and the side
effects associated with polypharmacy.
When medications become necessary
to the management of diabetes in an
older patient, informed practitioners can
correctly and safely write a prescription
for the proper drug, dose and frequency.
When evaluating the pharmacodynamic
effects of a drug on a body, the patient’s
age, comorbid conditions and concurrent
medications should be considered. 1
An older patient may exhibit alterations
in receptor affinity or number and
signal transduction mechanisms,
and impairment of cellular response
in affected organs that influence
the pharmacodynamics of a particular
Pharmacodynamic effects commonly
encountered with regard to neurologic
and cardiac functioning via the
autonomic and central nervous system
also play a role in pharmacotherapy for
diabetes. Drug sensitivity may increase
in older patients when the cellular
response to a given pharmaceutical
concentration is enhanced. 4
Physicians must realize that enhanced
concentration of some medications,
such as the sulfonylureas, can increase
the incidence of hypoglycemia in older
patients more than in younger patients. 5
Evaluating each diabetic medication
and its respective pharmacodynamic
properties is imperative to reduce
the risk of these potential effects.
Pharmacokinetics involves the effect
of body on a drug during the course of
travel from absorption, bioavailability,
distribution and metabolism through
excretion. 6 Many classes of diabetic
medications are taken orally and
absorbed via the gastrointestinal tract.
A net neutral absorption effect
of decreased intestinal motility is likely
in the older patient, which increases
the time for drug absorption in the
otherwise normal gastrointestinal tract
that may be offset by the patient’s
increasing pH level. 7-9 With normal
aging, there is a decrease in lean body
mass, water volume and organ blood
flow, with a concomitant increase in
adipose tissue, making it imperative
that the practitioner choose the lowest
possible effective dose for the patient.
Renal and hepatic elimination of
diabetic medications is certainly a main
concern of providers caring for older
inpatient and outpatient populations.
Some of the most common diseaseinduced
changes can affect both liver
and kidney function, further leading
to varying pharmacokinetics and
drug elimination. These issues make
treating the older adult with diabetes
even more challenging.
Adverse drug reactions
The most common and one of the most
devastating side effects of pharmacologic
treatment of older patients is hypoglycemia.
The risk of severe or fatal hypoglycemia
exponentially increases with age. 10
The landmark trial Action to Control
Cardiovascular Risk in Diabetes, or
ACCORD, was discontinued early when
interim results indicated a statistically
significant increase in mortality in
patients who received intensive therapy
with the goal of achieving a glycated
hemoglobin level of 6% or less. Further
analysis of data from this trial showed
that individuals in this group used more
medication and had more hypoglycemic
events, greater weight gain and greater
fluid retention than individuals in the
group that received standard therapy
with the goal of a glycated hemoglobin
level of 7% to 7.9%. 11
Although the Action in Diabetes
and Vascular Disease: Preterax and
Diamicron Modified Release Controlled
Evaluation, or ADVANCE trial, which
similarly compared intensive blood sugar
control to standard therapy, did not
show a difference in mortality between
the two groups, it did demonstrate an
increase in the number of hypoglycemic
events and hospitalization in those who
were more intensively treated. 12 In light
of these findings, the American Diabetes
Association has recommended that goals
be individualized, with more flexible
goals for older adults, those with
advanced disease and complications
or those with limited life expectancy. 13
Older patients also may experience
delayed psychomotor responses as
a result of interventions designed
AOA Health Watch
DOs Against DIABETES May 2011
to correct hypoglycemia. 14 Glucagon,
one of the main counter-regulatory
responses to hypoglycemia, is impaired
in older people and, to a greater
extent, older patients with diabetes. 15
Altered psychomotor and impaired
counter-regulatory responses must
be balanced with the functional and
cognitive status of the individual.
In addition to being aware of and
recognizing hypoglycemia, patients
must be able to access food or drink
to reverse this iatrogenic condition.
Hypoglycemia manifests through
an easily recognizable adrenergic
constellation of symptoms, most notably
tremor, sweats or weakness. However,
older patients commonly demonstrate
a primarily neuroglycopenic syndrome
(i.e., confusion, delirium, dizziness and
falls) that can be misdiagnosed as a
neurologic event such as a transient
ischemic attack or syncope.
Listed below are some common
classes of medications prescribed
for diabetes. Although this is not a
comprehensive list of medications
and corresponding adverse events,
notes are provided on the potential
for adverse reactions in this population.
Clear provider instructions and patient
(or caregiver) comprehension are
essential to ensure directed drug
dosing, timing and administration.
Adverse events associated with the
thiazolidinediones are weight gain,
edema, macular edema, congestive
heart failure, increased bone fracture
risk and, when combined with other
diabetic medications, hypoglycemia. 16
Of notable mention are several studies
that suggest the potential for adverse
cardiovascular events with rosiglitazone
and potential for benefits in cardiovascular
risk reduction from pioglitazone. 17-19
Further studies are needed regarding
these events and how they affect
the older population with diabetes.
Ongoing concerns about fluid retention
limit the utility of these studies for
older patients with diabetes.
Patients will commonly experience
gastrointestinal side effects that tend
to improve after the first few weeks of
treatment with metformin. Metformin
should not be used in individuals older
than age 80 until renal function has
been established. Lactic acidosis is
a potential side effect of metformin,
yet evidence is scant that it will
occur with contraindications to
metformin. 20,21 The biguanide class
is also contraindicated in patients
with renal disease, renal dysfunction
or abnormal creatinine clearance rates.
As previously mentioned, hypoglycemia
is a notable adverse event that can
occur with the sulfonylurea class of
drugs. There are conflicting data on
whether the sulfonylurea class increases
the risk of cardiovascular events, and
further research is needed. 22-24 Older
patients should be instructed about the
potential for weight gain as more insulin
is produced and glucose is utilized.
Weight gain is a common feature of
this class that includes the medications
repaglinide and nateglinide. Although
hypoglycemia is a possible side effect,
mealtime dosing of meglitinides enables
older patients to be flexible with their
dosing schedule. Repaglinide may also
be a good choice for an older patient or
a patient with renal disease, as 90% of
the drug can be recovered in the feces. 25
Insulin is often an underutilized
therapeutic modality in the older
patient with diabetes because of the
practitioner’s, patient’s or family’s
concerns about administration and
the risk of hypoglycemia. 26 Weight
gain is another common adverse effect
of insulin products. Patients should be
appropriately educated on the proper
administration, dosing and effects
of the various insulin products.
Visual and cognitive acuity
should be assessed prior to initiating
and tailoring products to ensure
that patients can easily administer
the amount of insulin prescribed.
Specifically, the use of insulin pens
can greatly assist older adults who
may have issues with vision or dexterity.
In some of the pens the correct dose
can be achieved even with clicks of
the pen, ensuring more accurate dosing.
With the advent of long-acting, oncedaily-administered
capable and willing caregivers can
often assist the older individual
with this pharmacologic intervention.
DOs Against DIABETES
AOA Health Watch
Dipeptidyl Peptidase-4 Inhibitors
Sitagliptin, a dipeptidyl peptidase-4
(DPP-4) inhibitor, has a favorable
safety profile, and a low incidence
of hypoglycemia. Nausea generally
resolves with dosing strategies during
the introduction of the medication. 27
Sitagliptin is being investigated to
determine whether it is linked to acute
pancreatitis. 28,29 Abdominal pain and
substantially decreased appetite should
be cause to discontinue this medication.
Saxagliptin has a similar adverse effect
profile but is associated with a decrease
in the absolute lymphocyte count (this
was not observed at the 2.5 mg dose). 30
Although the clinical importance of
this laboratory finding has not been
firmly established, saxagliptin has been
associated with an increased number
of upper respiratory infections,
as well as urinary tract infections. 31
Repeated infections should prompt
a review of saxagliptin’s clinical utility
in the individual’s case. Despite an
increased financial burden for the
elderly, DPP-4 inhibitors may be
particularly useful in older adults,
since they exhibit few drug-to-drug
interactions. In addition, these
medications can be used in adults
with all stages of renal disease,
including end-stage renal disease
(but dosage adjustment is needed).
Exenatide has a favorable safety
profile, with adverse events of
dizziness, headache and gastrointestinal
discomfort. 27 Incretin mimetics is
being investigated to determine whether
it is linked to acute pancreatitis and
thyroid cancer. 28, 29, 32 Liraglutide
has a similar safety concern but carries
the benefit of once daily dosing
administered in a pre-filled pen.
Since weight loss can be substantial in
patients using this medication, the role
of incretin mimetics is limited in the
vulnerable or frail elderly population. 33
The administration of multiple
pharmaceutical products in concert
(known as polypharmacy) may potentiate
or decrease the effects of common
diabetes medications in the older
population. Such patients commonly
have other systemic, related chronic
conditions; the physician must recognize
the variety of medications the patient
may be taking and the potential
interactions among these medications.
In one study of 18,968 patients with
diabetes, at least 16% were dispensed
a medicine that is associated with
adverse interactions, and 22.7% were
dispensed at least one potentially
inappropriate medicine. 34
Every six to 12 months, physicians
should request that their older patients
bring their medications with them to their
appointments as an audit for usage and
also as an educational opportunity. This
“brown bag” medication review is one
method to avert potential polypharmacy. 35
Physicians should also strive to partner
with family members who are often
caregivers for these patients.
As aging is a risk factor for chronic
care conditions such as diabetes,
physicians are faced with a growing
population of older patients with this
disorder. Ensuring that patients are
educated on both their medications
and potential adverse events is a
necessity in every care plan to limit
potential treatment complications.
AOA Health Watch
DOs Against DIABETES May 2011
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22. Evans JM, Ogston SA, Reimann F, Gribble FM,
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Joshua S. Coren, DO, MBA, is the acting chair and associate professor of the Department
of Family Medicine at the University of Medicine and Dentistry of New Jersey School of
Osteopathic Medicine in Stratford, New Jersey. He can be reached at firstname.lastname@example.org.
Kevin J. Overbeck, DO, is assistant professor of family medicine and works as a geriatric
educator and clinician with the New Jersey Institute for Successful Aging at the University of
Medicine and Dentistry of New Jersey School of Osteopathic Medicine in Stratford, New Jersey.
Frank A. Filipetto, DO, is associate professor of the Department of Family Medicine at
the University of Medicine and Dentistry of New Jersey School of Osteopathic Medicine
in Stratford, New Jersey.
May 2011 DOs Against DIABETES AOA Health Watch 7