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Polypharmacy in Elderly Patients With Diabetes

Article  in  Diabetes Spectrum · October 2002

DOI: 10.2337/diaspect.15.4.240

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 In Brief
Elderly diabetic patients often require multiple medications to adequately and
appropriately treat their diabetes and associated comorbidities. Careful atten-
tion to avoiding drug interactions, limiting unnecessary medications, and
choosing drugs most appropriate for elderly patients will lead to optimal out-
comes.
Polypharmacy in Elderly Patients With Diabetes
Elderly patients with diabetes pose a
particular challenge to clinicians with
respect to managing medications. Not
Chester B. Good, MD, MPH only are comorbidities common in
elderly diabetic patients, but also care-
ful management of these comorbidi-
ties is perhaps more important than in
patients without diabetes. While non-
pharmacological interventions for
managing diabetes and the associated
comorbidities are integral to the treat-
ment plan, in reality, the cornerstone
of management remains pharma-
cotherapy. As a consequence, there
are strong factors that favor polyphar-
macy in patients with diabetes.
Rational medication prescribing
dictates that the fewest medications be
used to achieve the therapeutic goals
as determined by clinician and
patient. Multiple medications not only
add to the cost and complexity of
therapeutic regimens, but also place
patients at greater risk for adverse
drug reactions and drug-drug interac-
tions. Studies evaluating appropriate
prescribing in the elderly consistently
find frequent polypharmacy and use
of excessive or potentially harmful
drugs. To address the problem of
inappropriate polypharmacy, efforts
have been studied in both inpatient
and outpatient settings to decrease use
of unnecessary medications, as well as
the overall number of medications,
both in inpatient and outpatient set-
tings.
240
Diabetes Spectrum Volume 15, Number 4, 2002
Thus, clinicians caring for people
with diabetes face a therapeutic
conundrum: balancing the needs of
their patients and attempting to
achieve optimum control of medical
problems while trying to keep the
medication profile as simple and small
as possible.
CASE STUDY
Consider the following patient who is
cared for in our clinic. He is a 70-
year-old man with longstanding type
2 diabetes, dyslipidemia, hypertension
for 8 years, chronic degenerative joint
disease of the knees and back, gas-
troesophageal reflux disease (GERD),
and angina pectoris status post
myocardial infarction. As a result of
his diabetes, he has elevated urinary
microalbumin and painful neuropathy
of the lower extremities. He is 25 kg
above his ideal body weight.
On presentation to the clinic, he
was complaining of worsening lower
urinary tract symptoms related to pro-
static hypertrophy, which we had been
following with watchful waiting. His
blood pressure in the clinic, repeated
several times, was 144/84 mmHg. It
has been borderline elevated for the
past several visits, and he was attempt-
ing weight loss and low-level exercise
in hopes of avoiding additional med-
ications. These attempts have been
hampered by his heart disease, arthri-
tis, and neuropathy.
 His blood pressure has been diffi-
cult to maintain, despite his being on
optimal doses of lisinopril (Prinivil),
hydrochlorothiazide (Hydrodiuril),
atenolol (Tenormin), and felodipine
(Plendil). To manage his diabetes, he
takes glyburide (Micronase) and met-
formin (Glucophage). His glycated
hemoglobin is 8.1%, similar to his
usual level of control. His LDL cho-
lesterol is well controlled (89 mg/dl)
with simvastatin (Zocor), but his
HDL cholesterol is low (28 mg/dl)
and his triglycerides are modestly ele-
vated (260 mg/dl). He takes aceta-
minophen (Tylenol) for his arthritis
and uses topical capsaicin cream as an
adjunct to this. He takes gabapentin
(Neurontin) for his neuropathic pain,
with some benefit. In addition to his
hypertension medications, he takes
aspirin as part of his cardiac regimen.
He takes sublingual nitroglycerin
(Nitrostat) as needed and wears a
nitroglycerin patch (Nitrodur) for
symptomatic angina. He uses raniti-
dine (Zantac) for his GERD.
What should be done with this
patient’s blood pressure? What should
be done with his complaint of lower
urinary symptoms? He is already tak-
ing 12 different oral medications and
two topical medications. He takes a
total of 26 pills daily. Theoretically,
he would benefit from better blood
pressure control, perhaps he would
benefit from improvement of his dys-
lipidemia with the addition of gemfi-
brozil (Lopid), and clearly he would
like to have his lower urinary symp-
toms treated.
We could add an -adrenergic–
blocking agent such as terazosin
(Hytrin) to treat both his urinary fre-
quency and blood pressure, but we are
concerned about the implications of
using this agent with the recent results
of the ALLHAT trial, which found a
greater incidence of heart failure with
that agent.1 We could use tamsulosin
(Flomax) for his urinary symptoms,
but this would not address his blood
pressure and would increase his costs.
We are reluctant to add gemfibrozil
with issues of polypharmacy, advanced
age, and the possibility of a drug inter-
action with simvastatin.
While this patient may seem to be
contrived, this scenario is not unusual
in patients with diabetes, especially
those who are elderly.
DEFINITION OF POLYPHARMACY
Although the term “polypharmacy”
is frequently used, it is not clearly
defined in the literature. Remarkably,
this term is not addressed in several
standard textbooks of pharmacology.
One simple definition is based on the
total number of different medications
a patient takes concomitantly. This
definition allows for easy identifica-
tion of patients with polypharmacy
issues for organizations that have a
unified formulary with pharmacy
benefits, such as health maintenance
organizations or the Department of
Veterans Affairs (VA). The number
of medications constituting polyphar-
macy may be as high as 10, 2 but
most definitions use five or six med-
ications.3–7
These definitions do not account
for as-needed medications or over-the-
counter (OTC) medications, including
herbal products. It is also not clear
how inhaled medications, ophthalmic
drops, or topical medications are
qualified in these definitions. Thus,
while this definition is simple and easy
to apply, it uses arbitrary numbers of
medications and does not account for
appropriate or inappropriate uses of
medications.
A more clinically useful definition
is “the prescription, administration,
or use of more medications than are
clinically indicated.”8 Inappropriate
drug combinations, unnecessary med-
ications, and inappropriate drugs for
specific patients (such as the elderly)
constitute the problems of polyphar-
macy. Thus, patients receiving only
two medications could have polyphar-
macy.
While intellectually more satisfying,
this definition is limited by several fac-
tors. Primarily, it generally requires
review of patient-specific information
and is labor intensive. Of some help
are computer programs that review
pharmacy profiles to identify inappro-
priate drug combinations, including
those with serious potential interac-
tions. Expert panels have developed
consensus-based lists of medications
considered to be inappropriate for use
in the elderly.9
For the purposes of this article,
polypharmacy will be defined using
the simpler definition of use of multi-
ple medications for a single patient.
FACTORS INFLUENCING
POLYPHARMACY
Although in theory use of excess med-
ications is recognized as problematic,
many forces continue to promote
addition of medications to therapeutic
regimens for individual patients.
Diabetes Spectrum Volume 15, Number 4, 2002
Quality assurance monitors often
From Research to Practice / Polypharmacy: Boon or Bane?
focus on identification of unrecog-
nized comorbidities, such as depres-
sion. Additional efforts have been
made to regularly assess and treat
pain (the “fifth vital sign”). These
efforts frequently lead to use of phar-
macotherapy to address new diag-
noses. In addition, quality assurance
monitors often focus on appropriate
pharmacotherapy for clinical diag-
noses, as these monitors lend them-
selves to easy measurement and are
backed by solid clinical evidence.
Thus, programs to assess use of
aspirin in coronary artery disease and
angiotensin-converting enzyme (ACE)
inhibitors for heart failure are com-
mon. While these efforts clearly are
clinically sound, their influence on
problems associated with polyphar-
macy is not known.
Another more recent influence on
prescribing practices is pervasive
direct-to-consumer advertising. In
addition, advertising of OTC medica-
tions and alternative medications like-
ly results in significant use of prod-
ucts. It is unclear how significantly
direct-to-consumer advertising affects
polypharmacy. Nevertheless, this
practice has been cause for significant
concern among both physicians and
policy makers.
Unlike pharmaceutical industry
promotions to health care providers,
which cover brand-name drugs exten-
sively, direct-to-consumer advertising
focuses on relatively few products.10
Advertising for lifestyle medications
(such as sildenefil [Viagra] for erectile
dysfunction or finasteride [Propecia]
for male baldness) or underrecognized
conditions (such as depression, aller-
gies, or dyslipidemia) is very common.
Presumably, this strategy is based on
marketing research that supports a
greater impact on addition of new
prescriptions.
Finally, remarkable improvements
in drug therapy offer far greater
options for treatment. Not only are
new drug classes available for new
indications, but also new medications
within existing drug classes now offer
improved efficacy, better side effect
profiles and tolerability, and longer-
acting preparations.
INCIDENCE OF POLYPHARMACY
IN THE ELDERLY
Regardless of the definition of
polypharmacy, it is prevalent, partic-
ularly in the elderly. In a study of
patients randomly chosen from an
241
 outpatient clinic at a VA Hospital
(primarily a geriatric population), the
mean number of medications was
five, and 65% were taking more than
four drugs.11 Another VA study found
that 42% of geriatric patients admit-
ted to a facility were taking five or
more medications. A study of
Swedish elderly found that 39% were
taking five or more drugs concomi-
tantly.5
Although these studies did not sep-
arate out diabetes patients, it is likely
that such patients will have an even
greater incidence of polypharmacy
than do elderly patients without dia-
betes. In a national survey in Finland,
type 2 diabetic patients used signifi-
cantly more medications, with signifi-
cantly greater cost, than nondiabetic
patients matched for sex, age, and
area of residence.12 The presence of
comorbidities associated with dia-
betes and advanced age is a strong
factor favoring addition of multiple
agents to an individual’s medication
regimen.
CLINICAL RELEVANCE OF
POLYPHARMACY
Use of multiple medications increases
in a variety of ways the likelihood of
an unintended therapeutic outcome.
This is especially true in the case of
elderly patients, who are particularly
susceptible to adverse drug events.
Although not specifically studied, it is
likely that diabetic elderly patients are
even more susceptible to problems
related to polypharmacy because of
significantly greater underlying physi-
cal disability.13 Thus, polypharmacy
adds expense for multiple drugs,
increases the chance of an adverse
reaction to a single agent, increases the
incidence of drug interactions, decreas-
es patient compliance, and plays a part
in unwanted geriatric syndromes.
Finally, polypharmacy increases the
likelihood of prescribing and dispens-
ing errors.
Drug interactions occur when two
or more medications interact in a way
not intended and with a nondesirable
outcome. The addition of each med-
ication increases the possibility of
drug interactions.
In one study of fatal adverse drug
events in Norway, drug interactions
were frequently suspected. During a
2-year period, 18% of deaths were
thought to be related to adverse drug
events directly or indirectly. Patients
on greater numbers of medications
were at greater risk of adverse events
242
leading to death. Investigators found
that nearly 24% of patients were on
12 or more medications at the time of
their death.14
In another study of elderly patients
presenting to an emergency room in
Canada, adverse drug-related events
accounted for more than 10% of vis-
its. The average number of medica-
tions was 4.2. Of these patients, half
had potential adverse drug interac-
tions in their medication profile.15
While use of numerous medications
is clearly a marker for greater burden
of disease and likely increased suscep-
tibility to adverse drug events, it is
also likely that polypharmacy increas-
es the probability of drug interactions
or adverse events independently. In a
nursing home study, number of med-
ications administered was associated
with greater risk of adverse drug
events. The risk increased from an
odds ratio of 2.0 for five to six med-
ications, to 3.3 for nine or more med-
ications.16
Elderly patients are susceptible to
geriatric syndromes associated with
inappropriate medications. Confusion
or cognitive impairment, falls and
fractures, and urinary retention are
well recognized as potential causes of
adverse drug reactions. 17 Elderly
patients are also more susceptible to
orthostatic hypotension, insomnia,
and constipation with commonly used
medications, such as narcotics, anti-
cholinergic medications, and -block-
ers. Diabetic patients with longstand-
ing disease are particularly susceptible
to all of these adverse events because
of neuropathy, dysautonomia, and
vascular disease.
Because of the increased relevance
of adverse drug interactions in the
elderly, several consensus panels have
developed lists of drugs or drug class-
es that should be avoided if possible.9
Medications considered to be poten-
tially problematic in elderly patients
include those with prolonged half-
lives, significant anticholinergic
actions, narrow therapeutic indices,
and highly sedating properties, as well
as medications with little evidence of
efficacy in the elderly.
These lists have been widely
employed in the assessment of appro-
priateness of drug therapy and suggest
that inappropriate prescribing is com-
mon in the elderly. In a 1987 national
survey of 6,171 community-dwelling
elderly patients, 23.5% were receiving
at least one of a list of 20 potentially
contraindicated drugs. The authors
Diabetes Spectrum Volume 15, Number 4, 2002
interpreted their findings to indicate a
strong need for broader educational
and regulatory initiatives to improve
drug prescribing in the elderly.18 More
recently, respondents in an epidemio-
logical study of elderly patients at
Duke University Medical Center
found inappropriate medication use in
22–27% of community-dwelling
elderly patients.19
Hanlon et al.20 have developed the
Medication Appropriateness Index
(MAI) to identify inappropriate pre-
scribing. This rating system evaluates
10 criteria (indication, effectiveness,
dosage, appropriateness of direc-
tions, practicality of directions, drug-
drug interactions, drug-disease inter-
actions, duration, duplication, and
cost) and has been validated in elder-
ly inpatients and outpatients. Using
this index, Schmader et al.21 found
that polypharmacy (five or more
medications) and MAI scores indicat-
ing less appropriate prescribing were
associated with adverse health out-
comes.21
Despite the concerns for polyphar-
macy in the elderly, paradoxically,
some have suggested that patients with
multiple chronic diseases are frequent-
ly undertreated with medications. In a
study of elderly patients in Ontario,
Canada, investigators found that med-
ical problems unrelated to chronic
medical disorders were less likely to be
given appropriate medical therapy. For
example, diabetic patients were signifi-
cantly less likely to receive estrogen
replacement therapy.22
For patients with diabetes, there
are especially significant treatment
goals and outcomes that are specifi-
cally tied to drug therapy. Thus, con-
cerns for polypharmacy must be bal-
anced against the need to adequately
treat diabetes, as well as associated
comorbidities.
DIABETIC ISSUES THAT FAVOR
POLYPHARMACY
Several factors contribute to polyphar-
macy in diabetic patents. Not only is
tight glycemic control important, but
multiple comorbidities associated with
diabetes also require drug therapy
(Table 1).
Importance of Glycemic Control
in Diabetes
There is an increasing understanding
of the importance of good glycemic
control in type 2 diabetes. The
American Diabetes Association has set
target A1C goals of <7%. 23 Infor-
 continues to expand. In addition to

From Research to Practice / Polypharmacy: Boon or Bane?

Table 1. Factors Contributing to Polypharmacy the insulins, there are five different
in Diabetic Patients oral antidiabetic classes: sulfony-
lureas, biguanides, -glucosidase
• Need for tight glycemic control, often requiring multi-drug regimen inhibitors, thiazolidinediones, and
• Frequent comorbidities requiring drug therapy:
non-sulfonylurea secretagogues.
–Hypertension: Tight control often requires a multiple-drug regimen.
–Dyslipidemia Further confusing the issue is the
–Coronary artery disease: Multiple drugs are beneficial. expanding number of specific drugs or
–Renal disease: Drug therapy early in the disease prevents progression. formulations in each class.
–Congestive heart failure: Multiple-drug therapy is usually required. Different mechanisms of actions
–Neuropathy: Pain management usually requires pharmacotherapy. and complementary effects on
–Glaucoma, peripheral vascular disease, lower-extremity ulcers, obesity, and gas- glycemic control have led to use of
trointestinal problems: Each occasionally requires therapy. diabetic drug combinations (Table
2). Multiple clinical trials focusing
mation from the Third National maintaining glycemic control were on combinations of two oral agents
Health and Nutrition Examination increased to maximum doses on have demonstrated additional (albeit
Survey (NHANES III) found that monotherapy and then increased modest) improvements in glycemic
18% of patients had poor glycemic again to addition of other agents if control.29 Although limited, there are
control defined as glycated hemoglo- glycemic control was not maintained. data supporting the effectiveness of
bin >9.5%. Patients >65 years of age Investigators found a progressive adding a third drug in patients not
did slightly better, with 14.5% having decline in glycemic control such that meeting glycemic goals on two oral
a glycated hemoglobin >9.5%.24 by 3 years, <55% of patients remained agents. For example, in patients on
Some medical organizations have on monotherapy. At 9 years, <25% maximal doses of a sulfonylurea and
made an effort to track glycemic con- remained on monotherapy.27 In prac- metformin, the addition of troglita-
trol among covered patients and have tice, it is likely that many patients will zone (Rezulin) resulted in improved
demonstrated improvement. The VA have diabetes of much longer dura- glycemic control.30 Although trogli-
follows national trends in glycemic tion, and thus it follows that most tazone is no longer available, piogli-
control among veteran patients. In patients will require multiple antidia- tazone (Actos) and rosiglitazone
1998, for more than 200,000 patients betic agents to meet the glycemic goals (Avandia) have replaced it as safer
with documented A1C results avail- that would be expected to derive the alternatives and are being used in
able, the median was 7.5%, with clinically relevant outcomes seen in combination with multiple agents.
60% of the patients having A1Cs of clinical trials.28 Finally, the addition of insulin to
<8.0% and 16% having A1Cs >9.5%. Adding to the likelihood that good oral agents is an option. Thus,
This information is provided to all glycemic control will result in use of although not approved by the Food
facilities with comparisons to other multiple antidiabetic agents is the fact and Drug Administration (FDA),
facilities so that performance can be that the therapeutic armamentarium three- and four-drug regimens are
monitored. Underlying this initiative
of providing feedback is the under-
Table 2. Therapeutic Options and Approved Combinations for
standing that improved glycemic con-
trol will result in improved outcomes Diabetes
for patients.25 Drug Approved Combinations
The landmark United Kingdom Sulfonylureas (SU) Insulin, metformin, TZD, AG
Prospective Diabetes Study (UKPDS)26 • Glyburide
established that intensive blood glu- • Glipizide
cose control reduced the risk of both • Glimepiride
microvascular and macrovascular
complications in patients with type 2 Biguanides Insulin, SU, non-SU, TZD
• Metformin
diabetes. The modest 11% reduction
in glycated hemoglobin over the 10- -Glucosidase inhibitors (AG) SU
year study for the intensively treated • Acarbose
patients resulted in reduction of clini- • Miglitol
cally relevant endpoints. There were
decreases in all diabetes-related end- Thiazolidinediones (TZD) Insulin, SU, metformin
• Rosiglitazone
points (12%), diabetes-related death
• Pioglitazone
(10%), and all-cause mortality (6%).
This study included only patients Non-sulfonylurea secretogogues (non-SU) Metformin
with newly diagnosed diabetes and • Repaglinide
thus offered the opportunity to follow • Nateglinide
responses to therapy, including the
Insulins SU, metformin, TZD
need for multiple agents. Patients
• Regular
were started on monotherapy consist- • Lispro, aspart
ing of diet alone, insulin, or sulfony- • NPH
lurea (and metformin for obese • Lente
patients). Patients not achieving or • Glargine
243
Diabetes Spectrum Volume 15, Number 4, 2002
 not inconceivable, especially as
patients progressively lose -cell
function.
Although drug combinations have
been shown to be effective at lowering
blood glucose in type 2 diabetic
patients, they have not been well stud-
ied in randomized, controlled trials
with regard to clinically relevant out-
comes. Indeed, in a substudy of the
UKPDS, addition of metformin to sul-
fonylurea was associated with a sig-
nificant increase in diabetes-related
death as well as overall death.31 This
unexpected finding has not yet been
replicated but perhaps should be con-
sidered when setting target glycemic
goals for fragile elderly diabetic
patients.
Prevalence of Comorbidities With
Diabetes
Complicating the management of dia-
betes is the remarkable number of
organ systems potentially affected by
the disease process. Cardiovascular
disease, including hypertension,
myocardial infarction, congestive
heart failure, cerebrovascular disease,
and peripheral vascular disease, is
particularly prevalent in patients with
diabetes. Likewise, dyslipidemia, obe-
sity, renal disease, erectile dysfunc-
tion, retinopathy, neuropathy, and
gastrointestinal problems such as gas-
troparesis are prevalent in patients
with type 2 diabetes.
In reviewing the presence of
comorbidities in elderly diabetic
patients from NHANES III, there was
significantly greater presence of con-
comitant myocardial infarction, con-
gestive heart failure, stroke, peripheral
vascular disease, and vision problems
in diabetic subjects compared to those
without diabetes.13 In another popula-
tion-based study, hypertension, con-
gestive heart failure, coronary artery
disease, dyslipidemia, renal disease,
and glaucoma were all significantly
more prevalent in patients with type 2
diabetes than in matched control sub-
jects.11
The presence of diabetes with these
diagnoses may dramatically increase
morbidity and mortality in affected
patients. Clinical trials have demon-
strated the benefits of aggressive man-
agement of disease comorbidities in
patients with type 2 diabetes. Because
treatment of hypertension, coronary
artery disease, and renal disease in
diabetic patients has been shown to
result in clinically relevant beneficial
outcomes, aggressive control of blood
244
pressure and dyslipidemia have special
importance.
Although nonpharmacological
interventions are an important part of
all diabetes care, adequate treatment
of these comorbidities relies on
aggressive pharmacotherapy. Thus,
the presence of comorbidities signifi-
cantly adds to the likelihood that mul-
tiple medications will be utilized in the
appropriate care of these patients.
Hypertension in diabetes
Hypertension is approximately twice
as common in type 2 diabetic patients
as in those without diabetes and is
found in up to 85% of patients with
nephropathy.32 Although the inci-
dence of hypertension increases with
duration of type 2 diabetes, a substan-
tial number of patients have hyperten-
sion present at the time of diabetes
diagnosis.33
Studies suggest that hypertension is
frequently less-than-adequately con-
trolled in diabetic patients. In the
UKPDS, 38% of all subjects had blood
pressure >160/90 mmHg and 62%
required combination therapy to
achieve tight blood pressure control,
which averaged 144/82 mmHg.26 In a
VA study of hypertension, 34% of
patients with hypertension also had
diagnosed diabetes, 40% of patients
had blood pressure >160/90 mmHg,
and <25% had blood pressure <140/90
mmHg. The presence of diabetes did
not predict more aggressive blood pres-
sure therapy.34
Multiple studies have conclusively
demonstrated that even modestly low-
ering blood pressure in type 2 diabetic
patients results in significant clinical
outcomes. Observational studies have
shown that the risk of diabetes com-
plications significantly decreases with
lower blood pressure, with the lowest
risk in patients with a systolic blood
pressure <120 mmHg.35
Intervention trials have also con-
firmed that aggressive lowering of
blood pressure is important. The
UKPDS evaluated tight (<150/85
mmHg) or less tight (<180/105
mmHg) blood pressure control in dia-
betic patients and demonstrated a
32% decrease in diabetes-related mor-
tality. Indeed, tight control of blood
pressure had greater benefits than
tight glycemic control.26
In the Hypertension Optimal
Treatment study, blood pressure tar-
gets were diastolic blood pressure ≤90,
85, or 80 mmHg. Although the differ-
ence between the highest and lowest
Diabetes Spectrum Volume 15, Number 4, 2002
group in actual blood pressure control
achieved was relatively modest (144/85
vs. 140/81 mmHg), there was a 51%
reduction of major cardiovascular
events in the lowest group.36 In light of
these studies, the National Kidney
Foundation recommends a target
blood pressure of 130/80 mmHg for all
diabetic patients, with more aggressive
blood pressure targets in the presence
of renal disease.
Multiple antihypertensive medica-
tions are required to achieve the
aggressive blood pressure goals rec-
ommended for diabetic patients. In
their observational hypertension study
in the VA, Berlowitz et al. 34 found
that despite less-than-adequate blood
pressure control, nearly 60% of sub-
jects were taking two or more blood
pressure medications. In five random-
ized clinical trials of blood pressure
treatment including diabetic patients,
subjects took an average of 3.2 anti-
hypertension medications (range
2.8–4.2) to achieve an average blood
pressure of ~140/90 mmHg.32 Despite
this, it should be noted that no ran-
domized controlled trial has yet
achieved a blood pressure of <130/80
mmHg. Thus, it is clear that efforts to
achieve target blood pressure levels
associated with beneficial clinical out-
comes will require multiple antihyper-
tensive agents.
Dyslipidemia in diabetes
Lipid abnormalities are very prevalent
in patients with diabetes. Not only
does poor glycemic control contribute
to elevations in triglycerides, low
HDL cholesterol, and, to a lesser
extent, elevated LDL cholesterol, but
obesity also complicates dyslipidemia.
Recent cholesterol treatment guide-
lines suggest treating diabetic patients
with dyslipidemia similarly to patients
with established coronary artery dis-
ease regardless of whether you are
treating for primary or secondary pre-
vention.37 These recommendations are
based on the high incidence of
myocardial infarction and death from
vascular disease in patients with dia-
betes.
One widely referenced study com-
pared 7-year incidence rates for
myocardial infarction in diabetic
patients without prior events to those
of patients with established coronary
artery disease but without diabetes.
Investigators found no difference in
rates for death from coronary artery
disease between the two groups even
after adjusting for age, sex, choles-
terol, hypertension, and smoking. 38
This study has been interpreted to
indicate that type 2 diabetes is a coro-
nary artery disease equivalent in terms
of risk for future cardiovascular
events.
Subgroup analysis of several trials
supports aggressive treatment of dys-
lipidemia in diabetic patients with doc-
umented cardiovascular disease. The
Scandinavian Simvastatin Survival
Study39 demonstrated that simvastatin
therapy was associated with significant
reductions in coronary events and
mortality compared to placebo both
for patients with established diabetes
and for those with impaired fasting
plasma glucose levels but no history of
diabetes. Subgroup analysis of the
Cholesterol and Recurrent Events
trial40 also demonstrated significant
reduction of absolute risk of coronary
events compared to placebo using
pravastatin as the lipid-lowering agent.
The recent Heart Protection Study
(HPS) is the first randomized trial to
demonstrate the benefit of lipid low-
ering with simvastatin in diabetic
patients for primary prevention. 41
There are no trials demonstrating
reductions in adverse clinical out-
comes in the treatment of elevated
triglycerides, the most common lipid
abnormality in diabetic patients.
Nonetheless, based on the HPS and
epidemiological evidence, it is pru-
dent to extend treatment of dyslipi-
demia for both primary and sec-
ondary prevention in diabetic
patients.
Treatment of dyslipidemia in dia-
betes is thus important, with focus on
lowering LDL cholesterol. However,
because triglycerides are frequently
elevated, therapy may not always be
straightforward. Initial efforts at low-
ering triglycerides should focus on
optimal glycemic control. Both sim-
vastatin and atorvastatin (Lipitor) are
potent cholesterol-lowering agents
that also have FDA indications for
lowering triglycerides. However, the
triglyceride-lowering efficacy is mod-
est in many patients, and these drugs
may not lower triglycerides to desired
levels. Niacin (Niaspan) is more
potent at lowering triglycerides, but
may worsen glycemic control. Thus, a
fibrate could be added to a statin, but
this increases the possibility of muscle
myopathy and rhabdomyolysis.
Theoretically, pravastatin (Pravachol)
might be safer because it is not
metabolized by the cytochrome P450
system, but this is not proven. In any
event, appropriate treatment of lipid
abnormalities in diabetic patients
offers clear benefit but adds to
polypharmacy in these patients.
Prevention of end-stage renal disease
in diabetes
End-stage renal disease in diabetes
can be delayed or prevented with
appropriate screening and aggressive
medical therapy in higher-risk
patients. Controlling blood pressure
is of paramount importance to the
prevention of renal disease. Screening
diabetic patients for microalbumin-
uria identifies those patients at the
earliest stage of diabetic nephropathy.
The National Kidney Foundation and
others recommend that these patients
receive even more intensive blood
pressure therapy, as well as tight
glycemic control, to preserve renal
function. 32 ACE inhibitors, angio-
tensin receptor blockers, -blockers
(including carvedilol [Coreg]), diuret-
ics, and calcium-channel blockers
have all been shown to reduce pro-
teinuria in high-risk diabetic
patients.32 However, ACE inhibitors
and angiotensin receptor blockers are
preferred in these patients because
they have shown the most consistent
benefit. Indeed, angiotensin blockade
provides renoprotective effects that
are independent of blood pressure
lowering.
Other common comorbidities in
diabetes
In addition to hypertension, dyslipi-
demia, and renal disease, other com-
mon comorbidities contribute to
polypharmacy in diabetes. Congestive
heart failure is more common in dia-
betes, and evidence is compelling for
use of multiple drugs to prevent its
morbidity and mortality. Indeed, the
standard of care in treating congestive
heart failure is polypharmacy includ-
ing ACE inhibitors, angiotensin recep-
tor blockers, -blockers, and
hydralazine/isosorbide dinitrate. 42
Symptoms may also dictate the use of
diuretics, digoxin, or dihydropyridine
calcium-channel blockers.
Diabetic neuropathy is also preva-
lent in diabetes. Clinical trials have
demonstrated benefit of tricyclic anti-
depressants, as well as gabapentin, in
relieving symptoms. Other analgesics
are frequently required. For example,
in a review of patients taking
gabapentin for chronic pain at my
facility, 40% required additional pain
medications.
Diabetes Spectrum Volume 15, Number 4, 2002
CONTROLLING INAPPROPRIATE
From Research to Practice / Polypharmacy: Boon or Bane?
POLYPHARMACY IN THE
ELDERLY
Having recognized the potential for
unintended patient outcomes with
polypharmacy in the elderly, various
groups have made attempts to inter-
vene with the goal of improving the
appropriateness of medication pre-
scribing. Most interventions rely on
pharmacy intervention, using either
lists of inappropriate drugs, such as
Beers, 9 or explicit criteria, such as
those given by MAI.43 Computer feed-
back using the Beers criteria in a large
cohort of elderly patients in a phar-
macy benefit plan resulted in a signifi-
cant change to more appropriate med-
ications. 44 A simple computer
reminder sent to clinicians for patients
on >10 medications in an extended
care facility resulted in a significant
decrease in the number of medications
for those patients.2
Even simple interventions can
decrease polypharmacy. A random-
ized trial in which residents caring for
inpatients received a simple medica-
tion grid of all the patients’ medica-
tions and times of administration led
to a significant decrease in the number
of medications in the intervention
group.45
Despite numerous reports of suc-
cessful interventions to alter prescrib-
ing for elderly patients by decreasing
either polypharmacy or inappropriate
prescribing, there is little evidence
documenting an impact on health out-
comes. One randomized trial of elder-
ly outpatients at a VA medical center
involved having a clinical pharmacist
meet with intervention patients to
make recommendations to patients
and clinicians concerning drug regi-
mens. Although there was a signifi-
cant decrease in inappropriate pre-
scribing in the intervention group,
there was no difference in health-relat-
ed quality of life.4 In another report of
the same trial, investigators found that
26% of drugs stopped as part of the
intervention (involving nearly one-
third of the patients) resulted in
adverse drug withdrawal events.
Approximately one-third of these
events resulted in hospitalization, an
emergency room visit, or an urgent
care visit.46
Thus, there is a lack of definitive
evidence that interventions to decrease
polypharmacy or improve medication
appropriateness result in measurable
clinical benefit. It makes sense intu-
itively that efforts to improve appro-
245
 priateness of prescribing for the elder- ed before adding a new drug when providers have access to complete lists
ly or to decrease polypharmacy would feasible. For example, use of assistive of medications. However, even in such
be beneficial. However, caution must devices or physical therapy for pain or a system, patients may not be taking
be taken to obtain careful, rational behavior modification for insomnia their medications as prescribed.
clinical input from the clinicians car- should be considered before resorting Patients should be encouraged to
ing for such patients. Elderly patients to oral medications. In addition, when maintain a list of all active medications
are more susceptible not only to assessing patient complaints, clinicians they are taking. Alternatively, they can
adverse outcomes from medications, should consider whether symptoms be asked to bring in all medications
but also to the absence of clinically are related to an adverse drug reac- (clinic “brown bag” day). Physicians
beneficial medications. This may be tion. Simply discontinuing a medica- frequently neglect to ask about OTC
particularly true in the case of elderly tion or changing to a different drug medications and nutritional supple-
type 2 diabetic patients, who are may be effective. ments. This can help identify impor-
prone to requiring multiple medica- When starting a new drug, patients tant potential interactions with pre-
tions for their multiple medical prob- should receive education about the scription drugs, such as patients with
lems. medication: indications for use, severe heart failure or poorly con-
instructions for taking it, common trolled hypertension taking nons-
RATIONAL DRUG PRESCRIBING side effects, and potential serious teroidal anti-inflammatory drugs
FOR ELDERLY DIABETIC adverse events. In doing so, compli- (NSAIDs). In these situations, NSAIDs
PATIENTS ance can be enhanced when side can decrease the effect of medications
As I have noted, many forces tend to effects are transient, temporary, or on the kidney, leading to fluid reten-
add to the drug regimens of type 2 easily controlled with simple mea- tion or elevated blood pressure.
diabetic patients. Given the frequency sures. For instance, some drugs initial- Because patients may see multiple
of comorbidities and compelling evi- ly may cause changes in bowel habits, providers, it is necessary to try to coor-
dence for treatment of each condition, which can be managed by nonphar- dinate medications, to avoid duplica-
it is likely that the average patient will macological measures. On the other tion of medications, and to avoid drug
require multiple medications to hand, patients should know when to interactions.
achieve therapeutic goals. Thus, the stop a medication immediately if they Patients or their caretakers should
goal of therapy is to treat all pertinent are experiencing a potentially serious know and understand the indications
medical problems using the most adverse outcome, such as recognizing for each medication. This can avoid
appropriate drug regimen, including that muscle pain may indicate early confusion about when a medication
issues of efficacy, dose frequency, side rhabdomyolysis when taking a statin. should be used, particularly for
effect profile, drug interaction poten- Simple measures can have a signifi- “p.r.n.,” or “as needed” medications.
tial, and, finally, cost. cant impact on managing complex Providers should regularly review
Various recommendations have medication profiles. Clinicians should with patients the therapeutic respons-
been made to improve prescribing for regularly review all of the medications es to each medication. Medications
the elderly (Table 3). their patients take. Patients being cared without a clear indication for use and
In fragile elderly patients, nonphar- for with a unified pharmacy benefit those that are not effective should be
macological means should be attempt- plan are at an advantage because discontinued with careful observation
for clinical deterioration.
Table 3. Suggestions for Appropriate Prescribing for the Elderly Clinicians should be familiar with
lists of medications to be avoided in
• Attempt nonpharmacological measures when feasible. vulnerable elderly patients and should
• Before starting a new drug, consider the possibility that the patient’s symptoms are
try to use alternative drugs when pos-
related to an adverse drug reaction. sible. Studies have documented fre-
quent continued use of these medica-
• When prescribing a new drug, provide education about indications for use, instruc-
tion for taking the medication, common side effects, and potential serious adverse tions in elderly patients. Clinicians
effects, as well as what to do when these side effects occur. should seek new treatment strategies
or even use nonpharmacological mea-
• Regularly review all medications. Include OTCs, herbal products, and vitamin and
mineral supplements. Encourage patients to maintain an active medication list. sures when possible to avoid them.
Whenever possible, use of a single
• Coordinate care with all providers to eliminate duplication of prescriptions.
drug to treat multiple conditions
• Identify indications for each medication. should be attempted. For this reason,
• Regularly assess therapeutic responses to medication. ACE inhibitors or angiotensin recep-
• Discontinue drugs without a clear indication for use. tor blockers are particularly appeal-
• Discontinue drugs that have not achieved the therapeutic goal. ing for diabetic patients because they
• Avoid medications with high incidence of adverse outcomes in the elderly (Beers list).
treat hypertension and heart failure
and are renoprotective or even car-
• When possible, combine indications with a single drug. dioprotective. Likewise, -blockers
• Regularly assess patient compliance, especially before changing doses of a drug or can be used to treat symptoms of
adding a new drug. lower urinary tract symptoms, as well
• Choose drugs with wide therapeutic windows when possible. as hypertension.
• Check for potential drug interactions; use available software programs. Because the elderly frequently have
• When considering pharmacotherapy for preventive purposes, consider the likelihood decreased renal and hepatic function
that a patient will benefit from treatment given his or her age and comorbidities. and a lower volume of distribution,
they are at greater risk for drug accu-
246
Diabetes Spectrum Volume 15, Number 4, 2002

mulation. Use of drugs with a wide
therapeutic window should be pre-
ferred because they are associated
with less drug toxicity.
Potential drug interactions must be
considered. Fortunately, software pro-
grams are increasingly available and
offer some assistance in identifying
potentially serious interactions.
Additionally, free software offering
drug interaction information is widely
available for handheld personal
devices.
Finally, when contemplating phar-
macotherapy for preventive purposes,
consider the likelihood that a patient
will benefit from the treatment being
offered. For example, the benefits of
tight glycemic control in the UKPDS
required years to be of significance,
and many of the benefits were for
microvascular complications, such as
the need for laser therapy for retinopa-
thy. Thus, when contemplating the
addition of medications to achieve
tight glycemic control or for micro-
albumuria, one must consider the
patient’s life expectancy and adjust
goals accordingly. Although an A1C
of <7% is certainly justified in younger
type 2 diabetic patients with longer life
expectancies, it cannot be justified in
elderly diabetic patients with severe
inoperable coronary heart disease or
congestive heart failure. Indeed, some
have suggested that tight control in
these patients is associated with worse
outcomes.47
In summary, elderly type 2 diabetic
patients will frequently require multi-
ple medications to adequately and
appropriately treat their diabetes and
associated comorbidities. The chal-
lenge to clinicians is to carefully evalu-
ate the medication profile and to
work with patients individually to
provide the safest, most efficacious,
and simplest medication regimen fea-
sible.
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Chester B. Good, MD, MPH, is a
staff physician at the VA Pittsburgh
Healthcare System and an associate
professor of medicine and pharmacy
at the University of Pittsburgh School
of Medicine and Pharmacy in
Pittsburgh, Pa. He is chair of the
Department of Veterans Affairs
Medical Advisory Panel for Pharmacy
Benefits Management.