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Holmboe ES. Oral Antihyperglycemic Therapy for Type 2 Diabetes: Clinical Applications. JAMA. 2002;287(3):373–376. doi:10.1001/jama.287.3.373
Author Affiliations: Department of Medicine, Yale University School of Medicine, New Haven, Conn, and Qualidigm (Connecticut Peer Review Organization), Middletown, Conn.
Scientific Review: Clinical Applications Section
Editor: Wendy Levinson, MD, Contributing Editor.
Oral agents are the mainstay of pharmacologic treatment for type 2 diabetes,
and physicians now have a number of agents to choose from. However, more choices
translate into more complex decision making. Many patients with diabetes have
associated comorbidities, and most diabetic patients will require more than
1 agent to achieve good glycemic control. This article illustrates several
of the pharmacologic approaches to type 2 diabetes through 4 situations that
use principles of evidence-based medicine. The scenarios also highlight some
of the difficulties in choosing the optimal pharmacologic treatment regimen
for individual patients. Physicians should also recognize that type 2 diabetes
is a multisystem disorder that requires multidisciplinary care, including
education and ongoing counseling for effective patient self-management of
the disease. Finally, patient preferences are a vital component of informed
decision making for pharmacologic treatment of diabetes.
Several clinical practice guidelines for type 2 diabetes are now available.
All advocate a hemoglobin A1c level of less than 7%, and at least
1 organization has adopted a target of 6.5%.1-3
Despite the number of agents to choose from, Inzucchi4
notes that the only ones evaluated in randomized controlled trials with regard
to clinically important outcomes are insulin, metformin, and the sulfonylureas.5-7 Two important clinical
trials have demonstrated that more aggressive glycemic control in type 2 diabetic
patients reduced microvascular complications. Questions remain about the effect
of all the oral agents and insulin on reducing macrovascular complications.6,7
Primary care physicians provide much of the care for patients with type
2 diabetes.8 Although this article discusses
primarily drug treatment, education on self-management, nutrition, and exercise
is essential to help patients achieve glycemic control. Self-management training
is effective in type 2 diabetes and should be recommended for all patients.9
Recommendations for the use of oral agents for each clinical situation
are based on the best evidence available and accepted clinical guidelines.
Informed decision making about therapy, however, must involve the patient
and include a clear explanation of therapeutic-choice rationale, an assessment
of his or her understanding, preferences, and barriers to care, and a discussion
of the risks and benefits of each therapy.10-12
An active patient-physician partnership facilitates treatment of this complex,
multifaceted disease.13Table 1 provides a brief summary of the available oral agents and
their relative costs. The BOX provides additional resources.
American Diabetes Association. Standards of medical care for patients
with diabetes mellitus. Diabetes Care. 2001;24(suppl
1):S33-S43. Web site available at: http://www.diabetes.org.
Institute for Clinical Systems Improvement (ICSI). Web site available
at: http://www.icsi.org. Printed copies can be obtained from ICSI,
8009 34th Ave S, Suite 1200, Bloomington, MN 55425.
American Association of Clinical Endocrinologists. Web site available
All guidelines listed above are also available at: http://www.guideline.gov (National Guideline Clearinghouse).
American Diabetes Association, 1701 N Beauregard St, Alexandria, VA
22311. Phone: (800) 842-6323. Information and educational brochures are available
for patients. The association has offices across the United States.
American Dietetic Association. Diabetes Care & Educational Practice
Group, 216 W Jackson Blvd, Suite 800, Chicago, IL 60606. Phone: (800) 366-1655.
Web site available at: http://www.eatright.org. Good source for
information about nutritional therapy in diabetes.
Centers for Medicare and Medicaid Services (CMS). Web site available
at: http://www.hcfa.gov. The CMS concentrates on diabetes improvement
efforts for Medicare patients. Quality of care programs for the CMS are managed
across the United States by peer-review organizations, all of which have educational
material and ongoing projects designed to help the primary care provider care
for Medicare patients with type 2 diabetes.
Centers for Disease Control and Prevention. Web site available at: http://www.cdc.gov/nccdphp/ddt/ddthome.htm.
National Diabetes Education Program. Web site available at: http://www.ndep.nih.gov.
A moderately obese 49-year-old woman (body mass index, 29 kg/m2) complains of increased thirst, polyuria, and fatigue. Her family
history is pertinent for diabetes in her mother and an older brother. A random
plasma glucose serum test shows a level of 480 mg/dL (26.6 mmol/L). Her serum
electrolyte and anion gap levels are normal.
At this visit, the patient meets American Diabetes Association criteria
for having diabetes.14 Given her symptoms and
high blood glucose level, the question is whether to start an oral agent or
insulin therapy. Guidelines are not prescriptive regarding the choice of the
One consideration in deciding whether to initiate insulin therapy or an oral
agent is glucose toxicity.16,17
High levels of glucose are toxic to pancreatic beta cells, impairing insulin
secretion in the face of relative insulin deficiency. Although not studied
in a randomized controlled trial, initial treatment with insulin has been
suggested to allow more rapid control of plasma glucose, recovery of beta
cell function, and better subsequent response to oral agents.17,18
Additionally, insulin dosage can be adjusted quickly, facilitating more rapid
control of hyperglycemia and associated symptoms.15-17
Once a stable target glucose level has been achieved, the patient may be able
to begin receiving an oral agent. However, insulin therapy does require immediate
patient education on injection techniques, use of a home glucose meter, and
identification and treatment of hypoglycemic reactions. If available locally,
certified diabetes nurse educators can be particularly helpful in this process.
Deciding whether to start insulin therapy also requires assessment of the
patient's understanding and wishes.10
When the patient is switched to an oral agent or an oral agent is used
as initial therapy, guidelines suggest that either a sulfonylurea or metformin
agent is appropriate. However, given that this patient is moderately obese,
metformin would be the recommended initial agent.4,7,15
It tends to promote weight loss and is equally effective in lowering hemoglobin
A1c compared with sulfonylurea and thiazolidinedione (TZD) agents.4 Given her degree of hyperglycemia, this patient may
eventually need 2 oral agents to achieve adequate control.
A 57-year-old man with type 2 diabetes treated for 9 years is currently
receiving glyburide at a dosage of 10 mg/d. His hemoglobin A1c
level a week ago was 8.5%. You suggest adding metformin, but the patient wonders
why he cannot increase his glyburide dose because his hemoglobin A1c level was always controlled well by this medication and he has been
told that 10 mg is only half the maximal dose.
Although daily doses of up to 20 mg of glyburide and 40 mg of glipizide
are approved and can be used, data have clearly shown that, above 10 to 12
mg/d, the additional gain in glycemic control is marginal.19
In addition, the failure rate of sulfonylurea therapy is 5% yearly, and this
patient has been receiving glyburide therapy for 9 years.4,6,7,15
Thus, increasing his sulfonylurea dose is highly unlikely to help him reach
the target level of hemoglobin A1c. Likewise, switching to another
single oral agent such as metformin, TZD, or meglitinide or another nonsulfonylurea
secretagogue is unlikely to lead to adequate glycemic control, given the duration
of his diabetes. Therefore, addition of another agent should be considered.
The United Kingdom Prospective Diabetes Study (UKPDS) and other trials found
that adding metformin to sulfonylurea therapy lowered hemoglobin A1c levels.4,7,20,21
The UKPDS, however, found an unexpected increase in diabetes-related mortality
with this combination, although when all patients who were actually treated
with metformin according to protocol analysis were investigated, a 19% reduction
in diabetes-related end points was observed.7,22
Another option is to add a TZD; this combination has also shown substantial
reductions in hemoglobin A1c levels.4
Although no definite evidence exists of severe hepatotoxicity with rosiglitazone
and pioglitazone, frequent monitoring of liver enzymes is still required because
of troglitazone's association with hepatotoxicity.
A 55-year-old woman was diagnosed with diabetes almost 10 years ago
and is receiving 20 mg of glipizide daily and 1000 mg of metformin twice daily.
Her hemoglobin A1c level is 8.5%. She is adamant about not starting
insulin therapy because she believes it signals the last step before dying
from diabetes. What are your options?
Before embarking on a discussion about therapy, the physician should
first acknowledge and discuss the patient's concerns about insulin therapy.
Regarding drug treatment, will any of the remaining available oral agents
lower hemoglobin A1c levels in this patient? Because of its relative
decreased efficacy in lowering hemoglobin A1c levels, acarbose
would not be a good therapeutic option.4,23
The meglitinides are insulin secretagogues and therefore would not be effective
in a patient already receiving a sulfonylurea agent.4
The only feasible additional oral agent to use would be rosiglitazone or pioglitazone,
both of which are approved for use in combination with metformin or a sulfonylurea
agent. A recent study found that 43% of patients receiving triple oral therapy
(sulfonylurea, metformin, and troglitazone) achieved a target hemoglobin A1c value (<8%) compared with only 6% of patients taking the metformin-sulfonylurea
Regardless of approach, the main goal for this relatively young patient
remains optimal glycemic control with a hemoglobin A1c level below
6.5%. Insulin therapy is another reasonable option and is less expensive than
adding a TZD (Table 1).1,4,15 If rosiglitazone or
pioglitazone is added, the full effect of the TZD therapy may not be apparent
for 4 to 12 weeks, but a hemoglobin A1c level should be assessed
at 3 months. Although this patient is resistant to starting insulin therapy,
better glycemic control through insulin therapy in the UKPDS6
and the Kumomato Trial5 led to a reduction
in microvascular complications. If the target hemoglobin A1c level
is not attained with the addition of a TZD, then insulin therapy is the best
option. Many patients will eventually require insulin therapy for adequate
glycemic control. In the UKPDS, for example, approximately 10% of patients
initially assigned to receive a sulfonylurea agent had to start receiving
insulin therapy during the trial.6 Talking
to the patient may help her overcome her reluctance to start insulin therapy.25
A 72-year-old man with a history of hypertension, myocardial infarction,
and New York Heart Association class II congestive heart failure comes to
the clinic for a routine follow-up visit. At his last visit 6 months ago,
his random blood glucose level was 180 mg/dL (10.0 mmol/L). He was not subsequently
tested for a fasting blood glucose level but was encouraged to lose weight
and maintain a proper diet. He now complains of having had polyuria and constant
thirst for the past 2 months. His random blood glucose level is tested in
your office and is 260 mg/dL (14.4 mmol/L). His creatinine level was 1.7 mg/dL
(129.63 µmol/L) 6 months ago. The patient weighs 83.3 kg. He is receiving
spironolactone, furosemide for his hypertension, and an angiotensin-converting
enzyme inhibitor for congestive heart failure. What are your therapeutic options?
Although determining a fasting glucose level and a baseline hemoglobin
A1c level will be helpful, the patient now has symptomatic diabetes
and warrants pharmacologic treatment. Although it appears that diet did not
control his blood glucose level, reinforcing the importance of diet and lifestyle
should still be attempted.26 Evidence exists
that suggests consulting a nutritionist or diabetes educator improves glycemic
Regarding drug therapy, there are several important issues to consider
for this older diabetic patient. First, what should the target hemoglobin
A1c level be? No outcome data for elderly diabetics exist. However,
several studies have found that lower hemoglobin A1c levels are
associated with lower costs for patients in all age groups, especially those
with cardiovascular disease,29-31
and better control of diabetes improves the quality of life for older diabetic
Second, what are the appropriate oral agents for this patient? Given his underlying
cardiovascular disease, metformin would be an ideal agent, but his history
of congestive heart failure and elevated serum creatinine levels are absolute
contraindications. Remaining agents to lower blood glucose levels are a sulfonylurea,
a rapid-acting secretagogue, or a TZD. A major concern about starting sulfonylurea
treatment in older patients is hypoglycemia that can be profound and prolonged
because of the long half-life of the second-generation agents. If a long-acting
sulfonylurea is chosen, the lowest possible starting dose (eg, 2.5 mg of glipizide)
should be initiated and the patient fully educated about hypoglycemic reactions
and treatment.4,34 His mild renal
insufficiency also places him at increased risk for hypoglycemia. If hypoglycemia
is a major concern related to other underlying health issues (eg, the patient
is at significant risk for falls or lives alone), a rapid-acting secretagogue
taken with meals may be safer because of its shorter half-life.4
The disadvantage is the frequent dosing schedule required with these agents.
Acarbose could be tried, but the magnitude of glucose-level reduction is less
than that with other agents, the adverse gastrointestinal effects may be difficult
for this older patient with congestive heart failure, and again the drug must
be taken several times a day.4 A TZD may be
prescribed but should be used only cautiously in this patient with class II
congestive heart failure. Because of their propensity to expand plasma volume,
TZDs are clearly contraindicated for patients with class III and IV congestive
heart failure. Therefore, for this patient an oral agent may not be the best
treatment and in fact may increase the risk of adverse events because of his
multiple comorbidities. Despite the mild degree of hyperglycemia, insulin
may be the best choice as an initial agent in this patient. It has several
advantages: flexibility with regard to dose and dosing adjustments and multiple
preparations that allow physicians to tailor a treatment regimen that best
meets the needs and goals of the patient.
Decisions about treatment with oral agents require a number of important
considerations, including drug efficacy and adverse effects, strength of evidence,
patient preferences, cost, and effective use of nonpharmacologic therapies
such as diet and exercise. Patient involvement in self-management is critical
to successful glycemic control, and all therapeutic choices must involve a
comprehensive dialogue and negotiation between patient and physician. Organizations
to obtain resources for caring for diabetic patients are provided in the BOX.
For the majority of patients, the overarching goal is to lower the hemoglobin
A1c level to as close to normal and as safely as possible.