By Rebecca Longo, BSN,
CCRN, ACNP-BC
Understanding Oral Antidiabetic Agents
How to make sense of this vast armamentarium.
ith the availability of new oral medications to treat type 2 diabetes, management has become increasingly confusing.
Currently, there are six major classes of oral antidiabetic agents available in the United States: the
biguanides, thiazolidinediones (TZDs), sulfonylurea
secretagogues, nonsulfonylurea secretagogues,
α-glucosidase inhibitors, and dipeptidyl-peptidase 4
(DPP-4) inhibitors. Because each class tackles diabetes differently, some classes are more appropriate
for certain patients than others. Understanding the
pathophysiologic targets of each class and the often
subtle differences in the ways they improve glycemic
control can make drug selection and disease management less bewildering.
W
PATHOPHYSIOLOGY OF TYPE 2 DIABETES
The hallmark of type 2 diabetes is insulin resistance, which occurs primarily in liver, muscle, and
fat tissue.1, 2 The body’s initial response is to boost
insulin secretion by pancreatic β-cells. Eventually,
however, β-cell function declines, and insulin secretion drops off.1, 2 As tissues become increasingly insulin resistant and insulin secretion slows,
blood glucose levels rise,1 especially after meals.
The incretin hormones of the gastrointestinal
tract, most notably glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), play a major role in this postprandial
hyperglycemia.2, 3 Normally, both hormones lower
blood glucose levels by enhancing insulin secretion; in addition, GLP-1 suppresses glucagon secretion. In type 2 diabetes, however, production
of these hormones is insufficient, causing excess
glucagon production, especially after meals when
glucagon suppression is essential.3 Diminished
insulin secretion, in conjunction with inappropriate glucagon secretion and subsequent unrestrained hepatic glucose production, further elevates
the blood glucose level,2 and the body is unable
to produce sufficient insulin fast enough to normalize it.3
The net effect is that body cells don’t receive
enough fuel, and the patient experiences hunger. But
because the cells cannot properly use glucose, if
any more is ingested, the blood glucose level will
rise even further.
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In deciding which medication is best to treat
this condition, practitioners must consider how the
drugs work, patients’ current and targeted glycosylated hemoglobin (HbA1c) levels, patients’ comorbidities, the adverse effects of the drugs, and the
ease of medication use (see Table 12, 4). The American Diabetes Association (ADA) and the European
Association for the Study of Diabetes (EASD) suggest that treatment be intensified every three months
until HbA1c is less than 7%—the recommended
goal for patients with type 2 diabetes.4
MEDICATIONS THAT IMPROVE INSULIN ACTION
Biguanides: metformin. Metformin (Glucophage)
is the only drug in this class currently approved
for use in the United States. It acts primarily to
normalize blood glucose levels by reducing hepatic
glucose production.1, 2 In addition, it helps boost
insulin sensitivity in muscle, fat, and liver tissues,
combating the insulin resistance characteristic of
type 2 diabetes.5 Because metformin has no effect
on β-cells, it doesn’t increase insulin levels.5 Patients
treated with metformin monotherapy, therefore,
face little risk of hypoglycemia.
Metformin, which is excreted primarily through
the kidneys, is contraindicated in patients with renal
dysfunction because it increases their risk of lactic
acidosis.2, 4 Based on results of recent studies, the
ADA and EASD deem metformin safe in patients
whose glomerular filtration rate is above 30 mL/min.4
As a general rule, serum creatinine should be below
1.5 mg/dL in men and 1.4 mg/dL in women for
whom metformin is prescribed.6 Metformin is not
recommended in patients who are dehydrated, are
receiving drug treatment for congestive heart failure, have liver disease or a history of alcohol abuse,
or have acute or chronic metabolic acidosis.2 It
should be stopped before any surgery or procedure
requiring a radiocontrast study and shouldn’t be
restarted for at least 48 hours thereafter, when
renal function is confirmed to have returned to
normal.5, 6
Metformin is usually started at 500 mg once
or twice a day or 850 mg once a day with meals
for the first week and, if tolerated, increased to
850 mg, or two 500-mg tablets, twice a day
to a maximum daily dosage of 2,550 mg until
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Table 1. Key Considerations in Prescribing Oral Antidiabetic Agents 2, 4
Drug target
Improved insulin
action
Stimulate insulin
secretion
Drug class
Mechanism of action
Biguanides
(metformin)
Reduce hepatic glucose
production
Expected reduction in HbA1c
1%–2%
Low risk of hypoglycemia,
well-established therapy,
possible weight loss,
adverse GI effects.
Thiazolidinediones Enhance insulin sensitivity
1%–2%
Low risk of hypoglycemia,
contraindicated in NYHA
Class III, IV heart failure.
Sulfonylurea insulin Increase insulin secretion
secretagogues
1%–2%
High risk of hypoglycemia.
Counsel patients regarding
hypoglycemia treatment
and medication and meal
scheduling. Associated
with weight gain.
Nonsulfonylurea
insulin
secretagogues
α-glucosidase
inhibitors
Increase insulin secretion
1.5%
Slow carbohydrate
absorption
DPP-4 inhibitors
(saxagliptin,
sitagliptin)
Improve insulin secretion and
suppress glucagon release by
increasing incretin activity
through inhibition of DPP-4
Shorter half-life than
sulfonylureas, hypoglycemia is an adverse
effect, less weight gain
than with sulfonylureas.
0.5%–1%
Do not cause hypoglycemia, but if combined
with insulin or a secretagogue, must treat hypoglycemia with glucose
source. Difficult to tolerate
because of adverse GI
effects.
0.6%–0.9%
Do not cause hypoglycemia, given in a fixed
dose.
Starch blockers
Restore incretin action
Comments
DPP-4 = dipeptidyl-peptidase 4; GI = gastrointestinal; HbA1c = glycosylated hemoglobin; NYHA = New York Heart Association.
glycemic goals are met.4 For many patients, such
goals are met at about 2,000 mg per day in divided doses.6
Patients who take metformin may experience
adverse effects such as abdominal discomfort,
stomach upset, diarrhea, anorexia, and stomach
fullness, which usually subside after several weeks.
Taking the medication with a meal can minimize
discomfort.1, 2
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Metformin is associated with weight loss or weight
stability.1 In addition, it has beneficial cardiovascular
effects, such as decreases in low-density lipoprotein
cholesterol and triglyceride levels.1
TZDs: pioglitazone and rosiglitazone. The TZDs,
pioglitazone (Actos) and rosiglitazone (Avandia), are
approved for use in combination with metformin,
sulfonylureas, glinides, and insulin. The primary
effect of these drugs is to combat insulin resistance
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by amplifying insulin sensitivity in muscle, fat, and
liver tissues.1, 4 Because, like metformin, these drugs
have no effect on insulin secretion, if taken alone,
they’re not associated with hypoglycemia.1
TZDs either improve (pioglitazone) or have no effect on (rosiglitazone) atherogenic lipid profiles.4 Although the data remain inconclusive on the potential
beneficial cardiovascular effects of pioglitazone and
adverse cardiovascular effects of rosiglitazone, the
ADA and EASD advise against using rosiglitazone,
given that seemingly safer options are available.4
The most common adverse effects of the TZDs
are weight gain and fluid retention. For this reason,
they’re contraindicated in patients with New York
Heart Association Class III or IV heart failure,2, 4, 7
and drug labeling was revised in 2007 to include a
black box warning that TZDs may “cause or exacerbate” heart failure. Heart failure risk is increased
in patients who are taking TZDs with insulin or
nitrates.7 The ADA and the American Heart Association have released a consensus statement on the
use of TZDs with detailed recommendations for
prescribing, managing, and monitoring their use.7
Pioglitazone is usually started at a daily dosage
of 15 mg, taken at breakfast.6 Dosages are increased
every four to eight weeks, as needed, to a maximum
of 45 mg per day.6 Rosiglitazone is started at 4 mg
daily at breakfast, or 2 mg twice daily, and increased every four to eight weeks to a maximum dosage
of 8 mg every morning, or 4 mg twice daily.6, 8 It
takes two to four months for TZDs to achieve
maximum effect.6
MEDICATIONS THAT IMPROVE INSULIN SECRETION
Sulfonylurea (long-acting) insulin secretagogues:
glimepiride (Amaryl), glipizide (Glucotrol), and
glyburide (Micronase, Glynase, DiaBeta), among
others. As the name “secretagogue” implies, these
drugs act to stimulate the pancreas to secrete insulin.6
They’re effective in patients who retain enough β-cell
function to allow insulin secretion with stimulation.
As β-cell function declines over time, close attention
must be paid to dose-response.6
One benefit of sulfonylureas is their quick onset
of action. But because they affect insulin secretion,
they can cause hypoglycemia. Patients must be counseled about the signs, symptoms, and treatment of
hypoglycemia. These drugs should be used with
caution by patients who skip or delay meals or reduce their intake. Sulfonylureas are contraindicated
in patients with advanced kidney or liver disease,
and in those with sulfa allergies.
Dosing is specific to each sulfonylurea, and lower
doses are recommended in elderly patients and in
those at elevated risk for hypoglycemia due to
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reduced drug clearance, as occurs in renal or hepatic
disease. For glyburide, the starting daily dosage is
2.5 to 5 mg (1.25 mg if the patient is elderly or
at elevated risk for hypoglycemia), which may be
titrated upward to a maximum daily dosage of
20 mg, in one or two doses, until glycemic goals are
met. Glipizide is started at a daily dosage of 5 mg
(2.5 mg daily for the elderly or those at high risk
for hypoglycemia) and titrated upward to a maximum daily dosage of 40 mg until glycemic goals
are met. Start glimepiride at a daily dosage of 1 to
2 mg in a single dose at breakfast or the main
meal, and titrate upward to a maximum daily dosage of 8 mg until glycemic goals are met.6, 9
Patients must be counseled about
the signs, symptoms, and treatment
of hypoglycemia.
Nonsulfonylurea (short-acting) insulin secretagogues, or glinides: repaglinide and nateglinide.
Repaglinide (Prandin) and nateglinide (Starlix)
stimulate the pancreas to produce insulin in response to ingested glucose. These nonsulfonylureas
have a more rapid onset and shorter duration of
action than sulfonylureas.2, 4 They’re taken up to
30 minutes before each meal, with doses adjusted
to account for the patient’s blood glucose levels
and the meal’s expected carbohydrate content, allowing patients more flexibility in their meal planning.5 Because these drugs affect insulin secretion
and can lower blood glucose appreciably, patients
need to understand the signs, symptoms, and treatment of hypoglycemia and know not to take these
medications if skipping a meal.2
For patients who have never taken an oral antidiabetic agent, elderly patients, and those whose
HbA1c level is below 8%, repaglinide is started at
a dose of 0.5 mg; for others, the starting dose is
typically 1 to 2 mg.2 Each dose can be increased to
a maximum of 4 mg, with patients taking up to
four doses daily (to a maximum of 16 mg daily)
before meals or snacks.6 Maximum effect is achieved
in one to two weeks.6 Nateglinide is prescribed at
a dosage of 60 or 120 mg taken three times daily,
15 to 30 minutes before meals.2 Elderly patients and
those who are close to their glycemic goals take the
lower dose.
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MEDICATIONS THAT SLOW
CARBOHYDRATE ABSORPTION
α -glucosidase inhibitors: acarbose and miglitol.
The α-glucosidase inhibitors, acarbose (Precose)
and miglitol (Glyset), slow carbohydrate absorption
in the small intestine,1, 2, 4 thereby giving the pancreas time to secrete sufficient insulin to moderate
postprandial blood glucose levels.1 This mechanism
of action may cause flatulence, bloating, abdominal
discomfort, or diarrhea, making this class of medications difficult for many patients to tolerate.2, 4
Although α-glucosidase inhibitors don’t directly
affect insulin secretion or lower blood glucose
levels, patients taking these medications in combination with insulin, a sulfonylurea, or a glinide are
susceptible to hypoglycemia. Because α-glucosidase
inhibitors slow carbohydrate absorption, patients
who develop hypoglycemia while taking these drugs
require treatment with glucose (tablets, gel, or intravenous solution); foods containing complex carbohydrates are ineffective in treating the condition.5, 6
Both acarbose and miglitol may be started at a
dosage of 25 mg three times daily, taken with the
first bite of each meal and adjusted upward every
four to eight weeks to a maximum dosage of 100 mg
three times daily, based on clinical need.2 Slow titration may reduce adverse gastrointestinal effects.2
MEDICATIONS THAT RESTORE INCRETIN ACTION
DPP-4 inhibitors: sitagliptin and saxagliptin.
Sitagliptin (Januvia) works by inhibiting the action
of DPP-4, which normally degrades the incretins
GLP-1 and GIP.3, 4 Sitagliptin was the first oral
DPP-4 inhibitor approved for use in the United
States; the second, saxagliptin (Onglyza), was
approved in August 2009; vildagliptin has been
approved for use in Europe, and others are in
development.4 By increasing available incretins,
sitagliptin promotes insulin secretion, suppresses
glucagon release,3 improves insulin sensitivity,6 and
increases satiety.2
Sitagliptin is taken at a fixed dose, based on renal
function: 100 mg daily for patients with mild or no
renal insufficiency, 50 mg daily for patients with
moderate renal insufficiency, and 25 mg daily for
patients with severe renal insufficiency or end-stage
renal disease.6
Sitagliptin is not associated with weight gain and
is reasonably well tolerated.4 It’s approved for use
as monotherapy or in combination with metformin
or a TZD.4
COMBINATION THERAPY
Often patients require more than one agent to
achieve their glycemic target, and several combination
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tablets have been formulated to accommodate this
need. These include combinations of metformin
and glyburide (Glucovance), metformin and glipizide (Metaglip), metformin and rosiglitazone
(Avandamet), and metformin and sitagliptin
(Janumet). These combination formulations can
improve adherence (patients take a single tablet
instead of two) while at the same time addressing
multiple pathophysiologic aspects of type 2 diabetes; for example, the metformin–glipizide combination both reduces insulin resistance and boosts
insulin secretion.6
Initially, each medication should be titrated separately until therapeutic dosages are reached for
each drug. At that point, it may be possible to
transition patients to a combination formulation.
Counsel patients on the actions and potential adverse effects of both medications contained in the
combination tablets. ▼
Rebecca Longo is an NP in Boston. Contact author: rlibbyrick@
mac.com. Diabetes Under Control is coordinated by Jane Jeffrie
Seley, MPH, MSN, GNP, BC-ADN, CDE: diabetesnp@
gmail.com.
REFERENCES
1. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002;287(3):360-72.
2. Rodbard HW, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the
management of diabetes mellitus. Endocr Pract 2007;13
Suppl 1:1-68.
3. McKennon SA, Campbell RK. The physiology of incretin
hormones and the basis for DPP-4 inhibitors. Diabetes Educ
2007;33(1):55-66.
4. Nathan DM, et al. Medical management of hyperglycemia
in type 2 diabetes: a consensus algorithm for the initiation
and adjustment of therapy: a consensus statement of the
American Diabetes Association and the European Association
for the Study of Diabetes. Diabetes Care 2009;32(1):
193-203.
5. Triplitt CL, et al. Diabetes mellitus. In: DiPiro JT, et al.,
editors. Pharmacotherapy: a pathophysiologic approach.
6th ed. New York City: McGraw-Hill Medical; 2005.
p. 1333-67.
6. Beaser RS. Pharmacotherapy of type 2 diabetes: medications
to match the pathophysiology. In: Beaser RS, Joslin Diabetes
Center, editors. Joslin’s diabetes deskbook: a guide for primary care providers. 2nd ed. Boston; Philadelphia: Joslin
Diabetes Center; [Wolters Kluwer Health/Lippincott
Williams and Wilkins]; 2007. p. 173-248.
7. Nesto RW, et al. Thiazolidinedione use, fluid retention, and
congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association.
Diabetes Care 2004;27(1):256-63.
8. GlaxoSmithKline. Avandia (rosiglitazone maleate) tablets
[prescribing information]. 2008.
9. Munshi MN, et al. Diabetes in the older adult. In: Beaser
RS, Joslin Diabetes Center, editors. Joslin’s diabetes deskbook: a guide for primary care providers. 2nd ed. Boston;
Philadelphia: Joslin Diabetes Center; [Wolters Kluwer Health/
Lippincott Williams and Wilkins]; 2007. p. 623-40.
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