The sulfonylureas are effective, inexpensive, and easy to titrate. Sulfonylureas are
generally used as add-on therapy to patients unable to achieve BG goals on
metformin monotherapy. Like the other antidiabetic agents discussed here,
sulfonylureas may also be considered as monotherapy in patients with
contraindications to metformin therapy. The doses of the sulfonylureas are displayed
i n Table 53-26. As a general rule, one should begin with low doses and titrate
upward every 1 to 2 weeks until the desired goal is achieved. Exceeding maximal
doses is not likely to produce improvement, but may put the patient at risk for
adverse effects (see Case 53-18, Questions 5 and 6).
The two available TZDs in the United States, rosiglitazone and pioglitazone, are
often referred to as insulin sensitizers. The precise molecular actions of these agents
remain to be clarified. TZDs bind to and activate a nuclear receptor (peroxisome
PPAR-γ regulates transcription of genes that influence glucose and lipid metabolism.
For example, PPAR- γ stimulation increases the transcription of GLUT-4, a glucose
transporter that stimulates glucose uptake.
185 Reduced expression of GLUT-4 may
contribute to the development of insulin resistance. Pioglitazone activates PPAR-α in
pioglitazone enables HDL to be raised and triglycerides to be lowered. PPAR- α
activation is involved in actions that are anti-inflammatory and the PPAR-y and -α
activation can improve insulin sensitivity and lipid profiles.
TZDs either directly or indirectly sensitize adipose tissue to insulin action.
The effects may include stimulating apoptosis of large adipocytes, increasing the
number of small adipose cells, and promoting fatty acid uptake and storage in
adipose tissue. The subsequent reduction in free circulating fatty acids may spare
other insulin-sensitive tissues (e.g., liver, skeletal muscle, β-cells) from the effects of
lipotoxicity. TZDs also lower expression of tumor necrosis factor-α, a cytokine
produced by adipose tissue that may contribute to insulin resistance and fatty acid
175,184 Other adipokines are likely involved, including adiponectin, resistin,
175 TZD interaction with adipocytes may be their primary mechanism of
action in sensitizing other tissues to insulin action. As with metformin, TZDs have
been shown to directly stimulate the AMPK pathway in liver and adipose tissue,
resulting in a lowering of glucose and free fatty acids.
Other observed effects of TZDs that may be beneficial in patients with Type 2
diabetes and metabolic syndrome include favorable effects on triglycerides,
reduction of inflammatory mediators, inhibition of vascular smooth muscle cell
proliferation, improved endothelial function, lowering microalbumin excretion, and
175,184 Despite these apparently favorable effects on surrogate
measures of vascular disease, the data regarding TZDs and vascular risk are mixed
and controversial. In 2009, the FDA added language to the label for rosiglitazone
indicating an increased risk of angina and MI. The Food and Drug Administration and
GlaxoSmithKline instituted a Risk Evaluation and Management Strategy (REMS) to
restrict the distribution and prescribing of rosiglitazone; however, in May, 2014, the
REMS was changed to allow for the prescribing and filling of prescriptions of
In summary, the TZDs clinically decrease insulin resistance in muscle and liver,
which enhances glucose utilization and decreases hepatic glucose output. They have
favorable effects on markers of vascular disease such as triglycerides and
Rosiglitazone is completely absorbed, with peak plasma concentrations reached in
187 Pioglitazone has a bioavailability of 83%, with peak plasma
concentrations reached within 2 hours.
185 Food delays the time to peak concentration,
but does not alter the extent of absorption of either drug. Both TZDs are extensively
(>99%) protein bound, primarily to albumin. The plasma elimination half-life of
rosiglitazone is 3 to 4 hours.
187 Pioglitazone has a serum half-life of 3 to 7 hours, and
its metabolites have a serum half-life of 16 to 24 hours.
extensively metabolized in the liver by CYP 2C8 and to a much lesser extent by 2C9.
Its conjugated metabolites are considerably less potent than the parent drug and are
excreted two-thirds in urine and one-third in feces.
187 Pioglitazone is hepatically
metabolized, mainly by CYP 2C8 and 3A4, and to a lesser degree by CYP 1A1, to
three active metabolites; however, the main metabolites found in serum are M-III and
M-IV. Approximately 15% to 30% of the dose is recovered in the urine as
metabolites, with the remainder excreted either into the bile as unchanged drug or
into the feces as metabolites.
Because the action of the TZDs relies on gene transcription and protein
production, the onset and duration of action are unrelated to the plasma half-life. The
onset of their effect occurs in 1 to 2 weeks, although maximal effects are not usually
seen before 8 to 12 weeks. No dose adjustment is necessary in patients with renal
impairment. There is no dose adjustment needed for hepatic impairment with
Liver failure has been very rarely reported with either rosiglitazone or pioglitazone,
although causality in most cases remains uncertain.
188–190 For both drugs, monitoring
of liver function tests (LFTs) is recommended at baseline, and then periodically
thereafter (see Contraindications and Precautions section). Many practitioners check
the LFTs every 3 to 6 months during the first year of therapy and then every 6 to 12
TZD therapy may result in small decreases in hemoglobin and hematocrit and,
175,184 These effects may be attributable to dilutional effects (see
Dose-related weight gain (2–3 kg for every 1% decrease in A1C) has been seen with
rosiglitazone and pioglitazone.
184 Weight gain is likely caused by fluid retention or fat
accumulation. The weight gain seems to be associated with an increase in peripheral
adipose tissue along with a reduction in visceral adiposity.
Vascular and Cardiovascular Effects
Increases in plasma volume and peripheral edema (4%–6%), possibly caused by
increased endothelial cell permeability, occur with the TZDs.
peripheral edema is greatly increased when TZDs are used in combination with
The FDA added black box warnings to rosiglitazone and pioglitazone based on the
association of their use with an increased risk of developing or exacerbating HF in
patients with Type 2 diabetes.
185,187 TZDs are contraindicated for use in patients with
NYHA class III or IV HF and are not recommended in patients with acute or systemic
HF. Meta-analysis and retrospective observational studies have suggested that
rosiglitazone is associated with risk of MI,
191–193 but not for overall cardiovascular or
193 Pioglitazone does not appear to increase the risk of MI or
194–197 TZDs should be used with caution in patients with preexisting edema,
which may increase the risk of developing new-onset HF or exacerbating preexisting
Hypersensitivity reactions including rash, pruritus, urticaria, angioedema,
anaphylactic reaction, and Stevens–Johnson syndrome have been rarely reported with
185,187 Macular edema has been rarely reported with TZDs.
Patients experiencing changes or worsening in vision should be referred to an
ophthalmologist for follow-up. In some cases, macular edema improved or resolved
after discontinuation of TZD therapy.
Pioglitazone has been associated with an increased risk of bladder cancer
compared to the general population and is contraindicated in patients with bladder
In patients with previous history of bladder cancer, the need for use of
pioglitazone for glycemic control must outweigh the potential recurrence of bladder
199 The FDA has released a safety communication warning that the use of
pioglitazone for longer than 1 year may increase the risk for bladder cancer.
Recently analyzed 10-year findings show no statistically significant increase in
Monitoring for causal effect of cancers should be continued.
An increased risk of distal limb bone fractures (e.g., forearm, hand, wrist, foot,
and ankle) and bone loss have been observed in women receiving TZDs.
may also be at increased fracture risk, but the evidence is not as strong.
mechanism is thought to be reduced osteoblast differentiation as a result of increased
adipogenesis in the bone marrow.
204 The potential for fractures in older female
patients and patients on chronic steroids should be carefully considered before using
CONTRAINDICATIONS AND PRECAUTIONS
Type 1 diabetes: Because insulin is required for their action, TZDs should not be
used in people with type 1 diabetes.
Patients with type 2 diabetes using insulin: TZDs should be used with caution
because of the increased risk of developing edema.
Preexisting hepatic disease: Pioglitazone and rosiglitazone should not be used in
patients whose ALT is more than 2.5 times normal. TZDs should be discontinued
if the ALT is more than 3 times normal, if serum bilirubin levels begin to rise, or
if the patient complains of any symptoms that could be attributed to hepatitis (e.g.,
fatigue, nausea, vomiting, abdominal pain, and dark urine).
Symptomatic or severe (NYHA classes III and IV) HF: See previous discussion.
Myocardial ischemia (rosiglitazone only): See previous discussion.
Premenopausal anovulatory women: TZDs may cause resumption of ovulation and
menstruation in women with polycystic ovarian syndrome, placing these patients
at risk for an unwanted pregnancy.
History of hypersensitivity to TZDs.
Patients with osteoporosis or at risk for bone fractures (e.g., chronic steroid use).
Drugs metabolized by CYP 3A4: See the Drug Interactions section for further
Patients with a current or previous history of bladder cancer should not use TZDs.
Macular edema: Patients should receive regular eye examinations to evaluate acute
Coadministration of a TZD with other antidiabetic medications or insulin does not
alter the pharmacokinetics of either drug, but may increase the patient’s risk for
induces CYP 3A4 and may, therefore, decrease effectiveness of other drugs
Ketoconazole may significantly inhibit the metabolism of pioglitazone.
taking oral contraceptives or estrogen-replacement therapy should be informed of the
possible risk of decreased effectiveness of estrogen therapy. Rosiglitazone does not
seem to inhibit any of the major CYP enzymes.
187 Rifampin decreases the area under
the plasma concentration–time curve (AUC) for both rosiglitazone and pioglitazone,
although the clinical significance of this interaction is unknown. Pioglitazone is a
substrate of CYP2C8; therefore, interactions may occur when administered with
drugs that inhibit or induce CYP2C8.
205 The maximum dose of pioglitazone is 15 mg
once a day if given with a strong CYP2C8 inhibitor.
increases the AUC of both drugs. For patients receiving both a TZD and a
gemfibrozil, a dose reduction of the TZD may be warranted.
The effects of TZDs on A1C and FPG are intermediate between those of acarbose
and the sulfonylureas or metformin.
175,184 When combined with other antidiabetic
agents in a poorly controlled type 2 diabetes patient, one can expect to see an
augmented effect on the A1C (0.9%–1.3% decrease with a sulfonylurea, 0.8%–1.0%
decrease with metformin, and 0.7%–1.0% decrease with insulin).
to the therapy of a type 2 diabetes patient taking insulin, rosiglitazone and
pioglitazone can enhance glycemic control (approximately 0.6% lower with
pioglitazone) while decreasing insulin requirements; however, weight gain (>3 kg)
and increased edema will likely occur.
Individuals who are minimally responsive
or unresponsive to TZD therapy may include those who are not obese and have lower
Other potential benefits of the TZDs are their favorable, but variable, effects on
184,185,187 Pioglitazone and to a lesser extent rosiglitazone may decrease
triglycerides. Both drugs may increase HDL-C levels by 10%. Rosiglitazone has
been observed to increase LDL-C by 8% to 16%, whereas pioglitazone may not
affect LDL-C. As noted, TZD therapy has been associated with weight gain, and this
may be substantial when used in combination with sulfonylureas or insulin.
Patients who are unable to take or have failed metformin or sulfonylurea
monotherapy or who have not responded to combination therapy with other oral
antidiabetic agents are usually candidates for TZD therapy. For monotherapy or
combination therapy with a sulfonylurea, metformin, or insulin, the starting dose for
pioglitazone is 15 or 30 mg once daily with or without food. The dose can be titrated
185 The starting dose for rosiglitazone is 4 mg given
once daily or in divided doses. The dose may be increased after 8 to 12 weeks if
adequate response is not seen. The maximum daily dose is 8 mg.
T h e α-glucosidase inhibitors, acarbose
glucosidases present in the brush border of the mucosa of the small intestine. These
enzymes break down complex polysaccharides and disaccharides into glucose and
other absorbable monosaccharides. Enzyme inhibition delays carbohydrate digestion
and subsequent glucose absorption. Postprandial BG concentrations are therefore
lowered when these agents are taken with a meal containing complex carbohydrates.
Acarbose is minimally absorbed from the GI tract, with an oral bioavailability of the
parent drug of less than 2.0%.
It is extensively metabolized by GI amylases to
inactive metabolites. The peak plasma concentration occurs in approximately 1 hour
and the elimination half-life for acarbose is 2 hours, although there may be a longer
terminal half-life. Unlike acarbose, miglitol is absorbed. Absorption of miglitol is
saturable at higher doses (>25 mg) and peak concentration occurs in 2 to 3 hours.
The drug is primarily distributed in extracellular fluids and is not metabolized. After
a 25-mg dose, 95% of the drug is excreted unchanged by the kidneys within 24 hours.
Flatulence, diarrhea, and abdominal pain are the most frequently reported adverse
effects of α-glucosidase inhibitors.
In placebo-controlled trials of acarbose,
these complaints were experienced by 74%, 31%, and 19% of subjects, respectively.
GI side effects are attributable to fermentation of unabsorbed carbohydrate in the
small intestine and can be minimized by slowly titrating the dose of either agent. GI
In studies using doses of acarbose 300 mg/day or more, a transient increase in
serum hepatic transaminases was reported.
209 The manufacturer recommends
monitoring hepatic transaminases every 3 months for the first year of therapy and
periodically thereafter. If an elevation of serum transaminases occurs, the dose
should be decreased or discontinued if elevations persist. Because miglitol is not
metabolized, it does not seem to affect hepatic function.
CONTRAINDICATIONS AND PRECAUTIONS
Acarbose and miglitol are contraindicated with known hypersensitivity to the
207,208 Both medications are contraindicated in patients with DKA and
acarbose is contraindicated in patients with cirrhosis.
Because of their profound GI effects (flatulence, diarrhea), acarbose and miglitol are
contraindicated in patients with malabsorption, inflammatory bowel disease, colonic
ulceration or other marked disorders of digestion or absorption, or with intestinal
Acarbose has not been studied in patients with severe renal impairment (SCr >2.0
mg/dL) and should not be used in these patients.
209 There is little information with
regard to safety of the use of miglitol in patients with a CrCl<25 mL/minute;
therefore, its use is contraindicated in these patients.
Patients who use acarbose or miglitol in combination with other antidiabetic agents
may experience hypoglycemia. These reactions should be treated with dextrose
because acarbose may limit the availability of the disaccharide sucrose (table sugar).
Because acarbose and miglitol delay carbohydrate passage through the bowel, they
could influence the absorption kinetics of concomitantly administered drugs.
Conversely, because their own absorption may be diminished by digestive enzyme
preparations and charcoal, they should not be taken concomitantly with these
207–209 The bioavailability of digoxin can be reduced and may require dose
adjustment. Miglitol decreases the bioavailability of ranitidine and propranolol by
By delaying the absorption of glucose after ingestion of complex carbohydrates and
disaccharides, the α-glucosidase inhibitors can lower postprandial plasma glucose
concentrations in patients with type 2 diabetes by 25 to 50 mg/dL.
concentrations remain unchanged or are slightly lowered (20–30 mg/dL), but this
effect may be related to decreased glucose toxicity, which improves insulin secretion
and action. Mean A1C values decline by 0.3% to 0.7%. Acarbose and miglitol have
no effect on weight or lipid profiles.
Because of limited effects on A1C and their side effect profile, α-glucosidase
inhibitors are used infrequently and, when used, are usually given as add-on therapy
in patients who have failed monotherapy or combination therapy with other oral
antidiabetic agents. The recommended initial dose of either drug is up to 25 mg TID,
taken at the start of each meal.
207,208 The dosage of acarbose can be gradually
increased (e.g., 25 mg/meal) every 4 to 8 weeks to a maximum of 50 mg TID for
individuals weighing 60 kg or less, or 100 mg TID for individuals weighing more
than 60 kg. The dose for miglitol is titrated up after 4 to 8 weeks to a dose of 50 to
100 mg TID if needed, regardless of a patient’s weight. A maximal response is
Incretins are insulinotropic hormones secreted from specialized neuroendocrine cells
in the small intestinal mucosa in response to carbohydrate ingestion and absorption.
The two hormones accounting for most incretin effects are glucose-dependent
insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). GIP and
GLP-1 stimulate pancreatic β-cells in a glucose-dependent manner, contributing to
the early-phase insulin response. GLP-1 also inhibits pancreatic α-cells, thus
reducing glucagon secretion and hepatic glucose production. Incretin action is
efficient, but short lived. As they enter the blood vessels, incretins undergo rapid
metabolism via proteolytic cleavage by dipeptidyl peptidase-4 (DPP-4) to inactive
metabolites. Thus, only small amounts are needed to exert their effects on glucose
Glucagon-like Peptide-1 Agonists (GLP-1
Exenatide, extended-release exenatide, albiglutide, liraglutide, and dulaglutide are
the five available GLP-1 agonists in the United States. The formulations available
GLP-1 mimetics and analogs have stability in the presence of DPP-4, resulting in a
longer duration of action than endogenous GLP-1. Exenatide is a synthetic form of
exendin-4, a peptide originally discovered from the saliva of the Gila monster.
Exendin-4 shares 50% of its amino acid sequence with GLP-1, demonstrating similar
affinity for receptor sites but a strong resistance to DPP-4. Liraglutide is a GLP-1
analog that is 97% homologous to human GLP-1, and reversibly binds to plasma
albumin owing to the C16 fatty acid side chain, thereby increasing resistance to DPP4 degradation.
211 Albiglutide has 2 tandem copies of modified human GLP-1 fused to
human albumin. The human fragment sequence has been modified to allow for
resistance to DPP-IV-mediated proteolysis, and in combination with the human
albumin moiety of the fusion protein, the half-life is extended allowing for onceweekly dosing.
212 Dulaglutide is a human GLP-1 receptor agonist that has 90%
homology to endogenous human GLP-1.
213 These agents augment early or first-phase
without impairing the normal glucagon response to hypoglycemia. They slow gastric
emptying, thereby reducing the rate at which glucose is absorbed. In addition, they
suppress appetite, which may contribute to the prevention of weight gain and the
weight loss (1.5–5 kg) observed in patients. A promising action of these agents is
their potential to increase β-cell mass and preservation, which has been shown in
After SC injection, exenatide reaches peak plasma concentrations in 2.1 hours.
injection site (abdomen, thigh, or upper arm) does not significantly alter its kinetics.
Both exenatide formulations are eliminated predominantly by glomerular filtration
with subsequent proteolytic degradation. The mean terminal half-life of exenatide is
2.4 hours, with levels measurable up to 10 hours, thus allowing for twice-daily
dosing. Its metabolism and elimination are dose independent. Extended-release
exenatide is released from microspheres over approximately 10 weeks after
administration. After discontinuation of therapy, minimal detectable concentrations
can be seen in approximately 10 weeks.
Absorption of liraglutide is delayed owing to its self-association in heptameric
aggregates within the injection depot that are too large to cross the capillary
216 On disassociation of the heptamers at the absorption site, liraglutide is
absorbed. This delayed absorption is the primary reason for its prolonged action.
Liraglutide is highly protein bound (>98%), with a half-life of 13 hours, allowing for
211,216 Metabolism of liraglutide occurs endogenously in a manner
similar to large proteins and there is no specific organ as its route of
Albiglutide administered SC resulted in maximum concentrations in 3 to 5 days.
Steady state is achieved after 4 to 5 weeks of administration. Metabolism to small
peptides and amino acids occurs through a metabolic pathway involving proteolytic
enzymes in the vascular endothelium. The elimination half-life is approximately 5
days, which allows for once-weekly administration.
Dulaglutide achieves maximum plasma concentration in about 48 hours, and steady
state occurs between 2 to 4 weeks with once-weekly administration. There is no
statistically significant difference of exposure to dulaglutide between the site of
administration in the abdomen, upper arm, or thigh. Metabolism occurs through
general protein catabolism pathways into its component amino acids. The elimination
half-life is approximately 5 days.
GI side effects are common and dose-dependent, particularly nausea, vomiting, and
diarrhea. Rates vary between agents with albiglutide appearing to have the lowest
rates in placebo-controlled trials.
212 These side effects may be lessened by starting
patients on lower doses for daily injections, ensuring correct timing and
administration of the drug, and titrating the dose slowly. Other reported side effects
have included decreased appetite and injection site reactions. Hypoglycemic risk can
be increased in patients who are also taking an oral insulin secretagogue (e.g.,
These agents have been rarely related to hypersensitivity reactions, acute
pancreatitis, and reduced renal function. Patients should be educated about symptoms
of acute pancreatitis, including severe abdominal pain accompanied by vomiting, and
instructed to report to their practitioner immediately. Patients in whom acute
pancreatitis is confirmed with no other probable cause should not be rechallenged
The development of antibodies against these agents is well established. In general,
the presence of antibodies does not appear to significantly affect the A1C reduction
seen with GLP-1 agonists, although some patients with high antibody titers may
217 Patients who demonstrate adherence to therapy,
yet experience no change or worsening in glycemic control, should discontinue
therapy and be switched to alternative agents.
CONTRAINDICATIONS AND PRECAUTIONS
GLP-1 agonists are contraindicated in patients with known hypersensitivity. They
should not be used in patients with a history of pancreatitis.
recommended for use in patients with severe GI disease. Exenatide should not be
used in severe renal impairment (CrCl <30 mL/minute) or end-stage renal failure, or
in those requiring hemodialysis.
215,218 Dulaglutide and albiglutide have limited
clinical experience in patients with end-stage renal disease and should be used with
caution in these patients. If these patients experience GI adverse effects, renal
function should be closely monitored.
GLP-1 agonists are contraindicated in patients with a personal or family history of
medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia
syndrome type 2 (MEN 2) due to risks in rodents. A causal relationship in humans
211–215 Currently, the FDA has required black box warnings
on each of the GLP-1 agonists for MTC, MEN 2, and thyroid cancer as well as a
REMS program for each medication.
GLP-1 agonists may increase the risk for hypoglycemia when used with sulfonylureas
or insulin. Because of their mechanism of action, they may reduce the rate and extent
of absorption of orally administered drugs.
211–215 They should therefore be used with
contraceptives. The manufacturers of twice-daily exenatide recommend that patients
take the affected medications at least 1 hour before exenatide administration.
have been case reports of an increased international normalized ratio, sometimes
associated with bleeding, in patients taking exenatide and warfarin. Patients should
be closely monitored, with dose adjustments to warfarin therapy made as
In clinical trials, maximal doses of exenatide combined with a sulfonylurea,
metformin, a TZD, or sulfonylurea plus metformin therapy for 30 weeks reduced
FBG by 5 to 25 mg/dL, 2-hour postprandial BG by 60 to 70 mg/dL, and A1C by
214,215 Exenatide use for 80 weeks has been reported to reduce body
weight by 4 to 5 kg. In a 24-week trial comparing exenatide with extended-release
exenatide, the extended-release formulation resulted in a reduction in A1C of 1.6%
and a reduction in FBG of 25 mg/dL.
214,215 Clinical trials with liraglutide
monotherapy demonstrate decreases in FBG of 15 to 26 mg/dL and A1C of 0.8% to
1.1%, and weight loss of 2.1 to 2.5 kg.
214 When used as combination therapy,
additional A1C lowering of 1% to 1.5% can be expected.
Albiglutide as monotherapy in a 52-week trial resulted in A1C reduction of 0.7%
to 0.9% and reduction in FBG of 16 to 25 mg/dL. When used in combination therapy,
albiglutide reduced A1C by 0.6% to 0.8% and reduced FBG by 18 to 23 mg/dL.
Dulaglutide monotherapy resulted in a decrease in A1C of 0.7% to 0.8% and a
reduction of FBG of 26 to 29 mg/dL, as well as weight loss of 1.4 to 2.3 kg. When
dulaglutide is used in combination therapy, it results in an A1C reduction of 0.8% to
1.5%, a reduction in FBG of 16 to 41 mg/dL, and a weight loss of 0.2 to 2.7 kg.
Exenatide (not the extended-release formulation) is approved for use as
monotherapy, whereas the other GLP-1 agonists are not recommended as
monotherapy per the manufacturers.
211–215 GLP-1 agonists are indicated as add-on
agents in patients with Type 2 diabetes who have been unable to reach target goals on
monotherapy with metformin or in combination therapy. Although not indicated for
weight loss, these agents may be helpful in patients with Type 2 diabetes who are
obese and struggling with obesity. Albiglutide and exenatide have been studied in
patients with Type 2 diabetes already on insulin glargine; albiglutide lowered the
A1C by 0.8%, whereas exenatide lowered the A1C by 1.7% and patients required
lower doses of insulin glargine compared with the placebo group.
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