DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1264 DPP-4 Inhibitors
Mechanism of Action. DPP-4 is a serine protease that is
widely distributed throughout the body, expressed as
an ectoenzyme on endothelial cells, on the surface of
T-lymphocytes, and in a circulating form. DPP-4 cleaves
the two N-terminal amino acids from peptides with a
proline or alanine in the second position. Although there
are many potential substrates for this enzyme, it seems
to be especially critical for the inactivation of GLP-1
and GIP (glucose-dependent insulinotropic polypeptide;
gastric inhibitory peptide) (Drucker, 2007). DPP-4
inhibitors increase the AUC of GLP-1 and GIP when
their secretion is by a meal (Figure 43-10).
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Dosage Forms. Several agents provide nearly complete and longlasting
inhibition of DPP-4, thereby increasing the proportion of
active GLP-1 from 10-20% of total circulating GLP-1 immunoreactivity
to nearly 100%. Two of these, sitagliptin (JANUVIA) and
saxagliptin (ONGLYZA), are now available in the U.S.; a third,
vildagliptin, is available in the E.U.; a fourth compound, alogliptin,
is in advanced stages of clinical trials. Sitagliptin and alogliptin are
competitive inhibitors of DPP-4, whereas vildagliptin and
saxagliptin bind the enzyme covalently. Despite these differences,
all four drugs can be given in doses that lower measurable activity
of DPP-4 by >95% for 12 hours. This causes a greater than 2-fold
elevation of plasma concentrations of active GIP and GLP-1 and is
associated with increased insulin secretion, reduced glucagon levels,
and improvements in both fasting and postprandial hyperglycemia.
Inhibition of DPP-4 does not appear to have direct effects
on insulin sensitivity, gastric motility, or satiety, nor does chronic
treatment with DPP-4 inhibitors affect body weight. DPP-4
inhibitors, used as monotherapy in type 2 diabetic patients, reduced
HbA 1c
levels by an average ~0.8%. These compounds are also effective
for chronic glucose control when added to the treatment of diabetic
patients receiving metformin, thiazolidinediones,
sulfonylureas, and insulin. The effects of DPP-4 inhibitors in combination
regimens appear to be additive. The recommended dose of
sitagliptin is 100 mg once daily. The recommended dose of
saxagliptin is 5 mg once daily.
Absorption, Distribution, Metabolism, and Excretion. DPP-4
inhibitors are absorbed effectively from the small intestine. They circulate
in primarily in unbound form and are excreted mostly
unchanged in the urine. DPP-4 inhibitors do not bind to albumin,
nor do they affect the hepatic cytochrome oxidase system. Both
sitagliptin and saxagliptin are excreted renally, and lower doses
should be used in patients with reduced renal function. Sitagliptin
has minimal metabolism by hepatic microsomal enzymes.
Saxagliptin is metabolized by CYP 3A4/5 to an active metabolite.
The dose saxagliptin should be lowered to 2.5 mg daily when coadministered
with strong CYP3A4 inhibitors (e.g., ketoconazole,
atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir,
ritonavir, saquinavir, and telithromycin).
Adverse Effects and Drug Interactions. There are no consistent
adverse effects that have been noted in clinical trials with any of the
DPP-4 inhibitors. With few exceptions the incidence of adverse
effects in drug-treated and placebo-treated patients has been similar.
DPP-4 is expressed on lymphocytes; in the immunology literature,
the enzyme is referred to as CD26. Although there is some evidence
of minor effects on in vitro lymphocyte function with DPP-4
inhibitors, there is no evidence from clinical studies of major adverse
effects in humans. This area bears scrutiny as more patients are
treated with these compounds.
OTHER HYPOGLYCEMIC AGENTS
Alpha Glucosidase Inhibitors
Mechanism of Action. α-Glucosidase inhibitors reduce
intestinal absorption of starch, dextrin, and disaccharides
by inhibiting the action of α-glucosidase in the
intestinal brush border. Inhibition of this enzyme slows
the absorption of carbohydrates from the GI tract and
blunts the rate of rise of postprandial plasma glucose.
These drugs also increase the release of the glucoregulatory
hormone GLP-1 into the circulation, which may
contribute to their glucose-lowering effects.
Dosage Forms. The drugs in this class are acarbose (PRECOSE, others),
miglitol (GLYSET), and voglibose; only acarbose and miglitol
are available in the U.S. Dosing of acarbose and miglitol are similar.
Both are provided as 25, 50, or 100 mg tablets that are taken
before meals. It is recommended that treatment start with lower
doses and be titrated as indicated by balancing postprandial glucose,
A1C, and GI symptoms. Acarbose and miglitol are most effective
when given with a starchy, high-fiber diet with restricted amounts
of glucose and sucrose.
Absorption, Distribution, Metabolism, Excretion, and Dosing.
Acarbose is minimally absorbed and the small amount of drug
reaching the systemic circulation is cleared by the kidney. Miglitol
absorption is saturable, with 50-100% of any dose taken into the circulation.
Miglitol is cleared almost entirely by the kidney, and dose
reductions are recommended for patients with creatinine clearance
<30 mL/minute.
Adverse Effects and Drug Interactions. The most prominent
adverse effects related to α-glucosidase inhibitors are malabsorption,
flatulence, diarrhea, and abdominal bloating. These side effects
are dose dependent and related to the mechanism of action of the
drugs, with greater amounts of carbohydrate available in the lower
intestinal tract for metabolism by bacteria. Mild to moderate elevations
of hepatic transaminases have been reported with acarbose, but
symptomatic liver disease is very rare. Cutaneous hypersensitivity
has been described but is also rare. α-Glucosidase inhibitors do not
stimulate insulin release and therefore do not result in hypoglycemia
when given alone. Hypoglycemia has been described when
α-glucosidase inhibitors are added to insulin or an insulin secretagogue.
For hypoglycemia in the setting of α-glucosidase use, glucose
rather than sucrose or more complex carbohydrates should be
used for treatment. Acarbose can decrease the absorption of digoxin
and miglitol can decrease the absorption of propranolol and ranitidine.
Alpha glucosidase inhibitors are contraindicated in patients
with stage 4 renal failure.