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

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SECTION V
HORMONES AND HORMONE ANTAGONISTS
istilan (not available in the U.S.), also reduced blood glucose in
diabetic subjects. This supports the idea that beneficial effects on
glucose metabolism are a shared effect among bile acid binding
resins.
Miscellaneous Agents.
Bromocriptine. A formulation of bromocriptine (CYCLOSET), a
dopamine receptor agonist, was approved by the FDA in 2009 for
the treatment of type 2 diabetes but is not yet available in the U.S.
Bromocriptine is an established treatment for Parkinson disease
and hyperprolactinemia (see Chapters 22 and -38). Studies to elucidate
the mechanism of bromocriptine to improve blood glucose
have not been definitive. In humans, DA agonists do not improve
insulin sensitivity, and in cultured islet cells they do not enhance
insulin secretion. Effects of bromocriptine on blood glucose may
reflect an action in the CNS. The effectiveness of bromocriptine
to improve glycemic control is modest (A1C reduction of 0.1-
0.4%). The dose range for CYCLOSET is 1.6 mg to 4.8 mg, taken
with food in the morning within two hours of awakening. Side
effects include nausea, fatigue, dizziness, orthostatic hypotension,
vomiting, and headache. The role of this agent in the treatment of
type 2 diabetes is uncertain.
COMBINED PHARMACOLOGICAL
APPROACHES TO TYPE 2 DIABETES
Progressive Management of Type 2
Diabetes
There are several useful algorithms or flow charts for the
treatment of type 2 diabetes (Figure 43–11; Nathan et al.,
2009). There are a number of pathways or combination
of drugs that are used for treatment of type 2 diabetes if
the glucose control does not reach the therapeutic target
(Inzucchi,2002; Monami et al., 2008). For example, the
addition of a second oral agent, such as an insulin sensitizer,
either alone or in combination with an oral insulin
secretagogue, also may provide good therapeutic results.
Another approach is to introduce basal insulin (often at
bedtime) in combination with oral hypoglycemic agents.
This combination allows the oral agents to provide postprandial
glycemic control while the basal insulin provides
the foundation for normalizing fasting or basal
glucose levels. Insulin can be combined with various oral
antihyperglycemic agents. Combination of glargine with
sulfonylureas and/or metformin can reduce both fasting
(basal) and postprandial glucose levels. The exact combination
of therapies can be guided by an estimation of
the β cell secretory reserve in each patient (i.e., a measurement
of circulating C peptide level). The progressive
insulin deficiency in type 2 diabetes often makes it
increasingly difficult to achieve tight glycemic control
solely with oral antihyperglycemic agents (Bretzel et al.,
2008; Lasserson et al., 2009). Table 43-9 summarizes
available pharmacological agents for the treatment of
diabetes.
Emerging Therapies for Diabetes
A number of immunomodulatory approaches are being
investigated to prevent or block the autoimmune
process that is central to type 1 diabetes. Interventions
with immune modifying agents, such as monoclonal
antibodies against the lymphocyte receptors CD3, CD20
and CD 25, and immunosuppressant mycophenolate
(Chapter 35), are currently ongoing. The use of
immunosuppressive agents, such as cyclosporine, glucocorticoids
and azathioprine, has been tested in small
numbers of patients with new-onset type 1 diabetes.
Although some of these studies have demonstrated that
immunosuppression can slow β cell loss, this approach
has not been widely accepted because of the acute and
long-term toxicities of these drugs.
Drugs in Development for Type 2 Diabetes. Inhibitors of the
sodium glucose co-transporter 2 (SGLT2) are designed to reduce
hyperglycemia by increasing urinary clearance of glucose. SGLT2
is expressed in the proximal renal tubule and functions to reabsorb
filtered glucose from the tubule lumen to epithelial cells; glucose
subsequently is returned to the circulation through the actions of
the glucose transporters 1 and 2. SGLT2 is a low-affinity, highcapacity
co-transporter that shuttles sodium and glucose in a 1:1
ratio and accounts for most of the recovery of filtered glucose in
the nephron; SGLT1 located in the distal tubule plays a lesser role.
Loss-of-function mutations in SGLT2 cause glucosuria. There are
several orally available, highly specific SGLT2 inhibitors in clinical
development. These compounds cause urinary losses of 50-100 g
per day of glucose in the urine, reduce fasting glucose by 0.5-2.0 mM,
lower A1C by 0.5-1.0%, and cause modest amounts of weight loss.
In clinical trials, SGLT2 inhibitors have been generally well tolerated.
There is a mild diuretic effect, rare instances of hypoglycemia,
and a slight increase in urinary tract infection, including genital
infections. Although there are yet no specific indications with this
class of drugs, the novel mechanism, the general action to reduce
glycemia in proportion to plasma levels and the blockade of reuptake
of renally filtered solute, raise the possibility that SGLT2
inhibitors could have application as adjuncts to a wide range of
other diabetes therapies.
A second area of new drug development is activators of glucokinase
(GK), the principle hexokinase in islet β cells and hepatocytes.
The half-maximal activity of GK is near 8 mM so that the
enzyme is highly functional as blood glucose increases from fasting
levels of 5 mM to postprandial levels of 7-9 mM. In mouse models
engineered to delete GK specifically from the islet or liver, hyperglycemia
develops; overexpression of GK leads to improved glucose
tolerance. Loss-of-function mutations of GK cause the autosomal
dominant form of diabetes, MODY-2. There are now orally available
small molecules that are allosteric activators of GK, which
lower blood glucose in hyperglycemic animals. Because GK has a