Diabetes Treatment (cont.)
Medications that decrease the amount of glucose produced by the liver
A class of drugs called biguanides has been used for many years in Europe and
Canada. In 1994, the FDA approved the use of the biguanide
metformin
(Glucophage) for the treatment of type 2 diabetes in the U.S. Glucophage is
unique in its ability to decrease glucose production by the liver. Briefly,
because metformin does not increase insulin levels, when used alone, it does not
usually cause hypoglycemia. In addition, metformin has an effect whereby it
tends to suppress appetite, which may be beneficial in diabetics who tend to be
overweight. Metformin may be used by itself or together with other oral drugs or
insulin. It should not be used in patients with kidney impairment and should be
used with caution in those with liver impairment. The older biguanides that
preceded metformin were associated with a serious condition called
lactic
acidosis, a dangerous acid build up in the blood resulting from accumulation of
the drug and its breakdown products. While metformin is safer in this regard, it
is recommended that the drug be discontinued for 24 hours before any procedure
involving the intravenous injection of dyes (such as for some x-ray studies of
the kidney) or surgery is performed. The dyes may impair kidney function and
cause a build up of the drug in the blood. Metformin can be restarted after
these procedures once the patient is urinating normally.
Medications that increase the sensitivity of cells to insulin
The class of drugs known as thiazolidinediones lowers blood glucose by
improving target cell response to insulin (that is, increasing the sensitivity
of the cells to insulin). Troglitazone (Rezulin) was the first of this class in
the U.S. Because of severe toxic liver effects, troglitazone has been taken off
the market. Sister compounds are now available with a better safety profile.
These drugs include
pioglitazone (Actos) and rosiglitazone (Avandia).
Pioglitazone (Actos) and
rosiglitazone (Avandia) are thiazolidinediones
approved for use in the U.S. While they are sister compounds to Rezulin,
extensive studies have failed to show that they are associated with any liver
problems. Both Avandia and Actos act by increasing the sensitivity
(responsiveness) of cells to insulin. They improve the sensitivity of muscle and
fat cells to insulin. These drugs have been effective in lowering blood sugars
in patients with type 2 diabetes, Actos and Avandia act within one hour of
administration and are taken once daily. It is important to note that it takes
up to six weeks to see a drop in blood glucose levels with these drugs and up to
12 weeks to see a maximum benefit. Actos and Avandia have been approved as first
line therapy in diabetes and for use in combination with other drugs. Both drugs
may be used in patients taking other oral drugs as well as those using insulin.
While reported liver problems with these agents are mild (and reversible with
discontinuation of the drug), most physicians choose to follow an earlier
recommendation to do blood tests to detect liver injury every two months or so
during the first year of therapy. Recently this recommendation has been removed.
If at any point the liver tests increase to three times the normal upper limit,
the drug should be stopped.
The most important contraindications to these medications include any type of
liver disease, and
heart failure. Fluid retention can be of particular concern in patients with signs or symptoms of heart failure and in those with ejection fractions of less than 40% which indicates poor function of the heart. While the reports are three to eight pounds, clinical experience shows up to 12-15 pounds of
weight gain can occur. Usually the majority of this is fluid, but an absolute body weight gain can also occur. This is likely to be dose-dependent and, therefore, the increases in weight may be greater with higher doses of drug. Weight gain is more pronounced in patients who are also taking insulin.
In general, the ankle swelling and puffiness due to the accumulation of fluid can be controlled with the addition of a
diuretic such as
spironolactone (Aldactone) —
(furosemide (Lasix) does not work as well) — or by reducing the dose. On occasion, patients may be symptomatic enough from fluid retention to warrant withdrawal of the drug. Some recent studies have suggested an association between pioglitazone and rosiglitazone and untoward cardiac events, for example,
heart attacks, though this association is controversial. Regardless of the controversy, it is well established that pioglitazone and rosiglitazone should be avoided in patients with symptomatic heart failure or heart failure.
Another newer concern is an association of treatment with a small
increase in the frequency of fractures of the distal long bones of the arms and
legs. At present, this does not translate into fractures of the hip and spine,
which would be clinically more worrisome. More data is needed to make a
definitive statement about cause and effect at this time.
As an aside, Actos and Avandia have an added benefit of changing
cholesterol
patterns in diabetes. HDL (or good cholesterol) increases with these
medications, and triglycerides often decrease. While there is some controversy
regarding what happens to bad cholesterol (LDL) levels, there is a suggestion
that Actos may be superior in changing lipid profiles than Avandia. In this
population of diabetics that is already at an increased risk for
heart disease, an
improvement in cholesterol profile is beneficial. As more and more data becomes
available, there is mounting evidence that this class of drugs may provide
direct benefits to the heart and large blood vessels and may actually be
valuable in preventing the progression of diabetes in high-risk individuals by
reducing inflammation and by decreasing clotting factors. As time goes on, I
have no doubt that the uses for this class of medications will expand.
Next: Medications that decrease the absorption of carbohydrates from the
intestine (Precose) »
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