[acb-diabetics] oral agents for lowering blood sugars

[Patricia LaFrance-Wolf]

Oral Agents for Lowering Blood Sugar in Type 2 Diabetes 

Author's note: Throughout this series, I will inject my own opinion, which
frequently differs from that of the medical establishment in this field.
Having had diabetes <http://www.diabeteshealth.com/>  for more than 66
years, I place my emphasis on the well-being of fellow patients.

There are currently eight categories of oral agents marketed in the US for
lowering blood sugar
<http://www.diabeteshealth.com/browse/monitoring/blood-sugar/>  in type
<http://www.diabeteshealth.com/browse/community/type-2-issues/>  2 diabetes.
Each category has different reasons for use, differing efficacies for
different individuals, different potential adverse effects, and possibly
different off-label applications for purposes other than blood sugar
control.

Before I begin to discuss these agents, I must point out three facts that
are frequently overlooked in conventional medical practice:

*	Far more effective for reducing blood sugars than any of these
medications is adherence to a very low-carbohydrate
<http://www.diabeteshealth.com/browse/food/low-carb/>  diet. The effect of
these products on lowering blood sugar is easily overwhelmed by the effect
of dietary carbohydrate on raising it.

*	Injected insulin is the most potent blood-sugar-lowering medication
we have. Furthermore, it always works. For this reason, most of my type
<http://www.diabeteshealth.com/browse/community/type-2-issues/>  2 patients
are obliged to inject insulin (in addition to possibly taking oral agents)
if they want truly normal blood sugars around the clock (about 83 mg/dL for
adults, and an A1C
<http://www.diabeteshealth.com/browse/monitoring/a1c-test/>  of 4.2% to
4.6%). Many physicians avoid the use of insulin, however, because they do
not know how to safely adjust doses of this potent hormone.

*	Diabetes is much easier to control if as many pancreatic beta cells
(which make insulin) as possible are preserved. Therefore, an important goal
of treatment should be beta cell preservation. This is most readily
accomplished by absolute normalization of blood sugar from the first sign of
impaired glucose tolerance. In the 1980s, Gerald Reaven actually
demonstrated partial beta cell recovery after keeping blood sugars normal
with the assistance of a mechanical pancreas. I have subsequently seen this
effect in my own patients with the help of diet and injected insulin. A
recent study from Korea again duplicated these results, as did another
recent study in the US.


Sulfonylurea Agents 

The sulfonylureas are the second oldest of the oral agents approved by the
FDA for lowering blood sugars. They include glipizide (Glucotrol), glyburide
(Micronase), and glimepiride (Amaryl), as well as the older drugs tolazamide
(Tolinase) and chlorpropamide (Diabinase). 

With the exception of timing of action after administration, all these drugs
(pills) are approximately equivalent. They share similar potency at the
recommended doses, similar benefits, and similar adverse effects. They all
work by stimulating the beta cells of the pancreas to make more insulin. The
more healthy beta cells a person with diabetes has, the more insulin will be
produced. 

For those of us who have many functioning beta cells, sulfonylureas and
meglitinides are by far the most potent oral agents we have. There is a
catch, however. The blood sugar effect depends on the dose administered, not
on the actual blood sugar--just like injected insulin. These drugs,
therefore, do not automatically keep blood sugars at the level we desire. It
is possible for blood sugar to go dangerously low (hypoglycemia
<http://www.diabeteshealth.com/browse/complications-and-care/low-blood-sugar
/> ) if the user is not very careful about adhering to a fixed meal plan and
frequently measured blood sugars. It is not a matter of taking a pill and
forgetting about everything else--even though that is often the approach to
treatment.

The most rapid acting of the sulfonylureas is glipizide. Onset of action
begins for most users about 30 minutes after taking the pill, and it
continues to work for several hours after administration. So, in principle,
this drug is appropriate for preventing blood sugar rise after meals. It may
not be totally effective for preventing the rise after eating
high-carbohydrate meals, because carbohydrates can raise blood sugar faster
than glipizide can lower it. A timed release version of glipizide, which is
also on the market, has a much longer-acting effect that closely resembles
the drugs described in the next paragraph.

Many people with type 2 diabetes find that their blood sugars increase even
when they are not eating, as during an overnight fast or between meals.
Glyburide, glimepiride, tolazamide, and chlorpropamide take longer to start
working and have blood-sugar-lowering effects that last much longer than
glipizide. It would thus be appropriate to take these drugs on arising and
at bedtime to cover the fasting state. 

Thirty years ago, before I became aware of the adverse effects of
sulfonylureas, I used glyburide to cover the fasting state, together with
glipizide before meals. The combination was very effective, provided users
were on fixed, low-carbohydrate diets. Unfortunately, it took a few years
for me to realize that these drugs were causing what I thought was
destruction of beta cells. A recent study on mice appeared to show that they
merely paralyzed beta cells so that the cells could no longer secrete
insulin. This effect was reversed if the drugs were discontinued for a
while. Another study showed that when beta cells were caused by the drugs to
secrete insulin, the beta cells expressed unique proteins on their surfaces.
These proteins can readily be attacked by our immune system, eventually
causing beta cell destruction--just as I had originally hypothesized. 

There is another major problem associated with sulfonylureas: Since 1970,
repeated studies have found them to be associated with excess mortality from
cardiac disease, independent of other risk factors such as high blood sugar.
It appears that when these drugs facilitate insulin production by closing
potassium channels in beta cells, they also close potassium channels in the
muscles that relax arteries. As a result, the arteries constrict, and
circulation (to the heart) is impaired. As recently as June 2012, a 24,000
person comparison of sulfonylureas with a totally different oral agent,
metformin <http://www.diabeteshealth.com/browse/medications/metformin/> ,
showed a 59 percent to 68 percent greater all-cause mortality among the
sulfonylurea users.

For some individuals, sulfonylureas can cause severe facial flushing after
consuming alcoholic beverages
<http://www.diabeteshealth.com/browse/food/beverages/> . This phenomenon,
called the "disulfuram effect," is certainly not life-threatening.
Sulfonylureas, along with the meglitinides described below, are the most
potent of the oral drugs in terms of blood sugar lowering. This potency is
probably the main reason for their popularity among physicians in spite of
their adverse effects upon beta cells and cardiac mortality. They can make a
physician's life easier by enabling the avoidance of teaching insulin
use--at least until beta cells stop functioning.

The Meglitinides

There are currently two newer medications on the market that work by pushing
beta cells to make insulin by the same mechanisms as sulfonylureas. However,
they are chemically different; for example, they do not cause the disulfuram
effect. The two meglitinides, repaglinide (Prandin) and meglitinide
(Starlix), are fast-acting and are typically taken before meals to reduce
blood sugar rise after meals. Because their mode of action is so similar to
sulfonylureas, I naturally fear both beta cell impairment and increased
cardiac mortality--even though I haven't seen any such studies of the
meglitinides.

I last prescribed sulfonylureas in the late 1980s, and have deliberately
refrained from prescribing meglitinides. Having diabetes myself, I cannot
envision exposing fellow patients to the problems described above. There
are, however, other oral agents for treating diabetes, which I do prescribe.
They will be discussed in subsequent articles of this series. 



Richard K. Bernstein, MD, FACE, FACN, FCCWS, has had type 1
<http://www.diabeteshealth.com/browse/community/type-1-issues/>  diabetes
for more than 66 years. His latest books include Diabetes Solution and
Diabetes Diet, both published by Little Brown, and the e-book Beating
Diabetes. He limits his medical practice in Mamaroneck, NY, to the treatment
of diabetes and obesity.

  _____  

Categories: <http://www.diabeteshealth.com/browse/monitoring/blood-sugar/> 

 

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