The
main advantages of extenatide and
Gliptins over SUs are Lack of weight
gain and hypoglycemic episodes. In addition in experimental
animals long term exposure of these agents has led to some degree of beta cell preservation Bea cell
regeneration replication as well as
reduced apoptosis have been postulated SUs do not have this properly Thus SUs are expected
to be gradually replaced by
these agents particularly in rich
countries . Due to economic limitations only a small fraction of diabetics can
afford these expensive agents thus time
tested SUs will continue to remain once of the mainstay of oral anti diabetic
therapy in our country for a long time to come. However it should be noted that while SUs have with stood the test of time these new
agents are in clinical use for very short
time. Thus it s a bit early to
write obituary of SUs and hail incretion
mimetics and DPPs inhibitors
as great discoveries and
wonder drugs. Type 3 Antidiabetic
drugs:- OAD ( oral antidiabetic drugs)::_Thiazolidinedione
Glitazones work as
insulin sensitizers. Like metformin they act only on peripheral tissues
mainly muscle and fat cells
and increase their sensitivity to insulin. They do not increase pancreatic insulin secretion thus when given alone or in combination with metformin
they do not cause hypoglycemia.
Their action is
mediated through activation of Par gamma
activated intra nuclear receptors. The cellular site of action is predominantly
adipocyte and muscle cells with some action
on hepatocytes Glitazones sensitize tissues
towards insulin and reduce
circulating free fatty acid
levels.
Rosiglitazone and Pioglitazone
were the two glitazones available
in our country till recently
In September 2010 the regulatory authorities of Govt of India
banned rosiglitazone following
its ban in advanc3ed countries .
Both have identical mechanism of action and indications water
retention leading increased volume of
fluid in intra vascular compartment is liable to occur with both the
compounds. Precipitation of
incipient cardiac failure has occurred
with both the glitazones thus they are
contraindicated in those in cardiac failure or those who have history of cardiac failure In addition a meta
analysis published in 2007 associated rosiglitazone
with higher prevalence of
myocardial infarction and sudden
cardiac death Pioglitazone has a
favorable influence on plasma lipids and
was not associated with increased prevalence of myocardial
infarction or sudden cardiac deaths
in any of the clinical
trials or meta analysis. The
usual daily dose of Pioglitazone is 15 to 45 mg in a single dose. Most of the Indian authorities do not prescribe
it beyond 30 mg /day both the
agents produce weight gain which
can be as much as ten kegs in
some patients. The weight gain is mainly due to water retention
with some contributions from adipogenesiis and weight
regain due to better metabolic
control . In those with
significant edema or weight gain
glitazones need to be discontinued.
Indications :
1)
In predominantly insulin resistant type 2 diabetic patients
Pioglitazone is used as an alternative to metformin particularly if the latter
is not tolerated or contra indicated. It can also be combined with metformin
when monotherapy with metformin fails to achieve glycemic targets.
2)
In
combination with SUs or other insulin secretogogues when latter agents alone are not sufficient to control
blood glucose level.
In triple drug combination
along with any two from SU
metformin and gliptin group in groups when two drug
therapy fails to meet glycemic targets and the patient is still some distance away from end stage beta cell
failure . Experienced clinicians
can make such a judgment
Uncommon agents: Quick Release Bromocriptine
Tablets
Conventional
Bromocriptine has been in
clinical practice for more
than two decades for the
management of parkinsonism and Galactorrhoea.
Quick release preparation of
Bromocriptine has been introduced in
India in mid 2010 and in USA in November 2010. It is indicated in the management of type 2 diabetes.
In type 2 diabetes dopaminergic tone in hypothalamic
area is reduced . This is associated
with increased secretion of
noradrenalin in hypothalamic
hypophyseal axis which in turn
leads to insulin resistance obesity and hyperglycemia Bromocriptine is dopamine
agonist Administration of quick release
version leads to rapid buildup of its
associated with reduction in
insulin resistance and improvement
in glycemic status particularly
post prandial hyperglycemia.
Quick release
bromocriptine has better bio availability than its
conventional version. It is available
in tablet form each tablet contains 0.8 mg of bromocriptine
in special quick release formulation. The therapeutic dosage
is 1.6 to 4.8 mg once daily two hours after getting
up in morning . preferably after
food. In order to avoid gastro intestinal
side effects treatement should be
started with 0.8 mg and dosage should be stepped up at weakly interval.
Quick release bromocriptine
is the first and so far only anti
diabetic medication which has successfully undergone elaborate
pre marketing cardio vascular
safety studies in USA. After the
publication of report of excess cardio
vascular mortality with
rosiglitazone in the New
Engalnd journal of medicine in June
2007 Th US FDA has made these tests
mandatory for any new and diabetic
agent before its introduction in the market.
Quick release
bromocriptine can be used as one
of the add on agents particularly in those
with manifestations of insulin resistance .
Tips from Dr S K Pal
in lieu of a good dinner : It is dinner time for this old man: send your
delicious dinner sharp by courier . Clinical
applications of OADs
OADs are indicated in type 2 DM patients when diet fails to control hyperglycemia.
Stressful conditions such as severe
infections pregnancy and major
surgery renal and hepatic insufficiency are contra indications to the use
of OADs These drugs do not work
in the absence of insulin
hence should not be used alone in Type 1 DM.
CRITERIA FOR CONTORL
One should aim at total freedom form
glycosuria and steady near normal blood glucose . Table 2
gives criteria for control
Note : Criteria for
control need to be modified as per the individual patient’s situation
In elderly people in
those who do not have warning adrenergic symptoms and in those with significant
cardiovascular affection with long
standing diabetes less stringent criteria should be applied.
During pregnancy fasting and 2 hours post prandial plasma glucose
values should be < 100 and 125
mg % respectively . In young ad
recently diagnosed diabetic
patients generally aggressive
criteria should be applied. Their all
the three glycemic values i.e. fasting
and post prandial plasma glucose values
and HbA1c should be at or very
near lower limit of the range mentioned above.
Failure of control
A common cause of failure is inadequate dietary regulations Some diabetes are under the wrong impression that since they are taking OAD
they are at liberty to eat anything . In
addition to review of diet in patients failing to respond to OAD
a systematic search for occult infection
should be made.
It is also advisable
to thoroughly analyze all the medicines
he/ she is taking . In addition to medicines prescribed by you he/ she may be taking say for example steroids for asthma strong
potassium wasting diuretics like Fursemide
and Diphenythydanatoin can also interfere with the action of OAD . If
a failure occurs even after proper dietary
regulations and maximal dose of
OAD drugs from other
groups should be added and the
dosage gradually increased
until optimal control is
achieved . After a prolonged use
for several years OAD
gradually start losing their
effect and ultimately a stage is reached in many
patients where a maximum dosage
of combined agents is also unable to control
hyperglycemia and . At this stage
OAD should be replaced by insulin.
Side effects
Sulphonylureas : A number
of non specific gastrointestinal
symptoms ranging from dyspepsia to diarrhea occur with the sulphonylura
in a small number of patients . A
variety of skin reactions also
occur . these are mostly of
minor significance and resolve
on drug cessation however an occasional
severe complication may arise such as exfoliative dermatitis or stevens
Johnson syndrome. A cholestatic type of
jaundice is rarely seen as is bone marrow depression . water retention
giving rise to delusional Hyponatraemia was first described with chlorpropamide but has also
been reported with other
sulphonylureas Hypoglycemia should be regarded
as a consequence of
excessive dosage rather than as a side effect unless due to drug interaction
What about Biguanides(metformin- My fair lady!!) : Gastro
intestinal side effects including
anorexia nausea and diarrhea occur in 10-15% of patients and being dose dependent these may limit the
opportunity to employ maximum dosage. Vitamin B12 deficiency
may result from the effect of
biguanides on the dowel . In contrast to the sulphonylureas hypoglycemia
is rare and usually is only
reported with suicidal drug use. We have
already discussed lactic acidosis.
Glitazones : Weight gain
swelling of feet due to edema and
cardiac failure when used
in patients with left ventricular
dysfunction are main side effects
Mild anemia is also seen This is due to dilution of blood
following increased blood volume due to water retention.
Alpha Glucosidase
Inhibitors : Abdominal distention
borbigmy and diarrhea are main
side effects.
DPPS inhibitors A variety
of skin reactions are
occasionally reported. These are mostly
of minor significance and resolve on drug cessation however
an occasional severe complication
such as exfoliative dermatitis or
Stevens johnson syndrome has been reported in those
on sitagliptin Rare cases of
pancreatitis in those on sitagliptin and incretin
mimetics have been reported however cause
and effect has not been proved As such pancreatitis is more common in diabetics as compared to others
Incretin mimetics : main side effects are gastro
intestinal intolerance . These can
be reduced by starting the therapy with smaller dose and subsequently stepping
up Pancreatitis has been reported in
rare cases.
Bromocriptin: Gastro intestinal intolerance is not uncommon
The prevalence and severity is reduced
by starting with lower dose and stepping
up after one week. Giddiness and
postural hypotension is seen in some patients . Bromocriptine should be avoided in those on other
ergot agents antipsychotic
agents and dopamine antagonists.
Drug Interactions
These occur mainly
with sulphonylureas Alcohol intolerance occurs in a number of patients
particularly those on chlorpropamide Many drugs potentiate hypoglycemic effects of sulphonylureas. These include clofibrate Dicumarol large doses of salcylates Beta
blockers NSAIDs and Biguanides In those taking biguanides the risk of lactic acidosis increases if they
consume alcohol.
The entire work was a joint effort of ADA EASD IDF and IFCC .
In order in express average blood glucose in patient
friendly and meaningful manner a large multi centric multinational work
was carried out in 700 persons . 300 each had type 1 and 2 diabetes and 100
were normal controls Originally 11
centers spread across North
America Europe Africa and Asia were included . One centre dropped out due to technical reasons.
Those having conditions such as anemia
haemoglobinopathies and renal impairment
were excluded from eh study A large amount of data on glycemic control was generated in
these people by studying was generated
in these people by studding them for 4
months in this period all were subjected
It is proposed that in future IFCC will standardize and cal liberate all the equipment used for estimation of HbA1c
and also officially release the mathematical formula subsequently the
laboratories will give report in HbA1c formal
expressed in % as currently done
in mmol/L format as well as in ear in
mg% format.
In
other words HbA1c will not be done
away with but will be
standardized and cal liberated by IFCC method . In addition eAG in mg% will be calculated by
mathematical formula and given along
with HbA1c report as an additional value
7% HbA1c
will be equivalent to 154 mg% of glucose instead of 150mg% as at present .
Hence in future indicators of long term
glycemic control and spot or point of
time glycemic control will be expressed in same units. This move will be very much
patient friendly
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