Download ORAL HYPOGLYCAEMIC AGENT

ORAL HYPOGLYCAEMIC AGENT
PRESENTER:UDIGWE CHIOMA
OUTLINE
• INTRODUCTION
• CLASSIFICATION
• MECHANISMS OF ACTION,INDICATIONS,
BENEFITS AND RISKS OF EACH CLASS.
• CONTRAINDICATIONS TO USE OF OHA.
• TARGETS OF TREATMENT WITH OHA.
• CONCLUSION.
INTRODUCTION
• Oral hypoglycemic agents are the group of drugs that
may be taken
singly or in combination to lower the blood glucose in
type 2 diabetes.
• Type 2 diabetes can be due to increased peripheral
resistance to insulin
or to reduced secretion of insulin.
• They should be used together with changes in diet and
lifestyle to achieve good glycaemic control.
• It is customary to monitor such changes for three
months before considering medication.
• Oral hypoglycaemic agent are not usually used
in type 1 diabetics but metformin may be of
use in combination with insulin for overweight
type 1 diabetics.
What is the role of an ideal OHA?
Conserve islet cell function
- delay the subsequent use of insulin.
Improve patient compliance- single daily
dosing.
Reduce the incidence of hypoglycaemic events
CLASSIFICATION
• Based on their mechanisms of action, oral
hypoglycaemic agents are broadly classified into four
major groups.
1. Those that increase insulin secretion eg
sulphonyureas,meglitinides,incretin-based therapies.
2. Reduce glucose production eg
biguanides,thiazolidinediones.
3. Increase insulin sensitvity eg
biguanides,thiazolidinediones.
4. Delay glucose absorption eg alpha-glucosidase
inhibitors.
BIGUANIDES
• Metformin, representative of this class of agents, reduces
hepatic glucose production and improves peripheral
glucose utilization slightly.
• Metformin activates AMP-dependent protein kinase and
enters cells through organic cation transporters .
• Metformin reduces fasting plasma glucose and insulin
levels,improves lipid profile and promotes modest weight
loss..
• The initial starting dose of 500 mg once or twice a day can
be increased to 1000 mg bid.
. An extended-release form is available and may have fewer
gastrointestinal side effects (diarrhea, anorexia, nausea,
metallic taste).
• Metformin is effective as monotherapy and can be used in
combination with other oral agents or with insulin.
The major toxicity of metformin, lactic acidosis is very rare
and can be prevented by careful patient selection.
Vitamin B12 levels are 30% lower during metformin
treatment.
Metformin should not be used in patients with renal
insufficiency [GFR < 60 mL/min], any form of acidosis, CHF,
liver disease, or severe hypoxemia.
Metformin should be discontinued in patients who are
seriously ill, in patients who can take nothing orally, and in
those receiving radiographic contrast material.
• Benefits and indications: Metformin is the only
oral hypoglycaemic shown to reduce
macrovascular complications and death.
• It is associated with fewer hypoglycaemic attacks
than sulphonylureas and does not cause weight
gain.
• It is more effective than sulphonylureas in
reducing any diabetes endpoint, all-cause
mortality, and stroke.
• These improvements have not been explained
entirely on the basis of glycaemic control.
• Risks: Metformin can increase susceptibility
to lactic acidosis.
• It’s use is contraindicated in patients with
impaired renal or hepatic function and in
those who drink alcohol in excess.
• Gastrointestinal side-effects occur commonly
with metformin at higher doses, and may
necessitate a change of drug
.
SULPHONYLUREAS
• Generation I: Tolbutamide, Chlorpropamide,
Tolazamide.
• Generation II: Glibenclamide, Glipizide,
Gliclazide, Gliquidone.
• Generation III: Glimepiride.
• Sulphonylureas stimulate insulin secretion by interacting
with the ATP-sensitive potassium channel on the beta cell .
• These drugs are most effective in individuals with type 2
DM of relatively recent onset (<5 years), who have residual
endogenous insulin production
• . First-generation sulfonylureas (chlorpropamide,
tolazamide, tolbutamide; have a longer half-life, a greater
incidence of hypoglycemia, more frequent drug
interactions, and are now rarely used. Second-generation
sulfonylureas have a more rapid onset of action and better
coverage of the postprandial glucose rise.
• . Sulfonylureas reduce both fasting and
postprandial glucose and should be initiated
at low doses and increased at 1- to 2-week
interval.
• In general, sulfonylureas increase insulin
acutely and thus should be taken shortly
before a meal; with chronic therapy, though,
the insulin release is more sustained.
• Benefits and indications:
– Sulphonylureas may be used as a first-line drug where
oral hypoglycaemic medication is required,
particularly in patients who cannot tolerate
metformin or in whom it is contra-indicated.
– Newer drugs in this group, such as glipizide and
glimipramide, appear to afford similar efficacy as the
older drugs such as gliclazide.
– Chlorpropamide is no longer recommended, as it has
more side-effects than other members of this group.
• Risks:
– The main risk with sulphonylureas is hypoglycaemia. This is increased
in older age groups, mild-to-moderate hepatic impairment, and renal
impairment.
– Glibenclamide, a long-acting sulfonylurea, is associated with a greater
risk of hypoglycaemia and therefore should be avoided in the elderly,
and shorter-acting alternatives, such as gliclazide should be used
instead.
– Hypoglycaemia is usually related to delayed meals, increased physical
activity,alchol intake or renal insufficiency.
– Some drugs can potentiate the hypoglycaemic effect of sulphonylureas
by displacing them from their plasma protein binding sites e.g.
salicylates,phenylbutazone and anti –fungal agents.
– Other problems can include weight gain, liver dysfunction and
gastrointestinal disturbance.
ALPHA-glucosidase inhibitors.
Alpha-Glucosidase inhibitors (acarbose and miglitol) reduce
postprandial hyperglycemia by delaying glucose absorption;
they do not affect glucose utilization or insulin secretion .
Postprandial hyperglycemia, secondary to impaired hepatic
and peripheral glucose disposal, contributes significantly to
the hyperglycemic state in type 2 DM.
These drugs, taken just before each meal, reduce glucose
absorption by inhibiting the enzyme that cleaves
oligosaccharides into simple sugars in the intestinal lumen.
Therapy should be initiated at a low dose (25 mg of acarbose
or miglitol) with the evening meal and may be increased to
a maximal dose over weeks to months (50–100 mg for
acarbose or 50 mg for miglitol with each meal)
. The major side effects (diarrhea, flatulence, abdominal distention)
are related to increased delivery of oligosaccharides to the large
bowel and can be reduced somewhat by gradual upward dose
titration.
alpha-Glucosidase inhibitors may increase levels of sulfonylureas and
increase the incidence of hypoglycemia.
. These agents should not be used in individuals with inflammatory
bowel disease, gastroparesis, or a serum creatinine >177 mol/L (2
mg/dL).
This class of agents is not as potent as other oral agents in lowering
the A1C but is unique because it reduces the postprandial glucose
rise even in individuals with type 1 DM. If hypoglycemia from other
diabetes treatments occurs while taking these agents, the patient
should consume glucose since the degradation and absorption of
complex carbohydrates will be retarded by the drug.
THIAZOLIDINEDIONES
• Thiazolidinediones reduce insulin resistance by binding to the PPAR(peroxisome proliferator-activated receptor ) The PPAR- receptor is found
at highest levels in adipocytes but is expressed at lower levels in many
other tissues.
• Agonists of this receptor regulate a large number of genes, promote
adipocyte differentiation, reduce hepatic fat accumulation, and promote
fatty acid storage .
• Thiazolidinediones promote a redistribution of fat from central to
peripheral locations.
• Circulating insulin levels decrease with use of the thiazolidinediones,
indicating a reduction in insulin resistance.
• Although direct comparisons are not available, the two currently available
thiazolidinediones appear to have similar efficacy; the therapeutic range
for pioglitazone is 15–45 mg/d in a single daily dose, and for rosiglitazone
the total daily dose is 2–8 mg/d administered either once daily or twice
daily in divided doses.
•
The prototype of this class of drugs, troglitazone, was withdrawn
from the U.S. market after reports of hepatotoxicity and an
association with an idiosyncratic liver reaction that sometimes led
to hepatic failure. Although rosiglitazone and pioglitazone do not
appear to induce the liver abnormalities seen with troglitazone,
• the FDA recommends measurement of liver function tests prior to
initiating therapy with a thiazolidinedione and at regular intervals
(every 2 months for the first year and then periodically).
• Rosiglitazone raises LDL, HDL, and triglycerides slightly.
• Pioglitazone raises HDL to a greater degree and LDL a lesser degree
but lowers triglycerides. The clinical significance of the lipid changes
with these agents is not known and may be difficult to ascertain
since most patients with type 2 diabetes are also treated with
statin.
• Benefits and indications:
– TDZs are usually used in combination with a sulphonylurea or
metformin.
– It has also been licensed as monotherapy.
– The combination with metformin or a sulphonylurea should only be
used in patients unable to tolerate metformin and sulphonylurea in
combination therapy, or in whom either metformin or a sulphonylurea
is contra-indicated.
• In such cases, the TDZ should replace whichever drug in the combination is
poorly tolerated or contra-indicated.
• A TDZ plus metformin is a useful combination for obese patients. The
introduction of a TDZ may cause a deterioration of blood glucose control
temporarily when used in combination therapy.
– Pioglitazone may be considered with insulin therapy in patients who
have previously had a marked glucose-lowering response to TDZ
therapy or in those on high-dose insulin therapy and whose blood
glucose is inadequately controlled.
•
Risks:
Do not commence or continue a TDZ in patients who have heart failure, or who
are at higher risk of fracture:
– Cardiovascular: the risk of heart failure is increased when pioglitazone is combined with
insulin and in patients with a history of cardiovascular disease. Patients who take pioglitazone
should be closely monitored for signs of heart failure, and treatment should be stopped
immediately if any deterioration in cardiac status occurs. Pioglitazone should not be used in
patients with heart failure or a history of heart failure.
– Risk of bladder cancer: there is a small increased risk of bladder cancer associated with
pioglitazone use. Pioglitazone should not be used in patients with active bladder cancer, a past
history of bladder cancer or for patients with uninvestigated macroscopic haematuria. .
– There have been rare reports of liver failure, but large-scale trials have shown no difference in
incidence between TDZs and other oral hypoglycaemics.Baseline LFTs and periodic monitoring
are recommended.
– There is an increased risk of fractures, especially in women
– It is also associated with weight gain(2-3kg),small reduction in the hematocrit and a mild
increase in plasma volume..
•
Only continue with a TDZ if there has been a beneficial metabolic response (HbA1c
falling 0.5% in 6 months).
MEGLITINIDES
• The two meglitinides in use are Repaglinide
and Nateglinide. They are relatively shortacting stimulators of insulin secretion (<6
hours).
• They act by binding to various sites on
pancreatic beta cells.
• They stimulate endogenous insulin secretion
through the sulphonylurea receptor and is
taken immediately before food.
• Benefits and indications:
– Meglitinides are characterised by short duration and
rapid onset of action, which requires them to be taken
before a main meal.
– Repaglinide may be suitable as monotherapy for nonobese patients in whom metformin is contra-indicated
or not tolerated, or in combination with metformin.
– Nateglinide is licensed only for use in combination
with metformin.
• Risks: as with the sulfonylureas, the main risk
with meglitinides is hypoglycaemia.
DIPEPTIDYLPEPTIDASE-4 INHIBITORS
• Examples of DPP-4 inhibitors are
sitagliptin,vildagliptin and saxagliptin.
• They are incretin-based therapies.
• They are inhibitors of the enzyme
dipeptidylpeptidase 4 which degrades GLP-1.
• By inhibiting the enzyme ,they prolong the
action of GLP-1.
• GLP-1 actions include stimulating insulin
secretion in a glucose-dependent manner’
• Suppresses glucagon secretion.
• Delays gastric emptying.
• Reduces appetite and encourages weight loss.
• Benefits and indications:
– They may be appropriate ahead of a TDZ when the latter is contraindicated, or if further weight gain would cause or exacerbate
significant problems associated with a high body weight.
– In these circumstances, they are considered as a third-line therapy in
combination with metformin and sulfonylurea when glycaemic control
is still inadequate.
– They can be considered second-line with metformin in patients at
particular risk of hypoglycaemia (elderly patients living alone; other
patients working at heights or with heavy machinery), or second-line
in combination with a sulfonylurea in patients intolerant of metformin.
– They are most useful in obese patient.
• Risks:
– Hypersensitivity reactions may occur (anaphylaxis, angioedema and
Stevens-Johnson syndrome).
Pharmacology – Bile Acid Sequestrants
Class
Bile acid sequestrants
Compound
Colesevelam (Welchol®)
Mechanism
Binds bile acids/cholesterol
Action(s)
Bile acids stimulate receptor on liver to produce glucose
Results
• Lowers fasting and post prandial glucose
Advantages
• No hypoglycemia
• LDL cholesterol 
Disadvantages
• Constipation
• Triglycerides 
• May interfere with absorption of other medications
Cost
High
.
Agents
Mechanis
Examples
m of action
AIC
reduction
Agent
specific
adv.
Agent
specific
disadv.
Biguanides
Decrease
hepatic
glucose
production
Metformin
1-2
Weight
neutral, do
not cause
hypoglyce
mia,
inexpensiv
e
Diarrhoea, Serum
nausea,lact creatnine>
ic acidosis 1.5mg/dl in
men,>1.4m
g/dl in
women,
radiographi
c
studies,aci
dosis,CHF,s
eriously ill
pxts
Acarbose,
Miglitol
0.5-0.8
Reduce
postprandi
al
glycaemia
Flatulence, Renal/liver
nausea,abd disease
ominal
bloating
AphaReduce GI
glucosidase glucose
inhibitors
absorption
DPP-4
Prolong
Saxagliptin, 0.5-0,8
INHIBITORS endogenou sitagliptin,v
s GLP-1
ildagliptin
action
Do not
cause
hypoglyce
mia
Contraindi
cation
Reduce
dose with
renal
disease.
Agents
Mechanism Examples
of action
Sulphonylu
reas
Increase
insulin
secretion
Glibenclami 1-2
de,glyburid
e
inexpensive Hypoglycae Renal, liver
mia,weight disease
gain.
Meglitinide Increase
s
insulin
secretion
Repaglinide 1-2
,Nateglinid
e
Short onset Hypoglycae Renal/ liver
of action,
mia
disease
lower post
prandial
glucose
Thiazolidin
ediones
Rosiglitazo 0.5-1.4
ne,pioglitaz
one.
Lower
insulin
requiremen
t.
Decrease
insulin
resistance,
increase
glucose
utilization
AIC
reduction
Agent
specific
adv.
Agent
specific
disadv.
Contraindica
tion
Peripheral CHF,liver dx.
oedema,wt
gain,fractur
es,macula
oedema,inc
rease cvs
risk
NEWER AGENTS .
• Bile acid sequestrants: are well established for the treatment of
dyslipidaemia, and reduce the risk of cardiovascular disease. They
also reduce glucose concentrations in patients with type 2 diabetes.
The mechanism of action is not known.
• Dopamine D2-receptor agonists :Bromocriptine is an ergot alkaloid
dopamine-D2receptor agonist Although bromocriptine quick
release has only been licensed since 2010 by the US Food and Drug
Administration (FDA) for the treatment of type 2 diabetes as an
adjunct to lifestyle changes, its effects on glycaemic variables have
been noted since 1980.
• Bromocriptine produces its effects without increasing insulin
concentrations, possibly by altering the activity of hypothalamic
neurons to reduce hepatic gluconeogenesis through a vagally
mediated route.
DETERMINANTS OF OHA USEAGE
1)Body Mass Index :
BMI> 22kg/m2
Metformin, Gliptins
2)Presence of GI symptoms: Sulpha, Gliptins, Glitazones
3)Renal Dysfunction: Gliptins, Glitazones(+/-),Sulpha (variable)
4) Aging
Meglitinides, Gliptins(?)
5) Hepatic Dysfunction
Nateglinide, Saxagliptin(?)
6) Compliance
Gliptins, Glitazones,
7) Cost
Metformin, Sulphas, Glitazones
CONCLUSION
In conclusion,OHA are agents that help in
lowering blood glucose in DM, more useful in
type 2 DM.the different classes target the
various pathophysiological mechanisms
involve in type2 dm.the main limitation to the
usage of available OHA is their inability to
alter the progressive nature of the dx. Efforts
should be geared towards developing drugs
that will address this problem.
• THANK YOU.