33. Hypoglycaemic Agents Flashcards
What classes of drugs are used to treat type 1 diabetes mellitus (DM)?
Describe what type of insulin is now used
> Insulin is the main class of drug used to treat type 1 DM.
> Insulin treatment has been available
since 1925, initially extracted from
beef and pork pancreases.
In the 1980s this was replaced by
synthetic human insulin,
which is now largely being replaced
by genetically engineered human insulin analogues.
Human and animal insulins, when injected subcutaneously, are more likely to clump,
resulting in a slower onset of action and
longer, more unpredictable duration of action
when compared to insulin analogues.
They are, therefore, more likely to cause hypoglycaemia between meals and at night,
followed by fasting hyperglycaemia
> Insulins can be categorised according
to onset of action,
peak and duration of action
> The main groups are rapid short intermediate- and long-acting
> Biphasic insulins are ready mixed
combinations of rapid- or short-acting
insulins with intermediate-acting insulins.
Rapid-acting insulin analogues
Eg
Onset
Peak
Duration
admin time
Rapid-acting insulin analogues
(aspart/Novorapid®, lyspro/ Humalog®, glulisine/Apidra®)
<15 min
1–2 h
4–6 h
Shortly before, during or immediately after meals
Short-acting human insulin
Eg
Onset
Peak
Duration
admin time
(regular soluble: Actrapid®/ Humulin R®)
0.5–1 h
2–4 h
6–8 h
30 min before meals (also used for IV infusions)
Intermediate-acting human
Eg
Onset
Peak
Duration
admin time
Intermediate-acting human insulin
(isophane/NPH/ Humulin I®,Insulatard®)
1–2 h
6–10 h
> 12 h
Twice daily regimens
(before morning and evening meals)
Long-acting insulin analogues
Eg
Onset
Peak
Duration
admin time
Long-acting insulin analogues
(glargine/Lantus®, detemir/ Levemir®)
1–1.5 h
Flat, maximal effect in 5 h
12–24 h (detemir)
24 h (glargine)
Once or twice daily
(physiologically similar to endogenous basal insulin
secretion)
What different types of insulin treatment regimens are you aware of?
> Once daily:
only suitable for type 2 diabetes.
> Twice daily: biphasic insulin is used. Episodes of hypoglycaemia followed by fasting hyperglycaemia may be minimised by using rapid acting analogues instead of short-acting human insulins.
Basal-bolus:
intermediate- or long-acting insulin is used at bedtime, in combination with rapid- or short-acting insulin at mealtimes.
> Continuous subcutaneous insulin infusion
(CSII) or insulin pump therapy:
useful for type 1 diabetics
with recurrent hypoglycaemia,
prebreakfast hyperglycaemia,
poorly controlled glucose
on multiple daily injections,
unpredictable lives or
delayed meals.
What classes of drugs are used to treat type 2 diabetes?
There are two main families of drugs that are used – oral hypoglycaemics
and non-insulin injectables.
Oral hypoglycaemic agents:
These agents are either used singly or in combination. They can be classified as follows:
1
Biguanides
metformin
2
Insulin secretagogues:
> Sulphonylureas
> Meglitinides
Thiazolidinediones
Biguanides
> Metformin
is the only licensed drug in this group.
> MOA: it enhances uptake of glucose in skeletal muscle cells via the glucose transporter protein GLUT4, and can only act in the presence of endogenous insulin,
therefore requiring pancreatic islet cells
with residual function
.
> Indication and benefits:
first-line drug in overweight
(and increasingly all) type 2 diabetics.
It causes less hypoglycaemia
and
weight gain than sulphonylureas
and reduces
macrovascular complications,
stroke and
death.
It may be of benefit in overweight type 1 diabetics.
> Side effects:
1 lactic acidosis
(especially in patients with renal insufficiency,
liver disease, cardiovascular disease, peripheral vascular disease, pulmonary disease, and those aged over 65)
and
2 gastrointestinal (GI) side effects.
> Contraindication:
renal failure (serum creatinine >150 μmol/L or eGFR <30 mL/min/1.73 m2)
Insulin secretagogues:
> Sulphonylureas
Example
MOA
other action
duration
indication
benefit
s/e
Insulin secretagogues:
> Sulphonylureas
• Gliclazide, glipizide, glimipramide, glibenclamide, tolbutamide
• MOA:
they promote the secretion of
insulin from pancreatic islet cells
(they bind to AT P-dependent potassium channels on islet cell membranes, cause depolarisation and voltage-gated calcium channels to open,
resulting in fusion of insulin granules
with the cell membrane and
release of pro-insulin).
They also act on the liver to:
promote glycolysis
and
inhibit the production of glucose.
Most have duration of action of 12–24 hours; tolbutamide is short-acting
(half-life of 4.5–6.5 hours).
• Indication and benefits:
first-line drug in type 2 diabetes when
metformin is contraindicated or not tolerated.
They are effective at long-term reduction
of glycosylated haemoglobin (HbA1c).
• Side effects:
hypoglycaemia
(especially in patients with renal and
hepatic impairment and in the elderly),
weight gain,
liver dysfunction
and GI disturbance.
> Meglitinides
> Meglitinides
• Repaglinide
and
nateglinide are the only two
licensed for use in the UK.
• MOA:
they are rapid-acting stimulators of
insulin secretion and
are taken before meals.
They act by binding to various sites
on pancreatic beta cells.
• Indications:
used in combination with
metformin where sulphonylureas
are not tolerated,
and especially in patients
with erratic eating habits.
Repaglinide can also be used as
monotherapy in non-obese patients
where metformin is contraindicated
or not tolerated.
• Side effects: hypoglycaemia.
> Thiazolidinediones
TDZ or ‘glitazones’
> Thiazolidinediones (TDZ or ‘glitazones’)
• Pioglitazone is the only one
currently licensed for use in the UK.
• MOA:
increases hepatic sensitivity to insulin,
promoting glucose clearance,
and is particularly effective
in patients with insulin resistance.
• Indications:
used in combination with either
metformin
or a
sulphonylurea where one or the
other is not tolerated or is contraindicated.
Also used as monotherapy
or in combination with insulin.
• Side effects:
1
increased risks of heart failure due to fluid retention
(rosiglitazone was withdrawn in 2010 for this reason and for its increased risk of MI),
2 hepatic enzyme derangement and liver failure (rare),
3
limb fractures
(in women with other risk factors for fractures)
4
and bladder cancer.
• Contraindications:
congestive cardiac failure,
patients at increased
risk of fractures.
> Alpha glucosidase inhibitors (acarbose)
> Alpha glucosidase inhibitors (acarbose)
• MOA: inhibition of intestinal alpha glucosidase, resulting in delayed absorption and digestion of sucrose and starch.
• Indications:
in combination with
metformin or sulphonylureas,
or as monotherapy where
other hypoglycaemic agents
are not tolerated or contraindicated.
• Side effects:
high chance of GI adverse effects,
particularly flatulence
and diarrhoea.
> Dipeptidyl peptidase-4 (DPP-4) inhibitors
> Dipeptidyl peptidase-4 (DPP-4) inhibitors
- Sitagliptin and vildagliptin
- MOA:
DPP-4 inhibitors ultimately
increase insulin secretion
and lower glucagon secretion.
Inhibition of the enzyme DPP-4 results
in reduced breakdown and
increased levels of incretins,
which are GI hormones including
glucagon-like peptide-1 (GLP-1)
and gastric inhibitory peptide (GIP).
Incretins increase insulin release from
beta cells and delay absorption of
nutrients by reducing gastric emptying.
• Indications:
used in combination with metformin,
sulphonylureas,
or TDZ.
Can also be used as monotherapy.
Sitagliptin may also be
added to insulin treatment.
• Side effects: hypersensitivity reactions: anaphylaxis, angioedema and Stevens–Johnson syndrome.
Non-insulin injectables:
Non-insulin injectables:
Glucagon-like peptide-1 mimetics (exenatide)
> MOA:
acts as incretin-mimetic
and is given by twice-daily
subcutaneous injection before meals.
> Indications:
in combination with metformin or sulphonylureas, or as an alternative to insulin in obese patients on maximal doses of oral treatments.
> Side effects:
significant weight loss
(therefore appropriate for patients
with BMI >35 kg.m2).
Non-insulin injectables:
Non-insulin injectables:
Glucagon-like peptide-1 mimetics (exenatide)
> MOA: acts as incretin-mimetic and is given by twice-daily
subcutaneous injection before meals.
> Indications: in combination with metformin or sulphonylureas, or as
an alternative to insulin in obese patients on maximal doses of oral
treatments.
> Side effects: significant weight loss (therefore appropriate for patients
with BMI >35 kg.m2).
