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Hypglycaemic Drug Therapy
Insulin Therapy
Summary of Insulin Classifications
Insulin Regimes
Oral Hypglycaemic Drugs
These will be linked to the following:
Insulin therapy
There are a large and confusing number of insulin preparations available. If patients
are satisfied with their treatment and achieving satisfactory control in the absence of
hypoglycaemia, no modification of their regimen is required.
Most insulin currently in use is biosynthetically manufactured of human sequence or
analogues with altered pharmacokinetic properties. Many patients prefer the ultra shortacting analogues/mixtures for convenience.
Some patients prefer to use animal derived insulin in the belief that use of human
sequence insulin may cause loss of awareness of hypoglycaemia. Although such a
conviction is quite widespread among the users, carefully conducted scientific studies
have consistently failed to provide evidence to support this hypothesis.
Some preparations are available in both human and porcine versions (e.g. human and
porcine actrapid) which can result in confusion in prescribing and dispensing. It is
important to realise that such preparations although similar in their characteristics are
not interchangeable, and patients should not be inadvertently changed from one to the
other. When patients are deliberately changed from animal to human/analogue insulin a
dose reduction of 25% is advised.
Insulins are most conveniently classified by duration of action as shown in the following
table.
Summary of insulin classification
Ultra short acting
Short acting analogues
Immediate onset
Humalog, Novorapid
Duration up to 4 hours
Peak action 60 minutes
Short acting
Soluble insulin
Onset 30 minutes
Duration up to 5 hours
(Human) Actrapid, Velosulin, Humulin S, Insuman Rapid , Pork
Actrapid ,
Peak action 3 hours
Hypurin Bovine Neutral, Hypurin Porcine Neutral.
Intermediate acting a:
Isophane insulin (contains protamine)
Onset 90 minutes
Duration: 16-20 hours
(Human Insulatard, Humulin I, Insuman Basal, Pork Insulatard,
Hypurin Bovine Isophane, Hypurin Porcine Isophane.
Peak action: 4-12 hours
Intermediate acting b:
Lente insulin (contains zinc 30% amorphous, 70% crystalline)
Onset 120 minutes
Monotard, Humulin Lente, Hypurin Bovine Lente.
Duration: 24 hours
Peak action: 6-18 hours
Long acting (a)
Ultralente insulin (contains crystalline zinc)
Onset 4 hours
Ultratard, Humulin Zn, Hypurin Bovine Protamine Zinc.
Duration greater than 24
hours
Long acting (b)
Lantus (insulin glargine)
Duration greater than 24
hours
Mixed preparations
Fixed mixtures of soluble and isophane insulin
Biphasic onset and duration
of action
(Human) Mixtard (10 20 30 40 50) Actrapid / Insulatard in ratios
of 10/90 to 50/50
Humulin M2, M3 or M5
Humulin S / Humulin I in ratios of
20/80 to 50/50
Insuman Comb 15, 25 or 50 Insuman Rapid/ Basal in ratios of
15/ 85 to 50/50
Humalog Mix 25 or 50
Lispro/LisproProtamine in ratios of
25/75 or 50/50
Novomix 30
Aspart/Aspart Protamine in a
ratio of 30/70
Pork Mixtard 30
Pork Actrapid /Pork
Insulatard in a ratio of 30/70
Hypurin Porcine 30/70 Mix
Note Ultra short-acting insulins (e.g. Humalog, Novorapid and mixtures i.e.
Humalog Mix 25 or 50 and Novomix 30) should be injected immediately
before eating or after food.
Other insulins should be injected
subcutaneously 30 minutes before eating.
Insulin regimens
Initiation of insulin
Patients are normally commenced on human insulin or an insulin analogue, in either a
twice daily or a multiple injection regimen. The choice of the initial regimen and
subsequent modifications should be made in consultation with the patient, taking due
regard of the patient’s occupation and lifestyle. The precise insulin formulation may be
determined by the patient’s preferred insulin delivery device. Most patients prefer to use
pen devices.
Once daily injections
Single daily injections do not usually result in good glycaemic control, and are relatively
rarely used. Such a regimen may be appropriate for patients where the therapeutic goal
is only to prevent ketosis or suppress symptomatic hyperglycaemia, and where there are
practical problems with insulin delivery, or particular concern over the risks of nocturnal
hypoglycaemia. Elderly patients living alone and patients requiring injections to be given
by a district nurse may fall into this category.
An intermediate acting lente or isophane insulin is usually most suitable in this context.
The long acting basal analogue insulins are under clinical evaluation.
Twice daily injections
This is a commonly used regimen, and suitable for patients starting on insulin. A
combination of short and intermediate acting insulins is taken before breakfast and
before the evening meal.
Multiple injections
This arrangement, involving up to 4 injections a day, has the main advantage of
increased flexibility with regard to exercise, meal timing and meal size. It is most likely
to work effectively in a well-motivated patient, prepared to do regular and frequent blood
glucose testing
The majority use an insulin analogue or soluble insulin before each meal, and an
injection of an intermediate or long acting insulin usually before bedtime to provide
background cover.
Oral hypoglycaemic drugs
These drugs are suitable for people with Type 2 diabetes when blood glucose control
through dietary measures alone proves inadequate. At present five types are available;
biguanides (metformin), sulphonylureas, prandial glucose regulators, the
thiazolidinediones and the -glucosidase inhibitor acarbose.
See Section Error! Reference source not found. for guidance on the role of these
drugs in the context of diet and other management strategies.
Since in practice the majority of patients are overweight, metformin is usually the drug of
first choice.
Early sulphonylurea treatment may be appropriate in the thin symptomatic patient
without ketonuria.
Patients should be educated about their drugs and should carry documentation of any
risk of hypoglycaemia.
Metformin
Action
Indications
Metformin works principally by reducing insulin resistance.
Primary drug treatment of overweight Type 2 diabetics.
As an adjuvant to other hypoglycaemic therapy in Type 2 patients.
Metformin may be continued in some obese patients with Type 2 diabetes
who ultimately require insulin therapy, to maximise insulin sensitivity and
minimise weight gain on insulin.
Side Effects
Diarrhoea, lethargy, anorexia, malabsorption of B12 and folate
Lactic acidosis is a very rare but often fatal side effect. It occurs almost
exclusively in alcoholics, patients with renal or severe cardiac failure, liver
disease, and those who are undergoing surgery or are shocked.
Caution
Contraindicated in renal failure (creatinine >150µmol/l), liver disease and
alcoholism.
Discontinue temporarily during severe intercurrent illness.
Discontinue for 48-hours following the injection of x-ray contrast media.
Dose
Initially 500mg daily with main meal, increasing gradually in 500mg
increments to a maximum of 1g tds. The dose is often limited by
diarrhoea.
Sulphonylureas
Action
Potentiates the pancreatic
Indications
Primary drug treatment of non-obese patients with Type 2 diabetes.
Primary drug treatment of overweight Type 2 patients unable to take
usual first line agents.
As adjuvant therapy with other agents.
Side Effects
Hypoglycaemia
Weight gain
Other side effects are rare.
Drugs
The three most commonly used sulphonylureas in Grampian are
Gliclazide, Glipizide and Glimepiride, the last having the advantage of a
once daily single tablet dose. Chlorpropamide and Glibenclamide are
particularly prone to cause hypoglycaemia and should not be initiated,
and their continued use should be reviewed periodically.
Doses
It is usually appropriate to start with a small dose before breakfast,
increasing progressively according to blood glucose response. The drug
should always be taken before meals.
Gliclazide
40-320mg daily (doses > 80mg should be divided).
Also available as a 30mg modified release tablet
(equivalent to 80 mg of standard preparation) – to achieve
maximum dose range, patient required to ingest several
tablets before breakfast.
Glimepiride
1-6 mg as a single daily dose.
Glipizide
2.5-20 mg (doses >10 mg should be divided).
Prandial glucose regulators
Action
These agents act as insulin secretagogues, potentiating the post-prandial
secretion of insulin that is impaired in the Type 2 diabetes. The
postprandial hyperglycaemia associated with increased cardiovascular
mortality in the DECODE Study can be improved by using these agents,
with dosage timed according to meals. However, the evidence of an
improvement in the clinical end-points of reduced cardiovascular events
and mortality is not yet available.
Indications
Repaglinide – As monotherapy or in combination with metformin
Nateglinide – In combination with metfomin
Side effects
Both agents can precipitate hypoglycaemia
Caution
Dose
main meals;
daily.
Avoid in severe hepatic impairment
Repaglinide (Novonorm)
- initially 500mcg within 30 minutes before
main meals (1mg if transferring from another oral hypoglycaemic),
adjusted according to response at 1-2 week intervals. Up to 4 mg as
single dose; max daily dose 16mg.
Nateglinide (Starlix) - initially 60 mg 3 times daily within 30 minutes of
adjust according to response to maximum 180mg 3 times
Thiazolidinediones
Action
A relatively new group of agents acting at the level of the PPAR-gamma
receptor to promote insulin sensitivity. To be effective, patients require to
have sufficient endogenous insulin production. The maximum
therapeutic benefit may not be apparent until after eight weeks.
Indications
Can be used as monotherapy although Metformin is the drug of first
choice.
As an adjunct to Metformin in the overweight patient with Type 2 diabetes
or with sulphonylurea therapy when Metformin cannot be tolerated in an
efficacious dose.
Not licensed for use with insulin.
Side-effects
May promote weight gain and fluid retention
Caution
Avoid in hepatic impairment – Do not initiate if AAT 2.5 x upper normal
limit
Use requires a commitment to LFT monitoring on a two-monthly basis for
the first year of therapy; thereafter, monitoring periodically is
recommended.
If AAT is  3x upper normal limit, therapy should be discontinued.
Absolute
Avoid use in patients with left ventricular impairment or heart failure.
Contraindication
Dose
Pioglitazone (Actos) -
15-45mg once daily
Rosiglitazone (Avandia)
4mg daily in combination with a
sulphonylurea
4-8mg daily may be used in combination
with Metformin
Acarbose
Action
An alpha-glucosidase inhibitor which acts within the gut to slow digestion
and absorption of carbohydrates.
Indications
Primary drug treatment of patients with Type 2 diabetes (especially the
obese) if other drugs are contraindicated.
As an adjuvant to other oral agents or insulin.
Side effects Flatulence and GI disturbance. As mono therapy it does not cause
hypoglycaemia.
Caution
Insulin or sulphonylurea induced hypoglycaemia in patients taking
acarbose must be treated with glucose (dextrose)
Dose
tolerance
25-50mg daily increased very gradually to 50-100mg tds according to