Details from eLFH learning module on hypoglycaemics

1. Oral Hypoglycaemics
(courtesy of e-LFH)

2. Introduction
• Diabetes affects over 3 % of the population and around 90 % of people
suffer from Type 2 diabetes.
• Type 2 diabetes is normally a result of insulin insensitivity and relative
insulin deficiency. The condition is managed largely in primary care.
• Targets for glycaemic control are included in the quality and outcomes
framework (QOF), which in 2009-10 recommended a target HBA1C of ≤7
%.
• The cost of Type 2 diabetes to the NHS in 2007 is estimated at 7-12 % of
total expenditure, equating to £28 billion.
• Glycaemic control is important in terms of reducing microvascular
complications in particular.
• With the incidence of diabetes expected to increase and the tighter
targets being set by QOF, it is essential that all GPs are confident and
competent in using oral hypoglycaemic agents to treat this increasingly
common disease.

3. Metformin
• The NICE guidelines recommend metformin
monotherapy if HBA1C ≥6.5 % after a trial of
lifestyle interventions.
• It is important to record Elizabeth’s:
• BMI
• Past medical problems
• Current symptoms

4. When To Use a Sulfonylurea Instead
• NICE recommends considering a sulfonylurea rather than
metformin if:
– The patient is not overweight
– Metformin is not tolerated or is contra-indicated
– Hyperglycaemic symptoms necessitate a rapid response to
treatment
• Contra-indications to metformin include renal impairment,
ketoacidosis, pregnancy, breastfeeding, recent MI, acute
intercurrent illness that may precipitate tissue hypoxia or
impaired renal function.
• Review the use of metformin if eGFR <45 (or creatinine
>130)
• Do not prescribe it if eGFR <30 (or creatinine >150).

5. Metformin side effects
• Gasto-intestinal
– Metformin is associated with significant
gastro-intestinal side-effects including:
– Anorexia
– Nausea
– Vomiting
– Diarrhoea
– Abdominal pain
– Up to 20 % of patients discontinue treatment
with metformin for this reason.
• Metformin is associated with taste disturbance
• Lactic Acidosis?
– Can precipitate lactic acidosis in certain patient groups
and this is listed as a rare side-effect in the British
National Formulary (BNF).
– The risk is greater in patients with renal impairment.
– The use of metformin should be reviewed if the GFR is
less than 45 ml/min/1.73m2 and metformin should be
withdrawn if the GFR falls below 30 ml/min/1.73m2.
– Similarly in acute intercurrent illness, where tissue
hypoxia or renal impairment may occur, the
withdrawal of metfomin should be considered (e.g.
dehydration, sepsis, or acute myocardial infarction).
– Metformin should also be suspended when using
contrast dye (e.g. cardiac angiography) and prior to
the administration of a general anaesthetic.
• Metformin does not cause weight gain
• Acts by inhibiting gluconeogenesis in the liver and
increasing peripheral glucose uptake. Insulin
production is not increased.
• It is associated with fewer hypoglycaemic episodes
than other oral hypoglycaemics, such as
sulfonylureas for example.
• In the UKPDS trial it was found that metformin
reduces the risk of macrovascular complications
and death.
• In addition, the benefit of metformin in reducing
diabetic complications and mortality has been
shown to be greater than that of sulfonylureas or
insulin. This may not be due to its hypoglycaemic
affects alone.

6. Starting dose
• Start with metformin 500 mg once daily for 1 week
• Then increase to metformin 500 mg twice daily for 1
week
• Then review the patient
• The NICE guidelines recommend starting on a low dose
of metformin and titrating the dose up over several
weeks.
• The rationale for this is to reduce the risk of the patient
suffering from gastro-intestinal side-effects.
• If patient still suffers from side-effects then NICE
recommends considering a trial of extended-
absorption metformin.

7. Sulfonylurea
• The NICE guidelines recommend a sulfonylurea if
the HBA1C remains uncontrolled (≥ 6.5%) despite
metformin monotherapy.
• NICE recommend that a DPP-4 inhibitor (such as
sitagliptin) be prescribed in combination with
metformin instead of a sulfonylurea if:
– There is a significant risk of hypoglycaemia or its
consequences
– A sulfonylurea is contra-indicated or poorly tolerated

8. Sulfonylurea Side effects
• Gastro-intestinal side-effects
– ....such as nausea, vomiting, diarrhoea and
constipation do occur.
– However, in contrast with the gastro-intestinal side-
effects that occur with metformin they are generally
mild and infrequent.
• Weight Gain
– Sulfonylureas act by stimulating insulin release from
the pancreas. As such their action depends on the
presence of functioning pancreatic beta cells.
– There is also a known risk of weight gain with
sulfonylureas. This is secondary to the anabolic effects
of the insulin which is secreted from the pancreas.
• Hypoglycaemia
– As sulfonylureas stimulate insulin release, there is an
associated risk of hypoglycaemia. The risk is felt to be
low and hypoglycaemic episodes suggest the
medication dose is too high.
– Hypoglycaemia with sulfonylureas is increased with:
• Renal impairment
• Longer acting medications (chlorpropamide and
glibenclamide)
• Elderly patients
• Hypoglycaemia which results from sulfonylureas can
persist for several hours due to the half-life of the
medications and as such should be treated in
hospital.
• Chlorpropamide should not be prescribed as it has a
high side-effect profile due to its longer duration of
action.
• LFT’s
– Occasionally deranged liver function tests can occur.
Gliclazide, the most commonly prescribed sulfonylurea
in the UK, is metabolized primarily in the liver.
– Rarely, the deranged liver functions may proceed to
cause cholestatic jaundice and hepatitis.
– Severe hepatic impairment is a contra-indication to
the use of sulfonylureas.
• Side effects due to renal function
– The risk of hypoglycaemia is increased with impaired
renal function. As such sulfonylureas should be used
with caution in patients with mild to moderate renal
impairment.
– Shorter acting medications, such as gliclazide and
tolbutamide, at the lowest required dose should be
used. Longer acting preparations should be avoided.
– Closer monitoring should be advised.
– Avoid sulfonylureas if the renal impairment is severe
and the GFR is less than 10 ml/min/1.73m2.
– Contra-indications include:
• Severe hepatic impairment
• Acute porphyria
• Pregnancy and breast feeding
• Ketoacidosis

9. Efficacy of sulfonylureas?
• Around 10-15 % have a poor initial response
to sulfonylureas.
• Around 5-7 % per year will cease responding.
• At 10 years the majority of patients will
require another agent.

10. When a patient is on metformin and a sulphonylurea and HBA1C
remains uncontrolled, what are the options?
• Answer:
• Consider insulin in combination with metformin and sulfonylurea.
• Consider adding sitagliptin if insulin is unacceptable because of:
– Obesity or
– Employment, social, recreational or personal issues
• Consider exenatide in combination with metformin and
sulfonylurea if:
– BMI >35 (for people of European descent; adjust this figure for other
ethnic groups) and there are problems associated with high weight
– BMI <35 but insulin is unacceptable or weight loss would benefit other
co-morbidities

11. Dipeptidyl peptidase-4 (DPP-4)
Mode of action
• Dipeptidyl peptidase-4 (DPP-4)
is an enzyme which breaks
down the gut hormones
glucagon-like peptide-1 (GLP-
1) and glucose-dependent
insulinotropic polypeptide
(GIP) which both stimulate
insulin release.
• Sitagliptin and vildagliptin are
both DPP-4 inhibitors,
reducing the degradation of
GLP-1, and increasing insulin
secretion.
Contraindications
• Contra-indications
• Pregnancy
• Ketoacidosis
• Breast feeding
• In addition vildagliptin is contra-indicated in hepatic
impairment. In rare cases, it can cause hepatic
impairment and failure, so intermittent monitoring
of LFTs is advised.
• Vildagliptin should also be used with caution in the
elderly or in patients with a history of heart failure.
Important note
Caution is advised when renal impairment is present
when prescribing both sitagliptin and vildagliptin.
• mportantly, when a DPP-4 inhibitor such as
sitagliptin is prescribed, the NICE guidelines suggest
that the medication should only be continued if
there is a reduction in HBA1C of at least 0.5 % over
a 6 month period.

12. Acarbose
Indications
• Acarbose works by inhibiting
the enzyme alpha-glucosidase.
This delays the digestion of
carbohydrates in the gastro
intestinal tract and
subsequently reduces the
amount of glucose absorbed.
• Due to its mechanism of
action it causes significant
gastro-intestinal side-effects.
Side-effects
• Flatulence
• Diarrhoea
• Abdominal distension and pain
• Nausea
• Deranged liver function tests
• Side-effects severely limit its use
and it is now recommended by
NICE only when other oral agents
cannot be used.
• The UKPDS study indicated that
30 % of patients develop
flatulence and 16 % develop
diarrhoea when using acarbose.

13. General Key Points During
Intercurrent Illness
• There is an increased basal insulin requirement during
illness
• The illness may make the patient unable to monitor
and manage her diabetes as (s)he normally would
• Increased frequency of blood sugar monitoring is
advisable - every 4 hours if possible
• Ensure good fluid and carbohydrate intake
• Remember to safety net and arrange suitably frequent
follow up for sick patients
• Consider admission if unable to tolerate oral fluids
• Treat the underlying illness

14. Gastroenteritis / Illness
• Acute deterioration in renal function may
precipitate lactic acidosis in those receiving
metformin. This may happen in gastroenteritis, if
a patient becomes dehydrated.
• Metformin should be stopped during acute
gastroenteritis, and slowly reintroduced when the
patient recovers.
• When metformin is stopped, insulin may be
required temporarily, if the sugars are particularly
high.

15. Indications for Admission
• The underlying illness requires hospital
admission, e.g. MI, pneumonia
• Inability to tolerate oral fluids, or signs of
dehydration requiring IV fluids
• Persistent vomiting and diarrhoea
• Suspected HONK or DKA
• Vulnerable patients unable to manage or
monitor the changes to diabetic care
suggested