Oral Hypoglycaemics

(courtesy of e-LFH)

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.

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

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).

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45 ml/min/1.73m2 and metformin should be withdrawn if the GFR falls below 30 ml/min/1.73m2.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.

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.

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

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

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.

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

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 noteCaution 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.

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.

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

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.

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