Oral Hypoglycaemic Agents OHAs

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Oral Hypoglycaemic Agents (OHAs)

• Theresa Smyth
• Nurse Consultant in Diabetes

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Indications for Use

• Not type 1 diabetes
• Pts with ketones
• Caution in people with
• Severe symptoms
• Short History
• Marked weight loss (gt10)
• Type 1 first degree relative
• Only withhold insulin in under 30yrs if
• Grossly obese
• Completely asymtomatic
• Have a family history suggestive of MODY
• Are Asian
• Take great care! Teach HBGM, Ketones and sick day
  rules document!

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Type 2 Diabetes

• Approx 85 of people with diabetes in developed
  countries
• Insulin resistance and beta cell dysfunction
  (damage 12 yrs prior to diagnosis UKPDS)
• Patients may have lost up to 50 of beta cell
  function at diagnosis
• A further 25 will be lost within 6 yrs of
  diagnosis (UKPDS, 1998)

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Extrapolation of the time of deterioration of
beta-cell dysfunction
10 8 6 4 2 0 2 4 6
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UKPDS 16, 1995
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Insulin Response Profile
Continuous glucose perfusion
Early phase
Insulin secretion
Late phase
Basal
0
10
100
Time (minutes)
Adapted from Ward1
1. Ward WK, et al. Diabetes Care 1984 7 491-502
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Beta Cell Dysfunction and Insulin Resistance

• gt 30 of patients have post prandial glucose
  (PPG) spikes, without evidence of raised fasting
  plasma glucose (FPG)
• Beta cell dysfunction leads to PPG spikes - the
  main cause of hyperglycaemia in some patients
  increased risk of CVD (DECODE Study group 1999)
• In others, defective insulin signalling and
  insulin resistance may be the root of their
  hyperglycaemia

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Treatment of Type 2 Diabetes
3. Acarbose slows glucose absorption
Carbohydrate
DIGESTIVE
ENZYMES
I
Glucose
G
Glucose (G)
I
I
G
I
Insulin
G
1. Sulphonylureas Meglitinides Amino acid
derivatives stimulates insulin secretion
G
(I)
I
G
I
G
I
G
I
G
I
G
I
G
I
G
G
2. Metformin mainly reduces hepatic glucose
output
2. Thiazolidinediones improve sensitivity of
tissues to insulin
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Initial Treatment of Type 2 Diabetes

• Diet and exercise are the most effective
  treatments for type 2 diabetes !
• Diet for approx 12 weeks unless dehydrated /
  severely symptomatic
• Then if control is poor (HbA1C gt 7)
• Overweight (BMI gt 25) - metformin
• If not sulphonylureas, metaglitinides, amino acid
  derivatives
• Contraindicated in pregnancy and when breast
  feeding
• Used in conjunction with diet and exercise

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Common Sulphonylureas
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Sulphonylureas (SUs)

• Interact with receptors on ß cell surface, closes
  K channels in the membrane, causing
  depolarisation allowing Ca to enter cells
  triggering release of insulin
• More insulin released
• Reduces hepatic glucose production
• Increases glucose uptake in the peripheral
  tissues

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Sulphonylureas - Efficacy

• First line oral treatment for those who are
  normal weight
• On average these agents
• Reduce Hba1c by 2
• Reduce FPG by 3.3-3.9 mmol/l
• 60-70 may achieve good control initially
• Do not prevent inevitable decline - approx. 7
  failure rate each year

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Sulphonylureas side effects

• Hypoglycaemia
• Elderly / irregular eating habits most risk
• Can be severe and prolonged
• Onset of symptoms can be slow
• Progressive confusion is a common presentation n
  the elderly
• Lowest recommended dose should be prescribed
  initially
• Longer acting agents such as glibenclamide should
  be avoided in the elderly
• Weight gain
• Skin rash 3 of pts

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Biguanides - Metformin

• Tablet size 500mg, 850mg
• Dose range 250mg bd to 1gram tds
• When to take with or after food
• Action
• Inhibits gluconeogenesis
• Stimulates peripheral glucose uptake
• Enhances insulin receptor binding
• Reduces intestinal glucose absorption

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Metformin

• UKPDS showed marked fall in microvascular
  complications and suggestion of cardioprotective
  properties
• The drug of choice in obese patients who have
  failed to lose weight
• Can be used in combination with SUs or insulin
• Similar efficacy to SUs

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Biguanides (cont)

• Side effects include
• Gastrointestinal discomfort
• Diarrhoea
• Nausea
• 30 of patients are unable to tolerate it
• Contraindications
• People with a history of renal, hepatic or
  cardiac impairment danger of lactic acidosis
• Notes
• Does not cause hypoglycaemia when used in
  monotherapy
• Must be stopped 48 hours prior to x-rays
  requiring contrast mediums

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Alpha Glucosidase Inhibitor - Acarbose

• Tablet size 50mg, 100mg
• Dose range 50mg od titrated up to 100mg tds
• When to take with the first mouthful of food,
  swallowed or chewed
• Action
• Slows absorptions of starchy foods from the
  intestine
• Has no effect on insulin production

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Alpha Glucosidase Inhibitor - Acarbose

• On average
• Reduces HbA1c by 0.7-1.0
• Reduces FPG by 1.1-1.7 mmol/l
• Common side effects include flatulence, abdominal
  bloating and diarrhoea caused by undigested CHO
• Poor compliance (51 self discontinue within 12
  months)

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Meglitinide Repaglinide (Prandin Daiichi
Sakyo)

• Tablet size 0.5mg, 1mg and 2mg
• Dose range starting dose 0.5mg per meal up to
  qds, to a maximum dose of 4mg per meal total
  daily dose not exceed 16mg.
• Duration of action 3-4 hours. Maximum plasma
  concentration occur 60 minutes after taking
  tablet
• No meal no tablet
• Action
• Rapidly absorbed, fast acting, short duration
  insulin secretagogue
• Derived from the meglitinide portion of
  glibenclamide binds with a different site on
  beta cell

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Meglitinide - Repaglinide

• Approved for use as monotherapy or in combination
  with Metformin
• Reduced risk of hypoglycaemia
• Reduced and weight gain compared to SU
• Contraindicated in
• lt18 or gt75 years
• Renal/Liver disease (metabolised by the liver
• Pregnancy

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Amino Acid Derivatives

• Generic name - Nateglinide
• Brand name - Starlix
• Tablet size 60mg, 120mg or 180mg
• Dosage start 60mg before meals (1-30mins).
  Usual maintenance dose is 120mg before meals,
  maximum 180mg TDS.
• Action
• Restores early phase of insulin release
• Reduces mealtime glucose spikes
• Short duration of action
• For use in people already taking Metformin where
  a sulphonylurea may be inappropriate

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Thiazolidinediones (glitazones)

• Generic names
• Rosiglitazone Pioglitazone
• Brand name
• Avandia Actos
• Tablet size
• 4mg, 8mg 15mg, 30mg
• Dose range
• 4mg od 8mg od 15mg 30mg od
• after 8 weeks

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Thiazolidinediones (glitazones)

• Action
• Targets insulin resistance at adipose tissue,
  skeletal muscle and liver by binding to specific
  nuclear receptors - peroxisome proliterator-activa
  ted receptor gamma (PPARy) agonists
• Improve sensitivity to insulin in muscle, fat
  tissues and liver
• Does not stimulate pancreatic insulin secretion

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Thiazolidinediones (glitazones)

• Not recommended as first line treatment (NICE)
• Rosiglitazone linked to increased relative risk
  of MI, angina or sudden death. Fractures in women
• Common side effects
• Weight gain and oedema (contraindicated in people
  with heart failure)
• Regular liver enzyme tests

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Adherence

• Diabetes Audit and Research in Tayside study
  (DARTS)(1999) showed that in people with type 2
  diabetes
• Less 1/3rd took their prescribed regimen of a
  single OHA for 90 of the time
• Where more that 1 agent was prescribed this
  figure fell to as low as 13
• Increasing frequency of SU and other
  co-medications was associated with decreasing
  adherence

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Conclusion

• Most type 2 patients will eventually require
  treatment with more than 1 OHA
• SU and Metformin are most commonly used
• These may lead to eventual treatment failure as
  the disease progresses
• New OHAs provides new options for
  pharmacotherapeutic combinations
• New agents that target the primary defects in
  type 2 are likely to assume a pivotal position