Therapeutics in
Diabetes
Kate Spittle
Prescribing Advisor
Cwm Taf LHB
Summary
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Issues around diabetes
Drugs used for control of hyperglycaemia
Monitoring of glucose control
NICE guidance
Hypertension in diabetes
 Lipids
 Aspirin
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Questions
Diabetes
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Around 7% in Wales are being treated for
diabetes
16% of these are > 65yrs
Incidence is increasing -predicted to rise to
10.3% in 2020, 11.5& in 2030
Poor diet, lack of physical activity and a
sedentary lifestyle are major contributors
½ adult population and around a 1/3 of
children in Wales are classified as overweight or
obese
Diabetes
Lifestyle interventions promoting moderate
weight loss together with an increase in physical
activity have been shown to result in a more
than 50% reduction in the risk of type 2
diabetes amongst at risk individuals
( Knowler et al 2002 )
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!!
Realistic Plans?
Aims of Management
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Prevent diabetes
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Early detection
Fast, effective treatment
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Lifestyle choices, minimise risk
Live longer and healthier lives
Support living with diabetes
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Patients are supported and informed to manage their
diabetes
Type 2 Diabetes
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90% of cases of diabetes
Often associated with obesity
Characterised by;
Insulin resistance ( a greater than normal amount of
insulin is required to produce a biological response )
 Relative insulin deficiency
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Symptoms
Financial Costs
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In Cwm Taf we spend per year;
£4.78million on drugs for diabetes
£2million on insulins
 £1million on blood glucose testing reagents
 £0.5million on metformin
 £0.5million on exenatide and liraglutide
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Treatment Aims
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Optimal glycaemic control
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‘target’ HbA1c of <6.5 – 7.5% ( 48-59mmol )
Cardiovascular risk reduction
Minimise the risk of long term complications
Polypharmacy
Therapeutic Options
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Lifestyle ( diet, exercise, weight loss, smoking )
Structured education ( not covered )
Treatment
Biguanides
 Sulfonylureas
 Thiazolidinedions
 Repaglinide / Nateglinide
 Incretins – DPP4 inhibitors and GLP-1 analogues
 Acarbose
 Insulin ( not covered )
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Biguanides - Metformin
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Decreases hepatic gluconeogenesis
Increases peripheral utilisation of glucose
Only acts in the presence of endogenous
insulin, so only effective if there are some
functioning pancreatic islet cells
No risk of hypoglycaemia
Metformin
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Drug of first choice in overweight patients
(May be considered if patient is not overweight)
Dosage – start low and go slow
BNF – initially 500mg once daily with breakfast
for at least a week, then 500mg twice daily for 1
week, then 500mg three times a day
Max dose ( BNF ) 2g daily ( 3g daily )
Metformin
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Side effects
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Nausea
Vomiting
Diarrhoea
Anorexia
Bloating and discomfort
Metallic taste
B12 malabsorption
Lactic acidosis ( rare )
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Contra-indications
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eGFR <30 ml/min
( care if <45ml/min)
Liver failure
Moderate / severe cardiac
failure
General anaesthesia (stop
on morning of surgery
and restart when renal
function returns to
baseline )
Metformin
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If GI problems occur, slow down titration
50% will tolerate the MR preparation if they
experience GI side effects
If swallowing difficulties, use sachets or check
with LHB prescribing team
How much do you think
we spend on Metformin
in Cwm Taf ?
.
Usage of Metformin in Cwm Taf
Sulfonylureas
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Gliclazide, Glipizide, Glimepiride, Glibenclamide,
Tolbutamide
Enhance insulin secretion – independent of glucose
Only effective when residual pancreatic beta-cell activity
is present
Lower HbA1c by 1.5%
Weight gain typically 2kg
Hypoglycaemia risk especially in elderly / renal
impairment
Sulfonylureas
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Side effects
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Hypoglycaemia
Weight gain
GI disturbance
Headache
Fever
Jaundice
Blood dyscrasias
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Contra-indications
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Pregnancy
breast feeding
Renal impairment
Hepatic impairment
Disadvantage
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Accelerates decline in
beta cell function
Sulfonylureas
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Choice of preparation is determined by side
effects and the duration of action
Gliclazide – short acting
Glibenclamide – long acting so should be
avoided in the elderly
Gliclazide
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Initially 40-80mg daily
Adjust dose according to response ( review in
one week?)
Up to 160mg as a single daily dose with
breakfast
Max dose 320mg daily in divided doses
Usage of Sulfonylureas in Cwm Taf
Thiazolidinediones
Pioglitazone
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Reduce peripheral insulin resistance leading to a
reduction in blood glucose
Sensitizes fat, muscle and liver to endogenous
and exogenous insulin
Rosiglitazone – withdrawn due to CV risk
Pioglitazone – concerns over bladder cancer risk
Pioglitazone
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Side effects
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GI disturbance
Weight gain
Fluid retention
Dizziness
Headache
anaemia
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Contra-indications
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Pregnancy
Breastfeeding
Hepatic impairment
Cardiac failure
Pioglitazone
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Dosage
Adult, initially 15-30mg daily , increased to 45mg
daily according to response
 Elderly, initiate with lowest possible dose and
increase gradually
 Review treatment after 3-6 months
 Dose of sulfonylurea or insulin may need to be
reduced if used concomitantly
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Pioglitazone
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Cardiovascular safety (Dec 07,Jan 11)
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Incidence of heart failure is increased if pioglitazone is
combined with insulin especially in patient with predisposing
factors. Patients should be closely monitored for signs of
heart failure
Bladder cancer ( July 11 )
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Small increased risk. Should not be used in patients with
active bladder cancer or past history of bladder cancer or in
those with uninvestigated macroscopic haematuria.
Pioglitazone should be used with caution in the elderly as the
risk of bladder cancer increases with age
Pioglitazone
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Review at 3-6 months
Stop if inadequate response to treatment
NICE – continue only if HbA1c is reduced by
0.5% within 6 months of starting treatment
Metiglinides
Prandial Glucose Regulators
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Nateglinide / repaglinide
Stimluate release of insulin
Early phase of insulin release in response to food lost
in type 2 diabetes
Rapid onset of action
Short duration of action – so do not stimulate beta
cells constantly
Take just before each main meal. Gives flexibility with
meal times
HbA1c reduction ~1%
Metiglinides
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Side effects
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Hypoglycaemia
Nausea
Vomiting
Constipation
Diarrhoea
Rash
pruritus
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Contra-indications
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Severe hepatic
impairment
Pregnancy
Breast feeding
Surgery – omit on
morning of surgery and
recommence when eating
and drinking normally
Metiglinides
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Nateglinide
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Adult, initially 60mg three
times a day within 30mins of
main meal.
Adjust according to response
Max 180mg three times a day
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Repaglinide
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Adult, initially 500mcg within
30mins of main meal ( 1mg if
transferring from other oral
hypoglycaemic )
Adjust according to response
at intervals of 1-2 weeks
Up to 4mg may be given as
single dose
Max 16mg daily
Over 75years not rec
Acarbose
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Slows rate of carbohydrate absorption
Reduces post prandial hyperglycaemia
Reduces HbA1c ~0.8%
Rarely used in UK due to GI side effects
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Flatulence, soft stools, diarrhoea, abdominal
distension and pain
Dose – Adult, 50mg daily increased to 50mg
three times a day, then 100mg three times a day
after 6-8 weeks. Max 200mg three times a day
The Sugar Coated Pill?
Progressive Defects in Type 2
Diabetes
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Progressive decline in beta cell function
Inadequate insulin secretion
Unsuppressed post prandial glucagon secretion
GLP – 1 Enzyme
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GLP -1 secretion is impaired in type 2 diabetes
Activation of the GLP-1 receptor
increases insulin secretion
 Suppresses glucagon secretion
 Slow gastric emptying
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Exenatide and Liraglutide both bind to and
activate the GLP-1 receptor
The gliptins block DPP-4, the enzyme that
degrades GLP-1
Exenatide
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Treatment is associated with the prevention of
weight gain and possible weight loss
Subcutaneous injection
NICE – treatment continued only if HbA1c is
reduced by at least 1% and a weight loss of at
least 3% within 6 months
How often are patients reviewed and treatment
stopped?
Exenatide
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Dose – s/c injection
Initially 5mcg twice daily,1 hour before 2 main
meals
Increased if necessary after at least 1 month to
10mcg twice daily
If dose is missed, do not administer after a meal,
continue with next scheduled dose
Dose of sulfonylurea may need to be reduced if
used together
Exenatide Usage in Cwm Taf
Liraglutide
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Dose – by s/c injection
Adult 0.6mg once daily
Increased after at least 1 week to 1.2mg daily
Further increased if nec. after at least 1 week to
max 1.8mg daily
Dose of sulfonylurea may need to be reduced
Liraglutide Usage in Cwm Taf
Exenatide / Liraglutide
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Side effects
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GI effects
Decreased appetite
Weight loss
Headache
dizziness
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Contra – indications
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Severe GI disease
Pregnancy
Pancreatitis
Severe renal impairment
Issues
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Long term safety data
Injection
Cost - expensive
DPP-4 Inhibitors ( Gliptins )
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Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin
Increase insulin sectrion
Lower glucagon secretion
Have theoretical advantages of SU’s but no long
term safety data
Expensive
DPP-4 Inhibitors
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Side effects
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GI disturbance
Oedema
URTI’s
Anorexia
Headache
hypoglycaemia
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Contra-indications
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Renal impairment ( check
gliptin used )
Pregnancy
Breast feeding
GLP-1 vs DPP-4
DPP-4
GLP-1
Route
Oral
Sub cut
Cost
~£30
~£70
Weight
Weight neutral
Weight loss
HbA1c
~0.6 – 0.8%
~0.8 – 1.1%
GI side effects
Less nausea
More nausea
Therapeutic Options
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Lots of choices
NICE guidance – see flow chart
Metformin
 Dual therapy
 Triple therapy
 Check licensing for combinations
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Cost
Monitoring
Monitoring Response
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Minimum – annual review
HbA1c
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BP
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<130/80
Lipid profile
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<6.5-7.5%
Chol <4, LDL <2
Lifestyle interventions
Self Monitoring
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Self care – vitally important in diabetes
Should be available ( NICE )
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to those on insulin
To those on oral glucose lowering medications to provide
info on hypglycaemia
To assess changes resulting from medication or lifestyle
changes
To ensure safety during activities including driving
To monitor changes during illness
Must be clear purpose of testing and information
obtained
Frequency of monitoring?
Self Monitoring
Diet alone – testing?
 Diet + metformin – once / twice a week?
( 1 -2 pot per year )
 Diet + tablets stimulating insulin secretion (
SU’s, metaglinides, gliptins )– twice a week and
at one other time pre meals ( 3 pots of strips per
year )
 Diet + injectable stimulators of insulin secretion
( exenatide / liraglutide ) – twice a week and at
one other time before meals ( 3 pots of strips
per year )
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Blood Glucose Testing in Cwm Taf
Cwm Taf - Glucose Blood Testing Reagents
255000
250000
245000
PrescriberBasicPrice
240000
235000
230000
225000
220000
215000
210000
Mar-11
Jun-11
Sep-11
Dec-11
Mar-12
Period
Glucose Blood Testing Reagents
Jun-12
Sep-12
Dec-12
NICE Guidance
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Clinical guideline 87
Management of hypertension
Management of lipids
Aspirin
Management of Hypertension in
Diabetes
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Targets
If kidney, eye or cerebrovascular damage <130/80
 Others 140<80
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If hypertensive and BP target is reached,
monitor every 4-6 months
Measure BP annually if not hypertensive or with
renal disease
Hypertension in Diabetes
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Lifestyle measures
Treatment;
Offer ACE inhibitor ( titrate dose ) (ramipril) 1St
dose effect
 For African-Caribbean descent offer ACE plus
diuretic or CCB
 Add diuretic ( bendrofluazide 2.5mg in the morning)
or CCB ( amlodipine 5mg daily )
 Add other drug ( diuretic or CCB )
 Add alpha-blocker, beta blocker of potassium
sparing diuretic (with caution)
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Lipid Management in Diabetes
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Review CV risk annually
Full lipid profile annually
If history of elevated serum TG, perform full
fasting lipid profile
Target
Total cholesterol <4.0mmol/L
 LDL <2.0mmol/L
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Assess lipid profile and modifiable risk factors 13 months after starting therapy
Lipid Management in Diabetes
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Age <40yrs, poor CV risk – consider statin
Age 40yrs+, CV risk >20% /10yrs – offer statin
Age 40yrs +, high CV risk – offer statin
High serum TG ( >4.5mmol/l ) – offer fibrate.
If lifestyle and fibrate ineffective, consider trial
of omega 3
Simvastatin is first line statin
NICE Guidance
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Aspirin is not licensed for the primary
prevention of vascular events. If aspirin is used
in primary prevention, the balance of benefits
and risks should be considered for each
individual, particularly the presence of risk
factors for vascular disease (including conditions
such as diabetes) and the risk of gastrointestinal
bleeding.
Secondary prevention?
NICE Guidance 87
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Age 50+ and BP <145/90
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Offer low dose aspirin or if clear intolerance,
clopidogrel
Age <50yrs and significant other CV risk factors
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Offer low dose aspirin or if clear intolerance,
clopidogrel
Summary
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Lifestlye issues are key
Patient must be at centre of care
Many options for treatment
Optimise treatment before adding in other
medications
Always check compliance
Clear plan
Prescribing Teams
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Merthyr and Cynon
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Rhondda and Taf Ely
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Kate Spittle ( based at PCH )
Bev Woods ( based at RGH )
Please ask us for information / support