1. Therapeutics in Diabetes
Kate Spittle
Prescribing Advisor
Cwm Taf LHB

2. Summary Issues around diabetes
Drugs used for control of hyperglycaemia
Monitoring of glucose control
NICE guidance
Hypertension in diabetes
Lipids
Aspirin
Questions

3. Diabetes 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

5. 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 )

6. !!

7. Realistic Plans?

8. Aims of Management Prevent diabetes Early detection
Lifestyle choices, minimise risk
Early detection
Fast, effective treatment
Live longer and healthier lives
Support living with diabetes
Patients are supported and informed to manage their diabetes

9. Type 2 Diabetes 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
Symptoms

10. Financial Costs 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

11. Treatment Aims Optimal glycaemic control Cardiovascular risk reduction
‘target’ HbA1c of <6.5 – 7.5% ( 48-59mmol )
Cardiovascular risk reduction
Minimise the risk of long term complications

12. Polypharmacy

13. Therapeutic Options 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 )

14. Biguanides - Metformin
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

15. Metformin 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 )

16. Metformin Side effects Contra-indications Nausea Vomiting Diarrhoea
Anorexia
Bloating and discomfort
Metallic taste
B12 malabsorption
Lactic acidosis ( rare )
Contra-indications
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 )

17. Metformin 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

18. How much do you think we spend on Metformin in Cwm Taf?.

19. Usage of Metformin in Cwm Taf

20. Sulfonylureas
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

21. Sulfonylureas Side effects Contra-indications Disadvantage
Hypoglycaemia
Weight gain
GI disturbance
Headache
Fever
Jaundice
Blood dyscrasias
Contra-indications
Pregnancy
breast feeding
Renal impairment
Hepatic impairment
Disadvantage
Accelerates decline in beta cell function

22. Sulfonylureas
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

23. Gliclazide 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

24. Usage of Sulfonylureas in Cwm Taf

25. Thiazolidinediones Pioglitazone
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

26. Pioglitazone Side effects Contra-indications GI disturbance
Weight gain
Fluid retention
Dizziness
Headache
anaemia
Contra-indications
Pregnancy
Breastfeeding
Hepatic impairment
Cardiac failure

27. Pioglitazone
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

28. Pioglitazone Cardiovascular safety (Dec 07,Jan 11)
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 )
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

29. Pioglitazone 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

30. Metiglinides Prandial Glucose Regulators
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%

31. Metiglinides Side effects Contra-indications
Hypoglycaemia
Nausea
Vomiting
Constipation
Diarrhoea
Rash
pruritus
Contra-indications
Severe hepatic impairment
Pregnancy
Breast feeding
Surgery – omit on morning of surgery and recommence when eating and drinking normally

32. Metiglinides Nateglinide Repaglinide
Adult, initially 60mg three times a day within 30mins of main meal.
Adjust according to response
Max 180mg three times a day
Repaglinide
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

33. Acarbose Slows rate of carbohydrate absorption
Reduces post prandial hyperglycaemia
Reduces HbA1c ~0.8%
Rarely used in UK due to GI side effects
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

34. The Sugar Coated Pill?

35. Progressive Defects in Type 2 Diabetes
Progressive decline in beta cell function
Inadequate insulin secretion
Unsuppressed post prandial glucagon secretion

36. GLP – 1 Enzyme GLP -1 secretion is impaired in type 2 diabetes
Activation of the GLP-1 receptor
increases insulin secretion
Suppresses glucagon secretion
Slow gastric emptying
Exenatide and Liraglutide both bind to and activate the GLP-1 receptor
The gliptins block DPP-4, the enzyme that degrades GLP-1

37. Exenatide
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?

38. Exenatide 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

39. Exenatide Usage in Cwm Taf

40. Liraglutide 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

41. Liraglutide Usage in Cwm Taf

42. Exenatide / Liraglutide
Side effects
GI effects
Decreased appetite
Weight loss
Headache
dizziness
Contra – indications
Severe GI disease
Pregnancy
Pancreatitis
Severe renal impairment

43. Issues
Long term safety data
Injection
Cost - expensive

44. DPP-4 Inhibitors ( Gliptins )
Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin
Increase insulin sectrion
Lower glucagon secretion
Have theoretical advantages of SU’s but no long term safety data
Expensive

45. DPP-4 Inhibitors Side effects Contra-indications GI disturbance Oedema
URTI’s
Anorexia
Headache
hypoglycaemia
Contra-indications
Renal impairment ( check gliptin used )
Pregnancy
Breast feeding

46. 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

47. Therapeutic Options Lots of choices NICE guidance – see flow chart
Metformin
Dual therapy
Triple therapy
Check licensing for combinations
Cost
Monitoring

48. Monitoring Response Minimum – annual review HbA1c BP Lipid profile
< % BP
<130/80
Lipid profile
Chol <4, LDL <2
Lifestyle interventions

49. Self Monitoring Self care – vitally important in diabetes
Should be available ( NICE )
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?

50. 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 )

52. Blood Glucose Testing in Cwm Taf

53. NICE Guidance Clinical guideline 87 Management of hypertension
Management of lipids
Aspirin

54. Management of Hypertension in Diabetes
Targets
If kidney, eye or cerebrovascular damage <130/80
Others 140<80
If hypertensive and BP target is reached, monitor every 4-6 months
Measure BP annually if not hypertensive or with renal disease

55. Hypertension in Diabetes
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)

56. Lipid Management in Diabetes
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
Assess lipid profile and modifiable risk factors 1-3 months after starting therapy

57. Lipid Management in Diabetes
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

58. NICE Guidance
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?

59. NICE Guidance 87 Age 50+ and BP <145/90
Offer low dose aspirin or if clear intolerance, clopidogrel
Age <50yrs and significant other CV risk factors

60. Summary 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

61. Prescribing Teams Merthyr and Cynon Rhondda and Taf Ely
Kate Spittle ( based at PCH )
Rhondda and Taf Ely
Bev Woods ( based at RGH )
Please ask us for information / support