1. Drugs for Type 2 Diabetes – where next after metformin ?
Dr Emily McMurray
Western General Hospital

2. Overview What are the drug options? What do the guidelines say?
Gliclizide, glipizide (SU)
Pioglitazone (TZDs)
Sitagliptin (DPP4 inhibitor)
Dulaglutide (GLP-1 receptor agonist)
Empagliflozin (SGLT2 inhibitor)
What do the guidelines say?
What about in our everyday practice?

3. A lot has changed! 1993 guidelines were simple
Start with metformin – unless fasting sugar >13
If that’s not enough add SU
If that’s not enough, stop them both and start insulin
Easy to remember, but not very patient- centred

4. Not everything has changed
Metformin is still first line
Stop if eGFR <30
Ask patient to stop it if at risk of dehydration, ongoing D+V – “sick day rules”

5. Sulphonylurea
Increase insulin secretion, regardless of blood glucose level
Pros:
Effective
Symptomatic relief
Extensive experience
Cheap

6. The downsides Weight gain Glucose monitoring Hypoglycaemia
Reduce dose in renal impairment
Avoid in hepatic failure

7. Pioglitazone Was the first of the “new” drugs
Reduces insulin resistance
Pros:
Effective
Rare hypoglycaemia
Sustained improvements in HbA1c
Cardiovascular benefits?
If HbA1c > 48mmol/mol after dietary input

8. The downsides Heart failure Fracture risk Bladder cancer
Hepatic impairment
Weight gain

9. sitagliptin Blocks the enzyme which breaks down GLP1
Increases insulin and decreases glucagon relative to plasma glucose
Moderate efficacy
Pros
Safe in renal impairment Weight neutral
Little hypo risk ??CV event reduction
Cons
GI side effects cost

10. dulaglutide GLP1 receptor agonist More effective than sitagliptin Pros
Increases insulin and decreases glucagon relative to blood glucose
More effective than sitagliptin
Pros
Weight loss often seen
Not associated with hypos
Study with liraglutide (daily) showed reduction in CV event rate and mortality

11. The downside Injectable medication Major hurdle for some patients
Extra training requirements
GI side effects
? pancreatitis

12. Empagliflozin SGTL2 inhibitor
Acts at kidney to prevent glucose resorption
Glycosuria and polyuria
Moderately effective (~7mmol/mol)
Pros:
Weight loss
BP reduction
Not associated with hypos
CV mortality improved

13. Empagliflozin EMPA-REG Published Nov 2015 (7000 pts, 3 years)
T2DM with established cardiovascular disease
Added to standard care
38% reduction in cardiovascular outcomes (death)
35% reduction in hospitilisation due to heart failure
32% reduction in death by any cause

14. SGLT2 inhibitors – the downside
Polyuria
Care with hypovolaemia / loop diuretics / pioglitazone
Genital infections
Cannot be given to >85 years
Cannot be used if eGFR<45
Cannot be initiated if eGFR<60
Risk of DKA with normal blood sugars – patients require to be counselled on symptoms to be aware of
Cost

15. What do the guidelines say?
SIGN, NICE, joint ADA/European society
All recognise that combination therapy is often required
No hard and fast rules as to which drug and when

16. Ideal Algorithm
Reality

17. Choosing a 2nd or 3rd line agent
If HbA1c rises to 48 mmol/mol (6.5%) on lifestyle interventions: ·
Offer standard–release metformin
· Support the person to aim for an HbA1c level of 48 mmol/ mol (6.5%)
FIRST INTENSIFICATION If HbA1c rises to 58 mmol/mol (7.5%): ·
Consider dual therapy with: -
metformin and a DPP-4i –
metformin and pioglitazone
metformin and an SU
metformin and an SGLT-2ib ·
Support the person to aim for an HbA1c level of 53 mmol/ mol (7.0%)

18. There’s more!
SECOND INTENSIFICATION If HbA1c rises to 58 mmol/mol (7.5%): · Consider: - triple therapy with:
metformin, a DPP4 and an SU
metformin, pioglitazone and an SU
metformin, pioglitazone or an SU, and an SGLT-2
insulin-based treatment ·
Support the person to aim for an HbA1c level of 53 mmol/ mol (7.0%)
If standard-release metformin is not tolerated, consider a trial of modified–release metformin
If triple therapy is not effective, not tolerated or contraindicated, consider combination therapy with metformin, an SU and a GLP-1 mimeticc for adults with type 2 diabetes who: - have a BMI of 35 kg/m2 or higher (adjust accordingly for people from black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or - have a BMI lower than 35 kg/m2, and for whom insulin therapy would have significant occupational implications, or weight loss would benefit other significant obesity- related comorbidities

19. Drug choice is patient centred
Effectiveness
Safety
Impact on weight
Hypoglycaemia risk
Co-morbidities
Polypharmacy
Patient preference
Combination products
Cost

20. Some patient scenarios
82 year old man
Tolerating metformin but HbA1c 82mmol/mol
Target sugars 8-14mmol/l
Still active – walks to the park via newsagents daily
Renal dysfunction: eGFR 52

21. considerations Hypo risk in the elderly Renal impairment
HbA1c target is not as low as 53mmol/mol
Avoid osmotic symptoms and hypos

22. considerations Hypo risk in the elderly Renal impairment
HbA1c target is not as low as 53mmol/mol
Avoid osmotic symptoms and hypos
2nd line: Sitagliptin
3rd line if symptomatic: low dose SU

23. Lost 2kg following dietary advice Metformin 1g BD
Man in his 30s
BMI 23kg/m2
Lost 2kg following dietary advice
Metformin 1g BD
HbA1c 70mmol/mol

24. Lost 2kg following dietary advice Metformin 1g BD
Man in his 30s
BMI 23kg/m2
Lost 2kg following dietary advice
Metformin 1g BD
HbA1c 70mmol/mol

25. Lost 2kg following dietary advice Metformin 1g BD
Man in his 30s
BMI 23kg/m2
Lost 2kg following dietary advice
Metformin 1g BD
HbA1c 60mmol/mol
2nd line: SU
3rd line………insulin

26. Trying hard to lose weight – HbA1c 67mmol/mol
Woman in her 40s
BMI 37kg/m2
Trying hard to lose weight –
managed 3Kg with great difficulty
HbA1c 67mmol/mol

27. Trying hard to lose weight – HbA1c 67mmol/mol
Woman in her 40s
BMI 37kg/m2
Trying hard to lose weight –
managed 3Kg with great difficulty
HbA1c 67mmol/mol

28. Trying hard to lose weight – HbA1c 67mmol/mol
Woman in her 40s
BMI 37kg/m2
Trying hard to lose weight –
managed 3Kg with great difficulty
HbA1c 67mmol/mol
Not keen on possible weight gain with SU or pio, but would be prepared to inject
2nd line by current guidelines: sitagliptin
GLP-1 agonist would offer best HbA1c results with weight loss
SGLT2 also good option

29. On met 1g BD, gliclazide 80mg BD HbA1c 62mmol/mol Wary of injections
68y old woman
On met 1g BD, gliclazide 80mg BD
Has had hypos on active days
HbA1c 62mmol/mol
Wary of injections
Has hypertension on 2 agents

30. On met 1g BD, gliclazide 80mg BD HbA1c 66mmol/mol BMI 32kg/m2
68y old woman
On met 1g BD, gliclazide 80mg BD
Has had hypos on active days
HbA1c 66mmol/mol
BMI 32kg/m2
Wary of injections
Has hypertension on 2 agents
3rd line empagliflozin
CV benefits

31. 3 year history of diabetes Couldn’t tolerate metformin
67year old man
3 year history of diabetes
Couldn’t tolerate metformin
Terrible diarrhoea
On maximal dose SU, but HbA1c 63mmol/mol
No Hx CCF
Urine dip clear

32. 3 year history of diabetes Couldn’t tolerate metformin
67year old man
3 year history of diabetes
Couldn’t tolerate metformin
Terrible diarrhoea
On maximal dose SU, but HbA1c 63mmol/mol
No Hx CCF
Urine dip clear

33. 3 year history of diabetes Couldn’t tolerate metformin
67year old man
3 year history of diabetes
Couldn’t tolerate metformin
Terrible diarrhoea
On maximal dose SU, but HbA1c 82mmol/mol
No Hx CCF
Urine dip clear
2nd line pioglitizone
without met no treatment
targeting IR

34. Monitoring / Effectiveness
At 6 months after change in therapy
Check HbA1c / therapeutic response
Check renal function
Discuss sick day rules

35. Summary Our options for treatment in T2DM so much wider than before
Metformin is first line
Subsequent choices influenced by many factors
HbA1c
Hypos
Weight
Co-morbidity
Side effects
Age
Duration of diabetes

36. SU TZDs DPP4 SGLT2 GLP1 insulin Efficacy High Intermed Highest
Hypo risk
Mod
low
Low
Weight
gain
neutral
loss
Gain
s/e
hypo
CCF, #
Bladder Ca
rare
GU, dehydration GI
hypos
cost
high