Oral Treatments
for Type 2 Diabetesfor Type 2 Diabetes
Prescribing Support Pharmacist
Learning Outcomes
• Familiar with classes of oral hypoglycaemic agents
(OHAs) used in controlling blood glucose levels
– When to use each class
– Advice for patients
– Monitor for side effects– Monitor for side effects
• Brief overview of mechanism of action and
evidence base of OHAs
• Clinical Guidelines
• Take a moment to think..
• You have been diagnosed with diabetes...
• You have been told you need to go on
medication...medication...
• WHAT WOULD YOU LIKE YOUR MEDICATION
TO DO?
• WHAT WOULD BE YOUR CONCERNS?
A brief history of diabetes medication...
CrossCross--sectional median valuessectional median values
��Conventional Treatment (n=1138)Conventional Treatment (n=1138)
��Intensive Treatment (n=2729)Intensive Treatment (n=2729)
��99
��88
Me
dia
n A
1C
Me
dia
n A
1C
(%)
(%)
Type 2 Diabetes is a Progressive
Disease: UKPDS1
��Time From Randomisation (years)Time From Randomisation (years)
��88
��77
��66
��ADA targetADA target
��ADA actionADA action��suggestedsuggested
��00��00 ��33 ��66 ��99 ��1212 ��1515
��M
ed
ian
A1
CM
ed
ian
A1
C
� 2 Control BP
� 5 consider
tight glucose
� 4 Add metformin
� 3 Add statin
control� 1 Lifestyle
(exercise, diet,
stop smoking)
�Let’s give our
diabetic patients a
hand!
��Don’t turn the Don’t turn the
hand aroundhand around
Why is good glycaemic control
important?important?
Where does controlling Blood Glucose fit
into the picture?
• No arguments in favour of poor BG control
• Importantly data from RCTs, found no benefit and possible harm from tight BG control -target< 6.5mmol/l
• Achieving good BG control, while addressing lifestyle, BP, • Achieving good BG control, while addressing lifestyle, BP, and lipids will prevent more complications, than a narrower approach focused on intensive BG control
• Individualise treatment
• Agree targets with patient
When would you start
treatment?treatment?
NICE • Hba1c rises to > 48mmol/mol on lifestyle start tx
• Target 48mmol/mol (6.5%)- on diet plus one drug
not associated with hypoglycaemia
– If drug associated with hypos target 53mmol/mol
• 1st intensification: HBA1C > 58mmol/mol (7.5%)
• Target 53mmol/mol (7%)
• 2nd intensification: HBA1C > 58mmol/mol ,
• target 53mmol/mol
Legacy EffectHolman RR et al. 10 year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med
2008: Oct 9; 359: 1577
• In type 2 diabetes, early intervention with intensive glucose control has long-lasting effects still evident at 10+ years
• UKPDS Study - 5000 randomly assigned to • UKPDS Study - 5000 randomly assigned to conventional tx or tight control (median HBA1C 7 ) (Metformin if overweight, su or insulin )
• Differences in HBA1C disappeared 1yr after the trial. Macro- and microvascular benefits remained 10 years later
UKPDS: A 1% decrease in HbA1c is associated
with a reduction in complications
�43%
�37%
�HbA
�Microvascular complications e.g. kidney disease and blindness *
�Amputation or fatal peripheral blood vessel disease*
�Stratton IM, et al. BMJ 2000; 321: 405–412.
�21%
�14%
�12%
�HbA1
C
�1%
�* p<0.0001
�** p=0.035 �Stroke**
�Deaths related to diabetes*
�Heart attack*
Individualise targets
• 45yr old male, young family, works, T2D 1 yr, takes
metformin HBA1C 62mmol/mol
• Any comments on HBA1C and target?
• 80 year old male, T2D 10yr, takes metformin and
gliclazide, HBA1C 48mmol/mol,
• any comments on HBA1C and target?
What would you use as first line
treatment?treatment?
WHY?
Metformin –
• First line in combination with lifestyle
• Meformin mechanism of action:• Meformin mechanism of action:
– It helps to stop the liver producing new
glucose
– It helps to overcome insulin resistance by
making insulin carry glucose into muscle
cells more effectively.
Benefits of Metformin
• Cardiovascular benefits • UK Prospective Diabetes Study: http://www.dtu.ox.ac.uk/ukpds/)
• Can cause weight loss
• Does not cause hypos • Does not cause hypos
• Use in combination with any OHA
• On the market a long time
• Inexpensive
Contra-indications and cautions
• Avoid if Egfr < 30mls/min - Risk lactic acidosis (rare)
– Other conditions that increase risk of lactic acidosis
– Dehydration – diarrhoea,
– NSAIDs, ACE, diuretics – can all affect renal fn– NSAIDs, ACE, diuretics – can all affect renal fn
– Iodinated contrast media – can cause acute renal
impairment, stop metformin for 48hours, renal fn
checked ......
• Avoid in severe liver disease
Advice for patients
• Gastro-intestinal problems are common.
• Occur more than 1 in 10 people
• Let us know. We can try and help!
• Minimise - start on a low dose and increase slowly • Minimise - start on a low dose and increase slowly
take with food or after food,
– spread the dose – take twice daily
– usually go away after a few days
– reducing the dose
– MR prep could be considered (non-formulary)
• Other side effects -taste disturbance, low Vit B 12
When to intensify treatment?
• If HbA1c is still <53mmol/mol or if
individualised target is not met
• The addition of a second oral agent is likely to • The addition of a second oral agent is likely to
improve HbA1c by no more than 9.0 – 16mmol/mol
• Withdraw treatment after 6 months if HbA1c has
decreased by less than 6mmol/mol
Case 1
Mr Smith is a 52 year old teacher. Mr Smith was diagnosed with Type 2
diabetes 2 years ago. He is a car driver.
HbA1c last week was 70mmol/mol
Weight is 80kg, height 5’ 8”, BMI 31.8Weight is 80kg, height 5’ 8”, BMI 31.8
Current medication:
� Metformin 500mg at a dose of 1g twice daily.
�What second line OHA would you choose?
Options --
• A – Add a sulphonylurea?
• B - Add pioglitazone?
• C – Add Gliptin?
• D – SGLT2?• D – SGLT2?
• NO WRONG ANSWER
• Remember to
• A – Reinforce Lifestyle advice• A – Reinforce Lifestyle advice
• B - Add a statin
Sulphonylurea eg Gliclazide
• Can use 1st line if intolerant to metformin
• Can use in combination with all other OHAs
• Mechanism of action• Mechanism of action
– Stimulate pancreatic cells to make insulin.
• Reduction in hepatic glucose production
• Improvement in clearance of glucose.
Sulphonylureas
• Pros
– Confidence and experience in using
– Cheap (generic: £6 per month)
– Effective (mean 11mmol/mol reduction HbA1c)– Effective (mean 11mmol/mol reduction HbA1c)
– Minimal responder variability
• Cons
– Significant hypoglycaemia risk – BGM may be
appropriate for 1st three months
– Can’t be used in severe renal /liver impairment or – Can’t be used in severe renal /liver impairment or
if breast feeding
– Weight gain
– Poor durability
What to advise the patient
• Take with meals - Regular meals are important
• Alcohol – increased risk prolonged hypo
• Weight gain – average 1 – 2 kg
• Hypo – recognise, how to treat• Hypo – recognise, how to treat
• Blood Glucose Meter – when to monitor?
• Driving – important to career?
• Groups at increased risk of hypo – elderly, mild
renal or liver impairment
Pioglitazone – Thiazolidinediones
• Second line therapy – add to metformin
• Triple therapy - combination with other OHA
• Contra-indicated• Contra-indicated
– Heart failure
– Hepatic impairment
– History bladder cancer, uninvestigated haematurea
• Mechanism of action - Reduces insulin resistance
Pioglitazone - benefits
• Reduce insulin resistance – unique mechanism
of action and durable effect
• Proactive study - all cause mortality lower in • Proactive study - all cause mortality lower in
Piogliazone group group (26.8% v 34.3%)
• Iris study -Pioglitazone may reduce CV events
after a CVA
Pioglitazone – adverse effects
• Fluid retention – can precipitate heart failure
– Avoid in patients with a MI, angina,? Elderly
• Bone fractures–increase in men and women > 50yrs
• Macular oedema – report blurred vision
• Bladder cancer – risk low however risk increased
with length of treatment and higher dose
• Liver – reports hepatic failure – test lfts periodically
�Pioglitazone
�Experience, low cost,
�CVD event reduction in PROactive
�Weight gain,� fluid retention, fractures,
uncertain safety (bladder cancer?)
Advice for Patient
• Once daily, can take at any time of day
• Report any fluid retention, blurred vision
• Increased risk weight gain and fractures
• Bladder cancer – risk increased with duration
and larger dose
Follow up?
• Check HBA1C - has there been a 6mmol/mol
reduction?
• If not stop pioglitazone • If not stop pioglitazone
• Consider alternative strategies
DPP4 Inhibitors - Mechanism
• DPP4 inhibitors (gliptins) – Alogliptin, Linagliptin
1st line in NHSGGC. Other available DDP4s include
sitagliptin, vildagliptin & saxagliptin
• Second line therapy – in combination with • Second line therapy – in combination with metformin
• Triple therapy in combination with other OHA
DPP-4 inhibitors - pros
– Very low hypo risk
– Weight neutral
– Low side-effect profile
– No major adverse cardiovascular outcomes / heart
failure (apart from saxagliptin – increased risk
hospitalisation for heart failure esp if renal impairment)
DPP4 inhibitors – Cons– Expensive (around £30 per month)
– Less effective (mean 5mmol/mol reduction HbA1c)
– Responder variability
– No long term safety information
– Risk Pancreatitis – small– Risk Pancreatitis – small
– Adjust dose in renal impairment – linagliptin most
suitable in renal impairment
Advice for Patient
• Take at any time of the day
• Risk of hypo if on gliclazide or insulin
• Pancreatitis – inform patients about the
symptoms of pancreatitis (ie, severe,
persistent abdominal pain sometimes persistent abdominal pain sometimes
radiating to the back)
• Seek medical advice if this is suspected.
• Advise patient to return for HbA1c review in 3-
6 months and that drug will be stopped if no
therapeutic response.
SGLT-2 Inhibitors
Newest class of oral hypoglycaemic agent
All on NHSGGC total formulary –
• Canagliflozin (Ivokana ®) ▲• Canagliflozin (Ivokana ®) ▲
• Dapagliflozin (Forxiga ®) ▲
• Empagliflozin (Jardiance®) ▲
SGLT-2 inhibitors• Dual therapy with metformin
• Triple therapy
• Mechanism of action –
– inhibit SGLT2 protein – sodium-glucose transport protein – inhibit SGLT2 protein – sodium-glucose transport protein
helps reabsorb glucose into blood in kidney.
– By blocking these proteins, less glucose reabsorbed &
excess glucose is passed out in the urine
Benefits SGLTS
• Can help with weight loss
• Can be used at all stages of Type 2 Diabetes
• Low hypo incidence (risk if on SU or insulin)
• EMPA-REG OUTCOME
– Cardiovascular benefits –
– Diabetic kidney disease – reduced risk – EMPA-REG
OUTCOME the placebo group.
CV benefits – EMPA-REG• Patients studied - T2DM pts high CVD risk
• Empagliflozin ↓ 1y end point (CV death, nonfatal
MI and stroke) by 14%
– driven by a 38% ↓ in CV mortality
– 35% ↓ in hospitalizaQon for heart failure– 35% ↓ in hospitalizaQon for heart failure
• SGLT2 inhibitors - many metabolic benefits
– (↓ HbA1c, body weight, BP and an↑ HDL chol)
• CV benefits due to hemodynamic effects, - ↓ BP
and ↓ in extracellular volume.
Cardiovascular Outcome Trials
• Empa-reg trial - published 2016
– Evidence of improved CV outcomes with this drug,
significantly lower rate of mortality
– Trial in patients with exisiting cardiovascular co-– Trial in patients with exisiting cardiovascular co-
morbidities
• CANVAS trial – expected 2018
• DECLARE trial – expected 2019
SGLT2 – renal benefits
• Empagliflozin group had a significantly lower
risk of microvascular outcome events
– driven by a lower risk of progression of kidney
disease. disease.
• Empagliflozin group had a significantly lower
risk of progression to macroalbuminuria
• More work needs to be done
SGLT2s - cons• Increase frequency – one extra voiding per day
• Increased risk infections – eg thrush, utis
• Renal impairment – don’t start if Egfr < 60
• Less effective in impaired renal fn
• Can cause acute renal failure – monitor renal function • Can cause acute renal failure – monitor renal function
before initiation, before initiation on other drugs which
may reduce renal function and annually thereafter.
• DKA – at near normal blood glucose levels
• Stop before surgery, sick day rules
• Caution elderly – risk of volume depletion
– More adverse effects >75yrs
SGLT-2 inhibitors
Hepatic and Renal Function
MHRA advice on SGLT-2 inhibitors
and Ketoacidosis
• Serious, life-threatening, fatal cases of DKA
reported
• Test ketones if signs DKA regardless of Glucose conc
• Risk factors identified include• Risk factors identified include
– a low beta cell function reserve, off label use T1D
– Restricted food intake or severe dehydration
– Change in insulin requirements
– surgery
– alcohol abuse
MHRA advice on SGLT-2 inhibitors
and Ketoacidosis
• Advice for HCPs
– Educate patients on symptoms of DKA and what
to do if experiencing symptoms.
– Test for raised ketones in patients with – Test for raised ketones in patients with
ketoacidosis symptoms, even if plasma glucose
levels are near-normal.
– Report suspected side effects to SGLT2 inhibitors
or any other medicines on a Yellow Card
�SGLT2 inhibitors
�Cost, �genital fungal infections,
�risk of DKA, �long term safety uncertain
�Weight loss,
�hypoglycaema rare,
�reduced CV events
SGLT2s – Advice for patients
• Report any symptoms of DKA - rapid weight loss,
feeling or being sick, stomach pain, fast and deep
breathing, sleepiness, sweet smelling breath…
• Increase urinary frequency
• Increased risk of infection
• Risk of hypo if on SU or insulin
Sick Day Sick Day
Rules Rules --
SGLTsSGLTs
Two Infrequently used Oral
Type 2 Hypoglycaemic Drugs
• Alpha-Glucosidase Inhibitors (Acarbose)
• Meglitinides (Repaglinide & Nateglinide)• Meglitinides (Repaglinide & Nateglinide)
Acarbose (Glucobay®)
• alpha glucosidase inhibitors – Acarbose
• GG&C Formulary restricted to patients who cant tolerate Metformin
• Acarbose - slows absorption of starchy foods from the intestine.
• blood glucose levels rise more slowly after meals. • blood glucose levels rise more slowly after meals.
• Acarbose should always be chewed with the first mouthful of food or swallowed whole with a little liquid immediately before the meal.
• Main side-effects are flatulence and diarrhoea
Meglitinides (Repaglinide &
Nateglinide)
• Like the sulphonylureas, these stimulate the cells in the
pancreas to produce more insulin.
• However, unlike the sulphonylureas, they work very quickly
but only last for a short time and are given within half an hour
before each meal. before each meal.
• If a meal is missed, the dose must be omitted. These tablets
are taken up to three times daily.
• Not in GG&C Formulary
WHAT NEXT?
Consider adding a third oral medication?
Consider adding a injectable GPL1-agonist?
– Only if BMI >30kg/m2
Consider starting insulin therapy?Consider starting insulin therapy?
– Can cause weight gain and requires more
intensive BGM
Unpicking Polypharmacy – SCI Diabetes
In summary
• First line Metformin
• Second line – individualise therapy
• Review efficacy of drug treatment • Review efficacy of drug treatment
– Stop treatment if ineffective
• Targets – treat aggressively when first diagnosed
– Consider patient when setting targets
Taken from GG&C Diabetes Guideline available from http://www.nhsggc.org.uk
Taken from GG&C Diabetes Guideline available from http://www.nhsggc.org.uk
• GGC Formulary
http://www.ggcprescribing.org.uk/
• Clinical guidelines
http://www.staffnet.ggc.scot.nhs.ukhttp://www.staffnet.ggc.scot.nhs.uk
• SMC Advice
https://www.scottishmedicines.org.uk/SMC_Advice
/Advice_Directory/SMC_Advice_Directory
References
• GG&C Diabetes Guideline
Available at: http://www.ggcprescribing.org.uk
• SIGN 116 March 2010
Available at: www.sign.ac.uk
• Nice NG28 Dec 2015
Available at: www.nice.org.uk
• BNF 69 Sept 2015• BNF 69 Sept 2015
Available at: www.bnf.org
• The Scottish Medicines Consortium
Available at: www. http://www.scottishmedicines.org.uk
• Diabetes and Driving:
Available at: https://www.gov.uk/diabetes-driving
Case 1
Mr Smith is a 52 year old teacher. Mr Smith was diagnosed with Type 2
diabetes 2 years ago. He is a car driver.
HbA1c last week was 70mmol/mol
Weight is 80kg, height 5’ 8”, BMI 31.8Weight is 80kg, height 5’ 8”, BMI 31.8
Current medication:
� Metformin 500mg at a dose of 1g twice daily.
�What second line OHA would you choose?
• Would you choose anything different now?
Case 2
Mr Mackie is a 54 year old male with Type 2 diabetes. He has been
prescribed his current medications for the last 2 years and his HbA1c
has increased to 64mmol/mol.
Current Medication:
– Metformin 1000mg twice daily– Metformin 1000mg twice daily
Mr Mackie has a history of hypertension, MI, BMI 29, U/Es and lfts normal.
You are carrying out her annual diabetes review.
What would you suggest when reviewing his current
medication regimen?
Options --
• A – No change as well controlled
• B – Start new OHA and review in 3-6 months
• A – SU
• B – Pioglitazone
• C - DPP4 inhibitor
• D - SGLT2
Case 3
Miss Carter is a 84 year old lady who has had Type 2 diabetes since
she was 72. HBA1C 51mmol/mol, Egfr 40
• Current Medication:
– Metformin 1g twice daily
– Gliclazide 160mg twice daily– Gliclazide 160mg twice daily
– Sitaglipin 100mg daily
What else would you want to know?
Any suggested changes?
What to do with Miss Carter
Review patients HbA1c – risk of hypos?
Altered hypo awareness
Reduced appetite, weight loss
Drive? Check blood glucose? Drive? Check blood glucose?
Consider reduced renal function:
• Reduce dose of sitagliptin and metformin?
Any questions?