Download DPP-4 Inhibitors (Gliptins)

Oral Treatments
for Type 2 Diabetes
Prescribing Support Pharmacist
Learning Outcomes
• Recognise the different oral agents used in
controlling blood glucose levels
• Describe the pharmacological effects of the
agents
• Explain the side effects of the agents
• Understand the rationale for clinical guidelines
Black Triangle▲
• ▲Identifies preparations in the BNF that
require additional monitoring by the European
Medicines Agency
• All suspected adverse reactions should be
reported by the yellow card scheme to the
Commission on Human Medicines:
www.yellowcard.gov.uk
Type 2 Diabetes is a Progressive
Disease: UKPDS1
Cross-sectional median values
Treatment (n=1138)
Intensive Treatment (n=2729)
Median
A1C (%)
Conventional
9
8
ADA action
suggested
7
ADA
target
6
0
0
3
Time
6
9
12
From Randomisation (years)
15


2 Control BP
3 Add statin

4 Add metformin
5 consider
tight glucose
control

1 Lifestyle
(exercise, diet,
stop smoking)

Don’t
Let’s
give our
diabetic patients a
hand!
turn the
hand around
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,
and lipids will prevent more complications, than a
narrower approach focused on intensive BG control
• Individualise treatment
• Agree targets with patient
Why is good glycaemic control
important?
Microvascular
Complications
Macrovascular
Complications
Stroke
Diabetic
Retinopathy
Leading cause of
blindness in
working-age adults1
Diabetic
Nephropathy
Leading cause of
end-stage renal
disease2
2-
to 4-fold increase
in cardiovascular
mortality and stroke4,5
Heart
Disease6
Diabetic
Neuropathy
Leading cause of
nontraumatic lower
extremity
amputations3
All
Peripheral
Vascular
Disease6
references last accessed April 2012: 1. IDF. Fact Sheet Diabetes and Eye Disease. Available at:
http://www.idf.org/node/1186?unode=C1CCADE9-4A03-4D17-A662-155B3ED59FDB. 2. The Renal Association. UK Renal Registry. Twelfth
Annual Report. December 2009. Available at http://www.renalreg.com/Reports/2009.html. 3. Dang, CN., Boulton, AJ., International Journal of
Lower Extremity Wounds. 2003; 2(1):4-12. 4. Jeerakathil, T., et al. Stroke. 2007;38(6):1739-43. 5. Kaul, S., et al. Circulation. 2010;121:186877. 6. IDF. Fact sheet: Diabetes and Cardiovascular Disease (CVD). Available at: http://www.idf.org/fact-sheets/diabetes-cvd.
Glucose Homeostasis
Biguanides - Metformin
Metformin
• 1st choice in obese patients - helps weight loss and
rarely causes hypoglycaemia, as it does not stimulate
insulin secretion
• Side-effects: GI upset (anorexia, nausea, vomiting,
diarrhoea), B12 malabsorption, and very rarely lactic
acidosis
• Renal impairment – dose should be reduced
• Can be used alone or in combination with any other
oral hypoglycaemic agent or insulin
Metformin
• If HbA1c remains at or below 53mmol/mol on Metformin
continue to review the patient 6 monthly
• Metformin has been shown to reduce CVD events
(UK Prospective Diabetes Study: http://www.dtu.ox.ac.uk/ukpds/)
• Has favourable effects on lipid metabolism – it reduces total
cholesterol, LDL cholesterol and triglyceride levels
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
improve HbA1c by no more than 9.0 – 16mmol/mol
• Withdraw treatment after 6 months if HbA1c has
decreased by less than 6mmol/mol
Options for second line drug therapy
•
•
•
•
Sulphonylurea
Pioglitazone
Gliptin (DPP-4 inhibitor)
SGLT-2 ▲
• Consider individual patient factors and contraindications
Sulphonylureas
Sulphonylureas
• Side-effects: GI, weight gain, hypoglycaemia
• Caution in hepatic/renal impairment (increased
chance of hypos). If hepatic/renal impairment is
severe - Avoid
• Contra-indicated: Pregnancy, breastfeeding, acute
porphyria, ketoacidosis
Sulphonylureas
• Pros
–
–
–
–
Confidence and experience in using
Cheap (generic: £6 per month)
Effective (mean 1% reduction HbA1c)
Minimal responder variability
• Cons
– Significant hypoglycaemia risk – BGM may be
appropriate for 1st three months
– Weight gain
– Poor durability
Thiazolidinediones (Glitazones)
Pioglitazone
• Side-effects
GI, weight gain, hypoglycaemia (rarely). It is associated with fluid
retention and has precipitated heart failure and pulmonary oedema
in patients at risk
• Cautions
– Monitor liver function: Check LFT’s before use and periodically
thereafter
• Contra-indications
– Hepatic impairment
– Pregnancy and breast-feeding
– Previous or active bladder cancer
Pioglitazone and Heart Failure
• PROactive Study
• Cardiac failure risk 39% higher in Pioglitazone
group compared to placebo. (5.7% v 4.1%)
• Of those with serious heart failure mortality
due to heart failure similar in both groups
• And all cause mortality lower in Pio group
(26.8% v 34.3%)
Pioglitazone & bladder cancer
Risk of Bladder Cancer July 2011:
• The European Medicines Agency has advised
that there is a small increased risk of bladder
cancer associated with pioglitazone use
• However, in patients who respond adequately
to treatment, the benefits of pioglitazone
continue to outweigh the risks
Pioglitazone and bone fractures
• 39% increased incidence of fractures in men
and women on TZDs.
• Increased incidence in all women and in men
> 50 years.
DPP-4 inhibitors (Gliptins)
DPP-4 inhibitors work by blocking the action of DPP4, an enzyme which destroys the hormone incretin.
DPP-4 Inhibitors (Gliptins)
Preferred List:
• Sitagliptin (Januvia®) – 1st choice
• Linagliptin (Trajenta®) ▲
Total Formulary:
• Saxagliptin (Onglyza®)
• Vildagliptin (Galvus®)
• Alogliptin (Vipidia®) ▲
DPP-4 inhibitors (Gliptins)
• Monotherapy – only if metformin or SU contraindicated
or not tolerated
• Combination with a sulphonylurea is restricted to
patients in whom metformin is contraindicated or not
tolerated.
• Combination with both metformin and a sulphonylurea
(i.e triple therapy) restricted to patients who are
inadequately controlled on max tolerated doses of
metformin and sulphonylurea.
• NB: dose of concomitant Sulphonylurea or insulin may
need to be reduced
DPP-4 inhibitors (Gliptins)
• Pros
– Very low hypo risk
– Weight neutral
– Low side-effect profile
• Cons
– Expensive (around £30 per month)
– Less effective (mean 1% reduction HbA1c)
– Responder variability
– No long term safety information
DPP-4 Inhibitors (Gliptins)
• Side-effects-GI disturbance, peripheral
oedema
• Caution: elderly
• Contra-Indications: Ketoacidosis, pregnancy,
breast feeding. Doses may need adjusted in
renal or hepatic impairment
SGLT-2 inhibitors
SGLT-2 Inhibitors
All on NHSGGC total formulary • Canagliflozin (Ivokana ®) ▲
• Dapagliflozin (Forxiga ®) ▲
• Empagliflozin (Jardiance®) ▲
SGLT–2 Inhibitors
• NOT recommended for monotherapy
• Restricted to initiation by clinicians
experienced in the management of diabetes
for the indications
• Side effects – constipation, genital infection,
nausea, polyuria, thirst, urinary frequency, UTI
SGLT–2 Inhibitors
• Pros
– Weight loss
– Very low hypo rate
– Effective at all stages of diabetes
• Cons
–
–
–
–
–
High cost
Urinary tract infections
Genital thrush
No long term safety information
Not licensed in eGFR <60mls/min
SGLT-2 inhibitors
Hepatic and Renal Function
MHRA advice on SGLT-2 inhibitors
and Ketoacidosis
• SGLT2 inhibitors are licensed for use in adults
with type 2 diabetes to improve glycaemic
control.
• Serious, life-threatening, and fatal cases of
DKA have been reported in patients taking an
SGLT2 inhibitor.
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
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
Two Infrequently used Oral
Type 2 Hypoglycaemic Drugs
•
Alpha-Glucosidase Inhibitors (Acarbose)
•
Meglitinides (Repaglinide & Nateglinide)
Acarbose (Glucobay®)
• The largest evidence base for the alpha glucosidase inhibitors
is with Acarbose and its in the GG&C Formulary restricted to
patients who cant tolerate Metformin
• Acarbose works by slowing down the absorption of starchy
foods from the intestine. This means that 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.
• 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?
DEPENDS ENTIRELY ON YOUR PATIENT...
Consider adding a third oral medication?
– Only likely to be effective if HbA1c is < 86
mmol/mol
Consider adding a injectable GPL1-agonist?
– Only if BMI >30kg/m2
Consider starting insulin therapy?
– Can cause weight gain and requires more
intensive BGM
Glucagon-Like Peptide-1 (GLP-1)
analogues
This type of medication works by increasing the
levels of hormones called ‘incretins’. These
hormones help the body produce more insulin only
when needed and reduce the amount of glucose
being produced by the liver when it’s not needed.
They reduce the rate at which the stomach digests
food and empties, and can also reduce appetite.
Glucagon-Like Peptide-1 (GLP-1)
analogues
5 GLP-1 analogues which have been approved by SMC for use in
NHSScotland Exenatide (Byetta®) - Twice daily s/c injections
Exenatide (Bydureon®) - Once weekly s/c injection
Liraglutide (Victoza®) - Once daily s/c injections
Lixisenatide (Lyxumia®) – Once daily s/c injections
Albiglutide (Eperzan®) – Once weekly s/c injection
Dulaglutide (Trulicity®) – Once weekly s/c injection
The Introduction of Insulin
• If there is suboptimal control with two (or
three) oral hypoglycaemic agents or if dual
therapy is contraindicated then insulin should
be introduced with one oral hypoglycaemic
agent, preferably metformin
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.uk
• SMC Advice
https://www.scottishmedicines.org.uk/SMC_Advice
/Advice_Directory/SMC_Advice_Directory
Driving and Type 2 Diabetes
• For further information see:
NHSGGC Self-monitoring of Blood Glucose
Guidelines
or
https://www.gov.uk/diabetes-driving
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
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 man who drives long distances in lorries for a living.
Mr Smith is a smoker and was diagnosed with Type 2 diabetes 5 years ago.
HbA1c last week was 70mmol/mol
Current medication:
 Metformin 500mg at a dose of 1g twice daily
• Do you want to change or add to Mr Smiths medication regimen?
• Discuss the options available and what medications you might add to his
current regimen.
What to do with Mr Smith
• Move to second line based on HbA1c being
>53mmol/mol
– Gliclazide not selected based on occupational
hazards with hypoglycaemia risk
Suitable options remaining:
– Glitazone
– Gliptin
– SGLT-2
Case 2
Mrs Mackie is a 78 year old lady with Type 2 diabetes. She has been
prescribed her current medications for the last 7 years and her HbA1c
has been stable under 53mmol/mol.
Current Medication:
– Metformin 1000mg twice daily
– Gliclazide 80mg twice daily
– Pioglitazone 30mg daily
Mrs Mackie has developed osteoporosis and has also suffered from an MI
with resulting Heart Failure NYHA Class 2 in the past 3 years.
You are carrying out her annual diabetes review. Are there any
considerations you may need to make when reviewing her current
medication regimen?
What to do with Mrs Mackie
• Pioglitazone
– Contra-indicated in Heart Failure
– Caution in osteoporosis as can increase the risk of
fractures
• Stop Pioglitazone
• Consider commencing Gliptin or SGLT2
Case 3
Miss Carter is a 84 year old lady who has had Type 2 diabetes since
she was 72.
• Current Medication:
–
–
–
–
Metformin 1g twice daily
Gliclazide 40mg twice daily
Empagliflozin 25mg once daily
Renal Function is being monitored by the practice nurse and has noted to be
falling. Most recently it is 53ml/min
What else would you want to know?
What do you do?
What to do with Miss Carter
Consider reduced renal function:
• If falling persistently below 60ml/min reduce dose to
10mg once daily. Stop if eGFR reduces below 45ml/min
Review patients HbA1c – does she need all this medication
for type 2 diabetes, often patients lose weight as they get
older and more frail therefore her HbA1c may be
reducing based on this.