Oral Treatments for Type 2 Diabetes

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Oral Treatments for Type 2 Diabetes

• Prescribing Support Pharmacist

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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

3
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

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Type 2 Diabetes is a ProgressiveDisease UKPDS1
Cross-sectional median values

• Conventional Treatment (n1138)

• Intensive Treatment (n2729)

• 9

• 8

• ADA action

• suggested

• Median A1C ()

• 7

• ADA target

• 6

• 0

• 0

• 3

• 6

• 9

• 12

• 15

• Time From Randomisation (years)

5

• 3 Add statin

• 4 Add metformin

• 2 Control BP

• 5 consider tight glucose control

• 1 Lifestyle (exercise, diet, stop smoking)

• Dont turn the hand around

• Lets give our diabetic patients a hand!

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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 -targetlt
  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

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Why is good glycaemic control important?
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• Microvascular Complications

• Macrovascular Complications

• Stroke
• 2- to 4-fold increase in cardiovascular mortality
  and stroke4,5

• Diabetic Retinopathy
• Leading cause of blindness in
• working-age adults1

• Diabetic Nephropathy Leading cause of
• end-stage renal disease2

• Heart Disease6

• Diabetic Neuropathy
• Leading cause of nontraumatic lower extremity
  amputations3

• Peripheral
• Vascular Disease6

• All references last accessed April 2012 1. IDF.
  Fact Sheet Diabetes and Eye Disease. Available
  at http//www.idf.org/node/1186?unodeC1CCADE9-4A
  03-4D17-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.
  200738(6)1739-43. 5. Kaul, S., et al.
  Circulation. 20101211868-77. 6. IDF. Fact
  sheet Diabetes and Cardiovascular Disease (CVD).
  Available at http//www.idf.org/fact-sheets/diabe
  tes-cvd.

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Glucose Homeostasis
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Biguanides - Metformin
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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

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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

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When to intensify treatment?

• If HbA1c is still lt53mmol/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

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Options for second line drug therapy

• Sulphonylurea
• Pioglitazone
• Gliptin (DPP-4 inhibitor)
• SGLT-2 ?
• Consider individual patient factors and
  contra-indications

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Sulphonylureas

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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

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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

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Thiazolidinediones (Glitazones)
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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 LFTs before use
  and periodically thereafter
• Contra-indications
• Hepatic impairment
• Pregnancy and breast-feeding
• Previous or active bladder cancer

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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)

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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

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Pioglitazone and bone fractures

• 39 increased incidence of fractures in men and
  women on TZDs.
• Increased incidence in all women and in men gt 50
  years.

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DPP-4 inhibitors (Gliptins)

• DPP-4 inhibitors work by blocking the action of
  DPP-4, an enzyme which destroys the hormone
  incretin.

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DPP-4 Inhibitors (Gliptins)

• Preferred List
• Sitagliptin (Januvia) 1st choice
• Linagliptin (Trajenta) ?
• Total Formulary
• Saxagliptin (Onglyza)
• Vildagliptin (Galvus)
• Alogliptin (Vipidia) ?

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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

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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

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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

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SGLT-2 inhibitors
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SGLT-2 Inhibitors

• All on NHSGGC total formulary -
• Canagliflozin (Ivokana ) ?
• Dapagliflozin (Forxiga ) ?
• Empagliflozin (Jardiance) ?

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SGLT2 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

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SGLT2 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 lt60mls/min

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SGLT-2 inhibitorsHepatic and Renal Function
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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.

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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

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Two Infrequently used Oral Type 2 Hypoglycaemic
Drugs

• Alpha-Glucosidase Inhibitors (Acarbose)
• Meglitinides (Repaglinide Nateglinide)

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Acarbose (Glucobay)

• The largest evidence base for the alpha
  glucosidase inhibitors is with Acarbose and its
  in the GGC 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

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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 GGC Formulary

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Depends entirely on your patient...

• What next?

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• Consider adding a third oral medication?
• Only likely to be effective if HbA1c is lt 86
  mmol/mol
• Consider adding a injectable GPL1-agonist?
• Only if BMI gt30kg/m2
• Consider starting insulin therapy?
• Can cause weight gain and requires more intensive
  BGM

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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 its not needed.
  They reduce the rate at which the stomach digests
  food and empties, and can also reduce appetite.

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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

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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

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Taken from GGC Diabetes Guideline available from
http//www.nhsggc.org.uk
45
Taken from GGC Diabetes Guideline available from
http//www.nhsggc.org.uk
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• 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/Ad
  vice_Directory/SMC_Advice_Directory

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Driving and Type 2 Diabetes

• For further information see
• NHSGGC Self-monitoring of Blood Glucose
  Guidelines
• or
• https//www.gov.uk/diabetes-driving

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References

• GGC 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.o
  rg.uk
• Diabetes and Driving
• Available at https//www.gov.uk/diabetes-driving
  

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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.

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What to do with Mr Smith

• Move to second line based on HbA1c being
  gt53mmol/mol
• Gliclazide not selected based on occupational
  hazards with hypoglycaemia risk
• Suitable options remaining
• Glitazone
• Gliptin
• SGLT-2

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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?

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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

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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?

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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.