Type 2 Diabetes
SALLIANNE KAVANAGHLEADPHARMACIST-DIABETES AND ENDOCRINOLOGY SHEFFIELD TEACHING HOSPITALS- NHS FOUNDATION TRUST
Aims and Objectives
This session will outline the increasing complexities of diabetes care, and the factors that differentiate the combinations of therapy, allowing individualisation of diabetes treatment. At the end of this session participants will be able to:
Understand current national strategies, standards and priorities for diabetes care
Make recommendations for new therapies based upon
decisions by NICE, EASD and ADA
Identify the individual patient and economic factors that
play a part in treatment choices for diabetes management
Illustrate the pharmacy input necessary for delivery of a
pharmaceutical service to diabetic patients
Case Study One: Miss S
45 year old female with a 2 year history of type 2 diabetes
Takes metformin 1g BD BMI 29 kg/m2 HbA1c level of 97
mmol/mol (11%) What would be your
next therapeutic intervention be?
What did you consider?
Sulphonylurea DPP-4 inhibitor Pioglitazone GLP-1 agonist Insulin
Each drug has its own set of actions, side effects, cautions and contraindications that affect their suitability for this patient
Modes of Action
Complex range of receptors, mechanisms of action and side effects gives huge potential for individualisation of therapy as well as differing risks for separate patients
Figure 2:
http://www.eguidelines.co.uk/eguidelinesmain/gip/vol_12/sep_09/goenka_diabetes_sep09.php#.UlrEu VCkoiQ
NICE
Figure 3.
Does the guidance really
help?
With so many options what is really needed?
Once past metformin it starts to require individualisation and careful consideration of options
Guidance indicates what options are appropriate at each stage
It does not give definitive answers to individual situations
Big Opportunities
The complexity of treatment offers huge opportunity for pharmacist involvement
Our expertise in licensing, interactions, side effects and critical appraisal mean that we can offer advice on treatment options and medicines optimisation
It demands up to date knowledge but provides a chance for multi-disciplinary involvement
So, a little more about the
options
Advantages Things to consider Mode of action Side effects Patient choice Individualised therapyThe ‘old’ agents and NICE
The 1
stline agents
Biguanide Metformin Sulphonylureas Gliclazide, Tolbutamide, Glimepiride, Glipizide,Glibencla mide Insulin- Human Intermediate acting agents (Isophane)
UKPDS
RCTs show help
patients live
longer or better
lives
Patient
Orientated
Outcomes
(POO)
Medicines Optimisation
The newer agents are usually 3rd line
progression to triple therapy should not be automatic
Need to discuss adherence to medication MURs and NMS
Need to assess honestly if the prescribed agent is the most
appropriate for the patient
Lifestyle, adherence, personal goals, barriers and
expectations
Consider the risks and benefits of triple therapy
Note newer agents still awaiting long term
benefit data and patient orientated outcome
data
The ‘new’ agents
DPP-4 Inhibitors
Sitagliptin Vildagliptin Saxagliptin Linagliptin Alogliptin GLP-1 mimetics
Exenatide Liraglutide Lixisenatide Dulaglutide The Glitazones
Pioglitazone SGLT2
Dapagliflozin Canagliflozin Empagliflozin Concentrated insulin
Degludec 200units/ml Humalog 200units/ml Glargine 300units/mlThe Glitazones
Pioglitazone is the only licensed product
in the UK
Enhances the action of insulin on insulin
sensitive tissue
Activate nuclear transcription factor
PPAR
Turns genes on and off that regulate
increasing glucose uptake in skeletal muscle and adipose tissue
decrease hepatic glucose production
NICE – only continue if HbA1c reduction
0.5%
dual therapy with Mt or SU
triple therapy with Mt & SU
The Glitazones
Positives
Oral
Similar HbA1c
reduction as Mt
or SU
Metabolic
patients
Can be used with
insulin
With caution
Negatives
Lack of POO
evidence
Weight gain
Safety
concerns
Heart failure
Fractures
Bladder cancer
DPP-4 Inhibitors and
GLP-1 mimetics
Incretin hormones are released by the intestine during
meal digestion (glucogon like peptide 1GLP1)
The incretin hormones augment post prandial insulin
response
Potentiate nutrient induced insulin secretion in a glucose
dependent mannerlow risk of hypos between meals
Reduces glucagon secretion at high glucose
concentrations- but not low
Produces a weight reducing satiety effect
Incretin hormones are degraded by the enzyme
DPP-4 Inhibitors and GLP-1
mimetics
DPP-4 Inhibitors
Slow the degradation of endogenous circulating incretin
hormones- raise levels 2-3 fold
NICE- only continue treatment if HbA1c reduction 0.5%
Sitagliptin & Vildagliptin can be used as dual therapy with Mt
or SU
Sitagliptin can be used in in triple therapy and also with pioglitazone
Saxagliptin
Combination therapy with Mt&/Su Linagliptin- alternative excretion route
Monotherapy, combination (Mt or Mt/SU, insulin +/- Mt) Alogliptin
Broad vague licence- ‘in combination with other glucose lowering agents
DPP-4 Inhibitors
Positives
Oral
Similar HbA1c
reduction as glitazones
No weight gain
possible weight loss
exploit the ‘incretin
effect’, but not as much satiety as with the injectable
Minimal risk of
hypoglycaemia
(except if with SU)
Negatives
No long term safety data
all black triangle drugs Concerns re pancreatitis
No POO data Cost
Not as effective as
injected GLP-1 agonists
possibly due to these
being able to significantly increase circulating incretin hormones
GLP-1 mimetics
NICE can be used as triple therapy if meet BMI criteria NICE only continue if HbA1c reduction 1% and weight
loss of 3%
Exanatide
Twice daily ( within hour before meal) Once weekly depot
Liraglutide
Once daily
Limited role in dual therapy
Lixisenatide
Once daily- within hour before a meal Dulaglutide Once weekly
GLP1 mimetics
Positive Similar HbA1c reductions as insulin Weight lossexploits the ‘incretin
effect’ Range of products to meet individualised needs OD BD Weekly Negative Parenteral Safety concerns No long term safety data
Debate regarding
pancreatitis and pancreatic cancer
No POO data from RCTs Cost
Black triangle
Review in renal impairement
New Class: SGLT-2 Inhibitors
Indicated as monotherapy or in combination with a range
Figure 6: http://annualreport.boehringer-
ingelheim.com/research-development/industry-leading-SGLT2 Inhibitors
Insulin independent mechanism of action
Can be used as add on therapy to other glucose
lowering agents
To be used in same situation where you could have previously considered DPP-4s
Not Mt + SU combination
May be used with insulin +/- other OHGs
Can be used as a single agent if intolerant of
metformin
Inhibition of SGLT2 urinary excretion of 70g
glucose a day
HbA1C reductions
Weight loss
SGLT2 Inhibitors
Positive Oral
Once daily dosage for
dapagliflozin
Flat dosing schedule Similar HbA1c reduction as other
oral agents
No weight gain weight loss
3.7 kg average in combination with metformin
Over 5 kg difference compared to gain that occurs with SU Lower risk of hypoglycaemia
Compared with SU Not been associated with
increased CV events
Some modest BP benefits
Negative
No long term safety data all black triangle drugs No POO data
Cost?
Side effect profile
UTIs,genital infections, dysuria
and polyuria
Patient education, counselling
and expectation management important
Volume depletion reactions Small risk therefore not
recommended for use with Loop diuretics
DKA risk?
Patient Centred
Approach
ADA standards of care (2013) are even clearer on the need for
personailsation:
“The management plan should be formulated as a collaborative therapeutic alliance among the patient and the physician…. implementation of the management plan requires that the goals and treatment plan are individualized and take patient preferences into account. …. in developing the plan, consideration should be given to the patient’s age, school or work schedule and conditions, physical activity, eating patterns, social situation and cultural factors, and presence of complications of diabetes or other medical conditions.”
NICE quality standards advocate the patient at the centre of all
decisions:
“People with diabetes agree with their healthcare professional a documented personalised HbA1c target, usually between 48 and 58 mmol/mol and receive an ongoing review of treatment to minimise hypoglycaemia”
Hypoglycaemia
Predominantly the biggest side effect fear of both patients and professionals Can have a wide ranging impact on both patient lifestyle and overall glycaemic
control.
Figure 4: Hypoglycaemia Study Group. Diabetologia (2007). 50:1140-7
The risk of severe hypoglycaemia is no different in T2 diabetes treated with insulin or SUs. Mild hypoglycaemia is marginally less frequent (39% vs. 51%)
Hypoglycaemia with SUs
Figure 5: Diabetes, Obesity and Metabolism (2008). 10(s1): 1-7 Comparator groups:
•Metformin alone (Charpentier et al; Marre et al) •Metformin + nateglinide (Ristic et al)
•Metformin + sitagliptin (Nauck et al) •Metformin + rosiglitazone (Garber et al) •Metformin + pioglitazone (Matthews et al)
New drugs;
new difficulties
New medications are being added to the type 2 diabetes treatment arsenal on a regular basis
Current guidance is already out of date and cannot keep up with drug development
Requires a good understanding of new drug mechanism of actions and where they are intended to fit in the treatment schedule
New Insulin: Concentrated
insulin
Degludec: Launched January 2013
Very long half life (approx 25 hours) which provides a flat basal
profile and demonstrates benefit in nocturnal hypoglycaemia
Available in two strengths (U100 and U200) giving the first licensed
concentrated insulin in the UK market
Considerably more expensive than other analogue insulins Analogue insulins are not recommended for type 2 diabetes in
the QIPP agenda
Humalog 200units/ml
More concentrated version of standard humalog
Still to come….
Expected in next few years (2015-2018): CCX140-B (Immunomodulation) Ertugliflozin (SGLT-2 inhibitor) Once monthly exenatide Fasiglifam (GPR40 agonist) Buccal insulin
Transdermal insulin Biosimilar insulin products
Information from UKMI New Drugs online database:
http://www.ukmi.nhs.uk/applications/ndo/default.asp
Back to Miss S
45 year old female with a 2 year history of type 2 diabetes
Takes metformin 1g BD BMI 29 kg/m2 HbA1c level of 97
mmol/mol (11%) What would be your
next therapeutic intervention be?
Factors to consider
Hypoglycaemia risk –unlikely given current results Side effect risk –does she have side effects with
her current medications or risk for others
Renal and liver function –what is it currently and is
she at risk for AKI?
Lifestyle –likely the biggest focus for the patient.
Consider driving, children, diet, exercise etc
Fear of injections or tablet burden –an individual
situation
What will you chose now?
Case Studies
For each case study consider the individual patient factors that will affect your choices.
What is your key priority for each patient?
What other information do you want to know? Are there extra details you need to help make a decision?
Formulate a plan for counselling, follow-up, monitoring and titration for your drug of choice.
Consider the licensing, contra-indications and cautions and side-effects of your drug of choice and whether this would affect the decision made.
Mr P
65 year old male with a 7 year history of type 2 diabetes
Smokes 10 cigarettes a day (has smoked for 40 years)
Takes metformin 1g BD, gliclazide 80mg BD and pioglitazone 30mg OD BMI 27 kg/m2
HbA1c level of 79 mmol/mol (…%) PMH: AF, Heart failure (LVEF 50%) and CKD
2
What would be your next therapeutic intervention be?
Mrs D
40 year old female with a 1 year history of type 2 diabetes
Takes metformin 1g BD, gliclazide 160mg BD
PMH: Asthma BMI 39 kg/m2
HbA1c level of 67 mmol/mol (…%) What would be your next therapeutic
Mr G
85 year old male with a 15 year history of type 2 diabetes
Originally from Pakistan and lives with his daughter and her family
Takes metformin 1g BD, gliclazide 80mg BD and liraglutide 1.2mg OD
BMI 32 kg/m2
HbA1c level of 112 mmol/mol (…%) PMH: CKD 3b, hypertension, NSTEMI in 2011 What would be your next therapeutic
intervention be?
Summary
Treatment for type 2 diabetes is becoming more and more complex
Huge opportunity for pharmacist involvement to help manage the conflicting opinions on different drug classes.
Refer to national and international guidance for a steer on where different classes are
recommended
Refer to individual patient factors to make final decision on therapy that needs to be stopped and started
