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. Type 2 Diabetes SALLIANNE KAVANAGH LEAD PHARMACIST - DIABETES AND ENDOCRINOLOGY SHEFFIELD TEACHING HOSPITALS- NHS FOUNDATION TRUST 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 What did you consider? 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 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 Which to choose?!?! 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 http://diabetesmanager.pbworks.com/w/page/17680289/oral%20pharmacological% 20Agents%20for%20Type%202%20Diabetes 1
NICE Figure 2: http://www.eguidelines.co.uk/eguidelinesmain/gip/vol_12/sep_09/goenka_diabetes_sep09.php#.ulreu VCkoiQ 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 therapy The old agents and NICE The 1 st line 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) 2
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/ml The Glitazones The 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 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 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 manner low 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 dipeptidyl dipeptidase4 DDP4 3
DPP-4 Inhibitors 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 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 GLP1 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 Positive Similar HbA1c reductions as insulin Weight loss exploits 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 SGLT2 Inhibitors Figure 6: http://annualreport.boehringeringelheim.com/research-development/industry-leadingdevelopment-of-oral-antidiabetes-drugs/ Indicated as monotherapy or in combination with a range of oral meds and insulin 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 a positive consequence not licensed for this 4
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 Hypoglycaemia with SUs 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. The risk of severe hypoglycaemia is no different in T2 diabetes treated with insulin or SUs. Figure 4: Hypoglycaemia Study Group. Diabetologia (2007). 50:1140-7 Mild hypoglycaemia is marginally less frequent (39% vs. 51%) 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 Insulin: Concentrated insulin 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 Complicated by local formulary guidance and specialist opinions 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 Lantus 300units/ml NOT the same as Glargine 100units/ml! Prolonged duration of action, smoother profile 5
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 Factors to consider Case Studies 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 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. What will you chose now? 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 Mrs D 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 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 6
Mr G Summary 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 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 7