The Optimisation and Intensification of Insulin Therapy in Type 2 Diabetes Speaker name and affiliation UKDBT01539 September 2013 Prescribing information is available on the last slide.

Intensification of insulin therapy When current regimen is failing to achieve goals of therapy

Agenda and learning points The reality of intensification Regimen change – the evidence Basal plus and basal bolus – the practicalities of adding mealtime insulin BD mixtures Next steps

What does intensification mean? Type 2 diabetes is characterised by the progressive loss of beta cell function in addition to certain levels of insulin resistance. Most people with Type 2 diabetes will need larger doses of insulin as compared to those with Type 1 diabetes, so understanding how to optimise the dose and intensify insulin therapy is vital if good glycaemic control is to be achieved. This is a keypad question slide for delegates to respond to and to stimulate discussion at the start of this session.

Intensification with insulin It becomes necessary when HbA1c goals / targets are not met despite optimum pharmacological interventions and lifestyle measures When compliance is not an issue. Note Managing sub-optimal diabetes control is not all about changing treatment The most important aspect is identifying the reason for poor control first, assessment should be thorough as: Changing treatment alone may not improve control

The patient’s perspective Insulin intensification usually means an increase in: Number of injections Frequency of blood glucose monitoring Risk of hypoglycaemia particularly when blood glucose levels are getting closer to normal Weight, majority of patients gain weight as glycaemic control improves Pay more attention to meeting dietary and lifestyle requirements

Insulin therapy in diabetes From the patient perspective, key messages are: Ensure the patient is aware there are many options for insulin intensification Self blood glucose monitoring is recommended in line with dose titration and ‘hypo’ awareness Patient must understand dose ‘titration’ – i.e. change in dose to match changes in daily glucose, meals, activity…. Patient needs to understand the practicality of ‘hypos’ – i.e. prevention, recognition and treatment Weight gain is a potential side effect – but can be managed Understanding key management e.g sick day care , driving restrictions

Typical initial insulin regimens Intermediate acting insulin often given nocte Humulin® I (isophane human insulin (prb)) Insulatard® (isophane insulin) Insuman® Basal (isophane insulin) Long acting analogue insulin Lantus® (insulin glargine) Levemir® (insulin detemir) Tresiba® (insulin degludec) BD Mixtures Analogue : Humalog™ Mix25™ (25% insulin lispro (rDNA) injection. 75%insulin lispro protamine suspension) Humalog™ Mix50™ (50% insulin lispro (rDNA) injection. 50%insulin lispro protamine suspension) NovoMix30® (biphasic insulin aspart) Human: Humulin® M3 (human insulin(prb) 30%soluble insulin 70%isophane insulin) Insuman® Comb 25 (biphasic isophane insulin) Speaker to acknowledge the first two bullet points show the typical initial insulin regimens BUT worth introducing BD mixtures as discussion to follow. Insultard®, Levermir® and Tresiba® and NovoMix 30® are registered trademarks of Novo Nordisk Ltd Insuman® Lantus® and Insuman® Comb 25 are registered trademarks of Sanofi Aventis

Intensifying insulin regimens: Options to consider Quick reference guide to NICE Guidelines: (CG87: May 2009) Monitor those using basal insulin regimens (NPH or a long-acting analogue [insulin detemir, insulin glargine]) for need for short-acting insulin before meals or pre-mixed insulin Monitor those using pre-mixed insulin once or twice daily for need for further injection of short-acting insulin before meals or change to mealtime plus basal regimen NICE Type 2 diabetes CG87. London: NICE; May 2009; n/a: 1-431

Treating-To-Target in Type 2 Diabetes (4-T Study) Three-year UK/Ireland study in 708 people with type 2 diabetes First Phase – Year 1 One-year head-to-head comparison of efficacy of three different analogue insulins, when used as add-on therapy with dual oral antidiabetic therapy Second Phase – Years 2 & 3 Evaluation over 2 more years of the need for more-complex insulin regimens, and the overall efficacy of three different randomized insulin treatment strategies

4-T study: 3 year efficacy of complex insulin regimens in Type 2 diabetes HbA1c (1year) % 6.5 or under Weight gain (kg) Hypoglycaemia Biphasic 7.1% 31.9 % 5.7 kg 3.0 Pre-prandial 6.8% 44.8% 6.4 kg 5.7 Basal 6.9% 43.2% 3.6 kg 1.7 *Grade 2 or 3, median rates per patient per year Holman RR et al N Engl J Med 2009 361:1736-1747

4-T study: 3 year efficacy of complex insulin regimens in Type 2 diabetes Demographics No difference between 3 groups Age , Duration of diabetes, BMI, HbA1c, Concomitant OHA’s Results No statistically difference in median HbA1c between groups Differences in proportions reaching target level Hypos lowest in basal group Weight gain highest in prandial group > 65% of patients who required intensification using a second insulin: 67.7% for biphasic 73.6% for prandial 81.6% for basal Holman RR et al N Engl J Med 2009 361:1736-1747

Intensifying insulin regimens Which regimen? There is no one ‘right’ choice, and one regimen is not necessarily forever. If it is unsuitable it should be changed Who decides? Your role is to explain the options and present all the pros and cons. The final decision must be made by the person themselves Royal College of Nursing. Starting insulin treatment in adults with Type 2 diabetes 2006; NA: 1-28

Intensifying insulin therapy from basal How do HCPs determine/define insulin “failure” ? HbA1c unacceptable despite good fasting glucose control Persistent hyperglycaemia during the day Problematic day or night-time hypoglycaemia Probable change required if large individual injection dose (e.g. >80 units) is escalating and still not approaching FPG target Increasingly patients with type 2 diabetes are being commenced on basal insulin

Common options for intensifying basal insulin regimens Switch to twice-daily premixed insulin Add once-daily prandial insulin with the largest meal (basal-plus) Additional prandial injections can be added Add three times daily prandial insulin with meals (basal-bolus) Intensify with an additional injection Adapted from Barnett A et al (2008) Int J Clin Pract 62: 1647–53

Insulin regimens for type 2 diabetes compared Frequent blood glucose monitoring To follow on from the previous slide, this graphic aims to illustrate some of the pros and cons of the different options for intensification from a basal insulin regimen in type 2 diabetes.

What next if not achieving goals of therapy on basal insulin alone? Insidious transfer to basal bolus or Basal + + + Initiation as above is within HCP skill range *Basal + indicates an insulin regimen of basal insulin, plus 1 bolus injection

What does basal bolus mean for the patient with Type 2 diabetes 4 – 5 injections per day Choice of short/rapid acting insulin Choice of long acting insulin Choice of pen devices Flexibility to adjust timing and dose of insulin Increased frequency of blood glucose monitoring Consider how many Type 2 patients either want to do this or could develop the skills to manage a complex regime

Matching insulin activity profiles to diet Options and Outcomes

Insulin activity profile of Basal +++ 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 1 1 2 3 Long Acting insulin Insulin activity Aim of Long acting insulin is to manage glucose levels between meals Aim of Rapid acting insulin is to manage the glucose from the meals. Rapid-Acting insulin These diagrams are theoretical representations based on known pharmacological profiles, e.g. see Heise T et al (1998) Diabetes Care 21: 800-803

Carbohydrate awareness and Basal +++ in Type 2 Insulin activity Long Acting insulin Rapid-Acting insulin 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 Time This patient is eating similar amounts of carbohydrate at each meal ( ~ 50grams) and is giving the same amount of rapid acting insulin at meals Check BG levels 2 hours after meal Eat similar amounts of carbohydrate at each meal Inject same amount of rapid acting insulin at meals Aim of Long acting insulin is to manage glucose levels between meals Aim of Rapid acting insulin is to manage the glucose from the meals. These diagrams are theoretical representations based on known pharmacological profiles, e.g. see Heise T et al (1998) Diabetes Care 21: 800-803

Challenges of Basal+++ in Type 2 diabetes Because of insulin resistance, insulin sensitivity is poor Self management of basal bolus / Basal+++ Carbohydrate counting or awareness Correction doses are rarely taught to patients with Type 2 diabetes Increasing insulin doses due to insulin resistance Weight gain Self titration/adjustment poor in many patients Question What makes Basal+++ successful in Type 2 diabetes?

Varying dose of rapid-acting insulin in Basal +++ Long Acting insulin Rapid-Acting insulin Insulin activity This patient is eating DIFFERENT amounts of carbohydrate at each meal and is VARYING THE DOSE of rapid acting insulin at meals 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 Time These diagrams are theoretical representations based on known pharmacological profiles, e.g. see Heise T et al (1998) Diabetes Care 21: 800-803

Adding pre-meal insulin to basal Patients who fail to reach treatment goals despite maximum oral therapy and basal insulin could require the addition of pre-meal short or rapid acting insulin in order to improve postprandial control. Start with the addition of one injection of pre-meal insulin with the biggest meal, largest carbohydrate intake Titrate on a meal by meal basis to achieve postprandial blood glucose goal Initially 10% of the patient’s basal insulin dose should be replaced by the pre -meal insulin These are general guidelines and management should be individualised for specific patients. Hirsch IB et al Clinical Diabetes 2005 23;2:78-86

Factors to consider before implementing a basal plus approach Is the patient willing and able to take 4 – 5 injections a day? Will the patient be able to develop an understanding of carbohydrate content of meals? Will the patient be able to adjust their insulin dose based on the above? If not........... Hirsch IB et al Clinical Diabetes 2005 23;2:78-86

What next if not achieving goals of therapy on basal insulin alone? Is a BD mixture more appropriate?

Transferring patients from a once-daily basal insulin to a BD mixture Assess patients suitability for fixed mixture Do they eat regular meals ? Do they miss meals ever ? Is the timing of meals similar each day Use structured blood glucose monitoring and diet assessment (discovery sheets) to determine above and how current basal insulin dose should be split when initiated

Discovery sheets Used for up to 7 days to facilitate a structured blood glucose monitoring approach Patients are asked to record pre and post prandial blood glucose results, alongside food eaten Helps determine pre prandial blood glucose control & post prandial response to carbohydrate intake Engages and facilitates patients making the connection between blood glucose monitoring results and food eaten Engages patients in identifying possible solutions. Facilitates HCP with the patient to decide next best insulin solution.

Discovery sheets

Transferring patients from a once-daily basal insulin to a BD mixture Caution should be taken when transferring from one insulin to another When transferring to either a 30/70 or 25/75 premixed insulin The total daily dose of basal insulin can be split by different ratios 50% of the total basal dose given pre breakfast 50% of the total basal dose given pre evening meal Or 70% of the total basal dose pre breakfast 30% of the total basal dose pre evening meal Initial targets for fasting and pre-evening meal glucose levels (5-7 mmol/l) Use fasting glucose to titrate evening dose and pre-evening meal to titrate am dose Use patients bgm diary and food diary (or discovery sheet) to determine how best to spilt insulin dose Hirsch IB et al Clinical Diabetes 2005 23;2:78-86 AccessMedicine Harrison's Online. Chapter 344: Diabetes Mellitus 2011; N/A: 1-12

Practicalities of changing from basal insulin to pre mixed insulin Having decided on how the pre mixed insulin is to be split between pre breakfast and evening meal (eg 50% am /50% pm or 70% am /30% pm) Day 1 First dose of pre mixed insulin is given with evening meal Basal insulin stopped Day 2 First dose of morning pre mixed insulin is given Followed by second dose of pre mixed insulin with evening meal

Challenges of BD mixtures in Type 2 Perceptions, seen as: More complex to initiate and titrate than a basal insulin Depending on individual lifestyle, may be seen as inflexible compared with Basal+++ Planned snacking required for some patients May cause more weight gain and more hypoglycaemia than basal regimens Basal bolus seen by some as the gold standard insulin therapy Raskin P et al. Diabetes Care, 2005 28: 260-265

Advantages of premixed insulin analogues Rapid acting insulin analogues exhibit earlier and higher peak metabolic activity and shorter duration of action than human insulin Both basal and rapid-acting prandial insulin are provided in every injection and are effective and simple for patients to use Can be injected up to 3x daily and can effectively control postprandial hyperglycaemia Potentially improve postprandial glycaemic excursions throughout a 24hr period Rosenstock J, et al. Diabetes Care 2008; 31:20-25

Activity profile of premixed insulin analogues For a 75/25 premixed insulin analogue this is how units break down Rapid-Acting insulin Long Acting insulin Reiterating the essential point that BD mix has long and short acting components. Size of meal is important. Long-acting insulin component manages glucose levels between meals Rapid-acting insulin component manages glucose load from the meals. These diagrams are theoretical representations based on known pharmacological profiles, e.g. see HeiseT et al (1998) Diabetes Care 21: 800-803

Activity profile of premixed insulin analogues Rapid-Acting insulin Long Acting insulin Aim of Long acting insulin is to manage glucose levels between meals Aim of Rapid acting insulin is to manage the glucose from the meals. These diagrams are theoretical representations based on known pharmacological profiles, e.g. see HeiseT et al (1998) Diabetes Care 21: 800-803

Eating under the curve! Patients need to be taught how to eat under the curve Patients taking mixtures need to be aware they need to eat similar amounts of carbohydrate. Post prandial blood glucose monitoring will help the patient determine carbohydrate portion size to match insulin profile

How do you determine/define BD premixed insulin “failure” HbA1c unacceptable Persistent hyperglycaemia (either pre-injection or post-prandial are high-risk times) Problematic day or night-time hypoglycaemia (pre lunch and pre/post bed are high-risk times) Variable hypoglycaemia and hyperglycaemia because of lack of flexibility in twice-daily regimen How do Health care professionals decide pre-mixed insulin isn't working ??

What next if not achieving goals of therapy on BD mixture? Options: Add in prandial insulin lunchtime Basal bolus TDS Mix Combination of different mixtures The next intensification option will be determined by blood glucose profiles and patients food diary If a patient is failing to achieve control on bd mixed insulin, what are the next options? These may include prandial insulin at lunchtime which would require a new pen device and an additional insulin. When choosing a Tds mix either the same mix or a new mix, this means the patient would only use one pen device, unlike basal bolus.

Intensifying insulin therapy Summary Changing insulin regimen alone may not improve control Assess factors influencing poor control Intensifying insulin therapy typically means increasing the number of injections per day Consider the patients physical and cognitive ability to take on a more complex insulin regimen Ensure patients are involved in their treatment – providing appropriate education so enabling them to make informed choices about the potential options when intensifying their insulin therapy

UKDBT01539 September 2013