Insulin Initiation for Type 2 diabetes in General Practice Nicole McGrath 2013

Does the patient need insulin? Not achieving target HbA1c 50-55 mmol/mol 1. Doing as much as possible re diet and exercise Gym membership deals Advice on food: types and amount Bariatric Surgery; Optifast Willingness to change? 2. Taking maximum doses of oral medication Metformin can be continued until eGFR<30ml/min Gliclazide 320mg/day; Glipizide 30mg/day Pioglitazone for young, obese Don’t forget Acarbose Drug adherence? Checking with patient and with dispensing

4. Is the target HbA1c realistic for the patient: 3. Is the patient actually primarily insulin deficient (rather than insulin resistant): Suboptimal HbA1c and slim with weight loss BMI <= 25; Overweight patient with duration of diabetes > 10 years; previously good glycaemic control on oral agents 4. Is the target HbA1c realistic for the patient: Frail, elderly, mentally ill: trigger HbA1c for commencement of insulin may be higher (e.g. HbA1c> 65 mmol/mol)

Diagnosis of type 2 diabetes Type 2 diabetes is a progressive disease that requires progressive treatment ß-cell function and insulin secretion progressively decline in type 2 diabetes Diagnosis of type 2 diabetes

Is insulin going to be effective? 1. How much is the patient prepared to do? Testing regularly: need to know the blood glucose (BG) profile to work out the best insulin regime Learning how to self-inject Learning how to adjust the doses 2. How much are you and your nurse prepared to do? Teaching how to inject Supervising titration of dose in a timely manner Giving advice on dose adjustment for meal content, exercise if on multidose regime

Education Required Lifestyle advice; BG monitoring Use of insulin pens Injection technique Insulin action, timing of injections, storage Disposal of sharps Hypo management, prevention Sick day management

How many injections per day? How many is the patient prepared to do? How high is the HbA1c? Are the oral agents providing any benefit? Likely if HbA1c is between 55 and 75 mmol/mol: Once daily insulin added on to oral agents indicated HbA1c > 75: oral agents failing and full switch to insulin may be best.

Insulin therapy. Pre mix – useful for Regular lifestyles Eat similar amounts of Carbohydrate Insulin depleted – slim Combination with OHA – 1injection start. BD Stop Actos / OHA Basal bolus - Most useful for – Type 1 diabetes Erratic lifestyle / eating patterns Need flexibility – shifts, sports Optimal control needed. Keep Metformin – Type 2 also. TYPE 1 OBESE Basal only will lower HbA1c by 1.8% in clinical trials for up to 28 weeks Patient with HbA1c of 8.5% - good starting point

Once daily basal insulin Glargine (Lantus) vs. Isophane (Protophane/Humulin NPH) NZ Guideline Group (NZGG): Isophane Commonly used: Glargine Isophane: cheaper, long and safe track record, 12-18 hours of action Protophane: Novo pen; Humulin NPH: Luxura pen i.e. no real difference between the two brands but specific pen needs to be given

Basal Insulin: provides background insulin but does not cover meals Start Slide 6 00:02:32:20 Transition to Slide 7 00:03:22:08 Isophane Glargine Schematic action profiles, theoretical representation of insulin injected once a day - results may vary from patient to patient.

Once daily Isophane insulin (Protophane or Humulin NPH): Indications Night dose: Good for patients whose blood sugars climb overnight but have even control during the day due to oral agents: Continue oral agents and prescribe Isophane insulin at 8-9pm Morning dose: Elderly patients often do not need much diabetes treatment overnight (reduced hepatic gluconeogenesis) and also useful for those on Prednisone mane Fasting BG 4-6 but climb during the day Continue oral agents and prescribe Isophane insulin at 8-9am

What are the pros and cons of the Novopen vs. the Luxura? slightly bigger numbers its mechanism makes counting the clicks (for the  sight impaired ) a little easier. need to pull the end out first before dialing up Luxura (Huma Pen) heavier mechanism feels a little looser - possibly easier to make mistakes you just dial.

Isophane insulin: Starting Dose NZGG suggest 10 units starting dose Insulin requirement relates to body weight If patient > 50kg, expect the dose will need to climb If patient overweight (BMI > 30) or HbA1c > 65 mmol/mol, suggest start at a higher dose, e.g. 0.2 units/kg body weight/day e.g. 100kg patient will likely need at least 20 units

Glargine (Lantus) insulin Only funded long-acting insulin analogue (Levemir not funded) Concerns about potential cancer risk have been disputed 24 hour action for approximately 70-80% patients Constant insulin profile with no peak action can be given at any time of the day so long as the same time each day More sensitive to heat than other insulins

Glargine (Lantus) Insulin Given either with disposable pen (Solostar Pen) or in penfill used in ClikSTAR Pen If prescribe Solostar, no need to provide pen and no need for patient to refill pen, but more waste Solostar Pen ready filled and dispensed at pharmacy ClikSTAR pen: satisfactory but not as robust as NovoPen/Luxura pen: Large numbers, easy to see

Once daily Glargine (Lantus): Indications 24 hour basal insulin needed: BG high in the morning and climb over the day HbA1c > 65 despite maximum oral agents An introduction to insulin for those who really need full insulin cover but reluctant/unwilling; more coverage than Isophane No need to time Glargine insulin injection with meals Still need to cover postprandial hyperglycaemia with something (oral agents or insulin)

...resulting in undesired mealtime glucose excursions The problem with type 2 diabetes The mealtime insulin secretory response is blunted… A normal insulin response following a meal is two-phased. Insulin is rapidly released by beta-cells into the portal circulation within minutes of glucose arrival in the bloodstream. This insulin spike lasts about 10 minutes giving rise to what is known as first-phase insulin release. This is followed by a second-phase release, which lasts for 1–2 hours and gradually falls back to normal levels. In type 2 diabetes, this first-phase insulin release is lost and the second phase is blunted resulting in postprandial hyperglycaemia. Although both phases of insulin release are needed, the first-phase insulin release is essential to overall glucose control. Reference: Polonsky KS et al. New Engl J Med 1988; 318:1231–39. ...resulting in undesired mealtime glucose excursions

Both fasting & mealtime glucose contribute to HbA1c Clinical evidence suggests that reducing PPG excursions is as important, or perhaps more important than fasting blood glucose (FBG), for achieving HbA1c goals

Oral hpoglycaemic agents (OHA) and basal insulin Tempting to stop all OHA and just have one injection per day Will achieve better control than no treatment Can result in worse control if patient was taking oral medication as prescribed Metformin useful agent to continue in most patients Reduces insulin resistance Treats post-prandial hyperglycaemia No hypoglycaemia due to Metformin itself Continue at same dose

Suphonylureas and basal insulin NZGG: Once daily Isophane: continue Sulphonylurea Twice daily Isophane: discontinue Sulphonylurea If control just above target HbA1c, then this may work But Isophane will not cover post-prandial hyperglycaemia: If HbA1c > 65, continue Sulphonylurea Once daily Glargine: similar to twice daily Isophane

Some typical treatment regimens: OHA and basal insulin Metformin 850mg tds, Gliclazide 160mg bd, Protophane 15 units nocte Metformin 1gm tds, Humulin N 12 units bd Gliclazide 80mg tds, Glargine 30 units daily (renal pt)

Other OHA Pioglitazone: usually discontinued at insulin commencement Increased risk of fluid retention But…. In young overweight patient maybe continued to help minimise the insulin dose Acarbose: can be continued if useful

Are OHA adding anything? If HbA1c > 75 mmol/mol and pt taking the OHA at maximum doses, then probably not If 2-hour post-prandial BG > 10, then probably not Will depend on pre-prandial BG Will need insulin to cover meals……unless patient can reduce carbohydrates / meal size

Insulin Mealtime Cover Rapid-acting insulin Onset approx 10 minutes after injection. Duration of action around 1–3 hours. Rapid-acting insulin should be given immediately before a meal (or can be given soon after meals) Brand names: Humalog, NovoRapid, Apidra Short-acting insulin Onset approx 30 minutes after injection. Duration of action around 3-6 hours. Short-acting insulin should be given 20-30 minutes before a meal Brand names: Humulin R, Actrapid Start Slide 5 00:01:47:16 Transition to Slide 6 00:02:31:16

Short acting insulin Actrapid and Humulin R not routinely used Can be useful to try and cover both breakfast and lunch or extended evening food intake E.g. children who do not want to inject at school Adults who eat most of their food in the evening but over an extended period (probably better in a pre-mixed formulation)

Rapid acting Insulins Novorapid vs Humalog vs Apidra No significant difference between them Novorapid: Novo pen; slightly longer tail of action, up to 4-5 hours Humalog: Luxura pen; action 3-4 hours Apidra: disposable solostar pen; action 3-4 hrs

Basal bolus insulin regimes Basal insulin (Isophane or Glargine) taken once or twice daily Bolus insulin (Novorapid, Humalog or Apidra) with meals Standard regimen for type 1 diabetes Becoming popular with insulin requiring type 2 pts Most flexible insulin regimen But… does require multiple insulin injections per day Plus education about adjusting bolus insulin doses for variable meals

Basal bolus regimens Usual: Rapid acting insulin tds + Glargine mane or nocte Examples of variations: Glargine once daily + Apidra with main evening meal+ Metformin tds (can give Glargine and Apidra at same time) Good for pt who eats large evening meal, snacks during day Humulin N mane + Humalog with breakfast and lunch + Metformin tds Pt on Prednisone 10mg mane for PMR Can become somewhat complicated!

Pre-mixed Insulins Avoid complicated regimens in patients who need more than basal insulin + OHA Cover background insulin requirements + meal cover Two injections per day timed with breakfast and evening meals Have to eat at these times Good opportunity to stress importance of regular meals Usually continue Metformin but discontinue sulphonylurea, other OHA

Pre-mixed Insulins: Covering meals and giving basal cover A mixture of either rapid or short-acting and intermediate-acting insulin which act just like two injections of the separate components taken at the same time Useful for many type 2 patients with tablet failure requiring insulin Start Slide 7 00:03:23:10 Cut to Rick 00:04:19:02

Pre-mixed Insulins: Short acting insulin + isophane Penmix 30: 30% Actrapid, 70% Protophane Penmix 50: 50% Actrapid, 70% Protophane Humulin 30/70: 30% Humulin R, 70% Humulin N Ideally injected 20 mins before meal Actrapid/Humulin R longer duration of action cover breakfast and lunch but can linger and potentiate hypoglycaemia overnight Most patients use Penmix 30 or Humulin 30 Penmix 50 useful for big eaters

Pre-mixed Insulins: Rapid acting insulin + isophane Humalog Mix 25: 25% Humalog, 75% Humulin N Novomix 30: 30% Novorapid, 70% Protophane Humalog Mix 50: 50% Humalog, 50% Humulin N Cover breakfast and dinner well, but not lunch Inject when meal served or just after Most patients use Humalog Mix 25 or Novomix 30: Not much difference Novomix 30: disposable pen Humalog Mix 50 can be useful to cover large evening meal

Pre-mixed Insulins Pros cover overnight hyperglycaemia and address postprandial excursions Humalog Mix/ Novomix: Inject at meal-time Less likelihood pre-prandial hypoglycaemia Penmix/Humulin Mix Improved cover lunch and late night snack Cons injections must be given at meal times; work best if regular time for breakfast and evening meal difficult to adjust dose if: large variation in carbohdrate component of meal sudden increase in physical activity Humalog/Novo Mix Not good lunch cover Penmix/Humulin Mix Inject 20 mins before meal

Insulin prescription How to get around expected increase of dose? Need to also prescribe insulin pen needles We recommend 5mm needle length to ensure subcutaneous administration (rather than intramuscular) for most people How to get around expected increase of dose? Prescribe higher dose but instruct patient to start with lower dose? May cause confusion Write on script that dose may be increased and repeats needed early Write another script if supplies run out early

Adjusting insulin doses The patient should be instructed in adjusting their own insulin – checking with the practice weekly. 2-4 unit adjustment every 3-4 days until target blood glucose is reached. Targets: Pre breakfast target <7.0mmol/L 2 hour post meal target <10.0mmol/L Pre-dinner target 6.0–7.0mmol/L Slide 18 00:14:27:01 Cut to Rick 00:14:46:16 Back to Slide 18 00:15:09:08 Cut to Rick 00:15:28:17

Insulin Dosage Adjustments – Pre-mixed insulin Regime (on HealthPoint)

Insulin Dosage Adjustments – Basal Bolus Regime (on HealthPoint) Blood Glucose Levels (mmols/litre) Less than 4 or hypo 4-8 8-15 15 or higher Blood testing times Before breakfast Reduce cloudy night time insulin by 2 units Good Control Increase cloudy night time insulin by 4 units. Before lunch breakfast insulin by 2 units breakfast insulin by 4 units Before evening meal lunch insulin by 2 units Lunch insulin by 2 units lunch insulin by 4 units Before bed evening insulin by 2 units evening insulin by 4 units

Increasing Insulin Doses: Isophane nocte Pre breakfast (fasting) BG Usually >8 mmol/L and never less than 4: Increase dose by 4–6 units Usually 6–8 mmol/L and never less than 4: Increase dose by 2–4 units Once receiving >20 units daily + 3 consecutive pre breakfast (fasting) BG results higher than agreed BG target AND BG never less than 4 mmol/L Insulin dose can be increased by 10–20% of total daily dose

Twice daily Isophane (= Glargine) Pre evening meal BG Usually >8 mmol/L and never less than 4 Increase pre breakfast insulin dose by 4–5 units Usually 7–8 mmol/L and never less than 4 Increase pre breakfast insulin dose by 2–4 units Once receiving >20 units daily 3 consecutive BG results (either pre breakfast or pre evening meal) higher than agreed BG target AND BG never less than 4 mmol/L Appropriate insulin dose can be increased by 10–20% of total daily dose

Post-prandial testing Check 2 hours after meal: target BG < 10 If on OHA, maximise If still not meeting target, make sure basal insulin dose is correct (pre-meal BG < 7) If basal insulin correct then need to add rapid acting insulin or Change to Premixed insulin regime

Not testing (or not very much)! Difficult to manage accurately Most patients will check fasting BG At least can adjust basal insulin (unless pt eats overnight) Alternate times of testing so once or twice daily test can give maximum information; certain days of the week Sometimes pre-prandial, sometimes post-prandial Evening meal usually largest so 2 hours after dinner Regular HbA1c (2-3 monthly)

HbA1c remains suboptimal Is basal insulin enough? Is the dose correct: fasting BG < 7 Some obese patients require large doses of insulin Basal insulin 0.5 units/kg body weight/day What about post-prandial hyperglycaemia? It always comes back to the food! If basal dose correct and on maximum OHA Change to Pre-mixed insulin / basal bolus

Changing Insulin Regimens Options if HbA1c suboptimal on basal insulin: If not on sulphonylurea: add it on and maximise If on once daily Isophane, change to bd or Glargine If on maximum orals: change to Pre-mixed bd insulin Stop sulphonylurea, give same insulin dose as basal Isophane 24 units bd: Penmix 30 24 units bd Or, continue with basal insulin, stop sulphonylurea and add rapid acting insulin Usually need same total daily dose as basal insulin Glargine 30 units daily: Novorapid 10 units tds

When to refer to Secondary services This will depend on your teams’ experience: Current situation (from my viewpoint): Some practices independently start patients on insulin Refer when issues with hypoglycaemia impact on improved control. Or not achieving any improvement in HbA1c Sometimes patients will self-refer Other practices refer everyone who is on OHAs with suboptimal HbA1c Appropriate if skill base and time not there

Secondary Services Expectation for the future (from Ministry of Health): Insulin for type 2 diabetes patients will be initiated by all GPs Mostly basal insulin + OHA, or pre-mixed insulin bd May mean more patients are started on insulin early (appropriately) Remember basal insulin only will not be sufficient for a number of patients and long-term adjustment is required We are interested to see young type 2 pts < 25 yrs to provide intensive input

Summary Checklist for commencement of insulin Maximised lifestyle changes, OHA Patient willing; skill base in practice Decision on insulin regime depends on BG profile ideally HbA1c Patient preference Familiarity of your team with regimen and follow-up required