Insulin Initiation and Intensification

Insulin Therapy at the diagnosis of T2DM Dr.Ravi Kant M.B.B.S,M.D (Medicine),P.Gd(Preventive cardiology), Master (European and American Heart Association), P.Gd.Diabetology (Boston University) Associate Professor Department of Internal Medicine All India Institute of Medical Sciences  Rishikesh, Uttarakhand

Overview Why Insulin: When to initiate insulin Advantages vs disadvantages When to initiate insulin Early vs late (OAD failure) Which insulin to initiate Basal, prandial, premix, basal-bolus What to do for follow-up Titration, hypoglycemia, achieving targets We're going to review some of the issues in terms of identifying candidates who may be appropriate for insulin therapy, selecting an appropriate insulin replacement--do we use basal insulin? Do we use a premix option? Do we go straight to basal-bolus insulin therapy--some strategies for initiating insulin therapy in terms of either weight-based or set strategies, and even more importantly, adjusting insulin doses. We all realize that initiating insulin is good, because some insulin is better than no insulin, getting the right dose may be just as important to getting our patients to goal -- and then looking at some of the expected outcomes in terms of A1C, in terms of side effect profile hypoglycemia.

Overview Why Insulin: Advantages vs disadvantages We're going to review some of the issues in terms of identifying candidates who may be appropriate for insulin therapy, selecting an appropriate insulin replacement--do we use basal insulin? Do we use a premix option? Do we go straight to basal-bolus insulin therapy--some strategies for initiating insulin therapy in terms of either weight-based or set strategies, and even more importantly, adjusting insulin doses. We all realize that initiating insulin is good, because some insulin is better than no insulin, getting the right dose may be just as important to getting our patients to goal -- and then looking at some of the expected outcomes in terms of A1C, in terms of side effect profile hypoglycemia.

Type 2 diabetes is a chronic condition with progressive loss of beta-cell function

Improving glycemic control reduces risks of long-term complications Every 1% drop in HbA1c can reduce long-term diabetes complications 43% 37% 19% 16% 14% 12% Stroke Myocardial infarction Significant in Post-Study Monitoring Programme! Heart failure Cataract extraction Microvascular disease Lower extremity amputation or fatal peripheral vascular disease UKPDS: Stratton et al. BMJ 2000;32:405–12

Insulin offer maximum HbA1c Reductions.. Subjects (n) 5783 13,847 1120 6655 5895 1050 4827 21,615 11,921 2597 2967 AGI, alpha-glucosidase inhibitor; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin; SU, sulphonylurea; TZD, thiazolidinedione. Esposito et al. Diabetes Obes Metab.2012;14:228–233.

Insulin Therapy: Advantages and Disadvantages Oldest of the currently available anti-glycemic therapy Most effective in improving glycemia and achieving therapeutic goal Beneficial effects on triglycerides and HDL Weight gain Hypoglycemia

Overview When to initiate insulin Early vs late (OAD failure) We're going to review some of the issues in terms of identifying candidates who may be appropriate for insulin therapy, selecting an appropriate insulin replacement--do we use basal insulin? Do we use a premix option? Do we go straight to basal-bolus insulin therapy--some strategies for initiating insulin therapy in terms of either weight-based or set strategies, and even more importantly, adjusting insulin doses. We all realize that initiating insulin is good, because some insulin is better than no insulin, getting the right dose may be just as important to getting our patients to goal -- and then looking at some of the expected outcomes in terms of A1C, in terms of side effect profile hypoglycemia.

Early insulin treatment prolongs β-cell function; promotes metabolic control 9 0.3 Glibenclamide § # 0.2 8 0.1 HbA1c (%) Delta C-peptide (mmol/L) # 7 0.0 * -0.1 6 * § -0.2 5 -0.3 Two key findings emerge from the present study. First, parameters of B-cell function were better preserved in the insulin than in the glibenclamide- treated patients. Most importantly, there was a more pronounced C-peptide response to glucagon in the insulin group 1 year after the start of the study. 1 2 1 2 1 2 Year Day *P< 0.01 year 0 vs. 1, § P< 0.005 year 0 vs. 2, #P< 0.01 year 1 vs. 2 *P= 0.02 glibenclamide vs. insulin §P< 0.05 year 1 day 1 vs. 2 P< 0.01 year 1 day 1 vs. year 2 day 2 Alvarsson M et al. Diabetes Care. 2003 Aug;26(8):2231-7

Early insulin therapy improves beta-cell function and glycaemic control 100 CSII MDI OHA 80 70 p=0.0012 n=382 60 Patients in remission (%) 40 Early intensive insulin therapy in patients with newly diagnosed type 2 diabetes has favourable outcomes on recovery and maintenance of beta-cell function and protracted glycaemic remission compared with treatment with oral hypoglycaemic agents. This figure shows the remission rates at 1 year in the three groups: 51.1% (68 of 133) in the CSII group, 44.9% (53 of 118) in MDI group, and 26.7% (27 of 101) in the oral hypoglycaemic agents group. The remission rate was significantly higher in both insulin groups than in the oral hypoglycaemic agents group (p=0.0012). The risk of relapse was reduced by 44% (95% CI 0.40–0.78, p=0.001) with CSII and by 31% (95% CI 0.50–0.97, p=0.032) with MDI compared with oral hypoglycaemic agents. 20 90 180 270 360 450 Time in remission (days) CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injection; OHA, oral hypoglycaemic agent Weng et al. Lancet 2008;371:1753–60

When to initiate insulin

Ideal candidates for insulin therapy All diabetes patients! Type 1 diabetes Gestational diabetes Type 2 diabetes on maximal doses of OADs Acute metabolic decompensation states Good control but fatigued/losing weight

Overview Which insulin to initiate Basal, prandial, premix, basal-bolus We're going to review some of the issues in terms of identifying candidates who may be appropriate for insulin therapy, selecting an appropriate insulin replacement--do we use basal insulin? Do we use a premix option? Do we go straight to basal-bolus insulin therapy--some strategies for initiating insulin therapy in terms of either weight-based or set strategies, and even more importantly, adjusting insulin doses. We all realize that initiating insulin is good, because some insulin is better than no insulin, getting the right dose may be just as important to getting our patients to goal -- and then looking at some of the expected outcomes in terms of A1C, in terms of side effect profile hypoglycemia.

This is a very good review done by Bolen in the Annals of Internal Medicine last year. If you haven't read it, I would encourage you to go over it. It was a systematic review that looked at the various therapies and looked at the expected outcomes, the expected effects on cardiovascular risk markers, and side effect profile. The conclusion was that all of these basically have a similar effect in terms of lowering A1C about 1%.

So that's what you would expect starting or adding oral antidiabetic drug (OAD) therapy to a patient. They have additive effects, so if you use different classes of OADs together, you can get incremental A1C lowering. With nateglinide and the alpha-glucosidase inhibitors, you may be having a slightly weaker effect in terms of A1C reduction. So we could have certainly tried 3 or 2 oral agents to see if we could have had a reduction in A1C

Maybe in going through the decision steps as to what's the next therapy to consider. One way of looking at it is to actually decide whether the priority that you have with the particular patient in front of you is one in terms of effectiveness. You want to get that blood sugar down, because it's extremely high. Is it one of durability? I mean, would using a thiazolidinedione or maybe an incretin therapy or maybe an alpha-glucosidase inhibitor prolong the control of that patient? Is hypoglycemia a concern? And if you want to minimize hypoglycemia, there are therapies that will do so better than others. You want to minimize weight gain. You want to minimize cost. Whatever the priority is for the patient in front of you, you may have different options in terms of the therapies that are available.

Which Insulin? Basal Prandial Premix Basal-bolus

Insulin regimen to be implemented depends on the level of overall hyperglycaemia Relative contribution of postprandial and fasting hyperglycaemia according to HbA1c quintiles 290 T2DM patients treated with diet ± oral agents without insulin Baseline (normal) plasma glucose defined as 6.1 mmol/L (110 mg/dL) Analysis of 4-point profiles 10 20 30 40 50 60 70 <7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2 Postprandial (PPBG) Fasting (FBG) Relative contribution of FBG vs PPBG (%) HbA1c (%) OHA=oral hypoglycaemic agent Initiate basal insulin therapy when glycaemic control is very poor Intensify insulin therapy with the stepwise addition of prandial insulin as HbA1c approaches target value Adapted from Monnier L, et al. Diabetes Care 2003;26:881–5.

Rationale for starting with basal insulin Predominant fasting hyperglycemia Simple titration One injection a day Start with 10 – 20 units at bedtime and adjust based on fasting glucose Self adjustment of insulin dose Effective A1c reduction by 1% - 2.5%, can be combined with OADs Safe Lower risk of hypoglycemia Less weight gain, “anytime injection” And the other idea is it's simple. It's 1 injection a day. I can start with either a simple 10 units per day, or I can make it based on this patient's weight. It was almost 100 kg. And you'll see the dose that we started. I can expect about 1% to 2.5% reduction in A1C, maybe a little bit more if I start with an A1C that's high enough. It's safe. It's easy to do.

Basal insulin: Simple way to add insulin Bedtime or morning long-acting insulin Daily dose: 10 U or 0.2 U/kg Initiate insulin with a single injection of a basal insulin Check FBG daily In the event of hypoglycemia or FBG level<70 mg/dL, reduce bedtime insulin dose by ≥4 units, or by 10% if >60 units Increase dose by 2 U every 3 days until FBG is 90–130 mg/dL If FBG is >180 mg/dL, increase dose by 4 U every 3 days Continue regimen and check HbA1c every 3 months FBG = Fasting blood glucose Nathan DM, et al. Diabetes Care 2009;32:193–203. 21 21

Basal Insulin Analogs Advantages of analogs More consistent absorption profile More predictable BG values Less pronounced peak activity Less nocturnal hypoglycemia Longer duration of action Better coverage with once daily dosing

Basal Insulin therapy The 4-T demonstrated the benefit of initiating with basal insulin in T2D inadequately controlled by OADs, compared with prandial/premixed insulins. People initiating basal insulin experienced significantly lower rates of hypoglycaemia & less weight gain compared with prandial/premixed insulin. The study also showed that, over the longer term (3 yrs), a premixed insulin with a midday prandial bolus (which could be added if required) was not as effective as basal plus prandial insulin at attaining & maintaining treatment targets. D. R. Owens Diabet. Med. 30, 276–288 (2013

Overview of Main Results Biphasic Prandial Basal Median HbA1c level achieved + HbA1c targets achieved ++ Mean SMBG level achieved Fewer hypoglycaemic episodes +++ Less weight gain Less increase in waist circumference

Insulin treatment patterns: common strategies Starting regimens Intensification regimens Basal insulin + OADs Basal plus therapy Premix insulin OD or BD Premix BD or TD Prandial insulin Basal–bolus therapy

Overview What to do for follow-up Titration, hypoglycemia, achieving targets We're going to review some of the issues in terms of identifying candidates who may be appropriate for insulin therapy, selecting an appropriate insulin replacement--do we use basal insulin? Do we use a premix option? Do we go straight to basal-bolus insulin therapy--some strategies for initiating insulin therapy in terms of either weight-based or set strategies, and even more importantly, adjusting insulin doses. We all realize that initiating insulin is good, because some insulin is better than no insulin, getting the right dose may be just as important to getting our patients to goal -- and then looking at some of the expected outcomes in terms of A1C, in terms of side effect profile hypoglycemia.

Calculating basal and prandial insulin dose based on weight (kg) Miami 4/12 (normal sensitivity) or 2/6 (poor sensitivity) rule Divide weight by 4 (or 2) to estimate basal insulin dose Basal insulin dose: 96/2 = 43 Divide weight by 12 (or 6) to estimate prandial insulin dose Prandial insulin dose: 96/6 = 16 units before each meal

Premix is also a good option for intensification New ADA 2015 Basal Insulin (Usually with Metformin) Start: 10U/day or 0.1-0.2U/day Adjust: once or twice weekly to reach FPG target If not controlled after FPG target is reached consider treating PPG excursions with meal time insulin ADD 1 rapid insulin injection before the major meal Change to premixed insulin twice daily Add ≥2 rapid insulin injections before meals If not controlled If not controlled Diabetes Care January 2015 vol. 38 no. 1 140-149

Multiple Injections & Dose Titrations: Switching From PreMix OD To BID, Or BID To TID Add 2–6 U or 10% of total daily Premixed Insulin dose before lunch Down-titration of morning dose (−2 to 4 U) may be needed after adding the lunch dose Titrate the doses preferably once a week according to the algorithm below Administer Premixed just before meals Continue metformin Consider discontinuing TZDs as per local guidelines and practice Split the OD dose into equal breakfast and dinner doses (50:50) Titrate the doses preferably once a week according to the algorithm Administer Premixed just before meals Discontinue SUs Continue metformin Consider discontinuing thiazolidinediones (TZDs) as per local guidelines and practice Algorithm for switch from OD to BID and from BID to TID. While talking about TID premixed insulin, must explain that the pre-lunch dose must be small to start with and there should be a reduction in the morning dose by 2 to 4 units to avoid hypoglycemia in the afternoon Unnikrishnan et al. Int J ClinPract 2009: 63(11):1571-77. 29

Multiple Injections & Dose Titrations: Adjusting Twice-daily Insulin These are general rules: always consult product-specific guidelines Elevated glucose during the night or early morning Increase evening dose by 10% (e.g. from 18 to 20 units) Elevated glucose during the day Increase morning dose by 10% (e.g. from 20 to 22 units) Titration for Premixed insulin if blood sugar is elevated. A twice-daily insulin regimen is fairly common in people with type 2 diabetes. As shown in the slide, increase the preceding dose by 10% to combat hyperglycaemia during the night or day. So, if your patient has elevated glucose before breakfast, increase the evening dose by 10%, and if they have elevated glucose before the evening meal, increase the morning dose by 10%. References Royal College of Nursing. Starting insulin treatment in adults with type 2 diabetes. http://www.rcn.org.uk/publications/pdf/ Starting%20insulin%20in%20adults%20with%20type%202%20diabetes.pdf, 2005 Elevated glucose during the day and night Increase morning dose by 10% and increase evening dose by 10% Royal College of Nursing. http://www.rcn.org.uk/publications/pdf/ Starting%20insulin%20in%20adults%20with%20type%202%20diabetes.pdf, 2005

Multiple Injections & Dose Titrations: Adjusting Basal-bolus Regimen These are general rules: always consult product-specific guidelines Elevated glucose before breakfast Increase basal dose by 10% Elevated glucose after meals Increase mealtime dose by 10% Titration of Basal bolus regimen if blood sugar is elevated When short- and intermediate-acting insulin are being used together in a basal-bolus regimen to control glycaemia, the dose of each can be adjusted separately to optimise glucose control. For example, if the patient experiences elevated morning blood glucose, increase the basal insulin dose. If the patient experiences elevated glucose after meals, increase the bolus dose. References Royal College of Nursing. Starting insulin treatment in adults with type 2 diabetes. http://www.rcn.org.uk/publications/pdf/ Starting%20insulin%20in%20adults%20with%20type%202%20diabetes.pdf, 2005

Treatment Strategies: Insulins Basal insulin: targets FPG > PPG Benefit: only 1-2 injections per day Drawback: patients may require prandial insulin to reach HbA1c targets Premixed insulin: targets both FPG and PPG Benefit: fewer injections than prandial Drawback: unable to adjust components separately Prandial (mealtime) insulin: targets PPG > FPG Benefit: most physiologic; best at targeting PPG Drawback: most injections; requires addition of basal insulin to target FPG Source: Advancing Insulin Therapy with Insulin Mixtures (Reviewed Deck) Main Point: Review the benefits and drawbacks of the various insulin treatment strategies listed. Different strategies for providing insulin: Basal is a very popular starter regimen, often just one injection per day, but postprandial excursions, although decreased, may still exist. Premixed insulin has components that address both FPG and PPG and has fewer injections per day than a prandial or basal/bolus regimen, but the components are unable to be adjusted separately. Prandial insulin is the most physiologic way to reduce the increase in glucose after meals—the best insulin for targeting PPG. Prandial insulin may require addition of basal insulin to cover FPG, so the downside is the number of injections, particularly for patients. Reference: Lasserson DS, Glasziou P, Perera R, Holman RR, Farmer AJ. Optimal insulin regimens in type 2 diabetes mellitus: systematic review and meta-analyses. Diabetologia. 2009;52(10):1990-2000. Lasserson DS, et al. Diabetologia. 2009;52(10):1990-2000.

Insulin Intensification: Major guidelines target an HbA1c of <7.0 % The overall aim is to achieve glucose levels as close to normal as possible This can minimise development and progression of microvascular and macrovascular complications FPG <130 mg/dL (7.2 mmol/L) HbA1c <7.0 % PPG <180 mg/dL (10.0 mmol/L) ADA1,2/ EASD2 Achieving target is important in diabetes management. Targets include HbA1c, FPG and PPG. There are minor differences in FPG & PPG targets. However a clear guideline for treatment. FPG <110 mg/dL (6.0 mmol/L) HbA1c <7.0 % PPG <160 mg/dL (9.0 mmol/L) IDF3 FPG, fasting plasma glucose; PPG, postprandial plasma glucose; ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; IDF, International Diabetes Federation 1. ADA. Diabetes Care 2014;37:S14–80; 2. Inzucchiet al. Diabetologia 2012;55:1577–96; 3. 2. IDF Clinical Guidelines Task Force. Global guidelines for type 2 diabetes. 2011/2012

Sliding Scales! The roller Coaster!!! Reactive rather than proactive Corrects for insulin doses when sugars are already risen In certain situations when it is not possible to predict the requirements, sliding scale may be used for 24-48 hrs Never give prandial insulin without basal cover

What about OADs while initiating insulin Metformin, AGIs, DPP4i & SGLT2i therapy may be continued SUs may be continued when basal insulin alone is used Usually SUs should be discontinued when initiated on basal- bolus or premix insulins

Clinical pearls while writing prescription Do not add basal and premix on same prescription Write clearly the relation between insulin timing and meals Specify insulin administration sites and frequency of insulin needle change Explain clearly about expectations regarding glycemic control Address patient concerns regarding insulin

Summary Identify candidates for insulin therapy Very high hba1c at presentation Not at goal with maximum tolerated therapy Select appropriate insulin replacement Basal, Prandial, Premix, Basal-Bolus Initiating insulin therapy Weight based vs set doses Do not use sliding scale Expected outcomes Most effective agent for lowering HbA1c Hypoglycemia Weight gain