Insulin Initiation and Intensification Insulin Therapy at the

+ Insulin Initiation and Intensification

+ Insulin Therapy at the diagnosis of T 2 DM 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 n Why Insulin: n Advantages vs disadvantages n When to initiate insulin n Early vs late (OAD failure) n Which insulin to initiate n Basal, prandial, premix, basal-bolus n What to do for follow-up n Titration, hypoglycemia, achieving targets

+ Overview n Why Insulin: n Advantages vs disadvantages

+ 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 Hb. A 1 c can reduce long-term diabetes complications 43% 37% Microvascular disease Lower extremity amputation or fatal peripheral vascular disease 19% Cataract extraction UKPDS: Stratton et al. BMJ 2000; 32: 405– 12 16% Heart failure 14% Myocardial infarction 12% Stroke Significant in Post-Study Monitoring Programme!

+ Insulin offer maximum Hb. A 1 c Reductions. . -0. 5 -1 -1. 5 -2 13, 847 1050 4827 21, 615 11, 921 2597 Basal bolus Prandial insulin Biphasic insulin 5895 Basal insulin 6655 Metformin 1120 Glinides SU 5783 TZD Subjects (n) AGI -3 DPP-4 i -2. 5 GLP-1 RA Change in Hb. A 1 c (%) 0 2967 AGI, alpha-glucosidase inhibitor; DPP-4 i, dipeptidyl peptidase-4 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; Hb. A 1 c, glycosylated haemoglobin; SU, sulphonylurea; TZD, thiazolidinedione. Esposito et al. Diabetes Obes Metab. 2012; 14: 228– 233.

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

+ Overview n When to initiate insulin n Early vs late (OAD failure)

+ Early insulin treatment prolongs β-cell function; promotes metabolic control Hb. A 1 c (%) 9 8 # 7 * 6 5 § 0 1 2 Delta C-peptide (mmol/L) Insulin 0. 3 Glibenclamide § # 0. 2 0. 1 0. 0 -0. 1 * -0. 2 -0. 3 Year *P< 0. 01 year 0 vs. 1, § P< 0. 005 year 0 vs. 2, #P< 0. 01 year 1 vs. 2 Alvarsson M et al. Diabetes Care. 2003 Aug; 26(8): 2231 -7 1 2 Day *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

+ Early insulin therapy improves beta-cell function and glycaemic control Patients in remission (%) 100 CSII 80 MDI OHA p=0. 0012 70 n=382 60 40 20 0 0 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 n All diabetes patients! n Type 1 diabetes n Gestational diabetes n Type 2 diabetes on maximal doses of OADs n Acute metabolic decompensation states n Good control but fatigued/losing weight

+ Overview n Which insulin to initiate n Basal, prandial, premix, basal-bolus

+ 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 Hb. A 1 c quintiles Initiate basal insulin therapy when glycaemic control is very poor Fasting (FBG) Intensify insulin therapy with the stepwise addition of prandial insulin as Hb. A 1 c approaches target value Postprandial (PPBG) Relative contribution of FBG vs PPBG (%) 70 60 290 T 2 DM patients treated with diet ± oral agents without insulin 50 40 30 20 Baseline (normal) plasma glucose defined as 6. 1 mmol/L (110 mg/d. L) 10 Analysis of 4 -point profiles 0 >10. 2 9. 3– 10. 2 OHA=oral hypoglycaemic agent 8. 5– 9. 2 7. 3– 8. 4 Hb. A 1 c (%) Adapted from Monnier L, et al. Diabetes Care 2003; 26: 881– 5. <7. 3

+ Rationale for starting with basal insulin n Predominant fasting hyperglycemia n Simple titration n n Effective n n A 1 c reduction by 1% - 2. 5%, can be combined with OADs Safe n n One injection a day Start with 10 – 20 units at bedtime and adjust based on fasting glucose Self adjustment of insulin dose Lower risk of hypoglycemia Less weight gain, “anytime injection”

+ 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 Increase dose by 2 U every 3 days until FBG is 90– 130 mg/d. L If FBG is >180 mg/d. L, increase dose by 4 U every 3 days In the event of hypoglycemia or FBG level<70 mg/d. L, reduce bedtime insulin dose by ≥ 4 units, or by 10% if >60 units Continue regimen and check Hb. A 1 c every 3 months FBG = Fasting blood glucose Nathan DM, et al. Diabetes Care 2009; 32: 193– 203.

+ Basal Insulin therapy n The 4 -T demonstrated the benefit of initiating with basal insulin in T 2 D inadequately controlled by OADs, compared with prandial/premixed insulins. n People initiating basal insulin experienced significantly lower rates of hypoglycaemia & less weight gain compared with prandial/premixed insulin. n 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 Hb. A 1 c level achieved + + + Hb. A 1 c 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 n What to do for follow-up n Titration, hypoglycemia, achieving targets

+ Calculating basal and prandial insulin dose based on weight (kg) n Miami 4/12 (normal sensitivity) or 2/6 (poor sensitivity) rule n Divide weight by 4 (or 2) to estimate basal insulin dose n n Basal insulin dose: 96/2 = 43 Divide weight by 12 (or 6) to estimate prandial insulin dose n 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: 10 U/day or 0. 1 -0. 2 U/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 If not controlled Diabetes Care January 2015 vol. 38 no. 1 140 -149 Change to premixed insulin twice daily Add ≥ 2 rapid insulin injections before meals If not controlled

+ Multiple Injections & Dose Titrations: Switching From Pre. Mix OD To BID, Or BID To TID OD to BID • Split the OD dose into equal breakfast and dinner doses (50: 50) • Titrate the doses preferably once a week according to the algorithm 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 • Administer Premixed just before meals • Titrate the doses preferably once a week according to the algorithm below • Discontinue SUs • Administer Premixed just before meals • Continue metformin • Consider discontinuing thiazolidinediones (TZDs) as per local guidelines and practice • Consider discontinuing TZDs as per local guidelines and practice Unnikrishnan et al. Int J Clin. Pract 2009: 63(11): 1571 -77.

+ 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 Elevated glucose during the day and night Royal College of Nursing. http: //www. rcn. org. uk/publications/pdf/ Starting%20 insulin%20 adults%20 with%20 type%202%20 diabetes. pdf, 2005 Increase evening dose by 10% (e. g. from 18 to 20 units) Increase morning dose by 10% (e. g. from 20 to 22 units) Increase morning dose by 10% and increase evening dose by 10%

+ 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%

+ Treatment Strategies: Insulins n Basal insulin: targets FPG > PPG n n n Premixed insulin: targets both FPG and PPG n n n Benefit: only 1 -2 injections per day Drawback: patients may require prandial insulin to reach Hb. A 1 c targets Benefit: fewer injections than prandial Drawback: unable to adjust components separately Prandial (mealtime) insulin: targets PPG > FPG n n Benefit: most physiologic; best at targeting PPG Drawback: most injections; requires addition of basal insulin to target FPG Lasserson DS, et al. Diabetologia. 2009; 52(10): 1990 -2000.

+ Insulin Intensification: Major guidelines target an Hb. A 1 c 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 ADA 1, 2/ EASD 2 FPG <130 mg/d. L (7. 2 mmol/L) Hb. A 1 c <7. 0 % PPG <180 mg/d. L (10. 0 mmol/L) IDF 3 FPG <110 mg/d. L (6. 0 mmol/L) Hb. A 1 c <7. 0 % PPG <160 mg/d. L (9. 0 mmol/L) 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: S 14– 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!!! n Reactive rather than proactive n Corrects for insulin doses when sugars are already risen n In certain situations when it is not possible to predict the requirements, sliding scale may be used for 24 -48 hrs n Never give prandial insulin without basal cover

+ What about OADs while initiating insulin n Metformin, AGIs, DPP 4 i & SGLT 2 i therapy may be continued n SUs may be continued when basal insulin alone is used n Usually SUs should be discontinued when initiated on basalbolus or premix insulins

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

+ Summary n Identify candidates for insulin therapy n n n Select appropriate insulin replacement n n Basal, Prandial, Premix, Basal-Bolus Initiating insulin therapy n n n Very high hba 1 c at presentation Not at goal with maximum tolerated therapy Weight based vs set doses Do not use sliding scale Expected outcomes n n n Most effective agent for lowering Hb. A 1 c Hypoglycemia Weight gain