Insulin Initiation and Titration in Type 2 Diabetes

Learning Objectives Insulin Initiation and Titration in Type 2 Diabetes Toronto East General Hospital Drugs & Therapeutics Update April 24, By the end of this session, participants will be able to: 1. Understand the different types of insulin, dosing regimens, and principles in the management of type 2 DM; and 2. Apply this knowledge to the initiation and titration of insulin in clinical practice. Jim Jim 54 yo M T2DM x 10 yrs HTN, hyperlipidemia Chronic knee pain Smoker, occ. EtOH Depression Limited exercise, irregular meals Married, 2 step children, stress ++, conflict ODSP metformin 1 g BID sitagliptin (Januvia) 100 mg OD glyburide 5 mg BID other meds for lipids, HTN, depression, chronic pain FBS 11.7 HbA1C 9.1% egfr 110 BMI 32 Now what? Increase the dose of metformin +/- glyburide? Add another hypoglycemic agent? Encourage greater lifestyle modification? Start insulin? Refer to Endo? Refer to your local DEP/DEC? Victor 59 years old FBS 6.7 mmol/l A1C 6.2% www.guidelines.diabetes.ca Does he have diabetes?

Diagnosis of Diabetes FPG 7.0 mmol/l Fasting = no caloric intake for at least 8 hours or A1C 6.5% (in adults) Using a standardized, validated assay, in the absence of factors that affect the accuracy of the A1C and not for suspected type 1 diabetes or 2hPG in a 75-g OGTT 11.1 mmol/l or Random PG 11.1 mmol/l Random= any time of the day, without regard to the interval since the last meal Diagnosis of Prediabetes* Test Result Prediabetes Category Fasting Plasma Glucose (mmol/l) 2-hr Plasma Glucose in a 75-g Oral Glucose Tolerance Test (mmol/l) Glycated Hemoglobin (A1C) (%) 6.1-6.9 Impaired fasting glucose (IFG) 7.8 11.0 Impaired glucose tolerance (IGT) 6.0-6.4 Prediabetes * Prediabetes = IFG, IGT or A1C 6.0-6.4% high risk of developing T2DM 2hPG = 2-hour plasma glucose; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test; PG = plasma glucose VICTOR Lost to follow up and shows up 3 years later FBS 9.0 mmol/l A1C 8.3% Targets Checklist A1C 7.0% for MOST people with diabetes A1C 6.5% for SOME people with T2DM A1C 7.1-8.5% in people with specific features What are the A1C targets for Victor? Individualizing A1C Targets Consider 7.1-8.5% if: What do you prescribe for his glucose control? which must be balanced against the risk of hypoglycemia

Pharmacotherapy in T2DM Checklist CHOOSE initial therapy based on glycemia START with Metformin +/- others INDIVIDUALIZE your therapy choice based on characteristics of the patient and the agent REH TARGET within 3-6 months of diagnosis GET TO TARGET WITHIN 3-6 MONTHS OF DIAGNOSIS Initial Choice of Therapy Depends on Glycemia Initial A1C <8.5% Start metformin OR Reassess in 2-3 months then decide on starting metformin Initial Choice of Therapy Depends on Glycemia Symptomatic Polyuria Hyperglycemia Polydipsia + Weight loss Metabolic Volume depletion Decompensation Initial A1C 8.5% Start metformin AND Consider combo therapy to achieve 1.5% A1C reduction Concern about Insulin Deficiency INSULIN +/- Metformin What Comes After Metformin? Depends Patient characteristics Degree of hyperglycemia Risk of hypoglycemia Weight Comorbidities (renal, cardiac, hepatic) Access to treatment Agent characteristics BG lowering efficacy & durability Risk of inducing hypoglycemia Effect on weight Contraindications & side effects Cost and coverage Patient preferences Other

What are the Barriers to Insulin Therapy? Resistance to Insulin Therapy Patient Low perceived clinical efficacy High self-blame/ failure Negative history, perceived harm Fear of needles Permanence/Restrictivenes s Weight gain, hypoglycemia Provider Wait until absolute necessity Reluctance/delay to use OHAs Low perceived clinical efficacy Use of strategy: insulin = poor self-management Perception of patients Lack of knowledge/experience Lack of time, support Insulin Insulin Manufactured insulin is designed to mimic the properties of endogenous insulin Properly dosed low risk Greatest potential reduction in A1C Hypoglycemia most frequent AE but not common Weight gain may occur Allergic reactions rare When to start? How to choose insulin type and regimen? How to dose? What to do with the oral agents? Insulin in T2DM: When to Start? Insulin in T2DM: The Rule of 3 s At any point when glycemic control is inadequate (KEY POINT) Metabolic decompensation End-organ failure Pregnant or planning pregnancy Temporarily for acute illness, stress or medical procedure/surgery 3 insulin categories 3 insulin regimens 3 insulin dosing principles Alice Cheng, 2011

Insulin in T2DM: 3 Categories Types of Insulin Insulin Type (trade name) Onset Peak Duration 1. Basal 2. Bolus (meal time) 3. Premixed Bolus (prandial) Insulins Rapid-acting insulin analogues (clear): Insulin aspart (NovoRapid ) Insulin glulisine (Apidra ) Insulin lispro (Humalog ) Short-acting insulins (clear): Insulin regular (Humulin -R) Insulin regular (Novolin getoronto) Basal Insulins Intermediate-acting insulins (cloudy): Insulin NPH (Humulin -N) Insulin NPH (Novolin ge NPH) Long-acting basal insulin analogues (clear) Insulin detemir (Levemir ) Insulin glargine (Lantus ) 10-15 min 10-15 min 10-15 min 1-1.5 h 1-1.5 h 1-2 h 3-5 h 3-5 h 3.5-4.75 h 30 min 2-3 h 6.5 h 1-3 h 5-8 h Up to 18 h 90 min Not applicable Up to 24 h (glargine 24 h, detemir 16-24 h) Types of Insulin (continued) Insulin in T2DM: 3 Regimens Insulin Type (trade name) Premixed Insulins Premixed regular insulin NPH (cloudy): 30% insulin regular/ 70% insulin NPH (Humulin 30/70) 30% insulin regular/ 70% insulin NPH (Novolin ge 30/70) 40% insulin regular/ 60% insulin NPH (Novolin ge 40/60) 50% insulin regular/ 50% insulin NPH (Novolin ge 50/50) Premixed insulin analogues (cloudy): 30% Insulin aspart/70% insulin aspart protamine crystals (NovoMix 30) 25% insulin lispro / 75% insulin lispro protamine (Humalog Mix25 ) 50% insulin lispro / 50% insulin lispro protamine (Humalog Mix50 ) Time action profile A single vial or cartridge contains a fixed ratio of insulin (% of rapid-acting or short-acting insulin to % of intermediate-acting insulin) 1. Basal insulin once daily 2. Basal + bolus insulin 3. Premixed insulin twice daily Serum Insulin Level Serum Insulin Level Time Human Basal: Humulin-N, Novolin ge NPH Human Bolus: Humulin-R, Novolin ge Toronto Analogue Basal: Lantus, Levemir Analogue Bolus: Apidra, Humalog, NovoRapid Time Human Premixed: Humulin 30/70, Novolin ge 30/70 Analogue Premixed: Humalog Mix25, NovoMix 30

Insulin in T2DM: 3 Dosing Principles 1. Whatever starting dose you select will be wrong 2.Titration is key to success 3.There is no maximum dose of insulin Jim Start Insulin? Jim 4 Weeks Later 54 yo M T2DM x 10 yrs HTN, hyperlipidemia Chronic knee pain Smoker, occ. EtOH Depression Limited exercise, irregular meals Married, 2 step children, stress ++, conflict ODSP metformin 1 g BID sitagliptin (Januvia) 100 mg OD glyburide 5 mg BID Other meds for lipids, HTN, depression, chronic pain FBS 11.7 HbA1C 9.1% egfr 110 BMI 32 Date Breakfast Lunch Supper Bedtime Sun 13.5 12.2 Mon 11.4 9.7 Tues 12.7 9.8 10.3 Wed 14.0 10.2 Thurs 11.3 9.9 Fri 10.8 11.3 Sat 14.2 12.2 You refer Jim to your local DEP where he is provided with a meter and teaching re SMBG The DEP providers have explored initiating insulin and he presents with his logbook and a readiness to start What will you do? Basal Insulin Once Daily To achieve A1C 7.0% Start at 10 U at bedtime A1C (%) Preprandial PG (mmol/l) 2-h postprandial PG (mmol/l) Increase by 1 U every night until target FBS achieved Most will require 40-50 U (but remember no max dose!) Reduce the dose if any hypoglycemia For most patients 7.0 4.0-7.0 5.0-10.0 (5-8 if A1C not at target)

Jim Another 4 Weeks Later Jim Yet Another 4 Weeks Later Date Breakfast Lunch Supper Bedtime Sun 9.9 6.2 Mon 8.2 4.9 Tues 7.9 6.9 7.5 Wed 6.9 4.0 Thurs 9.1 5.9 4.1 Fri 8.2 6.1 Sat 8.1 8.5 5.9 Jim has been titrating his glargine (Lantus) as directed He s now at 34 U at bedtime He reports feeling lightheaded & dizzy in the afternoon Jim presents to your office for follow up He has experienced no further lows since stopping the glyburide and generally is feeling better overall He has stopped titrating up because he hit 50 U Day Breakfast Sunday 6.4 Monday 7.3 Tuesday 6.8 Wednesday 7.9 Thursday 7.6 Friday 6.9 Saturday 8.7 Jim 2 Years Later Jim 2 Years Later 56 yo M BS have been well controlled until recently Tries hard to make lifestyle modifications but is continuing to struggle with a chaotic schedule metformin 1 g BID sitagliptin (Januvia) 100 mg OD glargine (Lantus) 55 U at QHS HbA1C 8.1% egfr 97 BMI 32 Date Breakfast Lunch Supper Bedtime Sunday 6.9 11.2 Monday 5.2 6.9 Tuesday 6.1 6.9 8.9 Wednesday 6.9 7.3 Thursday 5.8 5.9 6.2 Friday 6.4 10.6 Saturday 7.1 7.3 12.8 Basal + Bolus Insulin Bolus = Start with 2-4 U Titrate targeting 2 hr PC BS or next meal/hs Stop all OHAs except metformin Basal + Bolus Insulin If insulin naïve then: TDI = 0.5 U/kg 40% TDI = basal dose 60% TDI = bolus dose (divided into 3 meals) Titrate basal to FBS and bolus to either 2 hr PC BS or BS next meal Example 70 kg M TDI = 0.5 U/kg x 70 kg = 35 U Dosing regimen: 40% x 35 U = 14 U basal insulin at HS 60% x 35 U/3 meals = 7 U /@ meals

Nancy Nancy 3 weeks later 55 yo F New pt to practice T2DM x 12 yrs, started on insulin 1 yr ago HTN, hyperlipidemia, GERD Smokes, no EtOH Works PT, stressful job, married, 3 children Metformin 1 g BID gliclazide modified release (Diamicron MR) 120 mg OD NPH 22 U @ HS FBS 11.2 HbA1C 8.4% egfr 102 Unscheduled follow up appointment Nancy has been titrating her NPH as per instructions and is now at 36 U NPH @ HS She reports that her FBS have been running high recently (after initially improving) and notes that she is feeling more tired, less well overall FBS 11.3 Now what? Nancy 15 months later Nancy 15 months later NPH reduced to 28 U and she gradually has titrated upward and is now at 32 U FBS have normalized, and HbA1C was <7% at 6 months follow up But now her A1C is rising again and FBS remain normal Date Breakfast PC Breakfast PC Lunch PC Supper Monday 5.8 10.7 10.9 Tuesday 6.1 12.3 Wednesday 6.8 13.7 Thursday 7.1 14.0 Friday 5.9 13.0 Saturday 6.6 12.3 Sunday 11.8 Premixed Insulin Twice Daily To achieve A1C 7.0% Start at a dose of 5-10 U twice daily A1C (%) Preprandial PG (mmol/l) 2-h postprandial PG (mmol/l) Titrate breakfast dose to supper BS 4-7 Titrate supper dose to next day FBS 4-7 Safe to increase by 1 U/day For most patients 7.0 4.0-7.0 5.0-10.0 (5-8 if A1C not at target)

Nancy One Year Later Nancy Two Years Later Now 57 yo F Started on a premixed analogue now at 22 U at breakfast and 14 U at supper metformin 1 g BID A1C 6.7% FBS 6.2 Date Breakfast Lunch Supper Bedtime Sunday 5.8 6.8 Monday 6.3 4.1 Tuesday 6.7 6.3 5.9 Wednesday 7.0 3.9 Thursday 6.1 5.8 3.9 Friday 4.9 6.2 6.2 Saturday 6.8 6.5 George George 75 yo M T2DM x 20 yrs Meds: Metformin 1000 mg BID, glyburide 10 mg BID, sitagliptin 100 mg PO OD HbA1C 9% Wt 80 kg Options: Start basal insulin? Start mixed insulin? And what about the OHAs? Option #1 Start basal insulin at HS and titrate by 1 U daily until FBS 4-7 Start at 10 U Cont. metformin +/- sitagliptin D/C glyburide b/c risk of hypoglycemia Option #2 Start 5-10 U mixed insulin breakfast and supper Titrate to supper BS 4-7 and next day FBS 4-7 Cont. metformin, D/C glyburide + sitagliptin George Diabetes in the Elderly Checklist On pre-mixed (30/70) 25 U AM, 15 U supper HbA1C 7.8% Experiencing lows 2 hrs. after breakfast, corrects with orange juice Breakfast Lunch Supper 10 12 10 12 10 15 7 9 What s the pattern? Highs/lows? What decision re insulin? Bedtime ASSESS for level of functional dependency (frailty) INDIVIDUALIZE glycemic targets based on the above (A1C 8.5% for frail elderly) but if otherwise healthy, use the same targets as younger people AVOID hypoglycemia in cognitive impairment SELECT antihyperglycemic therapy carefully Caution with sulfonylureas or thiazolidinediones Basal analogues instead of NPH or human 30/70 insulin Premixed insulins instead of mixing insulins separately GIVE regular diets instead of diabetic diets or nutritional formulas in nursing homes

Among Frail Elderly Parameter A1C FPG or preprandial glucose FPG= Fasting Plasma Glucose Target 8.5% 5.0-12.0 mmol/l (depending on level of frailty) AVOID HYPOGLYCEMIA Add an agent best suited to the individual (agents listed in alphabetical order): Class Relative A1C Lowering Hypoglycemia Weight Other therapeutic considerations Cost glucosidase inhibitor (acarbose) Incretin agents: DPP 4 Inhibitors GLP 1 receptor agonists Rare Neutral to Improved postprandial control, GI side effects Rare N to May use detemir or glargine instead $$$ of to Rare GI side effects NPH or human 30/70 for less hypos $$$$ Premixed insulins and prefilled insulin pens instead of mixing insulin to Insulin Yes No dose reduce ceiling, dosing flexible errors regimens $ $$$$ Insulin secretagogue: *Less CAUTION hypoglycemia in the in elderly context of Meglitinide Yes* missed Initial meals doses but = usually HALF requires of usual dose $$ Sulfonylurea Yes TID Avoid to QID glyburide dosing $ Gliclazide Use gliclazide, and glimepiride gliclazide associated MR, with glimepiride, less hypoglycemia nateglinide than or repaglinide glyburide instead Thiazolidinediones Rare CHF, CAUTION edema, fractures, in the elderly rare bladder $$ cancer Increased (pioglitazone), risk of cardiovascular fractures controversy Increased (rosiglitazone), risk of heart 6 12 failure weeks required for maximal effect Weight loss agent (orlistat) None GI side effects $$$ $$ Diabetes Education Programs Education and support for people with T2DM, prediabetes and at risk Self-management support, incl. motivational interviewing, goal setting and action planning Medication support/consultation Insulin initiation and titration +/- ordering DM labs (A1C) **** Care coordination **** Staffed by RN and RD, generally CDE Community based Summary Counsel all Patients About Sick Day Medication List Insulin is safe and effective in the management of type 2 DM Most important step is titration and not the starting dose Use the rule of 3 s to guide its use Use your local DEP Be aware of your own resistance