2024 Management of Diabetes Mellitus with Injectable Agents

Management of Diabetes Mellitus with Injectable Agents KAREN S. FIANO, PHARM.D., BCACP A S S I S T A N T D E A N , A C C R E D I T AT I O N & A S S E S S M E N T EMAIL: [email protected] Lecture Objectives 1. Explain the role of injectable medications (insulin and non-insulin) in the management of dia...

Management of Diabetes Mellitus with Injectable Agents KAREN S. FIANO, PHARM.D., BCACP A S S I S T A N T D E A N , A C C R E D I T AT I O N & A S S E S S M E N T EMAIL: [email protected] Lecture Objectives 1. Explain the role of injectable medications (insulin and non-insulin) in the management of diabetes mellitus. 2. Assess patient appropriateness for initiation of GLP-1 agonists, amylin analogs, and insulin. 3. Compare and contrast between various injectable diabetes medications with regards to potential A1c lowering, CV and renal effects, and adverse effects. 4. Compare and contrast between different insulin delivery devices including insulin pens, pumps, and syringes 5. Discuss the use of continuous glucose monitors (CGMs) in the management of diabetes 6. Design a treatment plan for the following clinical scenarios: ◦ ◦ ◦ ◦ Initiation of a GLP-1 agonist Initiating and adjusting basal insulin Initiating and adjusting mealtime (bolus) insulin Switching between common insulin regimens Focusing Your Studies You are NOT responsible to memorize the brand/generic names of the injectable GLP-1 receptor agonists EXCEPTION – know the brand names for the GLP-1 agent that is available as both orally and as an injectable agent (semaglutide – Ozempic (injectable) vs. Rybelsus (oral tablet) You ARE responsible to know the injection frequency (e.g. weekly or daily) of the GLP-1 receptor agonists and which agents have demonstrated evidence of cardiovascular benefit For insulins Know the general onset, peak and duration of each insulin type (rapid-acting, intermediate acting, longacting) Know the brand and generic names (e.g. Novolog insulin = insulin aspart) Focus on objective #6 – you will be expected to review a patient cases to determine WHEN to initiate injectable agents and how to titrate them based on blood glucose results Supplemental Readings American Diabetes Association (ADA) – Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes – 2024 Section 9 – Pharmacologic Approaches to Glycemic Management Part I: Available Injectable Agents and Overall Principles of Use in DM Three Major Classes of Injectable Agents for DM Insulin GLP-1 Receptor Agonists Dual GLP-1 RA + GIP analog Amylin Analogs General Principles of Injectable Agents Type 1 diabetes mellitus (T1DM) Insulin use is required at the time of diagnosis and is LIFELONG → absolute insulin deficiency Insulin replacement is achieved through multiple daily injections (MDI) using a combination of basal insulin analogs (long-acting insulins) + bolus insulin analogs (rapid-acting insulin analogs) Other injectable agents (e.g. Amylin analogs, or GLP-1 RA (offlabel) may be used if inadequate control achieved Use of diabetes technology (insulin pumps, continuous glucose monitors (CGMs)) can lead to better control vs. MDI and greater quality of life Citation: Diabetes Care 2024;47(Supplement_1):S158–S178 General Principles of Injectable Agents Type 2 diabetes mellitus (T2DM) In patients with established or high/risk of ASCVD, heart failure, and/or CKD, treatment regimen should include agents that reduce cardiorenal risk (e.g. SGLT-2 inhibitors, GLP-1 receptor agonists +/- metformin) Choose regimens that provide adequate efficacy to achieve and maintain treatment goals (metformin, combination oral therapy, GLP-1 RA, combination injectables, insulin) Insulin use Early introduction of insulin should be considered in those with severe hyperglycemia (A1c >10 % or BG ≥ 300 mg/dL) or signs of catabolism Initiated with a basal insulin first (usually dosed once a day at bedtime) A GLP-1 RA is preferred BEFORE transitioning to insulin. GLP-1 RA can also be added to basal insulin to further lower A1c (if not at goal) and address post-prandial glucose elevations Metformin and SGLT-2 inhibitors are usually maintained even with insulin or GLP-1 RA use to limit insulin doses and minimize weight gain Multiple daily injections using a long-acting insulin plus rapid-acting insulin analogs at mealtime is usually the last step for injectable agents Citation: Diabetes Care 2024;47(Supplement_1):S158–S178 Oral medications (may start GLP-1 RA in treatment naïve, especially high-risk or established ASCVD) GLP-1 RA + oral meds GLP-1 RA + oral meds + long-acting insulin analog daily Progression of therapy in T2DM management Long-acting insulin analog daily + rapidacting insulin analogs at mealtime (+/GLP-1 RA and oral meds) Citation: Diabetes Care 2024;47(Supplement_1):S158–S178 ASCVD=atherosclerotic cardiovascular disease Available GLP-1 Receptor Agonists Exenatide (Byetta) Exenatide Extended Release (Bydureon) Liraglutide (Victoza) Dulaglutide (Trulicity) Semaglutide (Ozempic) *Rybelsus (oral tablet) GLP-1 RA – Efficacy, Safety, Monitoring MOA – Refer to Dr. Levin’s Lecture Route – Injected subcutaneously (pre-filled syringe) Efficacy A1c lowering varies based on baseline A1c and background therapy 0.9% to 1.4% reductions vs. placebo Adverse effects Common – Nausea, vomiting, diarrhea, headache, weakness, dizziness Hypoglycemia – more common when used with insulin, sulfonylureas and glinides Weight loss Injection site reactions Contraindications Severe renal impairment or end-stage renal failure (exenatide, lixisenatide) Black Box Warnings (thyroid tumors) Personal or family history of medullary thyroid cancer Personal history of Multiple-Endocrine Neoplasia (MEN) syndrome type 2 Cautions Not recommended in pregnancy or breastfeeding (limited data, other agents preferred) Hypoglycemia risk (see Adverse Effects) May delay gastric emptying – caution in patients with clinically meaningful gastroparesis Pancreatitis GLP-1 RA – Typical Dosing Agent Dosing Exenatide (Byetta) 5 mcg BID; after 1 month may increase to 10 mcg BID Exenatide LAR (Bydureon) 2 mg once weekly Liraglutide (Victoza) 0.6 mg once daily; after 1 week increase to 1.2 mg daily. Max dose 1.8 mg daily Dulaglutide (Trulicity) 0.75 mg weekly; after 1 month may increase to 1.5 mg weekly (may increase up to 4.5 mg/week) Semaglutide (Ozempic) 0.25 mg weekly; after 1 month increase to 0.5 mg weekly, then 1 mg weekly after another month (may increase up to 2 mg/week) Important to Remember – GLP-1 RA are usually titrated over the course of weeks to a month due to GI side effects. Start at lowest dose, then titrate! Agent Frequency of injection Cardiovascular Benefit (vs. placebo) Use in renal/hepatic impairment Exenatide (Byetta) Twice daily Unknown Renal: use not recommended if eGFR exenatide Apply Your Knowledge PJ IS A 52-Y.0. MALE WITH PMH OF T2DM (A1C TODAY= 8.4%), STEMI (2 YEARS AGO, DES PLACED IN LAD), AND HYPERTENSION. HE IS CURRENTLY TAKING METFORMIN 1000 MG BID, EMPAGLIFLOZIN 25 MG DAILY, LISINOPRIL 10 MG DAILY, AND ATORVASTATIN 80 MG DAILY. WHICH AGENT WOULD BE BEST TO ADD TODAY TO PJ’S REGIMEN TO IMPROVE HIS DIABETES CONTROL? A. Exenatide injected subcutaneously twice weekly B. Glipizide 5 mg daly C. Liraglutide injected once daily D. Sitagliptin 100 mg PO daily Apply Your Knowledge Mr. Jones comes to your community pharmacy counter to pick up a prescription for: Trulicity (Dulaglutide) 0.75 mg, Inject into the skin once weekly, 0 refills. He is scheduled to see his physician again in 1 month and has been instructed to bring in his blood sugar log. What are the most common side effects Mr. Jones is likely to experience with this medication? This Photo by Unknown Author is licensed under CC BY-SA-NC Amylin Analogs Indication – T1DM and T2DM currently treated with insulin and not achieving glycemic goals MOA Suppresses post-prandial glucagon secretion Increase satiety Slow gastric emptying Effectiveness – mean A1c reduction ~0.5% Dosing ◦ T1DM – 15 mcg prior to meals, titrated in 15 mcg increments to 60 mcg prior to each meal ◦ T2DM – 60 mcg prior to meals, titrate up to 120 mcg prior to each meal Adverse effects – nausea and hypoglycemia common Recommend reducing bolus insulin dose by 50% with initiation Role in therapy Teplizumab-mzwv (Tzield) to delay onset of T1DM Approved by FDA in November 2022 to delay the onset of Stage 3 type 1 diabetes in adults and pediatric patients aged ≥ 8 years with Stage 2 T1D Must confirm pancreatic islet cell autoantibodies MOA - CD3-directed monoclonal antibody; decreases autoimmune response and destruction of beta-cells Median time to diagnosis with teplizumab significantly longer vs. placebo (48.4 months vs. 24.4 months) Administer by IV infusion (over 30 min) once daily x 14 days (dosing based on body surface area) Cost - $193,000 for treatment course Challenges with implementation Lack of population screening for type 1 diabetes Innovations in Therapy TODAY 100 years ago – insulin created as a therapeutic treatment for type 1 diabetes Insulin Products Test Your Knowledge - Pathophysiology 1. Where is insulin produced in the body? 2. Describe the physiologic actions of insulin. 3. Insulin is released in response to _(increased or decreased)_ blood glucose levels. Glucagon is released in response to _(increased or decreased)_ blood glucose levels. Insulin Overview MOA in diabetes management T1DM – replacement of endogenous insulin T2DM – long-acting insulin suppress hepatic glucose production, leading to improved glucose utilization overnight and in between meals; rapid or short acting insulin provides bolus of insulin to improve glucose utilization at mealtime Adverse effects Injection site reactions (lipohypertrophy) Hypoglycemia (most common, treatment limiting side effect) Weight gain Insulin Overview Basal insulin – sometimes referred to as background insulin; regulates blood glucose between meals and is released 24 hours a day. Restrains hepatic glucose production. When delivered exogenously, basal insulin is injected once or twice a day. Also referred to as “long-acting” insulin. Bolus insulin - released by the pancreas in direct response to ingestion of food in order to manage the rise in blood glucose that occurs with absorption of carbohydrates and other mixed foods. When delivered exogenously, bolus insulin is delivered prior to meals and/or snacks or in between meals to correct elevated blood glucose. Also referred to as “short-acting,” “rapid-acting” or ”prandial” insulin. Availability Most insulin is prescription only OTC insulin preparations include regular insulin, NPH insulin, and Humulin/Novolin 70/30 insulin Pharmacokinetic profiles of currently available insulins. Bolus/Prandial insulin options Basal/Long-acting insulin options Citation: Chapter 91 Diabetes Mellitus, DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. Pharmacotherapy: A Pathophysiologic Approach, 11e; 2020. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577&sectionid=228901946 Accessed: April 09, 2021 Copyright © 2021 McGraw-Hill Education. All rights reserved Insulin Products Insulin is primarily available in a “strength” of U-100 (100 units per mL) More concentrated insulin products (e.g., U-200 lispro, U-300 glargine, U-500 regular insulin) are available Dosing is in UNITS Insulin is dispensed either in a 10-mL vial OR a prefilled insulin pen Insulin can also be delivered in an insulin pump Delivered subcutaneously Only regular insulin can be delivered intravenously (IV) Insulin can be stored in the refrigerator (until the printed expiration date) May be stored at room temperature for 14 to 42 days, depending on the product Exception – Afrezza (Technosphere insulin) is inhaled Apply Your Knowledge – Dr. Gazze Lecture Match the insulin product on the left with its onset on the right: NPH Insulin Regular insulin Insulin aspart (Novolog) 15 min 30 minutes 2 hours Available Insulin Products Product Onset Peak Duration Rapid-acting analogs Lispro “follow on” (Admelog) 15 – 30min Lispro-aabc (Lyumjev) (U-100 and U200 available) Lispro (Humalog) U-200 Humalog 15 -30 min 1.5 hours 1.5 hours 3 -5hours 3-5 hours 15 – 30min 1.5 hours 3 -5hours Glulisine (Apidra) 15 – 30min 1.5 hours 3 -5hours Aspart (Novolog) 15 – 30min 1.5 hours 3 -5hours Aspart (Fiasp) 15 – 20min 1.5 -2hours 5 -7hours 0.75 -1hour ~3 hours 2 – 3hrs 4 – 6hrs Vitamin B3 and L-arginine added *enters bloodstream in 2.5 minutes Technosphere inhaled insulin (Afrezza) 5 – 10min Short-acting insulin Regular insulin (Humulin, NovolinR) 0.5 – 1hr Table adapted from Table 91-7DiPiro et al, 11thedition. Chapter 91– DiabetesMellitus Available Insulin Products Product Onset Peak Duration 2 – 4hrs 4 – 8hrs 8 – 12hrs Insulin glargine U-100(Lantus) ~2 – 3 hrs None 22 – 24hrs Insulin glargine U-300(Toujeo) ~2 hrs None 24 – 30hrs Insulin glargine biosimilar U-100 (Basaglar) ~2-3 hrs None 22 – 24hrs Insulin glargine “interchangeable biosimilar”(glargine-yfgn) (Semglee) Insulin detemir U-100(Levemir) (pens discontinued April 2024; vials available until December 2024) Insulin degludec (Tresiba) U-100 and U-200 available 2-3 hrs None 22-24 hrs ~2 hrs None (debatable)a 14 – 24hrsb ~2 hrs None 30 – 36hrs Intermediate-acting NPH insulin (Humlin N, Novolin N, ReliOn) Long-acting Long-acting analogs offer less hypoglycemia, especially nocturnal hypoglycemia vs.NPH a =Small peak noted around 8 hrs b =Interindividual variation, lower units/kg/day generally need BID dosing of Levemir (such as in T1DM) Available Insulin Products – Combination Insulins  NPH and Regular combinations  Humulin/Novolin 70/30 – 70% NPH and 30% Regular  NPH-like (protamine added to rapid analog) + rapid-acting analog combinations  Novolog Mix 70/30 =70% aspart protamine +30% aspart  Humalog Mix 75/25 = 75% lispro protamine + 25% lispro  Humalog Mix 50/50 = 50% lispro protamine + 50% lispro  Using combination insulin  Formulations are cloudy; must mix suspension before use by rolling in hands 15 to 20 times  Adjusting dose adjusts BOTH both components  Base timing of dosing around the mealtime coverage component (regular or rapid-acting insulin)  Most useful for individuals with predictable/fixed schedules and regular meals Difference between Humulin/Novolin and Humalog/Novolog  Humulin and Humalog produced by Eli Lilly  Novolog and Novolin are produced by Novo-Nordisk  Remember Humulin OR Novolin can be NPH or R insulin Other Insulin Products  U-500 Insulin  5 times more potent than U-100 regular insulin  Considered in patients with total daily insulin doses >200 units per day and cases of extreme insulin resistance  Medication errors are common  BID to TID dosing leads to a “long-acting” kinetic profile similar to NPH  Patients usually ONLY use U-500 insulin; rarely additionalbolus coverage may be needed  May be used in insulin pumps 29 Combination Therapy – GLP-1 RA and Long-Acting Insulin Two products available: Insulin degludec/liraglutide (Xultophy 100/3.6) Insulin glargine/lixisenatide (Soliqua 100/33) Can be used in insulin naïve or GLP-1 naïve patients, or to transition a patient from insulin or GLP-1 RA alone to the combination (combo leads to better A1c reduction ~0.5 to 1% vs. insulin alone) Best used for patients with low to moderate insulin needs (15 to 60 units per day) Maximum doses are 50 units per day (Xultophy) and 60 units per day (Soliqua) Challenges with titration (adjusting BOTH components) Other Insulin Products – Inhaled Insulin  Technosphere insulin (Afrezza)  Dry-powder inhalation device  Cartridges available in 4, 8, and 12 unit doses  Contraindicated in those with asthma and COPD  Can reduce FEV1 which appears to resolve after discontinuing treatment  Discontinue if FEV1 decline ≥20% observed  Use not recommended in smokers  Pulmonary function testing (PFT) should be performed at baseline, 6 months after initiation and annuallythereafter Afrezza prescribing information: https://afrezza.com/wpcontent/uploads/2023/02/Full-Prescribing-Information-Feb-2023.pdf Insulin Delivery Devices Insulin Vial and Syringe Least costly option Technique is critical, re-evaluate often, avoid for patients with vision or dexterity issues Insulin Pens Often preferred by patients for ease of use. Good for those with vision/dexterity issues Beware of maximum delivery capacity (60 to 160 units depending on insulin pen) Insulin Pumps Can modestly improve A1c (~0.3%) vs. multiple daily injections Reduces severe and nocturnal hypoglycemia May be combined with continuous glucose monitors (CGMs) Calculating Days Supply of Insulin - Vials U-100 insulin vials contain 10 mL 100 units per mL x 10 mL = 1000 units per vial Mr. Carter presents the following prescription for Lantus insulin vials. Calculate the number of insulin vials needed to fulfill the prescription for a 30-day supply. Answer = 55 units x 30 days = 1650 units needed for 30 day supply 1650 units / 1000 units per vial = 1.65 vials → 2 vials needed to fulfill 30 day supply How many days will 2 vials last? 2000 units / 55 units per day = 36.4 → 36 days Lantus Insulin (U-100) vial #qs x 30 day supply Inject 55 units into the skin every night at bedtime. Dr. Madison Calculating Days Supply of Insulin – Insulin Pens Insulin pens are packaged with 5 pens per box Each pen contains 3 mL (U-100 insulin) 100 units per mL x 3 mL = 300 units per pen Mr. Carter is now taking Tresiba 60 units into the skin daily at bedtime. How many insulin pens should be dispensed to Mr. Carter for a 30-day supply of Tresiba? Answer: 60 units x 30 days = 900 units needed for a 30-day supply 900 units / 300 units per pen = 3 pens needed to fulfill a 30-day supply Continuous Glucose Monitors (CGMs) Measure interstitial glucose through use of a sensor which is placed below skin Replaced every 7 to 10 days Readings are sent to a receiving device May require calibration with fingerstick High and low alerts can be turned on to alert patient to rapid rises and falls in BG and when values cross programmed thresholds Integrate with insulin pumps to provide closed loop artificial pancreas technology Reduce hemoglobin A1c and reduce time spent in hypoglycemia Best results with consistent (daily) use Available products Real-time CGM – Dexcom G6 and G7, Freestyle Libre 3 Intermittently scanned CGM – Freestyle Libre 2 “Artificial Pancreas” Medtronic 770G Insulin Pump (with Guardian RT CGM) Tandem T:slim X2 with Control IQ Technology (Dexcom G6 or G7 CGM) Omnipod 5 with Dexcom G6 integration Part II: Initiation and Titration of Insulin Products Insulin Initiation – T1DM Insulin is initiated with both a long-acting and rapid-acting insulin and is based on weight Total daily dose is weight-based (estimated starting dose =0.5 units/kg/day) Amount split 50% between long-acting insulin (e.g. glargine, detemir, degludec) and 50% rapid-acting insulin analog (e.g. aspart, lispro, glulisine) Example – Jessie is a 10 yo F newly diagnosed with T1DM following episode of DKA Her weight is 65 pounds. Convert weight to kg →30 kg (remember 2.2 lbs per kg) Find total daily dose – 30 kg x 0.5 units/kg/day = 15 units of insulin needed per day Divide into long-acting and rapid-acting insulin amounts (remember – split 50/50) 7.5 units long-acting 7.5 units rapid-acting → split between 3 meals a day Example regimen = 7.5 units (~8 units) of insulin glargine at bedtime and 2 to 2.5 units of insulin aspart 15 minutes before each meal Diabetes Care 2024;47(Supplement_1):S158–S178 Advanced Insulin Dosing – T1DM Rapid-acting insulin analog doses must be matched with carbohydrate intake to produce stable post-prandial (after meal) blood sugar levels Carbohydrate ratios Amount of insulin delivered to cover X grams of carbohydrates Example – 1:10 Insulin sensitivity factors (ISF) Amount of insulin delivered to correct or lower elevated blood sugar to a pre-determined target BG Example – 1:50 >100 mg/dL = 1 unit of insulin is needed to lower blood glucose by 50 mg/dL to a target of 100 mg/dL Carbohydrate ratios and ISF may be used in some individuals with T2DM that are on multiple-daily insulin injections and can successfully count carbohydrates Insulin Initiation – T2DM Progress to insulin when: Signs of catabolism (weight loss), symptoms of hyperglycemia, and very high BG (A1c ≥ 10% or BG ≥ 300 mg/dL) OR Not achieving A1c goal despite use of multiple oral agents ± GLP-1 receptor agonist Initiate long-acting (basal) insulin FIRST Dosing 10 units per day (fixed dosing) OR 0.1 to 0.2 units/kg/day (weight-based dosing) Agent is usually dosed at bedtime, although can do AM if adherence issues Titrate by 2 units every 3 days to reach fasting plasma glucose target (goal 80 to 130 mg/dL) Reduce dose by 1 to 2 units if hypoglycemia occurs and cannot identify a cause (e.g. skipped meal) Diabetes Care 2024;47(Supplement_1):S158–S178 Apply Your Knowledge Alex B. is a 69-year-old male with long-standing T2DM. He is currently taking metformin 1000 mg BID, dapagliflozin 10 mg once daily, and liraglutide 1.2 mg injected once weekly. He also has hypertension, hyperlipidemia, and BPH. His current A1c is 9.2%. He weighs 224 lbs. He is covered through a Medicare Part D plan (formulary below). Drug Name Drug Tier (cost per 30day supply) Lantus Solution 100 unit/ml 3 ($30) Tresiba Solution 100 unit/mL 4 ($50) 1. Would you initiate insulin in this patient? Why or why not? 2. If you do initiate insulin, what dose and agent would you start him on? Choosing Between Long-Acting Insulins U-100 insulin glargine or detemir have reduced risk of nocturnal and symptomatic hypoglycemia vs. NPH insulin Modest effect and may not persist with long-standing therapy Newer ultra-long acting analogs (U-300 insulin glargine and degludec) have a lower hypoglycemia risk when combined with oral agents In practice, the BEST option is what is best for your patient’s lifestyle and insurance coverage/formulary Irregular lifestyle and adherence issues – Degludec (Tresiba) Cost issues (cash pay, underinsured) – NPH Insulin (least expensive) Medicare, Medicaid coverage or adequate commercial coverage – glargine or detemir are “gold standard” Diabetes Care 2024;47(Supplement_1):S158–S178 Titrating Basal Insulin Alex B. has returned to your clinic 1 month later. Below is a 7-day blood sugar log. He is still taking his metformin, dapagliflozin, and liraglutide. He has been injecting 15 units of insulin glargine (Lantus) into the skin every night at bedtime x 1 month. Day Fasting 1 186 2 192 3 201 4 152 5 140 6 163 7 138 Pre-Dinner 200 225 What adjustments, if any, would you make to the patient’s insulin dose? Adjusting or Discontinuing Oral DM meds with initiation of insulin Metformin should be continued SGLT-2 inhibitors usually continued with insulin therapy (may reduce the amount of insulin needed) May continue thiazolidinediones (TZDs) (insulin sensitizer), although weight gain common Sulfonylureas and DPP-4 inhibitors are typically weaned or discontinued Sulfonylureas = risk of hypoglycemia DPP-4 inhibitors = limited effectiveness in reducing A1c Glinides should typically not be used, especially as you progress to prandial/bolus insulin GLP-1 receptor agonists – often used with basal insulin (lower A1c vs. either agent as monotherapy), with prandial insulin must balance injection burden Diabetes Care 2024;47(Supplement_1):S158–S178 Initiating and Adjusting NPH Insulin NPH is intermediate acting insulin Initial dosing is usually once a day at bedtime 10 units or 0.1 to 0.2 units/kg/day If A1c remains above target, NPH insulin can be converted to twice daily 2/3 of total daily dose (TDD) before breakfast 1/3 of TDD in evening (usually at bedtime) Titration: 2 units every 2 to 3 days based on FASTING blood sugars. Adjusting Twice Daily NPH Insulin Breakfast dose usually peaks at lunchtime When adjusting NPH, remember to evaluate blood sugars during the peak of activity and before the next dose. Breakfast dose – duration 8 to 12 hours Bedtime dose– duration 8 to 12 hours Initiating Prandial Insulin Initiate when: Basal insulin is adequately titrated to FPG goal (80 to 130 mg/dL) and A1c is not controlled OR Basal dose is >0.5 units/kg/day and inadequate A1c control (“overbasalized”) Dosing Initiate at ONE meal (largest glucose excursion) 4 units before largest meal OR 10 % of basal dose Titrate by 1 to 2 units or 10-15% of dose twice weekly If hypoglycemia occurs, reduce dose by 10-20% Add to each subsequent meal Diabetes Care 2024;47(Supplement_1):S158–S178 Choosing Between Prandial Insulin Options Short-acting insulin Regular Insulin (Humulin R, Novolin R) Kinetics not ideal for mealtime insulin Dose 30 minutes prior to meal Rapid-acting insulin analogs – PREFERRED** Insulin lispro (Humalog), Insulin aspart (Novolog), Insulin glulisine (Apidra), biosimilars Dose 15 minutes prior to or at start of meal “Ultra-rapid” acting insulin analog Insulin aspart (Fiasp) – onset 2.5 minutes, however similar peak to Novolog Can be dosed within 20 minutes of start of meal per labeling If you skip a meal, skip your dose of prandial insulin Titrating Prandial Insulin Lunchtime BG = adjust prebreakfast ❑If patients are using a multiple daily injections (MDI) consisting of basal plus prandial insulin, they should ideally be monitoring blood glucose 3 to 4 times per day ❑Historically, post-prandial blood glucose values were recommended to be measured 2 hours after meals ❑Pre-meal blood glucose values can provide similar information and are easier for patients to incorporate into daily routine ❑Adjustments in prandial insulin can be performed using the following pre-meal value: Pre-bedtime BG =adjust predinner ❑Example – if pre-dinner value is elevated the pre-LUNCH prandial insulin amount should be adjusted Dinner BG =adjustpre-lunch Apply Your Knowledge Ned is a 56-year-old male who has had T2DM for the last 5 years. His weight =109 kg, height = 6’0”. His current medication includes metformin 1000 mg BID, dapagliflozin 10 mg once daily, and dulaglutide 3 mg weekly. His A1c today is 9.3%. His physician would like to initiate basal insulin today. What option is BEST to recommend today? (Select All that Apply) A. Novolog insulin 10 units into the skin at bedtime B. Tresiba insulin 15 units into the skin at bedtime C. NPH insulin 35 units into the skin at bedtime D. Lantus 10 units into the skin at bedtime Bonus question – What would you do with his oral agents? Apply Your Knowledge It is a year later and Ned is referred again to your diabetes clinic for management. At this time he is on Lantus 75 units of nightly at bedtime, metformin 1000 mg BID, and dapagliflozin 10 mg daily. He stopped the dulaglutide about 6 months ago due to cost. His weight today is 112 kg. His A1c today is 7.8% and his glucose log reveals glucose elevations prior to each meal, most notably at lunchtime. In speaking to him, he tells you his largest meal of the day is breakfast because he is “starving” in the morning. Which option(s) would be BEST to recommend for Ned at this time? A. Add insulin lispro 7 units before breakfast B. Add insulin lispro 7 units before each meal C. Increase Lantus to 80 units D. Add insulin lispro 4 units before breakfast Apply Your Knowledge NED COMES BACK TO CLINIC 1-MONTH AFTER INITIATING INSULIN LISPRO, 7 UNITS WITH BREAKFAST. HE CONTINUES WITH LANTUS 75 UNITS NIGHTLY AT BEDTIME AND METFORMIN 1000 MG BID. HIS BLOOD GLUCOSE LOG IS BELOW. WHICH ADJUSTMENT WOULD YOU RECOMMEND TO HIS INSULIN REGIMEN? A. Increase pre-breakfast insulin lispro dose to 9 units B. Increase pre-breakfast insulin lispro dose to 12 units C. Add insulin lispro 7 units before lunchtime D. Add insulin lispro 7 units before lunch and dinner. Day Fasting 1 2 3 4 5 6 7 152 120 138 101 122 130 97 PreLunch 198 183 182 225 190 157 168 PreDinner 205 172 210 255 162 191 203 Bedtime 152 148 136 201 159 140 132 Using Combination Insulin Products Less flexible than individual intermediate/longacting and rapid acting components Biphasic analogs (Novolog and Humalog mix) provide better post-prandial coverage but are more $$ Consistent schedules and meals (carbohydrates) are needed for success on this regimen Adjust doses backwards using pre-breakfast and pre-lunch/dinner values (same concept as prandial insulin)  NPH and Regular combinations  Humulin/Novolin 70/30 – 70% NPH and 30% Regular  Dosed ______ min before breakfast and dinner  NPH-like (protamine added to rapid analog) + rapid-acting analog combinations  Novolog Mix 70/30 =70% aspart protamine +30% aspart  Humalog Mix 75/25 = 75% lispro protamine + 25% lispro  Humalog Mix 50/50 = 50% lispro protamine + 50% lispro  Dosed ______ min before breakfast and dinner Switching Between Insulins Often necessary due to cost and insurance formulary changes While guidelines are provided, there can be interpatient variability In most cases, a 1:1 switch is appropriate, but there are exceptions Switching Insulins Chart Current Insulin Switching To Conversion Notes Lantus Levemir 1:1 Note – Levemir no longer available after 2024 Lantus or Levemir NPH 1:1 May need to split NPH dose to BID dosing for comparable 24hour coverage NPH (dosed BID) Lantus or Levemir Reduce dose by 20% and give Lantus/Levemir once a day Toujeo (glargine U-300) Glargine (U-100) or Basaglar Reduce dose by 20% Due to long half-life of U-300, increased risk of hypoglycemia Lantus or Levemir Toujeo (glargine U-300) 1:1 Full glucose lowering effect may take up to 5 days Degludec Lantus Levemir or glargine U-300 Reduce dose by 20% Lantus Basaglar or Semglee 1:1 See Helpful Chart posted in Canvas “How to Switch Insulin Products” Sociobehavioral Considerations in DM care Drug affordability – especially insulin Cultural beliefs, family influence – especially around food Carbohydrate rich diets and impact on glucose levels Fasting and Ramadan – management of medications Higher burden of depression in patients with diabetes Diabetes “burnout” High degree of patient motivation required Majority of care decisions are done AT HOME by the patient Questions?