Quick Reference Guide 2/2020 version Management of Type 2 Non- and Insulin Therapies

Soe Naing, MD, MRCP(UK), FACE Associate Clinical Professor of Medicine Director of Division of Medical Director of Community Diabetes Care Center UCSF-Fresno Medical Education Program

Page 1: Overview of -lowering agents Page 2: "Regimen" selection guide Page 3: "Medication class" selection guide Page 4: Prescription page Page 5: CKD and medication dose adjustment Page 6: Medications (brand names) in alphabetical order Page 7: Insulin therapy guide (basic) Page 8: "GLP1 RA and SGLT2" selection guide Page 9: ADA 2020 guide on non-insulin therapy Page 10: AACE 2020 guide on non-insulin therapy Page 11: Human insulin in patients with cost issue Page 12-15: Advanced insulin therapy

References:

STANDARD OF MEDICAL CARE IN DIABETES 2020 https://care.diabetesjournals.org/content/43/Supplement_1

American Association of Clinical Endocrinologists 2020 Comprehensive Management Algorithm https://www.aace.com/pdfs/diabetes/algorithm-exec-summary.pdf

For digital copy, please visit http://www.fresno.ucsf.edu/internal-medicine/endo_downloads/ or email [email protected]. Naing/2-2020 1

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Naing/2-2020 3 Comparison of Glucose-Lowering Medications # 1 Use this table to choose a class of medication – Consider the factors in first column, that will impact the medication choice.

4 Major groups Insulin Sensitizers Insulin Providers GLP1-based therapy Glucose Absorption Inhibitor

12 Classes Biguanide Thiazolidinedione Insulin secretagogues Insulin DPP4 GLP-1 Receptor SGLT2 Inhibitors α Glucosidase () (Pioglitazone) Inhibitors Agonists Inhibitors Sulfonylurea Glinides Cost Low Low Low Moderate Low - human insulin High High High Moderate High - Analog insulin

HYPOglycemia risk↑ No No Yes Yes Yes No No No No Weight Change Loss Gain Gain Gain Gain Neutral Loss Loss Neutral ASCVD + Potential benefit Potential benefit Neutral Neutral Neutral Neutral 1st choice Preferred Preferred add-on if GLP1 Neutral add-on. RA contraindicated. Lira- or Sema-glutide Empa- or Cana-gliflozin SubQ See page 8 for detail See page 8 for detail CHF + Neutral ↑ CHF risk Neutral Neutral ↑ CHF Risk with Preferred add-on if 1st choice - preferred add- Neutral Saxa- & Alo-gliptin SGLT2i contraindicated on if eGFR is adequate. Lira- or Sema-glutide Empa-,Cana- or Dapa- SubQ See page 8 for detail gliflozin – See page 8 for detail

CKD + Contraindicated if No dose adjustment Avoid Glyburide Repaglinide Lower doses required Linagliptin – no Preferred add-on if 1st choice - preferred add- Avoid if eGFR (See page 5 for details) (see page 5 for eGFR <30 needed can be used if eGFR ↓ need to adjust dose. SGLT2i contraindicated. on if eGFR is adequate. <30 details) Do not start or to in advanced Others – to reduce Lira- or Sema-glutide Empa-,Cana- or Dapa- reduce current CKD/ESRD. dose. SubQ See page 8 for detail gliflozin- See page 8 for detail dose if eGFR <45. See page 5 for dosing based on eGFR

Efficacy (↓A1c) 1 to 2% 1 to 1.5% 1 to 2% 1 to 1.5% No “ceiling” 0.6 to 0.8% 0.8 to 1.6% 0.5-1.0% eGFR dependent 0.5% High High High High Highest Intermediate High Intermediate to High Low Route Oral Oral Oral Oral SQ Oral SQ/Oral Oral Oral Other benefits Extensive Durability, ↑ HDL Extensive experience ↓ Postmeal Universal Well tolerated ↓ Postmeal glucose ↓ BP ↓ Postmeal experience Benefit in NASH glucose Response excursion glucose excursion excursion Other risks Nausea Edema Weight gain Weight gain Weight gain Angioedema Nausea, Vomiting DKA, GU tract Flatulence Diarrhea ↑Fracture risk High rate of Frequent Urticaria ↑ Heart rate ↑ K, ↑ LDL, ↑ Cr (brief) Diarrhea Lactic acidosis ? Bladder cancer secondary failure dosing ? Pancreatitis ? Pancreatitis Hypotension, Dehydration Frequent dosing B12 ↓ ? Macular edema ? Arthralgia Medullary thyroid cancer Fournier gangrene ? Bullous pemphigoid in animals ↑risk of amputation/fracture with Canagliflozin Contra- eGFR <30 NYHA III/IV heart Severe renal or Use with caution in PMH or FH of Most SGLT2 inhibitors are Cirrhosis MEN2/Medullary thyroid Inflammatory indication Acidosis failure hepatic impairment patients with a h/o contraindicated if eGFR Hypoxia Active bladder cancer pancreatitis. cancer <30 bowel disease Caution in h/o pancreatitis Dehydration Hepatic impairment (See page 5 for detail) Intestinal or gastroparesis. obstruction.

Naing/2-2020 Comparison of Glucose-Lowering Medications # 2 4 Use this table to prescribe a medication from the class chosen in previous table

4 Major groups Insulin Sensitizers Insulin Providers GLP1-based therapy Glucose Absorption Inhibitor 12 Classes Biguanide Thiazolidi- Insulin secretagogues Insulin DPP4 GLP-1 Receptor Agonists SGLT2 Inhibitors α Glucosidase (Metformin) Inhibitors nedione Sulfonylurea Glinides Inhibitors

Currently Metformin Pioglitazone Glipizide Repaglinide Meal insulin: Sitagliptin (Januvia) (Byetta,Bydureon) Canagliflozin (Invokana) Acarbose (Glucophage, (Actos) (Glucoterol), (Prandin), Novolog/Fiasp, Saxagliptin (Onglyza) Liraglutide (Victoza) Dapagliflozin (Farxiga) (Precose), Available Fortamet, Glimeperide Nateglinide Humalog/Admelog, Linagliptin (Trajenta) Lixisenatide (Adlyxin) Empagliflozin (Jardiance) Medications Glumetza) (Amaryl), (Starlix) Apidra, Alogliptin (Nesina) Dulaglutide (Trulicity) Ertugliflozin (Steglatro) (Glyset) Humulin/Novolin R Glyburide Semaglutide (Ozempic) (Brand name) Afrezza inhalor (Micronase, Basal insulin: Semaglutide (Rybelsus) Diabeta, Lantus/Basaglar/ Glynase) Toujeo/, Levemir, Tresiba Humulin/Novolin N Minimum – 500mg qd- Actos Glipizide Prandin No maximum Januvia Byetta 5-10 mcg bid/ac, SubQ Invokana 100-300 mg qam, po Precose or 1000 mg bid, 15-45 mg qd, 2.5-20 mg 0.5-4 mg dose 25-100 mg qam, po Bydureon or Bydureon Bcise Farxiga 5-10 mg qam, po Glycet Maximum dose po po bid/ac, po tid/ac, po Onglyza 2 mg qw, SubQ Jardiance 10-25 mg qam, po 25-100 mg & Glimeperide Starlix 2.5-5 mg qam, po Victoza 0.6-1.8 mg qam, SubQ Steglatro 5-15 mg qam, po tid/ac, po Dosing 1- 8 mg qam 60-120 mg Tradjenta Adlyxin 10-20mcg qam, SubQ Frequency Glyburide tid/ac, po 5 mg qam, po Trulicity 0.75-1.5 mg qw, SubQ 1.25-20mg Nesina Ozempic 0.25-1.0 mg qw, SubQ qam, po 6.25-25mg qam, po Rybelsus 7 or 14 mg qam, PO Available 500, 850, Actos Glipizide Prandin Pens (U-100): Januvia Byetta 5, 10mcg pen Invokana 100, 300 mg Precose or 1000 mg 15, 30, 5, 10 mg 0.5, 1, 2 mg 3ml (300 Units) 25,50,100 mg Bydureon or Bydureon Bcise 2mg Farxiga 5, 10 mg Glycet strength 45 mg Glimeperide Starlix Vial: Onglyza Victoza 0.6, 1.2, 1.8 mg pen Jardiance 10, 25 mg 25,50, 1, 2, 4 mg 60,120 mg 10ml (1000 Units) 2.5, 5 mg Adlyxin 10, 20mcg pen Steglatro 5, 15mg 100 mg Glyburide Tradjenta Trulicity 0.75, 1.5 mg pen 1.25, 2.5, 5mg 5 mg Ozempic 0.25, 0.5, 1.0 mg pen Nesina Rybelsus 7 or 14 mg tablet 6.25,12.5,25 mg Combination Metformin and TZD can be used Do not use Sulfonylurea and Do not use meal Do not use DPP4 inhibitors and GLP1 RA together. together. Glinides together. insulin and insulin secretagogues. Available WITH ACTOS: WITH DPP4 inhibitor: WITH a basal insulin: WITH SGLT2 inhibitor: Actoplus Met XR JanuMet XR (Januvia+metformin) Xultophy Invokamet XR (Invokana+metformin) combination (Actos+Metformin) 50/500, 50/1000, 100/1000 mg, qam Degludec (Tresiba) + liraglutide 50/500, 150/500, 50/1000 or 150/1000 mg, qam (2-in-1) 15/1000, 30/1000mg, qam (XR) Kombiglyze XR(Onglyza+metformin) (Victoza) Xigduo XR (Farxiga+met) medications 15/500, 15/850 mg, bid (generic) 2.5/1000, 5/500, 5/1000 mg, qam 2.5/1000, 5/500, 5/1000, 10/500 or 10/1000 mg, qam Duetact (Actos+Amaryl) Kazano (Nesina+metformin) Soliqua Synjardy XR (Jardiance+met) 30/2, 30/4 mg, qam 12.5/500, 12.5/1000 mg, bid glargine (Lantus) + lixisenatide 5 or 10 or 12.5 or 25/1000 mg, qam Oseni (Nesina+Actos) Oseni (Nesina+Actos) (Adlyxin) Glyxambi (Jardiance+Tradjenta) - 10/5 or 25/5 mg, qam 25/15, 25/30 or 25/45 mg, qam 25/15, 25/30 or 25/45 mg, qam Qtern (Farxiga+Onglyza) - 10/5mg qam Jentadueto (Tradjenta+metformin) Segluromet (Steglatro+Metformin) 2.5/500, 2.5/850, 2.5/1000 mg, bid 2.5/500, 2.5/1000, 7.5/500 or 7.5/1000 mg, bid Steglujan (Steglatro+Januvia) - 5/100 or 15/100 mg, qam

Naing/2-2020 5 6 7 Management of Type 2 Diabetes : Guide for Insulin Initiation and Titration Insulin regimens Starting dose Titration Step 1 One injection daily Basal insulin therapy: Patients may adjust the dose by 1 unit every night or with a basal insulin Start 0.2 Unit/kg body weight by 3 units or 10-15% every 3 nights until target To cont’ metformin, GLP1 RA ± other or 10 units QHS. BG of 80-130 mg/dl is achieved. non-insulin agents (Lantus/Toujeo/Basaglar, Levemir, Tresiba or NPH) Consider adding prandial insulin if A1c is not at goal though the patient has been taking at least 0.5 unit/kg of basal insulin or fasting BG has been at goal.

Basal+1 regimen: Patients may adjust the prandial insulin dose Add one dose of prandial insulin by 1 unit every day or by 2 units or 10-15% every 3 before main meal of the day. days until 2 hours post-meal BG of 100-160 or next Step 2 Start 0.1 U/kg, 4 units or 10% of current basal dose. pre-meal BG of 80-130 is achieved. Two injections daily (Novolog, Fiasp, Humalog, Admelog, Apidra or Human insulin R) with Basal+1 regimen or Breakfast dose: Pre-mixed insulin Pre-mixed insulin therapy: Patients may adjust the dose by 1 unit every day or Change basal insulin to pre-mixed insulin bid/ac. by 2 units or 10-15% every 3 days To cont’ metformin. Consider stopping other non-insulin agents. Divide current basal dose into ½ AM ½ PM or ⅔ until pre-dinner BG of 80-130 mg/dl is achieved. AM ⅓ PM or Dinner dose: Start 0.5 U/kg in 2 divided doses. Patients may adjust the dose by 1 unit every day or (Novolog 70/30, Humalog 75/25 or human insulin 70/30) by 2 units or 10-15% every 3 days until fasting BG of 80-130 mg/dl and/or bed-time BG of For patients on basal insulin or basal+1 regimen: 130-180 mg/dl is achieved. Add prandial insulin before each meal or tid/ac. Consider giving pre-mixed insulin tid/ac if bid/ac fails. Start 0.1 U/kg, 4 units or 10% basal dose per meal

Step 3 For patients on Pre-mixed insulin therapy: Patients may adjust the prandial insulin dose by 1 unit Multiple injections daily Use 80% of current total daily dose and give every day or by 2 units or 10-15% every 3 days with Basal Prandial Therapy 50% as basal insulin + 50% as prandial insulin in 3 until 2 hours post-meal BG of 100-160 mg/dl or next To cont’ metformin. Consider divided doses. pre-meal BG of 80-130 mg/dl is achieved. stopping other non-insulin agents. • Once insulin is initiated, the physician should readjust the For insulin-naïve patients: dose by 10-20% every 1-2 weeks and/or advise the patient Start total daily insulin dose of 0.5 U/kg and give 50% as basal insulin + 50% as prandial insulin in 3 divided doses. OR to self-titrate the dose until BG targets are met. Start basal insulin 0.2 U/kg + prandial insulin 0.1 U/kg tid/ac • For , determine the cause and reduce the corresponding dose by at least 10-20%. Naing/2-2020 GLP1-RA or SGLT2i with proven efficacy/labeled 8 indication is the preferred add-on anti-hyperglycemic agent in the following patients: . Established ASCVD . high ASCVD risk (age >55 with coronary, carotid, or lower-extremity artery stenosis >50% or LVH) . HFrFE with LVEF <45% . CKD with eFGR 30-60 mL/minute/1.73 m2 . UACR >30 mg/g (especially if >300)

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2020 Standards of Medical Care in Diabetes 10

Diabetes Management Algorithm: American Association of Clinical Endocrinologists 2020 11 Using Human insulin in patients with cost issue Insulin Rx Start with a basal insulin COST ISSUE+ Analog basal insulin qhs Human basal insulin (NPH) qhs Start at 0.2U/Kg weight Start at 0.2U/Kg weight Titrate till 0.5U/Kg or target FBG is achieved. Titrate till 0.5U/Kg or target FBG is achieved.

COST ISSUE+ UNCONTROLLED Split human basal insulin (NPH) qhs to bid Switch to 80-100% of current total BASAL dose – human basal 2 1 insulin (NPH) To split into /3 qam /3 qhs or ½ qam ½ qhs bid UNCONTROLLED . UNCONTROLLED Add analog rapid-acting insulin Add human short-acting insulin (Regular insulin) 10% of current BASAL dose or 4 U 10% of current BASAL dose or 4 U before each meal before each meal . . COST ISSUE+ Switch to human short-acting insulin (Regular insulin) Same dose of analog rapid-acting insulin before each meal . 12

Advanced Insulin Therapy

Tips for successful insulin therapy • NO SLIDING SCALE INSULIN • Start conservatively and adjust frequently • Maintain “50%-50% ratio” rule for basal and prandial insulin doses • Firstly, lower the fasting BG with the basal insulin. – Consider adding prandial insulin when basal insulin dose is > 0.5U/Kg. – Adjust the dose frequently until the desired FASTING BG (usually 80-130) is achieved. • Secondly, lower the post-meal BG with the prandial insulin. – Try to match amount and prandial insulin dose • Fixed prandial insulin dose with consistent amount of carbohydrate (consider using a plate method) • Flexible prandial insulin dose based on Insulin-to-Carbohydrate Ratio (ICR) (consider using a smart phone app for carb counter) – Adjust the dose frequently until the desired 2-H post-meal BG (usually <160) or next pre-meal BG (usually 80-130) is achieved. • Prandial insulin is for carbohydrate, and it should be given before a meal based on the meal (carbohydrate) size. Do not base on pre-dose BG level. – No meal  no prandial insulin – Smaller meal lower dose of prandial insulin – Larger meal higher dose of prandial insulin

Naing/2-2020 13 Overview of Insulin Therapy (Advanced) To use together with next page # 14 Step 1 1 injection daily with a basal insulin

Step 2 2 to 3 injections daily 2 to 3 injections daily Add with with Pre-mixed insulin GLP-1 Receptor Agonist “Basal+1” or “Basal+2” regimen bid/ac or tid/ac to basal insulin

2 ways to match carbohydrate amount and prandial insulin dose Step 3 Multiple injections daily Simple Fixed prandial insulin dose before each meal method and with Basal Prandial Therapy consistent amount of carbohydrate (plate method)

Advanced Flexible prandial insulin dose before each meal method based on Insulin-to-Carbohydrate Ratio (ICR) (see page 14) Step 4 Severe or high insulin dose (>150 Units daily) Flexible prandial insulin dose before each meal based on Humulin R U-500 concentrated insulin ICR and Insulin Sensitivity Factor (ISF) (see page 14) bid/ac or tid/ac (see page 14) Naing/2-2020 Supplement to "Overview of Insulin Therapy (Advanced)" at page 13 14

Insulin-to-Carbohydrate Ratio (ICR) based on body weight in Lbs

Patient’s weight in Lbs ICR ratio (carbohydrate in grams) 100-109 1:16 (1 unit insulin for 16 grams carb) 110-129 1:15 (1 unit insulin for 15 grams carb) 130-139 1:14 (1 unit insulin for 14 grams carb) 140-149 1:13 (1 unit insulin for 13 grams carb) 150-169 1:12 (1 unit insulin for 12 grams carb) 170-179 1:11 (1 unit insulin for 11 grams carb) 180-189 1:10 (1 unit insulin for 10 grams carb) 190-199 1:9 (1 unit insulin for 9 grams carb) >200 1:8 (1 unit insulin for 8 grams carb) 15

2020 Standards of Medical Care in Diabetes Insulin therapy