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Quick Reference Guide 1/2019 version

Management of Type 2 Diabetes: Non- and Insulin Therapies

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

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

Version: Naing/1-2019 1

Naing/1-2019 2 Management of Type 2 Diabetes : Overview 3

Intensive Lifestyle Modification†

Mild hyperglycemia Moderate hyperglycemia Severe hyperglycemia A1c <8% A1c 8-10% or A1c 1.5% above target A1c >10% or Random BG ≥300 mg/dl or Monotherapy Dual therapy Fasting BG ≥250 mg/dl with metformin Metformin + 2nd agent*

Triple therapy asymptomatic Metformin + 2nd + 3rd agent*

Severe symptoms Weight loss Insulin therapy See page 4 and 7 DKA/Hyperosmolar state Severe infection/surgery If A1c is not at goal in 3 months, move to next step. † healthy eating, increased physical activity, weight loss, and referral to a diabetes center for self-management education and medical nutrition therapy * A patient-centered approach should be used to guide the choice of glucose-lowering . Considerations include the patient- and drug-specific factors, efficacy, cost, benefit, risk, patient’s characteristics and patient’s preference. (see page 5)

Naing/1-2019 4 Overview of Insulin Therapy (Basic) See page 7 for insulin initiation and titration guide.

Step 1 One injection daily (basal insulin)

Step 2 Two injections daily Add GLP-1 Receptor (Basal+1 regimen or Agonist Pre-mixed insulin) to basal insulin

Step 3 Multiple injections daily (Basal Prandial therapy)

If A1c is not at goal in 3 months, move to next step.

Naing/1-2019 Pharmacological Therapy of Type 2 Diabetes : Comparison of Glucose-Lowering 5 Use this table to choose a class of medication – Consider the factors in first column, that will impact the medication choice. 5 Major Insulin Sensitizers Insulin Providers GLP1-based therapy Glucose Absorption Others (less popular) groups Inhibitor

12 Biguanide Thiazolidi- Insulin secretagogues Insulin DPP4 GLP-1 SGLT2 Inhibitors α Glucosi- Bile Acid Dopamine Classes (Metformin) nedione Inhibitors Receptor dase Sequestrant Agonist Mimetics Sulfonylurea Glinides Agonists Inhibitors

COST Low Low Low Moderate Low (NPH/R) High High High Moderate High High High

HYPOGLY- No No Yes Yes Yes No No No No No No No CEMIA RISK

WEIGHT Loss (modest) Gain Gain Gain Gain Neutral Loss Loss Neutral Neutral Neutral Loss ASCVD + Potential Potential Uncertain Uncertain Neutral ↑ CHF Risk CV benefit CV benefit Neutral Neutral ? ↓ ASCVD Neutral ASCVD ASCVD cardiovas- cardiovas- with with Lira- or with Empa- or or CHF + events benefit benefit with cular safety cular safety Saxagliptin Sema-glutide Cana-gliflozin pioglitazone. Alogliptin (CV Risk & ↑ CHF risk Preferred add- Preferred add-on if Benefit) on if ASCVD+ CHF+ or ASCVD+ CKD + Contraindicat- No dose Avoid Repaglinide Lower doses Linagliptin – – Empa- and Cana- Avoid if No dose No dose No dose (see page 15 ed if eGFR <30 adjustment Glyburide can be used required if no need to avoid if eGFR - avoid if eGFR <45 eGFR <30 adjustment adjustment adjustment for details) needed (See page 15) in advanced eGFR ↓ adjust dose. <30. Dapa- and Ertu- needed needed needed Do not start or CKD/ESRD. Others – to Others – no gliflozin to reduce reduce dose. need to adjust. -avoid if eGFR <60 current dose if eGFR <45. Preferred add- 1st choice preferred on (Lira- or add-on (Empa- or Sema-glutide) if Cana-gliflozin) SGLT2i is con- if eGFR is adequate traindicated

Efficacy 1 to 2% 1 to 1.5% 1 to 2% 1 to 1.5% No “ceiling” 0.6 to 0.8% 0.5 to 1.6% 0.5-0.9% eGFR dependent 0.5% 0.4 to 0.5% 0.4 to 0.7% 0.4 to 0.6%

(↓A1c) High High High High Highest Intermediate High Intermediate to High Low to Intermediate

Route Oral Oral Oral Oral SQ Oral SQ Oral Oral Oral Oral SQ Other Extensive Durability Extensive ↓ Postmeal Universal Well tolerated ↓ Postmeal ↓ BP ↓ Postmeal ↓LDL-C ↓ Postmeal experience Benefit in NASH experience glucose Response glucose glucose glucose benefits ↑ HDL excursions. excursions. excursions. excursions. Other Nausea Edema Weight gain Weight gain Weight gain Angioedema Nausea GU tract infection Flatulence Constipation Orthostatic Nausea Diarrhea ↑Fracture risk High rate of Frequent Urticaria Vomiting ↑ K, Dehydration Diarrhea ↑ Triglyceride hypotension Vomiting risks Lactic ? Bladder secondary dosing ? Pancreatitis ↑ Heart rate Hypotension, DKA, May ↓ Syncope Frequent Dizziness acidosis cancer failure ? Arthralgia ?Pancreatitis ↑ LDL, ↑ Cr (brief) Frequent absorption of dosing Medullary ↑ risk of other Nausea, Fatigue B12 ↓ ? Macular ? Bullous dosing Rhinitis edema pemphigoid thyroid cancer amputation/fracture Medications in animals with Canagliflozin Contra- eGFR <30 NYHA III/IV Severe renal Use with PMH or FH of Renal impairment Cirrhosis TG >500mg/dl Severe MEN2/Medullary Inflammatory indication Acidosis heart failure or hepatic caution in (See above CKD+ row h/o of bowel diabetic Hypoxia Active bladder impairment patients with a thyroid cancer and page 15) bowel obstruction. gastroparesis Caution in h/o Dehydration cancer h/o disease Hypertriglyceri pancreatitis or Intestinal Hepatic pancreatitis. demia-induced gastroparesis. obstruction. impairment pancreatitis. Naing/1-2019 Pharmacological Therapy of Type 2 Diabetes : Comparison of Glucose-Lowering Medications 6 Use this table to prescribe a medication from the class chosen in previous table 5 Major Insulin Sensitizers Insulin Providers GLP-1 (-like -1) Glucose Others Absorption groups -based therapy Inhibitor (less popular) 12 Biguanide Thiazolidi Insulin secretagogues Insulin DPP4 GLP-1 Receptor SGLT2 α Glucosi- Bile Acid Dopamine- Amylin (Metformin) -nedione Inhibitors Agonists Inhibitors dase Sequest- 2 Agonist Mimetics Classes Sulfonylurea Glinides Inhibitors rant Currently Metformin Pioglitazone Glipizide Repaglinide Meal insulin: Sitagliptin Exenatide Canagliflozin Acarbose Coleseve- Bromocrip- Pramlin- (Glucophage, (Actos) (Glucoterol), (Prandin), Novolog, Humalog (Januvia), (Byetta,Bydureon), (Invokana), (Precose), lam tine tide Available Fortamet, Glimeperide Nateglinide Apidra, Saxagliptin (Victoza), Dapagliflozin Miglitol (Welchol) (Cycloset) (Symlin) Medications Glumetza) (Amaryl), (Starlix) Humulin/Novolin R (Onglyza), (Adlyxin), (Farxiga), (Glyset) Afrezza inhalor Glyburide Linagliptin (Trulicity) Empagliflozin (Brand name) Basal insulin: (Micronase, (Trajenta), (Ozempic) (Jardiance) Lantus/Basaglar/ Diabeta, Toujeo/, Levemir, Alogliptin Ertugliflozin Glynase) Tresiba (Nesina) (Steglatro) Humulin/Novolin N Minimum – 500mg qd- Actos Glipizide Prandin No maximum Januvia All sq injections: Invokana Precose or 625-1250 0.8-4.8 mg sq 1000 mg bid 15-45 mg qd 2.5-20 mg 0.5-4 mg dose 25-100 mg qam Byetta 5-10 mcg bid/ac 100-300 mg qam Glycet mg tid qam injection Maximum bid/ac tid/ac Onglyza Victoza 0.6-1.8 mg qam Farxiga 25-100 mg dose Glimeperide Starlix 2.5-5 mg qam Adlyxin 10-20mcg qam 5-10 mg qam tid/ac 15-120 & 1- 8 mg qam 60-120 mg Tradjenta Bydureon or Bydureon Jardiance mcg Dosing Glyburide tid/ac 5 mg qam Bcise 2 mg qw 10-25 mg qam tid/ac 1.25-20mg Nesina Trulicity 0.75-1.5 mg qw Steglatro Frequency qam 6.25-25mg qam Ozempic 0.25-1.0 mg 5-15 mg qam qw Available 500, 850, Actos Glipizide Prandin Pen: Januvia Byetta 5,10mcg Invokana Precose or 625 mg 0.8 mg 15, 120 1000 mg 15, 30, 5, 10 mg 0.5, 1, 2 mg 3ml (300 Units) 25,50,100 mg Victoza 0.6, 1.2, 1.8 mg 100, 300 mg Glycet mcg pen strength 45 mg Glimeperide Starlix Vial: Onglyza Adlyxin 10, 20mcg Farxiga 25,50, 1, 2, 4 mg 60,120 mg 10ml (1000 Units) 2.5, 5 mg Bydureon or Bydureon 5, 10 mg 100 mg Glyburide Tradjenta Bcise 2 mg Jardiance 1.25, 2.5, 5 5 mg Trulicity 0.75, 1.5 mg 10, 25 mg mg Nesina Ozempic 0.25, 0.5, 1.0 Steglatro 6.25,12.5,25 mg mg 5, 15mg Combination Metformin and TZD can be Do not use Sulfonylurea and Do not use DPP4 inhibitors and GLP1 RA With meal used together. Glinides together. together. insulin only 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) + 50 or 150/500, 50 or 150/1000 mg qam (2-in-1) 15/1000, 30/1000mg qam (XR) Kombiglyze XR(Onglyza+metformin) liraglutide (Victoza) Xigduo XR (Farxiga+met) medications 15/500, 15/850 mg bid (generic) 2.5/1000, 5/500, 5/1000 mg qam 5 or 10/500, 5 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) + 5 or 10 or 12.5 or 25/1000 mg qam Oseni (Nesina+Actos) Oseni (Nesina+Actos) lixisenatide (Adlyxin) Glyxambi (Jardiance+Tradjenta) (12.5 or 25) + (15 or 30 or 45 mg) (12.5 or 25) + (15 or 30 or 45 mg) qam 10/5, 25/5 mg qam qam Jentadueto (Tradjenta+metformin) Qtern (Farxiga+Onglyza) 2.5/500, 2.5/850, 2.5/1000 mg bid 10/5mg qam Naing/1-2019 Management of Type 2 Diabetes : Guide for Insulin Initiation and Titration 7 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 fasting 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 0.7-1.0 unit/kg of basal insulin or fasting BG has been at goal. Add GLP1 RA. Move to step 2 or 3 If A1c is not 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 hypoglycemia, determine the cause and reduce the corresponding dose by at least 10-20%. Naing/1-2019 Tips for successful insulin therapy 8 • 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 >0.7-1.0 U/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 carbohydrate 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/1-2019 Overview of Insulin Therapy (Advanced) 9 To use together with next page # 10 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 10) Step 4 Severe insulin resistance 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 10) bid/ac or tid/ac (see page 10) INSULIN PUMP Naing/1-2019 Supplement to "Overview of Insulin Therapy (Advanced)" at page 9 10

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) 11

STANDARD OF MEDICAL CARE IN DIABETES 2019

Naing/1-2019 http://care.diabetesjournals.org/content/42/Supplement_1 12

STANDARD OF MEDICAL CARE IN DIABETES 2019

http://care.diabetesjournals.org/content/42/Supplement_1 Naing/1-2019 13 American Association of Clinical Endocrinologists : 2018 Comprehensive Type 2 Diabetes Management Algorithm

https://www.aace.com/sites/all/files/diabetes-algorithm-executive-summary.pdf Naing/1-2019 American Association of Clinical Endocrinologists : 2018 Comprehensive Type 2 Diabetes Management Algorithm 14

https://www.aace.com/sites/all/files/diabetes-algorithm-executive-summary.pdf Naing/1-2019 15