9/5/2019

Statement of disclosure NEW TOOLS IN THE • S. Mimi Mukherjee is an academic preceptor for an TOOLBOX FOR TYPE 2 industry fellowship program at -Genzyme

S. Mimi Mukherjee PharmD, CDE, BCPS

Objectives

After attending this educational session, participants will be able to: • Recommend appropriate treatment based on patient characteristics.

• Summarize the considerations when deciding whether to recommend , DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 agonists or to therapy THE BASICS Mellitus • Explain how to use in combination with non-insulin

• Identify the roles of the different types of insulin

What do we hope to achieve when treating patients with T2DM?

1 9/5/2019

ABCs Individualizing A1c goals A –

B –

C –

Why are certain medications for T2DM Metformin is 1st line in patients with type 2 diabetes mellitus. more likely to cause ? But sometimes patients aren’t on it…

Medications that increase insulin levels without regard to meals tend to cause hypoglycemia What is the most common reason for a patient not being on metformin?

Guidelines

• American Diabetes Association. Standards of medical care in diabetes – 2019. Diabetes Care.2019; 42(S1) 1- 193.

• Davies MJ, D’Alessio DA, Fradkin J, et al. Management of HOW TO DECIDE WHAT TO hyperglycemia in type 2 diabetes, 2018 – a consensus ADD AFTER METFORMIN report by the American Diabetes Association for the Study of Diabetes (EASD). Diabetes Care. 2018; 41(12):2669- Focus on sulfonylureas, DPP-4 inhibitors, SGLT2 2701. inhibitors, GLP-1 agonists, and thiazolidinediones

2 9/5/2019

Questions to ask when adding History of ASCVD to metformin Does the patient have…? • ASCVD GLP-1 RA SGLT2i • HF • CKD (“tide”) (“flozin”)

Is the patient at risk of falls or other complications due to 1. * hypoglycemia? 1. * 2. ** 2. Is the patient obese? 3. 3. ** 3. Is the patient without health insurance and/or is experiencing financial insecurity? Adapted from ADA/EASD 2018 Consensus Report on the Management of T2DM * Reduced all cause mortality and MACE ** Based on new clinical trial data

History of HF or CKD History of HF or CKD

In patients with HF, avoid SGLT2i 1. Empagliflozin • Thiazolidinediones 2. Canagliflozin • and (“flozin”) 3. Dapagliflozin* Renal dose adjustments not required for If patient can’t take SGLT2i, 1. Liraglutide • for CVD benefit, add 2. Dulaglutide* • All GLP-1 RAs except exenatide IR and ER GLP-1 RA 3. Semaglutide • Thiazolidinediones (“tide”) 4. Exenatide

Adapted from ADA/EASD 2018 Consensus Report on the Management of T2DM *Based on new clinical trial data

If weight is an issue If weight is an issue

Cautious use of medications that cause weight gain. GLP-1 RA SGLT2i Consider risk vs. benefit (“tide”) (“flozin”) • Sulfonylureas • Thiazolidinediones • Insulin 1. Semaglutide 2. Liraglutide If patient not on a GLP-1 RA, can add a DPP-4 inhibitor Any of the 4 3. Dulaglutide (“gliptin”) because they are weight neutral available 4. Exenatide 5.

Adapted from ADA/EASD 2018 Consensus Report on the Management of T2DM Adapted from ADA/EASD 2018 Consensus Report on the Management of T2DM

3 9/5/2019

Avoiding hypoglycemia Can’t afford medications

• All medications ok to use except the following: • Sulfonylureas • Later generation sulfonylureas • Insulin • Thiazolidinediones

Less  BS Degludec Glargine U100 NPH More  BS • Insulin regular, insulin NPH, insulin NPH/reg Glargine U300 Detemir 70/30

They can be used with caution if needed.

Adapted from ADA/EASD 2018 Consensus Report on the Management of T2DM

Sulfonylureas High efficacy

•

DRUG SPECIFIC • On Beers Criteria list CONSIDERATIONS • Glyburide Focus on sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 agonists, and thiazolidinediones

Most patients should take these medications a ½ hour before meals

DPP-4 inhibitors (“gliptins”) Bullous pemphigoid Intermediate efficacy

Considerations • Develops typically on areas • that flex (inner elbow, • Don’t use with GLP-1 RA armpits, lower abdomen)

• Linagliptin • Use with caution in patients • Can be triggered by with a h/o pancreatitis medications, but is autoimmune • Saxagliptin • Rare reversible severe joint pain • Treatment is supportive; • Rare bullous pemphigoid • Alogliptin corticosteroids to help with itching and suppress the immune system

4 9/5/2019

SGLT2 inhibitors GLP-1 RA Intermediate efficacy & weight loss High efficacy & weight loss, but injectable Considerations • Empagliflozin Considerations • Exenatide IR & ER • BBW: Thyroid T-cell or medullary cancer • SE: urogenital infections, euglycemic (except exena IR, lixi) DKA, fractures, hypotension • Liraglutide • Canagliflozin • SE: GI – dissipates after 1- 2 weeks; • May need to decrease BP meds when rarely severe N/V leads to ARF initiating • Semaglutide • Use with caution in patients with a h/o • Dapagliflozin • Canagliflozin: increases K+ with ACEi, pancreatitis ARB, K+ sparing diuretics • Dulaglutide • Multi-dose pens only need priming with • Dapagliflozin: breast/bladder CA • Lixisenatide first dose • association • All expire at room temp at 28 days except • All are contraindicated if CrCl < 45 dulaglutide and lixisenatide at 14 days

GLP1-RA Thiazolidinediones High efficacy, but weight gain Exenatide: • 5 mcg SC BID 60 min pre-meal, meals > 6 hrs apart (Max 10 mcg SC BID) Liraglutide: • Considerations • 0.6 mg SC daily x 1 week, then 1.2 mg SC once daily (Max 1.8 mg) Lixisenatide: • SE: rare risk of bladder cancer, rare • • 10 mcg once daily x 14 days, then 20 mcg once daily. Give 60 min pre-first atypical fractures, rare hepatic meal. (Max 20 mcg) impairment, weight gain, edema Exenatide XR: • BBW: exacerbation of HF • 2 mg SC once weekly (Max 2 mg) Dulaglutide: • Delayed onset – can take 4 weeks for • 0.75 mg SC once weekly onset and up to 12 weeks for full effect • (Max 1.5 mg) Semaglutide: • 0.25 mg SC q wk x 4wks, then 0.5 mg,q wk (max of 1 mg)

In boxes, GLP-1 RA that require titration to reach minimum effective dose

Basal insulin first

• Typically start with 10 units SC once daily

• In selected patients, can titrate every 3 to 4 days until FBS reaches specified goal ADDING INSULIN TO NON- INSULIN MEDICATIONS What to keep and what to discontinue

5 9/5/2019

Does basal insulin provide coverage for Need oral medications. Which ones? post-prandial blood sugar? Continue • Metformin • SGLT2i (counsel: euglycemic DKA) • DPP-4i in patients not on GLP-1 RA

Consider stopping or decreasing dose • Thiazolidinediones •

Adapted from ADA/EASD 2018 Consensus Report on the Management of T2DM

What if fasting blood sugars are controlled GLP1-RA and basal insulin combinations but post-prandial BS are high? /liraglutide (Xultophy)

1. Try a GLP-1 RA • Initial: 16 units (16 units insulin degludec/0.58 mg liraglutide) SC once daily • Max: 50 units (50 units insulin degludec/1.8 mg liraglutide) SC once 2. Add prandial insulin to largest carbohydrate meal daily)

Insulin glargine/lixisenatide (Soliqua) • If uncontrolled on < 30 units basal insulin or on lixisenatide • Initial:15 units (15 units /5 mcg lixisenatide) SC once daily • • If uncontrolled on 30 to 60 units of basal insulin: • Initial: 30 units (30 units insulin glargine/10 mcg lixisenatide) SC once daily

• Max: 60 units (60 units insulin glargine/20 mcg lixisenatide) SC once daily

Basal insulin

• Insulin degludec – long acting, doses can be taken at different times as long as 8 hours apart

• Insulin glargine – take at the same time every day WHICH INSULIN TO • – about 20% of patients require bid dosing RECOMMEND? • NPH insulin – inexpensive, peaks about 5 hours after injection Assuming cost and formularies are not an issue which can lead to hypoglycemia, often dosed bid (2/3 in am, 1/3 at pre-dinner or at bedtime)

Reserve higher concentrations for patients who need more than 100 units of basal insulin per day

6 9/5/2019

Prandial insulin Inhaled insulin

• Insulin regular – inject 30 min before meal • Available in 4 (blue), 8 (“green”) and 12 (yellow)unit increments

• , & – inject 0 to • Contraindicated in patients with 15 min before meal asthma or COPD, causes a measurable decrease in FEV1 (avoid in smokers) • Insulin aspart + niacinamide + L-arginine

• Dry powder inhaler • Inhaled insulin • Cough most common side effect

Reserve insulin lispro U-200 or insulin regular U-500 for patients who need • Keep at room temp 10 min before more than 100 units of prandial insulin per dose use

Nasal (Baqsimi)

• Approved in the U.S. in July 2019

• Single use atomizer spray

• Side effects similar to injectable glucagon plus watery eyes and nasal congestion NASAL GLUCAGON • Injectable glucagon causes nausea, vomiting and headache A new tool for patients on insulin • Lasts 20 min like injectable glucagon, so patient needs to eat and seek emergency care

Selected references Any questions?

• Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo- controlled trial. Lancet. 2019; 394(10193):121-130. • Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. New Engl J Med. 2019; 380(4):347-357. • Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE TIMI 58 randomised trial. Lancet. 2019; 7(8); 606-617.

7