Long-acting insulins for the management of type 2 diabetes

Transcription

1 In Control Long-acting insulins for the management of type 2 diabetes Faculty/presenter disclosure Presenter: Robert Schlosser Relationships with financial sponsors: Grants/Research Support: None Speakers Bureau/Honoraria: Novo Nordisk, Sanofi, Eli Lilly, AstraZeneca, Janssen, Merck, Boehringer Ingelheim, Amgen, FMF-CFPC Consulting Fees: Novo Nordisk, Sanofi, Eli Lilly, AstraZeneca, Janssen Patents: None Other: Clinical Studies: Novo Nordisk, Sanofi, Eli Lilly, AstraZeneca, Janssen 1

2 Disclosure of financial support This program has received financial support from Novo Nordisk Canada Inc. in the form of educational funding This program has received in-kind support from Novo Nordisk Canada Inc. in the form of logistical support Potential for conflict(s) of interest: Dr. Robert Schlosser has received payment/funding, from Novo Nordisk Canada Inc. AND organization whose product(s) are being discussed in this program Novo Nordisk Canada Inc. developed products that will be discussed in this program Mitigating potential bias Bias in this program has been mitigated using independent content validation as follows: All content has been reviewed by a physician steering committee, pharmacist expert reviewers, the College of Family Physicians of Canada, the FMOQ (Fédération des médecins omnipraticiens du Québec), the Canadian Council on Continuing Education in Pharmacy (CCCEP) and the Ordre du Pharmaciens Québec (OPQ) All data have been sourced from clinically accepted evidence All support used in justification of patient care recommendations conforms to generally accepted standards, the Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada, as well as the most recently available clinical data Dr. Robert Schlosser will receive an honorarium from the College of Family Physicians of Canada (CFPC) for this talk 2

3 Planning committee Robert Schlosser, MD, FRCPC Endocrinologist, LMC Diabetes & Endocrinology, Thornhill, ON Medical Director, Mackenzie Health Hospital Diabetes Education Centre Milan Gupta, MD, FRCPC, FACC Associate Clinical Professor of Medicine, McMaster University; Medical Director, Canadian Collaborative Research Network Pierre Filteau, MD, CCFP Family Physician, Centre médical des Carrières (GMF, groupe de médecine familiale), Saint-Marc-des-Carrières, QC Vance Pegado, MD, CCFP Family Physician, Caroline Family Health Team, Burlington, ON Kevin Saunders, MD, CCFP Family Physician, Rivergrove Medical Clinic, Winnipeg, MB Susie Jin, RPh, CDE, CPT, BCGP Community Pharmacist, Pharmacy 101, Cobourg, ON Robert Roscoe, B.Sc.Pharm, ACPR, CDE, CPT Collaborative Community Pharmacist, Consultant, Rothesay, NB Program objectives After attending this program, participants will be able to: Establish the role of basal insulin therapy in the management of type 2 diabetes mellitus (T2DM) as per the 2018 Diabetes Canada clinical practice guidelines Apply strategies to overcome common challenges associated with insulin initiation and optimization and employ knowledge of key concepts, including glucose variability, hypoglycemia and continuous glucose monitoring Compare agent-specific characteristics of the available basal insulins, with a focus on newer basal insulins 3

4 Basal Insulin Initiation Patient Case: Patrick Meet Patrick Health Status BMI: 26.7 kg/m 2 BP: 132/88 mmhg egfr: 78 ml/min/1.73m 2 ACR: Negative LDL: 1.5 mmol/l CV: No history of cardiovascular disease Exercise: Walks briskly 3 times/week for 20 minutes Diet: Eats a balanced diet when at home and has 2 alcoholic drinks, 3 days/week PATRICK 59-year-old male Flight attendant Type 2 diabetes Diagnosed 6 years ago Private insurance coverage Glycemic Parameters A1C: 8.5% FPG: 11.8 mmol/l What glycemic targets would you set for this patient? Medications Gliclazide modified release (90 mg QD) Sitagliptin and metformin HCL-extended release (100 mg sitagliptin/2000 mg metformin QD) Rosuvastatin (10 mg QD) Ramipril (10 mg QD) 4

5 Basal Insulin Initiation Part 1: The relationship between insulin and type 2 diabetes 2018 Diabetes Canada recommendations for pharmacotherapy in type 2 diabetes If metformin and healthy behaviour changes are not enough to control blood glucose, other antihyperglycemic agent (AHA) options can be added Next-line treatment for patients not reaching target: With CV disease Without CV disease On non-insulin AHAs On insulin Add: AHA with CV benefit Options: empagliflozin, liraglutide or canagliflozin* Add: Incretin agent and/or SGLT2i if lower risk of hypoglycemia and/or weight gain are priorities Options: GLP-1 RA or DPP-4i and/or an SGLT2i Add: once-daily basal insulin over premixed or bolus insulin if lower risk of hypoglycemia and/or weight gain are priorities Options: NPH insulin, insulin degludec, insulin detemir or insulin glargine Add: GLP-1 RA, DPP-4i or SGLT2i before adding or intensifying prandial insulin therapy *Avoid in people with prior lower extremity amputation CV, cardiovascular; RA, receptor agonist; DPP-4i, DPP-4 inhibitor; SGLT2i, SLGT2 inhibitor Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S325. 5

6 The need for basal insulin in T2DM therapy PAUSE AND REFLECT In general, for patients with T2DM, when do you choose to initiate basal insulin and why? Spotlight on Patrick Patrick has an FPG of >11 mmol/l despite being on oral glucose-lowering agents. How does this impact your next choice of treatment? Basal insulin is initiated later than the Guidelines recommend In a cohort of patients with T2DM treated with insulin by family physicians in Ontario: 9 years average delay to insulin initiation 9.5% mean A1C prior to insulin initiation 74% prevalence of diabetes-related complications prior to insulin initiation PAUSE AND REFLECT Why is basal insulin not being initiated? Harris SB, Kapor J, Lank CN, Willan AR, Houston T. Clinical inertia in patients with T2DM requiring insulin in family practice. Canadian Family Physician. 2010;56(12):e418-e24. 6

7 Patients may resist starting insulin therapy for various reasons Spotlight on Patrick PAUSE AND REFLECT What are the potential reasons Patrick has been so resistant to starting insulin therapy? Patrick has concerns about insulin and has been putting off starting injectable therapy for over one year I don t think my diabetes is that bad yet. I've been making lifestyle changes to improve my health. Basal Insulin Initiation Part 2: Basal Insulin Options 7

8 Basal insulins currently available in Canada Insulin type Insulin degludec Insulin detemir Insulin glargine NPH Brand name Tresiba 100 units/ml Tresiba 200 units/ml Levemir 100 units/ml Lantus 100 units/ml Basaglar 100 units/ml Toujeo 300 units/ml Novolin ge NPH 100 units/ml Humulin N 100 units/ml Total units per pen (units) Maximum single dose for injection (units) In-use time (days) Pre-filled pen FlexTouch FlexTouch FlexTouch * SoloSTAR * Kwikpen * SoloSTAR Cartridge only Kwikpen * *Also available in cartridges for use in durable/refillable pens; max dose in durable pen may differ from max dose in prefilled pens above Novo Nordisk Canada Inc. Novolin ge Product Monograph ; Eli Lilly Canada Inc. Humulin N Product Monograph. 2016; Novo Nordisk Canada Inc. Levemir Product Monograph ; Sanofi-aventis Canada Inc. Lantus Product Monograph. 2017; Eli Lilly Canada Inc. BASAGLAR TM Product Monograph. 2015; Sanofi-aventis Canada Inc. Toujeo TM Product Monograph. 2015; Novo Nordisk Canada Inc. Tresiba Product Monograph Basal insulin analogues vary in pharmacologic characteristics λ Half life (hours) Duration of action (hours) NPH 5 10 Up to 18 Insulin detemir 5 7 (dose dependent) Insulin glargine U100 U >30 Insulin degludec Up to Novo Nordisk Canada Inc. Novolin ge Product Monograph. 2016; Sanofi-aventis Canada Inc. Lantus Product Monograph. 2017; Sanofi-aventis Canada Inc. Toujeo TM Product Monograph. 2015; Novo Nordisk Canada Inc. Tresiba Product Monograph. 2017; Novo Nordisk Canada Inc. Levemir Product Monograph. 2016; Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1- S325. 8

9 Clinical factors for assessing antidiabetic therapy Effective glycemic control (A1C and FPG lowering) Reminder: no insulin dose ceiling Minimizing risk of hypoglycemia Key factors for Patrick Minimizing weight gain IN YOUR PRACTICE Cardiovascular safety In addition to the clinical factors above, patient characteristics and considerations should impact your decision-making process when individualizing treatment with basal insulin Learn more i Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S325. What does Diabetes Canada recommend for basal insulin selection? All basal insulins have essentially the same A1C lowering ability In T2DM, if lower risk of hypoglycemia is a priority: a. Long-acting insulin analogues should be considered over NPH insulin i Learn more b. Insulin degludec may be considered over insulin glargine U100 to reduce overall and nocturnal hypoglycemia, and severe hypoglycemia in patients at high CV risk i Learn more c. Insulin glargine U300 may be considered over insulin glargine U100 to reduce overall and nocturnal hypoglycemia i i Learn more T2DM, type 2 diabetes mellitus Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S325. 9

10 PAUSE AND REFLECT Diabetes Canada recommends long-acting basal insulins to reduce the risk of hypoglycemia Insulin degludec and insulin glargine U300 are the basal insulins most recently approved in Canada Both products demonstrated non-inferior A1C reduction when compared head-tohead with insulin glargine U100 with a higher dose of insulin glargine U300 required Insulin degludec demonstrated statistically significant reductions in the rates of nocturnal hypoglycemia and a reduction in the rates of overall hypoglycemia relative to insulin glargine U100 Insulin glargine U300 demonstrated reductions in the number of patients reporting nocturnal confirmed or severe hypoglycemia and confirmed or severe hypoglycemia compared to insulin glargine U100 over the maintenance period. Reductions were significant for nocturnal confirmed or severe hypoglycemia over the entire treatment period. Basal Insulin Initiation Part 3: Initiating Basal Insulin 10

11 Initiating Basal Insulin Checklist Spotlight on Patrick 1. Explain why insulin is needed and describe A1C and FPG targets 2. Demonstrate the pen and titration What is your next treatment approach, in addition to reinforcing and encouraging his healthy behaviour interventions? What factors are important to consider? 3. Teach the patient about self-monitoring blood glucose 4. Set expectations about hypoglycemia and other potential side effects 5. Book a follow-up appointment Canadian Diabetes Association. Insulin pen start checklist. Available at: Retrieved May 1, Explain why insulin is needed and describe A1C and FPG targets IN YOUR PRACTICE Declining pancreatic beta-cell insulin production is part of the natural history of T2DM. Therefore, insulin replacement is often necessary Spotlight on Patrick Patrick feels like he is failing on treatment and is resistant to new medications. How would you address his concerns? OF NOTE Insulin can help achieve glycemic control and prevent long-term complications. Ensure you discuss any changes to his other medications Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S

12 1. Explain why insulin is needed and describe A1C and FPG targets Recommended targets for most patients with T2DM A1C 7.0% FPG mmol/l 2-hr PPG mmol/l If A1C target not achieved: lower FPG target to mmol/l and/or 2-hr PPG target to mmol/l (must be balanced against risk of hypoglycemia) OF NOTE Consider glucose variability reduction as a glycemic target to reduce the risk of vascular diabetes complications i Learn more Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S Demonstrate the pen and titration IN YOUR PRACTICE Consider booking appointments exclusively for insulin initiation and training How will you guide patients in terms of administration and titration? What considerations do you have? Recommendation for T2DM Start: 10 Units once daily Titration: 1 Unit per day until target reached (detemir, glargine and NPH) Degludec should be titrated by 2 Units every 3 4 days or by 4 Units once a week Use the FIT Recommendations at fit4diabetes.com to teach your patients the appropriate injection technique Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S325; FIT Forum for Injection Technique Canada. Recommendations for Best Practice in Injection Technique 3rd Edition Available at: Retrieved May 1,

13 3. Teach the patient about self-monitoring blood glucose Recommendation for T2DM Basal insulin + AHAs SMBG at least once a day at variable times T1DM & T2DM: FGM to reduce time in hypoglycemia T1DM and not at target: CGM to improve glycemic control and reduce time in hypoglycemia T2DM, type 2 diabetes mellitus; AHA, antihyperglycemic agent; SMBG, self-monitoring of blood glucose; T1DM, type 1 diabetes mellitus; CGM, continuous glucose monitoring; FGM, flash glucose monitoring Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S Set expectations about hypoglycemia and other potential side effects IN YOUR PRACTICE Discuss hypoglycemia with your patients at every visit. Patients using insulin therapy should be counselled about the risk, prevention, recognition and treatment of hypoglycemia Mild hypoglycemia: Autonomic symptoms Autonomic Neuroglycopenic Moderate: Autonomic and neuroglycopenic symptoms Severe: Unable to self-treat Trembling Palpitations Sweating Anxiety Hunger Nausea Tingling Difficulty concentrating Confusion, weakness, drowsiness, vision changes Difficulty speaking, headache, dizziness Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S325; McAulay V, et al. Symptoms of hypoglycaemia in people with diabetes. Diabetic Med. 2001;18(9): ; Canadian Diabetes Association. Lows and highs: blood glucose levels Available at: 13

14 4. Set expectations about hypoglycemia and other potential side effects Recommendation for the treatment of hypoglycemia Test blood glucose Eat 15 g of fast-acting carbohydrate Wait 15 minutes Test again and repeat if necessary If next meal >1 hr away, eat another 15 g carbohydrate and 1 ounce protein Wait 40 minutes before driving Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S325. Symptomatic hypoglycemia treatment algorithm Predictable factors? (e.g., food, exercise, alcohol) Nonadherence/ cognitive issues? Secondary cause? (e.g., weight loss, liver/renal failure) Pattern of hypoglycemia? Post-prandial pattern Educate Provide psychosocial support Decrease dose bolus dose Change bolus type Review dose timing Review injection sites Review OADs Fasting/nocturnal/ pre-prandial pattern basal dose Change basal type Review dose timing Review injection sites OAD, oral anti-diabetic drug Blumer I and Clement M. Clin Ther. 2017;39(8S2):S1 S11; Seaquist ER, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. J Clin Endocrinol Metab. 2013;98(5):

15 5. Book a follow-up appointment IN YOUR PRACTICE When following up with patients, consider discussing the following topics to enhance your conversations: A1C FPG Current glycemic control Administration, timing and injection site rotation Assessing for low blood sugar* and variability Optimizing control See your handout for potential questions to ask patients at follow-ups and relevant patient considerations *Consider reducing or eliminating insulin secretagogues Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S325. Following up with Patrick PATRICK 59-year-old male Flight attendant Type 2 diabetes Diagnosed 6 years ago Private insurance coverage Health Status BMI: 26.7 kg/m 2 BP: 132/88 mmhg egfr: 78 ml/min/1.73m 2 ACR: Negative LDL: 1.5 mmol/l CV: No history of cardiovascular disease Exercise: Walks briskly 3 times/week for 20 minutes Diet: Eats a balanced diet when at home and has 2 alcoholic drinks, 3 days/week Glycemic Parameters A1C: 8.5% (A1C not measured at follow-up) FPG: 8.8 mmol/l Medications Gliclazide modified release (90 mg QD) Sitagliptin and metformin HCL-extended release (100 mg sitagliptin/2000 mg metformin QD) Rosuvastatin (10 mg QD) Ramipril (10 mg QD) Basal insulin 20 units PAUSE AND REFLECT What are you following up on at 1 month keeping in mind the enhancing conversations topics? What if Patrick returned to your practice after 6 months, his FPG was at target, he rarely experienced hypoglycemia, but his A1C was still high? What if his FPG was at target, but he was experiencing daytime hypoglycemia? 15

16 Basal Insulin Optimization Patient Case #2: Priyanka Meet Priyanka Health Status BMI: 29.4 kg/m 2 BP: 138/88 mmhg egfr: 68 ml/min/1.73m 2 ACR: Negative LDL: 1.9 mmol/l CV: No history of cardiovascular disease but strong family history Exercise: On her feet during the day at work Diet: Indian vegetarian diet; does not drink alcohol PRIYANKA 45-year-old female Office administrator Type 2 diabetes Diagnosed 10 years ago Private insurance coverage Insulin Treatment Regimen Basal: Insulin glargine U units at bedtime Glycemic Parameters A1C: 8.3% FPG: 8.5 mmol/l Medications Metformin 1000 mg BID Sitagliptin 100 mg QD Empagliflozin 10 mg QD Atorvastatin 10 mg QD Amlodipine 5 mg QD Was previously on gliclazide but stopped due to daytime hypoglycemia 16

17 Key findings during conversation with Priyanka A1C FPG Current glycemic control Priyanka is frustrated. Her morning FPG ranges greatly, from mmol/l Administration, timing and injection site rotation Very adherent to her treatment regimen and rotates injection sites appropriately Assessing for low blood sugar and variability Sometimes she s dizzy and grumpy during the day, but attributes this to tiredness or hunger Optimizing control Has not been titrating since her last appointment What glycemic targets would you set for Priyanka? She sleeps solidly through the night, but will occasionally have a headache in the morning Sometimes skips breakfast and/or lunch due to hectic work schedule Age: 45 A1C: 8.3% BMI: 29.4 kg/m 2 AHA medications: Metformin, sitagliptin, empagliflozin, atorvastatin and amlodipine Complications: None Basal Insulin Optimization Part 4: Hypoglycemia and its impact 17

18 The real-world impact of hypoglycemia on patients Fear of travelling, leaving home and being alone. ~Dr. Milan Gupta I don't want anyone around me to know I have diabetes. Why on earth would I risk a low? ~Patient of Dr. Vance Pegado During a return demonstration of a blood glucose meter, a patient s random blood glucose was 2.6 mmol/l. Her demeanor was that of shame. It seemed that she was concerned that I was thinking she couldn t care for herself or that she was irresponsible. I actually couldn t let her drive home from the appointment and alternate transportation was arranged. Hesitancy to titrate or increase their therapy/dose. ~Robert Roscoe ~Susie Jin Hypoglycemia is the most common adverse event of insulin therapy, regardless of A1C Canadian perspective 2/3 of patients with T2DM on basal insulin experience hypoglycemia 85% of patients who have experienced a low do not speak to their physicians about hypoglycemia OF NOTE Glucose variability may be a barrier to the optimization of glycemic control due to its association with hypoglycemia Leiter LA, Yale J, Chiasson J, Harris SB, Kleinstiver P, Sauriol L. Assessment of the impact of fear of hypoglycemic episodes on glycemic and hypoglycemia management. Can J Diabetes. 2005;29(3):186-92, Kovatchev B, et al. Glucose variability: timing, risk analysis, and relationship to hypoglycemia in diabetes. Diabetes Care. 2016;39(4):

19 Glycemic variability can manifest as both within-day variability Glucose (mmol/l) SMBG measurement Hyperglycemia Hypoglycemia Time (hours) SMBG, self-measured blood glucose Adapted from Penckofer, S et al. Diab Tech Ther 2012;14: and day-to-day variability Day 1 Day 3 Glucose (mmol/l) Day 2 Day Time (hours) Adapted from Penckofer S, et al. Diab Tech Ther 2012;14:

20 FPG variability plays a role in hypoglycemia risk FPG (mmol/l) 12.0 Average FPG Target zone Hypoglycemia zone Day FPG (mg/dl) FPG, fasting plasma glucose Adapted from Vora J and Heise T. Diabetes Obes Metab. 2013;15: Lower FPG variability may reduce the risk of hypoglycemia FPG (mmol/l) Average FPG Target zone Hypoglycemia zone FPG, fasting plasma glucose Adapted from Vora J and Heise T. Diabetes Obes Metab. 2013;15: Day Spotlight on Priyanka FPG (mg/dl) You suspect that Priyanka is experiencing nocturnal and daytime hypoglycemia unawareness. How would you confirm this? 20

21 Key features of continuous and flash glucose monitoring CGM FGM Instantaneous realtime display of glucose levels and rate of change of glucose Alerts for impending hyper- and hypoglycemia Ability to characterize glycemic variability Produces an ambulatory glucose profile IN YOUR PRACTICE Real-time CGM has been shown to reduce A1C and reduce time spent in hypoglycemia in adults with T2DM The use of FGM versus SMBG resulted in a similar drop in A1C but a significant reduction in time spent in hypoglycemia, reduced glycemic variability and improved quality of life in individuals with T2DM CGM, continuous glucose monitoring; FGM, flash glucose monitoring Rodbard D. Continuous glucose monitoring: a review of successes, challenges, and opportunities. Diabetes Technol Ther. 2016;18(S2):S2-3-S2-13; Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S325; Ish-Shalom M, Wainstein J, Raz I, Mosenzon O. Improvement in Glucose Control in Difficult-to-Control Patients With Diabetes Using a Novel Flash Glucose Monitoring Device. J Diabetes Sci Technol. 2016;10(6): Basal Insulin Optimization Part 5: Approach to switching to newer basal insulins 21

22 What does Diabetes Canada recommend for basal insulin selection? In T2DM, if lower risk of hypoglycemia is a priority: a. Long-acting insulin analogues should be considered over NPH insulin b. Insulin degludec may be considered over insulin glargine U100 to reduce overall and nocturnal hypoglycemia, and severe hypoglycemia in patients at high CV risk i Learn more c. Insulin glargine U300 may be considered over insulin glargine U100 to reduce overall and nocturnal hypoglycemia i Learn more T2DM, type 2 diabetes mellitus Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S325. PAUSE AND REFLECT Insulin degludec and insulin glargine U300 demonstrated non-inferior A1C reductions when compared head-to-head with insulin glargine U100 Insulin degludec demonstrated statistically significant reductions in the rates of overall and nocturnal hypoglycemia and a reduction in the rates of severe hypoglycemia relative to insulin glargine U100 In a randomized, double-blind CVOT, insulin degludec demonstrated statistically significant reductions in the rates of severe and nocturnal severe hypoglycemia relative to insulin glargine U100 Insulin glargine U300 demonstrated a statistically significant reduction in the number of patients reporting nocturnal confirmed or severe hypoglycemia and a reduction in confirmed or severe hypoglycemia compared to insulin glargine U100 Significant reductions in glucose variability demonstrated with insulin degludec compared to insulin glargine U100 and U300 (clamp study results) Low glucose variability is associated with a lower rate of severe hypoglycemia, MACE and all-cause mortality compared to medium or high variability. This rate was not significant for MACE after adjustment. CVOT, cardiovascular outcomes trial; MACE, major adverse cardiovascular events 22

23 Key findings during conversation with Priyanka A1C FPG What if Priyanka was using CGM? Current glycemic control Highly variable day-to-day fasting glucose values and high within-day variability Assessing for low blood sugar and variability Priyanka experiences nocturnal hypo, 2.9 mmol/l, at least 2x a week Still doesn t recognize nocturnal hypo symptoms. However, now that she checks her CGM throughout the day, we know she is not experiencing daytime hypo on a regular basis CGM, continuous glucose monitoring PAUSE AND REFLECT You now know that Priyanka is experiencing nocturnal hypoglycemia unawareness. What are your next steps? What considerations do you have for this patient? Review: How to switch to once-daily basal insulins in T2DM From once-daily From BID From IGlar basal 1,2,3,4 basal 1,2,3,4 U300 1,2 1:1 20% 20% Followed by daily or weekly titration (depending on insulin) 1. Sanofi-aventis Canada Inc. Lantus Product Monograph. 2017; 2. Eli Lilly Canada Inc. BASAGLAR TM Product Monograph. 2015; 3. Sanofi-aventis Canada Inc. Toujeo TM Product Monograph. 2015; 4. Novo Nordisk A/S. Tresiba Summary of Product Characteristics (SmPC). Bagsværd, Denmark

24 In Summary IN YOUR PRACTICE Goal of insulin treatment: Get to A1C target with as few adverse events as possible Enhance conversations with your patients Consider CGM and FGM to reduce A1C and hypoglycemia Nocturnal and symptomatic hypoglycemia: Use basal insulin analogues over NPH Overall and nocturnal hypoglycemia: Use insulin glargine U300 or insulin degludec over insulin glargine U100 Patients at high CV risk: Use insulin degludec over insulin glargine U100 to reduce risk of hypoglycemia Low glucose variability is associated with a lower rate of severe hypoglycemia, MACE and all-cause mortality compared to medium or high variability Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S325. Overview of your participant handout Key takeaways from the 2018 Clinical Practice Guidelines Summary table of insulin options and starting and switching algorithm(s) Enhancing Conversations Guide A1C FPG Current glycemic control Administration, timing and injection site rotation Assessing for low blood sugar and variability Optimizing control 24

25 THANK YOU! 25

26 In Control Long-acting insulins for the management of type 2 diabetes Participant Handout This program has received an educational grant and in-kind support from Novo Nordisk Canada Inc.

27 Patient Cases Patrick 59-year-old male Flight attendant Type 2 diabetes Diagnosed 6 years ago Private insurance coverage Priyanka 45-year-old female Office administrator Type 2 diabetes Diagnosed 10 years ago Private insurance coverage Health Status BMI: 26.7 kg/m 2 BP: 132/88 mmhg egfr: 78 ml/min/1.73m 2 ACR: Negative LDL: 1.5 mmol/l CV: No history of cardiovascular disease Exercise: Walks briskly 3 times/week for 20 minutes Diet: Eats a balanced diet when at home and has 2 alcoholic drinks 3 days/week Glycemic Parameters A1C: 8.5% FPG: 11.8 mmol/l Medications Gliclazide modified release (90 mg QD) Sitagliptin and metformin HCL-extended release (100 mg sitagliptin/2000 mg metformin QD) Rosuvastatin (10 mg QD) Ramipril (10 mg QD) Notes Health Status BMI: 29.4 kg/m 2 BP: 138/88 mmhg egfr: 68 ml/min/1.73m 2 ACR: Negative LDL: 1.9 mmol/l CV: No history of cardiovascular disease, but strong family history Exercise: On her feet during the day at work Diet: Indian vegetarian diet; does not drink alcohol Glycemic Parameters A1C: 8.3% FPG: 8.5 mmol/l Medications Metformin 1000 mg BID Sitagliptin 100 mg QD Empagliflozin 10 mg QD Atorvastatin 10 mg QD Amlodipine 5 mg QD Was previously on gliclazide but stopped due to daytime hypoglycemia Insulin Treatment Regimen Basal: Insulin glargine U units at bedtime 2

28 Initiating Basal Insulin in Type 2 Diabetes Start: 10 units once daily Titration: 1 unit per day until target reached (detemir, glargine and NPH) Degludec should be titrated by 2 units every 3 4 days or by 4 units once a week Switching Basal Insulin in T2DM From once-daily basal 2,3,4,5 1:1 From BID basal 2,3,4,5 20% From IGlar U300 2,3 20% Followed by daily or weekly titration (as described above) Basal Insulin Product Options and Features Insulin type Brand name Total units per pen (units) Maximum single dose for injection (units) In-use time (days) Pre-filled pen Insulin degludec Insulin detemir Tresiba 100 units/ml Tresiba 200 units/ml Levemir 100 units/ml Lantus 100 units/ml FlexTouch FlexTouch FlexTouch * SoloSTAR * Insulin glargine NPH Basaglar 100 units/ml Toujeo 300 units/ml Novolin ge NPH 100 units/ml Kwikpen * SoloSTAR Cartridge only Humulin N 100 units/ml Kwikpen * * Also available in cartridges for use in durable/refillable pens; max dose in durable pen may differ from max dose in prefilled pens above. 3

29 Enhancing Conversations Guide Use the following guide to help enhance your conversations with patients with type 2 diabetes who are taking basal insulin. Current glycemic control Questions What targets did we set for you? Fasting blood glucose (FPG)? Glycated hemoglobin (A1C)? Review blood glucose journal: How many of your morning FPG readings are at target? Does your FPG vary from day to day? Considerations What factors may contribute to: An above-target FPG (e.g., hypoglycemia, suboptimal insulin dose)? Day-to-day variability (e.g., changing schedule, insulin type) Administration Questions What time(s) do you typically inject basal insulin? In a typical week, how often do you miss the regular dosing time for your basal insulin? Show me how and where you normally inject your basal insulin each day Considerations If the patient takes basal insulin BID, consider switching to a longer-acting basal insulin If the patient is taking a high dose, consider a: More concentrated insulin for a smaller injection volume Pen with a different maximum dose Discuss how to manage missed/delayed doses for the patient s basal insulin Consider a basal insulin that affords some flexibility in the timing of administration and/or can be administered in the morning or at bedtime Regarding injection technique: Based on the type and features of the pen device (e.g., prefilled vs. refillable, ease of injecting), is a switch appropriate? Looking at the type and features of the pen needle (e.g., size, gauge), is a switch appropriate? Remind the patient that pen needles are designed for single-use only Reinforce injection-site rotation Assessing for low blood sugar Questions How often has your blood sugar dropped below 4 mmol/l in the last 3 months? How often have you experienced symptoms? (e.g., headaches, dizziness) When do they happen? (e.g., during the day, at bedtime, in the night) Are you snacking to prevent or treat low blood sugar? Have episodes of low blood sugar caused you to change your insulin regimen? Considerations Investigate possible causes of the hypoglycemia (e.g., alcohol consumption, chronic kidney disease, recent weight loss) Discuss ways to reduce the risk of hypoglycemia, such as: Reducing the basal/bolus insulin dose (depending on the timing of the hypoglycemic episode in comparison to time/action profile of injected insulin) Switching the patient to a basal insulin with a lower risk of hypoglycemia Reducing dose of concurrent sulfonylurea therapy For additional support, refer the patient to a diabetes educator If the patient experiences hypoglycemia unawareness, refer to an endocrinologist Optimizing control Questions What is your current dose of basal insulin? Are you still adjusting your insulin dose? If yes, what is your titration schedule? If no, why not? Considerations If the patient is not at their FPG target and not experiencing nocturnal, severe or frequent mild episodes of hypoglycemia, optimize the dose of basal insulin Discuss example dosage adjustment schedules, and remind the patient that insulin has no dose ceiling 4

30 Key Takeaways Goal of insulin treatment: Get to A1C target with as few adverse events as possible. Enhance conversations with your patients Consider CGM and FGM to reduce A1C and hypoglycemia Nocturnal and symptomatic hypoglycemia: Use basal insulin analogues over NPH Overall and nocturnal hypoglycemia: Use insulin glargine U300 or insulin degludec over insulin glargine U100 Patients at high CV risk: Use insulin degludec over insulin glargine U100 to reduce risk of hypoglycemia Low glucose variability is associated with a lower rate of severe hypoglycemia, MACE and all-cause mortality compared to medium or high variability CGM: continuous glucose monitoring; FGM: flash glucose monitoring; MACE: major adverse cardiovascular event REFERENCES 1. Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S Sanofi-aventis Canada Inc. Lantus Product Monograph Eli Lilly Canada Inc. BASAGLARTM Product Monograph Sanofi-aventis Canada Inc. Toujeo TM Product Monograph Novo Nordisk Canada Inc. Tresiba Product Monograph Rodbard D. Continuous glucose monitoring: a review of successes, challenges, and opportunities. Diabetes Technol Ther. 2016;18(S2):S2-3-S Ish-Shalom M, Wainstein J, Raz I, Mosenzon O. Improvement in Glucose Control in Difficult-to-Control Patients With Diabetes Using a Novel Flash Glucose Monitoring Device. J Diabetes Sci Technol. 2016;10(6):

31 Notes 6

32 Basal Insulin Dosing Guide Starting basal insulin for type 2 diabetes 1 With the help of your healthcare provider, fill out the form below to get started with your basal insulin treatment. Basal insulin prescribed: Starting dose: units, time(s) per day, taken Basal insulin should be adjusted until the pre-breakfast (fasting) blood sugar target is reached. Adjusting your basal insulin dose 1. Take your pre-breakfast (fasting) blood sugar measurement 2. Check where your blood sugar is on the chart below to see what to do Morning blood sugar measurement (mmol/l) Target range BELOW TARGET Reduce dose UNITS ON TARGET Dose remains the same ABOVE TARGET Increase dose + UNITS Check the days of the week you will adjust your insulin dose: Monday Tuesday Wednesday Thursday Friday Saturday Sunday Missed dose If a dose of insulin glargine is missed or if not enough has been injected, your blood sugar level may become too high (hyperglycemia). Do not take a double dose to make up for a forgotten dose. 2,3 If a dose of insulin degludec is missed, the missed dose should be taken as soon as you remember, making sure there are at least 8 hours between doses. Following that, continue with your regular dosing schedule. 4

33 Sick-day management Illness, especially with nausea and vomiting, diarrhea and/or fever, may change how much basal insulin you need. Even if you are not eating, you will still require insulin. You and your healthcare professional should establish a sick-day plan for you to use in case of illness. When you are sick, test your blood/urine frequently and call your healthcare professional as instructed. 2 Sick-day plan: What you need to know about hypoglycemia (low blood sugar) Treatment of diabetes with insulin can sometimes lead to hypoglycemia. Symptoms of hypoglycemia can include feeling shaky, light-headed, nauseated, nervous, anxious, hungry, confused, sweaty and weak. Measuring your blood sugar regularly will tell you if your blood sugar is too high or too low. When your blood sugar falls below your target range (for most people, this is usually about 4 mmol/l), this is called hypoglycemia. Hypoglycemia can happen quickly, so it is important to treat it right away. If your blood sugar drops very low, you may lose consciousness and need help from another person. 5 What should you do if you think you are experiencing hypoglycemia? Diabetes Canada suggests treating mild-to-moderate hypoglycemia with 15 g of fast-acting carbohydrate. For example 5 : 15 g of glucose in the form of glucose tablets 15 ml (1 tablespoon) or 3 packets of sugar dissolved in water 150 ml (2/3 cup) of juice or regular pop 6 Life Savers (1 = 2.5 g of carbohydrate) 15 ml (1 tablespoon) of honey (do not use for children less than 1 year old) Wait 15 minutes, then check your blood sugar again. If it is still below 4 mmol/l: Treat again; wait 15 minutes, check your blood sugar. Continue these steps until your blood sugar is above 4 mmol/l When your blood sugar is above 4 mmol/l: If your next meal is more than 1 hour away, or you are going to be active, eat a snack with 15 g of carbohydrate and a protein source (e.g., half a sandwich or cheese and crackers) Do not drive for 40 minutes DO NOT TAKE ANY INSULIN IF YOU ARE EXPERIENCING OR THINK YOU MAY BE EXPERIENCING HYPOGLYCEMIA. References: 1. Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018; 42:S1-S sanofi-aventis Canada Inc. Lantus Product Monograph sanofi-aventis Canada Inc. Toujeo SoloSTAR Product Monograph Novo Nordisk Canada Inc. Tresiba Product Monograph Diabetes Canada. Lows and highs: blood glucose levels Available at: Retrieved May 17, 2018.