Injectable Agents for Type 2 Diabetes. Richard Christensen, MD AACE Diabetes Day, Boise, ID September 2017

Transcription

1 Injectable Agents for Type 2 Diabetes Richard Christensen, MD AACE Diabetes Day, Boise, ID September 2017

2 Financial Disclosures Sanofi speaker honoraria No other relevant financial disclosures

3 Injectable Agents Available for Type 2 Diabetes Class Primary Mechanism of Action Agent(s) Available as GLP-1 receptor agonists Increase glucose-dependent insulin secretion Decrease glucagon secretion Slow gastric emptying Increase satiety Albiglutide Dulaglutide Exenatide Exenatide XR Liraglutide Lixisenatide Tanzeum Trulicity Byetta Bydureon Victoza Adlyxin Insulin Increase glucose uptake in muscle and fat Decrease hepatic glucose production Decrease lipolysis, etc Various Various Fixed combination GLP-1 receptor agonist + basal insulin All of the above Degludec/liraglutide Glargine/lixisenatide Xultophy 100/3,6 Soliqua 100/33. Amylin analog Decrease glucagon secretion Slow gastric emptying Increase satiety Garber AJ, et al. Endocr Pract. 2016;22: Inzucchi SE, et al. Diabetes Care. 2015;38: Pramlintide Symlin

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5 24 Hour Glucose Profile in Diabetes van Dijk JW, et al.. Diabetes Res Clin Pract 2011;93:31 37

6 Relative Contribution of Postprandial Hyperglycemia to Overall Glycemic Control 70% 51% 45% 40% 30% Monnier L, et al. Diabetes Care. 2003;26:

7 Glycemic Effects of Available Injectable Agents for T2D GLP1 receptor agonist Insulin Pramlintide FPG lowering Mild (albiglutide, exenatide) Moderate (dulaglutide, exenatide ER, liraglutide) Mod to marked (basal insulin or premixed) Mild PPG lowering Mod to marked Mod to marked (short/ rapid-acting insulin or premixed) Mod to marked Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.

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9 Percentage of Patients Attaining A1C < 7%, No Weight Gain, and No Hypoglycemic Events

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11 Profiles of GLP-1 RAs Drug Dosing Half-life Duration of Action Exenatide 5-10 mcg SC twice daily 2.4 hours Short-acting Lixisenatide mcg SC daily 2-4 hours Short-acting Albiglutide Dulaglutide mg SC once weekly mg SC once weekly 6-7 days Long-acting 5 days Long-acting Exenatide ER 2 mg SC once weekly 2.4 hours Long-acting Liraglutide mg SC once daily 13 hours Long-acting Pinelli NR and Hurren KM. The Annals of Pharmacotherapy. 2011;45(7-8): American Diabetes Association. Diabetes Care. 2015;38(suppl 1):S41-S48. US FDA. Drugs@FDA Website. data.fda.gov/scripts/cder/drugsatfda/. EU EMA. Medicines@EMA Website.

12 Comparing the Effects of GLP-1 RA Parameters Compounds Short-acting (Prandial) GLP-1 receptor agonists Exenatide BID, Lixisenatide Long-acting GLP-1 receptor agonists Albiglutide, Dulaglutide, Exenatide LAR, Liraglutide Half-life 2 5 hours 12h several days Effects l Fasting blood glucose levels Modest reduction Strong reduction l Postprandial hyperglycemia Strong reduction Modest Reduction l Fasting insulin secretion Modest stimulation Strong stimulation l Postprandial insulin secretion Reduction Modest stimulation l Glucagon secretion Reduction Reduction l Gastric emptying rate Deceleration No effect l Blood pressure Reduction Reduction l Heart rate No effect or small increase (0 2 bpm) Moderate increase (2 5 bpm) l Body weight reduction 1 5kg 2 5kg l Induction of nausea 20 50% attenuates slowly (weeks to many months) 20 40% attenuates quickly (~4 8weeks) Meier JJ. Nat Rev Endocrinol 2012; 8:

13 Glucose Control with GLP1 Receptor Agonists Monotherapy Add-on to Metformin Add-on to SU Alb 1 Dul 2 Exe 3 Exe Lir 5 Lix 6 Alb 7 Dul 8 Exe 9 Exe Lir 11 Lix 12 Alb 13, Exe 14 Exe Lir 16 ER 4 ER 10 * ER 15, Baseline A1C (%) Placebo-adjusted D A1C (%) Placebo-Adjusted Change from Baseline (Not Head-to-Head Trials) *Metformin with or without SU or TZD. Metformin with or without SU. Absolute change from baseline (active-controlled trial) Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Umpierrez G, et al. Diabetes Care. 2014;37: Moretto TJ, et al. Clin Ther. 2008;30: Russell-Jones D, et al. Diabetes Care. 2012;35: Garber A, et al. Lancet. 2009;373: Fonseca VA, et al. Diabetes Care. 2012;35: Ahrén B, et al. Diabetes Care. 2014;37: Dungan KM, et al. Lancet. 2014;384: DeFronzo RA et al. Diabetes Care. 2005;28: Bergenstal RM, et al. Lancet. 2010;376: Pratley RE, et al. Lancet. 2010;375: Rosenstock J, et al. Diabetes Care. 2013;36: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2004;27: Diamant M, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26:

14 Weight Change with GLP1 Receptor Agonists Absolute Change from Baseline (Not Head-to-Head Trials) D Weight (kg) Monotherapy Add-on to Metformin Add-on to SU Alb 1 Dul 2 Exe 3 Exe ER 4 Lir 5 Lix 6 Alb 7 Dul 8 Exe 9 Exe ER 10 Lir 11 Lix 12 Alb 13, * Exe 14 Exe ER 15, Lir *Metformin with or without SU or TZD. Metformin with or without SU. 1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Umpierrez G, et al. Diabetes Care. 2014;37: Moretto TJ, et al. Clin Ther. 2008;30: Russell-Jones D, et al. Diabetes Care. 2012;35: Garber A, et al. Lancet. 2009;373: Fonseca VA, et al. Diabetes Care. 2012;35: Ahrén B, et al. Diabetes Care. 2014;37: Dungan KM, et al. Lancet. 2014;384: DeFronzo RA et al. Diabetes Care. 2005;28: Bergenstal RM, et al. Lancet. 2010;376: Pratley RE, et al. Lancet. 2010;375: Rosenstock J, et al. Diabetes Care. 2013;36: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2004;27: Diamant M, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26:

15 GI adverse events Pancreatitis Pancreatic cancer Medullary thyroid cancer Renal impairment ER, extended release. Safety Considerations with GLP1 Receptor Agonists Common Usually dose dependent and transient Usually reduced with dose titration Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal relationship has been established Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected Labeling for GLP1 receptor agonists suggests consideration of other therapies for patients with a history of pancreatitis Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents Further assessments required from long duration-controlled studies or epidemiological databases Animal data showed an increased incidence of C-cell tumors with liraglutide and exenatide ER treatment, but confirmatory population studies are lacking Labeling for albiglutide, dulaglutide, exenatide ER, and liraglutide: Patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms of thyroid tumors Contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia syndrome type 2 Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration. Use caution when initiating or escalating doses in patients with renal impairment. Exenatide should not be used in patients with severe renal insufficiency or ESRD. Liraglutide was found to be safe in patients with moderate renal impairment and may confer a beneficial effect. Garber AJ, et al. Endocr Pract. 2016;22: ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28, Davies MJ, et al. Diabetes Care. 2016;39: Marso SP, et al. N Engl J Med. 2016;375:

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17 Why insulin?

18 Early Insulin Use in Type 2 Diabetes ORIGIN (N=12,537 patients with CV risk factors + prediabetes or T2D) ORIGIN, Outcome Reduction With an Initial Glargine Interventionl T2D, type 2 diabetes. ORIGIN Trial Investigators. N Engl J Med. 2012;367:

19 Current Insulin Options Type Basal Insulins Prandial Insulins Premixed Insulins Human U-100 NPH U-100 regular human insulin U-500 regular human insulin Technosphere inhaled insulin U /30 NPH/R Analog U-100 glargine U-100 glargine equivalent* U-100 detemir U-100 degludec U-200 degludec U-100 lispro U-100 aspart U-100 glulisine U-200 lispro U /50 lispro U /30 aspart U /25 lispro U /30 degludec/aspart U-300 glargine Analogue insulins are associated with less hypoglycemia than human insulins, although these differences are not always statistically significant *In the US, U-100 glargine equivalent is not approved as a biosimilar product. Singh SR, et al. CMAJ. 2009;180: Drugs@FDA. FDA.

20 Insulin Concentrations Concentration Units/mL Units/vial Units/pen Pen dose U (10 units per vial) 300 (3 ml/pen) 1-60 or 1-80 U-200 degludec 200 Not available in vials U-300 glargine 300 Not available in vials 600 (3 ml/pen) 450 (1.5 ml/pen) U-500 regular ,000 (20 units/vial) 1500 (1.5 ml/pen) Insulin pens significantly reduce the risk of dosing errors and hypoglycemic events Pens completely eliminate the need for converting doses based on the volume of insulin injected Dosing errors with U-500 insulin vials are common and dangerous but can be avoided with newly available pens or specific U-500 syringe 5-fold higher insulin dose relative to the same volume of a U-100 insulin Drugs@FDA. Newton C, et al. AACE Annual Meeting [abstract 271]. Segal AR, et al. Am J Health Syst Pharm. 2010;67:

21 Pharmacokinetics of Available Insulins Agent Onset (h) Peak (h) Duration (h) Considerations Basal NPH Glargine Detemir Degludec ~1-4 No pronounced peak* Up to 24 Greater risk of nocturnal hypoglycemia compared to insulin analogs Less nocturnal hypoglycemia compared to NPH Basal- Prandial Prandial Regular U ~ Regular ~0.5-1 ~2-3 Up to 8 Aspart Glulisine Lispro Inhaled insulin <0.5 ~ ~3-5 Inject 30 min before a meal Indicated for highly insulin resistant individuals Use caution when measuring dosage to avoid inadvertent overdose Must be injected min before a meal Injection with or after a meal could increase risk for hypoglycemia Can be administered 0-15 min before a meal Less risk of postprandial hypoglycemia compared to regular insulin * Exhibits a peak at higher dosages. Dose-dependent. NPH, Neutral Protamine Hagedorn. Moghissi E et al. Endocr Pract. 2013;19: Humulin R U-500 (concentrated) insulin prescribing information. Indianapolis: Lilly USA, LLC.

22 Types of insulin to meet needs Insulin degludec Modifed from Kennedy M. In: Katzung B & Masters S, eds. Basic & Clinical Pharmacology. 12th ed. NY, NY: McGraw- Hill; 2012:748.

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24 24 Hour Glucose Profile in Diabetes van Dijk JW, et al.. Diabetes Res Clin Pract 2011;93:31 37

25 Initiating Basal Insulin Therapy Add single dose of basal insulin Degludec, detemir, glargine, or NPH Usually administered at evening meal or bedtime (glargine, glargine U-300, degludec may be any consistent time of day) Use conservative starting dose 0.1 to 0.2 units/kg (A1c < 8) 0.2 to 0.3 units/kg (A1c > 8) 10 units (empiric) Endocr Pract. 2017; 23:

26 Titrating Basal Insulin Therapy Adjust dose according to fasting SMBG Titrate 1-2 times weekly by fasting glucose (FPG) FPG > 180: Add 20% Hypoglycemia: FPG : Add 10% BG < 70: Reduce 10-20% FPG : Add 1 unit BG < 70: Reduce 20-40% Other titration schemes acceptable Titrate to target fasting glucose AACE: <110 mg/dl Or individualized target Usually continue metformin at same dosage (reduce or stop sulfonylurea/secretagogues) Endocr Pract. 2017; 23:

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28 Combination of Basal Insulin with a GLP-1 Receptor Agonist Little S, et al. Diabetes Technol Ther. 2011:13(suppl 1):S53-S64. Cohen ND, et al. Med J Aust. 2013;199(4): Carris NW, et al. Drugs. 2014;74(18):

29 GLP-1 RAs in Combination with Insulin in T2DM Systematic Review Results reported as available from 7 RCTs and 15 clinical practice or observational studies including at least 30 patients with T2DM* Insulin Added to GLP-1 RA GLP-1 RA Added to Insulin GLP-1 RA + Insulin (sequence not specified) HbA1c Body Weight (kg) Insulin Dose (Units) Baseline Endpoint 100 Baseline Endpoint 30 Baseline Endpoint *Each line in the graph represents a study. Balena R, et al. Diabetes Obes Metab. 2013;15(6):

30 Exenitide vs prandial insulin added to metformin + basal insulin Diamant M, et al. Diabetes Care 2014;37:

31 Fixed-Ratio Degludec/Liraglutide Combination: Glycemia Deg/Lira was superior (p<0.001) to Lira and non-inferior to insulin Deg in reducing A1C A1C over Time Deg/Lira significantly reduced FPG compared to Lira (p<0.001) FPG over Time LIRA (n=414) IDeg (n=413) IDeg + LIRA (n=833) LIRA (n=414) IDeg (n=413) IDeg + LIRA (n=833) A1C (%) % 6.9% FPG (mg/dl) mg/dl 104 mg/dl % mg/dl Time (weeks) Time (weeks) LIRA = liraglutide. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:

32 Fixed-Ratio Degludec/Liraglutide Combination: Body Weight and Hypoglycemia Change in Body Weight over Time Confirmed Hypoglycemia Change in Body Weight over Time (kg) IDeg/Lira vs IDeg: -2.2 kg, p< IDeg/Lira vs Lira: kg, p< kg -0.5 kg IDeg/Lira vs Lira: rate ratio 7.61, p< IDeg/Lira vs IDeg: rate ratio 0.68, p= Mean Cumulative Episodes per Subject A1C 6.9% A1C 6.4% -3.0 kg A1C 7.0% Time (weeks) Time (weeks) LIRA (n=414) IDeg (n=413) IDeg + LIRA (n=833) Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:

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34 Intensifying Insulin Therapy after Basal A1C 7% after 2 3 months with fasting blood glucose in target range Perform SMBG before meals, bedtime Basal Plus: Add prandial insulin before largest meal or greatest excursion Before lunch: add breakfast dose Before dinner: add lunch dose Before bedtime: add dinner dose Basal bolus: Add prandial insulin at each meal

35 Intensifying Insulin Therapy Prandial insulin options Insulin aspart, glulisine, lispro, regular Prandial insulin initiation Basal Plus 10% of basal dose or 5 units largest meal Sequentially add to additional meals if not to target Basal Bolus Split 50% basal, 50% prandial (divide prandial between 3 meals) Prandial insulin titration (every 2-3 days) Increase 10% or 1-2 units if 2 hour postprandial or next premeal glucose > 140 Reduce basal and/or prandial if hypoglycemia 10-20% if BG consistently < % if severe hypoglycemia or BG < 40

36 Multicomponent Insulin Options: MDI, Premixed, NPH + R

37 Pros and Cons Premixed Insulin Simpler, fewer injections Less flexibility, hypoglycemia Premix NPH + R Usually twice daily 2/3 before breakfast, 1/3 before supper Premix analog multiple approaches Start before supper similar to bedtime basal, add AM dose after fasting control Start twice daily before breakfast and supper ½ AM and ½ PM, or 2/3 AM and 1/3 PM Can add pre-lunch dose (TID)

38 NPH and Regular (R) Insulin Less expensive alternative R should be given 30 minutes before meals Somewhat greater risk of hypoglycemia Converting from basal bolus total daily dose (TDD) commonly initiated as: 2/3 TDD before breakfast (2/3 NPH, 1/3 R) 1/3 TDD before supper (1/2 NPH, ½ R) Or preferably split PM dose: R before supper, NPH at bedtime New insulin start TDD = 0.4 unit/kg Divide as above May also use in basal bolus Bedtime N as basal (+/- small AM dose) R before each meal

39 Wysham C, et al. Endocr Pract. 2016;22: U-500 Regular Insulin Onset similar to R, duration similar to NPH >300 units: TID dosing often used >600 units: QID dosing often used U-500 pen or U-500 syringe reduces dosing errors

40 Modified from American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3 rd ed Adjusting Insulin Doses Out-of-Range Result Postbreakfast/prelunch Postlunch/presupper Postsupper/bedtime Early morning Insulin Component to Adjust Prebreakfast rapid-acting/short-acting insulin, Premix, U-500 Prelunch rapid-acting/short-acting insulin Morning NPH, Morning Premix, Morning U-500 Presupper rapid-acting/short-acting insulin, Premix, U-500 Long-acting insulin, Evening NPH, Evening Premix, Evening U-500

41 Intensive Insulin Maximal flexibility/control (motivated patients) Insulin-to-carbohydrate ratio for food Insulin to cover ingested carbohydrate Correction insulin for hyperglycemia Correction factor (insulin sensitivity factor) Correction dose Pattern management Insulin doses determined or adjusted by trends in SMBG data

42 Insulin-to-Carbohydrate Ratio (ICR) Amount of rapid-acting or short-acting insulin needed to cover carbohydrates in meals and snacks Patient may have different insulin-tocarbohydrate ratios for different meals Breakfast ICR often somewhat higher Example ICR: 6 for breakfast, 8 for lunch and supper

43 Insulin-to-Carbohydrate Ratio (ICR) Rule of 500 Method of estimating insulin-to-carbohydrate ratio from total daily dose (TDD) of insulin 500 TDD Example TDD = 30 units basal + 10 units rapid each meal = 60 units = 8.3 (round to 8) Test meal: 90 gm 8 = (11 units) Check 2 hour glucose excursion (peak < 180, optimal peak < 140)

44 Correction Factor (CF) Amount of rapid-acting or short-acting insulin needed to return an elevated blood glucose level to target level Quantifies degree of change in blood glucose value expected with injection of 1 unit insulin 1800 rule 1800 total daily dose of insulin (TDD) Example TDD = 30 units basal + 10 units rapid each meal = 60 units units = 30 CF = unit of rapid-acting or short-acting insulin will lower blood glucose by 30 mg/dl (round if needed for ease of use)

45 Correction Factor Applied Current blood glucose target blood glucose = amount of glucose over target Amount of glucose over target correction factor = correction dose [Blood glucose now] [Goal blood glucose] Example Correction factor = 90 = 3 units (added to meal dose) 30 30

46 ICR and Correction Factor Applied ICR 8, CF 30, target glucose 120 Determine meal carbohydrate (60 gm) Calculate meal dose Meal carbohydrate/icr = 60/8 = 7.5 (~ 8 units) Determine correction dose required (BG 210) (Actual glucose target glucose)/cf ( )/30 = 90/30 = 3 units Meal dose = 8 units for food + 3 units for correction = 11 units prandial insulin given prior to meal

47 Hypoglycemia: Risk Factors Patient Characteristics Older age Longer duration of diabetes Neuropathy Renal impairment Previous hypoglycemia Behavioral and Treatment Factors Missed meals Elevated A1C Exercise Alcohol Other drugs (beta blocker?, etc) Modified from Miller ME, et al. BMJ Jan 8;340:b5444. doi: /bmj.b5444.

48 Symptoms of Hypoglycemia Classification Blood Glucose Level (mg/dl) Typical Signs and Symptoms Mild hypoglycemia ~50-70 Neurogenic: palpitations, tremor, hunger, sweating, anxiety, paresthesia Moderate hypoglycemia ~50-70 Neuroglycopenic: behavioral changes, emotional lability, difficulty thinking, confusion Severe hypoglycemia <50* Severe confusion, unconsciousness, seizure, coma, death Requires help from another individual *Severe hypoglycemia symptoms should be treated regardless of blood glucose level. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.

49 Consequences of Hypoglycemia Cognitive, psychological changes (eg, confusion, irritability) Accidents Falls Recurrent hypoglycemia and hypoglycemia unawareness Refractory diabetes Dementia (elderly) CV events Cardiac autonomic neuropathy Cardiac ischemia Angina Fatal arrhythmia Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.

50 Frequency of Severe Hypoglycemia With Antihyperglycemic Agents Percentage of Patients Treated in 1 Year 6% Mixtures, rapid-acting, basal-bolus 5% 4% Insulin Basal 3% 2% 1% 0 Sulfonylureas Glinides DPP-4 inhibitors, GLP-1 receptor agonists, Metformin, TZDs, SGLT2 inhibitors Moghissi E, et al. Endocr Pract. 2013;19:

51 Relative Rates of Severe Hypoglycemia with Insulin Increasing rates of hypoglycemia Most frequent Prandial and premixed Human insulin Prandial analogs and inhaled insulin Premixed (70/30, 75/25) More frequent Basal + Basal plus 2-3 prandial Basal plus 1 prandial Less frequent Basal only NPH Basal analogs (glargine, detemir) Pipeline basal analogues (degludec, pegylated lispro) Moghissi E, et al. Endocr Pract. 2013;19:

52 Elements of Hypoglycemia Prevention Set appropriate glycemic targets for individual patients Educate patients Use self-monitoring of blood glucose Hold a high index of suspicion for hypoglycemia Choose appropriate therapy More stringent goals: young, newly diagnosed, no comorbidities, no micro- or macrovascular disease, strong and effective self-care skills Less stringent goals: older, limited life expectancy, history of hypoglycemia, longer disease duration, established comorbidities, established vascular disease, limited selfcare skills Signs and symptoms of hypoglycemia Dietary education for improved glycemic control and appreciation of triggers for hypoglycemia Avoiding missed or delayed meals Appropriate self-treatment Understanding of hypoglycemia unawareness Importance of reporting hypoglycemia Patient education: technique and action Observation of patient s procedure and reaction Patient access to providers for purposes of reporting results and for providing guidance Provider reaction to results increases effectiveness of SMBG Understand patients may not report typical symptoms When hypoglycemia is suspected, adjust therapy Consider use of continuous glucose monitoring to detect unrecognized hypoglycemia Use agents with a low risk of hypoglycemia Be aware of additive effects of combination therapies on hypoglycemia risk Recognize that long-term costs of hypoglycemia may offset the cost of using older, less physiologic medications Moghissi E, et al. Endocr Pract. 2013;19:

53 Treatment of Hypoglycemia Hypoglycemia symptoms (BG <70 mg/dl) Patient conscious and alert Patient severely confused or unconscious (requires help) Consume glucose-containing foods (fruit juice, soft drink, crackers, milk, glucose tablets); avoid foods also containing fat Repeat glucose intake if SMBG result remains low after 15 minutes Consume meal or snack after SMBG has returned to normal to avoid recurrence Glucagon injection, delivered by another person Patient should be taken to hospital for evaluation and treatment after any severe episode Rule of 15: 15 gm wait 15 minutes BG = blood glucose; SMBG = self-monitoring of blood glucose. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.

54 Common Principles in AACE/ACE and ADA/EASD T2D Treatment Algorithms Individualize glycemic goals based on patient characteristics Promptly intensify antihyperglycemic therapy to maintain blood glucose at individual targets Combination therapy necessary for most patients Base choice of agent(s) on individual patient medical history, behaviors and risk factors, ethno-cultural background, and environment Insulin eventually necessary for many patients SMBG vital for day-to-day management of blood sugar All patients using insulin Many patients not using insulin Garber AJ, et al. Endocr Pract. 2016;22: Inzucchi SE, et al. Diabetes Care. 2015;38:

55 Conclusions GLP-1 Receptor agonists Multiple desirable features (glycemic control, weight loss, low risk hypoglycemia) Effective alone or in combination with multiple antihyperglycemic agents Complementary actions with basal insulin Insulin Ultimately necessary in most patients (progressive insulin deficiency) Basal insulin is a simple starting point Highly flexible options to meet individual needs Reduce hypoglycemia risk by education, individiualized intensity/targets based on patient factors