Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials: • Baseline Survey – Located at the front of your syllabus • CME Evaluation with Post-activity Survey – Located at the back of your syllabus Disclosures • The relevant financial relationships reported by faculty that they or their spouse/partner have with commercial interests are located on page 5 of your syllabus • The relevant financial relationships reported by the steering committee that they or their spouse/partner have with commercial interests are provided on page 5 of your syllabus • The relevant financial relationships reported by the non-faculty content contributors and/or reviewers that they or their spouse/partner have with commercial interests are located on page 5 of your syllabus Off-label Discussion Disclosure This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: • Describe the relationships between glycemia and diabetes complications • Consider the HbA1C-lowering properties of GLP-1 agonists with their impacts on T2DM pathophysiology, CV risk factors, and hypoglycemic risk when individualizing treatment strategies for diabetic patients to reach target goals • Develop strategies to attain glycemic control throughout the life cycle of T2DM • Promote a collaborative approach to T2DM management, empowering the patient through individualized patient education to address and break down barriers for optimal outcomes, including adherence and injection-related barriers Polling Question Baseline Survey • Please take out the Baseline Survey from your packet • Fill out the demographic information at the top of the form; as polling questions are asked throughout the program, please take a moment to select your answer to the corresponding question on this form • Your answers are important and will help us shape and improve future CME activities Polling Question Baseline Survey Please rate your confidence in managing T2DM in patients with prevalent macro- and/or microvascular comorbidities: A. Expert B. Very confident C. Confident D. Somewhat confident E. Not confident Polling Question Baseline Survey Please rate your confidence in using GLP-1 receptor agonists to reduce HbA1C in your T2DM patients: A. Expert B. Very confident C. Confident D. Somewhat confident E. Not confident Polling Question Baseline Survey How often do you incorporate a shared decision-making (SDM) approach to T2DM management? A. Always B. Frequently C. Sometimes D. Never E. I do not know the definition of SDM Polling Question Baseline Survey A 42-year-old overweight man with a positive family history for MI presents with T2DM (A1C 8.5%). He also has uncontrolled hypertension and elevated cholesterol. He is being treated for his hypertension and cholesterol and receives metformin 1000 mg bid and glipizide 10 mg qd for his T2DM. He is tired of “taking so many pills.” What do you consider? A. Identify A1C target ~8% based on cardiovascular risk B. Consider adding third oral agent C. Recommend optimizing lifestyle interventions and re-evaluate therapy in 6 months if necessary D. Consider adding or switching to injectable therapy, such as basal insulin and/or GLP-1 agonist Polling Question Baseline Survey A 42-year-old obese woman is receiving metformin, glimepiride, and sitagliptin. Her A1C is 8.1%. You recommend initiating a GLP-1 agonist, but the patient is afraid of needles. What action do you take? A. Avoid use of injectable agents in this patient B. Tell the patient that taking shots is inevitable based on her history of type 2 diabetes C. Tell the patient that she needs injectable therapy because her lifestyle interventions are insufficient D. Show the patient needles used for GLP-1 injection and explain the difference between intramuscular and subcutaneous injections Case 1: Introduction • Marcus is a 33-year-old overweight man with 4-year history of T2DM – Current medications: metformin 1000mg BID, glipizide 10mg QD – He has gained 15 lbs in 11 months; current BMI: 28.3 kg/m2 • Lab evaluation – HbA1C: 8.2% – BP: 172/85 mm Hg – Total cholesterol: 242 mg/dL • Patient concerns – Robert reveals that he has not been adherent to his T2DM medications because he was “tired of taking so many pills every day” – He has experienced episodes of shakiness and extreme hunger before lunch and dinner – He is now worried about his health because his father recently suffered a fatal MI at age 57 I. Burden of T2DM and Its Complications Polling Question Baseline Survey Follow-up from the UKPDS study demonstrated that each 1% reduction in A1C was significantly associated with all of the following, EXCEPT: A. Reduced risk for myocardial infarction B. Reduced risk for death due to diabetes C. Reduced risk for microvascular complications D. Reduced risk for microvascular complications, but not macrovascular outcomes Diabetes Prevalence in the US, 2012 National Diabetes Statistics Report, 2014 Statistics shown are for all ages CDC. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States. Atlanta, GA: US Department of Health and Human Services, 2014. Pathophysiologic Progression of T2DM and Its Vascular Complications Relative function Glucose (mg/dL) 350 300 OBESITY IFG IGT T2DM UNCONTROLLED HYPERGLYCEMIA 250 DM diagnosis 200 150 100 50 250 200 β-cell failure 150 100 MACROVASCULAR COMPLICATIONS MICROVASCULAR COMPLICATIONS 50 0 –10 –5 0 5 10 Time (years) Adapted from Ramlo-Halsted BA et al. Clin Diabetes. 2000;18:80-84. 15 20 25 30 IFG = impaired fasting glucose IGT = impaired glucose tolerance T2DM = type 2 diabetes mellitus Relationship of HbA1C to Risk of Microvascular Complications 15 Retinopathy Nephropathy Neuropathy Microalbumin Relative Risk 13 11 9 7 5 3 1 6 7 8 9 10 HbA1C (%) Used with permission from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254. 11 12 UKPDS: Macrovascular Complications Increase as Glycemic Control Worsens Fatal and nonfatal MI Heart failure 10 10 Hazard ratio P=0.021 Hazard ratio P<0.0001 1 1 14% decrease per 1% reduction in A1C 0.5 5 6 7 8 9 16% decrease per 1% reduction in A1C 0.5 10 5 6 Updated mean A1C concentration (%) 14%-16% reduction in cardiovascular events per 1% A1C reduction Stratton IM et al. BMJ. 2000:321;405-412. 7 8 Updated mean A1C concentration (%) 9 10 UKPDS Study-End and 10-year Follow-Up Results UKPDS original results: intensive vs conventional treatment 10-year post-trial follow-up (non-interventional) 1997 2007 1977–1991 Randomization 9%* 12%* 16% Any diabetes-related endpoint Microvascular disease Myocardial infarction 25%* 15%* In type 2 diabetes, improvements in glycemic control reduce the risk of complications *P<0.05; intensive vs conventional treatment Adapted from Holman et al. N Engl J Med. 2008;359:1577-1589. UKPDS Study Group. Lancet. 1998;352:837-853. 24%* Implications of ACCORD, ADVANCE, and VADT for Microvascular Risk Microvascular disease: • Lowering A1C to ≤7.0% reduces microvascular and neuropathic complications in type 2 diabetes • If achievable without causing significant hypoglycemia or other adverse events, even lower A1C goals may be suggested for selected individuals having: – Short duration of diabetes – Long life expectancy – No significant CVD Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Garber AJ et al. Endocr Pract. 2013;19:1-48. Implications of ACCORD, ADVANCE, and VADT for Macrovascular Risk Macrovascular disease: • Controversies regarding the impact of intensive glycemic control that exceeds an A1C goal of <7.0% on CVD outcomes compared to standard glycemic control • Lowering A1C to a goal of ≤7.0% is a reasonable glycemic goal until more evidence becomes available • Long-term follow-up of the DCCT and UKPDS cohorts suggests that treating to an A1C goal below or near 7.0% yields long-term reductions in the risk of macrovascular disease, if instituted in the years soon after diagnosis of diabetes Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Garber AJ et al. Endocr Pract. 2013;19:1-48. Obesity and T2D: A Common Burden Obesity Prevalence Among US Adults, 2013 County-level Estimates of Diagnosed T2D Among US Adults, 2011 Obesity = BMI ≥30 kg/m2 or ~30 lbs. overweight for 5’4” person CDC Behavioral Risk Factor Surveillance Systems; CDC Diabetes Public Health Resource Center. II. How Well Are We Controlling T2DM? Progress in Achieving A1C Goals: 2007-2012 HbA1C <7.0% 60% HbA1C >9.0% 50% 43.1% 43.3% 42.1% 42.5% 42.2% 43.2% 40% 30% 29.4% 28.4% 28.2% 27.3% 28.3% 28.5% 20% 10% 0% 2007 2008 National Committee for Quality Assurance, 2013. 2009 2010 2011 2012 www.ncqa.org Lessons from the DCCT and UKPDS Sustained Intensification of Therapy is Difficult HbA1C (%) 9.0 DCCT (Type 1) EDIC 8.1 7.9 8 UKPDS (Type 2), Insulin Group 8 7.3 HbA1C (%) 10 7 Baseline 6 6 4 0 6.5 DCCT +4 + 6 yrs Normal 0 0 2 4 6 8 10 yrs EDIC DCCT/EDIC Research Group. N Engl J Med. 2000;342:381-389. Steffes et al. Diabetes. 2001 (suppl. 2) 50:A63. UK Prospective Diabetes Study Group (UKPDS) 33. Lancet. 1998;352:837-853. Adherence to Prescribed Drugs in Patients with Type 2 Diabetes Drug class n % Adherent 95% CI Oral antidiabetic drugs 66 50.0 37.9-62.1 Antihypertensive drugs 62 50.0 37.6-62.4 Lipid-lowering drugs 33 69.7 54.0-85.4 Antiplatelet drugs 40 77.5 64.6-90.4 All drugs 82 35.4 25.0-45.7 Mateo JF et al. Int J Clin Pract. 2006;60:422-428. Clinical Inertia Failure to Advance Therapy When Required Percentage of Subjects advancing when HbA1C >8% 100 80 % Age of Subjects 66.6% At Insulin Initiation, the average patient had: • 5 years with HbA1C >8% • 10 years with HbA1C >7% 60 44.6% 40 35.3% 18.6% 20 0 Diet Brown JB et al. Diabetes Care. 2004;27:1535-1540. Sulfonylurea Metformin Combination Barriers to Glycemic Control Hypoglycemia Risk Factors • Use of insulin or secretagogues [e.g. sulfonylureas (SUs)] • Drugs that affect SU levels* • Advanced age • Duration of diabetes • Renal failure • Liver failure • Hypothyroidism, hypoadrenalism • Missed/irregular meals • Advanced cancer, malnutrition • Hypoglycemia unawareness * aspirin, allopurinol, trimethoprim, warfarin Outcomes • • • • • • • • Increase glucose variability Decreased intensiveness of glucose control Employment challenges Loss of confidence Loss of independence Personal and family stress Increased CV events Increased rates of dementia Barriers to Glycemic Control Weight Gain is a Common Side Effect of Many Oral Agents for T2DM Oral antidiabetic agent* Weight change (kg) -3.8-0.5 Metformin1-3 -0.2-4.3 SUs1-4 0.9-4.6 TZDs4-6 0.3-3.0 Meglitinides4,7,8 -0.3-1.9 Metformin + SU1-3 0.8-2.1 Metformin + TZD5,6,9 *Data are not from head-to-head studies -5 1. Bristol-Myers Squibb. Glucophage® full prescribing Information. 2004. 2. Bristol-Myers Squibb. Glucovance® full prescribing Information. 2004. 3. Bristol-Myers Squibb. Metaglip® full Prescribing Information. 2002. 4. Malone M. Ann Pharmacother. 2005;39:2046-2055. 5. Eli Lilly. Actos® full Prescribing Information. 2004. -4 -3 -2 -1 0 1 2 3 4 5 6. GlaxoSmithKline. Avandia® full Prescribing Information. 2005. 7. Novartis. Starlix® full Prescribing Information. 2004. 8. Novo Nordisk. Prandin® full Prescribing Information. 2004. 9. GlaxoSmithKline. Avandamet® full Prescribing Information. 2005. III. Current T2DM Treatment Options and Their Places in Guideline-based Care ADA/ACC/AHA Position Statement on HbA1C Goals Individualized for Your Patient • Most non-pregnant adults <7% • For selected individuals, might reasonably suggest even lower if this can be achieved without significant hypoglycemia - Short duration of diabetes - Long life expectancy - No significant CVD • Less stringent goal for patients with: – History of severe hypoglycemia – Limited life expectancy – Advanced micro- or macrovascular complications, extensive comorbid conditions – Longstanding diabetes in which the general goal is difficult to attain despite diabetes self-management, etc. American Diabetes Association. Diabetes Care. 2012;35(Suppl 1):S11-S63. Medications for Hyperglycemia in Type 2 Diabetes: ADA 2014 Guidelines GLP = glucagon-like peptide American Diabetes Association. Diabetes Care. 2014;37(suppl 1):S14-S80. The Pathophysiology of Type 2 Diabetes Involves Multiple Dysfunctions Insulin secretion Glucose production α Glucagon secretion Glucose uptake Hyperglycemia Incretin effect Lipolysis Neurotransmitter function Glucose reabsorption DeFronzo RA. Diabetes. 2009;58:773-795.. β Incretins • Gut-derived hormones, secreted in response to nutrients, that potentiate insulin secretion and suppress glucagon secretion in a glucose dependent fashion – Many other tissue effects • Two predominant incretins – Glucagon-like peptide-1 (GLP-1) – Glucose-dependent insulinotropic peptide (GIP) • Rapidly inactivated by dipeptidyl peptidase-4 • Incretin effect is impaired in type 2 diabetes 1. Holst JJ et al. Diabetes. 2004;53(suppl 3):s197-s204. 2. Meier JJ et al. Diabetes Metab Res Rev. 2005;21:91-117. Incretin Effect 2.0 Oral glucose (50 g) or isoglycemic infusion 200 100 0 0 60 120 Time (min) IV glucose Oral glucose * C-Peptide (nmol/L) Plasma Glucose (mg/dL) Difference in the Insulin Response to Oral vs IV Glucose 180 1.5 * * * * 1.0 * * 0.5 0.0 0 60 120 180 Time (min) Reprinted with permission from Nauck MA et al. J Clin Endocrinol Metab. 1986;63:492-498. © 1986 The Endocrine Society. Reduced Incretin Effect in Type 2 Diabetes Patients Control Subjects 80 Type 2 Diabetes Patients 80 Intravenous Glucose Oral Glucose 60 Insulin (mU/L) Insulin (mU/L) 60 40 * * * * * * * 20 30 60 90 * * 20 0 0 40 120 150 180 Time (min) Reprinted with permission from Nauck M et al. Diabetologia. 1996;29:46-52. 0 0 30 * 60 90 120 150 180 Time (min) Role of Incretins in Glucose Homeostasis Pancreas2,3 Ingestion of food GI tract Release of gut hormones — Incretins1,2 Active GLP-1 & GIP Glucose-dependent Insulin from beta cells (GLP-1 and GIP) Blood glucose Beta cells Alpha cells DPP-4 enzyme Inactive GLP-1 Glucose uptake by muscles2,4 Inactive GIP 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876-913. 2. Ahrén B. Curr Diab Rep. 2003;2:365-372. Glucose dependent Glucagon from alpha cells (GLP-1) Glucose production by liver DPP-4 = dipeptidyl-peptidase 4 3. Drucker DJ. Diabetes Care. 2003;26:2929-2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430-441. Treatment Strategies Involving the Incretin System • GLP-1 receptor agonists – Exenatide, liraglutide – Long-acting exenatide QW, albiglutide, dulaglutide – Subcutaneous injection • DPP-4 enzyme inhibitors – – – – – Molecule selectivity inhibits activity of DPP-4 Sitagliptin, saxagliptin, linagliptin, alogliptin Oral Incretin enhancers Lack “high” GLP-1 effects Physician’s Desk Reference. Montvale, NJ. Thomson PDR; 2013. GLP-1 Receptor Agonists • Injectable • Efficacy – – – – Primary effect is on post-meal glucose levels Longer duration of action, better FPG and A1C lowering HbA1C lowering: 0.5%-2.0% Potential for weight loss • Safety – – – – Major side effect: nausea/vomiting No added hypoglycemia unless used with secretagogue or insulin C-cell hyperplasia and medullary cancer in rodents Pancreatitis – not seen in large database analyses Physician’s Desk Reference. Montvale, NJ. Thomson PDR; 2013. DPP-4 Inhibitors • Efficacy: – HbA1C reduction: ~0.5-0.9% – Weight neutral – Renal dosing adjustment – not for linagliptin • Safety: – No added hypoglycemia unless used with sulfonylurea – Rare instance of Stevens-Johnson – Evidence for no increased CV risk (saxagliptin and alogliptin)1,2 – No increased risk of pancreatitis or pancreatic cancer3 1. Scirica BM et al. New Engl J Med. 2014;369:1317-1326. 2. White WB et al. New Engl J Med. 2013;369:1327-1335. 3. Egan AG et al. New Engl J Med. 2014;370:7940797. Short, Long, and Very Long-acting GLP-1 RA Parameters Short-acting Long-acting Very Long-acting Compounds Exenatide Liraglutide Albiglutide, Dulaglutide, Exenatide QW Half-life Frequency of administration 2-5 hours 12-14 hours >1 week Twice daily Once daily Once weekly 0.7–1.7% 0.8–1.8% 0.8-0.9% albiglutide 0.7–1.6% dulaglutide 1.3%-1.9% exenatide QW Modest Strong Strong Strong Modest Modest Reduction Reduction Reduction Deceleration No effect No effect Reduction Reduction Reduction 1-5 kg 2-4 kg 0.6-2.5 kg HbA1C reduction FBG levels reduction PP hyperglycemia Glucagon secretion Gastric emptying rate Blood pressure Body weight reduction FBG = fasting blood glucose; PP = postprandial; QW = once weekly Meier JJ. Nat Rev Endocrinol. 2012;8:728-742. Physician’s Desk Reference. Montvale, NJ. Thomson PDR; 2013. Polling Question Baseline Survey The DURATION 3 trial, which compared exenatide once weekly to insulin glargine in patients with type 2 diabetes who were failing oral antidiabetic therapy, reported all of the following outcomes, EXCEPT: A. Significantly greater A1C reduction with exenatide B. Higher rate of discontinuations due to adverse events with exenatide C. Similar rates of hypoglycemia in the insulin glargine and exenatide groups D. Weight loss with exenatide and weight gain with insulin glargine, a significant difference Effects of Second-Line T2D Therapies as Add-on to Metformin • Meta-analysis of 39 RCTs (n=17,860) • Comparative A1C results: – GLP1-RA achieved greater reduction vs AGIs (-0.36%), DPP-4 inhibitors (-0.32%), glinides (-0.31%), SUs (-0.20%), and TZDs (-0.20%) – Reduction with GLP1-RA was comparable to basal and biphasic insulin • Other endpoints: – Hypoglycemia was more likely associated with SUs, glinides, basal insulin, and biphasic insulin; not with GLP1-RA – Weight increased with SUs, glinides, TZDs, basal insulin, and biphasic insulin – Weight reduced with AGIs and GLP-1 analogues Liu SC et al. Diabetes Obes Metab. 2012;14:810-820. DURATION-5: Mean A1C Reduction and Percent at A1C Targets • Randomized trial of once-weekly vs twice-daily exenatide in 252 patients on metformin (71%-80%), SU (28%-31%), and/or TZD (10%-17%) Blevins T et al. J Clin Endocrinol Metab. 2011;96:1301-1310. Baseline HbA1C <9.0% ≥9.0% ExBID 72% 28% ExQW 70% 30% DURATION-5: Adverse Events Adverse Event Nausea Diarrhea Upper respiratory infections Injection-site erythema Vomiting Headache Dizziness Blevins T et al. J Clin Endocrinol Metab. 2011;96:1301-1310. Exenatide BID (n=123) Exenatide QW (n=129) 35% 4.1% 4.1% 2.4% 8.9% 8.1% 6.5% 14% 9.3% 7.0% 5.4% 4.7% 4.7% 2.3% HARMONY 7: Change in A1C Over 32 Weeks • Randomized trial of once-weekly albiglutide vs once-daily liraglutide in 422 patients inadequately controlled on oral anti-diabetes drugs Baseline HbA1C Albiglutide – 8.1% Liraglutide – 8.1% -0.79% -0.98% P=0.08 for non-inferiority Pratley RE et al. Lancet Diabetes Endocrinol. 2014;2:289-297. HARMONY 7: Adverse Events Adverse Event Diarrhea Upper respiratory infection Nausea Injection-site reaction Urinary tract infection Headache Vomiting Withdrawal for AEs Pratley RE et al. Lancet Diabetes Endocrinol. 2014;2:289-297. Albiglutide (n=404) 14.9% 10.4% 9.9% 6.9% 6.2% 5.4% 5.0% 2.7% Liraglutide P Value (n=408) -0.79% 13.5% 0.57 11.0% 0.77 29.2% 1.2% 5.6% 5.4% 9.3% 0.2% <0.0001 <0.0001 0.74 0.97 0.0154 NR DURATION-3: Effects on A1C After 3 Years • Randomized trial of once-weekly exenatide vs insulin glargine in 456 patients inadequately controlled on glucose-lowering drugs Baseline HbA1C Exenatide 8.3% Glargine 8.3% -0.81% -1.01% P=0.03 Diamant M et al. Lancet. 2014;2:464-473. DURATION-3: Other Endpoints +2.01 kg -2.49 kg P<0.001 • More GI events with exenatide vs glargine: nausea (15% vs 2%), diarrhea (14% vs 7%), vomiting (6% vs 3%), constipation (5% vs 3%) • More discontinuations due to AEs with exenatide vs glargine: 9% vs 2% Diamant M et al. Lancet. 2014;2:464-473. Overall hypoglycemia rate: Insulin glargine: 0.9 events/pt year Exenatide: 0.3 events/pt year Other Adverse Effects with GLP-1 RAs Data from Exenatide and Liraglutide Studies* Odds ratio (95% confidence interval) P value Hypoglycemia 2.92 (1.49-5.75) 0.002 With SUs 4.62 (1.89-11.21) 0.001 Without SUs 1.37 (0.72-2.63) 0.34 0.99 (0.52-1.91) 0.98 Event Cardiovascular events *Meta-analysis of predominantly exenatide and liraglutide studies n=5429 receiving GLP-1 receptor agonists, n=3053 active comparators or placebo Monami M et al. Eur J Endocrinol. 2009;160:909-917. Incretin-related Drugs and Pancreatitis Risk • There has been much discussion regarding the safety of incretin agents (e.g. regarding exenatide, liraglutide, sitagliptin) – Recent published and unpublished data report an increased risk of pancreatitis and pancreatic duct metaplasia in T2DM patients receiving incretins • FDA investigated potential pancreatic toxicity associated with incretins • FDA stated that available data do not confirm recent concerns over an increased risk for pancreatic side effects with GLP-1 therapies • NIDDK experts also concluded that there is little evidence of increased risk for pancreatic cancer with GLP-1 agents • FDA study regarding pancreatitis and pancreatic cancer with incretins is ongoing 1. FDA. FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. 3-14-2013. Available at: www.fda.gov/drugs/drugsafety/ucm343187.htm. 2. Brooks M. FDA sides with EMA on incretin diabetes drugs. 8-1-2013. Available at: www.medscape.com/viewarticle/808830. Pancreatitis Recommendations for Health Care Professionals • Pancreatitis is more common in patients with diabetes1 • Recommendations for monitoring and management2-4 - Observe patients for symptoms of acute pancreatitis (persistent severe abdominal pain that may be accompanied by vomiting) - Discontinue drug if pancreatitis is suspected - Do not restart drug if pancreatitis is confirmed - Consider other anti-hyperglycemic therapies in patients with a history of pancreatitis 1. Yadav D et al. Gastroenterology. 2013;144:1252-1261. 2. Byetta® fact sheet. Available at: www.byettahcp.com/pdf/BYETTA_Fact_Sheet_Safety_Update.pdf. 3. US FDA Web site; Exenatide (marketed as Byetta) – Healthcare Professional Sheet text version (8/2008). Available at: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124713.htm. 4. Victoza [package insert]. Princeton, NJ: Novo Nordisk Inc.; 2011. Summary of GLP-1 Receptor Agonist Therapy in T2D • Incretin system is a powerful physiologic system impacting post-meal BG control • Defective in T2D • Intriguing constellation of clinical effects – Postprandial glucose control – Weight loss – Low risk of hypoglycemia – Potential for weekly dosing IV. Practical Considerations Polling Question Baseline Survey A recently reported analysis of compliance data from the HARMONY trials, which evaluated the once-weekly GLP-1 inhibitor albiglutide, reported what finding? A. Greater compliance with placebo injection than albiglutide injection B. Greater compliance with oral antidiabetic drugs compared to albiglutide injection C. Lower compliance with oral antidiabetic drugs compared to placebo injection or albiglutide injection D. No differences in compliance across all groups, including active and placebo and oral and injectable agents Psychosocial Predictors of Poor Adherence to Insulin Therapy in Patients with T2D • Survey of 1,530 adults with T2D treated with insulin – 35% reported ≥1 days of insulin omission per month (mean: 3 days) – Insulin omission more common in patients who were male (P<0.001), younger (P<0.0001), and had more frequent hypoglycemia (P<0.05) Prevalence or Mean Correlation Coefficient P Value 2.4* -0.12 <0.001 Insulin regimen adherence perceived as “important” 99.0% -0.05 <0.05 Injections perceived to affect lifestyle 43.3% +0.06 <0.05 Injection difficulty (from 1 “very easy” to 4 “very difficult”) 1.8 +0.07 <0.05 Satisfaction with ability to choose when to take injections (from 1 “very dissatisfied” to 4 “very satisfied”) 3.3 -0.07 <0.01 Psychosocial/Behavioral Correlates of Insulin Omission Adherence to non-medication regimens (number of succesful behaviors; range, 0-4) Peyrot M et al. Diabetes Obes Metab. 2012;14:1081-1087. Strategies to Improve Patient Acceptance and Self-management with GLP-1 Agonist Therapy Patient Barrier Recommendations Needle phobia • • • • Poor motivation • Discuss benefits such as weight loss and low hypoglycemia risk • Encourage patients to perform SMBG for 1-2 weeks after initiating to see reductions in FBG and PPG levels • Involve a dietitian to help patients identify strategies to maximize the potential for weight loss Nausea • Before initiation, educate patients that transient nausea is possible • Dose-escalate exenatide BID or liraglutide, but not exenatide QW, as described in prescribing information • Consider lengthening the time over which the dose is escalated • Administer exenatide BID <60 minutes before the meal • Temporarily reduce the dose • Counsel patients to stop eating when they feel full • Avoid administering the medication close to a large or high-fat meal Familiarize patients with pen devices or delivery kits Avoid using the word “shot” Differentiate between SC and IM injections Have patients self-inject the first dose in the office; alternatively, just use the needle FBG = fasting blood glucose; PPG = postprandial glucose; SMBG = self-monitoring of blood glucose. Reid T. Clin Diabetes. 2013;31:148-157. Compliance with T2D Medications: Injection vs Oral Therapy % of Patients with <80% Compliance HARMONY 3 Trial (Week 156) Leiter LA et al. ADA 2014 Annual Meeting. Abstract 994-P. HARMONY 5 Trial (Week 156) HARMONY 8 Trial (Week 52) New Delivery Options: Exenatide Suspension QW with Single-use Auto-injector Pen • 28-week open-label study of exenatide twice daily (ExBID) vs exenatide suspension given once-weekly via single-use auto-injector pen (ExSQW) in patients with inadequately controlled T2D ExBID (n=148) ExSQW (n=229) -1.02% -1.89 kg -1.39%* -1.48 kg 21.2% 11.6% 6.2% 0.7% 9.6% 5.2% 3.5% 12.7% Change in A1C Change in body weight Adverse events Nausea Diarrhea Vomiting Injection-site nodules *P = 0.007 vs ExBID Wysham CH et al. EASD 2014 Annual Meeting. Abstract 244. Case 1: Revisited • Marcus is a 33-year-old overweight man with 4-year history of T2DM – Current medications: metformin 1000mg BID, glipizide 10mg QD – He has gained 15 lbs in 11 months; current BMI: 28.3 kg/m2 • Lab evaluation – HbA1C: 8.2% – BP: 172/85 mm Hg – Total cholesterol: 242 mg/dL • Patient concerns – Robert reveals that he has not been adherent to his T2DM medications because he was “tired of taking so many pills every day” – He has experienced episodes of shakiness and extreme hunger before lunch and dinner – He is now worried about his health because his father recently suffered a fatal MI at age 57 Case Discussion • Individual HbA1C goal? • Treatment priorities – Improved glycemic control – Weight neutral or associated with weight loss – Low risk of hypoglycemia – Improved cardiovascular risk profile Summary • Poorly controlled hyperglycemia significantly increases the risk of microvascular and macrovascular complications – Despite effective therapies, <30% of patients with T2DM meet the treatment goal of A1C <7.0% • Patients require individualized therapy for effective glycemic control – Consider the effects of medications on T2DM pathophysiology, body weight, hypoglycemic risk, and other endpoints • Utilize a collaborative approach to T2DM management – Empower the patient through patient education on self-management strategies – Address barriers for optimal outcomes, including poor medication adherence and injection-related barriers Participant CME Evaluation • Please take out the Participant CME Post-survey and Evaluation Form from the back of your packet. • If you are not seeking credit, we ask that you fill out the information pertaining to your degree and specialty, as well as the few post-activity survey questions measuring the knowledge and competence you have garnered from this program. The post-survey begins on page 1 of the evaluation form. • Your participation will help shape future CME activities. Thank you for joining us today!