Emerging Challenges in Primary Care: 2017 GLP-1 Receptor Agonists: New Insights and New Strategies for Successful Long-Term Diabetes Management 1
Faculty Richard S. Beaser, MD Senior Staff Physician, Medical Director of Professional Education Joslin Diabetes Center Associate Clinical Professor of Medicine Harvard Medical School Boston, MA Robert S. Busch, MD, FACE Director of Clinical Research Albany Medical Faculty: Community Endocrine Group Albany, NY Richard Pratley, MD Senior Investigator and Diabetes Program Head Translational Research Institute for Metabolism and Diabetes Research and Education Director, Florida Hospital Diabetes Institute Orlando, FL Jeff Unger, MD, ABFM, FACE Director, Unger Primary Care Medical Group Rancho Cucamonga, CA Mark Stolar, MD Associate Professor of Clinical Medicine Feinberg School of Medicine Northwestern University Chicago, IL 2
Disclosures Richard S. Beaser, MD has no financial relationships to disclose. Robert S. Busch, MD, FACE serves as a speaker for Astra Zeneca, Eli Lilly, Boehringer Ingelheim, Novo Nordisk, and Shire. Dr. Busch also serves as a researcher for Astra Zeneca, Novo Nordisk, Janssen, and Amgen. Mark Stolar, MD serves as a speaker/advisory board member for Astra Zeneca. Richard Pratley, MD serves as a speaker/consultant for AstraZeneca. Dr. Pratley also serves as a consultant for Boehringer-Ingelheim, GlaxoSmithKline, Hanmi Pharmaceutical Co., Ltd., Janssen Pharmaceuticals, Inc., and Ligand Pharmaceuticals, Inc. Additionally, Dr. Pratley performs research under contract for for Lexicon Pharmaceuticals, Sanofi-Aventis US, LLC, Lilly, Merck, and Takeda. Dr. Pratley performs research, is a speaker and consultant for Novo Nordisk. All honoraria and fees are directed to a non-profit. Dr. Pratley does not receive any direct compensation for these activities. Jeff Unger, MD, ABFM, FACE serves on the advisory board for Abbott, Novo Nordisk, Janssen, and Intarcia. 3
Learning Objectives Discuss the role of postprandial hyperglycemia in the pathogenesis of diabetic complications. Incorporate GLP-1 RA therapy into practice to reduce post-prandial hyperglycemia and decrease glycemic variability. Compare GLP-1 RAs for glycemic efficacy and differential impact on postprandial glycemic control. Discuss various GLP-1 RA combination strategies with, or as a possible alternative to, basal insulin in the diabetic patient not at glycemic target. 4
PRE-TEST QUESTIONS 5
Pre-test ARS Question 1 At about what level of A1C does postprandial glucose account for >50% of total A1C? 1. ~7% 2. ~8% 3. ~9% 4. ~10% 6
Pre-test ARS Question 2 Comparing the differences between shorter and longer-acting GLP-1 receptor agonists, which of the following statements is true? 1. Longer-acting have a greater impact on reducing postprandial glucose 2. Longer-acting have a greater impact on fasting glucose 3. Shorter acting have a greater impact on increasing fasting insulin secretion 4. Shorter acting have a greater impact on fasting glucose 7
Pre-test ARS Question 3 The advantages of combining GLP-1 receptor agonists with basal insulin include all of the following, EXCEPT: 1. Less risk for weight gain compared to insulin alone 2. Reductions in both fasting and postprandial glucose levels 3. Significantly lower incidence of hypoglycemia compared to insulin alone 4. Potential for reduced doses of basal insulin when GLP-1 RA added to insulin therapy 8
Pre-test ARS Question 4 A 49-year-old man with 10-year history of T2DM and NSTEMI 2 years ago works on a farm and has long active days. His A1C is 7.8%, FBG 70-120 mg/dl and PPG 180-220 mg/dl. Meds include metformin 1000 mg bid and basal insulin 38 U qam. Which of the following might be appropriate to manage hyperglycemia and cardiovascular risk? 1. Add sulfonylurea 2. Add rapid-acting insulin before each meal 3. Discontinue basal insulin and start GLP-1RA 4. Add GLP-1RA and reduce dose of basal insulin 9
Pre-test ARS Question 5 When adjusting therapy in patients with type 2 diabetes, how often do you consider using GLP-1 receptor agonists in combination with basal insulin: 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 10
Pre-test ARS Question 6 Please rate your confidence in your ability to utilize GLP-1RAs in clinical practice: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 11
ADA 2016: Standards of medical care in diabetes Initial monotherapy Healthy eating, weight control, increased physical activity Metformin Two-drugs combined SU TZD DPP-4 i SGLT2i GLP-1 RA Insulin (basal) Threedrugs combined Combined injectable therapy TZD DPP-4i SGLT2i GLP-1 RA Insulin SU DPP-4i SGLT2i GLP-1 RA Insulin SU TZD SGLT2i Insulin SU TZD DPP-4i Insulin SU TZD Insulin Basal insulin + Mealtime insulin or GLP-1 RA Escalate therapy at 3 months if target not achieved DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT2i, sodium-glucose cotransporter 2 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SU, sulfonylurea; TZD, thiazolidinedione ADA. Diabetes Care. 2016;39(Suppl. 1):S1 S2. TZD DPP-4i SGLT2i GLP-1 RA 12
Likelihood of Monotherapy Failure in ADOPT 40 Glyburide Cumulative Incidence of Fasting Glucose Greater than 180 mg/dl 30 20 10 P<0.001 Metformi n P<0.001 Rosiglitazon e 1 2 3 4 5 N = 3652 3227 2796 2353 1918 776 N Eng J Med 2006;355:2427-43 13
Ominous Octet DeFronzo RA. Diabetes. 2009;58:773-795. 14
Progressive β-cell Dysfunction Is a Key Driver of Progressive Dysglycemia in T2D By the time of diabetes onset, up to 80% of β-cell function may be lost 1,2 Insulin Insulin Resistance Resistance Deteriorating β-cell function is partially driven by the incretin defect PPG FPG β-cell Function Insulin Secretion Insulin Production Normal Glucose Tolerance Impaired Glucose Tolerance Diagnosis Severity of Glucose Intolerance Time in Years PPG indicates postprandial plasma glucose; FPG, fasting plasma glucose; T2D, type 2 diabetes; 1. Defronzo RA. Diabetes 2009;58:773-795; 2. Fehse F, et al. J Clin Endocrinol Metab 2005;90:5991-5997; Figure adapted from Kendall DM, et al. Am J Med 2009;122(6 Supp):S37-S50 15
Fasting vs Postprandial Glucose Contribution to HbA1c Contribution 100% 80% 60% 40% 20% 30% 70% 50% 55% 60% 70% 50% 45% 40% 30% 0% <7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2 HbA1c Range (%) Postprandial Plasma Glucose Fasting Plasma Glucose Monnier L et al. Diabetes Care. 2003;26:881 885. 16
GLP-1 RAs Mimic and Extend Actions of Endogenous GLP-1 Inactivation Concentration Endogenous GLP-1 RA Rapid Cleavage by DPP-4 Renal elimination Physiologic GLP-1 RAs Delayed Resistance to DPP-4 Resistance to renal filtration Pharmacologic Timing of effects Prandial/early postprandial Prandial/early postprandial Fasting Meier JJ. Nat Rev Endocrinol. 2012 Dec;8(12):728-742. 17
GLP-1 RA Exenatide 5-10 mcg twice daily (Byetta 2005) 2 mg once weekly (Bydureon 2012) Liraglutide 1.2-1.8 mg daily (Victoza 2010) 3 mg daily (weight loss indication, Saxenda 2014) Albiglutide 30-50 mg once weekly (Tanzeum 2014) Dulaglutide 0.75-1.5 mg once weekly (Trulicity 2014) Lixisenatide 10-20mcg daily (Adlyxin 2017) 18
GLP-1 RA Exenatide, Exenatide LAR, Liraglutide, Albiglutide, Dulaglutide, Lixisenatide Mechanism Primary physiological action(s) Advantages Limitations Cost Activates GLP-1 RA glucose-dependent insulin secretion glucose-dependent glucagon secretion Satiety Slows gastric emptying Postprandial glucose excursions Weight Patient training requirements (injectable therapy) Gastrointestinal side effects (nausea, vomiting [less with longer-acting agents]) Hypoglycemia possible when used with insulin, if insulin doses are not reduced High (relative to other generic agents, ie metformin) Inzucchi SE, et al. Diabetes Care 2015. 19
Case 1: Meet Cherise Cherise is a 38 year old African American female with a 5 yr history of type 2 diabetes on maximum SFU and metformin. She could not tolerate TZDs due to edema and refused to start insulin. Her HbA1c for the past 2 years has been between 7.9% and 8.8%. Most recent: 9.0% PMH sig. for dyslipidemia, hypertension and central obesity (BMI 43). Her weight is not a concern for her. Strong family history of type 2 diabetes as her mother and grandmother are both on dialysis and a maternal aunt recently died of a CVA 20
ARS Question Which of the following might help Cherise improve her glycemic control? 1. Recommend GLP-1RA and show her an injection pen 2. Tell her that she will need insulin if she does not lose significant weight 3. Add DPP-4 inhibitor and consider SGLT-2 inhibitor if response insufficient 4. Recommend full basal-bolus regimen and remind her of her family history of kidney disease 21
Case 1: Helping Cherise Succeed (Current rx metformin 2000 max SU) Her PCP was concerned about the high HbA1C and recommended insulin, but she refused to start insulin as it made her too anxious and wanted to work harder on fitness and a medication that will help with weight loss. She agreed to start dulaglutide once weekly. She developed nausea for the first 3 weeks post injection and stopped the medication. She admits giving an injection was not a big deal, but stated taking insulin just made her nervous. Over the next two months she tried her best to diet and exercise but follow up HbA1c was still 8.6%. How can you now effectively transition Cherise to accepting insulin therapy or restarting her GLP-1 RA? 22
Barriers to Injectables: The CLINICIAN Side of the Equation Misperceptions The need to advance Rx is never-ending (therapeutic fatigue) Insulin: most appropriate for end-stage Rx Patients don t want to use injectables Reality-based Concerns Time demands of instructing patients about injections Unfamiliarity with the variety of devices (e.g., various pens) Misplaced Blame If only the patient would exercise and lose weight, they wouldn t need insulin Knowledge gaps Role of glucotoxicity in disease progression and therapeutic failure Typical weight changes (gain): insulin Typical weight changes (loss): GLP-1 RA Familiarity with ADA/EASD and AACE Guidelines 23
Suggestions for Overcoming Fear of Injections Dry run injection (Insert needle without injecting drug) Reinforce that injection is relatively painless Injection is into fatty tissue versus muscle Reinforce that injection is easy Injection devices are quick and easy-to-use Have pen available for demonstration 24
Patient-level meta-analysis: HbA1c reduction across baseline categories 0.5 7.5% >7.5% 8.0% >8.0% 8.5% >8.5% 9.0% >9.0% Change in HbHbA1c (%) from baseline to 26 weeks 0 0.5 1.0 1.5 * ** ** ** ** ** ** * * **** *** * 2.0 Liraglutide 1.8 mg Sitagliptin Glimepiride Rosiglitazone Exenatide Glargine HbA1c, glycosylated haemoglobin *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs. liraglutide 1.8 mg Henry et al. Endocr Pract 2011;17:906 913 25
HbA1c and Weight Change with Sitagliptin vs. Dulaglutide Once Weekly added to Metformin after 52 weeks (AWARD-5) LS Change in HbA1c (%) HbA1c Reductions (%) 0-0.2-0.4-0.6-0.8-1 -1.2-1.1 Dulaglutide 1.5 mg P<.001 Nauck M, et al. Diabetes Care. 2014. -0.87 Dulaglutide 0.75 mg -0.39 Sitagliptin 100 mg LS Change in Weight -0.5-1.5-2.5-3.5 Weight Loss (kg) 0-1 -2-3 -3.03 Dulaglutide 1.5 mg P<.001-2.6 Dulaglutide 0.75 mg -1.53 Sitagliptin 100 mg 26
GLP-1 RA Pharmacologic Activity Is Higher With GLP-1 RAs Than With DPP-4 Inhibitors Plasma Level (pm) 75 50 25 0 Baseline Sitagliptin Exenatide twice daily 7 15 Endogenous GLP-1 RA Activity 64 Added GLP-1 RA Activity N=61 metformin-treated, evaluable patients. 27 DeFronzo RA, et al. Curr Med Res Opin. 2008.
Comparing GLP-1 RAs Shorter-Acting vs Longer-Acting Formulations Compounds Shorter Acting Exenatide BID, lixisenatide Longer Acting Albiglutide, dulaglutide, exenatide QW, liraglutide, semaglutide a Half-life 2-5 hours 12 hours to several days Effects FPG reduction Postprandial hyperglycemia reduction Fasting insulin secretion stimulation Glucagon secretion Weight reduction Potential for nausea Modest Strong Modest Reduction Yes Yes Strong Modest Strong Reduction Yes Yes Clinical Pearl: Select GLP-1 RAs for T2DM based on the patient s hyperglycemia profile and preferences. a Not approved by the FDA for use in the United States. Brunton S. Int J Clin Pract. 2014;68(5):557-567; Fonseca VA. Clin Ther. 2014;36(4):477-484; Kalra S. Diabetes Ther. 2014;5(1):333-340. 28
Effects of Exenatide BID vs Exenatide QW on PPG 14 13 Exenatide QW (n = 129) Exenatide BID (n = 130) PPG (mmol/l) 12 11 10 9 8 7 6 Baseline Week 30 Pre Post Pre Post Pre Post 03:00 Breakfast Lunch Dinner Data presented are means ± SE PPG taken from SMBG profile Drucker DJ et al. Lancet 2008;372:1240-50 PPG = post-prandial plasma glucose SMBG = self-monitored blood glucose
Head-to-Head Trials Comparing Efficacy of GLP-1 RAs EXN BID 10 mcg LIRA 1.8 mg EXN QW 2.0 mg ALBI 50 mg DULA 1.5 mg 1 Δ A1C, % 0-1 -2 LEAD-6 1 DURATION-5 2 DURATION-6 3 HARMONY-7 4 AWARD-1 5 AWARD-6 6-0.8 a -1.1 Added to MET ± SU -0.9 a -1.6 Added to Drug-naïve or MET ± SU ± TZD a,b -1.5-1.3 Added to Drug-naïve or MET ± SU ± TZD b -1.0-0.8 Added to MET ± SU ± TZD a -1.5-1.0 Added to MET ± TZD c -1.4-1.4 Added to MET 1. Buse JB, et al. Lancet. 2009;374:39-47; 2. Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310; 3. Buse JB, et al. Lancet. 2013;381:117-124; 4. Pratley R, et al. Lancet Diabetes Endocrinol. 2014;2:289-297; 5. Wysham C, et al. Diabetes Care. 2014;37:2159-2167; 6. Dungan K, et al. Lancet. 2014; 384(9951):1349-1357. a P <.05 between groups. b Noninferiority vs LIRA not met. c DULA noninferior to LIRA, P <.0001.
Patient Education Talking Points for GLP-1 RA Instruct on good injection technique GI disturbances May cause hypoglycemia when used with sulfonylureas or insulin Exenatide twice daily or liraglutide: Prime or set up pen device only once when medication is first started Store refrigerated until pen is in use, then keep at room temperature Discuss signs and symptoms of pancreatitis when initiating therapy Triplitt CL, et al. Pharmacotherapy: A Pathophysiologic Approach. 2014. 31
ARS Question Which of the following can help minimize gastrointestinal side effects when initiating GLP-1RA? 1. Eat smaller meals and more slowly 2. Use short-term antiemetic therapy for select patients 3. Increase dose slowly, especially shorter-acting agents 4. All of the above 32
Nausea and Vomiting Pooled Results From Placebo-Controlled Trials Medication Nausea Incidence, % Vomiting Incidence, % Albiglutide 1 11 4 Dulaglutide 2 12-21 6-13 Exenatide twice daily 3 8-44 4-18 Exenatide once weekly 4 11-27 11 Liraglutide 5 8-35 6-17 Lixisenatide 6 25% 10% Potential approaches to reduce risks for nausea and vomiting 3,6 Educate patients on meal size, eating pace, and dose timing relative to meals Use incremental dosing, particularly with shorter-acting agents Prescribe short-term antiemetic therapy for select patients Clinical Pearl: Recommend that patients eat smaller meals and more slowly when initiating treatment with a GLP-1 RA. 1. Albiglutide prescribing information. www.gsksource.com/pharma/content/dam/glaxosmithkline/us/en/ Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF. Accessed May 29, 2015; 2. Dulaglutide prescribing information. http:/pi.lilly.com/us/trulicity-uspi.pdf. Accessed May 29, 2015; 3. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/ 2011/021773s029s030lbl.pdf. Accessed May 29, 2015; 4. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2014/022200s008lbl.pdf. Accessed May 29, 2015; 5. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2013/022341s020lbl.pdf. Accessed May 29, 2015; 6. Ellero C, et al. Diabet Med. 2010;27:1168-1173. 6. Drugs@FDA https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208471orig1s000lbl.pdf Accessed April 7, 2017 33
Weight Change (kg) Weight Loss With GLP-1 RAs Not Driven by Gastrointestinal Liraglutide (Meta-Analysis/6 26-Week Trials) 1 0-1 -2-3 -0.53 No NVD -1.08 a,b -1.56 a,b PBO 1.2 mg LIRA 1.8 mg LIRA P<0.05 Adverse Events -0.65 a Some NVD P<0.05-1.62 a -2.45 a,b Exenatide (30-Week DURATION-1 Trial) 2 In a 82-week exenatide completer cohort, weight loss was 1) similar across degrees of nausea, 2) progressive despite stable nausea incidence, and 3) unlikely to be driven by nausea. 3 0-1 -2-3 -4-5 -6 No Nausea -3.1 EXN QW EXN BID -3.4-5.4 Nausea -4.1 NVD, nausea, vomiting, diarrhea; PBO, placebo. a P<0.05 vs baseline; b P<0.05 vs placebo. 1. Russell-Jones D, et al. 70th ADA Scientific Sessions. 2010;1886-P; 2. Drucker DJ, et al. Lancet. 2008;372(9645):1240-1250; 3. Blonde L, et al. Diabetes Obes Metab. 2006;8(4):436-447. 34
GLP-1 RAs Added to Multiple Oral Agents: Comparisons With Basal Insulin 0 MET + SU (N=535) 1 2 3 2-3 OADs (N=235) MET + GLIM (N=576) MET ± SU (N=456) 4,* 5, MET ± SU (N = 216) A1C (%) -0.5-1 -1.5-2 -1.1-1.1 Noninferior vs. insulin -1.3-1.1-1.3-1.3 P=NS vs. insulin P=.0015 vs. insulin -1.3-1.5 P<.05 vs. insulin -0.9-1.3 P<.0001 vs. insulin GLAR EXN BID LIRA EXN QW IDET * 70% on MET monotherapy background 70% on MET + SU background 1 Heine R, et al. Ann Intern Med. 2005;143:559-569; 2 Davies M, et a. Diabetes Obes Metab. 2009;11:1153-1162; 3 Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055; 4 Diamant M, et al. Lancet. 2010;375:2234-2243; 5 Davies M, et al. Diabetes Care. 2013;36:1368-1376. 35
GLP-1 RAs vs Basal Insulin Change in HbA1c From Baseline, % 0-1 -2-3 1st 2nd 3rd 4th -0.6-0.8-0.9-1.2-1.3-1.3-2.1-2.3 Exenatide QW Glargine 0-1 -2-3 1st 2nd 3rd 4th -0.5-0.9-0.9-1.1-1.2-1.4-1.5-1.8 Liraglutide Glargine -4-4 LEAD-5, Liraglutide Effect and Action in Diabetes. Buse JB, et al. Diabetes Obes Metab. 2015;17(2):145-151; Diamant M. Lancet Diabetes Endocrinol. 2014;2(6):464-473; Russell-Jones D, et al. Diabetologia. 2009;52(10):2046-2055. 36
Intensifying Treatment with Combination Injectable Therapy When added to oral antihyperglycemic therapy, basal insulin alone may not be sufficient for reaching HbA1c goals, especially as fasting plasma glucose approaches normal levels Combination injectable therapy Basal insulin Essential component of the treatment strategy when HbA1c target is not achieved despite intensive therapy with 3 antihyperglycemic agents Options for intensified therapy Basal-bolus insulin Basal insulin + GLP-1 RA 37 Inzucchi SE et al. Diabetes Care. 2015;38:140-149; Woerle HJ et al. Diabetes Res Clin Pract. 2007;77:280-285.
Not at Goal: Intensifying Therapy Beyond OAD + Basal: Meet Dave 52 y/o Irish American Construction Foreman Type 2 diabetes for 8 years. Meds: metformin 1000 mg bid, glipizide 10mg bid and levemir 80 units bid. FBS 160-180 mg/dl. Sometimes misses evening insulin dose when falling asleep on the couch watching TV. Morning glucose seems no different when he misses his second dose. He doesn t check his blood sugar often in the evening because it was over 240 on the few times he checked. 38
More about Dave: Dave works 5-10 hour shifts during season and has to drive an hour each way to work. On his days off he helps his brother remodel a house. He has no other defined exercise as his arthritis of both knees is becoming quite symptomatic. His BMI is 36.8. His mother and sisters are all obese and all have type 2 diabetes, but only 2 of 5 are on insulin. He is hypertensive, hypercholesterolemic, and is an ex smoker having quit 5 years ago when his grandchildren were born. 39
Laboratory Assessment HbA1c 8.9% FBS 165 mg/dl Creatinine 1.5 mg/dl Microalbumin 75 mg/ g creat N <30 Tc 190 mg/dl HDL 35mg/dl TG 190mg/dl LDL 117mg/dl 40
ARS: Which of the following statements about Dave is correct? 1. Given his high CV risk, a GLP-1 RA or SGLT-2 inhibitor is recommended as part of his therapy 2. His beta cell function is gone since he is not responding to glipizide 3. Bolus insulin would control postprandial glucose in this patient more effectively than a GLP-1 RA 4. Addition of an SGLT-2 inhibitor could get this patient close to target 41
ARS: What is the next best step for Dave to get him to goal? 1. Add an SGLT-2 inhibitor 2. Add pioglitazone 3. Discontinue glipizide and add bolus insulin 4. Discontinue glipizide and add a GLP-1 RA 5. 2 and 4 6. 1 and 4 42
Combining GLP-1 RA and Basal Insulin Complementary actions Simple to initiate Basal insulin analogs Control nocturnal hyperglycemia and FPG Lower hypoglycemia risk than NPH Can cause weight gain Achieve HbA1c target in ~50% a GLP-1 RAs Simple to initiate Can control FPG and PPG Do not impair α-cell response to hypoglycemia (reduce risks of severe hypoglycemia) Weight-lowering Achieve HbA1c target in ~60% a Additive effects Potential for better overall HbA1c control a Percentage achieving <7% across baseline HbA1c quartiles for liraglutide and exenatide once weekly vs insulin glargine. Buse JB, et al. Diabetes Obes Metab. 2015;17:145-151; Holst JJ, Vilsbøll T. Diabetes Obes Metab. 2013;15:3-14; Vora J, et al. Diabetes Metab. 2013;39:6-15. 43
After Basal Insulin, Once-Weekly GLP-1 RA vs. Three Times Daily Prandial Insulin HbA1c Control 44 Rosenstock J, et al. Diabetes Care. 2014.
After Basal Insulin, Once-Weekly GLP-1 RA vs. Three Times Daily Prandial Insulin Weight Rosenstock J, et al. Diabetes Care. 2014. 45
Bolus Insulin vs GLP-1 RA in Combination with Optimized Basal Insulin + Metformin 3 Change in Key Endpoints* Exenatide BID Lispro TID 50 Safety 2 1 0-1 *P<.001 for all key endpoints Percent of Patients 40 30 20 10-2 0-3 Diamant M, et al. Diabetes Care. 2014;37;2763-2773. 46
GLP-1 RAs and Basal Insulin in T2DM Management: Complementary and Additive Features Basal insulin Primary effects Fasting glucose Interprandial glucose GLP-1 RA Postprandial glucose excursions Fasting glucose Mechanism Hepatic glucose production Glucose-dependent insulin secretion Non-glucose dependent endogenous insulin Glucagon secretion Insulin concentration Glucagon secretion Hepatic glucose production Gastric emptying Satiety Food intake Effect on weight Body weight Body weight Modified from Balena R et al. Diabetes Obes Metab. 2013;15:485-502. 47
Step-wise Process for Implementing GLP-1 RA and Basal Insulin Combination Therapy Identify patient who is not at HbA1c target despite oral antihyperglycemic medications and basal insulin >0.5 0.7 units/kg or appropriately titrated to morning glucose control* Discuss with patient the most common potential side effects. Consider reducing basal insulin dose by 20 % if HbA1c is < 8 % to minimize hypoglycemia risk Encourage patient to regularly self-monitor blood glucose and log the results Report any hypoglycemia (< 80 mg/dl) events for adjustment of insulin Teach the patient proper injection technique and dosing based on specific device Arrange a follow-up visit in approximately 1 month to evaluate treatment efficacy and to assess the patient for possible side effects *Chance of success may be maximized if HbA1c is within 1 1.5 percentage points of target. Rhinehart AS. Clin Diabetes. 2015; 33(2):73-75. 48
Dave: Using Combination Injectable Therapy Dave and his PCP agreed that more insulin was not likely to be effective and he admitted that sometimes he took less insulin as he was afraid of such high doses. Liraglutide once daily was initiated and glipizide discontinued. At his six week follow-up, he was tolerating the medication well and HbA1c had already decreased from 8.9% to 8.2%. The dose was increased to 1.8 mg. At his three month recheck, HbA1c was down to 7.6% and Dave had lost six lbs. What now is more important? Further glycemic lowering or reducing CV risk further? 49
CVD is the Leading Cause of Death in People With T2DM Years of life lost in people with diabetes compared with peers without diabetes 1,a Years of Life Lost 7 6 5 4 3 2 1 Men Nonvascular deaths Vascular deaths 0 0 40 50 60 70 80 90 7 6 5 4 3 2 1 Age, years Women 0 040 50 60 70 80 90 Mortality risk associated with diabetes (N=820,900) 1 Hazard Ratio (95% CI) for Diabetes vs No Diabetes 3 2 1 0 CV death All-cause mortality a Information on diabetes type (ie, type 1 or 2) was generally not available, although participants' ages suggest that a large majority with diabetes would have T2DM (in high-income countries, up to 91% of adults with diabetes have T2DM). 2 1. Seshasai SR, et al. N Engl J Med. 2011;364(9):829-841; 2. International Diabetes Federation. IDF Diabetes Atlas, 7th edition. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.org. 50
Potential Cardio protective MoA of GLP-1RA BP, blood pressure; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; MoA, mode of action 51
ELIXA Lixisenatide in Patients With T2DM After ACS Patients Experiencing Primary Outcome a, % 20 15 10 5 0 Lixisenatide Placebo HR, 1.02 (95% CI, 0.89, 1.17) P<0.001 for noninferiority P=0.81 for superiority 0 12 24 36 Months No significant between-group differences in the rates of hospitalization or death a Primary outcome: CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for UA. N=6068 patients with T2DM who had a myocardial infarction or had been hospitalized for UA within the previous 180 days. Pfeffer MA, et al. N Engl J Med. 2015;373(23):2247-2257. 52
LEADER Liraglutide in T2DM With High CV Risk Patients With Event, % 20 15 10 5 0 Primary Outcome a HR, 0.87 (95% CI: 0.78, 0.97) P<0.001 for noninferiority P=0.01 for superiority Placebo Liraglutide 0 6 12 18 24 30 36 42 48 54 20 15 10 5 0 CV-Related Death HR, 0.78 (95% CI: 0.66, 0.93) 10 P=0.007 Placebo Liraglutide 0 6 12 18 24 30 36 42 48 54 20 15 Months Since Randomization 5 0 Death From Any Cause HR, 0.85 (95% CI: 0.74, 0.97) P=0.02 Placebo Liraglutide 0 6 12 18 24 30 36 42 48 54 a Composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. N=9340 patients with T2DM and high CV risk. Marso SP, et al. N Engl J Med. 2016;375(4):311-312. 53
Patients With Event, % 10 8 6 4 2 0 SUSTAIN-6 Semaglutide in T2DM With High CV Risk Primary Outcome a Nonfatal Stroke Death From CV Causes Hazard ratio, 0.74 (95% CI, 0.58 0.95) P<0.001 for noninferiority P=0.02 for superiority Placebo Semaglutide 0 8 1624 32 40 48 5664 72 80 88 96 109 5 4 3 2 1 0 Hazard ratio, 0.61 (95% CI, 0.38 0.99) P=0.04 Placebo Semaglutide 0 8 1624 32 40 48 5664 72 80 88 96 109 Weeks Since Randomization a Composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. N=3297 patients with T2DM (A1c 7.0%) who were 50 years old with established CV disease or chronic kidney disease (Stage 3 or worse) OR were 60 years old with 1 CV risk factor were randomized to placebo or semaglutide 0.5 mg or 1.0 mg once weekly. Marso SP, et al. N Engl J Med. 2016 Sep 15. [Epub ahead of print]. 5 4 3 2 1 0 Hazard ratio, 0.98 (95% CI, 0.65 1.48) P=0.92 Placebo Semaglutide 0 8 1624 32 40 48 5664 72 80 88 96 109 54
Rationale for GLP-1 RA and Insulin The combination of a GLP-1 RA and insulin may be highly effective for optimal glucose control, ameliorating the adverse effects often associated with insulin. Data from clinical studies support the therapeutic potential of GLP-1 RA-insulin combination therapy, typically showing beneficial effects on: glycemic control body weight low incidence of hypoglycemia in established insulin therapy, facilitating reductions in insulin dose 55
GLP-1 RA/Basal Insulin Fixed-Ratio Combination 10 IDegLira IDeg Lira 1.8 mg 9.5 9.6 9 Initial A1c 8.3 Final A1c 8.0 8.8 A1c, % 8 7 6 5 6.4 a 6.9 7.1 a Total Trial Population 7.2 6.4 6.4 6.0 a a 7.5 7.1 6.7 6.2 a a a >7.5 8.5 7.2 7.3 6.6 a >8.5 9.0 Baseline A1c Category, % 7.6 7.7 7.0 a a >9.0 n= 833 413 414 208 124 117 299 123 139 136 59 72 190 107 86 a P<0.01. N=1660 insulin-naïve adults with T2DM (mean A1c, 8.3%; mean BMI, 31.2 kg/m 2 ) uncontrolled on oral agents assigned to IDegLira, insulin degludec, or liraglutide 1.8 mg daily (DUAL I Extension). Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2(11):885-893; Rodbard HW, et al. Diabetes Obes Metab. 2016;18(1):40-48. 56
Fixed-Ratio IGlarLixi vs Glargine/GlarLixi Add-on to Metformin in T2DM a P=0.013; b P<0.0001 vs glargine; c IGlarLixi formulation: insulin glargine 2 U/lixisenatide 1 µg. LOCF, last observation carried forward; LS, least squares. Mean Change in A1c ± SE, % 8.5 8.0 7.5 7.0 6.5 6.0 IGlarLixi (n=161) Glargine (n=162) LS mean difference, -0.17% a 95% CI, -0.312, -0.037 6.5 Sc 0 8 12 24 6.3 24 LOCF Weeks c Mean Change in Body Weight ±SE, kg 2.0 1.5 1.0 0.5 0.0-0.5-1.0-1.5-2.0 IGlarLixi (n=161) Glargine (n=162) 0 4 8 12 16 20 24 24 LOCF Visit Symptomatic hypoglycemia ( 70 mg/dl): 22% with IGlarLixi vs 23% with glargine Incidence of nausea/vomiting was 7.5%/2.5% with IGlarLixi c 0.39-1.16 b Rosenstock J, Diamant M, Aroda VR, Silvestre L, Souhami E, Zhou T, Perfetti R, Fonseca V; LixiLan PoC Study Group.. Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Lixisenatide and Insulin Glargine, Versus Insulin Glargine in Type 2 Diabetes Inadequately Controlled on Metformin Monotherapy: The LixiLan Proof-of-Concept Randomized Trial. Diabetes Care. 2016 Sep;39(9):1579-86. doi: 10.2337/dc16-0046. Epub 2016 Jun 9. PubMed PMID: 27284114; PubMed Central PMCID: PMC5001145 57
GLP-1 RA/Basal Insulin Fixed-Ratio Combination Confirmed Hypoglycemia d Events Per 100 Patient-Years 500 400 300 200 100 0 c a NS a b IDegLira IDeg Lira 7.5 >7.5 8.5 >8.5 9.0 >9.0 Total Trial Population Baseline A1c Category, % 5 severe hypoglycemic episodes reported (3 in 825 IDegLiratreated patients and 2 in 412 insulin degludec-treated patients) Fewer patients in the IDegLira group than in the liraglutide group reported GI adverse events (nausea, 8.8% vs 19.7%) a NS a a a a P<0.0001; b P=0.001; c P<0.05; d Confirmed hypoglycemia defined as of episodes requiring assistance (severe), or episodes in which self-monitored plasma glucose level was <3.1 mmol/l, irrespective of symptoms. N=1660 insulin-naïve adults with T2DM (A1c, 8.3%; BMI, 31.2 kg/m 2 ) uncontrolled on oral agents. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2(11):885-893; Rodbard HW, et al. Diabetes Obes Metab. 2016;18(1):40-48. 58
Intensifying Diabetes Therapy: Utilizing GLP-1 RA Effectively The need for insulin providing therapies is intrinsic in a chronic disease that progresses from relative to absolute insulin deficiency over time. Postprandial hyperglycemia plays an important and often unmonitored and undertreated role in the progression of diabetes. Use of basal insulin at bedtime is an effective means of lowering fasting and diurnal glycemia but does not address postprandial needs. The need for basal insulin implies deficiency post prandially as well. GLP-1 RA analogues and short acting insulin both meet that oft unmonitored need but with very different effects on hypoglycemia weight gain and beta cell function. GLP-1 RA analogues are a very effective means of providing endogenous insulin and are a very effective entry into injectable therapy as well as adjunct to basal insulin when intensified therapy is needed. 59
POST-TEST QUESTIONS 60
Post-test ARS Question 1 At about what level of A1C does postprandial glucose account for >50% of total A1C? 1. ~7% 2. ~8% 3. ~9% 4. ~10% 61
Post-test ARS Question 2 Comparing the differences between shorter and longer-acting GLP-1 receptor agonists, which of the following statements is true? 1. Longer-acting have a greater impact on reducing postprandial glucose 2. Longer-acting have a greater impact on fasting glucose 3. Shorter acting have a greater impact on increasing fasting insulin secretion 4. Shorter acting have a greater impact on fasting glucose 62
Post-test ARS Question 3 The advantages of combining GLP-1 receptor agonists with basal insulin include all of the following, EXCEPT: 1. Less risk for weight gain compared to insulin alone 2. Reductions in both fasting and postprandial glucose levels 3. Significantly lower incidence of hypoglycemia compared to insulin alone 4. Potential for reduced doses of basal insulin when GLP-1 RA added to insulin therapy 63
Post-test ARS Question 4 A 49-year-old man with 10-year history of T2DM and NSTEMI 2 years ago works on a farm and has long active days. His A1C is 7.8%, FBG 70-120 mg/dl and PPG 180-220 mg/dl. Meds include metformin 1000 mg bid and basal insulin 38 U qam. Which of the following might be appropriate to manage hyperglycemia and cardiovascular risk? 1. Add sulfonylurea 2. Add rapid-acting insulin before each meal 3. Discontinue basal insulin and start GLP-1RA 4. Add GLP-1RA and reduce dose of basal insulin 64
Post-test ARS Question 5 When adjusting therapy in patients with type 2 diabetes, as a result of attending this program, how often will you consider using GLP-1 receptor agonists in combination with basal insulin: 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 65
Post-test ARS Question 6 Please rate your confidence in your ability to utilize GLP-1RAs in clinical practice: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 66