MYTH VS FACT #1: GLP-1 RECEPTOR AGONISTS SHOULD BE RESERVED FOR PATIENTS WITH LONG-STANDING T2DM

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1 9:45 11: AM Separating Myth from Fact: The Role of Receptor Agonists for the Treatment of T2DM SPEAKERS James R. Gavin, III, MD, PhD John E. Anderson, MD Presenter Disclosure Information The following relationships exist related to this presentation: James R. Gavin, III, MD, PhD: Advisory Board for Abbott Diabetes Care; AstraZeneca; Intarcia Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; and vo rdisk Inc. Speaker s Bureau for AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Lilly; and vo rdisk Inc. John E. Anderson, MD: Advisory Board for Abbott Diabetes Care; AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Lilly; and Sanofi US. Speaker s Bureau for AstraZeneca; Boehringer Ingelheim Parmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Lilly; and Sanofi US. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. MYTH VS FACT #1: RECEPTOR AGONISTS SHOULD BE RESERVED FOR PATIENTS WITH LONG-STANDING T2DM James R Gavin III, MD, PhD Clinical Professor of Medicine Emory University School of Medicine CEO and Chief Medical Officer Healing Our Village, Inc Atlanta, Georgia Developed by the Institute for Medical and Nursing Education, Inc. Supported by an educational grant from Lilly. Current Treatment Algorithms Advocate s Beginning Early in the Progression of T2DM ADA Guidelines (216) 1 AACE Guidelines (216) 2 Current Treatment Algorithms Advocate s Beginning Early in the Progression of T2DM ADA Guidelines (216) 1 AACE Guidelines (216) 2 Metformin + Efficacy. Hypo risk.. Weight... Side effects.. Costs... receptor agonist high... low risk.... loss... GI.. high.. Listed in order of preference 1. ADA. Diabetes Care. 216;39(suppl 1):S1-S Garber AJ, et al. Endocr Pract. 216;22: ADA. Diabetes Care. 216;39(suppl 1):S1-S Garber AJ, et al. Endocr Pract. 216;22:

2 s Are Recommended Throughout the Progression of T2DM in Current Treatment Algorithms Understanding the Incretin Effect and Incretin Therapies Monotherapy With 1-2 oral agents With insulin Patients intolerant of metformin or other oral agents 1,2 Increased risk of hypoglycemia when used with insulin or sulfonylureas 1,2 Use in any combination except with DPP-4 inhibitors 1,2 t a substitute for insulin 3 Potential alternative to prandial insulin for patients unable to attain targets on basal insulin 1,2 Increases likelihood of attaining A1C < 7% without hypoglycemia or weight gain relative to comparator regimens 4,5,6 Meal Oral glucose load leads to secretion of incretin hormones, resulting in enhanced pancreatic insulin secretion 1-3 Effects achieved with s (supraphysiologic activity) 1-3 Intestinal release Active insulin synthesis and secretion β-cell function glucagon and hepatic glucose production weight loss appetite, caloric intake gastric emptying adverse gastrointestinal effects DPP-4 enzyme < 2 min Inactive Effects achieved with DPP-4 inhibitors 1,2 1. ADA. Diabetes Care. 216;39(suppl 1):S1-S111; 2. Garber AJ, et al. Endocr Pract. 216;22:84-113; 3. Usui R, et al. J Diabetes Investig. 213;27:4: ; 4. Freemantle N, et al. Diabetes Ther. 215; ; 5. Blonde L, et al. Lancet. 215;385: ; 6. Raccah D, et al. J Diabetes Complications. 214;28: Baggio L, Drucker D. Gastroenterology. 27;132: Holst JJ, et al. Trends Mol Med. 28;14: Madsbad S. Diabetes Obes Metab. 216;18: FDA-Approved Receptor Agonists Twice-Daily Injections Exenatide BID Daily Injections Liraglutide Lixisenatide Weekly Injections Albiglutide Dulaglutide Exenatide QW Within 6 min of 2 main meals (usually breakfast and dinner), but 6 h apart Once daily, any time Once daily, within 1 hour of first daily meal Once weekly, any time Once weekly, any time Once weekly, any time US FDA. A1C < 7%, % 1 With Insulin b data Each agent resulted in 5% of patients attaining an A1C of < 7% when used as monotherapy 1,6,7 A1C < 7%, % 1 5 s Demonstrate Clinical Efficacy Across the Natural History of T2DM With MET ± SU a EN 1 μg BID LIRA 1.8 mg QD LII 2 mg QD EN 2 mg QW ALBI 5 mg QW DULA 1.5 mg QW 1. US FDA Rosenstock J, et al. J Diabetes Complications. 214;28: Giorgino F, et al. Diabetes Care. 215;38: Riddle MC, et al. Diabetes Care. 213;36: Blonde L, et al. Lancet. 215;385: Fonseca VA, et al. Diabetes Care. 212;35: Zhang L, et al. Sci Rep. 216;6:1894. Meal Understanding the Incretin Effect and Incretin Therapies Oral glucose load leads to secretion of incretin hormones, resulting in enhanced pancreatic insulin secretion 1-3 Effects achieved with s (supraphysiologic activity) 1-3 Intestinal release Active insulin synthesis and secretion β-cell function glucagon and hepatic glucose production weight loss appetite, caloric intake gastric emptying adverse gastrointestinal effects Effects more prominently associated with long-acting s DPP-4 enzyme < 2 min Inactive Effects achieved with DPP-4 inhibitors 1,2 1. Baggio L, Drucker D. Gastroenterology. 27;132: Holst JJ, et al. Trends Mol Med. 28;14: Madsbad S. Diabetes Obes Metab. 216;18: Δ FPG, mg/dl FPG and PPG Effects of s Differ Twice Daily vs Once-Weekly s -43 EN 1 µg BID DULA 1.5 mg QW -22 EN 2. mg QW Once-Daily vs Once-Weekly s AWARD-1 1 DURATION-5 2 HARMONY-7 3 DURATION-6 4 AWARD LIRA 1.8 mg QD n-inferior ALBI 5 mg QW FPG improvement was similar with EN BID and LII 6 FPG improved more with LIRA QD vs EN BID or LII 7,8 Significant PPG improvement from baseline observed with all s 1,9 1. Wysham C, et al. Diabetes Care. 214;37: ; 2. Blevins T, et al. J Clin Endocrinol Metab. 211;96: ; 3. Pratley RE, et al. Lancet Diabetes Endocrinol. 214;2: ; 4. Buse JB, et al. Lancet. 213;381: ; 5. Dungan KM, et al. Lancet. 214;384: ; 6. Rosenstock J, et al. Diabetes Care. 213;36: ; 7. Nauck M, et al. Diabets Care. 216;39: ; 8. Buse JB, et al. Lancet. 29;374:39-47; 9. Drucker DJ, et al. Lancet. 28; 372:

3 s Demonstrate a Low Risk of Hypoglycemia Across the Natural History of T2DM Overall Hypo, % Overall Hypo, % With MET With Basal Insulin data 35.3 Consider decreasing insulin dose to reduce hypoglycemia risk EN 1 μg BID LII 2 μg QD LIRA 1.8 mg QD EN 2 mg QW ALBI 5 mg QW DULA 1.5 mg QW Week 26 Baseline Glycemic Variability Is Reduced When a Is Used With Prandial Insulin DULA 1.5 mg QW + LIS TID DULA.75 mg QW + LIS TID GLAR QD + LIS TID Hypoglycemia On-target Blood Glucose Hyperglycemia 7 mg/dl 7-18 mg/dl > 18 mg/dl 3% 41% 56% 3% 43% 54% 2% 45% 53% 3% 6% 5% 13% 21% 21% 84% 73% 74% 1. Drugs@FDA Ahmann A, et al. Diabetes Obes Metab. 215;17: Pozzilli P, et al. ADA Scientific Sessions 216 [abstract 237-OR]. Data shown are mean number of CGM readings within the specified ranges from a substudy of AWARD-4. Jendle J, et al. Diabetes Obes Metab. 216 Jun 9. [Epub ahead of print]. s Demonstrate a Low Risk of Weight Gain Across the Natural History of T2DM ΔWt, kg ΔWt, kg With MET ± SU With Insulin data EN 1 μg BID LIRA 1.8 mg QD LII 2 mg QD EN 2 mg QW ALBI 5 mg QW DULA 1.5 mg QW Each agent (except ALBI) resulted in 2- to 3-kg weight loss when used as monotherapy 1,7,8 1. US FDA Rosenstock J, et al. J Diabetes Complications. 214;28: Giorgino F, et al. Diabetes Care. 215;38: DeVries JH, et al. Diabetes Care. 212;35: Riddle MC, et al. Diabetes Care. 213;36: Blonde L, et al. Lancet. 215;385: Fonseca VA, et al. Diabetes Care. 212;35: Zhang L, et al. Sci Rep. 216;6:1894. Summary s are recommended early and throughout the progression of T2DM Due to related mechanisms of action and the limited improvement in glycemic efficacy, s should not be used in combination with DPP-4 inhibitors For appropriate patients, s are as effective as insulin, with a lower risk of hypoglycemia and with the potential for weight loss Adding a to insulin therapy may reduce glycemic variability, an emerging risk factor for poor outcomes FPG and PPG effects of s differ Administration frequencies among s differ Patient Priorities: Characteristics Desired in Injectable Antihyperglycemic Medications Ranked by Willingness to Pay a MYTH VS FACT #2: RECEPTOR AGONISTS ARE DIFFICULT TO USE John E Anderson, MD Past President The Frist Clinic Nashville, Tennessee 1 Greater glycemic efficacy (1% A1C reduction) Low risk of hypoglycemia Weight loss (2-3 kg) Avoid mixing (resuspension) 5 Fewer daily injections (reduce by 1 injection) a Survey of 646 adults with T2DM treated with injectable agents from the United States and Canada. Both studies asked patients to compare the attributes of hypothetical agents. Boegelund M, et al. Diabetes. 215;64(suppl 1): A349 [abstract 1341-P].

4 Predicting Patient Preferences: Specific Characteristics Desired in s Comparing Dosage and Administration of Current s: Daily s Injection frequency Most important predictor of choice Weekly preferred more than daily Type of injection device t a significant predictor Needle size and pain Significant predictor Shorter (eg, 4-5 mm), thinner (eg, G) preferred more than longer, thicker Refrigeration Injection-site reactions Significant predictor Eliminating reactions preferred t a significant predictor Exenatide BID a Liraglutide QD a Lixisenatide QD a Inject within 6 minutes prior to 2 main meals of the day, at least 6 h apart Initiate 5 μg per dose twice daily Increase to 1 μg twice daily after 1 month, based on clinical response Initiate at.6 mg once daily for 1 week b After 1 week, increase to 1.2 mg Can increase to 1.8 mg if 1.2 mg does not provide acceptable glycemic control Inject within 1 hour of the first daily meal Initiate 1 μg dose once daily Increase to 2 μg once daily at 15 days Multidose pen Multidose pen Multidose pen a Discrete-choice experiment of 643 adults with T2DM treated with EN QW, LIRA QD, insulin, or no injectable therapy. Hauber AB, et al. Curr Med Res Opin. 216;32: a May need needle prescription. b Dose intended to reduce gastrointestinal symptoms during titration; not effective for glycemic control. US FDA. Drugs@FDA. Comparing Dosage and Administration of Current s: Once-Weekly s Exenatide QW Albiglutide QW Dulaglutide QW 23-G needle (supplied) 29-G needle (supplied) 29-G needle (supplied) Administer 2 mg once weekly dose titration Available in a single-use vial and syringe or in a single-dose pen Initiate at 3 mg once weekly Can increase dose to 5 mg if needed Available in a singledose pen Initiate at.75 mg once weekly Can increase dose to 1.5 mg if needed Available in a singledose pen US FDA. Drugs@FDA. Adherence to s Is Higher With Less- Frequent Administration Studies From Europe Persistence With RA at 1 Year, % Once-daily injection 73 UK 64 Twice-daily injection P <.1 P <.1 Persistence to s was higher with once-daily than twice-daily dosing 1 Once-weekly s may further increase persistence and adherence 3 Generally, once-weekly dosing has higher adherence than once-daily dosing 4,a a Meta-analysis of medication possession ratios in 7 observational studies of osteoporosis medications Germany 69%: US 1-year average adherence to noninsulin therapies 2 1. Wilke T, et al. Diabetes Ther. 216;7: Kirkman MS, et al. Diabetes Care. 215;38: Garber AJ. Lancet Diabetes Endocrinol. 214;2: Iglay K, et al. Clin Ther. 215;37: Daily Weekly Agent Current s Vary Greatly in Their Ease of Use Patient must attach needle? Patient must reconstitute from powder? Patient must prime device before first use? Patient can adjust dose? Patient must count for dwell time (2-1 sec)? a Exenatide BID 1 Liraglutide QD 2 Lixisenatide QD 3 Exenatide QW (syringe) 4 Exenatide QW a (pen) 5 Albiglutide QW 6 a Dulaglutide QW 7 Patient-Related Considerations When Introducing Patients With T2DM to Receptor Agonists Identify a regimen that meets the patient s needs/desires/flexibility Smaller pen needle size is effective and preferred Equivalent glycemic control for obese vs nonobese participants 1 Have patient see/use pen and needle before leaving office with prescription 2 a Consult prescribing information for specific instructions on how to reconstitute (video); 6. Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF#page=35; Hirsch L, et al. Curr Med Res Opin. 212;28: Kruger DF, et al. Diabetes Educ. 21;36(suppl 3):44S-72S.

5 Educating Patients About Their Medications May Improve Adherence and Reduce Patient Concerns That May Interfere With Adherence Addressing and Assessing Patient Adherence: The Morisky Scale Adherence Category Highly adherent %-1% doses missed Mostly adherent 11%-26% doses missed Somewhat nonadherent 27%-47% doses missed nadherent 47%-1% doses missed Received information from primary care doctor Received information from other sources Complaints about medication interfering with lifestyle Patients who were referred to CDEs and community programs had the highest adherence Worried about side effects of medications Online survey of self-reported number of missed medication doses among 87 patients with diabetes (9% with T2DM). Larkin AT, et al. J Diabetes. 215;7: Do you ever forget to take your medicine? Are you careless at times about taking your medicine? When you feel better do you sometimes stop taking your medicine? Sometimes if you feel worse when you take the medicine, do you stop taking it? Scoring (per question): Yes = = 1 Add points for total score Interpreting the total score: High adherence: points Medium adherence: 1-2 points Low adherence: 3-4 points High adherence predicts better blood pressure control 81% sensitivity 44% specificity Morisky DE, et al. Med Care. 1986;24: Summary With proper patient education, s may be very easy to use Current s range from twice-daily to onceweekly agents Instructions for use vary by agent and have the potential to influence adherence Factors associated with greater likelihood of adherence include receiving education from primary care provider and community programs MYTH VS FACT #3: APPROPRIATE PATIENT SELECTION VARIES AMONG RECEPTOR AGONISTS James R Gavin III, MD, PhD Clinical Professor of Medicine Emory University School of Medicine CEO and Chief Medical Officer Healing Our Village, Inc Atlanta, Georgia Many Different Aspects of Care Are Used to Individualize Management of T2DM Potential risks with hypoglycemia, other AEs Low Disease duration Newly diagnosed Life expectancy Long Important comorbidities Absent Established vascular complications More stringent Absent A1C 7% Few/mild Few/mild Less stringent High Usually Long-standing not modifiable Short Severe Severe s May Decrease the Risk of Cardiovascular Events in Patients With T2DM Completed Studies LEADER (liraglutide) 1 ELIA (lixisenatide) 2 SUSTAIN 6 (semaglutide) 3,a Endpoint/Parameter MACE (CV death, nonfatal MI, nonfatal stroke) Rate of hospitalization for heart failure Mortality MACE (CV death, MI, stroke, or hospitalization for unstable angina) Rate of hospitalization for heart failure Mortality MACE (CV death, nonfatal MI, nonfatal stroke) Outcome Decreased risk for 3-point MACE increased risk 15% reduced risk increased risk increased risk increased risk 16% reduced risk 4 Patient attitude/expected treatment efforts Highly motivated, adherent, excellent self-care capabilities Resources and support system Readily available Frequent Less motivated, nonadherent, poor self-care capabilities Potentially modifiable Limited Inzucchi SE, et al. Diabetes Care. 215;38: Cardiovascular outcomes trials for exenatide QW, dulaglutide, and albiglutide are in progress 3 a t approved by US FDA. 1. Marso SP, et al. N Engl J Med. 216 Jun 13. [Epub ahead of print]. 2. Pfeffer MA, et al. N Engl J Med. 215;373: Marso SP, eta. NEJM Sep 16 [Epub ahead of print].

6 Large Real-World Study Shows Increased Risk of Heart Failure Hospitalization With s Treatment Patients Without a History of HF, ahr (95% CI) Patients With a History of HF, ahr (95% CI) 2 OADs Reference Reference Incretin class difference difference DPP-4 inhibitors difference difference s difference difference Duration of treatment with incretin-based drugs < 365 days difference difference days 21% lower risk a difference 73 days difference difference Daily Weekly Most Commonly Reported Adverse Events With Receptor Agonist Use Prescribing Information 1,2,a Agent Nausea Vomiting Diarrhea Headache Upper Respiratory Tract Infection Injection- Site Reaction Exenatide BID Liraglutide Lixisenatide Exenatide QW Albiglutide Dulaglutide ahr, adjusted hazard ratio. a P <.5, incretin-based drugs vs 2 OADs. Filion KB, et al. N Engl J Med. 216;374: a Adverse events reported in 5% of patients. 1. US FDA. Drugs@FDA Trulicity (dulaglutide) [package insert]. Indianapolis, IN: Eli Lilly and Company; 215. Important Points for Patient Education Regarding Gastrointestinal Adverse Events Discuss expectations (eg, nausea is transient, sense of fullness) 1 Titrate slowly 1 Suggest behavioral changes (eg, decrease portion sizes and fat content, keep a log of foods that cause nausea) 1 Be aware of persistent abdominal pain and pancreatitis risk 1,2 1. Kruger DF, et al. Diabetes Educ. 21;36 (suppl 3):44S-72S. 2. US FDA. Drugs@FDA. Pancreatitis and Pancreatic Cancer Are Rarely Reported in Clinical Trials or Observational Studies of s Pancreatitis 1-4,8,9 Pancreatic Cancer 5-9 evidence of increased risk Multiple studies evidence of increased risk Multiple studies However, providers should be aware and counsel their patients 1,11 : Persistent severe abdominal pain is a hallmark symptom of pancreatitis Discontinue promptly if pancreatitis symptoms occur: upper abdominal or back pain (may be sudden), nausea, vomiting Risk factors include previous pancreatitis, alcoholism, gallstones, and hypertriglyceridemia 1. Monami M, et al. Diabetes Obes Metab. 215;17:32-41; 2. Li L, et al. BMJ. 214;348:g2366; 3. Wang T, et al. Diabetes Obes Metab. 215;17:32-41; 4. Giorda CB, et al. Endocrine. 215;48: ; 5. Guo, et al. Clin Drug Investig. 216 Mar 15. [Epub ahead of print]; 6. Knapen LM, et al. Diabetes Obes Metab. 216;18: ; 7. Azoulay L, et al. BMJ. 216;352:i581; 8. Pfeffer MA, et al. N Engl J Med. 215;373: ; 9. Marso SP, et al. N Engl J Med. 216 Jun 13. [Epub ahead of print]; 1. US FDA. Drugs@FDA Recent Findings Regarding s and Thyroid Cancer Recommendations for Current s in Patients With Renal Impairment 1 RI Category Mild Moderate Severe ESRD Long-term exposure to s in rodents, but not monkeys or humans, has been associated with thyroid C-cell hyperplasia and tumors 1 Pooled analysis showed no increased risk of thyroid cancer 3,b 1 MTC case reported for dulaglutide in 1 trial, but it was determined to have been pre-existing 4 thyroid events reported for lixisenatide; no increased risk for liraglutide 5,6 a All approved s except EN BID. b 24-3 weeks; all studies DURATION-1 through -6 and Asian studies; EN QW (n = 1934), EN BID (n = 66), non-glp (non comparator, n = 1338), EN QW (n = 461), LIRA (n = 45). FDA black box warning on product inserts of long-acting s 2,a ; contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2 1. Knudsen LB, et al. Endocrinology. 21;151: ; 2. Drugs@FDA.gov; 3. MacConell L, et al. Diabetes Metab Syndr Obes. 215;8: ; 4. Jendle J, et al. Diabetes Metab Res Rev. 216 Apr 21. [Epub ahead of print]; 5. Pfeffer MA, et al. N Engl J Med. 215;373: ; 6. Marso SP, et al. N Engl J Med. 216 Jun 13. [Epub ahead of print]. egfr or CrCl, 9 ml/min EN BID Daily Weekly LIRA LII EN QW ALBI DULA dose adjustment Caution but no dose reduction Do not use Patients who are dehydrated are at increased risk of renal injury from s 1 Liraglutide is associated with a decreased risk of renal events 2 1. US FDA. Drugs@FDA Marso SP, et al. N Engl J Med. 216 Jun 13. [Epub ahead of print].

7 Summary s have shown to date a neutral to favorable effect on cardiovascular risks GI effects such as nausea are common but tend to diminish with time and proper patient education/counseling Counsel patients to recognize symptoms of pancreatitis; consider other classes of agents in patients with a history of pancreatitis Some agents should not be used in patients with a personal or family history of certain rare thyroid tumors Most s can be used in patients with renal impairment, although indications vary among agents consult prescribing information MYTH VS FACT #4: IF YOU START A PATIENT ON INSULIN, YOU HAVE PREVENTED THEM FROM EVER USING A RECEPTOR AGONIST John E Anderson, MD Past President The Frist Clinic Nashville, Tennessee -Cell Function, % β-cell Function Is Gradually Lost as T2DM Progresses Impaired glucose tolerance Postprandial Hyperglycemia Indirect evidence suggests that some antihyperglycemic agents (eg, TZDs, incretin agents) may preserve β-cell function or β-cell mass 1,2 T2DM Early T2DM T2DM Late Years From Diagnosis Secretagogues lose efficacy as β-cell function declines 3 Insulin needed when β-cell function is lost 3 1. Buchanan TA, et al. Diabetes. 22;51: Salehi M, et al. Endocr Rev. 28;29: Lebovitz HE. Diabetes Rev. 1999;7: Basal insulin decreases hepatic glucose production by targeting the liver to decrease gluconeogenesis and glycogenolysis Main clinical effect: fasting BG control Complementary Actions of Basal Insulin and s 1-4 Hepatic glucose overproduction Optimal glycemic control (A1C) β- and α-cell dysfunction improves β-cell (insulin) and α-cell (glucagon) function, delays gastric emptying Main clinical effects: Postprandial BG control (short-acting agents) Fasting and postprandial BG control (long-acting agents) 1. Baggio LL, Drucker DJ. Gastroenterology. 27;132: Balena R, et al. Diabetes Obes Metab. 213;15: Holst JJ. Physiol Rev. 27;87: Madsbad S. Diabetes Obes Metab. 216;18: Intensification of Antihyperglycemic Therapy in T2DM, Starting With Basal Insulin: Current Recommendations Approval Status for Use of s in Combination With Insulin Step 1 Basal insulin + 1 or 2 oral agents 1,2 Class Agent Basal Prandial t Recommended Step 2 Step 3 Add a (preferred alternative) 1,2 Add 1st prandial insulin dose ( basal-plus ) 1,2 Add 2nd prandial insulin dose 1,2 Switch to premixed insulin (less-preferred alternative) 1,2 Add DPP-4i, SGLT2i 2 Daily Weekly Exenatide 5-1 μg BID 1 Liraglutide mg QD 1 Tested 2 Lixisenatide 1-2 μg QD 1 Exenatide 2 mg QW 1 Albiglutide 3-5 mg QW 1 Dulaglutide mg QW 1 Tested 3 (Basal) Step 4 Add 3rd prandial insulin dose 1,2 1. ADA. Diabetes Care. 216;39(suppl 1):S1-S Garber AJ, et al. Endocr Pract. 216;22: US FDA. Drugs@FDA de Wit HM, et al. J Intern Med. 216;279: ; 3. Pozzilli P, et al. Diabetes. 216;65(suppl 1):A62 [abstract 237-OR].

8 Defining Composite Efficacy in Diabetes Therapy: Glycemic Control, Hypoglycemia, and Weight Gain vs Prandial Insulin Added to Long-Acting Basal Insulins Meta-Analysis Glycemic control A1C < 7% Composite efficacy: All 3 goals are met in the same patient Comparison A1C Hypoglycemia Weight + basal insulin vs other agents + basal insulin a.44% additional reduction with (P <.5) increased relative risk with (RR,.99; P = NS) Mean reduction of 3.22 kg with (P <.5) Hypoglycemia severe hypoglycemia Weight gain weight gain + basal insulin vs basal-bolus insulin therapy b.1% additional reduction with (P <.5) 33% lower risk with (P <.5) Mean reduction of 5.66 kg with (P <.5) Zinman B, et al. Diabetes Obes Metab. 212;14: a Background OADs included MET, SU, TZD, GLN, AGI. b Background OADs included MET, PIO. Eng C, et al. Lancet. 214;384: Patients Attaining Outcome, % vs Prandial Insulin Added to Long-Acting Basal Insulins Real-World Data Prandial insulin (n = 5577) (n = 1143) 3.9 P <.5 P.1 P A1C < 7% A1C < 7%, Hypoglycemia A1C < 7%, Hypoglycemia, Weight Gain Patients initiating s also had significantly fewer ED visits, hospitalizations, and specialist referrals than patients initiating prandial insulin Intensification of Antihyperglycemic Therapy in T2DM, Starting With a : Current Recommendations ADA Guidelines (216) 1 AACE Guidelines (216) 2 Metformin + receptor agonist + SU or or TZD Insulin a preference is implied by order of listing GLP -1 RA ± MET + Listed in order of preference US database study reporting results 1 year after addition of prandial insulin or a to basal insulin among patients matched for age, A1C, and body mass at baseline. Digenio A, et al. Postgrad Med. 214;126: a Usually a basal insulin (NPH, glargine, detemir, degludec). 1. ADA. Diabetes Care. 216;39(suppl 1):S1-S Garber AJ, et al. Endocr Pract. 216;22: Combining s a With Basal Insulin: Does Order of Addition Matter? Add DEG to LIRA 1,b Add DET to LIRA 2,c Add DULA to GLAR 3,d Add LII to GLAR 4,e 7.6% 7.6% 7.6% 7.6% 8.4% 8.4% 8.4% 8.4% Baseline A1C.5 8.3% 8.5%.2 8.2% 8.3% A1C, % Basal insulin LIRA DULA Basal insulin + LIRA DULA + Basal insulin LII + Basal insulin and basal insulin combination treatment improves glycemic control relative to basal insulin or alone, regardless of order of addition 1-4 LII P <.1 P <.1 P <.1 P =.2 Shared Decision-Making Points for Comparing a Receptor Agonist vs a Basal Insulin Aspect of Care Receptor Agonist Basal Insulin Analogue Number of injections per week 1to 14 7to 14 Dose adjustment for meals required? Yes Dose adjustment for exercise required? Yes Glucose monitoring needed multiple times daily? Maybe Most common adverse events? GI distress Hypoglycemia a Only EN BID, LIRA, LII, and ALBI are currently approved for use with basal insulin 5 ; b 24 -to 28-week randomized trials. 1. Aroda VR, et al. Diabetes Obes Metab. 216;18: ; 2. DeVries J, et al. Diabetes Care. 212;35: ; 3. Pozzilli P, et al. Diabetes. 216;65(suppl 1):A62 [abstract 237-OR]; 4. Riddle MC, et al. Diabetes Care. 213;36: ; 5. US FDA. Drugs@FDA. US FDA. Drugs@FDA.

9 Comparing 4 Different Strategies for Intensifying a Basal Insulin Regimen Composite Efficacy a Patients Attaining Composite Outcome, % Basal-Bolus Therapy (Long-Acting Basal Insulin + Rapid-Acting Prandial Insulin) 7.7 Uptitrating Long-Acting Basal Insulin P < Long-Acting Basal Insulin P = Ultralong-Acting Basal Insulin/ Coformulation a Pooled analysis and indirect comparison of 5 randomized controlled trials. Composite efficacy: A1C < 7% without hypoglycemia or weight gain. Freemantle N, et al. Diabetes Ther. 215;6: Patients Attaining Composite Endpoint, % Basal Insulin vs Other Intensification Strategies Add-On LIRA + INS vs INS 1,a 19 INS P <.1 P <.2 P <.5 67 LIRA + INS Add-On LIRA + DET vs LIRA 2,a a 12- to 26-week randomized controlled trials, BL A1C 8.2%-8.8%, BL Wt kg. b Meta-analysis of 5 randomized controlled trials. 9 LIRA 21 LIRA + DET Add-On GLULISINE + GLAR vs LII + GLAR 3,b 15 GLULISINE + GLAR 1. Li CJ, et al. Cardiovasc Diabetol. 212;11: DeVries JH, et al. Diabetes Care. 212;35: Raccah D, et al. J Diabetes Complications. 214;28: LII + GLAR Fixed-ratio coformulations of basal insulin and a have been recommended for FDA approval 4,5 Patients Attaining Composite Endpoint, % Insulin (Basal or Prandial) vs Lispro/Glargine Basal Bolus Therapy Basal U-1 GLAR QD + Basal U-1 GLAR QD + Prandial U-1 LIS TID + ALBI QW or LIS TID 1,a EN BID or LIS TID 2,a DULA QW or GLAR QD 3,a,b 25 LIS + GLAR P = NS 3 ALBI + GLAR 23 LIS + GLAR P <.5 P <.1 45 EN + GLAR 6 LIS + GLAR 33 LIS + DULA Summary s or basal insulins can be initiated in either order s are less burdensome for patients than insulin regimens SMBG and dose adjustments for meals and exercise are not required s used in combination with basal or prandial insulin is highly advantageous in terms of composite efficacy (A1C reduction, hypoglycemia, weight gain) relative to most comparator strategies s have varying indications for use with insulin consult prescribing information Fixed-ratio combination therapies + basal insulin have recently been recommended for FDA approval a 26- to 3-week randomized trials, BL A1C 8.4%-8.5%, BL Wt kg. b Composite endpoint at 52 wks was attained by 52% on LIS/DULA 1.5 mg and by 14% on LIS/GLAR. 1. Rosenstock J, et al. Diabetes Care. 214;37: Diamant M, et al. Diabetes Care. 214;37: Blonde L, et al. Lancet. 215;385: Questions?