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

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2 15 mins for presentation & ARS MYTH VS FACT #1: GLP-1 RECEPTOR AGONISTS SHOULD BE RESERVED FOR PATIENTS WITH LONG-STANDING T2DM Carol Hatch Wysham, MD Clinical Associate Professor of Medicine University of Washington School of Medicine Section Head, Rockwood Diabetes and Endocrinology Center Spokane, Washington Current Treatment Algorithms Advocate s Beginning Early in the Progression of T2DM ADA Guidelines (16) 1 AACE Guidelines (16) 2 Efficacy. Hypo risk.. Weight... Side effects.. Costs... Metformin + GLP-1 receptor agonist high... low risk.... loss... GI.. high.. Listed in order of preference 1. ADA. Diabetes Care. 16;39(suppl 1):S1-S Garber AJ, et al. Endocr Pract. 16;22: s Are Recommended Throughout the Progression of T2DM in Current Treatment Algorithms FDA-Approved GLP-1 Receptor Agonists Monotherapy With 1-2 oral agents Patients who are intolerant of metformin or other first-line 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 Twice-Daily Injections Exenatide BID Within 6 min of 2 main meals, but 6 h apart Daily Injections Liraglutide Once daily, any time With insulin 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 Weekly Injections Albiglutide Dulaglutide Exenatide QW Once weekly, any time Once weekly, any time Once weekly, any time 1. ADA. Diabetes Care. 16;39(suppl 1):S1-S111; 2. Garber AJ, et al. Endocr Pract. 16;22:84-113; 3. Usui R, et al. J Diabetes Investig. 13;27:4: ; 4. Freemantle N, et al. Diabetes Ther. 15; ; 5. Blonde L, et al. Lancet. 15;385:57-66; 6. Raccah D, et al. J Diabetes Complications. 14;28:-44. US FDA. Summary 1 mins for presentation & ARS s are recommended early and throughout the progression of T2DM 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 FPG and PPG effects of s differ Adding a to insulin therapy may reduce glycemic variability, an emerging risk factor for poor outcomes MYTH VS FACT #2: GLP-1 RECEPTOR AGONISTS ARE DIFFICULT TO USE Scott V Joy, MD, MBA, FACP Medical Director The Colorado Health Foundation Professor of Clinical Practice Division of General Internal Medicine University of Colorado School of Medicine Denver, Colorado

3 Predicting Patient Preferences: Specific Characteristics Desired in s Comparing Dosage and Administration of Current s: Shorter-Acting 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 Liraglutide QD Advise on needle size a Advise on needle size a Inject within 6 minutes prior to 2 main Initiate at.6 mg once daily for 1 meals of the day, at least 6 h apart week b Initiate 5 μg per dose twice daily After 1 week, increase to 1.2 mg Increase to 1 μg twice daily after 1 month, based on clinical response Can increase to 1.8 mg if 1.2 mg does not provide acceptable glycemic control Available in a multidose pen Available in a 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. 16;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. Persistence With at 1 Year, % Adherence to s Is Higher With Less- Frequent Injection Studies From Europe Once-daily dosing 72.8 UK 63.9 Twice-daily dosing P <.1 P < Germany 69%: US 1-year average adherence to noninsulin therapies 2 Persistence to treatment was higher with once-daily than twice-daily dosing 1 1. Wilke T, et al. Diabetes Ther. 16;7: Kirkman MS, et al. Diabetes Care. 15;38: Patient must attach needle? Current s Vary Greatly in Their Ease of Use Patient must reconstitute from powder? Patient must prime device before first use? Patient can adjust dose? Patient must count for dwell time (5-1 sec)? a EN BID 1 LIRA QD 2 EN QW (syringe) 3 EN QW b (pen) 4 ALBI QW 5 c DULA QW 6 Dwell time is the length of time that the needle should remain in the skin following an injection to ensure full dosing 1-6 Patient-Related Considerations When Introducing Patients With T2DM to GLP-1 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 Mix powder in vial, shaking vigorously. b Mix by tapping on pen ( 8 times, rotating pen every 1 taps). c Mix by gently waving the pen side to side 5 times, wait 15 min, then wave 5 times again (video); 5. formation/tanzeum/pdf/tanzeum-pi-mg-ifu-combined.pdf#page=35; Hirsch L, et al. Curr Med Res Opin. 12;28: Kruger DF, et al. Diabetes Educ. 1;36(suppl 3):44S-72S.

4 Educating Patients About Their Medications May Improve Adherence and Reduce Patient Concerns That May Interfere With Adherence Highly adherent %-1% doses missed Received information from their primary care provider and other sources Referred to CDE Participate in community-based nutrition and management programs Mostly adherent 11%-26% doses missed Less likely to have received information from their physician More likely to selftitrate Complain about lack of information from healthcare providers Somewhat nonadherent 27%-47% doses missed Self-conscious about medication administration More complaints that medication interferes with lifestyle More likely to report hypoglycemia Referring patients to CDEs and community programs may improve adherence nadherent 47%-% doses missed More likely to be younger, female, or recently diagnosed Have many excuses for nonadherence More likely to be worried about medication side effects Online survey of self-reported number of missed medication doses among 87 patients with diabetes (9% with T2DM) conducted April 3-May 7, 12. Larkin AT, et al. J Diabetes. 15;7: EN BID LIRA QD EN QW Patient Resources for s Patient Education Materials and Programs Patient Prescription and Payment Assistance Programs tes-patient-support/prescriptionsavings.html DULA QW ALBI QW 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 education from primary care provider and community programs 15 mins for presentation & ARS MYTH VS FACT #3: APPROPRIATE PATIENT SELECTION VARIES AMONG GLP-1 RECEPTOR AGONISTS Carol Hatch Wysham, MD Clinical Associate Professor of Medicine University of Washington School of Medicine Section Head, Rockwood Diabetes and Endocrinology Center Spokane, Washington 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 A1C 7% Patient attitude/expected treatment efforts Highly motivated, adherent, excellent self-care capabilities Resources and support system More stringent Absent Readily available Few/mild Few/mild Less stringent High Usually Long-standing not modifiable Short Severe Severe Frequent Less motivated, nonadherent, poor self-care capabilities Potentially modifiable Limited Inzucchi SE, et al. Diabetes Care. 15;38: Most Commonly Reported Adverse Events With GLP-1 Receptor Agonist Use Prescribing Information 1,2,a Agent Nausea Vomiting Diarrhea Headache Upper Respiratory Tract Infection Injection- Site Reaction EN BID LIRA EN QW ALBI DULA a Adverse events reported in 5% of patients. 1. US FDA. Drugs@FDA Trulicity (dulaglutide) [package insert]. Indianapolis, IN: Eli Lilly and Company; 15.

5 Increasing likelihood of event Gastrointestinal Effects for s and Comparator Agents Network Meta-Analysis Ranking Nausea (SUCRA) Vomiting (SUCRA) Diarrhea (SUCRA) 1 Dulaglutide (.36).5 mg/1. mg titration QW 2 Exenatide (.322) 2 mg QW 3 Albiglutide (.394) 3 mg Q2W 4 Exenatide (.398) 5 μg BID 5 Liraglutide (.442).6 mg QD 6 Lixisenatide (.58) mg BID Dulaglutide (.31) 1. mg/1. mg titration QW Exenatide (.345) 2 mg QW Albiglutide (.378) 3 mg Q2W Lixisenatide (.412) 3 mg BID Exenatide (.516) 5 μg BID Liraglutide (.537).6 mg QD Dulaglutide (.147) 1. mg/1. mg titration QW Lixisenatide (.25) 3 mg QD Exenatide (.471) 5 μg BID Albiglutide (.485) 3 mg QW Exenatide (.573) 2 mg QW Liraglutide (.591).6 mg QD Generally, for any given agent, higher rates of GI AEs were observed at higher doses Lower SUCRA scores indicate less likelihood of event. SUCRA, surface under the cumulative ranking curve. Sun F, et al. Diabetes Technol Ther. 15;17: 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. 1;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 Pancreatic Cancer evidence of increased risk 4 meta-analyses of randomized controlled trials and database studies, 1-4 including 1 with > 1 million patients 3 evidence of increased risk 1 systematic review of randomized controlled trials 5 ; 1 national database study 6,a ; 1 multicenter, multinational database study with > 1 million patients 7 increased risks of pancreatitis or pancreatic cancer were reported in ELIA 8 However, providers should be aware and counsel their patients: Persistent severe abdominal pain is a hallmark symptom of pancreatitis Risk factors include previous pancreatitis, alcoholism, gallstones, and hypertriglyceridemia Recent Data Regarding s and Thyroid Cancer Long-term exposure to GLP-1 RAs in rodents, but not monkeys or humans, has been associated with thyroid C-cell hyperplasia and tumors 1 FDA black box warning on product inserts of 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 All Studies b DURATION-6 Adverse Event 3 EN QW EN BID n-glp EN QW LIRA Thyroid neoplasm, % Thyroid neoplasms are rare events reported thyroid cancer or C-cell carcinoma in analyzed groups Pooled analysis showed no increased risk of thyroid cancer 3,b a After adjusting for disease severity; no relationship with duration of use. 1. Monami M, et al. Diabetes Obes Metab. 15;17:32-41; 2. Li L, et al. BMJ. 14;348:g2366; 3. Wang T, et al. Diabetes Obes Metab. 15;17:32-41; 4. Giorda CB, et al. Endocrine. 15;48: ; 5. Guo, et al. Clin Drug Investig. 16 Mar 15. [Epub ahead of print]; 6. Knapen LM, et al. Diabetes Obes Metab. 16;18: ; 7. Azoulay L, et al. BMJ. 16;352:i581; 8. Pfeffer MA, et al. N Engl J Med. 15;373: 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 GLP-1 comparator, n = 1338), EN QW (n = 461), LIRA (n = 45). 1. Knudsen LB, et al. Endocrinology. 1;151: Drugs@FDA.gov. 3. MacConell L, et al. Diabetes Metab Syndr Obes. 15;8: Dose Adjustment Recommendations for Current s in Patients With Renal Impairment RI Category Mild Moderate Severe ESRD egfr or CrCl, ml/min ALBI Longer-Acting Shorter-Acting DULA EN QW LIRA EN BID dose adjustment Caution but no dose reduction Do not use Patients who are dehydrated are at increased risk of renal injury from s US FDA. Drugs@FDA. Large Real-World Study Shows Increased Risk of Heart Failure Hospitalization With s Patients Without a History of HF 1,a Patients With a History of HF 1,b Treatment ahr (95% CI) Treatment ahr (95% CI) 2 OADs 1. (ref) 2 OADs 1. (ref) Incretin class.82 (.67-1.) Incretin class.86 ( ) DPP-4 inhibitors.84 ( ) DPP-4 inhibitors.87 ( ) s.95 ( ) s.75 ( ) Duration of treatment with incretinbased drugs < 365 days.83 ( ) days.79 ( ) c 73 days.96 ( ) ahr, adjusted hazard ratio. a Case patients, n =23,5; controls, n = 435,777. b Case patients, n = 6536; controls, n =,48. c P <.5, incretin-based drugs vs 2 OADs. Duration of treatment with incretinbased drugs < 365 days.68 ( ) days 1.9 ( ) 73 days.95 ( ) CV outcomes trials found an increased risk of HF hospitalization for some incretin agents, although these events were rare 2 increased risk was found in this large case-control study from Canada 1 The FDA recently added warnings to the labels for alogliptin and saxagliptin and encourages healthcare professionals to report any suspected AEs to MedWatch 3 1. Filion KB, et al. N Engl J Med. 16;374: Wang T, et al. Diabetes Metab Res Rev. 16 Apr 2. [Epub ahead of print]. 3.

6 s Do t Increase the Risk of Cardiovascular Events a in Patients With T2DM Completed Studies LEADER (liraglutide) 1,b ELIA (lixisenatide) 2,c SUSTAIN 6 (semaglutide) 3 Endpoint/Parameter MACE (CV death, nonfatal MI, nonfatal stroke) 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 announcement expected in June 16 at ADA increased risk d increased risk increased risk Studies in Progress Estimated Completion Date ESCEL (exenatide QW) April 18 REWIND (dulaglutide) April 19 HARMONY Outcomes (albiglutide) May 19 TBA Summary GI effects such as nausea are common but tend to diminish with time and proper patient education/counseling Pancreatitis is more common in patients with diabetes than in the general population; counsel patients to recognize symptoms Consider other classes of agents in patients with a history of pancreatitis or certain rare thyroid tumors Most s can be used in patients with renal impairment, although indications vary among agents consult prescribing information s have a neutral to favorable effect on cardiovascular risks a To obtain FDA approval as of 8, antidiabetic agents must demonstrate not only efficacy for lowering A1C but also no increased CV risk. b N = 93; years follow-up. c N = 668; 25 months median follow-up. d P <.1 for noninferiority vs PBO; P =.81 for superiority. 1. vo rdisk Pfeffer MA, et al. N Engl J Med. 15;373: mins for presentation & ARS MYTH VS FACT #4: IF YOU START A PATIENT ON INSULIN, YOU HAVE PREVENTED THEM FROM EVER USING A GLP-1 RECEPTOR AGONIST Scott V Joy, MD, MBA, FACP Medical Director The Colorado Health Foundation Professor of Clinical Practice Division of General Internal Medicine University of Colorado School of Medicine Denver, Colorado -Cell Function, % β-cell Function Is Gradually Lost as T2DM Progresses IGT 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. 2;51: Salehi M, et al. Endocr Rev. 8;29: Lebovitz HE. Diabetes Rev. 1999;7: Step 1 Step 2 Step 3 Intensification of Antihyperglycemic Therapy in T2DM, Starting With Basal Insulin: Current Recommendations Add a (preferred alternative) 1,2 Basal insulin + 1 or 2 oral agents 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 Approval Status for Use of s in Combination With Insulin Agent Basal Prandial t Recommended Albiglutide 3-5 mg QW 1 Dulaglutide mg QW 1 Exenatide 5-1 μg BID 1 Exenatide 2 mg QW 1 Liraglutide mg QD 1 Lixisenatide (NDA accepted by US FDA) 2 See note 3-5 Step 4 Add 3rd prandial insulin dose 1,2 1. ADA. Diabetes Care. 16;39(suppl 1):S1-S Garber AJ, et al. Endocr Pract. 16;22: te: Has been tested in combination with insulin glargine US FDA. Drugs@FDA Sanofi [press release]. Application-for-Lixisenatide-Accepted-for-Review-by-FDA. 3. Riddle MC, et al. Diabetes Care. 13;36: Meier JJ, et al. Diabetes Care. 15;38: Rosenstock J, et al. Diabetes Care. 16 May 23. [Epub ahead of print].

7 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.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.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. 12;14: Eng C, et al. Lancet. 14;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 (all P <.3) Intensification of Antihyperglycemic Therapy in T2DM, Starting With a : Current Recommendations ADA Guidelines (16) 1 AACE Guidelines (16) 2 Metformin + GLP-1 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 (aspart, glulisine, or lispro) or a (exenatide or liraglutide) to basal insulin (detemir, glargine, zinc insulin, or isophane/nph insulin) among patients matched for age, A1C, and body mass at baseline. Digenio A, et al. Postgrad Med. 14;126: a Usually a basal insulin (NPH, glargine, detemir, degludec). 1. ADA. Diabetes Care. 16;39(suppl 1):S1-S Garber AJ, et al. Endocr Pract. 16;22: Shared Decision-Making Points for Comparing a GLP-1 Receptor Agonist vs a Basal Insulin Aspect of Care GLP-1 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 Comparing 4 Different Strategies for Intensifying a Basal Insulin Regimen Composite Efficacy a Patients Attaining Composite Outcome, % 8 6 Basal-Bolus Therapy With 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/ GLP-1 Coformulation US FDA. Drugs@FDA. 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. 15;6:

8 Patients Attaining Composite Endpoint, % + Basal Insulin vs Other Intensification Strategies Add-On LIRA + INS vs INS 1,a INS 67 LIRA + INS Add-On Add-On LIRA + DET vs LIRA 2,b GLU + GLAR vs LII + GLAR 3,c,d P <.1 P <.2 P <.5 9 LIRA 21 LIRA + DET 15 GLU + GLAR 29 LII + GLAR Adding a to basal insulin was more effective than increasing the insulin dose, using the alone, or adding prandial insulin 1-3 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- GLAR QD + Basal U- GLAR QD + Prandial U- LIS TID + ALBI QW or LIS TID 1,a EN BID or LIS TID 2,b DULA QW or GLAR QD 3,c,d 3 ALBI + GLAR P = NS 25 LIS + GLAR 45 EN + GLAR P <.5 P <.1 23 LIS + GLAR 33 LIS + DULA 6 LIS + GLAR Adding a to basal or prandial insulin was more effective than a basal-bolus regimen with U- lispro 3 times daily and U- glargine once daily a Chinese study population, BL A1C 8.7%-8.8%, BL Wt kg; 12 weeks. b rth American and European study population, BL A1C 8.2%-8.3%, BL Wt 99 kg; 26 weeks. c LII and LII + GLAR are not US FDA approved. d Meta-analysis of 5 randomized controlled trials. 1. Li CJ, et al. Cardiovasc Diabetol. 12;11: DeVries JH, et al. Diabetes Care. 12;35: Raccah D, et al. J Diabetes Complications. 14;28: a Multiethnic study population, BL A1C 8.4%-8.5%, BL Wt 92 kg; 26 weeks. b Multinational study population, BL A1C 8.5%, BL Wt 89 kg; 3 wks. c Multinational study population, BL A1C 8.5%, BL Wt 91 kg; 26-wk results reported. d 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. 14;37: Diamant M, et al. Diabetes Care. 14;37: Blonde L, et al. Lancet. 15;385: 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