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Beyond metformin dr clayton feb 22
- 1. Beyond Metformin, Navigating The Treatment Continuum For Your Patients With Type 2 Diabetes Dr. Dale Clayton, MD, FRCPC, Endocrinologist, RCH
- 2. Faculty/Presenter Disclosure Faculty: Dr Dale Clayton Relationships with commercial interests: Grants/Research Support: none Speakers Bureau/Honoraria: Animas, Boehringer Ingelheim, Lilly, Medtronic, Novo Nordisk, Sanofi Aventis Consulting Fees: None Other: Staff Endocrinologist-Fraser Health, Clinical Assistant Professor-UBC Medicine
- 3. Disclosure of Commercial Support This program has received financial support from Novo Nordisk Canada Inc. in the form of an unrestricted educational grant Potential for conflict(s) of interest: Dr Clayton has received financial support/ honorariums from the companies listed in the disclosures whose products are discussed in the program, including: Eli Lilly Canada Inc.: insulin lispro sanofi-aventis Canada Inc.: insulin glargine, insulin glulisine Novo Nordisk Canada Inc. distributes products that will be discussed in this program: Victoza, Levemir and Novo Rapid
- 4. Mitigating Potential Bias Bias in this program has been mitigated using independent content validation as follows: All content has been reviewed by a physician steering committee, pharmacist expert reviewers, and the College of Family Physicians Canada All data has been sourced from evidence that is clinically accepted All support used in justification of patient care recommendations conform to generally accepted standards and CDA guidelines
- 5. Steering Committee Dr. Breay Paty (Endocrinologist) Dr. Dr. Dr. Dr. William Harvey (Family Physician) Orly Hermon (Family Physician) Gihane Zarifa (Family Physician) Mulluvila R.K. Suresh (Family Physician) Robert Roscoe (Pharmacist) Pascale Therrien (Pharmacist)
- 6. Today’s Objectives By the end of this program, attendees will be able to: Recognize the rationale for timely initiation and intensification of treatment to achieve glycemic targets Understand how currently available treatment options compare with respect to key challenges in diabetes management: A1C, weight and hypoglycemia Implement effective strategies to help patients and health practitioners overcome barriers to treatment at various stages of the treatment continuum Recognize importance of establishing individualized targets (i.e., A1C, weight) based on patient characteristics
- 7. Case Study: Meet Jason Image of Jason Jason 47 years old 47 years old Factory worker – works shifts Private insurance coverage Married Non-smoker Relies on fast-food during late shifts Mother had type 2 diabetes Willing to change lifestyle to treat diabetes Jason has just been diagnosed with Jason has just been diagnosed with type 2 diabetes type 2 diabetes
- 8. Jason: At diagnosis Diabetes duration Newly diagnosed Height 176 cm Weight 93 kg BMI 30 kg/m2 Waist circumference 110 cm A1C 8.7% FPG 10.5 mmol/L PPG 11.2 mmol/L Blood pressure 126/75 mm Hg eGFR 95 ml/min
- 9. Establishing individualized glycemic targets A1C should be tested every 3 months in most individuals To further lower risk of nephropathy and retinopathy (must be balanced against the risk of hypoglycemia) Most patients with type 2 diabetes - Limited life expectancy - Functional dependency - Extensive CVD and high risk of ischemic events - Multiple co-morbidities - Recurrent severe hypoglycemia - Longstanding diabetes and difficulty achieving A1C ≤7% despite therapy A1C testing can occur every 6 months in adults during periods of treatment and lifestyle stability when glycemic targets have been consistently achieved 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- 10. or or Unless contraindicated, metformin is the initial antihyperglycemic agent of choice. 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- 11. Jason: Initial diagnosis Jason’s A1C at diagnosis was 8.7% He started: Attending diabetes education classes Avoiding fast-food Going for walks with his wife Initiated metformin 500 mg BID After 2 weeks metformin was increased to 1000 mg BID as tolerated
- 12. Jason: 3 months After 3 months of treatment Jason’s A1C is still not at his target 3 months Weight 91 kg BMI 29.4 kg/m2 Waist circumference 108 cm A1C 7.8% FPG 8.9 mmol/L PPG 9.0 mmol/L Current treatment He has not experienced any hypoglycemic events but is worried because his meal time varies depending on his shifts Diabetes duration Lifestyle intervention Metformin (1000 mg BID) 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- 13. Early A1C reductions have important benefits ke tro s n tio ed l al lar at ac ta t l tr fa cu s fa re ts s ex on va nt on es n ct ro poi /n I et poi /n a l l c ar ta M ab d ta M i e nd at Di en Fa Fa C th ea d n/ re se ilu tio PVD a au lity a f t l-c a rt pu m Al ort m fro ea A H m A1C ed lat e -r y es alit t be rt ia mo D What can a 1% 21% 12%14% A1C reduction can do for your patients? 16% 19% 14% 21% 37% 43% Relative risk reduction 1. Stratton IM et al. BMJ 2000;321:405-412.
- 14. Legacy Effect: Early and aggressive control has long-term benefits The positive effect of early and intensive glucose control Any diabetesrelated endpoint 9% Myocardial infarction All-cause mortality Microvascular disease † reduced relative risk 15% † 13% † reduced relative reduced relative risk risk 24% † reduced relative risk * At the end of post-trial follow-up (median 8.5 years). † Significant reduction on intensive therapy vs. conventional therapy. 1. Holman et al. NEJM. 2008;359:1577-89.
- 15. Considerations in treatment selection to help patients achieve individualized targets Patient Characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obese Agent Characteristics A1C BG lowering efficacy and durability hypo Risk of hypoglycemia kg Effect on weight Comorbidities (renal, cardiac hepatic) Preferences and access to treatment (administration considerations) Contraindications/side effects Cost and coverage 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- 16. Hypoglycemia can be a silent burden for your patients hypo Hypoglycemia has been associated with:1,2 Reduced quality of life Reduced quantity and quality of sleep Impaired ability to drive Negative effects on interpersonal relationships Increased cardiovascular morbidity and mortality 85% of type 2 diabetes patients DO NOT REPORT mild/moderate hypoglycemia to their doctors3 1. Seaquist et al. Diabetes Care 2013;36:1384-1395. 2. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212. 3. Leiter, Yale et al. Can J Diabetes 2005; 29(3): 186-92.
- 17. Avoidance of weight gain is important in type 2 diabetes Glycemic control 5% Insulin sensitivity Lipid control Blood pressure control to 10% Greater BMI is associated with poorer quality of life Greater BMI is associated with poorer quality of life BMI=Body Mass Index; 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212. kg
- 19. What is important to your patient? Comparing antihyperglycemic agents kg hypo Relative A1C lowering Change in body weight Overall risk of hypoglycemia Cost Neutral to Rare $$ Neutral to Rare $$$ to Rare $$$$ Yes $-$$$$ Meglitinides Yes $$ Sulfonylureas Yes $ TZDs Rare $$ None $$$ A1C Alpha glucosidase inhibitor (acarbose) DPP-4 inhibitors GLP-1 receptor agonists Insulin Weight loss agent (orlistat) TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4. 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- 20. What is important to your patient? Comparing antihyperglycemic agents Alpha glucosidase inhibitor (acarbose) • Improved postprandial control, GI side effects DPP-4 inhibitors GLP-1 receptor agonists • GI side effects Insulin • No dose ceiling, flexible regimens Meglitinides • Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Sulfonylureas • Gliclazide and glimepiride associated with less hypoglycemia than glyburide TZDs • CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect Weight loss agent (orlistat) • GI side effects TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4. 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- 21. Discuss: Jason’s treatment options What agent would you choose for Jason? Jason’s A1C is above his target 91 kg BMI 29.4 kg/m2 Waist circumference 108 cm A1C 7.8% FPG 8.9 mmol/L PPG He is concerned about hypoglycemic events 3 months Weight He works shifts and it is hard for him to stick to a meal schedule Diabetes duration 9.0 mmol/L Current treatment Lifestyle intervention Metformin (1000 mg BID) Consider: A1C kg hypo
- 22. Jason: 6 months After 3 months on your chosen treatment Jason’s A1C is at target He maintains an active lifestyle and feels motivated to continue after recent weight loss Diabetes duration 6 months Weight 85 kg BMI 27.8 kg/m2 Waist circumference 100 cm A1C <7.0% FPG 6.8 mmol/L PPG 8.5 mmol/L Current treatment Lifestyle intervention Metformin (1000 mg BID) Your Treatment Choice
- 23. Jason: 5 years Recently, he has missed a few checkups and his A1C is above target 5 years Weight 87 kg BMI 28.4 kg/m2 Waist circumference 105 cm A1C 8.1% FPG 8.4 mmol/L PPG 10.0 mmol/L Current treatment Over the years Jason’s diabetes has progressed and modifications to treatment have been made Diabetes duration Lifestyle intervention Metformin (1000 mg BID) Your Treatment Choice 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- 24. After 2 agents, what next? Comparing antihyperglycemic agents kg hypo Relative A1C lowering Change in body weight Overall risk of hypoglycemia Cost Neutral to Rare $$ Neutral to Rare $$$ to Rare $$$$ Yes $-$$$$ Meglitinides Yes $$ Sulfonylureas Yes $ TZDs Rare $$ None $$$ A1C Alpha glucosidase inhibitor (acarbose) DPP-4 inhibitors GLP-1 receptor agonists Insulin Weight loss agent (orlistat) TZDs=thiazolidinediones; AGIs=alpha-glucosidase inhibnitors; GLP-1=glucagon-like Peptide 1; DPP-4=dipeptidyl peptidase-4. 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- 25. Survey Delay of oral medication initiation was the strongest correlate of insulin therapy delay I prefer to delay insulin until it is absolutely necessary 1 2 3 4 5 6 Fully Disagree Disagree Somewhat Disagree Somewhat Agree Agree Fully Agree of physicians delayed insulin therapy until absolutely necessary Peyrot et al. Diabetes Care. 2005;28:2673-2679.
- 26. Insulin initiation is improving, but targets are still not being met Canadian physicians completed a survey about type 2 diabetes patients 87% of type 2 diabetes patients were prescribed antihyperglycemic agents. Of those: 19% were on insulin only 42% were on insulin + AHA agent Only 50% of patients met A1C ≤7.0% Leiter et al. Can J Diabetes. 2013;37:82-89.
- 27. Choose a basal insulin Patient Characteristics Consider Jason’s A1C is above target (≤ 7.0%) A1C Shift work increases his risk of hypoglycemia hypo He continues to struggle with his weight kg Insulin detemir or glargine (long-acting analogues) instead of NPH to reduce the risk of nocturnal and symptomatic hypoglycemia Weight gain: Detemir < Glargine & NPH 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212. 2.Levemir product Monograph. Novo Nordisk Canada: 2011. 3. Lantus Product Monograph. sanofi-aventis Canada Inc. 2012.
- 28. A closer look at the basal insulins... Duration1 Variability2 NPH Up to 18 hours 68% • Greatest risk for hypoglycemia1 Detemir 16-24 hours 27% • Lower hypoglycemia risk3 Glargine 24 hours 48% • Lower hypoglycemia risk3 Insulin analogues are associated with a less pronounced peak Insulin analogues are associated with a less pronounced peak versus NPH insulin. versus NPH insulin. 1. Adapted from Nasrallah SN et al. Clinical Medical Insights: Endocrinology and Metabolism 2012;5:31-7; 2. T. Heise, et al. Diabetes 2004. 3. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- 29. When initiating basal insulin consider: Injection 7.0 mmol/L hypo kg • Demonstrate the 1st injection in your office Titration • Teach patient how to adjust insulin dose • Remind patient about signs and Minimize hypoglycemia symptoms of hypoglycemia, and what to do (consider handout) Weight • Re-communicate the importance • of weight management Consider choosing an insulin that minimizes weight gain 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- 30. Other considerations when starting insulin What to do with other therapies? Antihyperglycemic agents can be combined with basal insulin With the exception of TZDs which should not be combined with insulin Remember There is no maximum dose of insulin Adjust to glucose target & minimize hypoglycemia 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- 31. Jason: Starting on a basal insulin analogue Jason begins using 10 units of basal insulin analogue He is instructed to titrate 1 unit every night until his FPG is 4 - 7 mmol/L He continues taking his current medications He records his blood glucose levels before breakfast and before bed His doctor reminds him of the symptoms of hypoglycemia and provides a handout of instructions Oral antihyperglycemic agents may need to be reduced if daytime hypoglycemia occurs
- 32. Jason’s first week Jason’s Logbook: Representative of the previous week 8.4 mmol/L 10 units 8.4 8.4 8.3 8.3 8.2 8.2 mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L 11 12 13 14 15 16 units units units units units units Jason will continue to titrate insulin dose until he reaches his target FPG
- 33. Jason: 3 months on basal insulin analogue Jason has reached his A1C target with 20 units of insulin Jason can maintain this Jason can maintain this dose as long as his dose as long as his A1C target is met A1C target is met Diabetes duration 5 years Weight 87 kg BMI 28.4 kg/m2 Waist circumference 105 cm A1C <7.0% FPG 6.2 mmol/L PPG 8.9 mmol/L Current treatment Lifestyle intervention Metformin (1000 mg BID) Your Treatment Choice Basal insulin analogue (20 units)
- 34. Key Takeaways When considering type 2 diabetes treatment consider: Individualization of targets and treatment A1C A1C reduction kg Weight Timely initiation & intensification Hypoglycemia Coverage hypo $
- 35. Today’s Objectives Now we can: Recognize the rationale for timely initiation and intensification of treatment to achieve glycemic targets Understand how currently available treatment options compare with respect to key challenges in diabetes management: A1C, weight and hypoglycemia Implement effective strategies to help patients and health practitioners overcome barriers to treatment at various stages of the treatment continuum Recognize importance of establishing individualized targets (i.e., A1C, weight) based on patient characteristics
- 36. FAQs FAQs When & how to intensify insulin after basal insulin is initiated. How to help patients overcome injection barrier. Is there a cardiovascular risk with incretin therapies? Is there a pancreatitis risk with incretin therapies? Case examples - What would you consider for a patient with: Renal impairment for whom you are considering an incretin therapy Long-standing diabetes and high blood pressure currently on basal insulin Slightly elevated A1C currently on MET Long-standing diabetes on triple therapy of MET + SU + DPP-4 inhibitor Experiencing hypoglycemic episodes on MET + NPH Combining insulin and incretin
- 37. Reminder: Diabetes is progressive IFG=impaired fasting glucose; IGT=impaired glucose tolerance. Kendall DM et al. Am J Med. 2009;122(6)(suppl 6A):S37-S50.
- 38. Insulin intensification: Add mealtime insulin to maintain A1C targets If A1C >7%, FPG ≤7 mmol/L, add rapid-acting insulin analogue (RAIA) to basal insulin START WITH 1 MEAL RAIA can provide effective control when added just prior to a meal, with basal insulin. Choose the meal that is most convenient for the patient. START WITH 4 UNITS The pre-meal blood glucose at the meal following dosing (or the 2-hour PPG) can be used to titrate the dose for the next day. Choose the method that is most convenient for the patient. RAIA: Rapid-acting insulin analogue; PPG: postprandial plasma glucose 1. Meneghini et al. Endocr Pract. 2011;17(5):727-36.
- 39. Algorithm for adding mealtime insulin An example of mealtime insulin monitoring and dose adjustment Jenny injects 26 units of basal insulin and has an FPG that is regularly <7mmol/L. To reduce her PPG to target Jenny injects 4 units of insulin just before lunch, as instructed by her doctor. She then tests her blood sugar just before her bedtime and records the result in her dose diary. She has been instructed to add 1 unit of mealtime insulin per day until next pre-meal glucose is between 4-7 mmol/L
- 40. FAQs FAQs When & how to intensify insulin after basal insulin is initiated. How to help patients overcome injection barrier. Is there a cardiovascular risk with incretin therapies? Is there a pancreatitis risk with incretin therapies? Case examples - What would you consider for a patient with: Renal impairment for whom you are considering an incretin therapy Long-standing diabetes and high blood pressure currently on basal insulin Slightly elevated A1C currently on MET Long-standing diabetes on triple therapy of MET + SU + DPP-4 inhibitor Experiencing hypoglycemic episodes on MET + NPH Combining insulin and incretin
- 41. Useful consideration in overcoming potential injection barriers EVALUATE • Consider whether injection is a patient vs. physician barrier COMMUNICATE • Inform patient that currently available needles are very short/thin • Explain the advantages of achieving target glucose levels • Work with your patients diabetes healthcare team to address any of your patients concerns DEMONSTRATE • Administer the first injection in-clinic • Many educators perform a dry injection on themselves in the presence of the patient Needle used for intravenous blood draw (i.e., A1C test) 20G Needle used for intramuscula r vaccination (i.e., flu shot) 23G Needle used with GLP-1 RA or insulin 32G W idth of two hairs Funnell M. Clinical Diabetes 2007; 25(1):36-8. FIT Forum for Injection Technique Canada: Recommendations for Best Practice in Injection Technique. 2012; 1-28.
- 42. FAQs FAQs When & how to intensify insulin after basal insulin is initiated. How to help patients overcome injection barrier. Is there a cardiovascular risk with incretin therapies? Is there a pancreatitis risk with incretin therapies? Case examples - What would you consider for a patient with: Renal impairment for whom you are considering an incretin therapy Long-standing diabetes and high blood pressure currently on basal insulin Slightly elevated A1C currently on MET Long-standing diabetes on triple therapy of MET + SU + DPP-4 inhibitor Experiencing hypoglycemic episodes on MET + NPH Combining insulin and incretin
- 43. Is there an increased risk of CV events with incretin therapies? Linagliptin1 N=5,239 Saxagliptin2 N=4,607 0.16 0.23 Sitagliptin3 4 N=6,638 0.125 0.32 0.25 No increased risk of CV events observed with incretin therapies 1.24 0.63 Incretin agent better R 1.31 0.7 0.5 FDA upper bound 95% criterion for approvability 1.12 0.68 0.38 N=3,945 Liraglutide5 0.80 0.43 0.41 N=10,246 Exenatide 0.74 0.34 1 2 4 8 Comparator better 1. Johansen O-E., et al. Cardiovascular Diabetology. 2011;11:3;doi:10.1186/1475-2840-11-3. 2. Frederich R, et al. Postgrad Med. 2010;122(3):16–27. 3. Williams-Herman D, et al. BMC Endocr Disord. 2010;10:7. 4. Ratner R, et al. Cardiovascular Diabetology. 2011;10:22. 5. www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4422b2-01-FDA.pdf Accessed Sept. 23, 2011.
- 44. Ongoing cardiovascular trials with incretin therapies DPP-4 INHIBITORS Linagliptin 1 Saxagliptin2 Sitagliptin3 Completion Date CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes SAVOR-TIMI 53: Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes Medications TECOS: Sitagliptin Cardiovascular Outcome Study GLP-1 RECEPTOR AGONISTS R September 2018 July 2013 December 2014 Completion Date EXSCEL*: Exenatide Study of Cardiovascular Event Lowering Trial A Trial To Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly In Patients With Type 2 Diabetes Mellitus Exenatide4 Liraglutide 5 LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation March 2017 January 2016 *Exenatide once weekly is not approved or available in Canada. All found on www.clinicaltrials.gov. 1. Clinicaltrials.gov identifier: NCT01243424 2. Clinicaltrials.gov identifier: NCT01107886 3. Clinicaltrials.gov identifier: NCT00790205 4. Clinicaltrials.gov identifier: NCT01144338 5. Clinicaltrials.gov identifier: NCT01144338
- 45. FAQs FAQs When & how to intensify insulin after basal insulin is initiated. How to help patients overcome injection barrier. Is there a cardiovascular risk with incretin therapies? Is there a pancreatitis risk with incretin therapies? Case examples - What would you consider for a patient with: Renal impairment for whom you are considering an incretin therapy Long-standing diabetes and high blood pressure currently on basal insulin Slightly elevated A1C currently on MET Long-standing diabetes on triple therapy of MET + SU + DPP-4 inhibitor Experiencing hypoglycemic episodes on MET + NPH Combining insulin and incretin
- 46. Risk of pancreatitis with incretin therapy? Type 2 diabetes is associated with an elevated risk of pancreatitis 2.1 fold higher risk of pancreatitis for type 2 diabetes vs. general population. Incretin therapies have been associated with isolated cases of pancreatitis in trials and postmarketing reports Causality relationship has not yet been established Not recommended that these agents be used in patients with a history of pancreatitis 1. Garg R et al. Dia be te s Ca re 2010;33:2359-54; 2. Liraglutide Canadian Product Monograph, Novo Nordisk Canada Inc., 2011. 3. Linagliptin Canadian Product Monograph, Boehringher Ingelheim (Canada) Ltd. July 26, 2011. 4. Exenatide Canadian Product Monograph, Eli Lilly Canada, 2011.
- 47. FAQs FAQs When & how to intensify insulin after basal insulin is initiated. How to help patients overcome injection barrier. Is there a cardiovascular risk with incretin therapies? Is there a pancreatitis risk with incretin therapies? Case examples - What would you consider for a patient with: Renal impairment for whom you are considering an incretin therapy Long-standing diabetes and high blood pressure currently on basal insulin Slightly elevated A1C currently on MET Long-standing diabetes on triple therapy of MET + SU + DPP-4 inhibitor Experiencing hypoglycemic episodes on MET + NPH Combining insulin and incretin
- 48. Case studies: Carl What would you consider for Carl? Carl 42 years old Newly diagnosed with chronic kidney disease Private insurance coverage Diabetes duration 5 years Weight 92 kg BMI 29.4 kg/m2 Waist circumference 109 cm eGFR 64 ml/min A1C 7.6% FPG 7.2 mmol/L PPG 10.9 mmol/L Current treatment Metformin (1000 mg BID)
- 49. How does renal function influence the use of the different incretin therapies? CKD Stage: GFR (ml/min): 29-15 <15 30 Exenatide Liraglutide Linagliptin 59-30 Sitagliptin 50 10 цg bid 1.2 & 1.8 mg 15 5 mg 2.5 mg Saxagliptin 25 mg ≥90 50 5 цg bid Not Studied Not Studied 89-60 RENALLY CLEARED? 50 5 mg 30 50 100 mg 50 mg Contraindicated Not Recommended Caution/Reduced Dose Safe CKD=chronic kidney disease GFR=glomerular filtration rate 1. Saxagliptin Canadian Product Monograph, Bristol Myers Squibb/Astra Zeneca, 2012; 2. Sitagliptin Canadian Product Monograph, Merck Frosst, 2012; 3. Liraglutide Canadian Product Monograph, Novo Nordisk Canada, 2010; 4. Exenatide Canadian Product Monograph, Eli Lilly Canada, 2011. 5. Linagliptin Canadian Product Monograph, Boehringer Ingelheim (canada) Ltd., 2012; 6. CDA Guidelines. Can J Diabetes. 2013;37(suppl 1):S1-212.
- 50. Case studies: Carl What would you consider for Carl? Carl 42 years old Newly diagnosed with chronic kidney disease Private insurance coverage Diabetes duration 5 years Weight 92 kg BMI 29.4 kg/m2 Waist circumference 109 cm eGFR 64 ml/min A1C 7.6% FPG 7.2 mmol/L PPG 10.9 mmol/L Current treatment Metformin (1000 mg BID)
- 51. FAQs FAQs When & how to intensify insulin after basal insulin is initiated. How to help patients overcome injection barrier. Is there a cardiovascular risk with incretin therapies? Is there a pancreatitis risk with incretin therapies? Case examples - What would you consider for a patient with: Renal impairment for whom you are considering an incretin therapy Long-standing diabetes and high blood pressure currently on basal insulin Slightly elevated A1C currently on MET Long-standing diabetes on triple therapy of MET + SU + DPP-4 inhibitor Experiencing hypoglycemic episodes on MET + NPH Combining insulin and incretin
- 52. Case studies: Joan What would you consider for Joan? 71 years old Has had type 2 diabetes for 22 years Public insurance coverage Weight 70 kg BMI 27.3 kg/m2 Waist circumference 90 cm Blood Pressure 138/84 mm Hg A1C Joan 8.9% FPG 7.2 mmol/L PPG 11.9 mmol/L Current treatment Metformin (1000 mg BID) Gliclazide (80mg) Basal insulin (25 units) Statin
- 53. FAQs FAQs When & how to intensify insulin after basal insulin is initiated. How to help patients overcome injection barrier. Is there a cardiovascular risk with incretin therapies? Is there a pancreatitis risk with incretin therapies? Case examples - What would you consider for a patient with: Renal impairment for whom you are considering an incretin therapy Long-standing diabetes and high blood pressure currently on basal insulin Slightly elevated A1C currently on MET Long-standing diabetes on triple therapy of MET + SU + DPP-4 inhibitor Experiencing hypoglycemic episodes on MET + NPH Combining insulin and incretin
- 54. Case studies: Stephanie What would you consider for Stephanie? Stephanie 51 years old Newly diagnosed with type 2 diabetes Private insurance coverage Diabetes duration 6 months Weight 68 kg BMI 26.6 kg/m2 Waist circumference 101 cm A1C 7.5% FPG 8.7 mmol/L PPG 9.1 mmol/L Current treatment Metformin (1000 mg BID)
- 55. FAQs FAQs When & how to intensify insulin after basal insulin is initiated. How to help patients overcome injection barrier. Is there a cardiovascular risk with incretin therapies? Is there a pancreatitis risk with incretin therapies? Case examples - What would you consider for a patient with: Renal impairment for whom you are considering an incretin therapy Long-standing diabetes and high blood pressure currently on basal insulin Slightly elevated A1C currently on MET Long-standing diabetes on triple therapy of MET + SU + DPP-4 inhibitor Experiencing hypoglycemic episodes on MET + NPH Combining insulin and incretin
- 56. Case studies: George What would you consider for George? George 63 years old Has had diabetes for 7 years but recently has not been achieving his target A1C Public insurance coverage Diabetes duration 7 years Weight 83 kg BMI 27.7 kg/m2 Waist circumference 109 cm A1C 7.8% FPG 9.2 mmol/L PPG 10.4 mmol/L Current treatment Metformin (1000 mg BID) Sitagliptin (100mg QD) Glyburide (10mg QD)
- 57. FAQs FAQs When & how to intensify insulin after basal insulin is initiated. How to help patients overcome injection barrier. Is there a cardiovascular risk with incretin therapies? Is there a pancreatitis risk with incretin therapies? Case examples - What would you consider for a patient with: Renal impairment for whom you are considering an incretin therapy Long-standing diabetes and high blood pressure currently on basal insulin Slightly elevated A1C currently on MET Long-standing diabetes on triple therapy of MET + SU + DPP-4 inhibitor Experiencing hypoglycemic episodes on MET + NPH Combining insulin and incretin
- 58. Case studies: Tim What would you consider for Tim? Tim 65 years old Has recently been experiencing nocturnal hypoglycemia Public insurance coverage Diabetes duration 15 years Weight 88 kg BMI 27.2 kg/m2 Waist circumference 99 cm A1C 6.7% FPG 6.5 mmol/L PPG 8.4 mmol/L Current treatment Metformin (1000 mg BID) NPH (56 units)
- 59. FAQs FAQs When & how to intensify insulin after basal insulin is initiated. How to help patients overcome injection barrier. Is there a cardiovascular risk with incretin therapies? Is there a pancreatitis risk with incretin therapies? Case examples - What would you consider for a patient with: Renal impairment for whom you are considering an incretin therapy Long-standing diabetes and high blood pressure currently on basal insulin Slightly elevated A1C currently on MET Long-standing diabetes on triple therapy of MET + SU + DPP-4 inhibitor Experiencing hypoglycemic episodes on MET + NPH Combining insulin and incretin
- 60. Case studies: Andrea What would you consider for Andrea? Andrea 50 years old Currently taking metformin and GLP-1 RA Private insurance coverage Diabetes duration 4 years Weight 70 kg BMI 27.7 kg/m2 Waist circumference 101 cm A1C 7.7% FPG 8.1 mmol/L PPG 9.7 mmol/L Current treatment Metformin (1000 mg BID) GLP-1 RA
- 61. Adding-on insulin to GLP-1 receptor agonists A1C W eight Hypoglycemia BL 7.6% 0.286* -0.5% -0.05kg * vs. +0.02% * vs. -1.02kg events/ patientyear vs. 0.029 events/patient-year Metformin + Liraglutide 1.8 mg + Detemir Metforrmin + Liraglutide 1.8 mg *Significant difference. Liraglutide is not indicated for use with insulin in Canada. 1. DeVries et al. Diabetes Care 2012; 35(7):1446-54.
- 62. Adding-on GLP-1 receptor agonists to insulin A1C W eight Hypoglycemia BL 8.4% 1.4 -1.74% -1.8kg* * vs. -1.04% vs. +1.0kg events/ patientyear vs. 1.2 events/patient-year BID Exenatide + Glargine + Met +/- OAD BID Placebo + Glargine + Met +/- OAD *Significant difference. Liraglutide is not indicated for use with insulin in Canada. 1. Buse J et al. Ann Intern Med 2011; 154(2):103-12.
- 63. Incretin or insulin therapy: Which comes first? Reasons to start incretin before insulin: • Potential to delay need for insulin • No need to downwardly adjust established insulin dose • GLP-1 receptor agonist use may help to overcome phobias of insulin R • Lack of weight gain can help to offset weight gain associated with insulin • If nausea is a concern, tolerance is established before insulin is introduced Adapted from Vora et al. Diabetes & Metabolism 2013;39:6–15.
- 64. FAQs FAQs When & how to intensify insulin after basal insulin is initiated. How to help patients overcome injection barrier. Is there a cardiovascular risk with incretin therapies? Is there a pancreatitis risk with incretin therapies? Case examples - What would you consider for a patient with: Renal impairment for whom you are considering an incretin therapy Long-standing diabetes and high blood pressure currently on basal insulin Slightly elevated A1C currently on MET Long-standing diabetes on triple therapy of MET + SU + DPP-4 inhibitor Experiencing hypoglycemic episodes on MET + NPH Combining insulin and incretin
Notes de l'éditeur
- Notes to facilitator This slide must be visually presented to the audience AND verbalized by the speaker.
- Notes to facilitator This slide must be visually presented to the audience AND verbalized by the speaker.
- Notes to facilitator This slide must be visually presented to the audience AND verbalized by the speaker.
- Notes to facilitator List of the Steering Committee members who developed this program
- Notes to facilitator Read as per slide
- Notes to facilitator Jason’s case will be presented throughout this program (slides 7-43) Use his case to discuss appropriate treatment choices and next steps throughout his treatment continuum Metformin initiation 2nd line agent selection insulin initiation Rapid-acting insulin initiation can also be discussed in the FAQ section of the program (Slides 44-72)
- Notes to facilitator Use this slide to discuss an appropriate target for Jason. What factors influence your decision when choosing an A1C target for Jason? NOTE: The next slide details the criteria for individualized target selection outlined in the 2013 CDA guidelines
- Notes to facilitator In the 2008 guidelines, A1C ≤7% was the recommended target for patients with diabetes. Although in the 2013 guidelines this is no longer the case, A1C ≤7% is still the recommended target for MOST patients. Additionally, the 2013 guidelines have outlined specific criteria for individualizing target A1C. Like most patients, Jason’s A1C target should be ≤7%. A1C should be tested every 3 months in most individuals A1C testing can occur every 6 months in adults during periods of treatment and lifestyle stability when glycemic targets have been consistently achieved 2013 CDA Recommendations for glycemic targets: 1. Glycemic targets should be individualized based on age, duration of diabetes, risk of severe hypoglycemia, presence or absence of cardiovascular disease, and life expectancy [Grade D, Consensus]. 2. Therapy in most individuals with type 1 or type 2 diabetes should be targeted to achieve an A1C ≤7.0% in order to reduce the risk of microvascular [Grade A, Level 1A (1,2)] and, if implemented early in the course of disease, macrovascular complications [Grade B, Level 3 (22,23)]. 3. An A1C ≤6.5% may be targeted in some patients with type 2 diabetes to further lower the risk of nephropathy [Grade A, Level 1 (15)] and retinopathy [Grade A, Level 1 (24), but this must be balanced against the risk of hypoglycemia [Grade A, Level 1 (15)]. 4. Less stringent A1C targets (7.1%-8.5% in most cases) may be appropriate in patients with type 1 or type 2 diabetes with any of the following [Grade D, Consensus]: a) Limited life expectancy b) High level of functional dependency c) Extensive coronary artery disease at high risk of ischemic events d) Multiple comorbidities e) History of recurrent severe hypoglycemia f) Hypoglycemia unawareness g) Longstanding diabetes for whom it is difficult to achieve an A1C 7.0% despite effective doses of multiple antihyperglycemic agents, including Reference: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator Metformin can be initiated at diagnosis along with lifestyle modifications in the appropriate individuals The recommendation to use metformin as the initial agent in most patients is based on its effectiveness in lowering BG, its relatively mild side effect profile, its long-term safety track record, its negligible risk of hypoglycemia and its lack of causing weight gain. A1C targets help determine how soon metformin and other agents should be introduced/increased Discuss the course of action for Jason who has an initial A1C of 8.7% Reminder: Therapy should be adjusted to achieve A1C targets within 3-6 months; Key message: Start early to help patients achieve their targets as soon as possible NOTE: Initiation of 2nd line agent will be discussed later in this program BACK-UP information In people with type 2 diabetes, if glycemic targets are not achieved using lifestyle management within 2 to 3 months, antihyperglycemic agent therapy should be initiated [Grade A, Level 1A (3)]. Metformin may be used at the time of diagnosis, in conjunction with lifestyle management (Grade D, Consensus). If A1C 8.5%, antihyperglycemic agents should be initiated concomitantly with lifestyle management, and consideration should be given to initiating combination therapy with 2 agents, one of which may be insulin (Grade D, Consensus). Individuals with symptomatic hyperglycemia and metabolic decompensation should receive an initial antihyperglycemic regimen containing insulin [Grade D, Consensus]. Reference: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator Read as per slide
- Notes to facilitator Jason’s A1C is 7.8% (his target A1C is 7.0%) Remind audience: CDA recommends achieving glycemic targets within 3-6 months. The next slide shows the benefits of early A1C reductions NOTE: Use the following slides to guide participants through the 2nd line treatment selection process. At slide 25, there will be the opportunity to select the appropriate agent for Jason Reference: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator Use this slide to show the benefit early reductions in A1C can have. This slide highlights key findings from the UKPDS 351 In this trial, a 1% reduction in A1C was associated with a 21% risk of diabetes-related endpoints, diabetes-related mortality 12% risk of fatal/non-fatal stroke 14% risk of all-cause mortality and fatal/non-fatal MI 19% cataract extraction.1 37% risk reductions in microvascular complications including retinopathy, neuropathy, nephropathy, and peripheral vascular disease 16% risk of heart failure 43% risk of amputation/death PVD This supports the need to achieve glycemic control early, in order to prevent long-term diabetes complications Reference: Stratton IM et al. BMJ 2000;321:405-412. BACK-UP INFORMATION: OBJECTIVE: To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. DESIGN: Prospective observational study. Setting: 23 hospital based clinics in England, Scotland, and Northern Ireland. Participants: 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. OUTCOME MEASURES: Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA(1c) adjusted for possible confounders at diagnosis of diabetes.
- Notes to facilitator: This slide highlights key findings from the UKPDS In the 10-year follow-up of patients with type 2 diabetes, those treated with aggressive vs. conventional therapy had a greater reduction in multiple complications This demonstrates the positive impact that early and aggressive treatment can have in the long-term Reference: 1. Holman et al. NEJM. 2008;359:1577-89. BACK-UP INFORMATION INTRODUCTION During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes. METHODS: Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories.
- Notes to facilitator: Choosing which agent should be initiated after metformin from the multiple options available can challenging. This slide highlights the key characteristics highlighted by the 2013 CDA guidelines as important considerations. Along with A1C this slide presents other important considerations when choosing treatment including hypoglycemia and weight. The next couple of slides explain why hypoglycemia and weight are important. BACKGROUND INFORMATION:Choice of pharmacological treatment agents should be individualized, taking into consideration [Grade D, Consensus]: Patient characteristics: Degree of hyperglycemia Presence of comorbidities Patient preference and ability to access treatments Properties of the treatment: Effectiveness and durability of lowering BG Risk of hypoglycemia Effectiveness in reducing diabetes complications Effect on body weight Side effects Contraindications There is debate over which antihyperglycemic agent (including insulin) should be used initially and which agents should be added subsequently. There is also debate over which agents within a given class might be preferred in specific situations. Symptomatic patients with high BG and A1C levels require agents that lower BG levels substantially and quickly (e.g. insulin). However, the issue of how to reach glycemic targets may be less important than the need to achieve that target. Improved BG and A1C levels are associated with better outcomes, even if recommended glycemic targets cannot be reached (3). In deciding upon which agent to add after metformin, there must be consideration of multiple factors. First of all, the agent’s effectiveness at BG lowering must be considered in terms of both the degree of baseline hyperglycemia needing correction and any heightened concerns regarding hypoglycemia (e.g. elderly patients or those with renal or hepatic dysfunction). Multiple other agent-specific advantages and disadvantages should be weighed as treatment is individualized to best suit the patient’s needs and preferences. In particular, attention should be paid to the agent’s effects on body weight as this is a clinically relevant issue for many people with type 2 diabetes, and some agents cause significant weight gain while others can help to promote significant weight loss. GLP-1 receptor agonists are particularly effective at promoting concomitant glycemic control and weight reduction (45-48), but long-term efficacy and safety data are currently lacking for this class. Reference: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator Hypoglycemia is a burden for patients. Hypoglycemia has been associated with:1,2 Reduced QOL Reduced quantity/quality of sleep Impaired ability to drive Negative effects on interpersonal relationships Increased cardiovascular morbidity and mortality 85% of patients don’t report mild/moderate hypoglycemia to their doctors3 Key message: Risk of hypoglycemia is an important consideration for treatment selection References: Seaquist et al. Diabetes Care 2013;36:1384-1395. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212. Leiter, Yale et al. Can J Diabetes 2005; 29(3): 186-92.
- Notes to facilitator According to the CDA guidelines greater BMI is associated with a poorer quality of life 5-10% reduction in body weight is associated with increases in: Glycemic control Insulin sensitivity Lipid control Blood pressure control Key message: Weight control is an important consideration in the management of type 2 diabetes REFERENCE: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator: Although with the 2013 guidelines, the CDA has released multiple online interactive tools and guides to help physicians in the management of their patients with diabetes. Similarly to the following slide, there is an online tool to help individualize treatment selection according to agent and patient characteristics. guidelines.diabetes.ca is an active link to the website; only accessible when connected to internet.
- Notes to facilitator This table contains the drug classes available after metformin initiation. Based on a network meta-analysis allowing the comparison between classes that have not yet had direct head-to-head comparison in a randomized clinical trial, the relative BG and A1C lowering of the various antihyperglycemic agent classes when added to metformin is shown. Some of the other key considerations discussed earlier (weight, hypoglycemia risk, and cost) are also compared as per the 2013 CDA guidelines. The “Other considerations” column is depicted on slide 24. While using this interactive portion of the presentation keep in mind what factors are important to Jason when choosing an antihyperglycemic agent. Similarly to the online tool, this slide is interactive and allows you to reorder agents based on A1C, weight, hypoglycemia and cost by clicking on the respective icons (when in presentation mode). To return to presentation click on “” symbol. REFERENCE: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator This table contains the drug classes available after metformin initiation. Based on a network meta-analysis allowing the comparison between classes that have not yet had direct head-to-head comparison in a randomized clinical trial, the relative BG and A1C lowering of the various antihyperglycemic agent classes when added to metformin is shown. Some of the other key considerations discussed earlier (weight, hypoglycemia risk, and cost) are also compared as per the 2013 CDA guidelines. The “Other considerations” column is depicted on slide 24. Similarly to the online tool, this slide is interactive and allows you to reorder agents based on A1C, weight, hypoglycemia and cost by clicking on the respective icons (when in presentation mode). To return to presentation click on “” symbol. REFERENCE: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator This table contains the drug classes available after metformin initiation. Based on a network meta-analysis allowing the comparison between classes that have not yet had direct head-to-head comparison in a randomized clinical trial, the relative BG and A1C lowering of the various antihyperglycemic agent classes when added to metformin is shown. Some of the other key considerations discussed earlier (weight, hypoglycemia risk, and cost) are also compared as per the 2013 CDA guidelines. The “Other considerations” column is depicted on slide 24. Similarly to the online tool, this slide is interactive and allows you to reorder agents based on A1C, weight, hypoglycemia and cost by clicking on the respective icons (when in presentation mode). To return to presentation click on “” symbol. REFERENCE: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator This table contains the drug classes available after metformin initiation. Based on a network meta-analysis allowing the comparison between classes that have not yet had direct head-to-head comparison in a randomized clinical trial, the relative BG and A1C lowering of the various antihyperglycemic agent classes when added to metformin is shown. Some of the other key considerations discussed earlier (weight, hypoglycemia risk, and cost) are also compared as per the 2013 CDA guidelines. The “Other considerations” column is depicted on slide 24. Similarly to the online tool, this slide is interactive and allows you to reorder agents based on A1C, weight, hypoglycemia and cost by clicking on the respective icons (when in presentation mode). To return to presentation click on “” symbol. REFERENCE: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator This table contains the drug classes available after metformin initiation. Based on a network meta-analysis allowing the comparison between classes that have not yet had direct head-to-head comparison in a randomized clinical trial, the relative BG and A1C lowering of the various antihyperglycemic agent classes when added to metformin is shown. Some of the other key considerations discussed earlier (weight, hypoglycemia risk, and cost) are also compared as per the 2013 CDA guidelines. The “Other considerations” column is depicted on slide 24. Similarly to the online tool, this slide is interactive and allows you to reorder agents based on A1C, weight, hypoglycemia and cost by clicking on the respective icons (when in presentation mode). To return to presentation click on “” symbol. REFERENCE: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator This slide depicts the final column of the CDA guidelines table regarding key considerations for second-line therapies in the treatment of type 2 diabetes.
- Notes to facilitator Based on the previous slides, discuss what agent would be appropriate for Jason Consider: His A1C is above target (7.8%) His weight of 91 kg (BMI: 29.4) He works shifts and a set meal schedule is difficult He is concerned about hypoglycemic events Additionally, it may be important to further consider A1C efficacy, effects on Weight control, and risk of Hypoglycemia. Click the A1C, kg, and hypo icons to direct you to more information (slides 26, 27, 28, respectively).
- Notes to facilitator This meta-analysis compared antihyperglycemic agents as add-on to metformin. This graph depicts typical A1C reductions observed in clinical trials. GLP-1 receptor agonists and insulin have the greatest effect on A1C compared to other agents. REFERENCE: 1. Liu, Sung-Chen et al. Diab Obes & Metab 2012; 14:810-820. BACKGROUND INFORMATION: Aim: Most guidelines recommend metformin as first-line therapy in patients with type 2 diabetes. However, the choice of a second-line drug lacks consistent consensus. We aimed to assess available information of antidiabetic drugs added to metformin on the change in glycated haemoglobin A1c (A1C), risk of hypoglycaemia and change in body weight. Methods: PubMed and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) written in English through December 2011. We analysed direct and indirect comparisons of different treatments using Bayesian network meta-analysis. Results: Thirty-nine RCTs involving 17 860 individuals were included. Glucagon-like peptide-1 (GLP-1) analogues resulted in greater decrease in A1C compared with sulfonylureas, glinides, thiazolidinediones, α-glucosidase inhibitors and DPP-4 inhibitors [−0.20% (95% CI −0.34 to −0.04%), −0.31% (95% CI −0.61 to −0.02%), −0.20% (95% CI −0.38 to −0.00), −0.36% (95% CI −0.64 to −0.07%), −0.32% (95% CI −0.47 to −0.17%), respectively] and was comparable with basal insulin and biphasic insulin. A1C decrease was greater for sulfonylureas compared with DPP-4 inhibitors [−0.12% (−0.23 to −0.03%)], and for biphasic insulin compared with glinides (−0.36%; 95% CI −0.82 to −0.11%). Compared with placebo, the risk of hypoglycaemia was increased in the sulfonylureas, glinides, basal insulin and biphasic insulin. Weight increase was seen with sulfonylureas, glinides, thiazolidinediones, basal insulin and biphasic insulin, and weight loss was seen with α-glucosidase inhibitors and GLP-1 analogues. Conclusions: Biphasic insulin, GLP-1 analogues and basal insulin were ranked the top three drugs in terms of A1C reduction. GLP-1 analogues did not increase the risk of hypoglycaemia and resulted in a significant decrease in body weight. Most oral antidiabetic drugs had similar effects on A1C, but some agents had a lower risk of hypoglycaemia and body weight gain.
- Notes to facilitator This meta-analysis compared antihyperglycemic agents as add-on to metformin. This graph depicts typical weight effects observed in clinical trials. GLP-1 receptor agonists and alpha-glucosidase inhibitors have the greatest reduction in body weight compared to other agents which are weight neutral or can cause weight gain. REFERENCES: Liu, Sung-Chen et al. Diab Obes & Metab 2012; 14:810-820. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212. BACKGROUND INFORMATION (CDA GUIDELINES):2 “Multiple other agent-specific advantages and disadvantages should be weighed as treatment is individualized to best suit the patient’s needs and preferences. In particular, attention should be paid to the agent’s effects on body weight as this is a clinically relevant issue for many people with type 2 diabetes, and some agents cause significant weight gain while others can help to promote significant weight loss.” BACKGROUND INFORMATION:1 Aim: Most guidelines recommend metformin as first-line therapy in patients with type 2 diabetes. However, the choice of a second-line drug lacks consistent consensus. We aimed to assess available information of antidiabetic drugs added to metformin on the change in glycated haemoglobin A1c (A1C), risk of hypoglycaemia and change in body weight. Methods: PubMed and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) written in English through December 2011. We analysed direct and indirect comparisons of different treatments using Bayesian network meta-analysis. Results: Thirty-nine RCTs involving 17 860 individuals were included. Glucagon-like peptide-1 (GLP-1) analogues resulted in greater decrease in A1C compared with sulfonylureas, glinides, thiazolidinediones, α-glucosidase inhibitors and DPP-4 inhibitors [−0.20% (95% CI −0.34 to −0.04%), −0.31% (95% CI −0.61 to −0.02%), −0.20% (95% CI −0.38 to −0.00), −0.36% (95% CI −0.64 to −0.07%), −0.32% (95% CI −0.47 to −0.17%), respectively] and was comparable with basal insulin and biphasic insulin. A1C decrease was greater for sulfonylureas compared with DPP-4 inhibitors [−0.12% (−0.23 to −0.03%)], and for biphasic insulin compared with glinides (−0.36%; 95% CI −0.82 to −0.11%). Compared with placebo, the risk of hypoglycaemia was increased in the sulfonylureas, glinides, basal insulin and biphasic insulin. Weight increase was seen with sulfonylureas, glinides, thiazolidinediones, basal insulin and biphasic insulin, and weight loss was seen with α-glucosidase inhibitors and GLP-1 analogues. Conclusions: Biphasic insulin, GLP-1 analogues and basal insulin were ranked the top three drugs in terms of A1C reduction. GLP-1 analogues did not increase the risk of hypoglycaemia and resulted in a significant decrease in body weight. Most oral antidiabetic drugs had similar effects on A1C, but some agents had a lower risk of hypoglycaemia and body weight gain.
- Notes to facilitator This meta-analysis compared antihyperglycemic agents as add-on to metformin. This graph depicts the risk of hypoglycemia observed in clinical trials. Insulins, meglitinides, and sulphonylureas had statistically significantly greater risk of hypoglycemia compared to placebo. Alpha-glucosidase inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists and TZDs were not statistically significantly different from placebo. REFERENCE: 1. Liu, Sung-Chen et al. Diab Obes & Metab 2012; 14:810-820. BACKGROUND INFORMATION: Aim: Most guidelines recommend metformin as first-line therapy in patients with type 2 diabetes. However, the choice of a second-line drug lacks consistent consensus. We aimed to assess available information of antidiabetic drugs added to metformin on the change in glycated haemoglobin A1c (A1C), risk of hypoglycaemia and change in body weight. Methods: PubMed and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) written in English through December 2011. We analysed direct and indirect comparisons of different treatments using Bayesian network meta-analysis. Results: Thirty-nine RCTs involving 17 860 individuals were included. Glucagon-like peptide-1 (GLP-1) analogues resulted in greater decrease in A1C compared with sulfonylureas, glinides, thiazolidinediones, α-glucosidase inhibitors and DPP-4 inhibitors [−0.20% (95% CI −0.34 to −0.04%), −0.31% (95% CI −0.61 to −0.02%), −0.20% (95% CI −0.38 to −0.00), −0.36% (95% CI −0.64 to −0.07%), −0.32% (95% CI −0.47 to −0.17%), respectively] and was comparable with basal insulin and biphasic insulin. A1C decrease was greater for sulfonylureas compared with DPP-4 inhibitors [−0.12% (−0.23 to −0.03%)], and for biphasic insulin compared with glinides (−0.36%; 95% CI −0.82 to −0.11%). Compared with placebo, the risk of hypoglycaemia was increased in the sulfonylureas, glinides, basal insulin and biphasic insulin. Weight increase was seen with sulfonylureas, glinides, thiazolidinediones, basal insulin and biphasic insulin, and weight loss was seen with α-glucosidase inhibitors and GLP-1 analogues. Conclusions: Biphasic insulin, GLP-1 analogues and basal insulin were ranked the top three drugs in terms of A1C reduction. GLP-1 analogues did not increase the risk of hypoglycaemia and resulted in a significant decrease in body weight. Most oral antidiabetic drugs had similar effects on A1C, but some agents had a lower risk of hypoglycaemia and body weight gain.
- Notes to facilitator Jason has reached his A1C target of 7.0% using Your Treatment Choice.
- Notes to facilitator Jason remains on the same treatment for 4 ½ years Over time his diabetes has progressed and he has missed a few appointments His A1C is now above target
- Notes to facilitator When selecting a 3rd-line therapy, it may be useful to consider the patient and agent characteristics that were important when a 2nd-line agent was selected Given Jason’s higher A1C (8.1%) and 5 year duration of diabetes, might insulin be an appropriate option?
- Notes to facilitator This slide has an animation build: Ask attendees how strongly they agree or disagree with the statement “I prefer to delay insulin until it is absolutely necessary” Note: Individuals may have differing opinions on what “absolutely necessary” refers to. Consider discussing this. Note: Use this question to determine attendee comfort level with initiating insulin in their practice In the DAWN study: &gt;10 years ago, factors affecting insulin initiation were studied. On a scale of 1 to 6 (fully disagree 1 to fully agree 6) the average score for physicians delaying initiation of insulin therapy was 3.76 (closer to somewhat agree) Might a delay in insulin initiation prevent patients from achieving glycemic targets? BACK-UP information: Data are from the multinational Diabetes Attitudes, Wishes, and Needs (DAWN) study. All data are self-reports gathered during 2001 by structured interviews conducted face to face or by telephone The physician sample consisted of 2,705 respondents, with a quota of 250 per region, 200 in primary care and 50 specialists (endocrinologists and diabetologists with 2 years experience and treating 50 patients per month). Of this sample, 2,681 treated patients with type 2 diabetes and were used in the analyses The primary dependent variable for providers was insulin initiation delay (“I prefer to delay the initiation of insulin until it is absolutely essential”). Delay in prescribing oral blood glucose–lowering medication had the strongest relationship with delay in prescribing insulin. Providers tend to have a general orientation toward using glucose-lowering medications in managing diabetes. This orientation could reflect a lack of awareness about the need to keep glucose levels as close to normal as possible or it could reflect a more general orientation toward delayed prescribing of other medications for patients with diabetes or medications for other disorders. Clinical efficacy was the insulin-specific belief most strongly associated with provider inclination to delay insulin therapy. The scores on this measure were relatively low (just over half of physicians agreed that insulin can have a positive impact on care) Earlier introduction of insulin would reduce long-term costs of diabetes care; cost of insulin therapy is a barrier to effective management Many providers do not believe insulin can reduce the costs of diabetes care. References: 1. Peyrot et al. Diabetes Care. 2005;28:2673-2679.
- Notes to facilitator Previously, in the Canadian DICE study (Harris 2005): 12% of patients in family practice were on insulin 50% were reaching A1C 7% Use this slide to discuss how Canadian patients with type 2 diabetes are still not achieving target despite the increase in insulin initiation. Discuss with attendees why this may be; e.g.: Timing of initiation? (A1C level prior to initiation or duration of diabetes prior to initiation) Titration schedule? Maximum dose reached/maintained? Need for intensification with rapid-acting insulin? REFERENCE: 1. Leiter et al. Can J Diabetes. 2013;37:82-89. BACKGROUND INFORMATION: Objective: To gain insight into the current management of patients with type 2 diabetes mellitus by Canadian primary care physicians. Method: A total of 479 primary care physicians from across Canada submitted data on 5123 type 2 diabetes patients whom they had seen on a single day on or around World Diabetes Day, November 14, 2012. Results: Mean glycated hemoglobin (A1C) was 7.4%, low-density lipoprotein (LDL-C) was 2.1 mmol/L and blood pressure (BP) was 128/75 mm Hg. A1C 7.0% was met by 50%, LDL-C 2.0 mmol/L by 57%, BP &lt;130/80 mm Hg by 36% and the composite triple target by 13% of patients. Diet counselling had been offered to 38% of patients. Of the 87% prescribed antihyperglycemic agents, 18% were on 1 non-insulin antihyperglycemic agent (NIAHA) (85% of which was metformin), 15% were on 2 NIAHAs, 6% were on 3 NIAHAs, 19% were on insulin only and 42% were on insulin + ≥1 NIAHA(s). Amongst the 81% prescribed lipid-lowering therapy, 88% were on monotherapy (97% of which was a statin). Among the 83% prescribed antihypertensive agents, 39%, 34%, 21% and 6% received 1, 2, 3 and &gt;3 drugs, respectively, with 59% prescribed angiotensin-converting enzyme inhibitors and 35% angiotensin II receptor blockers. Conclusions: The Diabetes Mellitus Status in Canada survey highlights the persistent treatment gap associated with the treatment of type 2 diabetes and the challenges faced by primary care physicians to gain glycemic control and global vascular protection in these patients. It also reveals a higher use of insulin therapy in primary care practices relative to previous surveys. Practical strategies aimed at more effectively managing type 2 diabetes patients are urgently needed.
- Notes to facilitator Discuss Jason’s needs and ways to address them. Which basal insulin can be chosen? Long-acting analogues (detemir, glargine) may be considered instead of intermediate-acting (neutral protamine Hagedorn and insulin isophane) to give patients a better shot of achieving glycemic control by reducing the risk of nocturnal and symptomatic hypoglycemia.1,2 Insulin analogues have less weight gain than NPH. Insulin detemir also has less weight gain compared to insulin glargine.1,3 BACKGROUND INFORMATION on weight:3 Study duration: 20 weeks; +0.7 kg for insulin detemir once-daily vs. +1.6 kg for NPH insulin Study duration: 26 weeks; +1.2 kg for insulin detemir twice-daily vs. +2.8 kg for NPH insulin Study duration: 52 weeks; +2.3 kg for insulin detemir once-daily vs. +3.7 kg for insulin detemir twice-daily vs. +4.0 kg for insulin glargine (p&lt;0.02) REFERENCES: Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2013;37(suppl 1):S1-212. Cheng AYY. The rule of 3’s: Insulin use in type 2 diabetes. Canadian Diabetes. Spring 2011;24:3-9. Levemir product Monograph. Novo Nordisk Canada: 2011.
- Notes to facilitator A long-acting insulin analogue (detemir, glargine) may be considered as an alternative to an intermediate-acting as the basal insulin or NPH , to reduce the risk of hypoglycemia including nocturnal hypoglycemia. The reasoning is that basal analogues have more stable profiles, with less pronounced peaks. Key message: Insulin analogues are associated with a longer duration of action, reduced variability, lower hypoglycemic risk and a less pronounced peak versus NPH insulin.
- Notes to facilitator Insulin degludec is an ultra-long-acting once-daily basal insulin analogue. 4x lower day-to-day variability:1,2 This study examined the day-to-day variability in glucose-lowering effect at steady state of ultra-long-acting insulin degludec vs. insulin glargine in 54 subjects. The primary endpoint was the within-subject variability in the area under the GIR (glucose infusion rate) curve during one dosing interval (0–24 h) at steady state (AUCGIR,0-24h,SS). For insulin degludec, the day-to-day variability in glucose-lowering effect was four-times lower than for insulin glargine (AUCGIR,0-24h,SS, CV 20% vs. 82%), indicating that degludec has a significantly more predictable glucose-lowering effect from day to day than glargine which in term may impact risk of hypoglycemia. Long terminal half-life and extended duration of action:1,3 The pharmacokinetic and pharmacodynamic properties of insulin degludec were compared with insulin glargine under steady-state conditions in 66 patients with type 1 diabetes in this randomized, double-blind, two-period crossover trial. Patients with type 1 diabetes received one of three fixed doses (0.4, 0.6 or 0.8 U/kg) of insulin degludec and insulin glargine once daily for 8 days with 7–21 days wash-out between treatments. The mean terminal half-life was shown to be twice as long for insulin degludec vs. insulin glargine (25.4 vs. 12.5 h), resulting in a more evenly distributed and stable pharmacokinetic profile for insulin degludec at steady state. NOTE: Terminal half-life is the time required for the plasma concentration of a drug to decrease 50% in the final stage of elimination. For terminal half-life, it is recommended that harmonic mean (the average of a set of numbers) is used rather than arithmetic mean. The duration of action was observed to extend beyond 42 hours. Lower risk of nocturnal hypoglycemia in type 2 and type 1 diabetes:4,6 36% lower risk vs. insulin glargine in T2DM OBJECTIVE To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs). RESEARCH DESIGN AND METHODS In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7−10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9−4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis. RESULTS In all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI −0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG &lt;3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels &lt;7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar. CONCLUSIONS Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec. 25% lower risk vs. insulin glargine in T1DM A 52-week, randomized, active-controlled, treat-to-target, non-inferior, open-label, multicentre trial comparing the efficacy and safety of insulin degludec and insulin glargine in patients with type 1 diabetes mellitus (N=629). Patients were randomized to receive once-daily insulin degludec or insulin glargine in a basal-bolus regimen with mealtime insulin aspart. Basal insulin was titrated in a treat-to-target approach to an FPG goal of 3.9-4.9 mmol/L. Bolus doses were titrated to achieve glucose target of 3.9-4.9 mmol/L before the subsequent meal. The primary outcome was A1C. A1C treatment difference (insulin degludec OD - insulin glargine OD [95% CI]): -0.01[-0.14; 0.11] Low volume:5 OBJECTIVE: The 200 units/mL formulation of insulin degludec (IDeg 200 units/mL) contains equal units of insulin in half the volume compared with the 100 units/mL formulation. We compared the efficacy and safety of IDeg 200 units/mL once daily with 100 units/mL insulin glargine (IGlar) in insulin-naïve subjects with type 2 diabetes (T2DM) inadequately controlled with oral antidiabetic drugs. RESEARCH DESIGN AND METHODS: In this 26-week, open-label, treat-to-target trial, subjects (n = 457;mean HbA1c 8.3% [67 mmol/mol], BMI 32.4 kg/m2, and fasting plasma glucose [FPG] 9.6mmol/L [173.2 mg/dL]) were randomized to IDeg 200 units/mL or IGlar, both given once daily in combination with metformin with or without a dipeptidyl peptidase-4 inhibitor. Basal insulin was initiated at 10 units/day and titrated weekly to an FPG target of &lt;5 mmol/L (&lt;90 mg/dL) according to mean prebreakfast self-measured blood glucose values from the preceding 3 days. RESULTS: By 26 weeks, IDeg reduced HbA1c by 1.30% and was not inferior to IGlar. Mean observed FPG reductions were significantly greater with IDeg than IGlar (23.7 vs. 23.4 mmol/L [–67 vs. –61 mg/dL]; estimated treatment difference: 20.42 [95% CI 20.78 to 20.06], P = 0.02). Despite this difference, rates of overall confirmed hypoglycemia were not higher with IDeg than with IGlar (1.22 and 1.42 episodes/patient-year, respectively), as were rates of nocturnal confirmed hypoglycemia (0.18 and 0.28 episodes/patient-year, respectively). Mean daily basal insulin dose was significantly lower by 11% with IDeg 200 units/mL compared with IGlar. IDeg was well-tolerated, and the rate of treatment-emergent adverse events was similar across groups. CONCLUSIONS: In this treat-to-target trial in insulin-naïve patients with T2DM, IDeg 200 units/mL improved glycemic control similarly to IGlar with a low risk of hypoglycemia. KEY MESSAGE: With a lower volume, more insulin units can be injected in a single dose (up to 160 units), without the need to split the dose between injection sites References: Keating GM. Drugs. 2013 Apr 26 [Epub ahead of print]. Heise T, Hermanski L, Nosek L et al. Diabetes Obes Metab. 2012;14(9):859-64. Heise T, Nosek L, Bottcher SG et al. Diabetes Obes Metab. 2012;14(10):944-50. Zinman B, Philis-Tsimikas A, Cariou B, et al. Diabetes Care. 2012;35(12):2464-71. Gough SC, Bhargava A, Jain R et al. Diabetes Care. 2013 May 28 [Epub ahead of print]. Heller S, Buse J, Fisher M, et al. Insulin degludec, an ultra-long acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes. Lancet. 2012;379(9825):1489-1497
- Notes to facilitator This slide outlines some key considerations when initiating basal insulin including injection, titration, minimizing hypoglycemia and weight considerations. Also consider setting up your diabetes support team Assembling a diabetes support team could include some or all of these health care professionals: Physician Nurse Diabetes educator Pharmacist Dietitian Social workers and counselors Mental health experts Physical activity experts Eye care and foot care professionals External nursing support Pharmacy technician Reference: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator Most antihyperglycemic agents can be combined with basal insulin with the exception of TZDs When trying to achieve glycemic targets, remember, there is no maximum dose of insulin Titrate dose to achieve glycemic targets EARLY Reference: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator Jason has private insurance coverage and initiates a basal insulin analogue with 10 units once-daily and he continues use of his current medications. He is instructed to titrate 1 unit every night until his FPG is 4 - 7 mmol/L Frequency of SMBG The recommended frequency of SMBG must be individualized to each person’s unique circumstances. Factors influencing this recommendation will include type of diabetes, type of therapy, adequacy of glycemic control, literacy and numeracy skills, propensity to hypoglycemia, awareness of hypoglycemia, occupational requirements and acute illness. Type 1 and type 2 treated with insulin For people with type 1 diabetes, SMBG is an essential daily activity. In a large cohort study, performance of 3 self-tests per day was associated with a statistically and clinically significant 1.0% absolute reduction in A1C. The evidence is less certain in people with type 2 diabetes treated with insulin, although the above principles likely apply. In a large, nonrandomized study of individuals with stable type 2 diabetes using insulin, testing at least 3 times a day was associated with improved glycemic control. More frequent testing, including preprandial and 2-hour postprandial PG and occasional nocturnal BG measurements, is often required to provide the information needed to reduce hypoglycemia risk, including unrecognized nocturnal hypoglycemia. REFERENCE: 1. CDA Guidelines. Can J Diabetes. 2013;37(suppl 1):S1-S212
- Notes to facilitator This logbook is representative of Jason’s initial titration schedule of 10+1+1 With this in mind Jason should be able to achieve his target within 6 weeks Reminder: The optimal goal is to reach his target A1C of ≤7% within 3 to 6 months.1 A1C can be re-checked at 3 months FPG values between 4 to 7 mmol/L and PPG values between 5 to 10 mmol/L will give an A1C of ≤7%. It is important to note, that when A1C &gt;7%, PPG values between 5 to 8 mmol/L will be required to reach target. Remember, it may be important to intensify in order to reach A1C target. With timely adjustments to and/or additions of antihyperglycemic agents or insulin, an A1C level of ≤7% should be attainable.1 REFERENCE: 1. CDA Guidelines. Can J Diabetes. 2013;37(suppl 1):S1-S212
- Notes to facilitator Jason has achieved his A1C target of 7.0% with 20 units of insulin He continues to take metformin, Your Treatment Choice and a basal insulin analogue Jason can maintain this insulin dose as long as his A1C target is met. Consider discussing next steps: Follow-up appointments to check A1C Follow-up appointments to check other important parameters
- Notes to facilitator The 2013 CDA guidelines provide guidance on how to individualize targets and treatments for patients with type 2 diabetes. Reminders: A target of A1C ≤7% is appropriate for most patients with diabetes; use the interactive CDA online tool to easily determine if a particular patient should have a different target Target A1C should be achieved EARLY (within 3 to 6 months) If A1C &gt;8.5%, Metformin should be initiated at diagnosis with lifestyle modifications and initiation of a second-line agent can be considered If A1C &lt;8.5%, Metformin initiation can be considered at diagnosis with lifestyle modifications When selecting a second-line agent, consider both patient and agent characteristics. Key considerations include: A1C level / blood glucose lowering effect Current weight / effect of agent on weight Risk of hypoglycemia Coverage Consider utilizing the online CDA tool to rank the agents according to patient needs. Reference: 1. CDA. Can J Diabetes. 2013;37(suppl 1):S1-S212.
- Notes to facilitator Review the objectives that were set out to learn
- Notes to facilitator Ask your audience to select the questions that they want to cover. Once they have selected a question, simply click on the appropriate link in presentation mode. You will be link directly to the section that addresses the selected question or case. This slide will appear after each &quot;answer/case&quot;, to allow the audience to select the next question. Speakers are not required to go through ALL questions (time-dependent). Simply select the ones that are pertinent to the audience.
- Notes to facilitator Type 2 diabetes is characterized by insulin resistance and progressive beta-cell failure1-3 As beta-cell function declines, treatment will need to be adjusted and intensified in order to maintain glycemic control1-3 This image is a representative depiction of the natural history of type 2 diabetes mellitus highlighting the role of insulin resistance, insulin deficiency, and impaired incretin effect. Both the time course and relative function are descriptive. These 3 core pathophysiologic defects likely combine to contribute to the progressive nature of the disease, and may account for much of the deterioration in glucose control observed clinical in patients with type 2 diabetes.3 BACKGROUND INFORMATION:3 Impaired insulin secretion and β-cell dysfunction, insulin resistance, obesity and an impaired incretin effect all play a role in the pathogenesis and progression of type 2 diabetes. Understanding the interplay among these factors should enable clinicians to select the most appropriate therapy or therapies for the individual patient with type 2 diabetes. Studying the natural history of type 2 diabetes, it is clear that in response to insulin resistance, β-cells will secrete additional insulin, and the insulin levels will initially increase. This increase in insulin secretion actually still represents a relative deficiency of insulin because, as can be seen in the graph, early in the course of the natural history of type 2 diabetes, β-cell function starts to deteriorate. The existence of impaired β-cell function is a necessary and sufficient condition for the appearance of prediabetes and the onset of frank diabetes. The graph shows that at the onset of diabetes (when insulin secretion no longer keeps pace with insulin resistance), there is already a significant reduction in β-cell function. By the time diabetes is clinically diagnosed (often 10 years after the onset of diabetes according to the UKPDS), β-cell function may be reduced by ≥50%. β-Cell impairment is now recognized to arise and worsen years before the onset of diabetes and its initial manifestation of postprandial hyperglycemia. References: CDA Guidelines. Can J Diabetes. 2013;37(suppl 1):S1-212. Ross SA. Canadian Diabetes August 2011: 5-17 Kendall DM et al. Am J Med. 2009;122(6)(suppl 6A):S37-S50.
- Notes to facilitator Given that PPG contributes more to A1C than FPG as A1C approaches 7; if A1C &gt;7%, but FPG is &lt;7 mmol/L, mealtime insulin should be initiated. Initiation can be simple and started at just one meal. 4 units is a safe starting dose. Note that with time, many patients will require prandial insulin at more than 1 meal. Emphasize that the pre-meal blood glucose used to adjust dose is the pre-meal blood glucose at the meal following the meal when insulin is given. (i.e., if prandial insulin is given at lunch, adjust dose based on the pre-dinner blood glucose; if prandial insulin is given at dinner, adjust dose based on pre-bedtime blood glucose). Reference: 1. Meneghini et al. Endocr Pract. 2011;17(5):727-36.
- Notes to facilitator Use this example to illustrate mealtime insulin dose adjustment. Slide is animated. On June 21st, Jenny takes 4 units of mealtime insulin at lunch. Her pre-dinner (next meal) blood glucose reading is 8 mmol/L 8 mmol/L is above the target her physician has set for her (4 – 7 mmol/L) She adds one unit to her meal the next day On June 22nd, Jenny takes 5 units of mealtime insulin at lunch. Her pre-dinner (next meal) blood glucose reading is 6 mmol/L 6 mmol/L is within the target her physician has set for her (4 – 7 mmol/L) She maintains the same dose the next day NOTE: basal insulin dose remains constant in this example
- Notes to facilitator Ask your audience to select the questions that they want to cover. Once they have selected a question, simply click on the appropriate link in presentation mode. You will be link directly to the section that addresses the selected question or case. This slide will appear after each &quot;answer/case&quot;, to allow the audience to select the next question. Speakers are not required to go through ALL questions (time-dependent). Simply select the ones that are pertinent to the audience.
- Notes to facilitator Use the tips on this slide to help overcome injection barriers. Key points: Communicate the needles are very thin and short Demonstrate the injection in office to overcome their fear
- Notes to facilitator Ask your audience to select the questions that they want to cover. Once they have selected a question, simply click on the appropriate link in presentation mode. You will be link directly to the section that addresses the selected question or case. This slide will appear after each &quot;answer/case&quot;, to allow the audience to select the next question. Speakers are not required to go through ALL questions (time-dependent). Simply select the ones that are pertinent to the audience.
- Notes to facilitator According to FDA guidance for cardiovascular risk assessment: the upper-bound 95% confidence interval criterion for cardiovascular risk should not exceed 1.8 This slide highlights findings from meta-analyses of incretin therapy pivotal trials, assessing cardiovascular risk None of the upper bound 95% Cis appear to surpass the 1.8 limit These findings are not conclusive, but rather directional and are pending the results of larger outcome trials Reference: Johansen O-E., et al. Cardiovascular Diabetology. 2011;11:3;doi:10.1186/1475-2840-11-3 Frederich R, et al. Postgrad Med. 2010;122(3):16–27. Williams-Herman D, et al. BMC Endocr Disord. 2010;10:7. Ratner R, et al. Cardiovascular Diabetology. 2011;10:22. www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4422b2-01-FDA.pdf - Accessed Sept. 23, 2011. FDA. Guidance for Industry. Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071627.pdf
- Notes to facilitator This is a list of all the current large, controlled, long-term outcome studies which are underway for each of the different incretin therapies, which specifically looks at potential cardiovascular risk, if any, associated with incretin therapies. The SAVOR-TIMI 53 trial has failed to demonstrate the superiority of saxagliptin over placebo in reducing a composite end point of cardiovascular death, nonfatal MI, or nonfatal ischemic stroke when added to usual care in patients with type 2 diabetes with either a history of established CVD or multiple CVD risk factors. The preliminary results have demonstrated non-inferiority. Results are expected in the fall of 2013.
- Notes to facilitator Ask your audience to select the questions that they want to cover. Once they have selected a question, simply click on the appropriate link in presentation mode. You will be link directly to the section that addresses the selected question or case. This slide will appear after each &quot;answer/case&quot;, to allow the audience to select the next question. Speakers are not required to go through ALL questions (time-dependent). Simply select the ones that are pertinent to the audience.
- Notes to facilitatorThis slide demonstrates that patients with type 2 diabetes are at an elevated risk of pancreatitis.1 Incretin therapies have also been associated with pancreatitis; while causality has not been established, incretin therapies should not be used in patients with a history of pancreatitis It may be important to consider the other factors which may contribute to an increased pancreatitis risk BACKGROUND INFORMATION:The trial by Garg et al was a retrospective cohort study of a large medical and pharmacy claims database. Data for 785,656 patients were analyzed. Cox proportional hazard models were designed to assess the risk of acute pancreatitis between nondiabetic and diabetic patients as well as exenatide, sitagliptin and control medication use.1 The incidence of acute pancreatitis was 1.9, 5.6, 5.7 and 5.6 cases per 1,000 patient years for nondiabetic, diabetic, exenatide and sitagliptin patients respectively. The risk of acute pancreatitis was 2.1 for the combined diabetic group vs. nondiabetic group. Risk of acute pancreatitis was similar between patients treated with exenatide and sitagliptin.1 The incidence of acute pancreatitis for liraglutide was assessed independently from the Garg et al trial and was 2.2 vs. 0.6 cases per 1000 patient years.2 The risk of pancreatitis with linagliptin is estimated to be 1.9 vs. 0.0 for placebo3 Reference: Garg R et al. Diabetes Care 2010;33:2359-54. Liraglutide Canadian Product Monograph, Novo Nordisk Canada Inc., 2011. Linagliptin Canadian Product Monograph, Boehringer Ingelheim (Canada) Ltd., 2011. Exenatide Canadian Product Monograph, Eli Lilly Canada, 2011.
- Notes to facilitator Ask your audience to select the questions that they want to cover. Once they have selected a question, simply click on the appropriate link in presentation mode. You will be link directly to the section that addresses the selected question or case. This slide will appear after each &quot;answer/case&quot;, to allow the audience to select the next question. Speakers are not required to go through ALL questions (time-dependent). Simply select the ones that are pertinent to the audience.
- Notes to facilitator Use this case presentation to take attendees through the treatment selection process again (similarly to Jason). Consider: Appropriate A1C target Patient and treatment characteristics Current medications A1C, weight, risk of hypoglycemia, coverage In this particular case, you are considering an incretin agent for Carl As always consider A1C, weight and risk of hypoglycemia However, Carl’s stage 2 kidney disease is important factor when deciding on which incretin agent to choose The next slide contains recommendations for use of incretin agents depending on renal function. The slide following is this slide repeated for discussion on agent selection
- Notes to facilitator This slide gives an overview of the use of incretin therapies in patients with renal impairment. Many incretin therapies listed are currently “not recommended” for use in patients with moderate to severe renal impairment, however, much of this was based on a lack of clinical experience assessing the efficacy of these agents in this population. “Not recommended” does not mean contraindicated, and these recommendations should be individualized to each patient. BACKGROUND INFORMATION: Exenatide: Spontaneous report of altered renal function (increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring hemodialysis or kidney translantation. Some events occurred in patients receiving one or more pharmacologic agents known to affect renal function or hydration status such as ACE inhibitors, NSAIDs or diuretics. Some events occurred in patients who had been experiencing nausea, vomiting or diarrhea with or without dehydration. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents including exenatide. Since exenatide may induce nausea and vomiting with transient hypovolemia, which may worsen renal function, caution should be applied when initaiting or escalating doses of exenatide from 5ug to 10ug in moderate renal impairment (creatinine clearance 30-50 mL/min). Exenatide should be used in caution in patients with renal transplantation. Liraglutide: There is limited clinical experience with liraglutide in patients with mild renal insufficiency. There is very limited or no clinical experience in patients with moderate and severe renal insufficiency, including end-stage renal disease; use of liraglutide in these patients is not recommended Linagliptin: A multiple-dose, open-label study was conducted to evaluate the pharmacokinetics of linagliptin (5 mg dose) in patients (n=6 in each group) with mild and moderate renal impairment compared to subjects with normal renal function. A single-dose pharmacokinetic study of linagliptin was conducted in patients with severe renal impairment (n=6) and End Stage Renal Disease (n=6). The studies included patients with renal impairment classified on the basis of creatinine clearance as mild (50 to 80 mL/min), moderate (30 to 50 mL/min), and severe (&lt;30 mL/min), as well as patients with End Stage Renal Disease (ESRD) on hemodialysis. In addition, patients with T2DM and severe renal impairment (n=10) were compared to T2DM patients with normal renal function (n=11) in a multiple-dose study. Even though the PK studies did not show clinically relevant effects of severe renal impairment with T2DM, there is lack of clinical experiences in this population to support the long term safety. Therefore, use in this population, with severe renal impairment and ESRD, is not recommended. Saxagliptin:The experience in patients with severe renal impairment is very limited. Saxagliptin should be used with caution in patients with severe renal impairment, and is not recommended for use in patients with end-stage renal disease (ESRD) requiring hemodialysis. Sitagliptin: To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, dosage recommendations are as follows: For patients with mild renal insufficiency (creatinine clearance [CrCl] 50 mL/min), no dosage adjustment for sitagliptin is required. For patients with moderate renal insufficiency (CrCl 30 to &lt;50 mL/min), the dose of sitagliptin is 50 mg once daily. For patients with severe renal insufficiency (CrCl &lt;30 mL/min) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the timing of dialysis. Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of sitagliptin and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. When considering the use of sitagliptin in combination with another anti-diabetic product, its conditions for use in patients with renal impairment should be followed REFERENCES: Exenatide Canadian Product Monograph, Eli Lilly Canada, 2011. Liraglutide Canadian Product Monograph, Novo Nordisk Canada, 2010. Linagliptin Canadian Product Monograph, Boehringer Ingelheim (canada) Ltd., 2011. Saxagliptin Canadian Product Monograph, Bristol Myers Squibb/Astra Zeneca, 2011. Sitagliptin Canadian Product Monograph, Merck Frosst, 2013. CDA Guidelines. Can J Diabetes. 2013;37(suppl 1):S1-212.
- Notes to facilitator Now that you are aware of what agents can be selected based on renal function discuss which incretin agent would be appropriate for Carl
- Notes to facilitator Ask your audience to select the questions that they want to cover. Once they have selected a question, simply click on the appropriate link in presentation mode. You will be link directly to the section that addresses the selected question or case. This slide will appear after each &quot;answer/case&quot;, to allow the audience to select the next question. Speakers are not required to go through ALL questions (time-dependent). Simply select the ones that are pertinent to the audience.
- Notes to facilitator Use this case presentation to take attendees through the treatment selection process again (similarly to Jason). Consider: Appropriate A1C target Patient and treatment characteristics Current medications A1C, weight, risk of hypoglycemia, coverage In this particular case, Joan is currently on: Metformin 1000 mg BID Gliclazide 80 mg Basal insulin (25 units) Statin Attendees may consider: What is the appropriate A1C target Would mealtime insulin initiation be appropriate? If so, Starting dose & meal Pre-meal target Other medications When to check How to adjust the dose Book follow-up & next A1C Note: If bolus (mealtime) insulin is added at dinner, a decrease in basal insulin dose may need to be considered based on FPG. What should be done with Joan’s oral agents? Metformin should be continued, unless there is a contraindication to its use. The combination of metformin with insulin reduces insulin dose requirements and lessens weight gain; there was even a suggestion of cardiovascular benefit.2 Insulin secretagogues (sulfonylurea or meglitinides) can be continued when only basal insulin is used; however, discontinuation of SUs once bolus insulin is introduced (either as a basal + bolus regimen or as a premixed regimen), will reduce the risk of hypoglycemia.
- Notes to facilitator Ask your audience to select the questions that they want to cover. Once they have selected a question, simply click on the appropriate link in presentation mode. You will be link directly to the section that addresses the selected question or case. This slide will appear after each &quot;answer/case&quot;, to allow the audience to select the next question. Speakers are not required to go through ALL questions (time-dependent). Simply select the ones that are pertinent to the audience.
- Notes to facilitator Use this case presentation to take attendees through the treatment selection process again (similarly to Jason). Consider: Appropriate A1C target Patient and treatment characteristics Current medications A1C, weight, risk of hypoglycemia, coverage In this particular case, Stephanie’s A1C is 7.5% How would you decide an appropriate A1C target for Stephanie? What factors influence your decision? What agent would you choose for Stephanie? What are your considerations?
- Notes to facilitator Ask your audience to select the questions that they want to cover. Once they have selected a question, simply click on the appropriate link in presentation mode. You will be link directly to the section that addresses the selected question or case. This slide will appear after each &quot;answer/case&quot;, to allow the audience to select the next question. Speakers are not required to go through ALL questions (time-dependent). Simply select the ones that are pertinent to the audience.
- Notes to facilitator Use this case presentation to take attendees through the treatment selection process again (similarly to Jason). Consider: Appropriate A1C target Patient and treatment characteristics Current medications A1C, weight, risk of hypoglycemia, coverage In this particular case, consider asking participants whether they would: Add basal insulin Switch DPP-4 for a GLP-1 RA Increase lifestyle modifications Other Why? For patients initiating basal insulin discuss: Whether adjustments to current agents are needed Demonstrate the injection Discuss titration schedule Discuss other important considerations (i.e., weight and hypoglycemia) For patients switching to a GLP-1 RA: Whether adjustments to current agents are needed Demonstrate the injection Discuss other important considerations (i.e., weight and hypoglycemia) BACKGROUND INFORMATION: OBJECTIVE: To assess the efficacy and safety of switching from sitagliptin to liraglutide in metformin-treated adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: In an open-label trial, participants randomized to receive either liraglutide (1.2 or 1.8 mg/day) or sitagliptin (100 mg/day), each added to metformin, continued treatment for 52 weeks. In a 26-week extension, sitagliptin-treated participants were randomly allocated to receive instead liraglutide at either 1.2 or 1.8 mg/day, while participants originally randomized to receive liraglutide continued unchanged. RESULTS: Although 52 weeks of sitagliptin changed glycosylated hemoglobin (HbA1c) by 20.9% from baseline, additional decreases occurred after switching to liraglutide (1.2 mg/day, 20.2%, P = 0.006; 1.8 mg/day, 20.5%, P = 0.0001). Conversion to liraglutide was associated with reductions in fasting plasma glucose (FPG) (1.2 mg/day,20.8 mmol/L, P = 0.0004; 1.8mg/day, 21.4 mmol/L, P , 0.0001) and body weight (1.2 mg/day, 21.6 kg; 1.8 mg/day, 22.5 kg; both P , 0.0001) and with an increased proportion of patients reaching HbA1c ,7% (from; 30%to; 50%). Overall treatment satisfaction, assessed by the Diabetes Treatment Satisfaction Questionnaire, improved after switching to liraglutide (pooled 1.2 and 1.8 mg/day, 1.3; P = 0.0189). After switching, mostly transient nausea occurred in 21% of participants, and minor hypoglycemia remained low (3–4% of participants). Continuing liraglutide treatment at 1.2 mg/day and 1.8 mg/day for 78 weeks reduced HbA1c (baseline 8.3 and 8.4%, respectively) by 20.9 and 21.3%, respectively; FPG by 21.3 and21.7mmol/L, respectively; and weight by 22.6 and 23.1 kg, respectively, with 9–10% of participants reporting minor hypoglycemia. CONCLUSIONS: Glycemic control, weight, and treatment satisfaction improved after switching from sitagliptin to liraglutide, albeit with a transient increase in gastrointestinal reactions. REFERENCE Pratley RE et al, Diabetes Care 2012;35:1986-93.
- Notes to facilitator Ask your audience to select the questions that they want to cover. Once they have selected a question, simply click on the appropriate link in presentation mode. You will be link directly to the section that addresses the selected question or case. This slide will appear after each &quot;answer/case&quot;, to allow the audience to select the next question. Speakers are not required to go through ALL questions (time-dependent). Simply select the ones that are pertinent to the audience.
- Notes to facilitator Use this case presentation to take attendees through the treatment selection process again (similarly to Jason). Consider: Appropriate A1C target Patient and treatment characteristics Current medications A1C, weight, risk of hypoglycemia, coverage In this particular case, consider discussing: The potential impact of reducing Tim’s dose (i.e., would he maintain target?, would he experience less hypoglycemic episodes?) Alternative options (i.e., Would switching to a basal analogue help maintain target with less hypoglycemia?) How to switch from NPH to a basal insulin analog (1 unit to 1 unit)
- Notes to facilitator Ask your audience to select the questions that they want to cover. Once they have selected a question, simply click on the appropriate link in presentation mode. You will be link directly to the section that addresses the selected question or case. This slide will appear after each &quot;answer/case&quot;, to allow the audience to select the next question. Speakers are not required to go through ALL questions (time-dependent). Simply select the ones that are pertinent to the audience.
- Notes to facilitator Use this case presentation to take attendees through the treatment selection process again (similarly to Jason). Consider: Appropriate A1C target Patient and treatment characteristics Current medications A1C, weight, risk of hypoglycemia, coverage In this particular case, what would you do? Stop GLP-1 receptor agonist. Start basal insulin Stop GLP-1 receptor agonist. Start DPP-4 inhibitor Add basal insulin to GLP-1 receptor agonist + metformin Add DPP-4 inhibitor to GLP-1 receptor agonist + metformin Discuss the expected A1C change, weight effects and hypoglycemia for the choices assuming Andrea is currently on metformin +GLP-1 Should you add-on, or switch the 2nd agent for one of these choices? If added-on, does the choice of 3rd agent choice depend on 2nd agent? Or does it depend on treatment goals, side effects, patient characteristics?
- Notes to facilitator This slide outlines the changes in A1C, weight and hypoglycemia when insulin is added to GLP-1 RA therapy. Note: Patients were initially on liraglutide 1.8 mg + metformin for 12 weeks. After 12 weeks, patients not achieving A1C &lt;7% (baseline: 7.6%) were randomized to continue the same treatment or ADD insulin detemir. An additional reduction of 0.5% was observed for the group that added insulin detemir. BACKGROUND INFORMATION: In 988 participants uncontrolled on metformin ± sulfonylurea, sulfonylurea was discontinued and liraglutide 1.8 mg/day added for 12 weeks (run-in). Subsequently, those with A1C ≥7% were randomized 1:1 to 26 weeks’ open-label addition of insulin detemir to metformin + liraglutide (n = 162) or continuation without insulin detemir (n = 161). Patients achieving A1C &lt;7% continued unchanged treatment (observational arm). The primary end point was A1C change between randomized groups. Of 821 participants completing the run-in, 61% (n = 498) achieved A1C &lt;7% (mean change −1.3% from 7.7% at start), whereas 39% (n = 323) did not (−0.6% from 8.3% at start). During run-in, 167 of 988 (17%) withdrew; 46% of these due to gastrointestinal adverse events. At week 26, A1C decreased further, by 0.5% (from 7.6% at randomization) with insulin detemir (n = 162) versus 0.02% increase without insulin detemir (n = 157) to 7.1 and 7.5%, respectively (estimated treatment difference −0.52 [95% CI −0.68 to −0.36]; P &lt; 0.0001). Forty-three percent of participants with insulin detemir versus 17% without reached A1C &lt;7%. Mean weight decreased by 3.5 kg during run-in, then by 0.16 kg with insulin detemir or 0.95 kg without insulin detemir. In the randomized phase, no major hypoglycemia occurred and minor hypoglycemia rates were 0.286 and 0.029 events per participant-year with and without insulin detemir (9.2 vs. 1.3%). REFERENCE: 1. DeVries et al. Diabetes Care 2012; 35(7):1446-54.
- Notes to facilitator This slide outlines the changes in A1C, weight and hypoglycemia when a GLP-1 RA is added to insulin therapy. Note: patients were already on insulin glargine (baseline 8.4%) when they initiated exenatide 10 µg twice daily BACKGROUND INFORMATION: The primary objective was to determine whether exenatide injection, 10 µg twice daily, was superior to placebo, as measured by change in HbA1c level, in participants with type 2 diabetes who were receiving insulin glargine with or without metformin or pioglitazone (or both agents). At randomization, participants with HbA1c levels greater than 8.0% continued to receive their current insulin glargine dose; those with HbA1c levels of 8.0% or less decreased their dose by 20%. These doses were maintained for 5 weeks, after which participants began titration to achieve a fasting glucose level less than 5.6 mmol/L (&lt;100 mg/dL), on the basis of the Treat-to-Target Trial algorithm Note: direct comparisons between Buse 2011 and DeVries 2012 should not be made due to different baseline characteristics, comparators, and medications REFERENCE: 1. Buse J et al. Ann Intern Med 2011; 154(2):103-12.
- Notes to facilitator This slide outlines reasons for starting incretin before insulin
- Notes to facilitator Ask your audience to select the questions that they want to cover. Once they have selected a question, simply click on the appropriate link in presentation mode. You will be link directly to the section that addresses the selected question or case. This slide will appear after each &quot;answer/case&quot;, to allow the audience to select the next question. Speakers are not required to go through ALL questions (time-dependent). Simply select the ones that are pertinent to the audience.