Diabetes and Chronic Kidney Disease DR. JEREMY GILBERT, MD FRCPC ASSISTANT PROFESSOR, U OF T

Size: px

Start display at page:

Download "Diabetes and Chronic Kidney Disease DR. JEREMY GILBERT, MD FRCPC ASSISTANT PROFESSOR, U OF T"

Francine Heath
6 years ago
Views:

1 Diabetes and Chronic Kidney Disease DR. JEREMY GILBERT, MD FRCPC ASSISTANT PROFESSOR, U OF T

2 Objectives Recognize the impact that CKD has on diabetes management Review the current Canadian Diabetes Association Guidelines as they relate to Nephropathy Outline the risks and benefits of the latest insulin therapies

3 Canadian Diabetes Association Clinical Practice Guidelines Chronic Kidney Disease in Diabetes Chapter 29 (Updated July 2015) Phil McFarlane, Richard E. Gilbert, Lori MacCallum, Peter Senior 2015 diabetes.ca BANTING ( )

4 Chronic Kidney Disease (CKD) Checklist 2013 SCREEN regularly with random urine albumin creatinine ratio (ACR) and serum creatinine for estimated glomerular filtration rate (egfr) DIAGNOSE with repeat confirmed ACR 2.0 mg/mmol and/or egfr <60 ml/min DELAY onset and/or progression with glycemic and blood pressure control and ACE-inhibitor or Angiotensin Receptor Blocker (ARB) PREVENT complications with sick day management counselling and referral when appropriate

5 Patients with DM 6-12X more likely to be hospitalized for CKD or End-stage renal disease (ESRD) Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).

6 Diabetes is #1 Cause of New Cases of ESRD Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).

7 2013 ACR 2.0 mg/mmol CKD in Diabetes and / or egfr <60 ml/min

8 Stages of Diabetic Nephropathy Note: change in definition of microalbuminuria ACR 2.0 mg/mmol 2013

9 Beware of Transient Albuminuria

11 Screening and diagnosis of diabetic nephropathy

14 2013

17 2

18 Beware of Other Causes of CKD

19 When to Consider Other Causes of CKD

20 Prevention of Diabetic Nephropathy Optimal glycemic control in type 1 and type 2 diabetes has been shown to reduce the development and progression of nephropathy (see next slides)

21 DCCT: Reduction in Albuminuria Primary Prevention Secondary Intervention 34% RRR (p<0.04) 43% RRR (p=0.001) 56% RRR (p=0.01) Solid line = risk of developing microalbuminuria Dashed line = risk of developing macroalbuminuria RRR = relative risk reduction CI = confidence interval The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329: guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

22 EDIC: Continued Reduction in Albuminuria Return to normoalbuminuria Macroalbuminuria HR 1.92 (p<0.05) HR 0.64 (95% CI ) HR = hazard ratio CI = confidence interval deboer IH et al. Arch Intern Med 2011;171(5): guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

23 EDIC: Early Glycemic Control Reduces Long-term Risk of Impaired GFR Risk reduction with intensive therapy 50% (95% CI 18-69; p=0.006) DCCT/EDIC Research Group. N Engl J Med 2011;365:

24 UKPDS: Post-trial Monitoring Legacy Effect After median 8.5 years post-trial follow-up Aggregate Endpoint Any diabetes related endpoint RRR: 12% 9% P: Microvascular disease RRR: 25% 24% P: Myocardial infarction RRR: 16% 15% P: All-cause mortality RRR: 6% 13% P: Holman R, et al. N Engl J Med 2008;359. guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

ADVANCE: Primary Microvascular Outcomes 25 New/worsening nephropathy, retinopathy Cumulative incidence (%) 20 15 10 HR 0.86 (0.77-0.97) p = 0.

25 ADVANCE: Primary Microvascular Outcomes 25 New/worsening nephropathy, retinopathy Cumulative incidence (%) HR 0.86 ( ) p = 0.01 Standard control 5 0 Follow-up (months) Intensive control Intensive Standard HR p Nephropathy/retinopathy (%) Nephropathy (%) Retinopathy (%) NS Adapted from: ADVANCE Collaborative Group. N Engl J Med 2008;358: ADVANCE Collaborative Group. N Engl J Med 2008;358:24.

26 Reducing Progression of Diabetic Nephropathy Optimal glycemic control (as shown) Optimal blood pressure control ACE-inhibitor (ACEi) or Angiotensin Receptor Blocker (ARB) guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

27 ACE-inhibitor in T1DM with MAU Reduces Progression to Clinical Proteinuria Proportion with Event Laffel LM et al. Am J Med 1995;99(5): guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association Months of Therapy

29 Incidence of diabetic nephropathy (%) ARB in T2DM with MAU reduces progression Primary endpoint: Time to onset of diabetic nephropathy* (n=590) Follow-up (months) *defined by persistent albuminuria in overnight specimens, with urinary albumin excretion rate <200 μg/min and 30% higher than baseline level Parving et al. N Engl J Med 2001;345:870-8 guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association Placebo Irbesartan 150mg Irbesartan 300mg

30 ARB in T2DM with Macroalbuminuria Reduces Renal Outcomes Primary endpoint: Time to doubling of serum creatinine, ESRD, or death (n=1513) Cumulative % of patients with event Risk reduction = 16% p=0.02 Placebo Losartan Months Brenner et al. N Engl J Med 2001;345:861-9 guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

31 ARB in T2DM with Macroalbuminuria Reduces Renal Outcomes Primary endpoint: Time to doubling of serum creatinine, ESRD, or death (n=1,715) Irbesartan Amlodipine Placebo RRR 23% p=0.006 p=ns RRR 20% p=0.02 Patients (%) Lewis et al. N Engl J Med 2001;345: Follow-up (mo) 60

32 Counsel all Patients About Sick Day Medication List 2015

33 Insulin Secretagogues CKD Stage: egfr (ml/min/1.73 m 2 ): < Alpha-glucosidase Inhibitor GLP-1R agonists Antihyperglycemic agents and Renal Function Biguanide DPP-4 inhibitors Acarbose Not recommended 25 Canagliflozin mg 60* Dapagliflozin 60 Empagliflozin 45 Thiazolidinediones 30 Adapted from: Product Monographs as of March 2016 Harper W et al. Can J Diabetes 2015;39:440. Metformin Alogliptin Not recommended 6.25 mg mg 50 Linagliptin 15 Saxagliptin mg 50 Sitagliptin 25 mg mg 50 Albiglutide 50 Dulaglutide 50 Exenatide (BID/QW) Liraglutide Gliclazide/Glimepiride SGLT2 inhibitors Glyburide Repaglinide Contraindicated Not recommended 60* Caution and/or reduce dose Safe * = do not initiate if egfr <60 ml/min 2016

34 When to Refer.. Chronic, progressive loss of kidney function ACR persistently >60 mg/mmol egfr <30 ml/min Unable to remain on renal-protective therapies due to adverse effects such as hyperkalemia or a >30% increase in serum Cr within 3 months of starting ACEi or ARB Unable to achieve target BP (could be referred to any specialist in hypertension) guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

35 Types of Insulin 2016 Insulin Type (trade name) Onset Peak Duration Bolus (prandial) Insulins Rapid-acting insulin analogues (clear): Insulin aspart (NovoRapid ) Insulin glulisine (Apidra ) Insulin lispro (Humalog ) Insulin lispro U200 (Humalog 200 units/ml) min min min min h h 1-2 h 1-2 h 3-5 h 3-5 h h h Short-acting insulins (clear): Insulin regular (Humulin -R) Insulin regular (Novolin getoronto) 30 min 2-3 h 6.5 h Basal Insulins Intermediate-acting insulins (cloudy): Insulin NPH (Humulin -N) Insulin NPH (Novolin ge NPH) 1-3 h 5-8 h Up to 18 h Long-acting basal insulin analogues (clear) Insulin detemir (Levemir ) Insulin glargine (Lantus ) Insulin glargine U300 (Toujeo ) Insulin glargine (Basaglar TM ) 90 min 90 min Up to 6 h 90 min Not applicable Up to 24 h (detemir h) Up to 24 h (glargine 24 h) Up to 30 h Up to 24 h (glargine 24 h)

36 Types of Insulin (continued) Insulin Type (trade name) Premixed Insulins Premixed regular insulin NPH (cloudy): 30% insulin regular/ 70% insulin NPH (Humulin 30/70) 30% insulin regular/ 70% insulin NPH (Novolin ge 30/70) 40% insulin regular/ 60% insulin NPH (Novolin ge 40/60) 50% insulin regular/ 50% insulin NPH (Novolin ge 50/50) Time action profile A single vial or cartridge contains a fixed ratio of insulin (% of rapid-acting or short-acting insulin to % of intermediate-acting insulin) Premixed insulin analogues (cloudy): 30% Insulin aspart/70% insulin aspart protamine crystals (NovoMix 30) 25% insulin lispro / 75% insulin lispro protamine (Humalog Mix25 ) 50% insulin lispro / 50% insulin lispro protamine (Humalog Mix50 )

37 Desired Properties for a Basal Insulin Relative to Existing Basal Insulins Clinical needs Reduced risk of hypoglycemia Positive weight profile Increased flexibility Glycemic control Achieve and maintain good glycemic control with favorable safety profile More consistent (no peaks and troughs) and prolonged profile PK/PD profile Duration: steady 24 hour blood glucose control Low intra- and inter-individual variability Shah VN et al. Diabetes Technol Ther 2013;15:

38 Basal Insulin Therapy: a Historical Overview Protamine/ zinc Isophane (NPH) Lente insulin Lantus/ Glargine 100 U/mL Levemir/ Detemir * Not yet approved in Canada Tresiba/ Degludec* Toujeo/ Glargine 300 U/mL

39 Insulin Degludec Long-acting basal insulin currently approved in Europe, Japan and other markets. Not available in Canada and the USA. PK, pharmacokinetic; PD, pharmacodynamic Upon subcutaneous injection forms soluble and stable multi-hexamers, that allow slow and continuous absorption into the circulation Owens et al. Diabetes Metab Res Rev. 2014;30: ; Shah et al. Diabetes Tech & Ther. 2013;15(9): Press release: Accessed December 15, 2014.

40 Glycemic Control and Weight Change Similar A1C reduction vs. insulin glargine 100 U/ml (GLA-100) 1,3-6 Greater end-of-trial reduction in FPG compared to GLA-100 in T2D insulin-naïve patients (P<0.05) and numerically (but not significantly) greater in basal-bolus treated T2D 2 Similar weight changes vs. insulin GLA Owens et al. Diabetes Metab Res Rev. 2014;30: ; 2. Vora et al. Diabetes Ther DOI /s ; 3. Garber AJ et al. Lancet. 2012;379: ; 4. Zinman B et al. Diabetes Care. 2012;35: ; 5. Gough SCL et al. Diabetes Care. 2013; 36: ; 6. Onishi Y et al. J Diabetes Investig. 2013; 4 (6):

41 Reduced OVERALL Hypoglycemia Rates with Insulin Degludec vs. Insulin Glargine 100 U/ml (GLA-100) Meta-analysis of Phase 3a Trials in Overall T2D Population Estimated Rate Ratio Reduction (%) OVERALL Confirmed (BG <3.1 mmol/l ) or Severe Hypoglycemia Entire treatment period RR: 0.83 * ( ) Titration period RR: 0.92 ( ) Maintenance period RR: 0.75 * ( ) * Significant RR, rate ratio Clinical Implications Ratner RE et al. Diab Obes Metab. 2013;15: From pooled overall T2D population across entire treatment period: For every 3 subjects initiated and treated with degludec instead of GLA-100 for 1 year, 1 overall confirmed episode will be avoided

42 Reduced NOCTURNAL Hypoglycemia Rates with Insulin Degludec vs. Insulin Glargine 100 U/ml (GLA-100) Meta-analysis of Phase 3a Trials in Overall T2D Population Estimated Rate Ratio Reduction Nocturnal Confirmed (BG <3.1 mmol/l ) or Severe Hypoglycemia Entire treatment period RR: 0.68 * ( ) Titration period RR: 0.81 ( ) Maintenance period RR: 0.62 * ( ) * Significant RR, rate ratio Clinical Implications From pooled overall T2D population across entire treatment period: For every 8 subjects initiated and treated with degludec instead of GLA-100 for 1 year, 1 nocturnal confirmed episode will be avoided Ratner RE et al. Diab Obes Metab. 2013;15:

43 Safety of Insulin Degludec Similar rates of other adverse events were observed between insulin degludec and insulin glargine 100 U/ml across all T2D phase 3a studies FDA has requested a long term cardiovascular study Pooled hazard ratio estimates (degludec or degludec/aspart versus active control) for confirmed major adverse cardiovascular events (MACE) in phase 3 trials as reported in meta-analyses Dataset Original dataset, MACE+ (including unstable angina) Updated dataset, MACE+ (including unstable angina) Original dataset, MACE (excluding unstable angina) Updated dataset, MACE (excluding unstable angina) Hazard ratio (95% CI) Total number of subjects with MACE (N=total patients exposed) 1.10 (0.68 to 1.77) 80 (N=8,959) 1.30 (0.88 to 1.93) 132 (N=9,255) 1.39 (0.76 to 2.57) 54 (N=8,959) 1.67 (1.01 to 2.75) 91(N=9,255) Owens et al. Diabetes Metab Res Rev. 2014;30: ; Kalra S. Diabetes Ther. 2013;4: ; FDA Rejects Novo Nordisk's Insulin Degludec. Medscape. Feb 11, 2013; FDA Rejects Novo Nordisk's Insulin Degludec. Medscape. Feb 11, 2013; Degludec FDA Briefing Document: Accessed Jan 19, 2015; Degludec Novo Nordisk Briefing Document: Accessed Jan 19, 2015

44 Summary: Insulin Degludec Insulin degludec vs. insulin glargine 100 U/ml exhibited: o Glycemic Control: Similar glycemic efficacy, as defined by A1c when assessed over a period of 6-12 months. Numerically (but not significantly) greater reduction in FPG. o Weight Change: Similar weight changes o Hypoglycemia: Significantly lower rates of overall and nocturnal confirmed (<3.1 mmol/l) and/or severe hypoglycemia o Other safety: Long term cardiovascular safety study ongoing Insulin degludec is approved and marketed in USA, Japan, Europe and other markets. Not available in Canada

Insulin Glargine 300 U/mL: A New Long-acting Basal Insulin 1/3 of the volume Reduction of depot surface by 1/2 Same amount of units 100 U/mL 300 U/mL 100 U/mL 300 U/mL Insulin glargine 300 U/mL

45 Insulin Glargine 300 U/mL: A New Long-acting Basal Insulin 1/3 of the volume Reduction of depot surface by 1/2 Same amount of units 100 U/mL 300 U/mL 100 U/mL 300 U/mL Insulin glargine 300 U/mL contains insulin glargine Insulin glargine 300 U/mL is metabolized the same way as insulin glargine 100 U/mL Becker RHA et al. Diabetes Care. 2015;38: ; Steinstraesser A et al. Diabetes Obes Metab. 2014;16:

46 More constant glucose profile with Insulin Glargine 300 U/mL vs 100 U/mL CGM Study T1D 300 U/mL 100 U/mL 11 Morning injection 11 Evening injection Average glucose profiles, mean (SE), mmol/l Time, h Combined (morning and evening injection groups) Time, h Mean glucose profiles more constant with insulin glargine 300 U/mL compared with insulin glargine 100 U/mL, independent from the time of injection (morning or evening) Time, h Bergenstal RM et al. Poster presentation at EASD 2014; Abstract 949

EDITION Program: Phase III Trials Comparing Insulin Glargine 300 U/mL vs 100 U/mL EDITION 1* N=807 BB Basal

Basal Insulin Naive Basal insulin plus OAD SU) and/or GLP-1 receptor agonists EDITION JP 2 N=241 BOT Basal

Phase III, age of participants 18 years, randomization ratio 1:1 BB, basal-bolus therapy; BOT, basal only

diabetes mellitus, T1D type 1 diabetes mellitus, * in EDITION 1 and EDITION 2, people being treated with

b) Yki-Järvinen H et al. Diabetes Care. 2014;37(12):3235-43. c) Bolli GB et al. Diabetes Obes Metab.

47 EDITION Program: Phase III Trials Comparing Insulin Glargine 300 U/mL vs 100 U/mL EDITION 1* N=807 BB Basal insulin plus mealtime bolus insulin (fast-acting analogue) T2D EDITION 2* N=811 BOT Basal insulin plus OAD (excl. SU) T1D EDITION 4 N=549 BB Basal insulin plus mealtime bolus insulin (fast-acting analogue) EDITION 3 N=878 Basal Insulin Naive Basal insulin plus OAD (excl. SU) and/or GLP-1 receptor agonists EDITION JP 2 N=241 BOT Basal insulin plus OAD EDITION JP 1 N=243 BB Basal insulin plus mealtime bolus insulin (fast-acting analogue) All Phase III, age of participants 18 years, randomization ratio 1:1 BB, basal-bolus therapy; BOT, basal only therapy; GLP-1, glucagon-like peptide-1; OAD, oral antihyperglycemic drug; SU, sulfonylurea T2D type 2 diabetes mellitus, T1D type 1 diabetes mellitus, * in EDITION 1 and EDITION 2, people being treated with basal insulin 42U/day were recruited a) Riddle MC et al. Diabetes Care. 2014;37(10): b) Yki-Järvinen H et al. Diabetes Care. 2014;37(12): c) Bolli GB et al. Diabetes Obes Metab. 2015;17(4): d) Home PD et al. Diabetes Care. 2015; Published ahead of print: doi: /dc e) Matsuhisa M et al. poster presented at ADA 2014; abstract 88 -LB. f) Terauchi Y et al. Poster presented ADA 2014; abstract 94-LB

EDITION Study Design is Consistent Across the Program Randomized 1:1, open-label, parallel-group, multinational studies EDITION program has similar design across studies

A1C reduction at Month 6 Main secondary endpoint*: Confirmed or severe nocturnal hypoglycemia OAD, oral antihyperglycemic agents; *Incidence (%) of participants with at

2014;37(10):2755-62. b) Yki-Järvinen H et al. Diabetes Care. 2014;37(12):3235-43. c) Bolli GB et al. Diabetes Obes Metab. 2015;17(4):386-394. d) Home PD et al.

48 EDITION Study Design is Consistent Across the Program Randomized 1:1, open-label, parallel-group, multinational studies EDITION program has similar design across studies Participants Randomized (1:1) Glargine 300 U/mL ± OADs ± mealtime insulin Glargine 100 U/mL ± OADs ± mealtime insulin 6 months 6-month Extension period Primary endpoint: A1C reduction at Month 6 Main secondary endpoint*: Confirmed or severe nocturnal hypoglycemia OAD, oral antihyperglycemic agents; *Incidence (%) of participants with at least one confirmed ( 3.9 mmol/l) or severe nocturnal (00:00 05:59) hypoglycemia from Week 9 to Month 6 (Edition 1, 2, 3) a) Riddle MC et al. Diabetes Care. 2014;37(10): b) Yki-Järvinen H et al. Diabetes Care. 2014;37(12): c) Bolli GB et al. Diabetes Obes Metab. 2015;17(4): d) Home PD et al. Diabetes Care. 2015; Published ahead of print: doi: /dc e) Matsuhisa M et al. poster presented at ADA 2014; abstract 88 -LB. f) Terauchi Y et al. Poster presented ADA 2014; abstract 94-LB

49 EDITION Study Design Across the Program (Cont d) Compared against insulin glargine 100 U/mL (gold standard) In T1D and T2D populations: o T2D: Titrated to fasting SMBG target of mmol/l o T1D: Titrated to fasting SMBG mmol/l Representative of T2D population (high BMI and long duration of diabetes) Closely supervised titration scheme 49 a) Riddle MC et al. Diabetes Care. 2014;37(10): b) Yki-Järvinen H et al. Diabetes Care. 2014;37(12): c) Bolli GB et al. Diabetes Obes Metab. 2015;17(4): d) Home PD et al. Diabetes Care. 2015; Published ahead of print: doi: /dc e) Matsuhisa M et al. poster presented at ADA 2014; abstract 88 -LB. f) Terauchi Y et al. Poster presented ADA 2014; abstract 94-LB

50 EDITION T2D Pooled Analysis A1C T2D Difference between groups (6 months)* 0.00% (95% CI to 0.07) Mean ± SE A1C, % U/mL 100 U/mL Baseline Week 12 Month 6 Visit Modified intent-to treat population; * Mean Similar reductions in A1C Ritzel R et al. Diab Obes Metab 2015 Apr 30. doi: /dom

51 EDITION T2D Pooled Analysis Glycemic Control Over 12 Months T2D Significantly Lower A1C with insulin glargine 300 U/mL vs 100 U/mL at month 12 A1C (%) mean ± SE U/mL 300 U/mL BL W12 M6 LS mean difference (95% CI) between groups in change from baseline to 1 year 0.10 ( 0.18 to 0.02) % P= M9 M A1C (mmol/mol) mean ± SE 100 U/mL n= U/mL n= Ritzel et al., Abstract presented at 75 th American Diabetes Association congress (2015) abstract 1030-P

52 EDITION T2D Pooled Analysis Percentage of Participants Reporting 1 Hypoglycemic Event Hypoglycemia at any time (24 h) T2D Participants with 1 confirmed* or severe hypoglycemia, % 100 Participants, % RR 0.91 (95% CI ) RR 0.83 (95% CI ) RR 0.92 (95% CI ) U/mL (n=1,242) 100 U/mL (n=1,246) 20 0 Baseline to Month 6 Baseline to Week 8 Week 9 to Month 6 *Confirmed, 3.9 mmol/l RR, relative risk; Clinical Implications From pooled T2D population across entire treatment period: For every 15 subjects initiated and treated with glargine 300 U/mL instead of glargine 100 U/mL, 1 less patient will have confirmed or severe hypoglycemia at any time (24 h) Ritzel R et al. Diab Obes Metab 2015 Apr 30. doi: /dom

53 EDITION T2D Pooled Analysis Percentage of Participants Reporting 1 Hypoglycemic Event: Nocturnal Hypoglycemia Participants with 1 confirmed* or severe hypoglycemia, % T2D U/mL (n=1,242) 100 U/mL (n=1,246) Participants, % RR 0.75 (95% CI ) RR 0.69 (95% CI ) RR 0.80 (95% CI ) *Confirmed, 3.9 mmol/l Nocturnal, 00:00 05:59 h RR, relative risk 0 Baseline to Month 6 Baseline to Week 8 Week 9 to Month 6 Clinical Implications From pooled T2D population across entire treatment period: For every 10 subjects initiated and treated with glargine 300 U/mL instead of glargine 100 U/mL, 1 less patient will have nocturnal confirmed or severe hypoglycemia Ritzel R et al. Diab Obes Metab 2015 Apr 30. doi: /dom

54 Higher Glargine 300 U/mL Doses at Month 6 T2D T2D studies EDITION 1 BB EDITION 2 BOT switch EDITION 3 BOT start EDITION JP 2 BOT switch Mean weight (kg) Mean insulin dose 300 U/mL Mean insulin dose 100 U/mL Relative difference for 300 U/mL vs 100 U/mL (%) a) Riddle MC et al. Diabetes Care. 2014;37(10): b) Yki-Järvinen H et al. Diabetes Care. 2014;37(12): c) Bolli GB et al. Diabetes Obes Metab. 2015;17(4): d) Terauchi Y et al. Poster presented ADA 2014; abstract 94-LB

55 Less Weight Gain with Insulin Glargine 300 U/mL vs 100 U/mL at Month 6 T2D EDITION 1 BB EDITION 2 BOT switch EDITION 3 BOT start EDITION JP 2 BOT switch 1.5 Weight change from baseline, kg ,9 (3.2) 0,9 (3.1) 0,1 (3.5) 0,7 (3.0) 0,4 (3.8) 0,7 (3.8) -0,6 (2.0) 100 U/mL 300 U/mL 0,3 (2.2) (±SD) a) Riddle MC et al. Diabetes Care. 2014;37(10): b) Yki-Järvinen H et al. Diabetes Care. 2014;37(12): c) Bolli GB et al. Diabetes Obes Metab. 2015;17(4): d) Terauchi Y et al. Poster presented ADA 2014; abstract 94-LB

56 Insulin Glargine Safety Cardiovascular and cancer safety Health Canada & FDA satisfied with CV safety Insulin glargine 300 U/mL has the same metabolism as glargine 100 U/mL (M1 metabolite), extensive safety data available for glargine 100 U/mL (CV and cancer safety) expect to see the same profile for glargine 300 U/mL

57 Insulin Glargine 300 U/mL: Initiation and Switch Protocols for Patients with T2D Initiation 0.2 U/kg once daily Changeover Protocol Insulin glargine 300 U/mL once daily From insulin glargine 100 U/mL (Lantus ) OD or BID Change unit-to-unit (same dose) A higher daily insulin glargine 300 U/mL dose may be needed to achieve target ranges for plasma glucose level. From other basal insulins OD Change unit-tounit (same dose) From other basal insulins BID The recommended initial dose is 80% of the total daily dose of basal insulin that is being discontinued TOUJEO SoloSTAR. Product Monograph. May 2015

58 Insulin Glargine 300 U/mL in Comparison to 100 U/mL: Summary More constant and prolonged PK/PD profile Less glycemic variability Comparable A1C reduction in the treat-to-target RCT setting Lower risk of confirmed hypoglycemia (mostly nocturnal) even during the initial treatment period in T2D Similar hypoglycemic risk in T1D Flexibility with either am or pm dosing (confirmed in EDITION 4 and CGM) and within a ± 3 hours window (confirmed in EDITION 1 and 2) Higher dose of glargine 300 U/mL required compared to 100 U/mL Slightly lower or similar weight gain Similar overall safety and tolerability The same metabolism as insulin glargine 100 U/mL (M1) supporting long-term CV safety and cancer data Steinstraesser A et al. Diabetes Obes Metab. 2014;16:873-6; Becker RH et al. Diabetes Care. 2015;38(4): Becker RH et al. Diabetes Obes Metab. 2015;17:261-7; Bergenstal RM et al. Poster presentation at EASD 2014; Abstract 949; Riddle MC et al. Diabetes Care. 2014;37: ; Yki-Järvinen H et al. Diabetes Care. 2014;37: ; Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94; Terauchi Y et al. Poster presentation at EASD 2014; Abstract 976; Jeandidier N et al. Poster presentation at EASD 2014; Abstract 961; Home PD et al. Diabetes Care. 2015; Published ahead of print: doi: /dc ; Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975.

59 What is a Subsequent Entry Biologic (SEB)? A subsequent entry biologic (SEB) is a biologic molecule that is highly similar to an existing biologic medication 1,2 Has the same amino acid sequence as the reference product 1,2 Does not necessarily have the same 3-dimensional structure, safety, dosing, efficacy and certain other properties as the reference product 1,2 1. Fact Sheet: Subsequent Entry Biologics. Health Canada.

60 What is the Difference Between a Biosimilar and a Generic? Generics Copies of small molecule medicinal products derived from chemical manufacturing processes 1 Identical chemical structures to those of already marketed products 1 Biosimilars Similar versions of biological medicinal products derived from biotechnological manufacturing processes 1 Amino acid sequence should be identical to the reference product 2 Differences in biotechnological manufacturing processes between companies mean that biosimilar products cannot be described as identical 1,3 1. Sekhon BS, Saluja V. Biosimilars 2011;1:1 11; 2. EMA. Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Quality Issues (Revision 1). 2012; 3. Owens DR et al. Diabetes Technol Ther 2012;14:

61 SEB Health Canada Approval Requirements Health Canada approval process for SEBs requires completion of Phase I and Phase III clinical trials Phase II clinical trials are omitted because the goal is to establish that there are no clinically meaningful differences in the safety and efficacy of SEBs when compared to their reference products Analytical testing Biological assays Non-clinical data Clinical data The approval process for SEBs is more similar to the approval process for new molecules than for generic drugs.

62 PK Profiles of LY IGlar vs. EU IGlar* Mean (± SD) C-peptide-corrected Serum Insulin Concentration Relative to Time Mean C-peptide-corrected Insulin Concentration (pmol/l) *Healthy subjects PK=pharmacokinetic; SD=standard deviation Linnebjerg et al. Diab Care 2015; 38(12): Cmax Peak drug concentration after administration of dose AUC Area under the curve indicates drug exposure Time (hour) LY IGlar EU IGlar *IGlar=Lantus insulin glargine LY IGlar=LY insulin glargine EU=European Union-approved

63 PD Profiles of LY IGlar vs. EU IGlar* Mean (± SD) Glucose Infusion Rate (Top) and Corresponding Blood Glucose Levels (Bottom) Mean Glucose Infusion Rate (mg/kg/min) Mean Blood Glucose (mmol/l) Time (hour) LY IGlar EU IGlar The glucose infusion rate serves as a surrogate measure for insulin activity Rmax: Maximum response Gtot=Total glucose infusion over time Results; Mean glucose infusion rate profiles were similar between LY IGlar and EU IGlar *Healthy subjects PD=pharmacodynamic; SD=standard deviation *IGlar=Lantus insulin glargine LY IGlar=LY insulin glargine EU=European Union-approved Linnebjerg et al. Diab Care 2015; 38(12):

64 Insulin Lispro 200 unit/ml (prandial) - Bioequivalent to insulin lispro 100 unit/ml

Insulin Lispro 100 unit/ml and Insulin Lispro 200 unit/ml are Bioequivalent Pharmacokinetic Profiles (Linear [Mean ± SE Data]) Mean Free Serum IRI Concentration (pmol/l) Insulin lispro 100 unit/ml

65 Insulin Lispro 100 unit/ml and Insulin Lispro 200 unit/ml are Bioequivalent Pharmacokinetic Profiles (Linear [Mean ± SE Data]) Mean Free Serum IRI Concentration (pmol/l) Insulin lispro 100 unit/ml Insulin lispro 200 unit/ml Bioequivalent N=38 healthy subjects; subcutaneous administration of 20 units IRI=Immunoreactive insulin Time From Dose (h) de la Peña A et al. Clin Pharmacol Drug Dev 2016;5:69-75

66 Pharmacodynamic Profile of Insulin Lispro 100 unit/ml and 200 unit/ml Glucose Infusion Rate vs. Time Profiles (Mean ± SE) Insulin lispro 100 unit/ml Insulin lispro 200 unit/ml Glucose Infusion Rate (mg/min) Time From Dose (h) N=38 healthy subjects; subcutaneous administration of 20 units de la Peña A et al. Clin Pharmacol Drug Dev 2016;5:69-75

67 Summary CKD is common in patients with diabetes and leads to significant morbidity and mortality. Follow GFR and UMACR. Treatment with ACEIs/ARBS and controlling A1c and BP are important for management Be aware or the GFR when using anti-hyperglycemic agents Novel insulin therapies are useful in addressing various needs for patients

INSULIN 101: When, How and What

INSULIN 101: When, How and What Alice YY Cheng @AliceYYCheng Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form