What s New in Type 1 and Type 2 Diabetes? Updates from 2013 CDA CPGs and Advancements in Insulin Therapy

What s New in Type 1 and Type 2 Diabetes? Updates from 2013 CDA CPGs and Advancements in Insulin Therapy 2013 Rocky Mountain/ACP Internal Medicine Conference November 15, 2013 David C.W. Lau, MD, PhD, FRCPC Depts. of Medicine, Biochem. & Molec. Biol. Julia McFarlane Diabetes Research Centre Libin Cardiovascular Institute of Alberta University of Calgary dcwlau@ucalgary.ca

Research funding: Disclosures: David C. W. Lau AHFMR, Alberta Cancer Board, CIHR, AstraZeneca, Boehringer- Ingelheim, BMS, Eli Lilly, Novo Nordisk, Pfizer, sanofi Consultant or advisory board member: Abbott, Allergan, Amgen, AstraZeneca, Bayer, Boehringer- Ingelheim, BMS, Eli Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Roche, sanofi and Valeant Speaker bureau: CDA, HSFC, AstraZeneca, Abbott, Bayer, Boehringer-Ingelheim, BMS, Eli Lilly, Merck, Novo Nordisk, sanofi and Valeant Some slides are selected from accredited CHE programs sponsored by CDA and Novo Nordisk

Learning objectives Having completed this case-based program you will: 1. Understand key treatment-related updates from the Canadian Diabetes Association 2013 guidelines 2. Evaluate barriers to optimal glycemic control and assess the role and proper use of current insulins 3. Describe the efficacy and safety of emerging insulin options for the management of diabetes

Diabetes is a global disease! Estimated global prevalence of diabetes 151 million 366 million 552 million 2000 2011 2030 International Diabetes Federation. IDF Diabetes Atlas. Fifth Edition. 2011

Public Health Agency of Canada, Diabetes in Canada. Ottawa, 2011 Diabetes Prevalence Rates in Canada, 2008/09 Canada 6.8%, N=2,359,252 Age- and sex-adjusted diabetes prevalence will increase by 40% within the next 10 years, from 6.8% in a population to 9.9% or 3.4 million in 2020!

UKPDS: Legacy Effect of Earlier Glucose Control After median 8.5 years post-trial follow-up Aggregate Endpoint 1997 2007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P: 0.0099 0.001 Myocardial infarction RRR: 16% 15% P: 0.052 0.014 All-cause mortality RRR: 6% 13% P: 0.44 0.007 guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association Holman R, et al. N Engl J Med 2008;359:1577-1589

Questions to Address What should the A1C be for most people and why? Who should we be more aggressive with and why? Who should we be less aggressive with and why? CDA CPGs Can J Diabetes 2013;37:S31-S34 guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

Individualizing A1C Targets 2013 Consider 7.1-8.5% if: which must be balanced against the risk of hypoglycemia guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

To Achieve A1C 7.0% 2013 A1C (%) Preprandial PG (mmol/l) 2-h postprandial PG (mmol/l) For most patients 7.0 4.0-7.0 (5-8 if A1C not at 5.0-10.0 target) CDA CPGs Can J Diabetes 2013;37:S31-S34 guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

Insulin Therapy in Type 1 Diabetes BASAL BOLUS REGIMEN Bolus insulin at meal times + basal insulin once or twice a day OR CONTINUOUS SUBCUTANEOUS INSULIN INFUSION Insulin pump therapy with continuous subcutaneous infusion of insulin via a catheter guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

AT DIAGNOSIS OF TYPE 2 DIABETES L I F E S T Y L E Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin A1C <8.5% If not at glycemic target (2-3 mos) Start / Increase metformin A1C 8.5% Start metformin immediately Consider initial combination with another antihyperglycemic agent If not at glycemic targets Add an agent best suited to the individual: Patient Characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Comorbidities (renal, cardiac, hepatic) Preferences & access to treatment Other Symptomatic hyperglycemia with metabolic decompensation Agent Characteristics BG lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side-effects Cost and coverage Other Initiate insulin +/- metformin 2013 guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association See next page

From prior page L I F E S T Y L E If not at glycemic target Add another agent from a different class Add/Intensify insulin regimen 2013 Make timely adjustments to attain target A1C within 3-6 months guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

2013 CPG: Drug Therapy for Type 2 Diabetes Add an agent best suited to the individual (agents listed in alphabetical order): Class Relative A1C Lowering Hypoglycemia Weight Other therapeutic considerations Cost -glucosidase inhibitor (acarbose) Rare Neutral to Improved postprandial control, GI sideeffects $$ Incretin agents: DPP-4 Inhibitors GLP-1 receptor agonists to Rare Rare Neutral to GI side-effects $$$ $$$$ Insulin Yes No dose ceiling, flexible regimens $-$$$$ Insulin secretagogue: Meglitinide Sulfonylurea Yes* Yes *Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide Thiazolidinediones Rare CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect $$ $ $$ Weight loss agent (orlistat) None GI side effects $$$ CDA CPGs. Can J Diabetes 2013;37: S61-S68

Change in A1C from baseline to 26 weeks (%) Glucose Lowering Therapy in Diabetes: A1C Reduction by Baseline A1C 0.5 0 7.5% >7.5% - 8.0% >8.0% to 8.5% >8.5% to 9.0% >9.0% Diabetes disease progression -0.5-1.0-1.5-2.0 * ** Liraglutide Sitagliptin Glimepiride Rosiglitazone Exenatide Glargine ** ** ** ** ** * * **** *** * *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs. liraglutide 1.8 mg; Henry RR, et al. Endocr Pract 2011;17(6):907

Change in Glycated Hemoglobin (%) DPP-4 Inhibitors: A1C Lowering Efficacy in Relation to Baseline A1C Levels 0.5 0-0.5-1.0-1.5-2.0-2.5 Sitagliptin Vildagliptin Saxagliptin Linagliptin Alogliptin Mono Rx Initial Combo 6.0 7.0 8.0 9.0 10.0 Baseline Glycated Hemoglobin (%) Deacon CF. Diabetes Obes Metab 2011;13:7 18

Changes in A1C and Body Weight: Liraglutide, Exenatide and Sitagliptin = LEAD-6 = Lira-DPP-4 = LEAD-6 = Lira-DPP-4 Adapted from Niswender K et al, Diab Obes Metab 2012 doi: 10.1111/j.1463-1326.2012.01673.x

SAVOR TIMI-53: Study Design ~16,500 patients Documented T2DM and established CVD (secondary prevention) or multiple CV risk factors (primary prevention) SAXAGLIPTIN 2.5 or 5 mg/d RANDOMIZE 1:1 DOUBLE BLIND Dosing based on egfr All other diabetes therapy per treating doctors PLACEBO DURATION: Event driven; 1,040 events required to power the study Follow up visits Q6 months Final Visit PRIMARY ENDPOINT: CV death, non-fatal MI, non-fatal ischemic stroke Scirica BM, et al. Am Heart J 2011; 162:818-25

Kaplan Meier Rates of the Primary and Secondary End Points Scirica BM et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1307684

SAVOR-TIMI 53: Individual Components of the Composite Endpoints Saxagliptin Placebo n (%)* n (%)* Efficacy endpoint (N = 8,280) (N = 8,212) HR (95% CI) P value CV death 269 (3.2) 260 (2.9) 1.03 (0.87 1.22) 0.72 MI 265 (3.2) 278 (3.4) 0.95 (0.80 1.12) 0.52 Ischemic stroke 157 (1.9) 141 (1.7) 1.11 (0.88 1.39) 0.38 Hosp for UA 97 (1.2) 81 (1.0) 1.19 (0.89 1.60) 0.24 Hosp for HF 289 (3.5) 228 (2.8) 1.27 (1.07 1.51) 0.007 Hosp for coronary revasc. 423 (5.2) 459 (5.6) 0.91 (0.80 1.04) 0.18 *K-M event rates are presented after 2 yrs. Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.

Pancreatitis and Pancreatic Cancer Any pancreatitis Acute (definite or possible) Acute (definite) Acute (possible) Saxagliptin n (%) (N = 8,280) 24 (0.3) 22 (0.3) 17 (0.2) 6 (0.07) Placebo n (%) (N = 8,212) P value* 21 (0.3) 16 (0.2) 9 (0.1) 7 (0.09) 0.77 0.42 0.17 0.79 Pancreatic cancer 5 12 0.095 All cases of pancreatitis were independently adjudicated *Chi-square test or exact test. Patients may have had more than 1 type of event. Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.

Cardiovascular Safety of Sulfonylureas: Meta analysis of Randomized Clinical Trials Monami M, et al. Diab Obes Metab 2013;15:938-53

CV Outcome Trials of Glucose-lowering Drugs SAVOR-TIMI53 Saxagliptin Sept 2013 N=16,492 ACE Acarbose N = 7,500 July 2014 CAROLINA Linagliptin N = 6,000 Sep 2018 : DPP-4i : GLP-1 EXAMINE Alogliptin Sept 2013 N=5,380 TECOS Sitagliptin Dec 2014 N=14,00 CARMELINA Linagliptin N = 8,300 Jan 2018 2012 2013 2014 2015 2016 2017 2018 2019 ELIXA Lixisenatide N = 6,000 Jan 2015 LEADER Liraglutide N = 9,340 Oct 2015 EXSCEL Exenatide N = 9,500 Mar 2017 REWIND Dulaglutide N = 9,622 Apr 2019 SUSTAIN-6 Semaglutide N = 3,260 Jan 2016

Serum Insulin Level Basal-bolus Insulin Therapy Time Human Basal: Humulin-N, Novolin ge NPH Analogue Basal: Lantus, Levemir Human Bolus: Humulin-R, Novolin ge Toronto Analogue Bolus: Apidra, Humalog, NovoRapid guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

Serum Insulin Level Pre-mixed Insulin Therapy Time Human Premixed: Humulin 30/70, Novolin ge 30/70 Analogue Premixed: Humalog Mix25, NovoMix 30 guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

Types of Insulin for Use in T1DM Insulin Type (trade name) Onset Peak Duration Bolus (prandial) Insulins Rapid-acting insulin analogues (clear): Insulin aspart (NovoRapid ) Insulin glulisine (Apidra ) Insulin lispro (Humalog ) 10-15 min 10-15 min 10-15 min 1-1.5 h 1-1.5 h 1-2 h 3-5 h 3-5 h 3.5-4.75 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) Long-acting basal insulin analogues (clear) Insulin detemir (Levemir ) Insulin glargine (Lantus ) 1-3 h 5-8 h Up to 18 h 90 min Not applicable Up to 24 h (glargine 24 h, detemir 16-24 h) guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

Types of Insulin (continued) Premixed Insulins Insulin Type (trade name) 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 ) guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

Studies of Pump Therapy Alone: Forest Plot of Pump Therapy vs. MDI Trials, A1C Outcomes Misso ML et al. Cochrane Database Syst Rev 2010 (1)

Recommendations 1-3 1. To achieve glycemic targets in adults with type 1 diabetes, basalbolus insulin regimens or the use of CSII as part of an intensive diabetes management regimen should be used [Grade A, Level 1A] 2. Rapid-acting insulin analogues, in combination with adequate basal insulin, should be used instead of regular insulin, to minimize the occurrence of hypoglycemia, improve A1C [Grade B, Level 2] and achieve postprandial glucose targets [Grade B, Level 2] 3. Rapid acting insulin analogues (aspart or lispro) should be used with CSII in adults with type 1 diabetes [Grade B, Level 2] CDA CPGs. Can J Diabetes 2013;37:S56-60 guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

Recommendations 4 and 5 4. A long-acting insulin analogue (detemir, glargine) may be used as the basal insulin [Grade B, Level 2] to reduce the risk of hypoglycemia [Grade B, Level 2], for detemir; [Grade C, Level 3], for glargine], including nocturnal hypoglycemia [(Grade B, Level 2), for detemir ;(Grade D, Consensus), for glargine]. 5. All individuals with type 1 diabetes should be counseled about the risk and prevention of insulin-induced hypoglycemia, and risk factors for severe hypoglycemia should be identified and addressed [Grade D, Consensus] CDA CPGs. Can J Diabetes 2013;37:S56-60 guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

Diabetes Rx in Canada (DM SCAN) Survey of 479 Primary care physicians across Canada 5,123 patients with type 2 diabetes seen on November 14 th, 2012 (World Diabetes Day) Mean age 64 years Mean duration of DM = 9.2 years Mean A1C 7.4% Mean LDL-C 2.1 mmol/l Mean blood pressure = 128/75 mmhg Leiter LA et al. Can J Diabetes 2013;37:82-89

Diabetes Rx in Canada (DM SCAN) Many patients NOT achieving targets: A1C 7.0% was met by 50% LDL-C 2.0 mmol/l by 57% BP <130/80 mmhg by 36% Composite triple target only by 13% of patients Higher use of insulin compared to previous surveys (40% versus 12%) Longer duration of DM compared to previous surveys Leiter LA et al Can J Diabetes 2013;37:82-89

β-cell function (%, HOMA) Matching Diabetes Therapy to Disease Progression 100 80 60 2 nd or 3 rd OAD(s) OD basal insulin 40 20 Metformin Diet and exercise 0 0 2 4 6 Years from diagnosis 8 HOMA, Homeostasis Model Assessment; OAD, oral antihyperglycemic drug; OD, once daily

Case study Insulin initiation History Lucie is aged 57 years She has been diagnosed with type 2 diabetes for 9 years She works full-time in a bank and has an erratic meal schedule She is concerned about her weight and her glucose control

Case study Insulin initiation Medications: Metformin 1000 bid Glyburide 10 bid Sitagliptin 100 mg od Quinipril 40 mg od Pravastatin 40 mg od - Tried a TZD but did not tolerate edema

Case study Insulin initiation Vital signs and laboratory parameters at diagnosis Weight 91 kg (200 Lbs) Waist circumference 92 cm (36.2 inches) BMI 31.4 kg/m 2 (obese, class I) A1C 9.1%

What are the main reasons why your patients are reluctant to initiate insulin? 1. Fear of needles 2. Fear of weight gain 3. Fear diabetes is worsening 4. Insulin causes complications 5. Other

Resistance to Insulin Therapy Fear of needles and injections Fear of complications, particularly hypoglycemia Fear of weight gain Inconvenience: More time-consuming Inadequate support and/or resources: Lack of information Cost Sense of failure Poor self confidence Fear diabetes is worsening Belief that insulin causes complications Meece J. The Diabetes Educator 2006; 32:9S 18S Go to http://www.dawnstudy.com Peyrot M et al. Diabetes Care 2005; 28:2673 2679 Hunt LM et al. Diabetes Care 1997; 20:292 298

Lucie s SMBG diary (mmol/l) Date Pre-breakfast Pre- lunch Pre-supper Bedtime Sunday 9.4 9.4 11.8 Monday Tuesday 11.2 Wednesday 8.6 Thursday 10.9 Friday Saturday 12.4 10.6 10.3

Adapted from Canadian Diabetes Association. Canadian Journal of Diabetes 2008; 32:Appendix 3. Examples of insulin initiation regimens Example A Example B Bedtime basal + antihyperglycemic agents Premixed insulin + Antihyperglycmic agents Most common start Example C Prandial insulin +/- Basal (multiple injections or prandial insulin only or continuous infusion) and antihyperglycemic agents

Basal Insulins Insulin type (trade name) Onset Peak Duration Intermediate-acting Humulin -N Novolin ge NPH Long-acting basal analogues 1 3 hrs 5 8 hrs Up to 18 hrs Insulin detemir (Levemir ) Insulin glargine (Lantus ) 90 min Not applicable Up to 24 hrs CDA CPGs. Can J Diabetes 2013;37:S56-S60

Basal insulins Insulin type (trade name) Onset Peak Duration Intermediate-acting Humulin -N Novolin ge NPH Long-acting basal analogues Insulin detemir (Levemir ) Insulin glargine (Lantus ) 1 3 hrs 5 8 hrs Up to 18 90 min Not applicable Up to 24 hrs Long-acting basal analogues reduce the risk of overnight hypoglycemia by ~20% CDA CPGs. Can J Diabetes 2013;37:S56-S60

Example A Bedtime basal and antihyperglycemic agents Goal: Target fasting glucose (4.0 7.0 mmol/l) (70 125 mg/dl) Initiate basal insulin 5-10 units at bedtime Titrate up to 1 unit/day until target reached Patients should self-monitor at least once daily (fasting) Do not increase dose and consider decreasing dose if: Two hypos in 1 week or One nighttime hypo If daytime hypos occur, insulin secretagogues may need to be reduced Continue oral agents ( if on TZD consider stopping or close survellence CDA CPGs. Can J Diabetes 2013;37:S200

Basal Analogues Have Similar 24-hour Glucose Profile, Similar Dose Section 1.3 How How to initiate to initiate insulin insulin? 24 hour glucose profile for insulins detemir and glargine King AB. Diabetes Obes Metab 2009;11:69 71

Case study Insulin initiation Insulin is initiated with a long-acting insulin analogue (NPH could be used if cost was an issue) 10 U at bedtime was initiated She was asked to titrate up by 1 Unit every night until am glucose was less than 7.0 mmol/l (125 mg/dl)

Lucie s SMBG diary: 3 weeks later 22 U of Basal insulin at bedtime Date Pre-breakfast Pre-lunch Pre-supper Bedtime Sunday 7.4 6.4 8.8 Monday 7.2 Tuesday 6.2 7.1 Wednesday 6.9 6.6 Thursday 7.9 7.8 Friday 7.3 Saturday 7.4 7.6 8.3

Lucie s SMBG diary: 5 weeks later 32 U of Basal insulin at bedtime Date Pre-breakfast Pre-lunch Pre-Supper Bedtime Sunday 6.4 6.4 7.8 Monday 6.2 Tuesday 7.2 5.1 Wednesday 5.9 4.6 Thursday 6.9 6.8 Friday 6.3 Saturday 5.4 3.4 5.6 7.3

Lucie has hypoglycemic symptoms in the late am What would you like to do for Lucie now? Glyburide may be causing hypoglycemia in the late am Glyburide likely should be reduced or changed If discontinued, glucose levels may rise throughout the day Dietary changes are another option Glyburide was discontinued and insulin dosage increased

Lucie s SMBG diary: 18 weeks later 44 U of Basal insulin at bedtime, A1C = 7.2% Date Pre-breakfast Pre- lunch Pre-supper Bedtime Sunday 6.4 6.4 6.8 Monday 6.2 Tuesday 6.2 6.3 5.1 Wednesday 5.9 5.6 Thursday 6.9 6.8 Friday 6.3 Saturday 5.4 4.4 5.6 7.3

Premixed insulins Insulin type (trade name) Premixed regular insulin NPH Humulin 30/70, (70/30) Novolin ge 30/70, 40/60, 50/50, (70/30) (60/40) Premixed insulin analogues Biphasic insulin aspart (NovoMix 30)(Novolog 70/30) Insulin lispro/lispro protamine (Humalog Mix25 and Mix50 )(Humalog Mix 75/25) Notes A single vial or cartridge contains a fixed ratio of insulin (% rapid-acting or short-acting insulin to % intermediate-acting insulin) Adapted from Canadian Diabetes Association. Canadian Journal of Diabetes 2008; 32:S47 & S57.

Prandial (Bolus) Insulins Insulin type (trade name) Onset Peak Duration Rapid-acting insulin analogues Insulin aspart (NovoRapid ) 10 15 min 1 1.5 hrs 3 5 hrs Insulin glulisine (Apidra ) 10 15 min 1 1.5 hrs 3 5 hrs Insulin lispro (Humalog ) 10 15 min 1 2 hrs 3.5 4.75 hrs Short-acting insulins Humulin -R Novolin ge Toronto 30 min 2 3 hrs 6.5 hrs Analogues should be considered instead of regular insulin (CDA Guidelines) CDA CPGs. Can J Diabetes 2013;37:S56-S60

N Engl J Med 2009:361:1736-47 Published online October 22, 2009

4T Study: Insulin Initiation 708 patients starting insulin Inadequate glycemic control on metformin and SU Individuals randomized to 3 different regimes 1. pre-mixed biphasic insulin aspart (NovoMix 30) 2. prandial insulin aspart (NovoRapid per meal) 3. basal insulin detemir (Levemir at bed or BID if required) Holman RR et al. N Engl J Med 2009;361:1736-1747

A1C change (%) Reductions in A1C Seen With All Analogue Intensification Regimens Premix insulin analogue* start Mealtime insulin analogue start Basal insulin analogue start 0-0.5 8.6 8.6 8.4-1 -1.5-2 -2.5-3 -1.3-1.4-1.2 Intensification after initial insulin treatment failure: * Premix insulin analogue bid + mealtime insulin at lunch Mealtime insulin analogue tid + basal insulin analogue at bedtime Basal insulin analogue at bedtime + mealtime insulin tid P=0.28 versus mealtime insulin. P=0.67 versus basal insulin analogue. P=0.52 versus premix insulin analogue. Adapted from Holman RR et al. New Engl J Med 2007; 357:1716 1730 Holman RR et al. New Engl J Med 2009; 361:1736 1747

4T Study: Insulin Initiation - Results Mean A1C levels achieved were similar: 7.1% biphasic, 6.8% prandial, 6.9% basal Hypoglycemia rates (per patient per year) lowest in basal group (1.7%), biphasic group (3.0%), prandial group (5.7%) Mean weight gain highest in the prandial group The authors concluded that basal insulin had better control, less hypoglycemia, and less weight gain Holman RR et al. New Engl J Med 2009; 361:1736 1747

Patients (%) Glargine vs NPH: less hypoglycemia Type 2 DM Patients experiencing 1 episode of hypoglycemia * 60 50 p=0.022 Insulin Glargine (n=264) NPH Insulin (n=270) 40 30 p=0.012 20 10 p=0.0117 0 All Symptomatic Nocturnal Type of hypoglycemia Severe * Symptomatic, nocturnal or severe hypoglycemia confirmed by BG level <2mmol/L (month 2 to endpoint). Ratner RE et al. Diabetes Care 2000;23:639 643

NNT to Avoid One Nocturnal Hypoglycemic Episode: Glargine versus NPH Symptomatic (<3.9): NNT = 8 (p<0.001) Symptomatic (<2.0): NNT = 107 (p=0.002) Severe: NNT = 112 (p=0.047) Fritsche A et al. Diab Obes Metab 2010;12:772-779

Nocturnal hypoglycaemia (number of events) Levemir versus NPH: Less Nocturnal Hypoglycemia 400 300 RR=45% ** 349 Insulin detemir (n=237) NPH insulin (n=238) * 200 100 160 74 ** 187 85 161 0 0 1 All Major Minor confirmed Symptomatic unconfirmed **p<0.001 *p<0.01 Type of hypoglycemia Hermansen K et al. Diabetes Care 2006;29:1269 74

Key summary points Algorithms and therapies for initiating insulin There are many types of insulin available The simplest way to initiate insulin is to start with a basal insulin: 5-10 units at bedtime Titrate up to 1 unit/day until target reached Long-acting analogues reduce risk of hypoglycemia versus NPH For consideration as the disease progresses, adding an insulin to manage mealtime needs may become necessary CDA CPGs. Can J Diabetes 2013;37:S56-S60

New Ultra-longacting Basal Insulin Insulin Degludec

Molecular size determines rate of subcutaneous absorption the idea behind insulin degludec Brange et al. Diabetes Care 1990;13:923 54

Insulin Degludec: Design

Insulin degludec: immediately after injection Jonassen I et al. Pharm Res 2012;29:2104 14

Insulin degludec: slow release following injection Jonassen I et al. Pharm Res 2012;29:2104 14

Insulin degludec: slow release following injection Jonassen I et al. Pharm Res 2012;29:2104 14

Insulin degludec: slow release following injection Jonassen I et al. Pharm Res 2012;29:2104 14

Insulin Degludec vs. Glargine: Efficacy and Hypoglycemia in DM1 Heller S et al. Lancet 2012;379:1489-97

Insulin Degludec vs. Glargine: Efficacy and Hypoglycemia in DM2 Garber AJ et al. Lancet 2012;379:1498-1507

Insulin Degludec: Summary Through the formation of multihexamer chains of insulin in subcutaneous depots, degludec has an extra long duration of action (half-life >25 hours and activity > 40 hours) Insulin degludec effectively improves A1C and is noninferior to insulin glargine in bolus and basal-bolus therapy in both type 1 and type 2 diabetes Insulin degludec results in significantly less risk of hypoglycemia than insulin glargine 20% less risk of overall confirmed hypoglycemia 25% less risk of nocturnal hypoglycemia Degludec improves the quality of life of people with diabetes who require insulin therapy Heller S et al. Lancet 2012;379:1489-97 Garber AJ et al. Lancet 2012;379:1498-1507

Key Messages on Insulin Therapy Individuals must strive for self management of their diabetes Self management of insulin: individuals need to be proactive and less reactive Need to adjust insulin doses to reach the next upcoming target Patients should ask themselves: should I take more or less insulin with this injection?

Glycemic Management of Diabetes 2013 CDA guidelines recommend that glycemic management should be individualized, aiming for A1C 7% for most people Basal-bolus insulin therapy are the insulin regimens of choice for all adults with type 1 diabetes Metformin is the initial choice for type 2 diabetes, with additional antihyperglycemic agents selected on the basis of matching individuals with drug characteristics Metformin, incretin-based therapies and acarbose, are not associated with adverse CV outcomes Analogues should be considered instead of human insulin to improve A1C while minimizing the occurrence of hypoglycemia All individuals with diabetes should be counseled about the risk, prevention and treatment of hypoglycemia CDA CPGs. Can J Diabetes 2013;37:S31-S34

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