Presented By: Dr. Nadira Husein

Presented By: Dr. Nadira Husein

I have no conflict of interest

Disclosures I have received honoraria/educational grants from the following: Novo Nordisk, Eli Lilly, sanofi-aventis, Novartis, Astra Zeneca, GSK, Bristol Myers Squibb, Merck

Objectives Review the role of oral agents as well as insulin analogues in the management of diabetes 2008 CDA Guidelines Treatment of diabetes in the elderly

Targets for Glycemic Control Recommended Targets A1C (%) FPG (mmol/l) 2-hour postprandial (mmol/l) Type 1 and type 2 diabetes 7.0 4.0-7.0 5.0-10.0 (5.0-8.0 if A1C targets not being met) Canadian Diabetes Association Clinical Practice Guidelines. Can J Diabetes 2008;32(Suppl 1):S30.

Achieve Target A1C within 6 12 Months Clinical assessment and Lifestyle intervention (nutrition and activity) A1C < 9% A1C 9% If not at target, add metformin Acarbose DPP-4 inhibitor Insulin Secretagogue TZD Weight loss agent -Initiate Insulin or metformin with another agent from a different class immediately without waiting for effect from lifestyle changes -Symptomatic hyperglycemia, with metabolic decompensation: Initiate insulin ±metformin Timely adjustments/additions should be made to attain target A1C within 6 12 months. Adapted from: Canadian Diabetes Association Clinical Practice Guidelines. Can J Diabetes 2008;32(Suppl 1):S56.

If not at target Add an agent best suited to the individual based on the advantages/disadvantages listed bleow and the information contained in Table T 1 (agents listed in alphabetical order) Class A1C Hypoglycemia Other advantages Other disadvantages Alpha-glucosidase inhibitor Rare Improved postprandial control weight neutral GI side effects Incretin agent: DPP-4 inhibitor to Rare Improved postprandial control weight neutral New agent (unknown long-term safety) Insulin Yes No dose ceiling Many types, flexible regimes Weight gain Insulin secretagogue: Meglitinide Sulfonylureas to Yes* Yes Improved postprandial control Newer sulfonylureas (gliclazide, glimepiride) are associated with less hypoglycemia than glyburide Requires TID to QID dosing Weight gain *less hypoglycemia in the context of missed meals TZD Rare Durable monotherapy Requires 6-12 weeks for maximal effect Edema, rare CHF, rare fractures in females Weight loss agent None Weight loss GI side effects (orlistat) Increased heart rate/bp (subutramine)

Antiobesity agents Drug Expected decrease in A1C with monotherapy Hypoglycemia Other therapeutic considerations orlistat sibutramine None None Promote weight loss Glycemic benefit may be limited to those who actually lose weight Orlistat can cause diarrhea and other GI side effects Sibutramine can increase heart rate and BP = <1.0% decrease in A1C = 1.0 2.0% decrease in A1C = >2.0% decrease in A1C

Aggressive Therapy to Reach Target Early combination therapy: If targets are not achieved within 2 to 3 months of lifestyle management, pharmacotherapy should be initiated In patients with marked hyperglycemia (A1C 9.0%) agents should be initiated concomitantly with lifestyle management, and consideration should be given to combination therapy or initiating insulin Timely adjustments to and/or additions of antihyperglycemic agents should be made to attain target A1C within 6-12 months. Canadian Diabetes Association Clinical Practice Guidelines. Can J Diabetes 2008;32(Suppl 1):S53.

Insulin and Oral Antihyperglycemic Agents Combining insulin and the following oral agents* is effective in Type 2 diabetes: Biguanide (metformin) Alpha-glucosidase inhibitor (acarbose) Insulin secretagogues (meglitinide, sulfonylurea) Weight loss agent (orlistat, sibutramine) * TZDs are not currently indicated in combination with insulin in Canada. * Januvia has not been studied in combination with insulin. Canadian Diabetes Association Clinical Practice Guidelines. Can J Diabetes 2008;32(Suppl 1):S56 Januvia Prescribing Information 2006

Type 2 Diabetes Insulin Options Basal Insulin Options Glargine (Lantus ) once daily at any time of the day NPH (Novolin ge NPH or Humulin-N ) at bedtime and/or a.m. Detemir (Levemir ) once or twice daily

Type 2 Diabetes Insulin Options Pharmacologic Management of T2DM Canadian Diabetes Association Clinical Practice Guidelines. Can J Diabetes 2008;32(Suppl 1):S57.

Action Profiles of Basal Insulins Plasma Insulin Levels NPH 12 20 hours Detemir ~ 6 23 hours (dose-dependent) Glargine ~ 20 26 hours Hours Note: Action curves are approximations for illustrative purposes. Actual patient response will vary. Adapted from Insulin Therapy for the 21 st Century. American Diabetes Association; information from insulin glargine, insulin detemir, and NPH product monographs

Pharmacodynamic Profile of Insulin Glargine in Subjects with Type 1 Diabetes Glucose Utilization Rate (mg/kg/min) 6 5 4 3 2 1 0 0 10 20 Time since insulin injection (hours) 30 Insulin Glargine NPH insulin = 24 hours, end of observation period Lepore M, et al. Diabetes 2000;49:2142-2148 Lantus Product Monograph 2007

Insulin detemir NPH 0.2 U/kg 0.4 U/kg 0.3 IU/kg Duration of action (hr) 12 20 13 GIR max (mg/kg/min) 1.1 1.7 1.6 Insulin detemir dose (U/kg) 0.1 0.2 0.4 Glucose Utilization Rate 2.0 1.0 (mg/kg/min) 0 NPH, 0.3 (IU/kg) 0 2 4 6 8 10 12 14 16 18 20 22 24 Time since insulin injection (hours) Plank J, et al. Diabetes Care 2005;28:1107-1112 Levemir Product Monograph 2005

Insulin Activity Profile in Type 1 Diabetes 120 s.c. insulin 0.35 U/Kg N = 24 120 100 100 Activity (%) Mean ± SD 80 60 40 Glargine Detemir 80 60 40 20 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hours) Porcellati F, et al. Diabetes Care 2007;30:2447. 0

Insulin glargine vs. NPH in treat-to-target trial:hba 1c and Hypoglycaemia 18 HbA 1c (%) 9.0 8.5 8.0 7.5 7.0 6.5 NPH + OAD Insulin glargine + OAD Events per patient per year 16 14 12 10 8 6 4 2 21% risk reduction p <0.02 42% risk reduction p <0.01 0 4 8 12 16 20 24 Weeks Riddle. Diabetes Care. 2003; 26:3080-6. 0 Overall Nocturnal Hypoglycaemia

Variability of NPH Large inter- and intra- individual variations Cloudy - needs to be mixed properly (~20 times) Without re-suspension 5-214% variability A: Before (after 24 h sedimentation) B: After seven cycles C: After 20 cycles. Jehle PM. The Lancet 1999;354:1604-1607

Diabetes in the geriatric Population: concepts Targets are the same-but safety first Lean elderly patients with new onset diabetes: think insulin deficiency Long acting basal with orals through the day Premixes : for safety and less dosing errors SU should be used with caution due to risk of hypoglycemia which increases with age QID is also an option

Lantus vs. Detemir Type 2 Diabetes OADs in combination with insulin detemir once daily or twice daily* OADs unchanged *detemir twice daily if pre-dinner >7mmol with FPG <7mmol or if nocturnal hypos prevents achievement of FPG <6 mm OADs in combination with insulin glargine once daily T2 DM (583) insulin naïve, A1c 7.5-10%, BMI < 40kg.m2 failed on 1 or 2 OHAs Basal -insulin Rx initiated as once daily (evening) dose 12 U Rosenstock J., et al. Diabetologia. January 16 2008; ahead of print

Glycemic Control: QD/BID Detemir Once-daily Glargine Detemir Twice-daily N 104 252 127 A1c (SE) 7.12 (0.11)% 7.06% (0.085)% 7.06% (0.10)% FPG 7.27 (0.31) mmol/l 6.89 (0.24) 6.73 (0.25) mmol/l Ave. Insulin Dose.52 units/kg.44 units/kg 1.0 units/kg Refers to completed 52 weeks of treatment on once- or twice-daily insulin Rosenstock J., et al. Diabetologia. January 16 2008; ahead of print

Lantus Cartridges (for Autopen 24) Lantus Vials 10 ml (100U/mL) 5 x 3 ml (100 U/mL) Lantus SoloSTAR (pre-filled pens) 5 x 3 ml (100 U/mL)

Premixed 30% aspart/70% NPH Plasma Insulin (pm) 400 300 200 100 it should be the reverse mixture 70% aspart/30% NPH at each meal Isoglycemic clamp study HYPER risk HYPO HYPER HYPER risk HYPO 0 0 4 8 12 16 20 24 hrs Inadequate prandial insulin : Postprandial Hyperglycemia Excess inter-prandial supply: Increased risk of Hypoglycemia Luzio et al, 2004

Initiation of Insulin

What about targets in the elderly? CDA guidelines Think about co-morbid illnesses: ie strokes, MI, CHF, mobility issue Set targets based on patient s history Maybe 5-10 mmol/l Prevent significant hypo or hyperglycemia: SAFETY FIRST

Achieving Target Levels with Basal Insulin A1C target 7% Fix the fasting glucose first (FFF) Start with one initial injection (basal) for better patient acceptance; add mealtime insulin later if required As beta cells fail over time, basal insulin plus oral agent may no longer keep glucose levels optimal Mealtime insulin may be started at all meals, or possibly just at larger meals such as dinner Canadian Diabetes Association Clinical Practice Guidelines. Can J Diabetes 2008;32(Suppl 1):S1 152.

Example: Insulin Initiation and Titration If on oral agents, continue oral agents and add: Once-daily dose of basal insulin NPH Detemir Glargine Recommended starting dose: 10 U/day Increase insulin dose by 1 U/day until FPG target is achieved (4.0-7.0 mmol/l) Gerstein HC, et al. Diabet Med 2006;23(7):736 42 Canadian Diabetes Association Clinical Practice Guidelines.. Can J Diabetes 2008;32(Suppl 1): Appendix 3.

Follow the algorithm and The self-titration schedule is more likely to safely achieve near-physiological levels than a conventional therapeutic policy in which physicians defer adding insulin by increasing or adding oral agents. One unit at a time: The INSIGHT titration schedule Patient-managed Increase by 1 unit DAILY until FPG is 4.0-7.0 mmol/l Repeat Gerstein HC, et al. Diabet Med 2006;23(7):736 42 Canadian Diabetes Association Clinical Practice Guidelines.. Can J Diabetes 2008;32(Suppl 1): Appendix 3..

Switching from NPH to Long-Acting Insulin Insulin Detemir Switched unit for unit and given once or twice daily Insulin Glargine Patients on NPH once daily: Switched unit for unit once daily at bedtime Patients on NPH twice daily: Approximately 80% of NPH dose once daily at any time of day Levemir (insulin detemir [rdna origin] injection) prescribing information. Novo Nordisk, Inc. 2005. Lantus (insulin glargine) [rdna origin] injection) prescribing information. Sanofi-aventis, 2006.

Self-Titration of Insulin Insulin Dosage Instructions (Example) Your target fasting blood sugar level is between mmol/l You will inject units of insulin each day You will continue to increase by 1 unit every day until your blood sugar level is between mmol/l before breakfast Do not increase your insulin when your fasting blood sugar is mmol/l Canadian Diabetes Association Clinical Practice Guidelines. Can J Diabetes 2008;32(Suppl 1): S198

APIDRA (insulin glulisine) A novel rapid-acting insulin analogue

How about MDI? In the elderly we can still use intensive therapy Therapy should be individualized As long as the patient can do it, QID is an option We teach patients to adjust their insulin on their own This leads to autonomy and flexibility

An ideal insulin replacement therapy should mimic physiological insulin secretion The basal bolus insulin regimen 45 Breakfast Lunch Dinner Physiological insulin Ideal basal insulin Ideal prandial insulin Insulin (mu/l) 30 15 0 06:00 12:00 18:00 24:00 Time Figure adapted from Kruszynska YT, et al. Diabetologia 1987;30:16 21 06:00

If stop oral agents use insulin: General concepts SSS- sliding scales suck Use wt based insulin 4X per day No short acting insulin at hs as this increases the hypoglycemic risks

Example of a supplementary scale We give insulin to prevent highs and lows We don t give insulin only when high or low Example: 15 units of a rapid analogue with meals and 15 units of a long acting basal analogue at bedtime Then we add a subtract based on the glucose at the meal NO RAPID INSULIN AT BEDTIME

Apidra: a novel rapid acting inulin analogue Only insulin available without zinc Maintains PK/PD across all BMI Better glycemic control than RHI (especially when given just before meals) and less hypoglycemia More patients achieved target A1c with glulisine vs. lispro in the paediatric population Tendancy to fewer catheter occlusions and less unexplained hyperglycemia compared to aspart Better glycemic control compared to pre-mix in type 2 DM Improved glycemic control when added to basal insulin BEST PARTNER FOR LANTUS!

How should we manage patient s blood sugars while in hospital?

Necessary information Feeding status? Vomiting? Control pre-hospitalization? Renal function? Liver function?

NEJM 2006;355;1903

Whento stop oral agents Renal impairment (< 30 ml/min) Liver impairment Heart failure Not working to control the glucose! Not eating (sulfonylurea)

Typical orders Rapid acting insulin with MEALS ONLY 0.1-0.2 units per dose And bedtime insulin long acting analogue 0.1-.02 units Adjust insulin based on the action of the insulin and glucose response We add/subtract as needed

Supplemental scale good! Supplements ROUTINE insulin EXTRA bolus insulin ac meals ONLY CORRECTS hyperglycemia Can use supplemental needs to reassess standing doses

Pre-mix insulin Twice to three times per day Analogues (NovoMix 30 or Humalog mix 25 or 50) ar safer than 30/70 Taken immediately with meal or after meals May not be perfect control

Summary In the elderly we have the same targets but be aware of co-morbid illnesses QID insulin offers autonomy and flexibility with lifestyle and diet Consider long acting analogues with the orals as less nocturnal hypoglycemia than NPH Premix insulin can be given 2 or3 times per day Safety is of utmost concern