The Rules of 3s: Insulin Use in Type 2 Diabetes

Alice Y.Y. Cheng MD FRCPC

Staff Endocrinologist, Division of Endocrinology & Metabolism, St. Michaels Hospital and Credit Valley Hospital Assistant Professor (Adjunct), Department of Medicine, University of Toronto Toronto, Ontario

INTRODUCTION

Approximately one-half of Canadians with known type 2 diabetes are at the recommended glycated hemoglobin (A1C) target of 7.0% (1). Although this is quite an accomplishment and there has denitely been improvement over time (2,3), a large proportion of people with type 2 diabetes are not at glycemic target and require more aggressive glycemic management. Compared with other therapeutic areas that have a dearth of therapeutic options, diabetes is relatively rich in the number of effective glucose-lowering therapies available for use in Canada, with various routes of administration and mechanisms of action. Insulin remains the oldest and most effective therapy for glucose lowering; however, its use remains relatively low (1215%) given the care gap that still exists regarding glycemic control (1,3).

o understand the treatment gap, one must recognize the barriers and challenges to insulin use, which are both patient- and physician-related. Although many healthcare professionals are quick to cite the patient-related barriers, the physician-related barriers are equally important (4,5). Physicianrelated barriers include knowledge of and comfort with insulin selection, regimens and dosing. This article addresses this very important issue, and presents a simple and practical approach to selecting and dosing insulin.

WHEN SHOULD INSULIN BE CONSIDERED IN TYPE 2 DIABETES?

As outlined in the Canadian Diabetes Associations 2008 clinical practice guidelines, insulin use is appropriate in the following circumstances in type 2 diabetes (6): At any point when glycemic control is inadequate (A1C >7.0%).  As initial therapy if presenting A1C 9.0% in newly diagnosed diabetes.  Metabolic decompensation (hyperglycemic symptoms, diabetic ketoacidosis).

End-organ failure (renal failure, heart failure, liver failure). Pregnant or planning pregnancy. Temporarily, for acute illness, stress or medical procedure/ surgery. The guidelines recommend that the target A1C of 7.0% should be achieved within 6 to 12 months of diagnosis (6). In order to achieve this goal, clinicians must make the necessary additions or modifications to pharmacologic therapy in a timely fashionall the while encouraging continued efforts with lifestyle modifications. Depending on the degree of hyperglycemia, insulin may be started simultaneously with metformin, or may be the most appropriate next step after metformin. If A1C is 9.0% at the time of diagnosis, consideration should be given to starting insulin therapy immediately. If the person has any signs of metabolic decompensation (e.g. polyuria, polydipsia, blurred vision) related to marked hyperglycemia at any point in their disease course, insulin therapy should be considered. If a patient presents with unintentional weight loss in the context of marked hyperglycemia, insulin therapy should be started immediately, as the patient is in a catabolic state.

Canadian Diabetes / Le Diabte au Canada

Spring 2011

Editor-in-Chief Sara Meltzer MD FRCPC Montreal, Quebec

Editor Emeritus Danile Pacaud MD FRCPC Calgary, Alberta

Associate Editors Sarah Capes MD MSc FRCPC Victoria, British Columbia J. Robin Conway MD Smiths Falls, Ontario

In less severe cases, insulin can be started at any point in the treatment course. It is important to clarify, however, that the 9.0% A1C cited in the Canadian Diabetes Association guidelines (6) refers to the level at which one would consider going directly to insulin as initial therapy in a newly diagnosed person with diabetes. It is not intended as a trigger point to initiate insulin in someone already being treated for diabetes. In that case, insulin can be started at any point that A1C remains above the target of 7.0%.

Claire Lightfoot RD MEd CDE Campbell River, British Columbia Diana Sherifali RN PhD CDE Hamilton, Ontario

WHAT ARE THE AVAILABLE INSULINS?

In the last decade, 8 new insulin formulations have been introduced in Canada. Trying to remember all of the available insulins can be challenging. However, it is helpful to note that all currently available insulins (and all insulins to come in the future) fit into 1 of 3 categories (6): bolus (mealtime), basal and premixed (Table 1). Within each category, the insulins are further divided into human or analogue. Human insulins are the traditional ones that have been available for decades. Human regular insulin is the same molecule that is normally made by the pancreas. It exists as a zinc-containing hexamer and needs to dissociate into monomers to be absorbed from the subcutaneous space. NPH, the intermediate-acting human basal insulin has protamine (fish protein) added to prolong absorption from the subcutaneous space and was named neutral protamine Hagedorn after its creator, Hans Christian Hagedorn. Analogue insulins were created to further improve the timeaction profile of traditional insulins by modifying the insulin molecule. The bolus analogue insulins were modified so that they exist as monomers and can be absorbed from the subcutaneous space rapidly. Therefore, bolus analogue insulins start working faster, peak sooner and disappear faster than traditional regular insulin. Basal analogues were modified to peak much less and last longer than traditional NPH insulin. Premixed analogues are merely
Table 1. Currently available insulins in Canada Insulin category
Bolus

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Canadian Diabetes/le Diabte au Canada is published by the Canadian Diabetes Association. All articles published in Canadian Diabetes are the sole opinions of the authors and are not necessarily endorsed by the Canadian Diabetes Association. Copyright Canadian Diabetes Association, 2011; all rights reserved. Reproduction of this publication in whole or in part is prohibited without the written consent of the Publisher. Change of address notices to: Canadian Diabetes Association 1400-522 University Avenue Toronto, Ontario M5G 2R5 Canada Post Publication agreement number 40063447. ISSN0841-9388 Research and clinical experience are continually adding to medical knowledge of diagnosis, treatments and drug therapies. When authors refer to drug therapies, indications and/or dosage schedules, reference to product monograph and prescribing information is suggested to assure use of these products in accordance with the manufacturers recommendations. Reference in some articles to products by their trademark names without the trademark designation is not to be interpreted that the products or tradenames or trademarks are in the public domain.

Human insulin
Humulin Regular Novolin Toronto Humulin N Novolin NPH Humulin 30/70 Novolin 30/70 Novolin 40/60 Novolin 50/50

Analogue insulin
Aspart (NovoRapid) Glulisine (Apidra) Lispro (Humalog) Detemir (Levemir) Glargine (Lantus) Humalog Mix25 Humalog Mix50 NovoMix 30

Basal Premixed

mixtures of bolus analogue insulins and a basal insulin that is very similar to NPH. The primary advantage of the analogue insulins is that they cause less hypoglycemia; their primary disadvantage is higher cost, compared with traditional insulins (7-9).

in hypoglycemia because of the intermediate-acting component of the premixed insulin that would have already been injected earlier in the day. Also, there is a need for a bedtime snack to avoid the nocturnal hypoglycemia that may result from the intermediateacting portion of the premixed insulin injected at supper time.

WHAT ARE THE INSULIN REGIMENS USED IN TYPE 2 DIABETES?

There are 3 primary insulin regimens for type 2 diabetes: 1. Basal insulin once daily 2. Basal + bolus insulin 3. Premixed insulin twice daily

WHAT SHOULD BE DONE WITH ORAL ANTIHYPERGLYCEMIC AGENTS WHEN INSULIN IS STARTED?
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; in a recent study, there was even suggestion of cardiovascular benefit (12). There is an option to continue insulin secretagogues (sulfonylurea or meglitinides) when only basal insulin is used; however, discontinuation once bolus insulin is introduced (either as a basal + bolus regimen or as a premixed regimen) will reduce the risk of hypoglycemia. In general, thiazolidinediones (TZDs) should be discontinued once insulin is added, as they are not indicated for use in combination with insulin in Canada; moreover, TZDs increase the risk of peripheral edema and congestive heart failure, although they reduce insulin requirements significantly (13). With respect to the other antihyperglycemic agents, there is no general consensus. The dipeptidyl peptidase-4 (DPP-4) inhibitors (saxagliptin and sitagliptin) are not indicated for combination use with insulin in Canada; however, a recent study of sitagliptin added to basal insulin demonstrated improved postprandial glycemic control (14). As for the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, it is also not indicated for combination use with insulin in Canada, and there are no published studies of its combined use with insulin. However, there are published studies of exenatide, a GLP-1 mimetic, added to basal insulin and metformin that demonstrated improved A1C, postprandial glycemic control and weight loss (14,15).

1. Basal insulin once daily

In this regimen, patients take 1 injection of basal insulin per day (usually at bedtime), often in combination with metformin sulfonylurea. The result is improved fasting blood glucose (FBG) levels. The longer action profile of the basal insulins allows for the dose to be given at any time of day. The main advantage of this regimen is the convenience and ease of 1 injection. This is a good starting point for insulin therapy, and has been shown to result in less weight gain and less hypoglycemia as the initial regimen compared with the other analogue insulins (10). The disadvantage is lack of meal-time control.

2. Basal + bolus insulin

In this regimen, patients take bolus insulin with each meal and basal insulin (usually) at bedtime. Metformin is continued; however, sulfonylurea is usually discontinued once bolus insulin is introduced. There is an option of only giving bolus insulin at the largest meal and continuing the bedtime basal insulin (11). Over time, though, postprandial control of the other meals will gradually deteriorate and bolus insulin will also need to be added at these meals. The advantages of this regimen are its flexibility (timing and size of meals) and better mealtime control. The disadvantage is the higher number of injections.

HOW TO DOSE AND TITRATE INSULIN

There are 3 important principles to remember when dosing insulin: 1. Whatever starting dose you select will be wrong. 2. Titration is the key to success. 3. There is no maximum dose of insulin.

3. Premixed insulin twice daily

In this regimen, patients take an injection of premixed insulin before breakfast and before supper. The advantage of this regimen is the convenience of 2 injections; the primary disadvantage is the lack of flexibility since the insulin is premixed. Therefore, this regimen is ideal for the patient who leads a consistent and predictable lifestyle with regular meals (timing and quantity) and regular activity. This is an important factor to assess, as skipped or delayed meals can result

1. Basal insulin once daily

Start at a dose of 10 units at bedtime. Most patients will require 40 to 50 units of insulin before achieving target FBG levels (16,17). Therefore, the patient should self-titrate by increasing the dose by 1 unit every night until the FBG level is achieved. A number

of titration protocols have been used in various clinical trials of basal insulin initiation (10,16,17); however, the guiding principles remain the same, i.e. small incremental increases in insulin dose on a regular basis, using the FBG as the determinant of titration. An important consideration is to reduce the insulin dose in the event of hypoglycemia, especially as patients improve their lifestyle.

2. Basal + bolus insulin

If the patient has already been on basal insulin and bolus insulin is to be added to the regimen to achieve better mealtime control, one could add bolus insulin at a dose of 10% of the basal dose (10). For example, if the patient is taking 50 units of basal insulin at bedtime but his/her postprandial BG levels remain high, add 5 units of bolus insulin with meals. As per one of the basic prin-

ciples of insulin dosing, the starting bolus dose selected will likely be wrong. However, titration until target postprandial BG levels are achieved will ensure that the appropriate dose is found. If the patient is insulin-nave, one method of calculating the starting dose is as follows: Total daily insulin = 0.5 units/kg 40% of total daily insulin = basal dose  60% of total daily insulin = total bolus doses (divided into the 3 meals) Some people choose to divide the total daily insulin into 50% basal and 50% bolus. Either of these methods works because the most important step is the titration, not the starting dose! The basal dose can then be titrated based on the FBG level as discussed in the Basal insulin once daily section above. The bolus

Figure 1. Adjustments for usual insulin dose (adapted from reference 18) My target blood sugar range is: You may change your regular or rapid-acting insulin* before meals, your evening long-acting insulin or your mixed insulin taken morning and evening if your blood sugars have been as described below for an average of 4 to 7 days.
If before breakfast your blood sugars have been: Too low or one night reaction Within target range Too high If before lunch your blood sugars have been: Too low or one morning reaction Within target range Too high If before supper your blood sugars have been: Too low or one afternoon reaction Within target range Too high If before bed your blood sugars have been: Too low or one evening reaction Within target range Too high Decrease evening long-acting by ______ Do not change Increase evening long-acting by ______ Decrease breakfast regular or rapid-acting insulin by ______ Do not change Increase breakfast regular or rapid-acting insulin by ______ Decrease lunch regular or rapid-acting insulin by ______ Do not change Increase lunch regular or rapid-acting insulin by ______

NB: Patients taking BID basal NPH or mixed insulin adjust morning dose instead of lunch regular. Decrease supper regular or rapid-acting insulin by ______ Do not change Increase supper regular or rapid-acting insulin by ______

If you have a reaction 1 to 2 days in a row, decrease the insulin causing the reaction by 2 units: If hypoglycemic reaction is between: Breakfast & lunch Decrease breakfast regular or rapid-acting insulin by 2 units or if no lunch Lunch & supper Supper & bedtime Night-time & breakfast

dose, decrease morning NPH or mixed insulin by 2 units Decrease lunch regular or rapid-acting insulin by 2 units Decrease supper regular or rapid-acting insulin by 2 units Decrease evening long-acting insulin by 2 units

*Regular or rapid acting could be: Regular: Humulin R or Novolin Toronto Rapid acting: Apidra or Humalog or NovoRapid Evening long-acting could be Humulin N, Novolin ge NPH, Levemir or Lantus Mixed insulin could be: Humulin 30/70, Humulin 50/50, Humalog Mix25, Humalog Mix50 or Novolin ge 30/70, Novolin ge 40/60, Novolin ge 50/50, NovoMix 30

doses should also be titrated by the patient, based on their BG level either prior to the next meal or 2 hours after the meal.

IS THERE AN EASY WAY TO REMEMBER THE RULE OF 3S?

The Ontario College of Family Physicians (OCFP) recently developed a 2-page Insulin Prescription Tool, which serves the dual purpose of education and function (Figure 2). The front page of the tool is a prescription for insulin that allows physicians to select the insulin that they wish to prescribe and then complete dosing and titration instructions. The back page contains all of the information reviewed in this article regarding insulin regimens and dosing. A modifiable PDF version of the tool is available at http://www.ocfp.on.ca; alternatively, paper copies can be obtained from the OCFP. The steps to use the tool are as follows: 1.  Select an insulin type (basal, bolus or premixed). The 3 insulin types are represented in rows with the analogue and traditional

3. Premixed insulin twice daily

The easiest way to initiate this regimen is to start at a dose between 5 and 10 units before breakfast and supperthen titrate (6). The more complicated way would be to calculate the total daily insulin (as above), and then divide the dose into two-thirds at breakfast and one-third at supper or one-half at breakfast and one-half at supper. Again, the key is titration. Since the key to success is titration, it is most efficient to have the patient self-titrate their insulin doses. Figure 1 shows a sample instruction sheet that could be given to patients to guide their self-titration of insulin.

Figure 2. Insulin Prescription Tool, developed by the Ontario College of Family Physicians
PRESCRIBER'S NAME: ____________________________________ ADDRESS: __________________________ TEL: ______________ Fax: _____________ PATIENTS NAME: ____________________________________ ADDRESS: __________________________ ____________________________________

INSULIN PRESCRIPTION
BASAL

Choose insulin(s) from one of the columns AND complete the Dosing and Titration
INSULIN TYPE* DOSING AND TITRATION

Long-acting analogues
(Clear)

Levemir Humulin N

Cartridge

Lantus

Cartridge Vial SoloSTAR

Starting dose:
_____ units at bedtime Increase dose by _____ units every _____ nights until fasting blood glucose has reached the target of ______________ mmol/L

Intermediate-acting
(Cloudy)

Cartridge KwikPen Cartridge TM KwikPen

Vial

Novolin ge NPH
Cartridge

Vial

BOLUS

(Clear) **GIVE IMMEDIATELY BEFORE MEAL **

Rapid-acting analogues

Humalog

Vial

Cartridge Vial Limited Use 388 (type 1 DM) 389 (type 2 DM)

NovoRapid

Apidra
Vial

Cartridge SoloSTAR

Starting doses:
_________ units ac breakfast _________ units ac lunch _________ units ac supper

Short-acting (clear)

** GIVE 30 MINUTES BEFORE MEAL **

Humulin R
Cartridge

Vial

Novolinge Toronto
Cartridge Vial

PREMIXED

Premixed analogues
**GIVE IMMEDIATELY BEFORE MEAL**

Humalog Mix25
Cartridge Cartridge

KwikPen

TM

NovoMix 30
Cartridge

Starting doses :
_____ units ac breakfast _____ units ac supper Increase breakfast dose by _____ units every _____ days until presupper blood glucose has reached the target of ______________ mmol/L Increase presupper dose by _____ units every _____ days until fasting blood glucose has reached the target of ______________ mmol/L Beware of hypoglycemia post-breakfast or postsupper. Stop increasing dose if this occurs
ClikSTAR

Humalog Mix50 Humulin 30/70

Cartridge

KwikPen Vial

TM

Premixed regular

** GIVE 30 MINUTES BEFORE MEAL **

Novolinge 30/70
Cartridge

Vial

Novolinge 40/60
Cartridge Cartridge

Novolinge 50/50

Required if cartridges selected. Pen should match insulin brand.

PEN DEVICE

HumaPen Luxura HumaPen Memoir

NovoPen 4

OTHER SUPPLIES QUANTITY + REPEATS

Signature: Print Name:

Pen needles (if using pen) ___________________ Glucose test strips ___________________ Lancets ____________________ Insulin syringes (if using vial) _________________

INSULIN
Mitte:

_______ boxes

Repeats x ____________ Date: License #:

SUPPLIES
Mitte:

_______ boxes

Repeats x ____________

June 2010

Figure 2. Insulin Prescription Tool, developed by the Ontario College of Family Physicians (continued)

INSULIN INITIATION AND TITRATION SUGGESTIONS

(for type 2 diabetes)
People starting insulin should be counseled about the prevention, recognition and treatment of hypoglycemia .
The following are suggestions for insulin initiation and titration. Clinical judgment should always be used as the suggestions may not apply to every patient.

Basal Insulin added to Oral Antihyperglycemic Agents (Lantus, Levemir, Humulin N, Novolinge NPH)
Target fasting blood glucose (BG) of 4-7 mmol/L Most patients will need 40-50 units at bedtime to achieve target but there is no maximum dose Start at a low dose of 10 units at bedtime (may start at lower dose (0.1-0.2 units/kg) for lean patients (< 50 kg)) Patient should gently self-titrate by increasing the dose by 1 unit every night until fasting BG target of 4-7 mmol/L is achieved When fasting BG target is achieved, the patient should remain on that dose until reassessed by their diabetes team If fasting hypoglycemia occurs, the dose of bedtime basal should be reduced Metformin and the secretagogue are usually maintained when basal insulin is added If daytime hypoglycemia occurs, reduce the oral antihyperglycemic agents (especially secretagogues) Lantus or Levemir can be given at bedtime or in the morning When basal insulin is not enough to achieve glycemic control, bolus insulin should be added before meals. There is the option of only adding bolus insulin to the meal with the highest postprandial BG as a starting point for the patient who is not ready for more injections. For current basal insulin users, maintain the basal dose and add bolus insulin with each meal at a dose equivalent to 10% of the basal dose. For example, if the patient is on 50 units of basal insulin, add 5 units of bolus insulin with each meal For new insulin users starting with Basal + Bolus regimen, calculate total daily insulin dose (TDI) as 0.3 to 0.5 units / kg, then distribute as follows: o 40% of TDI dose as basal insulin (Lantus, Levemir, Humulin N, Novolinge NPH) at bedtime o 20% of TDI dose as bolus insulin prior to each meal Rapid-acting insulin analogues (Apidra, Humalog, NovoRapid ) should be given immediately before eating Short-acting insulin (Humulin R, Novolinge Toronto) should be given 30 minutes before eating Adjust the dose of the basal insulin to achieve the target fasting BG level (usually 4-7 mmol/L) Adjust the dose of the bolus insulin to achieve postprandial BG levels (usually 5-10 mmol/L) Consider stopping the secretagogue when bolus insulin is added

Basal Insulin Example Starting dose 10 units at bedtime Increase dose by 1 unit every 1 night until fasting blood glucose has reached the target of 4-7 mmol/L

Basal + Bolus Insulins

Basal + Bolus example (80kg person)

Total daily insulin = 0.5 units/kg = 0.5 x 80 TDI = 40 units Basal insulin = 40% of TDI = 40% x 40 units Basal bedtime = 16 units Bolus insulin = 60% of TDI = 60% x 40 units Bolus = 24 units = 8 units with each meal Premixed insulin example 10 units ac breakfast 10 units ac supper Increase breakfast dose by 1 unit every 1 day until presupper blood glucose has reached the target of 4-7 mmol/L Increase supper dose by 1 unit every 1 day until fasting blood glucose has reached the target of 4-7 mmol/L

Premixed Insulin before breakfast and before dinner (Humalog Mix25, Humalog Mix50, NovoMix 30, Humulin 30/70,
Novolin ge 30/70, Novolin ge 40/60, Novolin ge 50/50)

Target fasting and presupper BG levels of 4-7 mmol/L Most patients with type 2 diabetes will need 40-50 units twice a day to achieve target but there is no maximum dose Start at a low dose of 5 to 10 units twice daily (before breakfast and before supper) Patient can gently self-titrate by increasing the breakfast dose by 1 unit every day until the presupper BG is at target Patient can gently self-titrate by increasing the supper dose by 1 unit every day until the fasting BG is at target Beware of hypoglycemia post-breakfast or post-supper. Stop increasing dose if this occurs When target BG levels are achieved, the patient should remain on that dose until reassessed by their diabetes team Premixed analogue insulins (Humalog Mix25, Humalog Mix50, NovoMix 30) should be given immediately before eating Premixed regular insulins (Humulin 30/70, Novolinge 30/70 or 40/60 or 50/50) should be given 30 minutes before eating Continue the meformin and consider stopping the secretagogue

Reproduced with permission from the Ontario College of Family Physicians For an electronic copy of this tool, go to http://www.ocfp.on.ca For a printed copy of this tool (prescription pads), email ocfp@cfpc.ca

human insulins differentiated. 2.  Select an insulin brand. There are 3 brands of insulin, which are represented in alphabetical order in columns. 3.  Complete the corresponding dosing and titration column using the fill-in-the-blank format (refer to back page of the tool for suggestions). 4.  Select the insulin pen device using the corresponding column. 5.  Select the supplies needed by checking off the appropriate item(s). 6.  Complete the last row for the quantity of insulin and quantity of supplies.

7.  Sign and date at the bottom of the tool. On the back of the tool, insulin initiation and titration suggestions are provided, which represent the 3 potential regimens that physicians may choose. Although this tool was developed in Ontario, it can be used in any province in Canada.

CONCLUSIONS
Insulin is a proven and effective, yet underutilized, tool to achieve glycemic control. Hopefully, the simple and straightforward approach to insulin initiation described in this article, plus the Insulin Prescription Tool from the OCFP, can begin to make insulin

use easier and more practical. Remember the Rule of 3s: 3 categories of insulin (bolus, basal, premixed) 3 principles of dosing insulin: Whatever starting dose you select will be wrong. Titration is the key to success. There is no maximum dose of insulin.

mellitus. Cochrane Database Syst Rev. 2007(2):CD005613. 10. Holman RR, Farmer AJ, Davies MJ, et al. Three-year efcacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009;361:1736-1747. 11. Lankisch MR, Ferlinz KC, Leahy JL, et al. Introducing a simplied approach to insulin therapy in type 2 diabetes: a comparison of two single-dose regimens of insulin glulisine plus insulin glargine and oral antidiabetic drugs. Diabetes Obes Metab. 2008;10:1178-1185. 12. Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169:616-625. 13. Charbonnel B, DeFronzo R, Davidson J, et al; PROactive Investigators. Pioglitazone use in combination with insulin in the prospective pioglitazone clinical trial in macrovascular events study (PROactive19). J Clin Endocrinol Metab. 2010;95:2163-2171. 14. Arnolds S, Dellweg S, Clair J, et al. Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proofof-concept study. Diabetes Care. 2010;33:1509-1515. 15. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154:103-112. 16. Gerstein HC, Yale JF, Harris SB, et al. A randomized trial of adding insulin glargine vs. avoidance of insulin in people with type 2 diabetes on either no oral glucose-lowering agents or submaximal doses of metformin and/or sulphonylureas. The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study. Diabet Med. 2006;23:736-742. 17. Rosenstock J, Davies M, Home PD, et al. A randomized, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulinnave people with type 2 diabetes. Diabetologia. 2008;51:408-416. 18. Module 9: Intensive insulin treatment. In: Practical Diabetes Management: Clinical Support for Primary Care Physicians. 5th edition. Toronto, ON: Canadian Diabetes Association; 2004:9.1-9.12.

REFERENCES
1. Braga M, Casanova A, Teoh H, et al. Treatment gaps in the management of cardiovascular risk factors in patients with type 2 diabetes in Canada. Can J Cardiol. 2010;26:297-302. 2. Harris SB, Stewart M, Belle Brown, J, et al. Type 2 diabetes in family practice: room for improvement. Can Fam Physician. 2003;49:778-785. 3. Harris SB, Eko JM, Zdansowicz Y, et al. Glycemic control and morbidity in the Canadian primary care setting (results of the diabetes in Canada evaluation study). Diabetes Res Clin Pract. 2005;70:90-97. 4. Polonsky WH, Fisher L, Guzman S, et al. Psychological insulin resistance in patients with type 2 diabetes. Diabetes Care. 2005;28:2543-3544. 5. Nakar S, Yitzhaki G, Rosenberg R, et al. Transition to insulin in type 2 diabetes: family physicians misconception of patients fears contribute to existing barriers. J Diabetes Complications. 2007;21:220-226. 6. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2008;32(suppl 1):S1-S201. 7. Anderson JH Jr, Brunelle RL, Keohane P, et al. Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Multicenter Insulin Lispro Study Group. Arch Intern Med. 1997;157:1249-1255. 8. Anderson JH Jr, Brunelle RL, Koivisto VA, et al. Improved mealtime treatment of diabetes mellitus using an insulin analogue. Multicenter Insulin Lispro Study Group. Clin Ther. 1997;19:62-72. 9. Horvath K, Jeitler K, Berghold A, et al. A long-acting insulin analogue versus NPH insulin (human isophane insulin) for type 2 diabetes

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