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DM Guidelines
DM Guidelines
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.
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.
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
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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 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).
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.
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.
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
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)
Vial
Novolin ge NPH
Cartridge
Vial
BOLUS
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)
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
KwikPen Vial
TM
Premixed regular
Novolinge 30/70
Cartridge
Vial
Novolinge 40/60
Cartridge Cartridge
Novolinge 50/50
PEN DEVICE
NovoPen 4
Pen needles (if using pen) ___________________ Glucose test strips ___________________ Lancets ____________________ Insulin syringes (if using vial) _________________
INSULIN
Mitte:
_______ boxes
SUPPLIES
Mitte:
_______ boxes
Repeats x ____________
June 2010
Figure 2. Insulin Prescription Tool, developed by the Ontario College of Family Physicians (continued)
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
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 [email protected]
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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