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Canadian Pharmacists Association
Canadian Pharmacists Association
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Chapter 12: Pharmacotherapy in Type 1 Diabetes

Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada

Introduction
  • Insulin is lifesaving pharmacological therapy for people with type 1 diabetes.
  • Insulin preparations are classified according to their duration of action and are further differentiated by their time of onset and peak actions.
  • Premixed insulin preparations are not generally suitable for intensive treatment in patients with type 1 diabetes in whom frequent adjustments of insulin are required.
Insulin Delivery Systems
  • Insulin can be administered by syringe, pen or pump (continuous subcutaneous insulin infusion [CSII]).
  • CSII therapy is a safe and effective method of intensive insulin therapy in type 1 diabetes and has shown improvements in glucose control over NPH-based regimens and, in fewer studies, over long-acting analogue regimens with less severe hypoglycemia. It may also provide advantages over other therapies in individuals with higher baseline A1C.
  • Rapid-acting insulin analogues (aspart or lispro) should be used with CSII in adults with type 1 diabetes [Grade B, Level 2].
  • Advances in continuous glucose monitoring systems (CGMSs) may augment CSII.
Initiation of Insulin Therapy
  • Patients with type 1 diabetes will be initiated on insulin therapy immediately at diagnosis.
  • Patients must receive initial and ongoing education that includes comprehensive information on how to care for and use insulin; prevention, recognition and treatment of hypoglycemia; sick-day management; adjustments for food intake (e.g. carbohydrate counting) and physical activity; and self-monitoring of blood glucose (SMBG).
Insulin Regimens

TABLE 1

  • Insulin regimens should be tailored to the individual’s treatment goals, lifestyle, diet, age, general health, motivation, hypoglycemia awareness status and ability for self-management. Social and financial aspects also should be considered.
  • After insulin initiation, some patients go through a “honeymoon period,” during which insulin requirements may decrease. This period lasts for a few weeks to months, and insulin requirements will increase with time.
  • Fixed-dose regimens (conventional therapy) are not preferred.
  • The Diabetes Control and Complications Trial (DCCT) conclusively demonstrated that intensive treatment of type 1 diabetes significantly delays the onset and slows the progression of microvascular and macrovascular complications.
  • To achieve glycemic targets in adults with type 1 diabetes, basal-bolus insulin regimens or CSII as part of an intensive diabetes management regimen should be used [Grade A, Level 1A].
    • Basal insulin is provided by an intermediate-acting insulin or a long-acting insulin analogue once or twice daily.
    • Bolus insulin is provided by a short-acting insulin or a rapid-acting insulin analogue given at each meal. Such protocols attempt to duplicate normal pancreatic insulin secretion.
    • Prandial insulin dose must take into account the carbohydrate content and glycemic index of the carbohydrate consumed, exercise around mealtime and the fact that the carbohydrate-to-insulin ratio may not be the same for each meal (breakfast, lunch and dinner).
    • Prandial insulins also can be used for correction doses to manage hyperglycemia.
  • Rapid-acting bolus 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].
  • Regular insulin should ideally be administered 30 to 45 minutes prior to a meal.
  • Insulin aspart, insulin glulisine and insulin lispro should be administered 0 to 15 minutes before meals. In fact, their rapid onset of action allows for these insulins to be administered up to 15 minutes after a meal.
  • Preprandial injections achieve better postprandial control and, possibly, better overall glycemic control.
  • 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 determir; Grade C, Level 3 for glargine], including nocturnal hypoglycemia [Grade B, Level 2 for detemir; Grade D, Consensus for glargine].
  • Due to concerns that alterations in the pharmacokinetics may occur, mixing detemir or glargine with other insulins in the same syringe is not recommended by the manufacturers.

Adjunctive therapy for glycemic control

  • The use of metformin in type 1 diabetes reduces insulin requirements and the TC/LDL-C ratio and may lead to modest weight loss, but it does not result in improved A1C.
  • Metformin use in type 1 diabetes is off-label and potentially harmful in the setting of renal or heart failure.
Hypoglycemia
  • Insulin-induced hypoglycemia is a major obstacle for individuals trying to achieve glycemic targets.
  • Hypoglycemia can be severe and result in confusion, coma or seizure, requiring the assistance of other individuals.
  • Significant risk of hypoglycemia often necessitates less stringent glycemic goals.
  • The negative social and emotional impact of hypoglycemia may make patients reluctant to intensify therapy.
  • All individuals with type 1 diabetes should be counselled about the risk and prevention of insulin-induced hypoglycemia, and risk factors for severe hypoglycemia should be identified and addressed [Grade D, Consensus].

Intensive vs. conventional insulin therapy

  • Hypoglycemia is the most common adverse effect of intensive insulin therapy in patients with type 1 diabetes.
  • Studies have suggested that with adequate self-management education, appropriate glycemic targets, SMBG and professional support, intensive therapy may result in less hypoglycemia.
  • CSII leads to reductions in severe hypoglycemia compared to multiple daily injections. CGMS used in addition to CSII or with multiple daily injections is associated with less hypoglycemia than with the use of traditional glucose testing.

Insulin analogues vs. regular and intermediate-acting insulins

  • The frequency of hypoglycemic events has been shown to be reduced with rapid-acting insulin analogues compared with regular insulin.
  • Long-acting insulin analogues may reduce the incidence of hypoglycemia and nocturnal hypoglycemia when compared to intermediate-acting insulin as the basal insulin.

Lifestyle factors

  • Deviations from recommended or appropriate self-management behaviours (e.g. eating less food, taking more insulin, engaging in more activity) account for 85% of hypoglycemic episodes. Patients using fixed-dose insulin regimens should develop and follow an individualized meal and activity plan.
  • Adding bedtime snacks may be helpful to prevent nocturnal hypoglycemia among those taking NPH as the basal insulin or in those individuals at high risk of severe hypoglycemia (regardless of insulin type), particularly when bedtime plasma glucose levels are <7.0 mmol/L.
  • Low- to moderate-intensity exercise lowers blood glucose (BG) levels both during and after the activity, increasing the risk of a hypoglycemic episode. These effects on BG levels can be modified by altering diet, insulin, and the type and timing of exercise.
  • High-intensity exercise raises BG levels during and immediately after the event. SMBG before, during and especially for many hours after exercise is important for establishing response to exercise and guiding the appropriate management of exercise.
  • If ketosis is present (urine ketone level >8.0 mmol/L or blood ketone level >3.0 mmol/L), exercise should not be performed as metabolic deterioration will occur.
  • Exercise-induced hypoglycemia may be lessened with the use of detemir as the basal insulin.

Hypoglycemia unawareness and nocturnal hypoglycemia

  • Hypoglycemia unawareness occurs when the threshold for the development of autonomic warning symptoms is close to, or lower than, the threshold for the neuroglycopenic symptoms, such that the first sign of hypoglycemia is confusion or loss of consciousness.
  • Severe hypoglycemia (causing seizures) is often the primary barrier to achieving glycemic targets in people with type 1 diabetes. It occurs frequently during sleep or in the presence of hypoglycemia unawareness.
  • Asymptomatic nocturnal hypoglycemia is common and often lasts >4 hours.
  • In individuals with hypoglycemia unawareness, the following strategies may be used to reduce the risk of hypoglycemia and to attempt to regain hypoglycemia awareness:
  1. Increased frequency of SMBG, including periodic assessment during sleeping hours [Grade D, Consensus]
  2. Less stringent glycemic targets with avoidance of hypoglycemia for up to 3 months [Grade C, Level 3]
  3. A psychobehavioural intervention program (blood glucose awareness training) [Grade B, Level 2]
Health care provider tools (from CDA)

Insulin Pen Start Checklist – Quick reference guide regarding topics to discuss with patients who are initiated on insulin therapy.

Table 1: Types of Insulin
Insulin type (trade name) Onset Peak Duration
Bolus (prandial) insulins
Rapid-acting insulin analogues (clear)
Insulin aspart (NovoRapid*) 10-15 min 1-1.5 h 3-5 h
Insulin glulisine (Apidra*) 10-15 min 1-1.5 h 3-5 h
Insulin lispro (humalog*) 10-15 min 1-2 h 3.5-4.75 h
Short -acting insulins (clear)  
Humulin*R 30 min 2-3 h 6.5 h
Novolin*ge Toronto  
Basal insulins
Intermediate-acting (cloudy)
Humulin*-N 1-3 h 5-8 h Up to 18 h
Novolin*ge NPH
Long-acting insulin analogues (clear)  
Insulin detemir (Levemir*) 90 min Not Applicable Up to 24 h (glargine 24 h, detemir 16-24 h)
Insulin glargine (Lantus*)  
Premixed Insulins
Premixed regular insulin-NPH (cloudy) A single vial or cartridge contains a fixed ratio of insulin (% of rapid-acting or short-acting insulin to % of intermediate acting insulin)
Humulin* 30/70  
Novolin* ge 30/70, 40/60, 50/50  
Premixed insulin analogues (cloudy)  
Biphasic insulin aspart (NovoMix* 30)  
Insulin lispro/lispro protamine (Humalog* Mix25 and Mix50)  

Physicians should refer to the most current edition of Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association, Ottawa, Ontario, Canada) and product monographs for detailed information.

For definitions of the levels of evidence cited in this chapter, please refer to the Guideline Recommendations: Levels of Evidence.

If you would like more details on this topic, including references, please visit the Canadian Diabetes Association Clinical Practice Guidelines: Chapter 12.