Pharmacotherapy in Type 1 Diabetes

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee

Angela McGibbon MD, PhD, FRCPC Cindy Richardson MD, FRCPC Cheri Hernandez RN, PhD, CDE John Dornan MD, FRCPC, FACP

  • Key Messages
  • Recommendations
  • Figures
  • Full Text
  • References

Key Messages

  • Basal-bolus insulin regimens (e.g. multiple daily injections or continuous subcutaneous insulin infusion) are the insulin regimens of choice for all adults with type 1 diabetes.
  • 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.
  • All individuals with type 1 diabetes should be counseled about the risk, prevention and treatment of insulin-induced hypoglycemia.


Insulin is lifesaving pharmacological therapy for people with type 1 diabetes. Insulin preparations are primarily produced by recombinant DNA technology and are formulated either as structurally identical to human insulin or as a modification of human insulin (insulin analogues) to alter pharmacokinetics. Human insulin and insulin analogues are preferred and used by most adults with type 1 diabetes; however, preparations of animal-sourced insulin are still accessible in Canada (1).

Insulin preparations are classified according to their duration of action and are further differentiated by their time of onset and peak actions ( Table 1 ). Premixed insulin preparations are available and are not generally suitable for intensive treatment in patients with type 1 diabetes in whom frequent adjustments of insulin are required.

There may be a role for adjunctive therapy in some people with type 1 diabetes to aid in achieving optimal glycemic targets. Pharmacotherapy for prevention of complications and treatment of risk factors will be addressed in other chapters.

Insulin Delivery Systems

Insulin can be administered by syringe, pen or pump (continuous subcutaneous insulin infusion [CSII]). Insulin pen devices facilitate the use of multiple injections of insulin. 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 (2,3). Advancements in basal insulins may lessen the value of CSII in type 1 diabetes. CSII may provide some advantages over other methods of intensive therapy, particularly in individuals with higher baseline glycated hemoglobin (A1C) (4–9) In patients using CSII, insulin aspart and insulin lispro have been shown to be superior to regular insulin by improving postprandial glycemic control and reducing hypoglycemia (10–13). Advances in continuous glucose monitoring systems (CGMSs) may augment CSII (14,15). For CSII and CGMS, adverse events, cost and mortality data are lacking (3).

Initiation of Insulin Therapy

Patients with type 1 diabetes will be initiated on insulin therapy immediately at diagnosis. This will involve both the selection of an insulin regimen and the start of education. 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

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 is, however, transient (usually weeks to months), and insulin requirements will increase with time.

While fixed-dose regimens (conventional therapy) once were common and still may be used in some circumstances, they 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 (16,17). The most successful protocols for type 1 diabetes rely on basal-bolus (basal-prandial) regimens that are used as a component of intensive diabetes therapy. 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.

Table 1
Types of insulin
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.
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)
Humulin ® 30/70
Novolin ® ge 30/70, 40/60, 50/50
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)
Biphasic insulin aspart (NovoMix ® 30)
Insulin lispro/lispro protamine (Humalog ® Mix25 and Mix50)

Compared with regular insulin, insulin aspart, insulin glulisine or insulin lispro, in combination with adequate basal insulin, results in improved postprandial glycemic control and A1C while minimizing the occurrence of hypoglycemia (when using insulin lispro or insulin aspart) (18–23). Regular insulin should ideally be administered 30 to 45 minutes prior to a meal. In contrast, 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. However, preprandial injections achieve better postprandial control and, possibly, better overall glycemic control (22,24,25). Insulin aspart has been associated with improved quality of life (26). Insulin glulisine has been shown to be equivalent to insulin lispro for glycemic control, with greater A1C reduction when given preprandially as opposed to postprandially (22,27).

When used as a basal insulin in patients with good glycemic control, the long-acting analogues, insulin detemir and insulin glargine (with regular insulin or rapid-acting insulin analogues for meals), result in lower fasting plasma glucose levels and less nocturnal hypoglycemia compared with once- or twice-daily NPH insulin (18,28–37). Given the potential severe consequences of nocturnal hypoglycemia (discussed below), the avoidance of this complication is of critical clinical importance. Patients report increased treatment satisfaction and quality of life with use of insulin glargine compared with use of NPH in a basal-bolus insulin regimen (38,39).

When compared with 4-times-daily NPH insulin, insulin glargine was associated with lower A1C and less hypoglycemia (32). Among people with type 1 diabetes, insulin glargine has been shown to have a longer duration of action compared with detemir (40) ; however, 15% to 30% of patients using insulin glargine will experience preinjection hyperglycemia, which is prevented by twice daily administration of the insulin (41). Insulin detemir has a flatter pharmacodynamic profile than NPH insulin (33). Twice-daily insulin detemir as the basal component of a basal-bolus insulin regimen has been shown to reduce nocturnal hypoglycemia compared with twice-daily NPH insulin (34,42). There has been a trend toward improved A1C with both insulin detemir and insulin glargine that has reached significance in several studies (36,38,42–46). 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.

An ultra-long-acting insulin analogue, insulin degludec, has been shown to have comparable safety and tolerability to insulin glargine when used as a basal insulin in type 1 diabetes and less hypoglycemia (47).

Adjunctive therapy for glycemic control

As the incidents of obesity and overweight increase in the population, including those with type 1 diabetes, there is increasing interest in the potential use of oral medications that improve insulin sensitivity for these patients. The use of metformin in type 1 diabetes reduces insulin requirements and the total cholesterol/low-density lipoprotein ratio and may lead to modest weight loss, but it does not result in improved A1C (48). Metformin use in type 1 diabetes is off-label and potentially harmful in the setting of renal or heart failure.


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. The diabetes healthcare team should review the patient’s experience with hypoglycemia at each visit. This should include an estimate of cause, frequency, symptoms, recognition, severity and treatment, as well as the risk of driving mishaps with hypoglycemia.

Intensive vs. conventional insulin therapy

Hypoglycemia is the most common adverse effect of intensive insulin therapy in patients with type 1 diabetes. In the DCCT, 35% of patients in the conventional treatment group and 65% in the intensive group experienced at least 1 episode of severe hypoglycemia (49,50). In a meta-analysis of 14 trials, the median incidence of severe hypoglycemia was 4.6 and 7.9 episodes per 100 patient-years in the conventionally treated and intensively treated patients, respectively (51). Studies have suggested that with adequate self-management education, appropriate glycemic targets, SMBG and professional support, intensive therapy may result in less hypoglycemia than reported in the DCCT (52–55). CSII leads to reductions in severe hypoglycemia compared to multiple daily injections (56). CGMS used in addition to CSII or with multiple daily injections is associated with less hypoglycemia than with the use of traditional glucose testing (57,58).

Insulin analogues vs. regular and intermediate-acting insulins

Although there are no differences in the magnitude and temporal pattern of the physiological, symptomatic and counterregulatory hormonal responses to hypoglycemia induced by regular human insulin or rapid-acting analogues (59,60), the frequency of hypoglycemic events has been shown to be reduced with rapid-acting insulin analogues compared with regular insulin (18–21).

Long-acting insulin analogues may reduce the incidence of hypoglycemia and nocturnal hypoglycemia when compared to intermediate-acting insulin as the basal insulin (36,37,61–64).

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 (65,66). For patients managed with fixed-dose insulin regimens, care should be taken to develop an individualized meal and activity plan that the person can and will follow (67). 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 (68,69).

Knowledge of the acute effects of exercise is mandatory. 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. In contrast, 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 (70). Exercise-induced hypoglycemia may be lessened with the use of detemir as the basal insulin (71).

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 is often the primary barrier to achieving glycemic targets in people with type 1 diabetes (72) and occurs frequently during sleep or in the presence of hypoglycemia unawareness (73,74). The sympathoadrenal response to hypoglycemia is reduced during sleep (75,76). Asymptomatic nocturnal hypoglycemia is common and often lasts >4 hours (73,77–80). Severe hypoglycemia, resulting in seizures, is more likely to occur at night than during the day (81). To reduce the risk of asymptomatic nocturnal hypoglycemia, individuals using intensive insulin therapy should periodically monitor overnight BG levels at a time that corresponds with the peak action time of their overnight insulin.

In type 1 diabetes, hypoglycemia was reported to occur at a mean rate of approximately 2 episodes per week. Frequent hypoglycemia can decrease normal responses to hypoglycemia (82) and lead to hypoglycemia unawareness and defective glucose counterregulation. Both hypoglycemia unawareness and defective glucose counterregulation are potentially reversible. Strict avoidance of hypoglycemia for a period of 2 days to 3 months has been associated with improvement in the recognition of severe hypoglycemia, the counterregulatory hormone responses or both (52,82–88). Structured educational and psychobehavioural programs (e.g. BG awareness training) may help improve detection of hypoglycemia and reduce the frequency of severe hypoglycemia (89,90).


Insulin regimens for type 1 diabetes

  1. 1. 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 (16)].
  2. 2. 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 (19,21,23)] and achieve postprandial glucose targets [Grade B, Level 2 (23,91)].
  3. 3. Rapid-acting insulin analogues (aspart or lispro) should be used with CSII in adults with type 1 diabetes [Grade B, Level 2 (10,11)].
  4. 4. A long-acting insulin analogue (detemir, glargine) may be used as the basal insulin [Grade B, Level 2 (28-31)] to reduce the risk of hypoglycemia [Grade B, Level 2 (63) for detemir; Grade C, Level 3 (64) for glargine], including nocturnal hypoglycemia [Grade B, Level 2 (63) for detemir; Grade D, Consensus for glargine].


  1. 5. 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].
  2. 6. 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. a. Increased frequency of SMBG, including periodic assessment during sleeping hours [Grade D, Consensus]
    2. b. Less stringent glycemic targets with avoidance of hypoglycemia for up to 3 months [Grade C, Level 3 (87,88)]
    3. c. A psychobehavioural intervention program (blood glucose awareness training) [Grade B, Level 2 (90)]

CSII, continuous subcutaneous insulin infusion; SMBG, self-monitoring of blood glucose.


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