1998 clinical practice guidelines for the management of diabetes in Canada

Supplement to CMAJ 1998;159 (8 Suppl)

© 1998 Canadian Medical Association

Current approved categories of oral agents include sulfonylureas, biguanides, alpha-glucosidase inhibitors and thiazolidinediones. (As of September 1998, thiazolidinediones had been approved but not yet marketed in Canada.) Sulfonylureas (acetohexamide, chlorpropamide, glyburide, gliclazide, tolbutamide, tolazamide) stimulate pancreatic insulin release. Biguanides (metformin) primarily decrease hepatic glucose production and may also delay glucose absorption and enhance insulin-mediated glucose uptake. Alpha-glucosidase inhibitors (acarbose) slow absorption of starch and sucrose in the gut. Thiazolidinediones (troglitazone) potentiate insulin action, although the full range of mechanisms is not fully understood. Sulfonylureas may increase the risk of hypoglycemia; this effect is not seen with metformin, acarbose or troglitazone unless they are combined with insulin or a sulfonylurea. Specific details regarding the actions, metabolism and side effects of these drugs can be found in a number of review articles.^{99,100, 101,102, 103,104, 105,106, 107,108, 109}

All people with type 1 diabetes require insulin therapy to prevent hyperglycemia and life-threatening ketoacidosis. Although type 1 diabetes is usually acute, some adults with newly developed type 1 diabetes may present with a slowly progressive disease that could be misdiagnosed as type 2 diabetes; indeed it may even respond initially to oral agents. However, if these patients are started on oral agents instead of insulin, they will be at risk of decompensating relatively rapidly and developing ketoacidosis as their pancreas stops producing insulin. Therefore, the possibility that an adult with new-onset diabetes has type 1 diabetes (particularly if that person is not obese) and, thus, requires insulin must be carefully considered.

Recommendations

31. When changes in lifestyle fail to result in achievement of target glucose levels in 2 to 4 months or if symptoms or severe hyperglycemia persist, oral hypoglycemic agents should be initiated. If lifestyle changes and oral agents are unsuccessful or in the presence of signs of deterioration with significant symptoms of hyperglycemia, the person must begin insulin therapy directly. [Grade A, Level 1¹¹⁰]
32. The initial oral agent used can be (in alphabetical order) an alpha-glucosidase inhibitor, a biguanide or a sulfonylurea; the choice depends on the individual, taking into consideration the following points.
    • For those with a high degree of hyperglycemia (FPG >10 mmol/L), metformin or a sulfonylurea may be chosen as a first agent. [Grade A, Level 1¹¹⁰]
    • Metformin is associated with less weight gain and less hypoglycemia than sulfonylureas [Grade B, Level 1^110,111], but gastrointestinal side effects may be a limiting factor.
    • Metformin is contraindicated in the presence of significant renal or hepatic insufficiency, as it may cause lactic acidosis. [Grade D, consensus]
    • Acarbose may be added to diet, metformin or sulfonylurea therapy to improve glucose control [Grade A, Level 1¹¹²], but gastrointestinal side effects may be a limiting factor.
33. If target glucose levels are not attainable with a single agent, an agents or agents from other classes may be added, until the maximum dose of an agent of each class is reached. [Grade A, Level 1¹¹² for the addition of acarbose to other oral agents; Grade A, Level 1¹¹¹ for the addition of metformin to sulfonylurea; Grade D, Level 4^88,105 for the addition of sulfonylurea to other agents]

Insulin therapy

Insulin is available in human, analogue and animal formulations. Human insulin is associated with less anti-insulin antibody formation than animal insulin¹¹³ and should be used for people initiating insulin therapy. Insulin regimens should be adapted to an individual's treatment goals, lifestyle, diet, age, general health, motivation, capacity for hypoglycemia awareness and self-management, and social and financial circumstances. Anyone beginning insulin therapy must receive initial and ongoing education that includes comprehensive information on its care and use, recognition and treatment of hypoglycemia, management of sick days, and adjustments for food intake and physical activity. If the person with diabetes is not already self-monitoring blood glucose, he or she should learn or review the procedures.

Insulin preparations can be classified according to their time of onset and duration; in ascending order these include lispro, regular, NPH, lente and ultralente insulin. A variety of protocols using combinations of these insulins can successfully control glucose levels. The most frequently used protocols include

• multiple daily injections (basal-bolus protocol: regular or lispro insulin before each meal, NPH or ultralente as the basal type)
• 2 injections per day (split-mixed protocol: mixture of regular and NPH administered before breakfast and dinner)
• a single injection of NPH insulin at bedtime with oral agents during the day (for patients with type 2 diabetes only)

Premixed insulin preparations (mixtures of regular and NPH insulins in various proportions) are available and may facilitate the use of the split-mixed protocol, particularly in the elderly. Insulin pen devices are gaining in popularity because of their greater ease of use. Intensive insulin therapy using a subcutaneous pump (CSII) is an alternative to multiple daily injections, primarily in patients with type 1 diabetes.¹¹⁴

Insulin use in type 1 diabetes

Insulin is essential for life in people with type 1 diabetes. The associated significant beta-cell destruction occurs very quickly in the young and more slowly when the disease presents later in life.

As already noted, insulin is available in a number of formulations defined by their absorption rate, peak activity and duration of action. Long-acting (ultralente) and intermediate-acting (NPH and lente) insulins are best used as a background (basal) insulin, but may be used at mealtime. Short-acting insulins (regular and lispro) are rapidly absorbed and best used as mealtime (bolus) insulins. Combinations of these insulins and adjustment of the time of their administration are required for optimal blood glucose control.

Lispro is a new insulin analogue that is absorbed more rapidly than regular insulin after subcutaneous injection. It results in lower postprandial glucose levels, fewer nocturnal hypoglycemic events and improved quality of life in some people.^115,116 There is no strong evidence that it can result in lower HbA_1c compared with regular insulin, except in those using pump therapy.¹¹⁷ It should be used with caution in the presence of gastroparesis and should not be combined with acarbose. At present, lispro insulin is not recommended during pregnancy, as there are insufficient data to support its safety.^115,116

Recommendations

34. Most people with type 1 diabetes should aim for optimal glucose levels to prevent or delay microvascular complications of diabetes. [Grade A, Level 1⁷⁷]
35. To achieve target glucose levels, multiple daily injections (3 or 4 per day) or the use of continuous subcutaneous insulin infusion (CSII) as part of an intensified diabetes management regimen are usually required. [Grade A, Level 1⁷⁷]
36. Regular or lispro insulin, or both, can be used before meals in intensified therapy (multiple daily injections and CSII). Lispro has been associated with lower postprandial glucose levels and lower rates of hypoglycemia than regular insulin. [Grade A, Level 1^77,115,116] Lispro is the preferred insulin for use in CSII. [Grade B, Level 2¹¹⁷]

Insulin use in type 2 diabetes

Most people with type 2 diabetes will initially attain acceptable glucose control through diet and use of oral agents. Insulin therapy may be required temporarily during periods of illness or stress. Many others will become refractory to diet and oral agents and will require insulin for metabolic control. In these people, insulin doses (frequently high) and the number of injections (1–4) should be adjusted to achieve target glucose levels.⁸⁸ A combination of insulin and oral agents may effectively control glucose levels.

Recommendations

37. Intensive insulin therapy may prevent microvascular complications in people with type 2 diabetes. [Grade B, Level 1⁷⁶]
38. If individual treatment goals have not been reached on a regimen that includes appropriate use of diet, exercise and oral agents, then insulin therapy should be initiated to improve glycemic control. [Grade A, Level 1¹¹⁸]
39. When insulin therapy is initiated, the concomitant use of oral agents is an acceptable option. When insulin therapy is added to oral agents, a single injection of intermediate-acting insulin may be added at bedtime. [Grade B, Level 1¹¹⁹] This approach may result in better glucose control with a smaller insulin dose [Grade A, Level 1+¹²⁰] and may induce less weight gain than with the use of insulin alone.
40. Poor glucose control despite insulin therapy can be improved by the addition of one of the following oral agents:
    • acarbose [Grade A, Level 1¹²¹]
    • metformin [Grade B, Level 1¹²²]
    • troglitazone [Grade A, Level 1¹²³]

On initiating troglitazone therapy, liver enzymes should be evaluated due to potential, severe hepatic dysfunction; evaluation should occur before therapy, monthly for the first 8 months, bimonthly for the next 4 months and periodically thereafter. [Grade D, Level 5¹²⁴]

Diabetes in children and adolescents

Specific recommendations have been developed for children and adolescents because of considerations that are relevant for this age group.

Type 1 diabetes

The insulin regimen and distribution of carbohydrates in the meal plan must be flexible in children and adolescents to allow for normal growth and development while balancing the need for reasonable glycemic control. Ongoing education of the child or adolescent is essential, to achieve age-appropriate knowledge and skills and eventual self-sufficiency. Intensive education, with ongoing reinforcement regarding sick-day management and prevention of diabetic ketoacidosis, must be provided for all families.^125,126 All parents must be taught the use of glucagon for severe hypoglycemia.¹²⁷ Adolescents must receive ongoing counselling regarding disordered eating patterns,¹²⁸ smoking, contraception, alcohol and drug abuse, and driving, as these activities relate to diabetes care.

All children should be screened for associated autoimmune diseases, such as hypothyroidism, by determining thyroid-stimulating hormone (TSH) level. Selected children with poor growth, poor glycemic control or unpredictable, frequent hypoglycemia should be tested for celiac disease using antigliadin antibodies¹²⁹ and for Addison`s disease by determining adenocorticotropic hormone (ACTH) level.

Planning the transition from pediatric to adult diabetes care must be undertaken with sensitivity to the needs of the adolescent and recognition of the factors that predict noncompliance with medical follow-up.^130,131

Recommendations

41. The metabolic goals and therapeutic strategies for adolescents over 12 years of age are the same as those for adults. [Grade A, Level 1^77,132] The target HbA_1c for prepubertal children is 120% to 140% of the upper limit of normal with targets for glucose and HbA_1c graduated according to the child's age. [Grade D, consensus] Extreme caution is required to avoid hypoglycemia in children under 5 years of age, because of the permanent cognitive deficit that may occur in this age group. [Grade D, Level 4^133,134]
42. All children with diabetes should have access to an experienced DHC team. The complex physical, developmental and emotional needs of children and their families require specialized care to ensure the best long-term outcome. [Grade D, Level 4¹²⁶]
43. In children and adolescents with new-onset diabetes, initial outpatient education and management should be considered if appropriate personnel and a 24-h telephone consultation service are available in the community. [Grade C, Level 3¹³⁵]

Type 2 diabetes

Type 2 diabetes (as distinct from genetic maturity-onset diabetes of the young or MODY forms), occurs in special groups of children. Currently, it occurs in 1% to 2% of children of Aboriginal, Hispanic or black origin and up to 4% of adolescent girls. In Canada, type 2 diabetes has been reported in Aboriginal children aged 7 and older. Most children are not symptomatic and are currently identified by screening programs in high-risk populations.

Due to the relatively low frequency and short history of this problem, which was recognized only in the 1980s, the most appropriate screening guidelines have not been developed. However, owing to the devastating consequences of early-onset complications, it is prudent to consider screening in Aboriginal children. The best management strategy for this age group is unknown. Intensive programs to increase physical activity and nutritional interventions have proven beneficial in the summer camp setting and must be encouraged in the home and community. There are no controlled trials of safety or efficacy of oral agents or insulin for type 2 diabetes in this age group (see "Diabetes in Aboriginal people" for further discussion).

Diabetes in the elderly

Because the renal threshold for glucose increases with age, elderly people frequently do not have classic symptoms of hyperglycemia (polyuria, polydypsia) until blood glucose values are markedly elevated. When symptoms are present, they are generally nonspecific (fatigue, depression, failure to thrive).

A wide variety of factors affect the ability of elderly people to follow treatment regimens. Management plans must account for limited abilities, comorbidities and potentially limited lifespans.^136,137,138 Although the interpretation of biologic status must be considered, "elderly" in the present context refers to people over 70 years of age.

Recommendations

44. The same glucose targets apply to otherwise healthy elderly as to younger people with diabetes. In people with multiple comorbidity, the goal should be to avoid symptoms of hyperglycemia and prevent hypoglycemia. [Grade D, consensus] Closer to normal glucose levels are associated with a lower risk of complications in elderly people with type 2 diabetes. [Grade A, Level 1^136,138]
45. Elderly people with diabetes should be referred to a DHC team. Interdisciplinary interventions have been shown to improve glycemic control in the elderly. [Grade B, Level 2^139,140,141]
46. In chronic care institutions, specific dietary restrictions may not be useful in improving glycemic control. [Grade D, Level 4¹⁴²] The recommended distribution of nutrients is as suggested for the general aging population. [Grade D, consensus]
47. Moderate exercise is beneficial for elderly people with type 2 diabetes; however, comorbid conditions may prevent aerobic physical training [Grade D, Level 4¹⁴³], and any increase in activity levels may be difficult to achieve. [Grade D, consensus]
48. In elderly people, sulfonylureas should be used with caution because the risk of hypoglycemia increases exponentially with age. [Grade D, Level 5¹⁴⁴] In general, initial doses should be half those for younger people, and doses should be increased more slowly. [Grade D, consensus] Gliclazide may be the preferred sulfonylurea, as it is associated with a reduced frequency of hypoglycemic events compared with glyburide. [Grade A, Level 1¹⁴⁵]
49. In elderly people, the use of premixed insulins as an alternative to mixing insulins may minimize dosage errors. [Grade B, Level 2¹⁴⁶]

Diabetes and pregnancy

Currently, the major problems associated with excess glucose crossing the placenta in pregnancy include teratogenicity and metabolic and growth abnormalities in the fetus. Long-term metabolic sequelae for women with GDM and the offspring of women with any form of diabetes in pregnancy may also occur.^147,148

Pre-existing diabetes

In the absence of prepregnancy planning and careful follow-up, maternal diabetes may be associated with an increased risk of spontaneous abortion, perinatal mortality and perinatal morbidity. Congenital malformations continue to be the major cause of perinatal mortality in diabetic women and are 2 to 7 times more common than in nondiabetic women.¹⁴⁹

Both retinal and renal disease may become more severe during pregnancy. Because significant background retinopathy may lead to deterioration of vision, affected women must have their eyes carefully monitored before and during pregnancy. Similarly, women with significant proteinuria before pregnancy are at risk for hypertension during pregnancy (with or without eclampsia), as well as worsened renal function after pregnancy.

Thus, any woman planning a pregnancy should work with a specialized DHC team to assess the level of glycemic control and the status of microvascular complications,¹⁵⁰ and to plan appropriate ongoing monitoring of glucose, blood pressure and maternal and fetal status until delivery. Women taking oral hypoglycemic agents should discontinue them and initiate use of insulin before conception.

Recommendations

Before pregnancy

50. Pregnancy in women with diabetes should be carefully planned, preferably in consultation with a high-risk prepregnancy clinic. [Grade C, Level 3¹⁵⁰]
51. All women with diabetes should attempt to attain "ideal" blood glucose control (see Table 11). Glycated hemoglobin (HbA_1c) levels greater than 140% of the upper limit of normal nonpregnant values should be avoided as they are clearly associated with increased risk of spontaneous abortion and malformations. [Grade B, Level 2¹⁵¹]
52. Both diabetic nephropathy and diabetic retinopathy may progress during pregnancy and should be evaluated and followed carefully. [Grade B, Level 2^152,153] Women should also be assessed for CAD. [Grade D, consensus]

During pregnancy

53. All women with diabetes should aim for ideal glucose levels without significant hypoglycemia. [Grade D, Level 5¹⁵⁴]
54. Any woman on diet therapy alone who does not achieve target values should be started on insulin. Use of oral agents is not recommended. [Grade D, consensus]
55. Ketosis should be avoided, especially during the third trimester. [Grade B, Level 2¹⁵⁵] Weight gain should be monitored, normal weight gain should be the goal and weight-reducing diets should be avoided. [Grade D, consensus]
56. Retinal examination should be performed regularly, at least once in the first trimester with subsequent frequency adjusted to the severity of the retinopathy. [Grade B, Level 2¹⁵²]

Gestational diabetes mellitus

Gestational diabetes is glucose intolerance of varying severity detected or first recognized during pregnancy. Its prevalence varies widely according to the population studied and criteria used for diagnosis; it often reflects the prevalence of diabetes in a given population. It is associated with an increased risk of fetal macrosomia, neonatal hypoglycemia, hyperbilirubinemia, hypocalcemia and polycythemia. Perinatal mortality is rare today in women with diagnosed GDM. The children of mothers with GDM may have an increased risk of childhood obesity and diabetes as young adults.^147,148,155 The recognition of GDM indicates an increased risk of future diabetes in the mother (primarily type 2). The basis for therapy is diet adjustment, monitoring of maternal and fetal well-being and glucose control. Use of insulin is appropriate if glucose control is not attained with diet alone.¹⁵⁶

Recommendations

57. Women with GDM should receive dietary counselling and carry out frequent FPG and postprandial glucose monitoring. [Grade C, Level 3⁵⁹] The goals associated with the best neonatal outcome are an FPG level <5.3 mmol/L [Grade C, Level 3¹⁵⁷], a 1-h postprandial glucose level <7.8 mmol/L [Grade A, Level 1¹⁵⁸] and a 2hPG level <6.7 mmol/L. [Grade D, Level 3⁵⁹]
58. Dietary counselling should be provided to ensure a well-balanced diet, with a goal of achieving normal maternal glucose levels and normal weight gain in the mother and the fetus. Because of the risk of ketonemia, weight-reducing diets are not recommended. [Grade D, consensus]
59. FPG and postprandial glucose levels should be monitored. [Grade A, Level 1¹⁵⁸] If diet therapy does not result in achievement of glucose target values, insulin therapy should be initiated. [Grade D, consensus]
60. Regular and moderate exercise, particularly of the upper body, should be encouraged. [Grade A, Level 1¹⁵⁹]
61. Women who have had GDM should be advised to achieve a healthy body weight and exercise regularly postpartum to reduce the risk of subsequent diabetes. [Grade D, consensus]
62. Women who have had GDM are at high risk for subsequent diabetes or glucose intolerance. [Grade C, Level 3^160,161] An OGTT (75-g, 2-h) should be performed 6 weeks to 6 months postpartum to rule out the presence of glucose intolerance or diabetes. [Grade D, consensus]

Diabetes in Aboriginal people

Over the past 50 years, dramatic changes in lifestyle in Aboriginal communities across North America have had a profound impact on the social, environmental and health status of this population. Although morbidity associated with infectious diseases and starvation has decreased, chronic diseases such as obesity, diabetes and cardiovascular disease have emerged. Type 2 diabetes mellitus is now recognized as a major health problem among Aboriginal people. Indeed, recent population-based epidemiologic surveys in Canada have revealed age-adjusted prevalence rates of 19% to 26%, which are among the highest reported rates in the world.^162,163

Due to the relatively recent onset of this epidemic in Aboriginal populations, complications associated with diabetes are only beginning to emerge as significant health problems. Therefore, aggressive screening for CAD, neuropathy, nephropathy and retinopathy should accompany visits to physicians by Aboriginal people according to the recommended practice guidelines.

Most Aboriginal communities are aware of diabetes and its many complications; the establishment of the National Aboriginal Diabetes Association (NADA) in 1996 reflects this. However, diabetes is often not a priority for communities in which other important political and health issues predominate. According to some, diabetes is a social disease or, more appropriately, a result of social conditions. Geographic isolation, poor eating patterns, minimal physical activity, substance abuse, psychosocial issues and even absence of basic health care in isolated communities may be significant barriers to the recognition of diabetes as a priority.

Much of the responsibility for diabetes care in communities lies with community health representatives, who are usually overburdened with other duties. In some cases, community health representatives are able to provide better care with more training, and a number of initiatives across Canada are addressing this need. Expanded community-based prevention programs are also required.

Major challenges face health care professionals and policymakers in terms of providing appropriate and practical diabetes screening and treatment programs to Aboriginal populations. Culturally appropriate community-based intervention strategies must be developed by supporting community initiatives and providing technical and financial resources. Cooperation and partnership with political leaders in grassroots organizations are essential elements in the support of innovative strategies. Local input combined with the knowledge and experience of multidisciplinary teams is required.

The major focus of this strategy should be primary prevention, and a number of such initiatives are under way¹⁶⁴ (e.g., in Kahnawake, Que., and Sandy Lake, Ont.). Programs aimed at schoolchildren and their parents are critical for the prevention of diabetes in future generations. In addition to prevention strategies, efforts to improve metabolic control and assure regular surveillance for complications, are also needed. High-risk groups such as children and women in the childbearing ages require particular attention.^{165,166,167,168} Despite the significant challenges that accompany the institution of such programs, the management and prevention of diabetes and associated complications in Aboriginal populations should be a high priority in health care planning and delivery.

At present there is no evidence that therapeutic strategies should differ from those used for the general population.

Recommendations

63. Community-based screening programs based on measuring blood glucose levels should be established in Aboriginal communities. Urban people of Aboriginal origin should be screened for diabetes in primary care settings. [Grade D, consensus]
64. Primary prevention programs initiated by Aboriginal communities should be encouraged. [Grade D, consensus]
65. There must be recognition of, respect for and sensitivity regarding the unique language, culture and geographic issues as they relate to diabetes care in Aboriginal communities across Canada. [Grade D, consensus]