Treatment and Prevention of Diabetes in Canada

Treatment

Type 1 Diabetes

Insulin therapy is the cornerstone of treatment for type 1 diabetes mellitus. Synthetic insulin is primarily produced by recombinant DNA technology and is either chemically identical to human insulin or is a modification of human insulin (insulin analogues) designed to improve pharmacokinetics. Insulin preparations (Table 1) can be classified according to their duration of action and further differentiated by their onset or peak of action. Regardless of type or classification, there are a variety of different methods of insulin delivery available, including syringes, pen, and pumps.

Table 1. Insulin preparations in Canada[1]

Patients must receive initial and ongoing education that includes comprehensive information on use of insulin, recognition and treatment of hypoglycemia, adjustments for food intake and physical activity, and self-monitoring of blood glucose.[1] There are numerous insulin regimens that can be recommended; the type selected is dependent on treatment goals, lifestyle, diet, age, and general health of each individual. Adding to the complexity of insulin regimens and glycemic management are several factors that affect the bioavailability of injected insulin. These variables include site and depth of injection, insulin concentration, insulin mix, and prior exercise.

Intensive insulin therapies for patients with type 1 diabetes attempt to imitate normal pancreatic insulin secretion utilizing a basal component and a bolus component. The risk of nocturnal hypoglycemia and fasting hyperglycemia is increased with combination insulin regimens using both long-acting (basal) regimens and short-acting (bolus) regimens, as opposed to using either basal or bolus alone.[2]

Fasting hyperglycemia can be improved when NPH insulin is administered at bedtime instead of with the evening meal.[3] Lente insulin appears to have a longer duration of action and a later peak of action than NPH insulin.[4] Both lente and ultralente insulins contain excess zinc. When regular insulin is mixed with lente insulin, binding occurs with the zinc, and the regular insulin precipitates out of the solution. Consequently, if a mixture of regular and lente insulins remains in the syringe for more than a few minutes, the action of the regular insulin will be blunted.[5] Ultralente insulin has a broad peak of action, ranging from 8-10 hours in some studies and 12-16 hours in other studies.[6] Its duration of action ranges from 20-24 hours.[6] Ultralente insulin is best administered twice daily; if administered only once daily, it should be given at bedtime.[5] Because of its prolonged peak and duration of action, ultralente insulin given before the evening meal improves fasting blood glucose levels compared with NPH or lente insulin administered at the same time.[7]

Bolus insulins include regular, lispro, and aspart. Regular insulin should ideally be administered 30-45 minutes before a meal. Its effective duration is 3-6 hours.[8] Insulin lispro and insulin aspart should be administered 0-15 minutes before meals. However, since their onset of action is very fast, they can also be administered up to 15 minutes after a meal. Insulin lispro or insulin aspart, in combination with basal insulin, is preferred to regular insulin to achieve postprandial glycemic targets and improve A1C while minimizing the occurrence of hypoglycemia.[9],[10]

Severe hypoglycemic reactions are the primary barrier to achieving optimal glycemic control in people with type 1 diabetes.[11] Hypoglycemia can result in confusion, coma, or seizure. 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.[11] A diabetes healthcare team should review the patient’s experience with hypoglycemia at each visit, including an estimate of cause, frequency, symptoms, recognition, severity, and treatment.[1] In people with type 1 diabetes, hypoglycemia occurs at an average rate of approximately 2 episodes per week; increasing frequency can lead to a decrease in the hormonal responses to hypoglycemia,[12] which can then lead to decreased awareness of hypoglycemia and defective glucose counterregulation. The major risk factors for severe hypoglycemia include a prior episode of severe hypoglycemia, a current low A1C (<6.0%), hypoglycemia unawareness, long duration of diabetes, and autonomic neuropathy.[1]

Type 2 Diabetes

Type 2 diabetes mellitus is a chronic disease that is growing in prevalence worldwide.[13] The disease is characterized by both insulin resistance and progressive β-cell failure. With the growing elderly Canadian population, the increasing obesity epidemic, and the alarming increase in childhood and adolescent type 2 diabetes, the burden of this disease will continue to grow. The results of the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that improved control of blood glucose levels can substantially lower the overall morbidity associated with this disease, underscoring the urgency to maintain optimal glucose control in people with type 2 diabetes. Short-term hyperglycemia can result in vascular changes, and 20-50% of people already have microvascular and macrovascular complications at the time of diagnosis.[14] Therefore, it is recommended that management regimens of patients in Canada with type 2 diabetes be tailored to the individual patient, aiming for glycemic targets as close to normal as possible and, in most people, as early as possible.[1]

The Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada recommends a target A1C concentration of 7.0% or less for all patients with diabetes and, for those in whom it can be safely achieved, a target A1C concentration in the normal range (usually ≤6.0%) for patients with type 2 diabetes (Table 2).[1]

Table 2. Canadian Diabetes Association Clinical Practice Guidelines[1]

Nonpharmacologic therapy (eg, diet, exercise, and weight loss) remains a critical component in the initial treatment of diabetes. Unfortunately, lifestyle intervention often fails, and pharmacologic therapy is necessary to achieve optimal glycemic control. Despite the variety of available hypoglycemic agents, the control of blood glucose remains a treatment problem.[15] Several oral agents are currently available in Canada for patients with type 2 diabetes (Table 3).[1]

Table 3. Oral agents in Canada[1]

Biguanides

Over 30 years ago various biguanides were used in different countries for treating diabetes. All but metformin were removed from the market in the 1970s due to the high risk of lactic acidosis. The mechanisms by which metformin exerts its antihyperglycemic effects are still not entirely clear. Its major action is to decrease hepatic glucose output and, to a lesser degree, increase glucose uptake by skeletal muscles.[16] In placebo-controlled trials, metformin lowers A1C concentrations by about 1.0-1.5%.[17] Metformin also has beneficial effects beyond glycemic control. It is associated with weight loss, or at least with no weight gain. Metformin therapy also improves lipid profiles by reducting plasma levels of free fatty acids, triglycerides, and very low-density lipoproteins.[18] The UKPDS examined the long-term effects of metformin compared with conventional diet therapy and intensive sulfonylurea or insulin therapy in a subgroup of overweight patients.[19] The metformin group experienced less hypoglycemia and weight gain than the intensive groups. More importantly, the metformin group experienced a 36% relative risk reduction in all-cause mortality, a 39% relative risk reduction in myocardial infarction, and a 30% relative risk reduction in all macrovascular endpoints compared with the conventional group.

Metformin is approved for use in diabetes either as monotherapy or in combination with other oral agents and insulin. The Canadian Diabetes Association recommends it as first-line therapy for overweight patients with type 2 diabetes.[18] It should be started at a low dose (500 mg once daily) and titrated upward at 1-2 week intervals to a maximum dose of 1,000 mg twice daily. Gastrointestinal side effects such as abdominal discomfort, anorexia, bloating, and diarrhea are observed in 10-15% of patients.[18] Lactic acidosis with metformin therapy is extremely rare. Side effects usually improve with continued use and are minimal if started at a low dose (250-500 mg/d) and slowly titrated upward. Since insulin secretion is not altered, hypoglycemia is not a side effect of metformin.  

Thiazoladinediones

Thiazolidinediones (TZDs) improve insulin sensitivity. The two agents in this class currently used in Canada are rosiglitazone and pioglitazone. TZDs function as ligands for the peroxisome proliferator-activated receptor γ (PPAR γ) and are most highly expressed in adipocytes. PPAR γ receptors are ligand-activated transcription factors and play an integral role in regulating the expression of a variety of genes involved in carbohydrate and lipid metabolism. There is also growing evidence to suggest that TZDs improve and preserve pancreatic β-cell function, although this has not been demonstrated definitively.[20] In placebo-controlled trials, TZDs lower A1C concentrations to the same extent as metformin or sulfonylureas.[18] Preliminary data suggest that TZDs may have beneficial effects beyond their effects on glycemic control, including reduced urinary albumin excretion, increased levels of high-density lipoprotein cholesterol and reduced triglyceride levels, and lower blood pressure.[18] Some studies have also demonstrated improvement in surrogate markers of atherosclerosis, such as intimal-media thickness and neointimal proliferation after angioplasty.[21] However, there are currently no long-term microvascular or macrovascular clinical outcome data available on the use of TZDs in patients with diabetes.

TZDs are approved for use as monotherapy or in combination with metformin, sulfonylureas, meglitinides, or α-glucosidase inhibitors. Although some effect can be seen in 2-3 weeks, it may take 6-12 weeks to observe the full blood glucose-lowering effect. The major side effects of TZDs are weight gain, edema, anemia, pulmonary edema, and congestive heart failure.[22] The incidence of peripheral edema is increased when use of the drug is combined with another glucose-lowering medication, particularly insulin.[22] Thus, TZDs are not approved for use in combination with insulin in Canada.[1]

Sulfonylureas

Sulfonylureas (SUs) have remained a mainstay of antidiabetic therapy since the early 1950s. They work by binding to the SU receptor on the surface of pancreatic β cells and stimulating insulin release from the pancreas. SUs currently available in Canada include gliclazide, glimepiride, glyburide, and the older agents chlorpropamide and tolbutamide. SU monotherapy produces an average reduction in A1C concentrations of approximately 1.0-1.5%.[23] The UKPDS demonstrated that intensive glycemic control with either SUs or insulin resulted in significant reductions in microvascular complications, and a subsequent epidemiologic analysis demonstrated a reduction in macrovascular complications associated with improved glycemic control.[24] In general, it is best to start with a low dose and titrate upward every 1-2 weeks to achieve the desired glycemic control and avoid hypoglycemia, particularly in elderly patients[18]

The most frequent side effects of SUs are hypoglycemia and weight gain. The results of several large clinical trials indicate an average incidence of hypoglycemia of 1-2% per year.[18] Most episodes are mild and easily treated, but prolonged and severe hypoglycemia can occur, especially in the setting of renal or hepatic impairment or in frail, elderly patients. Hypoglycemia is more common with glyburide use than with gliclazide or glimepiride.[18] The weight gain observed with SU therapy, typically 2-5 kg, is related to the increase in plasma insulin levels.[25] SUs are also contraindicated in patients with moderate to severe liver dysfunction, since these medications are metabolized in the liver. Caution is recommended with SU use in patients with moderate renal dysfunction[18].

Meglitinides

Meglitinides are a relatively new class of medication represented by nateglinide and repaglinide. Nateglinide is a phenylalanine derivative, and repaglinide is a benzoic acid derivative. The mechanism of action of these medications is similar to that of the SUs, but they bind to the SU receptor at a different site and with different kinetics, resulting in a faster onset of action and shorter half-life.[26] The efficacy of repaglinide appears to be similar to that of Sus; the efficacy of nateglinide appears to be somewhat less, with a reduction in A1C concentrations of 0.5-1.0%.[26] Meglitinides are taken just before meals and may be taken 3 or even 4 times daily. They are particularly useful for patients who require meal-time flexibility. These medications can be used either as monotherapy or in combination with other oral agents (but not SUs). As with SUs, the main side effect of meglinitinides is hypoglycemia. However, the risk of hypoglycemia is lower than that with SUs. Similarly, the amount of weight gain appears to be less than that seen with SUs. The nonsulfonylurea insulin secretagogues are contraindicated in individuals with severe liver dysfunction, and the dose should be reduced in patients with severe kidney dysfunction.[18]

α-glucosidase inhibitors

α-glucosidase inhibitors inhibit enzymes in the small intestine that break down oligosaccharides and disaccharides into monosaccharides. Therefore, the intestinal absorption of carbohydrates and glucose entry into systemic circulation is delayed and postprandial hyperglycemia is reduced. α-glucosidase inhibitors demonstrate an average A1C lowering effect of about 0.5-1.0%.[21] Acarbose is the only α-glucosidase inhibitor available in Canada. It is rarely used alone and not recommended as initial therapy for moderate to severe hyperglycemia.[1] Gastrointestinal side effects are associated with α-glucosidase inhibitors and include bloating, abdominal discomfort, diarrhea, and flatulence.[21] Initiation of therapy at a low dose with slow titration may minimize these side effects, and symptoms may diminish with extended use. α-glucosidase inhibitors are contraindicated in patients with irritable bowel syndrome or severe kidney or liver dysfunction.

The initial use of combinations of submaximal doses of oral antihyperglycemic agents produces rapid and improved glycemic control when compared to monotherapy with the maximal dose, without a significant increase in side effects.[27] Many patients on monotherapy followed by subsequent addition of combination therapy may not attain target blood glucose (BG) levels, and combination therapy may be required to achieve glycemic targets.[28] The Canadian Diabetes Association suggests that the lag period before adding other antihyperglycemic agent(s) should be kept to a minimum, taking into account the pharmacokinetics of the different agents. With timely adjustments to and/or additions of antihyperglycemic agents, the target glycosylated A1C level should be attainable within 6-12 months.[1]

Prevention

Type 1 Diabetes

There are currently no known safe and effective preventive therapies to prevent type 1 diabetes, and this topic is therefore an active area of research. Several strategies have been or are being investigated for prevention.[29] Use of vaccines to prevent the immune system from destroying pancreatic β cells is one technique that has been effective in mice but has not yet proven efficacious in humans. Another approach is treating individuals with a family history of diabetes injected or oral insulin before they develop diabetes. Unfortunately, in persons at high risk for diabetes, insulin at the dosage used in the Diabetes Prevention Trial-Type 1 (DPT-1) did not delay or prevent type 1 diabetes.[30] The Canadian Diabetes Association states that any attempts to prevent type 1 diabetes should be undertaken only within the confines of formal research protocols.[1]

Type 2 Diabetes

There is great interest in the prevention of type 2 diabetes. Clinical studies have identified physical and biochemical variables associated with the subsequent development of type 2 diabetes. These variables include older age, certain ethnic backgrounds, obesity (especially abdominal obesity), physical inactivity, history of gestational diabetes mellitus, overt coronary artery disease, high fasting insulin level, and impaired glucose tolerance (IGT).[1] The greatest risk of developing diabetes is associated with IGT; for this reason, a number of type 2 diabetes prevention trials have included subjects with IGT. These trials compared intensive lifestyle modifications (diet, exercise, and weight loss), oral agents for diabetes, and placebo controls[31],[32]. The greatest success thus far has been achieved with intensive lifestyle modification, with a 58% reduction in progression from IGT to overt diabetes in 2 separate trials.[32],[33] Dietary modification used a low-calorie diet with reduced fat intake combined with physical activity of at least 150 minutes per week. This regimen resulted in weight loss of approximately 5% of initial body weight. In these same studies, the use of metformin resulted in a 33% relative reduction in the conversion to overt diabetes. However, subsequent analysis suggested that the diabetes prevention effect was accounted for by the pharmacologic action of metformin that did not persist when the drug was stopped, such that the preventive effect was actually lower, about 25%.[34]

References

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4. Hirsch IB. Type 1 diabetes mellitus and the use of flexible insulin regimens. Am Fam Physician. 1999;60: 2343-2352.
5. Hirsch IB. Intensive treatment of type 1 diabetes. Med Clin North Am.1998;82:689-719.
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7. Parillo M, Mura A, Iovine C, Rivellese AA, Lavicoli M, Riccardi G. Prevention of early-morning hyperglycemia in IDDM patients with long-acting zinc insulin. Diabetes Care. 1992;15:173-177.
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22. Nesto RW, Bell D, Bonow RO, et al. American Heart Association; American Diabetes Association. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation. 2003;108:2941-2948.
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25. Lebovitz HE. Alpha-glucosidase inhibitors. Endocrinol Metab Clin North Am. 1997;26:539-551.
26. Dailey G. Insulin secretagogues: who, what, when, and how? Curr Diab Rep. 2005;5:329-332.
27. Garber AJ, Larsen J, Schneider SH, et al. Simultaneous glyburide/metformin therapy is superior to component monotherapy as an initial pharmacological treatment for type 2 diabetes. Diabetes Obes Metab. 2002;4:201-208.
28. Turner RC, Cull CA, Frighi V, et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA. 1999;281:2005-2012.
29. Winter WE, Schatz D. Prevention strategies for type 1 diabetes mellitus: current status and future directions. BioDrugs. 2003;17:39-64.
30. Diabetes Prevention Trial–Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med. 2002;346:1685-1691.
31. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance (the STOP-NIDDM trial). JAMA. 2003;290:486-494.
32. Knowler WC, Barrett-Connor E, Fowler SE, et al. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
33. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350.
34. The Diabetes Prevention Program Research Group. Effects of withdrawal from metformin on the development of diabetes in the Diabetes Prevention Program. Diabetes Care. 2003;26:977-980.