RECENT ADVANCES IN PHARMACOTHERAPY

PHARMACOTHERAPIES NOUVELLES

Insulin-dependent (type I) diabetes mellitus Wilson Rodger, MD, FRCPC, CRCPC (E & M) Insulin-dependent (type I) diabetes mellitus is a chronic disease characterized by hyperglycemia, impaired metabolism and storage of important nutrients, evidence of autoimmunity, and long-term vascular and neurologic complications. Insulin secretory function is limited. Cell membrane binding is not primarily involved. The goal of treatment is to relieve symptoms and to achieve blood glucose levels as close to normal as possible without severe hypoglycemia. However, even with education and self-monitoring of the blood glucose level, attaining recommended target values (plasma glucose level less than 8.0 mmol/L before main meals for adults) remains difficult. Human insulin offers no advantage in glycemic control but is important in the management and prevention of immune-related clinical problems (e.g., injection-site lipoatrophy, insulin resistance and allergy) associated with the use of beef or pork insulin. Therapy with one or two injections per day of mixed short-acting or intermediate-acting insulin preparations is a compromise between convenience and the potential for achieving target plasma glucose levels. Intensive insulin therapy with multiple daily injections or continuous infusion with an insulin pump improves mean glycated hemoglobin levels; however, it increases rates of severe hypoglycemia and has not been shown to decrease the incidence of clinically significant renal, retinal or neurologic dysfunction. Future prospects include automated techniques of insulin delivery, immunosuppression to preserve endogenous insulin secretion and islet transplantation. Le diabete sucre insulinodependant (type I) est une maladie chronique caracterisee par l'hyperglycemie, des troubles du metabolisme et du stockage d'elements nutritifs importants, des signes d'auto-immunite et des complications vasculaires et neurologiques i long terme. La secretion d'insuline est limitee. La liaison des membranes cellulaires n'est pas atteinte au premier plan. Le traitement vise a soulager les sympt6mes et a etablir des niveaux de glycemie aussi pres de la normale que possible sans hypoglycemie grave. Toutefois, meme apres information et autosuivi de la glycemie, il demeure difficile d'atteindre les valeurs cibles recommandees (taux de glucose dans le plasma inferieur a 8,0 mmol/L avant le repas principal chez les adultes). L'insuline humaine n'offre aucun avantage pour le contr6le de la glycemie, mais elle joue un r6le important dans le contr6le et la prevention des problemes cliniques lies a l'immunite (par exemple, lipo-atrophie du point d'injection, insulinoresistance et allergies) causes par l'utilisation d'insuline de boeuf ou de porc. Un traitement constitue d'une ou deux injections quotidiennes de preparation d'insuline mixte a effet rapide ou a effet intermediaire constitue un compromis entre la commodite et la possibilite d'atteindre des taux cibles de glucose dans le plasma. Une insulinotherapie intensive par injections quotidiennes multiples ou infusion continue a l'aide d'une pompe a insuline ameliore les taux moyens d'hemoglobine glycosylee, mais elle eleve les taux d'hypoglycemie grave et il n'a pas ete demontre qu'elle reduit l'incidence de dysfonctions renales, retiniennes ou neurologiques importantes sur le plan clinique. Les perspectives futures comprennent les techniques automatisees d'injection d'insuline, l'immunosuppression afin de preserver la secretion d'insuline endogene et la transplantation d'ilots. From the Lawson Diabetes Centre, St. Joseph's Health Centre, and the Division ofEndocrinology and Metabolism, Department of Medicine, University of Western Ontario, London, Ont.

Reprint requests to: Dr. Wilson Rodger, St. Joseph's Health Centre, 268 Grosvenor St., London, ONN6A 4V2 -

For prescribing information see page 1342

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bout 4% of the general population are known to have diabetes mellitus, of whom about 10% to 15% have insulin-dependent (type I or juvenile-onset) diabetes.' Type I diabetes is characterized by onset typically in the teen-age years and usually before the age of 30 years, clinical and laboratory evidence of autoimmunity, the eventual absence of endogenous insulin, glycemic instability with ketosis, and long-term vascular and neurologic complications.2 Management is aimed at achieving normal growth and body composition, avoiding extremes of glycemia and preventing ketosis and disability due to long-term complications.3,4 Therapeutically the central issue is the absolute dependence on a continuing supply of exogenous insulin for survival. This was recognized early, and conventional therapy with one or two injections a day of beef or pork insulin achieved short-term clinical goals.5 However, in the past decade technical advances in the administration of insulin and the monitoring of glucose levels have provided a context in which the maintenance of near-normoglycemia may be examined in relation to the progress of long-term complications.6'7 This review is based on the results of clinical trials, recent reviews, practice recommendations, consensus conference reports and a guide for physicians.6- 14 Developments in insulin therapy are discussed in light of the dual requirements of safety from severe hypoglycemia and the prevention of long-term complications.

A

Properties and function of insulin

About half of secreted insulin is taken up by the liver.'8 Stimuli to insulin secretion may be nutritional (e.g., glucose and certain amino acids, such as arginine), hormonal (e.g., gastric inhibitory polypeptide and glucagon) or neural (vagal or f3-adrenergic). Inhibitors include epinephrine (a-adrenergic effect) and somatostatin.'8 Insulin is destroyed by a widely distributed insulinase, glutathione insulin transhydrogenase, which degrades the disulfide bridges and is excreted by the kidneys. Insulin normally circulates as a monomer in a "free" or "unbound" state, at a concentration of 75 to 150 pmol/mL in peripheral venous serum under basal conditions.'5 Small amounts of proinsulin and related fragments are also detectable. 9 Binding of insulin to the external portion of highly specific receptors embedded principally within the cell membranes of muscle, liver and adipose tissue activates the intracellular portion of the receptor,'720 whose function is to initiate important metabolic and growth-promoting effects. Immediate insulin effects include the promotion of membrane transport and entry of glucose, amino acids and potassium, the activation of enzymes responsible for glucose oxidation (glycolysis) and nutrient storage (glycogenesis), and the suppression of hepatic gluconeogenesis and ketogenesis, muscle proteolysis and adipose tissue lipolysis. 7 Later effects include the induction of enzymes by gene expression and the stimulation of cell proliferation. Hepatic glucose output is suppressed by insulin concentrations lower than are needed to stimulate resting peripheral (mainly muscle) glucose uptake.'5 The counterregulatory hormones in general have opposing metabolic effects.'5

Acting in concert with the counterregulatory hormones (glucagon, epinephrine, growth hormone Insulin pharmacokinetics and activity and cortisol) that respond to hypoglycemia, insulin is responsible for maintaining normal glucose homeo- Manufacture stasis.'5 The gene for insulin, on chromosome 11, is expressed in the : cell of the islets of Langerhans.'6 Historically, beef and pork pancreas have been Early in biosynthesis proinsulin is synthesized in the extracted in acidified alcohol and purified to proendoplasmic reticulum. This substance is then pro- duce beef and pork zinc-insulin crystals. Human cessed to insulin in the Golgi apparatus and proteolysed to the insulin molecule, which contains 51 amino acids arranged in A and B chains connected :---S-j by disulfide bonds (Fig. 1).1' The fragment of proinsulin formerly connecting the A and B chains A chain I_ (connecting peptide [C-peptide]) is stored with insu(21 AAs) lin in vesicles. Equimolar amounts of insulin and C S S peptide together with small amounts of proinsulin S S are secreted into the portal venous system through B chain fusion of the intracellular vesicles to the cell mem(30 Ms) brane. 30 Measurement of levels of C peptide in peripheral blood suggests that in healthy adults insulin Fig. 1: Diagrammatic representation of insulin molecule. secretion occurs at a basal rate of 1 U/h, with Sites of variability of amino acids (AAs) among species are additional meal-related surges of perhaps 3 to 5 U.18 numbered. 1228

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LE 15 NOVEMBRE 1991

m--

insulin is commercially produced in two ways. Biosynthetic human insulin is obtained from the purified culture media of large numbers of Escherichia coli genetically programmed by means of recombinant DNA techniques to synthesize proinsulin or the A and B chains separately. The products are processed biochemically to form the human insulin molecule.21 Alternatively, as animal insulin and human insulin differ only at three amino acid positions (Fig. 1), highly purified pork insulin can be chemically modified by substituting threonine for alanine at position 30 on the B chain to produce semisynthetic human insulin (Table 1).21,22 By convention, preparations of animal insulin containing less than 10 parts per million of proinsulin are considered pure. Contaminants of pancreatic origin, such as degraded insulin (desamido insulin) and other hormones (e.g., glucagon), are effectively absent from preparations of animal origin, as are bacterial contaminants (e.g., endotoxin) from biosynthetic human insulin.21 Human, beef and pork insulin behave similarly at the cellular level,23 but after injection human insulin appears more promptly in the serum than beef or pork insulin.21 Although the three types of insulin have similar metabolic clearance rates,24 under clinical conditions the use of human regular and isophane (NPH [neutral protamine Hagedorn]) insulin resulted in higher mean prebreakfast plasma glucose levels than were found with the use of Table 1: Amino acids represented at various sites in the insulin molecule

Type of insulin Human Pork Beef

Position; amino acid 8

Threonine Threonine Alanine

NOVEMBER 15, 1991

10 Isoleucine Isoleucine Valine

30 Threonine Alanine Alanine

similar formulations of pork insulin with equivalent purity and nitrogen content.25 However, in this and other double-blind randomized trials comparing human and animal insulin26-29 the earlier appearance and shorter duration of action of human preparations were not associated with differences in overall glycemic control, as measured by glycated hemoglobin levels. Insulin dosage requirements and rates of hypoglycemia were similar. Recent assertions from Europe that rates of severe hypoglycemia and patient unawareness of hypoglycemia (i.e., failure to recognize symptoms early) are higher during therapy with human insulin than with animal preparations have been effectively rebutted.30 Analysis of a number of studies suggests that the response of the counterregulatory hormones to hypoglycemia is similar during therapy with human or animal insulin.3",32 Human insulin preparations are about 40% more expensive than animal preparations.

Formulation Insulin preparations are classified on the basis of time of action (onset, peak and duration) as short acting (regular and semilente), intermediate acting (NPH and lente) and long acting (ultralente and protamine zinc).'4"7 The estimated times of action are longer for beef and pork preparations than for the equivalent human preparations (Table 2). However, as the absorption of insulin is extremely variable, these estimates should be viewed with scepticism, as should studies claiming similarities or differences among similar preparations from different manufacturers.33'34 For example, Galloway and colleagues35 reported that the intrasubject coefficient of variation for regular pork insulin (0.2 U/kg injected into the deltoid area) was approximately 20% for a decrease in the plasma glucose level of 30% to 40% below baseline and was 12% for the time

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of maximal hypoglycemia. The intrasubject and intersubject coefficients of variation for these responses to lente and NPH preparations were 20% to 40%. The therapist should thus attempt to determine in each case the individual response to the chosen preparation. In general, dosage changes should be made only when clear trends in the blood glucose level are apparent, usually over a period of several days. Regular insulin, which is in solution, is readily adapted to intravenous or intramuscular bolus injection.36-38 The onset of action is within a few minutes; the duration of action is such that in the treatment of diabetic ketoacidosis, for example, the effects will wane significantly unless injections are given hourly. 3738 The prediction of requirements with subcutaneous injection from those with intravenous injection is complicated by variability in absorption and degradation;39 one carefully controlled study suggested that there is little difference in requirements.40 Of the intermediate-acting preparations NPH insulin (a conmplex with the protein protamiine) has an earlier onset of action than lente insulin (a zinc-insulin complex precipitated in an acetate buffer in two physical forms, 70% crystalline [actually ultralente] and 30% amorphous [actually semilente]).33,4' The rapidity of the rise of serum insulin levels appears to be lessened when regular insulin is mixed with lente insulin, particularly if more than 5 minutes elapses between mixing and injection.4243 In practice sufficiently high serum insulin levels in lente insulinbased regimens appear to be achieved with a greater proportion of regular insulin;35'44 Oswald and Yudkin45 reported that glycemic control was similar with regimens of regular and of NPH or lente preparations. Current standards of purity together with accuracy of titration of protamine with insulin in the manufacture of NPH insulin have permitted the development of stable preparations of human regular and NPH insulin mixed by the manufacturer. These preparations have a biphasic insulin action that reflects the ratios of the two components (e.g., Novolin-30/70 [Connaught Novo Ltd., Willowdale, Ont.], Mixtard 30/70 Human [Nordisk Gentofte Canada Inc., Mississauga, Ont.] and Humulin 30/70 [Eli Lilly Canada Inc., Scarborough, Ont.]). In one study the predicted biphasic pattern of insulinemia was detected, and it was found to be equivalent to the pattern exhibited by the regular and NPH components injected separately.46 These mixtures are generally not suitable for use in patients with type I diabetes, in whom the ratio of shortacting to intermediate-acting insulin should be individualized and be subject to adjustment in accordance with current glucose levels, diet and activity level. In Canada insulin is marketed at a concentra1230

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tion of 100 U/mL (or "U 100," with 24 U/mg, the Fourth International Standard).2' To permit more accurate dispensing of fractions of units in cases of unusual insulin sensitivity in children a preparation of the required concentration may be made with diluent from the manufacturer.4 Regular insulin may be administered intravenously at concentrations as low as 5 U/L of infusate (e.g., to maintain glucose homeostasis during surgery).'4 Decreased bioavailability of insulin due to adsorption to the plastic of the infusion set occurs in particular with the first 50 to 100 mL of solution infused.47 In practice insulin adsorption is accommodated by the dosage adjustments necessary to control fluctuating plasma glucose levels. Preparations other than regular insulin are manufactured as suspensions and thus should be gently shaken before use.10,21 Buffers (e.g., sodium phosphate) and bacteriostatic agents (e.g., metacresol and phenol) used vary among manufacturers.'0 If the insulin is kept refrigerated and there are no temperature extremes, its potency is retained for long periods; potency may be lost if vials are kept at room temperature for more than a month.'0 Human NPH insulin preparations have occasionally been reported to form clumps ("flocculate").'0 Obvious change in the physical characteristics of the suspension or unexplained loss of glycemic control warrants a change to a new insulin vial.'0 Packaging incorporates colour, symbols and shape to minimize dosage errors by handicapped or confused patients.

Absorption Although the rate of absorption is determined mainly by the formulation,'7 rates and completeness of absorption reflect the amount of local degradation (2 1% of the injected dose in one well-designed study39) and subcutaneous blood flow (except possibly during insulin-induced hypoglycemia).48'49 Inhaled cigarette smoke decreases absorption.50 Absorption is increased with smaller volumes of injectate, lower concentrations (i.e., less than 40 U/mL), neutral pH (i.e., as supplied), exercise or massage of the injected limb, increased ambient temperature, deeper subcutaneous placement (unintended intramuscular injection being avoided, because it increases the absorption rate) and injection sites in the deltoid or abdominal regions (as compared with the thigh or buttock).2244 In a recent study it was found that rotation of injection sites in a single anatomic region improved glycemic control;5' this suggests that the same region should be used for injections at the same time of day.

Circulation Absorbed insulin circulates primarily as a free LE 15 NOVEMBRE 1991

monomer, but if ,B cells are functioning endogenous insulin or proinsulin may contribute bioactivity.19'52 Polymers (mainly dimers) also absorbed from the injection site play an unknown role in insulin-like action and appear to be immunogenic.'9 Low levels of antibodies to endogenous insulin are present in patients with type I diabetes before insulin treatment.53 In one study, after therapy was started with highly purified pork insulin or human insulin rising titres of insulin antibodies were detected in some patients within a few weeks and in 50% of subjects at 1 year.54 Titres were found to be higher with beef insulin, lower with pork insulin and lowest with biosynthetic or semisynthetic human insulin in both adults and children; this suggests that the main determinants of antibody formation are the sites of differing amino acid composition (Table 1).2254-56 The presence of zinc, protamine or impurities (e.g., animal proinsulin) also predisposes to antibody' formation.'9,2257'58 Antibodies to insulin are poorly selective, and those to the insulin of one species will bind insulin of another.59 Insulin antibodies must be removed to measure serum levels of free immunoreactive insulin. According to current methods of radioimmunoassay serum insulin levels in controlled type I diabetes are higher than normal.60 Antibodies to insulin are of two types, IgG and IgE. There is disagreement as to the effects of antibodies on metabolic control. In relatively high titres IgG antibodies bind circulating insulin, decreasing rates of rise and fall of free insulin levels.6' Although there is evidence that this may predispose to increased frequency of hypoglycemia,62 other investigators have postulated a potential advantage of the circulating "depot" of bound insulin63 or have reported that prolongation of the action of regular insulin is not associated with circulating insulin antibodies."r Maternal IgG antibodies to insulin appear to contribute to fetal macrosomatia.65 An early suggestion that insulin antibodies hasten the rate of decline of (3-cell function in children has not been confirmed.66'67 Although high titres of insulin antibodies were found to be associated with longterm diabetic complications68'69 there has never been evidence of causation. In rare cases high titres of IgG antibodies are associated with "insulin resistance," defined as an insulin requirement of over 200 U/d for more than 2 days70 due to binding of insulin before receptor interaction.7' IgE antibodies mediate local (e.g., erythema or a wheal) or generalized (e.g., urticaria or anaphylaxis) insulin allergy. Management of these problems consists of changing to an alternative insulin preparation (e.g., lente to NPH, or animal to human) and using sulfated insulin (a preparation chemically modified to lower immunogenicity), systemic corticosteroids or antihistamines.70'72'73 Inadequate glycemic control during NOVEMBER 15, 1991

treatment with beef insulin may be improved on transfer to less antigenic preparations (e.g., pork or human insulin).74 Some patients, such as those receiving more than 60 U/d, may experience severe hypoglycemia on transfer; in such cases a dosage reduction (for example, by 10% to 20%, which may be temporary) at the time of transfer is prudent, together with careful observation and further dosage adjustment if indicated.

Cellularfactors When non-antibody-bound (free) insulin crosses the endothelial barrier to the interstitial space it binds to receptors that in type I diabetes display normal characteristics.75 Binding of insulin inversely reflects serum insulin concentrations.76

Insulin therapy General approach The meal plan should suit the patient's lifestyle, but because meal-related insulin dosage reflects meal size, day-to-day variation in nutrient intake among meals and snacks should be minimized.77 Similarly, the timing of meals and physical activity should be appropriate to the patient's capabilities and should be consistent.9"' After diagnosis the patient should be instructed in the administration of insulin and self-monitoring of the blood glucose level.'0'78 Arrangements should be made for regular follow-up, measurement of glycated hemoglobin levels and professional support, which for children should be in a specialized unit.4"' Human insulin should be used in pregnant or potentially allergic patients. When previous control has been acceptable and costs are a consideration, the patient's requirements may be met with beef or pork insulin. The initial requirement of subcutaneously given insulin may be estimated with the use of a reasonable fraction, such as one-half to two-thirds, of the 24-hour insulin demand during the resolution of ketoacidosis; the fact that acute illness and acidosis increase insulin requirements should be kept in mind.4 For example, the need for 45 U of regular insulin every 6 hours over the previous 24 hours suggests a starting dosage of 30 U/d. Over the next few days the dosage should be adjusted by means of careful titration against frequently monitored blood glucose levels. Alternatively, therapy could be started with 0.3 to 0.5 U/kg per day, a relatively low dosage, in an outpatient unit with supervision.79 The daily dosage would be increased to 0.6 to 0.7 U/kg in the average adult and to 0.9 to 1.0 U/kg in the adolescent.80 In the first few weeks after diagnosis daily insulin requirements are low (0.5 U/kg or less), CAN MED ASSOC J 1991; 145 (10)

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reflecting endogenous insulin secretion.'4'8' A detailed position statement on injection has been published by the American Diabetes Association.'0 Disposable plastic syringes are available with needles as fine as 29-gauge. Accurate measurement, particularly of mixtures in the same syringe, and asepsis at the injection site should be emphasized when insulin therapy is started. Dosing errors can be minimized by matching the syringe size (e.g., 30, 50 or 100 U) to the prescribed dose, using regular/NPH preparations premixed by the manufacturer and using a magnifier attached to the barrel of the syringe. Because the number scale may smudge, plastic syringes should be reused with caution to avoid dosing errors. Preparations containing shortacting insulin should be injected 20 to 30 minutes before a meal for optimal control of postprandial glycemia.82 Repeated use of the same injection site may induce lipohypertrophy, with adverse effects on absorption; lipoatrophy due to a local immune response to contemporary insulin preparations83 is now rarely seen. Occasional bleeding at the site is no cause for concern.

Conventional insulin therapy Acceptable target levels of plasma glucose or self-monitored blood glucose are 4.4 to 10.0 mmol/L before breakfast and supper for children and less than 8.3 mmol/L before and less than 1 1.1 mmol/L 2 hours after the main meal for adults.2 To reduce the likelihood of hypoglycemia a major study group recommended that the overnight plasma glucose level be higher than 3.6 mmol/L.80 At present there seems to be general agreement that acceptable glycemic control is indicated by a glycated hemoglobin level less than 150% of (i.e., less than 0.03 to 0.04 above) the upper normal limit (usually the mean plus two standard deviations) for the laboratory concerned.'4 Aside from the period several months after clinical presentation, when regain of A-cell function makes near-normoglycemia possible with a relatively simple program such as a single daily dose of an intermediate-acting insulin preparation,79 it is generally considered that the best compromise between convenience and an approach to physiologic insulin replacement is a so-called "split-mixed" program of regular insulin and an intermediate-acting preparation.48 The ratio of regular to NPH or lente insulin may be 1:1 or 1:2. Two-thirds of the total dose may be given 30 minutes before breakfast and one-third before supper, with dosage adjustments according to self-monitored blood glucose values, laboratorybased plasma glucose values or, at least in the initial stages, degrees of glucosuria. The insulin dosage may be increased or decreased by 1 or 2 U (or by 10% 1232

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with higher dosages) in the injection bearing on the blood glucose level in question. In theory the dose of short-acting insulin before breakfast governs the plasma glucose level before the noon meal, the dose of intermediate-acting insulin before breakfast governs the level before supper, the dose of short-acting insulin before supper governs the level at bedtime, and the dose of intermediate-acting insulin before supper governs the level before breakfast the next morning. Obviously, different patients will respond differently to this idealized approach. For example, in a patient in whom the action of NPH insulin is protracted the hypoglycemic effects of the prebreakfast injection of NPH insulin may last through to that evening or overnight; consequently, the presupper dosage requirements would be decreased. In adjusting the insulin dosage some attention should be paid to interacting sequential values. For example, in a case in which an upward trend in the glucose level is observed between breakfast and lunch, followed by a plateau between lunch and supper, correction of the upward trend with an adjustment of the dose of regular insulin before breakfast may be sufficient to resolve the hyperglycemia before both lunch and supper. Thus, not only the absolute glucose value before a meal but also the antecedent direction of change in the glucose level are important in making insulin dosage adjustments. Although this type of program is attractive to many patients, attainment of acceptable or "average" glycemic goals is often difficult.80 Comparisons of split-mixed regimens with regimens containing a single daily dose of an extended-action preparation have not always shown differences in metabolic control, particularly in children.8'84 The absence of an injection before lunch is a convenience. However, the tendency for nocturnal hypoglycemia at the time of peak action (2 to 4 am) of the presupper dose of NPH insulin may be a problem in some patients.8 In such cases it may be useful to change the time of injection of the evening dose of NPH or lente insulin to bedtime.8 A decrease in the rates of nocturnal hypoglycemia was reported with a regimen of regular insulin before breakfast and supper and ultralente insulin before breakfast.85 Mild hypoglycemic reactions with adrenergic symptoms (tremor, palpitations and sweating) may occur once or twice per week and are relieved with 10 to 15 g of simple sugar (e.g., 100 to 150 mL of ginger ale). 14'86 With a more severe reaction the patient may need assistance owing to confusion (neuroglycopenia) or emergency treatment with intravenously given glucose or injected glucagon.'4 The number of severe insulin reactions (hypoglycemia necessitating assistance or coma) during conventional insulin therapy in children and adults appears to vary from 3 to 20 per 100 patient-years.84'87 Risk LE 15 NOVEMBRE 1991

factors for severe reactions include diabetes of long duration, absence of endogenous insulin secretion, recent history of strenuous activity or missed meals or snacks, abuse of alcohol, advanced renal failure, insulin dosage greater than 0.9 U/kg per day, inability to detect symptoms of hypoglycemia, achievement of strict diabetic control and use of f-adrenergic blockers.7'13'14'52'88-91 Self-monitoring of the blood glucose level at times of risk of hypoglycemia (e.g., when a meal is delayed) has been shown to decrease the frequency of admission to hospital among children.92 Parents and spouses should be educated in the various forms of assistance, including the injection of glucagon, the use of which appears to be less frequent than it should be, particularly in children.93 Hypoglycemia during the night (especially between midnight and 5 am) is an acknowledged hazard of programs incorporating a presupper dose of intermediate-acting or long-acting insulin.8 Furthermore, because there is a growth-hormone-related rise in glucose output early in the morning, the prebreakfast blood glucose level may not reflect the nadir of overnight values.94 Patients should therefore be instructed to obtain periodically a value at 3 am, particularly if an increase in the presupper insulin dosage has recently been advised. A relatively (less than 3.6 mmol/L) or absolutely (less than 2.8 mmol/L) low blood glucose level during the night may be managed in one of three ways. A bigger or later evening snack may be eaten, the patient being advised not to go to sleep with a blood glucose level lower than a specified value (e.g., 6.0 mmol/L). Second, changing the time of injection of the evening dose of intermediate-acting insulin to bedtime may place the peak action of the injection at the time of the early-morning increase in glucose output. Finally, a long-acting formulation may be substituted for NPH insulin at supper.4'7'8 A fourth option, to decrease the presupper dose of NPH insulin, has in the past been suggested in response to the concept that morning (i.e., 8 am) hyperglycemia is secondary to an excessive counterregulatory response to nocturnal hypoglycemia.95 This so-called "Somogyi" phenomenon is now considered to be quite exceptional.96

Intensive insulin therapy Intensive insulin therapy is designed to replicate the physiologic pattern of insulin secretion. Boluses of regular insulin are given before the main meals, together with a slowly absorbed component intended to provide background, or basal, insulinemia.6'7"8 Usually the daily dose is divided equally between the basal component and the meals.7 The dosage requirements at meals are proportionate to meal size," NOVEMBER 15, 1991

although the requirement at breakfast is usually disproportionately high owing to the added effect of the early-morning increase in glucose output.94 Thus, the ratio of the doses of regular insulin before the three main meals may be, say, 2.5:2.0:2.5.8 The least costly form of intensive insulin therapy involves multiple daily injections: three premeal injections of regular insulin are given together with an injection of an intermediate-acting formulation before supper or bedtime or of ultralente insulin before breakfast and, in some cases, supper.7'8 The acceptability of frequent injections of regular insulin may be improved through the use of a pen-like injection device (e.g., Insuject [Nordisk Gentofte Canada Inc.] or Novolin-Pen I [Connaught Novo Ltd.]) or a subcutaneous needle (e.g., Button-Infuser [Markwell Medical Institute, Racine, Wis.]) that remains in situ for 2 or 3 days into which insulin may be injected with a standard syringe.97 Jet insulin injections (e.g., Medijector II [Derata Corp., Minneapolis, Minn.] or Precijet [Advanced Medical Technologies Inc., Charlottetown]) may be adapted successfully to either intensive insulin therapy or split-mixed regimens.97 As the subcutaneous dispersion of insulin with these devices differs from that with standard injection, the dosage may have to be adjusted. For continuous subcutaneous insulin infusion two types of insulin pump are currently available (Minimed Pump, model 504S [Pacesetters Systems Inc., Sylmar, Calif.] and Medix Insulin Pump, model 209 [Medivix Inc., Natick, Mass.]), regular insulin being delivered with an indwelling needle or cannula. Problems with continuous subcutaneous insulin infusion include site infections and occlusion of the infusion set, which may be associated with diabetic ketoacidosis, the rate of which is higher than with conventional insulin therapy.7 Many patients find jet injectors and pumps too costly and too difficult to maintain. Essential to intensive insulin therapy regimens is the adjustment on a dose-to-dose basis of the premeal regular insulin component through individualized "algorithms" determined on the basis of accurate self-monitored blood glucose values, expected activity level and, in some cases, carbohydrate intake.7'8 Intensive insulin therapy is thus labour intensive, from both the patient's and the physician's point of view. This constant adjustment of the regular insulin dosage explains the higher potential for near-normoglycemia than with conventional insulin therapy.7'79 Suggested target self-monitored blood or plasma glucose levels during intensive insulin therapy are 4.0 to 7.0 mmol/L before meals and less than 10.0 mmolIL after meals, the glycated hemoglobin level being within 0.01 (1%) of the upper normal limit of the assay used.14 Most patients who use intensive insulin therapy CAN MED ASSOC J 1991; 145 (10)

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are probably motivated by a desire to achieve the best possible glycemic control. Many have been dissatisfied with the results of conventional insulin therapy. Underlying the use of intensive insulin therapy is the assumption that achieving near-normoglycemia helps prevent long-term complications. Cross-sectional, epidemiologic and natural history studies support the association of hyperglycemia and development of microvascular and neurologic complications.6'7'98 However, in controlled trials of the effect of intensive insulin therapy on the progress of

established retinopathy, early nephropathy (microalbuminuria or elevated serum creatinine levels) and neuropathy (reduced nerve conduction velocity) no clinically significant benefits were found.6'7'99 Similarly, in studies of renal and retinal disease in patients who underwent whole-pancreas transplantation the results have not been impressive.99 There has been no trial to examine whether near-normoglycemia delays or decreases the incidence of newly discovered complications (primary prevention). Thus, at present prospective studies fail to substantiate the concept that therapeutically attained target glucose levels alleviate diabetic complications. The Diabetes Control and Complications Trial (DCCT), sponsored by the US National Institutes of Health, has involved 1443 patients with type I diabetes randomly assigned to an experimental (intensive insulin therapy) group or a standard (conventional insulin therapy) group. It should show within the next few years whether complication rates are affected by intensive insulin therapy.80'87 In the meantime it is reasonable to strive for glucose levels as close to the normal range as is compatible with safety from severe hypoglycemia.100 Even with intensive professional supervision only a minority of patients will safely achieve the suggested target values.80'87 The patient should have an opportunity to weigh the expected benefits against the material and health-related costs of intensive insulin therapy. Recently published DCCT data show that the rate of severe hypoglycemia during such therapy was 25 events per 100 patient-years, at least twice the rate observed with conventional insulin therapy.87 During intensive insulin therapy about one-third of severe hypoglycemic episodes involved coma or seizure, one-half occurred during sleep, and onethird occurred without warning while the patient was awake.88 Unawareness of hypoglycemia has been reported to be a hazard of intensive insulin therapy,9' but in the DCCT the proportion of subjects reporting severe hypoglycemia who failed to recognize symptoms immediately while awake was similar in the experimental (51%) and standard (52%) groups.88 The DCCT also showed a significant association of intensive insulin therapy with weight gain in the first year of treatment.87 A transient increase 1234

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in the degree of background retinopathy without adverse effect on vision in patients starting intensive insulin therapy has also been observed.7

Treatment of associated conditions Because the rate of death from coronary artery disease is increased four to eight times in type I diabetes, management of risk factors for atherosclerosis is important.'01 The increased prevalence of dyslipidemia in type I diabetes is attributable to hyperglycemia.'02 Recommended treatment goals in patients with dyslipidemia aged 30 years or more are a blood total cholesterol level of 5.2 mmol/L or less, a low-density lipoprotein cholesterol level of 3.4 mmolIL or less, a high-density lipoprotein cholesterol level of 0.9 mmol/L or more and a triglyceride level of 2.3 mmol/L or less.'2 Dyslipidemia not corrected by improved control of diabetes should be managed as is recommended for nondiabetic patients.'02 The prevalence of hypertension, which is an important risk factor for macrovascular disease and nephropathy, is at least doubled in type I diabetes.'03 The recommended goal of therapy is a blood pressure of 160/90 mm Hg.'3 In patients at risk for progression of nephropathy a target value of less than 140/90 mm Hg has been suggested.104 Present consensus suggests that angiotensin-converting enzyme inhibitors and calcium-channel blockers should be the preferred drugs for the treatment of hypertension. If thiazides, which may worsen hyperlipidemia, must be used the dosage should be low (e.g., hydrochlorothiazide, 25 to 50 mg/d). Beta blockers, if indicated, should be cardioselective, be given at a low dosage (e.g., metoprolol tartrate, 100 to 200 mg/d) and be used with caution to avoid suppression of the adrenergic response to hypoglycemia, which is critically important to the safety of insulin pharmacotherapy in type I diabetes.

Future prospects Potentially important advances include the development of insulin preparations designed to enhance selected characteristics, such as a rapid onset of action,'05 an implantable glucose sensor permitting "closed-loop" automated insulin delivery97'99 and long-acting agents to control the secretion of hormones promoting hyperglycemia.'06 Although sufficient preservation of a-cell function to avoid the need for insulin therapy is an obvious objective the retention of even minimal endogenous insulin secretion improves the stability of diabetes control.52 Thus, the benefits and risks of immunosuppression, including the use of high-dose insulin therapy or cyclosporine early in the course of LE 15 NOVEMBRE 1991

type I diabetes, are being examined.81' 07 The development of agents selective to the ,8 cell and less toxic than cyclosporine is eagerly awaited. One such drug is niacinamide, randomized trials of which are now proposed in cases of prehyperglycemia detected on the basis of high titres of islet cell antibodies.'08 About 50% of recipients of whole-pancreas transplants are normoglycemic at 1 year.99 The hazards of immunosuppression are significant, and the benefits in terms of prevention of long-term complications are not impressive. The technically simpler alternative of transplantation of isolated pancreatic islets by means of injection into the portal system remains dependent on immunosuppression against rejection and against further expression of the immune process causing the destruction of the original, native fl cells. The implantation of porcine islets suitably encapsulated within a porous polymer membrane to mitigate immunogenicity is an attractive possibility.99 The number of treatment options in type I diabetes will undoubtedly continue to increase. We must ensure that the benefits and costs of these developments are assessed carefully under controlled clinical conditions. I am grateful to Dorothy Gibson for practical advice, Dr. Clive Burge for information on various insulin preparations, Dr. John Dupre for critical comment, and David Knoppert and Scott Wilton for advice on insulin pharmaceuticals. I thank Catherine Solly for typing the manuscript and June MacAlpine for assisting with the references.

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[In the Dec. 15, 1991, issue of CMAJ Dr. Rodger will review the advances in pharmacotherapy for type II (non-insulin-dependent) diabetes mellitus. - Ed.]

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