T R E A T M E N T R E P O R T

Diabetes MellitusNote: For data on treated rate or diagnosed rate, return to the IPD and run a two-keyword search on this topic with "treated rate" or "diagnosed rate" as the second keyword. View the Article Reviews or IPD Summary report (the "Subgroups and Trends" section specifically) in your search results list.

Treatment Regimens

A. Diet

1. American Diabetes Association (ADA) recommendations

2. Dietary fiber

3. Artificial sweeteners

B. Oral Drugs for Treating Hyperglycemia

1. Drugs that stimulate insulin secretion

2. Drugs that alter insulin action

3. Drugs that affect absorption of glucose

4. Drug combinations

5. Safety of the oral hypoglycemic agents

C. Incretins

D. Insulin

1. Characteristics of available insulin preparations

2. Insulin preparations

3. Methods of insulin administration

E. Transplantation

General Considerations in the Treatment of Diabetes

Steps in the Management of the Diabetic Patient

A. Diagnostic Examination

B. Patient Education (Self-Management Training)

C. Initial Therapy

1. 1. Type 2 diabetes

2. 2. Type 1 diabetes

Acceptable Levels of Glycemic Control

Prognosis

Treatment Regimens

A. Diet

A well-balanced, nutritious diet remains a fundamental element of therapy. However, in more than half of cases, diabetic patients fail to follow their diet. In prescribing a diet, it is important to relate dietary objectives to the type of diabetes. In obese patients with mild hyperglycemia, the major goal of diet therapy is weight reduction by caloric restriction. Thus, there is less need for exchange lists, emphasis on timing of meals, or periodic snacks, all of which are so essential in the treatment of insulin-requiring nonobese diabetics. This type of patient represents the most frequent challenge for the clinician. Weight reduction is an elusive goal that can only be achieved by close supervision and education of the obese patient.

1. American Diabetes Association (ADA) recommendations

The ADA releases an annual position statement on medical nutrition therapy that replaces the calculated ADA diet formula of the past with suggestions for an individually tailored dietary prescription based on metabolic, nutritional, and lifestyle requirements. They contend that the concept of one diet for "diabetes" and the prescription of an "ADA diet" no longer can apply to both major types of diabetes. In their recommendations for persons with type 2 diabetes, the 55-60% carbohydrate content of previous diets has been reduced considerably because of the tendency of high carbohydrate intake to cause hyperglycemia, hypertriglyceridemia, and a lowered HDL cholesterol. In obese type 2 patients, glucose and lipid goals join weight loss as the focus of therapy. These patients are advised to limit their carbohydrate content by substituting noncholesterologenic monounsaturated oils such as olive oil, rapeseed (canola) oil, or the oils in nuts and avocados. This maneuver is also indicated in type 1 patients on intensive insulin regimens in whom near-normoglycemic control is less achievable on higher carbohydrate diets. They should be taught "carbohydrate counting" so they can administer 1 unit of regular insulin or insulin lispro for each 10 or 15 g of carbohydrate eaten at a meal. In these patients, the ratio of carbohydrate to fat will vary among individuals in relation to their glycemic responses, insulin regimens, and exercise pattern.

The current recommendations for both types of diabetes continue to limit cholesterol to 300 mg daily and advise a daily protein intake of 10-20% of total calories. They suggest that saturated fat be no higher than 8-9% of total calories with a similar proportion of polyunsaturated fat and that the remainder of caloric needs be made up of an individualized ratio of monounsaturated fat and of carbohydrate containing 20-35 g of dietary fiber. Poultry, veal, and fish continue to be recommended as a substitute for red meats for keeping saturated fat content low. The present ADA position statement proffers no evidence that reducing protein intake below 10% of intake (about 0.8 g/kg/d) is of any benefit in patients with nephropathy and renal impairment, and doing so may be detrimental.

Exchange lists for meal planning can be obtained from the American Diabetes Association and its affiliate associations or from the American Dietetic Association, 216 W. Jackson Blvd., Chicago, IL 60606 (312-899-0040). Their Internet address is http://www.eatright.org.

2. Dietary fiber

Plant components such as cellulose, gum, and pectin are indigestible by humans and are termed dietary "fiber." Insoluble fibers such as cellulose or hemicellulose, as found in bran, tend to increase intestinal transit and may have beneficial effects on colonic function. In contrast, soluble fibers such as gums and pectins, as found in beans, oatmeal, or apple skin, tend to retard nutrient absorption rates so that glucose absorption is slower and hyperglycemia may be slightly diminished. Although its recommendations do not include insoluble fiber supplements such as added bran, the ADA recommends food such as oatmeal, cereals, and beans with relatively high soluble fiber content as staple components of the diet in diabetics. High soluble fiber content in the diet may also have a favorable effect on blood cholesterol levels.

3. Artificial sweeteners

Aspartame (NutraSweet) has proved to be a popular sweetener for diabetic patients. It consists of two amino acids (aspartic acid and phenylalanine) that combine to produce a nutritive sweetener 180 times as sweet as sucrose. A major limitation is that it cannot be used in baking or cooking because of its lability to heat.

The nonnutritive sweetener saccharin continues to be available in certain foods and beverages despite warnings by the Food and Drug Administration (FDA) about its potential long-term carcinogenicity to the bladder. The latest position statement of the ADA concludes that all nonnutritive sweeteners that have been approved by the FDA (such as aspartame and saccharin) are safe for consumption by all people with diabetes. Two other nonnutritive sweeteners have been approved by the FDA as safe for general use: sucralose (Splenda) and acesulfame potassium (Sunett, Sweet One, DiabetiSweet). These are both highly stable and, in contrast to aspartame, can be used in cooking and baking.

Nutritive sweeteners such as sorbitol and fructose have increased in popularity. Except for acute diarrhea induced by ingestion of large amounts of sorbitol-containing foods, their relative risk has yet to be established. Fructose represents a "natural" sugar substance that is a highly effective sweetener and induces only slight increases in plasma glucose levels. However, because of potential adverse effects of large amounts of fructose (up to 20% of total calories) on raising serum cholesterol and LDL cholesterol, the ADA feels it may have no overall advantage as a sweetening agent in the diabetic diet. This does not preclude, however, ingestion of fructose-containing fruits and vegetables or fructose-sweetened foods in moderation.

B. Oral Drugs for Treating Hyperglycemia

(Tables 27-7, 27-8, and 27-9.) The drugs for treating type 2 diabetes fall into three categories: (1) Drugs that primarily stimulate insulin secretion: Sulfonylureas remain the most widely prescribed drugs for treating hyperglycemia. The meglitinide analog repaglinide and the d-phenylalanine derivative nateglinide also bind the sulfonylurea receptor and stimulate insulin secretion. (2) Drugs that alter insulin action: Metformin works primarily in the liver. The thiazolidinediones appear to have their main effect on skeletal muscle and adipose tissue. (3) Drugs that principally affect absorption of glucose: The Α-glucosidase inhibitors acarbose and miglitol are such currently available drugs.

Table 27-7. Oral antidiabetic drugs that stimulate insulin secretion.

Drug Tablet Size

Daily Dose Duration of Action

Cost per Unit

Cost for 30 Days Treatment Based on Maximum Dosage 1

Sulfonylureas

    Tolbutamide (Orinase)

250 and 500 mg

0.5-2 g in 2 or 3 divided doses

6-12 hours $0.28/500 mg

$33.60

    Tolazamide (Tolinase)

100, 250, and 500 mg

0.1-1 g as single dose or in 2 divided doses

Up to 24 hours

$0.77/250 mg

$83.40

    Acetohexamide (Dymelor)2

250 and 500 mg

0.25-1.5 g as single dose or in 2 divided doses

8-24 hours $1.34/500 mg

$120.60

    Chlorpropamide (Diabinese)2

100 and 250 mg

0.1-0.5 g as single dose

24-72 hours

$0.67/250 mg

$40.20

    Glyburide        (Dia&bgr;eta, Micronase)

1.25, 2.5, and 5 mg

1.25-20 mg as single dose or in 2 divided doses

Up to 24 hours

$0.78/5 mg

$93.60

        (Glynase) 1.5, 3, and 6 mg

1.5-18 mg as single dose or in 2 divided doses

Up to 24 hours

$1.07/6 mg

$96.30

    Glipizide        (Glucotrol)

5 and 10 mg

2.5-40 mg as single dose or in 2 divided doses on an empty stomach

6-12 hours $0.59/10 mg

$70.80

        (Glucotrol XL)

5 and 10 mg

Up to 20 or 30 mg daily as a single dose

Up to 24 hours

$0.81/10 mg

$72.90

Gliclazide (not available in the US)

80 mg 40-80 mg as single dose; 160-320 mg as divided dose

12 hours - -

    Glimepiride (Amaryl)

1, 2, and 4 mg

1-4 mg as single dose

Up to 24 hours

$1.31/4 mg

$39.30

Meglitinide analogs

    Repaglinide (Prandin)

0.5, 1, and 2 mg

4 mg in two divided doses given 15 minutes before breakfast and dinner

3 hours $1.29/2 mg

$77.40

d-Phenylalanine derivative

    Nateglinide (Starlix)

60 mg and 120 mg

60 or 120 mg 3 times a day before meals

1.5 hours $1.29/120 mg

$116.10

1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 24, No. 4, April 2005. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions. 2There has been a decline in use of these formulations. In the case of chlorpropamide, the decline is due to its numerous side effects (see text).

Table 27-8. Oral antidiabetic drugs that are insulin-sparing.

Drug Tablet Size

Daily Dose Duration of Action

Cost per Unit

Cost for 30 Days Treatment Based on Maximum Dosage 1

Biguanides

    Metformin (Glucophage)

500, 850, and 1000 mg

1-2.5 g; one tablet with meals 2 or 3 times daily

7-12 hours $1.46/850 mg

$131.40

    Extended-release metformin (Glucophage XR)

500 mg 500-2000 mg once a day

Up to 24 hours

$0.88/500 mg

$105.60

Thiazolidinediones

    Rosiglitazone (Avandia)

2, 4, and 8 mg

4-8 mg daily (can be divided)

Up to 24 hours

$5.59/8 mg

$167.70

    Pioglitazone 15, 30, 15-45 mg daily Up to 24 $6.28/45 $188.42

(Actos) and 45 mg

hours mg

a-Glucosidase inhibitors

    Acarbose (Precose)

50 and 100 mg

75-300 mg in 3 divided doses with first bite of food

4 hours $0.99/100 mg

$89.10

    Miglitol (Glyset) 25, 50, and 100 mg

75-300 mg in 3 divided doses with first bite of food

4 hours $0.97/100 mg

$87.30

1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 24, No. 4, April 2005. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.

Table 27-9. Combination oral antidiabetic drugs.

Drug Tablet Size

Daily Dose Duration of Action

Cost per Unit

Cost for 30 Days Treatment Based on Maximum Dosage 1

Glyburide/metformin (Glucovance)

1.25 mg/250 mg 2.5 mg/500 mg 5 mg/500 mg

Maximum daily dose of 20 mg glyburide/2000 mg metformin

See individual drugs2

$1.13/5/500 mg

$135.60

Rosiglitazone/metformin (Avandamet)

1 mg/500 mg 2 mg/500 mg 4 mg/500 mg

Maximum daily dose of 8 mg rosiglitazone/2000 mg metformin

See individual drugs2

$1.75/2/500 mg

$210.00

1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 24, No. 4, April 2005. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions. 2Glyburide, Table 27-7; metformin, Table 27-8; and rosiglitazone, Table 27-8.

1. Drugs that stimulate insulin secretion

a. Sulfonylureas

The primary mechanism of action of the sulfonylureas is to stimulate insulin release from pancreatic B cells. Specific receptors on the surface of pancreatic B cells bind sulfonylureas in the rank order of their insulinotropic potency (glyburide with the greatest affinity and tolbutamide with the least affinity). It has been shown that activation of these receptors closes potassium channels, resulting in depolarization of the B cell. This depolarized state permits calcium to enter the cell and actively promote insulin release.

Sulfonylureas are not indicated for use in type 1 diabetes patients since these drugs require functioning pancreatic B cells to produce their effect on blood glucose. These drugs are used in patients with type 2 diabetes, in whom acute administration improves the early phase of insulin release that is refractory to acute glucose stimulation. Sulfonylureas are generally contraindicated in patients with hepatic or renal impairment. Idiosyncratic reactions are rare, with skin rashes or hematologic toxicity (leukopenia, thrombocytopenia) occurring in less than 0.1% of users.

(1) First-generation sulfonylureas (tolbutamide, tolazamide, acetohexamide, chlorpropamide)

Tolbutamide is supplied as 500-mg tablets. It is rapidly oxidized in the liver to inactive metabolites, and its approximate duration of effect is relatively short (6-10 hours). Tolbutamide is probably best administered in divided doses (eg, 500 mg before each meal and at bedtime); however, some patients require only one or two tablets daily with a maximum dose of 3000 mg/d. Because of its short duration of action, which is independent of renal function, tolbutamide is probably the safest sulfonylurea to use if liver function is normal. Prolonged hypoglycemia has been reported rarely with tolbutamide, mostly in patients receiving certain antibacterial sulfonamides (sulfisoxazole), phenylbutazone for arthralgias, or the oral azole antifungal drugs to treat candidiasis. These drugs apparently compete with tolbutamide for oxidative enzyme systems in the liver, resulting in maintenance of high levels of unmetabolized, active sulfonylurea in the circulation.

Tolazamide is supplied in tablets of 100, 250, and 500 mg. It has a longer duration of action than tolbutamide, lasting up to 20 hours, with maximal hypoglycemic effect occurring between the fourth and fourteenth hours. It is often effective, as are other longer-acting sulfonylureas also, when tolbutamide fails to correct prebreakfast hyperglycemia. Tolazamide is metabolized to several compounds that retain hypoglycemic effects. If more than 500 mg/d is required, the dose should be divided and

given twice daily. Doses larger than 1000 mg daily do not improve the degree of glycemic control.

Acetohexamide and chlorpropamide are now rarely used. Chlorpropamide has a prolonged biologic effect, and severe hypoglycemia can occur especially in the elderly as their renal clearance declines with aging. Its other side effects include alcohol-induced flushing and hyponatremia due to its effect on vasopressin secretion and action.

(2) Second-generation sulfonylureas (glyburide, glipizide, gliclazide, glimepiride)

Glyburide, glipizide, gliclazide, and glimepiride are 100-200 times more potent than tolbutamide. These drugs should be used with caution in patients with cardiovascular disease or in elderly patients, in whom prolonged hypoglycemia would be especially dangerous.

Glyburide is available in 1.25-mg, 2.5-mg, and 5-mg tablets. The usual starting dose is 2.5 mg/d, and the average maintenance dose is 5-10 mg/d given as a single morning dose; maintenance doses higher than 20 mg/d are not recommended. Some reports suggest that 10 mg is a maximum daily therapeutic dose, with 15-20 mg having no additional benefit in poor responders and doses over 20 mg actually worsening hyperglycemia. Glyburide is metabolized in the liver into products with hypoglycemic activity, which probably explains why assays specific for the unmetabolized compound suggest a plasma half-life of only 1-2 hours, yet the biologic effects of glyburide are clearly persistent 24 hours after a single morning dose in diabetic patients. Glyburide is unique among sulfonylureas in that it not only binds to the pancreatic B cell membrane sulfonylurea receptor but also becomes sequestered within the B cell. This may also contribute to its prolonged biologic effect despite its relatively short circulating half-life. A "Press Tab" formulation of "micronized" glyburide-easy to divide in half with slight pressure if necessary-is available in tablet sizes of 1.5 mg, 3 mg, and 6 mg.

Glyburide has few adverse effects other than its potential for causing hypoglycemia, which at times can be prolonged. Flushing has rarely been reported after ethanol ingestion. It does not cause water retention, as chlorpropamide does, but rather slightly enhances free water clearance. Glyburide is absolutely contraindicated in the presence of hepatic impairment and should not be used in patients with renal insufficiency, in elderly patients, or in those who would be put at serious risk from an episode of hypoglycemia.

Glipizide is available in 5-mg and 10-mg tablets. For maximum effect in reducing postprandial hyperglycemia, this agent should be ingested 30 minutes before meals, since rapid absorption is delayed when the drug is taken with food. The recommended starting dose is 5 mg/d, with up to 15 mg/d given as a single daily dose before breakfast. When higher daily doses are required, they should be divided and given before meals. The maximum dose recommended by the manufacturer is 40 mg/d, although doses above 10-15 mg probably provide little additional benefit in poor responders and may even be less effective than smaller doses.

At least 90% of glipizide is metabolized in the liver to inactive products, and 10% is excreted unchanged in the urine. Glipizide therapy is therefore contraindicated in patients with hepatic or renal impairment, who would be at high risk for hypoglycemia; but because of its lower potency and shorter duration of action, it is preferable to glyburide in elderly patients. Glipizide has also been marketed as Glucotrol-XL in 5-mg and 10-mg tablets. It provides extended release during transit through the gastrointestinal tract with greater effectiveness in lowering prebreakfast hyperglycemia than the shorter-duration immediate-release standard glipizide tablets. However, this formulation appears to have sacrificed its lower propensity for severe hypoglycemia compared with longer-acting glyburide without showing any demonstrable therapeutic advantages over glyburide.

Gliclazide (not available in the United States) is another intermediate duration sulfonylurea with a duration of action of about 12 hours. It is available as 80 mg tablets. The recommended starting dose is 40-80 mg/d with a maximum dose of 320 mg. Doses of 160 mg and above are given as divided doses before breakfast and dinner. The drug is metabolized by the liver; the metabolites and conjugates have no hypoglycemic effect. An extended release preparation is available.

Glimepiride is given once daily as monotherapy or in combination with insulin to lower blood glucose in diabetes patients who cannot control their glucose level through diet and exercise. Glimepiride achieves blood glucose lowering with the lowest dose of any sulfonylurea compound, and this tends to increase its cost-effectiveness. A single daily dose of 1 mg/d has been shown to be effective, and the maximal recommended dose is 8 mg. It has a long duration of action with a pharmacodynamic half-life of 5 hours, allowing once-daily administration, which improves compliance. It is completely metabolized by the liver to relatively inactive metabolic products.

b. Meglitinide analogs

Repaglinide is structurally similar to glyburide but lacks the sulfonic acid-urea moiety. It acts by binding to the sulfonylurea receptor and closing the ATP-sensitive potassium channel. It is rapidly absorbed from the intestine and then undergoes complete metabolism in the liver to inactive biliary products, giving it a plasma half-life of less than 1 hour. The drug therefore causes a brief but rapid pulse of insulin. The starting dose is 0.5 mg three times a day 15 minutes before each meal. The dose can be titrated to a maximal daily dose of 16 mg. Like the sulfonylureas, repaglinide can be used in combination with metformin. Hypoglycemia is the main side effect. In clinical trials, when the drug was compared with a long-duration sulfonylurea (glyburide), there was a trend toward less hypoglycemia. Like the sulfonylureas also, repaglinide causes weight gain. Metabolism is by cytochrome P450 3A4 isoenzyme, and other drugs that induce or inhibit this isoenzyme may increase or inhibit (respectively) the metabolism of repaglinide. The drug may be useful in patients with renal impairment or in the elderly. It remains to be shown that this drug has significant advantages over short-acting sulfonylureas.

c. d-Phenylalanine derivative

Nateglinide stimulates insulin secretion by binding to the sulfonylurea receptor and closing the ATP-sensitive potassium channel. This compound is rapidly absorbed from the intestine, reaching peak plasma levels within 1 hour. It is metabolized in the liver and has a plasma half-life of about 1.5 hours. Like repaglinide, it causes a brief rapid pulse of insulin, and when given before a meal it reduces the postprandial rise in blood glucose. The drug is available as 60-mg and 120-mg tablets. The 60-mg dose is used in patients who have mild elevations in HbA1c. For most patients, the recommended starting and maintenance dose is 120 mg three times a day before meals. Like the other insulin secretagogues, its main side effects are hypoglycemia and weight gain. This drug has been approved for use either alone or in combination with metformin.

2. Drugs that alter insulin action

a. Metformin

Metformin (1,1-dimethylbiguanide hydrochloride) is used, either alone or in conjunction with other oral agents or insulin, in the treatment of patients with type 2 diabetes. The exact mechanism of action remains unclear. It reduces both the fasting level of blood glucose and the degree of postprandial hyperglycemia in patients with type 2 diabetes but has no effect on fasting blood glucose in normal subjects. Metformin is particularly effective in reducing hepatic gluconeogenesis by interfering with lactate oxidation and uptake by the liver. Other proposed mechanisms include a slowing down of gastrointestinal absorption of glucose and increased glucose uptake by skeletal muscle, which have been reported in some but not all clinical studies. Because of its very high concentration in intestinal cells after oral administration, metformin increases glucose to lactate turnover, which may account for a reduction in hyperglycemia.

Metformin has a half-life of 1.5-3 hours, is not bound to plasma proteins, and is not metabolized in humans, being excreted unchanged by the kidneys.

Metformin may be used as an adjunct to diet for the control of hyperglycemia and its associated symptoms in patients with type 2 diabetes, particularly those who are obese or are not responding optimally to maximal doses of sulfonylureas. A side benefit of metformin therapy is its tendency to improve both fasting and postprandial hyperglycemia and hypertriglyceridemia in obese diabetics without the weight gain associated with insulin or sulfonylurea therapy. Metformin is not indicated for patients with type 1 diabetes and is contraindicated in diabetics with serum creatinine levels of 1.5 mg/dL or higher, hepatic insufficiency, alcoholism, or a propensity to develop tissue hypoxia.

Metformin is dispensed as 500 mg, 850 mg, and 1000 mg tablets. A 500 mg extended-release preparation is also available. Although the maximal dosage is 2.55 g, little benefit is seen above a total dose of 2000 mg. It is important to begin with a low dose and increase the dosage very gradually in divided doses-taken with meals-to reduce minor gastrointestinal upsets. A common schedule would be one 500 mg tablet three times a

day with meals or one 850 mg or 1000 mg tablet twice daily at breakfast and dinner. One to four tablets of the extended-release preparation can be given once a day.

The most frequent side effects of metformin are gastrointestinal symptoms (anorexia, nausea, vomiting, abdominal discomfort, diarrhea), which occur in up to 20% of patients. These effects are dose-related, tend to occur at onset of therapy, and often are transient. However, in 3-5% of patients, therapy may have to be discontinued because of persistent diarrheal discomfort.

Hypoglycemia does not occur with therapeutic doses of metformin, which permits its description as a "euglycemic" or "antihyperglycemic" drug rather than an oral hypoglycemic agent. Dermatologic or hematologic toxicity is rare.

Lactic acidosis has been reported as a side effect but is uncommon with metformin in contrast to phenformin. While therapeutic doses of metformin reduce lactate uptake by the liver, serum lactate levels rise only minimally if at all, since other organs such as the kidney can remove the slight excess. However, if tissue hypoxia occurs, the metformin-treated patient is at higher risk for lactic acidosis due to compromised lactate removal. Similarly, when renal function deteriorates, affecting not only lactate removal by the kidney but also metformin excretion, plasma levels of metformin rise far above the therapeutic range and block hepatic uptake enough to provoke lactic acidosis without associated increases in lactic acid production. Almost all reported cases have involved subjects with associated risk factors that should have contraindicated its use (renal, hepatic, or cardiorespiratory insufficiency, alcoholism, advanced age). Acute renal failure can occur rarely in certain patients receiving radiocontrast agents. Metformin therapy should therefore be temporarily halted on the day of the test and for 2 days following injection of radiocontrast agents to avoid potential lactic acidosis if renal failure occurs.

b. Thiazolidinediones

Drugs of this newer class of antihyperglycemic agents sensitize peripheral tissues to insulin. They bind a nuclear receptor called peroxisome proliferator-activated receptor gamma (PPAR-γ) and affect the expression of a number of genes and regulate the release of the adipokines-resistin and adiponectin-from adipocytes. Adiponectin secretion is stimulated, which sensitizes tissues to the effects of insulin, and resistin secretion is inhibited, which reduces insulin resistance. Observed effects of thiazolidinediones include increased glucose transporter expression (GLUT 1 and GLUT 4), decreased free fatty acid levels, decreased hepatic glucose output, and increased differentiation of preadipocytes into adipocytes. Like the biguanides, this class of drugs does not cause hypoglycemia. Troglitazone, the first drug in this class to go into widespread clinical use, has been withdrawn from clinical use because of drug-associated fatal liver failure.

Two other drugs in the same class are available for clinical use: rosiglitazone and pioglitazone. Both are effective as monotherapy and in combination with sulfonylureas or metformin or insulin. When used as monotherapy, these drugs lower HbA1c by about 1 or 2 percentage points. When used in combination with insulin, they can result in a 30-50%

reduction in insulin dosage, and some patients can come off insulin completely. The combination of a thiazolidinedione and metformin has the advantage of not causing hypoglycemia. Patients inadequately managed on sulfonylureas can do well on a combination of sulfonylurea and rosiglitazone or pioglitazone. About 25% of patients in clinical trials fail to respond to these drugs, presumably because they are significantly insulinopenic.

The thiazolidinediones not only lower glucose but also have effects on lipids and other cardiovascular risk factors. Rosiglitazone therapy is associated with increases in total cholesterol, low-density lipoprotein (LDL)-cholesterol (15%), and high-density lipoprotein (HDL)-cholesterol (10%). There is a reduction in free fatty acids of about 8-15%. The changes in triglycerides were generally not different from placebo. The increase in the LDL-cholesterol need not necessarily be detrimental-studies with troglitazone showed that there is a shift from the atherogenic small dense LDL particles to larger, less dense LDL particles. Pioglitazone in clinical trials lowered triglycerides (9%) and increased HDL-cholesterol (15%) but did not cause a consistent change in total cholesterol and LDL-cholesterol levels. A prospective randomized comparison of the metabolic effects of pioglitazone and rosiglitazone on patients who had previously taken troglitazone showed similar effects on HbA1c and weight gain. Pioglitazone-treated subjects, however, had lower total cholesterol, LDL-cholesterol, and triglycerides when compared with rosiglitazone. The thiazolidinediones have also been demonstrated to decrease levels of plasminogen activator inhibitor type 1, matrix metalloproteinase 9, C-reactive protein, and interleukin 6. These effects make these drugs particularly beneficial for patients with the metabolic syndrome. The thiazolidinediones also may limit vascular smooth muscle proliferation after injury, and there are reports that troglitazone and piogliotazone reduce neointimal proliferation after coronary stent placement. Also, in one double-blind, placebo-controlled study, rosiglitazone was shown to be associated with a decrease in the ratio of urinary albumin to creatinine excretion.

Anemia occurs in 4% of patients treated with these drugs, but this effect may be due to a dilutional effect of increased plasma volume rather than a reduction in red cell mass. Weight gain occurs especially when the drug is combined with a sulfonylurea or insulin. Edema occurs in about 3-4% of patients receiving monotherapy with rosiglitazone or pioglitazone. The edema occurs more frequently (10-15%) in patients receiving concomitant insulin therapy and may result in congestive heart failure. The drugs are contraindicated in diabetic individuals with New York Heart Association class III and IV cardiac status.

The dosage of rosiglitazone is 4-8 mg daily and of pioglitazone 15-45 mg daily, and the drugs do not have to be taken with food. Rosiglitazone is primarily metabolized by the CYP 2C8 isoenzyme and pioglitazone is metabolized by CYP 2C8 and CYP 3A4.

These two agents have so far not (unlike troglitazone) caused drug-induced hepatotoxicity. The FDA has, however, recommended that patients should not initiate drug therapy if there is clinical evidence of active liver disease or the alanine aminotransferase (ALT) level is 2.5 times greater than the upper limit of normal.

Obviously, caution should be used in initiation of therapy in patients with even mild ALT elevations. Liver function tests should be performed prior to initiation of treatment and periodically thereafter.

3. Drugs that affect absorption of glucose

Α-Glucosidase inhibitors competitively inhibit the Α-glucosidase enzymes in the gut that digest dietary starch and sucrose. Two of these drugs-acarbose and miglitol-are available for clinical use. Both are potent inhibitors of glucoamylase, Α-amylase, and sucrase but have less effect on isomaltase and hardly any on trehalase and lactase. Acarbose binds 1000 times more avidly to the intestinal disaccharidases than do products of carbohydrate digestion or sucrose. A fundamental difference between acarbose and miglitol is in their absorption. Acarbose has the molecular mass and structural features of a tetrasaccharide, and very little (about 2%) crosses the microvillar membrane. Miglitol, however, has a structural similarity with glucose and is absorbable. Both drugs delay the absorption of carbohydrate and lower postprandial glycemic excursion.

a. Acarbose

Acarbose is available as 50-mg and 100-mg tablets. The recommended starting dose of acarbose is 50 mg twice daily, gradually increasing to 100 mg three times daily. For maximal benefit on postprandial hyperglycemia, acarbose should be given with the first mouthful of food ingested. In diabetic patients, it reduces postprandial hyperglycemia by 30-50%, and its overall effect is to lower the HbA1c by 0.5-1%.

The principal adverse effect, seen in 20-30% of patients, is flatulence. This is caused by undigested carbohydrate reaching the lower bowel, where gases are produced by bacterial flora. In 3% of cases, troublesome diarrhea occurs. This gastrointestinal discomfort tends to discourage excessive carbohydrate consumption and promotes improved compliance of type 2 patients with their diet prescriptions. When acarbose is given alone, there is no risk of hypoglycemia. However, if combined with insulin or sulfonylureas, it might increase the risk of hypoglycemia from these agents. A slight rise in hepatic aminotransferases has been noted in clinical trials with acarbose (5% versus 2% in placebo controls, and particularly with doses > 300 mg/d). The levels generally return to normal on stopping the drug.

In the UKPDS, approximately 2000 patients on diet, sulfonylurea, metformin, or insulin therapy were randomized to acarbose or placebo therapy. By 3 years, 60% of the patients had discontinued the drug, mostly because of gastrointestinal symptoms. If one looked only at the 40% who remained on the drug, they had an 0.5% lower HbA1c compared with placebo.

b. Miglitol

Miglitol is similar to acarbose in terms of its clinical effects. It is indicated for use in diet- or sulfonylurea-treated patients with type 2 diabetes. Therapy is initiated at the lowest

effective dosage of 25 mg three times a day. The usual maintenance dose is 50 mg three times a day, although some patients may benefit from increasing the dose to 100 mg three times a day. Gastrointestinal side effects occur as with acarbose. The drug is not metabolized and is excreted unchanged by the kidney. Theoretically, absorbable Α-glucosidase inhibitors could induce a deficiency of one or more of the Α-glucosidases involved in cellular glycogen metabolism and biosynthesis of glycoproteins. This does not occur in practice because, unlike the intestinal mucosa, which sees a high concentration of the drug, the blood level is 200-fold to 1000-fold lower than the concentration needed to inhibit intracellular Α-glucosidases. Miglitol should not be used in renal failure, when its clearance would be impaired.

4. Drug combinations

A glyburide and metformin combination (Glucovance) is available in dose forms of 1.25 mg/250 mg, 2.5 mg/500 mg, and 5 mg/500 mg. A rosiglitazone and metformin combination (Avandamet) is available in dose forms of 1 mg/500 mg, 2 mg/500 mg, and 4 mg/500 mg. These drug combinations, however, limit the clinician's ability to optimally adjust dosage of the individual drugs and for that reason are of questionable usefulness.

5. Safety of the oral hypoglycemic agents

The UKPDS has put to rest previous concerns regarding the safety of sulfonylureas. It did not confirm any cardiovascular hazard among over 1500 patients treated intensively with sulfonylureas for over 10 years, compared with a comparable number who received either insulin or diet therapy. Analysis of a subgroup of obese patients receiving metformin also showed no hazard and even a slight reduction in cardiovascular deaths compared with conventional therapy.

The currently available thiazolidinediones have not to date exhibited the idiosyncratic hepatotoxicity seen with troglitazone. However, these drugs can precipitate congestive heart failure and should not be used in patients with New York Heart Association class III and IV cardiac status. Lactic acidosis from metformin (see above) is quite rare and probably not a major problem with its use in the absence of major risk factors such as impaired renal or hepatic disease or conditions predisposing to hypoxia.

C. Incretins

Oral glucose provokes a threefold to fourfold higher insulin response than an equivalent dose of glucose given intravenously because the oral glucose causes a release of gut hormones, principally glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP1), which amplify the glucose-induced insulin release. This "incretin effect" has been reported to be impaired in patients with type 2 diabetes. GLP-1, when infused in patients with type 2 diabetes, stimulates insulin secretion and lowers glucose levels. GLP-1, however, is rapidly proteolysed by dipeptidyl peptidase-IV

(DPP IV) and is not a practical therapeutic agent. Exenatide is a GLP-1 analog that is more resistant to DPP IV action, and it lowers blood glucose and HbA1c levels when given subcutaneously twice a day to patients with type 2 diabetes. Oral DPP IV inhibitors, which work by prolonging the action of endogenously released GLP-1, are also in clinical trials for use in type 2 diabetes.

D. Insulin

Insulin is indicated for type 1 diabetes as well as for type 2 diabetic patients with insulinopenia whose hyperglycemia does not respond to diet therapy either alone or combined with oral hypoglycemic drugs.

With the development of highly purified human insulin preparations, immunogenicity has been markedly reduced, thereby decreasing the incidence of therapeutic complications such as insulin allergy, immune insulin resistance, and localized lipoatrophy at the injection site. However, the problem of achieving optimal insulin delivery remains unsolved with the present state of technology. It has not been possible to reproduce the physiologic patterns of intraportal insulin secretion with subcutaneous injections of soluble or longer-acting insulin suspensions. Even so, with the help of appropriate modifications of diet and exercise and careful monitoring of capillary blood glucose levels at home, it has often been possible to achieve acceptable control of blood glucose by using various mixtures of short- and longer-acting insulins injected at least twice daily or portable insulin infusion pumps.

1. Characteristics of available insulin preparations

Commercial insulin preparations differ with respect to the animal species from which they are obtained, their purity and solubility, and the time of onset and duration of their biologic action. As many as 17 different formulations of insulin are available in the United States.

a. Species of insulin

Human insulin is produced by recombinant DNA techniques (biosynthetic human insulin) as Humulin (Eli Lilly) and as Novolin (Novo Nordisk). It is dispensed as either regular (R), NPH (N), lente (L), or ultralente (U) formulations (Table 27-10). Four analogs of human insulin-three rapidly acting (insulin lispro, insulin aspart, insulin glulisine) and one very long-acting (insulin glargine)-have been approved by the FDA for clinical use (see below). A limited supply of monospecies pork insulin (Iletin II) remains available for use in certain patients who may benefit from the slightly more prolonged and sustained effect of animal insulin compared with human insulin. The cost of human insulin is slightly less than the cost of purified pork insulin.

b. Purity of insulin

"Purified" insulin is defined by FDA regulations as the degree of purity wherein proinsulin contamination is less than 10 ppm, whether extracted from animal pancreas or produced from biosynthetic proinsulin. All human insulin and pork insulin products of Novo Nordisk and Eli Lilly presently available contain less than 10 ppm of proinsulin and are labeled as "purified." These purified insulins seem to preserve their potency quite well, so that refrigeration is recommended but not crucial. During travel, reserve supplies of insulin can thus be readily transported for weeks without losing potency if protected from extremes of heat or cold.

c. Concentration of insulin

At present, insulins in the United States are available in a concentration of 100 units/mL (U100), and all are dispensed in 10-mL vials. With the popularity of "low-dose" (0.5- or 0.3-mL) disposable insulin syringes, U100 can be measured with acceptable accuracy in doses as low as 1-2 units. For use in rare cases of severe insulin resistance in which large quantities of insulin are required, U500 regular human insulin (Humulin R) is available from Eli Lilly.

2. Insulin preparations

Four principal types of insulins are available: (1) rapid-acting insulin analogs with more rapid onset and a shorter duration of action than regular insulin after subcutaneous injection; (2) short-acting regular insulin; (3) intermediate-acting; and (4) long-acting, with slow onset of action.

Table 27-10. Some insulin preparations available in the United States.1

Preparation Species Source Concentration Cost 1

Rapid-acting insulin analogs

    Insulin lispro (Humalog, Lilly)

Human analog (recombinant)

U100 $67.58

    Insulin aspart (Novolog, Novo Nordisk)

Human analog (recombinant)

U100 $74.88

    Insulin glulisine (Apidra, Sanofi Aventis)

Human analog (recombinant)

U100  

Short-acting regular insulins    "Purified"2

        Regular Novolin (Novo Nordisk)3

Human U100 $30.50

        Regular Humulin (Lilly) Human U100, U500 20 mL $29.28, $210.68

        Regular Iletin II (Lilly) Pork U100 $47.98

Intermediate-acting insulins

    "Purified"2

        Lente Humulin (Lilly) Human U100 $29.28

        Lente Iletin II (Lilly) Pork U100 $47.98

        Lente Novolin (Novo Nordisk)3

Human U100 $30.50

        NPH Humulin (Lilly) Human U100 $29.28

        NPH Iletin II (Lilly) Pork U100 $47.98

        NPH Novolin (Novo Nordisk)3

Human U100 $30.50

Premixed insulins    % NPH/% regular

        Novolin 70/30 (Novo Nordisk)3

Human U100 $30.50

        Humulin 70/30 and 50/50 (Lilly)

Human U100 $29.28

    Other Mixes

        75% insulin lispro protamine/25% insulin lispro (Humalog Mix 75/25 [Lilly])

Human analog (recombinant)

U100 (insulin pen, prefilled syringes, 5 × 3-mL cartridges)

Pen $144.63, Vial $71.88

        70% insulin aspart protamine/30% insulin aspart (Novolog Mix 70/30 [Novo Nordisk])

Human analog (recombinant)

U100 (insulin pen, prefilled syringes, 5 × 3-mL cartridges)

Pen $144.62, Vial $74.88

Long-acting insulins    "Purified"2

        Ultralente Humulin (Lilly) Human U100 $29.28

        Insulin glargine (Lantus, Aventis)

Human analog (recombinant)

U100 $66.85

1All of these agents (except insulin lispro and U500) are available without a prescription. Average wholesale price (AWP, for AB-rated generic when available) for 10-mL vial unless otherwise specified. Source: Red Book Update, Vol. 24, No. 4, April 2005. Wholesale prices for all human preparations (except insulin lispro and U500) are similar. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions. 2Less than 10 ppm proinsulin. 3Novo Nordisk human insulins are termed Novolin R, L, and N.

Rapid-acting insulin analogs and regular insulin are dispensed as clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf life. The long-acting insulin analog insulin glargine is also dispensed as a clear solution but at acidic

pH. Other intermediate-acting and long-acting insulins are dispensed as turbid suspensions at neutral pH with either protamine in phosphate buffer (NPH insulin) or varying concentrations of zinc in acetate buffer (ultralente and lente insulins). The rapid-acting insulin analogs, intermediate-acting, and long-acting insulins are designed for subcutaneous administration only, while regular insulin can also be given intravenously.

a. Rapid-acting insulins

Insulin lispro (Humalog) is an insulin analog produced by recombinant technology, wherein two amino acids near the carboxyl terminal of the B chain have been reversed in position: Proline at position B28 has been moved to B29 and lysine has been moved from B29 to B28. Insulin aspart (Novolog) is a single substitution of proline by aspartic acid at position B28. Insulin glulisine (Apidra) differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 by glutamic acid. These changes result in these three analogs having less tendency to form hexamers, in contrast to human insulin. When injected subcutaneously, the analogs quickly dissociate into monomers and are absorbed very rapidly, reaching peak serum values in as soon as 1 hour-in contrast to regular human insulin, whose hexamers require considerably more time to dissociate and become absorbed. The amino acid changes in these analogs do not interfere with their binding to the insulin receptor, with the circulating half-life, or with their immunogenicity, which are all identical with those of human regular insulin.

Clinical trials have demonstrated that the optimal times of preprandial subcutaneous injection of comparable doses of the rapid-acting insulin analogs and of regular human insulin are 20 minutes and 60 minutes, respectively, before the meal. While this more rapid onset of action has been welcomed as a great convenience by diabetic patients who object to waiting as long as 60 minutes after injecting regular human insulin before they can begin their meal, patients must be taught to ingest adequate absorbable carbohydrate early in the meal to avoid hypoglycemia during the meal. Another desirable feature of insulin lispro is that its duration of action remains at about 4 hours irrespective of dosage. This contrasts with regular insulin, whose duration of action is prolonged when larger doses are used.

Table 27-11. Examples of intensive insulin regimens using rapid-acting insulin analogs (insulin lispro, aspart, or glulisine) and ultralente, NPH, or insulin glargine in a 70-kg man with type 1 diabetes.1-3

  Pre-Breakfast Pre-Lunch Pre-Dinner At Bedtime

Rapid-acting insulin analog 5 units 4 units 6 units -

Ultralente insulin 8 units - 8 units -

    OR    

Rapid-acting insulin analog 5 units 4 units 6 units -

NPH insulin 3 units 3 units 2 units 8-9 units

    OR    

Rapid-acting insulin analog 5 units 4 units 6 units -

Insulin glargine - - - 15-16 units

1Assumes that patient is consuming approximately 75 g carbohydrate at breakfast, 60 g at lunch, and 90 g at dinner. 2The dose of insulin lispro or insulin aspart can be raised by 1 or 2 units if extra carbohydrate (15-30 g) is ingested or if premeal blood glucose is > 170 mg/dL. Insulin lispro or insulin aspart can be mixed in the same syringe with ultralente or NPH insulin. 3Insulin glargine cannot be mixed with any of the available insulins and must be given as a separate injection.

b. Short-acting regular insulin

Regular insulin is a short-acting soluble crystalline zinc insulin whose effect appears within 30 minutes after subcutaneous injection and lasts 5-7 hours when usual quantities are administered. Intravenous infusions of regular insulin are particularly useful in the treatment of diabetic ketoacidosis and during the perioperative management of insulin-requiring diabetics. When intravenous insulin is needed for hyperglycemic emergencies, the rapid-acting insulin analogs have no advantage over regular human insulin, which is instantly converted to the monomeric form when given intravenously. Regular insulin is indicated when the subcutaneous insulin requirement is changing rapidly, such as after surgery or during acute infections-although the rapid-acting insulin analogs may be preferable in these situations.

The rapid-acting analogs are also commonly used in pumps. In a double-blind crossover study comparing insulin lispro with regular insulin in insulin pumps, persons using insulin lispro had lower HbA1c values and improved postprandial glucose control with the same frequency of hypoglycemia. The concern remains that in the event of pump failure, users of the rapid-acting insulin analogs will have more rapid onset of hyperglycemia and ketosis.

c. Intermediate-acting insulins

Lente insulin is a mixture of 30% semilente (an amorphous precipitate of insulin with zinc ions) with 70% ultralente insulin (an insoluble crystal of zinc and insulin). Its onset of action is delayed for up to 2 hours, and because its duration of action often is less than 24 hours (with a range of 18-24 hours), most patients require at least two injections daily to maintain a sustained insulin effect. Lente insulin has its peak effect in most patients between 8 and 12 hours, but individual variations in peak response time must be considered when interpreting unusual or unexpected patterns of glycemic responses in individual patients. NPH (neutral protamine Hagedorn or isophane) insulin is an intermediate-acting insulin whose onset of action is delayed by combining 2 parts soluble crystalline zinc insulin with 1 part protamine zinc insulin. This produces equivalent

amounts of insulin and protamine, so that neither is present in an uncomplexed form ("isophane").

The onset and duration of action of NPH insulin are comparable to those of lente insulin; it is usually mixed with regular insulin and given at least twice daily for insulin replacement in type 1 patients. Occasional vials of NPH insulin have tended to show unusual clumping of their contents or "frosting" of the container, with considerable loss of bioactivity. This instability is rare and occurs less frequently if NPH human insulin is refrigerated when not in use and if bottles are discarded after 1 month of use.

d. Long-acting insulins

Humulin ultralente is a crystalline insulin whose duration of action is less than that of the previously available beef ultralente. It is generally recommended that the daily dose be split into two equal doses given 12 hours apart. Its peak is less than that of NPH insulin, and it is often used to provide basal coverage while the short-acting insulins are used to cover the glucose rise associated with meals.

Insulin glargine is an insulin analog in which the asparagine at position 21 of the A chain of the human insulin molecule is replaced by glycine and two arginines are added to the carboxyl terminal of the B chain. The arginines raise the isoelectric point of the molecule closer to neutral, making it more soluble in an acidic environment. In contrast, human insulin has an isoelectric point of pH 5.4. Insulin glargine is a clear insulin which, when injected into the neutral pH environment of the subcutaneous tissue, forms microprecipitates that slowly release the insulin into the circulation. It lasts for about 24 hours without any pronounced peaks and is given once a day to provide basal coverage. This insulin cannot be mixed with the other human insulins because of its acidic pH. When this insulin was given as a single injection at bedtime to type 1 patients, fasting hyperglycemia was better controlled when compared with bedtime NPH insulin. The clinical trials also suggest that there may be less nocturnal hypoglycemia with this insulin when compared with NPH insulin.

In one clinical trial involving type 2 patients, insulin glargine was associated with a slightly higher progression of retinopathy when compared with NPH insulin. The frequency was 7.5% with the analog and 2.7% with the NPH. This finding, however, was not seen in other clinical trials with this analog. Insulin glargine does have a sixfold greater affinity for IGF-1 receptor compared with the human insulin. There has also been a report that insulin glargine had increased mitogenicity compared with human insulin in a human osteosarcoma cell line. The significance of these observations is not yet clear. Because of lack of safety data, use of insulin glargine during pregnancy is not recommended.

e. Mixtures of insulin

Since intermediate insulins require several hours to reach adequate therapeutic levels, their use in type 1 patients requires supplements of regular or lispro insulin preprandially.

It is well established that insulin mixtures containing increased proportions of lente to regular insulins may retard the rapid action of admixed regular insulin. The excess zinc in lente insulin binds the soluble insulin and partially blunts its action, particularly when a relatively small proportion of regular insulin is mixed with lente (e.g., 1 part regular to 1.5 or more parts lente). NPH preparations do not contain excess protamine and so do not delay absorption of admixed regular insulin. They are therefore preferable to lente when mixtures of intermediate and regular insulins are prescribed. For convenience, regular and NPH insulin may be mixed together in the same syringe and injected subcutaneously in split dosage before breakfast and supper. It is recommended that the regular insulin be withdrawn first, then the NPH insulin. No attempt should be made to mix the insulins in the syringe, and the injection is preferably given immediately after loading the syringe. Stable premixed insulins (70% NPH and 30% regular or 50% of each) are available as a convenience to patients who have difficulty mixing insulin because of visual problems or impairment of manual dexterity.

With increasing use of rapid-acting insulin analogs as a popular and convenient preprandial insulin, it has become evident that combination with a more sustained insulin is essential to maintain postabsorptive glycemic control. It has been demonstrated that the rapid-acting insulin analogs can be acutely mixed with NPH without affecting their rapid absorption. Insulin lispro can also be mixed with ultralente insulin. Premixed preparations of insulin lispro and NPH insulins are unstable because of exchange of insulin lispro with the human insulin in the protamine complex. Consequently, the soluble component becomes over time a mixture of regular and insulin lispro at varying ratios. In an attempt to remedy this, an intermediate insulin composed of isophane complexes of protamine with insulin lispro was developed called NPL (neutral protamine lispro). This insulin has the same duration of action as NPH insulin. Premixed combinations of NPL and insulin lispro (eg, 75:25, 50:50, and 25:75 of NPL:insulin lispro) have been tested. The 75% NPL:25% insulin lispro mixture (Humalog Mix 75/25) is available for clinical use. Similarly, a 70% insulin aspart protamine/30% insulin aspart (NovoLogMix 70/30) is now available. The main advantages of these new mixtures is that they can be given within 15 minutes of starting a meal and they are superior in controlling the postprandial glucose rise after a carbohydrate rich meal. These benefits have not translated into improvements in HbA1c levels when compared with the usual 70% NPH/30% regular mixture.

3. Methods of insulin administration

a. Insulin syringes and needles

Plastic disposable syringes are available in 1-mL, 0.5-mL, and 0.3-mL sizes. The "low-dose" 0.3-mL syringes have become increasingly popular, because many diabetics do not take more than 30 units of insulin in a single injection except in rare instances of extreme insulin resistance. Two lengths of needles are available: short (8 mm) and long (12.7 mm). Long needles are preferable in obese patients to reduce variability of insulin absorption. Ultrafine needles as small as 31 gauge reduce the pain of injections. "Disposable" syringes may be reused until blunting of the needle occurs (usually after

three to five injections). Sterility adequate to avoid infection with reuse appears to be maintained by recapping syringes between uses. Cleansing the needle with alcohol may not be desirable since it can dissolve the silicone coating and can increase the pain of skin puncturing.

Any part of the body covered by loose skin can be used, such as the abdomen, thighs, upper arms, flanks, and upper buttocks. Preparation with alcohol is no longer required prior to injection as long as the skin is clean. Rotation of sites continues to be recommended to avoid delayed absorption when fibrosis or lipohypertrophy occurs from repeated use of a single site. However, considerable variability of absorption rates from different sites, particularly with exercise, may contribute to the instability of glycemic control in certain type 1 patients if injection sites are rotated too frequently in different areas of the body. Consequently, it is best to limit injection sites to a single region of the body and rotate sites within that region. The abdomen is recommended for subcutaneous injections, since regular insulin has been shown to absorb more rapidly from there than from other subcutaneous sites. The effect of anatomic regions appears to be much less pronounced with the analog insulins.

b. Insulin pen injector devices

Insulin pens eliminate the need for carrying insulin vials and syringes. Cartridges of insulin lispro, insulin aspart, insulin glargine, regular insulin, NPH insulin, and 70% NPH/30% regular insulin are available for reusable pens (Novo Nordisk, Becton Dickinson, and Sanofi Aventis pens). Disposable prefilled pens are also available for insulin lispro, NPH, 70% NPH/30% regular, 75% NPL/25% insulin lispro, and 70% insulin aspart protamine/30% insulin aspart. Thirty-one gauge needles (5, 6, and 8 mm long) for these pens make injections almost painless.

c. Insulin pumps

In the United States, Medtronic Mini-Med, Animas, and Deltec Cozmo insulin infusion pumps are available for subcutaneous delivery of insulin. These pumps are small (about the size of a pager) and very easy to program. They offer many features, including the ability to set a number of different basal rates throughout the 24 hours and to adjust the time over which bolus doses are given. They also are able to detect pressure build-up if the catheter is kinked. Improvements have also been made in the infusion sets. The catheter connecting the insulin reservoir to the subcutaneous cannula can be disconnected, allowing the patient to remove the pump temporarily (e.g., for bathing). The great advantage of continuous subcutaneous insulin infusion (CSII) is that it allows for establishment of a basal profile tailored to the patient. The patient therefore is able to eat with less regard to timing because the basal insulin infusion should maintain constant blood glucose between meals. Also the ability to adjust the basal insulin infusion makes it easier for the patient to manage glycemic excursions that occur with exercise.

CSII therapy is appropriate for patients who are motivated, mechanically inclined, educated about diabetes (diet, insulin action, treatment of hypoglycemia and

hyperglycemia), and willing to monitor their blood glucose four to six times a day. Known complications of CSII include ketoacidosis, which can occur when insulin delivery is interrupted, and skin infections. Another disadvantage is its cost and the time demanded of physicians and staff in initiating therapy.

d. Inhaled insulin

A novel method for delivering preprandial insulin by inhalation has been reported. A 12-week study in type 1 patients showed that inhaled insulin is as efficacious as subcutaneously delivered insulin without additional side effects. Patients required 300-400 units of insulin a day, since only 10% of the inhaled insulin is bioavailable. Safety studies are in progress to determine whether long-term use affects pulmonary tissues.

E. Transplantation

Pancreas transplantation at the time of renal transplantation is becoming more widely accepted. Patients undergoing simultaneous pancreas and kidney transplantation have an 85% chance of pancreatic graft survival and a 92% chance of renal graft survival after 1 year. Solitary pancreatic transplantation in the absence of a need for renal transplantation should be considered only in those rare patients who fail all other insulin therapeutic approaches and who have frequent severe hypoglycemia or who have life-threatening complications related to their lack of metabolic control.

Islet cell transplantation is a minimally invasive procedure, and investigators in Edmonton, Canada, have reported initial insulin independence in a small number of patients with type 1 diabetes who underwent this procedure. Using islets from multiple donors and corticosteroid-free immunosuppression, percutaneous transhepatic portal vein transplantation of islets was achieved in over 20 subjects. Although all of the initial cohort was able to achieve insulin independence posttransplantation (some for more than 2 years of follow-up), a decline in insulin secretion has occurred over time and the subjects have again required supplemental insulin. All patients had complete correction of severe hypoglycemic reactions, leading to a marked improvement in overall quality of life. Even if long-term insulin independence is demonstrated, wide application of this procedure for the treatment of type 1 diabetes is limited by the dependence on multiple donors and the requirement for potent long-term immunotherapy.

General Considerations in Treatment of Diabetes

Insulin-treated patients with diabetes can have a full and satisfying life. However, "free" diets and unrestricted activity are still not advised. Until new methods of insulin replacement are developed that provide more normal patterns of insulin delivery in response to metabolic demands, multiple feedings with carbohydrate counting will

continue to be recommended, and certain occupations potentially hazardous to the patient or others will continue to be prohibited because of risks due to hypoglycemia. The American Diabetic Association can act as a patient advocate in case of employment questions.

Exercise increases the effectiveness of insulin, and moderate exercise is an excellent means of improving utilization of fat and carbohydrate in diabetic patients. A judicious balance of the size and frequency of meals with moderate regular exercise can often stabilize the insulin dosage in diabetics who tend to slip out of control easily. Strenuous exercise can precipitate hypoglycemia in an unprepared patient, and diabetics must therefore be taught to reduce their insulin dosage in anticipation of strenuous activity or to take supplemental carbohydrate. Injection of insulin into a site farthest away from the muscles most involved in exercise may help ameliorate exercise-induced hypoglycemia, since insulin injected in the proximity of exercising muscle may be more rapidly mobilized.

All diabetic patients must receive adequate instruction on personal hygiene, especially with regard to care of the feet, skin, and teeth. All infections (especially pyogenic ones) provoke the release of high levels of insulin antagonists such as catecholamines or glucagon and thus bring about a marked increase in insulin requirements. Supplemental regular insulin is often required to correct hyperglycemia during infection.

Steps in the Management of the Diabetic Patient

A. Diagnostic Examination

Any features of the clinical picture that suggest end-organ insensitivity to insulin, such as visceral obesity, must be identified. The family history should document not only the incidence of diabetes in other members of the family but also the age at onset, whether it was associated with obesity, and whether insulin was required. Other factors that increase cardiac risk, such as smoking history, presence of hypertension or hyperlipidemia, or oral contraceptive pill use, should be recorded.

Laboratory diagnosis should document fasting plasma glucose levels above 126 mg/dL or postprandial values consistently above 200 mg/dL and whether ketonuria accompanies the glycosuria. A glycohemoglobin measurement is useful for assessing the effectiveness of future therapy. Some flexibility of clinical judgment is appropriate when diagnosing diabetes mellitus in the elderly patient with borderline hyperglycemia.

Baseline values include fasting plasma triglycerides, total cholesterol and HDL-cholesterol, electrocardiography, renal function studies, peripheral pulses, and neurologic, podiatric, and ophthalmologic examinations to help guide future assessments.

B. Patient Education (Self-Management Training)

Since diabetes is a lifelong disorder, education of the patient and the family is probably the most important obligation of the clinician who provides initial care. The best persons to manage a disease that is affected so markedly by daily fluctuations in environmental stress, exercise, diet, and infections are the patients themselves and their families. The "teaching curriculum" should include explanations by the physician or nurse of the nature of diabetes and its potential acute and chronic hazards and how they can be recognized early and prevented or treated. Self-monitoring of blood glucose should be emphasized, especially in insulin-requiring diabetic patients, and instructions must be given on proper testing and recording of data. Patients should be provided with algorithms they can use to adjust the timing and quantity of their insulin dose, food, and exercise in response to measured blood glucose values. The targets for blood glucose control should be elevated appropriately in elderly patients since they have the greatest risk if subjected to hypoglycemia and the least long-term benefit from more rigid glycemic control. Advice on personal hygiene, including detailed instructions on foot care as well as individual instruction on diet and specific hypoglycemic therapy, should be provided. Patients should be told about community agencies, such as Diabetes Association chapters, that can serve as a continuing source of instruction. Finally, vigorous efforts should be made to persuade new diabetics who smoke to give up the habit, since large vessel peripheral vascular disease and debilitating retinopathy are less common in nonsmoking diabetic patients.

C. Initial Therapy

Treatment must be individualized on the basis of the type of diabetes and specific needs of each patient. However, certain general principles of management can be outlined for hyperglycemic states of different types.

1. Type 2 diabetes

a. The obese type 2 patient

The most common type of diabetic patient is obese, is non-insulin-dependent, and has hyperglycemia because of insensitivity to normal or elevated circulating levels of insulin.

(1) Weight reduction

Treatment is directed toward achieving weight reduction, and prescribing a diet is only one means to this end. Behavior modification to achieve adherence to the diet-as well as increased physical activity to expend energy-is also required. Cure can be achieved by reducing adipose stores, with consequent restoration of tissue sensitivity to insulin, but weight reduction is hard to achieve and even more difficult to maintain with our current

therapies. The presence of diabetes with its added risk factors may motivate the obese diabetic to greater efforts to lose weight.

(2) Hypoglycemic agents

Monotherapy with metformin (or Α-glucosidase inhibitors) is the first-line therapy in the obese patient with mild diabetes if pharmacotherapy is required since they are not associated with weight gain or drug-induced hypoglycemia. If metformin therapy (combined with a weight reduction regimen) is inadequate to control blood glucose levels, then a thiazolidinedione or a sulfonylurea should be added. Some individuals may require metformin, a thiazolidinedione, and a sulfonylurea to achieve adequate glycemic control.

Insulin therapy should be instituted if the combination of these three drugs fails to restore euglycemia. Weight-reducing interventions should continue and may allow for simplification of this regimen in the future.

b. The nonobese type 2 patient

In the nonobese diabetic, mild to severe hyperglycemia is usually due to refractoriness of B cells to glucose stimulation. Treatment depends on whether insulinopenia is mild (type 2 or mild type 1 in partial remission) or severe, with ketoacidosis.

(1) Diet therapy-

If hyperglycemia is mild, normal metabolic control can occasionally be restored by means of multiple feedings of a diet limited in simple sugars and with a caloric content sufficient to maintain ideal weight. Restriction of saturated fats and cholesterol is also strongly advised.

(2) Oral hypoglycemic agents

When diet therapy in nonketotic type 2 patients is not sufficient to correct hyperglycemia, a trial of sulfonylureas is often successful in reducing the glycohemoglobin concentration below 9.5%. Once the dosage of one of the more potent sulfonylureas reaches the upper recommended limit in a compliant patient without maintaining fasting blood glucose below 140 mg/dL during the day, combination therapy with metformin (up to 1000 mg twice daily) or a thiazolidinedione-or both-should be tried. When the patient fails the combination of these three drugs, insulin therapy is indicated.

c. Treatment of type 2 diabetes with insulin

When the combination of metformin, sulfonylurea, and a thiazolidinedione fails and patients with type 2 diabetes require insulin, various insulin regimens may be effective. A single nighttime injection of NPH or insulin glargine can be added and titrated to achieve target fasting blood glucose values while continuing the oral antidiabetic medications. If

the patient does not achieve target glucose levels during the day, daytime insulin treatment can be initiated. A convenient insulin regimen under these circumstances is a split dose of 70/30 NPH/regular mixture (or Humalog Mix 75/25 or NovoLogMix 70/30) before breakfast and before dinner. If this regimen fails to achieve satisfactory glycemic goals or is associated with unacceptable frequency of hypoglycemic episodes, then a more intensive regimen of multiple insulin injections can be instituted. Metformin principally reduces hepatic glucose output and the thiazolidinediones improve peripheral resistance, and it is a reasonable option to continue these drugs when insulin therapy is instituted. The sulfonylureas also have been shown to be of continued benefit. Thus, the continued use of the oral drugs may permit the use of lower doses of insulin and simpler regimens.

2. Type 1 diabetes

Traditional once- or twice-daily insulin regimens are usually ineffective in type 1 patients without residual endogenous insulin. In these patients, information and counseling based on the findings of the DCCT should be provided about the advantages of taking multiple injections of insulin in conjunction with self-blood glucose monitoring. If near-normalization of blood glucose is attempted, at least three or four measurements of capillary blood glucose and three or four insulin injections are necessary.

A combination of rapid-acting insulin analogs and long-acting insulins (ultralente or insulin glargine) allows for more physiologic insulin replacement. The rapid-acting insulin analogs have been advocated as a safer and much more convenient alternative to regular human insulin for preprandial use. In a study comparing regular insulin with insulin lispro, daily insulin doses and hemoglobin A1c levels were similar, but insulin lispro improved postprandial control, reduced hypoglycemic episodes, and improved patient convenience compared with regular insulin. However, because of their relatively short duration (no more than 3-4 hours), the rapid-acting insulin analogs need to be combined with longer-acting insulins to provide basal coverage and avoid hyperglycemia prior to the next meal. In addition to carbohydrate content of the meal, the effect of simultaneous fat ingestion must also be considered a factor in determining the ultra-fast-acting insulin dosage required to control the glycemic increment during and just after the meal. With low-carbohydrate content and high-fat intake, there is an increased risk of hypoglycemia from insulin lispro within 2 hours after the meal. Table 27-11 illustrates some regimens that might be appropriate for a 70-kg person with type 1 diabetes eating meals providing standard carbohydrate intake and moderate to low fat content.

Table 27-12. Prebreakfast hyperglycemia: Classification by blood glucose and insulin levels.

  Blood Glucose (mg/dL)

    Free Immunoreactive Insulin (microunit/mL)

  10:00 PM

3:00 AM

7:00 AM

10:00 PM

3:00 AM 7:00 AM

Somogyi effect 90 40 200 High Slightly high

Normal

Dawn phenomenon 110 110 150 Normal Normal Normal

Waning of insulin dose plus dawn phenomenon

110 190 220 Normal Low Low

Waning of insulin dose plus dawn phenomenon plus Somogyi effect

110 40 380 High Normal Low

Multiple injections of NPH insulin (or twice-daily ultralente insulin) can be mixed in the same syringe as the insulin lispro, insulin aspart, and insulin glulisine. Insulin glargine is usually given once in the evening to provide 24-hour coverage. This insulin cannot be mixed with any of the other insulins and must be given as a separate injection. There are occasional patients in whom insulin glargine does not seem to last for 24 hours, and in such cases it needs to be given twice a day.

Continuous subcutaneous insulin infusion (CSII) by portable battery-operated "open loop" devices currently provides the most flexible approach, allowing the setting of different basal rates throughout the 24 hours and permitting patients to delay or skip meals and vary meal size and composition. The dosage is usually based on providing 50% of the estimated insulin dose as basal and the remainder as intermittent boluses prior to meals. For example, a 70-kg man requiring 35 units of insulin per day may require a basal rate of 0.7 units per hour throughout the 24 hours with the exception of 3 am to 8 am, when 0.8 units per hour might be appropriate (for the dawn phenomenon). The meal bolus would depend on the carbohydrate content of the meal and the premeal blood glucose value. One unit per 15 g of carbohydrate plus 1 unit for 50 mg/dL of blood glucose above a target value (eg, 120 mg/dL) is a common starting point. Further adjustments to basal and bolus dosages would depend on the results of blood glucose monitoring. The majority of patients use the rapid-acting insulin analogs in the pumps. One of the more difficult therapeutic problems in managing patients with type 1 diabetes is determining the proper adjustment of insulin dose when the prebreakfast blood glucose level is high. Occasionally, the prebreakfast hyperglycemia is due to the Somogyi effect, in which nocturnal hypoglycemia leads to a surge of counterregulatory hormones to produce high blood glucose levels by 7 am. However, a more common cause for prebreakfast hyperglycemia is the waning of circulating insulin levels by the morning. Also, the "dawn phenomenon"-reduced tissue sensitivity to insulin between 5 am and 8 am-is present in as many as 75% of type 1 patients and can aggravate the hyperglycemia.

Table 27-12 shows that diagnosis of the cause of prebreakfast hyperglycemia can be facilitated by self-monitoring of blood glucose at 3 am in addition to the usual bedtime and 7 am measurements. This is required for only a few nights, and when a particular pattern emerges from monitoring blood glucose levels overnight, appropriate therapeutic measures can be taken. The Somogyi effect can be treated by eliminating the dose of intermediate insulin at dinnertime and giving it at a lower dosage at bedtime or by supplying more food at bedtime. When a waning insulin level is the cause, then either

increasing the evening dose or shifting it from dinnertime to bedtime (or both) can be effective. A bedtime dose either of insulin glargine or of NPH insulin made from pork insulin provides more sustained overnight insulin levels than human NPH or human ultralente insulin and may be effective in managing refractory prebreakfast hyperglycemia. If this fails, insulin pump therapy may be required. When the dawn phenomenon alone is present, the dosage of intermediate insulin can be divided between dinnertime and bedtime; when insulin pumps are used, the basal infusion rate can be increased (e.g., from 0.8 unit/h to 0.9 unit/h from 6 am until breakfast).

Acceptable Levels of Glycemic Control

See above for a discussion of the DCCT and the UKPDS and their implications for diabetes therapy. A reasonable aim of therapy is to approach normal glycemic excursions without provoking severe or frequent hypoglycemia. What has been considered "acceptable" control includes blood glucose levels of 90-130 mg/dL before meals and after an overnight fast, and levels no higher than 180 mg/dL 1 hour after meals and 150 mg/dL 2 hours after meals. Glycohemoglobin levels should be no higher than 1% above the upper limit of the normal range for any particular laboratory. It should be emphasized that the value of blood pressure control was as great as or greater than glycemic control in type 2 patients as regards microvascular as well as macrovascular complications.

Prognosis

The DCCT showed that the previously poor prognosis for as many as 40% of patients with type 1 diabetes is markedly improved by optimal care. DCCT participants were generally young and highly motivated and were cared for in academic centers by skilled diabetes educators and endocrinologists who were able to provide more attention and services than are usually available. Improved training of primary care providers may be beneficial.

For type 2 diabetes, the UKPDS documented a reduction in microvascular disease with glycemic control, although this was not apparent in the obese subgroup. Cardiovascular outcomes were not improved by glycemic control, although antihypertensive therapy showed benefit in reducing the number of adverse cardiovascular complications as well as in reducing the occurrence of microvascular disease among hypertensive patients. In patients with visceral obesity, successful management of type 2 diabetes remains a major challenge in the attempt to achieve appropriate control of hyperglycemia, hypertension, and dyslipidemia. Once safe and effective methods are devised to prevent or manage obesity, the prognosis of type 2 diabetes with its high cardiovascular risks should improve considerably.

In addition to poorly understood genetic factors relating to differences in individual susceptibility to development of long-term complications of hyperglycemia, it is clear that in both types of diabetes, the diabetic patient's intelligence, motivation, and awareness of the potential complications of the disease contribute significantly to the ultimate outcome.

Bibliography

American Association of Diabetes Educators http://www.aadenet.org/

American Diabetes Association http://www.diabetes.org/home

American Dietetic Association http://www.eatright.org

Juvenile Diabetes Foundation http://www.jdf.org/index.html

Abraira C et al: Intensive insulin therapy in patients with type 2 diabetes: implications of the Veterans Affairs (VA CSDM) feasibility trial. Am Heart J 1999;138:S360.

American Diabetes Association Position Statement: Diabetes nephropathy. Diabetes Care 2004;27(Suppl 1):S79.

American Diabetes Association Position Statement: Preventive foot care in people with diabetes. Diabetes Care 2004;27 (Suppl 1):S63.

American Diabetes Association: Standards of Medical Care in Diabetes. Diabetes Care 2005;28(Suppl 1):S4.

Atkinson MA et al: Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 2001;358:221.

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.

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.

Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998;317:713.

Frank RN: Diabetic retinopathy. N Engl J Med 2004;350:48.

Gaede P et al: Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383.

Genuth S et al: Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26:3160.

Harris R et al: Screening adults for type 2 diabetes: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2003;138:215.

Hebel G et al: Hypoglycemia: pathophysiology and treatment. Endocrinol Metab Clin North Am 2000;29:725.

Holst JJ et al: Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004;287:E199.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: 837.

Knowler WC et al: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393.

Lipshultz LI et al: Treatment of erectile dysfunction in men with diabetes. JAMA 1999;281:465.

Ohkubo Y et al: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103.

Owens DR et al: Insulins today and beyond. Lancet 2001;358:739.

Poncelet AN: Diabetic polyneuropathy. Risk factors, patterns of presentation, diagnosis, and treatment. Geriatrics 2003;58: 16.

Screening for type 2 diabetes mellitus in adults: recommendations and rationale. Ann Intern Med 2003;138:212:

Setter SM et al: Metformin hydrochloride in the treatment of type 2 diabetes mellitus: a clinical review with a focus on dual therapy. Clin Ther 2003;25:2991.

Snow V et al: The evidence base for tight blood pressure control in the management of type 2 diabetes mellitus. Ann Intern Med 2003;138:587.

Shichiri M et al: Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000;23(Suppl 2):B21.

Stumvoll M et al: Clinical features of insulin resistance and beta cell dysfunction and the relationship to type 2 diabetes. Clin Lab Med 2001;21:31.

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317: 703.

Van der Berghe G et al: Intensive insulin therapy in the critically ill patient. N Engl J Med 2001;345:1359.

Vijan S et al: Treatment of hypertension in type 2 diabetes mellitus: blood pressure goals, choice of agents, and setting priorities in diabetes care. Ann Intern Med 2003;138:593.

Yki-Jarvinen H: Thiazolidinediones. N Engl J Med 2004;351: 1106.

Yusuf S et al: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145. Erratum in: 2000;342:1376. N Engl J Med 2000;342:748.

Wajchenberg BL: Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21: 697.

Weissberg-Benchell J et al: Insulin pump therapy: a meta-analysis. Diabetes Care 2003;26:1079.

Zinman B et al: American Diabetes Association: Physical activity/exercise and diabetes. Diabetes Care 2004;27(Suppl 1):S58.

Source: Current Medical Diagnosis and Treatment 2006