1. American Diabetes Association (ADA) Recommendations

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

DiabetesMellitus

Note: 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. Type 2 diabetes
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, IL60606 (312-899-0040). Their Internet address is

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 Dosage1
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 Dosage1
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 (Actos) / 15, 30, and 45 mg / 15-45 mg daily / Up to 24 hours / $6.28/45 mg / $188.42
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

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 Dosage1
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.