The Pharmacologic Management of Patients with Type II Diabetes Mellitus in the Era of New Oral Agents and Insulin Analogs

John R. White, Jr., PharmD

The options exercised in the management of hyperglycemia secondary to type II diabetes in the United States had changed little for 45 years, until several months ago. Sulfonylureas, insulin, and sulfonylurea/insulin combinations have been used since the late 1950s.¹ The biguanide phenformin was used briefly in this country, but was removed from the market because of its association with lactic acidosis.² Thus, the recent approvals of the a-glucosidase inhibitor acarbose, the biguanide metformin, and the insulin analog lispro have dramatically increased the options available to health-care practitioners managing type II diabetes. Another medication, troglitazone, has shown promise in preliminary trials. This article briefly reviews the use of the above-mentioned medications (except troglitazone) and offers a proposed algorithm for the pharmacologic management of type II diabetes given these options.

Sulfonylureas
Sulfonylureas are widely used in the United States in the management of type II diabetes. Currently, sulfonylureas account for ~1% of all prescriptions written in the United States.³ Seventy-five percent of this market is controlled by three agents: glyburide, glipizide, and chlorpropamide.⁴ An estimated 40% of all type II diabetes patients are treated with sulfonylureas. A new sulfonylurea, glimepiride, was recently introduced in the United States.

Mechanism of action. Sulfonylureas exert both pancreatic and extrapancreatic effects but are useful only in patients with viable ß-cells.^4,5 Sulfonylureas directly stimulate the release of insulin in vitro.⁴ In vivo, sulfonylureas sensitize ß-cells to glucose, increasing insulin secretion indirectly. Thus, under the influence of sulfonylureas, more insulin is secreted at all glucose levels than would be secreted in the absence of the sulfonylurea.⁴ Other potential pancreatic effects include inhibition of glucagon release. Sulfonylureas may also affect glucose levels by several extrapancreatic mechanisms, such as increasing insulin receptor binding affinity, increasing insulin’s effect by a post-receptor action, and decreasing hepatic insulin extraction. The relative clinical importance of each of these mechanisms of action is still a subject of research and debate.⁴

Efficacy. Several factors are predictive of sulfonylurea response, including age, weight, duration of disease, prior treatment with insulin, and fasting blood glucose (FBG) levels.^6-8 Patients more likely to respond have a recent diagnosis (< 5 years), are > 40 years of age, weigh 110–160% of ideal body weight, have FBG < 200 mg/dl, have never required insulin or needed < 40 units of insulin per day. If these criteria are met, primary failure rates can be as low as 15%.₇ The secondary failure rate of sulfonylureas has been estimated to be 10% per year,⁴ although in many populations the failure rate may be much higher.

In a responding patient, one can expect a reduction in fasting plasma glucose (FPG) of ~50–60 mg/dl and a 1–2% reduction in HbA_1c.⁹ The new sulfonylurea glimepiride apparently has similar effects. Mean HbA1c reductions of 2% were observed in patients treated with 8 mg of glimepiride daily.¹⁰ Studies with glimepiride have also demonstrated 46–77.5 mg/dl reductions in FPG levels when compared to placebo.^11,12 The monotherapeutic effects of glimepiride are similar to those of other sulfonylureas.

Side effects and contraindications. Hypoglycemia and weight gain are the primary side effects of sulfonylureas. The incidence of hypoglycemia is variable, but one study revealed a 20% chance of hypoglycemia every 6 months in patients treated with sulfonylureas.⁴ Weight gain is common with this therapy. One study evaluating the effects of glyburide reported a mean weight increase of 2.8 ± 0.7 kg, while another study evaluating the effects of tolbutamide reported a mean weight increase of 1.8 kg.^13,14 Additional, less common side effects include dermatologic reactions, hematologic reactions, and gastrointestinal disturbances.⁴ Disulfiram-like reactions and hyponatremia have been reported with chlorpropamide.⁴

Since all of the sulfonylureas undergo hepatic metabolism, they should be used cautiously in patients with hepatic dysfunction.⁴ The active metabolite of acetohexamide, hydroxyhexamide, is renally cleared. Also, 20% of chlorpropamide is excreted unchanged in the urine. Therefore, aetohexamide and chlorpropamide should not be used in patients with renal dysfunction. Also, tolazamide and glyburide have partially active metabolites that accumulate in patients with clearances of < 30 ml/min. Glipizide and tolbutamide are preferred in patients with moderate to severe renal dysfunction.⁴

Acarbose
Acarbose is an oral a-glucosidase inhibitor indicated for the management of hyperglycemia secondary to type II diabetes. It was approved for use in the United States in early 1996 and has been used extensively in Europe and Canada for several years. Acarbose, a mild anti-hyperglycemic agent, may be used as a monotherapy in new onset or mild type II diabetes or in combination with other agents in more severe type II diabetes cases.

Mechanism of action. Acarbose competitively inhibits a-glucosidase enzymes in the brush border of the small intestine.15 Additionally, acarbose inhibits pancreatic a-amylase,16 which is responsible for the hydrolysis of complex starches to oligosaccharides in the lumen of the small intestine. The a-glucosidase enzymes are responsible for the hydrolysis of oligosaccharides, trisaccharides, and disaccharides in the brush border of the small intestine and include maltase, isomaltase, glucoamylase, and sucrase. Inhibition of these enzyme systems effectively reduces the rate of complex carbohydrate digestion and the subsequent absorption of glucose, lowering postprandial glucose excursions in patients with diabetes.

Efficacy. One monotherapeutic study evaluating the effects of acarbose monotherapy in 212 obese subjects with type II diabetes reported a reduction in HbA_1c of 0.59%, a reduction in FPG of 16 mg/dl, and a 50 mg/dl reduction in postprandial plasma glucose.¹⁷ Another study reported reductions in HbA_1c of 0.54%, a mean reduction in FPG of 20 mg/dl, and a 51 mg/dl reduction in 1-hour postprandial glucose concentrations.¹⁴

Acarbose is also effective in combination with metformin, sulfonylureas, and insulin.¹⁸ Chiasson and associates reported that the addition of acarbose to insulin, metformin, or sulfonylurea therapy resulted in additional reductions in glycosylated hemoglobin levels of approximately 0.4%, 0.8%, and 0.5% respectively.

Side effects and contraindications. The common side effects of acarbose are dose-related gastrointestinal complaints, which often can be attenuated by continued administration of the medication. These side effects include flatulence, diarrhea, and abdominal pain, which occurred in the U.S. phase III trials with an incidence of 77%, 33%, and 21%, respectively.¹⁶ While elevated hepatic enzymes have been reported at higher doses, elevated serum transaminase levels were no more frequent than observed with placebo when doses of 100 mg t.i.d. or less were used.²

Acarbose monotherapy is contraindicated in patients with type I diabetes or patients with a history of diabetic ketoacidosis.¹⁶ Acarbose should also be avoided in patients with inflammatory bowel disease, colonic ulceration, or obstructive bowel disorders. Relative contraindications include chronic intestinal disorders of digestion or absorption and medical conditions that might deteriorate with increased intestinal gas formation.¹⁶ Lastly, acarbose therapy should be avoided in patients with serum creatinine levels of > 2.0 mg/dl, since studies have suggested increases in acarbose plasma concentrations with renal dysfunction, and long-term studies have not been carried out in this population.¹⁶

Metformin
The biguanide metformin was introduced in 1957 as an anti-hyperglycemic agent in type II diabetes patients.¹⁹ The Food and Drug Administration (FDA) recently approved metformin for use in the United States. It has been used worldwide since the late 1950s and is a safe and effective medication for the management of hyperglycemia in type II diabetes.

Mechanism of action. Metformin is an oral anti-hyperglycemic agent and not a hypoglycemic agent. Its mechanism of action differs from that of sulfonylureas in that it does not increase insulin secretion, is not associated with hypoglycemia, and does not produce weight gain.

Metformin’s primary sites of action are the liver and muscle tissue. It lowers blood glucose (BG) by enhancing insulin-stimulated glucose transport in skeletal muscle. The range of observed enhancement of glucose uptake ranges from 10–40%, depending on the population being evaluated.²⁰ Metformin also reduces hepatic glucose production in type II diabetes patients. Initially, this effect was thought to be mediated via a reduction in glycogenolysis.²¹ However, a more recent study has suggested that it may be secondary to a reduction in gluconeogenesis.²²

Efficacy. In a randomized, parallel, double-blinded trial of 289 moderately obese type II diabetes patients, metformin reduced fasting glucose levels an average of 58 mg/dl and HbA1c an average of 1.8% compared to diet plus placebo.²³ In addition to its effects on glucose, metformin therapy was also associated with a reduction in triglyceride concentrations (16%), low-density lipoprotein (LDL) cholesterol (8%), and total cholesterol (5%), and is associated with an increase in high-density lipoprotein (HDL) cholesterol (2%).²³ Also, patients treated with metformin lost a mean of 0.6 kg body weight.²³

In a second arm of the same study, combination metformin-glyburide was compared to glyburide monotherapy and metformin monotherapy in 632 obese type II diabetes patients whose diabetes was previously not well controlled (FPG > 140 mg/dl) by glyburide.²³Metformin-glyburide therapy reduced FPG by 77 mg/dl and HbA_1c by 1.9% when compared to glyburide monotherapy. Patients whose diabetes was not previously well controlled on glyburide monotherapy were not well controlled on metformin monotherapy. Metformin-glyburide therapy was also associated with a reduction in triglyceride concentrations (9.2%), LDL cholesterol (6%), and total cholesterol (4.6%) and an increase in HDL cholesterol (5.4%).

Another trial demonstrated that metformin monotherapy was associated with a slight weight reduction (-0.8 ± 0.5 kg). Glyburide was associated with a significant (P = 0.001) weight increase (+2.8 ± 0.7 kg). Metformin-glyburide was associated with less weight gain (+0.7 ± 0.4 kg).¹³

Because of its ability to reduce BG levels while not causing weight gain and its beneficial effect on plasma lipids, metformin is a reasonable choice for obese or dyslipidemic type II diabetes patients who carry no contraindications.

Side effects and contraindications. Patients treated with metformin had 30% more reports of abdominal bloating, nausea, cramping, a feeling of fullness, and diarrhea than did patients receiving placebo.²⁴ These side effects are usually self limiting, transient, and can be mitigated by starting with a low dose and titrating up slowly, as well as by taking the medication with food. Additional, less common side effects include metallic taste and a reduction in vitamin B12 levels. Lactic acidosis can occur with the administration of metformin but is extremely rare (0.03 cases per 1,000 patient-years) and has occurred primarily in patients with significant renal dysfunction.²⁴

Metformin is contraindicated in patients with renal dysfunction (serum creatinine of > 1.5 mg/dl in males or > 1.4 mg/dl in females) since metformin is excreted renally and can accumulate in patients with renal dysfunction. Because acidosis is sometimes associated with hepatic dysfunction, metformin is contraindicated in patients with clinical or laboratory evidence of hepatic dysfunction. It is also contraindicated in patients with acute or chronic lactic acidosis or a history of alcoholism or binge drinking. Finally, metformin should be temporarily withheld in patients with acute conditions predisposing them to acute renal failure or acidosis, such as cardiovascular collapse, acute myocardial infarction, acute exacerbation of congestive heart failure, use of iodinated contrast media, or a major surgical procedure.²⁴

Insulin and Lispro
Insulin has been widely used since 1922 in the management of hyperglycemia. An estimated 29% of all patients diagnosed with diabetes mellitus are type II diabetes patients treated with insulin.²⁵ Additionally, type II diabetes patients account for ~ 76% of all insulin use in the United States. In June 1996, the FDA approved the insulin analog lispro. Lispro is rapid-acting and appears to be superior to regular human insulin in some type II diabetes patients, particularly those with advanced disease.^26-28 While numerous manuscripts have been published delineating the metabolic effects of insulin, few studies have directly compared the efficacy of various insulin regimens in type II diabetes patients.

Mechanism of action.
Most studies evaluating the short-term effects of insulin in normal-weight and obese type II diabetes patients have suggested that insulin reduces FPG, enhances insulin-stimulated glucose utilization, reduces hepatic glucose production, and increases endogenous insulin secretion.²⁹ Unfortunately, the pharmacokinetics and pharmacodynamics of conventional exogenous insulin sometimes limit its ability to attenuate the metabolic effects of type II diabetes.²⁵ This is primarily because no conventional preparation can provide the low insulin concentrations needed to suppress hepatic glucose production (i.e., “basal insulin”) in the postabsorptive phase and, until the recent release of lispro, no preparations were able to provide the high concentrations needed to stimulate postprandial peripheral glucose disposal.

Efficacy.
Insulin’s ability to lower BG levels is governed by dose, regimen, level of insulin resistance, and other factors. Insulin is effective in reducing BG levels in type II diabetes patients when used as monotherapy^25,29 and in combination with sulfonyulreas,²⁹ metformin,³⁰ or acarbose.¹⁸

Patients with moderately severe type II diabetes (i.e., FPG = 140–200 mg/dl) will usually show sufficient response to a single or twice daily dose of insulin in the range of 0.3–0.4 U/kg/day.³¹ The most appropriate time for a single daily injection is still being debated. One study has suggested that bedtime administration is superior to morning when using intermediate-acting insulin, while another has suggested that 9:00 p.m. is a reasonable time for the single daily insulin dose when used in combination with sulfonylureas.^32,33 The former study reported improved glycemic control and the later study reported less weight gain with the bedtime or evening insulin doses when compared to morning insulin.

Patients with severe type II diabetes (FPG > 200 mg/dl) or patients not responsive to these regimens may require “around-the-clock” insulin.31 This usually necessitates the addition of short-acting insulin before meals with total daily insulin doses ranging from 0.5–1.2 U/kg/day. However, in insulin resistant patients, doses of > 1.5 U/kg/day may be needed.

The insulin analog lispro effectively improves metabolic abnormalities in type II diabetes patients.^27,34-36 The largest study to date evaluated 722 patients in a 6-month crossover design.³⁴ Glycemic control was evaluated via fasting and postprandial BG levels, postprandial glucose excursions, and HbA1c. The incidence of hypoglycemia was also measured. FBG levels were lower for lispro (LP)-treated patients in comparison to human insulin (HI)-treated patients (LP: 192 mg/dl; HI: 183 mg/dl; P = 0.002). LP-treated patients had lower 1- and 2-hour postprandial BG concentrations (1-hour: 238 mg/dl for LP, 250 mg/dl for HI, P < 0.001; 2-hour: 218 mg/dl for LP, 237 mg/dl for HI, P < 0.001), and significantly lower 1-hour and 2-hour glucose excursions (1-hour: 46.7 mg/dl for LP, 67.4 mg/dl for HI, P < 0.001; 2-hour: 25.2 mg/dl for LP, 53.5 mg/dl for HI, P < 0.001) than HI-treated patients. No significant difference in hypoglycemic rates between the two treatment groups was noted (LP: 2.67 events/30 days; HI: 2.79 events/30 days; P = 0.310). The study concluded that treatment with LP resulted in improved postprandial BG and BG excursions in patients with type II diabetes.

Lispro is also effective in combination with sulfonylureas.³⁷When compared to sulfonylurea therapy, combined therapy resulted in reductions in FPG (154 vs. 193 mg/dl, P < 0.0001), 2-hour postprandial plasma glucose (251 vs. 331 mg/dl, P < 0.0001), and HbA1c (7.2 vs. 9%, P < 0.0001). Body weight was higher in the combination therapy group (209 vs. 202 lb., P = 0.0001).

Finally, another study evaluating the effects of lispro on glucose tolerance in type II diabetes patients concluded that lispro restored early plasma insulin rise, improved glucose tolerance, induced a prompt and transient hepatic glucose production inhibition, and reduced late hyperinsulinization.²⁷

Side effects and contraindications. Several possible side effects, including hypoglycemia, weight gain, and the potential for accelerated macrovascular disease, should be considered with insulin and lispro use in type II diabetes patients.

Severe hypoglycemia, while a major concern in type II diabetes patients, probably occurs with a lesser frequency than is observed in patients with type I diabetes.²⁹ Additionally, the counterregulatory response to hypoglycemia in type II diabetes patients is blunted to a lesser degree than in patients with type I diabetes.

The annual rates of hypoglycemia and severe hypoglycemia (requiring the assistance of another person) in insulin-using patients in the 3-year follow-up of the UK Prospective Diabetes Study (UKPDS) were 33.4 and 1.4%, respectively.³⁸ The annual rates of hypoglycemia and severe hypoglycemia in glyburide-managed subjects in this trial were 27.8 and 1.3%, respectively.

Another study reported the incidence of any hypoglycemia in patients treated with sulfonylurea/metformin combination to be 40%, combination ultralente/sulfonylurea to be 33%, and ultralente/regular insulin to be 47%.³⁹ However, unlike the Diabetes Control and Complications Trial (DCCT) and the UKPDS, none of the cases of hypoglycemia in this study was incapacitating. The Vignati study of 722 patients treated with lispro or human regular insulin reported no significant difference in hypoglycemic events (LP: 2.67 events/30 days; HI 2.79 events/30 days; P = 0.310) between the two preparations.³⁴ However another study of 269 previously insulin-naive patients treated with lispro or human regular insulin reported a lower incidence of hypoglycemia in those at high risk for hypoglycemia (HbA_1c < 1 standard deviation below the group mean and a fear score > group mean) when lispro was used (LP: 0.37; HI: 2.75).²⁸

Insulin therapy has also been associated with weight gain. Studies in type II diabetes patients treated with insulin for 6–12 months have reported average weight gains of up to 6 kg.²⁹

Epidemiologic studies demonstrating a correlation between hyperinsulinemia (patients with and without diabetes, treated and not treated with exogenous insulin) and the risk of macrovascular disease²⁹ are another major concern for clinicians. However, no prospective studies to date have demonstrated that exogenous insulin accelerates macrovascular disease. A recent American Diabetes Association consensus statement concluded, “Exo-genous insulin administration does not have direct adverse effects on cardiovascular events and may even favorably affect the cardiovascular risk profile if improved glycemic control and lipid profile are sustained.”⁴⁰

Treatment Algorithm
The treatment algorithm shown in Figure 1 is not entirely based on large-scale studies. Rather, it is simply “proposed,” based on available research. The rationales for many of the treatment decisions are referenced and discussed below. Unfortunately, few comparative studies evaluating the various combinations of therapeutic approaches have been completed. Therefore, many of the proposed treatment decisions are based on the available data (however sparse), logic, and the author’s opinion.

This algorithm is intended only as a framework for discussion and debate regarding a stepwise approach to the pharmacologic management of type II diabetes and to underline some key areas in need of further research. Contraindications and precautions are not shown in the algorithm but must be considered by the reader. For example, an obese patient with a serum creatinine of 2.4 mg/dl at the point of Step 2 should not be treated with metformin, as the algorithm suggests. Finally, this algorithm does not apply to all type II diabetes and does not cover all contingencies.

The goals of therapy and the point at which action is suggested have been defined by the American Diabetes Association and are shown in Table 1.

A newly diagnosed patient could be initially ranked based on fasting or postprandial plasma glucose.⁴² Pre-viously diagnosed patients who are currently at their glycemic goal would continue their current therapy, while those not at their goal would be ranked in the algorithm and moved to the next step.

Step 1: evaluation and non-pharmacologic approaches. This step should include appropriate medical nutrition therapy⁴³ and physical exercise measures,⁴⁴ as well as formal diabetes education, including training on self-management of blood glucose and developing patient-specific glycemic goals. Step 1 should be continued through all other steps of therapy. Formal diabetes education should be provided periodically to assure patients’ continued understanding and to keep them abreast of new developments.

Step 2: oral monotherapy. Oral therapy should be considered for patients with FPG of 200–300 mg/dl or those who have not been adequately controlled by Step 1 alone, unless the patient is ketotic or severely symptomatic. The question at this juncture, “Is the patient obese?” will help to determine the most appropriate oral agent.

In obese patients with FPG < 160 mg/dl, acarbose may be appropriate. One can expect a reduction in FPG of ~20 mg/dl without deleterious metabolic side effects or weight gain.^7,14,17,18 This FPG reduction would bring the patient into reasonable control.

For obese patients with FPG > 160 mg/dl, metformin may be the drug of choice, if no contraindications exist. One can expect an average reduction in FPG of ~60 mg/dl without deleterious metabolic effects or the weight gain observed with sulfonylurea or insulin therapy.²³ In the UKPDS, metformin was found to be as effective as sulfonylurea or insulin in reducing glycemic indices while significantly reducing endogenous plasma insulin concentrations, without causing weight gain when compared to insulin or SU.³⁸ Based on available evidence, one could expect that a significant fraction of those with FPG of < 200 mg/dl and a smaller fraction of those with FPG of 200–300 mg/dl would achieve reasonable control with this therapy.

In nonobese type II diabetes pa-tients, acarbose or sulfonylureas are reasonable choices.

Step 3: combination oral therapy. For obese patients who fail acarbose monotherapy, combination metformin/acarbose may bring glycemic parameters into range without adversely affecting other metabolic parameters or inducing weight gain.¹⁸ Obese patients who have not reached goal glycemic indices with metformin therapy could be placed on combination sulfonylurea/metformin therapy. This combination usually results in significant reduction in glycemic indices with an attenuation of the effects of weight gain and hyperinsulinemia normally associated with sulfonylurea monotherapy.²³ For patients who are within 20 mg/dl of their FPG goal with metformin monotherapy, the addition of acarbose rather than a sulfonylurea could be considered.

For nonobese patients who fail acarbose therapy, the addition of a sulfonylurea could be considered. Another consideration in this case would be to discontinue acarbose and initiate sulfonylurea monotherapy. Sulfonylureas may be preferable to metformin because of their ability to enhance insulin secretion in this population, which may be relatively insulinopenic. For nonobese patients treated with sulfonylurea monotherapy, one could consider adding metformin or acarbose depending on the patient’s glycemic characteristics.

One alternative not included in this algorithm is to treat patients with triple oral agent combination therapy. Unfortunately, triple oral therapy has not been evaluated in any large, randomized, prospective trials.

Patients who do not respond adequately to any of the combination therapies described here should be moved to Step 4.

Step 4: combination oral agent/ insulin therapy. For each of the Step 4 regimens discussed below, two insulin options are suggested. First, single evening or bedtime injections of NPH or lente. This form of insulin therapy in type II diabetes patients has been widely used and studied, although in the past insulin/sulfonylurea received the most attention.

The second insulin option is to initiate t.i.d. dosing of lispro with the single oral agent. A recent study evaluating the effects of the lispro/sulfonylurea combination concluded that combination therapy resulted in statistically significant reductions in FPG (154 vs. 193 mg/dl, P < 0.001), 2-hour postprandial glucose (251 vs. 331 mg/dl, P < 0.001), and HbA1c (7.2 vs. 9%, P < 0.001) when compared to sulfonylurea monotherapy.³⁷This form of insulin therapy would offer good postprandial glycemic control without the problem of insulin-dose/meal-timing encountered with regular human insulin.

For obese patients with inadequate response to metformin/acarbose therapy, discontinuing acarbose and adding insulin is the next step. (While one may elect to continue acarbose, no triple drug studies have yet been completed, and the added expense of three drugs may not be warranted.) In one study of 50 obese type II diabetes patients, metformin/insulin therapy resulted in significantly lower plasma glucose profile (35%), glycosylated hemoglobin (17%), insulin doses (25%), and fasting plasma insulin concentrations (30%) than did insulin monotherapy.²⁷ Add-itionally, combination therapy resulted in statistically lower total cholesterol, triglycerides, and arterial blood pressure and higher HDL than was observed with insulin monotherapy.

For nonobese patients without adequate response to acarbose/sulfonylurea, acarbose would be discontinued and insulin initiated. In nonobese patients treated with metformin/sulfonylurea, metformin would be discontinued and insulin added.

Patients who do not respond adequately to oral agent/insulin combination therapy should be moved to Step 5.

Step 5: insulin therapy. Five commonly encountered insulin regimens are delineated under the rubric of Step 5. These regimens were compiled using several key references and are, to a large degree, commonly used in clinical practice.^{25,29,31-33,42}

The suggestion in this algorithm that lispro be used in place of regular human insulin deviates from previous suggested stepped care approaches. This is due, in part, to the fact that lispro was not available until August 1996. Lispro’s improved pharmacokinetic profile and ease of use, coupled with its recent FDA approval for use in type II diabetes, make its use instead of regular human insulin a reasonable option.

Summary

The recent introduction to the U.S. market of two new oral agents and one new insulin has dramatically increased the number of options available to health-care providers managing type II diabetes patients. Unfortunately, no consensus exists regarding how type II diabetes patients should be managed from a pharmacologic standpoint. While no treatment algorithm offers contingencies for all possibilities and should never supersede good clinical judgment, such algorithms do offer a framework from which decisions can be made. Hopefully, ongoing and future trials will better delineate the most appropriate pharmacologic path to take when managing type II diabetes patients.

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⁴¹American Diabetes Association: Position statement: Standards of medical care for patients with diabetes mellitus. Diabetes Care 19 (Suppl 1): S8-15, 1996.

⁴²Mazze RS, Etzwiler D, Strock E, Peterson K, McClave CR II , Meszaros JF, Leigh C, Owens LW, Peterson A, Kummer M: Staged diabetes management. Diabetes Care 17 (Suppl 1):56-66, 1994.

⁴³American Diabetes Association: Position statement: Nutritional recommendations and principles for people with diabetes mellitus. Diabetes Care 19 (Suppl 1): S16-19, 1996.

⁴⁴American Diabetes Association: Position statement: Diabetes mellitus and exercise. Diabetes Care 19 (Suppl 1):S30, 1996.

John R. White, Jr., PharmD, is an associate professor of pharmacy practice and director of the Washington State University/Sacred Heart Medical Center Drug Studies Unit in Spokane, Wash.

Note of disclosure: Dr. White has received honoraria for speaking engagements from and/or served as a consultant to Eli Lilly and Company, Bristol Myers Squibb, Bayer, and Lifescan, which are all manufacturers of products for the treatment of diabetes.