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ORIGINAL ARTICLE

Oral Agent Therapy in the Treatment of Type 2 Diabetes

Mark N. Feinglos, MD, CM
M. Angelyn Bethel, BS

The control of type 2 diabetes in the U.S. remains unsatisfactory (1). The recently released results of the U.K. Prospective Study support our belief that improved control of type 2 diabetes can be helpful in ameliorating the substantial morbidity associated with the disease (2). However, controversy still exists over the appropriate choice of therapy. Diet and exercise alone should be used as initial treatment for most newly diagnosed type 2 diabetic patients (3), but, if hyperglycemia persists, a decision must be made to initiate either an oral hyperglycemic agent or insulin. Although criticisms of the oral agents exist, there is support for the idea that insulin therapy should be reserved to treat diabetes when oral agents have failed (4). In cases when the physician or patient desires to delay insulin therapy, one must decide which oral agent or agents to use, and what criteria require progression to insulin treatment.

Therapeutic agents have been developed to address each of the three metabolic disorders characteristic of type 2 diabetes: decreased pancreatic -cell function, elevated hepatic glucose output, and insulin resistance. The choice of a particular oral agent may be suggested by specific conditions, such as obesity, or dictated by problems, such as renal insufficiency. The characteristics of each therapeutic class must be carefully weighed before initiating therapy.

SULFONYLUREAS— Sulfonylureas act by enhancing insulin release from -cells and may decrease peripheral insulin resistance (5). On average, sulfonylurea therapy reduces fasting plasma glucose (FPG) by 50–70 mg/dl and reduces HbA_1c by 0.8–1.7% (6,7). However, sulfonylureas differ in their relative potency, duration of action, and side-effect profile (see Table 1), allowing one to choose the most appropriate agent for a specific patient. All sulfonylureas are associated with weight gain. The first-generation agents (tolbutamide, acetohexamide, tolazamide, and chlorpropamide) are characterized by ionic protein binding in the plasma, which increases the risk of drug interactions, especially with alcohol, chloramphenicol, acetazolamide, monoamine oxidase inhibitors, phenothiazines, propranolol, rifampin, salicylates, sulfonamides, and some nonsteroidal anti-inflammatory drugs. The newer agents (glipizide, glyburide, and glimepiride), which are non-ionically bound, are less likely to interact with other medications.

The most common adverse effect of sulfonylurea therapy is hypoglycemia; however, the incidence is dependent on the agent used. Chlorpropamide is the most dangerous agent in this regard because the drug is only partially metabolized, and most is excreted unchanged by the kidneys; thus, patients with renal dysfunction may accumulate the active drug, leading to prolonged and profound hypoglycemia, sometimes resulting in death (8). Among the second-generation agents, glyburide is the most likely to cause serious hypoglycemia. Two newer agents, glipizide gastrointestinal therapeutic system and glimepiride, are associated with a lower incidence of hypoglycemia and may offer an advantage compared with the older drugs.

The newly released repaglinide, although not a sulfonylurea, binds to the same ion channel as the sulfonylureas and causes the release of insulin from the -cell. The drug carries a reduced risk of hypoglycemia because of rapid onset and clearance. Its particular benefit may lie in its ability to blunt the postprandial glucose rise.

In the early 1970s, the use of sulfonylurea therapy fell from favor because of the results of the University Group Diabetes Program (UGDP) study, which implicated tolbutamide in increased mortality from myocardial infarction (9). However, this study has subsequently engendered controversy on the basis of a number of issues. For example, a substantial number of patients were not representative of the typical type 2 diabetes population: approximately one-third had FPG <110 mg/dl, and approximately half of the enrolled patients had a weight <125% of ideal body weight. Additionally, no deaths from myocardial infarction occurred in the placebo group after 8 years, potentially skewing the data, given the small absolute number of deaths in the study. A more detailed discussion of the UGDP is beyond the scope of this article, but it has been undertaken elsewhere (10). Although the UGDP study is flawed, the results cannot be ignored in the absence of any other large outcome studies. However, the U.K. Prospective Diabetes Study (UKPDS) of >4,000 patients with newly diagnosed type 2 diabetes treated with diet, insulin, metformin, glyburide, or chlorpropamide may help to clarify the cardiovascular effects of sulfonylurea therapy in this disease.

Despite the confusion over the UGDP results, at least one sulfonylurea has been shown to have a significant cardiovascular effect. Glyburide abolishes ischemic preconditioning in the heart, a process that attenuates the extent of myocardial damage with repeated ischemic events (11). Glimepiride, one of the newest sulfonylureas, may offer an advantage over other drugs in this class because it has a more pancreas-specific binding profile, with reduced binding in the myocardium. Unfortunately, the clinical importance of ischemic preconditioning is unclear, as is the clinical significance of glimepiride's binding specificity.

BIGUANIDES— Metformin is the only drug in this class currently available for clinical use in the U.S. The most important mechanism of action of the biguanides is to reduce hepatic glucose output. Metformin has been shown to reduce the FPG by 50–70 mg/dl and the HbA_1c by 1.4–1.8%. Hypoglycemia is not a danger with metformin monotherapy. Additionally, metformin, unlike the sulfonylureas, is not associated with weight gain and in some studies has been correlated with weight loss (12,13). Metformin monotherapy is also associated with an increase in HDL cholesterol and a reduction in triglyceride, LDL cholesterol, and total cholesterol levels (13).

Metformin typically has a benign side-effect profile characterized by transient gastrointestinal discomfort and nausea. However, in 0.03 cases/1,000 patient-years, lactic acidosis may occur (14) (compared with 0.64 cases/1,000 patient-years with phenformin therapy, a biguanide withdrawn from the market in the U.S.). Lactic acidosis is more likely to occur in patients with renal insufficiency, and metformin is not recommended in patients whose creatinine is >1.5 mg/dl. Additionally, metformin should be withheld from patients undergoing contrast studies from the time of the procedure until 48 h after the procedure; it may be started again when renal function is determined to be normal.

-Glucosidase inhibitors
Acarbose is the only -glucosidase inhibitor currently available for clinical use in the U.S. Two other members of this class, miglitol and voglibose, have been studied but are not yet available. These drugs work by inhibiting the absorption of carbohydrate from the gut after a meal, thereby directly impacting postprandial hyperglycemia. Absorption of dextrins, maltose, sucrose, and starch is impaired by acarbose, but the drug has no effect on glucose or lactose. Treatment with acarbose typically reduces FPG by 35–40 mg/dl and HbA_1c by 0.4–0.7% (15,16). Acarbose therapy is not associated with weight gain or hypoglycemia. The use of this drug is complicated by its gastrointestinal side effects: increased flatulence, abdominal pain, and diarrhea. These effects may be mitigated by beginning therapy at a low dose and slowly increasing to the maximally effective dose.

THIAZOLIDINEDIONES— Troglitazone is currently the only available thiazolidinedione, although pioglitazone, rosiglitazone, and englitazone are under development. Thaizolidinediones work by directly enhancing insulin sensitivity, without any effect on insulin secretion. Troglitazone is associated with a reduction in HbA_1c of 0.5–1.5% and an increase in HDL cholesterol. However, some studies have also shown an increase in total and LDL cholesterol (17). Troglitazone monotherapy is associated with modest weight gain, but hypoglycemia is not typically experienced. Recent concern has arisen over the effects of troglitazone on the liver. Some patients treated with troglitazone have experienced an idiosyncratic drug reaction characterized by increased serum transaminases; in some cases, patients have progressed to hepatitis, hepatic failure, and death. Although this adverse effect is rare, serum transaminases should be checked in patients before initiating therapy with troglitazone, each month for 6 months after therapy initiation, bimonthly over the next 6 months, and periodically thereafter. Patients should also be monitored for symptoms of hepatic damage: nausea, vomiting, dark urine, or jaundice.

FAILURE OF MONOTHERAPY—A subset of patients, called primary failures, will not initially respond to oral agent therapy. Another set of patients, secondary failures, will initially achieve acceptable control of their diabetes with oral agent monotherapy; however, with progression of the disease, single-drug therapy no longer achieves adequate glycemic control. Table 2 shows reported failure rates associated with commonly used oral agents. Although these rates vary among patient populations, this table may serve as a guide to expected efficacy.

Sulfonylureas
Primary sulfonylurea failure occurs in 30% of an unselected patient population. However, patients with the following specific characteristics are less likely to be primary failures (15% failure rate): age >40 years, duration of diabetes <5 years, body weight 110–160% of ideal, no previous insulin therapy or satisfactory control with <40 U per day, and FBG <180 (18).

Secondary failure to sulfonylurea therapy occurs in 5–10% of patients per year. Patients with poor dietary compliance, -cell exhaustion, or conditions requiring the use of a diabetogenic drug (i.e., corticosteroids, -blockers) are less likely to achieve long-term glycemic control with sulfonylurea therapy alone.

Biguanides
Approximately 5% of patients cannot tolerate metformin therapy because of sustained gastrointestinal side effects. Most patients who can tolerate the drug will evince an initial response; the secondary failure rate for metformin is similar to sulfonylureas.

-Glucosidase inhibitors
The success of therapy with -glucosidase inhibitors depends on adherence to a diet of >50% carbohydrate. These diets are difficult to maintain for some patients, but little benefit is derived from the drug unless a high-carbohydrate diet is followed. Secondary failure rates in patients consuming appropriate diets are not known.

Thiazolidinediones
At least 25% of patients are primary failures to troglitazone monotherapy (19,20). These patients have been shown to have low levels of insulin secretion, often with C-peptide levels <1.5 ng/ml. The secondary failure rate has not been established.

Although diabetes treatment must be tailored to individual patient needs, the goals of oral agent therapy in general should coincide with the current American Diabetes Association (ADA) targets for glycemic control, i.e., FBG of 80–120 mg/dl, bedtime glucose 100–140 mg/dl, and HbA_1c<7%. Failure of monotherapy should lead to consideration of combinations of oral agents.

COMBINATION THERAPY— A number of studies have investigated the benefits of combination therapies with oral agents (4,15,21–23). It is clear from these studies that glycemic control can be further improved by the addition of a second agent to the therapeutic regimen. The choice of a second agent should be based on individual patient characteristics, i.e., obese patients may derive more benefit from the addition of metformin to preexisting sulfonylurea treatment than from the addition of troglitazone, which is more likely to facilitate weight gain.

Figure 1—Examples of placebo-controlled combination therapy studies. Monotherapy, first agent listed + placebo; combination, first agent listed + second agent listed; SU, sulfonylurea. Data adapted from Chiasson et al. (15), DeFronzo et al. (13), and Iwamoto et al. (23).

Not all combinations of oral agents have been studied. Among those that have been investigated, some have demonstrated greater impact on glycemic control than others (see Fig. 1). Based on these results, the choice of a second agent may also be dictated by the magnitude of hyperglycemia at the time of combination therapy initiation. (Thus, a patient with an HbA_1c of 9% on sulfonylurea therapy is unlikely to benefit from the addition of acarbose to the regimen. However, the same patient may derive significant benefit from the addition of metformin.) Although no studies have been done to assess the benefits of three-drug combinations, some physicians advocate their use.

RECOMMENDATIONS FOR ORAL AGENT THERAPY— All patients newly diagnosed with type 2 diabetes should have an initial trial of diet and exercise therapy, except in cases of severe hyperglycemia (FBG >250 mg/dl or random blood glucose >400 mg/dl), which may require insulin therapy, at least on a temporary basis. If ADA glycemic guidelines are not achieved within 2–4 weeks, patients should begin therapy with an oral agent. As described above, choice of an oral agent is dictated by certain patient characteristics. In patients with abnormal liver function tests, all oral agents are contraindicated, necessitating insulin therapy. Patients with abnormal creatinine may use any oral hypoglycemic agent except metformin and the sulfonylurea chlorpropramide. In obese patients with creatinine <1.5 mg/dl, metformin should be considered as initial therapy. For nonobese patients, any oral hypoglycemic may be used.

If monotherapy fails, combination therapy can be initiated as discussed above. Despite the use of two- or three-drug combination therapy, some patients may not be able to achieve or maintain glycemic control consistent with ADA guidelines. For these patients, insulin therapy becomes necessary, either alone or in combination with oral agent therapy.

Acknowledgments— This work was supported in part by grant M01-RR-30 from the National Center for Research Resources, General Clinical Research Centers Program, National Institutes of Health.

References
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From the Division of Endocrinology and Metabolism (M.N.F.), Duke University Medical Center; and the Duke University School of Medicine (M.A.B.), Durham, North Carolina.

Address correspondence and reprint requests to Mark N. Feinglos, MD, Box 3921, DUMC, Durham, NC 27710. E-mail: feing002@mc.duke.edu.

Received for publication 6 July 1998 and accepted in revised form 1 October 1998.

M.N.F. has received honoraria and grant support from, and is a member of an advisory panel for, Pfizer, Lilly, Hoechst-Marion Roussel, Bayer, and Novo-Nordisk. M.A.B. has received unrestricted grant support from Lilly.

Abbreviations: ADA, American Diabetes Association; FPG, fasting plasma glucose; UGDP, University Group Diabetes Program.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

This article is based on a presentation at a conference organized by the Indiana University Diabetes Research and Training Center. The conference and the publication of this article were made possible by an unrestricted educational grant from Eli Lilly and Company.

Copyright © 1999 American Diabetes Association
Last updated: 3/99
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