Review

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ulfonylurea Drugs: Mechanism of Antidiabetic Action and Therapeutic Usefulness HAROLD E. LEBOVITZ AND MARK N. FEINGLOS

T

he usefulness of oral sulfonylurea drugs in the treatment of patients with insulin-independent ("adult-onset," "nonketotic") diabetes mellitus continues to be debated. Important questions have been raised regarding both the potential toxicity and the therapeutic effectiveness of these agents. Some clinicians have abandoned their use entirely, while others continue to prescribe them with varying frequency and await further information. This review will attempt to provide a rational approach to the administration of oral sulfonylureas, based on our current understanding of their mechanism of action and clinical effect. The hypoglycemic effect of the sulfonylureas was first discovered in France, during World War II, as a chance finding in the course of investigations concerning the antibiotic properties of modified sulfonamides. Much of the early work was undertaken by Auguste Loubatieres. Widespread clinical application of these drugs did not occur, however, until the synthesis of carbutamide after the war, in Germany, followed by the development of the agents most commonly used in the United States, tolbutamide and chlorpropamide. In recent years the first generation of sulfonylureas has been followed by a second generation of compounds, which are far more potent than the original compounds. Sulfonylureas of both generations are shown in figure 1. Since the early 1950s, sulfonylureas, mainly tolbutamide and chlorpropamide, have been used extensively in the treatment of diabetes. The incidence of adverse reactions is low, with a total rate for all side effects estimated at 3.2 per cent for tolbutamide and 6 per cent for chlorpropamide.1'2 The most frequently described significant side effects3 are hematologic (agranulocytosis, bone marrow aplasia, red cell aplasia) and gastrointestinal (nausea, vomiting, heartburn, abnormal liver function tests, jaundice). Other described effects3 include cutaneous reactions (rashes, pruritis), vasomotor effects (disulfiramlike reaction to alcohol—most commonly seen with chlor-

propamide), possibly hypothyroidism, and dilutional hyponatremia with water intoxication (due to the antidiuretic action of chlorpropamide and perhaps tolbutamide). In contrast to these two, some other sulfonylureas (e.g. tolazamide and acetohexamide) may have a diuretic action.4 Severe hypoglycemia may rarely occur, most often in patients with renal or hepatic impairment.5 The subject of drug interactions with sulfonylureas, which may significantly alter their activity, has recently been extensively reviewed.6 For the large majority of patients, administration of a sulfonylurea induces no obvious ill effects. However, in 1970, the report of the University Group Diabetes Program (U.G.D.P.) suggested that tolbutamide therapy is no more effective than diet alone in the treatment of diabetes and may be associated with an increased cardiovascular mortality.7 While a number of important critical analyses of the methodology and results of the U.G.D.P. have been published,2'8'9 the controversies initiated by the U.G.D.P. report concerning the safety and efficacy of tolbutamide treatment for patients with nonketotic diabetes mellitus have yet to be resolved. A serious consequence of this study has been the condemnation of the therapeutic use of the entire class of sulfonylurea drugs. However, a complete evaluation of the usefulness of the sulfonylureas requires examination of the following questions: • Does tolbutamide have specific cardiovascular toxicity? • Do sulfonylurea drugs effectively alter the metabolic abnormalities of patients with insulin-independent diabetes mellitus and, if so, by what mechanism? • Is this mechanism a unique property of the sulfonylureas? • Do the various sulfonylurea drugs function identically, or can alteration of molecular structure lead to the development of agents with more potent antidiabetic activity and fewer undesirable side effects? Currently available information regarding the cardio-

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R|-^ySO2NHCONH-R2

FIRST GENEF^ATION C OMPOUNDS NAME TOLBUTAMIDE CHLORPROPAMIDE TOLAZAMIDE

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500

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100-

750

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DOSAGE RANGE (mg)

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TABLET SIZE (mg)

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FIG. I. Characteristics of current sulfonylurea drugs.

vascular effects of sulfonylureas is inconclusive and has most recently been reviewed by Levey.10 In order to discuss the remaining questions, we will examine our present knowledge of the mechanism of action of the sulfonylureas and results of treatment with these compounds. MECHANISM OF ANTIDIABETIC ACTION OF SULFONYLUREA DRUGS

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ince the introduction of sulfonylureas into clinical usage more than twenty years ago, investigators have sought to determine the mechanism of their antidiabetic action. Initially, a great controversy existed as to whether they acted directly on extrapancreatic tissues or exerted their effects through increased release of pancreatic insulin. During the late 1950s and early 1960s most studies seemed to indicate that the primary action was an increase in insulin release. More recently, however, a large body of clinical investigative data has cast serious doubts on the significance of the role that insulin-secretory effects of sulfonylureas play in their chronic antidiabetic action. This section reviews the current status of our knowledge of the pancreatic and extrapancreatic effects of sulfonylurea drugs and attempts to 190

develop a basis for understanding which of these effects are important in the therapeutic action of these drugs. Binding of Sulfonylurea Drugs to Proteins and Tissues All the sulfonylurea drugs bind significantly to serum albumin, although some differences exist in the nature of the specific binding site, particularly in the case of the second-generation sulfonylureas, glipizide and glibenclamide.11"13 Tolbutamide and other sulfonylurea drugs appear to be restricted in their distribution to the extracellular space and probably do not penetrate into cells.14"16 Glibenclamide binds extensively to the plasma membrane of the beta cells.17'18 These data suggest that sulfonylurea drugs exert their primary actions on the cell plasma membrane and that responsive tissues may contain specific sulfonylurea plasma membrane receptors. Effects of Sulfonylurea Drugs on Proinsulin Biosynthesis Both in-vivo and in-vitro studies show that sulfonylureas inhibit the synthesis of proinsulin,19"22 in spite of increasing pancreatic islet DNA and protein content.23 These findings probably account for the numerous observations that insulin release from the pancreas of animals chronically treated with sulfonylurea drugs is diminished,24"26 in con-

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trast to the earlier studies of Loubatieres, which purported to show a beta-cytotropic action of sulfonylurea drugs.27 Acute Sulfonylurea Administration and Insulin Release Many studies have shown that the acute administration of sulfonylureas to animals or man results in increased secretion of insulin28"32 and degranulation of the beta cells. The hypoglycemic action of all sulfonylureas requires the presence of pancreatic tissue, since no effect on blood glucose is seen following administration of the drugs either to pancreatectomized33 -34 or alloxan-diabetic animals35 or to patients with juvenile-onset29'36 or pancreatic diabetes. Increases in insulin-like activity and immunoreactive insulin levels occur in both peripheral and portal vein blood following acute sulfonylurea administration. In vitro studies indicate that the mechanism by which sulfonylureas stimulate insulin secretion differs from that of glucose.32 Studies with isolated perfused pancreases demonstrate that sulfonylureas stimulate the first phase of insulin release and have little or no effect on the second phase. Sulfonylureas can stimulate insulin release in the absence of glucose, but they also potentiate glucose-mediated insulin release. Although sulfonylureas activate beta cell adenylate cyclase37'38 and inhibit adenosine 3', 5' monophosphate diesterase39'40 (both of which increase intracellular cyclic AMP), it appears unlikely that this is the mechanism responsible for their effect on insulin secretion.21 Rather, most of the evidence points to an effect on intracellular calcium ion redistribution or changes in fluxes of potassium or sodium ions as being more significant.32'41 Several recent reviews are available that examine in detail the possible mechanisms by which sulfonylurea drugs acutely stimulate insulin secretion.31'32 Chronic Sulfonylurea Administration and Insulin Release Chronic treatment of animals with sulfonylureas results in markedly diminished glucose- and amino-acid-stimulated insulin release.24"26 Similarly, many clinical studies have shown that glucose-stimulated insulin release, in patients with diabetes who have been chronically treated with sulfonylurea drugs, is either decreased or unchanged compared with pretreatment values.42"45 This failure to demonstrate increased insulin secretion, as well as the data indicating decreased insulin synthesis following chronic treatment, suggests that the chronic antidiabetic action of sulfonylurea drugs is unrelated to an effect on the beta cell. Sulfonylureas and Glucagon Secretion A decrease in glucagon secretion by the sulfonylureas could explain their antidiabetic action. Early studies in which sulfonylureas failed to lower the blood glucose in alloxan-diabetic animals were used as evidence to rule out an effect of these agents oh glucagon secretion. More recent studies, both in vivo and in vitro, have evaluated

the effects of sulfonylureas on glucagon secretion by measurement of glucagon with radioimmunoassay techniques. While studies with duck pancreas have shown sulfonylurea-induced suppression of glucagon secretion,46 those with rat pancreas show either stimulation or inhibition, depending on the experimental conditions.32 There is no good evidence that acute or chronic sulfonylurea therapy alters glucagon secretion in normal subjects or patients with diabetes mellitus.47"49 Thus, it is unlikely that the antidiabetic action of sulfonylureas is related to an alteration in glucagon secretion. Extrapancreatic Actions of Sulfonylurea Drugs Over the years a number of interesting extrapancreatic actions of sulfonylurea drugs have been described. Many of these actions have required concentrations of sulfonylureas far in excess of the therapeutic levels usually attained in the plasma. Additionally, many have been demonstrated only in broken-cell preparations and, as previously noted, it is unlikely that sulfonylureas penetrate the cell. Table 1 lists the more thoroughly studied extrapancreatic actions. It would seem from the available data that if an

TABLE 1 Extrapancreatic actions of sulfonylurea drugs A. Probably Related to Antidiabetic Action 1. Potentiation of insulin stimulation of carbohydrate transport in skeletal muscle.52 2. Potentiation of insulin action on the liver.3'3'54 B. Possibly Related to Antidiabetic Action 1. Direct effects on the liver (a) Inhibition of triglyceride lipase.55 (b) Limitation of anionic substrate movement across the inner membrane of hepatic mitochondria.55 (c) Inhibition of ketosis.50 (d) Inhibition of glucose output.50 2. Direct effects on adipose tissue (a) Inhibition of lipolysis.57 (b) Inhibition of triglyceride lipase.57 (c) Increase uptake and oxidation of glucose.50-57 C. Unlikely to be Related to Antidiabetic Action 1. Activation of adenylate cyclase.10 2. Inhibition of adenosine 3',5' monophosphate diesterase.10 3. Inhibition of catecholamine release in vitro.58 4. Alteration of rate of amino acid incorporation into protein.56 5. Inhibition of transaminase activity.50 6. Inhibition of the ratio of bound to free insulin.50 7. Reduction of intestinal glucose absorption.59 8. Inhibition in insulinases.60'61 D. Not Related to Antidiabetic Action 1. Increase cardiac contractility.10 2. Effects on water balance (either diuretic or antidiuretic).10 3. Inhibition of platelet aggregation.10

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extrapancreatic effect of a sulfonylurea drug is to be a pancreatectomized dogs potentiated the blood glucose fall to < significant factor in its action in adult-onset diabetes small (0.025 U./kg.) but not large (0.25 U./kg.) amounts' mellitus50 it should satisfy the following criteria: of exogenously administered insulin.72 Madsen reported a; similar potentiation of insulin action by tolbutamide in 1. The effect should be achieved in vivo or in vitro with eviscerated, glucose-infused cats.73 The reasons for the disconcentrations of sulfonylureas in the range of the plasma parate results in animal studies are not clear but may have levels ordinarily attained during chronic oral therapy. to do with the experimental designs utilized. Most studies 2. The effect should occur at a site in the cell that is in which acute sulfonylurea administration potentiates available to sulfonylurea localization. insulin action have utilized diabetic animals that were 3. The effect should occur only in the presence of insulin. chronically maintained on insulin therapy. Perhaps the Only a few of the numerous actions described in table 1 sulfonylureas do mobilize some insulin that has been bound meet these criteria. They are (1) the potentiation of in an inactive form. Those studies in which acute adinsulin action on muscle carbohydrate transport, (2) the ministration of sulfonylureas failed to potentiate insulin direct action on the liver to decrease hepatic glucose action used animals or patients who were not on chronic output, and (3) the potentiation of insulin action on the insulin therapy. liver. Several studies have assessed the effects of acute sulfonylSeveral reviews are available that discuss in detail the urea administration on the action of locally administered 74 75 nature and significance of these extrapancreatic effects.50'51 insulin in forearm metabolism. ' These studies indicate For the purposes of this review, however, the most per- that sulfonylureas do not potentiate insulin action on skeletal tinent and clinically relevant of these effects are those muscle. In contrast, Feldman and Lebovitz have demonrelated to the potentiation of insulin action. strated that chronic sulfonylurea therapy in normal mice alters diaphragm muscle such that in vitro the insulin 52 any of the early studies with sulfonylurea effect on carbohydrate transport is significantly potentiated. Recently we re-examined the question of whether drugs were directed toward determining in patients whether these agents alter insulin sensitivity. sulfonylurea therapy potentiates insulin action 76 Mirsky demonstrated that insulinase was with insulin-independent diabetes mellitus. Insulin sensiinhibited by sulfonylureas and suggested that perhaps tivity was measured in normal volunteers and in patients these drugs decreased the rate of insulin degradation.61 with untreated insulin-independent diabetes. The patients Subsequent studies, however, showed that the effects of with diabetes were then treated with either diet or diet sulfonylureas on insulinase activity occurred only with plus glipizide (a second-generation sulfonylurea) for five or concentrations that were far in excess of those achieved six weeks until they achieved normal plasma glucose in the plasma during treatment and that this action, levels. Insulin sensitivity was then remeasured. The inwhile interesting, was probably not therapeutically signif- sulin sensitivity was determined by calculating the rate of icant.50'62 The possibility that sulfonylureas might mobilize fall of plasma glucose in response to acutely adminissome in-vivo bound form of insulin into a free (avail- tered intravenous insulin. Figure 2 shows the response to able) form was also proposed but not substantiated 0.1 U. insulin/kg, body weight in the normal volunteers as compared with the patients with diabetes. The rate of experimentally.50 Acute administration of sulfonylureas to normal individuals or patients with diabetes is associated with a decrease in fasting blood glucose, no change in glucose tolerance, and no enhancement of the sensitivity to exogenously administered insulin.63"65 The effect of sulfonylureas on insulin sensitivity in normal and diabetic animals has been controversial. Fritz et al. found that carbutamide had no effect on the blood glucose response to exogenously administered insulin (0.02 U. to 0.2 U./kg.) in chronic pancreatectomized dogs.66 Lang and Sherry reported that tolbutamide does not enhance insulin sensitivity in either normal or alloxan-diabetic rats.67 Several investigators have reported modest falls in blood glucose in diabetic 4 5 animals given sulfonylureas within 24 hours after stopping K VALUE insulin therapy but no fall if sulfonylureas were given FIG. 2. Frequency distribution of glucose disposal constants in several days after withdrawal of insulin.68"71 Caren and response to 0.1 U. insulin/kg, in 15 normal volunteers and 11 uri' Carbo showed that acute administration of tolbutamide to treated insulin'independent diabetic patients.

M

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fall of plasma glucose is expressed as a K value, representing the per cent glucose removed from the plasma compartment per minute, which provides an indication of insulin action. As can be seen, patients with insulinindependent diabetes show marked impairment of insulin action as compared with age-matched normal volunteers. Following normalization of the fasting plasma glucose in patients with diabetes by diet, insulin action was unaltered (figure 3). In contrast, normalization of fasting plasma glucose by glipizide therapy was associated with a marked improvement in insulin sensitivity. Thus, chronic sulfonylurea therapy increases insulin sensitivity in patients with insulin-independent diabetes mellitus. The significance of these observations becomes more apparent if one correlates them with the data concerning the nature of the metabolic abnormalities in insulinindependent diabetes mellitus. This form of diabetes is associated with marked resistance to insulin action. Several studies in which insulin action was assessed by measuring the rate of fall of plasma glucose in response to intravenous insulin have demonstrated very low K values in patients with insulin-independent diabetes.76"80 Reaven and his co-workers have evaluated insulin action in a similar group of patients by determining the steady-state plasma glucose level that results from a constant infusion of glucose, insulin, epinephrine, and propranolol.81"83 They have shown that (1) patients with diabetes due to destruction of the pancreas have normal insulin sensitivity, as do newly diagnosed insulin-dependent diabetic patients;2 patients with insulin-independent diabetes have marked resistance to insulin action. Thus, while pancreatic insulin content may be modestly reduced and insulin secretion (relative to the absolute level of plasma glucose) impaired in insulin-independent diabetes, a major, if not the most important, metabolic aberration is an impairment of insulin action. Therefore, the ability of chronic sulfonylurea therapy to potentiate insulin action in patients with insulin-independent diabetes mellitus partially or completely ameliorates a major abnormality in these individuals and perhaps accounts for the antidiabetic action of sulfonylureas in the chronic treatment of insulin-independent diabetes mellitus. Although the sites at which chronic sulfonylurea therapy potentiates insulin action and the operative mechanisms are still speculative, some data allow us to develop hypotheses. Kimmerling et al. have suggested that the earliest abnormality in insulin action in insulin-independent diabetes may be an impairment in glucose uptake rather than an impairment in hepatic response.84 Subsequently, both responses to insulin are deficient. Olefsky has shown that chronic chlorpropamide therapy in patients with insulin-independent diabetes restores the deficient numbers of insulin receptors on circulating monocytes toward normal.85 Preliminary data from our laboratory indicate that

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the sulfonylurea-induced potentiation of insulin action in experimental animals is associated with a marked increase in the number of insulin receptors present in hepatic plasma membranes. Summary—Mechanisms of Action We would propose the following hypothesis for the mechanism of the antidiabetic action of sulfonylurea drugs: Insulin-independent diabetes mellitus is a membrane disease that manifests itself by marked resistance to insulin action and a relative impairment of insulin secretion in response to nutritional stimuli such as glucose and amino acids. Sulfonylureas initially stimulate pancreatic insulin release but chronically inhibit both pancreatic insulin synthesis and secretion. Chronic sulfonylurea therapy alters the plasma membrane of cells to increase their responsiveness to insulin action, perhaps by increasing the number of insulin receptors. The net effect of sulfonylurea action at any particular time in therapy will depend on the contributions of these two activities. Early in the course of treatment, insulin secretion will be enhanced and will contribute to the amelioration of the hyperglycemia in concert with the effect on potentiation of insulin action. Late in the course of treatment, potentiation of insulin action will be the primary mode of action. Many questions remain to be answered. What is the membrane defect in insulin-independent diabetes mellitus, and is it uniform? Is it progressive? How do the sulfonylureas increase insulin action? Does the effect on insulin action persist? The answer to these and many additional questions should provide new insight into the nature of insulin-independent diabetes mellitus, a further understanding of the mechanism of the antidiabetic action of sulfonylurea drugs, and a model for developing new and,

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we may hope, more effective drugs for the treatment of insulin-independent diabetes mellitus. THERAPEUTIC USEFULNESS OF SULFONYLUREA DRUGS

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ulfonylurea drugs have been widely used in the management of patients with "adult-onset" diabetes since 1955. In spite of this extensive usage, controversy still exists concerning the indications for sulfonylurea therapy, their effectiveness in ameliorating hyperglycemia, and the extent of their toxicity. The questions about toxicity raised by the University Group Diabetes Program study have been briefly discussed in the beginning of this review. That study, however, cannot be used to analyze efficacy, since it was not designed to achieve regulation of hyperglycemia by sulfonylurea therapy. Relatively few comprehensive studies have been carried out to evaluate the long-term results of sulfonylurea therapy in patients with diabetes mellitus. Bernhard, in 1965, reported the results of a six-year investigation of 8,538 diabetics treated with oral sulfonylureas.86 In that study, 73.3 per cent of the patients were considered to be successfully controlled at the time of the evaluation. Primary failure of therapy occurred in 455 (5.3 per cent), and secondary failure was observed in 1,258 (14.7 per cent). Good therapeutic responses were associated with (1) normal or excess body weight, (2) age of onset of diabetes at forty years or greater, (3) duration of diabetes of less than five years at the time oral therapy was initiated, and (4) either no previous history of insulin treatment, or insulin treatment with a dose of less than 20 U. per day. Primary failures occurred with greatest frequency in those patients who were underweight, had diabetes for longer than five years, or had been on insulin therapy previously. The highest incidence of secondary failures was noted at one to three years of therapy. Of the 5,052 patients in satisfactory control on the oral sulfonylureas, 756 (15.0 per cent) had been treated for five years and 741 (14.7 per cent) for six years. This contrasts with 34.3 per cent who were in their first year of therapy and suggests that 42.7 per cent of patients who have an initial good response to sulfonylurea treatment may be expected to maintain that effect for six years. Thirty-seven per cent of the 1,258 cases of secondary failure were associated with other complications (cardiovascular disorders, infectious diseases, accidents, operations, or serious dietary mistakes). Therefore, only 10.6 per cent (790) represented true secondary failures.

Balodimos and co-workers evaluated the effects of tolbutamide treatment for up to nine years in 3,387 patients at the Joslin Clinic.87 Primary failure occurred in 526 and satisfactory control for at least one month was seen in 2,555. During the period of observation, 2,056 patients had satisfactory control of their diabetes with to/butamide 194

while 499 became secondary failures. Thus, 75.4 per cent of the patients achieved satisfactory control (two-thirds good and one-third fair). As in the other studies, the best results were seen in overweight patients who had diabetes for less than one year and had been on either no or less than 20 U. of insulin per day previously. Of particular importance, they noted that only 430 patients were still being followed six to nine years after the initiation of therapy. This represented only 10 per cent of the expected number. The high attrition rate was due to death (504) and loss to follow-up (748). Some have interpreted this figure to mean that only 10 per cent of patients respond to sulfonylurea therapy for greater than six years. This does not seem to be a valid conclusion. Several other studies with smaller numbers of patients treated for shorter periods of time present data quite similar to the two previously described studies.88"92 DeLawter and Moss described results obtained in 200 diabetic patients treated with tolbutamide for five years.91 Primary failure occurred in 22 per cent and secondary failure in 36 per cent. Thirteen per cent were satisfactorily controlled, another 10 per cent had been switched to another agent and were controlled, while the remainder were dead or lost to follow-up. Powell et al. treated 676 patients with tolbutamide or chlorpropamide for up to four years.92 There were 67 primary failures (19 per cent). Of the remaining 589 patients, there were 66 secondary failures (11 per cent), 58 in fair control (10 per cent), and 465 (79 per cent) in good control. Large-scale longterm studies of the efficacy of second-generation sulfonylureas are not yet available. Several investigators have questioned whether longterm evaluations of sulfonylurea drugs are valid unless the patients are subsequently treated with placebo to see if the observed effect is the result of the sulfonylurea.93"95 Patients attending the Diabetes Outpatient Clinic of the Boston City Hospital were initially screened with diet therapy. Those who did not achieve satisfactory control of their diabetes were treated with either tolbutamide or chlorpropamide.93 The objective of therapy was maintainence of the postprandial blood sugar below 150 mg./dl. After six months, a placebo identical in form to their usual medication was substituted and maintained for six months, unless the degree of hyperglycemia or symptomatology necessitated a return to drug treatment. Drug therapy was then reinstituted, if indicated. Placebo trials were carried out every two years. In this study, 282 patients treated with tolbutamide were available for study. Of those, 29.5 per cent were considered primary failures; 70.5 per cent had an initial satisfactory response to the drug. However, 31.2 per cent subsequently demonstrated equally satisfactory control with the placebo substitute. An additional 18.1 per cent developed secondary failure, and only 21.3 per cent could be classified as having a

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satisfactory response to the drug. The chlorpropamide treatment group had 36.4 per cent primary failures, 16.9 per cent placebo responders, 14.9 per cent secondary failures, and 30.8 per cent satisfactory response to the drug. The average duration of treatment was three years. One major drawback of this study is that the patient selection included many who did not meet the criteria for oral sulfonylurea therapy. When the investigators corrected for this factor, the success rate for tolbutamide was 29.8 per cent and for chlorpropamide 51.1 per cent. The study did, however, clearly identify the need for placebo controls. Similar studies have been reported showing that patients who initially require sulfonylureas for control of their hyperglycemia may remain in good control following cessation of therapy or placebo substitution. Tompkins and Bloom found that, although 59 per cent of patients in whom sulfonylurea therapy was discontinued relapsed into hyperglycemia, 31 per cent remained in good control for at least six months.94 Lev-Ran replaced chloropropamide with placebo in 50 diabetic patients on long-term therapy. Twenty-seven had no change in their fasting blood glucose.95 These intriguing observations have been interpreted to indicate that a large number of patients are needlessly being maintained on sulfonylurea therapy. Unfortunately, several years' follow-up of these patients has not been reported. One might equally well hypothesize that chronic sulfonylurea treatment in some patients ameliorates the metabolic abnormality and that this effect persists for many months, only to reappear at a later date. At the present time, it seems reasonable to make the following statements regarding the therapeutic usefulness of sulfonylurea drugs: 1. Sulfonylureas are effective in controlling hyperglycemia for at least several years in selected insulin-independent diabetic patients. 2. The causes of primary and secondary failure are unknown. 3. The degree of effectiveness of chronic (greater than five years) sulfonylurea therapy in controlling hyperglycemia is unclear. 4. Uncertainty exists as to the potential risk of cardiovascular toxicity associated with the use of sulfonylureas. On the basis of current information, the use of sulfonylureas should be limited to patients with insulin independent diabetes. Patients who are forty years or older, are of normal weight or obese, and have recently diagnosed diabetes would be expected to show the best responses to treatment. The treatment goal should be to achieve fasting and two-hour postprandial plasma glucose levels less than 130 mg./dl. Sulfonylurea therapy must be accompanied by appropriate dietary modification. However, recent data concerning the mechanism of sulfonylurea action, presented in the preceding section, suggest that better criteria for

institution of sulfonylurea therapy may be available in the future. The observations that insulin-independent diabetes appears to result from insulin resistance and relative impairment of insulin secretion indicate that the assessment of these metabolic parameters may provide a useful means of choosing the proper therapeutic modality. Markedly impaired insulin action with modest insulin secretion may be a good indication for sulfonylurea therapy. Mildly impaired insulin action with only a modest impairment of insulin secretion may be a good criterion for intensive dietary therapy. Normal insulin action with marked impairment of insulin secretion (characteristic of insulin-dependent diabetes) would be an indication for insulin therapy. Further investigations will test these hypotheses. ACKNOWLEDGMENTS: The authors' own studies were supported by grants from Pfizer Pharmaceutical, Inc., the National Institutes of Arthritis, Metabolic, and Digestive Diseases (AM 01324 and 5T AM 07012), and by grant MO1 FR 30 from the Clinical Research Center Branch Division of Research Facilities and Resources, U. S. Public Health Service. From the Departments of Medicine and Physiology, Duke University Medical Center, Durham, North Carolina 27710. REFERENCES 1 O'Donovan, C. J.: Analysis of long-term experience with tolbutamide (Orinase) in the management of diabetes. Curr. Ther. Res. J: 69-87, 1959. 2 Shen, S. W., and Bressler, R.: Clinical pharmacology of oral antidiabetic agents. N. Engl. J. Med. 296: 493-97, 787-93, 1977. 3 Pannekoek, J. H.: Insulins, glucagon and oral hypoglycemic drugs. In Side Effects of Drugs, Vol. 8. Dukes, M. N. G., Ed. Amsterdam, Excerpta Medica, 1975, pp. 904-27. 4 Moses, A. M., Howaritz, J., and Miller, M.: Diuretic action of three sulfonylurea drugs. Ann. Intern. Med. 78: 541-44, 1973. 5 Seltzer, H. S.: Drug-induced hypoglycemia: A review based on 473 cases. Diabetes 21: 955-66, 1972. 6 Hansen, J. M., and Christensen, L. K.: Drug interactions with oral sulfonylurea hypoglycemic drugs. Drugs 13: 24-34, 1977. 7 University Group Diabetes Program: A study of the effects of hypoglycemia agents on vascular complications in patients with adult-onset diabetes. Diabetes J9 (Suppl. 2) 747-830, 1970. 8 Feinstein, A. R.: An analytic appraisal of the University Group Diabetes Program (UGDP) study. Clin. Pharmacol. Ther. 12: 167-91, 1971. 9 Karam, J. H., Martin, S. G., and Forsham, P. H.: Antidiabetic drugs after the University Group Diabetes Program (UGDP). Ann. Rev. Pharmacol. 25: 351-66, 1975. 10 Levey, G. S.: The effects of sulfonylureas on peripheral metabolic processes. Fed. Proc. 36: 2720-23, 1977. 11 Wishinsky, PL, Glasser, E. J., and Perkai, S.: Protein interactions of sulfonylurea compounds. Diabetes 11 (Suppl.): 18-25, 1962.

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