Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Use of oral agents in treating diabetes mellitus a perspective John A. Colwell To cite this article: John A. Colwell (1976) Use of oral agents in treating diabetes mellitus a perspective, Postgraduate Medicine, 59:1, 139-144, DOI: 10.1080/00325481.1976.11716531 To link to this article: http://dx.doi.org/10.1080/00325481.1976.11716531
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• Since the first report of the University Group Diabetes Program (UGDP) in 1970, 1 controversy has raged regarding the use of oral hypoglycemie agents in treating diabetes mellitus. Periodic scrutiny of this form of treatment is proper, in an attempt to provide a balanced view and give practicing physicians confidence th at they are using the best modem approach to this chronic disease. In this article, 1 shall attempt to provide a perspective on the use of the oral hypoglycemie agents which not only considers the ramifications of the important UGDP study but also provides a balanced view in light of historieal experience, pharmacology, clinical experience, and taxie side effects of these agents. Reflecting on similar articles that I have written in the past 18 years, 2 • 3 I find (perhaps somewhat to the credit of the oral agents) that therapeutic recommendations have changed only very slightly in that time, in spite of a vast accumulation of new know led ge. Hlstory
The frrst oral hypoglycemie agent was Synthalin, a guanidine derivative, which was studied extensively in the 1930s. After a few years, its use was abandoned because of hepatic and renal toxicity. It is likely th at the un favorable experience with this drug, in contrast to experience with the newly available insulin, made a lasting impression on physicians then active in diabetic management. In the early 1940s, Janbon, a French physician, noted that carbutamide (BZ-55), a sulfonamide, lowered the blood glucose leve! in sorne patients who received it for bacteriostatie purposes. 4 In Paris, Loubatières pioneered in physiologie work with this compound, demonstrating th at it exerted its acute hypoglycemie action by a stimulatory effect on pancreatic insulin secretion. 5 Application of Loubatières' work on carbutamide was interrupted until after World War II, when clinical experiments began, first in Europe and later (1955) in the United States. The drug was never marketed in the United States, however, because of taxie reactions. 2 Carbutamide was saon followed by tolbutamide, chlorpropamide, and acetohexamide. Phenformin (not a sulfonylurea) and tolazamide came later. Glibenclamide, the most
Vol. 59 • No. 1 • January 1976 • POSTORADUATE IEDICIIIE
use of oral agents in treating diabetes mellitus a perspective John A. Colwell, MD, PhD Medical University of South Carolina Charleston
consider When are oral hypoglycemie agents indicated? Contraindicated? What is the duration of action for acetohexamide? Chlorpropamide? Tolazamide? Tolbutamide?
139
cemed about the proper guidelines for use of these agents.
Downloaded by [Australian Catholic University] at 03:42 07 August 2017
Pharmacology
potent sulfonylurea on a weight basis, was introduced in Europe in the late 1960s. It has not yet been marketed in the United States. After se veral years of independent study of the oral sulfonylurea agents, 12 medical centers joined in 1961 in a classic study of the efficacy of these agents in the treatment of adult-onset diabetes mellitus. By 1962, phenformin had been added to the study. By 1969, because of the unexpected finding of increased cardiovascular mortality in patients treated with tolbutamide 1 or phenformin, 6 these agents were-withdrawn from the study. The implications of these findings are discussed later. In spite of these findings, sales of the oral agents have not changed. 7 The Food and Drug Administration is planning labeling changes, 8 and physicians are con-
The two general classes of oral antidiabetic compounds are sulfonylureas and biguanides. Their chemical structures are shawn in figure 1. The sulfonylureas have a common structural component which accounts for their hypoglycemie action. Phenformin, a biguanide, has a completely different structure. The sulfonylureas exert therr pnmary action through stimulation of pancreatic insulin secretion. 9 However, it was recognized earl y, and later confirmed, 10 that significant extrapancreatic actions may be operative. Sulfonylureas or insulin may act on the liver to decrease the hepatic glucose output and lower the blood glucose level. Like exogenous insulin, the sulfonylureas may be divided into short-, intermediate-, and long-acting compounds. The short-acting sulfonylureas, of which tolbutamide is the prototype, are metabolized in the li ver to inactive compounds which are excreted by the kidneys. The intermediate-acting compounds, such as acetohexamide and tolazamide, are also metabolized by the liver, but about 75% of acetohexamide is metabolized to another hypoglycemie compound, and tolazamide is metabolized to severa! hypoglycemie products. The long-acting compound chlorpropamide is tightly bound to protein and is dependent on renal excretion for clearance from the body. Phenformin is thought to lower glucose levels in blood by interfering with oxidative metabolism and accelerating anaerobie glycolysis. It also delays absorption of glucose from the gastrointestinal tract 11 and may decrease hepatic gluconeogenesis, particularly in diabetic animais. There is controversy asto whether this action is operative in man. Phenformin is partially metabolized by the liver, but as much as 65% may be excreted unchanged by the kidneys. Therefore, the drug should not be given to patients with hepatic or renal insufficiency. The practical consequences of these ph ar-
140
POSTGRADUATE MEDICINE • January 1976 • Vol. 59 • No. 1
Figure 1. Chemical structures of oral antidiabetic agents. Note that the sulfonylureas share a common hypoglycemie core. The biguanide radical, shown in rectangle, is active portion of phenformin.
macologic characteristics as they relate to dosages are shawn in table 1.
table 1. dosage of oral antldlabetlc agents Ganerlc narne
Trade nama Douge (gm/day)
Slde Effects
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Sulfonylureas-Many of the reported side effects of the oral sulfonylurea agents are mild and self-limited. Skin rashes or gastrointestinal complaints or bath are seen in an incidence approximating that with placebo therapy. Other side effects of a potentially lethal nature are, fortunately, rather rare. Thus, agranulocytosis, 12 generalized hypersensitivity reactions, 13 and hepatotoxicity 14 have been reported infrequently. One potentially serious side effect of chlorpropamide is potentiation of the effect of antidiuretic hormone (ADH, vasopressin) on the renal tubule. This action, along with the diabetic patient's tendency ta drink a large amount of water, may produce acute water intoxication. This condition can be suspected in a patient taking chlorpropamide who has a serum sodium level of 110 mEq/liter or below and a law serum chloride leve1 and who shows signs of mental confusion. Treatment is water deprivation and a switch ta a different antidiabetic preparation. Hypoglycemia is rarely seen in patients receiving oral sulfonylureas. However, when it occurs, it may be protracted and serious. 15 Usually, it results from overdosage, poor choice of therapeutic agent, or omission of meals. There may be interactions with other drugs, such as alcohol, salicylates, phenylbutazone, probenecid, and monoamine oxidase inhibitors. In particular, chlorpropamide produces hypoglycemia because of its prolonged half-life and dependence on the kidneys for excretion. Because of the likelihood of hypoglycemia, ali these drugs are contraindicated for patients with renal or hepatic insufficiency. Phenformin- The taxie effects of phenformin are more apparent and potentially more lethal than are those of the sulfonylureas. Unlike the sulfonylureas, phenformin may cause lactic acidosis. 16 Generally, this complication is not due ta the drug alone. It usually occurs in a patient who also has sorne candi-
Va. 59
o
No. 1 o January 1976 o POSTGAADUATE MEDICINE
Tolbutamide Acetohexamide Tolazamide Chlorpropamide Phenformin
Orinase Dymelor Tolinase Diabinese DBI-TD
Usual
Range
1.5 0.7 0.25 0.25 0.1
0.5-2.0 0.25-1.25 0.1-0.75 0.1-0.5 0.05-0.15
Doua /day
Duratlon of action (hr)
3 2 1 1 2
6-10 10-16 10-16 40-72 6-10
table 2. summary of UGDP study flndlngs on mortallty (823 patients)' Agent
Numbar of daatha Cardiovascularrelated
Total
Phenformin Tolbutamide Insu lin Standard dosage Variable dosage Placebo
31
26
30
26
20 18 21
13 12 10
table 3. therapy for adult-onset dlabetes Typa
of
Faatlng plasma lnaulln stores glucose (mg/dl)
dlabatas
Praacrlpllon•
Nonobese
Obese
Nonobese
Obese.
Normal
Sulfonyturea or insulin (1 dose)
Diet or sulfonyturea
Mild
120-160
~
Moderate
160-200
H
Severe
>200
~H
Brittle
>200
HU
Sulfonyturea lnsulln (1 or 2 dosest)· or insu lin (1 dose)
H
lnsulin (2 dosest)
Insu lin (1 dose)
lnsulin (2 dosest)
lnsulin (2 dosest)
·An patients are carefully and repetitively instructed on the American Diabetes Association diet indicated to achieve or malntain ideal weight. tlntermediate-actlng insu lin is used (NPH or Lente), with 75% of total dose glven before breakfast and 25% given before supper. ln severe or brlttle dlabetes, additlonal regular insulin (5 to 15 units) may be added to these split doses.
141
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DRUG SPOTUGHT ON ORAL ANTIDIABETIC DRUGS
The Drug Spotlight Program of the American Society for Clinical Pharmacology and Therapeutics is currently focused on the oral antidiabetic drugs. Because of the controversy which has existed, it is important for pharmacy and therapeutics committees to review the manner in which these drugs are being used. The foliowing questions are suggested as potential subjects for study: 1. What is the indication for antidiabetic treatment? 2. Does the patient have symptoms due to hyperglycemia? 3. Is the patient overweight? 4. What more can be done to help bring body weight dawn to an ideallevel? 5. Has significant Ii ver or kidney disease been ruled out prior to starting antidiabetic drug therapy? Interesting and important questions can also be raised concerning the management of patients who are already receiving oral antidiabetic drugs: 1. Has the possibility of a hypoglycemie response to the drugs been considered and ruled out, if appropriate? 2. Has the continuing need for antidiabetic drug therapy been established? GEORGE N. AAGAARD. MD,
Chairman, Subcommittee on Hospitai-Based Educarion in Therapeutics American Society for Clin ica/ Pharmacology and Therapeutics Department of Medicine University of Washington School of Medicine Seattle
The mortality figures in the UGDP study are shawn in table 2. In this study, equal numbers of patients were treated with placebo, tolbutamide, phenformin, or insulin. The number of deaths, particularly due ta cardiovascular disease, was higher in ali groups receiving oral hypoglycemie agents than in the group receiving placebo. Although objections have been raised ta experimental design and interpretation of
data, 17 it is general! y accepted that the findings do nothing to support a beneficiai action of the oral agents on the natural course of diabetic cardiovascular disease. The major findings of the UGDP study were: 1. Increased death rates from ali causes and from cardiovascular diseases in patients (mostly women) with adult-onset diabetes treated with fixed doses of tolbutamide or phenformin for over five years. 2. No c!ear benefit from either agent with reference to occurrence of nonfatal events, such as blindness, neuropathy, and retinopathy. 3. Increased incidence of hypertension and tachycardia and increased use of digitalis and diuretics in the phenformin-treated group. Balanced recommendations may be made regarding the use of oral agents in diabetes.
142
POSTGRADUATE MEDICINE • January 1976 • Vol. 59 1
tian that has caused tissue hypoxia, such as myocardial infarction, pulmonary embolism, hypovolemic shock, gangrene, or mesenteric thrombosis. Alcohol may lead ta excess lactate accumulation and thus aggravate lactic acidosis in patients taking phenformin. Less serious side effects of phenformin inelude anorexia, malaise, and a peculiar metallie taste sensation. Resulta and Implications of UGDP Study
No. 1
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Although the recommendations have changed very little from those set forth previously, 2 • 3 they are bolstered by the study findings cited. In spite of the disquieting data that have emerged from the UGDP study, it appears premature to conclude that oral agents are not indicated in the treatment of adult-onset diabetes. Indeed, FDA regulations now under scrutiny 8 state a more moderate approach: ''[The oral agent] is indicated to control symptoms due to hyperglycemia in patients with maturity-onset nonketotic diabetes mellitus whose symptoms cannat be controlled by diet alone and in whom insulin cannat be used because of patient unwillingness, erratic adherence to the injection regimen, poor vision, physical or mental handicap, insulin allergy, employment requirements, or other similar factors. . . . The patient should be informed of the advantages and potential risks of [oral agent] and of alternative modes of therapy and should participate in the decision to use this drug. '' These recommendations are reasonable and will probably be accepted and incorporated into labels and other widely circulated litera ture in the near future. Cllnlcal Use of Oral Agents
With antidiabetic therapy of any type, it is incumbent upon the physician to provide sound and repetitive dietary counseling (particularly regarding weight reduction), education, and therapeutic agents that will bring the biochemical state as close to normal as possible. The goals of therapy should be normal weight for height and frame, normal fasting and postprandial blood glucose levels, freedom from hypoglycemia, and normal blood lipid levels. To achieve these goals, it is first necessary to choose carefully the patients who might be candidates for use of oral agents. Only patients with slightly impaired: or almost normal pancreatic stores of insulin should be chosen. Fortunately, for clinical purposes these stores can be estimated from the fasting plasma glucose concentration (table 3). The average levels represent the best estimates based on
Vol. 59 o No. 1 • January 1976 • POSTGRADUATE IEDICINE
John A. Colwell Dr. Colwell is professer of medicine and director of the endocrinology, metabolism, and nutrition division, Medical University of South Carolina, Charleston.
many studies carried out over the past decade. 18 - 21 For nonobese patients with fasting plasma glucose levels over 160 mg/dl, diet and insulin therapy are prescribed. Obese patients are given a weight reduction diet, and insulin therapy is also started if their fasting plasma glucose level is over 200 mg/dl. If it is below this level, diet alone is tried for three months if diabetes is moderate and for six months if it is mild. If weight reduction is successful, plasma glucose and lipid levels will generally fall toward normal. If plasma glucose in an obese patient stabilizes at a hyperglycemie level after the period of diet therapy, one of the oral sulfonylurea agents is tried for three months. A short- or intermediate-acting agent is used, up to maximal safe dosage (table 1), and fasting glucose and lipid levels are checked monthly. If the se are normal, therapy is continued. If they are high, a long-acting agent is substituted in maximal safe dosages. If glucose and lipid levels do not become normal in the next three months, the patient is switched to insulin therapy. In any case, if glucose and lipid levels are not lowered to normal within six months of starting therapy with an oral agent, insulin is given. Oral agents are contraindicated in the following situations: 1. Obesity without a trial of diet therapy al one. 2. When an oral agent that originally lowered blood glucose level to normal is no longer effective (secondary failure). 3. Occurrence of hypoglycemia during oral antidiabetic drug therapy. ~
143
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4. Presence of acute complications, such as ketoacidosis, hyperosmolar states, lactic acidosis, infections, myocardial infarction, or a condition requiring surgery. 5. Presence of coronary heart disease or significant liver or kidney disease. In addition, it is prudent for the managing physician to inform each patient of the potential risks ofthese agents. Such informed consent need not be written but may be recorded at the discretion of the physician. Fin ally, there is no evidence to suggest that the benefits of phenformin ever outweigh its risks. It is suggested, therefore, that this drug not be prescribed for any diabetic patients. Summary
A comprehensive study by the University Group Diabetes Program compared the effects of therapy with oral antidiabetic agents, insulin, and placebo in patients with adult-
onset diabetes mellitus. Results showed an increased number of deaths, particularly due to cardiovascular diseases, among patients receiving oral agents. In spite of these findings, therapeutic recommendations have changed only slightly. An FDA proposai recommends moderate labeling changes. When possible, control of diabetes with diet alone should be attempted. If this is unsuccessful, an oral sulfonylurea should be added to the regimen. If glucose and lipid levels remain high after six months of such therapy, insulin should be used. • Address reprint requests to John A. Colwell, MD, Depanmcnt of Medicine, Medical University of South Carolina, 80 Barre St, Charleston, SC 29401. For ReadySource on diabetes, sec page 179. CME Credit Quiz on diabetes begins on page 185.
References 1. The University Group Diabetes Program: A study of the effects of hypoglycemie agents on vascular complications in patients with adult-onsct diabetes. 1. Design, methods and baseline results. Il. Mortality results. Diabetes 19(Suppl 2):747, 1970 2. Colwcll AR, Colwell JA: Clinical use of oral sulfonylurea compounds in diabetes mellitus. Q Bull Northwestcrn Univ Med Sch 31:1, 1957 3. Colwell JA: Thcrapy with oral hypoglycemie agents. ln Fajans SS, Sussman KE (Editors): Diabetcs Mcllitus: Diagnosis and Trcatment. New York, Amcrican Diabetcs Association, 1971, chap 26 4. Janbon M, Chaptal J, Vedel A, et al: Accidents hypoglycemiqucs graves par sulfamide thiadiazol. Montpell Med 21:441, 1942 5. Loubatièrcs A: Physiologie et pharmacodynamie de certains dérives sulfamides hypoglycemiants. Contribution à l'étude des substances sythetiques à tropisme endocrinien. Thesc Doct Sei Naturelles, Montpellier, No. 86. Montpellier, Causse, Graille et Castelnau, Ed, 1946 6. Knatterud GL, Meincrt CL, Klimt CR, et al: Effects of hypoglycemie agents on vascular complications in patients with adult-onsct diabetes. IV. A preliminary report on phenformin results. JAMA 217:777, 1971 7. Chalmers TC: The impact of controllcd trials on the practice of medicine. Mt Sinai J Med NY 41:753, 1974 8. Oral Hypoglycemie Drugs. Proposcd Labeling Requiremcnts and Public Hcaiing. Fed Regis ter 40:28587-28595, 1975 9. Colwell AR, Colwcll JA: Pancreatic action of the sulfonylureas. 1 Lab Clin Mcd 53:376, 1959 10. Roth J, Prout TE, Goldfme ID, et al: Sulfonylurcas: Effccts in vivo and in vitro. Ann lntcm Med 75:607, 1971
Il. Kruger FA, Altschuld RA, Hollollaugh SL, et al: Studies on the site and mechanism of action of phenformin. n. Phenformin inhibition of glucose transport by rat intestine. Diabetes 19:50-52, 1970 12. Page OC, Hare RL, Stephens JW, et al: Toxicity of carbutamide: Report of a fatal bone marrow depression and anuria. N Engl 1 Med 256:74, 1957 13. Clarke BF, Campbell lW, Ewing DJ, et al: Generalizcd hypcrsensitivity reaction and visceral aneritis with fatal outcome during glibenclamide thcrapy. Diabetes 23:739, 1974 14. VanThiel DH, De Bell R, Mellow M, ct al: Tolazamide hepatotoxicity. Gastrocnterology 67:506-510, 1974 15. Seltzer HS: Drug-induced hypoglycemia. A review based on 473 cases. Diabetes 21:955, 1972 16. Oliva PB: Lactic acidosis. Am 1 Med 48:209,1970 17. Schor SS: Statistical problems in clinical trials. Am 1 Mcd 55:727, 1973 18. Hales CN, Randle PJ: Effects of low-carbohydratc dict and diabetes mcllitus on plasma concentrations of glucose, non-esterified fatty acids, and insulin during oral glucose-tolerance tests. Lance! 1:790, 1963 19. Seltzer HS, Allen EW, Herran AL Jr, et al: lnsulin secretion in response to glycemie stimulus: Relation of dclaycd initial release to caibohydrate intolerance in mild diabetcs mcllitus. 1 Clin lnvest 46:323, 1967 20. Colwell JA, Lein A: Diminished insulin responsc to hypcrglycemia in prediabetes and diabetes. Diabetes 16:560, 1967 21. Kosaka K, Hagura R, Kuzuya T, ct al: lnsulin secrctory response of diabetics during the period of improvcmcnt of glucose tolerance to normal range. Diabetologia 10:775782, 1974
144
POSTORADUATE MEDICINE • January 1976 • Vol. 59 • No. 1
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Use of oral agents in treating diabetes mellitus a perspective John A. Colwell To cite this article: John A. Colwell (1976) Use of oral agents in treating diabetes mellitus a perspective, Postgraduate Medicine, 59:1, 139-144, DOI: 10.1080/00325481.1976.11716531 To link to this article: http://dx.doi.org/10.1080/00325481.1976.11716531
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 07 August 2017, At: 03:42
Downloaded by [Australian Catholic University] at 03:42 07 August 2017
• Since the first report of the University Group Diabetes Program (UGDP) in 1970, 1 controversy has raged regarding the use of oral hypoglycemie agents in treating diabetes mellitus. Periodic scrutiny of this form of treatment is proper, in an attempt to provide a balanced view and give practicing physicians confidence th at they are using the best modem approach to this chronic disease. In this article, 1 shall attempt to provide a perspective on the use of the oral hypoglycemie agents which not only considers the ramifications of the important UGDP study but also provides a balanced view in light of historieal experience, pharmacology, clinical experience, and taxie side effects of these agents. Reflecting on similar articles that I have written in the past 18 years, 2 • 3 I find (perhaps somewhat to the credit of the oral agents) that therapeutic recommendations have changed only very slightly in that time, in spite of a vast accumulation of new know led ge. Hlstory
The frrst oral hypoglycemie agent was Synthalin, a guanidine derivative, which was studied extensively in the 1930s. After a few years, its use was abandoned because of hepatic and renal toxicity. It is likely th at the un favorable experience with this drug, in contrast to experience with the newly available insulin, made a lasting impression on physicians then active in diabetic management. In the early 1940s, Janbon, a French physician, noted that carbutamide (BZ-55), a sulfonamide, lowered the blood glucose leve! in sorne patients who received it for bacteriostatie purposes. 4 In Paris, Loubatières pioneered in physiologie work with this compound, demonstrating th at it exerted its acute hypoglycemie action by a stimulatory effect on pancreatic insulin secretion. 5 Application of Loubatières' work on carbutamide was interrupted until after World War II, when clinical experiments began, first in Europe and later (1955) in the United States. The drug was never marketed in the United States, however, because of taxie reactions. 2 Carbutamide was saon followed by tolbutamide, chlorpropamide, and acetohexamide. Phenformin (not a sulfonylurea) and tolazamide came later. Glibenclamide, the most
Vol. 59 • No. 1 • January 1976 • POSTORADUATE IEDICIIIE
use of oral agents in treating diabetes mellitus a perspective John A. Colwell, MD, PhD Medical University of South Carolina Charleston
consider When are oral hypoglycemie agents indicated? Contraindicated? What is the duration of action for acetohexamide? Chlorpropamide? Tolazamide? Tolbutamide?
139
cemed about the proper guidelines for use of these agents.
Downloaded by [Australian Catholic University] at 03:42 07 August 2017
Pharmacology
potent sulfonylurea on a weight basis, was introduced in Europe in the late 1960s. It has not yet been marketed in the United States. After se veral years of independent study of the oral sulfonylurea agents, 12 medical centers joined in 1961 in a classic study of the efficacy of these agents in the treatment of adult-onset diabetes mellitus. By 1962, phenformin had been added to the study. By 1969, because of the unexpected finding of increased cardiovascular mortality in patients treated with tolbutamide 1 or phenformin, 6 these agents were-withdrawn from the study. The implications of these findings are discussed later. In spite of these findings, sales of the oral agents have not changed. 7 The Food and Drug Administration is planning labeling changes, 8 and physicians are con-
The two general classes of oral antidiabetic compounds are sulfonylureas and biguanides. Their chemical structures are shawn in figure 1. The sulfonylureas have a common structural component which accounts for their hypoglycemie action. Phenformin, a biguanide, has a completely different structure. The sulfonylureas exert therr pnmary action through stimulation of pancreatic insulin secretion. 9 However, it was recognized earl y, and later confirmed, 10 that significant extrapancreatic actions may be operative. Sulfonylureas or insulin may act on the liver to decrease the hepatic glucose output and lower the blood glucose level. Like exogenous insulin, the sulfonylureas may be divided into short-, intermediate-, and long-acting compounds. The short-acting sulfonylureas, of which tolbutamide is the prototype, are metabolized in the li ver to inactive compounds which are excreted by the kidneys. The intermediate-acting compounds, such as acetohexamide and tolazamide, are also metabolized by the liver, but about 75% of acetohexamide is metabolized to another hypoglycemie compound, and tolazamide is metabolized to severa! hypoglycemie products. The long-acting compound chlorpropamide is tightly bound to protein and is dependent on renal excretion for clearance from the body. Phenformin is thought to lower glucose levels in blood by interfering with oxidative metabolism and accelerating anaerobie glycolysis. It also delays absorption of glucose from the gastrointestinal tract 11 and may decrease hepatic gluconeogenesis, particularly in diabetic animais. There is controversy asto whether this action is operative in man. Phenformin is partially metabolized by the liver, but as much as 65% may be excreted unchanged by the kidneys. Therefore, the drug should not be given to patients with hepatic or renal insufficiency. The practical consequences of these ph ar-
140
POSTGRADUATE MEDICINE • January 1976 • Vol. 59 • No. 1
Figure 1. Chemical structures of oral antidiabetic agents. Note that the sulfonylureas share a common hypoglycemie core. The biguanide radical, shown in rectangle, is active portion of phenformin.
macologic characteristics as they relate to dosages are shawn in table 1.
table 1. dosage of oral antldlabetlc agents Ganerlc narne
Trade nama Douge (gm/day)
Slde Effects
Downloaded by [Australian Catholic University] at 03:42 07 August 2017
Sulfonylureas-Many of the reported side effects of the oral sulfonylurea agents are mild and self-limited. Skin rashes or gastrointestinal complaints or bath are seen in an incidence approximating that with placebo therapy. Other side effects of a potentially lethal nature are, fortunately, rather rare. Thus, agranulocytosis, 12 generalized hypersensitivity reactions, 13 and hepatotoxicity 14 have been reported infrequently. One potentially serious side effect of chlorpropamide is potentiation of the effect of antidiuretic hormone (ADH, vasopressin) on the renal tubule. This action, along with the diabetic patient's tendency ta drink a large amount of water, may produce acute water intoxication. This condition can be suspected in a patient taking chlorpropamide who has a serum sodium level of 110 mEq/liter or below and a law serum chloride leve1 and who shows signs of mental confusion. Treatment is water deprivation and a switch ta a different antidiabetic preparation. Hypoglycemia is rarely seen in patients receiving oral sulfonylureas. However, when it occurs, it may be protracted and serious. 15 Usually, it results from overdosage, poor choice of therapeutic agent, or omission of meals. There may be interactions with other drugs, such as alcohol, salicylates, phenylbutazone, probenecid, and monoamine oxidase inhibitors. In particular, chlorpropamide produces hypoglycemia because of its prolonged half-life and dependence on the kidneys for excretion. Because of the likelihood of hypoglycemia, ali these drugs are contraindicated for patients with renal or hepatic insufficiency. Phenformin- The taxie effects of phenformin are more apparent and potentially more lethal than are those of the sulfonylureas. Unlike the sulfonylureas, phenformin may cause lactic acidosis. 16 Generally, this complication is not due ta the drug alone. It usually occurs in a patient who also has sorne candi-
Va. 59
o
No. 1 o January 1976 o POSTGAADUATE MEDICINE
Tolbutamide Acetohexamide Tolazamide Chlorpropamide Phenformin
Orinase Dymelor Tolinase Diabinese DBI-TD
Usual
Range
1.5 0.7 0.25 0.25 0.1
0.5-2.0 0.25-1.25 0.1-0.75 0.1-0.5 0.05-0.15
Doua /day
Duratlon of action (hr)
3 2 1 1 2
6-10 10-16 10-16 40-72 6-10
table 2. summary of UGDP study flndlngs on mortallty (823 patients)' Agent
Numbar of daatha Cardiovascularrelated
Total
Phenformin Tolbutamide Insu lin Standard dosage Variable dosage Placebo
31
26
30
26
20 18 21
13 12 10
table 3. therapy for adult-onset dlabetes Typa
of
Faatlng plasma lnaulln stores glucose (mg/dl)
dlabatas
Praacrlpllon•
Nonobese
Obese
Nonobese
Obese.
Normal
Sulfonyturea or insulin (1 dose)
Diet or sulfonyturea
Mild
120-160
~
Moderate
160-200
H
Severe
>200
~H
Brittle
>200
HU
Sulfonyturea lnsulln (1 or 2 dosest)· or insu lin (1 dose)
H
lnsulin (2 dosest)
Insu lin (1 dose)
lnsulin (2 dosest)
lnsulin (2 dosest)
·An patients are carefully and repetitively instructed on the American Diabetes Association diet indicated to achieve or malntain ideal weight. tlntermediate-actlng insu lin is used (NPH or Lente), with 75% of total dose glven before breakfast and 25% given before supper. ln severe or brlttle dlabetes, additlonal regular insulin (5 to 15 units) may be added to these split doses.
141
Downloaded by [Australian Catholic University] at 03:42 07 August 2017
DRUG SPOTUGHT ON ORAL ANTIDIABETIC DRUGS
The Drug Spotlight Program of the American Society for Clinical Pharmacology and Therapeutics is currently focused on the oral antidiabetic drugs. Because of the controversy which has existed, it is important for pharmacy and therapeutics committees to review the manner in which these drugs are being used. The foliowing questions are suggested as potential subjects for study: 1. What is the indication for antidiabetic treatment? 2. Does the patient have symptoms due to hyperglycemia? 3. Is the patient overweight? 4. What more can be done to help bring body weight dawn to an ideallevel? 5. Has significant Ii ver or kidney disease been ruled out prior to starting antidiabetic drug therapy? Interesting and important questions can also be raised concerning the management of patients who are already receiving oral antidiabetic drugs: 1. Has the possibility of a hypoglycemie response to the drugs been considered and ruled out, if appropriate? 2. Has the continuing need for antidiabetic drug therapy been established? GEORGE N. AAGAARD. MD,
Chairman, Subcommittee on Hospitai-Based Educarion in Therapeutics American Society for Clin ica/ Pharmacology and Therapeutics Department of Medicine University of Washington School of Medicine Seattle
The mortality figures in the UGDP study are shawn in table 2. In this study, equal numbers of patients were treated with placebo, tolbutamide, phenformin, or insulin. The number of deaths, particularly due ta cardiovascular disease, was higher in ali groups receiving oral hypoglycemie agents than in the group receiving placebo. Although objections have been raised ta experimental design and interpretation of
data, 17 it is general! y accepted that the findings do nothing to support a beneficiai action of the oral agents on the natural course of diabetic cardiovascular disease. The major findings of the UGDP study were: 1. Increased death rates from ali causes and from cardiovascular diseases in patients (mostly women) with adult-onset diabetes treated with fixed doses of tolbutamide or phenformin for over five years. 2. No c!ear benefit from either agent with reference to occurrence of nonfatal events, such as blindness, neuropathy, and retinopathy. 3. Increased incidence of hypertension and tachycardia and increased use of digitalis and diuretics in the phenformin-treated group. Balanced recommendations may be made regarding the use of oral agents in diabetes.
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tian that has caused tissue hypoxia, such as myocardial infarction, pulmonary embolism, hypovolemic shock, gangrene, or mesenteric thrombosis. Alcohol may lead ta excess lactate accumulation and thus aggravate lactic acidosis in patients taking phenformin. Less serious side effects of phenformin inelude anorexia, malaise, and a peculiar metallie taste sensation. Resulta and Implications of UGDP Study
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Although the recommendations have changed very little from those set forth previously, 2 • 3 they are bolstered by the study findings cited. In spite of the disquieting data that have emerged from the UGDP study, it appears premature to conclude that oral agents are not indicated in the treatment of adult-onset diabetes. Indeed, FDA regulations now under scrutiny 8 state a more moderate approach: ''[The oral agent] is indicated to control symptoms due to hyperglycemia in patients with maturity-onset nonketotic diabetes mellitus whose symptoms cannat be controlled by diet alone and in whom insulin cannat be used because of patient unwillingness, erratic adherence to the injection regimen, poor vision, physical or mental handicap, insulin allergy, employment requirements, or other similar factors. . . . The patient should be informed of the advantages and potential risks of [oral agent] and of alternative modes of therapy and should participate in the decision to use this drug. '' These recommendations are reasonable and will probably be accepted and incorporated into labels and other widely circulated litera ture in the near future. Cllnlcal Use of Oral Agents
With antidiabetic therapy of any type, it is incumbent upon the physician to provide sound and repetitive dietary counseling (particularly regarding weight reduction), education, and therapeutic agents that will bring the biochemical state as close to normal as possible. The goals of therapy should be normal weight for height and frame, normal fasting and postprandial blood glucose levels, freedom from hypoglycemia, and normal blood lipid levels. To achieve these goals, it is first necessary to choose carefully the patients who might be candidates for use of oral agents. Only patients with slightly impaired: or almost normal pancreatic stores of insulin should be chosen. Fortunately, for clinical purposes these stores can be estimated from the fasting plasma glucose concentration (table 3). The average levels represent the best estimates based on
Vol. 59 o No. 1 • January 1976 • POSTGRADUATE IEDICINE
John A. Colwell Dr. Colwell is professer of medicine and director of the endocrinology, metabolism, and nutrition division, Medical University of South Carolina, Charleston.
many studies carried out over the past decade. 18 - 21 For nonobese patients with fasting plasma glucose levels over 160 mg/dl, diet and insulin therapy are prescribed. Obese patients are given a weight reduction diet, and insulin therapy is also started if their fasting plasma glucose level is over 200 mg/dl. If it is below this level, diet alone is tried for three months if diabetes is moderate and for six months if it is mild. If weight reduction is successful, plasma glucose and lipid levels will generally fall toward normal. If plasma glucose in an obese patient stabilizes at a hyperglycemie level after the period of diet therapy, one of the oral sulfonylurea agents is tried for three months. A short- or intermediate-acting agent is used, up to maximal safe dosage (table 1), and fasting glucose and lipid levels are checked monthly. If the se are normal, therapy is continued. If they are high, a long-acting agent is substituted in maximal safe dosages. If glucose and lipid levels do not become normal in the next three months, the patient is switched to insulin therapy. In any case, if glucose and lipid levels are not lowered to normal within six months of starting therapy with an oral agent, insulin is given. Oral agents are contraindicated in the following situations: 1. Obesity without a trial of diet therapy al one. 2. When an oral agent that originally lowered blood glucose level to normal is no longer effective (secondary failure). 3. Occurrence of hypoglycemia during oral antidiabetic drug therapy. ~
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4. Presence of acute complications, such as ketoacidosis, hyperosmolar states, lactic acidosis, infections, myocardial infarction, or a condition requiring surgery. 5. Presence of coronary heart disease or significant liver or kidney disease. In addition, it is prudent for the managing physician to inform each patient of the potential risks ofthese agents. Such informed consent need not be written but may be recorded at the discretion of the physician. Fin ally, there is no evidence to suggest that the benefits of phenformin ever outweigh its risks. It is suggested, therefore, that this drug not be prescribed for any diabetic patients. Summary
A comprehensive study by the University Group Diabetes Program compared the effects of therapy with oral antidiabetic agents, insulin, and placebo in patients with adult-
onset diabetes mellitus. Results showed an increased number of deaths, particularly due to cardiovascular diseases, among patients receiving oral agents. In spite of these findings, therapeutic recommendations have changed only slightly. An FDA proposai recommends moderate labeling changes. When possible, control of diabetes with diet alone should be attempted. If this is unsuccessful, an oral sulfonylurea should be added to the regimen. If glucose and lipid levels remain high after six months of such therapy, insulin should be used. • Address reprint requests to John A. Colwell, MD, Depanmcnt of Medicine, Medical University of South Carolina, 80 Barre St, Charleston, SC 29401. For ReadySource on diabetes, sec page 179. CME Credit Quiz on diabetes begins on page 185.
References 1. The University Group Diabetes Program: A study of the effects of hypoglycemie agents on vascular complications in patients with adult-onsct diabetes. 1. Design, methods and baseline results. Il. Mortality results. Diabetes 19(Suppl 2):747, 1970 2. Colwcll AR, Colwell JA: Clinical use of oral sulfonylurea compounds in diabetes mellitus. Q Bull Northwestcrn Univ Med Sch 31:1, 1957 3. Colwell JA: Thcrapy with oral hypoglycemie agents. ln Fajans SS, Sussman KE (Editors): Diabetcs Mcllitus: Diagnosis and Trcatment. New York, Amcrican Diabetcs Association, 1971, chap 26 4. Janbon M, Chaptal J, Vedel A, et al: Accidents hypoglycemiqucs graves par sulfamide thiadiazol. Montpell Med 21:441, 1942 5. Loubatièrcs A: Physiologie et pharmacodynamie de certains dérives sulfamides hypoglycemiants. Contribution à l'étude des substances sythetiques à tropisme endocrinien. Thesc Doct Sei Naturelles, Montpellier, No. 86. Montpellier, Causse, Graille et Castelnau, Ed, 1946 6. Knatterud GL, Meincrt CL, Klimt CR, et al: Effects of hypoglycemie agents on vascular complications in patients with adult-onsct diabetes. IV. A preliminary report on phenformin results. JAMA 217:777, 1971 7. Chalmers TC: The impact of controllcd trials on the practice of medicine. Mt Sinai J Med NY 41:753, 1974 8. Oral Hypoglycemie Drugs. Proposcd Labeling Requiremcnts and Public Hcaiing. Fed Regis ter 40:28587-28595, 1975 9. Colwell AR, Colwcll JA: Pancreatic action of the sulfonylureas. 1 Lab Clin Mcd 53:376, 1959 10. Roth J, Prout TE, Goldfme ID, et al: Sulfonylurcas: Effccts in vivo and in vitro. Ann lntcm Med 75:607, 1971
Il. Kruger FA, Altschuld RA, Hollollaugh SL, et al: Studies on the site and mechanism of action of phenformin. n. Phenformin inhibition of glucose transport by rat intestine. Diabetes 19:50-52, 1970 12. Page OC, Hare RL, Stephens JW, et al: Toxicity of carbutamide: Report of a fatal bone marrow depression and anuria. N Engl 1 Med 256:74, 1957 13. Clarke BF, Campbell lW, Ewing DJ, et al: Generalizcd hypcrsensitivity reaction and visceral aneritis with fatal outcome during glibenclamide thcrapy. Diabetes 23:739, 1974 14. VanThiel DH, De Bell R, Mellow M, ct al: Tolazamide hepatotoxicity. Gastrocnterology 67:506-510, 1974 15. Seltzer HS: Drug-induced hypoglycemia. A review based on 473 cases. Diabetes 21:955, 1972 16. Oliva PB: Lactic acidosis. Am 1 Med 48:209,1970 17. Schor SS: Statistical problems in clinical trials. Am 1 Mcd 55:727, 1973 18. Hales CN, Randle PJ: Effects of low-carbohydratc dict and diabetes mcllitus on plasma concentrations of glucose, non-esterified fatty acids, and insulin during oral glucose-tolerance tests. Lance! 1:790, 1963 19. Seltzer HS, Allen EW, Herran AL Jr, et al: lnsulin secretion in response to glycemie stimulus: Relation of dclaycd initial release to caibohydrate intolerance in mild diabetcs mcllitus. 1 Clin lnvest 46:323, 1967 20. Colwell JA, Lein A: Diminished insulin responsc to hypcrglycemia in prediabetes and diabetes. Diabetes 16:560, 1967 21. Kosaka K, Hagura R, Kuzuya T, ct al: lnsulin secrctory response of diabetics during the period of improvcmcnt of glucose tolerance to normal range. Diabetologia 10:775782, 1974
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