Diabetes Research and Clinical Practice, 11 (1991) 3-8
3
Elsevier DIABET 00448
Perspective
Combined insulin and sulfonylurea therapy for type 2 diabetes mellitus Matthew Oregon Health Sciences
C. Riddle
University, Portland. OR, U.S.A.
(Received 18 May 1990) (Accepted 29 July 1990)
Introduction Type 2 (non-insulin-dependent) diabetes mellitus presents a therapeutic dilemma. It is both very common and frequently uncontrolled, and increasing evidence links poor glycemic control with serious complications. Our lack of success in controlling type 2 diabetes is partly due to the progressive nature of this disorder. Both insulin secretion and the response of tissues to insulin tend to diminish with time. Therefore, a given patient may expect to need progressively more intensive therapy over the course of time. Dietary therapy is preferred, but it seldom continues to be effective for more than a few years. Sulfonylureas are initially effective about 70% of the time, but after 5 years remain so less than 30% of the time. At this point insulin is required, yet a single injection is not always effective. Thus, for many patients the use of two injections of mixtures of intermediate-acting plus fast-acting insulin is advised quite early in the course of type 2 diabetes. Aggressive insulin therapy of this kind presents
Correspondence to: Prof. M.C. Riddle, School of Medicine, Department of Medicine, Section Diabetes, 3181 S.W. Sam Jackson Park Road L345, Portland, OR 97201, U.S.A.
016%8227/91/$03.50
0 1991 Elsevier Science Publishers
many practical problems to older patients, their families and their physicians. While new means of therapy are on the way, none is yet available. To improve glycemic control, we must enhance the effectiveness of existing methods. Combining insulin with a sulfonylurea or other oral hypoglycemic agent is an approach which is under renewed scrutiny. While combined therapy may in practice be widely used, its proper role remains undefined. Among experienced diabetologists there is a spectrum of opinions. Some believe combined therapy has wide applicability, others that it may be used occasionally in special circumstances, and still others that it has little value.
The rationale for combined therapy Using pharmacotherapeutic agents in combination is an old concept. In some clinical settings, such as hypertension, use of two or more drugs together is accepted practice. Possible advantages of this approach may include greater efficacy, safety, or convenience. Which of these possible advantages may apply to the treatment of diabetes? All oral hypoglycemic agents are quite safe and convenient to use but lack the power to control glucose in many patients. Insulin has
B.V. (Biomedical
Division)
4
almost unlimited therapeutic power, but can cause significant hypoglycemia. Use of mixtures of fast acting and delayed acting insulin given two or more times daily is often necessary to avoid excessive hypoglycemia. Taking insulin by injection is also less convenient than using an oral agent. Thus, combined therapy seems unlikely to add much to the therapeutic efficacy of insulin under the intensive conditions possible during clinical research, but might be helpful in reducing the risk of hypoglycemia or improving convenience and thereby adherence to the prescribed regimen in clinical practice. Viewed this way, combined therapy might be argued to have no advantage over insulin alone in pharmacologic efficacy, but perhaps an advantage in clinical efficacy when safety and convenience influence the outcome.
Published experience with the use of combined therapy Older studies done shortly after the introduction of tolbutamide argue for this clinical benefit of combined therapy [ 1,2]. They describe improved convenience and stability of glycemic control with insulin plus tolbutamide as opposed to insulin alone. However, these were not scientifically designed comparisons. More recent objective studies of combined therapy fall generally into two groups: those using a fixed (and incompletely effective) dosage of insulin and focussing on the response to added sulfonylurea [3-61, and those allowing the dosage of insulin to be adjusted and focussing on the task of clinical management [7-lo]. Several studies of each kind are listed in Table 1.
TABLE 1 Results of objective studies comparing insulin alone (S - ) with combined insulin-sulfonylurea Fasting Glucose
therapy (S + ) for type 2 diabetes
Insulin (units/day)
(mM) -
Fixed insulin dosage Osei (1984) Lardinois (1985) Longnecker (1986) Schade (1987)
Variable insulin dosage Hamelbeck (1982) Simonson (1987) Holman (1987) Gutniak (1987)
s-
s+
difference
15.6 13.9 15.1 14.6 14.8
14.0 10.8 12.3 12.9 12.5
-
9.0 6.9 5.1 8.5 7.4
7.8 6.2 5.2 8.0 C8
S-
1.6 3.1 2.8 1.7 2.3
Sf
difference
-
-
- 1.2 - 0.5 + 0.1
33 59 40
24 46 25
-27% - 22% - 38%
- 0.5 - 0.5
55 47
34 32
-20% - 27%
The studies using a fixed insulin dosage to which a sulfonlyurea was added all show significantly better control of fasting plasma glucose with combined therapy, but the fasting values still averaged over 10 mM. The studies in which the insulin dose was varied show relatively good glycemic control with insulin alone, and in only one of these (Hamelbeck, 1982) was the fasting glucose significantly lower with combined therapy. However, combined therapy permitted an average of 27% less injected insulin.
3
Studies of the first kind have consistently found an additive effect of insulin and sulfonylureas, with a decline from a high fasting plasma glucose averaging about 2.3 mM when a sulfonylurea is added to insulin. However, the resulting glycemic control has been variable and generally unsatisfactory, with mean fasting values over 10 mM on combined therapy. Studies employing a variable dosage of insulin have shown better glycemic control, with mean fasting glucose values 8 mM or less. At the same time, the advantage of combined therapy over insulin alone appears small in these studies. The subjects in this second type of study were not preselected for poor glycemic control on insulin. In many cases, complex insulin regimens with multiple injections and mixtures of fast and intermediate acting insulin were used. Finding relatively good success with insulin alone and only a small further benefit from adding a sulfonylurea is not too surprising. Some diabetologists have concluded from these data that combined therapy has little place in clinical practice. They contend that combined therapy is relatively ineffective when intensive insulin therapy has already failed, and little better than insulin used alone vigorously by typical patients. This point of view is expressed in a consensus statement endorsed by the American Diabetes Association. This publication, ‘The Physican’s Guide To Non-Insulin Dependent (Type 2) Diabetes, states: Currently the only candidate for combination therapy may be the patient in whom glycemic control cannot be achieved with diet and sulfonylurea therapy and in whom reasonable control cannot be achieved with mixed and intermediate acting and Regular insulin each day [ll]. Thus, combined therapy is proposed as the last recourse for patients presenting the most difficult clinical problems. A more favorable view of combined therapy emerges from other more recent studies. An example is a report from Sydney, Australia [ 121. In this study a heterogenous group of 31 type 2 diabetic patients already reasonably well con-
trolled with various insulin regimens were given glyburide or placebo for 3 months and then switched to the alternate treatment. Limited changes of insulin dosage were allowed. A significant advantage of combined therapy was shown, with mean fasting plasma glucose 7.8 mM on combined therapy and 10.1 mM at the end of the insulin plus placebo period. A good outcome on combined therapy correlated strongly with short duration of insulin therapy and high levels of C-peptide in plasma.
Combined therapy at the Oregon Health Sciences University Our group in Oregon has also taken a favorable view of combined therapy. Like the investigators in Sydney, we have asked whether combined therapy might be useful in management of the typical rather than the unusual clinical situation. Instead of focussing on patients refractory to all usual methods for controlling glucose, we have considered the problem of the patient newly unresponsive to sufonylureas. Moreover, instead of studying such patients under conditions of intensive insulin therapy, we have used protocols more similar to usual ambulatory care. We have asked whether typical patients no longer responsive to sulfonylureas may achieve good control more predictably with a single injection of insulin supplemented by a sulfonylurea than with single injection of insulin alone. Our approach also differs from that of many other groups in the insulin regimen used. Since the main physiologic feature of type 2 diabetes is fasting hyperglycemia related to high hepatic glucose output, we have proposed an attack on this abnormality by injecting intermediate-acting insulin in the evening [ 13,141. This method has a dual physiologic rationale. Delivering insulin overnight should suppress hepatic glucose production directly, and may augment this effect by suppressing adipose tissue lipolysis, thereby preventing high overnight free fatty acid levels and improving hepatic responsiveness to insulin [ 151.
6
Proper timing of insulin delivery should allow blunting of the dawn phenomenon while avoiding nocturnal hypoglycemia. Our experience to date suggests that relatively slender, young, active patients achieve this objective best by taking intermediate-acting insulin close to bedtime, whereas more obese, older, inactive patients do better with intermediate-acting insulin given before supper with or without fast-acting insulin added to control the glycemic response to this large meal. Fig. 1 shows data from a study comparing the efficacy of bedtime NPH insulin alone with bedtime insulin plus a sulfonylurea [ 161. Subjects were selected for failing on a sulfonylurea, yet having diabetes no longer than 15 years and being no more than moderately obese. Twenty subjects completed a 4 month-4 month crossover protocol taking (in random order) 10 mg of glyburide
z
4
I
I
I
0
I
1
1 Time
1
I
I
I
I
I
2
3
4
(Months)
Fig. 1. Fasting plasma glucose and glycosylated hemoglobin values (mean f SE) for 20 patients treated with bedtime NPH insulin plus placebo (0) or insulin plus 10 mg of glyburide before breakfast (0). The study used a random order crossover design, with adjustment of insulin dosage to optimize glycemic control while minimizing hypoglycemia. Differences at 4 months were significant (P -C 0.01).
before breakfast or a placebo, and varying the insulin dose according to capillary blood glucose measurements with the assistance of their physicians. Neither the subjects nor the physicians knew which treatment was being used. Prior to entry into the study all patients received 20 mg of glyburide daily for several weeks, and the fasting plasma glucose on this treatment (mean 13.5 mM) confirmed frank failure on glyburide alone. At the end of 4 months on insulin plus placebo, fasting glucose averaged 11.1 mM, while at the end of 4 months on combined therapy the mean fasting glucose was 8.0 mM. All subjects achieved glycosylated hemoglobin values at or below 150% of the normal mean with combined therapy, while only half the subjects did so with insulin alone. The mean insulin dosage after 4 months of combined therapy was 36 units daily, compared to 46 units after 4 months on insulin with placebo. We have interpreted this study as showing that for this subpopulation of type 2 diabetes combined therapy using a single evening injection of insulin routinely yields acceptable glycemic control, while a single insulin injection alone is less successful. A similar study of more obese subjects using premixed 70% NPH/30% Regular insulin prior to supper with 10 mg of glyburide before breakfast has given similar results and is being prepared for publication. Whether the same patients could just as easily and safely achieve equally good glycemic control with more aggressive use of a single injection or multiple injections of insulin is not clear. Our view has been that this possibility remains unproved and is unlikely, especially in clinical practice as opposed to research conditions. The question of whether combined therapy using a single insulin injection can avoid or delay use of complex insulin regimens is not a trivial one. The limited epidemiologic evidence available suggests ongoing poor glycemic control is the rule rather than the exception for patients with type 2 diabetes not fully responsive to oral agents. If combining oral agents with a single injection of insulin enhances the long-term outcome without greater risk, cost, or effort it is a useful approach.
An emerging strategy for type 2 diabetes We propose a sequence of treatments for type 2 diabetes including combined therapy in a central position. Diet alone or with an oral agent is the initial approach, but failure of oral agents in most cases may be expected within 5 years. Adding a single evening injection of insulin to a reduced dose of sulfonylurea should in most cases reestablish good glycemic control [ 16,171. The sulfonylurea may be given only in the morning, or both morning and evening, depending on the response. In general, NPH insulin at bedtime is used for persons less than 50% over ideal weight, and 70/30 insulin before supper for those who are more obese. With longer duration of diabetes gradual failure of this regimen may be expected. After 15 years of diabetes, additional injections of insulin are usually required, and additive effects of sulfonylureas are more difficult to demonstrate. We do not usually continue a sulfonylurea once multiple injections of insulin become necessary. This scheme is routinely used in our clinic with gratifying results.
Remaining questions Much remains unknown about combined therapy. By what mechanism do sulfonylureas improve the outcome of insulin treatment? We believe the primary effect is enhancement of insulin secretion, but improved hepatic responsiveness remains possible. Is combined therapy less likely to cause hypoglycemia than insulin alone? We believe it is, because it allows lower doses of injected insulin and therefore less vulnerability to enhanced mobilization of subcutaneous insulin by exercise, and perhaps also because enhancement of P-cell function by the sulfonylurea permits greater suppression of endogenous insulin secretion when plasma glucose falls. What is the role of combining metformin or other oral agents with insulin? Virtually no objective data are available on this point. What patients are the most suitable for combined therapy ? This may be the hardest
question of all. We believe atypical forms of adultonset diabetes are not suited to combined therapy. Late-onset type 1 diabetes, steroid diabetes, and diabetes caused by pancreatic injury by alcohol, cystic fibrosis, or hemochromatosis are among the conditions for which we do not use combined therapy. Answering these questions should provide a challenge for clinical investigators in the near future.
References 1 Fabrykant, M. (1958) Use of Orinase as a basic adjuvant in management of insulin-dependent diabetes. Metabolism 7, 213-221. 2 Volk, B.W. and Lazarus, S.S. (1959) Significance ofeffectiveness of combined insulin-orinase treatment in maturity onset diabetes. Am. J. Med. Sci. 237, l-7. 3 Osei, K., O’Dorisio, T.M. and Falko, J.M. (1984) Concomitant insulin and sulfonylurea therapy in patients with type 2 diabetes. Am. J. Med. 77, 1002-1009. 4 Lardinois, C.K., Liu, G.C. and Reaven, G.M. (1985) Glyburide in non-insulin-dependent diabetes. Its therapeutic effect in patients with disease poorly controlled by insulin alone. Arch. Intern. Med. 145, 1028-1032. 5 Longnecker, M.P., Elsenhans, V.D., Leiman, S.M., Owen, O.E. and Boden, G. (1986) Insulin and a sulfonylurea agent in non-insulin-dependent diabetes mellitus. Arch. Intern. Med. 146, 671-676. 6 Schade, D.S., Mitchell, U.J. and Griego, G. (1987) Addition of sulfonylurea to insulin treatment in poorly controlled type 2 diabetes. J. Am. Med. Ass. 257, 2441-2445. I Hamelbeck, H., Klein, W., Zoltobrocki, M. and Schoffling, K. (1982) Glibenclamide-insulin in combination in the management of secondary failure of sulfonylurea medication. Dtsch. Med. Wochenschr. 107, 1581-1583. 8 Simonson, D.C., Delprato, S., Castellino, P., Groop, L. and De Fronzo, R.A. (1987) Effect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin-treated diabetic patients. J. Am. Med. Ass. 257, 2441-2445. 9 Holman, R.R., Steemson, J. and Turner, R.C. (1987) Sulfonylurea failure in type 2 diabetes: treatment with a basal insulin supplement. Diabetic Med. 4, 457-462. 10 Gutniak, M., Karlander, S.-G. and Efendic, S. (1987) Glyburide decreases insulin requirement, increases /?-cell response to mixed meal, and does not affect insulin sensitivity: effects of short and long-term combined treatment in secondary failure to sulfonylurea. Diabetes Care 10, 545-554.
8 11 The Physicians’ Guide to Non-Insulin-Dependent (Type 2) Diabetes. Diagnosis and Treatment. Second Ed., 1988, American Diabetes Association, Alexandria VA. 12 Lewitt, M.S., Yu, V.K.F., Rennie, G.C., Carter, J.N., Marcel, G.M., Yue, D.K.S. and Hooper, M.J. (1989) Effects of combined insulin-sulfonylurea therapy in Type 2 patients. Diabetes Care 12: 379-383. 13 Riddle, MC. (1985) New tactics for Type 2 diabetes: regimens based on intermediate-acting insulin taken at bedtime. Lancet i: 192-195. 14 Riddle, MC. (1990) An evening insulin strategy. Diabetes Care (Rev. 1990) (in press).
15 Taskinen, M.-R., Sane, T., Helve, E., Karonen, S.-K., Nikkila, E. and Yki-Jarvinen, H. (1989) Bedtime insulin for suppression of overnight free fatty acid, blood glucose and glucose production in NIDDM. Diabetes 38, 580-588. 16 Riddle, M.C., Hart, J.S., Bouma, D.J., Phillipson, B.E. and Youker, G. (1989) Efficacy of bedtime NPH insulin with daytime sulfonylurea for a subpopulation of Type 2 diabetes. Diabetes Care 12, 623-629. 17 Trischitta, V., Italia, S., Borzi, V., Tribulato, A., Mazzarino, S., Squatrito, S. and Vigneri R. (1989) Low-dose bedtime NPH insulin in treatment of secondary failure to glyburide. Diabetes Care 12, 582-585.
3
Elsevier DIABET 00448
Perspective
Combined insulin and sulfonylurea therapy for type 2 diabetes mellitus Matthew Oregon Health Sciences
C. Riddle
University, Portland. OR, U.S.A.
(Received 18 May 1990) (Accepted 29 July 1990)
Introduction Type 2 (non-insulin-dependent) diabetes mellitus presents a therapeutic dilemma. It is both very common and frequently uncontrolled, and increasing evidence links poor glycemic control with serious complications. Our lack of success in controlling type 2 diabetes is partly due to the progressive nature of this disorder. Both insulin secretion and the response of tissues to insulin tend to diminish with time. Therefore, a given patient may expect to need progressively more intensive therapy over the course of time. Dietary therapy is preferred, but it seldom continues to be effective for more than a few years. Sulfonylureas are initially effective about 70% of the time, but after 5 years remain so less than 30% of the time. At this point insulin is required, yet a single injection is not always effective. Thus, for many patients the use of two injections of mixtures of intermediate-acting plus fast-acting insulin is advised quite early in the course of type 2 diabetes. Aggressive insulin therapy of this kind presents
Correspondence to: Prof. M.C. Riddle, School of Medicine, Department of Medicine, Section Diabetes, 3181 S.W. Sam Jackson Park Road L345, Portland, OR 97201, U.S.A.
016%8227/91/$03.50
0 1991 Elsevier Science Publishers
many practical problems to older patients, their families and their physicians. While new means of therapy are on the way, none is yet available. To improve glycemic control, we must enhance the effectiveness of existing methods. Combining insulin with a sulfonylurea or other oral hypoglycemic agent is an approach which is under renewed scrutiny. While combined therapy may in practice be widely used, its proper role remains undefined. Among experienced diabetologists there is a spectrum of opinions. Some believe combined therapy has wide applicability, others that it may be used occasionally in special circumstances, and still others that it has little value.
The rationale for combined therapy Using pharmacotherapeutic agents in combination is an old concept. In some clinical settings, such as hypertension, use of two or more drugs together is accepted practice. Possible advantages of this approach may include greater efficacy, safety, or convenience. Which of these possible advantages may apply to the treatment of diabetes? All oral hypoglycemic agents are quite safe and convenient to use but lack the power to control glucose in many patients. Insulin has
B.V. (Biomedical
Division)
4
almost unlimited therapeutic power, but can cause significant hypoglycemia. Use of mixtures of fast acting and delayed acting insulin given two or more times daily is often necessary to avoid excessive hypoglycemia. Taking insulin by injection is also less convenient than using an oral agent. Thus, combined therapy seems unlikely to add much to the therapeutic efficacy of insulin under the intensive conditions possible during clinical research, but might be helpful in reducing the risk of hypoglycemia or improving convenience and thereby adherence to the prescribed regimen in clinical practice. Viewed this way, combined therapy might be argued to have no advantage over insulin alone in pharmacologic efficacy, but perhaps an advantage in clinical efficacy when safety and convenience influence the outcome.
Published experience with the use of combined therapy Older studies done shortly after the introduction of tolbutamide argue for this clinical benefit of combined therapy [ 1,2]. They describe improved convenience and stability of glycemic control with insulin plus tolbutamide as opposed to insulin alone. However, these were not scientifically designed comparisons. More recent objective studies of combined therapy fall generally into two groups: those using a fixed (and incompletely effective) dosage of insulin and focussing on the response to added sulfonylurea [3-61, and those allowing the dosage of insulin to be adjusted and focussing on the task of clinical management [7-lo]. Several studies of each kind are listed in Table 1.
TABLE 1 Results of objective studies comparing insulin alone (S - ) with combined insulin-sulfonylurea Fasting Glucose
therapy (S + ) for type 2 diabetes
Insulin (units/day)
(mM) -
Fixed insulin dosage Osei (1984) Lardinois (1985) Longnecker (1986) Schade (1987)
Variable insulin dosage Hamelbeck (1982) Simonson (1987) Holman (1987) Gutniak (1987)
s-
s+
difference
15.6 13.9 15.1 14.6 14.8
14.0 10.8 12.3 12.9 12.5
-
9.0 6.9 5.1 8.5 7.4
7.8 6.2 5.2 8.0 C8
S-
1.6 3.1 2.8 1.7 2.3
Sf
difference
-
-
- 1.2 - 0.5 + 0.1
33 59 40
24 46 25
-27% - 22% - 38%
- 0.5 - 0.5
55 47
34 32
-20% - 27%
The studies using a fixed insulin dosage to which a sulfonlyurea was added all show significantly better control of fasting plasma glucose with combined therapy, but the fasting values still averaged over 10 mM. The studies in which the insulin dose was varied show relatively good glycemic control with insulin alone, and in only one of these (Hamelbeck, 1982) was the fasting glucose significantly lower with combined therapy. However, combined therapy permitted an average of 27% less injected insulin.
3
Studies of the first kind have consistently found an additive effect of insulin and sulfonylureas, with a decline from a high fasting plasma glucose averaging about 2.3 mM when a sulfonylurea is added to insulin. However, the resulting glycemic control has been variable and generally unsatisfactory, with mean fasting values over 10 mM on combined therapy. Studies employing a variable dosage of insulin have shown better glycemic control, with mean fasting glucose values 8 mM or less. At the same time, the advantage of combined therapy over insulin alone appears small in these studies. The subjects in this second type of study were not preselected for poor glycemic control on insulin. In many cases, complex insulin regimens with multiple injections and mixtures of fast and intermediate acting insulin were used. Finding relatively good success with insulin alone and only a small further benefit from adding a sulfonylurea is not too surprising. Some diabetologists have concluded from these data that combined therapy has little place in clinical practice. They contend that combined therapy is relatively ineffective when intensive insulin therapy has already failed, and little better than insulin used alone vigorously by typical patients. This point of view is expressed in a consensus statement endorsed by the American Diabetes Association. This publication, ‘The Physican’s Guide To Non-Insulin Dependent (Type 2) Diabetes, states: Currently the only candidate for combination therapy may be the patient in whom glycemic control cannot be achieved with diet and sulfonylurea therapy and in whom reasonable control cannot be achieved with mixed and intermediate acting and Regular insulin each day [ll]. Thus, combined therapy is proposed as the last recourse for patients presenting the most difficult clinical problems. A more favorable view of combined therapy emerges from other more recent studies. An example is a report from Sydney, Australia [ 121. In this study a heterogenous group of 31 type 2 diabetic patients already reasonably well con-
trolled with various insulin regimens were given glyburide or placebo for 3 months and then switched to the alternate treatment. Limited changes of insulin dosage were allowed. A significant advantage of combined therapy was shown, with mean fasting plasma glucose 7.8 mM on combined therapy and 10.1 mM at the end of the insulin plus placebo period. A good outcome on combined therapy correlated strongly with short duration of insulin therapy and high levels of C-peptide in plasma.
Combined therapy at the Oregon Health Sciences University Our group in Oregon has also taken a favorable view of combined therapy. Like the investigators in Sydney, we have asked whether combined therapy might be useful in management of the typical rather than the unusual clinical situation. Instead of focussing on patients refractory to all usual methods for controlling glucose, we have considered the problem of the patient newly unresponsive to sufonylureas. Moreover, instead of studying such patients under conditions of intensive insulin therapy, we have used protocols more similar to usual ambulatory care. We have asked whether typical patients no longer responsive to sulfonylureas may achieve good control more predictably with a single injection of insulin supplemented by a sulfonylurea than with single injection of insulin alone. Our approach also differs from that of many other groups in the insulin regimen used. Since the main physiologic feature of type 2 diabetes is fasting hyperglycemia related to high hepatic glucose output, we have proposed an attack on this abnormality by injecting intermediate-acting insulin in the evening [ 13,141. This method has a dual physiologic rationale. Delivering insulin overnight should suppress hepatic glucose production directly, and may augment this effect by suppressing adipose tissue lipolysis, thereby preventing high overnight free fatty acid levels and improving hepatic responsiveness to insulin [ 151.
6
Proper timing of insulin delivery should allow blunting of the dawn phenomenon while avoiding nocturnal hypoglycemia. Our experience to date suggests that relatively slender, young, active patients achieve this objective best by taking intermediate-acting insulin close to bedtime, whereas more obese, older, inactive patients do better with intermediate-acting insulin given before supper with or without fast-acting insulin added to control the glycemic response to this large meal. Fig. 1 shows data from a study comparing the efficacy of bedtime NPH insulin alone with bedtime insulin plus a sulfonylurea [ 161. Subjects were selected for failing on a sulfonylurea, yet having diabetes no longer than 15 years and being no more than moderately obese. Twenty subjects completed a 4 month-4 month crossover protocol taking (in random order) 10 mg of glyburide
z
4
I
I
I
0
I
1
1 Time
1
I
I
I
I
I
2
3
4
(Months)
Fig. 1. Fasting plasma glucose and glycosylated hemoglobin values (mean f SE) for 20 patients treated with bedtime NPH insulin plus placebo (0) or insulin plus 10 mg of glyburide before breakfast (0). The study used a random order crossover design, with adjustment of insulin dosage to optimize glycemic control while minimizing hypoglycemia. Differences at 4 months were significant (P -C 0.01).
before breakfast or a placebo, and varying the insulin dose according to capillary blood glucose measurements with the assistance of their physicians. Neither the subjects nor the physicians knew which treatment was being used. Prior to entry into the study all patients received 20 mg of glyburide daily for several weeks, and the fasting plasma glucose on this treatment (mean 13.5 mM) confirmed frank failure on glyburide alone. At the end of 4 months on insulin plus placebo, fasting glucose averaged 11.1 mM, while at the end of 4 months on combined therapy the mean fasting glucose was 8.0 mM. All subjects achieved glycosylated hemoglobin values at or below 150% of the normal mean with combined therapy, while only half the subjects did so with insulin alone. The mean insulin dosage after 4 months of combined therapy was 36 units daily, compared to 46 units after 4 months on insulin with placebo. We have interpreted this study as showing that for this subpopulation of type 2 diabetes combined therapy using a single evening injection of insulin routinely yields acceptable glycemic control, while a single insulin injection alone is less successful. A similar study of more obese subjects using premixed 70% NPH/30% Regular insulin prior to supper with 10 mg of glyburide before breakfast has given similar results and is being prepared for publication. Whether the same patients could just as easily and safely achieve equally good glycemic control with more aggressive use of a single injection or multiple injections of insulin is not clear. Our view has been that this possibility remains unproved and is unlikely, especially in clinical practice as opposed to research conditions. The question of whether combined therapy using a single insulin injection can avoid or delay use of complex insulin regimens is not a trivial one. The limited epidemiologic evidence available suggests ongoing poor glycemic control is the rule rather than the exception for patients with type 2 diabetes not fully responsive to oral agents. If combining oral agents with a single injection of insulin enhances the long-term outcome without greater risk, cost, or effort it is a useful approach.
An emerging strategy for type 2 diabetes We propose a sequence of treatments for type 2 diabetes including combined therapy in a central position. Diet alone or with an oral agent is the initial approach, but failure of oral agents in most cases may be expected within 5 years. Adding a single evening injection of insulin to a reduced dose of sulfonylurea should in most cases reestablish good glycemic control [ 16,171. The sulfonylurea may be given only in the morning, or both morning and evening, depending on the response. In general, NPH insulin at bedtime is used for persons less than 50% over ideal weight, and 70/30 insulin before supper for those who are more obese. With longer duration of diabetes gradual failure of this regimen may be expected. After 15 years of diabetes, additional injections of insulin are usually required, and additive effects of sulfonylureas are more difficult to demonstrate. We do not usually continue a sulfonylurea once multiple injections of insulin become necessary. This scheme is routinely used in our clinic with gratifying results.
Remaining questions Much remains unknown about combined therapy. By what mechanism do sulfonylureas improve the outcome of insulin treatment? We believe the primary effect is enhancement of insulin secretion, but improved hepatic responsiveness remains possible. Is combined therapy less likely to cause hypoglycemia than insulin alone? We believe it is, because it allows lower doses of injected insulin and therefore less vulnerability to enhanced mobilization of subcutaneous insulin by exercise, and perhaps also because enhancement of P-cell function by the sulfonylurea permits greater suppression of endogenous insulin secretion when plasma glucose falls. What is the role of combining metformin or other oral agents with insulin? Virtually no objective data are available on this point. What patients are the most suitable for combined therapy ? This may be the hardest
question of all. We believe atypical forms of adultonset diabetes are not suited to combined therapy. Late-onset type 1 diabetes, steroid diabetes, and diabetes caused by pancreatic injury by alcohol, cystic fibrosis, or hemochromatosis are among the conditions for which we do not use combined therapy. Answering these questions should provide a challenge for clinical investigators in the near future.
References 1 Fabrykant, M. (1958) Use of Orinase as a basic adjuvant in management of insulin-dependent diabetes. Metabolism 7, 213-221. 2 Volk, B.W. and Lazarus, S.S. (1959) Significance ofeffectiveness of combined insulin-orinase treatment in maturity onset diabetes. Am. J. Med. Sci. 237, l-7. 3 Osei, K., O’Dorisio, T.M. and Falko, J.M. (1984) Concomitant insulin and sulfonylurea therapy in patients with type 2 diabetes. Am. J. Med. 77, 1002-1009. 4 Lardinois, C.K., Liu, G.C. and Reaven, G.M. (1985) Glyburide in non-insulin-dependent diabetes. Its therapeutic effect in patients with disease poorly controlled by insulin alone. Arch. Intern. Med. 145, 1028-1032. 5 Longnecker, M.P., Elsenhans, V.D., Leiman, S.M., Owen, O.E. and Boden, G. (1986) Insulin and a sulfonylurea agent in non-insulin-dependent diabetes mellitus. Arch. Intern. Med. 146, 671-676. 6 Schade, D.S., Mitchell, U.J. and Griego, G. (1987) Addition of sulfonylurea to insulin treatment in poorly controlled type 2 diabetes. J. Am. Med. Ass. 257, 2441-2445. I Hamelbeck, H., Klein, W., Zoltobrocki, M. and Schoffling, K. (1982) Glibenclamide-insulin in combination in the management of secondary failure of sulfonylurea medication. Dtsch. Med. Wochenschr. 107, 1581-1583. 8 Simonson, D.C., Delprato, S., Castellino, P., Groop, L. and De Fronzo, R.A. (1987) Effect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin-treated diabetic patients. J. Am. Med. Ass. 257, 2441-2445. 9 Holman, R.R., Steemson, J. and Turner, R.C. (1987) Sulfonylurea failure in type 2 diabetes: treatment with a basal insulin supplement. Diabetic Med. 4, 457-462. 10 Gutniak, M., Karlander, S.-G. and Efendic, S. (1987) Glyburide decreases insulin requirement, increases /?-cell response to mixed meal, and does not affect insulin sensitivity: effects of short and long-term combined treatment in secondary failure to sulfonylurea. Diabetes Care 10, 545-554.
8 11 The Physicians’ Guide to Non-Insulin-Dependent (Type 2) Diabetes. Diagnosis and Treatment. Second Ed., 1988, American Diabetes Association, Alexandria VA. 12 Lewitt, M.S., Yu, V.K.F., Rennie, G.C., Carter, J.N., Marcel, G.M., Yue, D.K.S. and Hooper, M.J. (1989) Effects of combined insulin-sulfonylurea therapy in Type 2 patients. Diabetes Care 12: 379-383. 13 Riddle, MC. (1985) New tactics for Type 2 diabetes: regimens based on intermediate-acting insulin taken at bedtime. Lancet i: 192-195. 14 Riddle, MC. (1990) An evening insulin strategy. Diabetes Care (Rev. 1990) (in press).
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