Insulin versus a combination of insulin and sulfonylurea in the treatment of NIDDM patients with secondary oral failure

ELSEVIER

Diabetes Research and Clinical Practice 30 (1995) 27-35

Insulin versus a combination of insulin and sulfonylurea in the treatment of NIDDM patients with secondary oral failure Maja Ravnik-Oblak*, Franc Mrevlje University Medical Centre Ljub&na, Department of Enabcrinolgy and Metabolism. Zaloska 7, 61OlXILjublanu. Slovenia Received 24 November 1994;revision received 17 August 1995;accepted 24 August 1995

AlthWt Aim: Comparison of the effectivenessof combined therapy vs. an insulin regimen in NIDDM patients with secondary failure of oral hypoglycemic agents. Researchdesign, patients and methodr: 27 NIDDM patients were randomly

allocated to Group A (n = 14, insulin) and Group B (n = 13, insulin and sulfonylurea) with crossover after 3 months. After the next 3 months a decision was made about the further treatment according to the metabolic control. The patients were then treated for another year with the more successfulregimen. Metabolic control, residual &cell secretory capacity, degreeof peripheral insulin resistance(clamp) and insulin dosewere followed during the whole study. Rest&s: (median, interquartile range, in brackets; *, statistically significant difference at P < 0,OS):the combined therapy was better then insulin alone in 2/3 of patients. Glycemic control was better (HbA,, at 3 months: Group A = 7.9(l.l)% vs. Group B = 7.0(0.5)%*; HbA,, at 6 months: Group A = 7.4(1.5)% vs. Group B = 8.1(1.5)%. Insulin dose was lower during the combined therapy in the first 3 months: Group A = 0.62(0.18)U/kg body weight vs. Group B = 0.39(0.16) U/kg body weight*. Combined treatment was associatedwith increasedC-peptide excretion both fasting and postprandially. No significant differences in peripheral insulin resistancewere noted between the two groups.The combined treatment remained successfuleven after one year. The two groups of patients with different effective treatment did not differ significantly in any of the observed parameters. Conclusions: the combined therapy was more effective than insulin alone. Its favourable effect persisted after treatment for a year. It seemsbetter to start the treatment of the oral failure with combined therapy compared with insulin first and later followed by combined therapy. On the basis of the observedparametersit is impossible to determine in advance which kind of treatment is more suitable for the individual patient. Keyworak NIDDM; Secondary drug failure; Combined therapy

1. Introduction

In the natural course of type 2 diabetes sometimes it reaches a stage when dietary measuresand oral hypoglycemic agents no longer prol

Corresponding author.

vide satisfactory glycemic control. At this stage, referred to as secondarydrug failure, further treatment must be decided upon. This can consist of oral hypoglycemic agents or insulin or a combination of the two. The combined therapy was recommended by some authors already in the late 1950s [ 1,2], but it did not gain support becauseof inade-

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M. Ravnik-Oblak,

F. Mrevlje / Diabetes Research and Clinical Practice 30 (1995) 27-35

quate knowledge of the pathogenesis of type 2 diabetes. Twenty years later studies using the clamp technique contributed to a better understanding of the condition [3,4]. This led to a greater interest in the combined therapy as an alternative to simple insulin regimens in the treatment of NIDDM patients with secondary drug failure [5]. The combined therapy has been found effective in numerous studies [6- 161.Most authors report significant reductions in the daily insulin dose (up to Xl%), compared to simple insulin regimens [8,9,13- 161.Unfortunately the favourable effects of combined therapy have not been observed in all patients [ 12,171.The reason for this is still unknown and so the question of which patients with secondary drug failure should be switched to a combined therapy, and which should be treated with insulin alone, remains open. It is also unclear whether the effect of the combined therapy is transient or whether it can persist for a longer period of several months or even years after its initiation. The aim of our study has been to determine which form of treatment - insulin given alone or in combination with sulfonylurea - is more effective, to evaluate the effects of the more successful regimen in individual patients after treatment for a year and, possibly, to clarify the mechanism of action of each method. 2. Patients and methods 2.1. Patients

The study was performed on 27 NIDDM patients, who developed secondary drug failure. 2.2. Inclusion criteria

The inclusion criteria were: NIDDM; fasting blood glucoselevels > 10 mmol/l, documented for the previous 3 months; HbAt, >9%; duration of diabetes > 3 years; age >35 years; BMI < 30 kg/m2; fasting serum C-peptide >0.3 mmohl; treatment with glibenclamide, 10 mg twice daily; no evidenceof kidney involvement, liver diseaseor heart failure, absenceof myocardial infarction in the past 6 months; absence of medication that might interact with oral hypoglycemic agents or insulin.

formation of new groups according to treatmenf effectiveness

Fig. 1. Study design. INS, insulin; SU, sulphonylurea; ALL, all patients.

2.3. Study design

All patients were admitted to the hospital and randomised into two groups: l Group A (n = 14), patients treated with diet and insulin; l Group B (n = 13), patients receiving diet and a combination of insulin and glibenclamide (Fig. 1). While the daily glibenclamide dose was constant for all patients (20 mg), the insulin dosesvaried according to the blood glucose values. We used a combination of intermediate- and short-acting human insulins (Protaphane HM and Actrapid HM, Novo Nordisk), given once or twice daily. After discharge, the patients were followed by fortnightly visits to the out-patient clinic. At each visit blood glucose (fasting, after breakfast and before lunch) was recorded. HbAr, was assayed every month. The insulin dose was adjusted according to blood glucose levels measured by selfcontrol at home as well as during visits to the outpatient clinic. Three months after discharge the patients were re-admitted to the hospital and, following a reevaluation of all observed parameters, a crossover was done between both groups: l Group A, patients receiving insulin and glibenclamide; l Group B, patients treated with insulin only. In the ensuing 3 months the patients were followed on an out-patient basis according to the sameprotocol as after the first hospital stay. They were then re-admitted and subjectedto the sametests as

hi. Ravnik-Oblak,

F. Mrevlje / Diabetes Research and Clinical Practice 30 (1995) 27-35

during the first two hospital stays. On the basis of these results they were divided into two new groups: l Group 1 (n = 9), patients in whom the insulin treatment was better than insulin and glibenclamide together (non-responder); l Group 2 (n = 18), patients in whom combined treatment was better than insulin alone (responder). The characteristics of Groups 1 and 2 were analyzed retroactively at the end of the study. We wished to identify the eventual differences among the two groups which would be of help in the decision for combined therapy or against it. The criteria for more successfultreatment were: improvement in metabolic control (lowering of fasting blood glucoselevel for more than 2 mmol/l, lowering of HbAi, for more than 1%); or achievement of equal metabolic control on lower insulin dose (more than 0.1 E/kg body weight). All patients, except the three who died of stroke, acute myocardial infarction and cancer, were readmitted after another year of treatment. To answer the questions posed in the study, we considered the following parameters. l Patient characteristics: age; duration of diabetes; BMI; duration of treatment with maximum glibenclamide doses. l Metabolic control: fasting; post-breakfast and pre-lunch glucose levels; daily blood glucose profile (with the mean level) and HbA,,. l Residual @-cellsecretory capacity: serum Cpeptide concentration in the fasting state and after stimulation with standard breakfast. l Insulin action on peripheral tissues: determining the number of insulin receptors and the site of insulin resistancein the periphery (receptor and/or post-receptor level) on the basis of the rate of glucose utilisation evaluated by the insulin clamp technique. The results obtained before and after the change of therapy were compared within each group and between the two groups. 2.4. Clinical methods

The patients were admitted to the Diabetes Ward, Department of Endocrinology and Metabolism, University Medical Centre Ljubljana, at the

29

beginning of the study, at 3 and 6 months during the study, and at the end of the study. Eight-point blood glucose profiles were obtained at the beginning and at the end of the first three hospital stays, and at the beginning of the fourth. Blood glucose was determined before and after the three main meals, at midnight and at 3 a.m. An insulin clamp test was performed during each hospital stay. The patients were instructed how to use the NovoPen and NovoPen II devices, and also how to monitor their own blood glucose. 2.5. Hyperinsulinaemic euglycaemic clamp

A Biostator GCIIS (Miles, USA) was used for the test. Baseline blood glucose level: the fasting blood glucose level determined on the day of the test. The patient received no anti-diabetic therapy on that day. The clamp test consisted of two parts: (1) clamp at a physiological insulinaemia (1st level, about 100 mu/l), achieved by continuous insulin infusion at a rate of 40 mU/m2/min; (2) clamp at a supraphysiological insulinaemia (2nd level, about 350mu/l), achievedby continuous insulin infusion at a rate of 240 mU/mVmin). Peripheral insulin resistance was evaluated on the basis of the mean rate of glucose utilisation, measured after a steady state had been achieved, i.e., in the last 30 min of clamp at each of the two levels studied. In a control group M values of 6.2 and 11 mg/kg/min (quoted in Ref. [ 181)were obtained at the lower and the upper level of insulinaemia, respectively. Because the baseline blood glucose level in our study exceeded 5.6 mmol/l, the glucose metabolic clearance rate (MCRG, ml/kg/min) was used instead of M as the measure of the peripheral insulin resistance. 2.6. Laboratory analyses

Glucose in the capillary blood was determined by the glucose-oxidase method with a Beckman Glucose Analyser II (normal range, 3.6-5.6 mmol/l). HbAi, in venous blood plasma was assayedby an HPLC method with a Diamat analyser (normal range, < 6.5%). Serum C-peptide was determined with a com-

30

M. Ravnik-Obti, F. Mrevlje / Diabetes Researchand Clinical Practice 30 (1995) 27-35

mercial RIA kit (Byk-Mallinkrodt) (normal range, 0.17-0.99 nmoliI). Serum insulin was assayed with a commercial RIA kit Phadebas(normal range, l-l 5 mu/l). Insulin receptors were determined by a stoichiometric method (NOVO), using 125rlabelled insulin (specific activity, 150-200 &i/mg) to measurespecific binding to insulin receptors on erythrocytes (normal range, 6.7-l 1.9%). All the analyses were done at the Institute of Clinical Chemistry and Clinical Biochemistry and the Department of Nuclear Medicine, University Medical Centre Ljubljana. 2.7. Statistical methods All the data are presentedas median values with interquartile range (in brackets). The differences between two groups were tested with a nonparametric test for the non-paired variables (Mann-Whitney V-test). The intragroup changes (differences between variables in different time points) are tested with analysis of variance for repeatedmeasurements.Differences were considered statistically significant, if P was lower than 0.05 (*). All the analyseswere made by the Statgraphics STSC statistical program. 3. ResuIts 3.1. Patient characteristics Patient characteristics are presented in Table 1. 3.2. Metabolic control HbAi, improved significantly in Groups A and

2 0

Parameter

GroupA

GroupB

Age (Years) Duration of DM b-1 Duration of MOT (months)

58 (12)

56 (11)

24.5

BOdyllUl!JSi&X

26.6 (4.8)

10.5.(7)

0

4

8

12

16

20

24

weeks of treatment Fig. 2. HbA,, during the !irst 6 months of the study.

B during the study. A significantly lower HbAi, was noted at the end of the initial period in Group B while there was no significant difference between both groups at the start of the study (Fig. 2). In both groups, there was a significant fall in HbAi, as early as after 4 weeksof treatment with insulin. The significantly lower value of HbAi, then persisted in both groups until the sixth month of the study (measured at each point in time). The mean blood glucose levels during the first hospital stay were significantly higher than on subsequentadmissions, while these values did not differ significantly between the two groups (Fig. 3). Differences did occur during the periods of outpatient follow up. Throughout the study the patients on combined therapy had lower blood glucose than patients on insulin alone. These differences occasionally reached statistical significance (Fig. 4a-c).

18

Tabk 1 Patient characteristics

I

crossover

MBGmmdL

8 (9) 20 26.5 (2.9)

DM, diabetes mellinu; MOT, maximum oral therapy with glibeaclamide.

0

St&A

StUtD

3mA

3mD

6mA

Fig. 3. Mean blood glucose(MBG) at lwpitaliSationS. Legend: 3 m, 3 months; 6 m, 6 monthg A, admission; D, dkcbarge.

hf. Ravnik-Oblak, l? Mrevrje / Diabetes Researchand Clinical Practice 30 (1995) 27-35

31

10 9

8

oJ/

, crqssover

7

2

4

6

8

10

14

16

18

20

, 0

22

cTos4ov~r 2

4

I

13

I c

11 9

crossover 4

6

8

10

14

16

18

20

22

weeks of treatment BG mmoWL 14 ,

*

(d -oco.osl

18

20

12

14

16

18

20

22

24

3.4. Body mass index Significant increases in body weight were observedin both groups after the switch to insulin therapy (Group A: 24.9(5)**** at start vs. 27.7(5.2)* at 3 months vs. 28.0(5.4) kg/m2** at 6 months; Group B: 26.6(1.9)*,** at start vs. 28.1(2.3)* at 3 months vs. 27.3 (2.9) kg/m*** at 6 months. There were no significant differences in these values between the two groups. 3.5. Residual &cell secretory capacity Before the switch to the insulin neither the baseline nor the postprandial C-peptide levels showed a significant difference between Groups A and B. After 3 months, the group treated with the combined regimen in the initial period had significantly higher fasting C-peptide than the group initially

12 10

P-

61

10

Fig. 5. Insulin dose during the first 6 months of the study.

(b)

15

2

8

weeks of treatment

weeks of treatment BGmmovL

6

, crqssoyer 2

4

6

8

10

14

16

22

weeks of treatment Fig. 4. Fasting (a), postprandial (b) and pre-lunch (c) blood glucose (BG) at out-patient controls during first 6 months of the study.

3.3. Insulin dose Compared to Group A, Group B patients were discharged after their first hospital stay on substantially lower insulin dosesand required less insulin in the period until their admission after 3 months. After the change of therapy the differencesbetweenthe two groups gradually decreased, practically disappearing by the time of the admission after 6 months (Fig. 5).

C-peptide nmol/L 411

:; L

3 months

6 months

Fig. 6. Residual C-peptidc secretion. CP-bas, fasting C-peptide; CP-pp, postprandial C-peptide.

32

,U. Ravnik-Oblak,

F. Mrevlje / Diabetes Research and Clinical Practice 30 (1995) 27-35

treated with insulin alone. After the crossover fasting postprandial C-peptide fell in the group switched to insulin and rose in the group switched to the combined regimen (Fig. 6). 3.6. Peripheral insulin resistance

There were no significant differences in the percentage of insulin binding to insulin receptors either within each group or between the two groups throughout the study (Group A: 3.65(2.45)%at start vs. 3.70(1.10)%at 3 months vs 3.65(1.70)%at 6 months; Group B: 3.35(1.40)%at start vs. 4.15(1.35)%at 3 months vs. 2.70(2.90)%at 6 months. A comparison of glucose utilisation in the periphery at both levels of insulinaemia is presentedin Fig. 7. There were no significant differencesat each level of insulinaemia during the study, but a trend of increasing glucoseuptake was apparent during treatment with the combined regimen. 3.7. Comparison of Groups 1 and 2

The two groups showed no significant differencesin the basic patient characteristics, metabolic control, residual &cell secretory capacity, or the degreeof peripheral insulin resistance.No significant differences between the two groups were apparent at the start and at the end of the study (Table 2).

3 months

6 months

Fig. 7. Glucose disposal during an euglycaemicclamp. MCRG, metabolic clearance rate of glucose.

4. Discussloo Numerous studies in the past years have indicated that the combined therapy has a place in the treatment of type II diabetes following secondary oral drug failure although the mechanism of action of this therapy, the duration of its effectiveness and the criteria for the selection of patients are not quite clear yet. In our study two thirds of the patients (18 of 27) showed better responseto combined therapy than to insulin alone (for classification see the section on Patients and methods). In these patients better

Table 2 Comparison of parameters between both groups at start and at the end of the study Parameter

Group 1, s

Group 1, E

Group 2, S

Group 2, E

Age(years)

59.5 (8.5) 8.0 (7.0) 18.5 (19.5) 27.3 (26.3) 10.7 (2.3) 15.5 (6.4) 0.69 (0.1) 1.30 (0.83) 3.45 (1.1) 2.39 (2.49) 7.05 (4.7)

-

57.0 (13) 10.0 (7.5) 24.5 (25.5) 26.3 (23.3) 9.8 (1.6) 16.0 (4.1) 0.57 (0.24) 1.03 (0.7) 3.8 (2.8) 3.4 (6.87) 7.3 (4.23)

-

Duration of DM (years) Duration of MOT (years) Body mass index Hbh MBG CP-bas CP-PP Insulin receptors MCRG-1 MCRG-2

l

* *

8.9 (3.3) 11.7 (4.7) 0.84 (0.89) 2.38 (1.72) 7.2 (4.5) 1.67 (1.98) 5.63 (5.29)

* l l

8.5 (1.3) 8.8 (2.2) 0.91 (0.59) I .97 (0.95) 5.0 (4.9) 2.46 (4.12) 8.3 (3.45)

S, start; E, end; DM, diabetes mellitus; MOT, maximum oral therapy; HbA,,, glycohaemoglobin c; MBG, mean blood glucose; CPhas, fasting C peptide, CP-pp. postprandial C peptide; MCRG-1, metabolic clearance rate of ghtcose, 1st level; MCRG-2, metabolic clearance rate of ghtcose, 2nd level. l P < 0.05.

M. Ravnik-Oblak,

I? MrevQe / Diabetes Research and Clinical Practice 30 (1995) 27-35

glycemic control was achieved with a lower insulin dose (27-37% during the first part of the study). Insulin reductions of up to 50% during the combined therapy have been reported also by other authors [13-16,191. When sulfonylurea is withdrawn, the need for insulin increases [20]. Most authors believe that sulfonylurea enhances insulin secretion by the P-cells [21-231, which is suppressed when exogenous insulin is applied alone [24]. A prerequisite, however, is adequate residual endogenous insulin secretion with a minimal basal level of 0.3 nmol/l [25,26]. In our patients, the basal C-peptide levels prior to insulin initiation averaged 0.62 nmol/l, none being lower than 0.3 nmol/l. The highest C-peptide levels were registered during combined treatment, which suggest that sulfonylurea can enhanceendogenous insulin production once blood glucose has been reduced and the inhibitory effect of hyperglycemia on &cell function diminished [27]. The effect of sulfonylurea, when given together with insulin, on the peripheral insulin resistance is not clear yet [13,24,28]. Our patients showed about 50% lower rates of insulin binding to insulin receptors, while their rates of glucose utilisation in the periphery were 20-40% lower at the receptor level and 35-50% lower at the post-receptor level compared to a control group of healthy subjects [18]. The group initially receiving the combined therapy showed a tendency for these parameters to increase during the first 3 months of the trial. The values obtained in other periods of the study revealed no further significant differences within this group, which could at least partly be ascribed to the wide range of variation in the results. Also when this group was compared to the group treated with insulin only no significant differences were found. Authors disagree on the length of time that the combined therapy remains effective [ 10,12,13,17, 19,26,29,30].In our study the effect was still evident after a year of treatment. The patients (including those treated with insulin only) even showed a tendency for increasedinsulin binding to insulin receptors and better glucose utilisation in the periphery at the post-receptor level. Also their C-peptide secretion was improving, probably as a result of improved &cell function due to the chronic reduction in blood glucose.

33

The treatment schedule is another issue still in debate: which type of insulin to use (short-, intermediate- or long-acting), when to apply it and when to add the tablets [31-33]? We used20 mg of glibenclamide and a combination of intermediate- and short-acting insulins administered once or twice daily. Since the new therapy was initiated in hospital, follow-up evaluation at the out-patient clinic often showed the starting dose of insulin, especially the short-acting type, to be too high. Evidently, the patients were much more active in their daily lives than during the hospital stay. Insulin reductions were necessaryespecially during the combined therapy. This was attributed to sulfonylurea promoting insulin secretion by the &cells, since the patients showed appreciably higher C-peptide levels after meals (Group B: 1.25(0.73) at 3 months vs. 0.97(0.61) nmol/l* at 6 months; Group A: 0.92(0.57) at 3 months vs. 1.32(0.81)nmol/l* at 6 months). Diabetologists differ in their opinions about when to initiate the combined therapy: should it be introduced directly after oral drug failure, or should tablets be added in patients who are poorly controlled on insulin or require very high insulin doses. Studies show the combined therapy to be more effective (positive responserates of 60-80%) if started as soon as possible [19,26,34]. This was confirmed also in our patients (HbA,,: 7.0(0.5)% in Group B vs. 7.4(1.5)%* in Group A; insulin dose: 0.39(0.16) in Group B vs. 0.52(0.17) U/kg body weight* in Group A). The most important question that has remained open concerns the patient selection. Looking at the patients as a group, it seemsthat responders have a higher basal C-peptide level, shorter duration of diabetesand greater body weight. In the individual patient, however, these variables cannot predict the response to the combined therapy [35,36]. Patient age, control of diabetes and postprandial C-peptide levels have proved equally uselessin predicting the successof the combined therapy [20]. In our study none of the parameters followed (patient age, duration of diabetes, duration of treatment with 20 mg glibenclamide, BMI, control of diabetes, residual secretory capacity of the &cells and peripheral insulin resistance) revealed a significant difference between patients

34

M. Ravnik-Oblak.

.^ I.^^_, -- -_ F. Mrevlje / Diabetes Research and Llmzal -St ’ rracnce xl ( IYYJJ 11-53

in whom the combined therapy was more successful (Group 2) and those showing an equal or better responseto insulin alone (Group 1) either at the beginning or at the end of the trial. We conclude that the combined therapy has proved better in two thirds of our patients. It gave better results if started directly after oral drug failure, and remained successfulafter a year of treatment. Sulfonylurea is believed to enhance endogenous insulin secretion. However, we have managedto find no parametersthat could serve as a basis for selecting the treatment method in a specific patient. Thus, until new findings are published, decisions concerning the therapy will have to be made individually. Acknowledgements The authors are grateful to colleagues at the Vuk Vrhovac Institute of Diabetes, Endocrinology and Metabolism, Zagreb, Croatia, especially to Prof. Dr. Mate Granic and Dr. Drazen Babic, for their cooperation in preparing the protocol of the study. We also thank the nurses, Majda MoriLukancic and Mira Klemenc, for their valuable assistance. References [I] Fabrykant, M. (1957) Favourable effect of supplemental Grinase in insulin-treated labile diabetics. Metabolism 6, 509-517. [2] Lazarus, S.S. and Volk, B.W. (1959) Physiological basis

of the effectiveness of combined insulin-tolbutamide. Ann. NY Acad. Sci. 82, 590-602. [3] Greenfield, MS., Dobeme, L., Kraemer, F., Tobey, T. and Reaven G. (1981) Assessmentof insulin resistance with the insulin suppression test and the euglycemic clamp. Diabetes 30, 387-392. [4] Proietto, J., Nankervis, A., Aitken, P., Caruso, G., Harewood, M. and Alford, P.P. (1983) The physiologic action of insulin on gh~coseuptake and its relevance to the interpretation of the metabolic clearance rate of ducase. Metabolism 32, 1022-1028. [5] B&IIMM, W., Sieger, C. and Lotz, N. (1983)Kombinabei TypIItionstherapie Insulin/Glibenclamid Diabetikem mit relativer Insulin-resistenz. In: W. Bachman and H. Mehnert (Eds.), Kombinationstherapie Insulir&ulfonylhamsrnstoff.BaseI, Karger, pp. 145-154. [61 Shade,D.S., Mitchell, W.J. and Griego, G. (1987) Addition

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sulfonylurea to insulin treatment in poorly con-

trolled type II diabetes. A double-blind, randomized clinical trial. J. Am. Med. Assoc. 257, 2441-2445. 171 Groop, L., Hamo, K. and Tolppanen, E.M. (1984) The combination of insulin and sulphonylurea in the treatment of secondary drug failure in patients with type II diabetes. Acta Endocrinol. 106, 97-101. 181Rosak, C., Schwarz, O., Althoff, P.H., Schiziflling, K. and Schmidt, F.H. (1985) Kombinierte Behandlung von Typ-II-Diabetikem mit Insulin und Glibenclamid nach Tablettensekundgrversagen. Dtsch. Med. Wschr. 110, 1975-1980. [91 Traumann, K.J., H6sl, W., Grom, E. and Wittemann, G. (1982) Kombination von Insulin und Sulfonylhamstoffen be.i der Therapie des Diabetes mellitus vom Erwachsenen-Typ, Dtsch. Med. Wschr. 107, 180-184. WI Scheen,A.J. and Lefebvre, P.J. (1989) Insulin versus insulin plus sulfonylureas in type 2 diabetic patients with secondary drug failure to sulfonylureas. Diabetes Res. Clin. Pratt 6, S33-S43. 1111Longnecker, M.P., Elsenhans, V.D., L&man, S.M., Owen, O.E. and Boden, G. (1986) Insulin and sulfonylurea agent in non-insulin-dependent diabetes mellitus. Arch. Intern. Med. 146, 673-676. 1121Reaven, G.M., Fraze, E., Chen, N.Y., Hollenbeck, C. and Chen, Y.I.R. (1989)The combined useof insulin and sulfonylurea therapy in patients with non-insulindependent diabetes mellitus. Horm. Metab. Res. 21, 132-136. iI31 Gutniak, M., Karlander, S.G. and Efendic, S. (1987) Glyburide decreasesinsulin requirement, increasesbeta cell responseto mixed meal, and does not affect insulin sensitivity: effectsof short and long-term combined treatmentin secondary failure to sulfonylurea. Diabetes Care 10, 545-554. iI41 Hamelbeck, H., Klein, W., Zoltobrocki, M. and SchBBling, K. (1982) Glibenclamide-insulin in combination in the management of secondary failure of sulfonylurea medication. Dtsch. Med. Wschr. 107, 1581-1583. v51 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. 1161Simonson, D.C., Del Prato, S., Castellino, P., Groop, L. and DeFronzo, R.A. (1987) Effect of glyburide on glycemic control, insulin requirement, and glucose me tabolism in insulin-treated diabetic patients. Diabetes 36, 136-M. 1171 Casner,P.R. (1988)Insulin-glyburide combination thera-

py for non-insulin-dependent diabetes mellitus: a longterm double-blind, placebo-controlled trial. Clin. Pharmacol. Ther. 44, 594-603. 1181DeFronzo, R.A. (1986) What causes hyperglycemia in non-insulin dependent diabetes mellitus. In: I.G.S.D. (Eds.), NIDDM: An update. Proceedingsof an Intemational Symposium in the Framework of the 22nd Annual Meeting of the European Association for the Study of Diabetes. Rome, pp. 14-25. [I91 Lotz, N., Bachmann, W., Ladik, T. and Mehnert, H.

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