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Effects of the combination of insulin and gliclazide compared with insulin alone in type 2 diabetic patients with secondary failure to oral hypoglycemic agents
Diabetes Research and Clinical Practice, 18 (1992) 23-30 0
1992 Elsevier Science Publishers
23
B.V. All rights reserved 0168-8227/92/$05.00
DIABET 0067 1
Effects of the combination of insulin and gliclazide compared with insulin alone in type 2 diabetic patients with secondary failure to oral hypoglycemic agents Pablo Aschner
and William Kattah
Colombian Diabetes Association and the Department of Internal Medicine, School of Medicine. Javeriana University. Bogotci. Colombia
(Received 21 March 1992) (Revision accepted 2 May 1992)
Summary Twenty non-insulin-dependent diabetic patients on insulin therapy for more than 2 months due to secondary failure to oral hypoglycemic agents (OHA) were additionally treated with gliclazide, 80 mg b.i.d., for 1 month and 160 mg b.i.d. for a further 2 months, while reducing insulin dose gradually according to glycemic control. At the end of the first month, fasting blood glucose had decreased from 12.8 k 0.7 to 9 t 0.8 mM (mean & standard error; P-c0.005) and thereafter remained stable. Insulin requirements decreased from 34.2 + 2.5 to 18.3 & 3.2 U/day (P
diabetes mellitus; Secondary
Introduction ‘Secondary failure’ to oral hypoglycemic agents (OHA), which eventually can be present in a conCorrespondence
to: P. Aschner, Asociacibn Colombiana Diabetes, Calle 39A No. 14-78, BogotB. Colombia.
de
failure; Gliclazide;
Combined
therapy
siderable number of non-insulin-dependent diabetic patients, is still an ill-defined condition and there is no general agreement as to its treatment. Based on the concept of ‘beta-cell exhaustion’, insulinotherapy is indicated when the patient can no longer be controlled with maximum doses of an OHA. In our Colombian Diabetes Associa-
24
tion, approximately 113, of non-insulin-dependent diabetic patients require insulin permanently. Nevertheless, recent studies show that although insulin secretion deteriorates gradually and this becomes more pronounced as the clinical situation advances, there is still decreased insulin sensitivity mainly in the liver and muscle and all these abnormalities affect each other, especially if hyperglycaemia persists [ l]. Since it was demonstrated that sulfonylureas potentiate insulin action and improve insulin sensitivity in diabetic patients [ 2,3], clinical trials combining them with insulin were reinstated in the treatment of secondary failure to OHA, at the beginning of the present decade [4]. Such combinations of OHA and insulin might, in addition, be expected to decrease insulin requirements, thus avoiding the hyperinsulinemia observed in these patients which has been involved in macroangiopathic complications [ 51. With this aim in mind, we decided to evaluate, in such combinations, the effectiveness of gliclazide, a second generation sulfonylurea which has additionally been shown to present some haemovascular properties. Also, since the results with respect to changes in basal insulin secretion have been equivocal, we designed this trial with emphasis on avoiding exogenous insulin suppression when this effect was evaluated. Materials and Methods Subjects
Twenty non-insulin-dependent diabetic patients who had failed on treatment with maximum doses of OHA (other than gliclazide) were included in the study. Failure was defined as fasting plasma glucose repeatedly above 11.1 mM while at maximal daily dosage of sulfonylurea. They were all on insulin monotherapy for more than 2 months without obtaining optimal control (fasting plasma glucose > 6.4 mM and/or 2 h post-prandial > 10 mM). None of the patients had secondary diabetes or clinical evidence of hepatic, renal or coronary dysfunction. Patients receiving any drug known to affect glucose metabolism were ex-
eluded. None were obese and no evidence of ketosis was present in their records. The clinical data of the patients are shown in Table 1. They all gave informed consent and the investigation was performed in accordance with the principles of the Declaration of Helsinki. Experimental protocol
All patients were followed during 2 months prior to their inclusion in the protocol. During this period their insulin dose was adjusted and if optimal control was not achieved, they were started on combined therapy with the addition of gliclazide. Fasting plasma glucose during insulin monotherapy was used as baseline (T_ J. Diet was kept constant in each patient throughout the study. Before starting (T,,) and at the end of the 3 months’ trial ( T3), insulin was suspended for 36 to 48 h and a fasting blood sample was obtained for measuring blood glucose, glycohaemoglobin (HbA,) and C-peptide. Post-prandial(2 h) blood glucose was also measured after a standard breakfast. Gliclazide (80 mg) tablets were given twice daily during the first month of combined therapy; thereafter the dose was increased to 160 mg twice daily and kept constant for 2 months. Insulin dose was reduced gradually if the patients had hypoglycemic episodes or their fasting blood glucose improved. Insulin dose was mainly adjusted by decreasing the morning dose when the patient was receiving insulin b.i.d. In those patients receiving insulin in a single morning dose, it was first divided (b.i.d.) and then decreased. During the entire study period the patients visited the outpatient clinic every 2-4 weeks or more often if necessary. Monthly evaluations included weight, pulse rate and blood pressure (supine and standing) recordings and fasting and postprandial (2 h) blood glucose measurements, which at the end of the first and second month (T, and Tz) were performed without suspending insulin therapy. Haemogram and urinalysis were also performed monthly; EKG and urine culture were carried out at T, and T3.
25 TABLE
1
Clinical characteristics Sex
4s (years)
of patients at entry to the combined treatment Body mass index (kg/m’)
HbA, (“,A)
Basal C-peptide (nmol/l)
15.0 0.2 0.5 8.0 4.0 4.0 4.0 2.0 9.0 3.0 2.0 8.0 5.0 5.0 3.0 4.0 4.0 4.0 0.2 0.8
28.6 27.1 22.5 24.3 23.9 25.7 25.8 23.3 28.5 26.3 24.7 20.6 23.4 23.9 19.4 26.8 25.6 21.2 21.5 22.5
10.8 13.4 10.9 9.8 8.3 6.9 14.7 11.3 18.7 12.8 12.4 8.2 20.0 14.7 17.0 6.0 9.9 10.9 9.3 10.7
0.10 0.04 0.02 0.18 0.22 0.58 0.16 0.14 0.03 0.36 0.04 0.06 0.61 0.17 0.51 0.17 0.95 0.03 0.43 0.09
4.3 0.8
24.3 0.6
11.8 0.8
0.24 0.06
Duration of diabetes
Duration of insulin therapy
(years)
(years)
F F F F F F F F F F F F F F F M M M M M
44 50 50 53 53 57 58 59 59 60 61 62 65 65 65 55 56 58 59 65
17 10 11 14 32 8 18 11 20 9 10 25 11 11 18 15 20 2.5 7 15
Mean SEM
57.1 1.3
15.4 1.5
Assays
Plasma glucose was measured by a hexokinase method. HbA, concentration in blood was determined by cation exchange microcolumn chromatography (Sigma Diagnostics, USA) and the upper normal limit for our Laboratory is 7.6 %. Serum C-peptide concentration was measured by radioimmunoassay (Diagnostic Products Corporation, CA, USA) and the sensitivity (minimal detectable dose) of the assay was 0.016 nmol/l. Statistical analysis
All data are expressed as mean k SEM. The significance of difference between treatments was tested with a two-tailed paired t-test using a computer program. Correlations were tested by linear regression analysis.
Results Glycaemic control and insulin requirements
The mean fasting blood glucose at the end of the insulin treatment period (T_ i) was 12.8 + 0.7 mM and after the first month of combined treatment there was a significant reduction of approximately 29.5% (to 9+ 0.8 mM; P~O.005) (Table 2). When the gliclazide dose was doubled, no further improvement was observed, but insulin dose could be reduced from 34.2k2.5 U/day at T,, to 2l.lk2.8 U/day at T2 and 18.3 k 3.2 U/day at T3 (P
26 TABLE 2 Glycaemic control and insulin requirements during insulin monotherapy (T_ ,) and throughout the combined treatment with insulin and gliclazide (GCZ) which lasted 3 months. Starting this treatment (To), insulin was suspended for 36 to 48 h. At the end of the first month (T,) patients were on insulin plus 160 mg/day GCZ. At the end of the second month (T?) patients were on insulin plus 320 mg/day GCZ. At the end of the third month they were still on 320 mg/day GCZ. but insulin was again suspended for 36 to 48 h.
T -I
Tu
T,
Fasting plasma glucose (mM) Mean 12.8 14.5 SEM 0.7 0.8 Post-prandial Mean SEM
9.0” 0.8
(2 h) plasma glucose (mM) 16.9 11.8 0.9 0.8
Insulin requirement (units/day) Mean 34.2 SEM 2.5
28.0’ 2.7
T2
T3
9.5 0.8
11.8h 1.0
12.8 0.8
15.1 0.8
2l.ld 2.8
18.3’
..3'
aP-cO.005 vs.T_ ,;b P
0 r’. Insulin required l
Wkgl 0.6.
l
pc 0.001
T
TO
T3
Fig. 1. Daily insulin requirements (units per kg of body weight) at the beginning (To) and after 3 months of combined treatment (T3)expressed as mean + SEM.
end of the combined treatment are compared, expressed as units per kilogram body weight. Before the trial, nine patients received a single dose before breakfast and 11 patients received insulin twice a day (also at bedtime). Only one in each group received a combination of NPH and regular insulin. The rest received NPH only. At the end of the trial, two patients were still receiving insulin twice a day and six patients were receiving a single dose before breakfast. Nine patients were only receiving a single dose at bedtime. All used NPH only. When insulin doses were compared separately (a.m. and p.m.) before (T,,) and at the end of the trial (T3), no statistical difference was found in the evening dose (5.4-~ 1.4 vs. 7.1 + 1.7 units), while in the morning dose there was a very significant reduction (26.3 t 1.9 vs. 11.2 5 3.3 units, P
27
increase (0.24 + 0.06 vs. 0.39 k 0.10 nmol/l), but heterogeneity was still present. The change in Cpeptide correlated with the change in basal blood glucose at the end of the study (Y= 0.52; PC 0.05). Since insulin was stopped 36 to 48 h prior to blood measurements at T,, and T,, we assume that basal C-peptide levels will depend on the corresponding blood glucose, which would act as a stimulus. Accordingly, we calculated a Cpeptide/glucose score, defined as fasting Cpeptide/BG x 100, and a significant difference was found between mean scores at T, and T3 (0.11+0.03 vs. 0.21+0.05, P
Discussion Only a minority of our patients normalized their fasting blood glucose levels (20x), but most were able to keep them below 10 mM. Although HbA, was not significantly different, the final fasting blood glucose levels were lower with a marked reduction in insulin requirement. Since only a minority normalized their fasting blood glucose and the change in post-prandial blood glucose did not reach a significant level, we believe that more time would be needed to observe a significant decrease in HbA,. Reduction of insulin requirement is a constant finding in most studies where combination therapy has been explored and it ranges from 25 to 50% [6-221. This sole fact justifies this treatment if we consider that patients with secondary failure to OHA frequently require hyperinsulinization to obtain good control and that seems to be atherogenic [ 51. How sulfonylureas improve insulin action is not clear. The effects of sulfonylureas in this respect can be summarized as follows: (1) increase
of islet B-cell sensitivity to glucose, (2) increase of plasma insulin levels, (3) reduction of hepatic insulin extraction, (4) reduction of basal hepatic glucose production, (5) potentiation of the effect of insulin on hepatic glucose production, (6) potentiation of insulin-stimulated glucose utilization
1211. Effects 1 and 2 have been explored mainly by measuring basal C-peptide or after stimulation by glucagon or a mixed meal. In most of the studies, no increase in C-peptide has been demonstrated after combined therapy [ 10,14- 16,24-261. Only a few studies have observed an improvement in B-cell function and mainly after stimulation of C-peptide measured in blood [ 9,12,27,28] or urine [22]. In the present study, only basal C-peptide was evaluated and although the response to combined therapy was mixed, in at least half of the patients it increased, including in some who had low initial values. C-peptide was measured under a hyperglycaemic milieu (endogenous stimulus) and exogenous insulin suppression was excluded by suspending it for a sufficient period of time. Under such conditions, we believe that the Cpeptide/glucose score would be a better indicator of P-cell response and, in fact, it increased significantly after combined treatment. This score has been shown to be better than C-peptide alone in predicting secondary failure to oral agents [29]. Insulin therapy suppresses C-peptide production (hence endogenous insulin secretion) by up to 50 % [ 301 and this is minimized when a sulfonylurea is added and insulin dose reduced, allowing the use of endogenous insulin on demand. The increased response of B-cells could also be attributed to a greater potency of gliclazide. Its potent and lasting effect on phases 1 and 2 of insulin secretion has been demonstrated [31,32] but it would be necessary to compare gliclazide with other second-generation sulfonylureas since they are also potent at this level. Effects 3 to 6 refer to peripheral actions of sulfonylureas. The fact that combined therapy improved basal blood glucose levels with insignificant effects on post-prandial values suggests that it is due mainly to a reduction in hepatic
28
glucose production since it correlates directly with fasting plasma glucose [ 141. This could be explained by an increase in the endogenous insulin available in the portal vein when combined therapy is used, since the liver is very sensitive to small changes at that level. The peripheral action has also been evaluated using a hyperinsulinemiceuglycaemic clamp: some have found an increase in glucose metabolic clearance, and therefore in insulin sensitivity, during combined therapy [7,8,10,25,26], but others have not [9,12]. Such improvement seems to be evident only when patients are under excellent control and can be observed also on diet alone or when using intensive insulin therapy [ 121. No change has been found in the number of receptors or in insulin binding when adding insulin to sulfonylureas [ 241 or when comparing combined therapy with sulfonylureas vs. placebo [ 271, but therapy with insulin alone does reduce receptor number by ‘down-regulation’ [ 151. Using gliclazide as a model, it has been shown that sulphonylureas’ action is exerted at the post-receptor level without affecting receptor number or insulin binding [33-351. In this study we could not identify any parameters that could be used to predict a good response to combined therapy, except that patients who had been on insulin monotherapy for a shorter period of time were those who could reduce their insulin requirement to a greater extent. This is in agreement with a recent study in which patients on insulin for more than 8 years seemed to gain no benefit from the addition of a sulfonylurea [28]. According to the present recommendations for combined therapy when secondary failure to OHA becomes evident, low dose insulin should be started without suspending sulfonylureas and not vice versa (starting sulfonylureas again after insulin monotherapy) [ 361 and the effect of insulin is best seen when added at bedtime [37,38]; in fact, most of our patients ended up using only one small insulin injection at bedtime. C-peptide is used as an indicator of B-cell functional reserve and its levels are usually lower in patients with secondary failure to OHA (nonresponders) when compared with sulfonylurea re-
sponders. Those who benefit from combined therapy seem to have higher basal levels of Cpeptide [28], although recently the contrary has been shown [ 221. Our study and others have been unable to establish a critical value which could be used in clinical practice due to marked individual overlapping [ 391. Positive islet-cell antibodies (ICA, CF-ICA) have been found more frequently among non-responders and this correlates with lower C-peptide levels [ 391. Also, non-responders have higher basal hepatic glucose production and it is less suppressed during the hyperinsulinemiceuglycaemic clamp [40]. In clinical practice, the treatment trial is still the best way to evaluate the response to combined therapy in non-insulindependent diabetic patients with secondary failure to OHA and perhaps should always be tried. It is not recommended for patients who are still obese and/or have diet failures. We also excluded from this study patients who became ketone prone. It is yet to be defined whether the benefits of this type of therapy last long enough, since most of the reported results have concerned less than 1 year of combined treatment. /n conclusim, this study confirms the benefit of sulfonylureas, in this case gliclazide, when combined with insulin in the treatment of noninsulin-dependent diabetic patients with secondary failure to OHA and compared with insulin monotherapy. The benefits were mainly that basal blood glucose levels improved with a marked reduction in insulin requirements, thus avoiding undesirable hyperinsulinization. Such an effect could be due to improvement in insulin secretion and basal hepatic glucose production, which are related to each other. There seems to be no better indicator of good response to this therapy than a treatment trial. Although it was not evaluated in the present study, the effect of gliclazide on thromboxane synthesis and platelet aggregation [ 4 1] could be an additional reason to prefer this sulfonylurea for combined therapy.
29
Acknowledgements We would like to thank the patients who participated in the study and the Institut de Recherches Internationales Servier for their support for the study. Gliclazide (Diamicron) tablets were kindly supplied by A.H. Robins, Colombia.
12
13
14
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nela, D., Cherem, J.J. and Lerario, A.C. (1987) Effect of gliclazide treatment on red blood cell insulin receptors, hepatic glucose production, and peripheral glucose utilization in non-insulin-dependent diabetes mellitus. Bull. IDF 32, 16-21. Ward, G., Harrison, L.C., Proietto, J., Aitken, P. and Nankervis, A. (1985) Gliclazide therapy is associated with potentiation of post-binding insulin action in obese noninsulin-dependent diabetic subjects. Diabetes 34, 241245. Bak. J.L.. Schmitz, O., Hjollund, E., Sorensen, N.S. and Pedersen. 0. (1988) Sulfonylureas enhance in vivo glucose disposal in type 2 (NID) diabetic patients in the presence of unchanged activities of insulin receptor kinase and glycogen synthase in skeletal muscle. Diabetologia 31,467A. Lotz, N., Bachmann, W. and Mehnert, H. (1988) Combination of sulphonylurea and insulin in the long-term treatment of ‘secondary failure’ in type-II diabetes. In: W. Bachmann, N. Lotz and H. Mehnert (Eds.), Insulin/ Sulphonylurea. Combination Therapy in Type-II Diabetes. Karger, Mllnchen, pp. 131-145. Trischitta, V., Italia, S., Borzi, V. et al. (1989) Low-dose bedtime NPH insulin in treatment of secondary failure to glyburide. Diabetes Care 12, 582-585. 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 subpopulation of type II diabetic subjects. Diabetes Care 12, 623-629. Groop, L.C., Pelkonen, R., Koskimies, S., Bottazzo, J.F. and Doniach, D. (1986) Secondary failure to treatment with oral antidiabetic agents in non-insulin-dependent diabetes. Diabetes Care 9, 129-133. Franssila-Kallunki, AI., Schalin, C., Groop, L., Ahola, A. and Widen, E. (1988) Characteristics of treatment failure in patients with type 2 (NID) diabetes. Diabetologia 31. 491A. Florkowski, C.M.. Richardson, M.R., LeGuen, C. et al. (1988) Effect of gliclazide on thromboxane B2, parameters of haemostasis, lipid peroxides and fluorescent IgG in type 2 (NID) diabetes mellitus. Diabetologia 3 1, 490A.
1992 Elsevier Science Publishers
23
B.V. All rights reserved 0168-8227/92/$05.00
DIABET 0067 1
Effects of the combination of insulin and gliclazide compared with insulin alone in type 2 diabetic patients with secondary failure to oral hypoglycemic agents Pablo Aschner
and William Kattah
Colombian Diabetes Association and the Department of Internal Medicine, School of Medicine. Javeriana University. Bogotci. Colombia
(Received 21 March 1992) (Revision accepted 2 May 1992)
Summary Twenty non-insulin-dependent diabetic patients on insulin therapy for more than 2 months due to secondary failure to oral hypoglycemic agents (OHA) were additionally treated with gliclazide, 80 mg b.i.d., for 1 month and 160 mg b.i.d. for a further 2 months, while reducing insulin dose gradually according to glycemic control. At the end of the first month, fasting blood glucose had decreased from 12.8 k 0.7 to 9 t 0.8 mM (mean & standard error; P-c0.005) and thereafter remained stable. Insulin requirements decreased from 34.2 + 2.5 to 18.3 & 3.2 U/day (P
diabetes mellitus; Secondary
Introduction ‘Secondary failure’ to oral hypoglycemic agents (OHA), which eventually can be present in a conCorrespondence
to: P. Aschner, Asociacibn Colombiana Diabetes, Calle 39A No. 14-78, BogotB. Colombia.
de
failure; Gliclazide;
Combined
therapy
siderable number of non-insulin-dependent diabetic patients, is still an ill-defined condition and there is no general agreement as to its treatment. Based on the concept of ‘beta-cell exhaustion’, insulinotherapy is indicated when the patient can no longer be controlled with maximum doses of an OHA. In our Colombian Diabetes Associa-
24
tion, approximately 113, of non-insulin-dependent diabetic patients require insulin permanently. Nevertheless, recent studies show that although insulin secretion deteriorates gradually and this becomes more pronounced as the clinical situation advances, there is still decreased insulin sensitivity mainly in the liver and muscle and all these abnormalities affect each other, especially if hyperglycaemia persists [ l]. Since it was demonstrated that sulfonylureas potentiate insulin action and improve insulin sensitivity in diabetic patients [ 2,3], clinical trials combining them with insulin were reinstated in the treatment of secondary failure to OHA, at the beginning of the present decade [4]. Such combinations of OHA and insulin might, in addition, be expected to decrease insulin requirements, thus avoiding the hyperinsulinemia observed in these patients which has been involved in macroangiopathic complications [ 51. With this aim in mind, we decided to evaluate, in such combinations, the effectiveness of gliclazide, a second generation sulfonylurea which has additionally been shown to present some haemovascular properties. Also, since the results with respect to changes in basal insulin secretion have been equivocal, we designed this trial with emphasis on avoiding exogenous insulin suppression when this effect was evaluated. Materials and Methods Subjects
Twenty non-insulin-dependent diabetic patients who had failed on treatment with maximum doses of OHA (other than gliclazide) were included in the study. Failure was defined as fasting plasma glucose repeatedly above 11.1 mM while at maximal daily dosage of sulfonylurea. They were all on insulin monotherapy for more than 2 months without obtaining optimal control (fasting plasma glucose > 6.4 mM and/or 2 h post-prandial > 10 mM). None of the patients had secondary diabetes or clinical evidence of hepatic, renal or coronary dysfunction. Patients receiving any drug known to affect glucose metabolism were ex-
eluded. None were obese and no evidence of ketosis was present in their records. The clinical data of the patients are shown in Table 1. They all gave informed consent and the investigation was performed in accordance with the principles of the Declaration of Helsinki. Experimental protocol
All patients were followed during 2 months prior to their inclusion in the protocol. During this period their insulin dose was adjusted and if optimal control was not achieved, they were started on combined therapy with the addition of gliclazide. Fasting plasma glucose during insulin monotherapy was used as baseline (T_ J. Diet was kept constant in each patient throughout the study. Before starting (T,,) and at the end of the 3 months’ trial ( T3), insulin was suspended for 36 to 48 h and a fasting blood sample was obtained for measuring blood glucose, glycohaemoglobin (HbA,) and C-peptide. Post-prandial(2 h) blood glucose was also measured after a standard breakfast. Gliclazide (80 mg) tablets were given twice daily during the first month of combined therapy; thereafter the dose was increased to 160 mg twice daily and kept constant for 2 months. Insulin dose was reduced gradually if the patients had hypoglycemic episodes or their fasting blood glucose improved. Insulin dose was mainly adjusted by decreasing the morning dose when the patient was receiving insulin b.i.d. In those patients receiving insulin in a single morning dose, it was first divided (b.i.d.) and then decreased. During the entire study period the patients visited the outpatient clinic every 2-4 weeks or more often if necessary. Monthly evaluations included weight, pulse rate and blood pressure (supine and standing) recordings and fasting and postprandial (2 h) blood glucose measurements, which at the end of the first and second month (T, and Tz) were performed without suspending insulin therapy. Haemogram and urinalysis were also performed monthly; EKG and urine culture were carried out at T, and T3.
25 TABLE
1
Clinical characteristics Sex
4s (years)
of patients at entry to the combined treatment Body mass index (kg/m’)
HbA, (“,A)
Basal C-peptide (nmol/l)
15.0 0.2 0.5 8.0 4.0 4.0 4.0 2.0 9.0 3.0 2.0 8.0 5.0 5.0 3.0 4.0 4.0 4.0 0.2 0.8
28.6 27.1 22.5 24.3 23.9 25.7 25.8 23.3 28.5 26.3 24.7 20.6 23.4 23.9 19.4 26.8 25.6 21.2 21.5 22.5
10.8 13.4 10.9 9.8 8.3 6.9 14.7 11.3 18.7 12.8 12.4 8.2 20.0 14.7 17.0 6.0 9.9 10.9 9.3 10.7
0.10 0.04 0.02 0.18 0.22 0.58 0.16 0.14 0.03 0.36 0.04 0.06 0.61 0.17 0.51 0.17 0.95 0.03 0.43 0.09
4.3 0.8
24.3 0.6
11.8 0.8
0.24 0.06
Duration of diabetes
Duration of insulin therapy
(years)
(years)
F F F F F F F F F F F F F F F M M M M M
44 50 50 53 53 57 58 59 59 60 61 62 65 65 65 55 56 58 59 65
17 10 11 14 32 8 18 11 20 9 10 25 11 11 18 15 20 2.5 7 15
Mean SEM
57.1 1.3
15.4 1.5
Assays
Plasma glucose was measured by a hexokinase method. HbA, concentration in blood was determined by cation exchange microcolumn chromatography (Sigma Diagnostics, USA) and the upper normal limit for our Laboratory is 7.6 %. Serum C-peptide concentration was measured by radioimmunoassay (Diagnostic Products Corporation, CA, USA) and the sensitivity (minimal detectable dose) of the assay was 0.016 nmol/l. Statistical analysis
All data are expressed as mean k SEM. The significance of difference between treatments was tested with a two-tailed paired t-test using a computer program. Correlations were tested by linear regression analysis.
Results Glycaemic control and insulin requirements
The mean fasting blood glucose at the end of the insulin treatment period (T_ i) was 12.8 + 0.7 mM and after the first month of combined treatment there was a significant reduction of approximately 29.5% (to 9+ 0.8 mM; P~O.005) (Table 2). When the gliclazide dose was doubled, no further improvement was observed, but insulin dose could be reduced from 34.2k2.5 U/day at T,, to 2l.lk2.8 U/day at T2 and 18.3 k 3.2 U/day at T3 (P
26 TABLE 2 Glycaemic control and insulin requirements during insulin monotherapy (T_ ,) and throughout the combined treatment with insulin and gliclazide (GCZ) which lasted 3 months. Starting this treatment (To), insulin was suspended for 36 to 48 h. At the end of the first month (T,) patients were on insulin plus 160 mg/day GCZ. At the end of the second month (T?) patients were on insulin plus 320 mg/day GCZ. At the end of the third month they were still on 320 mg/day GCZ. but insulin was again suspended for 36 to 48 h.
T -I
Tu
T,
Fasting plasma glucose (mM) Mean 12.8 14.5 SEM 0.7 0.8 Post-prandial Mean SEM
9.0” 0.8
(2 h) plasma glucose (mM) 16.9 11.8 0.9 0.8
Insulin requirement (units/day) Mean 34.2 SEM 2.5
28.0’ 2.7
T2
T3
9.5 0.8
11.8h 1.0
12.8 0.8
15.1 0.8
2l.ld 2.8
18.3’
..3'
aP-cO.005 vs.T_ ,;b P
0 r’. Insulin required l
Wkgl 0.6.
l
pc 0.001
T
TO
T3
Fig. 1. Daily insulin requirements (units per kg of body weight) at the beginning (To) and after 3 months of combined treatment (T3)expressed as mean + SEM.
end of the combined treatment are compared, expressed as units per kilogram body weight. Before the trial, nine patients received a single dose before breakfast and 11 patients received insulin twice a day (also at bedtime). Only one in each group received a combination of NPH and regular insulin. The rest received NPH only. At the end of the trial, two patients were still receiving insulin twice a day and six patients were receiving a single dose before breakfast. Nine patients were only receiving a single dose at bedtime. All used NPH only. When insulin doses were compared separately (a.m. and p.m.) before (T,,) and at the end of the trial (T3), no statistical difference was found in the evening dose (5.4-~ 1.4 vs. 7.1 + 1.7 units), while in the morning dose there was a very significant reduction (26.3 t 1.9 vs. 11.2 5 3.3 units, P
27
increase (0.24 + 0.06 vs. 0.39 k 0.10 nmol/l), but heterogeneity was still present. The change in Cpeptide correlated with the change in basal blood glucose at the end of the study (Y= 0.52; PC 0.05). Since insulin was stopped 36 to 48 h prior to blood measurements at T,, and T,, we assume that basal C-peptide levels will depend on the corresponding blood glucose, which would act as a stimulus. Accordingly, we calculated a Cpeptide/glucose score, defined as fasting Cpeptide/BG x 100, and a significant difference was found between mean scores at T, and T3 (0.11+0.03 vs. 0.21+0.05, P
Discussion Only a minority of our patients normalized their fasting blood glucose levels (20x), but most were able to keep them below 10 mM. Although HbA, was not significantly different, the final fasting blood glucose levels were lower with a marked reduction in insulin requirement. Since only a minority normalized their fasting blood glucose and the change in post-prandial blood glucose did not reach a significant level, we believe that more time would be needed to observe a significant decrease in HbA,. Reduction of insulin requirement is a constant finding in most studies where combination therapy has been explored and it ranges from 25 to 50% [6-221. This sole fact justifies this treatment if we consider that patients with secondary failure to OHA frequently require hyperinsulinization to obtain good control and that seems to be atherogenic [ 51. How sulfonylureas improve insulin action is not clear. The effects of sulfonylureas in this respect can be summarized as follows: (1) increase
of islet B-cell sensitivity to glucose, (2) increase of plasma insulin levels, (3) reduction of hepatic insulin extraction, (4) reduction of basal hepatic glucose production, (5) potentiation of the effect of insulin on hepatic glucose production, (6) potentiation of insulin-stimulated glucose utilization
1211. Effects 1 and 2 have been explored mainly by measuring basal C-peptide or after stimulation by glucagon or a mixed meal. In most of the studies, no increase in C-peptide has been demonstrated after combined therapy [ 10,14- 16,24-261. Only a few studies have observed an improvement in B-cell function and mainly after stimulation of C-peptide measured in blood [ 9,12,27,28] or urine [22]. In the present study, only basal C-peptide was evaluated and although the response to combined therapy was mixed, in at least half of the patients it increased, including in some who had low initial values. C-peptide was measured under a hyperglycaemic milieu (endogenous stimulus) and exogenous insulin suppression was excluded by suspending it for a sufficient period of time. Under such conditions, we believe that the Cpeptide/glucose score would be a better indicator of P-cell response and, in fact, it increased significantly after combined treatment. This score has been shown to be better than C-peptide alone in predicting secondary failure to oral agents [29]. Insulin therapy suppresses C-peptide production (hence endogenous insulin secretion) by up to 50 % [ 301 and this is minimized when a sulfonylurea is added and insulin dose reduced, allowing the use of endogenous insulin on demand. The increased response of B-cells could also be attributed to a greater potency of gliclazide. Its potent and lasting effect on phases 1 and 2 of insulin secretion has been demonstrated [31,32] but it would be necessary to compare gliclazide with other second-generation sulfonylureas since they are also potent at this level. Effects 3 to 6 refer to peripheral actions of sulfonylureas. The fact that combined therapy improved basal blood glucose levels with insignificant effects on post-prandial values suggests that it is due mainly to a reduction in hepatic
28
glucose production since it correlates directly with fasting plasma glucose [ 141. This could be explained by an increase in the endogenous insulin available in the portal vein when combined therapy is used, since the liver is very sensitive to small changes at that level. The peripheral action has also been evaluated using a hyperinsulinemiceuglycaemic clamp: some have found an increase in glucose metabolic clearance, and therefore in insulin sensitivity, during combined therapy [7,8,10,25,26], but others have not [9,12]. Such improvement seems to be evident only when patients are under excellent control and can be observed also on diet alone or when using intensive insulin therapy [ 121. No change has been found in the number of receptors or in insulin binding when adding insulin to sulfonylureas [ 241 or when comparing combined therapy with sulfonylureas vs. placebo [ 271, but therapy with insulin alone does reduce receptor number by ‘down-regulation’ [ 151. Using gliclazide as a model, it has been shown that sulphonylureas’ action is exerted at the post-receptor level without affecting receptor number or insulin binding [33-351. In this study we could not identify any parameters that could be used to predict a good response to combined therapy, except that patients who had been on insulin monotherapy for a shorter period of time were those who could reduce their insulin requirement to a greater extent. This is in agreement with a recent study in which patients on insulin for more than 8 years seemed to gain no benefit from the addition of a sulfonylurea [28]. According to the present recommendations for combined therapy when secondary failure to OHA becomes evident, low dose insulin should be started without suspending sulfonylureas and not vice versa (starting sulfonylureas again after insulin monotherapy) [ 361 and the effect of insulin is best seen when added at bedtime [37,38]; in fact, most of our patients ended up using only one small insulin injection at bedtime. C-peptide is used as an indicator of B-cell functional reserve and its levels are usually lower in patients with secondary failure to OHA (nonresponders) when compared with sulfonylurea re-
sponders. Those who benefit from combined therapy seem to have higher basal levels of Cpeptide [28], although recently the contrary has been shown [ 221. Our study and others have been unable to establish a critical value which could be used in clinical practice due to marked individual overlapping [ 391. Positive islet-cell antibodies (ICA, CF-ICA) have been found more frequently among non-responders and this correlates with lower C-peptide levels [ 391. Also, non-responders have higher basal hepatic glucose production and it is less suppressed during the hyperinsulinemiceuglycaemic clamp [40]. In clinical practice, the treatment trial is still the best way to evaluate the response to combined therapy in non-insulindependent diabetic patients with secondary failure to OHA and perhaps should always be tried. It is not recommended for patients who are still obese and/or have diet failures. We also excluded from this study patients who became ketone prone. It is yet to be defined whether the benefits of this type of therapy last long enough, since most of the reported results have concerned less than 1 year of combined treatment. /n conclusim, this study confirms the benefit of sulfonylureas, in this case gliclazide, when combined with insulin in the treatment of noninsulin-dependent diabetic patients with secondary failure to OHA and compared with insulin monotherapy. The benefits were mainly that basal blood glucose levels improved with a marked reduction in insulin requirements, thus avoiding undesirable hyperinsulinization. Such an effect could be due to improvement in insulin secretion and basal hepatic glucose production, which are related to each other. There seems to be no better indicator of good response to this therapy than a treatment trial. Although it was not evaluated in the present study, the effect of gliclazide on thromboxane synthesis and platelet aggregation [ 4 1] could be an additional reason to prefer this sulfonylurea for combined therapy.
29
Acknowledgements We would like to thank the patients who participated in the study and the Institut de Recherches Internationales Servier for their support for the study. Gliclazide (Diamicron) tablets were kindly supplied by A.H. Robins, Colombia.
12
13
14
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