Insulin plus a Sulfonylurea Agent for Treating Type 2 Diabetes Anne L. Peters, MD, and Mayer B. Davidson, MD
• Purpose: To review the recent literature on the efficacy of combined insulin and sulfonylurea therapy in patients with type 2 diabetes. • Data Sources: Pertinent articles were obtained through an English-language MEDLINE search from 1979 to 1990 and from the references of these articles. • Study Selection: We reviewed the studies in which patients with poorly controlled diabetes received insulin and a sulfonylurea agent and in which insulin treatment alone (usually given in conjunction with a placebo) was compared with insulin plus sulfonylurea therapy. • Data Extraction: Pre- and post-treatment insulin doses, blood glucose levels, glycated hemoglobin values, C-peptide levels, and insulin levels were analyzed. Other data were analyzed separately. • Results of Data Synthesis: Data from similar trials were compared. Data from concurrent trials were analyzed separately from data derived from cross-over trials. Weighted mean fasting blood glucose levels, glycated hemoglobin levels, insulin dosage, and fasting C-peptide concentrations were determined for insulin plus placebo and insulin plus sulfonylurea agent groups for both types of studies. In concurrent trials, the weighted mean post-treatment glycated hemoglobin level was 11.1% after insulin plus placebo compared with 10.0% after insulin plus a sulfonylurea agent. In cross-over trials, the corresponding values were 10.6% and 9.8%. • Conclusions: Combination therapy with insulin and a sulfonylurea agent only slightly improved glycemic control in patients with type 2 diabetes. When a sulfonylurea agent was used, less exogenous insulin was needed, but fasting serum insulin levels were not different between the treatment groups. Such therapy did not produce nearly normal blood glucose concentrations and therefore should not be used in patients with poorly controlled type 2 diabetes receiving insulin.
1 ype 2 diabetes can be difficult to treat adequately. An increasing amount of data confirms the need to maintain nearly normal blood glucose concentrations to avoid the long-term complications of diabetes (1); however, achieving nearly normal blood sugar levels is often an elusive goal. Treatment of type 2 diabetes should begin with diet therapy, which, if unsuccessful (often the case), should be followed by sulfonylurea agent therapy. Although recent data from controlled trials on the rate of failure with secondary sulfonylurea agent therapy are unavailable, an estimated 5% to 10% of patients receiving sulfonylurea agents cease to respond adequately to these drugs each year (2). After 10 years, only 50% of patients who initially responded to sulfonylurea agents continue to respond adequately. In the United States, initiating insulin therapy is the only option for improving glycemic control in patients for whom therapy with maximal doses of sulfonylurea agents has failed. Type 2 diabetes is characterized by insulin resistance (3). Patients receiving conventional doses of insulin therefore often do not achieve nearly normal blood glucose concentrations. In these patients, using insulin plus a sulfonylurea agent has been proposed to help to maximize endogenous insulin secretion and to enhance the response to both endogenous and exogenous insulin. We review the literature on the use of insulin plus sulfonylurea agents. Although many of the studies were flawed, the data allow some conclusions about the benefits and drawbacks of using this form of therapy to be drawn. The combined use of insulin and sulfonylurea agents was first investigated in the 1950s but was not used widely in clinical practice for the next 20 years (4-6). In the 1980s, studies evaluating the efficacy of combined therapy were conducted. The rationale for using this form of treatment is twofold: First, sulfonylurea agents are postulated to improve diabetic control through their pancreatic and extrapancreatic effects (see below). Second, using combined therapy is postulated to decrease the exogenous insulin requirement, producing less peripheral hyperinsulinemia. This effect may be beneficial; some evidence suggests that hyperinsulinemia may be atherogenic (7). Mechanism of Action of Sulfonylurea Agents
Annals of Internal Medicine. 1991;115:45-53. From the Cedars-Sinai Medical Center, Los Angeles, California. For current author addresses, see end of text.
Sulfonylurea agents enhance the pancreatic beta cells' ability to secrete insulin, and they decrease peripheral insulin resistance by ameliorating some, as yet undefined, post-receptor defect (2). Studies done to evaluate insulin levels after sulfonylurea agent therapy have yielded varying results (8-15). Chlorpropamide increased insulin levels acutely, but insulin levels returned to pretreatment levels with chronic use (8, 9). In ©1991 American College of Physicians
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Table 1. Study Design in Concurrent Trials* Investigators (Reference)
Study Period
Number of Patients Insulin Insulin plus plus SA Placebo
Type of SA
Dosage ofSA
Insulin plus Placebo
wk Osei et al. (28) Bieger et al. (29) Gutniak et al. (30) Reich et al. (31) Lins et al. (32) Casner (33) Mauerhoff et al. (34) Quatraro et al. (35) Weighted mean
Aget
mgld
Insulin plus SA
Duration of Diabetest Insulin plus Placebo
11 9 10 10 10 15
6 10 10 9§ 10 22
Glyburide Glyburide Glyburide Glyburide Glyburide Glyburide
20$ 12.5|| 7.0$ 19.9||
56 63 58 57 60 60
16
11
11
Glyburide
10.5$
59 ± 4
62 ± 2
52 15 15 Gliclazide 40-240 57 ± 2 27 ± 6.9t 11 ± 0 . 8 t 12 ± 3t
56 ± 2
± ± ± ± ± ±
1 9 2 4 3 0.1
Insulin plus S A
y
y
16 6 46 16 12 52
m 10.5$
Percentage of Ideal Body Weightt Insulin Insulin plus plus SA Placebo
59 60 56 59 67 56
± ± ± ± ± ±
3 7 2 3 2 0.1
128 ± 5 103 ± 16 114 ± 6 114 ± 6 105 ± 2 3111
129 118 121 110 104
115 ± 3
129 ± 2
29 ± 111
± 6 ± 17 ± 7 ±4 ± 3
3011
13 ± 2
15 16 10 9 11
12 ± 1
±6 17 ± 5 ± 4 12 ± 3 ± 3 9 ± 3 ± 2 8 ± 1 ± 0.1 14 ± 0.1
10 ± 2
11 ± 2
29 ± 111 12 ± 1
12 ± 1
* SA = sulfonylurea agent. t Percentage of ideal body weight except where noted. Data are presented as means ± SE. $ Fixed dosage. § In three patients in the insulin plus sulfonylurea group, insulin therapy was discontinued. || Mean dosage. 1 Body mass index (kg/m2). most studies, glyburide increased meal-stimulated insulin levels, both acutely and chronically (10-12). In a study with one of the longest follow-up periods (12 months) (13), however, insulin levels that were higher than pretreatment levels at 3 months were returning to baseline values at 12 months, particularly in patients who were responding to the drug. Gliclazide (14) (not available in the United
States) and glipizide (15) raised fasting and meal-stimulated insulin values with chronic use. In studies in which insulin concentrations were found eventually to return to pretreatment levels, beta-cell responsiveness was still enhanced, as illustrated by the return of insulin levels to pretreatment values but with blood glucose levels lower than before treatment. Pancreatic beta cells therefore may be sensitized by these drugs and thus are able to secrete similar amounts of insulin after as before therapy, but at lower glucose levels. Studies in which nonglucose secretagogues, such as arginine and isoproterenol, were used to stimulate insulin secretion have provided evidence supporting this theory (16, 17). The insulin response to these agents was similar before and after treatment with a sulfonylurea agent, but blood glucose values were much lower after than before treatment. When blood glucose levels were artificially raised to pretreatment values and stimuli were applied, the insulin response was markedly higher than the values seen before sulfonylurea agent therapy. In-vitro (18-21) and in-vivo (13, 22-25) evidence indicates that sulfonylurea agents potentiate the action of insulin. This phenomenon is seen in both peripheral (13, 18-25) and hepatic tissues (13, 23-25), and it does not seem to result from an enhancement of insulin binding (discussed in reference 26). Rather, the drugs seem to work at a site distal to the site where insulin binds to its plasma membrane receptor; the post-binding site where these drugs work is also the site of the insulin antagonism in type 2 diabetes (27). Methods
Figure 1. Mean fasting blood glucose levels. Data were obtained at the end of the treatment phase (placebo plus insulin or a sulfonylurea agent plus insulin) in each study. References 28 through 34 were concurrent studies; 36 through 49 were crossover studies {see text for definitions). 46
A computerized literature search using MEDLINE was done to find all relevant studies reported from 1976 to 1990. References that included the key words *"insulin" and ''sulfonylurea agents" were retrieved. Additional pertinent articles were obtained from the references of these articles. A manual search of the Index Me die us from 1986 to 1990 was done. Finally, one of the investigator's (MBD) extensive files on the diabetes
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literature were searched, and all relevant articles were reviewed. Eligible studies met the following criteria. Study patients had type 2 diabetes and either had unsatisfactory blood glucose control with insulin (most of the studies) or had begun insulin therapy during the initial phase of the study. Studies were done in either a concurrent or cross-over fashion. In concurrent studies (28-35), patients were randomly assigned to receive a sulfonylurea agent plus insulin or placebo plus insulin, and the responses of these treatment groups were compared. In cross-over studies (36-49), patients first were randomly assigned to receive one treatment (either placebo plus insulin or a sulfonylurea agent plus insulin). After a specified interval, they switched to the other form of treatment. Most of these trials did not have a "washout'' period between the two study phases. In cross-over studies, patients are compared with themselves. The studies in which the patients' responses to insulin plus a sulfonylurea agent are compared with their previous responses to insulin alone therefore are included in this category (36, 45, 46). Eligible concurrent studies provided mean pre- and posttherapy fasting blood glucose values, glycated hemoglobin levels, or both. In eligible studies, a group of patients receiving placebo plus insulin therapy was compared with a group receiving sulfonylurea agent plus insulin therapy. Eligible crossover trials had either a baseline period with insulin therapy alone (without sulfonylurea agent therapy) or a placebo plus insulin therapy phase for comparison with the sulfonylurea agent plus insulin therapy phase. Mean fasting blood glucose values or glycated hemoglobin levels had to be available for comparison from the end of the placebo (or baseline) arm and from the end of the treatment arm of the trial. If available, other data, including data on changes in total daily insulin dosage and C-peptide and insulin levels, were extracted from the articles. Results One investigator (ALP) extracted all of the data from the articles. Tables 1 (concurrent trials) and 2 (crossover trials) outline the basic design of each study. The Appendix describes the method used for calculating the
weighted means and weighted variance. The weighted mean pre- and post-treatment fasting blood glucose concentrations, glycated hemoglobin values, and total daily insulin dosage were calculated using data from all studies (Tables 3 and 4). Because not all studies provided these data, Tables 3 and 4 indicate which studies were used for each analysis. Weighted mean fasting C-peptide levels were also calculated (Tables 5 and 6).
Data from Clinical Trials Concurrent Trials Glyburide was used in all but one concurrent study; maximal doses (20 mg) were used in only two (Table 1). The studies lasted from 6 to 52 weeks, and the size of study samples varied. In general, half of the patients were randomly assigned to receive insulin plus an active sulfonylurea agent, and half were randomly assigned to receive insulin plus a placebo. Overall, 91 patients in the insulin plus placebo group and 93 patients in the insulin plus sulfonylurea group were studied in concurrent trials, and they were followed for an average of 27 weeks. Values obtained before and after treatment are shown for each group in Table 3 and Figures 1 and 2. For patients in the insulin plus placebo group, the weighted mean fasting blood glucose level was 11.6 mmol/L (209 mg/dL) before and 10.7 mmol/L (193 mg/dL) after treatment. For those in the insulin plus sulfonylurea group, the weighted mean fasting blood glucose level was 11.3 mmol/L (204 mg/dL) before and 9.4 mmol/L (169 mg/dL) after treatment. Weighted mean pre- and post-treatment glycated hemoglobin values were 10.8% and 11.1%, respectively, in the insulin plus placebo group and 10.7% and 10.0%, respectively, in the insulin plus sulfonylurea group. In all of the
Table 2. Study Design in Cross-over Trials* Investigators (Reference)
Duration of Number of Therapy Patients
Type of SA
wk Simonson et al. (36)$ Longnecker et al. (37) Kitabchi et al. (38) Holman et al. (39) Castillo et al. (40) Schade et al. (41) Stenman et al. (42) Lewitt et al. (43) Kyllastinen and Groop (44) Lardinois et al. (45)$ Allen et al. (46)$ Groop et al. (47) Groop et al. (48) Riddle et al. (49) Weighted meanH
8 8 12
8 11 12
8 6 16 16 12 8 12 8-40 8 8 16 10.6 ±1.0
15 10 16 15 29 9 14 6 13 13 20 14 ± 1.5
Dosage of SA
Age
mgld
y
Glyburide 20 Tolazamide 500 Tolazamide 1000 Chlorpropamide, glyburide, or tolbutamide Dosage varied Glipizide 30 Glyburide 15 Glyburide 20 Glyburide 15 Glyburide 10 Glyburide 20 Glipizide 30|| Glyburide 10 Glyburide 8 Glyburide 10
Percentage Duration of of Ideal Diabetes Body Weightt y
57 ± 3 62 ± 2 51 ± 3
131±4 147 ± 7 172 ±17
15±3 12 ± 2 10 ± 1
57 ± 11 55 ± 4 51 ± 3 58 ± 2 67 ± 5 73 ± 2 50 54 ± 4 56 ± 1 52 ± 3 61 ± 2
128 ± 36 100 ± 3 132 ± 6 24 ± 1§ 27 ± 3§ 32 ± 1§ 28§ 164 ± 7 123 ± 5 109 ± 3 124 ± 3
8±7 9±3 10 ± 1 10 ± 1 NA 11 ± 1 10 ± 2 14 ± 4 8±1 8±2 6±1
* SA = sulfonylurea agent. The sulfonylurea agent dosage was fixed in all studies, except as noted. NA = not available. t Data are presented as means ± SE. Percentage of ideal body weight except where noted. % A sulfonylurea agent was given to patients who were initially receiving insulin therapy only. Data obtained with combined therapy were compared with data previously obtained with insulin therapy alone. § Body mass index (kg/m2). || Mean dosage (range, 7.5 to 40 mg/d). 11 Data from the 13 cross-over trials were used to calculate the mean. The study results reported in reference 46 were not used.
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Table 3. Glycemic Control and Insulin Dosage in Concurrent Trials* Investigators (Reference)
Fasting Blood Glue ose Concentration Insulin plus Placebo Insulin plus SA Before After After Before Treatment Treatment Treatment Treatment
Glycated Hemoglobin Level Insulin pi us Placebo Insulin p lus SA After After Before Before Treatment Treatment Treatment Treatment
mmollL
* SA = sulfonylurea agent; U = units; NA = not available. t Mean of blood glucose concentrations obtained throughout the day. $ Units per kilogram body weight over a 24-hour period. § The study results reported in references 29 and 35 were not averaged, because these data were not fasting blood glucose values. || The study results reported in references 32 and 34 were not averaged, because these data were not given in units per 24 hours.
studies in which insulin dosage varied, it was lower at the end of the trial in the insulin plus sulfonylurea group than in the insulin plus placebo group. Cross-over Trials In cross-over trials, 191 patients were studied, with an average duration of 10.6 weeks per study arm (Table 2). As in the concurrent trials, the blood glucose concentrations of most of the patients were inadequately controlled with insulin. Because cross-over trials do not
provide pre- and post-treatment data for each treatment arm and generally do not have a washout phase between study arms, values are given for the end of each treatment arm only (Table 4) (Figures 1 and 2). Because each patient receives both treatments, the difference between values obtained at the end of the placebo phase and those obtained at the end of the sulfonylurea phase defines the sulfonylurea agent's effect. In these studies, the weighted mean fasting blood glucose concentration was 11.0 mmol/L (198 mg/dL) after the placebo phase and 9.0 mmol/L (162 mg/dL) after the sulfonylurea
Table 4. Glycemic Control and Insulin Dosage in Cross-o ver Trials* Investigators (Reference)
Simonson et al. (36)$ Longnecker et al. (37) Kitabchi et al. (38) Holmanetal. (39) Castillo et al. (40) Schade et al. (41) Stenman et al. (42) Lewittetal. (43) Kyllastinen and Groop (44) Lardinois et al. (45)$ Allen et al. (46)$ Groop et al. (47) Groop et al. (48) Riddle et al. (49) Number of patients Weighted mean ± SE
Fasting Blood Glucose Concentration! Insulin plus Insulin plus Placebo SA mmollL 6.9 14.9 9.3§ 5.1 NA 14.6 9.6 10.1 16.4 13.9 14.3 10.8 8.0 11.1 16911 11.0 ± 0.7
Insulin Dosage
Glycated Hemoglobin Level Insulin plus SA
Insulin plus Placebo
%
6.2 12.3 9.3 5.2 NA 12.9 7.9 7.8 11.8 10.8 9.7 10.7 7.0 8.0
10.3 12.8 9.2 10.1 8.2 10.9 9.0 10.3 14.1 8.4 NA 13.2 11.4 10.6
8.0 12.6 8.8 9.5 7.9 10.2 8.3 9.1 12.4 7.3 NA 13.4 11.0 9.8
9.0 ± 0.4
185 10.6 ± 0.3
9.8 ± 0.3
Insulin plus Insulin plus Si\ Placebo VI24h 72 Fixed 0.89|| 40 0.50|| 55 32 47 Fixed Fixed 67 Fixed 38 46 122 48 ± 5.3
58 dose 0.69 25 0.43 54 24 44 dose dose 61 dose 37 36 41 ± 5.7
* SA = sulfonylurea agent; NA = not available. t The result at end of therapy with either insulin and placebo or insulin and sulfonylurea agent. X A sulfonylurea agent was given to patients who were initially receiving insulin therapy only. Data obtained with combined therapy were compared with data previously obtained with insulin therapy alone. § Mean of blood glucose concentrations obtained throughout the day. || Units per kilogram of body weight over a 24-hour period. 11 The study results reported in reference 38 were not averaged, because these data were not fasting blood glucose values.
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Table 3. (Co ntinued) Insulin Dosage Insulin pliis Placebo Insulin r.>lus SA Before After Before After Treatment Treatment Treatment Treatment < > U/2>4h Fixed dose 30 28 62 55 48 38 0.42$ 0.42 67 79 0.44$ 0.46 88 85 59|| 63 ± 3.6
62 ± 3.7
Fixed d ose 46 63 36 0.45 66 0.50 90 66 64 ±4.8
40 35 20 0.30 62 0.46 57 48 ± 3.7
phase. The weighted mean glycated hemoglobin values were 10.6% and 9.8% after the placebo and sulfonylurea phases, respectively. As in the concurrent trials, in virtually all cross-over studies in which insulin dosage varied, the amount used was less in the insulin plus sulfonylurea phase than in the insulin plus placebo phase of the study.
Responders and Nonresponders In some of the studies, combined therapy produced nearly normal blood glucose concentrations in a few, but not in most, patients. In nine of the studies, predictors of a response to combined therapy were sought. In four studies, glycemic control was most improved in the patients who initially had the worst glycemic control and the greatest degree of obesity (29, 33, 43, 45). In one of these studies, responders had been receiving insulin for a shorter duration than had nonresponders (5 compared with 14 years), had a higher initial fasting C-peptide level (1.1 nmol/L compared with 0.4 nmol/L [3.2 ng/mL compared with 1.3 ng/mL]), and were heavier (body mass index [kg body weight/m2 body surface area] of 28.1 compared with 26.4) (43). In another study, higher basal C-peptide values were also found in responders (33). In four other studies in which responders were compared with nonresponders, however, the same baseline clinical characteristics (initial glycemic control, degree of obesity, fasting C-peptide levels) did not differ between the two groups (35, 40, 46, 49). In one small study, the two patients with the highest initial fasting blood glucose values were nonresponders (37). Thus, predicting which patients will respond clinically is difficult.
6). In general, both fasting and stimulated C-peptide levels were higher after combined therapy. This finding is consistent with evidence that sulfonylurea agents act, in part, by enhancing insulin secretion. Various approaches have been used to evaluate the effect of combined insulin and sulfonylurea therapy on insulin action. In several studies, the effects of combined therapy on insulin binding to erythrocytes or monocytes (or both) were measured, and essentially no difference was shown between treatment groups (41, 47, 48). Responders to the sulfonylurea agent were not evaluated separately from nonresponders. Insulin tolerance was tested in two studies (46, 47). In one study, patients were not classified as responders or nonresponders, and no correlation between changes in the response to an insulin tolerance test and changes in the glycated hemoglobin concentration was found (46). In the other study, the response to the insulin tolerance test improved in patients who responded to combination therapy and did not improve in other patients (47). In two studies in which glucose clamp techniques were used, the glucose metabolic clearance rate was found to improve, reflecting enhanced peripheral sensitivity to insulin. In one, the glucose metabolic clearance rate increased substantially in responders to combined therapy and increased little in nonresponders (40). In the other, improvement in the day-long postprandial glucose response correlated with an increase in the glucose metabolic clearance rate (45). In two other studies in which glucose clamp techniques were used, however, no difference was found between patients receiving in-
Mechanism of Action of Combined Therapy Many researchers have investigated how combined insulin and sulfonylurea agent therapy might better control blood glucose levels. In 18 studies, basal C-peptide levels were measured, and, in many, stimulated C-peptide values were examined. C-peptide levels were measured after the administration of various stimuli, including glucose, glucagon, and mixed meals (Tables 5 and
Figure 2. Mean glycated hemoglobin values. Data were obtained at the end of the treatment phase (placebo plus insulin or a sulfonylurea agent plus insulin) in each study. References 28 through 35 were concurrent studies; 36 through 49 were crossover studies (see text for definitions).
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Table 5. C-Peptide Levels in Concurrent Trials* Investigators (Reference)
Stimulated C-Peptide Levels Insulin plus SA Insulin plus Placebo After Before After Before Treatment Treatment Treatment Treatment
Fasting C-Peptide Levels Insulin plus Placebo Insulin plus SA Before After After Before Treatment Treatment Treatment Treatment
< Osei et al. (28) Gutniak et al. (30) Lins et al. (32) Casner (33) Mauerhoff et al. (34) Quatraro et al. (35) Number of patients Weighted mean ± SE
>
mmollL 0.3 0.3
0.3 0.2
0.5 0.3
0.7 0.3
0.4 1.1 0.3 NA
0.5 1.0 0.3 NA
0.4 1.2 0.5 NA
0.6 1.4 0.6 NA
57 0.53 ± 0.06
0.48 ± 0.04
59 0.71 ± 0.08
0.86 ± 0.08
62.7t 6.3* 7.0§ 0.6|| NA 0.5|| 8.21
67.6t 5.2* 9.6§ 0.7|| NA 0.5|| 9.211
128.7t 5.5* 5.9§ 0.8|| NA 0.8|| 7.311
130.4t 5.5* 22.8§ 1.2|| NA 1.5|| 22.411
* SA = sulfonylurea agent. NA = not available. t C-peptide area-under-the-curve after an oral glucose tolerance test (measured in nanomoles per litre during subsequent 180-minute period). * C-peptide area-under-the-curve after receiving 1 mg of intravenous glucagon (measured in nanomoles per litre during subsequent 15-minute period). § C-peptide incremental area-under-the-curve after a mixed meal (measured in nanomoles per litre during subsequent 150-minute period). || C-peptide concentration 120 minutes after a mixed meal (measured in nanomoles per litre). 11 C-peptide incremental area-under-the-curve after receiving intramuscular glucagon (measured in nanomoles per litre during subsequent 120-minute period).
sulin alone and patients receiving insulin plus a sulfonylurea agent (30, 36). In neither study were differences between responders and nonresponders evaluated. The investigators in one of the studies examined various measures, including basal hepatic glucose output, insulin sensitivity, as measured by a two-step insulin clamp,
total glucose metabolism, glucose and lipid oxidation and nonoxidative metabolism, and found no difference between the treatment groups (36). We think that enhanced endogenous insulin secretion (as indicated by C-peptide levels) is probably the major mechanism by which combined insulin and sulfonylurea therapy im-
Table 6. C-Peptide Levels in Cross-over Trials* Investigators (Reference)
Fasting C-Pe ptide Levels! Insulin plus SA
Insulin plus Placebo
Meal-Stimulated C-Peptide Levels Insulin plus Insulin plus Placebo SA
mmollL Simonson et al. (36) Longnecker et al. (37) Kitabchi et al. (38) Holman et al. (39) Castillo et al. (40) Schade et al. (41) S t e n m a n e t a l . (42)
0.1 0.1 NA 0.03 0.3** 0.1 ft 0.6 0.16
0.3 0.3 NA 0.3 0.4 0.1 0.6 0.21
Lewitt et al. (43) Kyllastinen and Groop (44) Lardinois et al. (45) Allen et al. (46) Groop et al. (47) Groop et al. (48) Riddle et al. (49)
0.7 0.8 0.5 0.4 0.4 0.4 0.5
0.9 0.9 0.7 0.5 0.4 0.6 0.6
Number of patients Weighted mean ± SE
179 0.41 ± 0.1
0.53 ± 0.2
0.2$ 53.8§ 0.5|| 0.11 0.5$** 0.2tt 39.9M 0.3§§ 0.3IHI NA 1.1§§ *** 0.411 *** 0.6* 0.8ttt
0.4$ 94.7§ 0.6|| 0.411 0.6*** 0.2tt 50.8M 0.3§§ 0.4|||| NA 1.2§§ Increased*** 0.5111 Increased*** 0.8$ l.Ottt
* SA = sulfonylurea agent. NA = not available. t The result obtained at the end of therapy with either insulin and placebo or insulin and a sulfonylurea agent. X C-peptide concentration 5 minutes after receiving 1 mg of intravenous glucagon (measured in nanomoles per litre). § C-peptide area-under-the-curve after a mixed meal (measured in nanomoles per litre during subsequent 180-minute period). || C-peptide concentration 120 minutes after a mixed meal (measured in nanomoles per litre). 11 Geometric mean C-peptide level over 24 hours (measured in nanomoles per litre). ** "Responders" (hemoglobin A,C decreased). tt "Nonresponders" (no change in hemoglobin A,C). %% C-peptide area-under-the-curve after an oral glucose tolerance test (measured in nanomoles per litre during subsequent 180-minute period). §§ C-peptide concentration 6 minutes after receiving 1 mg of intravenous glucagon (measured in nanomoles per litre). Illl Mean C-peptide concentration 180 minutes after a mixed meal (measured in nanomoles per litre). HH C-peptide concentration 120 minutes after an oral glucose tolerance test (measured in nanomoles per litre). *** C-peptide levels increased throughout the day in patients receiving combined therapy compared with insulin plus placebo. ttt C-peptide concentration 60 minutes after a mixed meal (measured in nanomoles per litre). 50
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Table 7. Insulin Levels in Concurrent and Cross-over Trials* Investigators (Reference)
Stimulated Insulin Levels
Fasting Insulin Levels Insulin plus Placebo
Insulin plus
Insulin plus Placebo
Insulin plus
SA
292 before, 184 after treatment
214 before, 214 after treatment
58 781 before, 48 607 after treatmentt
86 688 before, 42 926 after treatmentt
-28
NA 96§ 42 216 238
NA 96 63 202 238
382* 188|| 293011 396** No changett
360$ 173|| 478811 331** No changett
-14 -15 -1 -8 Fixed
SA
pmollL Concurrent trials Gutniak et al. (30)
Change in Insulin Dosage after Addition
Cross-over trials Simonson et al. (36) Holman et al. (39) Schadeetal. (41) Stenman et al. (42) Groop et al. (47)
ofSA U
* SA = sulfonylurea agent. For cross-over trials, data were obtained at the end of therapy with either insulin and placebo or insulin and a sulfonylurea agent. t Insulin incremental area-under-the-curve after a mixed meal (measured in picomoles per litre during the subsequent 150-minute period). X Mean plasma insulin concentration (measured in picomoles per litre over a 24-hour period). § Geometric mean fasting insulin concentration (measured in picomoles per litre). || Geometric mean insulin concentration after a mixed meal (measured in picomoles per litre during the subsequent 180-minute period). 11 Insulin area-under-the-curve after an oral glucose tolerance test (measured in picomoles per litre during the subsequent 180-minute period). ** Mean insulin concentration after a mixed meal (measured in picomoles per litre during subsequent 120-minute period). t t No difference in insulin levels during 18-h meal profile between combined therapy and insulin plus placebo.
proves control and that effects on peripheral insulin action are less important.
ilar in patients treated with either exogenous insulin or tolazamide (53, 54).
Peripheral Insulin Levels
Costs of Combined Therapy
Peripheral hyperinsulinemia has been associated with an increased risk for atherosclerosis (7). Most of these studies, however, were cross-sectional, and evidence about the atherogenic risk associated with hyperinsulinemia in diabetic patients is certainly not conclusive (50). Because the risk for atherosclerotic disease is higher in patients with diabetes (51, 52), however, decreasing peripheral insulin levels seems desirable. Decreasing these levels must be done while adequately controlling blood glucose levels, because chronic hyperglycemia is clearly associated with accelerated diabetic retinopathy, nephropathy, and neuropathy, whereas the risks associated with chronic peripheral hyperinsulinemia remain theoretic. The daily insulin dosage of patients receiving combined therapy with a sulfonylurea agent and insulin generally can be decreased (Tables 3 and 4). In studies in which insulin levels were measured (Table 7), however, little difference was found in circulating insulin levels, despite the decrease in exogenously administered insulin. This lack of a difference probably resulted from the pancreatic action of the sulfonylurea agents that enhance endogenous insulin secretion. Increased secretion of endogenous insulin thus offsets any decrease in peripheral insulin levels that might have resulted from decreasing the dosage of exogenously administered insulin. Glycemic control was slightly better in patients receiving combined therapy, for the same circulating insulin level. Most studies, however, did not provide data that allow comparison of circulating insulin levels in responded and nonresponders. In our view, exogenous insulin dosage should not have been decreased unless blood glucose levels were nearly normalized. This view is supported by other studies in which insulin levels were sim-
Combination therapy with insulin plus a sulfonylurea agent is more expensive than insulin therapy alone (33). Combination therapy also increases the risk for side effects, putting patients at risk for the adverse effects of a sulfonylurea agent as well as for those of insulin. Conclusions Achieving and maintaining nearly normal blood glucose levels in the long term is difficult in many patients with type 2 diabetes receiving single-agent therapy. Combination therapy with insulin plus a sulfonylurea agent, however, only slightly improves overall diabetic control (Tables 3 and 4) (Figures 1 and 2). Achieving this marginal response increases costs and the risk for side effects. In our view, this form of therapy does not achieve nearly normal blood glucose levels in patients with type 2 diabetes. No clinically important evidence indicates that reducing insulin dosage with the use of a sulfonylurea agent reduces the patient's atherosclerotic risk. Moreover, an increase in endogenous insulin secretion may offset the reduction in insulin dosage, resulting in little difference in peripheral insulin levels (Table 7). Other approaches, such as using a higher insulin dosage (55) and, in obese patients, reducing weight, therefore are necessary to achieve nearly normal blood glucose concentrations in patients with poorly controlled type 2 diabetes. Appendix. Treatment Effect and Corresponding Standard Error across Studies For each of the k studies used in this meta-analysis, let x h SEj, and n{ (i = 1, 2,...,k) represent the mean treatment effect, standard error for that treatment effect, and corresponding
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sample size, respectively. The estimate of treatment effect across studies (x) is estimated as a weighted average of the study means, where the weight is n-JN and N is the sum of nt over the k studies. Thus, x = /2,x,/N + «2x2/N + ...+ nkxk/N. The corresponding standard error is calculated as follows: SE(x) =Vvariance X where variance =
(s)
!(SE , +
' ' (^
,SE ),+
=
+
" (s)
!(SE 1
* '-
21.
22.
23.
24.
Acknowledgments: The authors thank Dr. David Eddy for use of the Confidence Profile Software and Drs. Vic Hasselblad and Sharon Nessim for statistical assistance. Requests for Reprints: Mayer B. Davidson, MD, Division of Endocrinology, Room B-131, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
25.
Current Author Addresses: Drs. Davidson and Peters: Division of Endocrinology, Room B-131, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
26.
References 1. Hanssen KF, Dahl-Jorgensen K, Lauritzen T, Feldt-Rasmussen B, Brinchmann-Hansen O, Deckert T. Diabetic control and microvascular complications: the near-normoglycemia experience. Diabetologia. 1986;29:677-84. 2. Gerich JE. Oral hypoglycemic agents. N Engl J Med. 1989:321: 1231-45. 3. Davidson MB. Pathogenesis of type 2 diabetes mellitus: an interpretation of current data. Am J Med Sci. 1986;29:35-9. 4. Kinsell LW, Brown FR, Friskey RW, Michaels GD. Insulin-sparing sulfonamides. Science. 1956; 123:585. 5. Friedlander EO. Use of tolbutamide in insulin-resistant diabetes: report of a case. N Engl J Med. 1957;257:11-4. 6. Volk BW, Lazarus SS. Significance of effectiveness of combined insulin-Orinase treatment in maturity-onset diabetes. Am J Med Sci. 1959;237:1-7. 7. Stout RW. Insulin and atheroma—20-year perspective. Diabetes Care. 1990;13:631-54. 8. Chu PC, Conway MJ, Krouse HA, Goodner CJ. The pattern of response of plasma insulin and glucose to meals and fasting during chlorpropamide therapy. Ann Intern Med. 1968;68:757-69. 9. Reaven GM, Dray J. Effect of chlorpropamide on serum glucose and immunoreactive insulin concentrations in patients with maturity-onset diabetes mellitus. Diabetes. 1967;16:487-92. 10. Jeng CY, Hollenbeck CB, Wu MS, Chen YD, Reaven GM. How does glibenclamide lower plasma glucose concentrations in patients with type 2 diabetes? Diabetic Med. 1989;6:303-8. 11. Hughes TA, Kramer JO, Segrest JP. Effects of glyburide therapy on lipoproteins in non-insulin-dependent diabetes mellitus. Am J Med. 1985;79(Suppl 3B):86-91. 12. Shapiro ET, Van Cauter E, Tillil H, et al. Glyburide enhances the responsiveness of the /3-cell to glucose but does not correct the abnormal patterns of insulin secretion in noninsulin-dependent diabetes-mellitus. J Clin Endocrinol Metab. 1989;69:571-6. 13. Kolterman OG, Gray RS, Shapiro G, Scarlett JA, Griffin J, Olefsky JM. The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects. Diabetes. 1984;33;346-54. 14. Couturier E. Gliclazide on long-term therapy increases insulin response to glucose of type II diabetics. Diabetes Res Clin Pract. 1985-86;l:343-7. 15. Reaven GM. Effect of glipizide treatment on various aspects of glucose, insulin, and lipid metabolism in patients with noninsulindependent diabetes mellitus. Am J med. 1983;75:8-14. 16. Judzewitsch RG, Pfeifer MA, Best JD, Beard JC, Halter JB, Porte D Jr. Chronic chlorpropamide therapy of noninsulin-dependent diabetes augments basal and stimulated insulin secretion by increasing islet sensitivity to glucose. J Clin Endocrinol Metab. 1982;55:321-8. 17. Pfeifer MA, Halter JB, Beard JC, Judzewitsch R, Porter D Jr. Insulin responses to nonglucose stimuli in non-insulin-dependent diabetes mellitus during a tolbutamide infusion. Diabetes. 1982;31: 154-9. 18. Fleig WE, Noether-Fleig G, Fussgaenger R, Ditschuneit H. Modulation by a sulfonylurea of insulin-dependent glycogenesis, but not of insulin binding, in cultured rat hepatocytes. Evidence for a postreceptor mechanism of action. Diabetes. 1984;33:285-90. 19. Maloff BL, Lock wood DH. In vitro effects of a sulfonylurea on insulin action in adipocytes. Potentiation of insulin-stimulated hexose transport. J Clin Invest. 1981;68:85-90. 20. Rinninger F, Kirsch D, Haring HU, Kemmler W. Extrapancreatic action of the sulphonylurea gliquidone: post-receptor effect on in-
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sulin-stimulated glycogen synthesis in rat hepatocytes in primary culture. Diabetologia. 1984;26:462-5. Salhanick Al, Konowitz P, Amatruda JM. Potentiation of insulin action by a sulfonylurea in primary cultures of hepatocytes from normal and diabetic rats. Diabetes. 1983;32:206-12. Greenfield MS, Doberne L, Rosenthal M, Schulz B, Widstrom A, Reaven GM. Effect of sulfonylurea treatment on in vivo insulin secretion and action in patients with non-insulin-dependent diabetes mellitus. Diabetes. 1982;31:307-12. Simonson DC, Ferrannini E, Bevilacqua S, et al. Mechanism of improvement in glucose metabolism after chronic glyburide therapy. Diabetes. 1984;33:838-45. Mandarino LJ, Gerich JE. Prolonged sulfonylurea administration decreases insulin resistance and increases insulin secretion in noninsulin-dependent diabetes mellitus: evidence for improved insulin action at a postreceptor site in hepatic as well as extrahepatic tissues. Diabetes Care. 1984;7(Suppl l):89-99. Ward G, Harrison LC, Proietto J, Aitken P, Nankervis A. Gliclazide therapy is associated with potentiation of postbinding insulin action in obese, non-insulin-dependent diabetic subjects. Diabetes. 1985; 34:241-5. Davidson MB, Sladen G. Effect of glyburide on glycogen metabolism in cultured rat hepatocytes. Metabolism. 1987;36:925-30. Davidson MB. Pathogenesis of type 2 diabetes mellitus: an interpretation of current data. Am J Med Sci. 1986;292:35-9. Osei K, O'Dorisio TM, Falko JM. Concomitant insulin and sulfonylurea therapy in patients with type II diabetes. Effects on glucoregulation and lipid metabolism. Am J Med. 1984;77:1002-9. Bieger WP, Duglosch R, Rettenmeier A, et al. Trial of sulfonylurea in combination with insulin in the therapy of diabetes type I and II. Evidence against a primary extrapancreatic receptor effect. Klin Wochenschr. 1984;62:631-9. Gutniak M, Karlander SG, Efendic S. Glyburide decreases insulin requirement, increases /3-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. 1987; 10:545-54. Reich A, Abraira C, Lawrence AM. Combined glyburide and insulin therapy in type II diabetes. Diabetes Res. 1987;6:99-104. Lins PE, Lundblad S, Persson-Trotzig E, Adamson U. Glibenclamide improves the response to insulin treatment in non-insulin-dependent diabetics with second failure to sulfonylurea therapy. Acta Med Scand. 1988;223:171-9. Casner PR. Insulin-glyburide combination therapy for non-insulindependent diabetes mellitus: a long-term double-blind, placebo-controlled trial. Clin Pharmacol Ther. 1988;44:594-603. Mauerhoff T, Ketelslegers JM, Lambert AE. Effect of glibenclamide in insulin-treated diabetic patients with a residual insulin secretion. Diabete Metab. 1986;12:34-8. Quatraro A, Consoli G, Ceriello A, Giugliano D. Combined insulin and sulfonylurea therapy in non-insulin-dependent diabetics with secondary failure to oral drugs: a one year follow-up. Diabete Metab. 1986;12:315-8. Simonson DC, Delprato S, Castellino P, Groop L, DeFronzo RA. Effect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin-treated diabetic patients. Diabetes. 1987;36:136-46. Longnecker MP, Elsenhans VD, Leiman SM, Owen OE, Boden G. Insulin and a sulfonylurea agent in non-insulin-dependent diabetes mellitus. Arch Intern Med. 1986;146:673-6. Kitabchi AE, Soria AG, Radparvar A, Lawson-Grant V. Combined therapy of insulin and tolazamide decreases insulin requirement and serum triglycerides in obese patients with noninsulin-dependent diabetes mellitus. Am J Med Sci. 1987;294:10-4. Holman RR, Steemson J, Turner RC. Sulphonylurea failure in type 2 diabetes: treatment with a basal insulin supplement. Diabetic Med. 1987;4:457-62. Castillo M, Scheen AJ, Paolisso G, Lefebvre PJ. The addition of glipizide to insulin therapy in type-II diabetic patients with secondary failure to sulfonylureas is useful only in the presence of a significant residual insulin secretion. Acta Endocrinol (Copenh). 1987;116:364-72. Schade DS, Mitchell WJ, Griego G. Addition of sulfonylurea to insulin treatment in poorly controlled type II diabetes. A doubleblind, randomized clinical trial. JAMA. 1987;257:2441-5. Stenman S, Groop PH, Saloranta C, Totterman KJ, Fyhrqvist F, Groop L. Effects of the combination of insulin and glibenclamide in type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral hypoglycaemic agents. Diabetologia. 1988;31:206-13. Lewitt MS, Yu VK, Rennie GC, et al. Effects of combined insulinsulfonylurea therapy in type II patients. Diabetes Care. 1989;12:37983. Kyllastinen M, Groop L. Combination of insulin and glibenclamide in the treatment of elderly non-insulin-dependent (type 2) diabetic patients. Ann Clin Res. 1985;17:100-4. Lardinois CK, Lui GC, Reaven GM. Glyburide in non-insulin-de-
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pendent diabetes. Its therapeutic effect in patients with disease poorly controlled by insulin alone. Arch Intern Med. 1985;145:102832. Allen BT, Feinglos MN, Lebovitz HE. Treatment of poorly regulated non-insulin-dependent diabetes mellitus which combination insulinsulfonylurea. Arch Intern Med. 1985;145:1900-3. Groop L, Harno K, Nikkila EA, Pelkonen R, Tolppanen EM. Transient effect of the combination of insulin and sulfonylurea (glibenclamide) on glycemic control in non-insulin-dependent diabetes poorly controlled with insulin alone. Acta Med Scand. 1985;217: 33-9. Groop L, Harno K, Tolppanen EM. The combination of insulin and sulfonylurea in the treatment of secondary drug failure in patients with type II diabetes. Acta Endocrinol (Copenh). 1984;106:97-101. Riddle MC, Hart JS, Bouma DJ, Phillipson BE, Youker G. Efficacy of bedtime NPH insulin with daytime sulfonylurea for subpopulation of type II diabetic subjects. Diabetes Care. 1989;12:623-9.
50. Jarrett RJ. Is insulin atherogenic? Diabetologia. 1988;31:71-5. 51. Brand FN, Abbott RD, Kannel WB. Diabetes, intermittent claudication, and risk of cardiovascular events. The Framingham Study. Diabetes. 1989;38:504-9. 52. Role of cardiovascular risk factors in prevention and treatment of macrovascular disease in diabetes. Diabetes Care. 1989;12:573-9. 53. Firth R, Bell P, Marsh M, Rizza RA. Effects of tolazamide and exogenous insulin on pattern of postprandial carbohydrate metabolism in patients with non-insulin-dependent diabetes mellitus. Results of a randomized crossover trial. Diabetes. 1987;36:1130-8. 54. Firth RG, Bell PM, Rizza RA. Effects of tolazamide and exogenous insulin on insulin action in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1986;314:1280-6. 55. Andrews WJ, Vasquez B, Nagulesparan M, et al. Insulin therapy in obese non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal. Diabetes. 1984;33:634-42.
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of Internal
Medicine
• V o l u m e 115 • N u m b e r 1
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• Purpose: To review the recent literature on the efficacy of combined insulin and sulfonylurea therapy in patients with type 2 diabetes. • Data Sources: Pertinent articles were obtained through an English-language MEDLINE search from 1979 to 1990 and from the references of these articles. • Study Selection: We reviewed the studies in which patients with poorly controlled diabetes received insulin and a sulfonylurea agent and in which insulin treatment alone (usually given in conjunction with a placebo) was compared with insulin plus sulfonylurea therapy. • Data Extraction: Pre- and post-treatment insulin doses, blood glucose levels, glycated hemoglobin values, C-peptide levels, and insulin levels were analyzed. Other data were analyzed separately. • Results of Data Synthesis: Data from similar trials were compared. Data from concurrent trials were analyzed separately from data derived from cross-over trials. Weighted mean fasting blood glucose levels, glycated hemoglobin levels, insulin dosage, and fasting C-peptide concentrations were determined for insulin plus placebo and insulin plus sulfonylurea agent groups for both types of studies. In concurrent trials, the weighted mean post-treatment glycated hemoglobin level was 11.1% after insulin plus placebo compared with 10.0% after insulin plus a sulfonylurea agent. In cross-over trials, the corresponding values were 10.6% and 9.8%. • Conclusions: Combination therapy with insulin and a sulfonylurea agent only slightly improved glycemic control in patients with type 2 diabetes. When a sulfonylurea agent was used, less exogenous insulin was needed, but fasting serum insulin levels were not different between the treatment groups. Such therapy did not produce nearly normal blood glucose concentrations and therefore should not be used in patients with poorly controlled type 2 diabetes receiving insulin.
1 ype 2 diabetes can be difficult to treat adequately. An increasing amount of data confirms the need to maintain nearly normal blood glucose concentrations to avoid the long-term complications of diabetes (1); however, achieving nearly normal blood sugar levels is often an elusive goal. Treatment of type 2 diabetes should begin with diet therapy, which, if unsuccessful (often the case), should be followed by sulfonylurea agent therapy. Although recent data from controlled trials on the rate of failure with secondary sulfonylurea agent therapy are unavailable, an estimated 5% to 10% of patients receiving sulfonylurea agents cease to respond adequately to these drugs each year (2). After 10 years, only 50% of patients who initially responded to sulfonylurea agents continue to respond adequately. In the United States, initiating insulin therapy is the only option for improving glycemic control in patients for whom therapy with maximal doses of sulfonylurea agents has failed. Type 2 diabetes is characterized by insulin resistance (3). Patients receiving conventional doses of insulin therefore often do not achieve nearly normal blood glucose concentrations. In these patients, using insulin plus a sulfonylurea agent has been proposed to help to maximize endogenous insulin secretion and to enhance the response to both endogenous and exogenous insulin. We review the literature on the use of insulin plus sulfonylurea agents. Although many of the studies were flawed, the data allow some conclusions about the benefits and drawbacks of using this form of therapy to be drawn. The combined use of insulin and sulfonylurea agents was first investigated in the 1950s but was not used widely in clinical practice for the next 20 years (4-6). In the 1980s, studies evaluating the efficacy of combined therapy were conducted. The rationale for using this form of treatment is twofold: First, sulfonylurea agents are postulated to improve diabetic control through their pancreatic and extrapancreatic effects (see below). Second, using combined therapy is postulated to decrease the exogenous insulin requirement, producing less peripheral hyperinsulinemia. This effect may be beneficial; some evidence suggests that hyperinsulinemia may be atherogenic (7). Mechanism of Action of Sulfonylurea Agents
Annals of Internal Medicine. 1991;115:45-53. From the Cedars-Sinai Medical Center, Los Angeles, California. For current author addresses, see end of text.
Sulfonylurea agents enhance the pancreatic beta cells' ability to secrete insulin, and they decrease peripheral insulin resistance by ameliorating some, as yet undefined, post-receptor defect (2). Studies done to evaluate insulin levels after sulfonylurea agent therapy have yielded varying results (8-15). Chlorpropamide increased insulin levels acutely, but insulin levels returned to pretreatment levels with chronic use (8, 9). In ©1991 American College of Physicians
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Table 1. Study Design in Concurrent Trials* Investigators (Reference)
Study Period
Number of Patients Insulin Insulin plus plus SA Placebo
Type of SA
Dosage ofSA
Insulin plus Placebo
wk Osei et al. (28) Bieger et al. (29) Gutniak et al. (30) Reich et al. (31) Lins et al. (32) Casner (33) Mauerhoff et al. (34) Quatraro et al. (35) Weighted mean
Aget
mgld
Insulin plus SA
Duration of Diabetest Insulin plus Placebo
11 9 10 10 10 15
6 10 10 9§ 10 22
Glyburide Glyburide Glyburide Glyburide Glyburide Glyburide
20$ 12.5|| 7.0$ 19.9||
56 63 58 57 60 60
16
11
11
Glyburide
10.5$
59 ± 4
62 ± 2
52 15 15 Gliclazide 40-240 57 ± 2 27 ± 6.9t 11 ± 0 . 8 t 12 ± 3t
56 ± 2
± ± ± ± ± ±
1 9 2 4 3 0.1
Insulin plus S A
y
y
16 6 46 16 12 52
m 10.5$
Percentage of Ideal Body Weightt Insulin Insulin plus plus SA Placebo
59 60 56 59 67 56
± ± ± ± ± ±
3 7 2 3 2 0.1
128 ± 5 103 ± 16 114 ± 6 114 ± 6 105 ± 2 3111
129 118 121 110 104
115 ± 3
129 ± 2
29 ± 111
± 6 ± 17 ± 7 ±4 ± 3
3011
13 ± 2
15 16 10 9 11
12 ± 1
±6 17 ± 5 ± 4 12 ± 3 ± 3 9 ± 3 ± 2 8 ± 1 ± 0.1 14 ± 0.1
10 ± 2
11 ± 2
29 ± 111 12 ± 1
12 ± 1
* SA = sulfonylurea agent. t Percentage of ideal body weight except where noted. Data are presented as means ± SE. $ Fixed dosage. § In three patients in the insulin plus sulfonylurea group, insulin therapy was discontinued. || Mean dosage. 1 Body mass index (kg/m2). most studies, glyburide increased meal-stimulated insulin levels, both acutely and chronically (10-12). In a study with one of the longest follow-up periods (12 months) (13), however, insulin levels that were higher than pretreatment levels at 3 months were returning to baseline values at 12 months, particularly in patients who were responding to the drug. Gliclazide (14) (not available in the United
States) and glipizide (15) raised fasting and meal-stimulated insulin values with chronic use. In studies in which insulin concentrations were found eventually to return to pretreatment levels, beta-cell responsiveness was still enhanced, as illustrated by the return of insulin levels to pretreatment values but with blood glucose levels lower than before treatment. Pancreatic beta cells therefore may be sensitized by these drugs and thus are able to secrete similar amounts of insulin after as before therapy, but at lower glucose levels. Studies in which nonglucose secretagogues, such as arginine and isoproterenol, were used to stimulate insulin secretion have provided evidence supporting this theory (16, 17). The insulin response to these agents was similar before and after treatment with a sulfonylurea agent, but blood glucose values were much lower after than before treatment. When blood glucose levels were artificially raised to pretreatment values and stimuli were applied, the insulin response was markedly higher than the values seen before sulfonylurea agent therapy. In-vitro (18-21) and in-vivo (13, 22-25) evidence indicates that sulfonylurea agents potentiate the action of insulin. This phenomenon is seen in both peripheral (13, 18-25) and hepatic tissues (13, 23-25), and it does not seem to result from an enhancement of insulin binding (discussed in reference 26). Rather, the drugs seem to work at a site distal to the site where insulin binds to its plasma membrane receptor; the post-binding site where these drugs work is also the site of the insulin antagonism in type 2 diabetes (27). Methods
Figure 1. Mean fasting blood glucose levels. Data were obtained at the end of the treatment phase (placebo plus insulin or a sulfonylurea agent plus insulin) in each study. References 28 through 34 were concurrent studies; 36 through 49 were crossover studies {see text for definitions). 46
A computerized literature search using MEDLINE was done to find all relevant studies reported from 1976 to 1990. References that included the key words *"insulin" and ''sulfonylurea agents" were retrieved. Additional pertinent articles were obtained from the references of these articles. A manual search of the Index Me die us from 1986 to 1990 was done. Finally, one of the investigator's (MBD) extensive files on the diabetes
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literature were searched, and all relevant articles were reviewed. Eligible studies met the following criteria. Study patients had type 2 diabetes and either had unsatisfactory blood glucose control with insulin (most of the studies) or had begun insulin therapy during the initial phase of the study. Studies were done in either a concurrent or cross-over fashion. In concurrent studies (28-35), patients were randomly assigned to receive a sulfonylurea agent plus insulin or placebo plus insulin, and the responses of these treatment groups were compared. In cross-over studies (36-49), patients first were randomly assigned to receive one treatment (either placebo plus insulin or a sulfonylurea agent plus insulin). After a specified interval, they switched to the other form of treatment. Most of these trials did not have a "washout'' period between the two study phases. In cross-over studies, patients are compared with themselves. The studies in which the patients' responses to insulin plus a sulfonylurea agent are compared with their previous responses to insulin alone therefore are included in this category (36, 45, 46). Eligible concurrent studies provided mean pre- and posttherapy fasting blood glucose values, glycated hemoglobin levels, or both. In eligible studies, a group of patients receiving placebo plus insulin therapy was compared with a group receiving sulfonylurea agent plus insulin therapy. Eligible crossover trials had either a baseline period with insulin therapy alone (without sulfonylurea agent therapy) or a placebo plus insulin therapy phase for comparison with the sulfonylurea agent plus insulin therapy phase. Mean fasting blood glucose values or glycated hemoglobin levels had to be available for comparison from the end of the placebo (or baseline) arm and from the end of the treatment arm of the trial. If available, other data, including data on changes in total daily insulin dosage and C-peptide and insulin levels, were extracted from the articles. Results One investigator (ALP) extracted all of the data from the articles. Tables 1 (concurrent trials) and 2 (crossover trials) outline the basic design of each study. The Appendix describes the method used for calculating the
weighted means and weighted variance. The weighted mean pre- and post-treatment fasting blood glucose concentrations, glycated hemoglobin values, and total daily insulin dosage were calculated using data from all studies (Tables 3 and 4). Because not all studies provided these data, Tables 3 and 4 indicate which studies were used for each analysis. Weighted mean fasting C-peptide levels were also calculated (Tables 5 and 6).
Data from Clinical Trials Concurrent Trials Glyburide was used in all but one concurrent study; maximal doses (20 mg) were used in only two (Table 1). The studies lasted from 6 to 52 weeks, and the size of study samples varied. In general, half of the patients were randomly assigned to receive insulin plus an active sulfonylurea agent, and half were randomly assigned to receive insulin plus a placebo. Overall, 91 patients in the insulin plus placebo group and 93 patients in the insulin plus sulfonylurea group were studied in concurrent trials, and they were followed for an average of 27 weeks. Values obtained before and after treatment are shown for each group in Table 3 and Figures 1 and 2. For patients in the insulin plus placebo group, the weighted mean fasting blood glucose level was 11.6 mmol/L (209 mg/dL) before and 10.7 mmol/L (193 mg/dL) after treatment. For those in the insulin plus sulfonylurea group, the weighted mean fasting blood glucose level was 11.3 mmol/L (204 mg/dL) before and 9.4 mmol/L (169 mg/dL) after treatment. Weighted mean pre- and post-treatment glycated hemoglobin values were 10.8% and 11.1%, respectively, in the insulin plus placebo group and 10.7% and 10.0%, respectively, in the insulin plus sulfonylurea group. In all of the
Table 2. Study Design in Cross-over Trials* Investigators (Reference)
Duration of Number of Therapy Patients
Type of SA
wk Simonson et al. (36)$ Longnecker et al. (37) Kitabchi et al. (38) Holman et al. (39) Castillo et al. (40) Schade et al. (41) Stenman et al. (42) Lewitt et al. (43) Kyllastinen and Groop (44) Lardinois et al. (45)$ Allen et al. (46)$ Groop et al. (47) Groop et al. (48) Riddle et al. (49) Weighted meanH
8 8 12
8 11 12
8 6 16 16 12 8 12 8-40 8 8 16 10.6 ±1.0
15 10 16 15 29 9 14 6 13 13 20 14 ± 1.5
Dosage of SA
Age
mgld
y
Glyburide 20 Tolazamide 500 Tolazamide 1000 Chlorpropamide, glyburide, or tolbutamide Dosage varied Glipizide 30 Glyburide 15 Glyburide 20 Glyburide 15 Glyburide 10 Glyburide 20 Glipizide 30|| Glyburide 10 Glyburide 8 Glyburide 10
Percentage Duration of of Ideal Diabetes Body Weightt y
57 ± 3 62 ± 2 51 ± 3
131±4 147 ± 7 172 ±17
15±3 12 ± 2 10 ± 1
57 ± 11 55 ± 4 51 ± 3 58 ± 2 67 ± 5 73 ± 2 50 54 ± 4 56 ± 1 52 ± 3 61 ± 2
128 ± 36 100 ± 3 132 ± 6 24 ± 1§ 27 ± 3§ 32 ± 1§ 28§ 164 ± 7 123 ± 5 109 ± 3 124 ± 3
8±7 9±3 10 ± 1 10 ± 1 NA 11 ± 1 10 ± 2 14 ± 4 8±1 8±2 6±1
* SA = sulfonylurea agent. The sulfonylurea agent dosage was fixed in all studies, except as noted. NA = not available. t Data are presented as means ± SE. Percentage of ideal body weight except where noted. % A sulfonylurea agent was given to patients who were initially receiving insulin therapy only. Data obtained with combined therapy were compared with data previously obtained with insulin therapy alone. § Body mass index (kg/m2). || Mean dosage (range, 7.5 to 40 mg/d). 11 Data from the 13 cross-over trials were used to calculate the mean. The study results reported in reference 46 were not used.
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Table 3. Glycemic Control and Insulin Dosage in Concurrent Trials* Investigators (Reference)
Fasting Blood Glue ose Concentration Insulin plus Placebo Insulin plus SA Before After After Before Treatment Treatment Treatment Treatment
Glycated Hemoglobin Level Insulin pi us Placebo Insulin p lus SA After After Before Before Treatment Treatment Treatment Treatment
mmollL
* SA = sulfonylurea agent; U = units; NA = not available. t Mean of blood glucose concentrations obtained throughout the day. $ Units per kilogram body weight over a 24-hour period. § The study results reported in references 29 and 35 were not averaged, because these data were not fasting blood glucose values. || The study results reported in references 32 and 34 were not averaged, because these data were not given in units per 24 hours.
studies in which insulin dosage varied, it was lower at the end of the trial in the insulin plus sulfonylurea group than in the insulin plus placebo group. Cross-over Trials In cross-over trials, 191 patients were studied, with an average duration of 10.6 weeks per study arm (Table 2). As in the concurrent trials, the blood glucose concentrations of most of the patients were inadequately controlled with insulin. Because cross-over trials do not
provide pre- and post-treatment data for each treatment arm and generally do not have a washout phase between study arms, values are given for the end of each treatment arm only (Table 4) (Figures 1 and 2). Because each patient receives both treatments, the difference between values obtained at the end of the placebo phase and those obtained at the end of the sulfonylurea phase defines the sulfonylurea agent's effect. In these studies, the weighted mean fasting blood glucose concentration was 11.0 mmol/L (198 mg/dL) after the placebo phase and 9.0 mmol/L (162 mg/dL) after the sulfonylurea
Table 4. Glycemic Control and Insulin Dosage in Cross-o ver Trials* Investigators (Reference)
Simonson et al. (36)$ Longnecker et al. (37) Kitabchi et al. (38) Holmanetal. (39) Castillo et al. (40) Schade et al. (41) Stenman et al. (42) Lewittetal. (43) Kyllastinen and Groop (44) Lardinois et al. (45)$ Allen et al. (46)$ Groop et al. (47) Groop et al. (48) Riddle et al. (49) Number of patients Weighted mean ± SE
Fasting Blood Glucose Concentration! Insulin plus Insulin plus Placebo SA mmollL 6.9 14.9 9.3§ 5.1 NA 14.6 9.6 10.1 16.4 13.9 14.3 10.8 8.0 11.1 16911 11.0 ± 0.7
Insulin Dosage
Glycated Hemoglobin Level Insulin plus SA
Insulin plus Placebo
%
6.2 12.3 9.3 5.2 NA 12.9 7.9 7.8 11.8 10.8 9.7 10.7 7.0 8.0
10.3 12.8 9.2 10.1 8.2 10.9 9.0 10.3 14.1 8.4 NA 13.2 11.4 10.6
8.0 12.6 8.8 9.5 7.9 10.2 8.3 9.1 12.4 7.3 NA 13.4 11.0 9.8
9.0 ± 0.4
185 10.6 ± 0.3
9.8 ± 0.3
Insulin plus Insulin plus Si\ Placebo VI24h 72 Fixed 0.89|| 40 0.50|| 55 32 47 Fixed Fixed 67 Fixed 38 46 122 48 ± 5.3
58 dose 0.69 25 0.43 54 24 44 dose dose 61 dose 37 36 41 ± 5.7
* SA = sulfonylurea agent; NA = not available. t The result at end of therapy with either insulin and placebo or insulin and sulfonylurea agent. X A sulfonylurea agent was given to patients who were initially receiving insulin therapy only. Data obtained with combined therapy were compared with data previously obtained with insulin therapy alone. § Mean of blood glucose concentrations obtained throughout the day. || Units per kilogram of body weight over a 24-hour period. 11 The study results reported in reference 38 were not averaged, because these data were not fasting blood glucose values.
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Table 3. (Co ntinued) Insulin Dosage Insulin pliis Placebo Insulin r.>lus SA Before After Before After Treatment Treatment Treatment Treatment < > U/2>4h Fixed dose 30 28 62 55 48 38 0.42$ 0.42 67 79 0.44$ 0.46 88 85 59|| 63 ± 3.6
62 ± 3.7
Fixed d ose 46 63 36 0.45 66 0.50 90 66 64 ±4.8
40 35 20 0.30 62 0.46 57 48 ± 3.7
phase. The weighted mean glycated hemoglobin values were 10.6% and 9.8% after the placebo and sulfonylurea phases, respectively. As in the concurrent trials, in virtually all cross-over studies in which insulin dosage varied, the amount used was less in the insulin plus sulfonylurea phase than in the insulin plus placebo phase of the study.
Responders and Nonresponders In some of the studies, combined therapy produced nearly normal blood glucose concentrations in a few, but not in most, patients. In nine of the studies, predictors of a response to combined therapy were sought. In four studies, glycemic control was most improved in the patients who initially had the worst glycemic control and the greatest degree of obesity (29, 33, 43, 45). In one of these studies, responders had been receiving insulin for a shorter duration than had nonresponders (5 compared with 14 years), had a higher initial fasting C-peptide level (1.1 nmol/L compared with 0.4 nmol/L [3.2 ng/mL compared with 1.3 ng/mL]), and were heavier (body mass index [kg body weight/m2 body surface area] of 28.1 compared with 26.4) (43). In another study, higher basal C-peptide values were also found in responders (33). In four other studies in which responders were compared with nonresponders, however, the same baseline clinical characteristics (initial glycemic control, degree of obesity, fasting C-peptide levels) did not differ between the two groups (35, 40, 46, 49). In one small study, the two patients with the highest initial fasting blood glucose values were nonresponders (37). Thus, predicting which patients will respond clinically is difficult.
6). In general, both fasting and stimulated C-peptide levels were higher after combined therapy. This finding is consistent with evidence that sulfonylurea agents act, in part, by enhancing insulin secretion. Various approaches have been used to evaluate the effect of combined insulin and sulfonylurea therapy on insulin action. In several studies, the effects of combined therapy on insulin binding to erythrocytes or monocytes (or both) were measured, and essentially no difference was shown between treatment groups (41, 47, 48). Responders to the sulfonylurea agent were not evaluated separately from nonresponders. Insulin tolerance was tested in two studies (46, 47). In one study, patients were not classified as responders or nonresponders, and no correlation between changes in the response to an insulin tolerance test and changes in the glycated hemoglobin concentration was found (46). In the other study, the response to the insulin tolerance test improved in patients who responded to combination therapy and did not improve in other patients (47). In two studies in which glucose clamp techniques were used, the glucose metabolic clearance rate was found to improve, reflecting enhanced peripheral sensitivity to insulin. In one, the glucose metabolic clearance rate increased substantially in responders to combined therapy and increased little in nonresponders (40). In the other, improvement in the day-long postprandial glucose response correlated with an increase in the glucose metabolic clearance rate (45). In two other studies in which glucose clamp techniques were used, however, no difference was found between patients receiving in-
Mechanism of Action of Combined Therapy Many researchers have investigated how combined insulin and sulfonylurea agent therapy might better control blood glucose levels. In 18 studies, basal C-peptide levels were measured, and, in many, stimulated C-peptide values were examined. C-peptide levels were measured after the administration of various stimuli, including glucose, glucagon, and mixed meals (Tables 5 and
Figure 2. Mean glycated hemoglobin values. Data were obtained at the end of the treatment phase (placebo plus insulin or a sulfonylurea agent plus insulin) in each study. References 28 through 35 were concurrent studies; 36 through 49 were crossover studies (see text for definitions).
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Table 5. C-Peptide Levels in Concurrent Trials* Investigators (Reference)
Stimulated C-Peptide Levels Insulin plus SA Insulin plus Placebo After Before After Before Treatment Treatment Treatment Treatment
Fasting C-Peptide Levels Insulin plus Placebo Insulin plus SA Before After After Before Treatment Treatment Treatment Treatment
< Osei et al. (28) Gutniak et al. (30) Lins et al. (32) Casner (33) Mauerhoff et al. (34) Quatraro et al. (35) Number of patients Weighted mean ± SE
>
mmollL 0.3 0.3
0.3 0.2
0.5 0.3
0.7 0.3
0.4 1.1 0.3 NA
0.5 1.0 0.3 NA
0.4 1.2 0.5 NA
0.6 1.4 0.6 NA
57 0.53 ± 0.06
0.48 ± 0.04
59 0.71 ± 0.08
0.86 ± 0.08
62.7t 6.3* 7.0§ 0.6|| NA 0.5|| 8.21
67.6t 5.2* 9.6§ 0.7|| NA 0.5|| 9.211
128.7t 5.5* 5.9§ 0.8|| NA 0.8|| 7.311
130.4t 5.5* 22.8§ 1.2|| NA 1.5|| 22.411
* SA = sulfonylurea agent. NA = not available. t C-peptide area-under-the-curve after an oral glucose tolerance test (measured in nanomoles per litre during subsequent 180-minute period). * C-peptide area-under-the-curve after receiving 1 mg of intravenous glucagon (measured in nanomoles per litre during subsequent 15-minute period). § C-peptide incremental area-under-the-curve after a mixed meal (measured in nanomoles per litre during subsequent 150-minute period). || C-peptide concentration 120 minutes after a mixed meal (measured in nanomoles per litre). 11 C-peptide incremental area-under-the-curve after receiving intramuscular glucagon (measured in nanomoles per litre during subsequent 120-minute period).
sulin alone and patients receiving insulin plus a sulfonylurea agent (30, 36). In neither study were differences between responders and nonresponders evaluated. The investigators in one of the studies examined various measures, including basal hepatic glucose output, insulin sensitivity, as measured by a two-step insulin clamp,
total glucose metabolism, glucose and lipid oxidation and nonoxidative metabolism, and found no difference between the treatment groups (36). We think that enhanced endogenous insulin secretion (as indicated by C-peptide levels) is probably the major mechanism by which combined insulin and sulfonylurea therapy im-
Table 6. C-Peptide Levels in Cross-over Trials* Investigators (Reference)
Fasting C-Pe ptide Levels! Insulin plus SA
Insulin plus Placebo
Meal-Stimulated C-Peptide Levels Insulin plus Insulin plus Placebo SA
mmollL Simonson et al. (36) Longnecker et al. (37) Kitabchi et al. (38) Holman et al. (39) Castillo et al. (40) Schade et al. (41) S t e n m a n e t a l . (42)
0.1 0.1 NA 0.03 0.3** 0.1 ft 0.6 0.16
0.3 0.3 NA 0.3 0.4 0.1 0.6 0.21
Lewitt et al. (43) Kyllastinen and Groop (44) Lardinois et al. (45) Allen et al. (46) Groop et al. (47) Groop et al. (48) Riddle et al. (49)
0.7 0.8 0.5 0.4 0.4 0.4 0.5
0.9 0.9 0.7 0.5 0.4 0.6 0.6
Number of patients Weighted mean ± SE
179 0.41 ± 0.1
0.53 ± 0.2
0.2$ 53.8§ 0.5|| 0.11 0.5$** 0.2tt 39.9M 0.3§§ 0.3IHI NA 1.1§§ *** 0.411 *** 0.6* 0.8ttt
0.4$ 94.7§ 0.6|| 0.411 0.6*** 0.2tt 50.8M 0.3§§ 0.4|||| NA 1.2§§ Increased*** 0.5111 Increased*** 0.8$ l.Ottt
* SA = sulfonylurea agent. NA = not available. t The result obtained at the end of therapy with either insulin and placebo or insulin and a sulfonylurea agent. X C-peptide concentration 5 minutes after receiving 1 mg of intravenous glucagon (measured in nanomoles per litre). § C-peptide area-under-the-curve after a mixed meal (measured in nanomoles per litre during subsequent 180-minute period). || C-peptide concentration 120 minutes after a mixed meal (measured in nanomoles per litre). 11 Geometric mean C-peptide level over 24 hours (measured in nanomoles per litre). ** "Responders" (hemoglobin A,C decreased). tt "Nonresponders" (no change in hemoglobin A,C). %% C-peptide area-under-the-curve after an oral glucose tolerance test (measured in nanomoles per litre during subsequent 180-minute period). §§ C-peptide concentration 6 minutes after receiving 1 mg of intravenous glucagon (measured in nanomoles per litre). Illl Mean C-peptide concentration 180 minutes after a mixed meal (measured in nanomoles per litre). HH C-peptide concentration 120 minutes after an oral glucose tolerance test (measured in nanomoles per litre). *** C-peptide levels increased throughout the day in patients receiving combined therapy compared with insulin plus placebo. ttt C-peptide concentration 60 minutes after a mixed meal (measured in nanomoles per litre). 50
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Table 7. Insulin Levels in Concurrent and Cross-over Trials* Investigators (Reference)
Stimulated Insulin Levels
Fasting Insulin Levels Insulin plus Placebo
Insulin plus
Insulin plus Placebo
Insulin plus
SA
292 before, 184 after treatment
214 before, 214 after treatment
58 781 before, 48 607 after treatmentt
86 688 before, 42 926 after treatmentt
-28
NA 96§ 42 216 238
NA 96 63 202 238
382* 188|| 293011 396** No changett
360$ 173|| 478811 331** No changett
-14 -15 -1 -8 Fixed
SA
pmollL Concurrent trials Gutniak et al. (30)
Change in Insulin Dosage after Addition
Cross-over trials Simonson et al. (36) Holman et al. (39) Schadeetal. (41) Stenman et al. (42) Groop et al. (47)
ofSA U
* SA = sulfonylurea agent. For cross-over trials, data were obtained at the end of therapy with either insulin and placebo or insulin and a sulfonylurea agent. t Insulin incremental area-under-the-curve after a mixed meal (measured in picomoles per litre during the subsequent 150-minute period). X Mean plasma insulin concentration (measured in picomoles per litre over a 24-hour period). § Geometric mean fasting insulin concentration (measured in picomoles per litre). || Geometric mean insulin concentration after a mixed meal (measured in picomoles per litre during the subsequent 180-minute period). 11 Insulin area-under-the-curve after an oral glucose tolerance test (measured in picomoles per litre during the subsequent 180-minute period). ** Mean insulin concentration after a mixed meal (measured in picomoles per litre during subsequent 120-minute period). t t No difference in insulin levels during 18-h meal profile between combined therapy and insulin plus placebo.
proves control and that effects on peripheral insulin action are less important.
ilar in patients treated with either exogenous insulin or tolazamide (53, 54).
Peripheral Insulin Levels
Costs of Combined Therapy
Peripheral hyperinsulinemia has been associated with an increased risk for atherosclerosis (7). Most of these studies, however, were cross-sectional, and evidence about the atherogenic risk associated with hyperinsulinemia in diabetic patients is certainly not conclusive (50). Because the risk for atherosclerotic disease is higher in patients with diabetes (51, 52), however, decreasing peripheral insulin levels seems desirable. Decreasing these levels must be done while adequately controlling blood glucose levels, because chronic hyperglycemia is clearly associated with accelerated diabetic retinopathy, nephropathy, and neuropathy, whereas the risks associated with chronic peripheral hyperinsulinemia remain theoretic. The daily insulin dosage of patients receiving combined therapy with a sulfonylurea agent and insulin generally can be decreased (Tables 3 and 4). In studies in which insulin levels were measured (Table 7), however, little difference was found in circulating insulin levels, despite the decrease in exogenously administered insulin. This lack of a difference probably resulted from the pancreatic action of the sulfonylurea agents that enhance endogenous insulin secretion. Increased secretion of endogenous insulin thus offsets any decrease in peripheral insulin levels that might have resulted from decreasing the dosage of exogenously administered insulin. Glycemic control was slightly better in patients receiving combined therapy, for the same circulating insulin level. Most studies, however, did not provide data that allow comparison of circulating insulin levels in responded and nonresponders. In our view, exogenous insulin dosage should not have been decreased unless blood glucose levels were nearly normalized. This view is supported by other studies in which insulin levels were sim-
Combination therapy with insulin plus a sulfonylurea agent is more expensive than insulin therapy alone (33). Combination therapy also increases the risk for side effects, putting patients at risk for the adverse effects of a sulfonylurea agent as well as for those of insulin. Conclusions Achieving and maintaining nearly normal blood glucose levels in the long term is difficult in many patients with type 2 diabetes receiving single-agent therapy. Combination therapy with insulin plus a sulfonylurea agent, however, only slightly improves overall diabetic control (Tables 3 and 4) (Figures 1 and 2). Achieving this marginal response increases costs and the risk for side effects. In our view, this form of therapy does not achieve nearly normal blood glucose levels in patients with type 2 diabetes. No clinically important evidence indicates that reducing insulin dosage with the use of a sulfonylurea agent reduces the patient's atherosclerotic risk. Moreover, an increase in endogenous insulin secretion may offset the reduction in insulin dosage, resulting in little difference in peripheral insulin levels (Table 7). Other approaches, such as using a higher insulin dosage (55) and, in obese patients, reducing weight, therefore are necessary to achieve nearly normal blood glucose concentrations in patients with poorly controlled type 2 diabetes. Appendix. Treatment Effect and Corresponding Standard Error across Studies For each of the k studies used in this meta-analysis, let x h SEj, and n{ (i = 1, 2,...,k) represent the mean treatment effect, standard error for that treatment effect, and corresponding
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sample size, respectively. The estimate of treatment effect across studies (x) is estimated as a weighted average of the study means, where the weight is n-JN and N is the sum of nt over the k studies. Thus, x = /2,x,/N + «2x2/N + ...+ nkxk/N. The corresponding standard error is calculated as follows: SE(x) =Vvariance X where variance =
(s)
!(SE , +
' ' (^
,SE ),+
=
+
" (s)
!(SE 1
* '-
21.
22.
23.
24.
Acknowledgments: The authors thank Dr. David Eddy for use of the Confidence Profile Software and Drs. Vic Hasselblad and Sharon Nessim for statistical assistance. Requests for Reprints: Mayer B. Davidson, MD, Division of Endocrinology, Room B-131, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
25.
Current Author Addresses: Drs. Davidson and Peters: Division of Endocrinology, Room B-131, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
26.
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50. Jarrett RJ. Is insulin atherogenic? Diabetologia. 1988;31:71-5. 51. Brand FN, Abbott RD, Kannel WB. Diabetes, intermittent claudication, and risk of cardiovascular events. The Framingham Study. Diabetes. 1989;38:504-9. 52. Role of cardiovascular risk factors in prevention and treatment of macrovascular disease in diabetes. Diabetes Care. 1989;12:573-9. 53. Firth R, Bell P, Marsh M, Rizza RA. Effects of tolazamide and exogenous insulin on pattern of postprandial carbohydrate metabolism in patients with non-insulin-dependent diabetes mellitus. Results of a randomized crossover trial. Diabetes. 1987;36:1130-8. 54. Firth RG, Bell PM, Rizza RA. Effects of tolazamide and exogenous insulin on insulin action in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1986;314:1280-6. 55. Andrews WJ, Vasquez B, Nagulesparan M, et al. Insulin therapy in obese non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal. Diabetes. 1984;33:634-42.
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