The Synergistic Effect of Miglitol Plus Metformin Combination Therapy in the Treatment of Type 2 Diabetes

This was a multicenter, double-blind, randomized, placebo-controlled parallel group study. Eligible patients were type 2 diabetic patients (men and women) >40 years of age in whom diabetes was inadequately controlled by diet alone, i.e., in whom HbA_1c level was ≥7.2 and ≤9.5%. The major exclusion criteria included type 1 diabetes, the presence of major debilitating diseases, recent cardiovascular events, gastrointestinal diseases, medications likely to affect intestinal motility or the absorption of nutrients, hypersensitivity to miglitol or metformin, and a history of lactic acidosis. Patients who were taking either sulfonylurea or metformin below the maximum dose could be eligible as long as the antidiabetic drug was discontinued. Before starting any study procedures, patients who fulfilled the eligibility criteria gave their written informed consent and entered a single-blind, 8-week placebo run-in period. All subjects were seen by a dietitian before the run-in period and were advised regarding a well-balanced weight-reducing diet (19). They were also advised regarding exercise, mainly walking 20–30 min at least three times per week. The diet was reinforced after 1 month, and if the HbA_1c was still ≥7.2% by 2 months, they were considered dietary failure. Patients with HbA_1c levels ≥7.2 but ≤9.5% (110–146% above the upper limit of the normal range) at the end of the run-in period were eligible for randomization to matching placebo or to active treatment with either miglitol plus placebo, metformin plus placebo, or metformin plus miglitol for 36 weeks. The miglitol dosage was force-titrated as follows: administration of the drug was started at 25 mg three times a day for 4 weeks, increased to 50 mg three times a day for 8 weeks, and then increased to 100 mg three times a day until the end of the study. Administration of metformin was started and maintained at 500 mg three times a day throughout the study. All patients were given an Elite Glucometer and were advised regarding regular home blood-glucose monitoring.

The primary efficacy criterion was the change in HbA_1c level from baseline to the end of the double-blind treatment for the intent-to-treat (ITT) population, which included any patient who had both a baseline value and at least one postrandomization efficacy value.

Secondary efficacy parameters included the change in fasting and postprandial plasma glucose and insulin levels and serum triglyceride levels from baseline to the end of treatment, measured at 0, 60, 90, and 120 min after a standardized liquid test breakfast (55% carbohydrate, 30% fat, and 15% protein; providing ∼450 kcal). The study medications were given with the tolerance test meal. The proportion of responders in the different treatment groups was also evaluated, in which a clinically significant response was defined as either a ≥15% reduction in HbA_1c from baseline or an HbA_1c level <7.0%.

HbA_1c was measured during screening, at week –2 and baseline, and thereafter at each visit (weeks 4, 8, 12, 16, 20, 28, and 36) after randomization. Routine fasting plasma glucose was measured at week −2 and at every subsequent visit. Fasting and postprandial (60, 90, and 120 min) glucose and insulin lev-els as well as triglyceride levels were specifically measured at baseline and at weeks 12, 16, and 36 or at premature termination.

Safety and tolerability were investigated by the occurrence of adverse events; hypoglycemic events; changes in vital signs; and changes in laboratory values, including biochemical parameters, hematology, vitamins (thiamine-dependent transketolase, folate, vitamin B₁₂, vitamin A, and retinol protein binding), and standard urinalysis. Adverse events were monitored and documented at week –2 and at all visits thereafter. Routine biochemistry, hematology, and urinalysis were performed at screening, baseline, and weeks 12, 20, and 36 or at premature termination; vitamin assays were performed at baseline and at the final visit. Physical examinations were conducted at screening, week –2, baseline, week 12, and the end of the study, whereas vital signs and weight were recorded at each visit. Routine laboratory determinations were performed using standard methodology by local laboratories, whereas the preprandial and postprandial efficacy measurements and vitamin evaluations were performed at a central laboratory.

To detect a mean difference of 0.6% in the change in HbA_1c between treatment groups from baseline to the end of treatment, with α = 0.05 and a power (1–β) of at least 90%, a minimum of 60 patients per treatment group were required. To account for multicenter variability, this was increased by 20% to 75 patients per treatment arm.

Treatment groups were compared at baseline for demographic variables and other prognostic factors, such as family history of type 2 diabetes, medical history, vital signs, and concomitant medications. The primary efficacy parameter was the change in HbA_1c from baseline to the end of treatment and was analyzed by analysis of variance techniques. All four treatment groups were included in the primary comparisons, which used orthogonal contrasts.

The primary analysis of efficacy was performed on the ITT population, which included all patients who had both baseline and postrandomization efficacy values. For end-of-treatment analysis, the last-observation-carried-forward method was used. All patients who received at least one dose of trial medication were included in the safety analysis. Adverse events and other safety parameters were analyzed in terms of the percentage of patients in whom they occurred.

A total of 324 patients were randomized in the study: 83 to placebo, 82 to miglitol monotherapy, 83 to metformin monotherapy, and 76 to metformin/miglitol combination therapy. Six patients (one each from the placebo and metformin/miglitol combination therapy groups and two each from the miglitol and metformin monotherapy groups) were excluded from the ITT analysis because of the absence of recorded HbA_1c values after randomization. A total of 318 patients (98%) were valid for the ITT analysis. Selected demographic parameters and clinical data for all randomized patients are shown in Table 1. Treatment groups were comparable for number of patients, age, race (predominately Caucasian), weight and BMI, sex ratio, duration of diabetes, and baseline HbA_1c. The mean durations of treatment exposure by treatment group were as follows: placebo 200.3 ± 93.3 days; miglitol 190.9 ± 90.5 days; metformin 231.6 ± 70.1 days; metformin plus miglitol combination 203.3 ± 94.6 days.

The primary comparison for all efficacy parameters was between the metformin plus miglitol combination and metformin monotherapy treatment groups. The mean changes in HbA_1c values (means ± SEM) in response to the different treatments are shown in Table 2. There was an increase of 0.38 ± 0.12% in the placebo group, virtually no change in the miglitol group (0.02 ± 0.10%), a decrease of −0.85 ± 0.12% in the metformin group, and a decrease of −1.39 ± 0.11% in the metformin plus miglitol combination group (P = 0.002, comparing miglitol plus metformin and metformin monotherapy). The placebo-substracted mean change in HbA_1c or the actual treatment effect is illustrated in Fig. 1. The mean reduction in HbA_1c compared with placebo was –0.37% for miglitol treatment, −1.25% for metformin treatment, and –1.78% for metformin plus miglitol treatment. The end-of-treatment mean ± SEM of HbA_1c was 8.5 ± 0.1% for placebo, 8.2 ± 0.2% for miglitol, 7.3 ± 0.1% for metformin, and 6.9 ± 0.1% for metformin plus miglitol combination. The latter group achieved the targeted HbA_1c level of <7.0% recommended by the American Diabetes Association (20). Furthermore, significantly (P = 0.0014) more patients were classified as responders (i.e., showed ≥15% reduction from baseline in HbA_1c or achieved HbA_1c <7.0%) to metformin plus miglitol combination therapy (70.6%) compared with metformin monotherapy (45.5%); even if only HbA_1c <7.0% was used to define responders, combination therapy still maintained a high responder rate (64.0%) compared with metformin monotherapy (34.6%).

Reductions in levels of postprandial plasma glucose were observed in all the active treatment groups, in contrast to an increase in patients taking placebo (Table 2). The reductions in patients receiving metformin plus miglitol combination therapy were significantly greater (P < 0.0001) than those in patients on metformin monotherapy. The reduction in fasting plasma glucose was also greater in patients receiving metformin plus miglitol combination therapy than in patients receiving metformin monotherapy (P = 0.0025).

Although the mean change in postprandial plasma insulin at 60 min did not reach statistical significance for the comparison between metformin plus miglitol combination therapy and metformin monotherapy, a statistically significant difference was observed in favor of the combination therapy at 90 and 120 min (P = 0.0143 and 0.0177, respectively) (Table 2). Postprandial plasma insulin levels decreased more in the placebo group than in the metformin group, which could be caused by bias in the patients’ disease status. Because the patients were not newly diagnosed, their duration of disease varied considerably, and some had previously been taking sulfonylurea, which stimulates release of pancreatic insulin. It is clear that lower postprandial plasma insulin levels despite higher postprandial plasma glucose levels suggests decreased β-cell function. This could be caused by glucotoxicity resulting from increased plasma glucose in the placebo group (21). Changes in fasting serum insulin and triglyceride levels observed from baseline to the end of treatment did not differ significantly between metformin plus miglitol combination therapy and metformin monotherapy and showed no consistent trend.

A total of 324 patients were valid for the safety analysis. After randomization, 302 (93.2%) patients reported adverse events. The proportion of patients experiencing adverse events in the metformin group was 78 of 83 (94.0%), compared with 74 of 76 (97.4%) on metformin plus miglitol combination therapy (Table 3), which is an increased incidence of 3.4%. For comparison, the incidence was 85.5% in the placebo group and 96.3% in the miglitol group. Most adverse events were gastrointestinal; flatulence and diarrhea were reported more frequently by patients receiving miglitol or metformin plus miglitol combination therapy than those receiving the other treatments.

A total of 37 (11.4%) randomized patients discontinued the study prematurely because of adverse events: 2 (2.4%) in the placebo group, 11 (13.4%) in the miglitol group, 5 (6.0%) in the metformin group, and 19 (25.0%) in the metformin plus miglitol combination therapy group. Flatulence and diarrhea were the most common adverse events associated with premature discontinuation from the study.

A total of 16 patients reported 18 serious adverse events postrandomization: 3 of these events occurred in the placebo group, 2 in the miglitol group, 4 in the metformin group, and 9 in the metformin plus miglitol combination group. None of these serious adverse events were deemed by the investigators to be either probably or possibly related to the study drug. No deaths occurred during this study. No severe hypoglycemic episodes were reported. The rate of hypoglycemia was slightly higher in patients receiving metformin plus miglitol combination therapy (13.2 vs. 9.6% receiving metformin), but this difference was not clinically significant.

Treatment groups did not show any clinically or statistically significant differences in hematological and biochemical parameters or urinalysis. One patient in the metformin group showed an elevation >1.8 times the upper limit of normal in alanine aminotransferase, but this was not considered clinically relevant. Glycosuria was observed considerably less frequently for the metformin plus miglitol combination group, with an incidence of 7% compared with 26% for metformin monotherapy. There was no significant laboratory abnormality or change in vital signs during the study. Although all treatment groups showed a mean decrease in body weight, intergroup comparison suggested that patients who received metformin plus miglitol combination therapy lost more weight (Table 2) than those in the other treatment groups: −1.87 kg for metformin plus miglitol combination compared with –0.79 kg for metformin alone, –0.42 kg for miglitol alone, and −0.69 kg for placebo (P = NS).

Previous studies have shown the efficacy and safety of miglitol as monotherapy and in combination with sulfonylureas in type 2 diabetes (11,13,18,20,22,23). The present study demonstrates that miglitol in combination with metformin provides a synergistic effect on glycemic control, as indicated by the marked reductions in HbA_1c and plasma glucose levels in middle-aged patients in whom type 2 diabetes is insufficiently controlled by dietary management. Combination therapy produced significantly greater reductions in HbA_1c, fasting plasma glucose, and particularly postprandial plasma glucose than metformin monotherapy. The mean HbA_1c at the end of treatment of patients receiving metformin was 7.3%, which is slightly higher than the goal HbA_1c level of <7% given by current clinical practice recommendations (20), whereas patients on metformin plus miglitol combination therapy achieved the treatment goal with a mean end-of-treatment HbA_1c level of 6.9%. The greater reduction in HbA_1c in patients on the metformin plus miglitol combination therapy is therefore clinically significant in achieving the treatment goal. The clinical importance of this is supported by the U.K. Prospective Diabetes Study data, which indicates that for every 1% reduction in HbA_1c, there is a 35% reduction in risk of microvascular complications (24). The superiority of the combination treatment was also demonstrated by the higher response rate of patients on the metformin plus miglitol combination therapy than on monotherapy. These observations support those of Mooradian in elderly type 2 diabetic subjects (18).

Postprandial hyperglycemia is recognized as an independent risk factor for macrovascular complications (25,26). However, the normalization of postprandial plasma glucose peaks in clinical practice is recognized as more problematic than the overall management of fasting plasma glucose levels. Because α-glucosidase inhibitors have been reported previously to smooth and lower postprandial plasma glucose peaks (8, 9, 10), miglitol in combination with metformin does offer an advantage in achieving the important goal of postprandial glucose management as well as overall glycemic control, especially for patients with postprandial hyperglycemia refractory to other treatments.

The reductions in fasting and postprandial plasma glucose as well as in HbA_1c in response to metformin plus miglitol combination therapy were greater than the added effects of both miglitol and metformin alone. It is suggested that the administration of the two drugs together has a synergistic effect on glycemic control; this is plausible because miglitol and metformin reduce plasma glucose levels through completely different mechanisms of action. Metformin acts on the liver directly by decreasing hepatic glucose production and release and indirectly by increasing peripheral tissue sensitivity to insulin (27); miglitol acts at the small intestine by delaying the digestion of complex carbohydrates (28). Interestingly, patients receiving metformin plus miglitol combination therapy tended to lose more weight than those on the other treatment regimens (4). Weight loss may indirectly improve glycemic control by decreasing insulin resistance (29), which might have been another positive contributory factor to the superiority of the metformin plus miglitol combination therapy. Although combination therapy did not have any significant effect on fasting plasma insulin compared with metformin alone (−12.4 ± 3.8 vs. −17.4 ± 4.7 pmol/l; P = NS), it did have a tendency to decrease the postprandial incremental plasma insulin area under the curve (AUC) (−60.1 ± 19.4 vs. +0.5 ± 17.7 pmol · h/l; P = 0.059). This is probably caused by the effect of miglitol because miglitol alone resulted in a decrease in postprandial plasma insulin AUC of −72.8 ± 21.9 pmol · h/l. The reduction in postprandial plasma glucose and insulin could result in improved insulin sensitivity, as we have shown in elderly type 2 diabetic subjects with acarbose treatment (30).

Monotherapy with miglitol alone resulted in a treatment effect of −0.37% in HbA_1c compared with placebo (Fig. 1). This is a much smaller effect than that observed in previously reported studies (11,13,22,23,31), in which a reduction in HbA_1c between 0.74 and 1.19% was shown. It is interesting that Johnston et al. (11) could not show any better efficacy of miglitol 100 mg three times a day compared with 50 mg three times a day. However, postprandial plasma glucose was lower after 100 mg three times a day on the test meal. It is possible that the discordance between HbA_1c and postprandial plasma glucose was caused by the lower compliance at 100 mg three times a day because of increased gastrointestinal side effects. Similarly, in the present study, the effect of miglitol on incremental postprandial plasma glucose AUC during the test meal was significantly greater than with metformin alone (−34.7 ± 7.2 vs. −18.0 ± 7.3 mg · h/dl; P < 0.001), confirming the efficacy of the drug. Again, the discordance between HbA_1c and postprandial plasma glucose could be caused by poor compliance with the study medication. It is possible that slower titration of miglitol would reduce the gastrointestinal side effects and improve compliance, resulting in better improvement in HbA_1c.

Miglitol in combination with metformin was found to be safe and well tolerated in the study cohort. The incidence of gastrointestinal adverse events was higher in the treatment groups receiving miglitol; this is in line with the known mechanism of action of an α-glucosidase inhibitor. It is possible that slower titration of the drug, as with acarbose, could diminish the incidence of gastrointestinal side effects (32). Overall, the incidence of side effects with metformin plus miglitol combination therapy was not significantly different from that observed for either miglitol or metformin monotherapy, although the rate of discontinuations was higher with combination therapy. Only a trend toward an increase in the number of gastrointestinal side effects in the metformin plus miglitol combination therapy group was observed. There was no evidence of any serious adverse events associated with this combination regimen. No severe hypoglycemic episodes were observed in this study, and the incidence of mild-to-moderate hypoglycemia was low and comparable across all study treatments. The lack of deleterious effects on liver enzymes indicates that regular monitoring of liver function during combination therapy with miglitol and metformin is not required.

From the present study, it can be concluded that miglitol, the first pseudomonosaccharide α-glucosidase inhibitor, can be combined effectively with metformin therapy to give significantly greater reductions in HbA_1c and postprandial plasma glucose levels than metformin alone, with a good safety profile, in patients in whom type 2 diabetes is insufficiently controlled by diet alone. Miglitol and metformin may act synergistically to confer this additional glycemic control, especially on postprandial plasma glucose peaks, and may thereby help to reduce the risk of microvascular and macrovascular diabetic complications.

The Miglitol University Canadian Investigator Group included: Dr. Hertzel C. Gerstein, McMaster University Medical Center; Dr. Robert J. Josse, St. Michael’s Hospital; Dr. David Lau, Ottawa Civic Hospital; Dr. Lawrence A. Leiter, St. Michael’s Hospital; Dr. Ruth McManus and Dr. N. Wilson Rodger, St. Joseph’s Health Center; Dr. Thomas M.S. Wolever, University of Toronto, Toronto, ON; Dr. John A. Hunt, Lion’s Gate Hospital; Dr. Hugh D. Tildesley, Vancouver, BC; Dr. Pierre Maheux, Center Universitaire de Santé de l’Estrie; Dr. Jean-François Yale, McGill Nutrition Center, Quebec; PQ; Dr. Liam Murphy, University of Manitoba, Winnipeg, MB; Dr. Stuart A. Ross, Calgary Metabolic Education and Research Center; Dr. Edmond A. Ryan, Heritage Medical Research Center, Edmonton, AB; and Dr. Makram A. Boctor, Royal University Hospital, Saskatoon, SK.

This study was funded by an unrestricted research grant from Bayer Canada, Inc., and additional financial support was received from Sanofi-Synthelabo.

We thank the coordinating nurses and dieticians in all centers for their contribution.

This study was presented as a poster at the 60th annual scientific sessions of the American Diabetes Association, San Antonio, Texas, 9–13 June 2000.