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O R I G I N A L
The Synergistic Effect of Miglitol Plus
Metformin Combination Therapy in the
Treatment of Type 2 Diabetes
EAN-LOUIS CHIASSON, MD
ISA NADITCH, MD
FOR THE MIGLITOL CANADIAN UNIVERSITY
mode of action; it blocks oligosaccharide INVESTIGATOR GROUP
catabolism, delays carbohydrate diges-tion and absorption, and smooths andlowers postprandial plasma blood glu-cose peaks (6 –9). Substantial evidencesupports their use as monotherapy or ad- OBJECTIVE — To investigate the efficacy and safety of miglitol in combination with met-
junct therapy for poorly controlled type 2 formin in improving glycemic control in outpatients in whom type 2 diabetes is insufficiently diabetes (5,10 –14). Miglitol is the first RESEARCH DESIGN AND METHODS — In this multicenter, double-blind, placebo-
controlled study, 324 patients with type 2 diabetes were randomized, after an 8-week placebo run-in period, to treatment with either placebo, miglitol alone, metformin alone, or miglitol plus metformin for 36 weeks. The miglitol was titrated to 100 mg three times a day and metformin was administered at 500 mg three times a day. The primary efficacy criterion was change in HbA1c nylureas (11) as a glucose-lowering agent from baseline to the end of treatment. Secondary parameters included changes in fasting and postprandial plasma glucose and insulin levels, serum triglyceride levels, and responder rate.
number of clinical studies. A study ofmiglitol in combination with metformin RESULTS — A total of 318 patients were valid for intent-to-treat analysis. A reduction in mean
of Ϫ1.78% was observed with miglitol plus metformin combination therapy, which was significantly different from treatment with metformin alone (Ϫ1.25; P ϭ type 2 diabetic patients (18). However, it 0.002). Miglitol plus metformin also resulted in better metabolic control than metformin alone is still unclear whether miglitol can en- for fasting plasma glucose (Ϫ44.8 vs. Ϫ20.4 mg/dl; P ϭ 0.0025), 2-h postprandial glucose area under the curve (Ϫ59.0 vs. –18.0 mg/dl; P ϭ 0.0001), and responder rate (70.6 vs. 45.52%; P ϭ 0.0014). All therapies were well tolerated.
aged type 2 diabetic patients and whetherthe safety and tolerability profile of migli- CONCLUSIONS — In type 2 diabetic patients, miglitol in combination with metformin
gives greater glycemic improvement than metformin monotherapy.
fected by such a combination. Therefore,this study was performed to investigate Diabetes Care 24:989 –994, 2001
the efficacy and safety of miglitol in com-bination with metformin in improvingglycemic control, compared with met- Maintainingnormalplasmaglucose in combination. The biguanide met- formin monotherapy, in middle-aged
formin is a frequent first-line choice of insufficiently controlled by diet alone.
dations supported by recent data from the agent eventually necessitates the use of in- exercise as the first-line approach, fol- atic ␤-cell function (5) and eventually re- RESEARCH DESIGN AND
antihyperglycemic agents, either alone or METHODS — This was a multicenter,
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● From the 1Research Group on Diabetes and Metabolic Regulation, Research Center, Centre Hospitalier de controlled parallel group study. Eligible l’Universite´ de Montre´al, Montreal, Quebec, Canada; and 2Sanofi-Synthelabo, Paris, France.
Address correspondence and reprint requests to Jean-Louis Chiasson, MD, Research Group on Diabetes and Metabolic Regulation, Research Center CHUM, Hoˆtel-Dieu CHUM, 3850 St. Urbain, 8 –202, Montreal,Quebec, Canada H2W 1T8. E-mail: [email protected].
Received for publication 28 November 2000 and accepted in revised form 6 February 2001.
L.N. is an employee of Sanofi-Synthelabo, which is involved in the marketing of the product miglitol for Abbreviations: AUC, area under the curve; ITT, intent to treat.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
DIABETES CARE, VOLUME 24, NUMBER 6, JUNE 2001 Miglitol plus metformin in type 2 diabetes
events, gastrointestinal diseases, medica- tions likely to affect intestinal motility or meal. The proportion of responders in the different treatment groups was also eval- tivity to miglitol or metformin, and a his- uated, in which a clinically significant re- tory of lactic acidosis. Patients who were analysis of variance techniques. All four ing, at week –2 and baseline, and there- procedures, patients who fulfilled the el- igibility criteria gave their written in- 20, 28, and 36) after randomization. Rou- sured at week Ϫ2 and at every subsequent least one dose of trial medication were in- diet (19). They were also advised regard- ing exercise, mainly walking 20 –30 min at least three times per week. The diet was analyzed in terms of the percentage of pa- reinforced after 1 month, and if the HbA1c gated by the occurrence of adverse events; considered dietary failure. Patients with RESULTS — A total of 324 patients
were eligible for randomization to match- transketolase, folate, vitamin B12, vitamin A, and retinol protein binding), and stan- and at all visits thereafter. Routine bio- force-titrated as follows: administration values after randomization. A total of 318 formed at baseline and at the final visit.
ters and clinical data for all randomized tal signs and weight were recorded at each patients, age, race (predominately Cauca- sian), weight and BMI, sex ratio, duration 200.3 Ϯ 93.3 days; miglitol 190.9 Ϯ 90.5 were performed at a central laboratory.
change in HbA1c level from baseline to the end of the double-blind treatment for the To detect a mean difference of 0.6% in the groups from baseline to the end of treat- ment, with ␣ ϭ 0.05 and a power (1–␤) of per treatment group were required. To ac- prandial plasma glucose and insulin levels count for multicenter variability, this was different treatments are shown in Table 2.
increased by 20% to 75 patients per treat- There was an increase of 0.38 Ϯ 0.12% in line to the end of treatment, measured at the placebo group, virtually no change in the miglitol group (0.02 Ϯ 0.10%), a de- formin group, and a decrease of Ϫ1.39 Ϯ DIABETES CARE, VOLUME 24, NUMBER 6, JUNE 2001 Chiasson and Naditch
Table 1—Demographic and clinical data on randomized patients
compared with metformin monotherapy(34.6%).
active treatment groups, in contrast to an increase in patients taking placebo (Table therapy were significantly greater (P Ͻ fasting plasma glucose was also greater in receiving metformin monotherapy (P ϭ prandial plasma insulin at 60 min did not reach statistical significance for the com- Data are means Ϯ SD and n (%). MIG, miglitol; MET, metformin.
monotherapy, a statistically significantdifference was observed in favor of the combination group (P ϭ 0.002, compar- (P ϭ 0.0143 and 0.0177, respectively) actual treatment effect is illustrated in Fig.
(P ϭ 0.0014) more patients were classi- fied as responders (i.e., showed Ն15% re- pared with placebo was – 0.37% for migli- tients’ disease status. Because the patients which stimulates release of pancreatic in- sulin. It is clear that lower postprandial plasma insulin levels despite higher post- Table 2—Mean change from baseline in selected study variables (ITT population)
Incremental plasma glucose AUC (mg ⅐ h/dl) Incremental plasma insulin AUC (pmol ⅐ h/l) Data are mean Ϯ SE. NS, not significant, MIG, miglitol, MET, metformin.
DIABETES CARE, VOLUME 24, NUMBER 6, JUNE 2001 Miglitol plus metformin in type 2 diabetes
and 19 (25.0%) in the metformin plusmiglitol combination therapy group. Flat-ulence and diarrhea were the most com-mon adverse events associated withpremature discontinuation from the study.
rious adverse events postrandomization:3 of these events occurred in the placebogroup, 2 in the miglitol group, 4 in themetformin group, and 9 in the metforminplus miglitol combination group. None ofthese serious adverse events were deemedby the investigators to be either probablyor possibly related to the study drug. Nodeaths occurred during this study. No se-vere hypoglycemic episodes were re-ported. The rate of hypoglycemia wasslightly higher in patients receiving met-formin plus miglitol combination therapy(13.2 vs. 9.6% receiving metformin), butthis difference was not clinically significant.
Figure 1—The mean absolute change (open bar) and the placebo-subtracted change (closed bar)in HbA from baseline to end of treatment for miglitol monotherapy, metformin monotherapy, and clinically or statistically significant differ- miglitol plus metformin combination therapy. ences in hematological and biochemicalparameters or urinalysis. One patient inthe metformin group showed an elevation decreased ␤-cell function. This could be caused by glucotoxicity resulting from in- alanine aminotransferase, but this was not which is an increased incidence of 3.4%.
considered clinically relevant. Glycosuria from baseline to the end of treatment did gastrointestinal; flatulence and diarrhea laboratory abnormality or change in vital signs during the study. Although all treat- those receiving the other treatments.
the safety analysis. After randomization, tients discontinued the study prematurely because of adverse events: 2 (2.4%) in the placebo group, 11 (13.4%) in the miglitol the other treatment groups: Ϫ1.87 kg formetformin plus miglitol combination Table 3—Incidence of most common adverse events
compared with – 0.79 kg for metforminalone, – 0.42 kg for miglitol alone, and Ϫ0.69 kg for placebo (P ϭ NS).
CONCLUSIONS — Previous studies
tion with sulfonylureas in type 2 diabetes tic effect on glycemic control, as indicated Data are n (%). Common adverse events are considered those with incidence patients in whom type 2 diabetes is insuf- group. MIG, miglitol, MET, metformin.
DIABETES CARE, VOLUME 24, NUMBER 6, JUNE 2001 Chiasson and Naditch
ication. It is possible that slower titration significantly greater reductions in HbA1c, rectly by increasing peripheral tissue sen- of miglitol would reduce the gastrointes- sitivity to insulin (27); miglitol acts at the tinal side effects and improve compliance, small intestine by delaying the digestion resulting in better improvement in HbA1c.
the end of treatment of patients receiving formin was found to be safe and well tol- erated in the study cohort. The incidence given by current clinical practice recom- decreasing insulin resistance (29), which mechanism of action of an ␣-glucosidase inhibitor. It is possible that slower titra- tributory factor to the superiority of the tion of the drug, as with acarbose, could diminish the incidence of gastrointestinal side effects (32). Overall, the incidence of did not have any significant effect on fast- side effects with metformin plus miglitol cally significant in achieving the treat- ment goal. The clinical importance of this formin alone (Ϫ12.4 Ϯ 3.8 vs. Ϫ17.4 Ϯ cantly different from that observed for ei- 4.7 pmol/l; P ϭ NS), it did have a ten- abetes Study data, which indicates that for dency to decrease the postprandial incre- although the rate of discontinuations was trend toward an increase in the number of complications (24). The superiority of the 17.7 pmol ⅐ h/l; P ϭ 0.059). This is prob- gastrointestinal side effects in the met- ably caused by the effect of miglitol be- strated by the higher response rate of pa- cause miglitol alone resulted in a decrease dence of any serious adverse events asso- Ϫ72.8 Ϯ 21.9 pmol ⅐ h/l. The reduction ciated with this combination regimen. No those of Mooradian in elderly type 2 dia- lin could result in improved insulin sen- served in this study, and the incidence of sitivity, as we have shown in elderly type ments. The lack of deleterious effects on macrovascular complications (25,26).
liver enzymes indicates that regular mon- sulted in a treatment effect of Ϫ0.37% in itoring of liver function during combina- dial plasma glucose peaks in clinical prac- HbA1c compared with placebo (Fig. 1).
plasma glucose levels. Because ␣-glucosi- (11,13,22,23,31), in which a reduction in dase inhibitors have been reported previ- monosaccharide ␣-glucosidase inhibitor, shown. It is interesting that Johnston et al.
plasma glucose peaks (8 –10), miglitol in (11) could not show any better efficacy of formin alone, with a good safety profile, as well as overall glycemic control, espe- cially for patients with postprandial hyper- the test meal. It is possible that the discor- insufficiently controlled by diet alone.
glycemia refractory to other treatments.
tically to confer this additional glycemic because of increased gastrointestinal side effects. Similarly, in the present study, the and macrovascular diabetic complications.
gested that the administration of the two drugs together has a synergistic effect on with metformin alone (Ϫ34.7 Ϯ 7.2 vs.
Acknowledgments — This study was funded
glycemic control; this is plausible because Ϫ18.0 Ϯ 7.3 mg ⅐ h/dl; P Ͻ 0.001), con- by an unrestricted research grant from Bayer firming the efficacy of the drug. Again, the Canada, Inc., and additional financial support glucose levels through completely differ- was received from Sanofi-Synthelabo.
We thank the coordinating nurses and die- on the liver directly by decreasing hepatic ticians in all centers for their contribution.
DIABETES CARE, VOLUME 24, NUMBER 6, JUNE 2001 Miglitol plus metformin in type 2 diabetes
This study was presented as a poster at the emergence of ␣-glucosidase inhibitors.
60th annual scientific sessions of the American 21. Rossetti L, Giaccari A, DeFronzo RA: Glu- Diabetes Association, San Antonio, Texas, 9. Holman RR, Steemson J, Turner RC: Post- cose toxicity. Diabetes Care 13:610 – 630, prandial glycaemic reduction by an ␣-glu- cosidase inhibitor in type 2 diabetic patients 22. Johnston PS, Feig PU, Coniff RF, Krol A, APPENDIX
with therapeutically attained basal normo- glycaemia. Diabetes Res 18:149 –153, 1991 The Miglitol University Canadian Investi- 10. Heinz G, Komjati M, Korn A, Waldhausl patients with ␣-glucosidase inhibition.
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Eur J Clin Pharmacol 37:33–36, 1989 trated-dose ␣-glucosidase inhibition in Hospital; Dr. Lawrence A. Leiter, St. Mi- Santiago JV, Pi-Sunyer FX, Krol A: Effects patients. Diabetes Care 21:409 – 415, 1998 Dr. N. Wilson Rodger, St. Joseph’s Health of the carbohydrase inhibitor miglitol in 24. Stratton IM, Adler AI, Neil HA, Matthews sulfonylurea-treated NIDDM patients. Di- versity of Toronto, Toronto, ON; Dr. John A. Hunt, Lion’s Gate Hospital; Dr. Hugh vascular complications of type 2 diabetes Maheux, Center Universitaire de Sante´ de l’Estrie; Dr. Jean-Franc¸ois Yale, McGill 25. Hanefeld M, Fischer S, Julius U, Schulze J, 13. Segal P, Feig PU, Schernthaner G, Ratz- Risk factors for myocardial infarction and The efficacy and safety of miglitol therapy low-up. Diabetologia 39:1577–1583, 1996 26. Coutinho M, Gerstein HC, Wang Y, Yusuf diet alone. Diabetes Care 20:687– 691, 14. Escobar-Jimenez F, Barajas C, De Leiva A, egression analysis of published data from 20 studies of 95,783 individuals followed References
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