C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n
`O R I G I N A L
`A R T I C L E
`
`The Synergistic Effect of Miglitol Plus
`Metformin Combination Therapy in the
`Treatment of Type 2 Diabetes
`
`1
`JEAN-LOUIS CHIASSON, MD
`2
`LISA NADITCH, MD
`FOR THE MIGLITOL CANADIAN UNIVERSITY
`INVESTIGATOR GROUP
`
`OBJECTIVE — To investigate the efficacy and safety of miglitol in combination with met-
`formin in improving glycemic control in outpatients in whom type 2 diabetes is insufficiently
`controlled by diet alone.
`
`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
`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.
`
`RESULTS — A total of 318 patients were valid for intent-to-treat analysis. A reduction in mean
`placebo-subtracted HbA1c of 21.78% was observed with miglitol plus metformin combination
`therapy, which was significantly different from treatment with metformin alone (21.25; P 5
`0.002). Miglitol plus metformin also resulted in better metabolic control than metformin alone
`for fasting plasma glucose (244.8 vs. 220.4 mg/dl; P 5 0.0025), 2-h postprandial glucose area
`under the curve (259.0 vs. –18.0 mg/dl; P 5 0.0001), and responder rate (70.6 vs. 45.52%; P 5
`0.0014). All therapies were well tolerated.
`
`CONCLUSIONS — In type 2 diabetic patients, miglitol in combination with metformin
`gives greater glycemic improvement than metformin monotherapy.
`
`Diabetes Care 24:989 –994, 2001
`
`M aintaining normal plasma glucose
`
`in combination. The biguanide met-
`formin is a frequent first-line choice of
`levels is a key factor in reducing
`antidiabetic medication (3,4). However,
`the risk of developing diabetes
`monotherapy with any hypoglycemic
`complications (1,2). Current recommen-
`agent eventually necessitates the use of in-
`dations supported by recent data from the
`creasing doses because type 2 diabetes
`U.K. Prospective Diabetes Study data em-
`worsens over time with declining pancre-
`phasize life-style management, diet, and
`atic b-cell function (5) and eventually re-
`exercise as the first-line approach, fol-
`lowed by therapy with hypoglycemic or
`quires addition of a second antidiabetic
`antihyperglycemic agents, either alone or
`medication.
`c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
`
`From the 1Research Group on Diabetes and Metabolic Regulation, Research Center, Centre Hospitalier de
`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, Hoˆ tel-Dieu CHUM, 3850 St. Urbain, 8 –202, Montreal,
`Quebec, Canada H2W 1T8. E-mail: jean.louis.chiasson@umontreal.ca.
`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
`the treatment of type 2 diabetes.
`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
`factors for many substances.
`
`The recently developed class of
`a-glucosidase inhibitors has a unique
`mode of action; it blocks oligosaccharide
`catabolism, delays carbohydrate diges-
`tion and absorption, and smooths and
`lowers postprandial plasma blood glu-
`cose peaks (6 –9). Substantial evidence
`supports their use as monotherapy or ad-
`junct therapy for poorly controlled type 2
`diabetes (5,10 –14). Miglitol is the first
`pseudomonosaccharide a-glucosidase in-
`hibitor derived from 1-deoxynojirimycin
`and is structurally a glucose analog
`(15,16). Its efficacy in monotherapy
`(13,17) and in combination with sulfo-
`nylureas (11) as a glucose-lowering agent
`in type 2 diabetes has been shown in a
`number of clinical studies. A study of
`miglitol in combination with metformin
`has been reported previously in elderly
`type 2 diabetic patients (18). However, it
`is still unclear whether miglitol can en-
`hance glycemic control when given in
`combination with metformin in middle-
`aged type 2 diabetic patients and whether
`the safety and tolerability profile of migli-
`tol and metformin as monotherapy is af-
`fected by such a combination. Therefore,
`this study was performed to investigate
`the efficacy and safety of miglitol in com-
`bination with metformin in improving
`glycemic control, compared with met-
`formin monotherapy, in middle-aged
`outpatients in whom type 2 diabetes was
`insufficiently controlled by diet alone.
`The primary control group in this study
`was the metformin arm. Comparisons
`with miglitol monotherapy and placebo
`were also performed.
`
`RESEARCH DESIGN AND
`METHODS — 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
`HbA1c level was $7.2 and #9.5%. The
`major exclusion criteria included type 1
`diabetes, the presence of major debili-
`tating diseases, recent cardiovascular
`
`DIABETES CARE, VOLUME 24, NUMBER 6, JUNE 2001
`
`989
`
`MYLAN Ex. 1012, Page 1
`
`

`
`Miglitol plus metformin in type 2 diabetes
`
`events, gastrointestinal diseases, medica-
`tions likely to affect intestinal motility or
`the absorption of nutrients, hypersensi-
`tivity to miglitol or metformin, and a his-
`tory of lactic acidosis. Patients who were
`taking either sulfonylurea or metformin
`below the maximum dose could be eligi-
`ble as long as the antidiabetic drug was
`discontinued. Before starting any study
`procedures, patients who fulfilled the el-
`igibility criteria gave their written in-
`formed 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 re-
`garding a well-balanced weight-reducing
`diet (19). They were also advised regard-
`ing exercise, mainly walking 20 –30 min
`at least three times per week. The diet was
`reinforced after 1 month, and if the HbA1c
`was still $7.2% by 2 months, they were
`considered dietary failure. Patients with
`HbA1c 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 match-
`ing 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. Adminis-
`tration 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 ad-
`vised regarding regular home blood-
`glucose monitoring.
`
`Efficacy and safety evaluation
`The primary efficacy criterion was the
`change in HbA1c 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 postran-
`domization efficacy value.
`Secondary efficacy parameters in-
`cluded the change in fasting and post-
`prandial plasma glucose and insulin levels
`and serum triglyceride levels from base-
`line to the end of treatment, measured at
`0, 60, 90, and 120 min after a standard-
`ized liquid test breakfast (55% carbohy-
`drate, 30% fat, and 15% protein;
`providing ;450 kcal). The study medica-
`
`tions were given with the tolerance test
`meal. The proportion of responders in the
`different treatment groups was also eval-
`uated, in which a clinically significant re-
`sponse was defined as either a $15%
`reduction in HbA1c from baseline or an
`HbA1c level ,7.0%.
`HbA1c was measured during screen-
`ing, at week –2 and baseline, and there-
`after at each visit (weeks 4, 8, 12, 16,
`20, 28, and 36) after randomization. Rou-
`tine fasting plasma glucose was mea-
`sured at week 22 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 investi-
`gated by the occurrence of adverse events;
`hypoglycemic events; changes in vital
`signs; and changes in laboratory values,
`including biochemical parameters, hema-
`tology, vitamins (thiamine-dependent
`transketolase, folate, vitamin B12, vitamin
`A, and retinol protein binding), and stan-
`dard urinalysis. Adverse events were
`monitored and documented at week –2
`and at all visits thereafter. Routine bio-
`chemistry, hematology, and urinalysis
`were performed at screening, baseline,
`and weeks 12, 20, and 36 or at premature
`termination; vitamin assays were per-
`formed 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 vi-
`tal signs and weight were recorded at each
`visit. Routine laboratory determinations
`were performed using standard method-
`ology by local laboratories, whereas the
`preprandial and postprandial efficacy
`measurements and vitamin evaluations
`were performed at a central laboratory.
`
`Statistical analysis
`To detect a mean difference of 0.6% in the
`change in HbA1c between treatment
`groups from baseline to the end of treat-
`ment, with a 5 0.05 and a power (1–b) of
`at least 90%, a minimum of 60 patients
`per treatment group were required. To ac-
`count for multicenter variability, this was
`increased by 20% to 75 patients per treat-
`ment arm.
`Treatment groups were compared at
`baseline for demographic variables and
`other prognostic factors, such as family
`history of type 2 diabetes, medical his-
`
`tory, vital signs, and concomitant medi-
`cations. The primary efficacy parameter
`was the change in HbA1c 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 or-
`thogonal contrasts.
`The primary analysis of efficacy was
`performed on the ITT population, which
`included all patients who had both base-
`line and postrandomization efficacy val-
`ues. 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 in-
`cluded in the safety analysis. Adverse
`events and other safety parameters were
`analyzed in terms of the percentage of pa-
`tients in whom they occurred.
`
`RESULTS — A total of 324 patients
`were randomized in the study: 83 to pla-
`cebo, 82 to miglitol monotherapy, 83 to
`metformin monotherapy, and 76 to met-
`formin/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 be-
`cause of the absence of recorded HbA1c
`values after randomization. A total of 318
`patients (98%) were valid for the ITT
`analysis. Selected demographic parame-
`ters and clinical data for all randomized
`patients are shown in Table 1. Treatment
`groups were comparable for number of
`patients, age, race (predominately Cauca-
`sian), weight and BMI, sex ratio, duration
`of diabetes, and baseline HbA1c. The
`mean durations of treatment exposure by
`treatment group were as follows: placebo
`200.3 6 93.3 days; miglitol 190.9 6 90.5
`days; metformin 231.6 6 70.1 days; met-
`formin plus miglitol combination
`203.3 6 94.6 days.
`The primary comparison for all effi-
`cacy parameters was between the met-
`formin plus miglitol combination and
`metformin monotherapy treatment
`groups. The mean changes in HbA1c val-
`ues (means 6 SEM) in response to the
`different treatments are shown in Table 2.
`There was an increase of 0.38 6 0.12% in
`the placebo group, virtually no change in
`the miglitol group (0.02 6 0.10%), a de-
`crease of 20.85 6 0.12% in the met-
`formin group, and a decrease of 21.39 6
`0.11% in the metformin plus miglitol
`
`990
`
`DIABETES CARE, VOLUME 24, NUMBER 6, JUNE 2001
`
`MYLAN Ex. 1012, Page 2
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`

`
`Table 1—Demographic and clinical data on randomized patients
`
`Parameters
`
`Placebo
`
`MIG
`
`MET
`
`MIG 1 MET
`
`83
`57.7 6 9.9
`88.6 6 14.1
`
`82
`57.3 6 9.0
`91.0 6 15.5
`
`n
`Age (years)
`Weight (kg)
`Race
`Caucasian
`Black
`Asian
`Other
`BMI (kg/m2)
`Male/female
`Duration of diabetes (years)
`Previous use of oral
`hypoglycemics agents
`42 (51.2)
`48 (57.8)
`None
`18 (22.0)
`22 (26.5)
`Metformin
`25 (30.5)
`33 (39.8)
`Sulphonylureas
`8.2 6 0.9
`8.1 6 0.7
`HbAlc(%)
`Data are means 6 SD and n (%). MIG, miglitol; MET, metformin.
`
`76 (91.6)
`1 (1.2)
`4 (4.8)
`2 (2.4)
`31.1 6 4.4
`56/27
`5.1 6 4.9
`
`73 (89.0)
`0 (0.0)
`4 (4.9)
`5 (6.1)
`31.1 6 4.5
`64/18
`5.2 6 4.7
`
`83
`57.9 6 8.6
`89.0 6 17.8
`
`76
`58.9 6 7.9
`85.6 6 13.1
`
`73 (88.0)
`1 (1.2)
`6 (7.2)
`3 (3.6)
`30.7 6 5.1
`61/22
`7.5 6 7.4
`
`70 (92.1)
`3 (3.9)
`3 (3.9)
`0 (0.0)
`29.5 6 3.8
`59/17
`6.1 6 5.5
`
`55 (66.3)
`19 (22.9)
`43 (51.8)
`8.2 6 0.9
`
`46 (60.5)
`16 (21.1)
`35 (46.1)
`8.3 6 0.8
`
`combination group (P 5 0.002, compar-
`ing miglitol plus metformin and met-
`formin monotherapy). The placebo-
`substracted mean change in HbA1c or the
`actual treatment effect is illustrated in Fig.
`1. The mean reduction in HbA1c com-
`pared with placebo was – 0.37% for migli-
`tol treatment, 21.25% for metformin
`treatment, and –1.78% for metformin
`plus miglitol treatment. The end-of-
`treatment mean 6 SEM of HbA1c was
`8.5 6 0.1% for placebo, 8.2 6 0.2% for
`miglitol, 7.3 6 0.1% for metformin, and
`6.9 6 0.1% for metformin plus miglitol
`
`combination. The latter group achieved
`the targeted HbA1c level of ,7.0% recom-
`mended by the American Diabetes Asso-
`ciation (20). Furthermore, significantly
`(P 5 0.0014) more patients were classi-
`fied as responders (i.e., showed $15% re-
`duction from baseline in HbA1c or
`,7.0%) to metformin
`achieved HbA1c
`plus miglitol combination therapy
`(70.6%) compared with metformin
`monotherapy (45.5%); even if only
`,7.0% was used to define re-
`HbA1c
`sponders, combination therapy still
`maintained a high responder rate (64.0%)
`
`Table 2—Mean change from baseline in selected study variables (ITT population)
`
`Chiasson and Naditch
`
`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 met-
`formin monotherapy. The reduction in
`fasting plasma glucose was also greater in
`patients receiving metformin plus migli-
`tol combination therapy than in patients
`receiving metformin monotherapy (P 5
`0.0025).
`Although the mean change in post-
`prandial plasma insulin at 60 min did not
`reach statistical significance for the com-
`parison 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 5 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 pa-
`tients’ 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 in-
`sulin. It is clear that lower postprandial
`plasma insulin levels despite higher post-
`prandial plasma glucose levels suggests
`
`Parameters
`
`Placebo
`
`MIG
`
`MET
`
`MIG 1 MET
`
`MET versus
`MIG 1 MET (P)
`
`82
`0.38 6 0.12
`20.9 6 5.7
`
`75
`81
`80
`0.02 6 0.10 20.85 6 0.12 21.39 6 0.11
`21.0 6 5.6
`220.4 6 5.1
`244.8 6 5.1
`
`228.7 6 7.0
`216.3 6 7.6
`6.2 6 7.8
`233.7 6 7.7
`224.1 6 8.5
`6.9 6 8.3
`237.9 6 7.9
`223.2 6 8.5
`4.0 6 8.5
`218.0 6 7.3
`234.7 6 7.2
`7.9 6 7.0
`20.3 6 14.0 218.5 6 14.0 217.4 6 4.7
`
`281.9 6 8.1
`295.4 6 9.1
`286.4 6 9.3
`259.0 6 7.2
`212.4 6 3.8
`
`n
`HbAlc (%)
`Fasting plasma glucose (mg/dl)
`Postprandial plasma glucose (mg/dl)
`60 min
`90 min
`120 min
`Incremental plasma glucose AUC (mg z h/dl)
`Fasting plasma insulin (pmol/l)
`Postprandial plasma insulin (pmol/l)
`248.8 6 18.0 268.2 6 18.1 219.9 6 15.0 233.5 6 14.4
`60 min
`240.3 6 17.4 288.4 6 18.6 218.9 6 14.8 281.6 6 18.1
`90 min
`248.4 6 19.0 263.6 6 19.8
`3.9 6 14.8 259.1 6 19.3
`120 min
`245.0 6 23.1 272.8 6 21.9
`0.5 6 17.7
`260.16 19.4
`Incremental plasma insulin AUC (pmol
`20.69 6 0.27 20.42 6 0.29 20.79 6 0.33 21.87 6 0.33
`Body weight (kg)
`Data are mean 6 SE. NS, not significant, MIG, miglitol, MET, metformin.
`
`z h/l)
`
`0.002
`0.0025
`
`,0.0001
`,0.0001
`,0.0001
`
`NS
`
`NS
`0.0143
`0.0177
`0.0592
`NS
`
`DIABETES CARE, VOLUME 24, NUMBER 6, JUNE 2001
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`991
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`MYLAN Ex. 1012, Page 3
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`

`
`Miglitol plus metformin in type 2 diabetes
`
`Figure 1—The mean absolute change (open bar) and the placebo-subtracted change (closed bar)
`in HbA1c from baseline to end of treatment for miglitol monotherapy, metformin monotherapy, and
`miglitol plus metformin combination therapy.
`
`decreased b-cell function. This could be
`caused by glucotoxicity resulting from in-
`creased plasma glucose in the placebo
`group (21). Changes in fasting serum in-
`sulin and triglyceride levels observed
`from baseline to the end of treatment did
`not differ significantly between met-
`formin 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 expe-
`riencing 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 pa-
`tients receiving miglitol or metformin
`plus miglitol combination therapy than
`those receiving the other treatments.
`A total of 37 (11.4%) randomized pa-
`tients 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,
`
`Table 3—Incidence of most common adverse events
`
`Placebo
`
`MIG
`
`MET
`
`MIG 1 MET
`
`and 19 (25.0%) in the metformin plus
`miglitol combination therapy group. Flat-
`ulence and diarrhea were the most com-
`mon adverse events associated with
`premature discontinuation from the study.
`A total of 16 patients reported 18 se-
`rious 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 se-
`vere hypoglycemic episodes were re-
`ported. The rate of hypoglycemia was
`slightly higher in patients receiving met-
`formin 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 differ-
`ences 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 frequent-
`ly for the metformin plus miglitol com-
`bination 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 treat-
`ment groups showed a mean decrease in
`body weight, intergroup comparison sug-
`gested that patients who received met-
`formin plus miglitol combination therapy
`lost more weight (Table 2) than those in
`the other treatment groups: 21.87 kg for
`metformin plus miglitol combination
`compared with – 0.79 kg for metformin
`alone, – 0.42 kg for miglitol alone, and
`20.69 kg for placebo (P 5 NS).
`
`CONCLUSIONS — Previous studies
`have shown the efficacy and safety of
`miglitol as monotherapy and in combina-
`tion with sulfonylureas in type 2 diabetes
`(11,13,18,20,22,23). The present study
`demonstrates that miglitol in combina-
`tion with metformin provides a synergis-
`tic effect on glycemic control, as indicated
`by the marked reductions in HbA1c and
`plasma glucose levels in middle-aged
`patients in whom type 2 diabetes is insuf-
`ficiently controlled by dietary manage-
`
`76
`74 (97.4)
`
`83
`71 (85.5)
`
`82
`79 (96.3)
`
`83
`78 (94.0)
`
`n
`Any adverse events
`Digestive system
`66 (86.8)
`50 (60.2)
`58 (70.7)
`29 (34.9)
`Any event
`48 (63.2)
`24 (28.9)
`46 (56.1)
`12 (14.5)
`Flatulence
`42 (53.3)
`23 (27.7)
`35 (42.7)
`9 (10.8)
`Diarrhea
`7 (9.2)
`7 (8.4)
`5 (6.1)
`5 (6.0)
`Constipation
`13 (17.1)
`14 (16.9)
`7 (8.5)
`2 (2.4)
`Nausea
`11 (14.5)
`7 (8.4)
`6 (7.3)
`2 (2.4)
`Dyspepsia
`6 (7.9)
`5 (6.0)
`4 (4.9)
`2 (2.4)
`Abdominal cramps
`10 (13.2)
`8 (9.6)
`7 (8.5)
`7 (8.4)
`Hypoglycemia
`Data are n (%). Common adverse events are considered those with incidence .7% in at least one treatment
`group. MIG, miglitol, MET, metformin.
`
`992
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`DIABETES CARE, VOLUME 24, NUMBER 6, JUNE 2001
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`MYLAN Ex. 1012, Page 4
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`

`
`ment. Combination therapy produced
`significantly greater reductions in HbA1c,
`fasting plasma glucose, and particularly
`postprandial plasma glucose than met-
`formin monotherapy. The mean HbA1c at
`the end of treatment of patients receiving
`metformin was 7.3%, which is slightly
`higher than the goal HbA1c level of ,7%
`given by current clinical practice recom-
`mendations (20), whereas patients on
`metformin plus miglitol combination
`therapy achieved the treatment goal with
`a mean end-of-treatment HbA1c level of
`6.9%. The greater reduction in HbA1c in
`patients on the metformin plus miglitol
`combination therapy is therefore clini-
`cally significant in achieving the treat-
`ment goal. The clinical importance of this
`is supported by the U.K. Prospective Di-
`abetes Study data, which indicates that for
`every 1% reduction in HbA1c, there is a
`35% reduction in risk of microvascular
`complications (24). The superiority of the
`combination treatment was also demon-
`strated by the higher response rate of pa-
`tients on the metformin plus miglitol
`combination therapy than on mono-
`therapy. These observations support
`those of Mooradian in elderly type 2 dia-
`betic subjects (18).
`Postprandial hyperglycemia is recog-
`nized as an independent risk factor for
`macrovascular complications (25,26).
`However, the normalization of postpran-
`dial plasma glucose peaks in clinical prac-
`tice is recognized as more problematic
`than the overall management of fasting
`plasma glucose levels. Because a-glucosi-
`dase inhibitors have been reported previ-
`ously to smooth and lower postprandial
`plasma glucose peaks (8 –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, espe-
`cially for patients with postprandial hyper-
`glycemia refractory to other treatments.
`The reductions in fasting and post-
`prandial plasma glucose as well as in
`HbA1c in response to metformin plus
`miglitol combination therapy were
`greater than the added effects of both
`miglitol and metformin alone. It is sug-
`gested 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 differ-
`ent mechanisms of action. Metformin acts
`on the liver directly by decreasing hepatic
`
`glucose production and release and indi-
`rectly by increasing peripheral tissue sen-
`sitivity to insulin (27); miglitol acts at the
`small intestine by delaying the digestion
`of complex carbohydrates (28). Interest-
`ingly, 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 con-
`tributory factor to the superiority of the
`metformin plus miglitol combination
`therapy. Although combination therapy
`did not have any significant effect on fast-
`ing plasma insulin compared with met-
`formin alone (212.4 6 3.8 vs. 217.4 6
`4.7 pmol/l; P 5 NS), it did have a ten-
`dency to decrease the postprandial incre-
`mental plasma insulin area under the
`curve (AUC) (260.1 6 19.4 vs. 10.5 6
`17.7 pmol z h/l; P 5 0.059). This is prob-
`ably caused by the effect of miglitol be-
`cause miglitol alone resulted in a decrease
`in postprandial plasma insulin AUC of
`272.8 6 21.9 pmol z h/l. The reduction
`in postprandial plasma glucose and insu-
`lin could result in improved insulin sen-
`sitivity, as we have shown in elderly type
`2 diabetic subjects with acarbose treat-
`ment (30).
`Monotherapy with miglitol alone re-
`sulted in a treatment effect of 20.37% in
`HbA1c 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
`HbA1c 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 com-
`pared with 50 mg three times a day. How-
`ever, postprandial plasma glucose was
`lower after 100 mg three times a day on
`the test meal. It is possible that the discor-
`dance between HbA1c 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 post-
`prandial plasma glucose AUC during the
`test meal was significantly greater than
`with metformin alone (234.7 6 7.2 vs.
`218.0 6 7.3 mg z h/dl; P , 0.001), con-
`firming the efficacy of the drug. Again, the
`discordance between HbA1c and post-
`prandial plasma glucose could be caused
`by poor compliance with the study med-
`
`Chiasson and Naditch
`
`ication. It is possible that slower titration
`of miglitol would reduce the gastrointes-
`tinal side effects and improve compliance,
`resulting in better improvement in HbA1c.
`Miglitol in combination with met-
`formin was found to be safe and well tol-
`erated 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 a-glucosidase
`inhibitor. It is possible that slower titra-
`tion 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 signifi-
`cantly different from that observed for ei-
`ther 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 met-
`formin plus miglitol combination therapy
`group was observed. There was no evi-
`dence of any serious adverse events asso-
`ciated with this combination regimen. No
`severe hypoglycemic episodes were ob-
`served in this study, and the incidence of
`mild-to-moderate hypoglycemia was low
`and comparable across all study treat-
`ments. The lack of deleterious effects on
`liver enzymes indicates that regular mon-
`itoring of liver function during combina-
`tion therapy with miglitol and metformin
`is not required.
`From the present study, it can be con-
`cluded that miglitol, the first pseudo-
`monosaccharide a-glucosidase inhibitor,
`can be combined effectively with met-
`formin therapy to give significantly
`greater reductions in HbA1c and post-
`prandial plasma glucose levels than met-
`formin alone, with a good safety profile,
`in patients in whom type 2 diabetes is
`insufficiently controlled by diet alone.
`Miglitol and metformin may act synergis-
`tically 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.
`
`Acknowledgments— 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 die-
`ticians in all centers for their contribution.
`
`DIABETES CARE, VOLUME 24, NUMBER 6, JUNE 2001
`
`993
`
`MYLAN Ex. 1012, Page 5
`
`

`
`Miglitol plus metformin in type 2 diabetes
`
`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.
`
`APPENDIX
`The Miglitol University Canadian Investi-
`gator Group included: Dr. Hertzel C. Ger-
`stein, McMaster University Medical
`Center; Dr. Robert J. Josse, St. Michael’s
`Hospital; Dr. David Lau, Ottawa Civic
`Hospital; Dr. Lawrence A. Leiter, St. Mi-
`chael’s Hospital; Dr. Ruth McManus and
`Dr. N. Wilson Rodger, St. Joseph’s Health
`Center; Dr. Thomas M.S. Wolever, Uni-
`versity of Toronto, Toronto, ON; Dr. John
`A. Hunt, Lion’s Gate Hospital; Dr. Hugh
`D. Tildesley, Vancouver, BC; Dr. Pierre
`Maheux, Center Universitaire de Sante´ de
`l’Estrie; Dr. Jean-Franc¸ois Yale, McGill
`Nutrition Center, Quebec; PQ; Dr. Liam
`Murphy, University of Manitoba, Win-
`nipeg, MB; Dr. Stuart A. Ross, Calgary
`Metabolic Education and Research Cen-
`ter; Dr. Edmond A. Ryan, Heritage Medi-
`cal Research Center, Edmonton, AB; and
`Dr. Makram A. Boctor, Royal University
`Hospital, Saskatoon, SK.
`
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