`Double-Blind, Placebo-controlled, Dose-Response Trial
`Alan J. Garber, MD, PhD, Houston, Texas, Theodore G. Duncan, MD, Philadelphia, Pennsylvania,
`Anita M. Goodman, MD, New York, New York, Donna J. Mills, RN, BSN, Princeton, New Jersey,
`Jane L. Rohlf, MD, West Point, Pennsylvania
`
`PURPOSE: To study the efficacy and safety of
`various dosages of metformin as compared with
`placebo in patients with type II diabetes mellitus.
`PATIENTS AND METHODS: A 14-week, multicenter,
`double-blind, dose-response study was
`conducted. After a 3-week, single-blind,
`placebo-controlled washout, 451 patients with
`fasting plasma glucose levels of at least 180
`mg/dL were randomized to receive an 11-week
`course of placebo or metformin given at 500,
`1000, 1500, 2000, or 2500 mg daily.
`RESULTS: Metformin improved glucose variables
`as compared with placebo. The adjusted mean
`changes in fasting plasma glucose from
`baseline associated with each metformin group
`at week 7, 11, or at endpoint exceeded those
`associated with placebo by 19 to 84 mg/dL at
`dosages of 500 to 2000 mg daily, respectively.
`The corresponding between-group differences in
`glycated hemoglobin (HbA1c) ranged from 0.6%
`to 2.0% at dosages of 500 to 2000 mg daily,
`respectively. All between-group differences
`were significant (P (cid:155) 0.05) for both fasting
`plasma glucose and HbA1c at week 7, week 11,
`and endpoint, except for the difference between
`placebo and metformin 500 mg in fasting
`plasma glucose at endpoint (P (cid:129) 0.054).
`Treatment-related adverse events occurred in
`15% of patients in the placebo group and in
`28% in the metformin group (P (cid:129) 0.02); these
`were primarily manifested as digestive
`disturbances, such as diarrhea.
`CONCLUSIONS: Metformin lowered fasting plasma
`glucose and HbA1c generally in a dose-related
`manner. Benefits were observed with as little as
`
`From the Department of Medicine (AJG), Baylor College of Medicine,
`Houston, Texas; Department of Medicine (TGD), Pennsylvania Hospital,
`Philadelphia, Pennsylvania; Lipha Pharmaceuticals, Inc. (AMG), New York,
`New York; Medical Department (DJM, JLR), Bristol-Myers Squibb Com-
`pany, Princeton, New Jersey; Merck & Co., Inc., West Point, Pennsylva-
`nia.
`This work was supported by Bristol-Myers Squibb Company, Princeton,
`New Jersey.
`Requests for reprints should be addressed to Dr. Alan J. Garber, 6550
`Fannin Street, Suite #1045, Houston, Texas 77030.
`Manuscript submitted February 14, 1997 and accepted in revised
`form June 28, 1997.
`
`500 mg of metformin; maximal benefits were
`observed at the upper limits of the
`recommended daily dosage. All dosages were
`well tolerated. Metformin appears to be a useful
`therapeutic option for physicians who wish to
`titrate drug therapy to achieve target glucose
`concentrations. Am J Med. 1997;102;491–497.
`Q 1997 by Excerpta Medica, Inc.
`
`The primary goal of treatment in patients with
`
`type II diabetes mellitus is to prevent chronic
`complications. The results of the Diabetes Control
`and Complications Trial1 indicate that intensive gly-
`cemic control prevents the development and delays
`the progression of chronic complications in patients
`with type I diabetes. The results of a similar, but
`smaller, study from Japan2 indicate that virtually
`identical benefits of glycemic control result from in-
`tensive management in patients with type II diabetes.
`Until 1995, the only therapeutic agents for glycemic
`control were diet, sulfonylureas, and insulin.3 Now
`three more therapeutic classes are available: a big-
`uanide, an a-glucosidase inhibitor, and a thiazolidi-
`nedione; there is also a new sulfonylurea.
`Metformin is an oral biguanide that has been avail-
`able in Europe for more than 30 years and in the
`United States since 1995. Metformin, which is clas-
`sified as an antihyperglycemic agent, lowers glucose
`variables by increasing insulin sensitivity in periph-
`eral tissues4 – 8 and inhibiting hepatic glucose produc-
`tion.4,5,9,10 Unlike sulfonylureas, metformin does not
`stimulate insulin secretion and, consequently, does
`not produce hypoglycemia.11 – 13 In fact, the plasma
`insulin response to glucose is unchanged or may be
`decreased in patients with hyperinsulinemia.11,14 In
`view of these complementary mechanisms of action
`for biguanides as compared with sulfonylureas, it is
`understandable that metformin has synergistic ac-
`tion with sulfonylureas.13 Metformin alone also has
`beneficial effects on plasma lipid concentrations and
`in dyslipidemias, which are independent of glycemic
`control.9,13,15 Finally, metformin promotes stabiliza-
`tion of weight and may even cause weight loss.11
`Despite this extensive clinical research and clini-
`cal experience worldwide, no formal dose-ranging
`study has been conducted because, when the drug
`was originally developed, such studies were not rou-
`
`Q1997 by Excerpta Medica, Inc.
`All rights reserved.
`
`0002-9343/97/$17.00
`PII S0002-9343(97)00254-4
`
`491
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`DOSE-RELATED EFFECTS OF METFORMIN/GARBER ET AL
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`tinely performed in patients. The initial daily dosage
`selected for clinical studies,16 – 18 approximately 3000
`mg, was based on animal data.19 – 21 Because this dos-
`age was often associated with digestive distur-
`bances, the initial dose was lowered and the drug
`was titrated at weekly intervals to the final mainte-
`nance dosage. Consequently, the current dosing
`strategy of metformin was determined empirically,
`rather than by an understanding of the minimal ef-
`fective dose or of its dose-response relationship in
`patients with type II diabetes.
`The purpose of the current trial was to study the
`pharmacodynamic effect of various dosages of met-
`formin as compared with placebo in patients with
`type II diabetes as measured by changes in fasting
`plasma glucose. Additionally, glycated hemoglobin
`(HbA1c) was evaluated. A secondary objective was
`to determine the minimal effective dose of metfor-
`min.
`PATIENTS AND METHODS
`Study Design
`This was a 14-week multicenter, double-blind,
`dose-response study of 451 patients in 6 parallel
`treatment groups. All patients were instructed to
`maintain their recommended dietary and exercise
`programs. After a 3-week, single-blind, placebo-con-
`trolled washout phase, patients were randomized to
`receive placebo or 1 of 5 dosages of metformin for
`11 weeks. The final daily metformin dosages were
`500, 1000, 1500, 2000, and 2500 mg. Metformin was
`supplied as 500-mg tablets. To maintain blinding,
`matching placebo tablets were used as needed, so
`that each patient received five tablets daily. The tab-
`lets were given 3 times daily (TID) with meals ac-
`cording to the following dose escalation schedule: 1
`tablet TID, which was increased over 3 weeks to 2
`tablets with breakfast, 1 with lunch, and 2 with din-
`ner. The final regimens, which were given for a min-
`imum of 8 weeks, were metformin 500 mg once daily;
`500 mg twice daily (BID); 500 mg TID; 1000 mg BID;
`and 1000 mg with breakfast, 500 mg with lunch, and
`1000 mg with dinner. Compliance was assessed by
`tablet count at each visit.
`
`Patients
`Eligible patients were men and women at least 30
`years old who had type II diabetes, which was su-
`boptimally controlled on diet alone or which was
`previously treated with an oral sulfonylurea. Three
`weeks after discontinuing previous drug therapy,
`they had to have a fasting plasma glucose of at least
`180 mg/dL without symptoms.
`Patients were excluded if any of the following was
`present: significant disease or conditions likely to af-
`fect their diabetes or ability to complete the study,
`
`markedly symptomatic diabetes, biguanide hyper-
`sensitivity, previous insulin therapy, or concomitant
`treatment with nephrotoxic drugs or other investi-
`gational drugs. Women who were pregnant, nursing,
`or not using adequate methods of contraception
`were also excluded.
`The study protocol was approved by each insti-
`tution’s review board or by the central review board.
`All patients gave written informed consent before
`enrollment.
`
`Evaluation of Safety and Efficacy
`Patients visited the local study site weekly during
`washout and during the first 3 weeks of double-blind
`treatment; thereafter, patients visited the center af-
`ter 7 and 11 weeks of double-blind treatment. Phys-
`ical examination was performed at enrollment and
`at study completion. Vital signs, adverse events, and
`concomitant medications were assessed at each
`visit. Fasting plasma glucose was measured at each
`visit. Other laboratory evaluations, including HbA1c,
`hematology profile, chemistry profile, and urinalysis,
`were performed at the beginning and end of wash-
`out, and after 7 and 11 weeks of double-blind treat-
`ment. Laboratory evaluations were performed by a
`central
`laboratory (MAYO Medical Laboratories,
`Rochester, Minnesota).
`The primary efficacy endpoint was defined as the
`last valid double-blind evaluation for each patient.
`To be eligible for the efficacy analysis, the patient
`had to have received at least 4 weeks of treatment
`and to have data from either week 7 or 11. The pri-
`mary efficacy variable was fasting plasma glucose at
`endpoint; data from double-blind treatment weeks 7
`and 11 were also analyzed. The other efficacy vari-
`able was HbA1c from corresponding evaluation pe-
`riods.
`
`Statistical Analysis
`Baseline demographic characteristics were com-
`pared for homogeneity across treatment groups us-
`ing a Cochran-Mantel-Haenszel test for categorical
`data and analysis of variance (ANOVA) for continu-
`ous variables.
`Efficacy analyses were based on intent-to-treat
`data, without regard to study withdrawal, compli-
`ance, or concomitant medications, and on change
`from baseline in fasting plasma glucose and HbA1c.
`ANOVA was performed using a two-way model with
`terms for treatment and center; treatment-by-center
`interactions were found to be insignificant. The dose
`response was evaluated by pairwise comparisons us-
`ing a general linear model. William’s t-bar test22 was
`used to determine the minimum effective dose.
`All patients were included in the safety analysis.
`Adverse experience data were analyzed by chi-
`
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`
`
`square or Fisher’s exact test. Laboratory variables
`were categorized as low, normal, or high. The Stuart-
`Maxwell statistic, McNemar’s test, or the sign test
`was performed to assess the change in distribution
`of laboratory variables across the 3 categories from
`baseline and at double-blind treatment weeks 7 and
`11. All tests were two-tailed with levels of signifi-
`cance of 0.05 for efficacy analyses, and 0.10 for treat-
`ment-by-center interaction and safety analyses.
`
`RESULTS
`Patients
`Six hundred ninety-three patients were entered
`into the single-blind, placebo-controlled washout in
`1995. Two-hundred forty-two patients (35%) were
`not randomized because of the presence of exclu-
`sion criteria (22%), patient withdrawal (6%), protocol
`violation (3%), loss to follow-up (2%), physician pref-
`erence (1%), or an adverse event (1%) during the
`washout. The remaining 451 patients were evenly
`distributed across treatment groups based on de-
`mographic characteristics, except for age (Table I).
`Mean glucose variables were similar across treat-
`ment groups at baseline.
`One hundred-ten patients did not complete the en-
`tire double-blind treatment but were included in the
`intent-to-treat analysis. Reasons for stopping treat-
`ment were evenly distributed across treatment
`groups (Table I), except for adverse events, which
`are addressed in the safety analysis.
`
`Efficacy Analysis
`In the placebo group, adjusted mean fasting
`plasma glucose increased by 0.4 mg/dL between
`baseline and 7 weeks, and decreased by 8 mg/dL at
`11 weeks and at endpoint (Table II). In contrast,
`metformin reduced adjusted mean fasting plasma
`glucose (FPG) by 24 to 88 mg/dL from baseline, de-
`pending on the dose and time of evaluation. The ad-
`justed mean differences between the change from
`baseline in the placebo group versus the correspond-
`ing changes in each metformin group were signifi-
`cant at all evaluation times, except for the difference
`associated with metformin 500 mg at endpoint (P (cid:129)
`0.054). At endpoint, these between-group differences
`ranged from 19 mg/dL at the lowest dosage to 78 mg/
`dL at the 2000 mg dosage (Figure 1).
`Analogous findings were observed for HbA1c. In
`the placebo group, adjusted mean HbA1c increased
`by 1.1%, 1.2%, and 1.2% between baseline and 7
`weeks, 11 weeks, and endpoint, respectively (Table
`II). In contrast, metformin reduced adjusted mean
`HbA1c by up to 0.9% from baseline. The adjusted
`mean between-group differences were significant at
`all evaluation times (P ¡ 0.01), ranging at endpoint
`
`DOSE-RELATED EFFECTS OF METFORMIN/GARBER ET AL
`
`from 0.9% at the lowest metformin dosage to 2.0% at
`the 2000 mg dosage (Figure 1).
`The results of the William’s t-bar test for the min-
`imum effective daily dosage (test statistic and two-
`sided critical values not shown) were consistent
`with the ANOVA results (P values shown in Table
`II). At the 500 mg dosage, the change in FPG from
`baseline to endpoint was marginally insignificant in
`the intent-to-treat population (P (cid:129) 0.054) and signif-
`icant when 13 patients who received concomitant
`antidiabetic therapy were excluded (P (cid:129) 0.03). At the
`500 mg dosage, the corresponding change in HbA1c
`was significant in both patient populations (P (cid:155)
`0.001 and P (cid:155) 0.001).
`Pairwise comparisons of adjusted mean changes
`in FPG from baseline between adjacent metformin
`dosages confirmed that the maximal response oc-
`curred at 2000 mg. All differences between 2000 and
`¡1500 mg were significant (P (cid:155) 0.001). The differ-
`ence between 2000 and 2500 mg was not significant
`(P (cid:129) 0.1), suggesting a plateau effect.
`
`Safety Analysis
`The incidence of adverse events, which were con-
`sidered by the investigator to be related to treatment,
`was higher in the collective metformin groups than
`in the placebo group (28% versus 15%; P (cid:129) 0.02)
`(Table III). This resulted primarily from digestive
`disturbances (24% versus 13%, P (cid:129) 0.025), which
`were usually manifested as diarrhea (15% versus 5%;
`P (cid:129) 0.02), nausea (9% versus 5%; P (cid:129) 0.4), or dys-
`pepsia (4% versus 1%; P (cid:129) 0.5). The only other ad-
`verse events that occurred in at least 2% of patients
`within a treatment group were anorexia (2% versus
`1%), abdominal pain (2% versus 0%), and hypergly-
`cemia as defined by clinical judgment (1% versus 3%).
`When all adverse events were considered, includ-
`ing those considered to be unrelated to treatment,
`placebo was associated with a twofold higher inci-
`dence of hyperglycemia than metformin (16% versus
`8%; P (cid:129) 0.02). The only other between-group differ-
`ences in all adverse events, digestive disturbances
`and diarrhea, were also reflected in the subset of
`treatment-related adverse events.
`Most treatment-related adverse events were mild
`or moderate. During treatment with metformin or
`placebo, only 11 patients experienced serious ad-
`verse events, including 1 who was hospitalized be-
`cause of shortness of breath and chest pain and who
`was ultimately diagnosed with dyspepsia, which was
`of moderate severity and possibly related to receiv-
`ing metformin 1500 mg daily. The other 10 cases
`were attributed to their underlying diseases.
`Metformin was stopped in 17 patients (5%) be-
`cause of treatment-related adverse events, usually
`digestive disturbances. All adverse events that led to
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`DOSE-RELATED EFFECTS OF METFORMIN/GARBER ET AL
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`TABLE I
`
`Variable
`Mean age { SD (y)*
`Mean weight { SD (kg)
`Mean height { SD (cm)
`Male (%)
`Caucasian (%)
`Black (%)
`Hispanic (%)
`Other (%)
`FPG‡ { SD (mg/dL)
`HbA1c { SD (%)
`Study status (%)
`Completed
`Incomplete
`Adverse event related)
`Treatment failure
`Lost to follow-up
`Personal preference
`Protocol violation
`Other
`* P(cid:129) 0.03 across all treatment groups.
`† Data missing for one patient.
`‡ FPG (cid:129) fasting plasma glucose.
`
`Baseline Demographic Characteristics, Baseline Glucose Variables, and Study Completion Status
`Metformin Dose (mg)
`1500
`(n (cid:129) 76)
`59 { 10
`89.6 { 16.2
`168 { 13
`63
`71†
`12†
`15†
`2†
`262 { 51.7
`9.7 { 1.5†
`
`500
`(n (cid:129) 73)
`57 { 10
`90.0 { 20.3
`168 { 10
`62
`74
`11
`14
`1
`282 { 59.5
`10.1 { 1.7†
`
`1000
`(n (cid:129) 73)
`55 { 10
`90.0 { 18.9
`168 { 10
`55
`77
`12
`10
`1
`281 { 60.3
`10.0 { 2.0†
`
`2000
`(n (cid:129) 73)
`60 { 11
`89.1 { 20.3
`170 { 10
`53
`70
`14
`12
`4
`288 { 61.1
`10.1 { 2.1
`
`2500
`(n (cid:129) 77)
`59 { 11
`94.5 { 23.4
`168 { 13
`65
`79
`10
`10
`0
`287 { 59.9
`10.0 { 1.8
`
`Placebo (n (cid:129) 79)
`55 { 11
`90.9 { 20.1
`168 { 10
`56
`66
`22
`11
`1
`279 { 59.1†
`9.9 { 1.9†
`
`70
`30
`6 (0)
`9
`1
`6
`3
`5
`
`74
`26
`4 (0)
`10
`3
`4
`4
`1
`
`75
`25
`5 (5)
`5
`3
`7
`3
`1
`
`82
`18
`7 (3)
`3
`3
`3
`4
`0
`
`82
`18
`7 (4)
`1
`0
`3
`4
`3
`
`71
`29
`14 (10)
`6
`1
`3
`3
`1
`
`TABLE II
`
`Adjusted Mean Changes from Baseline in Glucose Variables During Double-Blind Treatment
`Metformin Dose (mg)
`1500
`1000
`(n (cid:129) 73)
`(n (cid:129) 76)
`
`Placebo
`(n (cid:129) 79)
`
`500
`(n (cid:129) 73)
`
`Variable
`Fasting plasma glucose (mg/dL)
`049***
`041***
`024**
`/0.4
`Week 7
`052***
`043**
`029*
`08
`Week 11
`049***
`039**
`027†
`08
`Endpoint
`HbA1c (%)
`00.3***
`00.01***
`/0.4**
`/1.1
`Week 7
`00.6***
`00.1***
`/0.2***
`/1.2
`Week 11
`00.5***
`/0.01***
`/0.3**
`/1.2
`Endpoint
`* P(cid:155) 0.05; ** P(cid:155) 0.01; *** P(cid:155) 0.001 for mean difference from placebo, adjusting for center effect in linear model.
`† P(cid:129) 0.054 for mean difference from placebo, adjusting for center effect in linear model.
`
`2000
`(n (cid:129) 73)
`
`084***
`088***
`086***
`00.5***
`00.9***
`00.8***
`
`2500
`(n (cid:129) 77)
`
`062***
`073***
`070***
`00.1***
`00.5***
`00.4***
`
`discontinuation of metformin were mild or moder-
`ate, except for one case of severe diarrhea and one
`case of severe abdominal pain, diarrhea, nausea, and
`vomiting. All of these adverse events resolved after
`stopping metformin.
`There were no clinically relevant changes in vital
`signs. Mean weight changes were generally evenly
`distributed across treatment groups; there was a
`nonsignificant tendency toward weight loss in all
`treatment groups. There were no clinically relevant
`shifts in laboratory variables as measured by the pro-
`portions of patients who experienced changes rela-
`tive to normal values. There were only 3 episodes of
`
`hypoglycemia as defined by clinical judgment, 1 each
`at daily dosages of 1500, 2000, and 2500 mg; 2 were
`mild and 1 was moderate; none required discontin-
`uation of treatment.
`COMMENTS
`this double-blind, placebo-con-
`The results of
`trolled, multicenter trial in 451 patients with type II
`diabetes indicate that metformin lowered glucose
`variables in a generally dose-related manner. Met-
`formin improved glucose variables by more than did
`placebo. Metformin, at dosages of 500 to 2000 mg
`daily, reduced adjusted mean FPG from baseline by
`
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`DOSE-RELATED EFFECTS OF METFORMIN/GARBER ET AL
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`size may also have been a confounding factor. In any
`event, the corresponding between-group differences
`for HbA1c were 1.5% (P (cid:155) 0.001) and 1.8% (P (cid:155) 0.001)
`for the lower and higher dosages, respectively.
`In the current study, the maximal efficacy of met-
`formin was observed at 2000 mg, not at 2500 mg. The
`explanation for this finding is elusive. It is conceiv-
`able that the slightly higher discontinuation rate at
`the highest dosage may have diluted the effect on
`glucose variables at the highest dosage in this intent-
`to-treat analysis. Unfortunately, the current study
`was not designed to evaluate the clinical practice of
`titrating the dosage according to individual response
`because each patient was randomly assigned to a
`predetermined dosage. Although previous studies
`were not designed to evaluate dose relationships,
`their titration phases provide indirect evidence of a
`within-patient dose relationship up to daily dosages
`of 2500 mg. For example, the incremental reductions
`in mean FPG were 22, 23, and 15 mg/dL when the
`daily dosage was escalated from 850 mg to 1700 mg,
`then to 2550 mg, respectively.25 Similarly, the incre-
`mental reductions in FPG were 14, 28, 13, 11, and 23
`mg/dL when the daily dosage of metformin (in the
`presence of glyburide) was escalated from 500 mg
`to 2500 mg at 500-mg intervals.25
`The reductions in glucose variables observed in
`the current study are consistent with the findings of
`a previous study. A 29-week course of metformin
`2550 mg reduced mean FPG by 58 mg/dL and mean
`HbA1c by 1.8% more than did placebo in a double-
`blind study of 289 moderately obese patients with
`type II diabetes.25
`The improvements in glycemic control have also
`been reported for other newly available antidiabetic
`agents in similar studies of patients with type II di-
`abetes. Three daily dosages of the new sulfonylurea,
`glimepiride, were evaluated in a dose-response
`study.26 Glimepiride reduced median FPG by 43 to
`73 mg/dL and median HbA1c by 1.2% to 1.9% more
`than did placebo; however, the median within-treat-
`ment change from baseline was relatively slight for
`HbA1c, ranging from /0.2% to 00.3%.26 Three daily
`dosages of the new a-glucosidase inhibitor, acar-
`bose, significantly improved glucose variables com-
`pared with placebo, with between-group differences
`of 27 to 39 mg/dL for mean FPG and 0.8% to 1.0% for
`mean HbA1c.27 The new thiazolidinedione, troglita-
`zone, reduced mean FPG by 20 mg/dL and mean
`HbA1c by 0.6% more than did placebo.28 Of course,
`differences in study design and patient populations
`may have contributed to the between-study differ-
`ences in glucose-lowering activity. For example,
`mean baseline FPG values ranged from 180 mg/dL in
`the troglitazone study28 up to approximately 230 mg/
`dL in the other two studies26,27; mean baseline HbA1c
`
`Figure 1. Estimated difference from placebo ({SE) as measured by
`changes from respective baseline glucose variables at endpoint. *P
`(cid:129) 0.054; **P(cid:155) 0.01; ***P(cid:155) 0.001 for estimated difference from
`placebo.
`
`19 to 84 mg/dL and adjusted mean HbA1c by 0.6% to
`2.0% more than did placebo. This disproportionate
`effect on glucose variables is not surprising; FPG
`rapidly reflects the full effect of treatment whereas
`the time required for HbA1c to reflect the full effect
`of treatment may have exceeded the 11-week study
`period. Importantly, these findings indicate that the
`minimal effective daily dosage of metformin is 500
`mg, not 1500 mg as previously reported.23,24
`Only one previous double-blind study24 provides
`direct evidence of a dose relationship. When 75 pa-
`tients with type II diabetes were randomized to re-
`ceive placebo or metformin 1500 or 3000 mg daily
`for 6 months, the between-group differences from
`their respective baseline FPG values were approxi-
`mately 27 mg/dL for the lower dosage (NS) and 82
`mg/dL for the higher dosage (P (cid:129) 0.001). The au-
`thors24 attributed the lack of benefit at the lower
`dosage to good initial glycemic control; small sample
`
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`DOSE-RELATED EFFECTS OF METFORMIN/GARBER ET AL
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`TABLE III
`
`Drug-related Adverse Events Occurring in ¢2% of Patients Within a Treatment Group
`Percent of Patients with Adverse Event
`(Percent Who Stopped Treatment Due to Adverse Event)
`Metformin Dose (mg)
`1500
`(n (cid:129) 76)
`26 (3)
`4 (0)
`4 (1)
`24 (3)
`12 (3)
`8 (3)
`9 (0)
`3 (0)
`4 (0)
`1 (0)
`
`Placebo (n (cid:129) 79)
`Adverse Event
`15 (0)
`Any adverse event*,†
`3 (0)
`Whole body disturbances
`0 (0)
`Abdominal pain
`13 (0)
`Digestive disturbances*
`5 (0)
`Diarrhea*
`5 (0)
`Nausea
`1 (0)
`Dyspepsia
`1 (0)
`Anorexia
`3 (0)
`Metabolic disturbances
`3 (0)
`Hyperglycemia
`* P(cid:155) 0.05, metformin (all doses) versus placebo.
`† Some patients experienced more than one adverse event.
`
`500
`(n (cid:129) 73)
`25 90)
`4 (0)
`3 (0)
`16 (0)
`8 (0)
`7 (0)
`1 (0)
`0 (0)
`1 (0)
`1 (0)
`
`1000
`(n (cid:129) 73)
`30 (5)
`1 (1)
`1 (1)
`29 (5)
`21 (4)
`10 (3)
`1 (0)
`1 (0)
`0 (0)
`0 (0)
`
`2000
`(n (cid:129) 73)
`27 (4)
`0 (0)
`0 (0)
`23 (4)
`19 (3)
`1 (1)
`3 (0)
`1 (0)
`3 (0)
`0 (0)
`
`2500
`(n (cid:129) 77)
`30 (10)
`4 (0)
`3 (0)
`29 (10)
`14 (5)
`12 (5)
`4 (3)
`5 (1)
`3 (0)
`0 (0)
`
`values were between 8% and 9% in the three stud-
`ies.26 – 28 Nonetheless, these findings suggest that the
`slope of the dose-response curve is flatter for acar-
`bose and troglitazone than it is for glimepiride.
`A flat dose-response curve has also been observed
`with sulfonylureas.
`In a double-blind, crossover
`study of 24 patients with type II diabetes,29 increas-
`ing the daily dose of glipizide from 10 mg to 20 mg
`or 40 mg was not associated with concomitant im-
`provement in HbA1c. These findings underscore the
`importance of evaluating dose response in patients
`with type II diabetes and of defining the minimally
`and maximally effective doses.
`The dosages of metformin used in the current
`study were well tolerated. The most common ad-
`verse event, digestive disturbances, especially diar-
`rhea, is consistent with previous experience.25,30,31
`Although the incidence of digestive disturbances has
`been reported to be dose-related,30,31 there was no
`discernable association between the incidence of ad-
`verse events and metformin dosage in the current
`study. The higher incidence of digestive distur-
`bances and diarrhea in the metformin groups versus
`placebo group was primarily due to dosages greater
`than 500 mg because the 500 mg dosage was not as-
`sociated with any digestive disturbances. The inci-
`dences were essentially identical for dosages of 1000
`through 2000 mg and somewhat higher for 2500 mg.
`This lack of a linear dose relationship for adverse
`events indicates that the use of gradual dose esca-
`lation at weekly intervals was at least partially suc-
`cessful.
`The results of the current study demonstrate that
`the antihyperglycemic activity of metformin is gen-
`erally dose-dependent. Metformin is well tolerated
`with no significant differences in the incidence of
`adverse events compared with placebo, except for
`
`digestive disturbances. There were no cases of lactic
`acidosis or unexpected adverse events. When used
`in appropriately selected patients, metformin ap-
`pears to be a safe and effective therapeutic alterna-
`tive for physicians who wish to titrate drug therapy
`to achieve target glucose concentrations in individ-
`ual patients with type II diabetes. The efficacy of
`metformin at dosages as low as 500 mg, along with
`the minimal risk of hypoglycemia, suggests that this
`agent will be useful in patients with mild to moderate
`hyperglycemia, and that higher dosages will be use-
`ful in those with moderate to severe disease. These
`data also suggest that most patients will achieve
`maximal efficacy at a daily dosage of 2000 mg (1000
`mg BID), while some patients may achieve additional
`benefit if the dosage is increased to 2500 mg. We
`therefore conclude that twice-daily dosing may be
`sufficient for most patients with type II diabetes mel-
`litus.
`
`ACKNOWLEDGMENTS
`We are indebted to the following principal investigators and their staffs: Ste-
`phen Aronoff, MD, Endocrine Associates of Dallas, Dallas, Texas; David Bell,
`MD, Division of Endocrinology, Kirklin Clinic, University of Alabama at Birming-
`ham, Birmingham, Alabama; Lawrence Blonde, MD, Ochsner Clinic, New Or-
`leans, Louisiana; Dana Clarke, MD, Diabetes Health Center, Salt Lake City, Utah;
`Jamie A. Davidson, MD, Endocrine & Diabetes Associates of Texas, Dallas,
`Texas; Daniel Einhorn, MD, Diabetes, Endocrinology, Metabolic Disorders, San
`Diego, California; Stephen Farrow, MD, Division of Endocrinology, VA Medical
`Center, Allen Park, Michigan; Ronald B. Goldberg, MD, Diabetes Research In-
`stitute, University of Miami School of Medicine, Miami, Florida; Fred Hofeldt,
`MD, Department of Medicine, Denver General Hospital, Denver, Colorado; Willa
`Hsueh, MD, University of Southern California School of Medicine, Los Angeles,
`California; Charles Kilo, MD, FACP, Kilo Clinical Research, Ltd., St. Louis, Mis-
`souri; John Paul Lock, MD, Diabetes & Endocrinology Group, Worcester, Mas-
`sachusetts; Jennifer Marks, MD, University of Miami School of Medicine, Miami,
`Florida; Janet McGill, MD, Washington University School of Medicine, St. Louis,
`Missouri; Pasquale Palumbo, MD, Mayo Clinic, Scottsdale, Arizona; Anne Pe-
`ters, MD, UCLA Medical Plaza, Los Angeles, California; Lawrence Phillips, MD,
`The Emory Clinic, Atlanta, Georgia; Sherwyn L. Schwartz, MD, Diabetes & Glan-
`
`496
`
`December 1997 The American Journal of MedicineT Volume 103
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`/ 2215 5213 Mp 496 Friday Nov 21 05:32 PM EL–AJM (v. 103, no. 6) 5213
`
`MPI EXHIBIT 1050 PAGE 6
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`MPI EXHIBIT 1050 PAGE 6
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`
`
`dular Disease Clinic, PA, San Antonio, Texas; Stephen Swartz, MD, Endocrinol-
`ogy-Hypertension Division, Brigham & Women’s Hospital, Boston, Massachu-
`setts; Kenneth Ward, MD, Portland Diabetes & Endocrinology Center, Portland,
`Oregon; David Smith, MD, Memorial Research Medical Clinic, Long Beach, Cal-
`ifornia; Matthew Weir, MD, Division of Nephrology, University of Maryland Hos-
`pital, Baltimore, Maryland. We also thank Shein-Chung Chow, PhD, and William
`A. Fox, MS, Bristol-Myers Squibb Company, Princeton, New Jersey for perform-
`ing the statistical analysis.
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