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`Vol. 333 No. 9
`
`EFFICACY OF METFORMIN IN PATIENTS WITH NIDDM
`
`541
`
`EFFICACY OF METFORMIN IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES
`MELLITUS
`, M.D.,
`
` M
`
`ETFORMIN
`
` S
`
`TUDY
`
` G
`
`ROUP
`
`*
`
`R
`
`ALPH
`
` A. D
`
`F
`
`E
`
`RONZO
`
`, M.D., A
`
`NITA
`
` M. G
`
`OODMAN
`
`AND
`
`
`
`THE
`
` M
`
`ULTICENTER
`
`Abstract
`Sulfonylurea drugs have been
`Background.
`the only oral therapy available for patients with non-insu-
`lin-dependent diabetes mellitus (NIDDM) in the United
`States. Recently, however, metformin has been approved
`for the treatment of NIDDM.
`Methods.
`We performed two large, randomized, par-
`allel-group, double-blind, controlled studies in which met-
`formin or another treatment was given for 29 weeks to
`moderately obese patients with NIDDM whose diabetes
`was inadequately controlled by diet (protocol 1: metformin
`vs. placebo; 289 patients), or diet plus glyburide (protocol
`2: metformin and glyburide vs. metformin vs. glyburide;
`632 patients). To determine efficacy we measured plasma
`glucose (while the patients were fasting and after the oral
`administration of glucose), lactate, lipids, insulin, and gly-
`cosylated hemoglobin before, during, and at the end of
`the study.
`In protocol 1, at the end of the study the 143
`Results.
`patients in the metformin group, as compared with the
`146 patients in the placebo group, had lower mean
`⫾
`⫾
`(
`SE) fasting plasma glucose concentrations (189
`5
`⫾
`⫾
`⫾
`6 mg per deciliter [10.6
`0.3 vs. 13.7
`0.3 mmol
`vs. 244
`⬍
`per liter], P
`0.001) and glycosylated hemoglobin values
`⫾
`⫾
`⬍
`0.1 percent vs. 8.6
`0.2 percent, P
`0.001). In pro-
`(7.1
`
`I
`
`N the United States patients with non-insulin-
`dependent diabetes mellitus (NIDDM) are usually
` However,
`treated with diet and a sulfonylurea drug.
`1
`approximately 30 percent of patients initially treated
`with a sulfonylurea drug have a poor response, and in
`the remaining 70 percent the subsequent failure rate is
`approximately 4 to 5 percent per year.
` In most parts
`2
`of the world, an alternative or additive approach to oral
`therapy is available in the form of metformin.
` Clini-
`3,4
`cal experience has proved metformin, either alone or in
`combination with a sulfonylurea, to be safe and effica-
`cious in reducing plasma glucose concentrations in pa-
` Metformin is believed to work by
`tients with NIDDM.
`3-6
`inhibiting hepatic glucose production
` and increasing
`7-10
`the sensitivity of peripheral tissue to insulin
`; it
`8,9,11-13
`does not stimulate insulin secretion, which explains the
` Metformin also has
`absence of hypoglycemia.
`3,4,6,14,15
`beneficial effects on plasma lipid concentrations
`7,14-16
`and promotes weight loss.
` Because the primary action
`4
`of sulfonylurea drugs is to enhance insulin secretion,
`whereas metformin exerts its beneficial effects on gly-
`cemic control by enhancing peripheral and hepatic sen-
`sitivity to insulin,
` metformin should be equally ef-
`7-13
`
`From the Diabetes Division, University of Texas Health Science Center, San
`Antonio (R.A.D.), and Lipha Pharmaceuticals, New York (A.M.G.). Address re-
`print requests to Dr. DeFronzo at the Diabetes Division, University of Texas
`Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78284.
`Supported by a grant from Lipha Pharmaceuticals, Inc.
`Dr. Goodman is the executive vice president and chief operating officer of
`Lipha Pharmaceuticals.
`*The members of the Multicenter Metformin Study Group are listed in the Ap-
`pendix.
`
`tocol 2, the 213 patients given metformin and glyburide,
`as compared with the 209 patients treated with glyburide
`alone, had lower mean fasting plasma glucose concen-
`⫾
`⫾
`⫾
`trations (187
`4 vs. 261
`4 mg per deciliter [10.5
`0.2
`⫾
`⬍
`vs. 14.6
`0.2 mmol per liter], P
`0.001) and glycosylated
`⫾
`⫾
`hemoglobin values (7.1
`0.1 percent vs. 8.7
`0.1 per-
`⬍
`cent, P
`0.001). The effect of metformin alone was sim-
`ilar to that of glyburide alone. Eighteen percent of the pa-
`tients given metformin and glyburide had symptoms
`compatible with hypoglycemia, as compared with 3 per-
`cent in the glyburide group and 2 percent in the metfor-
`min group.
`In both protocols the patients given metformin had sta-
`tistically significant decreases in plasma total and low-
`density lipoprotein cholesterol and triglyceride concentra-
`tions, whereas the values in the respective control groups
`did not change. There were no significant changes in fast-
`ing plasma lactate concentrations in any of the groups.
`Conclusions.
`Metformin monotherapy and combina-
`tion therapy with metformin and sulfonylurea are well tol-
`erated and improve glycemic control and lipid concentra-
`tions in patients with NIDDM whose diabetes is poorly
`controlled with diet or sulfonylurea therapy alone. (N Engl
`J Med 1995;333:541-9.)
`
`fective when used as monotherapy and in patients
`receiving a sulfonylurea drug. This report describes the
`results of two randomized, placebo-controlled, multi-
`center trials in which moderately obese patients with
`NIDDM whose diabetes was poorly controlled with diet
`alone or with diet plus a sulfonylurea drug were treated
`with metformin for 29 weeks.
`
`M
`
`ETHODS
`
`Subjects
`
`Protocol 1
`A total of 289 obese patients who were treated with diet alone were
`assigned to protocol 1. After an eight-week phase during which the
`patients were counseled about the consumption of a hypocaloric
`diet,
` 143 patients were randomly assigned to receive metformin and
`17
`146 to receive placebo. The base-line characteristics of the two
`groups of patients are shown in Table 1.
`
`Protocol 2
`A total of 632 patients with NIDDM were assigned to protocol 2:
`210 were assigned to receive metformin, 209 to receive glyburide,
`and 213 to receive both metformin and glyburide (combination ther-
`apy). The base-line characteristics of the three groups are also shown
`in Table 1.
`The diagnosis of NIDDM was based on clinical history and the
`finding of a fasting plasma glucose concentration above 140 mg per
`deciliter (7.8 mmol per liter) on two occasions. To be included in the
`study all patients had to lack acceptable glycemic control (fasting
`⭓
`plasma glucose,
`140 mg per deciliter) after eight weeks of dietary
`therapy (protocol 1) or at least four weeks of dietary therapy plus 20
`mg of glyburide per day (protocol 2). Other inclusion criteria includ-
`ed a weight that was 120 to 170 percent of ideal (on the basis of 1983
`Metropolitan Life Insurance tables), an age of 40 to 70 years, normal
`⭐
`renal function (serum creatinine,
`1.4 mg per deciliter [124
`mol
`m
`
`Applications:Desktop Folder:2defr.oa
`Mon Aug 21 0
`12:51:47
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 20, 2018. For personal use only. No other uses without permission.
`
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
`AUROBINDO EX. 1020, 1
`
`

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`542
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Aug. 31, 1995
`
`cal-appearing placebo tablet daily with the evening meal. After two
`weeks, the metformin (or placebo) dose was doubled, with one 850-
`mg tablet also taken with breakfast. After four weeks, the metformin
`(or placebo) dose was again increased by 850 mg, so that one addi-
`tional tablet was taken with lunch. The metformin dose was in-
`creased in this fashion as long as the fasting plasma glucose concen-
`tration exceeded 140 mg per deciliter and the side effects were
`tolerable.
`After the fifth week, the
`Active metformin-treatment phase (phase III).
`maximal dose of metformin (or placebo) (2550 mg per day) was con-
`tinued unless side effects (primarily gastrointestinal) dictated a re-
`duction in the dose. The patients were seen every 4 weeks thereafter
`for a total of 29 weeks.
`At randomization the patients provided a medical history and un-
`derwent a physical examination (in which height and body weight
`were determined), routine blood chemical tests, urinalysis, electro-
`cardiography, and a glucose-tolerance test in which 75 g of glucose
`was administered orally and plasma glucose, insulin, and C-peptide
`levels were measured at base line and one, two, and three hours later.
`In addition, a complete blood count was performed and glycosylated
`hemoglobin; fasting plasma glucose; fasting plasma lactate; fasting
`serum total cholesterol, low-density lipoprotein (LDL) cholesterol,
`high-density lipoprotein (HDL) cholesterol, and triglycerides; serum
` and folic acid; and plasma metformin were measured.
`vitamin B
`12
`At each follow-up visit, we obtained information about compli-
`ance, drug side effects, and intercurrent medical events; measured
`blood pressure; and obtained blood samples while the patients were
`fasting in order to measure glycosylated hemoglobin and plasma glu-
`cose and lactate. At week 29, oral glucose-tolerance tests were per-
`formed and plasma lipid and serum vitamin B
` and folic acid con-
`12
`centrations were measured; plasma metformin was measured at
`weeks 9, 21, and 29.
`
`Table 1. Base-Line Characteristics of the Patients with NIDDM.
`
`*
`
`⭐
`mol per liter] in
`1.3 mg per deciliter [115
`per liter] in men and
`m
`⭐
`⫹
`women; and
`2
` proteinuria), and normal liver function. Patients
`were excluded if they had any of the following: symptomatic diabetes
`(polyuria, polydipsia, and weight loss), symptomatic cardiovascular
`disease, diastolic blood pressure above 100 mm Hg during antihyper-
`tensive-drug treatment, or any concurrent medical illness. They were
`also excluded if they had received insulin therapy within the previous
`six months, used medications known to affect glucose metabolism,
`⭓
`drank three or more alcoholic drinks per day (
`3 oz of alcohol per
`day), used illicit drugs, or had previously received metformin therapy.
`Therapy with estrogen and a progestin and chlorthalidone or a thia-
`zide was permitted in patients already taking these drugs as long as
`the dosage was not changed during the study. The protocols were ap-
`proved by the institutional review board of each participating center,
`and all patients gave written informed consent for the study.
`
`Study Design
`
`Protocol 1
`
`Potential study patients
`Preenrollment dietary-therapy phase (phase I).
`initially provided a complete medical history and underwent a phys-
`ical examination and screening laboratory tests (Fig. 1, top panel).
`On two occasions the patients kept a three-day dietary log; the pa-
`tients were then instructed in a hypocaloric diet, which they were told
`to follow for eight weeks before undergoing randomization. The diet
`for each patient was designed to provide 20 percent fewer calories
`than the patient’s calculated daily energy expenditure. Fasting plas-
`ma glucose concentrations were determined eight and four weeks
`before randomization and at base line (week 0). At the time of ran-
`domization (week 0), each patient again met with the dietitian to re-
`inforce the dietary instructions.
`At the end of phase I, the patients were randomly
`Randomization.
`assigned to treatment with metformin or placebo. Of the 535 pa-
`tients who entered the preenrollment dietary-therapy phase, 289
`went on to the active-treatment phase: 143 were assigned to metfor-
`min and 146 to placebo. Of the other 246 patients, 61 decided not to
`participate and 185 did not meet the entrance criteria, including 74
`who were excluded because they had achieved glycemic control and
`30 because they had a change in weight (loss or gain) of more than
`3 percent.
`After randomization, treat-
`Metformin-titration phase (phase II).
`ment was initiated with one 850-mg metformin tablet or one identi-
`
`C
`
`HARACTERISTIC
`
`P
`
`ROTOCOL
`
` 1
`
`P
`
`PLACEBO
`⫽
`(
`146)
`N
`
`METFORMIN
`⫽
`(
`143)
`N
`
`GLYBURIDE
`⫽
`(
`209)
`N
`
`Age (yr)
`Sex (M/F)
`Weight (kg)
`Body-mass index‡
`Duration of diabetes (yr)
`Family history of diabetes (%)
`Fasting plasma glucose (mg/dl)
`2-hr plasma glucose (mg/dl)
`Glycosylated hemoglobin (%)
`Fasting plasma insulin (
`U/ml)
`m
`Plasma C peptide (ng/ml)
`Plasma total cholesterol (mg/dl)
`Plasma LDL cholesterol (mg/dl)
`Plasma HDL cholesterol (mg/dl)
`Plasma triglycerides (mg/dl)
`
`⫾
`53
`11
`62/84
`⫾
`92.2
`1.21
`⫾
`0.31
`29.2
`⫾
`6.0
`0.6
`70
`⫾
`238
`611
`⫾
`368
`811
`⫾
`8.2
`0.2
`⫾
`15
`11
`⫾
`2.7
`0.1
`⫾
`212
`411
`⫾
`138
`311
`⫾
`41
`11
`185⫾911
`
`⫾
`11
`53
`62/81
`⫾
`94.4
`1.11
`⫾
`29.9
`0.31
`⫾
`6.0
`0.5
`80
`⫾
`241
`511
`⫾
`383
`811
`⫾
`8.4
`0.1
`⫾
`13
`11
`⫾
`2.7
`0.1
`⫾
`211
`311
`⫾
`136
`311
`⫾
`39
`11
`209⫾151
`
`⫾
`11
`56
`103/106
`⫾
`92.6
`1.01
`⫾
`29.1
`0.31
`⫾
`8.7
`0.4
`72
`⫾
`247
`311
`⫾
`399
`611
`⫾
`8.5
`0.1
`⫾
`16
`11
`⫾
`2.8
`0.1
`⫾
`215
`311
`⫾
`136
`311
`
`37⫾11
`210⫾811
`
`Protocol 2
`During a five-week prerandom-
`Prerandomization phase (phase I).
`ization phase, 788 patients with NIDDM began (or continued) to
`take glyburide; patients taking another sulfonylurea drug were
`switched to glyburide. The dose of glyburide was 5 mg twice daily
`for the first week and then 10 mg twice daily for the remaining four
`weeks of phase I (Fig. 1, bottom panel). The patients also kept a
`three-day dietary log and then met with a dietitian who instructed
`the patients in a weight-maintaining diet.
`
`17
`Of the 788 diabetic pa-
`Randomization.
`tients who were enrolled in phase I, 632 en-
`tered the active-treatment phase. At week 0,
`open-label glyburide was discontinued and
`the patients were randomly assigned to treat-
`ment with glyburide plus metformin placebo
`(209 patients), metformin plus glyburide pla-
`cebo (210 patients), or metformin plus gly-
`buride (213 patients). Of the other 156 pa-
`tients who completed phase I, 114 did not
`meet the randomization criteria (including 37
`because they had achieved glycemic control)
`and 42 decided not to participate.
`Metformin-titration phase (phase II). After
`
`randomization at week 0, the patients began
`taking one 500-mg tablet of metformin or one
`placebo tablet with their evening meal. After
`one week the metformin (or placebo) dose
`was increased to 1000 mg per day by adding
`a 500-mg tablet to the breakfast meal. After
`two weeks the metformin (or placebo) dose
`was increased to 1500 mg per day by adding
`a 500-mg tablet to be taken at lunch. After
`three weeks the dose was increased to 2000
`mg per day by adding a second 500-mg tablet
`to be taken with the evening meal, and after
`four weeks the daily dose was increased to
`2500 mg by adding a second 500-mg tablet to
`the breakfast dose. The daily dose was in-
`creased in this fashion to a maximum of 2500
`mg of metformin (or five placebo tablets) as
`
`ROTOCOL
`
` 2†
`
`METFORMIN
`⫽
`(
`210)
`N
`
`⫾
`11
`55
`196/114
`⫾
`92.6
`1.01
`⫾
`29.4
`0.31
`⫾
`8.4
`0.4
`72
`⫾
`254
`411
`⫾
`398
`611
`⫾
`8.9
`0.1
`⫾
`18
`11
`⫾
`2.9
`0.1
`⫾
`212
`311
`⫾
`134
`311
`37⫾11
`231⫾121
`
`⫹
`
`
`METFORMIN
`GLYBURIDE
`⫽
`(
`213)
`N
`
`⫾
`55
`11
`198/115
`⫾
`92.1
`1.11
`⫾
`29.0
`0.31
`⫾
`7.8
`0.4
`75
`⫾
`251
`411
`⫾
`391
`611
`⫾
`8.8
`0.1
`⫾
`17
`11
`⫾
`2.8
`0.1
`⫾
`216
`311
`⫾
`137
`311
`39⫾11
`216⫾101
`
`⫾
`SE. LDL denotes low-density lipoprotein, and HDL high-density lipoprotein. To convert
`*Plus–minus values are means
`values for glucose to millimoles per liter, multiply by 0.056; to convert values for total cholesterol, LDL cholesterol, and
`HDL cholesterol to millimoles per liter, multiply by 0.0259; to convert values for triglycerides to millimoles per liter, mul-
`tiply by 0.011; and to convert values for insulin to picomoles per liter, multiply by 6.
`†Base-line measurements were made while all patients were taking 20 mg of glyburide per day.
`‡Defined as the weight in kilograms divided by the square of the height in meters.
`
`Applications:Desktop Folder:2defr.oa
`Mon Aug 21 0
`12:51:47
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 20, 2018. For personal use only. No other uses without permission.
`
` Copyright © 1995 Massachusetts Medical Society. All rights reserved.
`
`AUROBINDO EX. 1020, 2
`
`

`

`Vol. 333 No. 9
`
`EFFICACY OF METFORMIN IN PATIENTS WITH NIDDM
`
`543
`
`Protocol 1
`
`Initial
`visit
`
`Randomization
`Phase I
`(Pre-
`enrollment) Phase II
`
`Diet
`therapy
`
`Metformin
`titration
`
`Phase III
`
`Active
`treatment
`
`⫺9⫺8
`
`0
`
`3
`
`5
`
`9
`
`13
`
`17
`
`21
`
`25
`
`29
`
`Week
`
`Protocol 2
`
`Randomization
`
`Phase I Phase II
`
`Phase III
`
`Glyburide
`
`Metformin
`titration
`
`Active
`treatment
`
`⫺5 ⫺4
`
`0
`
`3
`
`5
`
`9
`
`13
`
`17
`
`21
`
`25
`
`29
`
`Week
`
`Figure 1. Design of Protocols 1 and 2.
`
`long as the fasting plasma glucose concentration exceeded 140 mg
`per deciliter. Throughout this period and for the remainder of the
`study, the patients continued to take four tablets of glyburide (20 mg
`per day) or placebo per day, according to their treatment assignment.
`Active metformin-treatment phase (phase III). After the fifth week, the
`patients took the maximal dose of metformin (2500 mg per day) un-
`less side effects dictated a reduction in the dose. The patients were
`seen every 4 weeks thereafter for a total of 29 weeks. At these visits,
`the patients were questioned, examined, and studied as described in
`protocol 1.
`
`Analytic Methods
`Plasma glucose was measured enzymatically with a Hitachi Analyz-
`er (model 736.50, Boehringer–Mannheim Diagnostics, Indianapolis).
`Glycosylated hemoglobin was measured by ion-exchange high-per-
`formance liquid chromatography with a Bio-Rad Diamat Analyzer
`(Bio-Rad, Hercules, Calif.) (range for normal subjects, 3.3 to 6.8 per-
`cent; mean value, 4.7 percent). Plasma free insulin (Coat-A-Count,
`Diagnostic Products Corporation, Los Angeles) and C peptide (C-
`peptide RAI Kit, Incstar, Stillwater, Minn.) were measured by radio-
`immunoassay after plasma was treated with polyethylene glycol. Plas-
`ma total cholesterol and triglycerides were measured enzymatically
`with a Cobas Fera analyzer (Boehringer–Mannheim Diagnostics).
`Plasma HDL cholesterol was measured enzymatically with a Cobas
`Fera analyzer after precipitation with dextran sulfate–manganese
`chloride. Plasma LDL cholesterol was calculated with the Friedwald
`equation. Serum folic acid and vitamin B12 were measured by radio-
`immunoassay (Bio-Rad Quantaphase B12–Folate radioimmunoassay
`kit). Plasma lactate was measured enzymatically with a Cobas Mira
`analyzer (Sigma Diagnostics, St. Louis). Serum metformin was meas-
`ured with modified high-performance liquid chromatography.18
`
`Statistical Analysis
`The primary analysis was an intention-to-treat analysis in which
`the final visit (week 29, or earlier for patients leaving the study) was
`
`the primary end point. For efficacy and safety analyses, any patient
`who took the study medication and completed at least one visit dur-
`ing the active-treatment phase was included. Absolute values, as well
`as changes from base-line values, for all efficacy measures were com-
`pared. Two analyses were performed: one in which only data avail-
`able at each visit were analyzed and one in which the last available
`value was carried forward. In the latter analysis, missing values for
`evaluations during or at the end of treatment were replaced by the
`most recent previously recorded value. The results of the two analy-
`ses were similar. Statistical comparisons were performed with SAS
`software.19 Comparisons within groups were made with a two-tailed
`paired t-test. For continuous variables, comparisons between groups
`were made with linear models that included contrasts (LS means in
`SAS) for pairwise comparisons between the treatment groups. These
`models included effects of treatment and center (analysis of vari-
`ance),20 with selected models including an effect of base-line values
`(analysis of covariance).20 All values are given as means ⫾SE.
`
`RESULTS
`
`Protocol 1
`
`Metformin Dose
`At the end of the five-week titration phase 78 percent
`of the patients assigned to metformin were taking the
`maximal dose (2550 mg per day), and 85 percent even-
`tually took this dose. At week 29 the mean (⫾SE) fast-
`ing plasma metformin concentrations were 742⫾182
`and 872⫾99 ng per milliliter in the patients taking 1700
`and 2550 mg of metformin per day, respectively.
`
`Body Weight and Blood Pressure
`During the active-treatment phase, the patients in
`the metformin group lost 0.6⫾0.3 kg of weight and
`those in the placebo group lost 1.1⫾0.2 kg (P⫽0.21).
`The mean base-line blood pressure (supine) in the met-
`formin and placebo groups was normal and did not
`change during treatment.
`
`Fasting Plasma Glucose and Insulin Concentrations and
`Glycosylated Hemoglobin Values
`By week 29 the fasting plasma glucose concentration
`had decreased by 52⫾5 mg per deciliter (2.9⫾0.3 mmol
`per liter) to 189⫾5 mg per deciliter (10.6⫾0.3 mmol
`per liter) in the metformin group and increased by 6⫾5
`mg per deciliter (0.3⫾0.3 mmol per liter) to 244⫾6 mg
`per deciliter (13.7⫾0.3 mmol per liter) in the placebo
`group (P⬍0.001). The respective changes in glycosylat-
`ed hemoglobin were ⫺1.4⫾0.1 percent and 0.4⫾0.1
`percent (P⬍0.001). At week 29, 22 percent of the
`patients treated with metformin had fasting plasma
`glucose concentrations of 140 mg per deciliter or less,
`as compared with 6 percent in the placebo group
`(P⫽0.001).
`The fasting plasma glucose and glycosylated hemo-
`globin values during the active-treatment phase are
`shown in Figures 2 and 3, respectively. In the metfor-
`min group, the fasting plasma glucose concentration
`declined progressively during the metformin-titration
`phase, reaching a nadir that was about 55 mg per dec-
`iliter (3.1 mmol per liter) below base line between
`weeks 5 and 9, and remained at this level until the end
`of the study. The magnitude of the decline in fasting
`plasma glucose was correlated (r⫽⫺0.551, P⬍0.001)
`
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`

`544
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Aug. 31, 1995
`
`Protocol 1
`
`Diet ⫹ placebo
`
`*
`
`‡
`
`9
`
`Diet ⫹ metformin
`
`*
`
`*
`
`*
`
`*
`
`*
`
`Protocol 2
`
`Glyburide
`
`†
`
`‡
`
`†
`Metformin
`
`†
`
`†
`
`‡
`
`‡
`‡
`Metformin ⫹ glyburide
`
`‡
`
`13
`
`17
`
`21
`
`25
`
`29
`
`Week
`
`1
`
`0
`
`⫺1
`
`⫺2
`
`1
`
`0
`
`⫺1
`
`⫺2
`
`⫺3
`
`0
`
`Change in Glycosylated Hemoglobin Values (percentage points)
`
`with the base-line fasting plasma glucose concentration
`(Fig. 4). The declines in fasting plasma glucose and gly-
`cosylated hemoglobin values in the metformin group
`were independent of age (⭓65 years or ⬍65 years),
`race or ethnic group (white vs. black vs. Hispanic), du-
`ration of diabetes (⭓10 years or ⬍10 years), base-line
`body-mass index (the weight in kilograms divided by
`the square of the height in meters, ⭓29 or ⬍29), and
`base-line plasma lipid and insulin concentrations. The
`fasting plasma insulin and C-peptide concentrations
`did not change in either group.
`
`Oral Glucose-Tolerance Tests
`The plasma glucose and insulin concentrations
`(weighted mean of the values at 0, 1, 2, and 3 hours)
`before and after the oral administration of glucose at
`base line were similar in the metformin and placebo
`groups. At week 29 the mean plasma glucose concen-
`tration after glucose ingestion had not changed in the
`placebo group (337⫾10 vs. 337⫾7 mg per deciliter
`[18.9⫾0.6 vs. 18.9⫾0.4 mmol per liter]) but had de-
`creased in the metformin group (from 347⫾7 to 275⫾7
`mg per deciliter [19.3⫾0.4 to 15.3⫾0.4 mmol per liter],
`
`Figure 3. Mean (⫾SE) Changes in Glycosylated Hemoglobin
`Values in Patients with NIDDM Who Were Enrolled in
`Protocol 1 or 2.
`The asterisks indicate significant differences (P⬍0.001) between
`the groups in Protocol 1, the daggers significant differences
`(P⬍0.01) between the metformin and glyburide groups, and the
`double daggers significant differences (P⬍0.001) between the
`combination-therapy and glyburide groups.
`
`P⬍0.001 for the comparison with placebo); all of the
`decrease was the result of the decrease in the fasting
`plasma glucose concentration. The mean plasma insu-
`lin concentration did not change in the placebo group
`and rose slightly in the metformin group (to 36.2⫾2
`from 29⫾2 mU per milliliter [216⫾12 from 174⫾12
`pmol per liter], P⫽0.001 for the comparisons with base
`line and with placebo). The plasma C-peptide concen-
`trations closely paralleled the plasma insulin concentra-
`tions in both groups.
`
`Plasma Lipids
`Before treatment the fasting serum total cholesterol,
`LDL cholesterol, HDL cholesterol, and triglyceride
`concentrations were similar in the metformin and pla-
`cebo groups (Table 2). There were no changes during
`treatment in the placebo group. By week 29 the serum
`total cholesterol, LDL cholesterol, and triglyceride con-
`centrations in the metformin group had decreased and
`were significantly lower than in the placebo group (Ta-
`ble 2).
`
`Fasting Plasma Lactate
`The mean fasting plasma lactate concentrations at
`base line were slightly elevated in both groups (mean
`
`Protocol 1
`
`Diet ⫹ placebo
`
`*
`
`*
`
`*
`
`† † †
`
`Diet ⫹ metformin
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`Protocol 2
`
`Glyburide
`
`†
`Metformin
`
`†
`
`‡
`
`5
`
`‡
`9
`
`‡
`
`13
`
`‡
`
`17
`
`‡
`‡
`‡
`Metformin ⫹ glyburide
`
`21
`
`25
`
`29
`
`Week
`
`‡
`
`0
`
`‡
`
`‡‡
`
`20
`
`0
`
`⫺20
`
`⫺40
`
`⫺60
`
`40
`
`20
`
`0
`
`⫺20
`
`⫺40
`
`⫺60
`
`⫺80
`
`Change in Fasting Plasma Glucose Values (mg/dl)
`
`Figure 2. Mean (⫾SE) Changes in Fasting Plasma Glucose Con-
`centrations in Patients with NIDDM Who Were Enrolled in Pro-
`tocol 1 or 2.
`The asterisks indicate significant differences (P⬍0.001) between
`the groups in Protocol 1, the daggers significant differences
`(P⬍0.001) between the metformin and glyburide groups, the dia-
`monds significant differences (P⬍0.01) between the metformin
`and glyburide groups, and the double daggers significant differ-
`ences (P⬍0.001) between the combination-therapy and gly-
`buride groups. To convert values for glucose to millimoles per li-
`ter, multiply by 0.056.
`
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`AUROBINDO EX. 1020, 4
`
`

`

`Vol. 333 No. 9
`
`EFFICACY OF METFORMIN IN PATIENTS WITH NIDDM
`
`545
`
`Base-Line Fasting Glucose
`Concentrations (mg/dl)
`
`placebo group. There were no changes in hematocrit or
`hemoglobin in either group.
`
`Withdrawal of Patients and Adverse Effects
`Thirty-one patients in the metformin group (22 per-
`cent) and 41 patients in the placebo group (28 percent)
`withdrew from the study before week 29 (Table 3).
`More patients in the placebo group than in the metfor-
`min group withdrew because of treatment failure (18
`vs. 2 [12 percent vs. 1 percent], P⬍0.001). Adverse ef-
`fects were limited to the digestive system. Diarrhea
`and nausea were more common in the group receiving
`metformin, but were characterized as severe in only
`8 percent and 4 percent of patients, respectively. The
`frequency and severity of reported symptoms of hypo-
`glycemia were similar in the metformin and placebo
`groups (⬍2 percent). No patient had biochemically
`documented hypoglycemia.
`
`Protocol 2
`Metformin and Glyburide Dose
`At week 29, 90 percent of the patients in the metfor-
`min group and 70 percent in the group given metformin
`plus glyburide were receiving 2500 mg of metformin per
`day. The mean fasting plasma metformin concentra-
`tions in these two groups were 809⫾60 and 920⫾75
`ng per milliliter, respectively, at this time.
`
`Body Weight and Blood Pressure
`There was no significant change in body weight at
`week 29 in the glyburide group (⫺0.3⫾0.2 kg). The
`
`140 –179 180 –219 220 –259 260 –300 ⬎300
`27
`
`33
`
`41
`
`31
`
`24
`
`51
`
`23
`
`33
`
`32
`
`Diet ⫹ metformin (protocol 1)
`Metformin ⫹ glyburide (protocol 2)
`
`54
`
`0
`
`⫺20
`
`⫺40
`
`⫺60
`
`⫺80
`
`⫺100
`
`⫺120
`
`Change in Fasting Glucose
`
`Concentration (mg/dl)
`
`Figure 4. Relation between the Decrease in Fasting Plasma Glu-
`cose Concentrations at the End of Active Treatment and the
`Base-Line Concentrations in Patients with NIDDM.
`The numbers of patients in each subgroup are indicated. Values
`are means ⫾SE. To convert values for glucose to millimoles per
`liter, multiply by 0.056.
`
`in both groups, 1.41⫾0.10 mmol per liter; normal,
`⬍1.30 mmol per liter). The values were similar at all
`times during the active-treatment period in both
`groups.
`
`Serum Vitamin B12 and Folate
`Serum folate concentrations did not change in either
`the metformin or placebo groups. The serum vitamin
`B12 concentration at week 29 was lower in the metfor-
`min group (by 22 percent) but did not change in the
`
`Table 2. Plasma Lipid and Lactate Concentrations in the Five Groups before and after Treatment for 29 Weeks.*
`
`VARIABLE
`
`PLASMA TOTAL
`CHOLESTEROL
`
`P
`VALUE
`
`PLASMA LDL
`CHOLESTEROL
`
`P
`VALUE
`
`PLASMA HDL
`CHOLESTEROL
`
`PLASMA
`TRIGLYCERIDES
`
`P
`VALUE
`
`PLASMA LACTATE
`
`mg/dl
`
`mg/dl
`
`mg/dl
`
`mg/dl
`
`mmol/liter
`
`Protocol 1
`Before treatment
`Metformin
`Placebo
`After treatment
`Metformin
`Placebo
`Change
`Metformin
`Placebo
`Protocol 2
`Before treatment
`Metformin
`Glyburide
`Metformin ⫹ glyburide
`After treatment
`Metformin
`Glyburide
`Metformin ⫹ glyburide
`Change
`Metformin
`Glyburide
`Metformin ⫹ glyburide
`
`211⫾3
`212⫾4
`
`201⫾4
`213⫾4
`
`⫺11⫾3
`1⫾3
`
`212⫾3
`215⫾3
`216⫾3
`
`208⫾3
`220⫾4
`206⫾3
`
`⫺4⫾2
`5⫾2
`⫺10⫾2
`
`136⫾3
`138⫾3
`
`123⫾3
`135⫾3
`
`⫺11⫾3
`⫺2⫾2
`
`134⫾3
`136⫾3
`137⫾3
`
`129⫾3
`141⫾3
`128⫾3
`
`⫺6⫾2
`3⫾2
`⫺8⫾2
`
`39⫾11
`41⫾11
`
`40⫾11
`41⫾11
`
`209⫾151
`185⫾911
`
`193⫾101
`191⫾101
`
`1⫾1
`⫺1⫾1⫺
`
`⫺17⫾12⫺
`6⫾7
`
`37⫾11
`37⫾11
`39⫾11
`
`39⫾11
`38⫾11
`40⫾11
`
`2⫾1
`⬍1⫾1⬍
`1⫾1
`
`231⫾121
`210⫾811
`216⫾101
`
`221⫾131
`227⫾111
`194⫾911
`
`⫺16⫾7⫺1
`21⫾91
`⫺20⫾7⫺1
`
`0.01†0
`
`0.019†
`
`0.001‡
`
`0.001‡
`
`0.009‡
`
`0.001‡
`
`0.005†
`
`0.001†
`
`0.003‡
`
`0.001‡
`
`0.011‡
`
`0.001‡
`
`1.41⫾0.04
`1.40⫾0.04
`
`1.46⫾0.05
`1.41⫾0.04
`
`0.04⫾0.05
`0.00⫾0.05
`
`1.47⫾0.04
`1.45⫾0.03
`1.45⫾0.03
`
`1.54⫾0.04
`1.42⫾0.04
`1.51⫾0.04
`
`0.08⫾0.04
`⫺0.01⫾0.03⫺
`0.06⫾0.04
`
`0.004‡
`
`0.001‡
`
`0.001‡
`
`0.001‡
`
`*To convert values for total, LDL, and HDL cholesterol to millimoles per liter, multiply by 0.0259, and to convert values for triglycerides to millimoles per liter, multiply
`by 0.011.
`†For the comparison with metformin.
`‡For the comparison with glyburide.
`
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`AUROBINDO EX. 1020, 5
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`

`

`546
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Aug. 31, 1995
`
`Table 3. Withdrawals from the Study, According to Treatment Group.
`
`REASON FOR WITHDRAWAL
`
`PROTOCOL 1
`
`PROTOCOL 2
`
`PLACEBO
`(N ⫽ 146)
`
`METFORMIN
`(N ⫽ 143)
`
`GLYBURIDE
`(N ⫽ 209)
`
`METFORMIN
`(N ⫽ 210)
`
`METFORMIN ⫹
`GLYBURIDE
`(N ⫽ 213)
`
`number (percent)
`
`All
`Adverse effects†
`Treatment failure‡
`Other§
`
`41 (28)
`2 (1)
`18 (12)
`21 (14)
`
`31 (22)
`14 (10)
`2 (1)
`15 (10)
`
`35 (17)
`5 (2)
`6 (3)
`24 (11)
`
`53 (25)*
`5 (2)
`21 (10)
`27 (13)
`
`21 (10)
`4 (2)
`1.1 (0.5)
`16 (8)1
`
`*One patient in this group died of cardiac arrest, presumably caused by myocardial infarction.
`†Adverse effects included digestive symptoms (principally diarrhea) in 11 metformin-treated patients in protocol 1 and
`2 glyburide-treated patients, 3 metformin-treated patients, and 2 combination-therapy patients in protocol 2.
`‡Treatment failure was defined as symptomatic diabetes including marked polyuria, polydipsia, and weight loss.
`§Other reasons included intercurrent illness, abnormal laboratory results, patient’s decision to withdraw, noncompliance,
`and loss to follow-up.
`
`of 140 mg per deciliter or less, as
`compared with 3 percent in the met-
`formin group and 2 percent in the
`glyburide group. The fasting plasma
`insulin concentration did not change
`in either the glyburide group or the
`combination-therapy group and de-
`clined slightly in the metformin
`group (by 5⫾1 mU per milliliter
`[30⫾6 pmol per liter], P⫽0.01 for
`the comparison with the glyburide
`and combination-therapy groups).
`
`Oral Glucose-Tolerance Tests
`The mean plasma glucose and in-
`sulin concentrations before and af-
`ter the oral administration of glu-
`cose at base line were similar in all three groups. The
`mean plasma glucose concentrations after oral glucose
`did not change in the glyburide or metformin group but
`decreased in the combination-therapy group (by 61⫾6
`mg per deciliter [3.4⫾0.3 mmol per liter], P⫽0.001
`for the comparison with the other two groups). All the
`improvement resulted from the decrease in the fasting
`plasma glucose concentration. The mean plasma insu-
`lin and C-peptide concentrations did not change in
`the glyburide and combination-therapy groups, but the
`mean plasma insulin concentration decreased slightly
`(by 5⫾2 mU per milliliter [30⫾12 pmol per liter]) in
`the metformin group (P⫽0.05 for the comparison with
`the other two groups).
`
`Plasma Lipids
`Befor