INTRODUCTION

Optimal control of hyperglycemia and associated

risk factors reduces the risk of diabetes- related com-
plications. Metformin is the most widely prescribed
biguanide, which lowers blood glucose level primar-
ily through the inhibition of hepatic glucose produc-
tion. The UK Prospective Diabetes study (UKPDS)
showed that metformin reduces the risk of diabetes-
related endpoints, myocardial infarction, diabetes-
related death and all- cause mortality in overweight
patients with newly diagnosed type 2 diabetes (1, 2).
Moreover, recent observational studies reveal that
body mass index (BMI) of patients is unlikely to
influence the antihyperglycemic effect of metformin
(3- 5). Therefore, global guidelines now recommend
ORIGINAL
Effectiveness of metformin and lifestyle interventions as
an initial treatment in Japanese patients with newly
diagnosed type 2 diabetes : a prospective observational
study
Satoru Sumitani
1,2
, Shinya Morita
2
, Yoshihiko Utsu
2
, Kosuke Mukai
2
, Shunji Miki
2
,
Bunzo Sato
2
, Hideji Nakamura
1
, and Soji Kasayama
2
1
Center for Preventive Medicine and
2
Department of Medicine, Nissay Hospital, Osaka, Japan
Abstract : Although global guidelines recommend metformin and lifestyle interventions
as an initial treatment in patients with newly diagnosed type 2 diabetes (T2DM), few re-
ports exist about its effectiveness in Japanese patients. To examine its effectiveness, we
performed a prospective observational study within a routine clinical setting. We pro-
vided metformin ( 1,500 mg/day) and lifestyle interventions to 23 patients with newly
diagnosed T2DM (20 men and 3 women, mean age 53 years, mean body mass index [BMI]
25.7 kg/m
2
). After 16 weeks, HbA1c levels significantly decreased from 9.1 2.1% (mean
SD) to 6.6 0.8% (p 0.001). Thirteen patients (56.5%) achieved a target HbA1c 6.5%. We
did not find a significant correlation between baseline BMI and the changes in HbA1c
(!HbA1c) (r=-0.165, p=0.451). In contrast, we found a significant correlation between base-
line fasting plasma glucose and!HbA1c (r=-0.755, p 0.001). Body weight decreased from
73.3 13.3 kg to 69.8 11.6 kg (p 0.001). Total cholesterol, low density lipoprotein-choles-
terol, non-high density lipoprotein-cholesterol, and serum vitamin B-12 concentrations
also significantly decreased. Adverse events included diarrhea (26.1%) and mild eleva-
tion of liver enzymes (8.7%). These results suggest that metformin and lifestyle interven-
tions is effective and safe as an initial treatment in Japanese patients with newly diag-
nosed T2DM. J. Med. Invest. 59 : 166-173, February, 2012
Keywords : management, type 2 diabetes, metformin, lifestyle interventions, hypoglycemia
Received for publication November 15, 2011 ; accepted Decem-
ber 28, 2011.
Address correspondence and reprint requests to Satoru Sumitani,
MD, PhD, Center for Preventive Medicine, Nissay Hospital, 6-
3- 8 Itachibori, Nishi - ku, Osaka, Osaka 550- 0012, Japan and
Fax : +81- 6- 6532- 6402.
The Journal of Medical Investigation Vol. 59 2012
166
the use of metformin as an initial oral pharmacother-
apy for both overweight and normal weight patients
with type 2 diabetes (6, 7). The antihyperglycemic
effect of metformin is dose-dependent, and the maxi-
mal effect is obtained at 2,000 mg/day in most pa-
tients (8). Therefore, the maximal recommended
daily dose of metformin is 2,000 mg/day in the USA
and 3,000 mg/day in Europe and in other regions.
Importantly, the metabolic and clinical outcomes
for metformin in the UKPDS were obtained using
a median daily dose of 2,550 mg/day (1). The local
regulation in Japan, however, had placed an upper
limit of daily dose of metformin at 750 mg/day from
1977 to 2010. Therefore, we know few studies that
examined the antihyperglycemic effect of metformin
at doses greater than 750 mg/day in Japanese pa-
tients with newly diagnosed type 2 diabetes.
The American Diabetes Association (ADA) and
the European Society for the Study of Diabetes
(EASD) issued a consensus algorithm for the initial
management of hyperglycemia in patients with type
2 diabetes in 2006 (9) and updated it in 2009 (10),
where the standard dose of metformin ("1,500 mg/
day) (11) and lifestyle interventions is recommended
as an initial treatment in patients with newly diag-
nosed type 2 diabetes. We are, however, aware of
no published report that describes the effectiveness
of this approach in Japanese patients with type 2
diabetes. Therefore, we performed a prospective ob-
servational study to examine the effectiveness of
metformin and lifestyle interventions as an initial
treatment in Japanese patients with newly diagnosed
type 2 diabetes.
PATIENTS AND METHODS
Study design
We performed a prospective observational study
within a routine clinical setting to examine the ef-
fectiveness of metformin and lifestyle interventions
as an initial treatment in Japanese patients with
newly diagnosed type 2 diabetes. The follow- up
period of the study was 16 weeks. The study was
conducted in an outpatient clinic in a community-
based hospital located in Osaka, Japan. Between
June 2010 and November 2010, 23 patients with
newly diagnosed type 2 diabetes (20 men and 3
women) were consecutively enrolled in the study.
After diagnosis of type 2 diabetes, metformin and
lifestyle interventions were provided at the same
time. The patients were examined every two weeks
until the administered dose of metformin was fixed,
and thereafter every four weeks to 16 weeks. Bio-
chemical measurements and physical examinations,
including taking vital signs and measuring body
weight, were performed at every visit. At the base-
line, anthropometric characteristics and demographic
characteristics were also collected. The study was
conducted in accordance with the Declaration of
Helsinki and with the approval of the Ethics Com-
mittee of Nissay Hospital. Each patient provided
written informed consent for study participation and
the use of their data for research purposes. This
study is registered with the University Hospital
Medical Information Network (UMIN) clinical trial
registry, number 000004193.
Patients
Eligible patients were newly diagnosed patients
with type 2 diabetes aged 20- 75 years with HbA1c
levels"6.5%, and who had never taken an oral hy-
poglycemic agent. The diagnosis of type 2 diabetes
was made on the WHO 1999 criteria (12). Patients
were excluded from the study if they had fasting
plasma glucose (FPG) "300 mg/dL, proliferative
diabetic retinopathy, elevated serum creatinine
("1.3 mg/dL in men and "1.2 mg/dL in women),
elevated liver enzymes (aspartate transaminase
[AST], alanine transaminase [ALT] !2.5!the upper
limit of normal), or a history of lactic acidosis.
Treatments
Lifestyle interventions were composed of an in-
dividualized dietary counseling and an encourage-
ment to increase daily physical activities. Each pa-
tient received an individualized dietary counseling
from a registered dietitian, which was based on car-
bohydrate counting (13- 16). Briefly, each patient
was instructed to take a fixed amount of daily car-
bohydrate (180 g/day for men and 150 g/day for
women). The distribution of the total amount of
daily carbohydrate to each meal was negotiated with
the patients. No instruction regarding the energy
consumption and the amount of fat or protein was
provided. Specific instructions, however, were pro-
vided to the patients about the type of fat to be con-
sumed (recommendation of mainly monounsatu-
rated fatty acids and polyunsaturated fatty acids
with restriction of saturated fat). The patients were
encouraged to increase their daily physical activi-
ties through, for example, a habitual walking. Ad-
herence to lifestyle interventions was reinforced at
every visit.
The Journal of Medical Investigation Vol. 59 February 2012 167
Metformin was started with 250 mg two times a
day (500 mg/day) with meals (breakfast and din-
ner). Every two weeks, the dose was advanced to
500 mg two times a day (1,000 mg/day) with meals
and finally to 500 mg three times a day (1,500 mg/
day) with meals. When high plasma glucose level
(FPG "140 mg/dL) persisted with 1,500 mg/day,
the dose was further advanced to 750 mg three
times (2,250 mg/day) with meals. When the pa-
tients had gastrointestinal symptoms, we decreased
the dose to the previous lower dose and later tried
to advance the dose again.
Outcomes and adverse events
The primary outcomes of this study were the
change in HbA1c levels from the baseline to 16
weeks and the proportions of patients achieving tar-
get HbA1c levels (!6.5% and !7.0%) at 16 weeks.
The secondary outcomes were the changes in body
weight, BMI, FPG, glycated albumin (GA), total
cholesterol, triglyceride, high density lipoprotein
(HDL)- cholesterol, low density lipoprotein (LDL)-
cholesterol, non- HDL- cholesterol, and serum vita-
min B- 12 during the follow- up period. Vitamin B-
12 deficiency was defined as the serum level !200
pg/mL (17). Occurrence of adverse events, includ-
ing gastrointestinal adverse events and hypoglyce-
mia was assessed by medical interviews at every
visit. Hypoglycemia was defined as the presence of
typical adrenergic or neuroglycopenic symptoms
and signs. Gastrointestinal adverse events were de-
fined as the events by which the patient was unable
to advance the dose to 1,500 mg/day. They in-
cluded diarrhea, abdominal discomfort, constipation,
and nausea. All adverse events were recorded and
judged for severity and possible relationship to the
treatment.
Laboratory analysis
HbA1c levels were measured with HLC- 723G8
(Tosoh, Tokyo, Japan) by high performance liquid
chromatography (HPLC). The value for HbA1c (%)
was shown as an National Glycohemoglobin Stan-
dardization Program (NGSP) equivalent value (%)
calculated by the formula HbA1c (%)=HbA1c (Japan
Diabetes Society [JDS])(%)+0.4%, considering the
relational expression of HbA1c (%) measured by the
previous Japanese standard substance and measure-
ment methods and HbA1c (NGSP) (18). The differ-
ence of HbA1c level between the baseline and 16
weeks (HbA1c) was calculated by subtracting the
value of HbA1c at the baseline from that of at 16
weeks. GA was measured by the latex agglutination
method (Asahi Kasei Pharma, Tokyo, Japan). Serum
C- peptide and vitamin B- 12 concentrations were
measured by chemiluminescent enzyme immunoas-
says (CLEIA). FPG, total cholesterol, triglyceride,
HDL- cholesterol, were measured using standard
laboratory methods. LDL- cholesterol was calculated
by Friedwald equation (19). Non- HDL- cholesterol
was calculated by subtracting the value of HDL-
cholesterol from total cholesterol. The estimated
glomerular filtration rates (eGFR) were estimated
using serum creatinine values and the abbreviated
Modification of Diet in Renal Disease (MDRD)
study equation, modified with the Japanese coeffi-
cient (20). Assessment of diabetic retinopathy was
performed by fundoscopic examinations by an oph-
thalmologist. Diabetic retinopathy was graded as
follows : no diabetic retinopathy (NDR) ; non-prolif-
erative diabetic retinopathy (NPDR) ; and prolifera-
tive diabetic retinopathy (PDR). Diabetic nephropa-
thy was staged as follows : normoalbuminuria (uri-
nary albumin excretion !30 mg/g.creatinine[Cr]) ;
microalbuminuria (urinary albumin excretion 30- 299
mg/g.Cr) ; and macroalbuminuria (urinary albumin
excretion "300 mg/g.Cr). Diabetic neuropathy was
diagnosed using the Michigan Neuropathy Screen-
ing Instrument (MNSI) (21).
Statistical analysis
All statistical analyses were performed using
SPSS for Windows, Version 11.0 (SPSS, Chicago,
IL, USA). Continuous variables are expressed as
mean
!
SD or median [25%, 75%]. Categorical vari-
ables are expressed as number. Changes in HbA1c
level during the follow- up period were analyzed with
the Friedman test. The Wilcoxon signed- rank test
with the Bonferroni correction was used for multi-
ple comparisons. Spearmans correlation coefficients
were used to determine the correlations between
the HbA1c and the baseline FPG or BMI. Differ-
ences of the clinical variables between the baseline
and 16 weeks were analyzed with the Wilcoxon
signed- rank test. All p values were two- sided. A p
value!0.05 was considered to be statistically signifi-
cant.
RESULTS
Baseline and follow-up characteristics
Baseline characteristics of the study patients are
described in Table 1. All variables in the baseline
S. Sumitani, et al. Metformin and type 2 diabetes 168
characteristics were measured at the time of enroll-
ment. The mean age was 53 years, the mean HbA1c
level 9.1%, and the mean BMI 25.7 kg/m
2
. The fi-
nal dose of metformin at 16 weeks was 750 mg/
day in three, 1,000 mg/day in three, 1,500 mg/day
in fourteen, and 2,250 mg/day in three patients.
Primary outcomes
Time course of HbA1c level of each patient is
depicted in Fig. 1A. The mean HbA1c significantly
decreased at 4 weeks, and it progressively decreased
from 9.1
!
2.1% at baseline to 6.6
!
0.8% after 16
weeks (p!0.001, Fig. 1B). The mean HbA1c was
- 2.41% (95% confidence interval [CI] - 1.57- - 3.25).
We did not find a significant correlation between
baseline BMI and HbA1c (r = - 0.165, p=0.451,
Fig. 2A). In contrast, we found a significant cor-
relation between baseline FPG and HbA1c (r=
- 0.755, p!0.001, Fig. 2B). Among the 23 patients,
13 (56.5%) achieved HbA1c !6.5% and 16 (69.6%)
achieved HbA1c !7.0% at 16 weeks.
Fig. 1 Time course of HbA1c levels of each patient (A) and the change in the mean HbA1c levels (B) during the follow- up period.
The p and
2
values were by the Friedman test. Asterisks denote p!0.001 compared with the baseline HbA1c level by the Wilcoxon
signed- rank test.
Table 1 Baseline characteristics of patients
Variable
Men/Women 20/3
Age (years) 53!11
Body weight (kg) 73.3!13.3
Body mass index (kg/m
2
) 25.7!4.5
Systolic blood pressure (mmHg) 114!27
Diastolic blood pressure (mmHg) 74!12
Fasting plasma glucose (mg/dL) 182!59
HbA1c (%) 9.1!2.1
Fasting C- peptide (ng/mL) 1.67!1.04
eGFR (ml/min/1.73 m
2
) 86.9!18.5
Retinopathy (NDR/NPDR/PDR) 23/0/0
Nephropathy (norm/micro/macro) 21/1/1
Neuropathy (- /+) 22/1
Data are number or mean!SD. eGFR : estimated glomelular fil-
tration rate, NDR : no diabetic retinopathy, NPDR ; non-prolifera-
tive diabetic retinopthy, PDR : proliferative diabetic retinopathy,
norm : normoalbuminuria, micro : microalbuminuria, macro :
macroalbuminuiria.
The Journal of Medical Investigation Vol. 59 February 2012 169
Secondary outcomes
The changes in various clinical variables over the
study period are presented in Table 2. Body weight
significantly decreased from 73.3
!
13.3 kg at base-
line to 69.8
!
11.6 kg at 16 weeks (p!0.001). FPG
significantly decreased from 182
!
59 mg/dL to
116
!
15 mg/dL (p!0.001). Levels of total choles-
terol, LDL- cholesterol, and non- HDL- cholesterol
also significantly decreased. In contrast, levels of
triglyceride and HDL- cholesterol did not statistically
change. Serum vitamin B- 12 levels also significantly
Fig. 2 Correlation between baseline body mass index (BMI) and HbA1c (A), and between baseline fasting plasma glucose (FPG)
and HbA1c (B). HbA1c was calculated by subtracting the HbA1c values at the baseline from those at 16 weeks. r is Spearmans
rank correlation coefficient.
Table 2 Clinical variables at the baseline and after 16 weeks
Variable Baseline After 16 weeks p
Body weight (kg) 73.3!13.3 69.8!11.6 !0.001
Body mass index (kg/m
2
) 25.7!4.5 24.5!4.0 !0.001
Fasting plasma glucose (mg/dL) 182!59 116!15 !0.001
Glycated albumin (%) 25.1!8.5 15.9!2.8 !0.001
Total cholesterol (mg/dL) 214!30 184!24 !0.001
Triglyceride (mg/dL) 132 [92, 214] 126 [79, 189] 0.200
HDL-cholesterol (mg/dL) 51!11 51!10 0.910
LDL- cholesterol (mg/dL) 126!34 105!23 0.010
Non- HDL- cholesterol (mg/dL) 163!34 133!25 0.001
Vitamin B- 12 (pg/mL) 458 [277, 714] 353 [216, 577] 0.017
Data are mean!SD or median [25%, 75%]. HDL : high density lipoprotein, LDL : low density lipoprotein. Between group differences
were examined with the Wilcoxon signed- rank test.
S. Sumitani, et al. Metformin and type 2 diabetes 170
decreased. No patient, however, developed vitamin
B- 12 deficiency defined by the serum vitamin B- 12
level.
Adverse events
No hypoglycemia was observed in any patients.
Among the 23 patients, six patients (26.1%) were un-
able to advance to 1,500 mg/day because of diar-
rhea. Among them, however, no patient discontin-
ued taking metformin. No other gastrointestinal
adverse event, including abdominal discomfort, con-
stipation and nausea was observed. Two patients
(8.7%) showed slight elevation of ALT (less than
!1.5 of the upper limit of normal). No patient had
lactic acidosis.
DISCUSSION
We found that metformin and lifestyle interven-
tions decreased HbA1c levels by 2.41% (95% CI
1.57- 3.25) after 16 weeks. To our knowledge, this
is the first report on the effectiveness of metformin
("1,500 mg/day) and lifestyle interventions in Japa-
nese patients with newly diagnosed type 2 diabe-
tes within a routine clinical setting. In this regard,
Saito et al. reported the efficacy of high- dose met-
formin (1,500 mg/day) in 12 patients with type 2
diabetes (22). All of their study patients, however,
were inadequately controlled (HbA1c"7.4%) with
metformin alone (750 mg/day) or metformin plus
sulfonylureas at the baseline. Therefore, the efficacy
of high- dose metformin as an initial treatment in
patients with newly diagnosed type 2 diabetes was
not evaluated in their study. In the previous placebo-
controlled trials, metformin lowered HbA1c levels
by about 1.5% (8, 23). The difference between the
present results and the previous results may be
owing to the different study designs. The previous
studies included drug- naive patients who were in-
adequately controlled with lifestyle interventions to
rigorously examine the efficacy of metformin. In
contrast, our study did not aim to examine the effi-
cacy of metformin per se, but the effectiveness of
metformin and lifestyle interventions as an initial
treatment in patients with type 2 diabetes in a rou-
tine clinical setting. Therefore, the reduction in
HbA1c levels in the present study appears to be a
composite effect of metformin and lifestyle inter-
ventions. This may be one of the reasons why the
reduction of HbA1c in the present study is greater
than that observed in the previous studies.
Because of the results of the UKPDS34 (1), met-
formin had been preferentially administered to over-
weight or obese type 2 diabetic patients. We did
not find, however, a statistically significant correla-
tion between baseline BMI and HbA1c (Fig. 2A),
indicating that BMI does not influence the antihy-
perglycemic effect of metformin and lifestyle inter-
ventions. This is consistent with the recent studies
showing BMI does not influence the antihypergly-
cemic effect of metformin (3- 5) and supports the
notion that metformin may be effective as an initial
pharmacotherapy irrespective of BMI of the patients.
In contrast, we found a significant correlation be-
tween baseline FPG and HbA1c (Fig. 2B). This
indicates that antihyperglycemic effect of metformin
is more potent in patients with poorer glycemic con-
trol. Progressive deterioration of glycemic control
in type 2 diabetic patients correlates with the in-
creased hepatic glucose produciton (24). Therefore,
it is conceivable that antihyperglycemic effect of
metformin, which is chiefly through inhibition of
hepatic glucose production, is more potent in pa-
tients with poorer glycemic control. The proportion
of patients who achieved a target HbA1c !6.5% and
!7.0% was 56.5% and 69.6%, respectively, indicating
that about 30% of patients remained inadequate gly-
cemic control with metformin and lifeltyle interven-
tions. Although addition of a sulfonylurea or basal
insulin to patients who fail to achieve a target HbA1c
!7.0% with metformin and lifestyle interventions is
recommended in the ADA/EASD algorithm (10),
further studies are needed to confirm that this ap-
proach is effective as a second treatment in Japanese
patients with type 2 diabetes.
We found that metformin and lifestyle interven-
tions induced significant weight loss after 16 weeks.
Because weight gain is one of the unfavorable prob-
lems by treatment with thiazolidinediones or sul-
fonylureas (25), our finding further supports the
notion that an initial treatment with metformin has
a health benefit in overweight or obese patients.
Moreover, we found that levels of total choles-
terol, LDL- cholesterol, and non- HDL cholesterol
decreased significantly during the follow- up period.
In contrast, levels of triglyceride and HDL-choles-
terol did not change significantly. This is consistent
with the previous results obtained in randomized-
controlled study (23). Because control of LDL-cho-
lesterol is the primary focus of lipid management,
the property of metformin to decrease LDL-choles-
terol may add a further health benefit to patients
with type 2 diabetes. A recent study showed that
The Journal of Medical Investigation Vol. 59 February 2012 171
long- term treatment with metformin in patients with
type 2 diabetes has a risk of vitamin B- 12 deficiency
(26). Although we found a significant decrease in
the level of vitamin- B12 during the follow- up pe-
riod, no patients developed vitamin B- 12 deficiency.
A careful monitoring of vitamin B- 12 levels may be
warranted with long- term metformin treatment.
We observed no hypoglycemia in the study pa-
tients during the follow- up period. Because the pa-
tients did not have self- monitoring of blood glucose,
we are formally unable to exclude the occurrence
of asymptomatic hypoglycemia. Metformin is, how-
ever, an insulin sensitizer and does not stimulate
insulin secretion (27). Therefore, metformin rarely
induces hypoglycemia as a monotherapy. Because
hypoglycemia is the greatest obstacle to achieve
near normal glycemia, an initial treatment with met-
formin and lifestyle interventions appears to be a
safe approach to achieve near normal glycemia.
Gastrointestinal adverse events, including diar-
rhea, constipation, nausea and other symptoms,
have been shown common in patients taking met-
formin. Six patients (26.1%) were unable to advance
to 1,500 mg/day because of diarrhea. The incidence
of gastrointestinal adverse events is different among
previous studies, ranging from 6% to 43% (28). This
may be due to the different definition of gastroin-
testinal adverse events or the different doses of met-
formin.
The main limitation of the present study is its ob-
servational design without a parallel control group,
which prevents us drawing conclusions about cau-
sality. Another limitation is that the small number
of patients and short duration of the follow- up period
prevent the precise estimate of the effectiveness of
the treatment. Large- scale, long- term randomized-
controlled studies are needed to confirm the findings
of our study.
In conclusion, we found that metformin and life-
style interventions reduced HbA1c levels by 2.41%
after 16 weeks. Moreover, 56.5% of patients achieved
a target HbA1c !6.5% without hypoglycemia and
body weight gain. These results suggest that met-
formin and lifestyle interventions may be effective
and safe as an initial treatment in Japanese patients
with newly diagnosed type 2 diabetes.
CONFLICT OF INTEREST
The authors declare no conflict of interest rele-
vant to this manuscript
ACKNOWLEDGEMENTS
We thank Mizuho Yamahara R.D. and Rie Ikegami
R.D. for their expertise in dietary counseling.
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