The Benefits of Metformin Therapy During Continuous Subcutaneous Insulin Infusion Treatment of Type 1 Diabetic Patients

Abstract

This study was designed to assess the insulin-sparing effect of oral administration of metformin along with a continuous subcutaneous insulin infusion (CSII) for the treatment of type 1 diabetic patients.
A total of 62 patients (25 women and 37 men) were studied in a monocenter, randomized, double-blind placebo-controlled study, comparing metformin (850 mg b.i.d.) with placebo in association with CSII during a 6-month period.
Treatment with metformin was associated with a reduction in daily insulin requirements between V0 and V6 of -4.3 +/- 9.9 units (-7.8 +/- 18%) compared with an increase with placebo treatment of 1.7 +/- 8.3 units (2.8 +/- 12.7%) (P = 0.0043). A decrease in basal requirement of insulin was also observed in patients treated with metformin of -2.6 +/- 3.2 units (-7.9 +/- 23.8%) compared with an increase with placebo treatment of 1.9 +/- 5.7 units (8.8 +/- 27.1%) (P = 0.023). HbA(1c) remained unchanged in treatment with metformin and placebo between V0 and V6. The number of hypoglycemic events (<60 mg/dl) was similar in both groups. Significant reductions of total cholesterol (P = 0.04) and LDL cholesterol (P = 0.05) were observed in patients treated with metformin. Gastrointestinal events, including diarrhea and abdominal pain, were reported in three patients in the metformin group who discontinued the trial. Mild or moderate gastrointestinal side effects were also reported in eight patients treated with metformin and two patients treated with placebo (P = 0.069).
Metformin was found to be a safe insulin-sparing agent, when used in combination with CSII for the treatment of type 1 diabetes.

Full text

The Benefits of Metformin Therapy
During Continuous Subcutaneous Insulin
Infusion Treatment of Type 1 Diabetic
Patients
LAURENT MEYER,
MD
1
PHILIP BOHME,
MD
1
IRENE DELBACHIAN,
MD
1
PHILIPPE LEHERT,
PHD
2,3
NATHALIE CUGNARDEY,
MD
4
PIERRE DROUIN,
MD
1
BRUNO GUERCI,
MD, PHD
1
OBJECTIVE — This study was designed to assess the insulin-sparing effect of oral adminis-
tration of metformin along with a continuous subcutaneous insulin infusion (CSII) for the
treatment of type 1 diabetic patients.
RESEARCH DESIGN AND METHODS — A total of 62 patients (25 women and 37
men) were studied in a monocenter, randomized, double-blind placebo-controlled study, com-
paring metformin (850 mg b.i.d.) with placebo in association with CSII during a 6-month period.
RESULTS — Treatment with metformin was associated with a reduction in daily insulin
requirements between V0 and V6 of ⫺4.3 ⫾ 9.9 units (⫺7.8 ⫾ 18%) compared with an increase
with placebo treatment of 1.7 ⫾ 8.3 units (2.8 ⫾ 12.7%) (P ⫽ 0.0043). A decrease in basal
requirement of insulin was also observed in patients treated with metformin of ⫺2.6 ⫾ 3.2 units
(⫺7.9 ⫾ 23.8%) compared with an increase with placebo treatment of 1.9 ⫾ 5.7 units (8.8 ⫾
27.1%) (P ⫽ 0.023). HbA
1c
remained unchanged in treatment with metformin and placebo
between V0 and V6. The number of hypoglycemic events (⬍60 mg/dl) was similar in both
groups. Significant reductions of total cholesterol (P ⫽ 0.04) and LDL cholesterol (P ⫽ 0.05)
were observed in patients treated with metformin. Gastrointestinal events, including diarrhea
and abdominal pain, were reported in three patients in the metformin group who discontinued
the trial. Mild or moderate gastrointestinal side effects were also reported in eight patients treated
with metformin and two patients treated with placebo (P ⫽ 0.069).
CONCLUSIONS — Metformin was found to be a safe insulin-sparing agent, when used in
combination with CSII for the treatment of type 1 diabetes.
Diabetes Care 25:2153–2158, 2002
T
he Diabetes Control and Complica-
tions Trial (DCCT) (1) clearly dem-
onstrated that intensive insulin
therapy to achieve near normoglycemia
reduces the risk of development and pro-
gression of long-term complications of
type 1 diabetes but often leads to an in-
crease in hypoglycemic episodes. Contin-
uous subcutaneous insulin infusion
(CSII) can reduce the rate of severe hypo-
glycemia in type 1 diabetes, as compared
with that seen in patients receiving mul-
tiple daily injections (2), although the re-
sults remain controversial (1,3). It has
also been demonstrated that pump ther-
apy using insulin analogs improved blood
glucose control without increasing the in-
cidence of severe hypoglycemia (4,5).
Metformin is a biguanide that has
been used in management of type 2 dia-
betes for more than 40 years. It improves
glycemic control by enhancing insulin
sensitivity in the liver (leading to a de-
crease in basal hepatic glucose produc-
tion) and muscle (leading to an increase in
glucose uptake) (6). In insulin-treated
type 2 diabetic patients, the use of met-
formin improves insulin sensitivity and
glycemic control, leading to a reduction
in the daily insulin requirement (IR) (7–
9). In type 1 diabetes, addition of met-
formin to insulin therapy has been
assessed in a few trials involving few pa-
tients or in uncontrolled studies of short
duration (10 –12). These studies sug-
gested a mean reduction in IR of ⬃25%
with a variation of 20 –40%. In our study,
involving the use of metformin in type 1
diabetic patients treated with CSII, the ef-
fect on blood glucose control, IR, and hy-
poglycemic episodes is reported.
RESEARCH DESIGN AND
METHODS
Patient selection
The study was performed in a group of 62
type 1 diabetic patients. All were C-
peptide negative (C-peptide ⬍0.3 mmol/l
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
From the
1
Service de Diabe´tologie, Maladies Me´taboliques & Maladies de la Nutrition, CIC-INSERM,
Hoˆpital Jeanne d’Arc, Centre Hospitalo-Universitaire de Nancy, Toul, France; the
2
Faculty of Medicine,
University of Melbourne, Melbourne, Australia; the
3
Faculty of Economics, University of Mons, Mons,
Belgium; and
4
LIPHA Sante´, Nogent-sur-Marne, France.
Address correspondence and reprint requests to Dr. Bruno Guerci, Service de Diabe´tologie, Maladies
Me´taboliques & Maladies de la Nutrition, CIC-INSERM/CHU Nancy, Hoˆpital Jeanne d’Arc, Centre Hospi-
talo-Universitaire de Nancy, B.P. 303, 54201 Toul Cedex, France. E-mail address: b.guerci@chu-nancy.fr.
Received for publication 22 May 2002 and accepted in revised form 23 August 2002.
N.C. is employed by Merck Sante´ (formerly Lipha Sante´, 37 rue Saint Romain, 69379 Lyon Cedex 08,
France).
Abbreviations: CSII, continuous subcutaneous insulin infusion; DCCT, Diabetes Control and Compli-
cations Trial; IR, insulin requirement; SMBG, self-monitoring of blood glucose.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
factors for many substances.
Clinical Care/Education/Nutrition
ORIGINAL ARTICLE
DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER 2002 2153

after intravenous injection of 1 mg gluca-
gon). These patients had been selected
from 225 diabetic patients treated with
CSII at our outpatient clinic. All of the
patients in the study had been treated by
CSII for at least 1 year, had HbA
1c
con
-
centration ⬍9%, had good compliance
with home blood glucose monitoring,
and had hypoglycemia awareness. Exclu-
sion criteria were nonstable retinopathy,
any disease (endocrine, infectious, or in-
flammatory) that significantly modifies
blood glucose control, pregnancy, im-
paired renal function, and cardiac and he-
patic dysfunction.
Study design
This study was a randomized, mono-
center, double-blind, placebo-controlled
parallel group trial (metformin versus pla-
cebo) of 6 months’ duration. After a
2-month placebo run-in period, patients
were randomized (V0) to receive either
metformin (850 mg) or placebo twice
daily and were instructed to take the treat-
ment during or at the end of breakfast and
dinner. After randomization at V0, pa-
tients were evaluated at 8-week intervals
(V2, V4, V6), when clinical data, includ-
ing adverse effects, were assessed and
protocol compliance, monitored by pill
counting, was recorded. The daily IRs
during the preceding 7 days and body
weight were also recorded. IRs were eval-
uated separately, according to basal rate
and bolus doses (mean of the three pre-
meal bolus) given. Biological parameters,
including HbA
1c
, fasting blood glucose,
hypoglycemic episodes, and lipid param-
eters, were also assessed.
The protocol was approved by the
Ethical Committee of the University of
Nancy (France), and written consent was
obtained from all the patients after clear
explanation of the trial.
Patient instructions
All patients were treated with regular in-
sulin (Velosuline HM 100 IU/ml; Novo
Nordisk A/S, Bagsvaerd, Denmark) by
CSII, using an external pump (Minimed
infusor MMT 506, 507c, and 508; Mini-
Med Technologies, Northridge, CA) and
deconnectable catheters (Tender set; Dis-
etronic Medical Systems AG, Burgdorf,
Switzerland and Sofset QR; MiniMed
Technologies). The catheter infusion site
was changed every 3 days. The patients
had been taught to perform capillary
blood glucose estimations before meals,
2 h after meals, and at bed time using a
One Touch Profile memory meter (Life-
scan, Roissy, France). The memory meter
data were downloaded onto a computer
(In touch program; Lifescan). Adjust-
ments of the insulin doses were made by
the patient, based on the results of self-
monitoring of blood glucose (SMBG) as
previously described (13,14) and by the
investigator at each visit if needed. Pre-
meal, postmeal, and bedtime target
ranges were 80–130, 130–160, and
100–130 mg/dl, respectively. Supple-
mental doses were calculated using each
patient’s insulin sensitivity factor and tar-
get blood glucose level (15). The patients
were instructed to record in a notebook
all episodes of hypoglycemia in which the
blood glucose level was ⬍60 mg/dl. Se-
vere hypoglycemia, as defined by the
DCCT criteria (16), was also recorded.
Patients were instructed to treat hypogly-
cemia with 10 g of oral glucose and 20 g of
carbohydrates, to recheck the blood glu-
cose in 20 min to ensure an adequate re-
sponse, and to adjust their insulin dose in
response to an unexplained low blood
glucose level.
Recording of SMBG measurements
The time of all capillary SMBG measure-
ments (date and hour) was recorded in
the glucose meters. For the whole group
of 62 patients, a total of 44,666 SMBG
levels were recorded during the 6 months
of the study.
A glucose meter (One Touch Profile;
Lifescan) was given to each patient at ran-
domization (V0), when treatment with
placebo or metformin was begun. Conse-
quently, the recorded SMBG levels were
compared for each period of follow-up
(V0–V2, V2–V4, and V4 –V6), but not for
the period preceding randomization
(run-in period).
We analyzed the different intervals of
time for SMBG measurements, according
to the frequency of SMBG performance:
fasting period (5:00 –7:00
A.M.), lunch
preprandial period (11:00 A.M. to 12:00
P.M.), dinner preprandial period (6:00 –
7:00 P.M.), postprandial periods (9:00–
10:00 A.M. and 2:00–3:00 P.M.), and
bedtime period (9:00 –10:00 P.M.) assim-
ilated as a postprandial period.
Assay methods
Blood samples were collected at each visit
after a 12-h overnight fast. Plasma glucose
was measured by the glucose oxidase
method (Beckman Glucose Analyzer;
Beckman, Fullerton, CA). HbA
1c
was
measured by high-performance liquid
chromatography on Biorex resins (Bio-
Rad, Richmond, CA; normal range 4.3–
6%). Total cholesterol and triglycerides
were measured by immunoenzymatic as-
say (Bio-Me´rieux, Marcy l’e´toile, France).
HDL cholesterol was measured after pre-
cipitation by phosphotungstic acid/
manganese (Boehringer, Mannheim,
Germany). LDL cholesterol was calcu-
lated using the Friedewald formula (17).
Statistical analysis
Results are expressed as means ⫾ SD and
are shown as means ⫾ SE in Fig. 1. The
primary end point evaluated was the re-
duction of IR associated with decrease or
stability of HbA
1c
. Secondary end points
were number and severity of hypoglyce-
mic episodes, effect on plasma lipids and
weight, and clinical tolerance. Statistical
analyses were performed on an
intention-to-treat basis, and for patients
interrupting the trial, final measurements
were imputed by their last observation
carried out values. Difference between
metformin and placebo groups was as-
sessed by a ANCOVA with treatment as
the fixed factor and IR at randomization
(V0) as an adjustment covariate. The
mean change between the value at each
visit and randomization in each group
was assessed using Student’s t test. Inci-
dence of hypoglycemic episodes between
the two groups was evaluated by ANOVA,
and the frequency of severe hypoglycemia
was evaluated using ␹
2
test. The clinical
relevance of the main results was assessed
by responder analysis: a patient was con-
sidered a responder when HbA
1c
was sta
-
ble or improved, with a reduction of
ⱖ20% in IR since randomization and
without any severe hypoglycemic epi-
sodes. The response rate was compared
between the two treatments by logistic re-
gression, adjusting for initial IR and body
weight. P ⬍ 0.05 was considered statisti-
cally significant. All statistical analyses
were performed using SAS software (Ver-
sion 6.1; SAS Institute, Cary, NC) in the
Windows NT operating system.
RESULTS — A total of 62 patients (25
women, 37 men; 31 treated with met-
formin and 31 treated with placebo) were
included and were eligible for the inten-
tion-to-treat analysis. Three patients in
the metformin treatment group inter-
Metformin and CSII in type 1 diabetes
2154 DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER 2002

rupted the trial because of drug intoler-
ance. Compliance with treatment was
75% for patients who completed the
study. Clinical and biological characteris-
tics of the patients at randomization (V0)
are shown in Table 1; no difference was
noted between the two groups.
IR
A relative daily reduction in IR was ob-
served in patients treated with metformin
between V0 and V6 of ⫺4.3 ⫾ 9.9 units
(⫺7.8 ⫾ 18%) compared with an in-
crease in patients treated with placebo of
1.7 ⫾ 8.3 units (2.8 ⫾ 12.7%) (P ⫽
0.0043) (Table 2, Fig. 1). The decrease in
daily IR in the metformin group was sig-
nificant between V2 and V6 (Table 2). At
V6, the total daily insulin dose was lower
in the metformin group than in the pla-
cebo group (0.65 ⫾ 0.17 vs. 0.74 ⫾ 0.24
units 䡠 kg
⫺1
䡠 day
⫺1
, P ⫽ 0.086).
A decrease in basal requirements was
observed in the metformin group be-
tween V0 and V6 of ⫺2.6 ⫾ 3.2 units
(⫺7.9 ⫾ 23.8%) compared with an in-
crease in the placebo group of 1.9 ⫾ 5.7
units (8.8 ⫾ 27.1%) (P ⫽ 0.023) (Table 2,
Fig. 1). The decrease in basal require-
ments in the metformin group was signif-
icant from V4 to V6 (Table 2). Daily basal
IR at V6 was lower in the metformin
group than in the placebo group (0.27 ⫾
0.10 vs. 0.30 ⫾ 0.11 units 䡠 kg
⫺1
䡠 day
⫺1
).
Insulin bolus needs showed a de-
crease in the metformin group between
V0 and V6 of ⫺1.7 ⫾ 5.7 units (⫺5.5 ⫾
16.8%) and increased in the placebo
group by 0.03 ⫾ 6.0 units (0.1 ⫾ 20.2%),
but the difference was not significant (P ⫽
0.059) (Table 2, Fig. 1). However, signif-
icant differences were noted in the met-
formin group at V2 and V4 compared
with V0 (Table 2). Bolus doses at V6 were
not different between the metformin and
placebo groups (0.38 ⫾ 0.12 vs. 0.45 ⫾
0.17 units 䡠 kg
⫺1
䡠 day
⫺1
).
A total of 7 of 31 patients (23%)
treated with metformin and none of 31
patients (0%) treated with placebo were
considered therapy responders, as de-
fined by HbA
1c
stability or improvement,
at least a 20% reduction in insulin re-
quirement, and no severe hypoglycemic
episodes (P ⫽ 0.001). Clinical and bio-
logical characteristics were not signifi-
cantly different between responders and
the other study subjects, but the treat-
ment effect seemed better (but not signif-
icantly) in the youngest patients (ⱕ40
years of age) with highest HbA
1c
levels
(⬎7.5%) and lowest BMI (⬍25 kg/m
2
). A
backward logistic regression was per-
formed using response/nonresponse as
the dependent variable and including
treatment, age, sex, duration of diabetes,
BMI, HbA
1c
, and fasting glycemia as inde
-
pendent variables, to detect predictor fac-
tors of response rate. We found that only
treatment effect was highly significant
(P ⬍ 0.001), whereas BMI was close to
significant (P ⫽ 0.086).
Blood glucose control
HbA
1c
. HbA
1c
levels remained un
-
changed during the placebo run-in period
in the placebo group (7.38 ⫾ 0.75 vs.
7.57 ⫾ 0.76%, NS) and in the metformin
group (7.40 ⫾ 0.67 vs. 7.58 ⫾ 0.84%,
NS); they also remained unchanged in the
metformin and placebo groups between
V0 and V6, although there was a trend of
diminution between V0 and V2 in the
metformin group (7.58 ⫾ 0.84 vs. 7.23 ⫾
0.79%, P ⫽ 0.07). After 6 months of treat-
ment, HbA
1c
was not different between
the metformin and placebo groups
(7.45 ⫾ 0.78 vs. 7.46 ⫾ 0.60%, respec-
tively) and was not different from that at
randomization for the both groups.
Means and SDs of SMBG. The mean
number of SMBG estimations performed
Figure 1—Evolution of IR (total, basal, and bolus insulin needs) from V0 to V6 in type 1 diabetic
patients during placebo (E) or metformin (f) treatment. Results are shown as means ⫾ SE.
Meyer and Associates
DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER 2002 2155

by the patients was not different between
the metformin and placebo groups
(4.18 ⫾ 0.6 vs. 4.0 ⫾ 0.7 SMBG/day, re-
spectively), and the frequency of SMBG
remained unchanged throughout the
study. The mean daily fasting capillary
blood glucose levels were not significantly
different between V0 and V6 in either
group or between the metformin and pla-
cebo groups. In regard to the preprandial
blood glucose levels, the mean and SD
levels during the period V4 –V6 tended to
be lower in the metformin group than in
the placebo group, but the differences did
not reach statistical significance (P ⫽
0.065 and 0.061). We did observe, how-
ever, during the period V4–V6 that the
mean postprandial blood glucose level
was significantly lower in the metformin
group than in the placebo group (162 ⫾
61 vs. 188 ⫾ 31 mg/dl, P ⫽ 0.037); a
similar trend was evident during the pe-
riod V2–V4 (177 ⫾ 44 vs. 195 ⫾ 35 mg/
dl, P ⫽ 0.074).
Hypoglycemic and ketoacidosis epi-
sodes. According to the SMBG measure-
ments, the number of hypoglycemic
events (⬍60 mg/dl) with or without clin-
ical symptoms between V0 and V6 in the
metformin group compared with the pla-
cebo group was 47.2 ⫾ 26.8 vs. 45.1 ⫾
23.5 events 䡠 patient
⫺1
䡠 6 months
⫺1
, re-
spectively (7.8 ⫾ 4.5 vs. 7.5 ⫾ 3.9 events
䡠 patient
⫺1
䡠 month
⫺1
, NS). We analyzed
the absolute frequency of hypoglycemic
episodes for each period of the study, and
also the relative frequency (expressed as
the ratio between absolute frequency and
the number of SMBG measurements re-
corded by the patient). However, these
frequencies were not different between
the two treatment groups, whatever time
period was studied.
A total of 27 severe hypoglycemic ep-
isodes (19 in the metformin group, 8 in
the placebo group) were detected and re-
corded by the 62 patients during the 6
months of the study, corresponding to an
incidence of 87 per 100 patient-years.
These 27 severe hypoglycemic episodes
were experienced by 8 of the 62 (12.9%)
type 1 diabetic patients, five patients
(16.1%) on placebo treatment and three
patients (9.6%) on metformin therapy,
but the difference was not statistically sig-
nificant.
No cases of diabetic ketoacidosis were
observed throughout the study in the two
treatment groups.
Other biological parameters
Significant reductions of total cholesterol
(201 ⫾ 27 vs. 185 ⫾ 26 mg/dl, P ⫽ 0.04)
and LDL cholesterol (125 ⫾ 31 vs. 120 ⫾
23 mg/dl, P ⫽ 0.05) were observed in the
metformin group between V0 and V6. At
V6, total cholesterol was not different be-
tween the metformin and placebo groups.
HDL cholesterol was reduced in the met-
formin group from V0 to V6 (58 ⫾ 17 vs.
56 ⫾ 18 mg/dl, P ⫽ 0.04); a slight but not
significant increase in fasting plasma tri-
glycerides was noted (71 ⫾ 41 vs. 90 ⫾
48 mg/dl). At V6, fasting triglycerides
were not different between both groups.
There was no significant modification in
the metformin group (V0 versus V6) for
creatinine, weight, and systolic and dia-
stolic blood pressures (data not shown),
and no difference for these parameters at
V6 was seen between both groups.
Safety
During the study, in three patients in the
metformin group, minor digestive symp-
toms (abdominal pain, diarrhea) devel-
oped, causing interruption of the trial. No
patients required hospitalization during
the trial. Mild or moderate gastrointesti-
nal adverse effects were also reported in
another eight patients in the metformin
Table 1—Clinical and biological characteristics of the patients at randomization
Placebo
(n ⫽ 31)
Metformin
(n ⫽ 31) P
Age (years) 41.1 ⫾ 9.8 39.9 ⫾ 12.9 NS
Sex (men/women) 20/11 17/14 NS
Weight (kg) 74.5 ⫾ 11.7 78.4 ⫾ 18.1 NS
BMI (kg/m
2
) 25.8 ⫾ 3.6 26.4 ⫾ 4.6 NS
Systolic blood pressure (mmHg) 127 ⫾ 11 133 ⫾ 21 NS
Diastolic blood pressure (mmHg) 77 ⫾ 981⫾ 14 NS
Diabetes duration (years) 21.6 ⫾ 10.2 16.9 ⫾ 8.9 NS
CSII duration (years) 3.2 ⫾ 3.1 4.5 ⫾ 3.5 NS
Total insulin dose (units 䡠 kg
⫺1
䡠 day
⫺1
) 0.73 ⫾ 0.22 0.72 ⫾ 0.21 NS
Basal insulin rate (units 䡠 kg
⫺1
䡠 day
⫺1
) 0.28 ⫾ 0.09 0.30 ⫾ 0.15 NS
Bolus insulin dose (units 䡠 kg
⫺1
䡠 day
⫺1
) 0.44 ⫾ 0.16 0.42 ⫾ 0.13 NS
HbA
1c
(%) 7.57 ⫾ 0.76 7.58 ⫾ 0.84 NS
Fasting blood glucose (mg/dl) 148 ⫾ 72 135 ⫾ 63 NS
Total cholesterol (mg/dl) 202 ⫾ 32 201 ⫾ 27 NS
HDL cholesterol (mg/dl) 56 ⫾ 14 58 ⫾ 17 NS
LDL cholesterol (mg/dl) 130 ⫾ 29 125 ⫾ 31 NS
Triglycerides (mg/dl) 73 ⫾ 42 71 ⫾ 41 NS
Serum creatinine (mg/dl) 1.19 ⫾ 0.13 1.17 ⫾ 0.14 NS
Data are means ⫾ SD.
Table 2—Insulin requirements: relative mean change since randomization V0
Period
Daily total IR (%) Daily basal IR (%) Daily bolus IR (%)
PMPMPM
V0–V2 2.6 ⫾ 11.1 ⫺7.4 ⫾ 18.4* 4.8 ⫾ 19.5 ⫺4.3 ⫾ 24 2.0 ⫾ 16.3 ⫺9.4 ⫾ 14†
V2–V4 2.9 ⫾ 11.6 ⫺10.6 ⫾ 18.3‡ 7.2 ⫾ 23 ⫺9.2 ⫾ 28.5* 1.3 ⫾ 15.1 ⫺9.7 ⫾ 11†
V4–V6 2.8 ⫾ 12.7 ⫺7.6 ⫾ 19* 8.8 ⫾ 27.1 ⫺7.4 ⫾ 24.7* 0.1 ⫾ 20.2 ⫺5.1 ⫾ 17.6
V0–V6 2.8 ⫾ 12.7 ⫺7.8 ⫾ 18† 8.8 ⫾ 27.1 ⫺7.9 ⫾ 23.8* 0.1 ⫾ 20.2 ⫺5.5 ⫾ 16.8
Data are means ⫾ SD. P, placebo; M, metformin. *P ⬍ 0.05; †P ⬍ 0.01; ‡P ⬍ 0.001 versus randomization V0.
Metformin and CSII in type 1 diabetes
2156 DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER 2002

group (seven patients with one adverse
effect, one patient with two adverse ef-
fects) compared with only two patients in
the placebo group (P ⫽ 0.069).
CONCLUSIONS — Use of metformin,
along with insulin therapy, has been stud-
ied less frequently in type 1 than in type 2
diabetes, but insulin-sparing effects of
metformin have been observed (10 –
12,18). Most of these studies have been
small (11), were uncontrolled (12), or
were cross-over trials of short duration
(10). Even in one previous trial involving
the administration of insulin by CSII, the
duration of treatment was only 3 weeks
(19), and during this period, IR was not
modified. Pagano et al. (10) showed the
most marked reduction in IR in type 1
diabetic patients using large doses of met-
formin (850 mg three times a day). How-
ever, the 25% reduction in IR observed
during 24-h euglycemic clamp did not re-
ally correspond to insulin needs in clini-
cal practice.
In our study, we selected type 1 dia-
betic patients treated by CSII because this
therapy allows differentiation of basal and
prandial needs of insulin. We found a re-
duction in the basal rate of IR and, conse-
quently, a reduction in total daily IR when
metformin was added. To our knowledge,
our study is the first to investigate the ef-
fect of adding metformin to insulin ther-
apy in type 1 diabetes in a controlled,
randomized, double-blind trial for such a
long duration, which is the probable ex-
planation for the differences observed be-
tween this and previous studies. In our
study, the maximum effect of metformin
in reducing IR was not seen until after 4
months of treatment, followed thereafter
by a stabilization period. In contrast, pre-
vious studies showed that the insulin-
sparing effect in type 1 diabetes occurred
after a few days (20) or a few weeks of
metformin use (10,12).
Although studies concerning multi-
ple daily injections or CSII in type 1 dia-
betes have shown that metformin could
reduce the increase in postprandial blood
glucose by increasing insulin binding to
its receptor (10,11,19), we did not find
any significant reduction in bolus re-
quirements after 6 months of treatment,
although they did decrease significantly
after 2 and 4 months in patients in the
metformin group as compared with those
given placebo. One explanation for this
could be the ability of metformin to de-
crease fasting insulin resistance of type 1
diabetic patients that has been previously
demonstrated using the euglycemic-
hyperinsulinemic clamp procedure (21).
This effect of metformin could be medi-
ated by an increase of insulin-mediated
glucose transport via GLUT1 and/or
GLUT3 transporters (22) and/or an inhib-
itory action of metformin on gluconeo-
genesis (23) due to a primary inhibition of
hepatic lactate uptake (24,25). Recently,
in Sprague-Dawley rats, two mechanisms
have been proposed to explain metformin
action: inhibition of hepatic glucose
phosphatase activity promoting glycogen
sparing (26) and AMP-protein kinase ac-
tivation, which could provide an explana-
tion for the pleiotropic action of this drug
(27). Another possibility could be the ca-
pacity of metformin to improve glucose-
mediated glucose transport (28), which is
the ability of glucose itself to promote glu-
cose utilization (mass action effect of glu-
cose). In type 1 diabetes, glucose-
mediated glucose transport is impaired.
Comparing these results with those of
acarbose used in type 1 diabetes (29),
metformin demonstrates a more pro-
nounced insulin-sparing effect. To our
knowledge, only one study using thiazo-
lidinediones has been performed in pa-
tients with type 2 diabetes treated by CSII
(9), but no data are available on use of this
drug in type 1 diabetes.
In regard to glucose stability, as as-
sessed by SMBG monitoring, we found a
significant decrease in postprandial blood
glucose level during the last period of fol-
low-up in the metformin group. At the
opposite end of the spectrum, we found
no difference in fasting glycemia between
the two treatments. Currently, there is no
evidence of a protective effect of a de-
crease in blood glucose variability in re-
gard to diabetic complications. However,
as suggested by authors in the DCCT (30),
mean HbA
1c
is not the most complete ex-
pression of the degree of glycemia. In the
DCCT, development of diabetic retinop-
athy was only partly explained by total
glycemic exposure (mean HbA
1c
⫻ time
of follow-up). The risk of such complica-
tions may be more dependent on the ex-
tent of postprandial hyperglycemia (31)
and/or of glycemic excursions (32),
which are not reflected by HbA
1c
levels.
In the metformin group, the inci-
dence of hypoglycemia ⬍60 mg/dl was
not different from that seen in the placebo
group, and this incidence was close to
that reported in other studies (4,5). The
frequency of severe hypoglycemia in our
population of patients treated by CSII is of
the same order of magnitude reported in
the CSII group (81 per 100 patient-years)
of the DCCT cohort (33).
No difference in weight change was
found in our study. This is not surprising,
because most of our patients had been
treated with insulin for ⬎15 years, and
previous studies in type 1 diabetes (12)
showed similar results. This is in contrast
to the reduction of weight commonly ob-
served in overweight type 2 diabetic pa-
tients treated by insulin therapy and
metformin.
Metformin treatment was associated
with a decrease in total cholesterol, re-
lated to the decrease in LDL cholesterol.
HDL cholesterol was also slightly de-
creased and fasting plasma triglyceride
levels were surprisingly increased in the
metformin group, but the values still re-
mained in the normal range. These results
are different from those of previous stud-
ies performed in type 1 diabetic patients
(12,21).
On an intention-to-treat basis, the
success of a therapy depends on the ab-
sence of adverse effects. In this particular
trial, the main end point was the benefit
observed in terms of IR: not only did IR
have to be reduced, but blood glucose lev-
els had to be controlled and no hypogly-
cemic episodes had to have occurred. A
total of 23% of the patients in the met-
formin group and no patients in the pla-
cebo group were considered to have had
successful therapy. Therefore, we can
conclude that additional therapy using
metformin can be justified in type 1 dia-
betic patients treated by external pump
with important basal insulin needs.
Acknowledgments— We thank LIPHA
France for their support in the realization of
this work. We thank Dr. Michael Patterson for
his help in editing the English text.
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