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第７号（2015 年７月）

SWITCH FROM INSULIN THERAPYTO INTENSIVE COMBINATION THERAPY WITH PIOGLITAZONEAND OTHER ORAL HYPOGLYCEMIC AGENTS
IN PATIENTS WITH TYPE 2 DIABETESMasazumi FUJIWARA
Department of Diabetes Medicine, Saijo Central Hospital, Ehime, Japan

Abstract
Aim: Insulin therapy is considered the final option for patients with progressive type 2
diabetes. This study investigated, whether reconverting patients from insulin therapy to oral
medicine using thiazolidinedione pioglitazone is possible without further deterioration ofglycemic control.
Methods: One hundred sixty subjects (112 male and 48 female) aged 61.4 13.8 years withan mean insulin dose of 28.3
18.7 U/day, mainly using preprandial bolus dose of rapidacting or ultra-rapid-acting insulin preparations, a duration of insulin therapy of 3.1
1.0
years and an average hemoglobin A1c (A1c) of 9.9
1.8% were switched from insulin
therapy to combination therapy with pioglitazone and other oral hypoglycemic agents(biguanide, a-glucosidase inhibitor, and glinide).
Results: During the observation period (3.2
1.3 months), 113 patients (70.6%) treatedwith insulin injections (24.8
14.3 U/day), could be successfully switched from insulin
therapy to pioglitazone-based oral combination therapy. Their mean A1c significant
decreased from 9.9
2.0 to 6.2
0.5%, and all patients could achieve A1c < 7.0%.
Although the remaining 47 patients (29.4%) could not be successfully switched, their A1c
significant decreased from 10.1
1.47 to 7.4
0.8% and their mean insulin dose
signiﬁcantly decreased from 36.7 24.6 to 6.8 10.1 U/day. The success rate of switchingfrom insulin to oral agents was signiﬁcantly higher in the patients treated with non-insulin
secretagogues plus glinide, than in the patients treated with non-insulin secretagogues alone.
Conclusion: Pioglitazone-based oral combination therapy can eﬃciently and safely substitutefor insulin therapy in patients with type 2 diabetes, treated with mainly preprandial bolus
insulin injections.
Key words: thiazolidinedione, pioglitazone, mitiglinide, insulin therapy, therapy switch

INTRODUCTION
In Japan, sulfonylureas (SU) are often used as first-line
drugs for the treatment of type 2 diabetes mellitus,
probably based on the wide-spread view that reduced
insulin secretion is a primary factor in this disease inJapanese patients. Unnecessary use of SU for prolonged
periods can cause further exhaustion of pancreatic βcells, leading to further reduction in insulin secretion,and secondary failure of treatment may result in suchcases. At present, many patients with type 2 diabetes
mellitus for whom insulin therapy has been introduced
may be viewed as cases of secondary failure of SU
therapy.1)
Correspondence to: Dr. M. Fujiwara
Department of Internal Medicine, Saijo Central Hospital,
804 Tsuitachi, Saijo Ehime 793-0027, Japan
Tel: +81 897 56 0300; Fax: +81 897 56 0301
E-mail: fujiwara-m@saijo-c-hospital.jp

Amelioration of excessive insulin resistance (a primarypathogenesis of type 2 diabetes) and reduction ofexcessive insulin secretory requirement can lead toalleviation of pancreatic β-cell exhaustion and recovery
of insulin secretory capacity.2) This seems to apply well tocases of type 2 diabetes with poor blood glucose control
despite insulin therapy.3)
ADOPT (A Diabetes Outcome Progression Trial) has
provided interesting results.4) In newly diagnosed type 2
diabetic patients treated with SU, after an initial decline,
A1c rose continuously due to progressive loss of β-cellfunction. In contrast, TZDs caused an initial reduction in
A1c that was sustained over the 5-year duration of thestudy due to preservation of β-cell function. The ACTNOW (Actos Now for Prevention of Diabetes) revealed a
81% reduction in conversion of impaired glucose
tolerance to type 2 diabetes with pioglitazone. 5) In
addition to its insulin sensitizing effect, pioglitazone
yielded preservation of β-cell function.2)
The DPP (Diabetes Prevention Program) study showed

診療と新薬・第 52 巻

第７号（2015 年７月）

21 （697）

Table 1 Baseline characteristics of the patients and intervention using oral hypoglycemic agents
gender (Male/Female)…………………112/48

Age (years)…………………… 61.4

13.8

Weight (kg)…………………… 66.2

14.2

BMI (kg/m2) ……………………… 25.1 4.4
Insulin therapy duration (years) … 3.1 1.0
A1c (%) …………………………… 9.9 1.8
A1c < 7.0%……………………… 4.4% (7/160)
BMI: body mass index, A1c: hemoglobin A1c
a: non-insulin secretagogue,
b: insulin secretagogue

Insulin preparationsndose (min - max) [U/day]

Rapid-acting analogue

156

26.7

16.3 (3 - 150)

RegularLong-acting analogue
Intermediate-acting (NPH)
Daily total dosage

3
11
6
160

44.7
14.3
15.0
28.3

65.2 (6 - 120)
12.2 (4 - 48)
6.07 (72 - 24)
18.7 (8 - 150)

Oral hypoglycemic agentsndose (min - max) [mg/day]

TZD (Pioglitazone)a

160
124
41
119

35.3
144.6
0.56
51.5

Biguanide (Buformin)aalpha-GI (Voglibose)a
Glinide (Mitiglinide)bthat metformin (a biguanide) reduced the risk of diabetes
by 31% in subjects with impaired glucose tolerance, while
the STOP-NIDDM trial conﬁrmed the eﬃcacy of acarbose(an α-GI) in decreasing the risk of diabetes by 36% in asimilar high-risk population.6)7)This study investigated whether withdrawal frominsulin therapy is possible with intensive intervention
with a combination of oral agents, i.e., pioglitazone
combined as needed with voglibose (an α-GI), buformin(a biguanide), and mitiglinide (a glinide), without
deterioration of glycemic control in patients with type 2
diabetes treated with insulin therapy.
Of these drugs, mitiglinide is a rapid-acting insulin
secretagogue used for amelioration of postprandial
hyperglycemia through reproduction of physiologicalpostprandial additional insulin secretion, and has beenhighly appraised for lack of promotion of pancreatic βcell exhaustion and hypoglycemia because it does notstimulate excessive secretion of insulin, unlike SU.8) The
author previously reported that the use of mitiglinide in
combination with non-insulin secretagogues allowed
successful switching from SU therapy in patients with
type 2 diabetes, without causing hypoglycemia whileallowing further improvement in blood glucose control.9)
In the present study, mitiglinide was used to substitute orcomplement for the eﬀects of preprandial bolus doses of
rapid-acting insulin preparation.

MATERIAL AND METHODS
Insulin therapy was introduced for 495 type 2 diabetic
patients with inadequate glycemic control (A1c level of
8.0 to 11.5%), in spite of treatment with maximal dose of
SU at Saijo Central Hospital between April 2005 andFebruary 2009. One hundred ninety-six patients had
amelioration in their glycemic control with mainly
preprandial bolus dose of rapid-acting or ultra-rapidacting insulin preparations. Among 196 patients, 160
patients had deterioration in their glycemic control
gradually in spite of bolus insulin therapy as mentioned
above. In these 160 patients whose basal insulin secretory12.2 (7.5 - 45)
17.6 (30 - 150)
0.21 (0.2 - 0.9)
14.2 (10 - 60)

capacity might be reserved mostly (only 17 patients [11%]treated with basal dose of long-acting insulin
preparations), we deliberately attempted withdrawal frominsulin therapy with the use of combined oral
hypoglycemic agents, i.e., treatment with pioglitazone asa base drug combined as needed with buformin,
voglibose, and mitiglinide between March 2009 and April
2010.
In each case, we attempted to reduce the insulin doselevel gradually and withdraw the patient from insulin
therapy within 6 months, by evaluatiing the results ofself-monitoring blood glucose, and A1c level at each oﬃce
visit, according to our original insulin algorithm. (i.e.,
insulin therapy withdrawal could be decided, when
preprandial bolus insulin dose level ) 20 U/day and A1c <7.0% were achieved in each case.)
Of the oral agents used for intervention, pioglitazone
was administered as a base agent for all patients at doselevels between 7.5 and 45 mg/day. Buformin (30-150 mg/day), voglibose (0.2-0.9 mg/day) and mitiglinide (10-60
mg/day) were additionally used as needed.
This study was approved by the Institutional Review
Board of the Saijo Central Hospital, and all patients gave
informed consent. Most of the patients strongly desired
to discontinue insulin self-injections and receive
treatment with oral agents alone.
Results are expressed as the mean
SD. A1c wasexpressed in National Glycohemoglobin Standardization
Program (NGSP) units.9) The paired t-test was used foranalysis of intra-group differences in mean values, andthe independent t-test was used for analysis of intergroup diﬀerences in mean values. The chi-square test or
McNemar test was employed for testing of diﬀerences inpercentages.

RESULTS
Table 1 shows in detail of intervention using oral agentsand the background variables of the patients. The
duration of insulin therapy before the start of study was
relatively short (3.1 1.0 years). The number of patients22 （698）

診療と新薬・第 52 巻

insulinwithdrawal

achievement of A1c goal
< 7.0%> 7.0%−AC（n = 113） （n = 21）

insulin dose
reductionB（n = 11）

第７号（2015 年７月）

failing
successful
switch29.4%(n = 47)

D 4.4
C
18.1
A
70.6%
(n = 113)

B 6.9

D（n = 7）

Patients failing successful switch are
categorized as group B, C, and D.
Mean duration [min - max] : 3.2 1.3 [1 - 6]monthssuccessful switch

Patients with successful switch（n = 113）
P < 0.0001
14

Patients without successful switch（n = 47）

12

12

10
8

P < 0.0001
24.8

14.3
（8-120）

Before0
AfterInsulin dose
（U/day）

Insulin dose
（U/day）

10
8
6

6
4
40
30
20
10
0

P < 0.0001

14

A1c
（%）

A1c
（%）

Fig. 1 Success rate of switch from insulin to oral agents

4
40
30
20
10
0

P < 0.0001
36.7

24.6
（10-150）

6.8

10.1（0-36）

BeforeMean duration [min - max]: 3.2

After
1.3 [1 - 6] months

Fig. 2 Changes in HbA1c and insulin dose level before and after intervention
according to the success of the switch from insulin to oral agentsreceiving long-acting soluble type or intermediate type of
insulin (n = 17) was smaller than the number of thosereceiving rapid-acting insulin (n = 159). Mean BMI was
25.1
4.4 kg/m2, and about half of all patients wereobese (BMI over 25 kg/m2). Thus, basal insulin secretion
had been preserved relatively well in the patients studied,and the majority of the patients had been receiving bolus
insulin to compensate for inadequate additional
postprandial secretion.
Fig. 1 shows the success rate of switching from insulin
to oral agents after the start of intervention in all
patients. Switching from insulin therapy was achieved by
113 (70.6%) of the 160 patients by 3.2 1.3 months after
the start of intervention using oral agents. Among theremaining 47 patients (29.4%), 21 patients could beswitched without achievement of A1c goal (< 7.0%), 11
patients could achieve A1c goal without switch, and 7
patients could not achieve A1c goal and not be switched.
Changes in A1c were analyzed separately for thepatients with successful insulin switch and the patients

without successful insulin switch (Fig. 2). A1c was foundto have markedly improved in successful switch group(from 9.9
2.0% to 6.2
0.4%). Properly, all 113
patients could achieve A1c goal (< 7.0%), accompanied
by insulin withdrawal. Although remaining 47 patients
could not be successfully switched, their mean A1c
significantly decreased from 10.1
1.5 to 7.4
0.8 %and their mean insulin dose signiﬁcantly decreased from
36.7
24.6 to 6.8
10.1 U/day. Deterioration of blood
glucose control was not observed in any of these patients.
Baseline characteristics were compared between
patients with successful switch and patients without
successful switch (Table 2). There were no statistical
diﬀerences in gender (male/female ratio), age, BMI, A1c,and duration of insulin therapy between groups. But,
total insulin dose was signiﬁcantly lower in patients withsuccessful switch than those without successful switch(0.37
0.16 U/kg/day vs 0.56
0.38 U/kg/day), andthe percentage of patients using basal insulin preparations
was also significantly lower in patients with successful

診療と新薬・第 52 巻

第７号（2015 年７月）

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Table 2 Baseline characteristics of the patients according to the success of the switchfrom insulin to oral agents
Patients with

Gender (Male/Female)Age (years)
BMI (kg/m2)
A1c (%)
Duration of insulin therapy (years)
Total insulin dose (U/kg/day)Basal insulin prepaerations

Patients without

successful switch

successful(n = 113)

switch (n = 47)

P value81 [71.7%] / 32 [28.3%]
62.2 13.8
25.1 4.4
9.9 2.0
3.09 0.10
0.37 0.16
5 [4.2%]31 [66.0%] / 16 [34.0%]
59.3 13.9
25.3 4.5
10.1 1.5
3.09 1.02
056 0.38
12 [25.5%]

0.59590.23610.71580.41000.9845< 0.0001< 0.001

BMI: body mass index, A1c: hemoglobin A1c

combination patterns
Pioglitazone
BuforminVoglibose
Mitiglinide
number

without glinide

20

16

5

with glinide

974

successful
switch
56.1%

7

29

successful
switch75.6%

P = 0.0301

number of patientswith successful switch

23

90

without successful switch

18

29

113
47

total

41

119

160

Fig. 3 Success rate of switch from insulin therapy according to the combination
patterns of oral hypoglycemic agentsswitch (4.2% vs 23.4%).
When success rate of switching from insulin therapy
were compared between the non-insulin secretagogue
group and the group with mitiglinide addition, successrate was signiﬁcantly higher in the group with mitiglinide
addition than in the non-insulin secretagogue group (Fig.
3). Duration of insulin therapy was signiﬁcantly longer inthe group with mitiglinide addition (3.2
1.0 years vs
2.8
1.1 years; p < 0.05). BMI was signiﬁcantly lower
in the group with mitiglinide addition (24.5
3.9 kg/m2
2
vs 26.9 5.4 kg/m ; p < 0.01). Moreover, patients with
non-insulin secretagogues plus mitiginide weresignificantly older than patients with non-insulin
secretagogues alone (63.4
12.7 years vs 55.4
15.3
years; p < 0.01).
BMI was signiﬁcantly increased from 25.1 4.4 kg/m2
to 26.4
5.1 kg/m2 in the group of all patients. None ofthe patients withdrew from the study, although six
female patients developed mild peripheral edema. No
severe adverse event (including hypoglycemic
symptoms) was noted in any patients during intervention,

indicating good tolerability.

DISCUSSION
Among type 2 diabetic patients had amelioration in theirglycemic control with mainly preprandial bolus dose of
rapid-acting/ultra-rapid-acting insulin preparations due
to secondary failure of SU therapy at Saijo Central
Hospital, patients who had deterioration in theirglycemic control gradually in spite of bolus insulin
therapy as mentioned above, were enrolled in this study.
Thus, it was thought that basal insulin secretory capacity
in these patients might be reserved mostly (only 17
patients [11%] treated with basal dose of long-acting
insulin preparations). This study was deliberately
conducted whether withdrawal from insulin therapy is
possible with intensive intervention with pioglitazonebased oral combination therapy, without further
deterioration of glycemic control in type 2 diabetic
patients could be well characterized by insulin secretory
capacity. Consequently, switching from insulin therapy
was achieved by 113 (70.6%) of the 160 patients after the24 （700）

診療と新薬・第 52 巻

start of intervention. When baseline characteristics of thepatients with or without successful switch were analyzed,
it was observed that total insulin dose and the percentageof patients using basal insulin preparations weresignificantly lower in patients with successful switch(Table 2). These results indicate that pioglitazone-based
oral combination therapy may become an efficient
substitutive option for type 2 diabetic patients treatedwith mainly bolus insulin preparations, whose basal
insulin secretory capacity was mostly reserved.
Few published studies have deal with withdrawal frominsulin therapy by means of intervention with
pioglitazone-based oral combination therapy in patientswith type 2 diabetes. Okamoto et al. attemptedintervention with pioglitazone (26.4
12.4 mg/day),voglibose (0.84
0.22 mg/day), and glimepiride (2.3
1.2 mg/day) in 36 Japanese patients with type 2 diabetes
with a duration of insulin therapy of 6.4
8.5 years,
insulin dose level of 27.2
12.4 U/day, fasting plasma
C-peptide level of 1.95
0.75 ng/mL, and A1c of 7.2
1.3%. They reported that switch from insulin therapy
was successful in 30 of the 36 patients, with A1cmaintained at 6.3% at 4 months after switching.11) They
additionally reported that pre-intervention insulin doselevel was significantly lower for the 30 patients
successfully switched from insulin therapy than for the 6patients in whom switching failed, and that no change
was noted in body weight after intervention from the preintervention level. In the present study, body weightincreased by 3.4
5.7 kg after intervention, probably
because the pioglitazone dose level was high (35.3 12.2
mg/day) and insulin strongly suppressed lipolysis
following amelioration of insulin resistance.
The PIO switch study, conducted in Germany, wasdesigned to attempt intervention with pioglitazone
combined as needed with glimepiride in type 2 diabetic
patients with BMI 30.9
5.2 kg/m2 receiving insulin
therapy.12) Switch from insulin therapy was possible in 75(77%) of the 98 patients, with A1c kept on the order of
6% at 6 months later. The pre-intervention insulin doselevel was signiﬁcantly lower in the successful switchinggroup than in the failed switching group (0.31 0.2 vs
0.50
0.4 U/kg/day, p = 0.004). Moreover, theglucagon challenge test was performed before and after
intervention, and plasma C-peptide/pro-insulin ratio wasevaluated as an indicator of insulin secretory capacity.
This ratio decreased markedly (by 10.1%) in the failed
switching group, while the successful switching groupexhibited a 5.2% increase in this ratio, with significant
improvement. It appeared that amelioration of insulin
resistance reduced the excessive load on insulin
secretion, resulting in alleviation of exhaustion of
pancreatic β-cells. Furthermore, mean A1c level in the
successful switching group was slightly decreased,accompanied by significant elevation of adiponectin andsignificant reduction of high-sensitivity CRP. These

第７号（2015 年７月）

findings suggest that switching insulin to pioglitazonebased treatment may yield advantages in terms ofsuppression of progression of atherosclerosis.
In the present study, 119 of the 160 patients
additionally received mitiglinide (Fig. 3). Mitiglinide
stimulates insulin secretion mildly but very rapidly, and isused as a means of reproducing physiological postprandial
additional insulin secretion. The results of the present
study indicate that in cases in which insulin resistancehas been reduced by pioglitazone, mitiglinide may be anadequate substitute for a preprandial bolus dose of rapidacting or ultra-rapid-acting insulin preparations.
Yoshihara et al. reported a study of 30 patients with
type 2 diabetes who were hospitalized to maintainglycemic control with long-acting soluble insulin glargine
and ultra-rapid-acting insulin aspart. In that study, which
was designed to evaluate the diurnal profile of plasma
glucose level following switching from insulin aspart tomitiglinide (60 mg/day), good glycemic control wasmaintained in 15 of 30 cases after switching. 13) They
additionally reported that responders (n = 15) had asignificantly higher body weight and significantly lower
aspart dose level than nonresponders (n = 15) (69.1
13.3 vs 57.6 11.6 kg, 0.27 0.13 vs 0.42
0.14 U/day/kg). Since 69.1 x 0.27 = 18.7, it appears thatmitiglinide dose of 60 mg/day is equivalent to a 19 U
aspart dose. In the present study, addition of mitiglinide
resulted in a significant increase in the percentage ofpatients with successful switching from insulin (Fig. 3).
This finding suggests that mitiglinide can adequately
reproduce postprandial additional insulin secretion.
In the present study, it was suggested that insulin
resistance persisted during insulin therapy, thatpancreatic β-cell function can partially resume with
pioglitazone (and buformin)-induced amelioration of
insulin resistance,4)14) and that the insufficient additional
postprandial insulin secretion can be adequately
compensated for mitiglinide, 13) resulting in successful
switching from mainly bolus insulin therapy.
Notably, withdrawal from insulin therapy was
successful in a considerably high percentage of patients(70.6%, 113 of 160 patients) with amelioration ofglycemic control. These results indicate that pioglitazonebased oral combination therapy may become an eﬃcient
substitutive option for type 2 diabetic patients treatedwith mainly bolus insulin preparations, whose basal
insulin secretory capacity was mostly reserved.
In the future, we plan to follow these patients toensure that they maintain good glycemic control without
return to insulin therapy.
CONFLICT OF INTEREST
There are no conﬂicts of interest.

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