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N A L

A R T I C L

Comparison of Different Insulin Regimens


in Elderly Patients With NIDDM
BRUCE H . R . WOLFFENBUTTEL, MD, PHD
Jl-AN-PlFRRt J.E. SHLS, MD, PHD
GABRIELLEJ.W.M. RONDAS-COLBERS

PAUL P.C.A. MENHEERE, PHD


ARtE C . NlEUWENHUIJZEN K R U S E M A N , MD, PHD

OBJECTIVE To compare the metabolic effects of three different frequently used regimens of insuliti administration on blood glucose control and serum lipids, and the costs associated with this treatment, in .subjects with NIDDM, who were poorly controlled with oral
antihyperglycemic agents.
RESEARCH DESIGN A N D METHODS We studied 95 elderly patients with NIDDM
(age 68 9 years, BMI 26.0 4.6 kg/m-, and tnedian time since diagnosis of diabetes 9 years
Irange 1-371; 37 men, 58 women), who were poorly controlled, despite diet and maximal
doses of oral antihyperglycemic agents. Three insulin administration regimens were compared
during a 6-month period: patients were randomized for treatment with a two-injection scheme
(regimen A) or a combination of glibenclamide with one injection of NPH insulin, administered either at bedtime (regimen B) or before breakfast (regimen C), and insulin treatment was
mainly instituted in an outpatient setting.
RESULTS After 6 months of insulin treatment, fasting blood glucose of the total patient
population had decreased from an average of 14.1 2.2 to 8.3 2.0 mmol/1 (P < 0.001), and
HbA,, fell from 11.0 1.3 to 8.3 1.2% (P < 0.001); 34 patients reached HbAi, levels below
8.0%, 25 of them even below 7.5%. With two insulin injections daily, HhAi^ decreased from
11.2 1.3 to 8.2 1.2%, while during combined treatment, HbA^. fell from 10.5 1.2 to 8.1
1.1% (regimen B) and from 11.1 1.3to8.5 1.1% (regimen C). Comparable improvement
of the other measures of glycmie control, lipids and lipoproteins, was observed in the different treatment regimens. Body weight increase was rnoderate (mean 4.0 kg) and similar in all
patient groups. One-third of patients starting with one insulin injection daily needed a second
injection to control glycemia. One episode of severe hypoglycemia was observed. Combined
insulin-sulfonylurea treatment was almost 20% more expensive than twice-daily administration of insulin alone.
CONCLUSIONS Insulin treatment can safely be instituted in elderly patients with
NIDDM. However, it is difficult to obtain optimal glycmie control. Insulin has moderate
beneficial effects on seritm lipoproteins. Although on the basis of glycmie control and weight
gain, no preference for any treatment regitnen cati he discerned, twice-daily insulin administration is the most simple and cost-effective regimen.

atients with NIDDM are usually


treated with oral antihyperglycemic
agents when diet therapy alone fails
10 tiormalize glucose metalDolism (1,2).
For patients not achieving adequate control with such therapy, insulin treatment is
the available option (3-5); the aim of this

treatment is to diminish hyperglycmie


complaints, improve blood glucose control, and treat plasma Upid disturbances
(6,7) to improve quality of life and prevent
the development or worsening of diabetic
complications. Weight gain during insulin
therapy may pose a problem, especially in

liom the LX'partmenl ol Inlcrnal Medicine. Division ol Endocrinology, and Department o Clinical Chemistry' (PPC.A.M.). University Hospital Maaslricht, Maastiicht. The Netherlands.
Address correspondence and reprint requests to Bruce H.R. Wolffenbutlel, MD, PhD, Dept. of Internal
Medicine. Division of Endocrinology and Metabolism, tjniversity Hospital Maastricht. PO. Box 5800, NL6202 AZ Maastricht. The Netherlands. E-mail: bwo@sint.azm.nl.
Received for publication 6 February 1996 and accepted in revised form 11 July 1996,
apo, apolipoprotein; AUC, area under the curve; AUCFBG, ratio of C-peptide AUC and fasting blood
glucose; Lp(a). lipoprotein(a); RIA. radioimmunoassay; UGDP, University Group Diabetes Project.

1326

Lbese patients. Further, the resulting


peripheral hyperinsulinemia might be of
importance, since some authors (8,9) consider increased plasma insulin levels as an
independent risk factor for the development of atherosclerosis. In addition, the
incidence of hypoglycemia during insulin
therapy is reported to be higher than during oral treatment (10).
Various insulin regimens have been
proposed. During recent years, the interest
in the combination of insulin with sulfonylureas has revived (11). This combination may be beneficial by reducing the
dose of insulin needed and, thus, possibly
diminishing the degree of peripheral
hyperinsulinemta. The injection of intermediate-acting insulin at bedtime,
together with daytime sulfonylurea use,
was especially advocated (12-14) to suppress the excessive nocturnal hepatic glucose production. This regimen trtay also
provoke less weight gain (14), but negative effects of combined insulin-sulfonylurea therapy on HDL cholesterol have
been described (15).
The purpose of thts study was to
assess the metabolic effects of insulin therapy on blood glucose control and serum
lipids, and the costs associated with this
treatment, in subjects with NIDDM, who
were poorly controlled with maximal
doses of oral agents. Three different frequently advocated regimens of insulin
administration, alone or combined with
sulfonylureas, were compared during a 6month period. In contrast to other studies
(14), it was performed largely in an outpatient setting.

RESEARCH DESIGN AND


METHODS
Patients
A total of 95 of the 102 eligible consecutive
patients with NIDDM (mean age [ SD] 68
9 years, BMl 26.0 4.6 kg'm^, median
time since diagnosis of diabetes 9 years
[range 1-37]; 37 men and 58 women),
according to World Health Organization
(WHO) ctitena (16), completed the study
Seven patients did not complete the study
because of intercurrent problems, mainly
cardiovascular events. All were poorly con-

DlABETtlS CARE, VOLUME 19, NtJMBER 12. DECEMtER 1 9 9 6

Wolffenbuttel and Associates

trolled, despite diet and maximal doses of


oral anlihyperglycemic agents (15 mg
glihenclamide daily, or, in 29 patients,
glihenclamide with metformin). Poor hlood
glucose control was defined as a fasting
blood glucose concentration (mean of last
three measurements within 2 months)
>8.0 mmol/1 and HhAj, >8.0%. A complete history and physical examination was
performed to exclude intercurrent illness or
cardiac, hepatic, renal, or other endocrine
disease. No patient had severe untreated
hypertension (diastolic hlood pressure
>110 mmHg), impaired kidney function
(serum creatinine >140 pmol/1), or was
treated with corticosteroids. All patients
gave their informed consent hefore participating. The study was approved hy the Ethical Committee of the University Hospital.
Study design
During a run-in period of at least 1 month,
oral therapy was continued, dietary treatment optimized, and instruction in selfmonitoring of hlood glucose (if possible)
and insulin injections, as well as formal
diabetes education, was given. The
patients suhsequently started insulin treatment with one of the foUovvang schemes:
A. Twice-daily injections of a mixture
of fast-acting and NPH insulin (Mixtard
30/70, Novo Nordisk A/S, Bagsvaerd,
Denmark, regimen A, n = 34); patients
were instructed to inject the doses of
insulin suhcutaneously 30 min before
hreakfast and dinner.
B. Combination of NPH insulin (Insulatard. Novo Nordisk A/S) administered
once daily at hedtime at 10:00 P.M. (regimen B, n = 28), with glihenclamide during
the day (10 mg hefore hreakfast and 5 mg
hefore dinner). Patients were instructed to
take the glihenclamide 5 min hefore
meals. When hlood glucose values during
the day and evening consistently exceeded
10.0 mmol/1, patients switched to a twicedaily regimen with insulin hefore hreakfast
and the evening meal, while continuing
the glihenclamide.
C. Comhination of NPH insulin (Insulatard) administered 30 min hefore hreakfast (regimen C, n = 33), with glihenclamide during the day (10 mg hefore
hreakfast and 5 mg hefore dinner). When
hedtime hlood glucose levels exceeded
10.0 mmol/1, a second injection of NPH
insulin hefore dinner was added, with
continuation of the glihenclamide.
Thus, patients on regimerts B and C
tailing to normalize with one daily injec-

tion converted to the same treatment


scheme, i.e., insulin hefore hreakfast and
the evening meal, in comhination with
glihenclamide (regimen D).
To obtain a diurnal profile of glucose,
patients were instructed to measure their
blood glucose with an electronic device
(Glucometer II, Bayer, Germany, or One
Touch, Lifescan) hefore hreakfast, lunch,
and the evening meal, and at hedtime.
Insulin dose was adjusted on the basis of
these hlood glucose measurements. In 26
patients, who were for various reasons not
capable or willing to measure their own
hlood glucose, three determinations during the day, i.e., hefore the main meals,
were performed in the hospital 1 week
hefore each visit to the outpatient clinic.
Patients not performing home hlood glucose measurements were equally distributed among the three groups. Goals of
therapy were fasting hlood glucose levels
<7.0 mmol/1, daytime preprandial hlood
glucose values <10.0 mmol/1, and HhA]^.
levels <8.0%. All patients visited the outpatient clinic 2 and 4 weeks after starting
insulin therapy and, thereafter, monthly,
when measurements were made of hody
weight, hlood glucose, serum fructosamine, and HhA^.

determined with enzymatic methods on a


Cohas Bio analyzer. HDL cholesterol was
measured enzymatically after precipitation
of LDL and VLDL with polyethylene glycol 6000. Apolipoprotein (apo) Al and B
were determined v^ath an immunoturhidimetric assay (Roche, Basel, Switzerland)
on a Cohas MIRA analyzer. Lipoprotein(a)
[Lp(a)l was measured hy radioimmunoassay (RlA)(Pharmacia, Upp.sala, Sweden).
Serum free fatty acids were measured hy a
colorimetric method. Seruin free insulin
levels (immunoreactive insitlin) were analyzed with RIA (Pharmacia, Uppsala, Sweden) after polyethylene glycol pretreatment, and serum C-peptide was measured
with RIA (Mallinckrodt, Germany).
Between-assay variation of insulin RIA was
7.5% and of C-peptide, 9%.

Statistics and calculations


Residual -cell function was assessed in
three ways: J) as the release of C-peptide
after intravenous injection of 1 mg
glucagon, calctilated as the incremental
area under the curve (C-peptide AUC) and
the ratio of C-peptide AUC and fasting
hlood glucose (AUCFBG); 2) from the fasting levels of hlood glucose, insulin (fasting
immunoreactive insulin), and C-peptide,
At baseline and after 6 months, blood hy calculating the formulas of Matthews
was drawn in the fasting state for the (17); and 3) as the level of C-peptide 5 min
determination of hlood glucose, serum after glucagon injection (C-peptide-nin).
fructosamine, HhA|^, nonesterified fatty Relative insulin resistance was calculated as
acids, lipids and apolipoproteins, and R = [fasting serum insulin (mU/1) X hlood
serum insulin. Before the initiation of the glucose]/22.5 (17).
insulin treatment, residual -cell function
All data are expressed as means SD
was assessed hy the response of serum C- or median and range when not normally
peptide and insulin levels to intravenous distributed. Calculations were performed
administration of 1 mg glucagon.
with the SPSS/PC + version for Windows
For comparison, glucagon-stimulated 6.0 statistical software package (SPSS,
insulin and C-peptide secretion and hlood Chicago, IL). Group differences in baseline
glucose and lipid determinations were variables were compared hy one-way
performed in a group of 18 nonohese con- analysis of variance for continuous variables and X'^ tests for categorical variables.
trol suhjects.
Student-Newman-Keuls correction was
applied for multiple comparisons.
Analytical procedures
Blood glucose was measured in venous Changes of blood glucose control hetween
whole hlood vvath an automated hexoki- the treatment groups (HhA]^ and fasting
nase method on the Cohas Bio analyzer. hlood glucose) and lipid variables were
HbAi^. was determined with high-perfor- compared hy analysis of variance; when
mance liquid chromatography (HPLC) the changes were not normally distrib(DIAMAT, Bio-Rad, Richmond, CA; nor- uted, Kruskal-Wallis analy.sis of variance
mal values 4.4-6.2%, hetween-assay coef- was used. Linear regression analysis was
ficient of variation 2.6%) and serum fruc- used to determine the relationship
tosamine with a Fructosamine Roche kit hetween two variables. P values <0.05
(Roche, Basel, Switzerland). Cholesterol were considered statistically significant.
(CHOD-PAP, Boehringer Mannheim, Germany) and triglycrides (Tdglycerid RESULTS At haseline, metabolic
Rapid, Roche, Basel, Switzerland) were control, as assessed hy hlood glucose and

DIABETES CARE, VOLUME 19, NUMBER 12, DECEMBER

1996

1327

Insulin therapy in NIDDM

Table 1Baseline parameters in the various groups and changes of these parameters with insulin therapy on an intention-to-treat basis
Regimen A (n = 34)
Baseline
6 months
Insulin dose (U)
Body weight (kg)
Fasting blood glucose (mmol/1)
Mean blood glucose (mmol/1)
Serum fructosamine (pmoUl)
Glycated hemoglobin (%)
Total cholesterol (mmol/1)
HDL cholesterol (mmol/1)
Triglycrides (mmol/1)
Apo(Al) (g/1)
Apo(B) (g/1)
Free fatty acids (mmol/1)
Lp(a) (U/1)
Insulin (pmol/1)

67.4 11.8
14.5 1.9
17.1 2.6
467 53
11.2 1.3
7.0 1.2*
1.09 0.30
2.36
(1.11-14.7)
1.36 0.18
1.48 0.22
927 333
236
(13-1,381)
64
(18-151)

Regimen B (n = 28)
Baseline
6 months

39 12
71.4 12.8t 76.1 16.4
8.5 2.0+
14.4 1.9
9.2 1.7t
16.7 2.3
293 32
416 24
8.2 1.2t
10.5 1.2
6.4 1.3
6.2 L i t
1.210.33t 1.02 0.34
1.62t
2.00
(0.39-6.6)
(0.82-9.1)
1.450.20t 1.24 0.15
1.310.23t 1.41 0.17
581 297t 994 347
264
281
(17-1,420)
(21-2,470)
71
81t
(30-343)
(37-212)

Regimen C (n = 33)
Nondiabetic
Baseline
6 months control subjects

_
24 9
80.5 16.8t 69.2 10.3
8.4 1.9
13.6 2.7
9.5 1.2t
17.1 3.0
311 21t
433 36
8.1 l.lt
11.1 1.3
6.1 1.2
6.10.9t
1.06 0.34 1.05 0.32
1.70
2.21
(0.76-6.6)
(1.03-7.0)
1.420.24t 1.36 0.19
1.320.17t 1.35 0.28
470 252t 1,001 338
273
170
(21-3,050)
(8-1,142)
67
97t
(33-163)
(34-286)

26 17
72.6 10.7t
8.12.2t
9.91.9t
320.25T
8.5l.lt
5.8 l.Ot
1.100.36t

4.1 0.3
4.5 0.4

5.2 0.5
5.0 0.4
1.40 0.29
1.91t
1.50
(0.64-4.4)
(0.51-2.00)
1.39 0.22
1.53 0.22
1.280.24t 1.130.15
607 304t 480120
206
101
(8-1,148)
(8-1,747)

92t
(33-360)

Dala are means SD or median (range). ' P < 0.05 vs. regimen C; tP < 0.05 vs. baseline (corrected for multiple comparisons).

i^^ levels, was poor (Table 1). No differences in glycmie control and serum
lipids was observed between the randomization groups, besides slightly higher
serum cholesterol in group A patients.
Residual -cell function was slightly better
in patients starting with regimen C, especially, the increment of G-peptide levels
after glucagon levels, either calculated as
area under the curve (G-peptide AUG) or
corrected for fasting blood glucose
(AUGEBG), was higher in this group
(Table 2). HbAi^ at the start of the study
was inversely correlated with insulin
secretion (HbA,, vs. AUGEBG, r = -0.45,
P < 0.001; HbA|, vs. G-peptide AUG, r =
-0.33, P = 0.002) but not with calculated
insulin resistance. This suggests that the
poor glycmie control was caused mainly
by -cell insufficiency.

During insulin therapy, blood glucose


control improved considerably In the total
patient population, HbAij^^ levels decreased
from 11.0 1.3 to 8.3 1.2% (P < 0.001),
and fasting blood glucose levels decreased
from 14.1 2.2 to 8.3 2.0 mmol/1 (P <
0.001). Mean increase in body weight was
4.0 kg. Also, significant reductions were
observed in total cholesterol, triglycrides,
apoB, and free fatty acids, whereas HDL
cholesterol and apoAl increased by 10%.
Table 1 and Eig. 1 depict the changes
in the three randomization groups on the
basis of an intention-to-treat analysis.
Insulin dose was significantly lower in
patients on combination therapy (regimens B and G). The decrease of fasting
and daily mean blood glucose, and HbAi^
was not different in the three groups, neither was the increase in body weight. Of

the patients, 34 achieved HbAi^ levels


<8.0% (15 of 34 on regimen A, 11 on regimen B, and 8 on regimen G); 25 patients
even achieved HbAi^ levels <7.5%. Subjects stariing with two injections were
more likely to achieve good glycmie control than subjects starting with one injection (Table 3). The improvement of metabolic control, calculated as the decrease of
HbAu between baseline and 6 months,
correlated with baseline HbAi^ (r = 0.63, P
< 0.001) and with AUGEBG (r = -0.39,
P = 0.001), but not with insulin dose.
Similar improvements of lipid abnormalities were observed, although the
reduction of serum cholesterol was slightly
greater in group A patients, probably
because of the higher cholesterol levels at
baseline. The largest reduction of free fatty
acid levels was observed in group B (bed-

Table 2Baseline values of indices of -cell function and insulin resistance in the various groups

I asting C-peptide (pmol/1)


Fasting insulin (pmol/1)
C-peptide, (pmol/1)
C-peptide AUC (nmol/1 30 min)
AUCFBG
-cell function-C-peptide (%)
-cell function-insulin (%)
Relative insulin resistance

Regimen A

Regimen B

Regimen C

Nondiabetic
control subjects

730 417
60(18-151)
1,081 533
5.7(1.9-18.6)
381 (153-1,358)
16 (4-61)
15(5-42)
5.5(2.5-13.0)

887 424
71 (37-212)
1,340 618
5.4(0.7-18.6)
346(54-1,721)
22 (9-85)
17 (9-59)
5.8(2.6-21.9)

913415
67 (34-286)
1,503 774
9.1(1.0-32.6)*
708(64-2,217)*
23 (10-499)
20(10-589)
5.2(2.1-26.3)

551 201
46 (32-66)
1,760 400
29.8(19.8-45.1)
7,345 (5,016-10,620)
150(100-312)
120(84-159)
1.4(1.0-2.3)

Data are means SD or median (range). *P < 0.05 vs. regimens A and B.

1328

DiABErES CARE, VOLUME 19, NUMBER 12, DECEMBER

1996

Wolffenbuttel and Associates

tion to improve metabolic control bad


lower levels of fasting C-peptide and
insulin, as well as C-peptide levels 5 min
after intravenous glucagon. The other cell parameters were slightly, but not
significantly lower (Table 4).
One patient wbo was treated with regimen C suffered from severe hypoglycemia, necessitating help from others
by injection of glucose. This occurred during a gastrointestinal infection. He recovered completely No other patients suffered from severe hypoglycemia. Most
patients reported improvement of wellbeing and (if present before institution of
insulin therapy) abolishment of byperglycemic complaints.

12.0 -,
Two-injections (A)
Evening insulin + S.U. (B)
Morning insulin + S.U. (C)

11.0 -

10.0 \
\

o
9.0

8.0

7.0

Time (months)
Figure 1Changes during Insulin therapy oj HbA^ in the three different treatment regimens. A-C
represent the different insulin regimens on an intention-to-treat basis. Regimen A: twice-daily insulin
injections; regimen B; evening insulin plus daytime sulfonylurea; regimen C: morning insulin plus daytime sulfonylurea.

time insulin), altbougb the difference witb


tbe otber groups was not statistically
significant. Baseline Lp(a) levels were elevated compared witb nondiabetic control
subjects, but with insulin therapy, no
changes of serum levels of Lp(a) were
observed.
Nine patients who were starting with
the once-daily insulin regimen B and 11
patients starting with regimen C needed a
second insulin injection. The insulin dose
of these patients after 6 months of treatment (i.e., regimen D) was significantly
higher (34 19 U) than that of tbe
patients wbo could be maintained on one
injection (23 9 and 20 7 U, respec-

tively). But eventually, comparable


improvements of metabolic control (Eig.
2) and serum lipids were acbieved. Subjects who needed a second insulin injec-

CONCLUSIONS Secondary failure


to oral antihyperglycemic agents after an
initial favorable response may occur in
5-10% of patients with NIDDM on a
yearly basis (18,19). The results of this
study confirm the effectiveness of insulin
therapy, alone or in combination with
glibenclamide, to improve blood glucose
control. In all treatment groups, a clear
decrease of fasting and mean daily blood
glucose and a 25-30% decrease of HbA,c
was observed. Mean HbA], levels of 8.3%
were achieved, which is intermediate
between the conventional and intensive

I
I Two-injections (A)
^ ^ Evening insulin * SU, (B)
^ ^ Morning insulin + S.U. (C)
I Two-injections + SU. {D)

Table 3Number of patients achieving


good giycemic control or remaining insufficiently controlled after 6 months

- -6 -

<8.0%

>9.0%

15
11

6
6

13*

34

25

-10

Tviiice-daily insulin
Bedtime insulin
plus sulfonylurea
Morning insulin
plus sulfonylurea
Total
*X^ significance 0.03.

Figure 2Changes after 6 months of insulin therapy of body weight and measures of glycmie control. A-D represent the different insulin regimens on a post hoc analysis basis. Regimen A: twice-daily
insulin injections (n = 34); reamen B: subjects who remained on one evening insulin injection plus
daytime sulfonylurea throughout the study (n = 19); reamen C: subjects who remained on one moming insulin injection plus daytime sulfonylurea throughout the study (n = 22); regimen D; subjects who
started with one daily insulin injection but needed a second insulin administration (n = 20).

DIABETES CARE, VOLUME 19, NUMBER 12, DECEMBER

1996

1329

Insulin therapy in NIDDM

treatment groups of the Diabetes Control


and Complications Trial (20). It must be
taken into consideration that our patients
were considerably older, with an average
age of almost 70 years. Patients using twieedaily insulin injections were more likely to
achteve HbAi,' levels <8.0% (Table 3).
However, insulin dose was also the highest
in these subjects, compared with those who
received combined treatment. In addition,
it may be postulated that postprandial
blood glucose levels were lower in these
subjects because they received an insulin
mixture that included fast-acting insulin.
There was no difference in the increase of
body weight between the three treatment
groups. Of the patients who were initially
randomized for once-daily insulin injections in combination with glibenclamide,
20 (33%) did not reach adequate improvement of metabolic eontrol and needed a
second insulin injection.
Approximately 40 years ago, it was recommended that insulin be combined with
sulfonylureas in the treatment of NIDDM
subjects poorly controlled with tablets
alone (21). Thereafter, a period followed in
which the sole use of higher doses of
itisulin was recommended rather than the
combination with sulfonylureas. The
results of the widely criticized University
Group Diabetes Project (UGDP) study,
which suggested an increased risk of cardiovascular deaths in patients treated with
sulfonylureas (22), also contributed to this
view. The last 10-15 years, however, show
a revival of combined therapy (23-25).
Most studies reported during short-term
observations that patients treated with the
combination of insulin and sulfonylurea
required a lower insulin dose and exhibited
better glycmie control than patients using
insulin and placebo. Despite these favorable
effects of combined therapy, it was, in general, difficult to attain (near) normoglycemia in the individual patient. Some
studies have reported only transient beneficial effects of combined therapy (24,25).
Riddle and colleagues (12,13) have
widely advocated the use of a regimen
combining bedtime NPH insulin with daytime sulfonylureas. This approach aims at
reducing fasting blood glucose values by
suppression of the increased (nocturnal)
hepatic glucose production and high nocturnal concentrations of free fatty acids,
which may contribute to hepatic insensitivity to insulin and fasting hyperglycemia.
It was suggested that this approach would
prevent an increase of body weight. Taski1330

Table 4Differences of -cell function and insulin resistance in patients who remained on
one insulin injection and those who needed a second insulin injection to improve

Fasting C-peptide (ptnol/1)


Fasting insulin (pmol/1)
C-peptide5n,,n (pmol/1)
C-peptide AUC (nmol/1 30 min)
AUCFBG
-cell function C-peptide (%)
-cell function insulin (%)
Relative insulin resistance

One injection

Two injections

922 (300-2,350)
76 (39-286)
1,405(640-4,260)
7.4(1.85-32.6)
532 (136-2,217)
24 (10-499)

752(330-1,295)*
62 (34-149)*
1,115(450-2,010)*
6.6(0.71-15.5)
428(54-1,385)
20 (9-51)
17 (9-40)
4.6(2.1-12.9)*

20(11-589)
6.0 (2.7-26.3)

*P < 0.05 vs. one injection.

nen et al. (26) raised the possibility that the


improvement in glycmie control by bedtime insulin was related to the reduction of
plasma free fatty aeids concentrations. This
hypothesis remains to be proven. Our data
show a slightly, but not significantly (P =
0.18), larger reduction of fasting plasma
free fatty acids in the bedtime insulin
group; however, the decrease of HbAi^ was
not greater in this group compared with
the other regimens.
In a prospective study of 3 months'
duration in tablet-treated NIDDM
patients, Yki-Jarvinen et al. (14) showed
that the addition of NPH-insulin in the
evening equally improved metabolic control as did a two-injeetion or a multipleinjection regimen. However, weight gain
with evening insulin was less: a mean
increase of 1.2 kg was observed in this
group, against 1.8 kg and 2.9 kg in the
other groups. We did not observe differences in weight gain between the different
insulin regimens. But, metabolic control
before institution of insulin treatment was
considerably poorer in our patients compared with Yki-Jarvinen's patients. At the
start of the study, mean HbA,c, measured
with comparable methodology and reference values, was 11.0% in our patients vs.
9.7% in theirs, while after 6 and 3 months
of insulin therapy, respectively, these levels
were 8.3 vs. 8.1%. These results are in
agreement with the observations that the
change in body weight was inversely correlated with the ehange in glycated hemoglobin. With regard to serum insulin levels, the average increase of fasting insulin
in our patients was 40% and was comparable between the treatment regimens. We
did not perform 24-h insulin profiles,
which were shown to increase less with
combined therapy than with insulin treatment alone (14). In addition to the effeets

on glycmie control, we observed a significant decrease of total serum cholesterol


and triglycrides, both in patients on
insulin alone and in patients on combined
therapy. Also, an increase of HDL cholesterol was observed. Thus, with insulin
therapy, a less atherogenic profile was
achieved. In aceordance with earlier
reports from our group (27), we did not
observe any changes of serum Lp(a) levels.
Total cholesterol and triglycride levels,
however, remained elevated, and HDL
cholesterol remained somewhat lower
compared with nondiabetic subjects
(Table 1), as was already demonstrated by
others (6,7). Concomitant with the
increase of HDL cholesterol, we observed
an increase of apoAl, suggesting an
increase in the total number of HDL particles. Our findings are in contrast with
observations made by Stenman et al. (15),
who reported that during combined therapy, HDL cholesterol was significantly
lower than with insulin alone. These
observations were made in a small number of only 15 patients who were treated
with insulin alone (most of them only one
injection) or insulin in combination with
glibenclamide in a 4-month crossover
study.
Groop et al. (19) studied possible factors influencing secondary drug failure
during treatment with oral antihyperglycemic agents. Patients failing to sulfonylurea had a lower relative body weight and
lower basal and post-glucagon plasma Cpeptide concentrations than patients who
were well controlled. In a previous study,
we measured C-peptide levels before and
during 15 min after intravenous injection
of glueagon in NIDDM patients failing on
dietary therapy (28). An incremental area
under the response curve of <5.0 nmol/1
15 min identified those patients who

CARE, VOLUME 19, NUMBER 12, DECEMBER 1996

Wolffenhutel and Associates

Table 5Estimated monthly costs of insulin and combined insulin-sul/onylurea therapy in


patients with NIDDM who inject themselves with use of an insulin pen

Number of insulin injections


Average amount of insulin (U/day)
Costs (Dfl.)
Insulin
Needles
Glihenclamide ( 15 mg/day)
Insulin pen
Total costs (Dn.)

Insulin alone

Insulin plus sulfonylureas

2
39

lor 2
25

70.12
24.27
0.00
Free of charge
94.39
(U.S. $59.00)

44.95
18.20
48.70
111.85
(U.S. $70.00)

. Dutch guilders. 1 U.S. $ = Dil. 1.60.

exhibited better glycmie control on


insulin therapy compared with treatment
with sulfonylureas. Thefindingin the present study that HbAi^. was inversely correlated with glucagon-stimulated insulin
secretion implies that secondary failure to
oral agents was mainly caused by -cell
insufficiency However, this insufficiency
was not adequately reflected by other variables, such as fasting insulin or C-peptide
levels, or by calculation of specific -cell
function formulas, which make use of
these parameters. It must be noted in this
respect that combining sulfonylureas and
insulin was successful only in those
patients, who exhibited residual -cell
function, as estimated by fasting and postglucagon C-peptide levels (29). Also in our
patients, those who needed a second
insulin injection showed lower fasting
plasma C-peptide and insulin levels and Cpeptide response after glucagon, thus having lower residual islet -cell function
before the initiation of insulin treatment.
However, glucagon-stimulated insulin
secretion, although it followed the same
pattern, was not related. Thus, parameters
of insulin secretion cannot be used to predict in the individual patient the efficacy of
insulin therapy
Results of long-term studies in which
different insulin regimens have been compared are scarce. Some authors advocate
that patients start with the least complex
treatment, for instance continuation of
their tablet treatment and the addition of
insulin at bedtime. Because maximal oral
therapy often comprises the use of two
drugs (i.e., a sulfonylurea combined with
metformin, as 60% of Yki-Jar\'inen's
patients were using), one may wonder
whether introducing a third medication
for the control of diabetes is more benefi-

cial for the patient than completely switching to insulin therapy alone. Based on the
present results, the latter approach seems
to be more realistic in light of other treatments that patients may be receiving for
hypertension, dyslipidemia, cardiovascular disease, etc. An additional disadvantage
may be the higher cost of combined therapy Table 5 gives an estimate of the cost of
treatment of the individual patient, as
derived from the use of insulin and glibenclamide in the different patient groups of
our study Combined therapy was 15%
more expensive than insulin alone.
We conclude that in elderly patients
with NIDDM, improvement of glycmie
control can be achieved at the expense of
some weight gain. Insulin treatment has
moderate beneficial effects on serum
lipoproteins. Although on the basis of
glycmie control and weight gain, no preference for any treatment regimen can be
discerned, twice-daily insuhn administration is the most simple and cost-effective
regimen.

Acknowledgments This study was supported by a grant from the Diabetes Research
Foundation (Diabetes Fonds Nederland).

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DIABETES CARE, VOLUME 19, NUMBER 12, DECEMBER

1996

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