Insulin therapy in type 2 diabetes
Priscilla Hollander, MD, PhD
The recognition of the importance of good glucose control and
new insights into the pathophysiology of type 2 diabetes have
led to a renewed focus on the role of insulin therapy in patients
with type 2 diabetes. Current approaches to insulin therapy in
type 2 diabetes include various combinations of oral agents
and insulin and various forms of insulin monotherapy.
Combinations of oral agents and insulin have been expanded
to include both basal and prandial forms of insulin. New insulin
analogs and new methods of insulin delivery have also
expanded the potential for various types of insulin
monotherapy. Further studies are needed to determine the role
of intensified insulin therapy in helping patients with type 2
diabetes reach their glucose goals. Curr Opin Endocrinol Diabetes
2002, 9:139–144 © 2002 Lippincott Williams & Wilkins, Inc.
Ruth Collins Diabetes Center, Baylor University Medical Center, Dallas, Texas,
USA.
Correspondence to Priscilla Hollander, 656 Wadley Tower, 3600 Gaston Avenue,
Dallas, TX 75246, USA; e-mail: Priscilh@baylordallas.edu
Current Opinion in Endocrinology & Diabetes 2002, 9:139–144
Abbreviations
MDI multiple daily injection
NPH neutral protamine Hagedorn insulin
ISSN 1068–3097 © 2002 Lippincott Williams & Wilkins, Inc.
Background
During the past decade several large clinical trials have
demonstrated that intensive glucose control reduces the
risk of microvascular complications in patients with both
type l and type 2 diabetes [1,2,3]. Based on those results,
goals for glucose control have been set at levels close to
euglycemia, HbAlc less that 7.0% (American Diabetes
Association), or 6.5% (American Association of Clinical
Endocrinologists) [4]. To reach and maintain such glucose
goals in most patients, aggressive therapeutic regimens
will be needed. Insulin has generally been regarded as
the most potent of the anti-hyperglycemic agents, but its
use in the treatment of type 2 diabetes has been marked
by many questions about efficacy, adverse effects, and
patient acceptance.
New evidence about the pathophysiology of type 2 dia-
betes has focused interest on the role of insulin therapy
in the treatment of type 2 diabetes. Until recently type 2
diabetes was thought to be characterized mainly by in-
sulin resistance and hyperinsulinemia. It is now under-
stood that progressive loss of ␤-cell function may play an
equally important role [5••]. Insulin insufficiency, ini-
tially relative and with time more absolute, would appear
to be a major factor in the hyperglycemia seen in type 2
diabetes.
Recognition that type 2 diabetes is a progressive disease
is not new, but the need for progressive therapy was
confirmed by the data from the UKPDS study [6]. In the
traditional approach to step therapy, insulin has usually
been the treatment of last resort. In general patients are
started on lifestyle therapy, then moved to monotherapy
with an oral agent, then to double-combination therapy
with oral agents and often to triple-combination therapy
with oral agents. Insulin may then be started in combi-
nation with an oral agent or the patient might be started
on insulin monotherapy. Insulin as monotherapy in type
2 diabetes falls into several categories. Use of long-acting
insulin as basal insulins, fixed combinations of long-
acting and short-acting insulins, freely mixed combina-
tions of long-acting and short-acting insulins, and deliv-
ery of short-acting insulins by insulin pump.
Although insulin has been used for many years to treat
type 2 diabetes, there is not a consensus in regard to an
optimal treatment approach. Approximately 35% of pa-
tients with type 2 diabetes are receiving some form of
insulin therapy, either in combination with oral agents or
as monotherapy, and yet it is unclear whether there is
139
140 Diabetes and the endocrine pancreas
clinical trial evidence to support a common pathway.
This brief review examines recent clinical trial data to
outline current knowledge on insulin treatment in pa-
tients with type 2 diabetes.
Insulin and oral agent combination
The introduction of several major classes of oral agents
has extended the potential for combination therapy with
insulin. A recent review of combination therapy with
insulin noted that insulin alone has been compared with
insulin and oral agent combination therapy in a total of
34 prospective clinical trials [7••]. The majority of those
trials used insulin in combination with sulfonylureas;
however, a lesser number of trials also reviewed combi-
nations of metformin or a thiazolidinedione. Increased
potential for synergy with insulin might be expected for
either of these two classes of drugs based on their mecha-
nisms of action; however, these agents also have their
own adverse effect profiles that must be considered
when they are used with insulin.
Sulfonylureas
Early insulin and oral agent combination regimens added
a long-acting insulin to patients whose diabetes was un-
responsive to sulfonylurea. The goal was to improve glu-
cose control, decrease required insulin dose, and also to
minimize hypoglycemia and weight gain. In clinical prac-
tice an additional goal in prescribing such a regimen of-
ten is to improve patient transition to insulin therapy.
Riddle et al. suggest the idea of BIDS (bedtime insulin,
daytime sulfonylurea) in a study comparing glipizide and
bedtime neutral protamine Hagedorn (NPH) insulin
with bedtime NPH insulin alone [8]. Efficacy was equal,
and a decrease in insulin dose and hypoglycemia were
seen with the combination therapy. 70/30 insulin has also
been given in the evening in combination with daytime
glimepiride, with results that were similar to trials with
NPH [9].
Metformin
Metformin has been used both with bedtime insulin and
as addition to patients on an insulin monotherapy regi-
men. Aviles-Santa et al. studied patients with poor glu-
cose control using various insulin monotherapies, includ-
ing 70/30 insulin, NPH only, and NPH and regular
combinations [10]. Patients were randomized either to
placebo or metformin in a blinded fashion. Baseline Hb
Alc was 9.0%. In the metformin-treated patients HbAlc
decreased by 2.5% whereas the placebo group decreased
by 1.6%, a significant difference. Less weight gain and
hypoglycemia was seen in the metformin group. Bergen-
stal et al. initially intensified patients on multiple insulin
injection regimen, moving from an HbAlc average 8.7 to
7.6, and then randomized patients to metformin or pla-
cebo in a blinded fashion [11]. Both groups decreased,
placebo by 0.6% and metformin by 0.5%; however, the
metformin group had significantly less weight gain and
required less insulin.
Thiazolidinediones
The thiazolidinediones have been used mainly in com-
bination with patients receiving insulin monotherapy
regimens. Troglitazone was the first thiazolidinedione to
be studied in combination studies with insulin [12]. Sev-
eral dose levels were given to patients whose glucose
levels were poorly controlled with conventional insulin
regimens. At the maximal dose of troglitazone 600 mg/d,
HbAlc decreased by 1.4%, from 9.2% to 7.8%, and the
average dose of insulin decreased by 30% as compared to
the placebo treated patients. However glucose did not
reach goal range and average weight gain was 4.2 kg per
patient. Troglitazone was later withdrawn because of
liver toxicity. Two newer agents, roseglitazone and pio-
glitazone, have both been used in combination with in-
sulin [13,14]. In a trial reported by Raskin et al. addition
of rose-glitazone to patients poorly controlled on conven-
tional insulin regimens resulted in a decrease of HbAlc to
7.9% from a baseline level of 9.0%; however, an average
weight gain of 9 kilos for patients at the highest treat-
ment dose of 8 mg a day was seen [14•]. Although liver
toxicity has not been seen, concerns about weight gain
and edema have led to restrictions on the use of both
agents in patients with moderate to severe heart disease.
Multiple oral agents
Yki-Jarvinen et al. studied 100 patients whose diabetes
was unresponsive to maximum sulfonylurea therapy. All
patients were treated with bedtime NPH and were then
randomized to the addition of metformin, glyburide, a
combination of glyburide and metformin, or a second
injection of NPH in the morning [15]. HbAlc results are
featured in Figure l. As can be seen, a substantial de-
crease in HbAlc was seen in all four groups, with even a
significantly lower level of 7.2% seen in the
metformin/NPH group as compared to an average of ap-
proximately 8% in the other three. However because
there were a large number of dropouts in the
metformin/NPH group, it is difficult to say whether it is
more effective than the other 3 therapies.
Oral agents and prandial insulins
Most combinations of oral agents and insulin have fea-
tured combinations of oral agents that affect basal glu-
cose with basal insulins or with premixed insulin combi-
nations of prandial and basal insulin. More recently
several studies have combined a bolus of subcutaneously
injected insulin or inhaled insulin with oral agents that
affect basal glucose. Bastyr et al. compared the combina-
tion of lispro insulin and glyburide at each meal to com-
binations of metformin and glyburide, and to combina-
tions of NPH and glyburide [16••]. Baseline HbAlc level
was 9.2%. HbAlc decreased by 2.2% for the patients in
the lispro group, as compared to 1.6% and 1.8% for those

Figure 1. Change in glycosylated hemoglobin value during 12
months of insulin treatment.
Change in glycosylated hemoglobin value,
0
percentage points
—1
—2
**
* * *
—3
0 3 6 9 12
Time, mo
䊉, patients receiving bedtime insulin plus metformin; 䊐, patients receiving
bedtime insulin plus glyburide;
䊊, patients receiving bedtime insulin plus oral agents; 䉭, patients receiving
bedtime and morning insulin. *, P < 0.05; ** P < 0.01 for bedtime insulin plus
glyburide and metformin compared with bedtime and morning insulin.
Reproduced with permission [15].
in the metformin group and the NPH group, respec-
tively. Fasting blood glucose (FBG) did not decrease
significantly, but postprandial glucose did in the lispro
group, whereas the reverse was seen in the other two
groups. Hypoglycemia was similar in each group. Inhaled
insulin was added to patients whose diabetes was unre-
sponsive to maximum doses of a combination of gluco-
phage and sulfonylureas, and HbAlc decreased 2% below
baseline levels with minimal weight gain and hypogly-
cemia [17].
Other oral agents
Various other oral agents that affect glycemia have been
tried in combination with insulin. In a large multi-center
trial of acarbose, an ␣ glucosidase inhibitor, Kelly et al.
[18] found a decrease of HbAlc of 0.5% with no increase
in hypoglycemia or weight in patients being treated with
conventional insulin therapy. Efficacy of the combina-
tion is limited, and adverse gastrointestinal effects have
limited the popularity of this class of drugs. More recent
studies have examined the effect of anti-obesity drugs on
patients taking insulin. A multicenter trial with orlistat
carried out for patients taking insulin showed an average
decrease in HbAlc of 0.42%, and a weight loss of 4% of
basal body weight [19].
Basal insulin therapy
A number of studies have evaluated monotherapy with
long-acting insulins as basal insulins. The UKPDS insu-
lin arm started newly diagnosed type 2 patients on one
injection of insulin per day [6]. After 6 years of the study
only 39% of thin patients and 37% of obese patients had
Insulin therapy in type 2 diabetes Hollander 141
HbAlc less than 7.0%. Short-acting insulin had been
added to some of the patients’ regimens, but it is unclear
from the article how many patients received a mixed
insulin regimen. Average insulin dose at that point was
34 units per day. In the VA Cooperative study, a step
approach study to glucose control was used with a goal of
normalizing HbAlc [20••]. The first treatment step was
one injection of basal insulin per day. At the end of the
2-year feasibility study % of the patients were still using
this regimen with an HbAlc average of 7.%
* Taylor et al. examined the efficacy of one injection of
ultralente versus two injections of NPH as monotherapy
in patients whose diabetes was unresponsive to maxi-
mum oral agent therapy in a 6-month crossover design
[21]. The NPH group decreased from a baseline of
11.2% to 9.0% at 6 months and when changed to ultra-
lente increased to 9.7% at 12 months. The ultralente
group decreased from a baseline of 10.6% to 9.7% and
when changed to NPH fell to 9.0%. The incidence of
hypoglycemia was higher during the ultralente treatment
periods, although daily insulin doses were higher in the
NPH group, ranging from 60 IU to 72 IU a day, with
greater doses given in the NPH group.
Glargine, an insulin analog, is the newest long-acting
insulin and has been tested in patients as a basal insulin.
Rosenstock et al. reported on a group of type 2 patients
already receiving insulin monotherapy, either NPH in-
sulin or NPH insulin and regular insulin [22]. Individuals
were randomized to either NPH once daily, twice daily
morning and bedtime, or once-daily glargine given at
bedtime. If patients were taking prandial insulins they
were continued, but no effort was made to intensify by
adding or adjusting the prandial insulin. All three groups
started at a baseline of 8.5%, and improvement of HbAlc
was no different between the groups, approximately
0.4l%; however, nocturnal hypoglycemia was signifi-
cantly lessened in the glargine group.
Premixed insulins
Recognition of the basal/bolus needs for an adequate
insulin regimen for treating patients with type l diabetes
and those with type 2 diabetes led to the idea of using
premixed insulins. It was thought that premixed insulins
offer more convenience and decrease mixing errors. Al-
though premixed insulins have been available in Europe
for a number of years, the first premixed insulin, a com-
bination of 70% NPH and 30% regular insulin, was in-
troduced in the United States in the mid-1980s with
initial studies to prove efficacy and safety [23]. 70/30
insulin was soon followed by the introduction of a 50/50
combination. The 70/30 combination has become the
most widely used insulin in the treatment of type 2 dia-
betes in the United States, whereas the 50/50 mixture is
used infrequently.
142 Diabetes and the endocrine pancreas
More recently a premixed combination of 25% lispro/
75% neutral protamine lispro (NPL) has been introduced
in the United States. Both 50% lispro/50% NPL and a
75% NPH/25% lispro are also manufactured but are not
available in the United States. Most studies performed
with the 25 lispro/75 NPH mix have compared it to 70/30
insulin. An initial study showed that the 25/75 mix pro-
duced a greater reduction in postprandial glucose re-
sponse to a breakfast meal than either 30/70 or NPH
insulin in patients with type 2 diabetes [24]. Roach et al.
compared the 50% lispro/50% NPL mix to 50/50 insulin
at breakfast and the 25/75 mix to 70/30 insulin at dinner
in a 3-month crossover study of type 2 diabetic patients.
No difference in final HbAlc or hypoglycemia was
seen between the two groups; however, post-prandial
glucose was better controlled in the lispro-mix treated
group [25].
New prandial insulins
A number of more recent studies have been performed
to evaluate giving prandial insulin at each meal to pa-
tients with type 2 diabetes. The goals of these studies
have not always been to achieve maximal glucose control
but rather to test the efficacy and safety of new insulin
analogues or new methods of insulin delivery. Anderson
et al. examined the usefulness of the insulin analog lispro
versus regular insulin as prandial insulins in a large mul-
ticenter study [26]. In this group HbAlc decreased from
baseline HbAlc 8.7% to an average HbAl of 7.0% for both
groups. Less hypoglycemia and better post-prandial glu-
cose control was seen in the lispro group. Another pran-
dial insulin analogue, Aspart, has been tested against
regular insulin in type 2 patients with similar results [27].
Regular insulin in an inhaled form has also been tried in
patients with type 2 diabetes using insulin regimens.
Cephalu [28••] reported on a 3-month trial of inhaled
insulin therapy in patients previously using conventional
2- or 3-injection conventional regimens. In this study
patients inhaled regular insulin at each meal and injected
ultralente insulin at bedtime. Because this was the first
Table 1. Overall effects of treatment phases in the intensive treatment arm
Phase 1†
Patients (n) 75
Duration (mo) 8.7 ± 7
FSG [mmol/L (mg/dL)]*
Initial 11.4 ± 3.3 (205 ± 59)
Final 7.0 ± 2.6 (125 ± 46)
HbAlc (%)*
Initial 9.3 ± 1.8
Final 7.9 ± 1.5
Insulin dose (U)*
Initial 22.9 ± 13.6
Final 61.3 ± 38.1
*Data are means ± SD at entry and end of each phase for those patients who remained in the phase at the end of the study, as well as those who
“failed” and progressed to the next phase(s). Consequently, a patient may be counted in more than one phase. †, one evening injection of insulin;
‡
, one evening injection of insulin plus daytime glipizide; §, two daily injections of insulin with no glipizide; ¶, three or more daily injections of insulin.
FSG, fasting serum glucose; SD, standard deviation. Reproduced with permission [20].
study to use inhaled insulin in a larger population, pre-
meal glucose goals were set at 100 to 160 mg/dL. HbAlc
decreased from a baseline level of 8.6% to 7.9% at the
end of the study. Hypoglycemia was minimal and weight
gain was not seen. An early trial of an oral mucosal–
absorbed insulin in 33 patients whose diabetes was un-
responsive to maximal oral therapy given at each meal
saw a 0.8% decrease in HbAlc at 3 months compared to
placebo [29]. Although not an insulin, pramlintide, an
analog of amylin, has been shown to lower HbAlc in
patients receiving insulin therapy [30]. Pramlintide af-
fects postprandial glucose levels and is given as a sub-
cutaneous injection either two or three times a day with
insulin. In a large multicenter trial an average HbAlc
decrease of 0.8% was seen. Hypoglycemia was minimal
and patients actually lost weight.
Multiple insulin injections
The ultimate insulin therapy for patients with type 2
diabetes may be to freely mix and self-administer basal
and prandial insulins using multiple injections to better
mimic natural pancreatic function. As in type l diabetes
this approach works best in patients who check glucose
multiple times a day, are able to quantitate diet, and can
self-adjust insulin on the basis of diet and glucose levels.
Studies of intensive therapy in type 2 diabetes are lim-
ited. Two long-term studies have shown that treatment
to goal is possible in such patients. The best example of
this is the Kumamoto study, where patients in the inten-
sive group used multiple injections of a combination of
regular insulin and NPH to decrease baseline HbAlc
from 9.0% to 7.0% [3]. In the VA multi-center feasibility
study, a stepwise approach to treatment was used to help
patients meet their glucose goals [20]. The protocol had
four stages: 1. One injection of basal insulin at bedtime;
2. AM glipizide and basal insulin at bedtime; 3. Two
injections of mixed basal and prandial insulin a day; 4.
Three or more injections per day. If the patient did not
meet the goal of HbAlc of 7.0% or less at one level, he or
she would be moved to the next level of therapy. Final
average HbAlc was 6.9% (Table 1).
Phase II‡ Phase III§ Phase IV¶
66 48 25
10.6 ± 7 7.4 ± 5 5.2 ± 3
6.7 ± 3.0 (121 ± 55) 6.7 ± 2.4 (120 ± 43) 6.9 ± 1.9 (125 ± 34)
6.5 ± 2.2 (117 ± 39) 6.6 ± 2.1 (119 ± 39) 6.6 ± 2.1 (118 ± 37)
7.8 ± 1.3 7.7 ± 0.8 7.2 ± 0.7
7.4 ± 0.8 7.4 ± 0.9 6.9 ± 0.7
64.8 ± 39.8 82.5 ± 43.9 113.4 ± 66.8
64.0 ± 41.9 116.2 ± 68.6 133.0 ± 79.9

Not all studies have shown a marked advantage with an
intensified insulin therapy approach Yki-Jarvian reported
on a study that matched five different therapies in pa-
tients whose diabetes was unresponsive to oral agent
therapy [31]. Patients were randomized to oral agent
therapy only, oral agent therapy plus NPH in the morn-
ing, oral agent plus NPH at bedtime, NPH and regular
insulin given in a 70/30 ratio in the morning and at bed-
time, and NPH insulin at bedtime and regular insulin at
each meal. From a baseline HbAlc of 10% an average of
decrease of 1.8% was seen, with no significant difference
between the treatment groups. Thus, none of the groups
reached glucose goal and no significant difference in hy-
poglycemic episodes or weight gain was seen between
the insulin groups.
Insulin pump therapy
Insulin pump therapy has not been studied extensively
in patients with type 2 diabetes. The Veterans Affairs
Implantable Insulin Pump Program evaluated treatment
with an implantable insulin pump versus multiple daily
injection (MDI) for 6 months [32]. Average baseline
HbAlc for the 110 patients was 8.7%. At the end of the
study HbAlc was 7.6 for the implantable pump group and
7. 4% for the MDI group. No weight gain, and less hy-
poglycemia were seen in the implantable pump group. A
recently reported study of 12 patients switched from
MDI to continuous subcutaneous insulin infusion (CSII)
found no change in HbAlc: 7.6% at baseline and 7.5% at
the end of the study, or total daily insulin dose [33]. All
patients wished to continue with the pump as opposed to
return to MDI. A larger study randomized 126 patients to
either MDI with insulin pen or CSII. Baseline HbAlc
was 8.1%, and at the end of 24 weeks it had decreased by
0.62% for the pump group and 0.46% for the pen group
[34]. Pump patients all preferred the pump therapy to
their previous insulin injection therapy. Currently an
ADA-sponsored study on the usefulness of insulin pump
therapy in patients over 65 is ongoing at two sites.
Insulin therapy and acute care
Insulin therapy in type 2 diabetes may have implications
for acute care as well as chronic care. The Diabetes and
Insulin-Glucose Infusion in Acute Myocardial Infarction
(DIGAMI) study has shown that intensive therapy with
insulin in place of conventional therapy in the setting of
an acute myocardial infarction leads to a decrease in sub-
sequent mortality [35] A recent report found that inten-
sive insulin therapy in a surgical intensive care unit
setting reduced mortality by 50% compared to conven-
tional insulin therapy [36••]. It also reduced overall hos-
pital mortality by 34%, and had a favorable effect on
acute renal failure, transfusion rate, and critical illness
polyneuropathy.
Conclusions
Insulin therapy in type 2 diabetes is evolving. The ques-
tion is how to best utilize it in terms of replacing lost
Insulin therapy in type 2 diabetes Hollander 143
insulin secretory capacity and in limiting weight gain and
minimizing hypoglycemia. Treating to optimal glucose
must be the goal. The key to the complexity of an insulin
program will depend on the point at which a patient is
started on insulin. By the time most patients fail the
current oral agent combinations, monotherapy with one
injection or even two injections of basal insulin may not
be adequate. The need for both basal and bolus coverage
with insulin therapy will depend on the level of insulin
insufficiency of the patient. It is unclear how many pa-
tients can reach goal glucose control on premixed insu-
lins. Considering the wide use of such insulins, more
studies are needed to determine which patient popula-
tions can benefit. Although studies are limited, intensi-
fied insulin therapy using multiple injections may be the
optimal therapy to bring the majority of patients to glu-
cose goal.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
• Of special interest
•• Of outstanding interest
1 The Diabetes Control and Complications Trial Research Group: The effect of
intensive treatment of diabetes on the development and progression of long-
term complications in insulin-dependent diabetes mellitus: N Eng J Med
1993, 329:977–986.
2 UK Prospective Diabetes Study Group: Intensive blood glucose control with
sulfonylureas or insulin compared with conventional treatment and risk of
complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998,
352:837–853.
3 Ohkubo Y, Kishikawa H, Araki E, et al.: Intensive insulin therapy prevents the
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5 Weyer C, Bogardus C, Mott DM, et al.: The natural history of insulin secretory
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7 Yki-Jarvinen H: Combination therapies with insulin in type 2 diabetes. Diabe-
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8 Riddle MC, Hart JS, Bouma DJ, et al.: Efficacy of bedtime NPH insulin with
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9 Riddle Mc, Schneider J: Beginning insulin treatment of obese patients with
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Interesting article the most studied noval non-injection approach to the delivery of
insulin.
29 Schwartz S, Shade S, Eton J, et al.: Replacement of failing sulfonylurea drugs
with oral insulin, a long-term efficacy study in treatment of type 2 diabetes.
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30 Hollander PA, Levy P, Fineman M, et al.:. Pramlintide as an adjunct to insulin
therapy improves long-term glycemic and weight control in patients with type
2 diabetes mellitus: a one year randomized controlled trial. Submitted for
publication 2002
31 Yki-Jarvinen H, Kaupila M, Kujansuu E, et al.: Comparison of insulin regimens
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35 Malmberg K, Norhammar A, Wedel H, et al.: Glycometabolic state at admis-
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36 Van Den Berghe G, Wouters P, Weekers F, et al.: Intensive insulin therapy in
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This article is interesting because it gives further evidence for implementing inten-
sive insulin therapy in the acute care unit.