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Strategies for Insulin Therapy in Type 2
Diabetes
Steven V. Edelman, MD; Candis M. Morello, PHARMD, CDE
South Med J. 2005; 98 (3): 363-371. ©2005 Lippincott Williams & Wilkins
Abstract and Introduction
Abstract
Chronic hyperglycemia in type 2 diabetes is responsible for an array of
microvascular and macrovascular complications that can lead to significant
morbidity and mortality. Several well-conducted large clinical studies have
shown that normalizing blood glucose levels can help prevent the onset
and slow the progression of complications from diabetes. As many as 25%
of patients treated with oral hypoglycemic agents require the addition of
insulin therapy to compensate for the progression of β-cell failure and an
inability to maintain glycemic control. Various strategies incorporating the
use of insulin early in the course of the disease have been developed to
meet this goal, and include the use of basal-bolus insulin regimens as well
as bedtime insulin injections. The pharmacokinetic properties of the new
insulin analogs (eg, insulin lispro, insulin aspart, insulin glargine) offer
significant advantages, such as improved control of nocturnal
hypoglycemia with basal insulin glargine, and improved postprandial
glucose control, with insulin lispro or insulin aspart.
Introduction
Type 2 diabetes, the second most common disease necessitating patientphysician contact in the United States,[1] is a group of related disorders with
distinct pathogenic mechanisms. Hyperglycemia, the common
denominator, is associated with comorbidity that includes obesity,
hypertension, and peripheral vascular disease. The natural history of
diabetes is often complicated by various microvascular and macrovascular
sequelae that can lead to blindness, end-stage renal disease, lower-
extremity amputation, and atherosclerosis resulting in heart attack or
stroke.[2,3]
Much has been learned about the pathogenesis of this frequently
encountered and difficult-to-manage metabolic disorder. The basic
pathogenic factors in type 2 diabetes have been identified as impaired
insulin secretion, decreased glucose uptake by muscles and other tissues
(insulin insensitivity), and increased hepatic glucose production.[4]
Diabetes mellitus affects approximately 18 million people in the United
States, roughly 6% of the overall population, with more than 1 million new
cases diagnosed annually.[5] Diabetes may actually be more endemic than
these figures indicate; potentially one undiagnosed individual exists for
every one identified.[6] By far, the largest number of individuals with
diabetes-approximately 90% of the overall total diabetes population-has
type 2 diabetes.[2]
Approaches to Management
Traditional Approach
The traditional approach to the management of type 2 diabetes includes
dietary modification and exercise.[7] When these modalities prove
inadequate in controlling the patient's hyperglycemia, pharmacologic
intervention is indicated, in the form of oral hypoglycemic agents, insulin,
or both.[8] Five classes of oral hypoglycemic agents are currently available:
the sulfonylureas, the nonsulfonylurea insulin secretagogues, the
biguanides, the α-glucosidase inhibitors, and the thiazolidinediones. Each
class of drugs has a distinct mechanism of action ( Table 1 ),[9] and the
drugs may be used as monotherapy or in combination with other oral
hypoglycemic agents or insulin. An extensive review of the various oral
hypoglycemic therapies useful in the treatment of type 2 diabetes indicates
that most of these agents lower glycated hemoglobin (A1C) concentrations
by approximately 1 to 2% ( Table 1 ).[9]
Among insulin therapies, options include rapid-acting, intermediate-acting,
and long-acting human insulin preparations (regular, neutral protamine
Hagedorn [NPH], lente [Lente; Eli Lilly and Co, Indianapolis, IN] and
ultralente [Ultralente; Eli Lilly and Co] insulins, respectively),[2] and the new
insulin analogs ( Table 2 ).[10]
Monitoring and Therapeutic Goals
The management of diabetes requires vigilant attention to blood glucose
levels and alteration of the therapy or dosage as needed. Blood glucose
levels can be monitored directly, or indirectly by measuring the A1C
fraction. A1C results from a nonenzymatic interaction between glucose and
the hemoglobin A molecule. Unlike direct measurements of blood glucose,
which assess glycemic control at the moment of testing, measurement of
A1C is an indication of the extent of the patient's glycemic control over the
preceding 8 to 12 weeks.[2]
The goal of treatment in patients with type 2 diabetes is euglycemia. The
individualized treatment should lower blood glucose levels sufficiently to
prevent microvascular and macrovascular complications associated with
chronic hyperglycemia while also limiting hypoglycemic episodes and
excessive weight gain. The American Diabetes Association recommends
that A1C concentrations should be lowered to less than 7%, fasting plasma
glucose levels should be maintained at 90 to 130 mg/dL (5.0 to 7.2
mmol/L), and 2-hour postprandial plasma glucose concentrations should
be less than 180 mg/dL (<10 mmol/L).[8] The American College of
Endocrinology recommends even lower glycemic control targets: A1C
concentrations of 6.5%, fasting plasma glucose levels of less than 110
mg/dL (<6.1 mmol/L), and postprandial plasma glucose levels of less than
140 mg/dL (<7.8 mmol/L).[11]
Intensive Therapy
As a result of the natural progression of type 2 diabetes and loss of β-cell
function, traditional treatment regimens incorporating oral agents often fail
to help patients achieve these goals over the long term, exposing them to
nocturnal hypoglycemia and fasting and postprandial hyperglycemia. Many
different regimens of intensive insulin treatment have been developed and
studied for their ability to provide better 24-hour glycemic control and to
decrease the frequency and severity of long-term complications.[6]
The Diabetes Control and Complications Trial was the first to show that
maintaining blood glucose levels as near to normal as possible by way of
intensive insulin therapy in patients with type 1 diabetes reduced the risk of
microvascular complications.[12] With a cohort of approximately 1,400
patients, one half of whom were free of retinopathy at baseline and the
other half of whom had mild retinopathy, the study showed that intensive
therapy in the retinopathy-free patients resulted in a reduction of the
adjusted mean risk for development of retinopathy of 76%, compared with
conventional therapy, and slowed progression among the patients with
mild retinopathy by 54%.[12] Further, in comparison with conventional
therapy, intensive therapy reduced the occurrence of clinical neuropathy
by 60%, albuminuria by 54%, and microalbuminuria by 39%.[12]
Evidence that such improvements could also be achieved in patients with
type 2 diabetes subsequently emerged.[13] In 1998, a report of the United
Kingdom Prospective Diabetes Study (UKPDS) showed that intensive
control of blood glucose levels with an oral sulfonylurea (chlorpropamide,
glibenclamide, or glipizide) or insulin significantly decreased the risk of
microvascular complications in patients with type 2 diabetes.[14] When
compared with a control group treated by conventional means (diet alone),
patients in the intensive-treatment group had a 12% lower risk of diabetesrelated end points ( P = 0.029) and, although not significant, had a 10%
lower risk for diabetes-associated death and a 6% lower risk of all-cause
mortality. The investigators concluded that most of the risk reduction in any
diabetes-related aggregate end point was due to a 25% risk reduction in
diabetes-associated microvascular end points ( P = 0.0099). No significant
difference in microvascular risk reduction was observed among the
chlorpropamide, glibenclamide, and glipizide treatment modalities. The
UKPDS also showed a trend toward a reduction in diabetes-associated
macrovascular complications with intensive treatment compared with
conventional treatment, although the difference was not statistically
significant.
The Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial
Infarction Study Group demonstrated that an insulin-glucose infusion
followed by intensive subcutaneous insulin injection in diabetic patients
who had endured an acute myocardial infarction significantly improved
their long-term survival.[15] This effect was sustained over 3.5 years,
resulting in an absolute reduction in mortality rate of 11% among patients
in the intensive-therapy group.
Berger et al[16] hypothesized that on the basis of pathophysiologic and
clinical possibilities, the earlier insulin treatment is begun in the natural
history of type 2 diabetes, the greater the amount of available endogenous
insulin reserves. To this end, they tested various management strategies
involving preprandial insulin injections in a multicenter study of 550
patients with type 2 diabetes.[16] At the end of the 2-year observation
period, mean A1C concentrations had declined from 9.6% to 8.1%, with
virtually no change in mean body mass index. The incidence of severe
hypoglycemia was relatively low, at 0.04 cases per patient per year.[16]
Intensive insulin therapy also reduces certain macrovascular risk factors,
such as lipoprotein abnormalities and fibrinolytic profiles associated with
atherothrombotic risk.[17-19]
Thus, it has been firmly established that intensive therapy, including the
early use of insulin in patients with type 2 diabetes, can significantly alter
the course of long-term microvascular and, to some extent, macrovascular
complications, decreasing morbidity and, in some circumstances, mortality.
New Insulin Analogs
Before the introduction of insulin analogs, insulin therapy was limited in its
ability to mimic normal physiologic insulin secretion. Traditional
intermediate- and long-acting insulins (NPH insulin, lente insulin, and
ultralente insulin) are limited by inconsistent absorption and peaks of
action that may result in hypoglycemia ( Table 2 and Fig. 1).[10] The
pharmacokinetic profiles of the new insulin analogs are distinct from those
of the regular insulins, and their onsets and durations of action range from
rapid to prolonged ( Table 2 ).[10] Currently, two rapid-acting insulin analogs,
insulin lispro and insulin aspart, and one long-acting insulin analog, insulin
glargine, are available (Fig. 1).
Figure 1. Pharmacokinetic profiles of regular insulin, derivatives of insulin,
and insulin delivered from the pancreas. Duration of insulin effect for each
insulin type over 24 hours is shown, which reflects utilization for either
basal or bolus administration.[55] NPH, neutral protamine Hagedorn.
Insulin Lispro
Insulin lispro was compared with human regular insulin in a 6-month,
randomized, open-label, crossover trial involving 722 patients with type 2
diabetes.[20] The patients were treated with either insulin lispro immediately
before meals or human regular insulin 30 to 45 minutes before meals.
Over the study course of 24 weeks, the increase in postprandial serum
glucose levels was significantly lower in the insulin lispro group than in the
human regular insulin group. At the conclusion of the study, the increase in
serum glucose levels at 1 and 2 hours postprandially was 30% and 53%
lower, respectively, for the patients receiving insulin lispro compared with
the patients receiving human regular insulin. The rates of nocturnal and
overall hypoglycemia and the number of asymptomatic hypoglycemic
episodes were also lower during treatment with insulin lispro than with
human regular insulin. However, A1C concentrations decreased
significantly ( P < 0.001) and equally with each of the two treatments.
Insulin Aspart
A comparison of insulin aspart with regular insulin in a double-blinded,
randomized study of 90 men with type 1 diabetes showed that insulin
aspart was superior to regular insulin in controlling 24-hour plasma glucose
levels[21]; 22% fewer instances of hypoglycemia, defined as plasma glucose
levels of 72 to 126 mg/dL (4 to 7 mmol/L), occurred with insulin aspart ( P
< 0.01). Home blood glucose monitoring confirmed that insulin aspart
significantly improved plasma glucose control after lunch and dinner ( P <
0.05). Insulin aspart also provided better control of hypoglycemic events
than did regular insulin (22 versus 44 events, P < 0.002). Regular insulin
proved to be superior for controlling nighttime hyperglycemia, although the
investigators noted that the doses of NPH, administered as bedtime basal
insulin, may not have been adjusted properly.
Insulin Glargine
The long-acting insulin analog insulin glargine was studied in comparison
with NPH insulin in 518 patients with type 2 diabetes in an open-label, 28week, multicenter study.[22] All patients had been treated previously with
NPH insulin with or without regular insulin for postprandial serum glucose
control. In this study, patients were randomly assigned to receive either
insulin glargine or NPH insulin, and the doses were adjusted to attain a
target fasting glucose level of less than 121 mg/dL (<6.7 mmol/L). At the
conclusion of the trial, the median daily dose of insulin was 0.75 IU/kg in
both groups. The two forms of insulin produced similar improvements in
A1C concentrations and similar reductions in fasting glucose levels;
however, the incidence of nocturnal hypoglycemia was significantly lower
among patients treated with insulin glargine than among patients treated
with NPH insulin ( P = 0.0136) (Fig. 2).[22] This difference represented a
25% reduction in occurrences of nocturnal hypoglycemia between the
hours of 12 am and 6 am.
Figure 2. Effects of NPH insulin and insulin glargine on A1C
concentration, FBG levels, and nocturnal hypoglycemia. Both insulin
glargine ( white bars ) and NPH insulin ( black bars ) significantly
decreased the A1C concentration and FBG levels; however, patients
receiving insulin glargine had significantly fewer episodes of nocturnal
hypoglycemia. * P < 0.01 vs baseline. † P < 0.02 insulin glargine versus
NPH insulin. A1C, Glycated hemoglobin; FBG, fasting blood glucose; NPH,
neutral protamine Hagedorn. Adapted from Rosenstock et al.[22]
Clinical experience with once-daily insulin glargine has led to the opinion
that its therapeutic effects may not last for a full 24 hours in all patients.
Rather than the flat action profile typically seen in most patients, a slight
early peak followed by a waning effect toward the end of the dosing
interval is experienced by some patients. This effect may be more evident
in patients with type 1 diabetes. Theoretically, twice-daily administration
may be an alternative, yet results from a recent study conducted by Burge
and Schroeder[23] do not confirm this hypothesis. Comparing an equal dose
of insulin glargine administered once-daily versus twice-daily in seven
patients with type 1 diabetes, insulin concentrations were equivalent after
24 hours regardless of dosing frequency.
When insulin glargine became available, the recommended dosing interval
was once daily at bedtime. More recently, however, insulin glargine has
been approved for use at any time of the day as long as it is administered
at the same time each day.[24] Insulin glargine should not be mixed with any
other insulin products, as such mixing could alter its pharmacokinetic and
pharmacodynamic profiles and make them unpredictable.[25]
Defining a Treatment Strategy
To achieve optimal glycemic control, insulin delivery should mimic a
pattern that simulates the normal pattern of insulin production. Despite the
fact that oral therapy is easier for patients to initiate than selfadministration of one or more daily subcutaneous injections, oral therapy is
not always successful. The UKPDS showed that approximately 25% of
patients randomly assigned to receive oral agents had to be switched to
insulin treatment within 6 years because of lack of efficacy of the oral
agents in maintaining good glycemic control.[26]
The progressive deterioration of β-cell function that characterizes the
natural history of type 2 diabetes suggests that earlier initiation of insulin
therapy may protect β cells from the increasing functional impairment
caused by extended exposure to hyperglycemia.[16,27] A study with early
insulin treatment conducted in 13 mildly overweight, newly diagnosed type
2 diabetes patients who had failed to respond to diet and exercise alone
showed promising results.[28] The patients were given 2 weeks of
continuous subcutaneous insulin infusion (CSII) immediately after the
cessation, of which they were instructed to maintain glycemic control on
diet alone. These patients achieved endogenous insulin levels similar to
those during CSII treatment. At 6 months after termination of CSII, 85% of
the subjects still maintained good glycemic control. Other investigators
also have concluded that using an aggressive insulin regimen to restore
glycemic control in the early stages of type 2 diabetes, thus reducing
glucose toxicity, may have long-lasting benefits, including the restoration of
β-cell function and possible reduction in the rate of β-cell deterioration.[27]
Several special circumstances should be considered when prescribing
insulin and insulin analogs; these include gastroparesis, renal failure,
pregnancy, and advanced age. In patients with gastroparesis, food stays in
the stomach much longer than usual, and blood glucose levels rise only
after the nutrients leave the stomach and enter the small intestine. If a
patient has severe gastroparesis, the use of a fast-acting insulin analog
may lead to immediate postprandial hypoglycemia and eventual
hyperglycemia, as the insulin analog will begin to lower blood glucose
levels before the nutrients are absorbed in the small intestine. Most
patients who have gastroparesis still have some degree of gastric function
and can control their symptoms of abdominal bloating and gas by
spreading out their consumption of food over time, not over-eating, and
adjusting the types of food they eat. In a few patients with severe
gastroparesis, the use of the older human regular insulin may be more
effective at matching the absorption of nutrients to insulin action. There is
usually no need to make adjustments in the doses of intermediate- or longacting insulin.
The kidney is partly responsible for the clearance of insulin, and, like the
liver, contributes to glucose production, but to a smaller degree. Renal
failure leads to prolonged insulin action and altered pharmacokinetics. The
clinician should watch for delayed hypoglycemia due to the delayed
peaking of insulin action. For this reason, we prefer the use of the fastacting insulin analogs with meals as they have the shortest course of
action. Normally, if the basal insulin requirements are known and the
patient's meal plan is consistent in terms of times and amounts, the dose
does not need to be altered.
The primary issue regarding diabetes during pregnancy is that aggressive
postprandial glucose control to less than 130 to 140 mg/dL has become
the gold standard for women throughout gestation. The rate of perinatal
morbidity and mortality is essentially the same as that in the nondiabetic
population when proper glucose control is maintained. Although not
specifically approved for this purpose by the Food and Drug
Administration, fast-acting insulin analogs are routinely used in this patient
population along with intermediate-acting insulins, such as NPH insulin.
Insulin glargine is relatively new to the US market and is only now being
considered in pregnant women, although it has not yet been approved by
the Food and Drug Administration for use in this population.
As with all medical conditions, diabetes should be managed with caution in
the elderly. It is important to maintain good glycemic control to avoid the
acute complications of diabetes such as poor wound healing, cognitive
dysfunction, and electrolyte imbalance. It is also very important to avoid
hypoglycemia, which could lead to injuries such as falls and broken hips.
There must be a balance between adequate glucose control and an
avoidance of hypoglycemia. The saying start low and go slow works well
with the elderly.
Combination Therapy
Regular, long-acting, and NPH insulin, as well as insulin analogs, have
been combined with various oral agents to control glycemia and
successfully lower fasting plasma glucose levels and A1C
concentrations.[29-31] In the UKPDS,[17] the addition of insulin to sulfonylurea
therapy resulted in significantly lower A1C concentrations than did insulin
alone ( P = 0.0066) and a greater number of patients achieving A1C
concentrations of less than 7% (47 versus 35, P = 0.011). Median insulin
doses used in combination insulin-plus-sulfonylurea therapy at 6 years
were also significantly lower than those used in insulin monotherapy: 0.24
IU/kg (range, 0.16 to 0.40) versus 0.30 IU/kg (range, 0.24 to 0.40) ( P =
0.0088).[32]
In a 24-week study in patients poorly controlled on sulfonylurea therapy,
the combination of insulin and a sulfonylurea, compared with insulin alone,
produced comparable declines in A1C concentrations (2.2 ± 1.0% and 2.1
± 1.0%, respectively) but faster declines in fasting plasma glucose levels (
P < 0.0001 at 2 and 4 weeks).[31] Furthermore, improvement in fasting
hyperglycemia in the combination group was achieved with an insulin dose
approximately 40% lower than that required in patients treated with insulin
alone.
Insulin in combination with metformin was shown to be significantly more
effective than insulin alone in reducing A1C concentrations (-2.5% versus 1.7%, P < 0.01), with a lower daily insulin dose (mean change from
baseline, -4.5 IU/d versus +22.8 IU/d; P = 0.002).[33] In one study, insulin in
combination with acarbose has also been shown to cause a statistically
significant decrease in A1C concentrations (-0.58% versus +0.11%, P =
0.0001) and postprandial hyperglycemia ( P = 0.0001) compared with
insulin and placebo after 26 weeks of treatment.[34,35] Thiazolidinediones
added to established insulin therapy have significantly reduced A1C
concentrations (≥1%) and daily insulin dose requirements compared with
insulin alone.[29,30,36]
In a 24-week trial, patients who had been inadequately controlled on one
or two oral hypoglycemic agents were found to attain target A1C
concentrations of 7% or less when bedtime insulin glargine or NPH insulin
was added to their regimen.[37] Insulin doses were systematically and
aggressively titrated by using a simple algorithm to achieve a fasting
plasma glucose level of 100 mg/dL or less ( Table 3 ). This resulted in
patients reaching A1C targets in both the insulin glargine group (58.0%)
and the NPH insulin group (57.3%). However, complete treatment
success, rigorously defined as reaching target A1C levels without a
documented episode of hypoglycemia, was achieved by more subjects
receiving insulin glargine than subjects receiving NPH insulin (33.2 versus
26.7%, P < 0.05). Insulin doses increased in a similar manner in both
groups, although at study end the mean daily doses of insulin glargine
were higher (total dose, 47.2 ± 1.3 IU; dose adjusted for body weight, 0.48
± 0.01 IU/kg) than were the daily doses of NPH insulin (total dose, 41.8 ±
1.3 IU; dose adjusted for body weight, 0.42 ± 0.01 IU/kg). Despite the
higher doses of insulin glargine, rates of hypoglycemia, expressed as
events per patient-year, were significantly lower with the insulin analog
than with NPH insulin (symptomatic events, 13.9 versus 17.7, P < 0.02), as
were confirmed events of episodes of plasma glucose levels of 72 mg/dL
or less (≤4 mmol/L) (9.2 versus 12.9, P < 0.05) and 56 mg/dL or less (≤3.1
mmol/L) (3.0 versus 5.1 episodes, P < 0.003). The hypoglycemia data from
this study demonstrate that insulin glargine is better suited for use as a
once-daily basal insulin regimen than is NPH insulin.
Bedtime NPH Insulin
The use of NPH insulin at bedtime has been studied as a means of strictly
controlling fasting plasma glucose levels. A study among 12 obese men
with type 2 diabetes whose fasting plasma glucose levels were poorly
controlled, even with maximal doses of sulfonylureas, showed that good
glycemic control could be achieved with insulin.[38] After a 4-week
sulfonylurea washout period, during which the study subjects were treated
by diet alone, the subjects received NPH insulin at bedtime for 16 weeks,
beginning at a dose of 0.15 IU/kg, which was titrated upward until a fasting
glucose level of 80 to 115 mg/dL (4.4 to 6.4 mmol/L) was achieved. Within
6 weeks, mean fasting plasma glucose levels had been reduced from 263
± 16 mg/dL (14.6 ± 0.9 mmol/L) to 106 ± 11 mg/dL (5.9 ± 0.6 mmol/L); the
mean bedtime dose of NPH insulin was 80 ± 9 IU/d (0.86 ± 0.10 IU/kg).
The target level for normalization was maintained until the end of the
study, 72.0 ± 0.5 mg/dL (4.00 ± 0.03 mmol/L) at week 16. A1C
concentrations declined over the course of the 16 weeks, from 10.90 ±
0.05% to 7.2 ± 0.2%, confirming good glycemic control. Episodes of mild or
moderate hypoglycemia occurred at a rate of 3.4 ± 1.0 per patient, and
there were no instances of severe hypoglycemia. This regimen also
resulted in improved insulin secretion and insulin sensitivity.
Premixed Insulin
In patients with type 2 diabetes, twice-daily regimens of insulin mixtures
provide similar glycemic control as an intense regimen of multiple daily
injections.[39] Split self-mixed insulin regimens are effective for helping
patients achieve glycemic control, yet an inherent risk of error exists. By
combining the insulins themselves, patients can encounter problems with
mixing technique and inaccurate dosing ratios, potentially reducing the
effectiveness of the short-acting insulin. The benefits of premixed insulin
formulations, such as a human insulin 70/30 mixed suspension (70% NPH
insulin and 30% regular insulin), include reduced errors and improved
dosing accuracy as well as the convenience of using a single vial.[40,41]
Premixed Rapid-Acting Insulin Analogs
Rapid-acting insulin analogs are also available as manufactured premixed
insulin formulations in combination with intermediate-acting insulin. Various
fixed-ratio mixtures of insulin preparations exist, including mixtures of
insulin lispro, which contains 75% protamine-based intermediate-acting
neutral protamine lispro (NPL) and 25% rapid-acting insulin lispro, and
insulin aspart, which contains 70% insulin aspart protamine suspension
and 30% insulin aspart. The pharmacokinetic and pharmacodynamic
profiles of NPL have been shown to be comparable with those of NPH
insulin.[42] In a study comparing the pharmacodynamic parameters of 70/30
human insulin with those of 70/30 insulin aspart protamine/insulin aspart,
the insulin aspart formulation demonstrated faster onset and greater peak
of action.[43]
Premixed 75/25 NPL/insulin lispro was studied in comparison with
premixed 70/30 human insulin in 89 patients with type 2 diabetes in a 6month, randomized, open-label, two-period crossover study.[44] During a 2to 4-week lead-in period, patients were treated with 70/30 human insulin.
After this, they received either (1) twice-daily therapy with 75/25
NPL/insulin lispro for 3 months, after which they were crossed over to
receive 70/30 human insulin using the same dosing frequency for an
additional 3 months, or (2) the alternate treatment sequence. Mean insulin
doses were similar between treatments. Blood glucose levels after the
morning meal were significantly lower during treatment with 75/25
NPL/insulin lispro than with 70/30 human insulin (8.95 ± 2.17 versus 10.00
± 2.28 mmol/L [161 ± 39 versus 180 ± 41 mg/dL], respectively, P = 0.017).
Treatment with 75/25 NPL/insulin lispro produced similar significant blood
glucose results 2 hours after the evening meal as well (75/25 NPL/insulin
lispro, 9.28 ± 2.15 [167 ± 39 mg/dL] versus 70/30 human insulin, 10.27 ±
2.76 mmol/L [185 ± 50 mg/dL], P = 0.014). Blood glucose levels at other
time points, A1C concentrations, daytime hypoglycemia, or nocturnal
hypoglycemia did not differ significantly between treatment groups.
In another study, the premixed 70/30 aspart mixture was compared with
premixed 70/30 human insulin administered twice a day in a randomized
12-week, open-label trial in 294 patients with type 1 or type 2 diabetes.[45]
There was no significant difference in A1C concentration between groups,
although mean blood glucose levels after treatment with the aspart mixture
were significantly lower (by approximately 1.0 mmol/L, P < 0.05) after
breakfast, before lunch, after dinner, and at bedtime, compared with blood
glucose levels after treatment with the human insulin mixture at each time
point. The incidence of hypoglycemia did not differ between groups, and
weight gain was not significant during the study period with either insulin
mixture.
Basal-Bolus Insulin
The basal-bolus insulin strategy, which can be used in patients with either
type 1 or type 2 diabetes, incorporates the concept of providing continuous
basal insulin secretion throughout the day and night with brief increases in
insulin levels at the time of meal ingestion through the administration of
bolus doses.
The use of preprandial regular insulin with bedtime NPH insulin as the
basal insulin (Fig. 3A) has been a common strategy for intensive insulin
therapy in the United States. However, since regular insulin should be
administered 20 to 40 minutes before a meal, a risk of hypoglycemia exists
if the meal is delayed. If regular insulin is given just before a meal, high
postprandial glucose levels and delayed hypoglycemia may result. A
strategy that provides flexibility in the mealtime administration of insulin is
the use of the rapid-acting insulin analogs insulin lispro and insulin aspart,
administered immediately before meals, and a long-acting insulin, such as
ultralente insulin, as the basal insulin (Fig. 3B). However, these regimens
are associated with unpredictable nocturnal hypoglycemia and day-to-day
instability of blood glucose patterns because of intrapatient variability of the
effect of ultralente insulin and its peak action profile.[46] NPH insulin, which
exhibits peak action 5 to 7 hours after administration, has also been used
in combination with rapid-acting insulin analogs, commonly given twice
daily, but the disadvantages of NPH insulin used in this manner are similar
to those of ultralente insulin.[47] Because of its time to peak action, NPH
insulin should be given every 6 hours, or 4 times per day, to be effective as
a basal insulin.[48]
Figure 3. Basal-bolus insulin regimens showing time of administration and
number of injections per type of insulin. Shaded area depicts normal
insulin secretion, showing relation of each insulin therapy to normal
physiologic conditions. Convergence or nonconvergence between the
shaded areas and each insulin therapy as marked by dotted or dashed
lines can measure insulin effect. NPH, Neutral protamine Hagedorn; B,
breakfast; HS, bedtime; L, lunch; S, supper.
Improved mealtime glucose control with the rapid-acting insulin analogs
has exposed the gaps in basal insulin coverage provided by the traditional
intermediate- and long-acting insulin preparations. Administration of a
once-daily basal insulin analog, such as insulin glargine, which has a
relatively smooth pharmacokinetic profile, may result in a more physiologic
pattern of basal insulin replacement. Insulin glargine in combination with a
rapid-acting insulin (Fig. 3C) has demonstrated effective glycemic control
and is associated with a lower incidence of nocturnal hypoglycemia[49] than
are other insulin preparations currently used for basal insulin
supplementation.[49-53]
In a 4-week trial, 256 patients with type 1 diabetes who had already been
receiving a basal-bolus multiple daily insulin regimen were given blinded
treatment with insulin glargine once daily (at bedtime) or unblinded
treatment with NPH insulin once daily (at bedtime) or twice daily (at
bedtime and before breakfast).[52] Injections of regular insulin were
administered before meals, according to the patient's usual regimen. Basal
insulin doses were titrated to maintain fasting blood glucose levels
between 72 and 126 mg/dL (4 and 7 mmol/L) during the first 3 weeks of
the study. The study required that the initial insulin glargine dose be
calculated from the total of the two doses of NPH insulin for patients who
were receiving NPH insulin twice daily before the study; this resulted in a
downward titration of the insulin glargine doses. Thus, at study end point,
after the completion of titration, median basal doses of insulin glargine
were similar to the prestudy doses in patients receiving NPH insulin once
daily. Blood glucose measurements were obtained by patient selfmonitoring. At the conclusion of the study, insulin glargine demonstrated
better efficacy than NPH insulin in lowering fasting plasma glucose levels,
with adjusted mean levels of 166 mg/dL (9.2 mmol/L) and 203 mg/dL (11.3
mmol/L) for insulin glargine and NPH insulin, respectively ( P = 0.0001).
This clinically meaningful effect was seen as early as 1 week.
The availability of mealtime and basal insulin analogs, combination therapy
with oral agents, and the use of insulin regimens comprising basal and
mealtime (bolus) insulin components that better simulate normal insulin
secretion represent important advances in insulin therapy. All of these
approaches can have a significant impact on treatment outcomes.
As described in this review, insulin analogs offer several therapeutic
benefits, yet one potential drawback is the expense of these newer agents.
The analogs typically cost twice as much as older insulin products, such as
human regular insulin and NPH insulin. Some patients and providers may
view this as a deterrent, particularly if these drugs are not covered by
insurance plans. However, for patients with type 1 diabetes who require an
insulin pump, the cost of using insulin analogs may be less costly. In a
study by Garg et al,[54] multiple daily injections of insulin glargine and insulin
lispro or insulin aspart in a basal-bolus regimen were shown to be less
costly than an external insulin pump. As with all drug therapies, the
potential benefits of the analogs will need to be weighed against cost when
determining individualized drug regimens.
Conclusion
The effective management of diabetes can significantly alter the course of
long-term microvascular and, to some extent, macrovascular
complications, thus reducing both morbidity and mortality. Clinical
experience with intensive therapy for type 2 diabetes offers convincing
evidence of the benefits of early insulin use in a regimen providing strict
24-hour control of blood glucose levels. New insulin analogs offer
significant advantages in terms of pharmacokinetics, resulting in improved
postprandial glycemic control (with insulin lispro and insulin aspart) and
enhanced control of nocturnal hypoglycemia (with insulin glargine).
Table 1. Efficacy of Oral Hypoglycemic Drugs
Table 2. Characteristics of Insulin and Insulin Analog
Formulations
Table 3. Weekly Titration Schedule
References
1. American Academy of Family Physicians: Number of office visits (in
thousands) to selected specialties by age of patient and ranked by
the 20 most frequent principal diagnoses by the physician (by ICD-9
three digit code in parentheses): United States, 2001 [table 36A].
2004. Data source: US Department of Health and Human Services,
Public Health Service, Centers for Disease Control and Prevention,
National Center for Health Statistics, 1999 data. Unpublished data.
Available at: http://www.aafp.org/x25061.xml. Accessed July 19,
2004.
2. Sherwin RS. Diabetes mellitus, in Goldman L, Bennett JC (eds):
Cecil Textbook of Medicine. Philadelphia, WB Saunders, 2000, pp
1263-1285.
3. Hiatt WR. Atherosclerotic peripheral arterial disease, in Goldman L,
Bennett JC (eds): Cecil Textbook of Medicine. Philadelphia, WB
Saunders, 2000, pp 357-362.
4. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus.
Ann Intern Med 1999;131:281-303.
5. Centers for Disease Control and Prevention. National Diabetes Fact
Sheet: national estimates on diabetes. 2002. Available at:
http://www.cdc.gov/diabetes/pubs/estimates.htm. Accessed October
24, 2003.
6. Bennett PH, Rewers MJ, Knowler WC. Epidemiology of diabetes
mellitus, in Porte DJ, Sherwin RS (eds): Ellenberg and Rifkin's
Diabetes Mellitus. Stamford, Appleton & Lange, 1997, pp 373-397.
7. UK Prospective Diabetes Study (UKPDS) Group. UK Prospective
Diabetes Study, II: reduction in HbA1c with basal insulin supplement,
sulfonylurea, or biguanide therapy in maturity-onset diabetes: a
multicenter study. Diabetes 1985;34:793-798.
8. American Diabetes Association. Clinical practice recommendations
2003. Diabetes Care 2003;26(suppl 1):S1-S156.
9. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes:
scientific review. JAMA 2002;287:360-372.
10.
Burge MR, Schade DS. Insulins. Endocrinol Metab Clin North
Am 1997;26:575-598.
11.
American College of Endocrinology, American Association of
Clinical Endocrinologists. American College of Endocrinology
Consensus Statement on Guidelines for Glycemic Control. Endocr
Pract 2002;8(suppl 1):5-11.
12.
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 Engl J Med 1993;329:977-986.
13.
Buse JB. The use of insulin alone and in combination with oral
agents in type 2 diabetes. Prim Care 1999;26:931-950.
14.
UK Prospective Diabetes Study (UKPDS) Group. Intensive
blood-glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with type
2 diabetes (UKPDS 33). Lancet 1998;352:837-853.
15.
Malmberg K, for the DIGAMI (Diabetes Mellitus Insulin
Glucose Infusion in Acute Myocardial Infarction) Study Group.
Prospective randomised study of intensive insulin treatment on long
term survival after acute myocardial infarction in patients with
diabetes mellitus. BMJ 1997;314:1512-1515.
16.
Berger M, Jorgens V, Muhlhauser I. Rationale for the use of
insulin therapy alone as the pharmacological treatment of type 2
diabetes. Diabetes Care 22(suppl 3):C71-C75, 1999.
17.
Edelman SV, Henry RR. Insulin therapy for normalizing
glycosylated hemoglobin in type II diabetes: application, benefits,
and risks. Diabetes Rev 1995;3:308-334.
18.
Beckman JA, Creager MA, Libby P. Diabetes and
atherosclerosis: epidemiology, pathophysiology, and management.
JAMA 2002;287:2570-2581.
19.
Tanaka A, Kobayashi Y, Tamura M, et al. Metabolism of
triglyceride-rich lipoproteins and their role in atherosclerosis. Ann N
Y Acad Sci 2001;947:207-212.
20.
Anderson JHJ, Brunelle RL, Keohane P, et al. Mealtime
treatment with insulin analog improves postprandial hyperglycemia
and hypoglycemia in patients with non-insulin-dependent diabetes
mellitus. Arch Intern Med 1997;157:1249-1255.
21.
Home PD, Lindholm A, Hylleberg B, et al, for the UK Insulin
Aspart Study Group. Improved glycemic control with insulin aspart: a
multicenter randomized double-blind crossover trial in type 1 diabetic
patients. Diabetes Care 1998;21:1904-1909.
22.
Rosenstock J, Schwartz SL, Clark CM Jr, et al. Basal insulin
therapy in type 2 diabetes: 28-week comparison of insulin glargine
(HOE 901) and NPH insulin. Diabetes Care 2001;24:631-636.
23.
Burge MR, Schroeder E. Is twice-daily insulin glargine
superior to once-daily administration [507-P]. Diabetes
2004;53(suppl 2):A120.
24.
Hamann A, Matthaei S, Rosak C, et al, for the HOE901/4007
Study Group. A randomized clinical trial comparing breakfast, dinner,
or bedtime administration of insulin glargine in patients with type 1
diabetes. Diabetes Care 2003;26:1738-1744.
25.
Lantus Prescribing Information. Physicians' Desk Reference.
Montvale, NJ, Medical Economics Company, Inc, 2003, pp 735-739.
26.
UK Prospective Diabetes Study Group. UK Prospective
Diabetes Study 16: overview of 6 years' therapy of type II diabetes: a
progressive disease. Diabetes 1995;44:1249-1258.
27.
Glaser B, Cerasi E. Early intensive insulin treatment for
induction of long-term glycaemic control in type 2 diabetes. Diabetes
Obes Metab 1999;1:67-74.
28.
Ilkova H, Glaser B, Tunçkale A, et al. Induction of long-term
glycemic control in newly diagnosed type 2 diabetic patients by
transient intensive insulin treatment. Diabetes Care 1997;20:1353-
1356.
29.
Raskin P, Rendell M, Riddle MC, et al, for the Rosiglitazone
Clinical Trials Study Group. A randomized trial of rosiglitazone
therapy in patients with inadequately controlled insulin-treated type 2
diabetes. Diabetes Care 2001;24:1226-1232.
30.
Schwartz S, Raskin P, Fonseca V, et al, for the Troglitazone
and Exogenous Insulin Study Group. Effect of troglitazone in insulintreated patients with type II diabetes mellitus. N Engl J Med
1998;338:861-866.
31.
Riddle MC, Schneider J, for the Glimepiride Combination
Group. Beginning insulin treatment of obese patients with evening
70/30 insulin plus glimepiride versus insulin alone. Diabetes Care
1998;21:1052-1057.
32.
Wright A, Burden ACF, Paisey RB, et al, for the UK
Prospective Diabetes Study Group. Sulfonylurea inadequacy:
efficacy of addition of insulin over 6 years in patients with type 2
diabetes in the UK Prospective Diabetes Study (UKPDS 57).
Diabetes Care 2002;25:330-336.
33.
Avilés-Santa L, Sinding J, Raskin P. Effects of metformin in
patients with poorly controlled, insulin-treated type 2 diabetes
mellitus: a randomized, double-blind, placebo-controlled trial. Ann
Intern Med 1999;131:182-188.
34.
Kelley DE, Bidot P, Freedman Z, et al. Efficacy and safety of
acarbose in insulin-treated patients with type 2 diabetes. Diabetes
Care 1998;21:2056-2061.
35.
Chiasson J-L, Josse RG, Hunt JA, et al. The efficacy of
acarbose in the treatment of patients with non-insulin-dependent
diabetes mellitus: a multicenter controlled clinical trial. Ann Intern
Med 1994;121:928-935.
36.
Rubin C, Egan J, Schneider R, for the Pioglitazone 014 Study
Group. Combination therapy with pioglitazone and insulin in patients
with type 2 diabetes. Diabetes 1999;48(suppl 1):A110.
37.
Riddle MC, Rosenstock J, Gerich J, on behalf of the Insulin
Glargine 4002 Study Investigators. The Treat-to-Target Trial:
randomized addition of glargine or human NPH insulin to oral
therapy of type 2 diabetic patients. Diabetes Care 2003;26:30803086.
38.
Cusi K, Cunningham GR, Comstock JP. Safety and efficacy of
normalizing fasting glucose with bedtime NPH insulin alone in
NIDDM. Diabetes Care 1995;18:843-851.
39.
Lindstrom TH, Arnqvist HJ, von Schenck HH. Effect of
conventional and intensified insulin therapy on free-insulin profiles
and glycemic control in NIDDM. Diabetes Care 1992;15:27-34.
40.
Bell DSH, Clements RS Jr, Perentesis G, et al. Dosage
accuracy of self-mixed vs premixed insulin. Arch Intern Med
1991;151:2265-2269.
41.
Coscelli C, Calabrese G, Fedele D, et al. Use of premixed
insulin among the elderly: reduction of errors in patient preparation
of mixtures. Diabetes Care 1992;15:1628-1630.
42.
Roach P, Woodworth JR. Clinical pharmacokinetics and
pharmacodynamics of insulin lispro mixtures. Clin Pharmacokinet
2002;41:1043-1057.
43.
Jacobsen LV, Sogaard B, Riis A. Pharmacokinetics and
pharmacodynamics of a premixed formulation of soluble and
protamine-retarded insulin aspart. Eur J Clin Pharmacol
2000;56:399-403.
44.
Roach P, Yue L, Arora V, Humalog Mix25 Study Group.
Improved postprandial glycemic control during treatment with
Humalog Mix25, a novel protamine-based insulin lispro formulation.
Diabetes Care 1999;22:1258-1261.
45.
Boehm BO, Home PD, Behrend C, et al. Premixed insulin
aspart 30 vs premixed human insulin 30/70 twice daily: a
randomized trial in type 1 and type 2 diabetic patients. Diabet Med
2002;19:393-399.
46.
Leahy JL. Intensive insulin therapy in type 1 diabetes mellitus,
in Leahy JL, Cefalu WT (eds): Insulin Therapy. New York, NY,
Marcel Dekker, Inc, 2002, pp 87-112.
47.
Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics
and pharmacodynamics of subcutaneous injection of long-acting
human insulin analog glargine, NPH insulin, and ultralente human
insulin and continuous subcutaneous infusion of insulin lispro.
Diabetes 2000;49:2142-2148.
48.
Bolli GB, Di Marchi RD, Park GD, et al. Insulin analogues and
their potential in the management of diabetes mellitus. Diabetologia
1999;42:1151-1167.
49.
Yki-Järvinen H, Dressler A, Ziemen M, for the HOE 901/3002
Study Group. Less nocturnal hypoglycemia and better post-dinner
glucose control with bedtime insulin glargine compared with bedtime
NPH insulin during insulin combination therapy in type 2 diabetes.
Diabetes Care 2000;23:1130-1136.
50.
Raskin P, Klaff L, Bergenstal R, et al. A 16-week comparison
of the novel insulin analog insulin glargine (HOE 901) and NPH
human insulin used with insulin lispro in patients with type 1
diabetes. Diabetes Care 2000;23:1666-1671.
51.
Heinemann L, Linkeschova R, Rave K, et al. Time-action
profile of the long-acting insulin analog insulin glargine (HOE901) in
comparison with those of NPH insulin and placebo. Diabetes Care
2000;23:644-649.
52.
Rosenstock J, Park G, Zimmerman J, et al. Basal insulin
glargine (HOE 901) versus NPH insulin in patients with type 1
diabetes on multiple daily insulin regimens. Diabetes Care
2000;23:1137-1142.
53.
Pieber TR, Eugene-Jolchine I, Derobert E, et al. Efficacy and
safety of HOE 901 versus NPH insulin in patients with type 1
diabetes. Diabetes Care 2000;23:157-162.
54.
Garg SK, Walker AJ, Hoff HK, et al. Glycemic parameters with
multiple daily injections using insulin glargine versus insulin pump.
Diabetes Technol Ther 2004;6:9-15.
55.
Edelman SV, Henry RR: Diagnosis and Management of Type
2 Diabetes. 4th ed. Caddo, OK, Professional Communications, Inc;
2001.
Sidebar: Key Points



Clinical studies reveal that normalizing blood glucose and mimicking
normal insulin secretion in patients with type 2 diabetes may prevent
the onset and delay the progression of diabetic complications.
Traditional regimens have failed to maintain glycemic control
because of the progressive decline of β-cell function, resulting in
patients requiring insulin therapy.
Strategies have been developed to provide exogenous insulin.
Reprint Address
Reprint requests to Steven V. Edelman, MD, Division of Diabetes and
Metabolism, San Diego Veterans Affairs Medical Center, 3350 La Jolla
Village Drive (111G), San Diego, CA 92161. Email: [email protected]
Steven V. Edelman, MD , and Candis M. Morello, PHARMD, CDE ,
Division of Diabetes and Metabolism, San Diego Veterans Affairs Medical
Center, and University of California, San Diego, School of Pharmacy and
Pharmaceutical Sciences, San Diego, CA