INSULIN THERAPY

INTRODUCTION Type 2 diabetes is by far the most common type of diabetes in adults
and is characterized by hyperglycemia and variable degrees of insulin deficiency and
resistance. It is a common disorder whose prevalence rises markedly with increasing
degrees of obesity. Treatment of patients with type 2 diabetes mellitus includes
education, evaluation for microvascular and macrovascular complications, normalization
of glycemia, minimization of cardiovascular and other long-term risk factors, and
avoidance of drugs that can aggravate abnormalities of insulin or lipid metabolism.
Weight reduction, diet, and oral medication (typically metformin) can all be used to
improve glycemic control, although the majority of patients with type 2 diabetes fail to
maintain glycemic targets after a successful initial response to therapy. The therapeutic
options for such patients include adding a second or third oral agent or an injectable
agent, including insulin, or switching to insulin.
The role of insulin in achieving optimal glycemic control in patients with type 2 diabetes
will be reviewed here. Options for initial therapy, options for the management of
persistent hyperglycemia, and other therapeutic issues in diabetes management, such as
the frequency of monitoring and evaluation for microvascular and macrovascular
complications, are discussed separately.
(See "Initial management of blood glucose in adults with type 2 diabetes mellitus".)
(See "Management of persistent hyperglycemia in type 2 diabetes mellitus".)
(See "Overview of medical care in adults with diabetes mellitus".)
GENERAL PRINCIPLES
Normal patterns of insulin secretion Insulin is secreted in a pulsatile manner; pulses
occur under basal (unstimulated) conditions and in response to meals [1]. Basal insulin
secretion represents approximately 50 percent of 24-hour insulin production, with the
remainder accounted for by prandial (mealtime) excursions.
The term "intensive insulin therapy" has been used to describe complex regimens that
separate basal insulin delivery (given as one to two daily injections of intermediate- or
long-acting insulin) with superimposed doses of short- or rapid-acting insulins three or
more times daily before meals to limit postprandial glycemic excursions. While intensive
regimens were initially used for patients with type 1 diabetes, they are used for patients
with type 2 diabetes as well.
Insulin preparations In type 2 diabetes, insulin is generally provided in three ways:
As a basal supplement with an intermediate- to long-acting preparation (NPH, neutral
protamine lispro [NPL], glargine, or detemir; the very long-acting degludec has been
approved in Europe, but not the United States) to suppress hepatic glucose production
and maintain near normoglycemia in the fasting state.
As a premeal (prandial) bolus dose of short-acting (regular) or rapid-acting (lispro,
aspart, glulisine) insulin to cover the extra requirements after food is absorbed.
As a premixed combination of intermediate-acting and short-acting or rapid-acting
insulin.
The approximate time of onset, peak activity, and duration of action of the most
commonly used insulins are reviewed in the table (table 1) and in more detail elsewhere.

(See "General principles of insulin therapy in diabetes mellitus", section on 'Insulin

preparations'.)
For many patients with type 2 diabetes, basal insulin alone is often adequate for good
glycemic control, as endogenous insulin secretion will control the postprandial
excursions. Some patients with type 2 diabetes will require additional premeal boluses,
similar to treatment for type 1. For patients with type 2 diabetes who require prandial
insulin, the goal is to adjust the dose of short-acting or rapid-acting insulin immediately
prior to a meal, and therefore we prefer to keep basal and premeal insulin injections
separate and adjust them independently. Patients may draw up their premeal and basal
insulins (except for glargine and detemir, which cannot be mixed with rapid-acting
insulin) in the same syringe prior to injection.
Some insulins are commercially available in a premixed formulation. Most premixed
(biphasic) preparations contain an intermediate-acting insulin and either a short- or a
rapid-acting insulin, and some patients who require premeal insulin in addition to basal
insulin prefer premixed insulins for convenience. Premixed insulin preparations are
sometimes used in type 2 diabetes, but we almost never use them in patients with type 1
diabetes. (See "General principles of insulin therapy in diabetes mellitus", section on
'Premixed insulins'.)
Glycemic targets The importance of glycemic control in minimizing complications
related to diabetes has been well established in type 1 diabetes [2,3]. Similarly, the
United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that strict glycemic
control in patients with type 2 diabetes results in a similar reduction in risk of
microvascular disease as in type 1 diabetes (although the impact on prevention of
macrovascular complications in type 2 diabetes remains uncertain) (figure 1) [4]. Based
upon the results of the UKPDS, glycemic control as close to the normal range as safely
possible, with an A1C level <7 percent for most patients, is now the goal for patients with
type 2 diabetes. However, target glycated hemoglobin (A1C) levels in patients with type
2 diabetes should be tailored to the individual, balancing the improvement in
microvascular complications with the risk of hypoglycemia. The A1C goal should also be
set somewhat higher for older patients and those with a limited life expectancy. (See
"Glycemic control and vascular complications in type 2 diabetes mellitus", section on
'Glycemic targets'.)
Indications for insulin Initial treatment of type 2 diabetes should begin with diet,
weight reduction, and exercise, which may achieve target A1C levels if compliance is
optimal. Metformin therapy (in the absence of contraindications) may be initiated,
concurrent with lifestyle intervention, at the time of diabetes diagnosis. (See "Initial
management of blood glucose in adults with type 2 diabetes mellitus", section on
'Medications for initial therapy'.)
Oral agents become less effective as beta cell function declines (figure 2). The
therapeutic options for patients who fail initial therapy with lifestyle intervention and
metformin are to add a second oral or injectable agent, including insulin, or to switch to
insulin. There is no consensus on which option is most effective. However, insulin is the
preferred second-line medication for patients with A1C >8.5 percent or with symptoms of
hyperglycemia despite metformin titration. Patients should be made aware that initiating
insulin does not represent a personal "failure" and that most patients with type 2
diabetes will eventually require exogenous insulin, due to decline in endogenous insulin
production. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus",
section on 'Treatment options'.)
Insulin, rather than oral hypoglycemic agents, may be indicated for initial treatment for
some patients with type 2 diabetes, depending on the severity of the baseline metabolic
disturbance. Insulin should be particularly considered for patients presenting with A1C
>10 percent, fasting plasma glucose >250 mg/dL (13.9 mmol/L), random glucose

consistently >300 mg/dL (16.7 mmol/L), ketonuria, or with unplanned weight loss in
association with hyperglycemia. (See 'Insulin as initial therapy' below.)
In patients in whom it is difficult to distinguish type 1 from type 2 diabetes (patients who
are underweight, are losing weight, or are ketotic), initial treatment with insulin is
required. (See 'Adult-onset type 1 diabetes' below.)
Insulin therapy in pregnant women with diabetes is reviewed separately. (See
"Pregestational diabetes mellitus: Prenatal glycemic control", section on 'Insulin' and
"Gestational diabetes mellitus: Glycemic control and maternal prognosis", section on
'Insulin'.)
Disadvantages The major drawbacks associated with insulin therapy in type 2 diabetes
are weight gain and hypoglycemia. Weight gain is a particular problem as A1C levels are
lowered from >9 to 7 percent with more intensive insulin regimens, and may result in
noncompliance with insulin. The magnitude of the weight gain depends upon the
intensity of regimen (dose and frequency of insulin) [5]. However, it is uncertain if the
means of lowering the A1C (type of insulin) promotes weight gain independent of the
lowering of the A1C.
In the UKPDS, the average weight gain after 10 years of insulin therapy was about 7 kg
for patients with type 2 diabetes, with the most rapid weight gain occurring when insulin
was first initiated [4]. Less intensive therapy with either insulin or a sulfonylurea (which
increases endogenous insulin secretion) was associated with a 3.5 to 4.8 kg weight gain
at three years versus no change with metformin monotherapy [6]. In a subsequent trial,
weight gain was greater with prandial than basal insulin (4.8 versus 3.1 kg) [7]; however,
patients receiving prandial insulin also received a greater insulin dose, which could
account for the small difference in weight gain. In other trials, premixed rapid-acting
preparations were more often associated with weight gain than long-acting insulin or oral
agents [8].
It is not clear if the weight gain is clinically important, as microvascular complications
were reduced with insulin monotherapy in the UKPDS despite weight gain [4].
Nevertheless, patients initiating insulin therapy should be aware of the potential for
weight gain, and major emphasis should be placed on lifestyle modification to prevent it.
(See "Initial management of blood glucose in adults with type 2 diabetes mellitus",
section on 'Nonpharmacologic therapy'.)
An increased risk of hypoglycemia is a potential complication of insulin therapy. However,
patients with type 2 diabetes experience less hypoglycemia than patients with type 1 [9].
Basal insulin is associated with less hypoglycemia than prandial insulin (see 'Basal versus
prandial' below). Among basal insulin preparations, insulin glargine and detemir may
have some relatively modest clinical advantages over NPH (less symptomatic and
nocturnal hypoglycemia) with the important disadvantage of high cost (see 'Basal insulin'
below). The management of hypoglycemia in patients with diabetes is reviewed in more
detail separately. (See "Management of hypoglycemia during treatment of diabetes
mellitus".)
The safety of human insulin versus insulin analogs, including concerns about diabetic
complications and risk of cancer, is reviewed in detail elsewhere. (See "General principles
of insulin therapy in diabetes mellitus", section on 'Safety'.)
DESIGNING AN INSULIN REGIMEN The glycemic differences achieved among different
insulin regimens, assuming that they are adequately titrated, are modest. The majority of
the studies provide information on lowering of glycemia but do not provide information
regarding the effects of various insulin regimens on microvascular or macrovascular
complications or mortality. When differences in glycated hemoglobin (A1C) levels have
been found, they are often offset by adverse events (hypoglycemia, weight gain). We

advise clinicians to familiarize themselves with a limited number of regimens (to facilitate
addressing patient preferences, lifestyle [meal and activity patterns], etc) and use them
consistently.
Patients with persistent hyperglycemia despite oral hypoglycemic therapy may add
insulin to oral medication or may stop the oral drug(s) and begin insulin. The rationale for
combination oral hypoglycemic drug and insulin therapy is that, by suppressing hepatic
glucose production, the patient can retain the convenience of oral agents while
minimizing total insulin requirements and weight gain [10]. Metformin is often continued
with the addition of a second agent, including insulin. Other agents including
sulfonylureas, thiazolidinediones, glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl
peptidase 4 (DPP-4) inhibitors, and sodium-glucose co-transporter 2 (SGLT2) inhibitors
can also be continued when insulin is added, although the putative advantages of doing
so may not merit the increased cost. Sulfonylureas are usually tapered and stopped,
especially when preprandial insulin is started. (See "Management of persistent
hyperglycemia in type 2 diabetes mellitus", section on 'Combination oral and insulin
therapy'.)
For patients who are initiating insulin (in addition to oral agents, in place of oral agents,
or as initial treatment), we suggest initiating basal rather than prandial insulin (algorithm
1). Either insulin NPH or detemir given at bedtime, or insulin glargine given in the
morning or at bedtime, is a reasonable initial regimen. Subsequent modifications can be
made according to fasting blood glucose and A1C values. Although basal and prandial
insulin are similarly effective in improving A1C, basal insulin is associated with greater
patient satisfaction and less hypoglycemia [11,12]. Initiation of insulin therapy with a
basal insulin has the advantage of convenience and simplicity in patients who are using
insulin for the first time. (See 'Glycemic efficacy' below.)
For patients with persistently elevated A1C levels who have fasting blood glucose levels
is in the target range (70 to 130 mg/dL [3.9 to 7.2 mmol/L]), we advise the patient to
check fingerstick capillary glucose levels fasting, pre-lunch, pre-dinner, and before bed
while the insulin regimen is further adjusted. If pre-dinner glucose values are elevated,
options include adding a breakfast dose of NPH or prandial insulin at lunchtime. If blood
glucose values are elevated before lunch and/or bed, we typically add prandial insulin
(algorithm 1). For patients with type 2 diabetes who require prandial insulin, either short(regular) or rapid-acting insulin can be given. In this setting, oral agents other than
metformin are discontinued (in the absence of contraindications or intolerance,
metformin can be continued). The choice of prandial insulin is based upon availability,
patient preference, and cost. Most patients prefer rapid-acting insulin because of the
ability to inject the rapid-acting insulins immediately before meals, as opposed to the 30
to 45 minutes before the meal recommended for short-acting insulins.
For patients who require prandial insulin, we prefer to keep basal and prandial insulin
injections separate and adjust them independently. From a practical point of view,
adherence may be better for some patients using premixed insulins even though
flexibility in adjusting doses is limited. (See 'Basal and/or prandial versus premixed'
below and "General principles of insulin therapy in diabetes mellitus", section on
'Premixed insulins'.)
COMBINATION ORAL AGENT AND INSULIN THERAPY When insulin is combined with oral
agents, a basal (long- or intermediate-acting) rather than a short-acting premeal
(prandial) insulin is a reasonable first choice. There is some debate as to which insulin
regimen is more effective in improving glucose control and diabetes outcomes. The
addition of basal insulin will improve nocturnal and fasting blood sugar, whereas prandial
(premeal) bolus insulin will decrease postprandial glucose excursions. A number of
randomized trials have evaluated different insulin regimens in patients with type 2
diabetes, almost all of whom were also treated with oral agents. These trials primarily

used glycemic control as the endpoint, and many studies have shown that glycemia
improves with insulin combination therapy. (See 'Glycemic efficacy' below.)
Data are more limited on cardiovascular outcomes. Whether a basal or a prandial
(premeal) bolus strategy is more effective in improving important diabetes endpoints
(microvascular and macrovascular complications) remains uncertain. In the absence of
such data, we prefer initiating basal insulin, rather than prandial insulin, in patients who
are poorly controlled on oral agents (algorithm 1). (See 'Cardiovascular effects' below.)
Glycemic efficacy
Basal versus prandial Both basal and prandial (premeal) regimens are similarly
effective in reducing glycated hemoglobin (A1C) concentrations when insulin doses are
aggressively titrated to achieve glycemic goals. This was illustrated by a randomized trial
of once-daily insulin glargine versus prandial insulin lispro in 415 patients who were
inadequately controlled with metformin and a sulfonylurea [11]. There were similar
improvements in A1C (mean decrease of 1.7 and 1.9 percent, respectively) and target
A1C concentrations between 6.5 and 7.0 percent were achieved by 27 and 30 percent of
subjects, respectively. Basal insulin was associated with greater patient satisfaction and
less hypoglycemia.
Similar findings were noted in the HEART2D (Hyperglycemia and its Effect After Acute
Myocardial Infarction on Cardiovascular Outcomes in Patients with Type 2 Diabetes
Mellitus) trial, which was designed to evaluate the effects of prandial (lispro) or basal
(NPH twice daily or insulin glargine once daily) insulin on cardiovascular outcomes in
1115 patients after myocardial infarction (MI) [7]. At baseline, 50 percent of the patients
were taking metformin, sulfonylureas, or both, whereas the remaining patients were
treated with insulin monotherapy. At a mean follow-up of 2.7 years, the trial was stopped
early due to lack of efficacy. There was no difference between the prandial and basal
groups in A1C (7.7 versus 7.8 percent). The cardiovascular outcomes are reviewed below.
(See 'Cardiovascular effects' below.)
Basal and/or prandial versus premixed Premixed insulin regimens with fixed
combinations of short- or rapid-acting insulin with long- or intermediate-acting insulin
claim to provide two peaks of insulin activity from just one injection, although in practice
the peaks from the rapid- and intermediate-acting insulins tend to merge together and
form a single peak of insulin action. (See 'Insulin preparations' above.)
Premixed rapid-acting preparations offer little glycemic advantage compared with
adequately titrated basal and bolus insulin. In a meta-analysis of trials comparing
premixed rapid-acting insulin preparations with other treatments (premixed regular/NPH
insulin, long-acting insulin, and non-insulin agents), premixed rapid-acting preparations
were more effective in reducing A1C levels than long-acting insulin and oral agents
(pooled differences of -0.4 and -0.5 percent, respectively) [8]. However, in many of the
trials included in the meta-analysis, the dose of insulin or oral agent in the control group
was not aggressively titrated to achieve optimal glycemic control. Compared with other
insulin therapy (long-acting or regular/NPH mix), premixed rapid-acting insulin
preparations were more effective in reducing postprandial blood glucose levels but less
effective in reducing fasting blood glucose (FBG). Premixed rapid-acting preparations
were more often associated with minor hypoglycemia and weight gain than long-acting
insulin or oral agents.
In a subsequent trial of longer duration than the trials in the meta-analysis, 708 patients
with type 2 diabetes who were suboptimally controlled with metformin and a sulfonylurea
were randomly assigned to premixed biphasic insulin aspart (twice daily), prandial insulin
aspart (three times daily), or basal insulin detemir (once or twice daily) [12]. After three
years, there was no difference in median A1C levels among the three groups (7.1, 6.8,
and 6.9 percent, respectively), but significantly more patients in the basal and prandial

groups achieved an A1C level of 6.5 percent than in the biphasic premixed group (43,
45, and 32 percent, respectively). The majority of all three treatment groups used a
second type of insulin, per protocol, during the trial to obtain the stipulated glycemic
goals. Patients in the basal group had the fewest episodes of hypoglycemia.
Cardiovascular effects Combination oral agent and glargine therapy does not appear
to reduce or increase cardiovascular outcomes compared with oral agent(s) only, as
illustrated by the findings of the Outcome Reduction with Initial Glargine Intervention
(ORIGIN) trial [13]. In this trial, over 12,500 patients with cardiovascular risk factors plus
type 2 diabetes or prediabetes were randomly assigned to an evening dose of glargine or
to standard care. Approximately 60 percent of the patients with prior diabetes were using
oral glucose-lowering agents (predominantly metformin or sulfonylurea). The glargine
was titrated to achieve a fasting glucose level of <95 mg/dL (5.3 mmol/L). After a median
follow-up of six years, the achieved median FBG levels were 94 and 123 ng/dL (5.2 and
6.8 mmol/L), respectively. The rates of incident cardiovascular outcomes were similar in
the glargine and standard care groups (2.94 and 2.85 per 100 person-years). Only 11
percent of the patients in the standard therapy group received insulin. A1C values were
similar at baseline (6.4) and at study end (6.2 and 6.5). Approximately 60 percent of
patients in both groups were treated with statins and 75 percent with angiotensinconverting enzyme inhibitors or angiotensin II receptor blockers.
In contrast to the findings in the ORIGIN trial, a retrospective cohort study of United
States veterans taking metformin showed that the addition of insulin versus sulfonylurea
was associated with an increased risk of a composite outcome of nonfatal cardiovascular
outcomes and all-cause mortality [14]. Of the two outcomes included in the composite,
only the rate of all-cause mortality was significantly increased (33.7 versus 22.7 events
per 1000 person-years). MI and stroke rates were similar (10.2 and 11.9 events per 1000
person-years). The main limitation of this non-randomized retrospective study is the
inadequate control for unmeasured confounders, including bias by indication, that could
be responsible for the findings. In comparison to the number of metformin and
sulfonylurea users (39,990), there were very few metformin and insulin users (2948). The
patients receiving insulin had higher A1C levels and more comorbidities. Thus, those
treated with insulin were sicker and may have had greater insulin resistance and/or other
factors to explain the higher rate of mortality.
The type of insulin (basal or prandial) does not appear to affect cardiovascular outcomes,
as illustrated by the findings of the HEART2D trial, which was designed to evaluate the
effects of prandial (lispro) or basal (NPH twice daily or insulin glargine once daily) insulin
on cardiovascular outcomes in 1115 patients after MI [7]. At baseline, 50 percent of the
patients were taking metformin, sulfonylureas, or both, whereas the remaining patients
were treated with insulin monotherapy. At a mean follow-up of 2.7 years, the trial was
stopped early due to lack of efficacy. There was no difference between the prandial and
basal groups in the time to a subsequent cardiovascular event (cardiovascular death,
nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for an acute
coronary syndrome).
Choice of insulin
Basal insulin If once-daily insulin is added to oral hypoglycemic therapy in patients
with type 2 diabetes, a single daily dose of either insulin NPH or detemir given at
bedtime or insulin glargine given in the morning or at bedtime is a reasonable initial
regimen. If nocturnal hypoglycemia or symptomatic hypoglycemia occurs in patients
taking bedtime NPH, we adjust the dose or switch to insulin glargine.
Available basal insulin preparations include intermediate-acting agents NPH and neutral
protamine lispro (NPL, also called insulin lispro protamine suspension [ILPS]); long-acting
agents glargine and detemir; and the very long-acting degludec, which has been

approved in Europe, but not the United States (table 1). (See "General principles of
insulin therapy in diabetes mellitus", section on 'Insulin preparations'.)
Insulin detemirs duration of action appears to be substantially shorter than that of
insulin glargine and often results in the need to administer detemir twice per day (table
1). As an example, in a 52-week study of supplementation of oral therapy with insulin
glargine or detemir, there were similar improvements in glycemic control (mean A1C 7.1
and 7.2 percent, respectively), but over half of the participants (55 percent) required
twice-daily dosing with detemir, as opposed to once-daily dosing with glargine [15].
Meta-analyses of trials in patients with type 2 diabetes comparing once-daily insulin
glargine or detemir to once- or twice-daily NPH insulin report similar glycemic control
between groups [16-19]. However, the rates of symptomatic overall and nocturnal
hypoglycemia, while relatively infrequent with either basal insulin, were lower in patients
treated with either insulin glargine or detemir compared with NPH [16-19]. Thus, while
intermediate-acting NPH insulin has been used commonly at bedtime to supplement oral
hypoglycemic drug therapy, longer-acting insulins, such as insulin glargine (once daily)
and detemir (once or twice daily), added to oral agents are equally effective for reducing
A1C values and may cause less nocturnal hypoglycemia, albeit at greater cost [20-29].
In a meta-analysis of four trials comparing NPL with insulin glargine or determir, there
were similar improvements in A1C with all three types of basal insulin. Although there
was no difference in overall hypoglycemia, nocturnal hypoglycemia occurred significantly
more with NPL than with glargine and detemir [30]. The total frequency of hypoglycemia
was the same with NPL and glargine regimens, so while nocturnal hypoglycemia may be
less with glargine, daytime hypoglycemia increases.
Another longer-acting basal insulin, insulin degludec, is available in some countries. It is
not available in the United States, owing to concern regarding a potential increase in
cardiovascular risk [31]. It appears to have similar glycemic efficacy as that of insulin
glargine, as illustrated by the findings of a one-year, open-label, non-inferiority trial
comparing insulin glargine with insulin degludec (both administered once daily) in 1030
patients with type 2 diabetes treated with metformin [32]. The reduction in A1C (1.19
versus 1.06 percent) and rates of overall confirmed hypoglycemic episodes were similar
in the two groups. The rate of nocturnal hypoglycemic episodes was significantly lower
with insulin degludec (0.25 versus 0.39). However, the overall rate of nocturnal
hypoglycemia was low in both groups, and the difference is of uncertain clinical
significance. The long-term safety profile of insulin degludec is unknown [31].
Prandial insulin For patients who are initiating insulin (in addition to oral agents, in
place of oral agents, or as initial treatment), we suggest initiating basal, rather than
prandial, insulin (algorithm 1). However, if the addition of prandial insulin to oral agents
is preferred, either short- (regular) or rapid-acting insulin can be given premeal. The
newer rapid-acting insulins may have a minor glycemic advantage over regular insulin in
patients with type 1 diabetes, but they do not have a clinically significant advantage in
patients with type 2 diabetes [33,34]. This was illustrated in a meta-analysis of five
randomized, controlled trials (involving 2028 patients with type 2 diabetes) that
compared rapid-acting insulin analogues to regular insulin as premeal bolus doses [33].
No significant differences were seen in serum A1C concentrations or the number of
hypoglycemic episodes. However, the ability to inject the rapid-acting insulins
immediately before meals, as opposed to the 30 to 45 minutes before the meal
recommended for short-acting insulins, may provide improved convenience for patients.
(See "Insulin therapy in adults with type 1 diabetes mellitus", section on 'Rapid-acting
insulin'.)
There are also several trials in patients with type 2 diabetes comparing inhaled insulin to
subcutaneous rapid-acting insulin, which report similar improvements in A1C in the
inhaled and subcutaneous insulin groups [35]. However, in these studies, neither the

inhaled insulin nor the control arms achieved optimal glycemic efficacy that has been
achieved with injection regimens in previous trials with insulin. An inhaled form of rapidacting insulin was available for a short time before it was discontinued by the
manufacturer in 2007, as the new technology failed to gain acceptance by patients or
clinicians. In 2014, another formulation of inhaled insulin (Afrezza) received approval by
the US Food and Drug Administration (FDA) and is expected to become available for
clinical use in early 2015. (See "Inhaled insulin therapy in diabetes mellitus".)
SWITCHING TO INSULIN MONOTHERAPY Patients with persistent hyperglycemia despite
oral hypoglycemic therapy may stop the oral drug and begin insulin monotherapy. When
switching to insulin monotherapy, it is reasonable to begin with a similar regimen
consisting of basal insulin (NPH, detemir, or glargine insulin) given once or twice daily.
This approach is cheaper than combined oral agent-insulin therapy (although generic
metformin is relatively inexpensive) but results in more weight gain and more episodes of
hypoglycemia, few of which are severe [10]. The oral agent can be discontinued when
insulin is initially added or after the patient is on adequate basal insulin. The former
approach may be associated with elevations in glucose levels until the dose of injected
insulin is sufficient to achieve metabolic control. (See "Interactive diabetes case 2:
Switching from oral agents to insulin in type 2 diabetes".)
INSULIN AS INITIAL THERAPY Insulin, rather than oral hypoglycemic agents, may be
indicated for initial treatment for some patients with type 2 diabetes, depending on the
severity of the baseline metabolic disturbance. Insulin should be particularly considered
for patients presenting with glycated hemoglobin (A1C) >10 percent, fasting plasma
glucose >250 mg/dL (13.9 mmol/L), random glucose consistently >300 mg/dL (16.7
mmol/L), ketonuria, or with unplanned weight loss in association with hyperglycemia
[36,37]. In addition, a brief period (two to four weeks) of intensive insulin treatment at
the onset of type 2 diabetes may be beneficial, although this approach is not widely used
[38-40]. By inducing near normoglycemia with intensive insulin therapy, both
endogenous insulin secretion and insulin sensitivity improve [38,40,41]. The
improvement in insulin secretion is presumably due to the elimination of the deleterious
effects of hyperglycemia on beta cell secretory function, and in some patients, it results
in better glycemic control that can then be maintained with diet and exercise for many
months or even years thereafter [40].
This was illustrated in a randomized trial of short-term (two to five weeks) intensive
insulin therapy versus oral agents (gliclazide and/or metformin) in 410 Chinese patients
with newly diagnosed type 2 diabetes (mean fasting glucose 202 mg/dL [11.2 mmol/L])
[42]. Insulin and oral agents were titrated to achieve a fasting glucose of <110 mg/dL
(6.1 mmol/L). Therapy was discontinued two weeks after meeting goal glucose. The
patients were instructed to continue diet and exercise only and were closely followed for
recurrence of hyperglycemia (fasting glucose >126 mg/dL [7.0 mmol/L] or postprandial
glucose >180 mg/dL [10.0 mmol/L]). Patients who failed to achieve the glycemic target
within two weeks (n = 23) or could not tolerate oral agents (n = 7) were excluded from
the efficacy analysis.
A greater proportion of patients receiving insulin achieved glycemic goals in less time
than those assigned to oral agents (over 90 percent within 4.0 to 5.6 days versus 84
percent in 9.3 days). Remission rates after one year were higher in the insulin groups
(insulin pump or multiple daily injections) than in the oral hypoglycemic group (51 and 45
versus 27 percent). Patients in remission had lower initial fasting glucose and A1C, and
they achieved glycemic goals more quickly than those with recurrent hyperglycemia.
Thus, insulin can be considered as initial therapy for all patients with type 2 diabetes and
can result in remission for one year or longer.
Adult-onset type 1 diabetes In patients in whom it is difficult to distinguish type 1 from
type 2 diabetes (patients who are underweight, are losing weight, or are ketotic), initial
treatment with insulin is required.

A potential problem is that patients who are initially thought to have type 2 diabetes may
actually have type 1 diabetes and therefore require insulin as initial therapy. Although the
peak incidence of type 1 diabetes occurs around the time of puberty, approximately 25
percent of cases present after 35 years of age [43]. There are certain clinical features
that, if present at any age, suggest the diagnosis of type 1 diabetes. These include
marked and otherwise unexplained recent weight loss (irrespective of the initial weight),
a short history with severe symptoms, and the presence of moderate to heavy ketonuria.
Diabetic ketoacidosis at first presentation suggests that the patient has type 1 diabetes
and will require lifelong insulin treatment, although there are exceptions to this general
rule [44]. (See "Classification of diabetes mellitus and genetic diabetic syndromes".)
Some individuals with adult-onset type 1 diabetes may slowly progress to insulin
dependence and at presentation may be indistinguishable from a patient with type 2
diabetes. This is sometimes referred to as "latent autoimmune diabetes in adults" (LADA)
(see "Classification of diabetes mellitus and genetic diabetic syndromes", section on
'Distinguishing type 1 from type 2 diabetes'). LADA can be distinguished from type 2
diabetes by the presence of pancreatic autoantibodies, such as glutamic acid
decarboxylase antibodies. These individuals are likely to respond poorly to oral
hypoglycemic drug therapy, and the use of sulfonylureas as initial therapy may cause
earlier insulin dependence [45,46]. The best initial treatment strategy for LADA is
unclear. Studies are required to determine whether early treatment with insulin or use of
immunomodulator therapy may prevent disease progression.
DOSING
Initial dose For patients with type 2 diabetes, the initial dose of insulin (whether in
addition to oral agents, in place of oral agents, or as initial treatment) is similar
(algorithm 1) [25,47,48]. We start with bedtime NPH or detemir, taken at 10:00 PM if the
person is testing his or her fasting blood glucose (FBG) at 7:00 AM or 8:00 AM, or
bedtime or morning glargine. The initial dose is 0.2 units per kg (minimum 10 units) daily.
FBG should be measured every day. An increase of 2 to 4 units in the bedtime insulin
dose should be made periodically (approximately every three days) if the mean FBG is
above 130 mg/dL (7.2 mmol/L) during this time (algorithm 1) [47]. In this way, the
bedtime insulin dose can be titrated over a period of several weeks or months.
If fasting glucose levels are very elevated (>250 mg/dL [13.9 mmol/L]), or if a patient is
known to be very insulin resistant, initial doses can be higher and titration more
aggressive.
Optimal timing For patients with type 2 diabetes on combination therapy (oral
hypoglycemics and once-daily insulin), the optimal timing is once-daily NPH or detemir at
bedtime or once-daily insulin glargine in the morning or bedtime [49,50]. The timing of
daily insulin glargine is based on patient preference and when the patient is less likely to
miss a dose.
A morning rather than a bedtime dose of insulin glargine may provide better glycemic
control in patients with type 2 diabetes who are also treated with a sulfonylurea. This
issue was addressed in a randomized, controlled trial of 695 patients with type 2 diabetes
who were treated with glimepiride [26]. The following findings were noted:
Glimepiride given with a morning dose of insulin glargine lowered glycated hemoglobin
(A1C) significantly more than a bedtime dose of NPH (-1.24 versus -0.84 percentage
points, difference of 0.40 percent) or a bedtime dose of insulin glargine (-1.24 versus
-0.96 percentage points, difference of 0.28 percent).
Nocturnal hypoglycemia was less frequent with morning and bedtime insulin glargine
than with bedtime NPH.

The frequency of severe hypoglycemia (needing assistance) was very low (<3 percent)
with all three regimens and was not significantly different for NPH, morning, or bedtime
glargine.
Persistent hyperglycemia Among patients who are taking insulin and have A1C values
above the desired target, diet and exercise patterns should first be reviewed. We advise
the patient to check fingerstick capillary glucose levels fasting, pre-lunch, pre-dinner, and
before bed while the regimen is being adjusted. Insulin doses should then be adjusted to
achieve target levels of glycemia. Patients should reduce their insulin dose if
hypoglycemia develops. (See "Blood glucose self-monitoring in management of adults
with diabetes mellitus".)
In general, dietary indiscretion and/or inadequate doses of insulin underlie the apparent
failure of many patients treated with insulin regimens. Daily insulin doses typically
exceed 65 to 100 units per day, and may sometimes be much higher, before obese type
2 diabetic patients can achieve near-normal glycemia.
Twice-daily regimens If the goal is control of persistent hyperglycemia with a regimen
that is simple and inexpensive, then twice-daily NPH insulin will be effective in many
patients [25,51]. The addition of a second dose of NPH at breakfast may be particularly
helpful when pre-dinner blood glucoses are above goal. When the insulin preparation is
detemir, serum insulin concentrations over a 24-hour period may also be more stable in
patients taking two doses daily [15]. (See 'Basal insulin' above.)
Basal bolus regimens For patients with type 2 diabetes, basal insulin alone is often
adequate for good glycemic control, but for others, prandial (premeal or preprandial)
boluses are necessary, as they are in type 1 diabetes. (See "Insulin therapy in adults with
type 1 diabetes mellitus", section on 'Rapid-acting insulin'.)
For patients with type 2 diabetes who require prandial insulin (typically, patients with
pre-lunch and/or pre-bedtime blood glucoses above goal), either short- (regular) or rapidacting insulin can be given. The choice of prandial insulin is based upon availability,
patient preference, and cost. Most patients prefer rapid-acting insulin because of the
ability to inject the rapid-acting insulins immediately before meals, as opposed to the 30
to 45 minutes before the meal recommended for short-acting insulins. (See 'Prandial
insulin' above.)
If premeal bolus insulin needs to be added, the optimal dose depends upon many factors,
including current and target blood glucose values, carbohydrate content of the meal, and
activity. A typical starting dose is approximately 4 to 6 units (algorithm 1). The dose can
be increased by 2 to 3 units every three days until the postprandial blood glucose target
is achieved.
A more complex method for adjusting premeal insulin is to match insulin delivery to the
anticipated glucose excursion with meals. With this approach (called carbohydrate
counting), insulin-to-carbohydrate ratios are determined based upon an individual's usual
insulin requirements and carbohydrate intake. A dose is then calculated that will control
postprandial blood glucose excursions. Insulin-to-carbohydrate ratios can vary with the
time of day, and are affected by stress, illness, and variations in physical activity. These
issues are discussed in detail elsewhere. (See "Nutritional considerations in type 1
diabetes mellitus", section on 'Advanced carbohydrate counting'.)
Most patients require specific training in carbohydrate counting, which requires some
arithmetical computations that some patients find difficult or burdensome. Furthermore,
it is uncertain if there is a glycemic advantage to carbohydrate counting in patients with
type 2 diabetes. As an example, in a 24-week randomized trial in 277 adults with type 2
diabetes, there was no difference in A1C values when mealtime insulin adjustments were
based upon a simple algorithm (according to previous weeks blood glucose monitoring

results) or carbohydrate counting, using an insulin-to-carbohydrate ratio for each meal

[52]. Thus, either method is acceptable, and patient preference can guide the choice of
method for premeal dosing.
Intensive insulin regimens If intensive insulin therapy is chosen in a patient with type 2
diabetes, the pretreatment considerations, choice of regimen, and management issues
are similar to those for patients with type 1 diabetes. Insulin pump therapy is used
infrequently in patients with type 2 diabetes, but it may have a role in a select group of
patients with poorly controlled type 2 diabetes taking multiple daily injections [53].
Intensive insulin therapy is reviewed in detail elsewhere. (See "Insulin therapy in adults
with type 1 diabetes mellitus".)
Use of an intensive insulin regimen (similar to that used in type 1 diabetes) results in
higher serum insulin concentrations and better glycemic control than that achieved with
either an oral drug or conventional insulin therapy alone [6]. A potential problem is the
weight gain (averaging 8.7 kg in one study) that can occur with intensive regimens that
achieve near normal glycemia [54]. This weight gain may in some instances result in
partial noncompliance with therapy, particularly in women. (See 'Disadvantages' above
and "Nutritional considerations in type 2 diabetes mellitus".)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials,
The Basics and Beyond the Basics. The Basics patient education pieces are written in
plain language, at the 5th to 6th grade reading level, and they answer the four or five key
questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10 th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you
to print or e-mail these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on patient info and the keyword(s) of
interest.)
Basics topics (see "Patient information: Using insulin (The Basics)")
Beyond the Basics topics (see "Patient information: Diabetes mellitus type 2: Insulin
treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Initial therapy in most patients with type 2 diabetes should begin with diet, weight
reduction, exercise, and metformin therapy (in the absence of contraindications), which
may induce normoglycemia if compliance is optimal. After a successful initial response to
oral therapy, most patients fail over time (figure 2) and require additional therapy (add a
second oral or injectable agent, including insulin, or switch to insulin). (See "Initial
management of blood glucose in adults with type 2 diabetes mellitus" and "Management
of persistent hyperglycemia in type 2 diabetes mellitus".)
For patients with inadequate glycemic control on metformin and a glycated hemoglobin
(A1C) >8.5 percent, we suggest adding insulin (Grade 2B). Patients may add insulin to
oral medication or may stop the oral drug(s) and begin insulin. (See 'Indications for
insulin' above and "Management of persistent hyperglycemia in type 2 diabetes
mellitus", section on 'Treatment options'.)
Insulin can also be considered initial therapy for all patients with type 2 diabetes,
particularly patients presenting with A1C >10 percent, fasting plasma glucose >250

mg/dL (13.9 mmol/L), random glucose consistently >300 mg/dL (16.7 mmol/L), or
ketonuria. (See 'Indications for insulin' above and 'Insulin as initial therapy' above.)
A potential problem is that patients who are initially thought to have type 2 diabetes may
actually have type 1 diabetes and therefore require insulin as initial therapy. In patients
in whom it is difficult to distinguish type 1 from type 2 diabetes (patients who are
underweight, are losing weight, or are ketotic), initial treatment with insulin is required.
(See 'Adult-onset type 1 diabetes' above.)
The glycemic differences achieved among different insulin regimens, assuming that
they are adequately titrated, are modest. Most of the studies provide information on
lowering of glycemia but do not provide information regarding the effects of various
insulin regimens on microvascular or macrovascular complications or mortality. We
advise clinicians to familiarize themselves with a limited number of regimens (to facilitate
addressing patient preferences, lifestyle [meal and activity patterns], etc) and use them
consistently.
For patients who are initiating insulin (in addition to oral agents, in place of oral agents,
or as initial treatment), we suggest initiating basal, rather than prandial, insulin (Grade
2B). This is predominantly due to greater patient satisfaction and less hypoglycemia. In
addition, basal insulin has the advantage of convenience and simplicity for patients who
are using insulin for the first time (algorithm 1). (See 'Designing an insulin regimen'
above and 'Basal versus prandial' above.)
Either insulin NPH or detemir given at bedtime or insulin glargine given in the morning or
at bedtime is a reasonable initial regimen. (See 'Designing an insulin regimen' above and
'Basal insulin' above.)
The initial dose is 0.2 units per kg (minimum 10 units) daily. Subsequent modifications
can be made according to fasting blood glucose and A1C values, until the fasting blood
glucose is in the target range (70 to 130 mg/dL [3.9 to 7.2 mmol/L]) (algorithm 1). (See
'Initial dose' above and 'Designing an insulin regimen' above.)
Among patients who are taking insulin and have A1C values above the desired target
but fasting blood glucose in target range, diet and exercise patterns should be reviewed.
We advise the patient to check fingerstick capillary glucose levels fasting, pre-lunch, predinner, and before bed while the regimen is being adjusted. Insulin doses should then be
adjusted to achieve target levels of glycemia (algorithm 1). (See 'Designing an insulin
regimen' above and 'Persistent hyperglycemia' above.)
For patients with type 2 diabetes who require prandial insulin, either short- (regular) or
rapid-acting insulin can be given. In this setting, oral agents other than metformin are
discontinued. The ability to inject the rapid-acting insulins immediately before meals, as
opposed to the 30 to 45 minutes before the meal recommended for short-acting insulins,
may provide improved convenience for patients. (See 'Designing an insulin regimen'
above and 'Prandial insulin' above and 'Basal bolus regimens' above.)
For patients with type 2 diabetes who require prandial insulin, we suggest not using
premixed insulin initially (Grade 2B). The goal is to adjust the dose of short-acting or
rapid-acting insulin immediately prior to a meal and therefore, we prefer to keep basal
and premeal insulin injections separate and adjust them independently. However,
premixed insulin is a reasonable option for patients with type 2 diabetes who are doing
well on a stable, fixed ratio. (See 'Basal and/or prandial versus premixed' above and
"General principles of insulin therapy in diabetes mellitus", section on 'Premixed
insulins'.)
More complex insulin regimens can be used in patients with type 2 diabetes in an
attempt to achieve near normoglycemia by adding short- or rapid-acting insulin before

meals. The principles of intensive insulin regimens are the same for type 1 and type 2
diabetics and are discussed separately. (See "Insulin therapy in adults with type 1
diabetes mellitus".)