MINI REVIEW

Insulin therapy for type 2 diabetes

Luigi F. Meneghini

Received: 9 April 2012 / Accepted: 8 October 2012 / Published online: 27 October 2012

� Springer Science+Business Media New York 2012

Abstract Insulin therapy provides effective glycemic

control in patients with diabetes who have deficient beta-

cell function and insulin secretion. Subjects with type

2 diabetes not adequately controlled on oral agents or

incretin therapies can initiate basal insulin replacement to

correct fasting hyperglycemia. While all basal insulin

preparations have similar efficacy in lowering fasting

plasma glucose and improving A1C, the newer basal

insulin analogs are associated with a lower risk of hypo-

glycemia than NPH insulin. Patients whose A1C levels

remain above goal despite adequate basal insulin replace-

ment need to evaluate and correct post-prandial hypergly-

cemia. With progressive beta-cell deficiency, rapid-acting

insulin preparations can be introduced before one or more

meals and titrated to achieve post-prandial glycemic con-

trol. For many patients requiring full basal/bolus insulin

replacement, a strategy of fixed prandial insulin doses can

yield acceptable glycemic control when compared to a

more sophisticated approach utilizing carbohydrate count-

ing and matching to insulin. Concentrated insulin prepa-

rations such as U-500 have also been of value in patients

with resistant type 2 diabetes. Regardless of the type of

insulin replacement used, the blood glucose lowering

effects of insulin need to be carefully balanced with the

increasing risk of hypoglycemia, and the weight gain

associated with insulin intensification.

Keywords Basal insulin � Oral antidiabetic agents �Basal/bolus therapy � Type 2 diabetes

Introduction

At diagnosis of type 2 diabetes beta-cell function and mass

are already substantially reduced [1]. Over time progres-

sive loss of beta-cell function requires the introduction of

exogenous insulin, as oral agent drugs (OADs) fail to

maintain adequate glycemic control. Insulin is usually

added to ongoing OAD treatment, with subsequent

adjustments to both insulin therapy and OADs to optimize

glycemic control while mitigating treatment side effects,

such as hypoglycemia, weight gain, and fluid retention [2].

While basal insulin is often favored when initiating insulin

therapy due to its simplicity and relative low risk profile,

many patients with type 2 diabetes will eventually require

the addition of prandial insulin to achieve appropriate

glycemic targets [3]. Patients who experience frequent

episodes of hypoglycemia, or develop hypoglycemia

unawareness and severe hypoglycemia as a result of

aggressive insulin treatment, will need adjustment of their

glycemic targets, as well as modification of insulin therapy

[4]. This article will briefly review the evidence-based tools

and strategies available for the management of the insulin-

deficient patient with type 2 diabetes.

Insulin preparations

Insulin preparations can be categorized as basal, prandial,

and premix insulin types, as well as human and analog

preparations. While in human preparations the amino acid

sequence is identical to physiologically secreted insulin,

insulin analogs on the other hands are peptides that have

undergone amino acid alterations to enhance specific

pharmacokinetic (PK) and pharmacodynamic (PD) prop-

erties of the insulin preparation [5, 6]. Basal insulin

L. F. Meneghini (&)

University of Miami Miller School of Medicine,

1450 NW 10th Ave, Miami, FL 33136, USA

e-mail: lmeneghi@med.miami.edu

123

Endocrine (2013) 43:529–534

DOI 10.1007/s12020-012-9817-6

preparations are intermediate or long-acting formulations

that are injected once or twice daily, and are meant to

provide insulin coverage for the post-absorptive periods

during the day, as well as overnight. Ideal basal insulin

replacement should result in stable glucose levels during

periods of fasting; basal insulin is usually adjusted based

on the patterns of a patient’s fasting plasma glucose level.

Prandial insulin preparations are rapidly absorbed formu-

lations that are administered before meals and should be

titrated to limit the post-prandial glucose levels according

to professional guidelines: less than 140 mg/dl 2 h

after meals [7] or peak post-prandial values of less than

180 mg/dl [8].

The three basal insulin preparations currently available

in the USA, neutral protamine Hagedorn (NPH), glargine,

and detemir insulin, have similar effectiveness in lowering

fasting plasma glucose and A1C, but slightly different PK/

PD characteristics [9–11]. The two basal insulin analogs,

glargine and detemir, have a longer duration of action than

NPH insulin, as well as a lower peak of biologic activity

and less variability in biologic action over a 24-h period

[12, 13]. Of note is that while euglycemic clamps per-

formed in patients with type 1 diabetes demonstrated a

shorter duration of action for insulin detemir as compared

to insulin glargine, those done in type 2 diabetes showed

similar effect over 24 h [14, 15]. Regardless, the more

‘‘physiologic’’ properties of the basal insulin analogs

translate into a lower risk of hypoglycemia, especially

overnight hypoglycemia, since basal insulin is often

administered at bedtime [16]. In several of these studies,

detemir has also demonstrated less weight gain than either

NPH or glargine insulin even though higher amounts of

insulin detemir were needed to achieve similar glycemic

targets [17]. NPH can certainly be used to correct very

elevated fasting blood glucose levels at less expense than a

basal insulin analog (according to www.drugstore.com a

vial of glargine costs $119, detemir $136, and NPH $70);

as fasting plasma glucose approaches target and overnight

hypoglycemia becomes more frequent, a basal insulin

analog can be substituted.

Prandial insulin preparations include human regular

insulin and the three rapid-acting analogs, lispro, aspart,

and glulisine insulin. In controlled clinical trial settings, the

difference in clinical outcomes between regular insulin and

analog preparations is modest at best [18]. However, the

prandial insulin analogs do have a more rapid onset, and

shorter duration of action, than regular insulin allowing for

more flexibility with respect to timing of insulin to meal, as

well as the potential for less hypoglycemia 3–6 h following

a mealtime injection of insulin [19]. While rapid-acting

analogs have also been tested in a post-prandial scheme in

patients with type 1 diabetes [20–22], this option should be

reserved for special situations in which food intake or

tolerance is highly variable and unpredictable (critically ill

patient, gastroparesis, young children, etc). Of note is that a

recent PK/PD study of lispro insulin demonstrated signif-

icantly delayed and blunted biologic activity following

subcutaneous injections in obese patients with type 2 dia-

betes, putting in question the appropriateness of post-

prandial insulin administration in routine clinical practice

[23].

Insulin initiation and intensification

Patients not achieving recommended glycemic targets on

lifestyle and diet intervention, plus non-insulin therapies

(including GLP-1 receptor agonists), will need to address

decreasing beta cell function with exogenous insulin

administration [2, 24]. The new ADA/EASD guidelines

suggest using basal insulin as one of the many options after

metformin treatment, especially if maximum A1C efficacy

is desired [25]. Initiating and optimizing basal insulin

therapy results in the improvement in fasting plasma glu-

cose and A1C, while minimizing the known side effects of

insulin, namely hypoglycemia and weight gain; side effects

that are more prevalent as rapid-acting insulin formulations

are introduced into the treatment plan [3, 26]. While the

usual starting doses of basal insulin, which is often initiated

in the evening, range from a set dose of 10 U to a variable

dose of 0.1–0.2 U/kg/day, on average most patients will

require between 0.4 and 0.7 U/kg/day to adequately

replace basal insulin needs [9, 27–29]. After starting

insulin the treating physician should actively optimize the

basal insulin dose, and can, when appropriate, also instruct

patients on self-titration of the basal insulin amount [25,

28, 30]. For patients experiencing overnight hypoglycemia

with basal insulin despite inadequate replacement doses or

glycemic outcomes, the injection time can be shifted to the

morning time or NPH switched to a basal insulin analog

[27, 31, 32]. Evidence-based information on what to do

with oral agent therapy after initiation of insulin therapy is

lacking. Assuming no contraindications to continued use of

OADs, metformin seems to have beneficial effects that

support its use in combination with insulin; other OADs

can be discontinued although often at the expense of a

temporary loss of glycemic control or increased insulin

requirements [33, 34].

Patients on adequate replacement doses of basal insulin

whose A1C levels fail to achieve target might need to

introduce more effective coverage of post-prandial hyper-

glycemia. In patients not on a GLP-1 receptor agonist or

pramlintide, these two therapies can complement basal

insulin replacement while minimizing the risk of weight

gain as blood glucose control improves [35–39]. The

combination of a DPP-4 inhibitor and a GLP-1 receptor

agonist together would be an expensive approach that has

530 Endocrine (2013) 43:529–534

123

not been adequately tested and is not currently

recommended.

Another common approach for insulin initiation and/or

intensification is the use of twice-daily pre-mixed insulin.

A number of studies have demonstrated superior A1C

reduction for the pre-mix insulin analogs, when compared

to basal insulin replacement, especially when baseline A1C

levels exceed 8.5 %, albeit at the expense of more frequent

hypoglycemia and weight gain [26, 40]. When compared to

basal/bolus insulin therapy, pre-mix insulin twice daily was

equally effective in insulin naı̈ve subjects, but less effective

in patients intensifying from prior basal insulin therapy [41,

42]. For patients with consistent schedules and eating

habits, or patients challenged by a more complex basal/

bolus approach, the use of pre-mix insulin is an appropriate

treatment option.

The most effective approach to post-prandial glycemic

control in patients with failing beta-cell function is the use

of a rapid-acting insulin formulation administered subcu-

taneously at least 15 (for the rapid-acting analogs) or 30

(for regular insulin) minutes before the start of the meal.

The regimen of patients desiring mealtime flexibility can

be intensified through a ‘‘basal plus’’ approach, specifically

adding one or more injections of a rapid-acting insulin

preparation before one or more meals [43–45]. Start with a

pre-prandial dose of 4–6 U administered either before the

largest meal of the day, or the meal with the largest post-

prandial glucose excursion. Subsequently, adjust the

prandial insulin dose to achieve target 2 h post-prandial

values of less than 180 mg/dl or the next scheduled fin-

gerstick test value (usually 4–5 h later) of less than

130 mg/dl [8]. Alternatively, for patients requiring lower

doses of basal insulin (less than 40 U daily), the first

prandial dose can be calculated by estimating 10 % of the

patient’s basal insulin dose [46]. On average about 8–12 U

are eventually needed before a meal for adequate prandial

coverage. If A1C levels remain elevated on a basal plus

one regimen, a second (and eventually third) dose of

prandial insulin can be initiated and titrated to target [47].

In most studies of basal/bolus insulin coverage in subjects

with type 2 diabetes, the end-study total daily insulin doses

range on average from 1.0 to 1.5 U/kg/day [45, 47, 48].

Fixed prandial insulin doses, as opposed to dosing insulin

based on planned carbohydrate intake (flexible dosing) and

blood glucose levels, can be an effective approach in type 2

diabetes, and considerably simplify the complexity of

basal/bolus insulin therapy [48].

A number of patients with type 2 diabetes fail to achieve

glycemic targets despite high doses of both basal and

prandial insulin ([200 U daily). If dietary interventions fail

to improve glycemic control, one option is to switch them

to concentrated insulin preparations such as U-500 (avail-

able as Humulin Regular U-500). While it is unclear how

the mechanism of action might be different from equivalent

doses of a U-100 insulin preparation [49], a number of

studies have documented significant improvement in A1C

after transitioning insulin-resistant type 2 diabetes patients

to U-500 regular insulin [50–53].

The risk of hypoglycemia increases with the introduc-

tion and intensification of rapid-acting insulin to cover

prandial needs. While the risk of severe hypoglycemia is

well recognized in patients with type 1 diabetes, it also

represents a substantial concern in individuals with type 2

diabetes that have been on insulin therapy for some years

[54]. Outcomes from recent studies aggressively pursuing

strict glycemic targets in older patients with long-standing

type 2 diabetes and elevated cardiovascular risk have led to

a re-assessment of our approach to diabetes management in

the vulnerable population, as well as to a more active

‘‘individualization’’ of treatment goals [55]. Intensive

therapy in these studies led to a significant and clinically

worrisome increase in the risk of severe hypoglycemia [55,

56], which was most evident in patients not responding

appropriately to intensive therapy [57, 58]. While an A1C

under 7 % is still recognized as an appropriate general

goal, in some patients less aggressive targets might be

warranted [59]. A recent review of the ADVANCE trial did

support a close correlation between A1C levels and both

micro- and macrovascular complications, which seemed to

reach a threshold when A1C levels fell below 6.5 and

7.0 %, respectively [60].

Perspective and conclusions

Insulin management remains the cornerstone of therapy in

patients with failing beta cell function, regardless of dia-

betes etiology. While initiation of insulin therapy is rela-

tively simple, effective, and safe, subsequent intensification

of insulin regimens introduces additional complexities,

costs, and side effects. Available insulin analogs, which are

purportedly more ‘‘physiologic’’ than human insulins, have

facilitated the management of insulin-requiring patients in

real-world clinical practice, yet limitations and challenges

to optimal diabetes management still remain. Patient and

clinicians would benefit from insulin preparations which

are easier to administer with respect to alternative routes

of administration, timing of insulin administration (for

example to meal), variability of insulin absorption and

resulting biologic activity, and side effect profile (weight

gain, hypoglycemia, and fluid retention). For example,

ultra-long acting basal insulin preparations, such as insulin

degludec (currently under FDA review) which appears to

provide more consistent biologic activity over a 24-h per-

iod than current basal insulin analogs [61], might prove an

incremental step toward improving our ability to safely

manage patients requiring insulin therapy.

Endocrine (2013) 43:529–534 531

123

Disclosure L. Meneghini is on the Advisory Board/Panel of Novo

Nordisk; he is also the Consultant for Novo Nordisk and sanofi-

aventis. Grant/Research Support were provided by MannKind, Pfizer,

and Boehringer Ingelheim.

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