Curso Insulin Therapy

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Insulin therapy in type 2 diabetes

Trent Davis, MD, Steven V. Edelman, MD*

Section of Diabetes/Metabolism, Veterans Affairs San Diego HealthCare System,

3350 La Jolla Village Drive 111G, San Diego, CA 92161, USA

Diabetes mellitus affects approximately 18 million people in the United

States, which is approximately 6% of the overall population, and over

800,000 new cases are diagnosed annually [1]. Diabetes may actually be

more endemic than these figures indicate because there are no symptoms in

the early stages of the disease, and potentially one undiagnosed individual

exists for every one that is identified [2]. Of the total diabetic population,

85% to 90% of individuals have type 2 diabetes whereas 10% to 15% have

type 1 diabetes[3].

Type 2 diabetes leads to a tremendous amount of death and disabilityand uses a large portion of the health care dollar [4]. Although diabetes is

associated with multiple disorders with distinct pathologic mechanisms,

insulin resistance is the common denominator and is associated with several

comorbidities, including obesity, hypertension, and vascular disease. The

natural history of the disease 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 [3,5]. Although most of the human suffering is caused by

end-stage microvascular disease, 80% of diabetics die of macrovascularcardiovascular disease. There is now clear evidence from the United

Kingdom Prospective Diabetes Study (UKPDS) and the Kumamoto study

that improved glycemic control through intensive diabetes management

delays the onset and significantly retards the progression of microvascular

complications in patients with type 2 diabetes mellitus[6,7]. The results from

the UKPDS are reassuring in that, although intensive treatment with insulin

was associated with increased weight gain and hypoglycemia, there is no

evidence of any harmful effect of insulin on cardiovascular outcomes, which

has been a controversial issue. An epidemiologic analysis of the UKPDS

* Corresponding author.

E-mail address:[email protected](S.V. Edelman).

0025-7125/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.mcna.2004.04.005

Med Clin N Am 88 (2004) 865895
mailto:[email protected]:[email protected]


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data shows a continuous association between the risk of cardiovascular

complications and glycemia, such that for every percentage point of decrease

in HbA1c(eg, from 9% to 8%), there is a 25% reduction in diabetes-relateddeaths, a 7% reduction in all-cause mortality, and an 18% reduction in

combined fatal and nonfatal myocardial infarction [6].

To achieve glycemic goals in patients with type 2 diabetes, we now have

multiple pharmacologic agents with different mechanisms of action, in-

cluding sulfonylureas, meglitinides, metformin, a-glucosidase inhibitors,

thiazolidinediones, and insulin. It must be emphasized, however, that unlike

patients with type 1 diabetes, who have no significant insulin secretion and

hence require insulin therapy from the onset of their disease, a prominent

feature in the early stages of the disease for patients with type 2 diabetesis insulin resistance with hyperinsulinemia. Therefore, improving insulin

sensitivity be means of caloric restriction, exercise, and weight management

early in the disease process will benefit type 2 diabetics. When these measures

fail, glycemic goals can often be achieved with oral agents used alone or

in combination with each other. When patients are diagnosed late in the

natural history, however, there is progressive loss of pancreatic beta-cell

function and endogenous insulin secretion, making diurnal glycemic control

difficult. At this late stage, most patients require exogenous insulin therapy

to achieve optimal glucose control. The American Diabetes Association(ADA) now recommends that the glycemic objective for patients with type 2

diabetes to normalize glycemia and glycosylated hemoglobin concentrations

should be similar to that for type 1 diabetes.

Pathogenesis and natural history of type 2 diabetes

Of the Americans diagnosed with type 2 diabetes, 80% to 90% are obese,

and the remainder are lean [8]. The genesis of hyperglycemia in type 2diabetes involves a triad of abnormalities: excessive hepatic glucose pro-

duction, impaired pancreatic insulin secretion, and peripheral resistance

to insulin action, occurring principally in liver and muscle tissue [9]. The

severity of these abnormalities and their contribution to the degree of

hyperglycemia can vary considerably, causing heterogeneity in the metabolic

expression of the diabetic state. Such differences are best exemplified by the

lean and obese varieties of type 2 diabetes, which have the same underlying

pathophysiologic basis but differ in the extent to which each abnormality

contributes to the development of the hyperglycemic state. Of these ab-normalities, peripheral insulin resistance to insulin action and impaired

pancreatic beta-cell secretion are early and primary abnormalities, whereas

increased hepatic glucose production is a late and secondary manifestation.

Early in their disease, patients with type 2 diabetes compensate for increased

insulin resistance at the tissue level by increasing pancreatic beta-cell insulin

secretion[10]. When this compensation is no longer adequate to overcome

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the insulin resistance, blood glucose levels begin to rise. Over the course

of the disease, endogenous insulin levels slowly begin to decrease and,

ultimately, many patients with type 2 diabetes are unable to achieve optimalglycemic control with oral agents [11].

In subjects with type 2 diabetes who are lean, impaired insulin secretion is

the predominant defect, and insulin resistance tends to be less severe than in

the obese variety [12]. On the other hand, insulin resistance and hyper-

insulinemia are the classical abnormalities of obese persons with type

2 diabetes [12]. In type 2 diabetes, insulin secretion is often excessive

compared with the nondiabetic situation but is still insufficient to overcome

the insulin resistance that is present. It is important to understand and

appreciate these fundamental differences when considering insulin therapyin type 2 diabetes. Based on this knowledge, lean type 2 diabetic subjects

usually fail oral agents faster and will require considerably less insulin to

control their hyperglycemia than their obese counterparts. In contrast, large

doses of exogenous insulin are the rule in the obese form of this disorder

when euglycemia is desired[13].

The need for large amounts of exogenous insulin in obese type 2 diabetes

also raises the question of the most appropriate methods of insulin delivery.

Under normal circumstances, insulin is secreted from the pancreas into the

portal vein, going directly to the liver in which a large first-pass extractionof portal insulin occurs [14]. When insulin is injected subcutaneously,

absorption occurs directly into the peripheral circulation, without the initial

effects of hepatic extraction. Therefore, the tissues are exposed to greater

levels of insulin than if insulin was provided by the portal route. Because the

primary target of exogenous insulin is the liver, type 2 diabetes may be

uniquely suited to delivery of insulin through the portal vein. Such a

situation occurs when insulin is delivered intraperitoneally, and the majority

of insulin is absorbed into the portal circulation[15].Intraperitoneal insulin

delivery systems will not be discussed in this section, however, this methodholds considerable promise in type 2 diabetes because of the more

physiologic delivery of insulin and because of selective and effective

inhibition of hepatic glucose output, with less peripheral insulinemia than

occurs with subcutaneous insulin injections[16].

Intensive insulin therapy

Successful insulin management requires an educated and motivatedpatient, as well as the participation of a multidisciplinary health care team.

Intensive insulin therapy requires a substantial input of physician and

support staff time, which has a significant economic impact on the health

care system [17]. Although long-term data on costs are not yet available,

projections suggest that substantial savings from the high costs of end-

stage disease could be achieved by following ADA guidelines [18].

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Furthermore, as discussed later, we now have the opportunity to use

combinations of insulin and a variety of oral antidiabetic agents with

differing mechanisms of action. The use of these potent combinationspermit us to safely and effectively lower blood glucose levels and to

achieve ADA target glycemic levels with relatively low risk for hypogly-

cemia or weight gain.

In addition to the natural history of type 2 diabetes, there is heterogeneity

in the pathophysiology of type 2 diabetes mellitus that may influence when

patients require insulin. Some patients who have been diagnosed with type 2

diabetes may actually have a condition more closely related to insulin-

dependent or type 1 diabetes, with severe insulinopenia. Many of these pa-

tients have been shown to have islet cell antibody positivity or antibodies toglutamic acid decarboxylase, with a decreased C-peptide response to

glucagon stimulation and a propensity for primary oral medication failure

[19]. These individuals are now labeled with the condition latent autoimmune

diabetes in adults [20]. There are also wide geographic and racial differences

that may influence the need for insulin therapy. For example, Asian patients

with type 2 diabetes tend to be thinner, are diagnosed with diabetes at an

earlier age, fail oral hypoglycemic agents much sooner, and are more

sensitive to insulin therapy than the classic centrally obese patient in the

United States and some parts of Europe[21].The goals of therapy should be tailored to individual patients. Candidates

for intensive management should be motivated, compliant, and educable,

and be without other medical conditions and physical limitations that

preclude accurate and reliable home glucose monitoring (HGM) and insulin

administration; caution is advised in patients who are aged or have hypo-

glycemic unawareness. Other limitations to achieving normoglycemia

may include high titers of insulin antibodies, especially in patients with a

history of intermittent use of insulin of animal origin. The site of insulin

injection also may change the pharmacokinetics, and absorption can behighly variable, especially if lipohypertrophy is present. The periumbilical

area has been shown to be one of the most desirable areas to inject insulin

because of the rapid and consistent absorption kinetics observed at this

location; however, rotating the injection site is usually advised[22]. It is also

advisable to inject in the same body location for a certain meal time (ie,

triceps fat pad for breakfast, abdomen for lunch, and upper thighs for

dinner)[23].

In summary, before starting insulin therapy, the patient should be well

educated in the techniques of HGM, proper insulin administration, and self-adjustment of the insulin dose, if appropriate, as well as knowledgeable

about dietary and exercise strategies, including carbohydrate counting. The

patient and family members also need to be informed about hypoglycemia

prevention, recognition, and treatment. Initial and ongoing education by a

diabetes management team, including a certified diabetes educator, is crucial

for long-term success and safety.



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Insulin treatment strategies

Combination therapy

Combination therapy usually refers to the use of daytime oral antidia-

betic agents together with a single injection of intermediate or long-acting

insulin at bedtime. Several studies [2436] have looked at the safety and

efficacy of combination therapy. For many of the reasons mentioned earlier,

the analysis of studies to evaluate the efficacy and safety of combination

therapy is difficult. Several review articles using meta-analysis conclude that

combination therapy results in only modest improvements in glucose con-

trol and contribute to increased medical costs of diabetes management

compared with insulin therapy alone. These earlier studies, however, wereconducted when sulfonylureas were the only available type of oral agent.

Because of heterogeneity in type 2 diabetes together with variability in the

design and clinical situations of previous studies, however, the use of meta-

analysis may be inappropriate for making generalized statements regarding

this form of therapy [27,37]. Based on several recent reports, the use of

combination therapy has been quite successful in selected patients, especially

with the newer oral agents used alone or together with insulin [26

29,35,36,3841].

For a number of practical reasons, combination therapy may bebeneficial. The patient does not need to learn how to mix different types

of insulin, and patient compliance and acceptance are better with a single

injection than with multiple injections of insulin. Combination therapy also

requires a lower total dose of exogenous insulin than regimens of two or

three injections per day. Combination therapy also contributes to less

weight gain and peripheral hyperinsulinemia. Last, combination therapy is

ideally suited to suppress excessive hepatic glucose production overnight.

The rationale for combination therapy with insulin and sulfonylureas is

based on the assumption that, if evening insulin lowers the fasting glucoseconcentration to normal, then daytime oral agents will be more effective

in controlling postprandial hyperglycemia and maintaining euglycemia

throughout the day. Metabolic profiles of patients who have type 2 diabetes

have demonstrated that fasting blood glucose contributes significantly to

daytime hyperglycemia[42]. In addition, the fasting blood glucose concen-

tration is highly correlated with the degree of hepatic glucose production

during the early morning hours [13]. Hepatic glucose output is directly

decreased by insulin[43]and indirectly inhibited by the ability of insulin to

reduce adipose tissue lipolysis, with lower concentrations of free fatty acidsand gluconeogenesis [41]. Also, the peak of bedtime intermediate-acting

insulin coincides with the onset of the dawn phenomenon (early morning

resistance to insulin caused by diurnal variations in growth hormone

and possibly in levels of norepinephrine), which usually occurs between

3 and 7 AM. Bedtime insulin also increases the morning serum insulin



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concentration and may assist in reducing the post-breakfast glucose rise in

addition to the fasting value.

Combination of insulin and sulfonylurea agents

In one of the first large studies demonstrating the efficacy of insulin/

sulfonylurea combination therapy, Yki-Jarvinen et al [38] compared com-

bination therapy with regimens of two and four insulin injections per day

in patients with type 2 diabetes. These patients were on submaximal doses

of glyburide (12.5 mg/d), glipizide (20 mg/d), and metformin (1.4 g/d),

with fasting blood glucose concentrations at approximately 225 mg/dL and

mean fasting serum C-peptide values of 0.66 nmol/L. After 3 months, alltreatment groups had similar reductions in mean diurnal glucose con-

centrations and glycosylated hemoglobin levels (1.6%1.9%) compared

with the control group, who were taking oral agents alone. The group

treated with a combination of oral agents and bedtime neutral protamine

Hagedorn (NPH) insulin, however, had the least weight gain (1.2 0.5 kg)

of any group and a 50% to 65% lower increment in mean diurnal serum-free

insulin concentrations. There was no evidence of severe hypoglycemia with

combination therapy, and patient acceptance was excellent.

Several other recent publications [26,28,29,31,34,40] also support theadditional efficacy and safety of combination therapy in patients who are

inadequately controlled by oral hypoglycemic agents alone. A recent study

conducted by Riddle and Schneider[36]demonstrates the efficacy and safety

of a combination consisting of 70% NPH insulin and 30% regular insulin

(70/30) insulin at dinnertime and sulfonylurea therapy. In this study, 145

type 2 diabetics with uncontrolled hyperglycemia (fasting plasma glucose

level [FPG] 180300 mg/dL), on maximum sulfonylurea therapy (glimepir-

ide, 8 mg orally, twice daily) were randomized to placebo plus insulin or

glimepiride plus insulin for 6 months. The dose of 70/30 insulin atdinnertime was titrated to keep fasting fingerstick capillary blood glucose

to less than 120 mg/dL. At 24 weeks, HbA1c levels decreased significantly

and similarly in both groups (9.9%7.6%). The combination therapy

group, however, needed nearly 35% less insulin than the insulin-only group

(49 versus 78 units) and achieved glycemic control faster, with fewer

dropouts (3% versus 15%,P\ 0.01). Surprisingly, weight gain was similar

(4.0 kg) in both groups.

Insulin and metformin

Weight gain is a constant occurrence in most clinical trials in which

insulin or sulfonylureas, or both agents, are used to treat type 2 diabetes.

Although it was attenuated with combination therapy with sulfonylureas in

the study by Yki-Jarvinen[38],weight gain remains a problem because it can

exacerbate insulin resistance and hyperinsulinemia. The use of metformin in



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this situation may prove advantageous because its use is associated with

reduced weight gain.

The safety and efficacy of metformin in combination with insulin hasbeen demonstrated in a recent multicenter study by Yki-Jarvinen et al [35].

In this placebo-controlled study, 96 type 2 diabetics who were poorly

controlled with oral sulfonylurea therapy (mean glycosylated hemoglobin

value 9.9% 0.2%; mean fasting plasma glucose level 214 5 mg/dL) were

randomized to 1 year of treatment with bedtime intermediate-acting insulin

plus either glyburide (10.5 mg), metformin (2 g), glyburide and metformin,

or a second injection of intermediate-acting insulin in the morning. Patients

were taught to adjust the bedtime insulin dose on the basis of fasting glucose

measurements. At 1 year, body weight remained unchanged in patientsreceiving bedtime insulin plus metformin (mean change 0.9 1.2 kg) but

increased by 3.9 0.7 kg, 3.6 1.2 kg, and 4.6 1.0 kg, respectively, in

patients receiving bedtime insulin plus glyburide, bedtime insulin plus both

oral drugs, and bedtime and morning insulin. In addition, the greatest

decrease in the glycosylated hemoglobin value was observed in the bedtime

insulin and metformin group (from 9.7 0.4% to 7.2 0.2%, a difference

of 2.5 0.4 percentage points) at 1 year (P 0.001 compared with

baseline and P 0.05 compared with other groups). This group also had

significantly fewer symptomatic and biochemical cases of hypoglycemia(P 0.05) than the other groups. The authors conclude that combination

therapy with bedtime insulin plus metformin not only prevents weight gain

but also seems superior to other bedtime insulin regimens, with respect to

improvements in glycemic control and frequency of hypoglycemia.

In a more recent study [44] of approximately 390 type 2 diabetics, the

combination of insulin and metformin led to a significant improvement in

glycemic control that was greater than with insulin alone. The mean daily

glucose level decreased from 141 34 to 137 31 mg/dL in the insulin-only

group (mean decrease 0.16; 95% confidence interval [CI]; 104 mg/dL)and from 141 40 to 140 31 mg/dL in the metformin group (P= 0.006

versus placebo; mean decrease 1.04; 95% CI; 27 to 9 mg/dL). The

mean daily glucose level decreased by 13 mg/dL more in the metformin

group compared with the placebo groupFig 1.

Insulin and thiazolidinediones

The glitazones are potent insulin sensitizers and are, therefore, well suited

for use in insulin-resistant patients with type 2 diabetes. In several earlystudies, troglitazone was documented to not only improve glycemic control

but also to reduce exogenous insulin requirements in obese patients with

type 2 diabetes [45,46]; however, troglitazone was withdrawn from the

US market as a result of an increased risk of severe idiosyncratic liver

damage. Presently there are two glitazones available, rosiglitazone and

pioglitazone, for clinical use in the US, and several more are in development.



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In one 16-week study, Rubin et al[47]demonstrated that the daily additionof 15 and 30 mg of pioglitazone to the regimen of patients receiving a median

dose of 61 units of insulin resulted in mean FPG reductions of 36 and 49 mg/

dL and HbA1c reductions of 0.7% and 1.0%, respectively, compared with

placebo. The insulin-sparing properties of rosiglitazone were shown in a 6-

month study conducted by Raskin et al [48]. They demonstrated that the

addition of 2 and 4 mg orally twice daily of rosiglitazone improved HbA1c

Fig. 1. (A) Blood glucose levels measured at home. (B) Change in blood glucose levels

measured at home. Data are means with SD error bars. For each time point indicated, the first

and the second bars show values at baseline and the third and the fourth show values at

16 weeks. Blood glucose levels in the metformin group compared with the placebo group are all

significantly lower at 16 weeks (P 0.05). The change in glucose values is also significantly

greater in the metformin than in the placebo group at all times during the day (P 0.05). (From

Wulffele MG, Kooy K, Lehert P. Bets D Ogterop JC, Van Der Burg BB, Donker AJM,

Stehouwer CDA. Combination of insulin and metformin in the treatment of type 2 diabetes.

Diabetes Care 2002;25(12):213340; with permission.)



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levels by 0.6% and 1.2%, respectively, compared with placebo, in 312

patients with type 2 diabetes who were uncontrolled on approximately 70

units of insulin daily (baseline HbA1c 9%). Moreover, insulin requirementswere also reduced by approximately 5 and 10 units, respectively, in the two

groups treated with rosiglitazone, in keeping with the insulin sensitizing

effects of the glitazones. In summary, both rosiglitazone and pioglitazone

improve glucose control in poorly controlled, insulin-treated patients with

type 2 diabetes mellitus. There have been no reports of insulin added to

subjects treated with glitazones alone.

Insulin and a-glucosidase inhibitors

The addition of acarbose to insulin therapy may be an option in patients

who have pronounced postprandial hyperglycemia. The first long-term

controlled study to demonstrate a beneficial effect of acarbose in patients

on insulin therapy was reported by Chiasson et al[49]. Of the total number

of patients in this study, 91 were receiving insulin and had glycosylated

hemoglobin values greater than 7%. Postprandial plasma glucose levels at

90 minutes were significantly reduced to 282 mg/dL with the addition of

acarbose, compared with 331 mg/dL seen with insulin alone. Glycosylated

hemoglobin values decreased by 0.4% in the acarbose group, but, as ex-

pected, no significant decreases in fasting plasma glucose levels were seen.

Acarbose may be initiated in patients on insulin treatment by starting with

a low dose of 25 mg with breakfast and titrating up by 25 mg weekly to 50

to 100 mg three times daily with meals (100 mg three times daily for

patients 60 kg body weight), depending on gastrointestinal tolerance and

efficacy.

Insulin glargine and oral agents

The long-acting analog insulin glargine was studied in comparison with

NPH insulin in 756 patients with type 2 diabetes in an open-label, 24-week,

multicenter study [50]. In this study, patients who were inadequately

controlled on oral agents including sulfonylurea, metformin, and glitazones

were randomized to receive either bedtime insulin glargine or NPH insulin,

and the doses were adjusted to obtain a target fasting glucose level of less

than 100 mg/dL (5.6 mmol/L). At the conclusion of the trial, the median

daily dose of insulin was approximately 0.45 IU/kg of body weight in bothgroups. The two forms of insulin produced a similar improvement in HbA1c(6.96 versus 6.97%) and similar reductions in fasting glucose levels (117

versus 120 mg/dL); however, the incidence of mild nocturnal hypoglycemia

was significantly lower among patients treated with insulin glargine than in

the group treated with NPH insulin (P\ 0.001)[50]. There was a reduction

of approximately 45% of nocturnal hypoglycemia with glargine compared



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with NPH[50]. Treatment with NPH or glargine in addition to oral therapy

in type 2 diabetic patients resulted in a decrease of fasting glucose in both

groups, reaching a plateau by 12 weeks. HbA1c declined at a predictablyslower rate, stabilizing after 18 weeks (Fig. 2) [50].

Fig. 2. (A) FPG and (B) HbA1cduring the study. Values in both figures are means; error bars

indicate SE. (FromRiddle MC, Rosenstock J, Gerich J. 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(11):30806; with permission.)



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Selection of patients most likely to succeed on combination treatment

The most common type of patient in whom combination therapy will

succeed is the one who is failing oral treatment without significant glucose

toxicity and has some evidence of responsiveness to oral agents. Patients

have a higher likelihood of success using combination therapy if they are

obese, have had overt diabetes for less than 10 to 15 years, are diagnosed

with type 2 diabetes after the age of 35, do not have fasting blood glucose

values consistently over 250 to 300 mg/dL, and have evidence of endogenous

insulin secretory ability. Although standard measurement conditions and C-

peptide concentrations have not been established for this clinical situation,

a fasting C-peptide concentration (0.2 nmol/L) or glucagon-stimulated

level (0.40 nmol/L) indicates some degree of endogenous insulin secretory

ability[51,52]. Patients with type 2 diabetes diagnosed before the age of 35

more often have atypical forms of diabetes. Patients who have had diabetes

for more than 10 to 15 years tend to have a greater chance of beta-cell

exhaustion and, thus, tend to be less responsive to oral hypoglycemic agents

and combination therapy. Thin patients are more likely to be hypoinsuli-

nemic and often respond inadequately to oral agents, which lead to

combination therapy failure. In addition, markedly elevated fasting glucose

concentration is often associated with a concomitant decrease in endoge-

nous insulin secretory ability, which renders oral agents ineffective. The

actual number of patients who might respond favorably to combination

therapy is unknown but is estimated to be between 20% and 40%.

Initiating combination therapy

Calculation of the initial bedtime dose of intermediate-acting insulin can

be based on clinical judgment or various formulas based on the fasting

blood glucose concentration or body weight. For example, the average

fasting blood glucose (mg/dL) can be divided by 18 or body weight (kg) canbe divided by 10 to calculate the initial dose of NPH or insulin glargine to be

started at bedtime[43]. Also, 5 to 10 units of insulin can be safely started for

thin patients, and 10 to 15 units can be started for obese patients at bedtime,

as an initial estimated dose. In either case, the dose is increased in

increments of 2 to 5 units every 3 to 4 days until the morning fasting blood

glucose concentration is consistently in the range of 70 to 120 mg/dL [53].

The best time to give the evening injection of intermediate-acting insulin

is between 10 PM and midnight. Insulin glargine has been shown to be

effective when taken either in the morning or evening. Many reliable pa-tients can make their own adjustments using HGM.

Based on the results of HGM, combination therapy can be altered to

reduce hyperglycemia at identified times during the day. For example, a

common situation seen with daytime oral agents and bedtime intermediate-

acting insulin therapy is an improvement in the fasting, pre-lunch, and pre-

dinner blood sugar values, although the post-dinner blood glucose



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concentration remains excessively high (200 mg/dL). In this clinical

situation, an injection of premixed insulin (70/30 or 75/25 mix) can be

given before dinner instead of a bedtime dose of intermediate- or long-actinginsulin. This regimen will often improve the post-dinner blood glucose

values because the premixed insulin contains rapid-acting analogs yet allows

overnight glucose control secondary to the intermediate-acting component.

With this regimen, however, one must be more cautious about early

morning hypoglycemia because the intermediate-acting insulin given before

dinner will exert its peak effect earlier. In the experience of these authors,

this has not been a major clinical problem in obese patients with type 2

diabetes compared with those with type 1 diabetes mellitus. Normally the

dose of bedtime intermediate- or long-acting insulin can be converted to thedose of premixed insulin, dose per dose, and adjustments can be made

through HGM.

Dose adjustment

Once the fasting blood glucose concentrations are consistently in a desir-

able range, the pre-lunch, pre-dinner, and bedtime blood sugar values must

be monitored to determine if the oral hypoglycemic agents are maintaining

daylong glycemia. It is recommended that after the addition of evening

insulin patients continue to take the maximal dose of the oral sulfonylurea

agent. If the daytime blood glucose concentrations become excessively low,

the dose of oral medication must be reduced. The morning dose of sul-

fonylurea should be reduced or discontinued first. This situation is common

because glucose toxicity may be reduced because of improved glucose

control, leading to enhanced sensitivity to both oral agents and insulin. If

the pre-lunch and pre-dinner blood glucose concentrations remain exces-

sively high on combination therapy, it is likely that the oral agents are not

contributing significantly to glycemic control throughout the day. In this

situation, a more conventional or intensive regimen of two injections perday is indicated.

Multiple-injection regimens

One of the most common insulin regimens used in type 2 diabetes mellitus

is the split-mixed regimen consisting of a pre-breakfast and pre-dinner dose

of intermediate- and fast-acting insulin. This split-mixed regimen of two

injections per day is often inadequate for patients with type 1 or leanpatients with type 2 diabetes and can result in persistent early morning

hypoglycemia and fasting hyperglycemia. Such problems do not appear to

occur as frequently in obese type 2 diabetes. This is likely caused by

pathophysiologic differences, particularly in endogenous insulin secretory

ability, insulin resistance, and counter-regulatory mechanisms in type 1 and

type 2 diabetes.



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In a landmark trial with type 2 diabetes by Henry et al [54], daylong gly-

cemia and glycosylated hemoglobin were essentially normalized by 6 months

of intensive treatment with a split-mixed insulin regimen. In this study,14 typical obese patients with type 2 diabetes mellitus (age 59 2 years;

duration of diabetes 7 2 years; body mass index 31 2 kg/m2; fasting

blood glucose concentration 283 13 mg/dL) failing therapy with oral

antidiabetic agents were intensively managed with pre-breakfast and pre-

dinner NPH and regular insulin over a 6-month period. The insulin dose

was adjusted based on HGM results of four injections per day. Glycemic

control was rapidly achieved within 1 month and was maintained for the

duration of the study.

The average total insulin dose needed to maintain glycemic controlapproached 100 units per day, with approximately 50% of the total dose

required before breakfast and 50% before dinner. The ratio of NPH to

regular insulin was approximately 75%:25%. There was a very low incidence

of mild hypoglycemic reactions, which decreased as the study progressed,

and no reactions were severe or required assistance. In addition, patient

compliance and sense of well being were excellent. Near-normalization of

the glycosylated hemoglobin, however, led to some adverse effects in these

patients. The mean serum insulin concentration obtained during 24-hour

metabolic profile studies increased from 308 80 pmol/L at baseline to510 102 pmol/L (P 0.05) at completion of the 6-month study. The

exacerbation of hyperinsulinemia by exogenous insulin therapy was strongly

correlated with weight gain throughout the study. Despite biweekly visits

with the study dietitian and instructions to reduce the daily caloric intake,

a mean weight gain of approximately 9 kg or 18.8 pounds occurred.

Interestingly, the total daily insulin dose was 86 13 units at 1 month and

100 24 units at 6 months, despite minimal additional improvement in

glycemic control during that period. Most of the improvement in glycemic

control was caused by the suppression of basal hepatic glucose production(from 628 44 to 350 17 lmol/m2/min,P 0.001), with a more modest

but significant improvement in peripheral glucose uptake (from 1418 156

to 1657 128 lmol/m2/min,P 0.05), as determined by the glucose clamp

technique.

This study emphasizes a number of important aspects of intensive glucose

control with insulin in obese subjects with type 2 diabetes. First, the average

daily dose of insulin needed to control such patients approximates 1 unit per

kilogram of body weight. Second, the total daily insulin requirement can be

split equally between the pre-breakfast and pre-dinner injections. Third, thesplit-mixed regimen in patients with type 2 diabetes is usually devoid of the

common problems seen with this regimen in type 1 diabetes, particularly

early morning hypoglycemia and fasting (pre-prandial) hyperglycemia.

Fourth, both severe and mild hypoglycemic events are much less fre-

quent in patients with type 2 compared with patients with type 1 diabetes

undergoing intensive insulin therapy. And finally, weight gain with



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peripheral hyperinsulinemia occurs, which may contribute to metabolic and

vascular complications.

A similar but larger 3-month clinical trial [38] compared a split-mixedcombination with a multiple-injection regimen consisting of pre-meal

regular and bedtime NPH insulin injections. Both the split-mixed and

multiple-injection regimen treatment groups achieved equivalent and near-

normal glycosylated hemoglobin values. These therapies, however, were

associated with weight gain of 0.8 0.05 and 2.9 0.05 kg, a 39% and 36%

increase in mean diurnal serum-free insulin levels, and a total daily insulin

dose of 43 and 45 units, respectively. The authors demonstrated that the

change in body weight was negatively correlated with the change in

glycosylated hemoglobin values and positively correlated with the meandiurnal serum-free insulin values. The differences between these two studies

with regard to total insulin requirements, mean insulin concentrations, and

weight gain are primarily the result of differences in patient characteristics.

Patients in the latter study were leaner (body mass index 29 versus 31 kg/

m2), had lower baseline fasting blood glucose values (225 versus 283 mg/dL)

and reduced baseline mean diurnal serum-free insulin values (138 versus 308

pmol), and were previously treated with submaximal doses of sulfonylureas,

compared with the patients in the former study. In addition, the latter study

was conducted over a shorter period of time (3 months versus 6 months).Another long-term (5-year) clinical trial using a split-mixed regimen of two

injections per day in 102 nonobese type 2 diabetic patients demonstrated

that excellent glycemic control could be achieved with intensive split-dose

insulin without significant hypoglycemia but at the expense of progressive

weight gain[55]. All these studies clearly demonstrate the efficacy of various

insulin regimens and the adverse consequences of such therapy.

Premixed insulin approach: rapid-acting insulin analogs

Rapid-acting insulin analogs are also available as manufactured, pre-

mixed insulin formulations. One such insulin preparation is Humalog Mix

75/25, which is a fixed-ratio mixture of 25% rapid-acting insulin lispro and

75% novel protamine-based intermediate-acting insulin called neutral

protamine lispro (NPL). NPL was developed to solve the problem of

instability with prolonged storage that occurs with NPH combined with

insulin. Studies of the pharmacokinetic and pharmacodynamic profiles of

NPL show they are comparable to those of NPH insulin[56].Humalog Mix 75/25 was studied in comparison to premixed human

insulin 70/30 in 89 patients with type 2 diabetes in a 6-month randomized,

open-label, two-period crossover study[57]. All patients had been previously

treated with mixed insulin therapies, including short- or rapid-acting and an

intermediate- or long-acting insulin, twice daily for at least 30 days before

enrollment. During a 2 to 4 week lead-in period, patients were treated with



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human insulin 70/30. The patients were randomized to receive one of two

treatment sequences: therapy twice per day with Humalog Mix 75/25 in-

jected before morning and evening meals for 3 months, after which theywere crossed over to receive human insulin 70/30 using the same dosing

frequency for an additional 3 months, or the alternate treatment sequence.

Patients performed self-monitoring blood glucose (SMBG) at scheduled

intervals during the study period (preprandial, 2-h postprandial, and

occasional 3 AM readings) and recorded this information along with any

hypoglycemic episodes in a study diary. Mean insulin doses were similar or

identical between treatments. Blood glucose values after the morning meal

were significantly lower during treatment with Humalog Mix 75/25

(Humalog Mix 75/25 8.95 2.17 versus human insulin 70/30 10.00 2.28 mmol/L, P= 0.017). Treatment with Humalog Mix 75/25 produced

similar significant blood glucose results 2 hours after the evening meal as

well (Humalog Mix 75/25 9.28 2.15 versus human insulin 70/30 10.27

2.76 mmol/L,P = 0.014). Blood glucose results at other time points, HbA1clevels, daytime hypoglycemia, and nocturnal hypoglycemia were not sig-

nificantly different between treatments. Compared with human insulin 70/

30, twice-daily injections of Humalog Mix 75/25 in patients with type 2

diabetes resulted in improved postprandial glycemic control after the

morning and evening meals, similar overall glycemic control, and the addedconvenience of administration immediately before meals.

Insulin aspart, another rapid-acting insulin analog, is available in a

premixed formulation with a protamine-retarded insulin aspart called

Novolog Mix 70/30 (70% insulin aspart protamine suspension and 30%

insulin aspart). A comparison study [58] of the pharmacokinetic and

pharmacodynamic parameters of the Novolog Mix 70/30 and human

insulin 70/30 in healthy patients showed that the faster onset and greater

peak action of insulin aspart was preserved in the aspart mixture.

Another study [59] compared premixed aspart mixture 70/30 withpremixed human insulin 70/30 administered twice daily in a randomized

12-week open-label trial in 294 patients with type 1 and type 2 diabetes.

Patients were instructed to inject the human insulin 70/30 30 minutes before

morning and evening meals and the premixed aspart mixture 10 minutes

before morning and evening meals. SMBG levels and hypoglycemia

incidence were recorded in diaries. Patients required a small increase in

the total daily aspart mixture dose compared with human insulin 70/30

(mean difference at 12 weeks [95% CI 0.01; 0.05]), P 0.01; 0.03 U/kg.

There was no significant difference in HbA1c between groups, yet the meanblood glucose values after treatment with the aspart mixture showed

statistically significant treatment differences after breakfast, before lunch,

after dinner, and at bedtime. Blood glucose values were approximately

1.0 mmol/L lower compared with the human insulin 70/30 group at each

time point (P 0.05). The incidence of hypoglycemia was not found to be

different between the two groups, and weight gain was not significant during



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the study period with either type of insulin. Treatment with twice-daily

premixed aspart mixture 70/30 resulted in similar overall glycemic control;

yet postprandial control improved without additional hypoglycemia andwith injections immediately before meals compared with premixed human

insulin 70/30 given 30 minutes before the meal.

In a more recent study that focused on changes in lipid levels, Schwartz

et al [60] compared insulin 70/30 mix taken twice per day plus metformin

versus triple oral therapy (secretagogues, metformin, and thiazolidine-

diones) and clearly demonstrated that insulin plus metformin are superior

in lowering total cholesterol and triglycerides levels. The baseline values for

total cholesterol, low-density lipoprotein, high-density lipoprotein, and

triglycerides indicated no differences between the triple OHA and insulin/metformin groups. By the end of the study (week 24) significant decreases in

total cholesterol and triglycerides were evident in the insulin plus metformin

group (P= 0.038 and 0.033, respectively, compared with the triple oral

therapy group). Subjects in the triple oral therapy group showed a small

increase in cholesterol and less of a decrease in triglyceride levels [60]. For

glucose control, both groups had similar FPG values at the beginning of the

study. After 24 weeks of treatment, the changes from baseline mean FPG

values were 55 and 65 mg/dL for the triple oral therapy and insulin plus

metformin, respectively[60]. Baseline HbA1c values were 9.62 1.25% forsubjects in the triple oral therapy and 9.65 1.62% in the insulin group.

HbA1cvalues at weeks 2 and 6 demonstrated the efficacy of both treatments;

however, insulin plus metformin treatment achieved improvements in

HbA1c values at weeks 2 and 6 (9.03 1.35% and 8.11 1.20%,

respectively) that were significantly greater than the response to triple oral

therapy (P= 0.001 and 0.001, respectively). At weeks 12 and 24, no

statistically significant difference in HbA1c between the two groups were

observed (final values at week 24 were 7.59 1.4% for triple oral therapy

and 7.59 1.25% for insulin plus metformin [P= 0.772]) (Fig. 3)[60].Along with SMBG, the use of rapid-acting premixed insulin analogs is

convenient and can be beneficial in reducing postprandial hyperglycemia

and in helping patients achieve glycemic control without the increased

incidence of hypoglycemia. In addition, protocols are currently underway to

assess the efficacy of using rapid-acting premixed insulin analogs three times

per day before breakfast lunch and dinner, based on HGM data. This

regimen is more related to a basal bolus strategy discussed below.

Basalbolus strategy

The basalbolus insulin strategy, which can be used in patients with

either type 1 or type 2 diabetes, incorporates the concept of providing

continuous basal insulin levels throughout the day and night with brief

increases in insulin levels at the time of meal ingestion by bolus doses.



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The use of pre-meal regular insulin with bedtime NPH as the basal insulin

has been a common strategy for intensive insulin therapy in the United

States, but because regular insulin should be administered 20 to 40 minutes

before meals, a risk of hypoglycemia exists if the meal is delayed. If regular

Fig. 3. (A) Mean FPG values at screening and weeks 12 and 24 by treatment group. No

statistically significant changes were observed between the triple oral therapy () and insulin

plus metformin (). (B) Mean SEM changes for the total cholesterol, HDL, LDL, andtriglycerides at week 24. * Statistically significant (P 0.05) reduction in total cholesterol and

triglyceride levels in the insulin plus metformin group compared with the triple oral therapy

group. HDL, high-density lipoprotein; LDL, low-density lipoprotein; OHA, XXX. (From

Schwartz S, Sievers R, Strange P Lyness W, Hollander P. Insulin 70/30 mix plus metformin

versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs:

efficacy, safety, and cost analysis. Diabetes Care 2003;26(8):2598603; with permission.)



18/31

insulin is given just before a meal, high postprandial glucose levels and

delayed hypoglycemia may result. A strategy that provides for some

flexibility in the mealtime administration of insulin with the use of rapid-acting insulin analogs, lispro or aspart, administered immediately before

meals, and long-acting insulin, such as glargine, ultralente, lente, or NPH as

the basal insulin. These regimens that use multiple doses of intermediate-

acting insulin such as NPH can be associated with unpredictable nocturnal

hypoglycemia and day-to-day instability of blood glucose patterns in part

because of intrapatient variability of the effect of subcutaneous injected

insulin and the patients peak action profile[61]. NPH, which exhibits peak

action 5 to 7 hours after administration, has also been used in combination

with rapid-acting insulin analogs, commonly given at least twice daily,although the disadvantages of NPH used in this manner are similar to those

associated with Ultralente [62]. Because of its time to peak action, NPH

should be given every 6 hours or 4 times per day to be effective as a basal

insulin, in many patients [63].

Improved mealtime glucose control with the rapid-acting analogs has

exposed the gaps in basal insulin coverage provided by therapy with the

traditional intermediate- and long-acting insulin preparations. Taking

a basal insulin analog with a relatively constant and flat pharmacokinetic

profile such as insulin glargine once per day will result in a morephysiologic pattern of basal insulin replacement. Insulin glargine in

combination with a rapid-acting insulin analog has demonstrated effective

glycemic control and a lower incidence of nocturnal hypoglycemia[64]than

other insulin preparations currently used for basal insulin supplementation

[6468].

Patients on multiple-injection basalbolus regiments should use carbo-

hydrate counting to estimate their pre-meal bolus dose of a rapid-acting

analog. In addition, a correction factor should be determined by HGM

before and after rapid-acting insulin boluses. For example, a typicalinsulin-resistant subject with type 2 diabetes may need 1 unit of lispro or

aspart for every 8 g of carbohydrate compared with a 1:15 ratio for a lean

insulin-sensitive person with type 1 diabetes. A typical correction factor

would be 1 unit of lispro or aspart to bring down the blood glucose value

to 25 mg/dL compared with a person with type 1 diabetes whose cor-

rection factor is 1 unit of lispro or aspart to bring down the blood glucose

value to 50 mg/dL. The carbohydrate to insulin ratio and correction factor

may be different depending on the time of the day and degree of

hyperglycemia.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.



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External insulin pump therapy

External insulin pump therapy or continuous subcutaneous insulin

infusion (CSII) has been traditionally used mainly in people with type 1

diabetes. However, insulin pump therapy is extremely valuable in patients

with type 2 diabetes who require insulin but who have not achieved glycemic

control with subcutaneous injections or who are seeking for a more flexible

lifestyle. All of the benefits that are enjoyed by patients with type 1 diabetes

are shared with people with type 2 diabetes. Many experts believe that

because of the more physiologic delivery of insulin, glucose control is

achieved with less insulin than was needed with the subcutaneous insulin

regimen. This may be caused by a reduction in glucose toxicity and im-

provement of insulin resistance and beta-cell secretory function as a result of

improved glycemic control with pump therapy. Weight gain is less of an

issue because the patient is using less insulin than was used before insulin

pump therapy. In addition, with the reduction of hypoglycemic events there

is less overeating to compensate for excessive insulin. Last, it is possible that

pump therapy may result in less strain placed on the pancreatic beta-cells of

patients with type 2 diabetes, and this may help with overall glycemic

control because a functioning beta-cell can also autoregulate against hyper-

and hypoglycemia, as seen in non-diabetic individuals.

Many older patients with the diagnosis of insulin-requiring type 2

diabetes have acute, true, late-onset type 1 diabetes. The literature

documents large groups of patients with insulin-requiring type 2 diabetes

who were tested for anti-glutamic acid decarboxylase antibodies with a

positivity rate of approximately 5% to 8%. These individuals are thinner at

the time of diagnosis, generally do not respond well to oral agents, and

require insulin, although they do not present in severe diabetic ketoacidosis.

These patients generally should be put on an intensive insulin injection

regimen, and insulin pump therapy should be considered.

Insulin pump therapy allows for increased flexibility in meal timing and

amounts, increased flexibility in the time and intensity of exercise, improved

glucose control while traveling across time zones or with variable working

schedules, and quality of life in terms of self-reliance and control.

Because pumps use only regular and fast-acting insulin, there is no

peaking of injected intermediate- and long-acting insulins, which do not

provide as constant a basal rate caused by variable absorption and

pharmacokinetics. Insulin glargine is an exception in that it serves as

excellent basal insulin. Variable insulin absorption and pharmacokinetics

are probably responsible for up to 50% to 60% of the day-to-day

fluctuation in blood glucose values in individuals using multiple-injection

regimens with various insulin types. Insulin pump therapy allows for more

regular insulin absorption and pharmacokinetic profile, resulting in im-

proved reproducibility in insulin availability and reduced fluctuations in

glycemic control [62].



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Presently, there is a paucity of clinical trials using insulin pumps in type 2

diabetes, but pump therapy is a viable option in insulin-requiring patients

with type 2 diabetes who are unable to achieve adequate glycemic controlwith multiple-injection regimens. Although some studies demonstrate

metabolic benefits of pump therapy in type 2 diabetes, all are limited by

a relatively short period of evaluation and a small number of heterogeneous

subjects. Interpretation of these studies is further confounded by the

random assignment of subjects to dissimilar conventional insulin regimens,

making comparison between studies difficult.

Garvey et al[69]studied the effect of intensive insulin therapy on insulin

secretion and insulin action before and after 3 weeks of CSII therapy in 14

patients with type 2 diabetes (age 50 3 years, duration of diabetes 7.8 2.1 years, and 119% ideal body weight). In 3 weeks of therapy, the mean

fasting plasma blood glucose and glycosylated hemoglobin values fell 46%

and 38%, respectively. The mean daily insulin dose stabilized at approxi-

mately 110 units/d, and there was a 74% increase in the insulin-stimulated

glucose disposal rate and a 45% reduction in hepatic glucose output to

mean levels similar to those of normal subjects. In addition, there were

significant improvements in both endogenous insulin and C-peptide

secretion. This study demonstrated that pump therapy was feasible and ef-

fective at improving metabolic control and reversing glucose toxicity inthese poorly controlled subjects with type 2 diabetes.

Jennings et al[70]randomized 20 type 2 diabetic subjects (median age 61

years, duration of diabetes 6 years, and percentage of ideal body weight

120%) to either CSII or twice-daily injections of regular and NPH insulin for

4 months. Glycemic control improved in both groups, although there was

a 30% reduction in the glycosylated hemoglobin in the CSII-treated group

and only a 17% reduction in the twice-daily injection-treated group. There

were no significant differences between the two groups in median daily

insulin requirement (0.58 versus 0.65 units/kg), weight gained (4.5 versus4.2 kg), prevalence of mild hypoglycemic reactions, or patient acceptance. In

addition, in the CSII group 58% of the total daily insulin requirement was

given as a basal infusion, with the remainder as pre-meal bolus injections

using insulin algorithms. This ratio of basal to bolus insulin requirements are

similar to the rates commonly used in type 1 diabetes, but there are

characteristics of pump therapy that are very different in type 2 diabetes.

In a more recent study, Pouwels et al[71]prospectively studied 8 patients

with poorly controlled (HbA1c 12.0 1.7%) type 2 diabetes with high

insulin requirements (1.92 0.66 U/kg/d). The subjects where aggressivelytreated with intravenous (IV) insulin for approximately 1 month followed by

12 months of CSII therapy. Insulin sensitivity and secretion were measured

before and after the IV insulin treatment phase.

Euglycemia was achieved after 12 days of IV therapy, and the insulin

requirements eventually reduced from 1.7 0.09 to 1.1 0.06 U/kg/d (P

0.005) during the IV treatment phase of the protocol. Whole-body glucose



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uptake increased from 12.7 5.7 to 22.4 8.8 lmol/kg/min (P 0.0005), and

in 1 month of intensive therapy, the HbA1cdropped to 8.9% 1.2% with no

significant change in the patients body weight. After 6 and 12 months of CSIItherapy, the mean HbA1c values were 7.1 0.6% and 8.3 1.4%, respectively

(P 0.001 versus pretreatment values for all time points)[71].

In another recent study [72], 132 CSII nave type 2 diabetics were

randomized to the pump or multiple daily injections (MDI). This study

showed that pump therapy provided efficacy and safety equivalent to MDI

therapy. Lower 8-point blood glucose values were shown by the CSII group at

most time points (values were only significant 90 min after breakfast; 167

47.5 mg/dL versus 192 65.0 mg/dL for CSII and MDI, respectively;

P= 0.019) (Fig. 4).In summary, insulin pump therapy has not been fully evaluated in

patients with type 2 diabetes. From published studies, however, it is

apparent that CSII therapy can safely improve glycemic control while

limiting hypoglycemia. CSII may be particularly useful in treating patients

with type 2 diabetes who do not respond satisfactorily to more conventional

insulin treatment strategies.

Alternative insulin delivery systems

Inhaled insulin is currently under development by several pharmaceutical

companies for use in people with type 1 and type 2 diabetes. The insulin is

Fig. 4. Baseline and end-of-study 8-point blood glucose profiles (mean SEM) for the intent-

to-treat population. Dashed lines represent baseline profiles; solid lines represent end-of-studyprofiles; , means for CSII; n, means for MDI therapy. Number of patients at each time point:

CSII, 5663; MDI, 5459. *P, 0.02. BB, before breakfast; B90, 90 minutes after breakfast;

BL, before lunch;L90, 90 minutes after lunch; BD, before dinner;D90, 90 minutes after dinner;

BE, at bedtime. (From Raskin P, Bode BW, Marks JB, Hirsh IB, Weinstein RL, McGill

JB, Peterson GE, Mudaliar SR, Reinhardt RR. Continuous subcutaneous insulin infusion and

multiple daily injection are equally effective in type 2 diabetes: a randomized, parallel-group,

24-week study. Diabetes Care 2003;26(9):2598603; with permission.)



22/31

contained in a pellet and is vaporized in an inhaler, which aerosolizes the

liquid insulin. Inhaled insulin can also be delivered to the pulmonary

microvasculature as a dry powder system and inhaled through a mouthpiece.It provides the obvious incentive for diabetic patients to use insulin without

the need for injections.

Cefalu et al[73]conducted a randomized, open-label, 3-month study with

26 patients (16 men, 10 women; average age, 51.1 years) with type 2 diabetes

(average duration of diabetes, 11.2 years). Patients received inhaled insulin

before each meal plus a bedtime injection of ultralente insulin, performed

HGM, and adjusted their insulin dose weekly. The target level for

preprandial plasma glucose was 100 to 160 mg/dL. At the end of 3 months,

inhaled insulin treatment significantly improved glycemic control comparedwith baseline, and mean HbA1c levels decreased by 0.07%. Hypoglycemic

events were mild, and patients showed no significant weight gain or change

in pulmonary function compared with baseline. Thus in this study, pul-

monary delivery of insulin in type 2 diabetic patients who require insulin

improved glycemic control was well tolerated and demonstrated no short-

term adverse pulmonary effects [74].

A new Aerodose insulin inhaler proved to be comparable to sub-

cutaneous injections through overlapping dose-response curves, with con-

sistent relative bioavailability and relative biopotency. The inhaler delivereda pharmacologically predictable insulin dose to type 2 diabetics, similar

to that with subcutaneous insulin injections[75].The Aerodose inhaler used

regular insulin (Humulin R), U-500, whereas Humulin R, U-100 was used

for subcutaneous injections. Serum insulin levels before exogenous insulin

administrations were similar between inhaled and subcutaneously inject

insulin (t, baseline,P = 0.12). At the end of dosing (t, 0 min), serum insulin

levels were significantly higher for inhalation treatments than for sub-

cutaneously injected treatments, indicating rapid, systemic insulin absorp-

tion following inhalation. The area under the curve (AUC)0-8h andmaximum serum insulin concentration demonstrated a clear dose-response

relationship for the three doses of inhaled insulin and the three doses of

subcutaneously injected insulin (Fig. 5)[75].

Insulin can also be taken orally by capsules, enterocoated with a soybean

trypsin inhibitor that prevents insulin degradation. This approach has

clinical potential, but large clinical trials have not been carried out.

Chemically modified human insulin, called hexyl insulin, using proprietary

conjugation technology to improve its stability and oral absorption has

shown promise. Preliminary results reported that in healthy humanvolunteers, hexyl insulin caused dose-dependent glucose lowering, was safe,

and was well tolerated. In a small clinical study, oral insulin illustrates the

similarities and differences among hexyl insulin monoconjugate (HIM)2 oral

insulin, subcutaneous insulin, and placebo. All three curves are indistin-

guishable from each other during the first hour postdose. The placebo curve

then separates from the other two curves, displaying a significantly higher



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peak excursion. The HIM2 and subcutaneous insulin curves remain nearly

indistinguishable for at least another hour. During the fourth hour

postdose, the HIM2 curve clearly separates from the subcutaneous insulincurve, becoming nearly identical to the placebo curve, as the glucose

excursion values in all three groups decline toward baseline. Peripheral

plasma insulin revealed an initial peak in peripheral plasma insulin

concentrations following administration of HIM2; however, this initial

insulin peak was caused by one patient who had a rapid peak of insulin. The

median insulin Cmax values, following administration of HIM2 and sub-

cutaneous regular insulin, were nearly identical (Fig. 6)[76].

Amylin analog: a novel injectable peptide that compliments the action

of insulin

Destruction and dysfunction of pancreatic beta-cells, resulting in

absolute and relative insulin deficiency, represent key abnormalities in the

pathogenesis of type 1 and type 2 diabetes, respectively [77]. Following the

Fig. 5. Glucose infusion rate (GIR) registered following administration of inhaled insulin (,

80 units; n,160 units; , 240 units) and subcutaneous injection (}, 8 units; , 16 units; , 24

units) in patients with type 2 diabetes. GIRs have been averaged over 30-minute periods. Datapoints are means SE (n = 16) at each time point for low, medium, and high doses for inhaled

and injected insulin. (From Kim D, Mudaliar S, Chinnapongse S, Chu N, Boies SM, Davis T,

Perera AD, Fishman RS, Shapiro DA, Henry R. Dose-response relationships of inhaled insulin

delivered via the Aerodose insulin inhaler and subcutaneously injected insulin in patients with

type 2 diabetes. Diabetes Care 2003;26(10):28427; with permission.)



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25/31

discovery of amylin in 1987, a second beta-cell 37-amino acid hormone that

is co-secreted with insulin in response to nutrient stimuli, it was realized that

diabetes represents a state of bi-hormonal beta-cell deficiency and that a lackof amylin action may contribute to abnormal glucose homeostasis.

Experimental studies show that amylin acts as a neuroendocrine hormone

that complements the effects of insulin in postprandial glucose regulation

through several centrally mediated effects. These include a suppression of

postprandial glucagon secretion and a vagus mediated regulation of gastric

emptying, thereby helping to control the inflow of endogenous and

exogenous glucose, respectively. In animal studies, amylin also reduces

food intake and body weight, consistent with an early satiety effect[78].

Insulin is the major hormonal regulator of glucose disposal. Preclinicaland clinical studies indicate that amylin complements the effects of insulin

by regulating the rate of glucose inflow to the bloodstream, suppressing

glucagons secretion and inducing satiety.

Pramlintide is a soluble, nonaggregating, injectable, synthetic analog of

human amylin currently under development for the treatment of type 1 and

insulin-using type 2 diabetes. Long-term clinical studies have consistently

demonstrated that prandial subcutaneous. injections of pramlintide, in

addition to the current insulin regimen, reduce HbA1c and body weight in

type 1 and type 2 diabetic patients, without an increase in insulin use or inthe incidence of severe hypoglycemia[79].

Treatment with 120 lg twice per day of pramlintide in subjects with type

2 diabetes led to a sustained reduction from baseline in HbA1c (0.68 and

0.62% at weeks 26 and 52, respectively) that was significantly greater than

that in the placebo group (P\ 0.05) (Fig. 7)[80]. The greater reduction of

HbA1c observed with pramlintide was not accompanied by an increase in

body weight. Instead, patients in both pramlintide treatment groups

experienced a sustained reduction in body weight that was significantly

different from placebo at week 26 (both P 0.05) [80]. In the group ofsubjects who took 120 lg twice daily, the reduction in body weight was

sustained to week 52 (P 0.05 versus placebo).

The most commonly observed side effects were gastrointestinal-related,

mainly mild nausea, which typically occurred on initiation of treatment and

Fig. 6. 0.5 mg/kg and 1.0 mg/kg HIM2 dose groups; pooled data. (A) Mean plasma glucose

excursion versus time profiles and (B) mean plasma insulin concentration versus time profiles.

At time 0, patients received 0.5 or 1.0 mg/kg oral HIM2, 8 units subcutaneous regular insulin or

oral placebo. At 30 min, patients began ingesting the standardized meal (Boost Plus). Patientsingested the entire meal over a 10-minute period. Postprandial plasma glucose excursions and

insulin concentrations were determined from blood samples collected a the time points

indicated. Data are expressed as means SE (n = 12 patients). , oral HIM2 (0.5) and 1.0 mg/kg

dose groups combined); , 8 units of subcutaneous regular insulin; , oral placebo. (From Kipnes

M, Dandona P, Tripathy D, Still JG, Kosutic G. Control of postprandial plasma glucose by an

oral insulin product (hexyl-insulin monoconjugate 2 [HIM2]) in patients with type 2 diabetes.

Diabetes Care 2003;26(2):4216; with permission.)

=



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resolved within days or weeks. Amylin replacement with pramlintide as an

adjunct to insulin therapy is a novel physiological approach toward

improved long-term glycemic and weight control in patients with type 1

and type 2 diabetes.

Summary

Type 2 diabetes is a common disorder often accompanied by numerous

metabolic abnormalities leading to elevated rates of cardiovascular morbid-

ity and mortality. Improved glycemia will delay or prevent the development

of microvascular disease and reduce many or all of the acute and subacute

complications that worsen the quality of daily life. Exogenous insulin is

Fig. 7. Change from baseline in mean HbA1c (A) and weight (B) (intent-to-treat population).

*P 0.05 for treatment arm versus placebo. , placebo; n, 90 lg twice daily; , 120 lg. (FromHollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, et al. Pramlintide as

an adjunct to insulin therapy improves long-term glycemic and weight control in patients with

type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 2003;26(3):78490; withpermission.)



27/31

usually the last line of treatment used to normalize glycosylated hemoglobin

in patients with type 2 diabetes who have failed other therapeutic modalities.

Not all patients are candidates for aggressive insulin management; therefore,the goals of therapy should be tailored to the individual. Candidates for

intensive management should be motivated, compliant, educable, and

without other medical conditions and physical limitations that would

preclude accurate and reliable HGM and insulin administration.

In selected patients, combination therapy with insulin and oral antidia-

betic medications can be an effective method for normalizing glycemia

without the need for rigorous insulin regimens. The most common clinical

situation in which combination therapy can be successful occurs in patients

who are failing daytime oral agents therapy and still show some evidence ofresponsiveness to the medications. Bedtime intermediate- and long acting-

insulin are administered and progressively increased until the fasting blood

glucose concentration is normalized. Additional benefits of combination

therapy include ease of administration, excellent patient compliance and

safety, and lower exogenous insulin requirements with less peripheral

hyperinsulinemia and weight gain. If combination therapy is not successful,

a split-mixed regimen of an intermediate- and a fast-acting insulin equally

divided between the pre-breakfast and pre-dinner periods can be effective

especially in obese patients.For patients who do not achieve glucose control on combination or split-

mixed regimens, an intensive basal bolus multiple-injection regimen is

indicated. Continuous subcutaneous insulin infusion pumps can be partic-

ularly useful in treating patients with type 2 diabetes mellitus who do not

respond satisfactorily to more conventional treatment strategies. The use of

fast-acting insulin analogs should be used in the majority of insulin-requiring

diabetics because of its more physiologic pharmacokinesis. Inhaled insulin

and the amylin analog pramlintide also hold promise to intensively control

glycemia in patients with insulin-requiring type 2 diabetes.The glycemic objectives for patients with type 2 diabetes should be similar

to those for patients with type 1 diabetes, namely, to normalize glycemia and

glycosylated hemoglobin without causing undue weight gain or hypoglyce-

mia or adversely affecting the quality of daily life. This is best achieved in

a multidisciplinary setting using complementary therapeutic modalities that

include a combination of diet, exercise, and pharmacologic therapy.

Emphasis should be placed on diet and exercise initially, and throughout

the course of management as well, since even modest success with these

therapies will enhance the glycemic response to both oral antidiabetic agentsand insulin.

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