Harnessing endocrine physiology for better clinical outcomes

Clinical Cornerstone • THERAPEUTIC OPTIONS FOR CARDIOMETABOLIC RISK FACTORS • Vol. 9, Supplement 1

Harnessing Endocrine Physiology for Better Clinical Outcomes STEPHEN N. DAVIS, MD, FRCP Chief, Division of Diabetes, Endocrinology

and Metabolism Rudolph Kampmeier Professor, Medicine

and Molecular Physiology and Biophysics Vanderbilt University Medical School Nashville, Tennessee

GARY A . MANKO, M D

Clinical Associates, PA Reisterstown, Maryland

SUSAN RENDA, CRNP, CDE

Clinical Associates, PA Reisterstown, Maryland

Diabetes is a highly prevalent and costly disease with debilitating vascular and metabolic complications. The

effects of both fasting plasma glucose (FPG) and postprandial glucose (PPG) excursions independently lead to

an increased risk of morbidity and mortality. In patients with glucose levels that are fairly well controlled (ie,

glycosylated hemoglobin [HbAlc] <7.3%), PPG excursions are the predominant form of hyperglycemia. In patients with poor HbAlc values (>8.5%), the pattern is one of both elevated FPG and PPG levels, with the

predominant contribution resulting from an increase in fasting hyperglycemia. These data point to the need for

a physiologically based basal-bolus insulin replacement strategy, with administration of basal insulin working

to restore interprandial glucose levels and bolus insulin to simulate mealtime actions of the pancreas. Insulin

also may offer beneficial anti-inflammatory, vasodilatory, antithrombotic, and antiapoptotic effects. Reductions

in cardiometabolic risk factors and other parameters, therefore, focus attention on the early use of a basal-bolus

insulin strategy. Challenges faced in the treatment of diabetes, including barriers and myths associated with the

use of insulin, represent an area that urgently needs to be addressed. Patients and their caregivers need to be

educated about the progressive nature of diabetes and the benefits of insulin to help them make informed

decisions to ensure optimal diabetes care. (Clinical Cornerstone. 2008;9[Suppl 1]:$28-$40) © 2008 Excerpta

Medica Inc.

Diabetes mellitus (DM) represents a significant and grow-

ing burden to the public health system in the United States.

Approximately 14.6 million people have been diagnosed

with diabetes; but 6.2 million people are undiagnosed,

and an additional 54 million can be classified as having

prediabetes, 1 a new category described in the 2007

American Diabetes Association (ADA) treatment guide-

lines. Individuals with prediabetes have impaired fasting

glucose levels (_> 100 but <126 mg/dL) or impaired glucose

tolerance (2-hour postload values _>140 but <200 mg/dL)

and are at an increased risk for developing diabetes. 2

Diabetes affects adolescents as well as adults. Roughly

176,500 adolescents (<20 years of age) have diabetes, rep-

resenting 0.22% of all people in this age group. Whereas

type 2 DM was rarely observed in this age group, it is being

diagnosed with increasing frequency. This is of particular

concem in Native, African, and Latino American popula-

tions, as these groups are at a 1.7 to 2.2 times greater risk

of developing diabetes. Although total prevalence data

for Asian Americans and Pacific Islanders living in the

continental United States are unavailable, in Hawaii, Asian

Americans, Native Hawaiians, and Pacific Islanders are

known to be at a 1.5 to 2 times greater risk for diabetes than

non-Hispanic whites. These rates are consistent with those

observed among Asian populations in California)

Diabetes is associated with increased morbidity and mor-

tality. Between 12,000 and 24,000 people are diagnosed

with diabetic retinopathy each year, 3 and the unadjusted

rate of visual impairment among adults with diabetes in

2005 was 21%. 4 Approximately two thirds of patients

with diabetes have neuropathy, which greatly affects

their quality of life. 3 Sensory neuropathy in the feet, a

condition that is present in -30% of people with diabetes

who are _>40 years of age, increases the possibility of

lower-limb amputations; in fact, >60% of all nontrau-

matic lower-limb amputations occur in people with dia-

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betes. 3 Diabetes is the leading cause of renal failure,

accounting for 44% of all new cases in 2002. In that year,

44,400 people with diabetes in the United States and

Puerto Rico began treatment for end-stage kidney dis-

ease, joining the 153,730 people with diabetes requiring

chronic dialysis or having received a kidney transplant. 3

Adults with diabetes have a 2- to 4-fold higher likeli-

hood of dying from heart disease or stroke compared

with nondiabetic adults. Indeed, heart disease or stroke

accounts for -65% of deaths in people with diabetes. 3

Khaw et al 5 report that the relative risk of death due to

cardiovascular disease (CVD) or ischemic heart disease

(IHD) increases as glycosylated hemoglobin (HbAlc)

concentrations increase. The HbAlc concentration is

indicative of blood glucose levels over several months.

Risk of death from CVD or IHD increases >5-fold in

diabetic patients with HbAlc levels >7% versus those

with HbAlc levels _<5% (P < 0.001). In addition, -73%

of adults with diabetes have blood pressure levels

_>130/80 nun Hg or are taking medication for hyperten-

sion. 3 Hypertension increases the already high risk of

CVD in patients with diabetes, but tight control of blood

pressure levels reduces the morbidity and mortality associated with hypertension. 6

Although intensive metabolic control is an effective

treatment strategy, diabetes remains a progressive disease

with high associated costs] In 2002, total direct and indi-

rect costs in the United States were estimated at $132 bil-

lion. This figure is likely an underestimation of the

actual burden of the disease, as it neither accounts for

intangibles such as pain and suffering or care provided

by unpaid caregivers, nor includes costs for podiatric

care, vision care, or care provided by certified diabetes

educators or licensed dieticians. In addition, this figure

does not include health care spending or costs associated

with undiagnosed diabetes. Even without factoring in

these omissions, costs are expected to be $192 billion by

2020. 7 The burden of diabetes must be addressed, and

solutions that can alleviate its impact employed.

THE PROBLEM: INSULIN SECRETORY DEFICITS A N D INSULIN RESISTANCE Insulin secretory deficits and insulin resistance (ie,

diminished tissue response to insulin or defects in

insulin action) are present even before the clinical

diagnosis of type 2 DM. Deficits in insulin secretion

frequently coexist with defects in insulin action in the

same patient, and it is often unclear which is the pri-

mary cause of hyperglycemia. 8

KEY P O I N T

Deficits in insulin secretion frequent-

ly coexist with defects in insulin

action in the same patient, and it is

often unclear which is the pr imary

cause of hyperglycemia.

Prediabetic patients may have a degree of hyperglycemia

sufficient to cause a pathologic effect on target tissues, but

patients also may present with no clinical symptoms. The

extent of hyperglycemia may change over time, depend-

ing on the underlying pathophysiology of the disease.

Alternatively, an underlying disease process may be present

but not be extensive enough to induce hyperglycemia, s

Figure 1 describes the pathophysiology underlying

the development of hyperglycemia in prediabetic and

diabetic patients. 9 Under normal conditions, insulin

represses hepatic glucose production overnight, regulat-

ing fasting plasma glucose (FPG) levels. Insulin also

represses glucose production during food consumption

and removes glucose from the circulation by increasing

hepatic and skeletal muscle uptake, 9 regulating postpran-

dial glucose (PPG) levels. In diabetic patients, dysregula-

tion of these 2 important homeostatic mechanisms, when

coupled with insulin resistance, increases plasma glucose levels both postprandially and in the fasting state. 1°,11

CONSEQUENCES OF POSTPRANDIAL HYPERGLYCEMIA During the postprandial period, carbohydrates are

absorbed and glucose concentrations rise. Considering

that people generally eat 3 meals a day, 3 postprandial

periods of -4 to 5 hours each are observed; therefore,

people spend more than half of their day in a postpran-

dial state. The postprandial state overlaps with a post-

absorptive state lasting -6 hours, during which time

glucose is removed from the circulation. In reality, then,

only -2 hours at the end of an individual's night are spent

in a true fasting state (Figure 2), when there is a shift

from glycogenolysis to gluconeogenesis.12 Consequently,

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Impaired insulin secretion

Figure 1.

Decreased glucose uptake Increased HGP

The pathophyslology of hyperglycemia in predlabetes and type 2 diabetes. Impaired secretion of insulin by the pancreas, increased production of glucose by the liver, and decreased glucose uptake by skeletal muscle contribute to the development of hyperglycemia. HGP = hepatic glucose production. Copyright © 1988 American Diabetes Association. From Diabetes ®, Vol. 37, 1988; 667-687. Modified with permission from the American Diabetes Association.

the fasting state may not accurately reflect a patient's

24-hour metabolic profile and should not be used as a

measure of glycemic control. Since most of a patient's

day is spent in a postprandial state, postprandial mea-

surements may be more useful for monitoring.

KEY P O I N T

Only -2 hours at the end of an indl- vldual's night are spent in a true fasting state. Consequently, the fasting state may not accurately reflect a patient's 24-hour metabolic profile.

Several independent clinical studies have demon-

strated that the PPG level, independent of the FPG level,

is a risk factor for cardiovascular morbidity and mortali-

ty. These studies include the Diabetes Epidemiology:

Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study, 13 the Rancho Bemardo Study, 14 the

Whitehall Study, 15 the Paris Prospective Study, 15 and the

Helsinki Policemen Study. 15

Chronic hyperglycemia is one cause of endothelial dys-

function. Endothelial dysfunction contributes to the devel-

opment of atherosclerosis and precedes the clinically vascu-

lar pathology that leads to CVD. Some patients with type 2

DM or impaired glucose tolerance experience hyperglyce-

mia only in the postprandial state. Hyperglycemia induced

by oral glucose loading suppresses endothelium-dependent

dilation of the brachial artery, and this suppression of bra-

chial artery dilation is a step in the development and pro-

gression of atherosclerosis) 6 Patients with diabetes also

demonstrate increased levels of circulating intercellular

adhesion molecule-l, which increases atherogenic risk) 7,18

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• Postprandial • Postabsorptive [] Fasting

F Breakfast

I LI

I I I I Lunch Dinner Midnight 4 AM Breakfast

t t t t 8AM 11 AM 2PM 5PM

L I Blood Sampling

Figure 2. Time in postprandial , postabsorptive, and fasting states. Blood samples were taken at 8 AM, 11 AM, 2 PM, and 5 PM to determine the diurnal blood glucose profile. Monnier L. Is postprandial glucose a neglected cardiovascular risk factor in type 2 diabetes? Eur J Clin Invest. 2000;30(Suppl 2):3-11. Adapted wi th permission from Wiley-Blackwel l Publishing.

In addition to postprandial hyperglycemia, increased

triglyceride levels associated with type 2 DM work

through independent mechanisms to further decrease

endothelial cell function. Taken together, the effects of

postprandial hyperglycemia and hypertriglyceridemia are

additive39 Levels and activity of plasminogen activator

inhibitor-1 increase in response to hypertriglyceridemia

and are associated with the development of myocardial

infarction (MI) due to inhibition of fibrinolysis in patients with type 2 DM. 2°,21

BENEFITS OF INSULIN BEYOND GLYCEMIC CONTROL Elevated FPG and PPG levels contribute to the elevated

HbAlc concentrations observed in patients with type 2

DM to varying degrees. PPG excursions are the pre-

dominant form of hyperglycemia in patients whose

HbAlc is <7.3%, whereas a pattern of predominantly

fasting hyperglycemia is observed among patients with

HbAlc >8.5%. 11 This points to the role of insulin therapy

for patients who are unable to achieve HbAlc <7.0%

with (1) lifestyle intervention alone, (2) lifestyle inter-

vention plus metformin, or (3) lifestyle intervention plus

metformin and a sulfonylurea or a thiazolidinedione

(TZD), or for patients who present with weight loss and glucose values between 250 and 300 mg/dL. 22 The addi-

tion of insulin, a sulfonylurea, or a TZD will depend on

the patient's HbAlc level, the cost of therapy, and/or the

characteristics and side effects of the agent chosen.

According to a consensus statement from the ADA and

the European Association for the Study of Diabetes, 23

when insulin therapy is initiated, basal insulin should be

used first and rapid-acting bolus insulin added if the

HbAlc target is not reached. Basal insulin works inter-

prandially to restore glucose levels, while bolus insulin

KEY P O I N T

Basal insulin works interprandial ly to restore glucose levels, whi le bolus

insulin works during mealtimes,

simulating the normal activity of the pancreas.

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Clinical Cornerstone • THERAPEUTIC OPTIONS FOR CARDIOMETABOLIC RISK FACTORS • V01. 9, Supplement 1

works during mealtimes, simulating the normal activity

of the pancreas. When administered at an appropriate dose, insulin not

only lowers blood glucose levels but also may have

favorable anti-inflammatory, vasodilatory, antithrombotic, and antiapoptotic effects (Figure 3). 24 Vehkavaara and Yki-J~irvinen 25 showed that long-term basal insulin ther-

apy with insulin glargine significantly improves both endothelium-dependent and endothelium-independent vascular function in patients with type 2 DM. After

3.5 years of treatment with insulin glargine plus metformin, blood flow during administration of high-dose acetylcholine (an endothelium-dependent vasoactive agent) in pa-

tients with type 2 diabetes (n = 11) increased 86% from baseline (8.8-14.7 mL/dL per minute; P < 0.01). Similarly, blood flow during administration of high-dose

sodium nitroprusside (an endothelium-independent vasoactive agent) increased 72% from baseline (10.7- 16.6 mL/dL per minute; P < 0.05). Prior to treatment, blood flow during infusions of both low-dose and high-

dose acetylcholine was significantly lower in participants with type 2 DM than in normal subjects (P = 0.021).

The use of fast-acting insulin has been compared with that of regular insulin to determine the effects of post-

prandial hyperglycemia on myocardial perfusion abnor- malities, which are early markers of atherosclerosis in patients with type 2 DM. Administration of a fast-acting

insulin analog was shown to improve postprandial glycemic control, partially reverse myocardial perfusion abnor- malities, and improve coronary vessel flow by reducing glycemic excursions. 26

BASAL-BOLUS INSULIN THERAPY MIMICS METABOLIC PHYSIOLOGY The concept of basal-bolus insulin therapy (BBT) is

based on sustaining near-normal blood glucose levels by using insulin replacement therapy to closely match normal physiologic response. In patients with diabetes, regu-

lar insulin administered as a bolus before meals is used to mimic prandial insulin requirements by simulating the insulin surge produced in anticipation of eating and to

correct incidences of hyperglycemia. Plasma insulin concentrations peak at -1 to 2 hours after administration of a soluble insulin bolus and return to basal levels at -6 to

Anti-i nflammatory #NF-KB, 21KB,

#MCP-1, #ICAM-1, #CRP

Antioxidant # ROS

Mechanism of the Benefits of Insulin in Acute Illness

Antithrombotic #TF, # PAl- 1

Vasodilation and Platelet Inhibition

~NO release, #cAMP, ~eNOS

Figure 3.

Cardioprotective Neuroprotective Antiapoptotic

Glucose Lowering

Current v iew of the actions of insulin, specifically the benefits of insulin in acute illness. # = decrease; NF-lcB = nuclear factor kappa B; # = increase; hoB = inhibitor kappa B; MCP-1 = macrophage chemoattractant protein- I ; ICAM-1 = intercellular adhesion molecule- 1; CRP = C-reactive protein; ROS = reactive oxygen species; TF = tissue factor; PAl-1 = plasminogen activator inhibitor-1; NO = nitric oxide; cAMP = cyclic adenosine monophosphate; eNOS = endothelial NO synthase. Copyright © MedReviews, LLC. Modified with permission of MedReviews, LLC. Dandona P, Chaudhuri A, Gharim H, Mohanty P. Anti-inflammatory effects of insulin and proinflammatory effects of glucose: Relevance to the management of acute myocardial infarction and other acute coronary syndromes. Rev Cardiovas Med. 2006;7(Suppl 2 ) :$25 -$34 . Reviews in Cardiovascular Medicine is a copyrighted publication of MedReviews, LLC. All rights reserved.

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KEY P O I N T

The concept of basal-bolus insulin

therapy is based on sustaining near-

normal blood glucose levels by using

insulin replacement therapy to

closely match normal physiologic

response.

8 hours after administration. With regular insulin remain-

ing in the plasma for -6 to 8 hours, episodes of hypogly-

cemia may occur, particularly in the early morning hours,

after administration of insulin with the evening meal. 27

This trend is in contrast to the physiologic response observed in individuals without diabetes. 27 In an indi-

vidual with normal physiology, plasma insulin concen-

tration peaks 30 to 60 minutes after eating and returns to

basal levels within -2 to 3 hours.

Rapid-acting insulin analogs, such as glulisine, lispro,

and aspart, differ in activity from regular insulin in several respects. 27 29 Rapid-acting analogs, which begin to

work in -15 minutes, limit PPG fluctuations more effec-

tively than does regular insulin. Plasma insulin concen-

trations peak in -1 to 2 hours after administration of a

rapid-acting analog and return to basal levels after -3 to

4 hours. These actions provide increased dosing flexibili-

ty and decrease the possibility of severe postprandial hypo-

glycemia, especially in individuals attempting to maintain normoglycemia. 27 29

Intermediate- and long-acting insulins mimic basal

insulin secretion to control FPG levels. These insulins

include neutral protamine Hagedorn (NPH) insulin,

lente, ultralente, insulin glargine, and insulin detemir.

Intermediate-acting insulins such as NPH or lente show

activity -2 to 4 hours after administration and return to

baseline plasma concentrations in 16 to 24 hours. Insulin

glargine and insulin detemir begin to work -1 to

2 hours after administration and retain activity for

24 hours without major fluctuations in FPG levels.

The need to increase basal insulin levels was identi-

fied after it was observed that continuous administra-

tion of the rapid-acting insulin analog lispro lowered

HbAlc concentrations. 27

DETERMINING BOLUS INSULIN DOSES Initiation of a basal-bolus regimen presents manageable

challenges to patients and their health care providers. BBT

requires calculation of the appropriate dose of bolus in-

sulin to be administered before meals, which will vary

depending on what kinds of food and how much food a

patient plans to eat. Carbohydrate counting assists patients

in adjusting their insulin dose based on carbohydrate dis-

tribution and is often used by patients on BBT. For many

patients, however, this process is too complex.

Bergenstal et al 3° compared the process of carbohy-

drate counting with the use of an algorithm based on

preprandial glucose patterns to adjust mealtime doses of

bolus insulin. This randomized, open-label study found

that after 24 weeks of combination therapy with rapid-

acting glulisine plus insulin glargine, both patient groups

achieved mean HbAlc levels of 6.6% (P < 0.0001).

However, patients who used the algorithm to adjust

mealtime glulisine doses had fewer incidences of hypo-

glycemia compared with those using carbohydrate count-

ing (4.9 vs 8.0 events/patient-year; P = 0.02). Thus the

algorithm based on preprandial glucose patterns may

provide patients with an easier method to determine opti-

mal dosing of mealtime bolus insulin.

PREMIXED INSULIN PREPARATIONS VERSUS COMBINATION ORAL AGENT/ INSULIN THERAPY Premixed insulin preparations contain both a long-acting

insulin and a short- or rapid-acting insulin to provide both

basal and prandial activity. Despite their intended conve-

nience, premixed formulations may force patients into

rigid routines of eating and physical activity, limiting flexi-

bility in the control of their treatment. Because of the dif-

ficulty of adhering to a strict treatment regimen with these

preparations, more incidences of hypoglycemia may result, which represents a major safety concern. 31

Several randomized clinical studies of patients taking

oral insulin sensitizers found that the addition of once-

daily insulin glargine had comparable or superior effica-

cy with an improved safety profile versus the addition of premixed insulin at a 70/30 ratio. 31,32 In a study by

Raskin et al, 32 233 insulin-naive patients were random-

ized to receive either once-daily insulin glargine or

biphasic insulin aspart 70/30 twice daily in addition to

their oral agents. In the efficacy analysis, which was

based on the intent-to-treat population (insulin glargine,

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C l i n i c a l Corners tone • THERAPEUTIC OPTIONS FOR CARDIOMETABOLIC RISK FACTORS • Vol. 9, Supplement 1

n = 114; biphasic insulin aspart 70/30, n = 108), patients

randomized to insulin glargine had fewer incidences of

hypoglycemia than those randomized to biphasic insulin

aspart 70/30 (mean [SD], 3.4 [6.6] vs 0.7 [2.0] episodes/

year; P < 0.05). Patients administered insulin glargine

also demonstrated significantly less weight gain than

those treated with biphasic insulin aspart 70/30 (3.5 [4.5]

vs 5.4 [4.8] kg; P < 0.01), while reductions in HbAlc

were greater with the addition of premixed insulin than

with that of insulin glargine (-2.79% [0.11] vs -2.36%

[0.11]; P < 0.01). Janka et a131 demonstrated the supe-

rior safety profile of insulin glargine plus glimepiride

and metformin versus premixed NPH and regular insu-

lin administered at a 70/30 ratio (4.07 vs 9.87 hypogly-

cemic incidences/patient-year; P < 0.0001) in a ran-

domized study of 364 patients with inadequate glyce-

mic control on sulfonylurea plus metformin. In this

study, patients randomized to insulin glargine had a

significantly greater mean reduction from baseline in

HbAlc than did patients receiving the premixed insulin

formulation (-1.64% vs -1.31%; P = 0.0003). Reasons

for the contradictory results between the Raskin et al

and Janka et al studies regarding greater HbAlc reduc-

tions with premixed insulin versus glargine are unclear;

however, it has been suggested that the withdrawal of

secretagogues in both treatment arms of the Raskin et al

study may have disadvantaged insulin glargine. 32

The Treat-to-Target trial, 33 a randomized, open-label

study of 756 overweight patients with inadequate glyce-

mic control on oral agents, compared the efficacy and

safety of oral agents plus insulin glargine versus oral

agents plus NPH insulin. Both treatment groups reached

similar FPG end points (117 vs 120 mg/dL, respectively)

and HbAlc levels (6.96% vs 6.97%). Incidence of hypo-

glycemia, however, was significantly lower in the glargine

group than in the NPH group (26.7% vs 33.2%;

P < 0.05). The reduced incidence of hypoglycemia with

insulin glargine may be due to its flatter pharmacokinetic/

pharmacodynamic profile compared with the pronounced peaking effects observed with NPH-like compounds. 31 33

Morning or evening administrations of once-daily

detemir were recently compared with an evening admin-

istration of NPH insulin added to a regimen of oral agents

in a randomized, open-label study of 504 patients with poorly controlled type 2 DM. 34 Reductions in HbAlc

were comparable with detemir administered morning or

evening and NPH administered in the evening (-1.58%,

-1.48%, and -1.74%, respectively). However, to achieve

glycemic control with detemir comparable to that with

NPH, it was necessary to administer more total insulin

units with detemir morning and evening than with NPH

(43 and 37 vs 33 U). Incidence of nocturnal hypoglyce-

mia was significantly reduced with administration of

evening detemir (65%; P = 0.031) and morning detemir

(87%; P < 0.001) compared with NPH, and weight gain

was significantly reduced with evening detemir versus

NPH (0.7 vs 1.6 kg, respectively; P = 0.005).

Holman et a135 demonstrated that the addition of

biphasic or prandial insulin aspart to metformin and sul-

fonylurea was more effective than adding basal detemir

for lowering HbAlc; however, biphasic and prandial

insulin aspart were associated with an increased incidence

of hypoglycemia (5.7, 2.0, and 2.3 incidences/patient-year,

respectively) and mean weight gain (4.7, 5.7, and 1.9 kg,

respectively) compared with detemir. At 1 year, mean

HbAlc levels were similar in the biphasic and prandial

aspart groups (7.2%; P = 0.08) but higher in the basal

detemir group (7.6%; P < 0.001 for both comparators). Rosenstock et a136 recently compared insulin

detemir with insulin glargine in a 52-week, random-

ized (1:1), open-label trial in 582 insulin-naive adults

with type 2 DM. Participants received either insulin

detemir or insulin glargine once daily, in the evening,

titrated to a target FPG <6.0 mmol/L (<108 mg/dL).

Patients receiving detemir were allowed an additional

morning dose if their predinner glucose level was

>7.0 mmol/L (>126 mg/dL) after having achieved

FPG <7.0 mmol/L. In accordance with labeling restric-

tions, patients receiving glargine were only allowed

one daily dose. At the end of the study, mean reduction

in HbAlc was 1.5% for both study drugs, with com-

parable values of 7.2% and 7.1% for the detemir (n =

268) and glargine (n = 275) treatment groups, respec-

tively. Overall, 33% of participants in the detemir

group and 35% in the glargine group achieved HbAlc

goal without hypoglycemia. FPG response was also

comparable, with values declining from a mean of

10.8 mmol/L (194.6 mg/dL) at baseline to 7.1 mmol/L

(127.9 mg/dL) in the detemir group and 7.0 mmol/L

(126 mg/dL) in the glargine group. Mean weight gain

was significantly less with detemir than with glar-

gine among study completers (3.0 vs 3.9 kg; P =

0.01) and the intent-to-treat population (2.7 vs 3.5 kg;

P = 0.03).

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GLYCEMIC GOALS NOT MAINTAINED WITH MONOTHERAPY Elevated blood glucose is a risk factor for multiple macrovascular outcomes, including CVD, peripheral vascu-

lar disease, and cerebrovascular disease. As shown in Figure 4, a meta-analysis of 6 independent, randomized studies evaluating 4472 patients with type 2 DM demon-

strated that aggressive treatment to maintain glycemic control reduced the incidence of macrovascular disease. 37

Aggressive treatment for this patient population included

subcutaneous insulin injections or hypoglycemic agents combined with insulin injections, generally with frequent blood glucose monitoring, whereas conventional treat-

ment consisted of fewer daily insulin injections or treatment with hypoglycemic agents or diet alone, with less intensive glucose monitoring.

Diabetes is a progressive disease and, eventually, most patients will require insulin to control their blood glucose levels. In the United Kingdom Prospective Diabetes Study (UKPDS), 38 a randomized controlled

trial of 4075 patients with newly diagnosed type 2 DM, patients were randomized to monotherapy with insulin,

a sulfonylurea, or metformin, or to regulation of blood glucose levels with diet alone. After 3 years, approxi-

mately twice as many (-50%) patients could attain their

target FPG and HbAlc goals with insulin, sulfonylurea, or mefformin monotherapy compared with diet alone. After 9 years, only -25% of patients could attain these goals with monotherapy; the majority of patients need-

ed combination therapy to attain their goals. Corresponding values for patients treated with diet alone were 19% and 25% for FPG and HbAlc, respec-

tively, after 3 years, and 8% and 9%, respectively, after 9 years.

In a study by Wright et al, 39 826 patients with newly

diagnosed type 2 DM were randomized to treatment with a sulfonylurea (n = 339), insulin (n = 245), or dietary

control (n = 242). Over 6 years of follow-up, 53% of the patients receiving a sulfonylurea also required insulin therapy to achieve target glycemic goals.

NEWER AGENTS ALSO MIMIC NORMAL PHYSIOLOGY When choosing agents for the treatment of type 2 DM, several important factors should be considered. For example, when HbAlc levels are high, clinicians should

consider the types of insulin that produce large and rapid reductions in blood glucose levels. When HbAlc levels

Peripheral vascular 0

Cerebrovascular 0

Cardiac

Any macrovascular

I I 0.1 0.2

I 0.5

0

I I 2 10

Incidence Rate Ratio

Figure 4. Effect of intensified glycemic control on the risk for any type of macrovascular event and of peripheral vascular, cerebrovascular, and cardiac events in patients with type 2 diabetes. Combined estimates from a meta-analysis of 6 randomized controlled trials. This figure was published in American Heart Journal, 152. Stettler C, Allemann S, JiJni P, et ah Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: Meta-analysis of randomized trials, 27-38 . Copyright Elsevier © 2006. Adapted with permission.

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are closer to normal, the types of insulin that provide

slower, smaller reductions in glucose levels are required. 23

As with insulin, some of the newer agents that closely

mimic normal physiology may be appropriate to address

the issues of insulin deficiency and insulin resistance.

Several newer agents have been used successfully in

combination with oral antidiabetic agents or insulin. The

glucagon-like peptide-1 (GLP-1) agonist exenatide is

approved for use with metformin, a sulfonylurea, or a

TZD. Exenatide stimulates insulin secretion, suppresses

glucagon concentrations, and slows gastric motility,

thereby lowering PPG levels. Furthermore, weight loss

of -3 to 4 kg is commonly seen in patients administered

exenatide. 23,4° Exenatide lowers HbAlc levels by 0.5%

to 1%, but it is associated with transient gastrointestinal

(GI) side effects in 30% to 45% of patients.

The amylin agonist pramlintide is an antihyperglyce-

mic agent used in patients with diabetes who are being

treated with insulin. Administered preprandially, amylin

slows gastric emptying, suppresses glucagon secretion, and

decreases PPG excursions. Like GLP-1, amylin decreases

HbAlc levels by 0.5% to 0.7%, and it is also associated

with weight loss. GI side eflects, however, have been observed in -30% of patients treated with pramlintide. 23

Dipeptidyl peptidase (DPP)-IV inhibitors, which en-

hance the activity of the hormone incretin, preserve the

GLP-1 incretin eflect, slow gastric emptying, improve

[3-cell function, and enhance insulin secretion. The

DPP-IV inhibitor sitagliptin is indicated as an adjunct to

diet and exercise to improve glycemic control in adult

patients with type 2 DM. It can be taken as a single agent

or in combination with metformin, a sulfonylurea, or a

TZD. Treatment with sitagliptin reduces HbAlc by

-0.6% to 1.0%, is weight neutral, and does not generally cause GI side eflects. 18,41

PATIENTS NEED TO BE EDUCATED ABOUT DIABETES A N D INSULIN Insulin has become easier to administer with the advent

of insulin pens and pumps, and with improvements to

needles and syringes. Moreover, there are aids, including

syringe magnifiers, auditory or tactile measurement

devices, needle guides, and vial stabilizers, as well as

voice modules and synthesizers, that can help visually or

physically impaired people administer insulin and moni-

tor their glucose levels. How, then, should clinicians

discuss initiation of insulin therapy with their patients?

Diabetes educators believe that the progressive nature

of diabetes and the eventual need for insulin should be

discussed with patients and their caregivers from the time

of diagnosis. The need for insulin should be presented

n o t as a failure on the part of the patients to manage their

disease, but as part of the normal process of managing

diabetes. Educating patients about insulin deficiency and

insulin resistance and making the use of insulin a life-

style choice can allow patients greater control over their

treatment and more flexibility with meals and exercise.

Physicians and diabetes educators can help ease patients

into making the eventual transition from lifestyle modifi-

cations and oral agents to the addition of insulin.

KEY P O I N T

The progressive nature of diabetes

and the eventual need for insulin

should be discussed with patients

from the time of diagnosis. The need

for insulin should be presented not

as a failure, but as part of the normal

process of managing diabetes.

It is important to point out to patients that diabetes, if

not properly managed, will lead to microvascular and

macrovascular consequences. But the worst of these

complications is not inevitable. Adding insulin to the

treatment regimen can help patients maintain control,

even as the disease progresses.

PATIENT SELF-MONITORING IS CRITICAL Self-monitoring of blood glucose is critical to optimal

glycemic control. Patients should be educated about the

importance of monitoring their glucose levels, as well as

the various types of monitors that are available to them.

A monitor should be chosen based on a patient's needs,

abilities, and concerns, whether that means cost, ease of

use, speed, or a large visual display. It also may be help-

ful for patients to speak with others who are using the

device being considered. Contact information on care-

fully selected patients willing to share their experience

may be available from nurses, diabetes educators, phar-

macists, or other health care providers who care for these

patients.

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Once the device has been chosen and purchased,

patients must be taught how to use the monitor properly

to get accurate measurements and what these measure-

ments mean. Obtaining measurements at different times

throughout the day can guide patients in making lifestyle

choices and assist them in adjusting medication doses.

Accuracy of the monitor should be tested at least once

monthly. 29 Readings can be checked by the patient or the

patient's caregiver using a control solution provided by the

manufacturer or purchased at a pharmacy. Another alterna-

tive is to have the patient bring the monitor to a regular

follow-up visit and then have the patient test his or her

glucose level within 1 minute of the time a blood sample

is drawn for the laboratory. The monitor's result should be

similar (within -15%) to that provided by the laboratory.

As with the disease itself and the administration of

insulin, educating patients about the importance of self-

monitoring, helping them choose the correct device, and

training them to use their monitors correctly and effectively

may best be handled by a certified diabetes educator.

O V E R C O M I N G BARRIERS A N D MYTHS There Is Grea te r Cardiovascular Risk wi th Insulin Use

Results from the UKPDS demonstrate that intensive

control of blood glucose levels to achieve an HbAlc

level of <7% had no adverse effects on cardiovascular outcomes 42 and indicate that reductions in HbAlc levels

reduce the risk of diabetic complications. 43 In addition,

randomized controlled trials have demonstrated the clear

benefits of insulin use in reducing cardiovascular mor-

tality. In a study by Van den Berghe et al, 44 critically ill

patients in cardiothoracic intensive care units demon-

strated a significant reduction in mortality (42.5%;

P < 0.04) when treated intensively with insulin to main-

tain glucose levels between 80 and 110 mg/dL compared

with conventional insulin therapy, which maintains blood

glucose at higher levels.

The Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study group 45

examined the effects of intensive treatment with insulin-

glucose infusion during an acute MI followed by multi-

dose insulin treatment. This regimen improved long-term

survival, with an absolute reduction in mortality of 11%.

The effect observed at 1 year continued for >3.5 years.

However, these results were not confirmed in the second

DIGAMI trial (DIGAMI 2). 46 Results of a post hoc

analysis of data from the DIGAMI 2 trial showed no

significant difference in mortality with sulfonylurea,

metformin, and insulin treatment after controlling for

confounders, including glycemic control. Moreover, the

risk of nonfatal MI and stroke increased significantly

(P = 0.0007) with insulin treatment, whereas treatment

with metformin appeared to be protective. In their con-

clusion, the authors emphasized that the findings of

DIGAMI 2 were based on an epidemiologic analysis and

should be confirmed in randomized trials.

The RAndomized study of Basal-Bolus Insulin Therapy (RABBIT) 2 study 47 demonstrated that BBT

with glargine and glulisine provided superior glucose

control compared with sliding-scale regular insulin treat-

ment in noncritically ill, hospitalized, insulin-naive

patients with type 2 DM. BBT was safe and effective in

this patient population, 40% of whom were admitted for

CVD. It should be noted, however, that this study had no

cardiovascular end points.

There Is No Time to Teach Patients Many physicians believe it is their responsibility to

teach patients all aspects of diabetes management. This

expectation is difficult in a demanding, high-volume

practice. Although it is true that a patient with diabetes

has a lot to learn, a referral to a certified diabetes educa-

tor can free the physician to address the medical aspects

of care, while the diabetes educator can provide the

patient with information on the disease, nutritional man-

agement, lifestyle changes, using and monitoring medi-

cations and glucose meters, and managing complications.

Teaching materials and programs for diabetes educators

are available through many sources, including govern-

ment agencies such as the National Institutes of Health,

National Institute of Diabetes and Digestive and Kidney

Diseases; medical school diabetes research and training

centers (DRTCs), for example, Vanderbilt University

DRTC and the University of Michigan DRTC; and

associations/advocacy agencies, including the ADA and

the American Association of Diabetes Educators. Medical

assistants, nurses, or physician assistants in the office can

also be trained to teach patients about diabetes care.

The Need le Wi l l Hurt , and It Is Not W o r t h the Trouble

Many patients are afraid of pain; however, the value of

glycemic control and symptom relief should be empha-

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sized. In addition, by advising patients of the ultrafine

needles and insulin pens that are available today and

instructing them to inject the insulin into the abdomen,

pain can be minimized.

Peop le W h o Use Insul in G a i n W e i g h t The actual amount of weight gain observed with

insulin-containing regimens is not great, generally -2 to

4 kg, and is proportional to the level of glycemic control

(ie, the worse the level of control, the greater the weight

gain), 23 which underscores an advantage of earlier insu-

lin therapy. Moreover, the amount of weight gained var-

ies with the treatment regimen followed.

In a 28-week open-label comparison of insulin glargine versus NPH insulin, 48 patients administered glargine

experienced a 0.4-kg increase in weight from baseline,

whereas those in the NPH group experienced a 1.4-kg weight gain (P < 0.0007). Yki-J~rvinen et a149 compared

5 treatment regimens in 153 patients with type 2 DM as

follows: oral hypoglycemic agents plus NPH insulin at

7 AM (morning-NPH group); oral hypoglycemic agents

plus NPH insulin at 9 eM (evening-NPH group); NPH

plus regular insulin (ratio, 70:30) administered before

breakfast and dinner (2-insulin-injection group); NPH

insulin at 9 eM and regular insulin before meals (multiple-

insulin-injection group); and oral hypoglycemic agents

alone (control group). Weight gain after 3 months was

significantly less (1.2 [0.5] kg) in the evening-NPH

group than in the other insulin groups (range, 1.8 [0.5]-

2.9 [0.5] kg; P < 0.05).

In a subsequent study, Yki-J~rvinen et al 5° showed

that after 1 year of treatment with bedtime intermediate-

acting insulin plus glyburide or mefformin alone, gly-

buride and metformin in combination, or a second in-

jection of intermediate-acting insulin in the morning,

body weight remained unchanged in those receiving

bedtime insulin plus mefformin (0.9 [1.2] kg; P < 0.001

vs all other treatment groups). In a recent Japanese study, Kusaka et a151 found decreased plasma levels of

ghrelin after glucose load in type 2 diabetes patients

treated with metformin. Ghrelin, a powerful orexigenic

mediator produced mainly by the stomach and pancre-

as, may interact via signaling pathways with cannabi-

noid receptor 1, which is involved in the control of food

intake and energy expenditure at both central and peripheral levels. 52,53 Thus, the decrease in ghrelin lev-

els associated with mefformin may at least partially

account for the weight stability observed in patients

treated with this agent. 51 Lastly, in the study by

Rosenstock et al, 36 the head-to-head comparison of

insulin detemir and insulin glargine showed that treat-

ment with detemir resulted in less weight gain than did

treatment with glargine. This difference was largely

associated with the detemir once-daily regimen. Patients

who completed the study on this treatment schedule had

a mean weight gain of 2.3 kg compared with 3.7 kg for

those treated with detemir twice daily and 3.9 kg for

those treated with glargine.

While greater understanding of the mechanisms

underlying weight gain with the various diabetes treat-

ments is important, it is likewise important that clinicians

emphasize to patients who are considering insulin that

the gains are quite minimal and are a small price to pay

for good glycemic control.

C O N C L U S I O N S Elevated FPG and PPG levels independently lead to an

increased risk of morbidity and mortality for patients

with type 2 DM. Patients will benefit from education

about the progressive nature of diabetes and the eventual

need for insulin to restore basal glucose levels and simu-

late normal activity of the pancreas in response to food

intake. This knowledge can help them make informed

decisions about their treatment and thereby achieve the

greatest possible therapeutic benefit. The potential benefits

beyond glycemic control that may be offered by insulin

therapy augment the argument for early use of basal-bolus

insulin treatment strategies for patients with type 2 DM.

A C K N O W L E D G M E N T S The authors would like to thank Susan Turner and

Norman Nagl for editorial assistance in developing this

manuscript.

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Address correspondence to: Stephen N. Davis, MD, FRCP, Chief, Division of Diabetes, Endocrinology, and

Metabolism, Rudolph Kampmeier Professor, Medicine and Molecular Physiology and Biophysics, Vanderbilt University

Medical School, 715 PRB, 2220 Pierce Avenue, Nashville, TN 37232-6303. E-mail: [email protected]

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