Diagnosis and Management of Type 2 Diabetes and Prediabetes

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Diagnosis and Management of Type 2

Diabetes and Prediabetes

Jeff Unger, MDChino Medical Group, Diabetes and Headache Intervention Center, 5475 Walnut Avenue,

Chino, CA 91710, USA

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by

abnormalities at multiple organ target sites, including the pancreatic beta

cells, skeletal muscles, adipose tissue, and liver. The hyperglycemia charac-

teristic of T2DM develops slowly over time as the pancreatic beta cells fail

to produce insulin in response to a glucose stimulus. The resulting elevated

plasma glucose levels become cytotoxic, leading to the loss of beta cell func-

tion and mass.In the United States, 6.3% of the population (18 million individuals) have

diabetes, with estimates of between 90% to 95% having T2DM [1]. For in-

dividuals born in the year 2000, the estimated lifetime risk for developing

T2DM is 33% for males and 39% for females [2]. The risk for death among

individuals who have diabetes mellitus is almost twice that of individuals

who do not have diabetes of similar age [2]. A recent published report indi-

cates that nearly 45% of newly diagnosed cases of diabetes among US chil-

dren and adolescents are classified as T2DM [3]. The prevalence of T2DM

among American children is expected to continue to increase and exceedthat of T1DM over the next 10 years [3]. Non-Hispanic black individuals

and Mexican-American individuals are 1.8 times and 1.7 times, respectively,

more likely to have diabetes than non-Hispanic white individuals [2]. T2DM

is a prominent comorbid condition associated with obesity, coronary artery

disease, and mental illness [46]. Approximately 90% of patients who have

diabetes are managed by primary care physicians (PCPs), many of whom

have had little education in screening for, diagnosing, and managing this

complicated metabolic disorder [7].

The development of T2DM diabetes is strongly influenced by geneticsd39% of patients who have T2DM have at least one parent who has the dis-

ease [8].

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The lifetime risk for a first-degree relative of a patient who has T2DM

diabetes is 5 to 10 times higher than that of age- and weight-matched sub-

jects without a family history of diabetes [9]. Among monozygotic twin pairswith one affected twin, T2DM eventually develops in 60% to 90% of unaf-

fected twins [8]. First-degree relatives of patients who have T2DM often

have impaired glucose tolerance, delayed first-phase insulin response, and

beta-cell dysfunction years before diabetes develops [10].

Successful management of T2DM requires an understanding of the

pathophysiology of insulin resistance (IR), a strategy to promote lifestyle

modifications, surveillance for identifying and preventing long-term diabe-

tes-related complications, knowledge of intensive pharmacologic interven-

tions, and professional skills for providing patient education. Pursuing anaggressive approach to diabetes management can lead to positive treatment

outcomes as well as to improvement in the quality of life for these patients.

Screening for and prevention of type 2 diabetes

Screening for diabetes should be performed by a health care provider

annually, beginning at age 30 for all patients at risk for developing type 2

diabetes as shown in Box 1.

The easiest way to screen for diabetes is by obtaining a fasting plasma glu-

cose (FPG) level (Fig. 1). Patients who have elevated FPGs (O126 mg/dL)

Box 1. Risk factors for prediabetes and diabetes mellitus [11]

1. Family history of diabetes

2. History of cardiovascular disease3. Overweight or obese (BMI >25 kg per m2)

4. Sedentary lifestyle

5. Latino/Hispanic, nonHispanic black, Asian American, Native

American, or Pacific Islander ethnicity

6. Previously identified impaired glucose tolerance or impaired

fasting glucose

7. History of hypertension

8. Increased levels of triglycerides, low concentrations of

high-density lipoprotein cholesterol, or both9. History of gestational diabetes

10. History of delivery of an infant with a birth weight >9 pounds

11. Polycystic ovary syndrome

12. Psychiatric illness (bipolar depression, major depression,

schizophrenia)

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should be considered high risk and should be retested on a different day

using a 75 g 2-hour glucose challenge.

When the FPG is less than 126 mg per dL and a high index of suspicionexists for diabetes based on the patients risk factors (see Box 1), a 2-hour

postchallenge glucose test should be administered on an alternate day.

Two hours after consuming a 75-g glucose drink, a blood glucose level is ob-

tained. A level above 140 mg per dL indicates that the patient has abnormal

glucose homeostasis.

Prediabetes is the term that describes those metabolic states that occur

when blood glucose levels are elevated, but remain below levels that are

established for the clinical diagnosis of T2DM. Prediabetes includes states

of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).The 2-hour oral glucose tolerance test is more sensitive for diagnosing pre-

diabetes than the FPG test, and is the recommended screening method for

this condition; however, because performing the oral glucose tolerance

test is not always practical in an ambulatory care setting, the FPG test

may be used to identify patients who have IFG. In the absence of interven-

tion, prediabetes often progresses to T2DM [12]. The hyperglycemia which

begins in prediabetes and progresses in partnership with a deterioration of

pancreatic b-cell dysfunction and heightened peripheral insulin resistance in-

creases ones risk of cardiovascular complications [13,14]. Cardiovasculardisease may develop years before the clinical onset of diabetes mellitus.

When current glycemic goals are achieved early in the progression of the dis-

ease, b-cell function is preserved and the patient gains residual long-term

benefits in reducing vascular complications [15].

Results from large randomized controlled trials demonstrate the effec-

tiveness of lifestyle interventions (with and without pharmacologic therapy)

Fasting Glucose 2-Hour Glucose Challenge

Diabetes mellitus

IFG

Normal

Diabetes mellitus

IGT

Normal

200

mg/dL

140

mg/dL

126

mg/dL

100

mg/dL

Fig. 1. Diagnosing diabetes. Patients with normal glycemia have fasting blood glucose levels of

100 mg per dL or less. A blood glucose level between 100 and 126 mg per dL suggests the pres-

ence of impaired fasting glucose (IFG). A fasting blood glucose higher than 126 is diagnostic ofdiabetes. Patients with multiple diabetes risk factors who have a normal fasting blood glucose

level, should also undergo a 2-hour, 75-g glucose challenge. Blood glucose levels less than 140

mg per dL are considered normal. Glucose levels between 141 and 200 mg per dL are diagnostic

of impaired glucose tolerance (IGT). A blood glucose higher than 200 mg per dL is diagnostic of

diabetes. (Adapted from Unger J. Screening for type 2 diabetes in primary care. The Female

Patient 2004;29:279.)

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in preventing the progression of impaired glucose tolerance to T2DM

[12,16]. The development of T2DM can be delayed or prevented by modest

weight loss (5% to 7% of total body weight) and regular physical activity(eg, 30 minutes of walking, 5 days a week) [12,16].

Bariatric surgery may play a role in reducing ones risk of T2DM devel-

oping. A nonrandomized clinical trial consisting of 136 subjects who had

IGT and severe obesity (O45 kg excess body weight) were followed up

for 2 to 10 years [17]. Of the 109 of these individuals who underwent bari-

atric surgery, diabetes developed in only 1, in comparison with 6 new cases

within the control group. The study authors concluded that surgical inter-

vention in the severely obese, high-risk patients reduced the progression

from IGT to diabetes more than 30 fold.The exact mechanisms by which bariatric surgery reverses hyperglycemia

or improves ones risk of developing T2DM is uncertain; however, patients

who have T2DM are deficient producers of the incretin gut hormone, GLP-1.

Individuals who have normal glucose tolerance will release GLP-1 in

response to an oral glucose load. The GLP-1 then stimulates pancreatic

b-cell production and release of endogenous insulin. Following bariatric

surgery, endogenous levels of incretin hormones remain elevated for up

to 20 years [18].

Pathogenesis of type 2 diabetes

T2DM is characterized by hyperglycemia, insulin resistance, and relative

impairment of insulin secretion. The clinical features associated with T2DM

are based on genetic and environmental influences. Whether an individual

remains euglycemic or advances toward the hyperglycemic pathway is ulti-

mately determined by the ability of ones pancreatic b-cell to produce and

secrete enough insulin to maintain normoglycemia.Unlike autoimmune type 1 diabetes (T1DM), the progression to T2DM

occurs over a period of from 7 to 10 years. In the prediabetes states of IFG

and IGT, pancreatic b-cell excrete increasing amounts of insulin in an at-

tempt to maintain normal glycemia. This higher insulin output is accompa-

nied by reduced insulin activity in the liver, adipose tissue, and skeletal

muscles, resulting in diminished intracellular glucose disposal. A further de-

cline in b-cell insulin secretion and an increase in hepatic glucose production

lead to overt diabetes with fasting and postprandial hyperglycemia. At the

time one is initially diagnosed as having T2DM, less than 50% of theb-cell mass remains functioning [19].

Several hormones (insulin, glucagon, amylin, leptin, epinephrine, resistin,

GLP-1, and adiponectin) must interact in unity to maintain a normal meta-

bolic environment. Insulin plays a crucial role in modulating the metabolism

of fats and protein, while being the primary regulator of cellular uptake and

the use of glucose. An elevated plasma free fatty acid (FFA) level antagonizes

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insulin action and is the cornerstone of IR, reduced b-cell response to hyper-

glycemia, and b-cell death (apoptosis). Animal studies suggest that b-cell fail-

ure and death are preceded by an increase in plasma FFAs, accompanied byan accumulation of triglyceride within the b-cell [20]. IR is characterized by

a reduction in the ability of insulins target tissues (skeletal muscle cells, adi-

pocytes, and hepatocytes) to promote glucose use, which is 30% to 60% lower

in diabetics than in normoglycemic subjects [21].

Insulin secretion and insulin sensitivity are interrelated. In T2DM, insulin

secretion initially increases in response to IR, to maintain normal blood glu-

cose regulation. At first, the insulin secretory defect is mild and selectively

involves glucose-stimulated insulin secretion. Over time, insulin secretion

deteriorates and becomes inadequate in response to glucose stimulation.Chronic hyperglycemia paradoxically impairs b-cell function and leads to

worsening hyperglycemia. Improvement in glycemic control and weight re-

duction is often associated with improved b-cell function [16]. Insulin resis-

tance can result in a 33% reduction in b-cell function over 4 years in some

genetically susceptible individuals [22].

Endogenous insulin produced and secreted by the pancreatic b-cell regu-

lates hepatic glucose production [21]. The amount of glucose released from

the liver determines ones fasting (basal) plasma glucose level. Insulin di-

rectly inhibits glycogenolysis (the conversion of hepatic stored glycogen toglucose) and gluconeogenesis (the synthesis of glucose from noncarbohy-

drate sources). Glucagon is secreted in response to a hypoglycemic trigger

from the pancreatic alpha cells located around the periphery of the islet.

The protective mechanism of glucagon activates hepatic gluconeogenesis

and glycogenolysis, thereby raising ambient plasma glucose levels. When re-

leased from the adrenal glands in response to stress or a threat, epinephrine

also induces glycogenolysis.

As prediabetes progresses toward b-cell failure, the reduced levels of cir-

culating plasma insulin can no longer inhibit glucogenesis or glycogenolysis.When blood glucose levels cannot be maintained within the normal range of

70 to 140 mg per dL, postprandial and fasting hyperglycemia begins to de-

velop. A reduction of 50% of ones b-cell function will result in persistent

hyperglycemia regardless of ones fasting state. The increased hepatic glu-

cose production in diabetes is coupled with the reduction of insulins ability

to facilitate glucose transport into skeletal muscle cells, further intensifying

the severity of the hyperglycemic state.

Before initiating any metabolic effects in peripheral target tissues, insulin

must bind to receptors. Although insulin receptor numbers are reduced inobese individuals, no reduction in insulin receptor activity occurs in hepato-

cytes or skeletal muscle cells of patients who have T2DM. This suggests that

IR arises from intracellular postreceptor abnormalities, which may have ge-

netic or environmental origins [21]. Patients who have T2DM therefore have

difficulty transporting glucose into the cell to be used as an energy source

once insulin binds to the target receptor.



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Finally, insulin resistance is heightened by elevated levels of circulating

FFA. In response to IR, lipotoxicity results in the mobilization of FFA

from adipocytes. Adipocytes store and release FFA in response to thebodys need for an immediate energy source. When plasma glucose levels

are diminished, such as during a prolonged fast or period of starvation,

the FFAs supply energy in the form of ketone bodies. This alternative

fuel is used primarily by the skeletal muscle and heart, ensuring that the

central nervous system will lay claim to any remaining glucose as its oblig-

atory energy source. Unregulated FFA release, however, promotes IR and

impaired insulin secretion [21].

Whereas insulin promotes hepatic glucose storage, FFA has the opposite

effect by promoting the breakdown of glycogen to glucose as an energysource. Insulin also favors hepatic storage of FFA and the production of tri-

glycerides. As pancreatic b-cell functioning diminishes, insulin levels de-

crease. Rather than being stored as an energy source, FFA plasma levels

increase, adding to ones IR.

Treatment of patients who have prediabetes

Treatment of patients who have IFG or IGT is being openly debated. Pa-tients who are identified as having prediabetes have a distinct advantage

when compared with newly diagnosed T2DM patients who present to the

clinicians office for the first time with symptomatic disease and an A1C of

11%. A treatment-nave T2DM patient has already been exposed to the

effects of chronic hyperglycemia and insulin resistance for 7 to 10 years

before diagnosis, and has lost at least 50% of his pancreatic b-cell function.

Although patients who have prediabetes have early signs of glucose intoler-

ance, their b-cell function and mass remain, relatively intact. Lifestyle

changes and pharmaceutical interventions can be introduced that can pre-serve the patients endogenous insulin production.

Lifestyle intervention forms the cornerstone of for prediabetes manage-

ment. Based upon the diabetes prevention program, patients should target

a 5% to 7% reduction in total body weight and exercise 30 minutes daily

5 days per week [23]. Patients should be assessed for cardiovascular risk

before beginning any moderate or intensive exercise program.

The use of the insulin sensitizersdmetformin and the thiazolidinediones

(TZDs)dhas been shown to be beneficial in delaying the progression from

prediabetes to diabetes [12,24]. In the Diabetes Prevention Program, metfor-min, 850 mg twice daily, reduced the relative risk of progression to type 2

diabetes by 31%. Metformin may additionally improve outcomes by induc-

ing weight loss. Although conducted in women who had a history of gesta-

tional diabetes, the Troglitazone in the Prevention of Diabetes (TRIPOD)

study demonstrated a 56% reduction in relative risk in progression of pre-

diabetes to diabetes. Treatment was terminated prematurely because of

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the withdrawal of troglitazone from the US market, yet persistent protective

effects were observed more than 8 months after the drug was discontinued.

Long-term clinical trial data are not yet available for the newer TZDs, butthere is a reasonable expectation that the currently available medications in

this drug class may provide similar benefits. Until further clinical trial data

become available, clinician judgment based upon individualized patient

characteristics will determine the use of insulin sensitizers in prediabetes.

The use of nonapproved pharmacologic therapy in patients who have pre-

diabetes has not been advocated by the American Diabetes Association or

the American Association of Clinical Endocrinologists [7,11]. Age-related

differences in response to therapy are important factors to consider, because

weight loss in elderly patients, for example, may be deleterious. There isa general consensus that reducing postprandial hyperglycemia may decrease

the risk of cardiovascular events in patients who have IGT as well as T1DM

[15] and T2DM [25].

Studies of selected angiotensin-converting enzyme inhibitors (ramipril)

and statins (pravastatin) have suggested that these drugs may also delay

the progression of prediabetes to diabetes [26,27].

The Diabetes Reduction Assessment with Ramiprial and Rosiglitazone

Medication (DREAM) study [28] followed 5269 subjects who had IFG or

IGT (prediabetes) for 3 years, evaluating their development of diabetes,death, and regression to normoglycemia. Participants were randomized to

receive either placebo or ramipril 15 mg per day, or to receive placebo or

rosiglitazone 8 mg per day. The rosiglitazone cohort demonstrated a 60%

reduction in the primary outcome of progression to diabetes or death com-

pared with those given placebo, and a 62% reduction in the rate of diabetes

development alone. The DREAM trial investigators suggested that for every

1000 people treated with rosiglitazone for about 3 years, 144 cases of diabe-

tes will be prevented and 200 people who have prediabetes will progress to

normoglycemia. Although rosiglitazone may be associated with a slight in-crease in the risk of heart failure, especially in individuals who have diastolic

dysfunction, this study did suggest that patients who have either IFG or

IGT can benefit from chemoprevention [28].

Management of type 2 diabetes

The goals of pharmacologic intervention in T2DM are to normalize

hyperglycemia, improve insulin sensitivity, preserve pancreatic b-cell, reducehepatic glucose output, improve peripheral glucose use, and delay or pre-

vent long-term complications. Many factors must be considered when

designing treatment programs for patients who have T2DM, including

The age and gender of the patient

The length of time the patient has had T2DM



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The individual patients coexisting metabolic abnormalities (hyperlipid-

emia, hypertension, obesity, hypertension, infertility, thyroid disorder)

The presence of microvascular or macrovascular complications A family history of microvascular or macrovascular complications

Socioeconomic status

Type of employment as well as work hours (sleep dysfunction or erratic

sleep schedules may complicate the ability of the patient to achieve tar-

geted A1C levels)

Lifestyle variables: smoking, alcohol, or substance-abuse history, activ-

ity level, meal schedule

Prior treatment successes and failures

Presence and severity of diabetes-related symptoms

The development of new classes of blood glucose-lowering agents (incre-

tin mimetics, dipeptidyl peptidase IV inhibitors [DPP-IV], insulin analogs,

inhaled insulin, and combination drugs) has increased treatment options

for T2DM while supplementing our traditional therapies. Whether used

alone or in combination with other blood glucose-lowering interventions,

the availability of these novel agents has provided an increased number of

choices for practitioners and patients, and some degree of uncertainty

regarding the most appropriate means of treating this ubiquitous disease.

Regardless of the apparent complexity of the pharmacologic options, suc-

cessful management of diabetes can be attained by integrating the following

strategies into each patients treatment protocol:

1. Follow the national standards of care as published by the American

Diabetes Association (http://care.diabetesjournals.org/content/vol30/

suppl_1/) and the American Association of Clinical Endocrinologists

(http://www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf).

2. Although individualization of therapy is encouraged, treatment should,

with rare exceptions, be intensified for all patients until the recommen-ded glycemic targets have been attained.

3. Successful management of diabetes requires patient participation. Un-

like other chronic disease states (eg, cancer, hypertension, or depres-

sion), patients who have diabetes must make multiple decisions on

a daily basis on how maintain euglycemia. Not every decision made

will result in a perfect outcome. Patients should be provided with the ed-

ucational tools they will need to make appropriate management choices.

Praise should always be provided to those who succeed. Those who are

struggling to attain success should be re-educated and encouragedrather than criticized. As physicians, we must do our absolute best to

find ways to help our patients become successful at managing their

diabetes.

4. Avoid referring to patients as being noncompliant. For those of us

who believe they can do better at managing diabetes than our patients,

we should ask yourselves, Can I check my blood sugar 4 times a day,

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correctly interpret the results, provide the proper amount of insulin

based upon the severity of my insulin resistance at that particular

time of the day, accurately count the amount of carbohydrates I willeat for the next meal, and inject the insulin 10 to 15 minutes before eat-

ing? Did I account for any increase in physical activity I plan to do

within two hours after eating? If my blood sugar drops below 60, how

can I reverse the hypoglycemia safely without eating an excessive

amount of calories? Did I check my glucose level before I drove my

kids to school today to make sure I was not hypoglycemic? Did I re-

member to check my blood glucose before and after exercise? Did I

take my three blood pressure pills, my two cholesterol pills, and my as-

pirin today? Did I remember to call my pharmacy to get all of my pre-scription refills this month? Did I check my feet before I went to bed last

night? When was the last time I went to see the eye doctor? The dentist?

Do I wake up at 3 AM to check my blood glucose levels each night? Re-

member, your pancreas is very likely working normally, whereas your

patient is using his or her brain as pancreas. Give them credit for

what they are doing to help themselves. Treatment plans should be

concordant or acceptable to both the patient and the prescriber.

Treatment plans should also be flexible. Patients should be informed

that intensification and changes in the treatment strategy can be ex-pected at each visit based upon whether or not target glycemic goals

are being attained.

5. Home blood glucose monitoring is an essential component to successful

management of T2DM. Table 1 [29] lists suggestions on how often pa-

tients should perform self-blood glucose monitoring.

6. Diabetes is a progressive disorder. As such, the easiest patients to man-

age are those who have prediabetes. Patients who have multiple end-

stage complications are extremely challenging. Therefore, practice

aggressive and intensive management as soon as the diagnosis of IGT,IFG, or T2DM is made. Healthy lifestyle choices, self-blood glucose

monitoring and regularly scheduled exercised should be strongly

encouraged. Patients should be screened and treated for any other

Table 1

Optimal frequency of home blood glucose monitoring for patients with type 2 diabetes

A1C level Frequency of testing

%7% Fasting and postabsorptive (bedtime) first 7 days of each month

R8.5% Fasting, 10 AM (2 hours postprandial) and bedtime

(postabsorptive) on Monday, Wednesday,

and Sunday each week.

Data from Unger J. Assessing gylcemic control using home blood glucose monitoring, conti-

nuous glucose sensing, and glycated hemoglobin (A1C) testing. In: Unger J, editor. Diabetes

management in primary care. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 32162.



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metabolic abnormalities such as hypertension, hyperlipidemia, microal-

buminuria and obesity. Unless contraindicated, patients should be

started on low-dose aspirin and a statin to minimize their risk of cardio-vascular disease.

Pharmacologic intervention should be considered based upon our under-

standing of the variable and changing relationship between how much fast-

ing and postprandial glucose levels impact ones A1C. The relative

contribution of fasting glucose levels to overall glycemia is approximately

70% in patients who have A1C levels greater than 10.2% [25]. The contri-

butions of fasting and postprandial glucose levels are approximately equal

when A1C levels are between 7.3% and 8.4% [25]. In a more recent studyusing continuous glucose sensing, Monnier and colleagues [30] demon-

strated that postbreakfast hyperglycemia is most often the initial metabolic

abnormality noted in patients who have early T2DM. As the disease prog-

resses, patients developed prolonged nocturnal hyperglycemia caused by ex-

cessive hepatic glucose production. Patients will then experience fasting

hyperglycemia. Because postprandial hyperglycemia is linked with the devel-

opment of cardiovascular disease, and fasting hyperglycemia marks the pro-

gression of T2DM, one should target fasting glucose concentrations

primarily, and then focus on reducing postprandial (especially postbreak-fast) glucose concentrations. Clearly, effective management of both fasting

and postprandial hyperglycemia levels simultaneously should allow the

patients to achieve their targeted A1C levels.

Treatment options for newly diagnosed patients who have T2DM as well

as those who are currently treated with oral and parenteral agents are listed

in Table 2 [21].

The six available classes of oral agents target different metabolic defects

associated with T2DM. Each drug promotes improved glycemia when used

alone or in combination therapy. Initiation of an oral agent should beguided by the targeted metabolic defect that must be managed at any given

time. Once oral hypoglycemic therapy is initiated, patients must become ac-

tive participants in diabetes self-management. Contrary to the belief held by

many patients, T2DM is certainly not a mild form of diabetes. Blood glu-

cose self-monitoring, medical nutrition therapy, enhancing ones active life-

style, and professional surveillance to determine if the targeted metabolic

goals are being achieved are all necessary to lessen the impact associated

with diabetes-related complications. Patients should be aware of the poten-

tial risks and clinical benefits of the different types of oral hypoglycemicagents. Some medications may increase weight or induce hypoglycemia,

whereas others (metformin) must be held before undergoing certain diag-

nostic procedures. Insulin is the preferred drug for patients who have diabe-

tes admitted to the hospital for acute illness. Insulin may also be necessary in

special situations that complicate the management of T2DM, such as during

the concomitant use of corticosteroids, for patients requiring surgery, for

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Table 2

Pharmacologic regimens for treating type 2 diabetes mellitus

A1C level Pharmacologic choices CommentPart I. Treatment-nave patients

6%7% Metformin

Sulfonulurea (SU)

Meglitinide

TZD

DPP-IV inhibitors

a-glucosidase inhibitor (AGI)

Monitor and titrate medication every

23 months.

Adjust dose or begin combination

therapy if A1C is R7%

7%8% Oral agents

Secretagogue metformin

Secretagogue TZD

Secretagogue AGI

TZD metformin

DPP-IV metformin

DPP-IV TZD

SU metformin TZD

Fixed combination drugs

Pioglitazone metformin

Rosiglitazone metformin

Rosiglitazone glimepiride

Pioglitazone glimepiride

Glyburide metformin

Inhaled insulin

For prandial glycemic

control as monotherapy

For prandial glycemic control

in combination with

long-acting insulin analog

Basal insulin analogs

With any oral agent

(preferably metformin)

With short-acting insulin analog

for prandial glycemic control

Intensify therapy as soon as AIC rises

O7%

Check status of glutamic acid

decarboxylase (GAD)-65

autoantibodies. If positive, patient

has latent autoimmune diabetes of

adulthood (LADA). These patients

should be placed on intensive

insulin therapy [21]

Doses of medications and treatment

protocols should be based upon

results of patients self-blood

glucose testing.

Always suggest using insulin pens as

a preferred method of insulin

delivery.

8%10% Initiate and intensify combination

therapies (oral agents or oral

agents insulin) listed above

Normalize both fasting and

postprandial glucose

hyperglycemia

Consider premixed insulin

analogs if A1C is !9.5%, given

once, twice, or three times daily

with or without oral agents [21].

Frequent home blood glucose

monitoring is essential.

Patients who are symptomatic should

be placed on insulin therapy.

Test GAD antibody status as above.

Premixed insulins should be reserved

for patients who eat three regularly

scheduled meals daily.

O10% Initiate insulin therapyBasal bolus insulin

Prandial rapid acting insulin analog

long-acting insulin analog

Inhaled insulin long-acting

insulin analog

Patients may be placed on oral agentsif their A1Cs improve and if they

recover some of their pancreatic

beta cell function over time.

(continued on next page)



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patients who have restricted oral intake, or in those patients who become

pregnant while taking oral agents.

The pharmacologic agents used to treat patients who have T2DM are

summarized in Table 3 [21].

Treatment targets and potential risks of therapeutic agents

The primary goals of diabetes management are to minimize short- and

long-term complications. This can best be accomplished by targeting fastingand postprandial blood glucose levels to fall within the ranges suggested by

the American Diabetes Association and the American Association of Clin-

ical Endocrinologists (Table 4). Although treatment must be individualized,

most patients should be intensively managed so that they may be successful

in achieving these goals. Exceptions may be made for elderly patients, those

who live alone, or individuals who have had a recent myocardial infarction

Table 2 (continued)

A1C level Pharmacologic choices Comment

Part II. Patients with T2DM currently treated pharmacologicallyO7% All combination therapies listed

above are also appropriate for

patients who are receiving

ongoing therapy for T2DM,

but whose A1C is above the

recommended treatment target.

Add exenatide to an oral agent

Exenatide metformin

Exenatide metformin SU

Exenatide TZD

Exanatide SU

Add pramlintide to prandial insulin

Begin insulin replacement therapy

for patients on maximum oral

combination therapies or on

oral exenatide whose A1C

levels are O7% (as listed above

for treatment-nave patients).

O8.5% Begin physiologic insulin

replacement therapy

(basal-bolus insulin protocol)

Multiple daily injections

Inhaled insulin for prandial glucose

control long acting insulin

analog

Continuous subcutaneous insulin

infusion (insulin pump therapy)

Continue metformin to minimize

weight gain and cardiovascular

risk.

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or stroke. Induction of hypoglycemia in these patients could have devastat-

ing consequences.

Many patients believe that because they do not have to take insulin, theirdisease is less severe than their injecting counterparts. Nothing can be fur-

ther from the truth. Diabetes should be considered a toxic metabolic state

regardless of the etiology of diabetes or the age at which the patient is af-

fected. Patients who have T2DM have a two to four times higher increased

risk of cardiovascular events than those who have normal glycemia [31]. Yet

for every 1% reduction in A1C, one can expect a 35% reduction in micro-

vascular complications and a 14% reduction in macrovascular risk [19].

Most importantly, patients who are able to achieve an A1C of less than

7% should expect to live 5 years longer and experience 15 years of free ofcomplications when compared with those who have A1Cs greater than

7% [32].

With all the new and powerful pharmacologic agents we have at our dis-

posal, controversy still exists regarding their specific risks and benefits. A

recently published meta-analysis of 42 studies reported an increased risk

of myocardial infarction (odd ratio 1.43) and cardiovascular death (odds ra-

tio 1.64) in patients taking rosiglitazone compared with control patients

[33]; however, the authors also discussed some important limitations with

their data: (1) they did not have access to the original source data, and con-sequently were unable to perform either time-to-end analyses or calcula-

tions of dose-response relationships from the data they did obtain; (2) the

trials they analyzed were not powered to explore cardiovascular outcomes

as a primary or secondary endpoint; (3) some of the adverse events they re-

ported were ambiguous, and some cardiovascular events may even have

been misclassified; and (4) the actual number of adverse events was small.

When compared with the number of patients taking rosiglitazone, the

risk of having a cardiovascular event in patients who have an inherent ele-

vated risk for cardiovascular disease appears to be very small.Definitive resolution regarding the magnitude and statistical and clini-

cal significance of these findings will require a more sensitive time-to-

event (life-table) analysis and the final results of the ongoing phase 3

trial (RECORD) to evaluate cardiovascular outcomes in patients receiv-

ing rosiglitazone; the latter are expected in 2009. Interim analysis of

the results of the RECORD trial with 4447 patients after 3.75 years of

follow-up shows no statistically significant increased risk of myocardial

infarction, cardiac death, or all-cause mortality in individuals receiving

rosiglitazone [34]. This has been called an inconclusive study because ofthe limited number of cardiac events observed to date. To date, TZDs

do not appear to be associated with an increased risk of cardiovascular

disease [34].

TZDs appear to be safe when used as indicated, in patients who have

T2DM who do not have clinical evidence of New York Heart Association

Class III or IV cardiac disease [35,36].



14/29

Table 3

Oral hypoglycemic agents for treating type 2 diabetes

Drug class and generic

(brand) name Initial dose Maximum dose

Mechanism

of action

Sulfonylureas By binding to sulfo

receptors on the s

of pancreatic b-ce

these agents caus

voltage-dependen

potassium adenos

triphosphate chan

close, which facili

cell-membrane

depolarization, caentry into the cel

insulin secretion [

Glimepiride

(Amaryl)

12 mg/d 8 mg/d

Glipizide

(Glucotrol)

5 mg daily

2.5 mg daily in

elderly patients

20 mg twice a day

Glipzide XL

(Glucotrol XL)

10 mg/daily 20 mg daily as a single dose

Glyburide (Micronase,

Glynase, Diabeta)

1.255 mg daily 20 mg in 12 divided doses


15/29

Meglitinides Stimulate a rapid b

short-lived release

insulin from panc

b-cells that lasts

hours. Mechanism

action similar tosulfonylureas.

Repaglinide (Prandin) Elderly patients and

patients not previously

treated with

hypoglycemic agents or

patients with an A1C

!8% use 0.5 mg 3 times

a day. Patients previously

treated with

hypoglycemic agents, orthose with A1CO8% use

12 mg three times a day.

16 mg/day

Nateglinide (Starlix) 120 mg 3 times a day

60 mg 3 times a day in

elderly patients

120 mg 3 times a day

Metformin Primary mechanism

of action is the

reduction of hepa

glucose productio


16/29

Table 3 (continued)



Mechanism

of action


17/29

Metformin (Glucophage) 500 mg twice a day or 850

mg once daily in the

morning with food

2550 mg in three divided

doses with meals

Metformin XL (Fortamet) 5001000 mg once daily 2500 mg once daily

Metformin XR

(Glucophage XR)

5001000 mg once daily 15002500 mg once daily

Metformin XR (Glumetza) 500 mg once daily 10002000 mg 12 times

daily

Metformin oral suspension

(Riomet)

500 mg (5 cc) twice a day 2550 mg (25.5 mL) per day

a glucosidase inhibitors Use slow titration to avoid

GI side effects: 25 mg

once daily for 2 weeks,

then 25 mg twice daily for

2 weeks, then 25 mg 3

times daily for 8 weeks.

Maximum dose is 100 mg

3 times daily.

Delays carbohydrat

absorption from

thereby minimizin

postprandial

hyperglycemia


18/29

Table 3 (continued)



Mechanism

of action

Acarbose (Precose) 25 mg daily 100 mg 3 times a day

Miglitol (Glyset) 25 mg daily 100 mg 3 times a dayThiazolidinediones Enhances insulin se

Thiazolidinediones

pharmacological

for a nuclear rece

known as peroxis

proliferator-activ

receptor g. When

activated, this rec

binds to response

elements on DNA

alters transcriptiovarious genes tha

regulate carbohyd

and lipid metabo


19/29

Pioglitazone (Actos) 15 mg daily with or without

food

45 mg daily

Rosiglitazone (Avandia) 2 mg twice daily or 4 mg

once daily, with or

without food

4 mg twice daily or 8 mg

once daily

Dipeptidyl-peptidase 4inhibitor (DPP-IV

inhibitors)

Stabilize endogenouGLP-1 at physiol

concentrations, a

induce insulin sec

a glucose-depend

manner

Sitagliptin (Januvia) 100 mg daily with or

without food

If creatinine clearance is

3050 mL/min/1.73 m2,

reduce dosage to 50 mgdaily.

If creatinine clearance is

!30 mL/min/1.73 m2,

reduce dosage to 25 mg

daily

100 mg daily

Combination drugs

Pioglitazone metformin

(Actosplusmet)

15 mg/500 mg or 15 mg/850

mg once or twice daily

with food

Same

Rosiglitazone metformin

(Avandamet)

2 mg/500 mg twice daily

with food


with food

Rosiglitazone glimepiride

(Avandaryl)

4 mg/1 mg or 4 mg/2 mg

once daily

8 mg (rosi)/4 mg (glim) daily


20/29

Table 3 (continued)



Mechanism

of action

Glyburide metformin

(Glucovance)

1.25 mg/250 mg once or

twice daily with food

5 mg/500 mg (two pills twice

daily) with food

Glipizide metformin

(Metaglip)

2.5 mg/25 mg once or twice

daily with food

5 mg/500 mg (two pills twice

daily with food)

Sitagliptin metformin

(Janumet)


with food


with food

Parenteral agentsExenatide (Byetta) 5 micrograms twice daily

administered within 60

minutes of breakfast and

dinner. After 1 month, if

patient is tolerating this

10 micrograms twice daily

administered within 60

minutes of breakfast and

dinner

Gut incretin hormo

which is deficient

patients with T2D

Stimulates release o

from pancreatic b


21/29

dose, increase to the 10

microgram dose.

in a glucose depe

fashion.

Reduces postprandi

hyperglycemia by

lowering pancrea

cell glucagon proIn animal models,

stimulates beta ce

growth and preve

apoptosis.

Improves gastric em

As a neuroendocrin

hormone, reduces

appetite and ofte

in weight reductio


22/29

Table 3 (continued)



Mechanism

of action

Pramlintide (Symlin) For T2DM initiate at 60

micrograms injected1015 minutes before

each meal.

Maximum recommended

dose is 120 microgramsinjected 1015 minutes

before each meal.

Reduces postprandi

hyperglycemia bylowering pancrea

alpha-cell glucago

release.

As a neuroendocrin

hormone, reduces

appetite.

Improves gastric em

Reduces oxidative

stress, which can

induce long-term

diabetes-relatedcomplications [21

Insulin See text

Data from AACE diabetes mellitus guidelines. Endocr Pract 2007;13 (Suppl 1):1634; and Unger J. Managing

Diabetes management in primary care. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 11891.


23/29

Initiating insulin in patients who have type 2 diabetes

Patients who are either unable to achieve their targeted A1C with the use

of oral agents at maximum doses with or without parenteral augmentation

(exenatide) or those patients who remain symptomatic while on such thera-

pies should be transitioned to insulin. Many physicians and patients mayfeel that insulin initiation is synonymous with the beginning of a more seri-

ous phase of ones disease state; however, as when less than 80% of pancre-

atic b-cell function remains, there is little likelihood that oral agents will

successfully lower fasting or postprandial glucose levels into their normal

therapeutic ranges. Therefore, the initiation of insulin simply marks the for-

ward progression of ones chronic state of hyperglycemia. Eventually, if one

lives long enough, insulin replacement therapy will be required to maintain

euglycemia.

Several options are available for transitioning patients to insulin therapy.Although no one treatment strategy works for every patient, several unique

and simple protocols are discussed below, each of which may be easily ini-

tiated within the primary care setting.

Treat-to-trial protocol

Patients who have an A1C of less than 9% who have had T2DM for usu-

ally less than 7 years might be successful at lowering their A1C to target (! 7%)

by simply using a single dose of basal analog insulin (glargine or detemir)combined with metformin alone in combination with another sulfonylurea

[37,38]. Studies have demonstrated that approximately 60% of patients

who have T2DM having an A1C greater than 8.5% can attain an A1C

less than 7% using such a protocol. Although the initial published studies

suggested using 10 units of basal insulin as a starting dose and increasing

the dose weekly based upon the average fasting blood glucose levels, most

Table 4

Recommended treatment targets for patients with type 2 diabetes

Parameter

American DiabetesAssociation

recommendations

American Association ofClinical Endocrinologists

recommendations

A1C !7% %6.5%

Preprandial plasma glucosea 90130 mg/dL !110 mg/dL

Postprandial plasma

glucoseb!180 mg/dL !140 mg/dL

a Preprandial glucose levels include fasting glucose as well as any glucose level obtained

before eating a meal.b Postprandial glucose levels are obtained 12 hours after eating.

Data from ACE/ACE consensus conference on the implementation of outpatient manage-ment of diabetes mellitus: consensus conference recommendations. Endocr Pract 2006;12(Suppl

1):8; and American Diabetes Association. Clinical practice recommendations. Diabetes Care

2007;30(Suppl 1):S10.



24/29

physicians tend to take a much more aggressive approach. The author has

found success in the following treat-to-target protocol:

Initial basal insulin dose (glargine or detemir) is determined using the

following formula:

Initial basal insulin dose patients weight in kilograms=2 0:4

Thus, a 100 kg patient would require an initial starting dose of 100

0.4 40 units, which is given at a consistent time each evening before

bedtime.

Check the fasting blood glucose level each morning

Increase the dose of basal insulin by 2 to 3 units every 2 to 3 days untilall fasting glucose levels for 7 consecutive days are !110 mg/dL

If any single fasting glucose level is !60 mg/dL, decrease the dose of

basal insulin by 2 units and discontinue the insulin dose titration.

All-to-target regimen

If the patient is using greater than 70 units of basal insulin and the A1C

remains between 7.5% and 8.5%, consider adding an injection of fast-acting

insulin analog targeting postprandial hyperglycemia for the largest meal of

the day. In most cases, this would include dinner. The patient would con-tinue using the treat-to-target regimen as above. Metformin would be con-

tinued, but the patient would be asked to discontinue the sulfonylurea if

they are taking one. The dose of the dinner time (evening) insulin would

be determined as below: Note that carbohydrate counting is not necessary

using this regimen. Patients can simply estimate the size of the meal while

adding or subtracting insulin as needed:

0.1 units (u)/kg given 10 minutes before the meal. (glulisine can be given

up to 20 minutes after the conclusion of a meal). Thus a 100 kg manwould require 10 units of insulin for dinner.

The dose of the insulin can be adjusted simply according to the size of

the meal:

-For very large meals, add 23 units

-For moderate sized meals, add 2 units

-For small meals, subtract 12 units

If the A1C does not reach the target of!7% within 3 months, use a sim-

ilar dosing strategy and target breakfast. Repeat the A1C again after 3

months. If stillO

7%, use the same protocol and target breakfast, lunch,and dinner. You have now transitioned the patient into a basal-bolus

regimen.

Predictive 303 protocol

This protocol has been shown to be effective in allowing insulin nave

patients to adjust their own dose of basal insulin within primary care

754 UNGER


25/29

settings. Over 5000 patients who have poorly controlled T2DM were ran-

domized to either self-adjust their basal insulin regimen based on a simple

regimen or to have the medical staff dose their insulin based upon thecommunity standard of care [39]. The patients who were insulin nave

were found to be just as adept at lowering their fasting blood glucose

levels and A1Cs as were the medical staff, suggesting that insulin adjust-

ments are not very difficult to incorporate into ones daily routine. The

US Predictive 303 Trial used insulin detemir as the basal insulin of choice

[39].

The initial dose of basal insulin averaged 0.4 u/kg.

Fasting blood glucose levels should be obtained daily, and the basal in-

sulin should be ajdusted according to the protocol listed in Table 5.

Patients may continue to use their prescribed oral agents while adjusting

the dose of their basal insulin.

1,2,3 protocol for premixed insulin analogs

Premixed insulin analogs might be useful for patients having a baseline

A1C between 8.5% and 10%. Candidates who might be successful users

of premixed insulin analogs include those who eat three meals daily and

keep a regular scheduled routine of work and physical activity. The mixed

insulin analogs lower postprandial glucose levels as well as improve fasting

glucose levels. The analogs are preferred over the human premixed insulins

because of their more predictable rates of absorption and less frequent in-

duction of hypoglycemia [4042].

In a 48-week, multicenter, open-label trial [43], patients who had T2DM

and who were not achieving targets on oral agents (with or without once-

daily basal insulin therapy with neutral protamine Hagedorn [NPH] or glar-

gine) were titrated with Aspart Mix 70/30 to target plasma glucose levels.

The study included 100 patients and was conducted in three separate phases.In phase 1, patients initiated treatment with Aspart Mix 70/30 once before

supper. Dosing frequency was increased to twice-daily in phase 2, and to

three-times daily in phase 3 at 16 and 32 weeks, respectively, if patients

did not achieve an A1C of less than 6.5%. Patients completed end-of-study

when they achieved A1C less than or equal to 6.5% or 48 weeks, whichever

came first. At the end of the trial, 77% of patients achieved A1C levels of

Table 5

Basal insulin adjustment

Average fasting blood glucose over 3 days Adjust basal insulin dose

! 80 mg/dL 3 units (3)

80110 mg/dL No change (0)

O 10 mg/dL 3 units (3)



26/29

less than 7.0%, and 60% of patients attained an A1C level of less than or

equal to 6.5% through once, twice or three-times daily dosing of Aspart

Mix 70/30 [43].

The 1,2, 3 protocol is described below:

Begin by dosing Aspart Mix 70/30 12 units 1015 units before dinner.

Increase dose of Aspart Mix 70/30 by 2 units every 2 days until the pre-

breakfast glucose level is %110 mg/dL.

Check the A1C after 3 months. If not less than 6.5%, add a second in-

jection of Aspart Mix 70/30, beginning with 6 units given 1015 minutes

before breakfast. Continue monitoring the AM glucose readings and ad-

justing the dinner dose of insulin as before. Increase the breakfast dose 2 units every 2 days if the dinner glucose

readings are averaging R110 mg/dL.

Check A1C after 3 months.

If the A1C remainsO6.5%, begin using a lunchtime dose of Aspart Mix

70/30, starting with 4 units injected 1015 minutes before eating. Mon-

itor a 2-hours postlunch blood glucose level. Increase the lunchtime dose

of Aspart Mix every 2 days by 2 units until the postlunch glucose levels

are %140 mg/dL.

Check A1C after 3 months. If not 7%, other treatment options shouldbe considered.

Summary

Effective treatment of T2DM requires early initiation of appropriate

therapies, frequent monitoring, and reassessment to make certain that ther-

apeutic goals are being attained. T2DM is a progressive disease. Exposure

to chronic hyperglycemia can cause macrovascular and microvascular

complications, many of which may already be apparent when a patient is

initially diagnosed as having T2DM. As b-cell unction deteriorates and

insulin resistance intensifies, patients will find that their oral pharmacologic

therapy is becoming less effective at minimizing the effects of their chronic

hyperglycemia. Eventually, most all patients will require exogenous insulin

therapy to normalize both fasting and postprandial hyperglycemia. PCPs,

as a group, manage over 90% of all patients who have T2DM. As such,

we must have a better understanding of our role as patient educators,

advocates, and medical providers for patients suffering from this complex

metabolic disorder. We must never forget that simply achieving an A1C

of close to 7% is not considered acceptable. A patient who does not

have diabetes has an A1C of 6.1%. We should therefore do everything

in our power to help our patients achieve the lowest and safest A1C

possible.

756 UNGER


27/29

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Diagnosis and Management of Type 2 Diabetes and Prediabetes