Diabetes Mellitus, Type 2 - CECityDiabetes Mellitus, Type 2 PIER is copyrighted ©2014 by the...

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the criteria above.

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Disclosures: Rajesh K. Garg, MD, current author of this module, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Deborah Korenstein, MD, FACP, Editor-in-Chief, PIER, has no financial relationships with pharmaceutical companies, biomedical device manufacturers,

or health-care related organizations. Richard B. Lynn, MD, FACP, Editor, PIER, has no financial relationships with pharmaceutical companies, biomedical device manufacturers,

or health-care related organizations. Patrick C. Alguire, MD, FACP, Senior Vice President, ACP Medical Education, author of PIER CME quizzes discloses the following

relationships: stock options/holdings with Amgen, Bristol Myers Squibb, MedTronics, Stryker Corporation, Zimmer Orthopedics, and Teva Pharmaceuticals; his spouse holds consultantships with Johnson & Johnson Consumer Products and Astella Pharma.

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Diabetes Mellitus, Type 2 View online at http://pier.acponline.org/physicians/diseases/d296/d296.html

Module Updated: 2014-04-21

CME Expiration: 2017-04-21

Author

Rajesh K. Garg, MD

Table of Contents

1. Prevention .........................................................................................................................2

2. Screening ..........................................................................................................................5

3. Diagnosis ..........................................................................................................................7

4. Consultation ......................................................................................................................12

5. Hospitalization ...................................................................................................................15

6. Therapy ............................................................................................................................16

7. Patient Counseling ..............................................................................................................34

8. Follow-up ..........................................................................................................................38

References ............................................................................................................................43

Glossary................................................................................................................................52

Tables ...................................................................................................................................54

Figures .................................................................................................................................71

http://pier.acponline.org/physicians/diseases/d296/d296.html

Diabetes Mellitus, Type 2


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1. Prevention Top

Take measures to prevent the onset of type 2 diabetes in groups of patients who may be particularly susceptible to the disease.

1.1 Recommend healthy lifestyle changes in patients with impaired glucose tolerance or who are at high risk for type 2 diabetes based on obesity, the

presence of polycystic ovarian disease, metabolic syndrome, or strong family history.

Recommendations

• In patients at high risk for diabetes (fasting plasma glucose ≥100 mg/dL and <126 mg/dL) or

plasma glucose, 140 to 200 mg/dL after 2 hours of 75 g oral glucose, or HbA1c, 5.7% to 6.4%,

recommend daily exercise (at least 30 minutes per day, 5 days a week), and dietary changes for

5% to 10% weight loss.

Evidence

• The 2014 Standards of Medical Care in Diabetes from the American Diabetes Association

recommended lifestyle intervention including weight loss (targeting loss of 7% of body weight) and

exercise for prevention of diabetes in patients with impaired fasting glucose, impaired glucose

tolerance, or HbA1c, 5.7% to 6.4% (1).

• A 2013 systematic review of lifestyle interventions to treat or prevent diabetes in high-risk patients

included 9 studies of prevention in high-risk patients and 11 studies of treatment. In the

prevention studies, specific interventions and comparator groups varied; all interventions included

diet and exercise components. Overall, lifestyle interventions reduced the rate of diabetes at the

end of the intervention (RR, 0.35 [CI, 0.14 to 0.85]) and for as long as 10 years (RR, 0.80 [CI,

0.74 to 0.88) (2).

• In a randomized, unblinded controlled trial of 522 patients between 40 and 65 in Finland, who were

overweight with impaired glucose tolerance, reducing total and saturated fat intake, reducing

weight by >5% and increasing activity to 30 minutes daily decreased the incidence of newly

diagnosed type 2 diabetes by 56% over a median of 4 years (3). Beneficial lifestyle changes

achieved by participants in the intervention group were maintained after the discontinuation of the

intensive lifestyle intervention, and during the postintervention follow-up (median 3 years), there

was still a 36% reduction in relative risk (4).

• In the Diabetes Prevention Project, a randomized, controlled trial of 3234 people with elevated

fasting plasma glucose concentration but no diabetes, a lifestyle modification program consisting of

7% weight loss and 150 minutes of exercise per week reduced the incidence of diabetes over 3

years from 29% in the control group to 14% in the lifestyle modification program, a relative risk

reduction of 58% (5).

• A study from China, in which groups of people with impaired glucose tolerance were randomized to

different lifestyle interventions, found that those in the group assigned to a program of diet and

exercise had a decreased incidence of diabetes mellitus (6).

• An evaluation of the data from 3140 men and women in the Framingham Offspring Study found

that parental diabetes, obesity, and metabolic syndrome traits (hypertension [BP >130/85 mm

Hg], low HDL levels [<40 and 50 mg/dL in men and women, respectively], high triglycerides [>150

mg/dL], and impaired fasting glucose [100 to 125 mg/dL]) effectively predicted type 2 diabetes

risk in a middle-aged, white population sample. These data have been used to develop a simple

prediction algorithm to estimate risk of new type 2 diabetes during a 7-year follow-up interval (7).

http://care.diabetesjournals.org/content/37/Supplement_1/S5.full#sec-8

http://annals.org/article.aspx?articleid=1748845



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• In the Physicians' Health Study of 21,271 male physicians aged 40 to 84, the relative risk for

developing diabetes mellitus was 0.71 (CI, 0.56 to 0.91, P=0.0006) compared to sedentary men

with similar results when controlling for age, BMI, smoking, alcohol use, blood pressure,

hypertension, hypercholesterolemia and family history of MI (8).

Rationale

• Clinical trials have suggested that changes in dietary and exercise habits decrease the incidence of

developing type 2 diabetes mellitus in patients at high risk for diabetes.

Comments

• Note that in the DREAM study, among persons with impaired fasting glucose levels, impaired

glucose tolerance, or both, the use of ramipril for 3 years did not significantly reduce the incidence

of diabetes or death but did significantly increase regression to normoglycemia (9; 10).

1.2 Consider metformin for prevention of diabetes in patients at very high risk for type 2 diabetes due to impaired glucose tolerance, obesity, or history

of gestational diabetes. Strongly consider metformin treatment in patients with HbA1c of 5.0% to 5.5%.

Recommendations

• Consider metformin along with lifestyle changes in patients at very high risk for diabetes due to:

Impaired fasting glucose, impaired glucose tolerance, or HbA1c of 5.7% to 6.4%

BMI >35 kg/m2

History of gestational diabetes in women under age 60

• Do not use acarbose or thiazolidinediones to prevent diabetes because the potential harms from

side effects and potential toxicities outweigh any potential benefits.

Evidence


recommended considering metformin use for prevention of diabetes in patients with impaired

fasting glucose, impaired glucose tolerance, or HbA1c, 5.7% to 6.4%, especially in patients under

age 60, with BMI >35 kg/m2, or with a personal history of gestational diabetes (1).

• In the Diabetes Prevention Project, metformin, 850 mg bid, decreased the incidence of diabetes

over 3 years from 29% in the control group to 22% in the metformin group, an absolute reduction

of 7%. However, in younger and more obese subjects, metformin was as effective as lifestyle

changes, reducing the relative risk of diabetes by ~50% (5).

• There is evidence for the use of acarbose in preventing diabetes in patients with elevated fasting

glucose. In the Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM),

acarbose, 100 mg tid, decreased the incidence of diabetes from 42% in the placebo group to 32%

in the acarbose group (relative risk reduction, 25%) over 3 years (11).

• In the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study,

rosiglitazone, 8 mg daily for 3 years, substantially reduced incident type 2 diabetes by 62% and

also increased the likelihood of regression to normoglycemia in adults with impaired fasting

glucose, impaired glucose tolerance, or both. Of note, cardiovascular event rates were much the

same in both groups, although more participants in the rosiglitazone group developed heart failure

(0.5% vs. 0.1%, P=0.01) (12). Similarly, pioglitazone was shown to reduce the risk of type 2

diabetes by 72% in the ACT NOW trial but it was associated with significant weight gain and edema

(13). Due to potential side effects of thiazolidinedione drugs, rosiglitazone and pioglitazone are not

recommended for the prevention of diabetes.

Rationale




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• Treatment with metformin in high-risk or pre-diabetic patients can delay or prevent the diagnosis

of diabetes.

• The impact of early treatment with metformin on long-term clinical outcomes has not been studied.

Comments

• Some of the major antihypertensive drug classes appear to exert differing effects on glycemic

control and diabetes incidence. Thiazide diuretics and β-blockers are potentially diabetogenic,

whereas calcium channel blockers appear neutral. Inhibitors of the renin-angiotensin system are

associated with improvements in glycemic control and may lower diabetes incidence. In the

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in

nondiabetic participants, more than 18,000 subjects were randomized to receive treatment with

chlorthalidone (n=8419), amlodipine (n=4958), or lisinopril (n=5034) and observed for a mean of

4.9 years. A post-hoc subgroup analysis showed that fasting glucose levels increase in older adults

with hypertension regardless of treatment type. For those taking chlorthalidone vs. other

medications, the risk of developing fasting glucose levels above 125 mg/dL is modestly greater, but

there is no conclusive or consistent evidence that this diuretic-associated increase in diabetes

mellitus risk increases the risk of clinical events (14).

• In a meta-analysis of 12 randomized, controlled trials of ACE inhibitors and ARBs, it was shown

that these medications were associated with a reduction in the incidence of newly diagnosed

diabetes by 27% and 23%, respectively, and by 25% in the pooled analysis (15). However, in the

NAVIGATOR trial, valsartan decreased the risk of new diabetes by a small degree from 36.8% in

the placebo group to 33.1% in the valsartan group, a relative risk reduction of 14% (16).

• A plasma glucose level after an oral glucose load or an oral glucose tolerance test with relevant

cutoffs can also be used to define insulin resistance syndromes without frank diabetes and are

sometimes the method of choice in clinical trials.

• At present, there are no clear data to suggest that patients should be routinely screened for

impaired glucose tolerance, and the impact of delaying the onset of frank diabetes on long-term

outcomes and resource utilization require further study. Some patients in whom screening for

diabetes is recommended (see Screening) will be found to have impaired glucose tolerance.



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2. Screening Top

Consider screening for type 2 diabetes mellitus in selected patient groups.

2.1 Obtain a fasting plasma glucose level or HbA1c to screen for type 2 diabetes mellitus in patients with selected comorbidities or risk factors for the

disease.

Recommendations

• Consider screening for diabetes in adults with risk factors for type 2 diabetes or cardiovascular

disease, such as family history of diabetes, obesity, gestational diabetes, polycystic ovarian

syndrome, membership in high-risk ethnic groups, hyperlipidemia, or cardiovascular disease.

• Do not screen for diabetes in adults without risk factors for cardiovascular disease or risk factors

for type 2 diabetes.

• Do not conduct routine screening for secondary causes of diabetes unless suggestive signs or

symptoms of certain diseases are present.

• See module Screening for Type 2 Diabetes.

• See table Risk Factors for Diabetes Mellitus.

• See table Screening and Diagnostic Tests for Diabetes Mellitus.

• See Comparative Guidelines: Screening for Diabetes.

Evidence

• A 2008 USPSTF guideline recommends screening only adults with hypertension (17).


recommended screening all patients over age 45 and younger patients who are overweight or

obese and have one additional risk factor every 3 years (1).

• A 2012 randomized, controlled trial compared screening followed by intensive treatment, screening

followed by no mandatory treatment, and no screening, in over 15,000 high-risk patients in the

UK. After 10 years follow-up, the study found no difference in overall (HR, 1.06 [CI, 0.9 to 1.25]),

cardiovascular (HR, 1.02 [CI, 0.75 to 1.38]), or diabetes-related (HR, 1.26 [CI, 0.76 to 2.1])

mortality between screened and unscreened patients (18).

• Type 2 diabetes often is present for at least 4 to 7 years before diagnosis (19).

• Cardiovascular disease is the most common complication of type 2 diabetes, and the benefits of

screening are most apparent in patients with a high risk of cardiovascular disease (20; 21; 22).

• Management of hypertension, use of lipid-lowering agents, and use of aspirin in high-risk patients

all have benefits in patients with type 2 diabetes (23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33).

• Epidemiologic data show the increased risk for diabetes in patients with a family history of type 2

diabetes, obesity, hypertension, personal history of gestational diabetes, membership in certain

ethnic groups, and the presence of atherosclerotic disease (34; 35; 36; 37; 38; 39; 40; 41; 42).

• A 2004 cost-effectiveness analysis of screening for diabetes found that screening patients with

hypertension at age 55 was cost effective ($34,375/QALY) and that universal screening was not

($360,966/QALY) (43).

Rationale

http://pier.acponline.org/physicians/screening/s370/s370.html

http://www.acponline.org/clinical_information/guidelines/comparative_guidelines/cgtables/tcgd002.pdf

http://www.uspreventiveservicestaskforce.org/uspstf/uspsdiab.htm





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• Early recognition and aggressive treatment of risk factors for diabetes complications such as

hypertension, hyperlipidemia, and hyperglycemia may delay or prevent common diabetes

complications.

• Although there is no direct evidence that screening for type 2 diabetes improves health outcomes

or mortality, there is good evidence that detecting diabetes improves estimates of cardiovascular

risk and may provide an opportunity for earlier and more aggressive interventions (e.g., more

aggressive hypertension and lipid control) to reduce cardiovascular events in patients with

diabetes. However, it is not clear at this time whether screening is cost-effective.

• Ethnicity and the presence of certain comorbid diseases influence the prevalence of diabetes.

• Secondary causes of type 2 diabetes are rare and should be considered only when there are

suggestive signs or symptoms.

Comments

• Although a large randomized, controlled trial failed to show a mortality benefit, 10 years of follow-

up may not have been adequate to detect a benefit from screening. The limited available data

suggest that, even for a high-risk group such as blacks, screening is cost-effective only when done

once and in those under age 55 (44).

• It is estimated that only a small proportion of cases (perhaps 1% to 2%, although there are few

good studies) of type 2 diabetes are due to secondary cases, such as genetic disorders,

medications, and other underlying diseases (45).

• The simulation model constructed by the CDC is useful but has some major limitations. It assumed

a particularly long duration of diabetes before diagnosis (10.5 years; most assume a 4- to 7-year

duration of disease before diagnosis), and modeled only once-in-a-lifetime screening, an

intervention unlikely to occur in the primary care setting (19). Further, it does not address the

critical area of modifiable cardiovascular risk. The findings are not particularly convincing in terms

of providing support for screening the general population.

• More study is needed on the costs and effectiveness of screening in high-risk groups.



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3. Diagnosis Top

Use appropriate laboratory testing to confirm the diagnosis in patients with a clinical picture compatible with the disease.

3.1 Establish the diagnosis of diabetes using a glucose tolerance test, a fasting plasma glucose level >126 mg/dL, a random glucose level >200

mg/dL, or an HbA1c >5.5%.

Recommendations

• Several tests can be used to establish the diagnosis of diabetes:

A 2-hour plasma glucose level ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test after a 75-mg glucose load, considered the gold standard

A plasma glucose level ≥126 mg/dL (7 mmol/L) after an 8-hour fast, confirmed by repeat testing

A random plasma glucose level ≥200 mg/dL (11.1 mmol/L) in patients with symptoms of hyperglycemia or several readings in patients without symptoms

HbA1c has been included in guidelines, with diabetes established in patients with HbA1c≥6.5%

Evidence

• The 2014 guidelines from the American Diabetes Association for the care of patients with diabetes

recommended diagnosing diabetes in patients with an HbA1c≥6.5%, a fasting plasma glucose level

≥126 mg/dL (7.0 mmol/L), an oral glucose tolerance test with a 2-hour plasma glucose level ≥200

mg/dL (11.1 mmol/L), or classic symptoms of diabetes with a random plasma glucose level ≥200

mg/dL (11.1 mmol/L). The guideline did not differentiate diagnostic criteria for type 1 and type 2

diabetes (1).

• A study of the accuracy of HbA1c compared with glucose tolerance testing for the diagnosis of

diabetes in a screening population found that HbA1c≥6.5% had sensitivity of 30% and specificity of

99%, indicating that a positive test (i.e., higher HbA1c) could rule in diabetes but that a lower HbA1c

was less helpful in ruling it out (46).

• A study of the diagnostic accuracy of HbA1c compared with oral glucose tolerance testing in a

screening population found that in clinical settings HbA1c≥7% was helpful for ruling in diabetes with

a positive likelihood ratio of 25, and the HbA1c≤5.5% was helpful for ruling out diabetes with a

negative likelihood ratio of 0.08, but that intermediate values were less helpful (47).

Rationale

• Multiple different tests can be indicative of hyperglycemia.

Comments

• Because HbA1c does not require that patients fast and can be done easily in the office, it may be

useful in the diagnosis of diabetes despite imperfect accuracy.

3.2 Confirm the diagnosis in patients with symptoms of hyperglycemia and

symptoms suggestive of known complications of the disease.

Recommendations

• Use diagnostic testing in patients with symptoms consistent with diabetes.

• Other symptoms include:

Unexplained weight loss

Frequent infections

Impotence

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Evidence

• Patients with symptoms of polyuria and polydipsia frequently are more hyperglycemic than

asymptomatic patients (48).

• Diagnosing and treating symptomatic patients may have long-term benefits; however, short-term

follow-up does not show marked differences in diabetes-related outcomes between symptomatic

and asymptomatic patients (48).

• Definitive diagnosis allows attempts to improve glycemic control, education, and other preventive

measures that might affect eventual outcomes (49; 50; 51; 52; 53; 54).

Rationale

• Symptomatic diabetes usually is associated with substantial hyperglycemia, which warrants

treatment.

• The prevalence of undiagnosed diabetes in patients with these symptoms, although likely higher

than in the general population, is not well studied.

3.3 Confirm the diagnosis in patients with physical findings suggestive of

known complications and epiphenomena of the disease.

Recommendations

• Confirm the diagnosis in patients with signs of diabetic retinopathy, or peripheral neuropathy,

looking for the following signs:

Diabetic retinopathy (retinal microaneurysms, dot-blot hemorrhages, macular edema)

Peripheral neuropathy (typically symmetric, sensory, stocking-glove distribution)

• See figure Diabetic retinopathy, left eye.

• See figure Diabetic retinopathy, right eye.

Evidence

• Up to 15% to 30% of patients with diabetes have retinopathy at the time of diagnosis; thus,

retinopathy can be the first physical sign of type 2 diabetes (19).

• Acanthosis nigricans is often a marker for insulin resistance and can precede the diagnosis of type

2 diabetes (55; 56).

• Symmetrical peripheral neuropathy can be present at the diagnosis of type 2 diabetes, although it

is less common than with retinopathy (57).

Rationale

• Physical findings suggesting diabetes often indicate the presence of complications that require

specific preventive measures and treatment.

Comments

• Physical findings are rarely pathognomonic of diabetes, but the presence of the above findings is

associated with diabetes (19; 57).

3.4 Confirm the diagnosis of type 2 diabetes in any patient with a random plasma glucose level above the normal range.

Recommendations

• Confirm the diagnosis of type 2 diabetes in all patients who are incidentally found to have a

random plasma glucose level above the normal range using available diagnostic tests.




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Evidence

• Patients with mild-to-moderate elevations of random blood sugar (glucose >126 mg/dL but less

than the diagnostic 200 mg/dL) are at elevated risk for developing overt type 2 diabetes (58);

these patients might have impaired glucose tolerance or impaired fasting glucose (59).

• Furthermore, the risk of microvascular complications is associated strongly with elevated blood-

glucose levels (60).

Rationale

• Generally, random plasma glucose levels are not considered diagnostic and should not serve as a

screening test for type 2 diabetes; however, in instances in which patients are found to have

elevations in random plasma glucose levels, further testing for diabetes may be warranted.

Comments

• Because of the elevated risk and increased likelihood of benefit in this population, periodic

monitoring for the development of diabetes might be warranted.

3.5 Perform a careful history and physical examination in all patients with

hyperglycemia to evaluate for the complications of diabetes.

Recommendations

• Document key items from the patient's history regarding risk factors for diabetes, prior history of

diabetes, and complications of diabetes, including:

Medication history including the use of antihyperglycemic agents in the past, including during hospitalizations

Cardiovascular risk factors

Diet and exercise

Infections, particularly fungal infections, recurrent urinary tract infections, or non-healing skin infections

Other endocrine disorders including thyroid and adrenal disorders

Visual disturbances

Neuropathic pain, especially in the feet

• Document key items from the patient physical exam that are manifestations of diabetes or its

complications, including:

Height and weight for calculation of BMI

Blood pressure and pulse

Skin exam for acanthosis nigricans or striae

Eye exam for retinopathy, macular edema, glaucoma, cataracts (dilated exam should be done by specially trained personnel or by an ophthalmologist)

Thyroid exam

Cardiac exam

Foot exam including sensory exam

• See figure Acanthosis nigrans.

• See figure Diabetic Pre-ulcer.

• See figure Diabetes-Associated Callous Formation.

• See figure Pressure Erythema on a Diabetic Foot.

• See figure Diabetic Foot Ulcer.

• See figure Proliferative Diabetic Retinopathy.

• See figure Panretinal Laser Photocoagulation.



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• See figure Testing the Diabetic Foot with a Monofilament.

• See figure Monofilament Testing Recording Form.

• See figure Schema of Ulcer Formation.

Evidence

• Gathering data on lifestyle factors such as diet, exercise, and smoking sets the stage for important

interventions in each of these areas (61; 62).

• Many medications can hinder diabetes management (glucocorticoids can worsen degree of glycemic

control and hypertension, high-dose thiazide diuretics can increase blood glucose and lipid levels

(63; 64).

• Eye examination by untrained primary care providers does not detect retinopathy or macular

edema adequately (65); thus, referral to an ophthalmologist is recommended at diagnosis.

• Hypertension is a potentially modifiable risk factor for both micro- and macrovascular disease in

patients with type 2 diabetes and should be treated aggressively (24).

• Foot examination has not been evaluated by itself, but interventions that include a foot

examination and education are effective in reducing rates of developing diabetic foot ulcers (54).

• Monofilament-detected neuropathy is predictive of eventual foot ulceration in observational studies,

and early detection seems to be associated with fewer admissions for foot ulcers and amputations

(54; 66).

• Patients can have neuropathy at the diagnosis of diabetes (57).

• The American Diabetes Association has published standards of medical care for patients with

diabetes mellitus (23).

Rationale

• The history and physical examination are focused on systems that frequently manifest

complications of type 2 diabetes or can predispose to type 2 diabetes.

3.6 Order laboratory tests to establish baselines and to screen for

complications of diabetes.

Recommendations

• Order the following tests to establish baselines and screen for complications of diabetes:

Fasting blood sugar level

Glycosylated hemoglobin/HbA1c level

Fasting lipid profile

Serum electrolyte, blood urea nitrogen, and creatinine levels

Urinary microalbumin and creatinine

Electrocardiogram in select patients

Evidence


recommended checking HbA1c at least two times per year in patients who are meeting treatment

goals and quarterly in those who are not or in whom therapy has changed, testing lipids annually,

and testing for urinary albumin excretion annually in patients who have had diabetes for 5 or more

years (1).

• A 2014 systematic review of the accuracy of point-of-care tests for detecting albuminuria included

16 studies with 3356 participants. The semiquantitative test had pooled sensitivity of 76% and


http://www.annals.org/article.aspx?volume=160&page=550



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pooled specificity of 93%; the quantitative test had pooled sensitivity of 96% and pooled specificity

of 98% (67).

• Glycosylated hemoglobin (HbA1c) level predicts rates of microvascular disease (68), and

interventions to improve the HbA1c level reduce rates of diabetes complications (69; 70).

• Hyperlipidemia is a potentially modifiable risk factor for macrovascular disease in patients with type

2 diabetes (71; 72; 73).

• Diabetic nephropathy is the leading cause of end-stage renal disease in the United States (45).

• Microalbuminuria (a daily urinary albumin excretion of 30 to 300 mg) and proteinuria are predictors

of progression to more advanced stages of nephropathy (74). Studies have shown that progression

rates can be slowed with therapy, so that detection (via screening) and treatment are almost

certain to reduce the rates of end-stage renal disease (75).

• Both microalbuminuria and proteinuria are associated with increased cardiovascular mortality in

type 2 diabetes compared with patients who do not have nephropathy (76; 77).

• Treatment for documented nephropathy may delay the progression of microalbuminuria,

proteinuria (49) and the onset of end-stage renal disease (78; 79).

Rationale

• The laboratory tests allow the diagnosis and prevention of the major complications of diabetes.

Comments

• Overt proteinuria, positive on dipstick test, corresponds to >300 mg of urinary albumin excretion

daily.

3.7 Consider the limited differential diagnosis for type 2 diabetes.

Recommendations

• Consider type 1 diabetes in younger patients who are prone to ketoacidosis.

• Consider diabetes insipidus in normoglycemic patients who have polyuria and polydipsia.

• See table Differential Diagnosis of Diabetes Mellitus, Type 2.

Evidence

• Consensus.

Rationale

• Diseases in the differential diagnosis of type 2 diabetes require specific management.



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4. Consultation Top

Consult a specialist when secondary diabetes is suspected or when a suspected complication of diabetes may have another cause. Consider obtaining consultation for management of diabetes and its complications in complex treatment situations.

4.1 Consult an endocrinologist to help establish a diagnosis.

Recommendations

• Consult an endocrinologist for help in establishing a diagnosis.

• See table Secondary Forms of Diabetes or Impaired Glucose Tolerance.

• See also modules Essential Hypertension and Lipid Disorders.

Evidence

• Consensus.

Rationale

• Interpreting data, determining severity of disease and complications, and recognizing uncommon

conditions associated with hyperglycemia may require specialist expertise.

4.2 Consider referral for diabetes self-management education for all patients

with type 2 diabetes.

Recommendations

• Refer all patients for diabetes self-management education, which should stress the importance of

self-management in type 2 diabetes and address topics such as diet, glycemic management,

exercise programs, and strategies to prevent complications.

• Reinforce self-management topics with the patient at every visit.

Evidence

• Meta-analyses suggest that education is effective in improving knowledge, skill, self-care

behaviors, psychosocial outcomes, and metabolic control (80).

• Patient education was a part of an intervention that was shown to reduce rates of serious foot

lesions (54).

• Randomized trials of dietary education show an improvement in the level of glycemic control (81).

Rationale

• Diabetes education is complex and involves many disciplines.

• Referral for specific self-management education programs may be beneficial.

4.3 Consider referral to an endocrinologist for help in managing certain

patients with diabetes.

Recommendations

• Refer the patient to an endocrinologist if:

Management is complicated

Stepped treatment regimen fails to achieve the desired level of glycemic control

There is recurrent hypoglycemia, ketoacidosis, or a desire to plan a pregnancy





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Evidence

• Over time, a substantial proportion of patients with type 2 diabetes fail to achieve goals for

glycemic control (69). Patients who are compliant but do not respond to the above regimens may

have secondary causes of diabetes, or the progression of disease may require more intensive

insulin management (e.g., tid or qid injections).

• Recommendation is based on expert opinion (82).

Rationale

• Endocrinologists might be better equipped to provide intensive management of type 2 diabetes.

4.4 Refer patients with diabetes to an ophthalmologist.

Recommendations

• Obtain consult to screen for diabetic eye disease at diagnosis and every 1 to 3 years, depending on

risk, to reduce the risk of visual loss from diabetic retinopathy and macular edema.

Evidence


recommended screening patients older than 10 years who have had diabetes for 5 years,

optimizing glycemic and BP control to stop the progression of retinopathy, and referring patients

with retinopathy to an ophthalmologist for treatment (1).

• General practitioners and diabetologists fail to detect many important diabetic eye lesions (65).

• Annual screening is the standard, although some experts suggest that patients with good glycemic

control and no retinopathy on a baseline examination do not need annual examination (65).

• Randomized trials demonstrate that panretinal photocoagulation for proliferative retinopathy

reduces the rate of progression from proliferative retinopathy to blindness by 50% to 90% (50;

51).

• Randomized trials show that focal photocoagulation for macular edema reduces the rate of

progression to blindness by 30% to 50% (51).

• Cost-effectiveness analyses shows that screening for retinopathy and macular edema is cost-

effective; however, for low-risk patients (those with good glucose control and no known

retinopathy), screening every 2 to 3 years is probably adequate(52; 83; 84), although incremental

comparisons of annual to every-other-year or every-third-year screening have not been published.

Rationale

• Screening should be performed on dilated eyes and by an ophthalmologist, an optometrist, or

specifically trained personnel.

• Newer modalities, such as fundus photography, might become viable alternatives to screening by

ophthalmologists or optometrists, although sensitivity and specificity of the examination vary

dramatically by manufacturer and whether or not the eyes are dilated.

• Laser-photocoagulation treatment of retinopathy or macular edema should be performed by trained

ophthalmologists.

4.5 Consult other specialists as needed.

Recommendations

• Consult for podiatry:

Recommend use of orthotic footwear for patients with foot deformities and to cushion high-pressure areas to prevent foot ulcers

Refer patients with diabetic foot ulcers to multidisciplinary foot clinics for management




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• Consult for cardiology:

Perform a diagnostic cardiac stress test in patients with typical/atypical cardiac symptoms and an abnormal resting ECG

Also consider a screening cardiac stress test for those with a history of peripheral or carotid artery occlusive disease and those over age 35 with a sedentary lifestyle who plan to begin a vigorous exercise program

Recognize that patients with diabetes and coronary artery disease who need intervention (e.g., percutaneous transluminal coronary angioplasty [PTCA], coronary artery bypass grafting [CABG]) seem to have better outcomes with CABG

• Consult for nephrology:

Consider referral when the GFR has fallen to <60 mL/min·1.73 m2 or is <30 mL/min·1.73 m2 or with difficult-to-control BP or hyperkalemia

Refer to a nephrologist patients who have nephrotic-range proteinuria (>3 g per 24 hours) or those with active urine sediment

Evidence

• A randomized, controlled trial has shown that patient education about foot care and increased

surveillance result in a decrease in serious foot lesions (54).

• A randomized, controlled trial has shown improved foot outcomes with management by a

multidisciplinary foot clinic (85).

• Subgroup analysis of a randomized study showed that patients with type 2 diabetes who undergo

coronary artery bypass grafting (CABG) have a better 5-year survival rate than those who undergo

angioplasty (80.6% vs. 65.5%) (86).

• Recommendation for referral to a cardiologist and nephrologist is based on expert opinion (23).

Rationale

• Consultation may be required for specific specialists that cannot be provided by primary caregivers.

• Early referral of patients with reduced GFR to a nephrologist has been found to reduce cost,

improve quality of care, and keep patients off of dialysis longer.



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5. Hospitalization Top

Consider hospitalization for patients with uncontrolled diabetes, severe metabolic abnormalities, and other complications.

5.1 Hospitalize the patient when diabetes or its acute complications cannot be controlled in an outpatient setting.

Recommendations

• Hospitalize the patient with diabetes only if admission is required to determine cause and to initiate

treatment for hyperglycemia with volume depletion

Evidence

• Consensus.

Rationale

• Acute complications of diabetes may require close inpatient monitoring and intensive management.

Comments

• There is no experimental evidence that evaluates hospitalization for uncontrolled diabetes.

5.2 Consider hospitalization when potentially fatal metabolic abnormalities

develop.

Recommendations

• Hospitalize patients with:

Diabetic ketoacidosis (blood glucose >250 mg/dL, pH <7.3, presence of ketones).

Hyperosmolar state with impaired mental status.

Hypoglycemia with neurologic impairment that does not respond promptly to treatment, is associated with seizures or coma, especially if a responsible adult cannot be with the patient for the following 12 hours, or if hypoglycemia is due to a sulfonylurea with a long half-life.

• Other complications (end-stage renal disease, cardiovascular complications, foot ulcers) depending

on severity.

Evidence

• Consensus.

Rationale

• Severe complications may require close inpatient monitoring and intensive management.



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6. Therapy Top

Establish treatment goals, begin with lifestyle modifications, and use drug therapy if diet and exercise do not adequately control hyperglycemia and to prevent and treat micro- and macrovascular complications. Manage potential complications of diabetes.

6.1 Use patient characteristics and preferences to set treatment goals,

generally with a goal HbA1c <7%.

Recommendations

• Set treatment goals and choose initial agent based on patient characteristics and preferences:

Target glucose control in most patients to achieve HbA1c <7%.

Consider goal of HbA1c <6.5% in select motivated patients at high risk for complications who are not at risk for hypoglycemia.

Individualize therapy for patients with co-morbidities and the elderly, with higher goal HbA1c up to 8% in frail elderly patients and those with limited life expectancy.

Evidence


recommended an HbA1c goal <7% for most patients with diabetes, noting that a lower goal HbA1c

level (<6.5%) is reasonable in select patients without hypoglycemia and a high goal HbA1c level

(<8.0%) is reasonable for patients with a history of severe hypoglycemia, a limited life expectancy,

multiple comorbid conditions, and other factors (1).

• A 2011 systematic review and meta-analysis of studies of intensive vs. standard glycemic control

found that intensive control did not have an impact on all-cause or cardiovascular mortality, but did

lead to a reduction in microvascular complications (RR, 0.88 [CI, 0.79 to 0.97]), and an increase in

severe hypoglycemia (RR, 2.39 [CI, 1.17 to 3.34]) (87).

• A large randomized trial in patients with newly diagnosed type 2 diabetes has shown that a 0.9%

reduction in HbA1c is associated with a 12% reduction in the development of diabetes-related

outcomes, almost all of which were intermediate microvascular endpoints, particularly retinopathy

(69).

• The ACCORD study was a randomized trial of goal HbA1c <6% vs. goal HbA1c 7% to 7.9% in

patients with type 2 diabetes. The study found that patients randomized to tight control had no

reduction in cardiovascular events, higher rates of hypoglycemia requiring assistance (NNH, 15),

and a nearly significant trend toward higher mortality over 3.5 years (NNH, 117), suggesting that

tight control is not beneficial in type 2 diabetes (88).

• The ADVANCE trial randomized 11,140 patients with type 2 diabetes to either standard glucose

control or intensive glucose control (goal HbA1c <6.5%) and found no significant effects of intensive

glucose control on major macrovascular events or death from cardiovascular causes after 5 years

of follow-up. There was, however, a significant decrease in nephropathy (NNT, 9) (89).

• Guidelines vary somewhat. The American Association of Clinical Endocrinologists/American College

of Endocrinology recommends an HbA1c goal <6.5%, and the American Diabetes Association and

the European Association for the Study of Diabetes recommend an HbA1c goal <7% (90; 91). The

NICE guidelines (UK) recommend beginning first-line therapies at HbA1c >6.5% but beginning

therapies with fewer proven clinical benefits or more side effects, such as thiazolidinediones and

insulin, at HbA1c <7% in healthy older patients, with consideration of higher goals (<8%) in frail

patients or those with limited life expectancy (92).




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• Reduction in end-stage complications (e.g., blindness, end-stage renal disease) has not been

shown in randomized studies (69).

• Models based on randomized and cohort studies have shown that improving glycemic control can

be expected to improve rates of end-stage complications, although the cost-effectiveness of

glycemic control alone has not been well-evaluated in patients with type 2 diabetes (60; 93).

• Level of glycemic control clearly is related to rates of developing microvascular complications (68;

94; 95).

• Some observational data suggest that higher circulating insulin levels are associated with increased

rates of macrovascular disease; however, the role of insulin remains controversial and many

believe that there is no increased risk associated with higher insulin levels stimulated by drugs

such as sulfonylureas (96; 97; 98; 99; 100).

Rationale

• Tight glucose control reduces microvascular complications.

• Risk-benefit analysis of tighter glucose control is different for different patients.

6.2 Recommend diet and exercise programs as the cornerstones of therapy

for diabetes.

Recommendations

• Initiate diet and exercise regimens for patients with diabetes, even if severe hyperglycemia

demands immediate drug therapy.

• Consider referral to a dietician.

• Follow general diet principles:

Stress the importance of moderation.

Base calorie recommendations on the goal of achieving near-ideal body weight.

Use a reasonable starting formula of 10 calories per pound of current body weight plus 20% for sedentary patients, 33% for those who engage in light physical activity, 50% for those who are moderately active, and 75% for heavily active patients.

Avoid saturated fats.

Follow a regular meal schedule, particularly if on insulin

Note that frequent, small meals might aid in weight loss and control of blood-glucose levels.

Choose complex carbohydrates (e.g., starches, cereals) over simple sugars.

• Individualize exercise regimen to the patient.

• Be aware that exercise can lower blood-glucose levels; caution patients regarding hypoglycemia

during and after exercise.

• Consider beginning with 15 minutes of low-impact aerobic exercise three times per week for

patients who can exercise and gradually increasing the frequency and duration to 30 to 45 minutes

of moderate aerobic activity 3 to 5 days per week.

Evidence


recommended nutritional therapy for all patients with diabetes (1).

• A 2013 systematic review of lifestyle interventions to treat or prevent diabetes in high-risk patients

included 9 studies of prevention in high-risk patients and 11 studies of treatment. In the studies of

patients diagnosed with diabetes, specific intervention, comparator groups, and duration of follow-

up varied; all interventions included diet and exercise and at least one additional component.

Overall, lifestyle interventions did not significantly reduce all-cause mortality (RR, 0.75 [CI, 0.53 to





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1.06]); findings regarding cardiovascular endpoints were mixed and many studies found

improvements in secondary outcomes of unclear clinical significance (2).

• A 2006 Cochrane review of exercise for type 2 diabetes included 14 randomized, controlled trials

involving 377 participants. Exercise significantly improved glycemic control and reduced visceral

adipose tissue and plasma triglycerides but not plasma cholesterol. These improvements occur

even without weight loss (101).

• In a study of newly diagnosed type 2 diabetes patients, diet improved HbA1c by 2.25% at initial

diagnosis (69; 102; 103); however, it is important to note that control deteriorated over time, and

most patients eventually required a switch to pharmacologic therapy (69).

• A randomized study showed that patients who underwent ongoing medical nutrition therapy had

better metabolic control than those who did not (81).

• Exercise improves insulin sensitivity; studies have shown that HbA1c can be reduced by up to 10%

to 20%, but randomized studies showing long-term benefit are lacking (104).

Rationale

• Diet and exercise can help manage glucose levels and can provide other long-term patient benefits.

Comments

• Most patients eventually require pharmacologic therapy.

• The ADA recommends a diet aimed at moderate weight loss to help achieve metabolic goals; ideal

body weight is difficult to achieve or maintain, even with very-low-calorie diets.

• The ADA recommends that patients with diabetes who are at high risk for cardiovascular disease

should have a diagnostic stress test before beginning a vigorous exercise program (23).

• In patients with severe hyperglycemia or marked symptoms, it may be reasonable to begin

pharmacologic therapy at the time of diagnosis. Some suggest that patients with fasting glucose

levels >250 to 300 mg/dL are reasonable candidates, although there are no clear data in this area.

Patient preferences and shared decision-making should be the prominent features when making

the decision.

6.3 Begin oral hypoglycemic agents in patients in whom diet and exercise do not adequately control diabetes and adjust as needed to achieve target level

of glycemic control. Use metformin as the first-line oral agent in most patients with diabetes.

Recommendations

• Use metformin (unless contraindicated) as a first-line agent for most patients with type 2 diabetes

who require medication, because it causes less hypoglycemia and weight gain and may reduce

cardiovascular risk. Consider sulfonylureas as first-line agents in patients who are not obese.

• Maximize dosage of agent before adding additional agents, although escalating doses may be of

limited effectiveness.

• Add a sulfonylurea in most patients on metformin requiring a second agent; consider a

thiazolidinedione or incretinomimetic drugs in those at risk for hypoglycemia.

• Given minimal differences in efficacy and limited data about long-term outcomes, use combinations

of oral agents based on patient preference, provider familiarity, and consideration of issues such as

side effect profiles and costs.

• Consider pharmacologic therapy at the time of diagnosis in patients with severe hyperglycemia

(fasting blood glucose >250 to 300 mg/dL) or marked symptoms.

• Consider all of the following factors when making individual treatment decisions:



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Minimization of weight gain

Minimization of injections

Minimization of patient effort

Avoidance of hypoglycemia

Minimization of cost

• Consider adding acarbose, thiazolidinedione, or GLP-1 agonist in patients who have not achieved

adequate glycemic control on metformin, a sulfonylurea, or a combination of metformin and a

sulfonylurea.

• See table Drug Treatment for Glucose Control in Type 2 Diabetes.

• See table Dosages for Various Sulfonylureas.

Evidence

• The 2009 NICE guidelines (UK) for the care of patients with type 2 diabetes include a helpful

treatment algorithm, which recommended metformin as the first-line agent in most patients with

diabetes (105).

• A 2012 clinical practice guideline from the American College of Physicians recommends metformin

as first-line therapy in patients with type 2 diabetes in whom lifestyle interventions do not achieve

treatment goals (106).


recommended metformin as the preferred first agent for most patients with type 2 diabetes (1).

• A 2011 systematic review of the comparative effectiveness and safety of oral medication for type 2

diabetes found limited evidence of long-term benefits and no demonstrated differences among

most agents. Metformin decreased HbA1c more than DPP-4 inhibitors and had benefits including

weight loss and improvements in the lipid profile (107).

• The UK Prospective Diabetes Study compared metformin as initial oral agent to insulin and

sulfonylureas and compared the addition of metformin to sulfonylureas alone in overweight

patients with type 2 diabetes. Patients receiving therapy had fewer diabetes-related complications

(RRR, 32% [CI, 13% to 47%]) and lower mortality (RRR, 36% [CI, 9% to 55%]) and combination

therapy with metformin and sulfonylureas led to improved glycemic control (108).

• There are few differences in outcomes with different drug classes for treatment of hyperglycemia in

patients with type 2 diabetes, except metformin. In obese patients, use of metformin as a first-line

agent may reduce cardiovascular events and all-cause mortality, although these findings remain

controversial (108).

• In the ADOPT study, 4360 subjects with type 2 diabetes were randomized to receive rosiglitazone,

metformin, or glyburide as initial monotherapy. After 5 years, the cumulative incidence of

monotherapy failure in the rosiglitazone group was 15% compared to 21% with metformin and

34% with glyburide, but rosiglitazone was associated with more weight gain than metformin or

glyburide (109).

• Studies have shown that various combinations of oral agents are effective in lowering blood

glucose levels (110).

• In large multicenter, randomized, controlled studies, the addition of exenatide to existing

sulfonylurea, metformin, thiazolidinedione, or combination sulfonylurea and metformin therapy

resulted in a mean decrease of HbA1c of approximately 0.9% and a mean weight loss of 1.4 Kg

when compared to placebo treatment. Exenatide therapy was also associated with a low incidence

of hypoglycemia, but a higher incidence of gastrointestinal side effects, especially nausea (111;

112; 113; 114). Similar data are available with liraglutide and long-acting preparation of

exenatide.






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• In patients with diabetes, increased frequency and number of medications are associated with

decreased compliance with taking medications as prescribed (115).

• A meta-analysis suggested that rosiglitazone therapy was associated with a significant increase in

the risk for myocardial infarction (OR, 1.43 [CI, 1.03 to 1.98]) and death from cardiovascular

causes (OR, 1.64 [CI, 0.98 to 2.74]) (116). Rosiglitazone is no longer available in routine

pharmacies in the U.S.

• In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) Study, 5238

patients with type 2 diabetes and evidence of preexisting cardiovascular disease were randomly

assigned to receive pioglitazone or placebo in addition to their usual glucose-lowering and other

medications. After 34.5 months, the pioglitazone group had no reduction in the primary composite

endpoint, but had higher rates of heart failure (NNH, 23) (117; 118).

• Many combinations of glucose-lowering agent have been shown to be effective (119).

• Second-generation sulfonylureas may have fewer side effects than do first-generation agents,

particularly in hypoglycemia (120).

Rationale

• Management of blood-glucose elevation can prevent early microvascular complications, but the

broad variety of options and varying effects on lifestyle make patient characteristics and

preferences particularly important.

• Substantial differences in reduction of diabetes endpoints with different hypoglycemic agents have

not been established.

• Many combinations of glucose-lowering agents can be used.

• Combination therapy has been shown repeatedly to be effective in improving glucose control rather

than continuing with monotherapy in patients who are short of glycemic targets.

• Most patients with diabetes have worsening glycemic control over time and are likely to need

medication adjustment.

Comments

• A meta-analysis conducted by the FDA concluded that rosiglitazone may increase the risk of

myocardial infarction. Therefore, this drug is now available only through the FDA's Rosiglitazone

Medicine Access Program.

• A review of the safety data in a recent study showed that significantly more female patients who

received rosiglitazone experienced fractures (mainly in the upper arm, hand, or foot) than did

female patients on metformin or glyburide (109). Similar findings were observed in an interim

analysis of fractures in another large, ongoing, long-term, controlled clinical trial of rosiglitazone to

investigate cardiovascular endpoints in patients with type 2 diabetes (GlaxoSmithKline letter).

Pioglitazone therapy has also been linked to an increased risk for fracture in women. Data from the

manufacturer's clinical trial database show that the fracture incidence (per 100 patient-years) was

found to be 1.9 in the pioglitazone group vs. 1.1 for those receiving a comparator drug (excess

risk, 0.8). The majority of cases involved fractures of the distal upper limb (e.g., forearm, hand,

wrist) or lower limb (e.g., foot, ankle, tibia, fibula), which differ from those commonly associated

with postmenopausal osteoporosis (e.g., hip or spine). No increased risk for fracture was identified

in men. At present, the mechanism for the observed increase in fractures and the clinical

significance of the findings from these two long-term trials is not clear.

6.4 Provide pneumococcal vaccination and annual influenza vaccination for all

patients with type 2 diabetes.

Recommendations

• Vaccinate all patients with diabetes with the seasonal influenza vaccine each year.

https://www.avandia.com/Public/default.aspx

https://www.avandia.com/Public/default.aspx

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• Provide pneumococcal vaccination to all patients. Repeat pneumococcal vaccination in patients over

the age of 65 who received initial vaccination before age 65 and in whom more than 5 years

elapsed since initial vaccination.

Evidence


recommended annual influenza vaccination in all patients with diabetes over the age of 6 months

and pneumococcal vaccination to all diabetic patients over the age of 2 years (1).

• A case-control study of patients with diabetes hospitalized for pneumonia suggested that receipt of

influenza vaccine can reduce hospital admissions by 79% (CI, 19% to 95%) (121).

• Guidelines from the ADA and other organizations recommend routine annual influenza vaccination

in patients with diabetes (122).

• An observational study showed that adults under age 65 with diabetes who died were more likely

to have had influenza or pneumococcal infection than those without diabetes who died (OR, 4 [CI,

2.3 to 7.7]). Results were similar, but less clear, for patients over age 65 (123).

Rationale

• Patients with type 2 diabetes are at increased risk for complications from influenza and

pneumococcal infection.

Comments

• Vaccination rates for influenza and pneumonia among patients with diabetes are commonly tracked

performance measures.

6.5 Consider using a combination of insulin and oral agents if oral agents do

not achieve the desired level of glycemic control.

Recommendations

• Consider adding insulin to oral medications when patients have not reached therapeutic goals.

• Consider initiating treatment with insulin at the time of diagnosis in patients who are highly

symptomatic or have very high (>300 mg/dL) plasma glucose levels.

• Begin with adding once daily insulin

Begin insulin NPH or insulin detemir at bedtime or insulin glargine in the morning or at bedtime, 10 units;

titrate doses over time to achieve target glycemic control (morning fasting glucose ~80 to 120 mg/dL).

• Continue metformin when beginning insulin.

• Continue sulfonylureas initially when beginning insulin, but consider decreasing the dose in patients

who develop hypoglycemia.

• Consider continuing therapy with thiazolidinediones in patients who have responded particularly

well to those medications or who cannot tolerate other medications. Watch for heart failure and

fluid retention.

• Basal insulin along with GLP-1 agonists has also been used with satisfactory results.

• Educate patients about hypoglycemia and self-monitoring when beginning insulin therapy.

• See table Drug Treatment for Glucose Control in Type 2 Diabetes.

• See table Dosages for Various Sulfonylureas.

Evidence

• The 2008 NICE guidelines recommend continuing sulfonylureas and metformin when starting

insulin (124).




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recommended a patient-centered approach to therapy, noting that insulin is often needed in

patients with severe hyperglycemia at the time of diagnosis and is eventually indicated for most

patients with type 2 diabetes (1).

• A 2007 Cochrane review compared long-acting insulin analogues (glargine or detemir) to

intermediate-acting insulin (NPH) in patients with type 2 diabetes. There were no differences in

overall glycemic control, but treatment with long-acting insulin resulted in less symptomatic (NNT,

10 [CI, 7 to 32]) and nocturnal (detemir: NNT, 7 [CI, 6 to 11]; glargine, NNT, 8 [CI, 6 to 14])

hypoglycemia (125; 126).

• A 2004 Cochrane review evaluated insulin alone vs. insulin added to oral agents for type 2 diabetes

and concluded that the two approaches result in similar glycemic control, with less weight gain in

combination regimens which include metformin (127).

• A randomized study (128) of stepped therapy in type 2 diabetes showed that most patients were

able to achieve target HbA1c goals of 7% using combination therapy, although this was in a

controlled setting and for a limited follow-up period. A longer term study (69) has suggested that

many patients fail to achieve glycemic goals over time.

• A short-term study (129) of 1 year suggests that combination metformin and bedtime insulin is

more effective than twice-daily insulin or bedtime insulin plus daytime sulfonylureas (BIDS)

therapy, due in part to easier insulin titration and less hypoglycemia. Long-term follow-up of

combination therapy and its effect on outcomes is not available.

• Long-term studies suggest that (BIDS) therapy improves glycemic control, with decreases in HbA1c

from 1% to 3% (130); over 1 year, metformin/insulin combination decreased HbA1c by 2.5%

(129).

Rationale

• Stepped therapy with bedtime insulin is effective in achieving glycemic targets in patients for whom

oral agents alone are ineffective; it is also effective in controlling a substantial proportion of

patients for whom oral therapy is unsuccessful.

Comments

• In patients started on insulin, preexisting oral agents (metformin or the thiazolidinediones

pioglitazone or rosiglitazone) should be continued for their insulin-sensitizing and insulin-sparing

effects.

• However, due to the increased risk of weight gain, edema, and congestive heart failure in patients

using maximum doses of a thiazolidinedione drug and insulin, consideration should be given to

reducing the dose of the thiazolidinedione.

6.6 Consider using other insulin regimens and other medications if oral agents and bedtime insulin combined do not achieve the desired level of

glycemic control.

Recommendations

• Continue preexisting oral agents such as metformin and thiazolidinediones for their insulin-

sensitizing and insulin-sparing effects.

• Consider any of the possible multiple combinations:

Once-a-day injection of long-acting insulin such as glargine or detemir

Pre-meal short-acting insulin such as aspart or lispro

Twice-daily intermediate-acting insulin such as NPH or lente

Twice-daily split-mixed insulin before breakfast and dinner; there are several available preparations of combination intermediate and short-acting or regular insulin:




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o Humulin 70/30 or Novolin 70/30 have 70% intermediate-acting insulin and 30% regular insulin

o Novolog 70/30 has 70% intermediate-acting insulin and 30% aspart

o Humulin 50/50 has intermediate-acting insulin and lispro

o Humalog mix 75/25 has 75% intermediate-acting insulin and 25% lispro

Few patients receive multiple daily injections of regular insulin

• Start with a dose of 0.2 units/kg divided in one or two doses.

• Adjust dosages based on home glucose monitoring at 1-week intervals; typically, increase or

decrease doses in 10% increments.

• If glycemic control remains inadequate in the postprandial period, consider adding pramlintide and

reducing pre-meal insulin by 50% to avoid hypoglycemia.

• See table Onset and Mechanisms of Action of Various Types of Insulin.

Evidence


recommended a patient-centered approach to therapy, noting that insulin is often needed in

patients with severe hyperglycemia at the time of diagnosis and is eventually indicated for most


• There is no documented advantage to multiple daily injections in patients with type 2 diabetes

(131).

• Randomized controlled trials of different insulin dosing regimens demonstrate that insulin can

reduce HbA1c by 1% to 2%; there is minimal advantage to dosing insulin more than twice daily in


• Studies of newer short-acting forms of insulin suggest that they can help control blood glucose

(132).

• A systematic review and meta-analysis of the effects of pramlintide on glycemic control and weight

loss found modest improvements in HbA1c with pooled mean HbA1c reduction of 33% (CI, -0.51 to -

0.14) and NNT of 17 to achieve goal HbA1c over 16 to 52 weeks, and a mean weight loss of 2.21

kg. The main side effect was nausea. Studies, however, compared pramlintide to no change in

therapy and may overestimate its effect compared with other therapeutic adjustments (133).

Rationale

• Twice-daily intermediate-acting insulin or once-daily insulin glargine provides around-the-clock

coverage for patients who no longer respond to sulfonylureas or other oral agents.

Comments

• Lispro, aspart, and glulisine insulin are newer rapid-onset, shorter-acting forms of insulin that may

be useful in managing postprandial hyperglycemia or when patients inject insulin immediately

before meals (134; 135; 136).

• Glargine cannot be mixed with any other type of insulin and, in converting from NPH, a 20% initial

reduction in number of units is required. It is currently significantly more expensive than other

types of insulin (137; 138).

• Due to the increased risk of weight gain, edema, and congestive heart failure in patients using

maximum doses of a thiazolidinedione drug and insulin, consideration should be given to reducing

the dose of the thiazolidinedione.

6.7 Encourage smoking cessation in all patients.

Recommendations




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• Discuss and implement methods, including pharmacologic therapy or dedicated cessation

programs, that may help patients cease smoking.

Evidence


recommended advising all patients not to smoke and stated that smoking cessation counseling

should be a routine part of diabetes care (1).

• Epidemiologic evidence suggests that smoking and type 2 diabetes synergistically increase risk of

macrovascular disease (20; 139).

Rationale

• Smoking is a substantial risk factor for macrovascular disease and may be even more important in

patients with diabetes than in the general population.

Comments

• The effect of smoking cessation has not been evaluated specifically in patients with type 2

diabetes.

6.8 Treat hypertension preferentially with an ACE inhibitor or ARB, to reduce

the risk of adverse microvascular (e.g., retinopathy, nephropathy) and macrovascular (e.g., MI, stroke) outcomes, with a goal blood pressure

<140/90 mm Hg.

Recommendations

• Treat to a target blood pressure of 140/90 mm Hg; consider a target blood pressure of <130/80

mm Hg in patients in whom lower blood pressures can be achieved without side effects or

excessive medication burden.

• Initiate treatment of hypertension with ACE inhibitors. Use ARBs as first-line agents in patients who

develop cough from ACE inhibitors.

• Add a thiazide diuretic in most patients whose blood pressure is not at goal on a maximal dose of

an ACE inhibitor.

• Recognize that most patients with type 2 diabetes will require multiple agents (the use of three or

more agents is common) to achieve the target blood pressure goal.

• Consider β-blockers and calcium-channel blockers as agents if combinations of the initial agents

(thiazide diuretics, ACE inhibitors, ARBs) do not control blood pressure or are not tolerated.

• Reserve α-blockers for patients who cannot achieve adequate blood pressure control using other

agents.

• Consider cost, patient preferences, side-effect profile, and especially comorbidities to make

individualized decisions about therapy, e.g., using:

A β-blocker in patients who have had a MI

A diuretic, ACE inhibitor, and β-blocker in patients with congestive heart failure

An ACE inhibitor or ARB in patients with proteinuria or overt diabetic nephropathy

• See module Essential Hypertension.

Evidence

• A 2014 guideline from the JNC 8 panel members recommended a target blood pressure of <140/90

mm Hg for patients aged under 60 years and <150/90 mm Hg for patients aged 60 years or older,

regardless of the presence of diabetes. The guideline recommended using ACE inhibitors, ARBs,

calcium-channel blockers, or thiazide diuretics as first-line agents in diabetic and nondiabetic,



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nonblack populations, and recommended calcium-channel blockers and thiazide diuretics as first-

line agents in diabetic and nondiabetic black patients (140).

• A 2013 science advisory from the AHA, ACC, and CDC on effective control of high blood pressure

recommended a goal blood pressure of <140 mm Hg systolic and <90 mm Hg diastolic for most

patients, noting that lower targets may be appropriate for some populations. The guideline noted

that appropriate drugs for patients with diabetes include ACE inhibitors, ARBs, thiazide diuretics,

calcium-channel blockers and β-blockers (141).


recommended a goal BP <140/80 mm Hg in most patients with diabetes, and the use of ACE

inhibitors or ARBs as first-line medical therapy in diabetic patients with hypertension (1).

• A 2008 NICE guideline on the management of type 2 diabetes recommended that patients with

diabetes and hypertension be offered lifestyle advice and to begin medical management if the

blood pressure remains above 140/80 in the absence of end-organ damage or 130/80 in the

presence of end-organ damage. The guideline recommended that patients who are not of

African/Caribbean descent be started on an ACE inhibitor as initial therapy, and that those of

African/Caribbean descent be started on both an ACE inhibitor and either a thiazide diuretic or

calcium-channel blocker.

• A 2014 systematic review of the effect of ACE inhibitors and ARBs on mortality in patients with

diabetes included 35 studies, among which 23 studies compared ACE inhibitors to placebo or a

comparator drug and 13 compared ARBs to placebo or another drug. Compared to control therapy,

ACE inhibitors reduced all-cause mortality (RR, 0.87 [CI, 0.78 to 0.98]), cardiovascular death (RR,

0.83 [CI, 0.70 to 0.99]), and major cardiovascular events (RR, 0.86 [CI, 0.77 to 0.95]). Compared

to control, ARBs did not reduce all-cause mortality (RR, 0.94 [CI, 0.82 to 1.08]) or cardiovascular

death (RR, 1.21 [CI, 0.81 to 1.80]), although there was a trend toward reduced major

cardiovascular events (RR, 0.94 [CI, 0.85 to 1.01]) (142).

• A 2013 review and network meta-analysis of renin-angiotensin blockers and other antihypertensive

drugs in patients with diabetes included 63 studies with 36,916 participants. Compared to placebo,

ACE inhibitors reduced the risk of serum creatinine doubling (OR, 0.58 [CI, 0.32 to 0.90]) and β-

blockers increased mortality. There were trends toward ACE inhibitors being superior to ARBS for

several outcomes (143).

• The ACCORD study was a large randomized trial comparing “normal” target blood pressure

(systolic <120 mm Hg) to a target systolic blood pressure of 135 to 140 mm Hg in high-risk

patients with type 2 diabetes. After 1 year follow-up, mean systolic blood pressure was lower in the

group with a lower target blood pressure (119.3 mm Hg vs. 133.5 mm Hg). Rates of the primary

outcome (non-fatal MI or stroke or cardiovascular death) were similar in the two groups (HR, 0.88

[CI, 0.73 to 1.06]). The group with lower target blood pressure had lower rates of stroke (a

secondary outcome) with NNT, 95 (CI, 64 to 354) and higher rates of serious adverse events due

to hypertensive medication (NNH, 50) (144; 145).

• A sub-study of the HOPE study which included nearly 3600 diabetic patients (of whom 2% had type

1 diabetes) found that ramipril prevented cardiovascular outcomes compared with placebo (NNT,

25) (146).

• A meta-analysis of tight control of blood pressure in diabetic patients (primarily type 2) found that

tight control led to reductions in stroke (RR, 31%) but not myocardial infarction (147).

• A randomized trial of tight blood pressure control in patients with newly diagnosed type 2 diabetes

found that tight control reduced progression of retinopathy (NNT, 6, over 7.5 years) (26).

• Thiazide diuretics, ACE inhibitors, ARBs, β-blockers, and calcium-channel blockers are all effective

in reducing cardiovascular event rates compared to placebo (24; 28; 29; 30).

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• There are conflicting data from randomized trials on the effectiveness of primary prevention of

renal disease using ACE inhibitors versus other agents (24; 148). However, in the double-blind

RENAAL study of 1513 diabetic patients of which half were randomized to losartan, and half to

placebo, and all treated with additional open label non-ACE, non-ARB medications, losartan therapy

showed a significant reduction in doubling of serum creatinine (RR, 25%; P=0.006), and significant

decrease in the number of patients who went onto dialysis (RR, 28%; P=0.002) (149).

• In the double-blind IDNT of 1715 patients, similar significant reductions in doubling of serum

creatinine were noted when comparing 579 patients on irbesartan with 567 on amlodipine and 569

given placebo, and all treated with additional open label non-ACE, non- ARB, non-CCB medications.

Irbesartan therapy showed a significant reduction in doubling of serum creatinine (RR, 33%;

P=0.003, compared with placebo; RR, 37%; P<0.001 compared with amlodipine) (78).

• In a study of 593 hypertensive diabetics with microalbuminuria, irbesartan at a dose of 300 mg/d

significantly reduced the likelihood of progression to overt (> 200 mcg/minute of albumin

excretion, and at least a 30% increase over baseline) compared with placebo. In this study 30 of

201 patients given placebo progessed to overt nephropathy, compared with 19 of 195 patients

given irbesartan at 150 mg/d and 10 of 194 patients treated with 300 mg/d (79).

• Both the RENAAL and IDNT studies have shown significant reductions in hospital admissions for

newly diagnosed heart failure (RR in RENAAL, 32%; P=0.005; RR in IDNT, 23% compared with

placebo, no statistical test applied) (78; 149).

• Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow

nephropathy progression but slowed the progression of retinopathy (150). Thus, the role of ACE

inhibition for primary prevention of complications if diabetes is unclear.

Rationale

• Control of blood pressure improves the risk of macrovascular disease in patients with type 2

diabetes.

• Control of hypertension reduces the risk of microvascular disease in patients with type 2 diabetes.

• ACE inhibitors prevent progression of diabetic kidney disease and death in patients with diabetes.

• The benefits and harms of tighter blood pressure control must be balanced for each patient.

Comments

• The use of ACE inhibitors in pregnancy is contraindicated, and the FDA recommends discontinuing

these drugs as soon as possible if a patient becomes pregnant.

6.9 Treat with moderate- or high-intensity statin therapy to reduce the risk of

macrovascular complications.

Recommendations

• For secondary prevention, begin all patients with type 2 diabetes on high-intensity statin therapy,

regardless of LDL and total cholesterol levels.

• For primary prevention, provide patients with diabetes with moderate- or high-intensity statin

therapy:

Provide high-intensity statin therapy for patients with LDL ≥190 mg/dL

Consider high-intensity statin therapy if the calculated 10-year risk for atherosclerotic events is ≥7.5%

Provide moderate-intensity statin therapy for patients with diabetes and calculated 10-year risk for atherosclerotic events of <7.5%

• See the therapy section in the module Lipid Disorders (Dyslipidemia).

Evidence




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• A 2013 guideline from the ACC/AHA on the treatment of blood cholesterol to reduce the risk for

cardiovascular disease recommended high-intensity statin therapy for patients with known

cardiovascular disease or LDL ≥190 mg/dL, and moderate-intensity statin therapy for most

patients with diabetes with no history of cardiovascular disease and LDL <190 mg/dL, with

consideration of high-intensity therapy for diabetic patients with calculated 10-year risk for

atherosclerotic events of ≥7.5% (151).


recommended measuring a fasting lipid panel annually in patients with diabetes and treating with

lifestyle modification and then statin therapy with a goal LDL level <100 mg/dL (2.6 mmol/L). The

guideline recommended statin therapy regardless of LDL in patients with diabetes and known

cardiovascular disease and suggested an optional goal LDL level <70 mg/dL in patients with known

cardiovascular disease (1).

• A 2013 Cochrane review of statins for primary prevention of cardiovascular disease included 18

randomized trials. The review found that statin therapy reduced all-cause mortality (RR, 0.86 [CI,

0.79 to 0.94]). This study included patients with diabetes but was not specific to that population

(152).

• A systematic review of diabetic (types 1 and 2) and non-diabetic patients included in randomized

trials of statins showed that diabetic patients on statins had similar benefit to non-diabetic patients

in terms of cardiovascular outcomes, with trends toward reduction in cardiovascular and all-cause

mortality (153).

• Studies of statin use in high-risk type 2 diabetic patients showed no effect on cardiovascular events

(154).

• The Collaborative Atorvastatin Diabetes Study randomly assigned patients with type 2 diabetes and

one other risk factor (hypertension, retinopathy, microalbuminuria, macroalbuminuria, or smoking)

to either atorvastatin, 10 mg, or placebo. The trial was halted 2 years prematurely because

atorvastatin, 10 mg, significantly reduced the risk for any acute cardiovascular event by 32% and

death from any cause by 27% (155).

Rationale

• Macrovascular disease is the primary complication of type 2 diabetes; up to 80% of patients with

diabetes will develop or die from macrovascular complications.

• Prevention of macrovascular disease is of paramount importance, and managing risk factors such

as hyperlipidemia is a critical component.

6.10 Use aspirin for secondary prevention of cardiovascular disease in

patients with diabetes and consider its use for primary prevention in select patients.

Recommendations

• For secondary prevention, initiate aspirin therapy in patients with diabetes and a history of

cardiovascular disease.

• For primary prevention, consider aspirin therapy in patients with type 2 diabetes who are at

increased risk for cardiovascular disease, including those over age 50 (men) or 60 (women) and

those with additional risk factors such as hypertension, smoking, dyslipidemia, albuminuria, or a

family history of cardiovascular disease.

• See Comparative Guidelines: Aspirin for Primary Prevention.

Evidence

• The 2014 Standards of Medical Care for Diabetes from the American Diabetes Association

recommended considering low-dose aspirin for primary prevention in patients at increased risk for

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cardiovascular disease and for secondary prevention in all patients with known cardiovascular

disease (1).

• A well-done randomized trial of diabetic patients at high risk for cardiovascular disease but without

known disease found that treatment with low-dose aspirin (vs. placebo) did not prevent

macrovascular disease (156).

• A meta-analysis of antiplatelet trials showed that aspirin decreased the risk of recurrent vascular

events in both diabetic and nondiabetic patients (33).

• The POPADAD study, a large randomized trial of aspirin vs. placebo for the prevention of

cardiovascular disease in patients with diabetes found no benefit to aspirin in primary prevention

(156).

• In the Hypertension Optimal Treatment trial, aspirin at a dose of 75 mg daily reduced major

cardiovascular events by 15% and MI by 36% in diabetic and nondiabetic patients with

hypertension. In this study, the 1500 patients with diabetes had the same relative benefit as the

whole study population (25).

• In the Early Treatment Diabetic Retinopathy Study, there was a 17% nonsignificant reduction in

the occurrence of MI in diabetic patients randomly selected to receive aspirin at a dose of 750

mg/d (157).

• The U.S. Physicians' Health Study showed that aspirin at a dose of 325 mg every other day

reduced cardiovascular events by 14% (158).

Rationale

• Although patients with diabetes are at increased risk for cardiovascular disease, aspirin therapy has

not been shown to be useful in preventing disease.

Comments

• Many physicians continue to prescribe aspirin for primary prevention in diabetic patients.

6.11 Prevent and treat diabetic nephropathy, preferentially with ACE

inhibitors, to reduce the risk of progression to end-stage renal failure in patients with type 2 diabetes.

Recommendations

• Treat hypertension aggressively to a target blood pressure of 130/80 mm Hg.

• Use ACE inhibitors and ARBs as first-line agents for hypertension and consider their use in non-

hypertensive patients with microalbuminuria or overt proteinuria.

• Consider titration to the maximum tolerated dose.

• Monitor urine microalbumin, serum creatinine, and serum potassium while on therapy.

Evidence


recommended ACE inhibitors or ARBs (but not both) for patients with nephropathy and suggested

following urinary albumin excretion (1).

• A 2006 Cochrane review of the effects of ACE inhibitors and ARBs in patients with diabetic

nephropathy included 50 studies with 13,215 participants. Neither ACE inhibitors nor ARBs reduced

all-cause mortality and both resulted in similar improvements in renal outcomes such as creatinine

doubling and progression of renal disease (159).

• A 2014 systematic review of the effect of ACE inhibitors and ARBs on mortality in patients with

diabetes included 35 studies, among which 23 studies compared ACE inhibitors to placebo or a

comparator drug and 13 compared ARBs to placebo or another drug. Compared to control therapy,




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ACE inhibitors reduced all-cause mortality (RR, 0.87 [CI, 0.78 to 0.98]), cardiovascular death (RR,

0.83 [CI, 0.70 to 0.99]), and major cardiovascular events (RR, 0.86 [CI, 0.77 to 0.95]). Compared

to control, ARBs did not reduce all-cause mortality (RR, 0.94 [CI, 0.82 to 1.08]) or cardiovascular

death (RR, 1.21 [CI, 0.81 to 1.80]), although there was a trend toward reduced major

cardiovascular events (RR, 0.94 [CI, 0.85 to 1.01]) (142).

• Microalbuminuria and proteinuria are predictive of the eventual decline of renal function (74; 75).

• Randomized controlled trials of ACE inhibitors demonstrate that they can slow the decline of renal

function and slow the progression of proteinuria in patients with type 2 diabetes independent of

blood pressure control (49; 148; 160).

• In the double blind RENAAL study of 1513 diabetic patients of which half were randomized to

losartan, and half to placebo, and all treated with additional open label non-ACE non-ARB

medications, losartan therapy showed a significant reduction in doubling of serum creatinine (risk

reduction, 25%; P=0.006), and significant decrease in the number of patients who went onto

dialysis (risk reduction, 28%; P=0.002) (149).

• In the double blind IDNT of 1715 patients, similar significant reductions in doubling of serum

creatinine were noted when comparing 579 patients on irbesartan, with 567 on amlodipine and 569

given placebo, and all treated with additional open label non-ACE non-ARB non-CCB medications,

irbesartan therapy showed a significant reduction in doubling of serum creatinine (risk reduction,

33%; P=0.003 compared with placebo; risk reduction, 37%; P<0.001 compared with amlodipine)

(78).

• In another study of 593 hypertensive diabetics with microalbuminuria, irbesartan at a dose of 300

mg/d significantly reduced the likelihood of progression to overt (>200 mcg/minute of albumin

excretion, and at least a 30% increase over baseline) compared with placebo. In this study 30 of

201 subjects given placebo progressed to overt nephropathy, compared with 19 of 195 given

irbesartan at 150 mg/d and 10 of 194 patients treated with 300 mg/d (79).

• Dietary protein restriction has not been shown to be useful in patients with type 2 diabetes (161).

• In the ONTARGET trial, combination therapy with ACE inhibitors and ARBs reduced proteinuria to a

greater extent than monotherapy but it worsened overall major renal outcomes (162). A

combination of ACE inhibitors and ARBs is not recommended.

Rationale

• Hypertension is an independent risk factor for developing renal failure, and aggressive control

reduces this risk.

• ACE inhibitors and ARBs have beneficial effects on renal disease progression independent of blood

pressure control, and many experts recommend that they be titrated to maximum tolerated

dosages.

• Annual measurement of creatinine and urine microalbumin allows tracking of renal function over

time; measurement of potassium is important because it may be elevated in type 2 diabetes

patients who are on ACE inhibitors or in those who develop type IV renal tubular acidosis.

6.12 Institute foot-care strategies to prevent ulceration and amputation in

patients with documented diabetic neuropathy.

Recommendations

• Educate patients about foot care; recommend preventive measures and orthotic footwear if

necessary.

Educate regarding daily inspection of feet, wearing appropriate shoes, avoiding high-impact exercise, not going barefoot, testing water temperature before entering.



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Emphasize increased surveillance by patient and physicians for callus formation, deformities, and structural

changes

Use orthotic footwear for patients with foot deformities and to cushion high-pressure areas

Evidence


recommended foot-care education for all patients with diabetes and a multidisciplinary approach to

foot ulcers (1).

• A randomized, controlled trial has shown that patient education and increased surveillance results

in decreased serious foot lesions (54).

• Cohort data suggest a similar relationship between surveillance, education, and a lower risk of foot

lesions (163).

Rationale

• Ulceration and amputation may be preventable outcomes with proper education and treatment.

6.13 Treat foot ulcers in patients with type 2 diabetes and neuropathy.

Recommendations

• Initiate aggressive wound care, and consider use of antibiotics.

Consider the use of biological skin equivalents for non-healing ulcers

Consider the use of negative pressure wound therapy

Refer patients to a multidisciplinary foot clinic, if available

• Consider the diagnosis of osteomyelitis if ulcers persist despite treatment.

Evidence


recommended foot-care education for all patients with diabetes and a multidisciplinary approach to

foot ulcers (1).

• A 2013 systematic review of advanced wound care therapies for non-healing diabetes and vascular

ulcers included 35 trials of treatment for diabetic ulcers. Biological skin equivalents (RR, 1.58 [CI,

1.2 to 2.08]) and negative pressure therapies (RR, 1.49 [CI, 1.11 to 2.01]) resulted in improved

healing compared to control therapies. In addition, there was low quality evidence in support of

platelet-derived growth factors and liver cream (164).

• Referral to multidisciplinary clinic that specializes in diabetic foot care can improve outcomes in the

diabetic foot (85).

• There are no data on the appropriate timing and use of antibiotics.

Rationale

• Amputation may be preventable with proper treatment of foot ulceration.

• A foot ulcer is defined as any transdermal interruption of skin integrity and is predictive of

amputation.

6.14 Consider home glucose monitoring for select patients with type 2 diabetes.

Recommendations

• Initiate home glucose monitoring:

For patients on oral agents; home blood glucose monitoring may help make patients more aware of their glycemic control during symptomatic hyper- or hypoglycemia






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For patients on insulin; consider using home blood glucose monitoring to prevent and document the timing

and severity of hyperglycemia and hypoglycemia

For patients using an insulin pump or requiring multiple insulin injections; consider monitoring blood glucose three or more times daily

• Note that glucose monitoring generally should be done preprandially and at bedtime.

• Consider measuring postprandial levels as well, particularly for patients with elevations in

glycosylated hemoglobin despite normal preprandial glucose levels.

• At regular intervals, evaluate the proficiency of patients to measure their blood glucose with a

glucometer.

• If a patient on insulin therapy is unable or unwilling to perform blood glucose testing, consider

urine glucose monitoring as an alternative.

Evidence


recommended home glucose monitoring for patients on multiple daily insulin injections or an insulin

pump, and noted that home glucose monitoring can be helpful in patients on other therapies (1).

• A 2012 Cochrane review of self-monitoring of blood glucose in patients with type 2 diabetes not on

insulin showed no effect on glucose control or quality of life after 1 year of follow-up (165).

• There are no studies that show home glucose monitoring improves glycemic control in patients with

type 2 diabetes on insulin injections; thus, recommendations are based on expert opinion (23).

Note, however, that sensible adjustment of insulin doses requires glucose monitoring to achieve

target goals and to prevent hypoglycemia.

• A study providing free glucose monitors to patients in a health maintenance organization

population resulted in improved rates of self-monitoring, possibly by offering an initial incentive for

patients to engage in more desirable patterns of care. Furthermore, initiating home blood glucose

monitoring was associated with increased regularity of medication use and a reduction in high

blood glucose levels (166).

• Postprandial glucose levels are associated with a degree of cardiovascular risk independent of

fasting glucose levels. However, routine monitoring and intervention based on prostprandial

glucose levels have not been studied and it is thus not clear if there is benefit associated with

targeting elevations in post-meal glucose levels (167).

• Urine glucose level lags behind blood glucose level and is not an adequate reflection of immediate

glycemic status (patients may be hypoglycemic yet have glycosuria); therefore, many feel that

urine testing should not be used routinely unless patients are unwilling or unable to perform blood

glucose testing or if the only goal is to detect symptomatic hyperglycemia (23).

• Currently there are no studies showing that interventions based on postprandial glucose levels

have an effect on patient outcomes, except in gestational diabetes (168).

Rationale

• Although few data actually support home glucose monitoring, it can be useful in select motivated

patients to allow medication adjustment and to monitor for hypoglycemia.

• Patients receiving insulin should perform home glucose monitoring.

• Some experts are advocating postprandial monitoring to limit after meal glucose excursions; these

recommendations are based upon observational data that suggest that prostprandial glucose levels

are independently associated with macrovascular risks in patients with diabetes.

Comments

• Despite the low cost and ease of performance of urine glucose testing, blood glucose testing

remains the preferred method of monitoring glycemic status day to day.




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• According to the FDA, some types of blood glucose monitoring systems, such as those that base

readings on glucose dehydrogenase pyrroloquinolinequinone or some glucose-dye-oxidoreductase

methods, may be falsely influenced by maltose or galactose contained in parenteral products. This

can result in falsely elevated glucose reasings and, consequently, in inappropriate administration of

insulin and/or other hypoglycemic agents and life-threatening hypoglycemia. Furthermore, cases of

true hypoglycemia can go untreated if the hypoglycemic state is masked by false elevation of

glucose readings.

6.15 Consider treating painful neuropathy preferentially with pregabalin or

tricyclic antidepressants.

Recommendations

• Individualize management options based on patient preferences and comorbidities:

Consider starting with tricyclic antidepressants (e.g., 25 mg nortriptyline at bedtime) and titrate based on pain relief but watch for anticholinergic side effects, particularly in the elderly.

Consider several other agents with proven benefit in randomized trials including pregabalin, venlafaxine, duloxetine, and gabapentin

Consider topical capsaicin cream but watch for a burning sensation early in treatment.

Consider opioids in patients with severe symptoms who have not responded to other agents.

Individualize treatment based on cost and patient comorbidities and preferences.

Evidence

• A 2011 systematic review showed benefit to pregabalin, venlafaxine, duloxetine, amitriptyline,

gabapentin, valproate, and opioids, with few head-to-head comparisons. Included studies had large

placebo effects (169).

• Randomized controlled trials have shown tricyclic antidepressants to be effective in the

management of neuropathic pain (170; 171).

• Randomized controlled trials have shown that carbamazepine and gabapentin are effective in the

management of neuropathic pain in patients with type 2 diabetes (172; 173; 174). However,

carbamazepine is rarely used in this setting.

• Randomized controlled trials have shown that capsaicin is effective in decreasing pain scores and

increasing function in diabetic patients with neuropathic pain (175; 176).

Rationale

• There are few head-to-head drug comparisons.

Comments

• Duloxetine is also FDA-approved for the treatment of diabetic neuropathy.



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7. Patient Counseling Top

Educate patients with type 2 diabetes about key elements of the disease and about self-management.

7.1 Educate patient about microvascular disease and its close relationship to blood-sugar control.

Recommendations

• Discuss the increased risk of microvascular disease with poor glycemic control.

Evidence

• Retinopathy is very common, occurring in 30% to 50% of patients after 20 years; however, after

20 years with the disease, <5% of patients with diabetes are blind, and <1% become blind as a

result of retinopathy (60; 177).

• Early diabetic nephropathy occurs in >20% of patients with type 2 diabetes (178). Diabetic

patients with early renal disease have markedly increased mortality (relative risk = 2.8-4.0)

compared with diabetes patients in general (76; 77); however, development of frank end-stage

renal disease (ESRD) in patients with type 2 diabetes is fairly rare; simulation modeling suggests

that the risk for the average diabetes patient is <2% (60).

• Neuropathy is also a common complication of diabetes, occurring in as many as 50% of patients

with type 2 diabetes after 15 years (45).

Rationale

• Glycemic control decreases the risk of microvascular disease.

Comments

• Although educational interventions have been proven effective as a whole, individualized

components (e.g., explaining the incidence of microvascular disease) have not been well evaluated.

7.2 Educate the patient about macrovascular disease.

Recommendations

• Stress to the patient the importance of hypertension and lipid control.

Evidence

• Within 8 years after diagnosis, as many as 45% of patients experience macrovascular

complications of diabetes (179).

• Cardiovascular complications—the most common advanced complications associated with type 2

diabetes—account for 50% to 60% of all diabetes-related mortality (180; 181).

• Modification of macrovascular risk factors can reduce risk of disease. Aggressive hypertension

control, in particular, has been shown to reduce macrovascular event rates (26).

• Patients with diabetes have mortality rates almost twice that of the general population (182; 183;

184).

• Younger patients, in particular, have high excess mortality; the incremental mortality risk seems to

decrease with older age of onset (25; 185).

Rationale

• Treatment of concomitant risk decreases the risk of coronary events.

Comments



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• Although educational interventions have been proven effective as a whole, individualized

components (e.g., explaining the incidence of macrovascular disease) have not been well

evaluated.

7.3 Instruct patients and family members on the signs, symptoms, and

treatment of hypoglycemia.

Recommendations

• Discuss adrenergic and neurological symptoms of hypoglycemia with patients and family members:

Typical: Rapid heartbeat, shakiness, anxiety, perspiration, hunger

Severe: Change in level of consciousness; seizure

• Advise patients and family regarding treatment:

Ingest sugar (e.g., fruit juice), glucogel, or other easily absorbed glucose formulations

Administer subcutaneous glucagon injection in severe cases (e.g., when patient cannot take oral carbohydrates)

Evidence

• Hypoglycemia is the major side effect of glucose-lowering therapy and occurred in >2% of patients

on an annual basis in a large randomized, controlled trial of intensive glucose-lowering therapy

(69).

• Studies suggest a relationship between the severity of hypoglycemia and mortality in inpatients

(186); chronically, in type 1 diabetes, hypoglycemia may be associated with impaired cognitive

function (187). The effects of frequent hypoglycemia, however, have not been studied in a

prospective, long-term fashion.

Rationale

• Hypoglycemia can interfere with patients' ability to make rational judgments or may render

patients unconscious; family members should be aware of this risk and of the treatments for

hypoglycemia.

7.4 Educate the patient about smoking cessation.

Recommendations

• Discuss the elevated risks involved with smoking and diabetes.

• Educate patient on methods, including pharmacologic therapy or dedicated cessation programs,

that may help patients stop smoking.

Evidence


recommended advising all patients not to smoke and stated that smoking cessation counseling

should be a routine part of diabetes care (1).

• Epidemiologic evidence suggests that smoking and having type 2 diabetes synergistically increase

the risk of macrovascular disease (20; 139).

Rationale

• Smoking is a substantial risk factor for macrovascular disease and may be even more important in

patients with diabetes than in the general population.

Comments

• The effect of smoking cessation has not been evaluated specifically in patients with type 2

diabetes.

7.5 Educate the patient about the importance of diet and exercise.




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Recommendations

• Note that there is no single, specific diet for diabetes that applies to all patients; individualized

planning should be the goal.

• Consider referral to a dietician.

• Consider the following general diet principles:

Stress the importance of moderation.

Base calorie recommendations on the goal of achieving near-ideal body weight.

Use a reasonable starting formula of 10 calories per pound of current body weight plus 20% for sedentary patients, 33% for those who engage in light physical activity, 50% for moderately active patients, and 75% for those who are heavily active.

Avoid saturated fats.

Follow a regular meal schedule, particularly if on insulin

Note that frequent small meals might aid in weight loss and in control of blood-glucose level.

Choose complex carbohydrates (e.g., starches, cereals) over simple sugars.

• Individualize exercise regimen to the patient.

• Caution patients regarding hypoglycemia during and after exercise.

• For those patients who can exercise, consider beginning with 15 minutes of low-impact aerobic

exercise three times per week with aim to eventually achieve accumulative exercise of 150 minutes

per week.

Evidence


recommended that all patients with diabetes receive self-management support and should be

encouraged to exercise at least 3 days per week (1).

• In a study of newly diagnosed patients with type 2 diabetes, diet improved HbA1c by 2.25% at

initial diagnosis (69; 102; 103); however, it is important to note that control deteriorated over

time, and most patients eventually required a switch to pharmacologic therapy (69).

• A randomized study showed that patients who underwent ongoing medical nutrition therapy had

better metabolic control than those who did not (81).

• Exercise improves insulin sensitivity; studies have shown that HbA1c can be reduced by up to 10%

to 20%, but randomized studies showing long-term benefit are lacking (104).

Rationale

• Diet and exercise can help manage glucose levels and can provide other long-term patient

benefits; because these are largely self-managed, patient education and awareness play a vital role

in optimal management.

Comments

• Unfortunately, diet and exercise are rarely effective in long-term achieving of normoglycemia. They

are reasonable first-line interventions, but most patients eventually require pharmacologic therapy.

• The ADA recommends a diet to achieve moderate weight loss (7%) to help achieve metabolic

goals; ideal body weight is difficult to achieve and maintain, even with very-low-calorie diets.

7.6 Encourage patients to have information about their condition with them

at all times.

Recommendations

• Patients with diabetes should wear a medical-alert bracelet.




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Evidence

• Consensus.

Rationale

• Patients with diabetes are at risk for many complications that might render them unable to

communicate with emergency personnel; as a result, a medical condition bracelet may accelerate

diagnosis and treatment.



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8. Follow-up Top

Follow-up the clinical examination, order laboratory tests, and reinforce key patient education messages.

8.1 Update key elements of the initial history and physical examination on each follow-up visit.

Recommendations

• Ask patients about symptoms related to glycemic control and complications including:

New medications and medical conditions

Glycemic control and hypoglycemia

Medication adherence and side effects

Diet, exercise, and smoking

Visual changes

Neuropathic symptoms

Skin changes

• Perform a physical exam, focusing on identifying possible diabetic complications:

Blood pressure, heart rate, and weight

Cardiovascular exam including checking peripheral pulses

Foot exam, looking for skin changes, and checking sensation with a monofilament exam (at least annually)

Evidence

• Gathering follow-up data on lifestyle factors such as diet, exercise, and smoking sets the stage for

ongoing interventions in each of these areas (62).

• Many medications can hinder diabetes management (e.g., glucocorticoids can worsen the degree of

glycemic control and hypertension, high-dose thiazide diuretics can increase blood-glucose and

lipid levels) (64).

• Hypertension is a potentially modifiable risk factor for both micro- and macrovascular disease in

patients with type 2 diabetes; it should be screened for and treated aggressively (25).

Rationale

• Specific history and physical examination findings may allow early detection of complications and

prevention of long-term adverse outcomes.

8.2 Monitor glycemic control by checking HbA1c every 3 to 6 months.

Recommendations

• Measure the degree of glycemic control regularly, using glycosylated hemoglobin (HbA1c)

referenced to a Diabetes Control and Complication Trial-based assay every 3 to 6 months and

home glucose monitoring when appropriate.

• Consider point-of-care HbA1c testing.

• Consider checking fructosamine in patients in whom HbA1c is inaccurate because of

hemoglobinopathies or other issues.

• Consider less-frequent measurement in patients who are stable on diet control alone or in those

who are not undergoing diabetes treatment because of limited life expectancy.

Evidence



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recommended checking HbA1c levels at least two times per year in patients who are meeting

treatment goals and quarterly in those who are not or in whom therapy has changed (1).

• A randomized trial which included evaluation of point-of-care compared with laboratory-based

HbA1c measurement found that patients receiving point-of-care testing were more likely to have

HbA1c at goal after 24 weeks (NNT, 20) (188).

• Recommendations are based on expert opinion and on the average half-life of glycosylated

hemoglobin (23; 189; 190; 191).

• At this time, there are no studies evaluating how often glycosylated hemoglobin values need to be

measured. The ADA recommends HbA1c measurement every 6 months in patients at goal and every

3 months in those not at goal.

Rationale

• Glycemic control reduces the risk of early microvascular complications in diabetes; the glycosylated

hemoglobin is the most accurate predictor of these complications and should guide therapy.

• The average half-life of measures of glycosylated hemoglobin is 2 to 3 months; thus, changes in

therapy or lifestyle will not have a consistently measurable effect until the level has stabilized.

8.3 Consider annual measurement of lipids and treatment of hyperlipidemia with statins in patients with type 2 diabetes.

Recommendations

• Obtain an annual fasting lipid profile, including low-density lipoprotein (LDL) cholesterol,

triglyceride, high-density lipoprotein, and total cholesterol levels, and apply the following treatment

criteria:

For secondary prevention, begin all patients with type 2 diabetes on statins, regardless of LDL and total cholesterol levels

For primary prevention, consider statin therapy in patients over age 40 with one other cardiovascular risk

factor, regardless of baseline LDL cholesterol levels

Maintain serum LDL cholesterol levels at 100 mg/dL; in patients with diabetes and cardiovascular disease, it is reasonable to attempt to achieve an LDL cholesterol level <70 mg/dL

Trials have failed to prove benefits of using fibrates or niacin in addition to statin therapy in patients with high triglycerides or low HDL

Be especially vigilant for the development of rhabdomyolysis and hepatitis in patients taking both a statin and fibric acid derivative

See module Lipid Disorders.

Evidence


recommended checking lipids annually (1).

• Lipid-lowering therapy with an HMG-CoA reductase inhibitor substanially lowers the risk of

cardiovascular events and mortality in patients with diabetes, both with and without known heart

disease (e.g., it is effective in both primary and secondary prevention) (31; 32).

• In the Heart Protection Study, patients with diabetes randomized to simvastatin had a 22%

reduction in cardiovascular events. This reduction was independent of baseline cholesterol levels

and was also observed in patients with baseline LDL cholesterol <116 mg/dL (31).

• In the recent Collaborative Atorvastatin Diabetes Study (the first randomized trial exclusively in

patients with type 2 diabetes), nearly 2838 patients with type 2 diabetes and one other risk factor

(hypertension, retinopathy, microalbuminuria, macroalbuminuria, or smoking) were randomized to

either atorvastatin, 10 mg, or placebo. The trial was halted 2 years prematurely because






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atorvastatin, 10 mg, significantly reduced the risk for any acute cardiovascular event by 32% and

death from any cause by 27% (155).

• Treatment of patients with diabetes or insulin resistance, known coronary artery disease, low HDL

cholesterol (<40 mg/dL) and low or normal LDL cholesterol (<140 mg/dL) with gemfibrozil may be

effective in lowering the risk of cardiovascular events (192).

• Combination therapy results in an increased risk of rhabdomyolysis (about 0.1%) and has not to

date been shown to improve clinical outcomes; however, combination therapy is more effective in

lowering LDL cholesterol and triglycerides, and raising HDL cholesterol, than with either drug alone

(193).

Rationale

• Lipid abnormalities are common in patients with type 2 diabetes.

• Hypertriglyceridemia is often present in patients who have poor glycemic control.

• Hypertriglyceridemia is also a risk factor for the development of pancreatitis.

8.4 Consider annual screening for diabetic nephropathy.

Recommendations

• Screen annually for diabetic nephropathy with a urine dipstick for overt proteinuria or spot urine for

microalbuminuria.

If screening is performed, begin with a urine dipstick for overt proteinuria.

Defer screening in the presence of urinary tract infection or hematuria.

If the dipstick is positive for protein, confirm the test with a repeat dipstick on another day.

If dipstick testing is negative, consider screening for microalbuminuria with a spot urinary albumin-to-creatinine ratio; values of >30 mg albumin per gram of creatinine are considered positive.

Confirm positive tests with repeat testing; if repeat testing is negative, use a third test as a “tiebreaker.”

• Note that microalbuminuria is defined as 30 to 300 mg/d of urinary albumin excretion. Overt

proteinuria, which is dipstick positive, corresponds to >300 mg/d of urinary albumin excretion.

• In addition to urine albumin, perform annual measurement of serum creatinine to measure

creatinine clearance.

Evidence


recommended screening patients older than age 10 who have had type 1 diabetes for 5 years for

retinopathy, albuminuria, and peripheral neuropathy annually, and checking a fasting lipid profile

annually in all patients with diabetes (1).

• A 2014 systematic review of the accuracy of point-of-care tests for detecting albuminuria included

16 studies with 3356 participants. The semiquantitative test had pooled sensitivity of 76% and

pooled specificity of 93%; the quantitative test had pooled sensitivity of 96% and pooled specificity

of 98% (67).

• Diabetic nephropathy is the leading cause of end-stage renal disease in the United States (45).

• Microalbuminuria, which is 30 to 300 mg/d of urinary albumin excretion, and proteinuria are

predictors of progression to more advanced stages of nephropathy (74), although no specific data

suggest that screening is effective in reducing rates of end-stage renal disease.

• Both microalbuminuria and proteinuria are associated with increased cardiovascular mortality in

type 2 diabetes compared with patients without nephropathy (76; 77).

• Treatment for documented nephropathy potentially may delay the progression of microalbuminuria

and proteinuria (49).


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• The ADA and others recommend annual screening for microalbuminuria and creatinine clearance

(194).

Rationale

• The first sign of diabetic nephropathy is often protein spillage in the urine.

• However, a substantial number of patients develop advanced nephropathy without developing

proteinuria.

• Patients with more advanced nephropathy often have rising creatinine levels and can develop

hyperkalemia.

• Use of timed urine measurements to determine creatinine clearance is a more refined way to track

renal function, particularly in the elderly and with declining renal function.

• Measurement of potassium is important because it might be elevated in patients with type 2

diabetes who are on ACE inhibitors or in those who develop type IV renal tubular acidosis.

Comments

• The appropriate intervals and the cost-effectiveness of screening for nephropathy have not been

evaluated in patients with type 2 diabetes.

8.5 Perform a dilated eye exam or refer to an ophthalmologist for the exam at diagnosis and annually thereafter.

Recommendations

• Refer for dilated eye exam to screen for retinopathy annually.

• Refer for an initial exam at the time of diagnosis.

Evidence


recommended screening patients older than age 10 who have had type 1 diabetes for 5 years for

retinopathy, albuminuria, and peripheral neuropathy annually, and checking a fasting lipid profile

annually in all patients with diabetes (1).

• No randomized trials have shown that screening reduces blindness rates. An analysis of the cost-

effectiveness of screening for retinopathy estimated that cost-effectiveness varied widely based on

patient age, glycemic control, and screening interval, but that annual screening (compared with

less frequent screening) was more cost effective in younger patients with poorer glycemic control

(84). A study showed that few patients without diabetic retinopathy at the initial screening exam

developed preproliferative retinopathy or sight-threatening maculopathy after 5 to 10 years of

follow-up. Therefore, screening interval longer than a year may be appropriate for such patients

(195).

Rationale

• Early intervention can improve vision in diabetic retinopathy.

• Because patients newly diagnosed with type 2 diabetes often have a history of undiagnosed occult

disease, they may have retinopathy at the time of diagnosis.

Comments

• Referral for annual eye exam is a widely used Healthcare Effectiveness Data and Information Set

(HEDIS) quality measure.

8.6 On follow-up visits, reinforce some or all key educational messages.

Recommendations




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• Reinforce key issues of self-care, hypoglycemia, medication, blood glucose monitoring, and

lifestyle.

• Reinforce on an ongoing basis (not all need to be done at each visit):

Importance of active responsibility for daily diabetes care

Glucose goals

Blood glucose monitoring for patients taking insulin

Medications

Exercise and meal plan

Stress and coping

• Reinforce annually:

Emergency situations, such as hypoglycemia

Identification, such as a medical-condition bracelet

Screening for complications

Foot care

Injection site care, for patients on insulin therapy

Evidence

• Diabetes self-management education is effective in improving knowledge, skill, self-care behaviors,

psychosocial outcomes, and metabolic control (196; 197)

• The specific topics outlined above are based on expert opinion, although all represent important

areas of the self-management education interventions that have been studied (196; 197).

Rationale

• Diabetes management is complex, and reinforcement may increase patient understanding of key

issues.

• Diabetes self-management education is effective in improving knowledge, skill, self-care behaviors,

psychosocial outcomes, and metabolic control.



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Glossary Top

ACE angiotensin-converting enzyme

ARB angiotensin-receptor blocker

bid twice daily

BMI body mass index

BP blood pressure

BUN

blood urea nitrogen

CABG coronary artery bypass graft(ing)

DPP-IV dipeptidyl peptidase-IV

ECG

electrocardiogram

FDA

Food and Drug Administration

GFR glomerular filtration rate

GHb glycosylated hemoglobin

GI gastrointestinal

GIP glucose-dependent insulinotropic polypeptide

GLP-1 glucagon-like peptide-1

HbA1c

glycosylated hemoglobin

HDL high-density lipoprotein

LDL low-density lipoprotein

MI

myocardial infarction

NNH number needed to harm

NNT number needed to treat

NYHA New York Heart Association



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OGTT

oral glucose tolerance test

POPADAD Prevention of Progression of Arterial Disease and Diabetes

PTCA percutaneous transluminal coronary angiography

qd

once daily

qid four times daily

rDNA ribosomal deoxyribonucleic acid

RR relative risk

sc subcutaneous

tid three times daily



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Tables Top

Differential Diagnosis of Diabetes Mellitus, Type 2

Disease Characteristics

Diabetes mellitus, type 1 Younger onset, history of ketoacidosis, not overweight

Requires insulin for therapy

Diabetes insipidus Polyuria, polydipsia, no hyperglycemia

Maturity onset diabetes of the young Strong familial transmission. Monogenetic defects in β-cell function

Variable requirement for oral agents or insulin





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Drug Treatment for Glucose Control in Type 2 Diabetes

Drug or Drug Class Dosing Side Effects Precautions Clinical Use

Biguanide

Metformin (Glucophage,

Glucophage XR)

Regular-release: 500 mg bid or 850 mg

qd, up to 2550 mg total daily dose,

given bid-tid. Extended-release:

depends on formulation: 500-1000 mg

qd, up to 2000-2500 mg qd with PM

meal

GI side effects, diarrhea Rare lactic acidosis. Avoid with: CKD

(SCr >1.4 in women or >1.5 in men),

HF, hepatic disease

First line agent- causes less

hypoglycemia and weight gain, and

may improve risk of death and CV

outcomes compared with other oral

agents

Sulfonylureas Hypoglycemia Caution with hepatic disease. Start

with lowest dose in elderly

Second line in many patients but more

hypoglycemia than other oral agents

Glyburide (Diabeta, Glynase) 1.25-20 mg total daily dose, dosed qd

or bid. Start at 2.5 or 5 mg qd.

Micronized (Glynase): 0.75-12 mg total daily dose, dosed qd or bid. Start at

1.5-3 mg qd

Avoid if CrCl<50.

Glipizide (Glucotrol, Glucotrol XL) Regular-release: 5-15 mg qd, up to 40

mg total daily dose. Dose bid if total

daily dose >30 mg. Extended-release:

5-20 mg qd

Headache, dizziness Can be used in CKD

Glimepiride (Amaryl) 1-4 mg qd, maximum dose 8 mg qd Start with lowest dose in CKD

Thiazolidnediones Weight gain, edema, bone fractures in

women

HF. Avoid with moderate hepatic

disease. Check hepatic enzymes before

use

Third-line agent for most patients

Pioglitazone (Actos) 15-45 mg qd Bladder cancer

Rosiglitazone (Avandia) 4-8 mg total daily dose, dosed qd or

bid

Abdominal pain, diarrhea, nausea

Dipeptidyl-peptidase-4 (DPP-IV)

inhibitors

Pancreatitis, serious hypersensitivity

reactions

Limited long-term data

Sitagliptin (Januvia) 100 mg qd Decrease dose if CrCl<50

Linagliptin (Tradjenta) 5 mg qd Hypoglycemia Not studied with insulin

Saxagliptin (Onglyza) 2.5-5 mg qd Lymphopenia, hypoglycemia Decrease dose if CrCl<50

Incretin mimetics Hypoglycemia, nausea, vomiting,

pancreatitis, hypersensitivity, weight

loss

Caution in CKD

Exenatide (Regular-release injection

[Byetta]; extended-release injection

[Bydureon])

Regular-release: 5-10 mcg SC bid 1

hour before meals. Extended-release:

2 mg SC once weekly

Extended release: Thyroid C-cell

tumors. Avoid if CrCl<30

Regular release can be used with

insulin glargine. Extended release not

studied with insulin

Liraglutide (injection) (Victoza) 0.6-1.8 mg SC qd Acute renal failure Thyroid C-cell tumors. Caution with

hepatic disease



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Meglitinides For postprandial glucose control

Repaglinide (Prandin) 0.5-4 mg before meals. Maximum 16

mg total daily dose

Hypoglycemia Decrease dose if CrCl<40

Nateglinide (Starlix) 60-120 mg tid before meals Low incidence of hypoglycemia Caution in hepatic disease

α-glucosidase inhibitors GI side effects (diarrhea, flatulence,

abdominal pain)

Avoid with bowel disease For postprandial glucose control; poorly

tolerated

Acarbose (Precose) 25-100 mg tid with first bite of meals Avoid with cirrhosis. Caution with

severe CKD

Miglitol (Glyset) 25-100 mg tid with first bite of meals Avoid if CrCl<25 or SCr>2

Amylin analog

Pramlintide (Symlin) (injection) 60-120mcg SC before meals Nausea, vomiting, weight loss Severe hypoglycemia. Avoid with

gastroparesis

Used in conjunction with other agents;

limited long-term data

Combination agents (oral)

Sulfonylurea/Metformin

Glyburide/Metformin (Glucovance) 1.25/250 mg, 2.5/500 mg, 5/500 mg;

dosed 1 tablet with AM and PM meal.

Maximum 20/2000 mg total daily dose

Glipizide/Metformin (Metaglip) 2.5/250 mg, 2.5/500 mg, 5/500 mg;

dosed qd or bid with meals. Maximum 20/2000 mg total daily dose

DPP-IV inhibitor/Metformin

Sitagliptin/Metformin (Janumet, Janumet XR)

Regular-release: 50/500 mg, 50/1000 mg; dosed bid with meals. Extended-

release: 50/500 mg, 50/1000 mg,

100/1000 mg; dosed 1 tablet qd with

PM meal. Maximum 100/2000 mg total

daily dose

Linagliptin/Metformin (Jentadueto) 2.5/500 mg, 2.5/850 mg, 2.5/1000

mg; dosed 1 tablet bid

Saxagliptin/Meformin (Kombiglyze XR) 5/500 mg, 5/1000 mg, 2.5/1000 mg;

dosed 1 tablet qd with PM meal.

Maximum 5/2000 mg total daily dose

Thiazolidinedione/metformin

Pioglitazone/Metformin (Actoplus Met,

Actoplus Met XR)

Immediate-release: 15/500 mg,

15/850 mg; dosed 1 tablet qd or bid

with food. Maximum 45/2550 mg total

daily dose. Extended-release: 15/1000

mg, 30/1000 mg; dosed 1 tablet qd with PM meal. Maximum 45/2000 mg

qd with PM meal

Rosiglitazone/Metformin (Avandamet) 2/500 mg, 4/500 mg, 2/1000 mg,



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4/1000 mg; dosed 1 tablet bid

Meglitinide/Metformin

Repaglinide/Metformin (PrandiMet) 1/500 mg, 2/500 mg; dosed 1 tablet

bid 15 min before meals. Maximum

10/2500 mg total daily dose or 4/1000 mg per meal

Thiazolidinedione/Sulfonylurea

Pioglitazone/Glimepiride (Duetact) 30/2 mg, 30/4 mg; dosed 1 tablet qd

Rosiglitazone/Glimepiride (Avandaryl) 4/1 mg, 4/2 mg, 4/4 mg, 8/2 mg, 8/4

mg; dosed 1 tablet qd with breakfast

Insulin/insulin analogs (for SC injection)

Individualize dosing Hypoglycemia, hypokalemia, weight gain

Caution in CKD or hepatic disease Consider combining insulin and oral agents if oral agents are inadequate

Rapid-acting insulins Used to cover meals in conjunction with long-acting insulin and/or oral

agents

Lispro (Humalog) Within 15 min before or 15 min after

meal start

Aspart (NovoLog) 5-10 min before meals

Glulisine (Apidra) Within 15 min before or 20 min after

meal start

Short-acting insulin

Regular (Humulin R, Novolin R) 30-60 min before meals

Intermediate-acting insulins

Isophane/NPH (Humulin N, Novolin N) 1-2 injections daily, 30-60 min before a meal or bedtime

Detemir (Levemir) Once daily with PM meal or bedtime, or twice daily 12 hrs apart

Long-acting insulin

Glargine (Lantus) Once daily Lower incidence of hypoglycemia

Pre-mixed insulin combinations Combination of long- and short-acting insulin. Generally given before the first

and last meals of the day

NPH/Regular (Humulin 50/50, Humulin

70/30, Novolin 70/30)

Aspart Protamine/Aspart (NovoLog Mix

70/30)

Lispro Protamine/Lispro (Humalog Mix

50/50, Humalog Mix 70/30)



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= first-line agent; = black box warning; AM = morning; bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular; GI =

gastrointestinal; HF = heart failure; IM = intramuscular; IV = intravenous; MI = myocardial infarction; PM = evening; PO = oral; qd = once daily; qid = four times daily; SC = subcutaneous; SCr = serum

creatinine; tid = three times daily

PIER provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.



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Screening and Diagnostic Tests for Diabetes Mellitus

Test Threshold Value Recommended Follow-up Advantages Disadvantages Comment

Fasting plasma glucose >126 mg/dL diagnostic for type

2 diabetes

Confirm by repeat testing on

another day

Time since last meal easily

defined (compared with random

glucose level)

Harder to draw than random

glucose level (i.e., less

convenient for patient)

Can be inconvenient because

patients need to be fasting

Fasting plasma glucose 100-125 mg/dL suggests

“impaired fasting glucose”

Monitor and modify risk factors

for diabetes and cardiovascular

disease

Time since last meal easily

defined (compared with random

glucose level)

Harder to draw than random

glucose level (i.e., less

convenient for patient)

None

Random plasma glucose >200 mg/dL plus symptoms

(polyuria, polydipsia).

Confirms diagnosis of diabetes

No repeat test necessary Convenience Lower sensitivity than other

tests; connection between

levels and risk not well

established

Least acceptable test for

screening

Oral glucose tolerance (OGTT;

2-hour)

≥200 mg/dL diagnostic for type

2 diabetes

Confirm with second OGTT or

fasting plasma glucose level on another day

Difficult to administer Refers to administration of a

75-g glucose load with a single measurement of plasma glucose

2 hours later

Oral glucose tolerance (OGTT;

2-hour)

140-199 mg/dL suggests

impaired glucose tolerance

Follow-up same as for impaired

fasting glucose

Cost Refers to administration of a

75-g glucose load with a single

measurement of plasma glucose

2 hours later

Measures of glycosylated

hemoglobin (GHb; total

glycosylated Hb, HbA1c, or

HbA1)

HbA1c: >6.5% Confirm by repeat testing on

another day

Common-sense diagnostic test,

because treatment decisions

and goals usually are set using

GHb

Many different measures of GHb Test needs to be standardized

with DCCT

Measures of glycosylated

hemoglobin (GHb; total

glycosylated Hb, HbA1c, or

HbA1)

HbA1c: 5.7% -6.4% Ease of testing with random

blood draw

HbA1c is not the universally

implemented standard

Test needs to be standardized

with DCCT

ADA = American Diabetes Association; GHb = glycosylated hemoglobin; Hb = hemoglobin; OGTT = oral glucose tolerance test.



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Secondary Forms of Diabetes or Impaired Glucose Tolerance

Pancreatic disorders

Pancreatectomy

Pancreatitis, pancreatic malignancy

Malnutrition-related diabetes

Hemochromatosis

Endocrinopathies

Growth-hormone excess (acromegaly) and deficiency states

Glucocorticoid excess (Cushing's syndrome)

Catecholamine excess (pheochromocytoma)

Primary hyperaldosteronism

Hyperthyroidism

Tumors of endocrine, pancreas, or gut

Glucagonoma, somatostatinoma, pancreatic cholera syndrome, carcinoid syndrome, multiple endocrine neoplasia syndromes

Polyendocrine autoimmunity syndromes

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes)

Drugs, chemical agents, and toxins

Diuretics and antihypertensive agents:

Thiazides (metolazone), chlorthalidone, loop diuretics (furosemide, ethacrynic acid), diazoxide, clonidine, β-adrenergic antagonists

Hormones:

Glucocorticoids, adrenocorticotropic hormone, β-adrenergic agonists, growth hormone, glucagon, oral contraceptives, progestational agents

Psychoactive agents:

Lithium, opiates, ethanol, phenothiazines

Anticonvulsants:

Diphenylhydantoins (Dilantin)

Antineoplastic agents:

Streptozotocin, L-asparaginase, mithramycin

Antiprotozoal:

Pentamidine

Rodenticides:

Pyriminil (Vacor)



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Miscellaneous:

Nicotinic acid, cyclosporine, N-nitrosamines, theophylline

Genetic syndromes

Pancreatic deficiencies:

Congenital absence of pancreatic islets

Cystic fibrosis

Hereditary relapsing pancreatitis

Mutant insulin syndromes

Severe to extreme insulin resistance syndromes

Type A syndrome—classic and variants

Type B syndrome—associated with autoantibodies to insulin-receptor

Leprechaunism

Lipodystrophic syndromes

Rabson-Mendenhall syndrome (precocious puberty, dental dysplasia, dystrophic nails)

Ataxia-telangiectasia

Alström syndrome (obesity, retinitis pigmentosa, deafness)

Dystrophia myotonica

Glucokinase gene mutations

Mitochondrial tRNA gene mutation

Obesity-associated insulin resistance:

Laurence-Moon-Biedl syndrome

Bardet-Biedl syndrome

Prader-Willi syndrome

Achondroplasia

Progeroid syndromes:

Werner's syndrome

Cockayne's syndrome (microcephaly, dwarfism, deafness, nephropathy)

Chromosomal defects:

Down's syndrome (Trisomy 21)

Klinefelter's syndrome (47, XXY)

Turner's syndrome (45, XO)



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Hereditary neuromuscular disorders:

Muscular dystrophy

Huntington's disease

Friedreich's ataxia (spinocerebellar ataxia)

Machado disease (ataxia, dysarthria, nystagmus)

Herrmann's syndrome (photomyoclonus, dementia, deafness, nephropathy

Stiff-man syndrome

DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) and variants

Kearns-Sayre syndrome (ophthalmoplegia, retinitis pigmentosa, mitochondrial myopathy, heart block)



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Factors Affecting the Benefits and Risks of Tight Glycemic Control

Tight control may not be easy to achieve and may not be beneficial in patients with these

conditions:

Tight control may be harmful (cause hypoglycemia) in patients with these conditions:

Comorbidities (terminal malignancy, severe heart failure) History of severe hypoglycemia (inability to treat without assistance): any episodes within the past

year and/or more than 2 episodes ever

Advanced diabetes complications (proliferative retinopathy, renal failure) Hypoglycemia unawareness

Inability to carry out treatment regimen (financial constraints, availability of needed supplies) Advanced cardiovascular or cerebrovascular disease

Patient unwillingness to use modes of therapy necessary to achieve tight control (e.g., insulin in those

who have failed oral agents)

Autonomic neuropathy (especially cardiac)

Limited life expectancy Comorbidities/medications that impair the detection of hypoglycemia (drugs acting on the central

nervous system, alteration in mental status)

Lack of mobility or patient lives alone



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Dosages for Various Types of Sulfonylureas

Generation Generic Name (Trade Name) Dose Range Dosing Frequency

1st Acetohexamide (Dymelor) 250-1500 mg/d qd-bid

1st Chlopropamide (Diabinese) 100-750 mg/d qd

1st Tolazamide (Tolinase) 100-1500 mg/d qd-bid

1st Tolbutamide (Orinase) 250-3000 mg/d bid-qid

2nd Glimepiride (Amaryl) 1-8 mg/d qd

2nd Glipizide (Glucotrol) 2.5-40 mg/d qd-bid

2nd Glipizide-GITS (Glucotrol XL) 5-20 mg/d qd

2nd Glyburide (Diabeta, Micronase) 1.25-20 mg/d* qd-bid

2nd Micronized glyburide (Glynase/PresTab) 1.5-12 mg/d qd-bid

bid = twice daily; qd = once daily; qid = four times daily.

* Doses >10 mg/d typically do not provide improvements in glycemic control.



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Onset and Mechanisms of Action of Various Types of Insulin

Type Onset and Mechanisms of Action

Lispro/Aspart/Glulisine Very short acting; onset of action within 15 minutes; peak action 30-90 minutes; maximum 5 hours

Regular Short acting; onset of action within 1 hour; duration typically 4-8 hours, maximum 12 hours

NPH Intermediate acting; onset within 2-3 hours; duration typically 8-12 hours, maximum 24 hours

Lente Intermediate acting; onset within 2-3 hours; duration typically 8-12 hours, maximum 24 hours

Glargine Long acting up to 24 hours

Ultralente Longest acting (up to 28 hours)

Premixed (regular and long acting [usually NPH]; concentrations vary) Onset and duration are similar to the component parts

Detemir Long-acting up to 18 hours

Note: All insulins ( regular insulin ; insulin aspart ; insulin lispro ; insulin glulisine ; isopahne insulin [NPH] ; lente insulin ; ultralente insulin ; insulin glargine ; insulin detemir ; insulin lispro, insulin lispro

protamine ; insulin aspart, insulin aspart protamine ; regular insulin, isophane insulin [NPH] ; semilente insulin ; protamine zinc insulin [PZI] ) act directly on glucose metabolism. Starting dose is highly

variable; weight based algorithms can be used with a total starting dose of 0.1 to 0.15 units per kg (NPH or Lente insulin) divided into two doses being typical. Insulins improve HbA1c by 1-2%; in some studies, titrated doses can result in all patients achieving HbA1c <7%



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Risk Factors for Diabetes Mellitus

Age ≥45 years

Overweight

Family history of diabetes (parents or siblings with diabetes)

Race/ethnicity (black, Hispanic, Asian, Native American, Pacific Islanders)

Previously identified impaired glucose tolerance or impaired fasting glucose (100-125 mg/dL)

History of gestational diabetes or delivery of baby weighing ≥9 lbs

Hypertension

Low HDL cholesterol (≤35 mg/dL) and/or high triglyceride (≥250 mg/dL)

Polycystic ovary syndrome

History of vascular disease



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Figures Top

Acanthosis nigricans

Acanthosis nigricans is characterized by velvety or cobblestoned, thickened, brown or “dirty” appearing thin plaques, frequently in skin folds. Acanthosis nigricans is associated with insulin resistance. Photograph courtesy of the Division of Dermatology, Kansas University Medical Center.



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Nonproliferative diabetic retinopathy, right eye

Dot-and-blot hemorrhages and clusters of hard, yellowish exudates characteristic of nonproliferative diabetic retinopathy. Photograph courtesy of Richard Hackel, CRA Wake Forest University Eye Center, Winston-Salem, NC



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Nonproliferative diabetic retinopathy, left eye

Dot-and-blot hemorrhages and clusters of hard, yellowish exudates characteristic of nonproliferative diabetic retinopathy. Photograph courtesy of Richard Hackel, CRA Wake Forest University Eye Center, Winston-Salem, NC



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Diabetic Pre-ulcer

Hemorrhage within a callous, a condition that predisposes to cutaneous ulcer formation (diabetic pre-ulcer).



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Diabetes-Associated Callous Formation

Diabetic foot with thick callous formation.



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Pressure Erythema on a Diabetic Foot

Diabetic foot showing persistent rubor at pressure site, a risk factor for ulcer formation.



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Diabetic Foot Ulcer

Diabetes-associated neuropathic ulcers have a hyperkeratotic rim and occur over pressure points such as the metatarsal heads.



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Proliferative Diabetic Retinopathy

Diabetic proliferative retinopathy with neovascularization.



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Panretinal Laser Photocoagulation

Panretinal laser photocoagulation delivers several thousand small burns to the periphery of the retina, which results in the avascular scarring and shriveling of new vessels.



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Testing the Diabetic Foot with a Monofilament

In the Semmes-Weinstein monofilament test, patients who cannot reliably detect application of the monofilament to designated sites on the plantar surface of their feet are considered to have lost protective sensation.



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Monofilament Testing Recording Form

Testing four areas on the plantar aspect of the foot is nearly as sensitive as testing nine areas. Absent sensation in any area diagnoses an insensate foot and is a risk for ulcer formation.



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Schema of Ulcer Formation

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