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Last Updated: 10/3/2014  

Diabetes Mellitus, Type 2

Prevention
  • Recommend healthy lifestyle changes in patients who have pre-diabetes or are at high risk for type 2 diabetes based on obesity, the presence of polycystic ovarian disease, metabolic syndrome, or a strong family history.

  • Consider treatment with metformin in addition to lifestyle changes in the prevention of diabetes in certain high-risk populations.

Screening
  • Obtain a fasting plasma glucose level, oral glucose tolerance test, or HbA1C level to screen for type 2 diabetes in patients with risk factors for type 2 diabetes, including obesity, gestational diabetes, polycystic ovarian syndrome, membership in a high-risk ethnic group, hyperlipidemia, hypertension, or a history of cardiovascular disease and family history of diabetes.

Diagnosis
  • Establish the diagnosis of diabetes using a glucose tolerance test (2-hour plasma glucose level of ≥200 mg/dL), a fasting plasma glucose level ≥126 mg/dL, or an HbA1c level 6.5% or greater).

  • Establish the diagnosis in patients with symptoms of hyperglycemia with a random plasma glucose level ≥200 mg/dL. Note that repeat testing is needed to confirm the diagnosis in patients without classic symptoms for hyperglycemia.

  • Confirm the diagnosis of type 2 diabetes in any patient with a random plasma glucose level above the normal range, symptoms of hyperglycemia, or possible complications of diabetes.

  • Perform a careful history and physical exam in all patients with hyperglycemia, and evaluate for possible complications of diabetes.

  • Order lab tests to establish baselines and to screen for complications of diabetes, checking HbA1c, urine microalbumin, lipid profile, creatinine and electrolyte levels.

Therapy
  • Individualize the glycemic control goal based on the patient's life expectancy, comorbid conditions, and risk for complications from hypoglycemia.

  • Target glucose control to achieve an HbA1c level less than 7% in most patients; consider a lower goal in select motivated patients who are low risk for hypoglycemia and a higher goal (8%) in some elderly patients.

  • Recommend diet and exercise programs as the cornerstones of therapy for diabetes.

  • Begin oral hypoglycemic agents in patients in whom diet and exercise do not adequately control diabetes, and adjust as needed to achieve the target level of glycemic control. Use metformin as the first-line oral agent in most patients with diabetes.

  • Consider using a combination of insulin, glucagon-like peptide-1 analogs, and non-insulin agents if non-insulin agents do not achieve the desired level of glycemic control, with individual therapies based on patient preference, side-effect profiles, costs, and patient comorbid conditions.

  • Treat hypertension preferentially with an ACE inhibitor or ARB, to reduce the risk for adverse microvascular (e.g., retinopathy, nephropathy) and macrovascular (e.g., MI, stroke) outcomes, with a goal blood pressure <140/90 mm Hg.

  • Treat hyperlipidemia with moderate- or high-intensity statin therapy to reduce the risk for macrovascular complications.

  • Use aspirin for secondary prevention of cardiovascular disease in patients with diabetes, and consider its use for primary prevention in select patients.

  • Treat diabetic nephropathy, preferentially with ACE inhibitors, to reduce the risk for progression to end-stage renal failure.

  • Institute foot-care strategies to prevent ulceration and amputation in patients with documented diabetic neuropathy.

  • Consider treating painful neuropathy preferentially with pregabalin or tricyclic antidepressants.

  • Provide pneumococcal vaccination and annual influenza vaccination.

  • Encourage smoking cessation.

Recommend healthy lifestyle changes in patients who have pre-diabetes or are at high risk for type 2 diabetes based on obesity, the presence of polycystic ovarian disease, metabolic syndrome, or a strong family history. 
  • Recommend daily exercise (at least 30 minutes per day, 5 days a week) and dietary changes for 5% to 10% weight loss in patients at high risk for diabetes, including those with

    • Impaired fasting plasma glucose levels (≥100 mg/dL and <126 mg/dL)

    • Impaired glucose tolerance (140 to 200 mg/dL after 2 hours of 75 g oral glucose)

    • HbA1c level, 5.7% to 6.4%

Evidence
  • A 2014 guideline 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 levels, impaired glucose tolerance, or an HbA1c level of 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 trial of 522 patients with a mean age of 55 in Finland, who were overweight with impaired glucose tolerance, reducing total and saturated fat intake, reducing weight by more than 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 Program, an RCT, 3234 people with elevated fasting plasma glucose concentration but no diabetes were assigned to placebo, lifestyle changes, or metformin. 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% as found in the control group to 14% in the lifestyle modification group, an RRR of 58% (5). A follow-up study of the Diabetes Prevention Program showed sustained reduction in the incidence of diabetes by 34% during 10 years of follow-up (6).

  • A study from China, in which groups of people with impaired glucose tolerance were randomly assigned 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 (7).

  • 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 [blood pressure >130/85 mm Hg], low HDL levels [<40 and 50 mg/dL in men and women, respectively], high triglyceride levels [>150 mg/dL], and impaired fasting glucose levels [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 the risk for new type 2 diabetes during a 7-year follow-up interval (8).

  • In the Physicians' Health Study of 21,271 male physicians age 40 to 84, the relative risk for developing diabetes mellitus was 0.71 (CI, 0.56 to 0.91; P=0.0006) compared with sedentary men with similar results when controlling for age, BMI, smoking, alcohol use, blood pressure, hypertension, hypercholesterolemia, and family history of MI (9).

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.

Consider metformin for prevention of diabetes in patients at very high risk for type 2 diabetes with impaired glucose tolerance, obesity, or a history of gestational diabetes. Strongly consider metformin treatment in patients with an HbA1c level of 5.7% to 6.4%. 
  • Consider metformin along with lifestyle changes in patients at very high risk for diabetes due to

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

    • BMI >35 kg/m2

    • History of gestational diabetes in women younger than age 60

  • Note that

    • Alpha-glucosidase inhibitors may lower the risk for progression to diabetes, but their use has been limited by high incidences of gastrointestinal side effects.

    • Thiazolidinedione drugs have been shown to reduce the incidence of type 2 diabetes but are not recommended due to their potential harms.

Evidence
  • A 2014 guideline from the American Diabetes Association recommended considering metformin use for prevention of diabetes in patients with impaired fasting glucose levels, impaired glucose tolerance, or an HbA1c level of 5.7% to 6.4%, especially in patients younger than age 60, with BMI >35 kg/m2, or with a personal history of gestational diabetes (1).

  • The Diabetes Prevention Program was a randomized trial comparing metformin (850 mg bid), lifestyle change, and placebo in 3234 patients with pre-diabetes. The incidence of diabetes was 11 per 100 person-years in the control group, 7.8 per 100 person-years in the metformin group, and 4.8 per 100 person-years in the lifestyle intervention group (5).

  • The DREAM study was a randomized trial comparing rosiglitazone, 8 mg daily, with placebo in 5269 patients with pre-diabetes. The primary outcome was a composite of diabetes or death. After a follow-up time of 3 years, fewer patients in the rosiglitazone group developed diabetes or died compared with the placebo group (11.6% vs. 26%; P<0.0001) and more patients in the rosiglitazone group became normoglycemic (50.5% vs. 30.3%; P<0.0001). Of note, more participants in the rosiglitazone group developed heart failure (0.5% vs. 0.1%; P=0.01) (10).

  • A randomized trial compared pioglitazone with placebo in 602 patients with pre-diabetes. The annual rate of developing diabetes was lower in the pioglitazone group (2.1% vs. 7.6%; P<0.001), with more patients in the pioglitazone group becoming normoglycemic (48% vs. 28%; P<0.001). Weight gain was greater with pioglitazone (3.9 kg vs. 0.77 kg; P<0.001) and edema was more common (12.9% vs. 6.4%; P=0.007) (11).

Rationale
  • 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 ALLHAT trial in nondiabetic participants, more than 18,000 subjects were randomly assigned to receive treatment with chlorthalidone (n=8419), amlodipine (n=4958), or lisinopril (n=5034) and were 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 for 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 for clinical events (12).

  • In a 2005 meta-analysis of 12 RCTs of ACE inhibitors and ARBs, 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 (13). However, in the NAVIGATOR trial, valsartan decreased the risk for 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% (14).

  • In the STOP-NIDDM trial, acarbose, 100 mg three times daily, decreased the incidence of diabetes from 42% in the placebo group to 32% in the acarbose group (RRR, 25%) over 3 years. However, acarbose is poorly tolerated and is not generally used for prevention (15).

Obtain a fasting plasma glucose level, oral glucose tolerance test, or HbA1c level to screen for type 2 diabetes mellitus in patients with selected comorbidities or risk factors for the disease.  
Evidence
  • A 2008 USPSTF guideline recommended screening adults with hypertension for diabetes (16).

  • A 2014 guideline from the American Diabetes Association recommended screening every 3 years all patients older than age 45 as well as patients younger than age 45 who are overweight or obese and have one additional risk factor (1).

  • A 2012 RCT 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 of 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 (17).

  • 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) (18).

  • Epidemiologic data show the increased risk for diabetes in patients with a family history of type 2 diabetes, obesity, hypertension, a personal history of gestational diabetes, membership in certain ethnic groups, and the presence of atherosclerotic disease (19; 20; 21; 22; 23; 24; 25; 26; 27).

Rationale
  • Early recognition of diabetes and aggressive treatment of other 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.

Comments
  • Although a large RCT failed to show a mortality benefit, 10 years of follow-up may not have been adequate to detect a benefit from screening.

  • 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 (28). Therefore, screening for secondary causes should be considered only in the presence of suggestive signs and symptoms.

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

Establish the diagnosis of diabetes using a glucose tolerance test (2-hour plasma glucose level of ≥200 mg/dL), a fasting plasma glucose level ≥126 mg/dL, an HbA1c level of 6.5% or higher, or a random plasma glucose level ≥200 mg/dL in patients with hyperglycemic testing.  
  • Use one of the following 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

    • A plasma glucose level ≥126 mg/dL (7 mmol/L) after an 8-hour fast

    • A random plasma glucose level ≥200 mg/dL (11.1 mmol/L) in patients with classic symptoms of hyperglycemia or hyperglycemic crisis

    • An HbA1c level of 6.5% or higher

  • Note that repeat testing on subsequent days, preferably with the same test, is needed to confirm the diagnosis in patients without classic symptoms of hyperglycemia.

  • See table Screening and Diagnostic Tests for Diabetes Mellitus.

Evidence
  • A 2014 guideline from the American Diabetes Association for the care of patients with diabetes recommended diagnosing diabetes in patients with an HbA1c level of 6.5% or higher, 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 testing compared with glucose tolerance testing for the diagnosis of diabetes in a screening population found that an HbA1c level of 6.5% or higher had a sensitivity of 30% and a specificity of 99%, indicating that a positive test result (i.e., higher HbA1c level) could rule in diabetes but that a lower HbA1c level was less helpful in ruling it out (29).

Rationale
  • Multiple different tests can be indicative of hyperglycemia.

Comments
  • Because HbA1c testing does not require that patients fast and can be done easily in the office, it may be more useful in the diagnosis of diabetes despite lower sensitivity.

Confirm the diagnosis in patients with symptoms of hyperglycemia. 
  • Use diagnostic testing in patients with symptoms consistent with diabetes.

  • Note that classic symptoms of hyperglycemia include polydipsia, polyuria, unexplained weight loss, and blurry vision.

  • Note that other symptoms include

    • Frequent infections

    • Impotence

  • See table Screening and Diagnostic Tests for Diabetes Mellitus.

Evidence
  • Consensus.

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.

Comments
  • Acanthosis nigricans is often a marker for insulin resistance and can precede the diagnosis of type 2 diabetes (30; 31).

Confirm the diagnosis in patients with physical findings suggestive of known complications and epiphenomena of the disease. 
Evidence
  • A retrospective cohort study evaluated the likely duration of diabetes at diagnosis among American and Australian patients with type 2 diabetes. The prevalence of retinopathy at diagnosis was 20.8% in the U.S. cohort and 9.9% in the Australian cohort. The study estimated that retinopathy was likely present 4 to 7 years before the diagnosis of diabetes (32).

Rationale
  • Physical findings suggesting the presence of complications of diabetes often require specific measures for prevention and treatment.

Comments
  • Symmetrical peripheral neuropathy can be present at the diagnosis of type 2 diabetes, although it is less common than with retinopathy.

  • Acanthosis nigricans is often a marker for insulin resistance and can precede the diagnosis of type 2 diabetes (30; 31).

Confirm the diagnosis of type 2 diabetes in any patient with a random plasma glucose level above the normal range. 
Evidence
  • A cross-sectional study assessed the accuracy of random plasma glucose testing for the diagnosis of diabetes in a general population of 3425 Europeans and 3469 South Asians. The diagnosis was made by glucose tolerance tests, which were performed in all patients with elevated random plasma glucose levels and in 10% of those with normal random glucose levels. Random glucose levels of >126 mg/dL were seen in 8% of Europeans and 6.7% of South Asians, and had a sensitivity of 51.7% in Europeans and 68.4% in South Asians (33).

Rationale
  • Generally, random plasma glucose levels are not considered diagnostic and should not serve as a screening test for type 2 diabetes in asymptomatic patients. 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.

Perform a careful history and physical exam in all patients with hyperglycemia to evaluate for the complications of diabetes.  
  • Document key items from the patient's history regarding risk factors for diabetes, previous history of diabetes, and complications of diabetes, including

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

    • History of hyperglycemic crisis with diabetic ketoacidosis or hyperosmolar hyperglycemic state

    • Cardiovascular risk factors

    • Diet and exercise

    • Infections, particularly fungal infections, recurrent urinary tract infections, or nonhealing skin infections

    • Other endocrine disorders, including thyroid and adrenal disorders

    • Microvascular complications:

      • Visual disturbances (retinopathy)

      • Neuropathic pain, especially in the feet (neuropathy)

      • Sexual dysfunction (autonomic neuropathy)

    • Macrovascular complications: cardiovascular disease, cerebrovascular accident, peripheral arterial disease

  • 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

    • Complete foot exam with inspection, palpation for distal pulses, testing for reflexes and sensory loss

  • 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.

  • See figure Testing the Diabetic Foot with a Monofilament.

  • See figure Monofilament Testing Recording Form.

  • See figure Schema of Ulcer Formation.

Evidence
  • A 2014 guideline from the American Diabetes Association recommend screening for retinopathy and distal symmetric polyneuropathy at the time of diagnosis and recommended a complete foot exam (1).

  • A 1992 systematic review of screening for diabetic retinopathy included studies of the accuracy of office-based fundoscopic exams for the detection of retinopathy. While the accuracy of the fundoscopic exam performed by primary care providers varied across studies, the sensitivity was generally less than 80% (34).

  • A 2004 narrative review of issues related to foot ulceration and amputation in diabetes noted that risk factors include peripheral neuropathy and peripheral vascular disease (35).

Rationale
  • The history and physical exam are focused on systems that frequently manifest complications of type 2 diabetes.

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

    • HbA1c level

    • Fasting lipid profile

    • Serum electrolyte, blood urea nitrogen, and creatinine levels

    • Urinary microalbumin and creatinine level

    • ECG in select patients

Evidence
  • A 2014 guideline from the American Diabetes Association 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, testing lipid levels annually, and testing for urinary albumin excretion annually in patients with type 2 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 a pooled sensitivity of 76% and a pooled specificity of 93%; the quantitative test had a pooled sensitivity of 96% and a pooled specificity of 98% (36).

  • A 2005 systematic review evaluated the prognostic significance of urinary albumin testing in patients with diabetes. Overall, among patients with type 2 diabetes, microalbuminuria was associated with all-cause mortality (RR, 1.9 [CI, 1.7 to 2.1]), clinical proteinuria (RR, 7.5 [CI, 5.2 to 10.9]), and end-stage renal disease (RR, 3.6 [CI, 1.6 to 8.4]), but was not associated with the development of retinopathy (37).

  • A population-based study evaluated the relationship between HbA1c level and the development of diabetic retinopathy. Patients in the highest quartile of HbA1c were at increased risk for retinopathy among those with type 2 diabetes on insulin (RR, 1.9), those with type 2 diabetes not on insulin (RR, 4.0), and those with young-onset diabetes (RR, 1.9) (38).

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

Consider the limited differential diagnosis for type 2 diabetes. 
Evidence
  • Consensus.

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

Consider referral for diabetes self-management education for all patients with type 2 diabetes.  
  • 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
  • A 1988 systematic review of the effects of educational interventions in patients with diabetes included 47 studies. In the pooled analysis, education was effective in improving knowledge, skill, self-care behaviors, psychosocial outcomes, and metabolic control (39).

  • A randomized trial compared one visit with three visits for dietary education by nutritionists in patients with type 2 diabetes. After 6 months, fasting plasma glucose levels were reduced more in the three-visit than in the single-visit group (10.5% vs. 5.3% reduction) (40).

Rationale
  • Diabetes education is complex and involves many disciplines.

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

Consider referral to an endocrinologist for help in making the diagnosis or managing patients with complicated presentations or disease courses. 
Evidence
  • Consensus.

Rationale
  • Interpreting data, determining severity of disease and complications, and recognizing uncommon conditions associated with hyperglycemia may require specialist expertise.

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

Comments
  • Over time, a substantial proportion of patients with type 2 diabetes fail to achieve goals for glycemic control. Patients who are adherent but do not respond to standard medications may have secondary causes of diabetes or the progression of disease may require intensive insulin management.

Refer patients with diabetes to an ophthalmologist. 
  • Obtain consultation to screen for diabetic eye disease at diagnosis and every 1 to 3 years, depending on risk, to reduce the risk for visual loss from diabetic retinopathy and macular edema.

Evidence
  • A 2014 guideline from the American Diabetes Association recommended screening for retinopathy in patients with type 1 diabetes who are older than 10 years and have had diabetes for 5 years, and at disease onset for patients with type 2 diabetes. The guideline also recommended efforts to optimize glycemic and blood pressure control to slow the progression of retinopathy and referral of patients with retinopathy to an ophthalmologist for treatment (1).

  • A 1992 systematic review of screening for diabetic retinopathy included studies of the accuracy of office-based fundoscopic exams for the detection of retinopathy. While the accuracy of the fundoscopic exam performed by primary care providers varied across studies, the sensitivity was generally less than 80% (34).

  • A 2000 cost-effectiveness analysis of screening intervals for diabetic retinopathy modeled a population older than age 40 with variable glycemic control. In the analysis of a 45-year-old with an HbA1C level of 11%, screening every 5 years decreased the days spent blind by 164 days; screening every 3 years further reduced days spent blind by 24 additional days; and annual screening reduced days spent blind by an additional 21 days (41).

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 the sensitivity and specificity of the exam 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.

Consult other specialists as needed. 
  • 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 or who are at risk for the formation of a diabetic foot ulcer (e.g. patients with loss of protective sensation, peripheral vascular disease) to multidisciplinary foot clinics for management.

  • Consult for cardiology:

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

    • Consider a screening cardiac stress test for those who are at high risk due to a history of peripheral or carotid artery occlusive disease and who plan to begin a vigorous exercise program.

    • Note that due to a lack of evidence supporting improvement of overall outcomes, routine screening for coronary heart disease in asymptomatic diabetic patients with a stress test is not recommended.

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

  • Consult for nephrology:

    • Consider referral when the etiology of kidney failure is uncertain, progression of kidney dysfunction cannot be explained by diabetes alone, or the GFR falls to <30 mL/min·1.73 m2 or is <60 mL/min·1.73 m2 with difficult-to-control blood pressure or hyperkalemia.

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

Evidence
  • Consensus.

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 delay the requirement for dialysis.

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

Hospitalize patients with potentially fatal metabolic abnormalities. 
  • Hospitalize patients with

    • Diabetic ketoacidosis (blood glucose level >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

  • See module Diabetic Ketoacidosis.

Evidence
  • Consensus.

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

Use patient characteristics and preferences to set treatment goals, generally with a goal HbA1c level less than 7%. Consider life expectancy, comorbid conditions, and risk for complications from hypoglycemia when individualizing therapy. 
  • Set treatment goals and choose the initial agent based on patient characteristics and preferences:

    • Target glucose control in most patients to achieve an HbA1c level of less than 7%.

    • Consider a goal HbA1c level of less than 6.5% in select motivated patients with shorter duration of diabetes who are at high risk for complications but at low risk for hypoglycemia.

    • Individualize therapy for patients with comorbidities and the elderly, setting a higher goal HbA1c level of up to 8% for frail elderly patients, patients with a limited life expectancy, and patients at higher risk for hypoglycemia.

Evidence
  • A 2014 guideline from the American Diabetes Association recommended a goal HbA1c level of less than 7% for most patients with diabetes, noting that a lower goal HbA1c level (less than 6.5%) is reasonable in select patients without hypoglycemia and a high goal HbA1c level (less than 8.0%) is reasonable for patients with a history of severe hypoglycemia, a limited life expectancy, multiple comorbid conditions, and other factors (1).

  • A 2013 Cochrane review of intensive vs. standard glycemic control for patients with type 2 diabetes included 28 studies with 34,912 participants. Intervention durations varied widely, and many studies had a substantial risk for bias. In the pooled analysis, intensive glycemic control did not reduce all-cause (RR, 1.00 [CI, 0.92 to 1.08]) or cardiovascular (RR, 1.06 [CI, 0.94 to 1.21]) mortality or macrovascular complications (RR, 0.91 [CI, 0.82 to 1.02] in the random-effects model). Intensive glycemic control reduced rates of nonfatal MI (RR, 0.87 [CI, 0.77 to 0.98]) and lower-extremity amputation (RR, 0.65 [CI, 0.45 to 0.94]), and increased rates of serious (RR, 1.06 [CI, 1.02 to 1.10]) and severe hypoglycemia (RR, 2.18 [CI, 1.53 to 3.11]) (42).

  • A large randomized trial (the UK Prospective Diabetes Study) in patients with newly diagnosed type 2 diabetes showed 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 (43).

  • The ACCORD study was a randomized trial of a goal HbA1c level of less than 6% vs. a goal HbA1c level of 7% to 7.9% in patients with type 2 diabetes. The study found that patients randomly assigned 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 the potential risk from tight control may outweigh the benefits in certain groups of patients with type 2 diabetes (44).

  • The ADVANCE trial randomly assigned 11,140 patients with type 2 diabetes to either standard glucose control or intensive glucose control (goal HbA1c level less than 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) (45).

Rationale
  • Tight glucose control reduces microvascular complications.

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

Comments
  • Stricter glycemic goals have been shown to reduce incidence and slow progression of microvascular complications. However, the evidence remains unclear regarding the relationship between aggressive glycemic control and macrovascular complications. Some studies have suggested no significant reduction or even a mild increase in cardiovascular incidents with very strict glycemic control in certain groups of patients.

Recommend diet and exercise programs as the cornerstones of therapy for diabetes.  
  • Initiate diet and exercise regimens for patients with diabetes, even if severe hyperglycemia demands immediate drug therapy.

  • Consider referral to a dietitian to provide comprehensive support and promote adherence to dietary modifications.

  • Recommend the following:

    • Moderate weight loss

    • Basing calorie intake on the goal of achieving near-ideal body weight

    • Avoiding saturated fats and trans fats

    • Following a regular meal schedule, particularly if on insulin

    • Eating small meals to aid in weight loss and control of blood-glucose levels

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

  • Individualize the 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, with a total of 150 minutes per week.

Evidence
  • A 2014 guideline from the American Diabetes Association 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 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 RCTs involving 377 participants. Exercise significantly improved glycemic control and reduced visceral adipose tissue and plasma triglyceride levels but not plasma cholesterol levels. These improvements occur even without weight loss (46).

  • A randomized trial (Look AHEAD: Action for Health in Diabetes) assigned 5145 obese patients with type 2 diabetes to intensive lifestyle intervention or diabetes education only. The intensive intervention group achieved greater weight loss of 6% vs. 3.5% in the education only group at a mean of 9.6 years of follow-up, and was able to achieve greater reduction in HbA1c levels with improvements in all cardiovascular risk factors, although there was no reduction in the rate of cardiovascular events (47).

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 American Diabetes Association 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.

  • 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.

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

  • Consider sulfonylureas as first-line agents in patients who are not obese or in those who do not tolerate metformin.

  • Maximize dosage of the agent before adding additional agents, although escalating doses may be of limited effectiveness.

  • Note that many patients will not reach glycemic goals with monotherapy.

  • Individualize the use of combinations of non-insulin agents based on patient preference, provider familiarity, and consideration of issues such as side-effect profiles and costs.

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

    • Minimization of weight gain

    • Minimization of injections

    • Minimization of patient effort

    • Avoidance of hypoglycemia

    • Minimization of cost

  • Note that

    • Sulfonylureas can be used in combination with metformin

    • Incretin-based therapies, including glucagon-like peptide-1 analogs or dipeptidyl peptidase-4 inhibitors, can be added while continuing first-line oral medications or basal insulin

    • Addition of a thiazolidinedione can effectively lower HbA1c levels, although the risks for potential side effects may outweigh the benefits, especially in high-risk patients

    • Other medications, such as acarbose, alpha-glucosidase inhibitors, and bromocriptine, can also be considered as additional oral therapies

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

  • See table Dosages for Various Types of Sulfonylureas.

Evidence
  • A 2012 clinical practice guideline from the American College of Physicians recommended metformin as first-line therapy in patients with type 2 diabetes in whom lifestyle interventions do not achieve treatment goals (48).

  • A 2014 guideline from the American Diabetes Association recommended metformin as the preferred first agent for most patients with type 2 diabetes (1).

  • The 2009 NICE guideline for the care of patients with type 2 diabetes included a helpful treatment algorithm, which recommended metformin as the first-line agent in most patients with diabetes.

  • 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 levels more than dipeptidyl peptidase-4 inhibitors and had benefits including weight loss and improvements in the lipid profile (49).

  • A 2011 systematic review of second-line oral agents for patients with diabetes with inadequate control on metformin alone included 49 trials. In the pooled analysis, there were no differences among classes of medication in terms of glycemic control. Sufonylureas, meglitinides, and insulin were more likely to cause hypoglycemia compared with placebo, and weight gain was seen compared with placebo with sulfonylureas, meglitinides, thiazolaminediones, and biphasic insulin (50).

  • A 2011 systematic review of the effects of pramlintide on glycemic control and weight loss found modest improvements in HbA1c levels, with a pooled mean HbA1c level reduction of 33% (CI, -0.51 to -0.14) and an NNT of 17 to achieve goal HbA1c levels over 16 to 52 weeks, and a mean weight loss of 2.21 kg. The main side effect was nausea. Studies, however, compared pramlintide with no change in therapy and may have overestimated its effect compared with other therapeutic adjustments (51).

  • A 2010 systematic review of the impact of rosiglitazone on MI and cardiovascular mortality included 56 studies with 35,531 participants. In the pooled analysis, rosiglitazone compared with control therapies increased the risk for MI (OR, 1.28 [CI, 1.02 to 1.63]) but not cardiovascular mortality (OR, 1.03 [CI, 0.78 to 1.36]) (52).

  • The UK Prospective Diabetes Study compared metformin as the initial oral agent with insulin and sulfonylureas and compared the addition of metformin with 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 (53).

  • In the ADOPT study, 4360 subjects with type 2 diabetes were randomly assigned 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 with 21% with metformin and 34% with glyburide, but rosiglitazone was associated with more weight gain than metformin or glyburide (54).

  • In the 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 (which included mortality, MI, stroke, and other vascular outcomes) but had higher rates of heart failure (NNH, 23) (55; 56).

Rationale
  • Metformin controls blood glucose and can help contribute to weight loss.

  • 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
  • Sulfonylureas are usually well tolerated, although they can cause hypoglycemia and should be used with caution in the elderly and patients at risk for hypoglycemia, such as those with renal insufficiency.

  • Therapy with glucagon-like peptide-1 analogs is usually associated with a lower risk for hypoglycemia and lower weight gain, and may promote weight loss. However, side effects including diarrhea, nausea, and bloating may be significant limitations for long-term compliance with the medication. Glucagon-like peptide-1 agonists are contraindicated in patients with a history of medullary thyroid cancer or a family history of medullary thyroid cancer. Pancreatitis has been reported in association with the use of incretin-based therapy and should be monitored.

  • Rosiglitazone has been associated with increased cardiovascular adverse events, and its use was restricted by the FDA. In 2013, after re-evaluation of the RECORD study, the FDA concluded that no increased risk for cardiovascular disease was seen in patients treated with rosiglitazone and reversed the restriction. Studies on pioglitazone did not show any changes in the rate of cardiovascular events, although the incidence of heart failure was significantly greater. Thiazolidinediones are contraindicated in patients with heart failure or liver dysfunction and should be used with caution in patients with increased risk for osteoporosis or bladder cancer.

  • A review of the safety data in a 2006 study showed that significantly more female patients who received rosiglitazone experienced fractures (mainly of the upper arm, hand, or foot) than did female patients on metformin or glyburide (54). Pioglitazone therapy has also been linked to an increased risk for fracture in women.

Consider using a combination of insulin and non-insulin agents if non-insulin agents do not achieve the desired level of glycemic control. 
  • 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.

  • Consider adding insulin to oral medications when patients have not reached therapeutic goals after an adequate trial of non-insulin agents.

  • Begin with adding once-daily insulin:

    • Begin 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 level ~80 to 120 mg/dL).

  • Continue metformin when beginning insulin.

  • Continue sulfonylureas initially when beginning insulin but decrease 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.

  • Note that basal insulin along with glucagon-like peptide-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 Types of Sulfonylureas.

Evidence
  • The 2009 NICE guideline on the management of type 2 diabetes recommended continuing sulfonylureas and metformin when starting insulin.

  • A 2014 guideline from the American Diabetes Association 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) with 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 (57; 58).

  • 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 that include metformin (59).

  • A randomized trial compared insulin lispro with insulin glargine in 116 patients with type 2 diabetes who had inadequate glycemic control with metformin plus a sulfonylurea. After 36 weeks, the groups had similar improvement in HbA1C levels (with 1.83% and 1.89% reductions) (60).

  • A randomized trial compared bedtime insulin plus glyburide, metformin, both glyburide and metformin, and a second insulin injection in 96 patients with type 2 diabetes and poor control on a sulfonylurea alone. After 1 year, the metformin-alone group had stable weight, while all other groups gained weight, and had the greatest decrease in HbA1C level (61).

  • A 2012 narrative review discussed initiating insulin therapy in patients with type 2 diabetes (62).

Rationale
  • Stepped therapy with bedtime insulin is effective in achieving glycemic targets in patients for whom non-insulin agents alone are ineffective.

Comments
  • In patients started on insulin, most preexisting non-insulin 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 for weight gain, edema, and heart failure in patients using maximum doses of a thiazolidinedione drug and insulin, consideration should be given to reducing the dose or stopping the thiazolidinedione.

  • Combination therapy with basal insulin and glucagon-like peptide-1 agonists is being used more often.

Consider using other insulin regimens and other medications if non-insulin agents and once-daily insulin combined do not achieve the desired level of glycemic control.  
  • Continue preexisting non-insulin agents, such as metformin, for their insulin-sensitizing and insulin-sparing effects.

  • Consider any of the possible insulin 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:

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

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

      • Humulin 50/50 has equal amounts of intermediate-acting insulin and lispro.

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

    • Few patients receive multiple daily injections of regular insulin.

  • When beginning 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.

    • Note that patients who have insulin resistance, such as those who are obese or use glucocorticoids, usually require higher doses, while patients with decreased renal function may require a lower dose.

    • Consider adding short-acting insulin if the patient has persistent postprandial hyperglycemia. Start with 3 to 4 units and adjust every 3 days until reaching the therapeutic goal.

    • Consider using concentrated insulin (U-500) when the total daily requirement of insulin exceeds 200 units.

  • Educate patients regarding the risk for hypoglycemia and the management of hypoglycemia while on insulin, and advise them about possible weight gain with insulin use.

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

Evidence
  • A 2014 guideline from the American Diabetes Association 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) with 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 (57; 58).

  • A randomized trial compared insulin lispro with insulin glargine in 116 patients with type 2 diabetes who had inadequate glycemic control with metformin plus a sulfonylurea. After 36 weeks, the groups had similar improvement in HbA1C levels (with 1.83% and 1.89% reductions) (60).

  • A prospective cohort study evaluated the effect of starting insulin detemir, insulin aspart, or biphasic insulin aspart in 66,726 patients with type 2 diabetes and a mean baseline HbA1C level of 9.5%. Overall, the HbA1C level was reduced by 2.1% after 6 months of therapy, with no difference seen among specific insulin regimens and no increase in hypoglycemia (63).

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 rapid-onset, shorter-acting forms of insulin that may be useful in managing postprandial hyperglycemia or when patients inject insulin immediately before meals (64; 65; 66).

  • Glargine cannot be mixed with any other type of insulin, and, in converting from NPH insulin, a 20% initial reduction in number of units is required.

  • Due to the increased risk for weight gain, edema, and heart failure in patients using maximum doses of a thiazolidinedione drug and insulin, consideration should be given to reducing the dose of the thiazolidinedione.

Treat hypertension, preferably with an ACE inhibitor or ARB, to reduce the risk for adverse microvascular and macrovascular outcomes, with a goal blood pressure of <140/90 mm Hg. 
  • Treat hypertension 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, particularly in those with proteinuria.

  • Initiate treatment of hypertension with ACE inhibitors, and use ARBs as first-line agents in patients who develop cough from ACE inhibitors.

  • 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.

  • In patients who do not achieve the target blood pressure with a maximal dose of an ACE inhibitor,

    • Add a thiazide diuretic in most patients.

    • Consider adding a long-acting dihydropyridine, such as amlodipine, as a second agent.

    • Consider β-blockers and other calcium-channel blockers as agents if combinations of the initial agents (thiazide diuretics, ACE inhibitors, ARBs, amlodipine) 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 an MI

    • A diuretic, ACE inhibitor, and β-blocker in patients with 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 panel members of the Eighth Joint National Committee recommended a target blood pressure of <140/90 mm Hg for patients younger than age 60 and <150/90 mm Hg for patients age 60 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, nonblack populations, and recommended calcium-channel blockers and thiazide diuretics as first-line agents in diabetic and nondiabetic black patients (67).

  • 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 (68).

  • A 2014 guideline from the American Diabetes Association recommended a goal blood pressure of <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 2009 NICE guideline on the management of type 2 diabetes recommended that patients with diabetes and hypertension be offered lifestyle advice and that medical management should begin if the blood pressure remains above 140/80 mm Hg in the absence of end-organ damage or 130/80 mm Hg 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 with placebo or a comparator drug and 13 compared ARBs with placebo or another drug. Compared with 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 with control therapy, 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]) (69).

  • A 2013 systematic 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 with placebo, ACE inhibitors reduced the risk for serum creatinine level 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 (70).

  • A 2013 Cochrane review of blood pressure targets in patients with diabetes and hypertension included 5 trials with 7314 participants. In the single trial that addressed tight vs. standard systolic control, tight control reduced stroke (RR, 0.58 [CI, 0.39 to 0.88]) but increased serious adverse events (RR, 2.58 [CI, 1.70 to 3.91]). In the 4 studies addressing tight vs. standard diastolic control, there was a trend toward lower total mortality in the tight control group (RR, 0.73 [CI, 0.53 to 1.01]), with no reduction in stroke, MI, or heart failure (71).

  • A 2011 systematic review of tight control of blood pressure in diabetic patients included 31 studies with 73,913 participants (primarily type 2). In the pooled analysis, compared with standard blood pressure control, intensive control reduced stroke (RR, 0.61 [CI, 0.48 to 0.79]) but not MI (RR, 0.87 [CI, 0.74 to 1.02]) (72).

  • The ACCORD study was a large, randomized trial comparing “normal” target blood pressure (systolic <120 mm Hg) with a target systolic blood pressure of 135 to 140 mm Hg in high-risk patients with type 2 diabetes. After 1 year of follow-up, the 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 (nonfatal 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) (NNT, 95 [CI, 64 to 354]) and higher rates of serious adverse events due to hypertensive medication (NNH, 50) (73; 74).

  • The ACCOMPLISH trial was a randomized trial comparing benazepril-amlodipine or benazepril-hydrochlorothiazide in patients with hypertension who were at risk for cardiovascular complications, among whom 60% had diabetes (75). In a subgroup analysis of 6946 patients from the ACCOMPLISH study with diabetes, the benazepril-amlodipine group had a slightly lower risk for cardiovascular events (HR, 0.79 [CI, 0.68 to 0.92]) (76).

Rationale
  • Control of blood pressure may improve the risk for macrovascular disease in patients with type 2 diabetes.

  • Control of hypertension reduces the risk for 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.

Treat most patients with diabetes with moderate- or high-intensity statin therapy to reduce the risk for macrovascular complications.  
  • Advise all patients with diabetes to undergo lifestyle modifications, including lowering saturated and trans fats in their diet, lowering their total cholesterol intake, and exercising.

  • Treat diabetic patients with known cardiovascular or other vascular disease with high-intensity statin therapy.

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

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

    • Consider high-intensity statin therapy if the calculated 10-year risk for atherosclerotic events is 7.5% or higher.

    • Provide moderate-intensity statin therapy for patients with diabetes and a calculated 10-year risk for atherosclerotic events of less than 7.5%.

    • Consider withholding statin therapy in patients younger than age 40 without additional risk factors for cardiovascular disease.

  • See table Therapeutic Intensity of Statin Disorders.

  • See module Lipid Disorders (Dyslipidemia).

Evidence
  • 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 levels ≥190 mg/dL, and moderate-intensity statin therapy for most patients with diabetes with no history of cardiovascular disease and LDL levels <190 mg/dL, with consideration of high-intensity therapy for diabetic patients with a calculated 10-year risk for atherosclerotic events of 7.5% or higher (77).

  • A 2014 guideline from the American Diabetes Association recommended measuring a fasting lipid panel annually in patients with diabetes and treating them 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 (78).

  • A 2008 systematic review of diabetic (types 1 and 2) and nondiabetic patients included in randomized trials of statins showed that diabetic patients on statins had similar benefit to nondiabetic patients in terms of cardiovascular outcomes, with trends toward reduction in cardiovascular and all-cause mortality (79).

  • A 2014 systematic review of the effect of HDL-raising medication on mortality and cardiovascular outcomes included 12 studies with 26,858 participants. In the pooled analysis, there was no difference in mortality (OR, 1.07 [CI, 0.98 to 1.16]) or other outcomes with treatment with HDL-raising medication (80).

  • A 2010 systematic review of the relationship between statin therapy and the development of diabetes included 13 trials. In the pooled analysis, statin therapy was associated with an increased risk for incident diabetes (OR, 1.09 [CI, 1.02 to 1.17]). Older patients were at higher risk. It was estimated that treatment of 244 patients with statins for 4 years would result in one extra case of diabetes (81).

  • A randomized trial compared atorvastatin with placebo in 1255 patients with diabetes and end-stage renal disease on dialysis. After a median follow-up time of 4 years, there was no difference between the groups in the rate of the primary outcome (death, cardiac events, or cerebrovascular events) (82).

  • 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% (83).

  • In the ACCORD trial, patients with type 2 diabetes who were treated with simvastatin were randomly assigned to receive either fenofibrate or placebo in addition to their therapy regimens. During a mean follow-up of 4.7 years, the combination therapy with fenofibrate did not reduce cardiovascular events (2.24 events/years vs. 2.41 events/years; HR, 0.92 [CI, 0.79 to 1.08]) (84).

  • In the AIM-HIGH trial, 3414 patients with cardiovascular disease and low HDL and high triglyceride levels, were randomly assigned to extended-release niacin or placebo. All patients received simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed, to maintain an LDL cholesterol level of 40 to 80 mg/dL. After a mean of 36 months of follow-up, no difference in the primary outcomes that included first event of the composite of death from coronary heart disease, nonfatal MI, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary, or cerebral revascularization were seen (85).

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.

Comments
  • Optimal levels are triglycerides <150 mg/dL and HDL >40 mg/dL. However, combining other drugs like fenofibrate or nicotinic acid with statins to achieve these levels has not shown to improve cardiovascular mortality.

  • Statin use is associated with a slight increase in the incidence of diabetes in patients with risk factors for diabetes. However, the benefit for cardiovascular protection may outweigh the relative small increase in the risk for development of diabetes.

Use aspirin for secondary prevention of cardiovascular disease in patients with diabetes and consider its use for primary prevention in select patients.  
  • 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 older than 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
  • A 2014 guideline from the American Diabetes Association recommended considering low-dose aspirin for primary prevention in patients at increased risk for cardiovascular disease and for secondary prevention in all patients with known cardiovascular disease (1).

  • A 2002 systematic review of antiplatelet therapy for primary prevention of MI, stroke, and death in high-risk patients included 287 studies. In the subgroup of patients with diabetes (9 trials), antiplatelet agents did not reduce the rate of vascular events. Among patients with previous MI (OR, 0.75) and stroke (OR, 0.78), antiplatelet agents reduced vascular events (86).

  • The POPADAD study was a randomized trial that compared aspirin with placebo in 1276 diabetic patients with asymptomatic peripheral arterial disease. For the primary outcome, nonfatal MI or stroke or death from MI or stroke, the aspirin and placebo rates did not differ (18.2% vs. 18.3%) (87).

  • The Early Treatment Diabetic Retinopathy Study was a randomized trial comparing aspirin, 750 mg/d, with placebo in 3711 patients with diabetes. The aspirin group had similar mortality to the placebo group (RR, 0.91 [CI, 0.75 to 1.11]) (88).

Rationale
  • Although patients with diabetes are at increased risk for cardiovascular disease, aspirin therapy has not been shown to be useful in primary prevention.

Prevent and treat diabetic nephropathy, preferentially with ACE inhibitors, to reduce the risk for progression to end-stage renal failure in patients with type 2 diabetes. 
  • Treat hypertension to a target blood pressure of 140/80 mm Hg.

  • Use either ACE inhibitors or ARBs as first-line agents for hypertension, and consider their use in nonhypertensive patients with microalbuminuria or overt proteinuria.

  • Consider titration to the maximum tolerated dose.

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

  • See module Chronic Kidney Disease.

Evidence
  • A 2014 guideline from the American Diabetes Association recommended ACE inhibitors or ARBs (but not both) for patients with nephropathy and suggested following urinary albumin excretion (1).

  • 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 with placebo or a comparator drug and 13 compared ARBs with placebo or another drug. Compared with 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 with control therapy, 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]) (69).

  • A 2013 systematic review of the effects of combined angiotensin blockade with ACE inhibitors and ARBs compared with either agent alone in patients with chronic kidney disease included 59 trials. Overall, in the pooled analysis, combined angiotensin blockade was associated with a higher rate of regression to normoalbuminuria (OR, 1.8 [CI, 1.3 to 2.4]), a higher rate of hyperkalemia (OR, 2.2 [CI, 1.7 to 2.8]), and significant decreases in mean albuminuria and GFR. Results were similar in diabetic and nondiabetic populations (89).

  • A 2006 Cochrane review of the effects of ACE inhibitors and ARBs in patients with diabetic nephropathy included 50 studies with 13,215 participants. In the pooled analysis, overall there was no reduction in mortality with either ACE inhibitors (RR, 0.91 [CI, 0.71 to 1.17]) or ARBs (RR, 0.99 [CI, 0.85 to 1.17]). Among the subgroup of studies using full-dose ACE inhibitors, compared with placebo, there was reduced mortality (RR, 0.78 [CI, 0.61 to 0.98]). The review found inadequate data to directly compare ACE inhibitors and ARBs (90).

  • In the double-blind RENAAL study of 1513 diabetic patients, of which half were randomly assigned 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 levels (risk reduction, 25%; P=0.006) and a significant decrease in the number of patients who went onto dialysis (risk reduction, 28%; P=0.002) (91).

  • In the double-blind Irbesartan Diabetic Nephropathy Trial, irbesartan (n=579), amlodipine (n=567), and placebo (n=569) were compared in patients with diabetic nephropathy, all of whom were treated with additional open-label, non-ACE, non-ARB, non-calcium-channel-blocker medications. The irbesartan group had a significant reduction in the doubling of serum creatinine levels (risk reduction, 33%; P=0.003 compared with placebo; and risk reduction, 37%; P<0.001 compared with amlodipine) (92).

  • In a study of 593 hypertensive diabetics with microalbuminuria, irbesartan at a dose of 300 mg/d, compared with placebo, significantly reduced the likelihood of progression to overt (>200 mcg/minute of albumin excretion, and at least a 30% increase over baseline). Thirty 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 (93).

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 serum creatinine and urine microalbumin levels 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.

Comments
  • A combination of ACE inhibitors and ARBs is not recommended.

Institute foot-care strategies to prevent ulceration and amputation in patients with documented diabetic neuropathy.  
  • 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, and testing water temperature before entering.

    • 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.

  • Consider referral for patients who are high risk for foot ulcers (e.g., patients with a history of foot ulcers, structural abnormalities, etc.) to foot-care specialists for close monitoring and comprehensive preventative care.

Evidence
  • A 2014 guideline from the American Diabetes Association recommended foot-care education for all patients with diabetes and a multidisciplinary approach to foot ulcers (1).

  • A randomized trial compared a comprehensive intervention, which included foot-care education, a contract to perform foot self-care, and provider prompts to perform foot exams and foot-care education, with usual care in 395 patients with type 2 diabetes. After 1 year, patients in the intervention group were less likely than control patients to have serious foot lesions (OR, 0.41 [CI, 0.16 to 1.00]) (94).

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

Treat foot ulcers in patients with type 2 diabetes and neuropathy.  
  • Initiate aggressive wound care:

    • Refer patients to a multidisciplinary foot clinic, if available.

    • Consider the use of biological skin equivalents for nonhealing ulcers.

    • Note that debridement, repeat wound care, infection control with antibiotics, and methods to reduce pressure on ulcer sites may be necessary to promote ulcer healing.

  • Consider diagnosis and treatment of osteomyelitis in high-grade ulcers or in ulcers that persist despite treatment.

Evidence
  • A 2014 guideline from the American Diabetes Association 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 nonhealing 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 with control therapies. In addition, there was low-quality evidence in support of platelet-derived growth factors and liver cream (95).

  • A 2006 narrative review discussed foot care in patients with diabetes (96).

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.

Comments
  • There are no data on the appropriate timing and use of antibiotics for the treatment of diabetic foot ulcers.

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

  • Note that

    • Home blood glucose monitoring may help make patients more aware of their glycemic control

    • Glucose monitoring maybe helpful in evaluating treatment response and guiding therapy modifications

  • For patients performing home glucose monitoring,

    • Instruct patients to monitor their glucose level preprandially, at bedtime, and whenever low blood sugar is suspected.

    • Consider advising patients who use an insulin pump or require multiple insulin injections to monitor their blood glucose three or more times daily.

    • Consider advising patients to measure postprandial levels, particularly patients with elevations in HbA1c level despite normal preprandial glucose levels.

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

Evidence
  • A 2014 guideline from the American Diabetes Association 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 level 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 (97).

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.

Comments
  • There are no studies showing that interventions based on postprandial glucose levels have an effect on patient outcomes, except in gestational diabetes (98).

Treat painful neuropathy preferentially using pregabalin or tricyclic antidepressants as first-line agents for most patients. 
  • Individualize management options based on patient preferences, comorbidities, and cost:

    • Consider starting with tricyclic antidepressants (e.g., nortriptyline, 25 mg, 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.

Evidence
  • A 2011 guideline from the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation on the treatment of painful diabetic neuropathy recommended pregabalin and noted that other drugs with likely efficacy included venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, and opioids, with few head-to-head comparisons. The guideline was based on a systematic review that included four studies of pregabalin, which found a small consistent reduction in pain; one high-quality study of gabapentin, which found a reduction in pain; and lower-quality evidence in support of other medications (99).

  • A 2014 Cochrane review of gabapentin for chronic neuropathic pain included 21 total studies. Among patients with diabetic neuropathy, gabapentin was more likely than placebo to reduce pain by at least 50% (RR, 1.9 [CI, 1.5 to 2.3]; NNT, 5.9) (100).

  • A 2013 Cochrane review of high-concentration capsaicin for chronic neuropathic pain included 6 studies with 2073 participants. Capsaicin was more likely than control therapy to result in pain relief in the short term (2 to 10 weeks), with an NNT of approximately 10. Compared with control therapy, there was no increase in serious adverse events, although local reactions were common (101).

  • A 2012 Cochrane review of amitriptyline for neuropathic pain and fibromyalgia included 21 studies with 1437 participants. Overall, there was evidence that amitriptyline improved pain in neuropathic conditions (including diabetic neuropathy), with an RR of benefit of 2.3 (CI, 1.8 to 3.1) (102).

Rationale
  • There are few head-to-head drug comparisons.

Comments
  • Duloxetine is also FDA approved for the treatment of diabetic neuropathy.

Provide pneumococcal vaccination and annual influenza vaccination for all patients with type 2 diabetes. 
  • Vaccinate all patients with diabetes with the seasonal influenza vaccine each year.

  • Provide pneumococcal vaccination to all patients. Repeat pneumococcal vaccination in patients older than age 65 who received initial vaccination before age 65 and in whom more than 5 years elapsed since initial vaccination.

  • See module Influenza.

  • See module Community Acquired Pneumonia.

Evidence
  • A 2014 guideline from the American Diabetes Association recommended annual influenza vaccination in all patients with diabetes aged 6 months or older and pneumococcal vaccination to all diabetic patients aged 2 years or older (1).

  • A case-control study evaluated the impact of influenza vaccination on hospitalization for influenza, pneumonia, or diabetic events in 80 patients with diabetes who were hospitalized and 160 controls. In the logistic regression analysis, influenza vaccination was associated with a lower likelihood of hospitalization (adjusted OR, 0.21 [CI, 0.05 to 0.81]) (103).

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.

Encourage smoking cessation in all patients. 
  • Discuss and implement methods, including drug therapy or dedicated cessation programs that may help patients stop smoking.

Evidence
  • A 2014 guideline from the American Diabetes Association recommended advising all patients not to smoke and stated that smoking-cessation counseling should be a routine part of diabetes care (1).

  • A cohort study assessed the interaction of diabetes and cigarette smoking as risk factors for cardiovascular mortality in a cohort of 2620 white Americans age 60 to 79. Cigarette smoking was a more potent risk factor for cardiovascular mortality among diabetics (adjusted RR, 2.2) than among nondiabetics (adjusted RR, 1.2) (104).

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.

Educate the patient about microvascular disease and its close relationship to blood sugar control. 
  • Educate the patient on the different microvascular complications associated with diabetes and its related symptoms.

  • Note that microvascular complications include

    • Retinopathy

    • Neuropathy

    • Nephropathy

  • Emphasize that achieving good glycemic control can reduce the incidence and slow the progression of diabetes-related microvascular disease.

Evidence
  • A 1997 decision analysis estimated the benefits of tight glycemic control on microvascular complications of type 2 diabetes. The model estimated that reducing HbA1C levels from 9% to 7% would reduce the lifetime risk for blindness from 2.6% to 0.3% in patients who developed diabetes before age 50 and from 0.5% to less than 0.1% in patients who developed diabetes after age 65 (105).

  • A cross-sectional study evaluated the prevalence of proteinuria in patients with diabetes over time. At the time of diagnosis, 20% of patients diagnosed in 1970 had proteinuria, 11% of those diagnosed in 1980 had proteinuria, and 8% of those diagnosed in 1990 had proteinuria (106).

Rationale
  • Glycemic control decreases the risk for microvascular disease.

Comments
  • Neuropathy is also a common complication of diabetes, occurring in as many as 50% of patients with type 2 diabetes after 15 years (28).

  • 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.

Educate the patient about macrovascular disease. 
  • Discuss the risk for macrovascular complications, such as coronary heart disease, cerebrovascular disease, and peripheral vascular disease.

  • Stress to the patient the importance of hypertension and lipid control for the prevention of macrovascular complications.

Evidence
  • A 2013 Cochrane review of blood pressure targets in patients with diabetes and hypertension included 5 trials with 7314 participants. In the single trial that addressed tight vs. standard systolic control, tight control reduced stroke (RR, 0.58 [CI, 0.39 to 0.88]) but increased serious adverse events (RR, 2.58 [CI, 1.70 to 3.91]). In the four studies addressing tight vs. standard diastolic control, there was a trend toward lower total mortality in the tight control group (RR, 0.73 [CI, 0.53 to 1.01]) with no reduction in stroke, MI, or heart failure (71).

  • A prospective cohort study described the incidence of macrovascular complications among 497 patients followed for 8 years after the diagnosis of diabetes. At the end of follow-up, 45% of patients had macrovascular complications of diabetes, including 43% with ischemic heart disease, 4.5% with cerebrovascular disease, and 4.2% with peripheral vascular disease (107).

  • A cross-sectional study evaluated causes of death in 4713 patients with diabetes. Cardiovascular disease was the cause of death among 52% of patients with type 2 diabetes who died, and renal disease was the cause of death in 11% of patients with type 2 diabetes who died (108).

Rationale
  • Treatment of concomitant risk factors decreases the risk for coronary events.

Comments
  • 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.

Instruct patients and family members on the signs, symptoms, and treatment of hypoglycemia. 
  • 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
  • A randomized trial compared intensive with standard glycemic control in 3867 patients with diabetes. The risk for a major hypoglycemic episode was 0.7% per year with standard therapy and ranged from 1.0% to 1.8% with intensive therapy (43).

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.

Encourage smoking cessation in all patients. 
  • Discuss the elevated risks involved with smoking and diabetes.

  • Educate patient on methods, including drug therapy or dedicated cessation programs that may help them stop smoking.

Evidence
  • A 2014 guideline from the American Diabetes Association recommended advising all patients not to smoke and stated that smoking-cessation counseling should be a routine part of diabetes care (1).

  • A cohort study assessed the interaction of diabetes and cigarette smoking as risk factors for cardiovascular mortality in a cohort of 2620 white Americans aged 60 to 79. Cigarette smoking was a more potent risk factor for cardiovascular mortality among diabetics (adjusted RR, 2.2) than among nondiabetics (adjusted RR, 1.2) (104).

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.

Educate patients about the importance of diet and exercise. 
  • 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 dietitian.

  • Recommend the following:

    • Aiming for moderate weight loss

    • Basing calorie intake on the goal of achieving near-ideal body weight

    • Avoiding saturated fats and trans fats

    • Following a regular meal schedule, particularly if on insulin

    • Frequent, small meals to aid in weight loss and control of blood glucose levels

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

  • Individualize the 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 with a total of 150 minutes per week.

Evidence
  • A 2014 guideline from the American Diabetes Association 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 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 RCTs involving 377 participants. Exercise significantly improved glycemic control and reduced visceral adipose tissue and plasma triglyceride levels but not plasma cholesterol. These improvements occur even without weight loss (46).

  • A randomized trial (Look AHEAD: Action for Health in Diabetes) assigned 5145 obese patients with type 2 diabetes to intensive lifestyle intervention or diabetes education only. The treatment group achieved greater weight loss of 6% vs. 3.5 % at a mean of 9.6 years of follow-up, and was able to achieve greater reduction in HbA1c level with improvements in all cardiovascular risk factors, although there was no reduction in the rate of cardiovascular events (47).

Rationale
  • Diet and exercise can help manage glucose levels and can provide other long-term patient benefits; because these factors are largely self-managed, patient education and awareness play a vital role in optimal management.

Comments
  • Unfortunately, diet and exercise are rarely effective in the long-term achievement of normoglycemia. They are reasonable first-line interventions, but most patients eventually require drug therapy.

  • The American Diabetes Association 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.

Encourage patients to have information about their condition with them at all times. 
  • Encourage patients with diabetes to wear a medical-alert bracelet.

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.

Update key elements of the initial history and physical exam on each follow-up visit.  
  • 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:

    • Check blood pressure, heart rate, and weight

    • Do a cardiovascular exam, which should include checking peripheral pulses

    • Do a foot exam, looking for skin changes and checking sensation with a monofilament exam (at least annually)

Evidence
  • Consensus.

Rationale
  • Specific history and physical exam findings may allow early detection of complications and prevention of long-term adverse outcomes.

Monitor glycemic control by checking HbA1c levels every 3 to 6 months. 
  • Measure the degree of glycemic control (using HbA1c referenced to a Diabetes Control and Complication Trial-based assay)

    • Every 3 months in patients who have not reached therapeutic goals

    • Every 6 to 12 months in patients who are stable and have achieved therapeutic goals

  • 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
  • A 2014 guideline from the American Diabetes Association 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 compared point-of-care HbA1c measurement with either usual titration or active (weekly) titration of insulin with lab HbA1C measurement with either usual or weekly titration in 7893 patients with uncontrolled type 2 diabetes receiving insulin. Overall, after 24 weeks, the active titration groups had greater reduction in HbA1C levels (1.5% vs. 1.3%; P<0.0001). Among patients in the active titration groups, those receiving point-of-care testing were more likely than those receiving lab testing to reach the HbA1C goal (41% vs. 36%; P<0.0001) (109).

Rationale
  • Glycemic control reduces the risk for early microvascular complications in diabetes; HbA1c level is the most accurate predictor of these complications and should guide therapy.

  • The average life of erythrocytes is 2 to 3 months; thus, changes in therapy or lifestyle will not have a consistently measurable effect for several months.

Obtain annual measurement of lipids, and treat hyperlipidemia with statins in patients with type 2 diabetes.  
  • Obtain an annual fasting lipid profile, including LDL cholesterol, triglyceride, HDL cholesterol, and total cholesterol levels, and apply the following treatment recommendations:

    • 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 older than 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.

    • Note that trials have failed to prove benefits of using fibrates or niacin in addition to statin therapy in patients with high triglyceride or low HDL levels.

    • Be especially vigilant for the development of rhabdomyolysis and hepatitis in patients taking both a statin and fibric acid derivative.

  • See module Lipid Disorders (Dyslipidemia).

Evidence
  • 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 levels ≥190 mg/dL, and moderate-intensity statin therapy for most patients with diabetes with no history of cardiovascular disease and LDL levels <190 mg/dL, with consideration of high-intensity therapy for diabetic patients with a calculated 10-year risk for atherosclerotic events of 7.5% or higher (77).

  • A 2014 guideline from the American Diabetes Association recommended performing a fasting lipid panel annually in patients with diabetes and treating with lifestyle modification and then statin therapy with a goal LDL level of <100 mg/dL (2.6 mmol/L). The guideline recommended statin therapy regardless of LDL level 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 (78).

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.

Implement annual screening for diabetic nephropathy. 
  • Screen annually for diabetic nephropathy.

  • Screen with spot urine to measure the albumin-to-creatinine ratio.

    • If results are abnormal, repeat testing as needed for confirmation.

    • Be aware that certain conditions, such as menstruation, fever, and exercise, can cause transient microalbuminuria.

    • Defer screening in the presence of urinary tract infection or hematuria.

  • Use caution when using dipsticks for screening because this is an insensitive method for detecting microalbuminuria.

  • 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 checking urine albumin, annually measure serum creatinine levels in order to measure creatinine clearance.

Evidence
  • A 2014 guideline from the American Diabetes Association recommended screening all patients with type 2 diabetes and 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 a pooled sensitivity of 76% and a pooled specificity of 93%; the quantitative test had a pooled sensitivity of 96% and a pooled specificity of 98% (36).

  • A 1995 narrative review discussed factors that can result in variability in measurement of urine albumin. Factors such as urinary tract infection, symptomatic cardiac failure, exercise, and hematuria can influence the urinary albumin excretion (110).

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.

Perform a dilated eye exam by an ophthalmologist or eye specialist at diagnosis and annually thereafter. 
  • Refer for dilated eye exam to screen for retinopathy annually.

  • Refer for an initial exam at the time of diagnosis.

Evidence
  • A 2014 guideline from the American Diabetes Association recommended screening all patient with type 2 diabetes and 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).

  • 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 (41).

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
Table Grahic Jump Location
 Differential Diagnosis of Diabetes Mellitus, Type 2

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DiseaseCharacteristics
Diabetes mellitus, type 2Tends to have older onset, although can be seen in children and young adults who are overweight. Patients are generally overweight or obese and often have a family history. Most patients are asymptomatic at presentation
Diabetes mellitus, type 1Younger onset, history of ketoacidosis, not overweight.
Requires insulin for therapy
Diabetes insipidusPolyuria, polydipsia, no hyperglycemia
Maturity onset diabetes of the youngStrong familial transmission. Monogenetic defects in β-cell function.
Variable requirement for oral agents or insulin
Table Grahic Jump Location
 Drug Treatment for Glucose Control in Type 2 Diabetes

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Drug or Drug ClassDosingSide EffectsPrecautionsClinical Use
Biguanide
FirstLineIconblackboxiconMetformin (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 mealDiarrhea, vomiting, flatulenceblackboxicon Rare lactic acidosis. Avoid with CKD (SCr >1.4 in women or >1.5 in men), HF, hepatic diseaseFirst line agent- causes less hypoglycemia and weight gain, and may improve risk for death and CV outcomes compared with other oral agents
SulfonylureasHypoglycemiaCaution with hepatic disease. Start with lowest dose in elderlySecond 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 qdAvoid 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 qdHeadache, dizzinessCan be used in CKDMonitor for hypoglycemia during therapy
Glimepiride (Amaryl)1-4 mg qd, maximum dose 8 mg qdStart with lowest dose in CKD
blackboxiconThiazolidnedionesWeight gain, edema, bone fractures in women, macular edemablackboxicon HF. Avoid with moderate hepatic disease. Check hepatic enzymes before useThird-line agent for most patients
Pioglitazone (Actos)15-45 mg qdBladder cancer
Rosiglitazone (Avandia)4-8 mg total daily dose, dosed qd or bidPossible increased risk for cardiovascular events
Dipeptidyl-peptidase-4 (DPP-IV) inhibitorsPossible increased risk for pancreatitis, serious hypersensitivity reactionsLimited long-term data
Sitagliptin (Januvia)100 mg qdDecrease dose if CrCl<50
Linagliptin (Tradjenta)5 mg qdHypoglycemiaNot studied with insulin
Saxagliptin (Onglyza)2.5-5 mg qdLymphopenia, hypoglycemiaDecrease dose if CrCl<50
Alogliptin (Nesina)6.25-25 mg qdDecrease dose if CrCl <30-60
Incretin mimeticsHypoglycemia, vomiting, pancreatitis, hypersensitivity, weight lossCaution in CKD
blackboxiconExenatide (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 weeklyblackboxicon Extended release: Thyroid C-cell tumors. Avoid if CrCl<30. Monitor for signs and symptoms of pancreatitisRegular release can be used with insulin glargine. Extended release not studied with insulin
blackboxiconLiraglutide (injection) (Victoza)0.6-1.8 mg SC qdblackboxicon Thyroid C-cell tumors. Caution with hepatic disease.
Monitor for signs and symptoms of pancreatitis
blackboxiconAlbiglutide injection (Tanzeum)30 mg–50 mg SC once every 7 daysblackboxicon Thyroid C-cell tumorsLong-term study lacking
MeglitinidesFor postprandial glucose control
Repaglinide (Prandin)0.5-4 mg before meals. Maximum 16 mg total daily doseHypoglycemiaDecrease dose if CrCl<40
Nateglinide (Starlix)60-120 mg tid before mealsLow incidence of hypoglycemiaCaution in hepatic disease
α-glucosidase inhibitorsDiarrhea, flatulence, abdominal painAvoid with bowel diseaseFor postprandial glucose control; poorly tolerated
Acarbose (Precose)25-100 mg tid with first bite of mealsAvoid with cirrhosis. Caution with severe CKD
Miglitol (Glyset)25-100 mg tid with first bite of mealsAvoid if CrCl<25 or SCr>2
Amylin analog
blackboxiconPramlintide (Symlin) (injection)60-120 mcg SC before mealsVomiting, weight lossblackboxicon Severe hypoglycemia. Avoid with gastroparesisUsed in conjunction with other agents; limited long-term data
SGLT2 inhibitorsGenital infections, such as vulvovaginal candidasis and UTI. Volume depletion, nephrotoxicity, hyperlipidemia, hypersensitivity reactionsCaution with CKDLong-term efficacy and safety data are limited. Usually used as third-line agents with metformin and other non-insulin agents
Dapagliflozin (Farxiga)5-10 mg qd in the morning, with or without a mealBone fractures in patients with CKDAvoid if eGFR <60 mL/min
Canagliflozin (Invokana)100-300 mg qdAvoid if eFGR < 45 mL/min. Avoid with severe hepatic disease. Substrate of P-gp
Additional agent
Bromocriptine (Cycloset)0.8–4.8 mg qd in the morningNausea, dizziness, headache, sedation, visual disturbance, hypotensionCaution with hepatic disease, CKD, cardiac disease, psychiatric disordersMinimal reduction in HbA1c level when used as monotherapy or adjuvant therapy
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, 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
SGLT2 inhibitors/Metformin
Canagliflozin/Metformin (Invokamet)50/500 mg, 50/1000 mg, 150/500 mg, 150/1000 mg; dosed bid with meals. Maximum daily dose 300/2000 mg
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 dosingHypoglycemia, hypokalemia, weight gainCaution in CKD or hepatic diseaseConsider combining insulin and oral agents if oral agents are inadequate
Rapid-acting insulinsUsed 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 dailyLower incidence of hypoglycemia
Pre-mixed insulin combinationsCombination 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)

FirstLineIcon = first-line agent; blackboxicon = black box warning; AM = morning; bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular; eGFR = estimated glomerular filtration rate; GI = gastrointestinal; HbA1c = glycosylated hemoglobin; HF = heart failure; IM = intramuscular; IV = intravenous; MI = myocardial infarction; PM = evening; PO = oral; qd = once daily; SC = subcutaneous; SCr = serum creatinine; tid = three times daily; UTI = urinary tract infection.

ACP Smart Medicine provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Table Grahic Jump Location
 Screening and Diagnostic Tests for Diabetes Mellitus

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TestThreshold ValueRecommended Follow-upAdvantagesDisadvantagesComment
Fasting plasma glucose>126 mg/dL diagnostic for type 2 diabetesConfirm by repeat testing on another dayTime since last meal easily defined (compared with random glucose level)Fasting needed for at least 8 hoursCan be inconvenient because patients need to be fasting
Fasting plasma glucose100-125 mg/dL suggests “impaired fasting glucose”Monitor and modify risk factors for diabetes and cardiovascular diseaseTime since last meal easily defined (compared with random glucose level)Fasting needed for at least 8 hoursNone
Random plasma glucose>200 mg/dL plus symptoms (polyuria, polydipsia).
Confirms diagnosis of diabetes
No repeat test necessary if patient has classic symptoms of hyperglycemiaConvenienceLower sensitivity than other tests; connection between levels and risk not well establishedLeast acceptable test for screening
Oral glucose tolerance (OGTT; 2-hour)≥200 mg/dL diagnostic for type 2 diabetesConfirm by repeat testing on another dayDifficult to administerRefers 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 toleranceFollow-up same as for impaired fasting glucoseCostRefers 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 dayCommon-sense diagnostic test, because treatment decisions and goals usually are set using GHbMany different measures of GHbTest 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 drawHbA1c is not the universally implemented standardTest needs to be standardized with DCCT

DCCT = Diabetes Control and Complication Trial; GHb = glycosylated hemoglobin; Hb = hemoglobin; HbA1c = glycosylated hemoglobin; OGTT = oral glucose tolerance test.

Table Grahic Jump Location
 Secondary Forms of Diabetes or Impaired Glucose Tolerance

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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)
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)
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)

tRNA = transfer ribonucleic acid.

Table Grahic Jump Location
 Dosages for Various Types of Sulfonylureas

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GenerationGeneric Name (Trade Name)Dose RangeDosing Frequency
FirstAcetohexamide (Dymelor)250-1500 mg/dqd-bid
FirstChlopropamide (Diabinese)100-750 mg/dqd
FirstTolazamide (Tolinase)100-1500 mg/dqd-bid
FirstTolbutamide (Orinase)250-3000 mg/dbid-qid
SecondGlimepiride (Amaryl)1-8 mg/dqd
SecondGlipizide (Glucotrol)2.5-40 mg/dqd-bid
SecondGlipizide-GITS (Glucotrol XL)5-20 mg/dqd
SecondGlyburide (Diabeta, Micronase)1.25-20 mg/d*qd-bid
SecondMicronized glyburide (Glynase/PresTab)1.5-12 mg/dqd-bid

bid = twice daily; qd = once daily; qid = four times daily.

* Doses >10 mg/d typically do not provide improvements in glycemic control.

Table Grahic Jump Location
 Onset and Mechanisms of Action of Various Types of Insulin

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TypeOnset and Mechanisms of Action
Lispro/aspart/glulisineVery short-acting; onset of action within 15 minutes; peak action 30-90 minutes; maximum 5 hours
RegularShort-acting; onset of action within 1 hour; duration typically 4-8 hours, maximum 12 hours
NPHIntermediate-acting; onset within 2-3 hours; duration typically 8-12 hours, maximum 24 hours
LenteIntermediate-acting; onset within 2-3 hours; duration typically 8-12 hours, maximum 24 hours
GlargineLong-acting (up to 24 hours)
UltralenteLongest-acting (up to 28 hours)
Premixed (regular and long acting [usually NPH]; concentrations vary)Onset and duration are similar to the component parts
DetemirLong-acting (up to 18 hours)

Note: All insulins ( regular insulin ; insulin aspart ; insulin lispro ; insulin glulisine ; isophane 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 resulted in all patients achieving HbA1c <7%.

HbA1c = glycosylated hemoglobin; NPH = neutral protamine Hagedorn insulin (isophane insulin).

Table Grahic Jump Location
 Risk Factors for Diabetes Mellitus

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Age 45 years or older
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) level
Polycystic ovary syndrome
History of vascular disease

HDL = high-density lipoprotein.

Table Grahic Jump Location
 Therapeutic Intensity of Statin Doses*

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DrugHigh-intensity DosingModerate-intensity DosingLow-intensity Dosing
Atorvastatin40-80 mg10-20 mg
Flusvastatin80 mg (or 40 mg bid)10-20 mg
Lovastatin40 mg20 mg
Pitavastatin2-4 mg1 mg
Pravastatin40-80 mg10-20 mg
Rosuvastatin20-40 mg5-10 mg
Simvastatin†80 mg20-40 mg10 mg

*Adapted from (77).

†Not recommended by the FDA.

  • 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.
  • 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
  • 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
  • Diabetic Pre-Ulcer Hemorrhage within a callous, a condition that predisposes to cutaneous ulcer formation (diabetic pre-ulcer).
  • Diabetes-Associated Callous Formation Diabetic foot with thick callous formation.
  • Pressure Erythema on a Diabetic Foot Diabetic foot showing persistent rubor at pressure site, a risk factor for ulcer formation.
  • Diabetic Foot Ulcer Diabetes-associated neuropathic ulcers have a hyperkeratotic rim and occur over pressure points such as the metatarsal heads.
  • Proliferative Diabetic Retinopathy Diabetic proliferative retinopathy with neovascularization.
  • 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.
  • 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.
  • 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.
  • Schema of Ulcer Formation
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Cheng J, Zhang W, Zhang X, Han F, Li X, He X, et al. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis. JAMA Intern Med. 2014;174:773-85. (PMID: 24687000)
 
Wu HY, Huang JW, Lin HJ, Liao WC, Peng YS, Hung KY, et al. Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and bayesian network meta-analysis. BMJ. 2013;347:f6008. (PMID: 24157497)
 
Arguedas JA, Leiva V, Wright JM. Blood pressure targets for hypertension in people with diabetes mellitus. Cochrane Database Syst Rev. 2013;(10):CD008277. (PMID: 24170669)
 
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Weber MA, Bakris GL, Jamerson K, Weir M, Kjeldsen SE, Devereux RB, et al.; ACCOMPLISH Investigators. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol. 2010;56:77-85. (PMID: 20620720)
 
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Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, et al.; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117-25. (PMID: 18191683)
 
Kaur N, Pandey A, Negi H, Shafiq N, Reddy S, Kaur H, et al. Effect of HDL-raising drugs on cardiovascular outcomes: a systematic review and meta-regression. PLoS One. 2014;9:e94585. (PMID: 24728455)
 
Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735-42. (PMID: 20167359)
 
Wanner C, Krane V, März W, Olschewski M, Mann JF, Ruf G, et al.; German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238-48. (PMID: 16034009)
 
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ACC

American College of Cardiology

ACE

angiotensin-converting enzyme

AHA

American Heart Association

ARB

angiotensin II receptor blocker

BMI

body mass index

CDC

Centers for Disease Control and Prevention

CI

confidence interval

ECG

electrocardiogram

FDA

Food and Drug Administration

GFR

glomerular filtration rate

HbA1c

glycosylated hemoglobin

HDL

high-density lipoprotein

HR

hazard ratio

LDL

low-density lipoprotein

MI

myocardial infarction

NICE

National Institute for Health and Care Excellence

NNH

number needed to harm

NNT

number needed to treat

NPH (insulin)

neutral protamine Hagedorn insulin (also called isophane insulin)

OR

odds ratio

QALY

quality-adjusted life-year

RR

relative risk

RRR

relative risk reduction

USPSTF

U.S. Preventive Services Task Force


Study-Name Acronyms
ACCOMPLISH

Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension

ACCORD

Action to Control Cardiovascular Risk in Diabetes

ADOPT

A Diabetes Outcome Progression Trial

ADVANCE

Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation

AIM-HIGH

Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes

ALLHAT

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

DREAM

Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication

NAVIGATOR

Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research

POPADAD

Prevention of Progression of Arterial Disease and Diabetes

PROactive

Prospective Pioglitazone Clinical Trial in Macrovascular Events

RECORD

Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes

RENAAL

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

STOP-NIDDM

Study to Prevent Non-Insulin-Dependent Diabetes Mellitus


Guidelines

Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation

2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention

NICE: Type 2 diabetes: The management of type 2 diabetes

Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians

American Diabetes Association: Executive summary: Standards of medical care in diabetes--2014

Systematic Reviews

Self-monitoring of blood glucose in patients with type 2 diabetes mellitus who are not using insulin (Cochrane review)

Advanced wound care therapies for nonhealing diabetic, venous, and arterial ulcers: a systematic review

Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease (Cochrane review)

Efficacy and safety of combined vs. single renin-angiotensin-aldosterone system blockade in chronic kidney disease: a meta-analysis

Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis

Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73,913 patients

Blood pressure targets for hypertension in people with diabetes mellitus (Cochrane review)

Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and bayesian network meta-analysis

Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis

Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus (Cochrane review)

Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus (Cochrane review)

Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality

Second-line therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a systematic review and mixed-treatment comparison meta-analysis

Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations

Exercise for type 2 diabetes mellitus (Cochrane review)

Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus (Cochrane review)

Diagnostic accuracy of point-of-care tests for detecting albuminuria: a systematic review and meta-analysis

Lifestyle interventions for patients with and at risk for type 2 diabetes: a systematic review and meta-analysis

DOI: 10.7326/d296
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.
Authors and Disclosures:
Sandeep Vijan, MD has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Norra Kwong, MD has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Rajesh K. Garg, MD has received a research grant from AstraZeneca Company.

The following editors of ACP Smart Medicine have nothing to disclose: Deborah Korenstein, MD, FACP, Editor in Chief; Richard B. Lynn, MD, FACP, Editor; and Davoren Chick, MD, FACP, Editor.

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