The Journal of Family Practice

Illustrative Case

A 55-year-old man with hypertension and stage 3 chronic kidney disease (CKD) comes in to your office for routine care. His blood pressure is 135/85 mm Hg, and he is presently taking lisinopril 40 mg daily. Should you increase his antihypertensive regimen?

Hypertension is common and leads to significant morbidity and mortality, but pharmacologic treatment reduces incidence of stroke by 35% to 40%, myocardial infarction (MI) by 15% to 25%, and heart failure by up to 64%.^2-4 Specific blood pressure targets for defined populations continue to be studied.

In patients with diabetes, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial found that more intensive BP targets did not reduce the rate of major CV events, but the study may have been underpowered.⁵ The members of The Eighth Joint National Committee recommended treating patients over age 60 years to BP goals <150/90 mm Hg.⁶ This was based on evidence from 6 randomized controlled trials (RCTs),^7-12 but there remains debate—even among the members of the Committee—as to appropriate BP goals in patients of any age without CV disease who have BP measurements of 140-159/90-99 mm Hg.¹³

Study Summary

Treating to SBP <120 mm Hg lowers mortality

The Systolic Blood Pressure Intervention Trial (SPRINT) was a multicenter RCT designed to determine if treating to lower SBP targets in non-diabetic patients at high risk for CV events improves outcomes as compared to standard care. Patients were at least 50 years of age with SBP of 130 to 180 mm Hg and were at increased CV risk as defined by clinical or subclinical CV disease other than stroke, CKD with glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m², 10-year risk of CV disease >15% on Framingham risk score, or age ≥75 years of age. Patients with diabetes; prior stroke; polycystic kidney disease; significant proteinuria within the past 6 months; symptomatic heart failure within the past 6 months; or left ventricular ejection fraction <35% were excluded.¹

Patients (N=9361) were randomly assigned to an SBP target <120 mm Hg in the intensive group or <140 mm Hg in the standard treatment group, in an open-label design. Allocation was concealed. The study protocol encouraged, but did not require, the use of thiazide-type diuretics, loop diuretics (for those with advanced renal disease), angiotensin-converting enzyme inhibitors or angiotensin receptor blocker agents, calcium channel blockers, and beta-blockers. Clinicians could add other agents as needed. All major classes of antihypertensives were used.

Medication dosing adjustments were based on the average of 3 BP measurements taken with an automated measurement system (Omron Healthcare, Model 907) with the patient seated after 5 minutes of quiet rest. Target SBP in the standard therapy group was 135 to 139 mm Hg. Medication dosages were lowered if SBP was <130 mm Hg at a single visit or <135 mm Hg at 2 consecutive visits.¹

The primary composite outcome included the first occurrence of MI, acute coronary syndrome, stroke, heart failure, or death from CV causes. Secondary outcomes were the individual components of the primary composite outcome, death from any cause, and the composite of the primary outcome or death from any cause.¹

In a group of 1000 patients, an estimated 16 patients will benefit from intensive BP treatment, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.

Study halted early. The study was stopped early due to significantly lower rates of the primary outcome in the intensive therapy group vs the standard therapy group (1.65% per year vs 2.19% per year, respectively, hazard ratio [HR] with intensive treatment=0.75; 95% confidence interval [CI], 0.64-0.89; P<.001). The resulting median follow-up time was 3.26 years.¹ This corresponds to a 25% lower relative risk of the primary outcome, with a decrease in event rates from 6.8% to 5.2% over the trial period. All-cause mortality was also lower in the intensive therapy group: 3.4% vs 4.5% (HR=0.73; 95% CI, 0.60-0.90; P=.003).

The number needed to treat (NNT) over 3.26 years to prevent a primary outcome event, death from any cause, and death from CV causes was 61, 90, and 172, respectively. Serious adverse events occurred more frequently in the intensive therapy group than in the standard therapy group (38.3% vs 37.1%; HR=1.04; P=.25) with a number needed to harm (NNH) of 46 over the study period.¹ (When looking at serious adverse events identified as likely associated with the intervention, rates were 4.7% vs 2.5%, respectively [P<.001].) Hypotension, syncope, electrolyte abnormalities, and acute kidney injury/acute renal failure reached statistical significance. The incidence of bradycardia and injurious falls was higher in the intensive treatment group, but did not reach statistical significance. In the subgroup of patients ≥75 years of age, 48% in each study group experienced a serious adverse event.¹

Throughout the study, mean SBP was 121.5 mm Hg in the intensive therapy group and 134.6 mm Hg in the standard treatment group. This required an average of one additional BP medication in the intensive therapy group (2.8 vs 1.8, respectively).¹

What’s New

Lower SBP produces mortality benefits in those under, and over, age 75

This trial builds on a body of evidence that shows the advantages of lowering SBP to <150 mm Hg^7,11,12 by demonstrating benefits, including lower all-cause mortality, for lower SBP targets in non-diabetic patients at high risk of CV disease. The SPRINT trial also showed that the benefits of intensive therapy remained true in a subgroup of patients ≥75 years of age.

The incidence of the primary outcome in the cohort ≥75 years of age receiving intensive therapy was 7.7% vs 10.9% for those receiving standard therapy (HR=0.67; 95% CI, 0.51-0.86; NNT=31). All-cause mortality was also lower in the intensive therapy group than in the standard therapy group among patients ≥75 years of age: 5.5% vs 8.04% (HR=0.68; 95% CI, 0.50-0.92; NNT=38).¹

Caveats

Many do not benefit from—or are harmed by—increased medication

Identifying patients most likely to benefit from more intensive blood pressure targets remains challenging.

The absolute risk reduction for the primary outcome is 1.6%, meaning 98.4% of patients receiving more intensive treatment will not benefit. In a group of 1000 patients, an estimated 16 patients will benefit, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.¹⁴ The difference between how BP was measured in this trial (an average of 3 readings after the patient had rested for 5 minutes) and that which occurs typically in clinical practice could potentially lead to overtreatment in practice.

Also, reducing antihypertensive therapies when the SBP was about 130 to 135 mm Hg in the standard therapy group likely exaggerated the difference in outcomes between the intensive and standard therapy groups, and is neither routine nor recommended in clinical practice.⁶ Finally, the trial specifically studied non-diabetic patients at high risk of CV disease ≥50 years of age, limiting generalizability to other populations.

Challenges to implementation

Who will benefit/who can achieve intensive SBP goals?

Identifying patients most likely to benefit from more intensive BP targets remains challenging. The SPRINT trial showed a mortality benefit, but at a cost of increased morbidity.^1,14 In particular, caution should be exercised in the subgroup of patients ≥75 years. Despite a lower NNT than the rest of the study population, serious adverse events happened more frequently. Also, this particular cohort of volunteers may not be representative of those ≥75 years of age in the general population.

Additionally, achieving intensive SBP goals can be challenging. In the SPRINT trial, only half of the intensive target group achieved an SBP <120 mm Hg.¹ And in a 2011-12 National Health and Nutrition Examination Survey, only 52% of patients in the general population achieved a BP target <140/90 mm Hg.¹⁵ Lower morbidity and mortality should remain the ultimate goals to the management of hypertension, requiring physicians to carefully assess an individual patient’s likelihood of benefit vs harm.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative Case

A 55-year-old man with hypertension and stage 3 chronic kidney disease (CKD) comes in to your office for routine care. His blood pressure is 135/85 mm Hg, and he is presently taking lisinopril 40 mg daily. Should you increase his antihypertensive regimen?

Hypertension is common and leads to significant morbidity and mortality, but pharmacologic treatment reduces incidence of stroke by 35% to 40%, myocardial infarction (MI) by 15% to 25%, and heart failure by up to 64%.^2-4 Specific blood pressure targets for defined populations continue to be studied.

In patients with diabetes, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial found that more intensive BP targets did not reduce the rate of major CV events, but the study may have been underpowered.⁵ The members of The Eighth Joint National Committee recommended treating patients over age 60 years to BP goals <150/90 mm Hg.⁶ This was based on evidence from 6 randomized controlled trials (RCTs),^7-12 but there remains debate—even among the members of the Committee—as to appropriate BP goals in patients of any age without CV disease who have BP measurements of 140-159/90-99 mm Hg.¹³

Study Summary

Treating to SBP <120 mm Hg lowers mortality

The Systolic Blood Pressure Intervention Trial (SPRINT) was a multicenter RCT designed to determine if treating to lower SBP targets in non-diabetic patients at high risk for CV events improves outcomes as compared to standard care. Patients were at least 50 years of age with SBP of 130 to 180 mm Hg and were at increased CV risk as defined by clinical or subclinical CV disease other than stroke, CKD with glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m², 10-year risk of CV disease >15% on Framingham risk score, or age ≥75 years of age. Patients with diabetes; prior stroke; polycystic kidney disease; significant proteinuria within the past 6 months; symptomatic heart failure within the past 6 months; or left ventricular ejection fraction <35% were excluded.¹

Patients (N=9361) were randomly assigned to an SBP target <120 mm Hg in the intensive group or <140 mm Hg in the standard treatment group, in an open-label design. Allocation was concealed. The study protocol encouraged, but did not require, the use of thiazide-type diuretics, loop diuretics (for those with advanced renal disease), angiotensin-converting enzyme inhibitors or angiotensin receptor blocker agents, calcium channel blockers, and beta-blockers. Clinicians could add other agents as needed. All major classes of antihypertensives were used.

Medication dosing adjustments were based on the average of 3 BP measurements taken with an automated measurement system (Omron Healthcare, Model 907) with the patient seated after 5 minutes of quiet rest. Target SBP in the standard therapy group was 135 to 139 mm Hg. Medication dosages were lowered if SBP was <130 mm Hg at a single visit or <135 mm Hg at 2 consecutive visits.¹

The primary composite outcome included the first occurrence of MI, acute coronary syndrome, stroke, heart failure, or death from CV causes. Secondary outcomes were the individual components of the primary composite outcome, death from any cause, and the composite of the primary outcome or death from any cause.¹

In a group of 1000 patients, an estimated 16 patients will benefit from intensive BP treatment, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.

Study halted early. The study was stopped early due to significantly lower rates of the primary outcome in the intensive therapy group vs the standard therapy group (1.65% per year vs 2.19% per year, respectively, hazard ratio [HR] with intensive treatment=0.75; 95% confidence interval [CI], 0.64-0.89; P<.001). The resulting median follow-up time was 3.26 years.¹ This corresponds to a 25% lower relative risk of the primary outcome, with a decrease in event rates from 6.8% to 5.2% over the trial period. All-cause mortality was also lower in the intensive therapy group: 3.4% vs 4.5% (HR=0.73; 95% CI, 0.60-0.90; P=.003).

The number needed to treat (NNT) over 3.26 years to prevent a primary outcome event, death from any cause, and death from CV causes was 61, 90, and 172, respectively. Serious adverse events occurred more frequently in the intensive therapy group than in the standard therapy group (38.3% vs 37.1%; HR=1.04; P=.25) with a number needed to harm (NNH) of 46 over the study period.¹ (When looking at serious adverse events identified as likely associated with the intervention, rates were 4.7% vs 2.5%, respectively [P<.001].) Hypotension, syncope, electrolyte abnormalities, and acute kidney injury/acute renal failure reached statistical significance. The incidence of bradycardia and injurious falls was higher in the intensive treatment group, but did not reach statistical significance. In the subgroup of patients ≥75 years of age, 48% in each study group experienced a serious adverse event.¹

Throughout the study, mean SBP was 121.5 mm Hg in the intensive therapy group and 134.6 mm Hg in the standard treatment group. This required an average of one additional BP medication in the intensive therapy group (2.8 vs 1.8, respectively).¹

What’s New

Lower SBP produces mortality benefits in those under, and over, age 75

This trial builds on a body of evidence that shows the advantages of lowering SBP to <150 mm Hg^7,11,12 by demonstrating benefits, including lower all-cause mortality, for lower SBP targets in non-diabetic patients at high risk of CV disease. The SPRINT trial also showed that the benefits of intensive therapy remained true in a subgroup of patients ≥75 years of age.

The incidence of the primary outcome in the cohort ≥75 years of age receiving intensive therapy was 7.7% vs 10.9% for those receiving standard therapy (HR=0.67; 95% CI, 0.51-0.86; NNT=31). All-cause mortality was also lower in the intensive therapy group than in the standard therapy group among patients ≥75 years of age: 5.5% vs 8.04% (HR=0.68; 95% CI, 0.50-0.92; NNT=38).¹

Caveats

Many do not benefit from—or are harmed by—increased medication

Identifying patients most likely to benefit from more intensive blood pressure targets remains challenging.

The absolute risk reduction for the primary outcome is 1.6%, meaning 98.4% of patients receiving more intensive treatment will not benefit. In a group of 1000 patients, an estimated 16 patients will benefit, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.¹⁴ The difference between how BP was measured in this trial (an average of 3 readings after the patient had rested for 5 minutes) and that which occurs typically in clinical practice could potentially lead to overtreatment in practice.

Also, reducing antihypertensive therapies when the SBP was about 130 to 135 mm Hg in the standard therapy group likely exaggerated the difference in outcomes between the intensive and standard therapy groups, and is neither routine nor recommended in clinical practice.⁶ Finally, the trial specifically studied non-diabetic patients at high risk of CV disease ≥50 years of age, limiting generalizability to other populations.

Challenges to implementation

Who will benefit/who can achieve intensive SBP goals?

Identifying patients most likely to benefit from more intensive BP targets remains challenging. The SPRINT trial showed a mortality benefit, but at a cost of increased morbidity.^1,14 In particular, caution should be exercised in the subgroup of patients ≥75 years. Despite a lower NNT than the rest of the study population, serious adverse events happened more frequently. Also, this particular cohort of volunteers may not be representative of those ≥75 years of age in the general population.

Additionally, achieving intensive SBP goals can be challenging. In the SPRINT trial, only half of the intensive target group achieved an SBP <120 mm Hg.¹ And in a 2011-12 National Health and Nutrition Examination Survey, only 52% of patients in the general population achieved a BP target <140/90 mm Hg.¹⁵ Lower morbidity and mortality should remain the ultimate goals to the management of hypertension, requiring physicians to carefully assess an individual patient’s likelihood of benefit vs harm.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative Case

A 55-year-old man with hypertension and stage 3 chronic kidney disease (CKD) comes in to your office for routine care. His blood pressure is 135/85 mm Hg, and he is presently taking lisinopril 40 mg daily. Should you increase his antihypertensive regimen?

Hypertension is common and leads to significant morbidity and mortality, but pharmacologic treatment reduces incidence of stroke by 35% to 40%, myocardial infarction (MI) by 15% to 25%, and heart failure by up to 64%.^2-4 Specific blood pressure targets for defined populations continue to be studied.

In patients with diabetes, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial found that more intensive BP targets did not reduce the rate of major CV events, but the study may have been underpowered.⁵ The members of The Eighth Joint National Committee recommended treating patients over age 60 years to BP goals <150/90 mm Hg.⁶ This was based on evidence from 6 randomized controlled trials (RCTs),^7-12 but there remains debate—even among the members of the Committee—as to appropriate BP goals in patients of any age without CV disease who have BP measurements of 140-159/90-99 mm Hg.¹³

Study Summary

Treating to SBP <120 mm Hg lowers mortality

The Systolic Blood Pressure Intervention Trial (SPRINT) was a multicenter RCT designed to determine if treating to lower SBP targets in non-diabetic patients at high risk for CV events improves outcomes as compared to standard care. Patients were at least 50 years of age with SBP of 130 to 180 mm Hg and were at increased CV risk as defined by clinical or subclinical CV disease other than stroke, CKD with glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m², 10-year risk of CV disease >15% on Framingham risk score, or age ≥75 years of age. Patients with diabetes; prior stroke; polycystic kidney disease; significant proteinuria within the past 6 months; symptomatic heart failure within the past 6 months; or left ventricular ejection fraction <35% were excluded.¹

Patients (N=9361) were randomly assigned to an SBP target <120 mm Hg in the intensive group or <140 mm Hg in the standard treatment group, in an open-label design. Allocation was concealed. The study protocol encouraged, but did not require, the use of thiazide-type diuretics, loop diuretics (for those with advanced renal disease), angiotensin-converting enzyme inhibitors or angiotensin receptor blocker agents, calcium channel blockers, and beta-blockers. Clinicians could add other agents as needed. All major classes of antihypertensives were used.

Medication dosing adjustments were based on the average of 3 BP measurements taken with an automated measurement system (Omron Healthcare, Model 907) with the patient seated after 5 minutes of quiet rest. Target SBP in the standard therapy group was 135 to 139 mm Hg. Medication dosages were lowered if SBP was <130 mm Hg at a single visit or <135 mm Hg at 2 consecutive visits.¹

The primary composite outcome included the first occurrence of MI, acute coronary syndrome, stroke, heart failure, or death from CV causes. Secondary outcomes were the individual components of the primary composite outcome, death from any cause, and the composite of the primary outcome or death from any cause.¹

In a group of 1000 patients, an estimated 16 patients will benefit from intensive BP treatment, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.

Study halted early. The study was stopped early due to significantly lower rates of the primary outcome in the intensive therapy group vs the standard therapy group (1.65% per year vs 2.19% per year, respectively, hazard ratio [HR] with intensive treatment=0.75; 95% confidence interval [CI], 0.64-0.89; P<.001). The resulting median follow-up time was 3.26 years.¹ This corresponds to a 25% lower relative risk of the primary outcome, with a decrease in event rates from 6.8% to 5.2% over the trial period. All-cause mortality was also lower in the intensive therapy group: 3.4% vs 4.5% (HR=0.73; 95% CI, 0.60-0.90; P=.003).

The number needed to treat (NNT) over 3.26 years to prevent a primary outcome event, death from any cause, and death from CV causes was 61, 90, and 172, respectively. Serious adverse events occurred more frequently in the intensive therapy group than in the standard therapy group (38.3% vs 37.1%; HR=1.04; P=.25) with a number needed to harm (NNH) of 46 over the study period.¹ (When looking at serious adverse events identified as likely associated with the intervention, rates were 4.7% vs 2.5%, respectively [P<.001].) Hypotension, syncope, electrolyte abnormalities, and acute kidney injury/acute renal failure reached statistical significance. The incidence of bradycardia and injurious falls was higher in the intensive treatment group, but did not reach statistical significance. In the subgroup of patients ≥75 years of age, 48% in each study group experienced a serious adverse event.¹

Throughout the study, mean SBP was 121.5 mm Hg in the intensive therapy group and 134.6 mm Hg in the standard treatment group. This required an average of one additional BP medication in the intensive therapy group (2.8 vs 1.8, respectively).¹

What’s New

Lower SBP produces mortality benefits in those under, and over, age 75

This trial builds on a body of evidence that shows the advantages of lowering SBP to <150 mm Hg^7,11,12 by demonstrating benefits, including lower all-cause mortality, for lower SBP targets in non-diabetic patients at high risk of CV disease. The SPRINT trial also showed that the benefits of intensive therapy remained true in a subgroup of patients ≥75 years of age.

The incidence of the primary outcome in the cohort ≥75 years of age receiving intensive therapy was 7.7% vs 10.9% for those receiving standard therapy (HR=0.67; 95% CI, 0.51-0.86; NNT=31). All-cause mortality was also lower in the intensive therapy group than in the standard therapy group among patients ≥75 years of age: 5.5% vs 8.04% (HR=0.68; 95% CI, 0.50-0.92; NNT=38).¹

Caveats

Many do not benefit from—or are harmed by—increased medication

Identifying patients most likely to benefit from more intensive blood pressure targets remains challenging.

The absolute risk reduction for the primary outcome is 1.6%, meaning 98.4% of patients receiving more intensive treatment will not benefit. In a group of 1000 patients, an estimated 16 patients will benefit, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.¹⁴ The difference between how BP was measured in this trial (an average of 3 readings after the patient had rested for 5 minutes) and that which occurs typically in clinical practice could potentially lead to overtreatment in practice.

Also, reducing antihypertensive therapies when the SBP was about 130 to 135 mm Hg in the standard therapy group likely exaggerated the difference in outcomes between the intensive and standard therapy groups, and is neither routine nor recommended in clinical practice.⁶ Finally, the trial specifically studied non-diabetic patients at high risk of CV disease ≥50 years of age, limiting generalizability to other populations.

Challenges to implementation

Who will benefit/who can achieve intensive SBP goals?

Identifying patients most likely to benefit from more intensive BP targets remains challenging. The SPRINT trial showed a mortality benefit, but at a cost of increased morbidity.^1,14 In particular, caution should be exercised in the subgroup of patients ≥75 years. Despite a lower NNT than the rest of the study population, serious adverse events happened more frequently. Also, this particular cohort of volunteers may not be representative of those ≥75 years of age in the general population.

Additionally, achieving intensive SBP goals can be challenging. In the SPRINT trial, only half of the intensive target group achieved an SBP <120 mm Hg.¹ And in a 2011-12 National Health and Nutrition Examination Survey, only 52% of patients in the general population achieved a BP target <140/90 mm Hg.¹⁵ Lower morbidity and mortality should remain the ultimate goals to the management of hypertension, requiring physicians to carefully assess an individual patient’s likelihood of benefit vs harm.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

The US Preventive Services Task Force made 8 recommendations in 2015 that family physicians should implement in their practices (TABLE 1¹). The conditions addressed are high blood pressure, abnormal blood glucose, breast cancer, depression, and tobacco use. The Task Force also issued 13 “I” statements (TABLE 2¹) reflecting insufficient evidence to recommend for or against a particular intervention—once again underscoring the inadequate evidence base for many commonly-accepted practices aimed at prevention. Four such interventions were targeted toward children.

High blood pressure: Verify before starting treatment

The Task Force continues to give strong backing to the practice of screening for high blood pressure (HBP) and treating those with HBP to prevent cardiovascular and renal disease. The new recommendation, however, recognizes there is significant over-diagnosis of this condition and advises that, before starting treatment, HBP found with office measurement be confirmed with either ambulatory blood pressure monitoring or home blood pressure monitoring. This topic was covered in more depth in a recent Practice Alert.²

Since cardiovascular disease is the leading cause of death in the United States and much of this mortality is preventable, the Task Force also has recommendations in place for screening and treatment of other risks for cardiovascular disease, including obesity, hyperlipidemia, elevated blood glucose (discussed below), and tobacco use.¹

Blood glucose: Focus is now on overweight/obese individuals

The Task Force’s new recommendation for diabetes screening differs from the one made in 2008, which recommended screening for type 2 diabetes (T2DM) only in adults with hypertension. The Task Force now recommends screening for abnormal blood glucose in all obese and overweight adults between the ages of 40 and 70. The Task Force analysis is detailed³ and will be the subject of the next Practice Alert, with only the highlights described here.

The recommendation is limited to overweight and obese adults because they are most likely to have abnormal blood glucose and to benefit from interventions. Screening can be done by measuring fasting blood glucose levels, performing a glucose tolerance test, or measuring glycated hemoglobin levels. The optimal screening frequency is unknown but suggested to be every 3 years. Refer patients with abnormal screen results to an intensive behavioral counseling program that promotes healthy eating and physical activity. Those with T2DM should also receive these services and consider pharmacotherapy.

The Task Force examined the potential of electronic nicotine delivery systems for smoking cessation and concluded that the evidence was insufficient to make a recommendation.

Breast cancer: Mammography advice is age dependent

The Task Force breast cancer screening recommendations, first proposed in 2015 and finalized in early 2016, essentially reaffirm those made in 2009. Women ages 50 through 74 should be screened with mammography every 2 years, and individuals younger than age 50 should make a decision to receive screening—or not—based on the known benefits and risks of mammography at their age and their personal risks and preferences.

Insufficient evidence exists to make recommendations regarding mammography for women ages 75 and up, the use of digital breast tomosynthesis as a primary screening tool, and the use of any modality to augment screening in women with dense breasts who have normal mammogram results. Details of these recommendations were described in a Practice Alert last year.⁴

Depression: Use screening tools designed for specific patients

The 2015 updates on screening for depression essentially reconfirm the Task Force’s previous findings and recommendations on this topic. Screening for depression is recommended for all adults, including pregnant and postpartum women,⁵ and adolescents starting at age 12.⁶ Once again, the evidence is insufficient to make a recommendation on screening for depression in children younger than age 12.

Both recommendations emphasize the importance of follow-up steps after screening to ensure accurate diagnosis, adequate treatment, and appropriate follow-up. Treatment for adults and adolescents can include pharmacotherapy, cognitive-behavioral therapy, and/or psychosocial counseling. However, pharmacotherapy is not recommended for pregnant and breastfeeding women because of potential harms to the fetus and newborn.

The Task Force notes that screening all young children for autism spectrum disorder is problematic because of possible over-diagnosis and unclear benefits of early intervention.

The Task Force deems a number of screening tools acceptable. For adolescents, it suggests the Patient Health Questionnaire for Adolescents and the primary care version of the Beck Depression Inventory.⁶ For adults, the Task Force suggests the Patient Health Questionnaire, the Hospital Anxiety and Depression Scales, the Geriatric Depression Scale for older adults, and the Edinburgh Postnatal Depression Scale for postpartum and pregnant women.⁵

There is no known optimal frequency of screening or evidence on the value of repeated screening. The Task Force suggests one initial screen with repeated screening based on individual characteristics.

Tobacco use: Ask every adult patient about it

Preventing the harms from tobacco use is one of the most important and productive primary care interventions. The Task Force has affirmed its previous recommendation to ask all adults about tobacco use, encourage those that use tobacco to quit, and to offer behavioral and pharmacologic interventions to assist with quitting.⁷ The new recommendations emphasize the importance of smoking cessation during pregnancy; however, because of concern about the unknown potential harms from pharmacologic interventions, they advise only behavioral therapy to assist pregnant women to quit smoking.

The Task Force also examined the potential of electronic nicotine delivery systems for smoking cessation and concluded the evidence is insufficient to make a recommendation. It also concluded that the availability of other proven methods of smoking cessation make them the preferred alternatives.

Services with insufficient evidence

TABLE 2¹ lists the interventions that the Task Force studied this past year and found insufficient evidence to support a recommendation for or against. For adults, these “I” recommendations include screening for visual acuity disorders in older adults, screening for thyroid disorders, screening for iron deficiency anemia during pregnancy, and routinely providing iron supplementation during pregnancy.

The persistent inadequate evidence for the effectiveness of preventive services in infants and children was highlighted by the results of last year’s examination of 4 screening tests, all recommended by the American Academy of Pediatrics, but given an “I” recommendation by the Task Force. These included screening for autism spectrum disorder (ASD) in young children (18-30 months), iron deficiency anemia in children ages 6 to 24 months, depression in those ages 11 and younger, and speech and language delay and disorders in children ages 5 or younger. (Ages noted are from the Task Force.)

The Task Force is careful to emphasize that the statement about ASD screening refers to infants and children who appear normal and for whom no concerns of ASD have been raised by their parents. Screening all young children for this disorder is problematic, according to the Task Force, because of possible over-diagnosis and unclear benefits of early intervention.⁸

The US Preventive Services Task Force made 8 recommendations in 2015 that family physicians should implement in their practices (TABLE 1¹). The conditions addressed are high blood pressure, abnormal blood glucose, breast cancer, depression, and tobacco use. The Task Force also issued 13 “I” statements (TABLE 2¹) reflecting insufficient evidence to recommend for or against a particular intervention—once again underscoring the inadequate evidence base for many commonly-accepted practices aimed at prevention. Four such interventions were targeted toward children.

High blood pressure: Verify before starting treatment

The Task Force continues to give strong backing to the practice of screening for high blood pressure (HBP) and treating those with HBP to prevent cardiovascular and renal disease. The new recommendation, however, recognizes there is significant over-diagnosis of this condition and advises that, before starting treatment, HBP found with office measurement be confirmed with either ambulatory blood pressure monitoring or home blood pressure monitoring. This topic was covered in more depth in a recent Practice Alert.²

Since cardiovascular disease is the leading cause of death in the United States and much of this mortality is preventable, the Task Force also has recommendations in place for screening and treatment of other risks for cardiovascular disease, including obesity, hyperlipidemia, elevated blood glucose (discussed below), and tobacco use.¹

Blood glucose: Focus is now on overweight/obese individuals

The Task Force’s new recommendation for diabetes screening differs from the one made in 2008, which recommended screening for type 2 diabetes (T2DM) only in adults with hypertension. The Task Force now recommends screening for abnormal blood glucose in all obese and overweight adults between the ages of 40 and 70. The Task Force analysis is detailed³ and will be the subject of the next Practice Alert, with only the highlights described here.

The recommendation is limited to overweight and obese adults because they are most likely to have abnormal blood glucose and to benefit from interventions. Screening can be done by measuring fasting blood glucose levels, performing a glucose tolerance test, or measuring glycated hemoglobin levels. The optimal screening frequency is unknown but suggested to be every 3 years. Refer patients with abnormal screen results to an intensive behavioral counseling program that promotes healthy eating and physical activity. Those with T2DM should also receive these services and consider pharmacotherapy.

The Task Force examined the potential of electronic nicotine delivery systems for smoking cessation and concluded that the evidence was insufficient to make a recommendation.

Breast cancer: Mammography advice is age dependent

The Task Force breast cancer screening recommendations, first proposed in 2015 and finalized in early 2016, essentially reaffirm those made in 2009. Women ages 50 through 74 should be screened with mammography every 2 years, and individuals younger than age 50 should make a decision to receive screening—or not—based on the known benefits and risks of mammography at their age and their personal risks and preferences.

Insufficient evidence exists to make recommendations regarding mammography for women ages 75 and up, the use of digital breast tomosynthesis as a primary screening tool, and the use of any modality to augment screening in women with dense breasts who have normal mammogram results. Details of these recommendations were described in a Practice Alert last year.⁴

Depression: Use screening tools designed for specific patients

The 2015 updates on screening for depression essentially reconfirm the Task Force’s previous findings and recommendations on this topic. Screening for depression is recommended for all adults, including pregnant and postpartum women,⁵ and adolescents starting at age 12.⁶ Once again, the evidence is insufficient to make a recommendation on screening for depression in children younger than age 12.

Both recommendations emphasize the importance of follow-up steps after screening to ensure accurate diagnosis, adequate treatment, and appropriate follow-up. Treatment for adults and adolescents can include pharmacotherapy, cognitive-behavioral therapy, and/or psychosocial counseling. However, pharmacotherapy is not recommended for pregnant and breastfeeding women because of potential harms to the fetus and newborn.

The Task Force notes that screening all young children for autism spectrum disorder is problematic because of possible over-diagnosis and unclear benefits of early intervention.

The Task Force deems a number of screening tools acceptable. For adolescents, it suggests the Patient Health Questionnaire for Adolescents and the primary care version of the Beck Depression Inventory.⁶ For adults, the Task Force suggests the Patient Health Questionnaire, the Hospital Anxiety and Depression Scales, the Geriatric Depression Scale for older adults, and the Edinburgh Postnatal Depression Scale for postpartum and pregnant women.⁵

There is no known optimal frequency of screening or evidence on the value of repeated screening. The Task Force suggests one initial screen with repeated screening based on individual characteristics.

Tobacco use: Ask every adult patient about it

Preventing the harms from tobacco use is one of the most important and productive primary care interventions. The Task Force has affirmed its previous recommendation to ask all adults about tobacco use, encourage those that use tobacco to quit, and to offer behavioral and pharmacologic interventions to assist with quitting.⁷ The new recommendations emphasize the importance of smoking cessation during pregnancy; however, because of concern about the unknown potential harms from pharmacologic interventions, they advise only behavioral therapy to assist pregnant women to quit smoking.

The Task Force also examined the potential of electronic nicotine delivery systems for smoking cessation and concluded the evidence is insufficient to make a recommendation. It also concluded that the availability of other proven methods of smoking cessation make them the preferred alternatives.

Services with insufficient evidence

TABLE 2¹ lists the interventions that the Task Force studied this past year and found insufficient evidence to support a recommendation for or against. For adults, these “I” recommendations include screening for visual acuity disorders in older adults, screening for thyroid disorders, screening for iron deficiency anemia during pregnancy, and routinely providing iron supplementation during pregnancy.

The persistent inadequate evidence for the effectiveness of preventive services in infants and children was highlighted by the results of last year’s examination of 4 screening tests, all recommended by the American Academy of Pediatrics, but given an “I” recommendation by the Task Force. These included screening for autism spectrum disorder (ASD) in young children (18-30 months), iron deficiency anemia in children ages 6 to 24 months, depression in those ages 11 and younger, and speech and language delay and disorders in children ages 5 or younger. (Ages noted are from the Task Force.)

The Task Force is careful to emphasize that the statement about ASD screening refers to infants and children who appear normal and for whom no concerns of ASD have been raised by their parents. Screening all young children for this disorder is problematic, according to the Task Force, because of possible over-diagnosis and unclear benefits of early intervention.⁸

The US Preventive Services Task Force made 8 recommendations in 2015 that family physicians should implement in their practices (TABLE 1¹). The conditions addressed are high blood pressure, abnormal blood glucose, breast cancer, depression, and tobacco use. The Task Force also issued 13 “I” statements (TABLE 2¹) reflecting insufficient evidence to recommend for or against a particular intervention—once again underscoring the inadequate evidence base for many commonly-accepted practices aimed at prevention. Four such interventions were targeted toward children.

High blood pressure: Verify before starting treatment

The Task Force continues to give strong backing to the practice of screening for high blood pressure (HBP) and treating those with HBP to prevent cardiovascular and renal disease. The new recommendation, however, recognizes there is significant over-diagnosis of this condition and advises that, before starting treatment, HBP found with office measurement be confirmed with either ambulatory blood pressure monitoring or home blood pressure monitoring. This topic was covered in more depth in a recent Practice Alert.²

Since cardiovascular disease is the leading cause of death in the United States and much of this mortality is preventable, the Task Force also has recommendations in place for screening and treatment of other risks for cardiovascular disease, including obesity, hyperlipidemia, elevated blood glucose (discussed below), and tobacco use.¹

Blood glucose: Focus is now on overweight/obese individuals

The Task Force’s new recommendation for diabetes screening differs from the one made in 2008, which recommended screening for type 2 diabetes (T2DM) only in adults with hypertension. The Task Force now recommends screening for abnormal blood glucose in all obese and overweight adults between the ages of 40 and 70. The Task Force analysis is detailed³ and will be the subject of the next Practice Alert, with only the highlights described here.

The recommendation is limited to overweight and obese adults because they are most likely to have abnormal blood glucose and to benefit from interventions. Screening can be done by measuring fasting blood glucose levels, performing a glucose tolerance test, or measuring glycated hemoglobin levels. The optimal screening frequency is unknown but suggested to be every 3 years. Refer patients with abnormal screen results to an intensive behavioral counseling program that promotes healthy eating and physical activity. Those with T2DM should also receive these services and consider pharmacotherapy.

The Task Force examined the potential of electronic nicotine delivery systems for smoking cessation and concluded that the evidence was insufficient to make a recommendation.

Breast cancer: Mammography advice is age dependent

The Task Force breast cancer screening recommendations, first proposed in 2015 and finalized in early 2016, essentially reaffirm those made in 2009. Women ages 50 through 74 should be screened with mammography every 2 years, and individuals younger than age 50 should make a decision to receive screening—or not—based on the known benefits and risks of mammography at their age and their personal risks and preferences.

Insufficient evidence exists to make recommendations regarding mammography for women ages 75 and up, the use of digital breast tomosynthesis as a primary screening tool, and the use of any modality to augment screening in women with dense breasts who have normal mammogram results. Details of these recommendations were described in a Practice Alert last year.⁴

Depression: Use screening tools designed for specific patients

The 2015 updates on screening for depression essentially reconfirm the Task Force’s previous findings and recommendations on this topic. Screening for depression is recommended for all adults, including pregnant and postpartum women,⁵ and adolescents starting at age 12.⁶ Once again, the evidence is insufficient to make a recommendation on screening for depression in children younger than age 12.

Both recommendations emphasize the importance of follow-up steps after screening to ensure accurate diagnosis, adequate treatment, and appropriate follow-up. Treatment for adults and adolescents can include pharmacotherapy, cognitive-behavioral therapy, and/or psychosocial counseling. However, pharmacotherapy is not recommended for pregnant and breastfeeding women because of potential harms to the fetus and newborn.

The Task Force notes that screening all young children for autism spectrum disorder is problematic because of possible over-diagnosis and unclear benefits of early intervention.

The Task Force deems a number of screening tools acceptable. For adolescents, it suggests the Patient Health Questionnaire for Adolescents and the primary care version of the Beck Depression Inventory.⁶ For adults, the Task Force suggests the Patient Health Questionnaire, the Hospital Anxiety and Depression Scales, the Geriatric Depression Scale for older adults, and the Edinburgh Postnatal Depression Scale for postpartum and pregnant women.⁵

There is no known optimal frequency of screening or evidence on the value of repeated screening. The Task Force suggests one initial screen with repeated screening based on individual characteristics.

Tobacco use: Ask every adult patient about it

Preventing the harms from tobacco use is one of the most important and productive primary care interventions. The Task Force has affirmed its previous recommendation to ask all adults about tobacco use, encourage those that use tobacco to quit, and to offer behavioral and pharmacologic interventions to assist with quitting.⁷ The new recommendations emphasize the importance of smoking cessation during pregnancy; however, because of concern about the unknown potential harms from pharmacologic interventions, they advise only behavioral therapy to assist pregnant women to quit smoking.

The Task Force also examined the potential of electronic nicotine delivery systems for smoking cessation and concluded the evidence is insufficient to make a recommendation. It also concluded that the availability of other proven methods of smoking cessation make them the preferred alternatives.

Services with insufficient evidence

TABLE 2¹ lists the interventions that the Task Force studied this past year and found insufficient evidence to support a recommendation for or against. For adults, these “I” recommendations include screening for visual acuity disorders in older adults, screening for thyroid disorders, screening for iron deficiency anemia during pregnancy, and routinely providing iron supplementation during pregnancy.

The persistent inadequate evidence for the effectiveness of preventive services in infants and children was highlighted by the results of last year’s examination of 4 screening tests, all recommended by the American Academy of Pediatrics, but given an “I” recommendation by the Task Force. These included screening for autism spectrum disorder (ASD) in young children (18-30 months), iron deficiency anemia in children ages 6 to 24 months, depression in those ages 11 and younger, and speech and language delay and disorders in children ages 5 or younger. (Ages noted are from the Task Force.)

The Task Force is careful to emphasize that the statement about ASD screening refers to infants and children who appear normal and for whom no concerns of ASD have been raised by their parents. Screening all young children for this disorder is problematic, according to the Task Force, because of possible over-diagnosis and unclear benefits of early intervention.⁸

Since JFP’s launch of the PURL department in November of 2007, 122 PURLs—Priority Updates from the Research Literature—have been published. The Journal of Family Practice is the exclusive publication venue for these items. Because they have stood the test of time and are one of the more popular columns in JFP, I thought it would be worthwhile to describe the rigorous evaluation they undergo before they are published.

Many studies, but few PURLs. Each year, approximately 200,000 new human medical research studies are indexed on PubMed. Very few of these studies are pertinent to family medicine, however, and even fewer provide new patient-oriented evidence for primary care clinicians.

In 2005, the leaders of the Family Physician Inquiries Network (FPIN), which produces another popular JFP column, Clinical Inquiries, set about identifying high-priority research findings relevant to family medicine. A group of family physicians and librarians began combing the research literature monthly to find those rare randomized trials or high-quality observational studies that pertained to our specialty. To qualify as a PURL, a study had to meet 6 criteria. It had to be scientifically valid, relevant to family medicine, applicable in a medical care setting, immediately implementable, clinically meaningful, and practice changing. These criteria still stand today.

Making the cut. When a study is identified as a potential PURL, it is submitted to one of FPIN’s PURL review groups for a critical appraisal and rigorous peer review. If the group cannot convince the PURLs editors that the original research meets all 6 criteria, the study falls by the wayside. Most potential PURLs do not make the cut. I was one of the early PURL “divers,” and I was amazed at how few PURLs existed. Given the emphasis of research on subspecialties and the dearth of primary care research funding in the United States, I probably shouldn’t have been surprised.

Interested in research that is clinically meaningful and practice changing for family physicians? Then check out our PURLs column.

Holding their value. I reviewed all 122 PURLs this week and am proud to say that nearly all still provide highly pertinent, practice-changing information for family physicians and other primary care clinicians. For a quick review of our string of PURLs, go to www.jfponline.com, select “Articles” in the banner, and then “PURLs,” and read the short practice changer box for each one. I guarantee it will be time well spent!

If you would like to become part of the PURLs process, either by nominating or reviewing a PURL, please contact the PURLs Project Manager at purls@fpin.org.

Since JFP’s launch of the PURL department in November of 2007, 122 PURLs—Priority Updates from the Research Literature—have been published. The Journal of Family Practice is the exclusive publication venue for these items. Because they have stood the test of time and are one of the more popular columns in JFP, I thought it would be worthwhile to describe the rigorous evaluation they undergo before they are published.

Many studies, but few PURLs. Each year, approximately 200,000 new human medical research studies are indexed on PubMed. Very few of these studies are pertinent to family medicine, however, and even fewer provide new patient-oriented evidence for primary care clinicians.

In 2005, the leaders of the Family Physician Inquiries Network (FPIN), which produces another popular JFP column, Clinical Inquiries, set about identifying high-priority research findings relevant to family medicine. A group of family physicians and librarians began combing the research literature monthly to find those rare randomized trials or high-quality observational studies that pertained to our specialty. To qualify as a PURL, a study had to meet 6 criteria. It had to be scientifically valid, relevant to family medicine, applicable in a medical care setting, immediately implementable, clinically meaningful, and practice changing. These criteria still stand today.

Making the cut. When a study is identified as a potential PURL, it is submitted to one of FPIN’s PURL review groups for a critical appraisal and rigorous peer review. If the group cannot convince the PURLs editors that the original research meets all 6 criteria, the study falls by the wayside. Most potential PURLs do not make the cut. I was one of the early PURL “divers,” and I was amazed at how few PURLs existed. Given the emphasis of research on subspecialties and the dearth of primary care research funding in the United States, I probably shouldn’t have been surprised.

Interested in research that is clinically meaningful and practice changing for family physicians? Then check out our PURLs column.

Holding their value. I reviewed all 122 PURLs this week and am proud to say that nearly all still provide highly pertinent, practice-changing information for family physicians and other primary care clinicians. For a quick review of our string of PURLs, go to www.jfponline.com, select “Articles” in the banner, and then “PURLs,” and read the short practice changer box for each one. I guarantee it will be time well spent!

If you would like to become part of the PURLs process, either by nominating or reviewing a PURL, please contact the PURLs Project Manager at purls@fpin.org.

Since JFP’s launch of the PURL department in November of 2007, 122 PURLs—Priority Updates from the Research Literature—have been published. The Journal of Family Practice is the exclusive publication venue for these items. Because they have stood the test of time and are one of the more popular columns in JFP, I thought it would be worthwhile to describe the rigorous evaluation they undergo before they are published.

Many studies, but few PURLs. Each year, approximately 200,000 new human medical research studies are indexed on PubMed. Very few of these studies are pertinent to family medicine, however, and even fewer provide new patient-oriented evidence for primary care clinicians.

In 2005, the leaders of the Family Physician Inquiries Network (FPIN), which produces another popular JFP column, Clinical Inquiries, set about identifying high-priority research findings relevant to family medicine. A group of family physicians and librarians began combing the research literature monthly to find those rare randomized trials or high-quality observational studies that pertained to our specialty. To qualify as a PURL, a study had to meet 6 criteria. It had to be scientifically valid, relevant to family medicine, applicable in a medical care setting, immediately implementable, clinically meaningful, and practice changing. These criteria still stand today.

Making the cut. When a study is identified as a potential PURL, it is submitted to one of FPIN’s PURL review groups for a critical appraisal and rigorous peer review. If the group cannot convince the PURLs editors that the original research meets all 6 criteria, the study falls by the wayside. Most potential PURLs do not make the cut. I was one of the early PURL “divers,” and I was amazed at how few PURLs existed. Given the emphasis of research on subspecialties and the dearth of primary care research funding in the United States, I probably shouldn’t have been surprised.

Interested in research that is clinically meaningful and practice changing for family physicians? Then check out our PURLs column.

Holding their value. I reviewed all 122 PURLs this week and am proud to say that nearly all still provide highly pertinent, practice-changing information for family physicians and other primary care clinicians. For a quick review of our string of PURLs, go to www.jfponline.com, select “Articles” in the banner, and then “PURLs,” and read the short practice changer box for each one. I guarantee it will be time well spent!

If you would like to become part of the PURLs process, either by nominating or reviewing a PURL, please contact the PURLs Project Manager at purls@fpin.org.

THE CASE

A 58-year-old woman sought care at our clinic for recurrent syncopal and near-syncopal events following surgical repair of a left hip fracture. The first syncopal event occurred one day post-surgery shortly after standing and was attributed to orthostatic hypotension. Subsequently, the patient experienced 2 events during her hospital stay. Both events occurred in the upright position and were preceded by lightheadedness, warmth, and diaphoresis. They were short in duration (<30 seconds) with spontaneous and complete recovery. The patient had no associated chest pain or palpitations.

The patient’s past medical history included osteopenia, dyslipidemia, and vasovagal syncope, averaging one to 2 events per year. Given her past history, the physicians caring for her assumed that she was having recurrences of her vasovagal syncope. She was discharged home on fludrocortisone 0.1 mg/d, sodium chloride 1 g tid, enoxaparin 40 mg/d, and acetaminophen and oxycodone as needed for pain.

One week later, the patient experienced another syncopal event at home, prompting her to visit our clinic for further evaluation. On arrival, her vital signs were stable. Her oxygen saturation level was 98%, she was not orthostatic, and her physical exam and blood studies were unremarkable. An echocardiogram showed preserved left ventricular function with no evidence of right ventricular dilatation or strain.

THE DIAGNOSIS

The patient’s revised Geneva Score for pulmonary embolism (PE) was 2 to 5 depending on the heart rate used (66-80 beats per minute), putting her in a low-to-intermediate risk group with an estimated PE prevalence between 8% and 28%.¹ Given her recent surgery and the increase in the frequency of her vasovagal events, a computed tomography pulmonary angiogram (CT-PA) was performed. The CT-PA showed a PE in the lateral and posterior basal subsegmental branches of the right lower lobe. Doppler ultrasound revealed no evidence of acute deep vein thrombosis.

DISCUSSION

Syncope may develop in 9% to 19% of patients with PE.^2-6 While syncope in patients with PE is often attributed to reduced cardiac filling secondary to massive emboli, it is important to recognize that patients can also present with vasovagal syncope in the absence of massive emboli.

One mechanism for the development of syncope is right ventricular failure with subsequent impairment of left ventricular filling, leading to arterial hypotension. Indeed, the majority of patients with PE and syncope have a massive embolism defined as greater than a 50% reduction in the pulmonary circulation.⁷ In one study, 60% of patients with PE who presented with syncope had a massive PE compared to 39% of patients presenting without syncope (P=.036).⁸

Another reported mechanism for syncope in a patient with PE is transient high-degree atrioventricular (AV) block.⁹ Sudden increases in right-sided pressure can lead to transient right bundle branch block, which may result in complete heart block in the setting of baseline left bundle branch block.

One could argue that the PE finding in our case was incidental, but we had several reasons for believing it was the cause of our patient’s syncope.

Lastly, patients with PE may develop a vasovagal-like reaction, such as the Bezold-Jarisch reflex, which results in transient arterial hypotension and cerebral hypoperfusion.¹⁰ In such instances, the postulated mechanism is activation of cardiac vagal afferents, which results in an increase in vagal tone and peripheral sympathetic withdrawal leading to hypotension and syncope. It is important to note that this mechanism can occur in the absence of massive PE. In one study, up to 40% of patients with PE and syncope did not have a massive PE, and almost 6% had thrombi only in small branches of the pulmonary artery.⁸

This patient had isolated subsegmental defects, identified on the CT-PA. The sensitivity of CT-PA to detect subsegmental PE ranges from 53% to 100%.¹¹ While this test has its limitations, the introduction of the multi-detector CT technique has significantly increased the rate of detection with a specificity of 96%.^12,13

Was PE the cause of the syncope, or just an incidental finding?

In this case, we believe the CT-PA findings were diagnostic for PE. What is less clear is whether the PE was the cause of the syncope.

Asymptomatic post-operative PE with isolated subsegmental defects has been reported.^14-16 When compared to patients with a defect at a segmental or more proximal level, these patients often have less dyspnea, are less likely to be classified as having a high clinical probability of PE, and have a lower prevalence of proximal deep vein thrombosis (3.3% vs 43.8%; P<.0001).¹⁷ Therefore, one could argue that the PE finding in our case was incidental. While this is a possibility, we believe the patient’s syncope was due to PE for the following reasons.

First, several investigators have reported transient increases in vagal tone and syncope following PE consistent with a vasovagal-like response.^7,18 Therefore, it is possible that the reduction in preload associated with PE triggered a Bezold-Jarisch-like reflex leading to syncope. The patient’s history of vasovagal syncope was certainly indicative of increased susceptibility to reflex-mediated events, thus supporting our hypothesis.

Second, our patient had a cluster of events following surgery compared to the one to 2 events she experienced per year prior to surgery. The increased incidence of events would be an unusual progression of her syncope in the absence of clear triggers, again rendering our hypothesis more plausible.

The patient was admitted to our hospital and started on a higher dose of enoxaparin (60 mg twice daily). She was subsequently discharged home on rivaroxaban 15 mg twice daily and midodrine 2.5 mg twice daily in addition to the medications she was already taking. At her 6-week follow-up visit, she reported no recurrences.

THE TAKEAWAY

This case demonstrates that non-massive PE can present as vasovagal syncope. Recognizing that PE could lead to reflex-mediated syncope in the absence of massive emboli, it is important to rule it out in the evaluation of patients with vasovagal syncope when risk factors for PE are present.

THE CASE

A 58-year-old woman sought care at our clinic for recurrent syncopal and near-syncopal events following surgical repair of a left hip fracture. The first syncopal event occurred one day post-surgery shortly after standing and was attributed to orthostatic hypotension. Subsequently, the patient experienced 2 events during her hospital stay. Both events occurred in the upright position and were preceded by lightheadedness, warmth, and diaphoresis. They were short in duration (<30 seconds) with spontaneous and complete recovery. The patient had no associated chest pain or palpitations.

The patient’s past medical history included osteopenia, dyslipidemia, and vasovagal syncope, averaging one to 2 events per year. Given her past history, the physicians caring for her assumed that she was having recurrences of her vasovagal syncope. She was discharged home on fludrocortisone 0.1 mg/d, sodium chloride 1 g tid, enoxaparin 40 mg/d, and acetaminophen and oxycodone as needed for pain.

One week later, the patient experienced another syncopal event at home, prompting her to visit our clinic for further evaluation. On arrival, her vital signs were stable. Her oxygen saturation level was 98%, she was not orthostatic, and her physical exam and blood studies were unremarkable. An echocardiogram showed preserved left ventricular function with no evidence of right ventricular dilatation or strain.

THE DIAGNOSIS

The patient’s revised Geneva Score for pulmonary embolism (PE) was 2 to 5 depending on the heart rate used (66-80 beats per minute), putting her in a low-to-intermediate risk group with an estimated PE prevalence between 8% and 28%.¹ Given her recent surgery and the increase in the frequency of her vasovagal events, a computed tomography pulmonary angiogram (CT-PA) was performed. The CT-PA showed a PE in the lateral and posterior basal subsegmental branches of the right lower lobe. Doppler ultrasound revealed no evidence of acute deep vein thrombosis.

DISCUSSION

Syncope may develop in 9% to 19% of patients with PE.^2-6 While syncope in patients with PE is often attributed to reduced cardiac filling secondary to massive emboli, it is important to recognize that patients can also present with vasovagal syncope in the absence of massive emboli.

One mechanism for the development of syncope is right ventricular failure with subsequent impairment of left ventricular filling, leading to arterial hypotension. Indeed, the majority of patients with PE and syncope have a massive embolism defined as greater than a 50% reduction in the pulmonary circulation.⁷ In one study, 60% of patients with PE who presented with syncope had a massive PE compared to 39% of patients presenting without syncope (P=.036).⁸

Another reported mechanism for syncope in a patient with PE is transient high-degree atrioventricular (AV) block.⁹ Sudden increases in right-sided pressure can lead to transient right bundle branch block, which may result in complete heart block in the setting of baseline left bundle branch block.

One could argue that the PE finding in our case was incidental, but we had several reasons for believing it was the cause of our patient’s syncope.

Lastly, patients with PE may develop a vasovagal-like reaction, such as the Bezold-Jarisch reflex, which results in transient arterial hypotension and cerebral hypoperfusion.¹⁰ In such instances, the postulated mechanism is activation of cardiac vagal afferents, which results in an increase in vagal tone and peripheral sympathetic withdrawal leading to hypotension and syncope. It is important to note that this mechanism can occur in the absence of massive PE. In one study, up to 40% of patients with PE and syncope did not have a massive PE, and almost 6% had thrombi only in small branches of the pulmonary artery.⁸

This patient had isolated subsegmental defects, identified on the CT-PA. The sensitivity of CT-PA to detect subsegmental PE ranges from 53% to 100%.¹¹ While this test has its limitations, the introduction of the multi-detector CT technique has significantly increased the rate of detection with a specificity of 96%.^12,13

Was PE the cause of the syncope, or just an incidental finding?

In this case, we believe the CT-PA findings were diagnostic for PE. What is less clear is whether the PE was the cause of the syncope.

Asymptomatic post-operative PE with isolated subsegmental defects has been reported.^14-16 When compared to patients with a defect at a segmental or more proximal level, these patients often have less dyspnea, are less likely to be classified as having a high clinical probability of PE, and have a lower prevalence of proximal deep vein thrombosis (3.3% vs 43.8%; P<.0001).¹⁷ Therefore, one could argue that the PE finding in our case was incidental. While this is a possibility, we believe the patient’s syncope was due to PE for the following reasons.

First, several investigators have reported transient increases in vagal tone and syncope following PE consistent with a vasovagal-like response.^7,18 Therefore, it is possible that the reduction in preload associated with PE triggered a Bezold-Jarisch-like reflex leading to syncope. The patient’s history of vasovagal syncope was certainly indicative of increased susceptibility to reflex-mediated events, thus supporting our hypothesis.

Second, our patient had a cluster of events following surgery compared to the one to 2 events she experienced per year prior to surgery. The increased incidence of events would be an unusual progression of her syncope in the absence of clear triggers, again rendering our hypothesis more plausible.

The patient was admitted to our hospital and started on a higher dose of enoxaparin (60 mg twice daily). She was subsequently discharged home on rivaroxaban 15 mg twice daily and midodrine 2.5 mg twice daily in addition to the medications she was already taking. At her 6-week follow-up visit, she reported no recurrences.

THE TAKEAWAY

This case demonstrates that non-massive PE can present as vasovagal syncope. Recognizing that PE could lead to reflex-mediated syncope in the absence of massive emboli, it is important to rule it out in the evaluation of patients with vasovagal syncope when risk factors for PE are present.

THE CASE

A 58-year-old woman sought care at our clinic for recurrent syncopal and near-syncopal events following surgical repair of a left hip fracture. The first syncopal event occurred one day post-surgery shortly after standing and was attributed to orthostatic hypotension. Subsequently, the patient experienced 2 events during her hospital stay. Both events occurred in the upright position and were preceded by lightheadedness, warmth, and diaphoresis. They were short in duration (<30 seconds) with spontaneous and complete recovery. The patient had no associated chest pain or palpitations.

The patient’s past medical history included osteopenia, dyslipidemia, and vasovagal syncope, averaging one to 2 events per year. Given her past history, the physicians caring for her assumed that she was having recurrences of her vasovagal syncope. She was discharged home on fludrocortisone 0.1 mg/d, sodium chloride 1 g tid, enoxaparin 40 mg/d, and acetaminophen and oxycodone as needed for pain.

One week later, the patient experienced another syncopal event at home, prompting her to visit our clinic for further evaluation. On arrival, her vital signs were stable. Her oxygen saturation level was 98%, she was not orthostatic, and her physical exam and blood studies were unremarkable. An echocardiogram showed preserved left ventricular function with no evidence of right ventricular dilatation or strain.

THE DIAGNOSIS

The patient’s revised Geneva Score for pulmonary embolism (PE) was 2 to 5 depending on the heart rate used (66-80 beats per minute), putting her in a low-to-intermediate risk group with an estimated PE prevalence between 8% and 28%.¹ Given her recent surgery and the increase in the frequency of her vasovagal events, a computed tomography pulmonary angiogram (CT-PA) was performed. The CT-PA showed a PE in the lateral and posterior basal subsegmental branches of the right lower lobe. Doppler ultrasound revealed no evidence of acute deep vein thrombosis.

DISCUSSION

Syncope may develop in 9% to 19% of patients with PE.^2-6 While syncope in patients with PE is often attributed to reduced cardiac filling secondary to massive emboli, it is important to recognize that patients can also present with vasovagal syncope in the absence of massive emboli.

One mechanism for the development of syncope is right ventricular failure with subsequent impairment of left ventricular filling, leading to arterial hypotension. Indeed, the majority of patients with PE and syncope have a massive embolism defined as greater than a 50% reduction in the pulmonary circulation.⁷ In one study, 60% of patients with PE who presented with syncope had a massive PE compared to 39% of patients presenting without syncope (P=.036).⁸

Another reported mechanism for syncope in a patient with PE is transient high-degree atrioventricular (AV) block.⁹ Sudden increases in right-sided pressure can lead to transient right bundle branch block, which may result in complete heart block in the setting of baseline left bundle branch block.

One could argue that the PE finding in our case was incidental, but we had several reasons for believing it was the cause of our patient’s syncope.

Lastly, patients with PE may develop a vasovagal-like reaction, such as the Bezold-Jarisch reflex, which results in transient arterial hypotension and cerebral hypoperfusion.¹⁰ In such instances, the postulated mechanism is activation of cardiac vagal afferents, which results in an increase in vagal tone and peripheral sympathetic withdrawal leading to hypotension and syncope. It is important to note that this mechanism can occur in the absence of massive PE. In one study, up to 40% of patients with PE and syncope did not have a massive PE, and almost 6% had thrombi only in small branches of the pulmonary artery.⁸

This patient had isolated subsegmental defects, identified on the CT-PA. The sensitivity of CT-PA to detect subsegmental PE ranges from 53% to 100%.¹¹ While this test has its limitations, the introduction of the multi-detector CT technique has significantly increased the rate of detection with a specificity of 96%.^12,13

Was PE the cause of the syncope, or just an incidental finding?

In this case, we believe the CT-PA findings were diagnostic for PE. What is less clear is whether the PE was the cause of the syncope.

Asymptomatic post-operative PE with isolated subsegmental defects has been reported.^14-16 When compared to patients with a defect at a segmental or more proximal level, these patients often have less dyspnea, are less likely to be classified as having a high clinical probability of PE, and have a lower prevalence of proximal deep vein thrombosis (3.3% vs 43.8%; P<.0001).¹⁷ Therefore, one could argue that the PE finding in our case was incidental. While this is a possibility, we believe the patient’s syncope was due to PE for the following reasons.

First, several investigators have reported transient increases in vagal tone and syncope following PE consistent with a vasovagal-like response.^7,18 Therefore, it is possible that the reduction in preload associated with PE triggered a Bezold-Jarisch-like reflex leading to syncope. The patient’s history of vasovagal syncope was certainly indicative of increased susceptibility to reflex-mediated events, thus supporting our hypothesis.

Second, our patient had a cluster of events following surgery compared to the one to 2 events she experienced per year prior to surgery. The increased incidence of events would be an unusual progression of her syncope in the absence of clear triggers, again rendering our hypothesis more plausible.

The patient was admitted to our hospital and started on a higher dose of enoxaparin (60 mg twice daily). She was subsequently discharged home on rivaroxaban 15 mg twice daily and midodrine 2.5 mg twice daily in addition to the medications she was already taking. At her 6-week follow-up visit, she reported no recurrences.

THE TAKEAWAY

This case demonstrates that non-massive PE can present as vasovagal syncope. Recognizing that PE could lead to reflex-mediated syncope in the absence of massive emboli, it is important to rule it out in the evaluation of patients with vasovagal syncope when risk factors for PE are present.

Prevention of diabetes, as well as early detection and treatment of both prediabetes and diabetes, is critical to the health of our country. Because evidence-based guidelines are key to our ability to effectively address the nation’s diabetes epidemic, the American Diabetes Association (ADA) updates its “Standards of Medical Care in Diabetes” annually to incorporate new evidence or clarifications.

The 2016 standards,¹ available at professional.diabetes.org/jfp, are a valuable resource. Among the latest revisions: an expansion in screening recommendations, a change in the age at which aspirin therapy for women should be considered, and a change in A1C goals for pregnant women with diabetes.

As members of the ADA’s primary care advisory group, we use a question and answer format in the summary that follows to highlight recent revisions and review other recommendations that are of particular relevance to physicians in primary care. It is important to note, however, that ADA recommendations are not intended to preclude clinical judgment and should be applied in the context of excellent medical care.

Diagnosis and screening

Have the 2016 ADA standards changed the way diabetes is diagnosed?

No. The criteria for a diagnosis of diabetes did not change. Diabetes and prediabetes are still screened for and diagnosed with any of the following: a fasting plasma glucose (FPG); a 2-hour 75-g oral glucose tolerance test (OGTT); a random plasma glucose >200 mg/dL with symptoms of hyperglycemia; or A1C criteria (TABLE 1).^1,2 The wording was changed, however, to make it clear that no one test is preferred over another for diagnosis.

Yes. In addition to screening asymptomatic adults of any age who are overweight or obese and have one or more additional risk factors for diabetes, the 2016 standards recommend screening all adults 45 years and older, regardless of weight.

Is an A1C <7% the recommended treatment goal for everyone with diabetes?

No. An A1C <7% is considered reasonable for most, but not all, nonpregnant adults. In the last few years, the ADA has focused more on individualized targets.

Tighter control (<6.5%)—which is associated with lower rates of eye disease, kidney disease, and nerve damage—may be appropriate for patients who have no significant hypoglycemia, no cardiovascular disease (CVD), a shorter duration of diabetes, or a longer expected lifespan.

Conversely, a higher target (<8%) may be appropriate for patients who are older, have longstanding diabetes, advanced macrovascular or microvascular disease, established complications, or a limited life expectancy.^3,4

The latest ADA revisions include an expansion in screening recommendations and changes in the age at which aspirin therapy for women should be considered and in A1C goals for pregnant women with diabetes.

Pregnancy. The 2016 standards have a new target for pregnant women with diabetes: The ADA previously recommended an A1C <6% for this patient population, but now recommends a target A1C between 6% and 6.5%. This may be tightened or relaxed, however, depending on individual risk of hypoglycemia.

In focusing on individualized targets and hypoglycemia avoidance, the ADA notes that attention must be paid to fasting, pre-meal, and post-meal blood glucose levels to achieve treatment goals. The 2016 standards emphasize the importance of patient-centered diabetes care, aligned with a coordinated, team-based chronic care model.

Diabetes self-management education and support is indicated for those who are newly diagnosed, and should be provided periodically based on glucose control and progression of the disease. All patients should receive education on hypoglycemia risk and treatment.

Prediabetes and prevention

What is prediabetes and what can I do to prevent patients with prediabetes from developing diabetes?

Patients with impaired glucose tolerance, impaired fasting glucose, or an A1C between 5.7% and 6.4% are considered to have prediabetes and are at risk for developing type 2 diabetes.

Family physicians should refer patients with prediabetes to intensive diet, physical activity, and behavioral counseling programs like those based on the Diabetes Prevention Program study (www.niddk.nih.gov/about-niddk/research-areas/diabetes/diabetes-prevention-program-dpp/Pages/default.aspx). Goals should include a minimum 7% weight loss and moderate-intensity physical activity, such as brisk walking, for at least 150 minutes per week.

For patients with diabetes, a sustained weight loss of 5% may improve glycemic control and reduce the need for medication.

Lifestyle modification programs have been shown to be very effective in preventing diabetes, with about a 58% reduction in the risk of developing type 2 diabetes after 3 years.⁵ The 2016 standards added a recommendation that physicians encourage the use of new technology, such as text messaging or smart phone apps, to support such efforts.

Should I consider initiating oral antiglycemics in patients with prediabetes?

Yes. Pharmacologic agents, including metformin, acarbose, and pioglitazone, have been shown to decrease progression from prediabetes to type 2 diabetes. Thus, antiglycemics should be considered for certain patients. Metformin is especially appropriate for women with a history of gestational diabetes, patients who are younger than 60 years, and those who have a body mass index (BMI) ≥35 kg/m².⁶

How often should I screen patients with prediabetes?

Patients with prediabetes should be screened annually. Such individuals should also be screened and treated for modifiable cardiovascular risk factors. There is strong evidence that the treatment of obesity can be beneficial for those at any stage of the diabetes spectrum.

© 2016 Joe Gorman

Obesity management

What do the 2016 ADA standards recommend for obese patients with diabetes?

With more than two-thirds of Americans either overweight or obese, the ADA added a new section on obesity management and calls on health care providers to:

• weigh patients and calculate and document their BMI at every visit, and
• counsel those who are overweight or obese on the benefits of even modest weight loss.

The ADA recommends a sustained weight loss of 5%, which can improve glycemic control and reduce the need for diabetes medications,^7-9 although weight loss of ≥7% is optimal. Physicians are also called on to assess each patient’s readiness to engage in therapeutic lifestyle change to maintain a modest weight loss.

Treatment for obesity can include therapeutic lifestyle change (reduction in calories, increase in physical activity) and behavioral therapy. For refractory patients, pharmacologic therapy and bariatric surgery may be considered.

Interventions should be high-intensity (≥16 sessions in 6 months) and focus on diet, physical activity, and behavioral strategies to achieve a 500 to 750 calorie deficit per day.¹⁰ Long-term (≥1 year) comprehensive weight maintenance programs should be prescribed for those who achieve short-term weight loss.^11,12 Such programs should provide at least monthly contact and encourage ongoing monitoring of body weight (weekly or more frequently), continued consumption of a reduced-calorie diet, and participation in high levels of physical activity (200 to 300 minutes per week).

Glycemic treatment

What are some of the key factors that distinguish the different type 2 diabetes medications from one another?

An increasing understanding of diabetes pathophysiology has led to a wider array of medications, making treatment more complex than ever. It is important for physicians to have a strong working knowledge of the various classes of antidiabetic agents and the subtleties between drugs in the same class to best individualize treatment.

Here are the highlights of each class of medication listed in the ADA/European Association for the Study of Diabetes algorithm for the management of type 2 diabetes,¹³ which is available at http://care.diabetesjournals.org/content/38/1/140/F2.large.jpg):

Metformin is the preferred initial medication for all patients who can tolerate it and have no contraindications. The drug is cost-effective, weight neutral, and has had positive cardiovascular and mortality outcomes in long-term studies. Adverse gastrointestinal (GI) effects, including nausea, diarrhea, and dyspepsia, are common but can be reduced with a slow titration of the drug. Metformin should be used with caution in those with renal disease. The dose should be reduced if the estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m² and the drug discontinued if eGFR <30 mL/min/1.73 m².

Sulfonylureas/meglitinides stimulate insulin secretion in a glucose-independent manner. They are cost-effective and have high efficacy early in the disease and with initial use, but the effect wanes as the disease progresses. This class of drugs is associated with weight gain and hypoglycemia. Second-generation sulfonylureas (glipizide, glimepiride) are recommended; meglitinides are more expensive than sulfonylureas.

Patients who fail to achieve or maintain their A1C goal after one year may need to begin insulin therapy.

Thiazolidinediones work to improve insulin sensitivity in the periphery and have a low risk of hypoglycemia. They have been associated with fluid retention, weight gain, and worsening of pre-existing congestive heart failure, but previous cardiovascular concerns (with rosiglitazone)¹⁴ and bladder cancer risks (with pioglitazone)^15-17 have been refuted. Thiazolidinediones are contraindicated in those with Class III and IV congestive heart failure, however, and patients taking them require careful monitoring for weight gain, fluid retention, and exacerbation of heart failure.

Dipeptidyl peptidase-4 inhibitors (DPP4Is) work to reduce the breakdown of endogenous incretin hormones. These oral agents increase insulin secretion in a glucose-dependent manner; more insulin is secreted when glucose is higher and less when glucose is closer to normal. This means that there is a much lower risk of hypoglycemia when a DPP4I is used as monotherapy.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs), which are injectable, also work via incretin hormones and stimulate insulin in a glucose-dependent manner. They are associated with weight loss and low rates of hypoglycemia. Adverse GI effects are common with this class of drugs, but can be reduced by titrating the medication and avoiding overeating. GLP-1RAs can be taken twice daily to once weekly, depending on the specific agent.

Sodium glucose transporter 2 inhibitors (SGLT2Is) are oral agents and the newest class of antidiabetes drugs. The drugs help block the reabsorption of glucose, thereby lowering glucose levels, blood pressure, and weight in many patients. The most common adverse effects are urinary tract and genital yeast infections. SGLT2Is should not be given to patients with advanced renal disease (chronic kidney disease Stages 3B-5) because they will not be effectively absorbed.

The US Food and Drug Administration (FDA) recently issued a warning about the risk of ketoacidosis with these agents,¹⁸ and patients should be advised to stop taking them and to seek immediate medical attention if they develop symptoms of ketoacidosis, such as excessive thirst, frequent urination, nausea and vomiting, abdominal pain, weakness or fatigue, shortness of breath, fruity-scented breath, or confusion.

Insulin is eventually needed by most patients with type 2 diabetes who live long enough to see the disease progress. The most common adverse effects are weight gain and hypoglycemia. There are many types of insulin, but only one that is delivered via inhalation—human insulin inhaled powder. Inhaled insulin, however, has the potential for adverse pulmonary effects, including cough and reduction of peak expiratory flow. Therefore, pulmonary function testing is recommended prior to its use.

Treatment goal attainment should be evaluated every 3 months, and treatment titrated at 3-month intervals if goals are not achieved. The ADA/European Association for the Study of Diabetes’ algorithm indicates that patients are likely to need insulin a year after diagnosis if their A1C goal has not been achieved or maintained.¹³

The following medications are not included in the algorithm but are included in the 2016 standards, and may be helpful for certain patients:

Alpha-glucosidase inhibitors delay the absorption of glucose from the proximal to distal GI tract, thereby reducing postprandial hyperglycemia. Flatulence and leakage of stool—the most common adverse effects—have limited their use in the United States.

Patients ≥40 years will need moderate- to high-intensity statin therapy to lower their atherosclerotic cardiovascular disease risk.

Bile acid sequestrants (colesevelam) treat both hyperlipidemia and diabetes. The medications work by reducing glucose absorption from the GI tract. They reduce postprandial hyperglycemia, with a low risk of hypoglycemia. Colesevelam’s use is limited, however, because of the number of pills needed (6 daily).

Bromocriptine affects satiety levels via the central nervous system, and is available in a specific formulation for the treatment of diabetes. “First-dose” hypotension, however, is an adverse effect of considerable concern.¹

Pramlintide, an injectable amylin mimetic given to patients on prandial insulin, can reduce postprandial glucose levels. The most common adverse effects are upper GI symptoms and hypoglycemia. Due to the adverse effects and the need for an injection with each meal, pramlintide is used infrequently.

Cardiovascular risk reduction

Has the ADA revised its recommendations for cardiovascular disease risk management?

Yes. There have been several changes. The first is in terminology, with atherosclerotic cardiovascular disease (ASCVD) replacing CVD alone. While new recommendations for statin therapy for adults older than 40 years (TABLE 2)¹ were also added, the emphasis remains on therapeutic lifestyle change as an effective treatment for hypertension. These modifications should include at least 150 minutes of moderate physical activity per week and, for most patients, a reduction in total calories, saturated fat, and sodium.

It is important to remind patients that to maximize the benefits in terms of treating hyperglycemia, hypertension, and dyslipidemia, such changes must be maintained over the long term.

Aspirin therapy. The ADA also revised its recommendation regarding aspirin therapy. Based on new evidence in the treatment of women with ASCVD risk, the standards now call for considering aspirin therapy (75-162 mg/d) in both women and men ≥50 years as a primary prevention strategy for those with type 1 or type 2 diabetes with a 10-year ASCVD risk of >10%. (The previous standards recommended this only for women older than 60 years.)

Antiplatelet therapy is now recommended for patients younger than 50 years with multiple risk factors, and as secondary prevention in those with a history of ASCVD.^19-21

Hypertension. The ADA’s recommendations for treating hypertension in patients with diabetes have not changed; the goal remains <140/<90 mm Hg. Lower targets may be appropriate for younger patients, those with albuminuria, and individuals with additional CVD risk factors; however, systolic pressure <130 mm Hg has not been shown to reduce CVD outcomes, and diastolic pressure <70 mm Hg has been associated with higher mortality.²²

Optimal medication and lifestyle therapy are important to achieve goals, with avoidance of undue treatment burden. Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), but not both, should be included as part of treatment. Other agents, such as a thiazide diuretic, may be needed to achieve individual goals. Serum creatinine/eGFR and serum potassium levels should be monitored with the use of diuretics.

Lipids. The 2016 standards include notable changes in lipid management. The ADA sees a role for ezetimibe for select patients, based on studies such as the IMPROVE IT trial²³ that included participants with diabetes. The ADA also added a table highlighting statin recommendations and delineating high and moderate-intensity statins (TABLE 3).¹ Those younger than 40 years with no other risk factors may not need a statin, but patients ages 40 or older will need moderate- to high-intensity statin therapy to effectively lower ASCVD risk.^24-28

These recommendations reflect a comprehensive plan to reduce ASCVD in this at-risk population, which should also include lifestyle modification, including smoking prevention and quit strategies, as needed.

Microvascular complications

DIABETIC KIDNEY DISEASE

How should I diagnose nephropathy?

The ADA changed the terminology, referring to “diabetic kidney disease” (DKD) rather than nephropathy to highlight the fact that the focus is on kidney disease directly linked to diabetes.

Other recommendations include an annual assessment of urinary albumin (eg, spot urine albumin-to-creatinine ratio and eGFR) for patients who have had type 1 diabetes for ≥5 years and all patients who have type 2 diabetes. Two out of 3 abnormal specimens collected within a 3- to 6-month period indicate the presence of albuminuria.

What can be done to prevent or slow the progression of DKD?

Optimal BP and glycemic control are key,^29-35 along with diet and medication. For patients with DKD, dietary protein intake should be 0.8 g/kg body weight per day. ACE inhibitors and ARBs have been shown to slow the decline in eGFR in patients with elevated urinary albumin excretion (≥30 mg/day).

The ADA sees a role for ezetimibe for select patients, based on studiessuch as the IMPROVE IT trial that included participants with diabetes.

However, neither an ACE inhibitor nor an ARB is recommended for the primary prevention of DKD in patients who have normal BP, normal urine albumin-to-creatinine ratio (<30 mg/g), and normal eGFR. In addition, combined use of an ACE inhibitor and an ARB should be avoided, as it provides no additional benefit and increases the risk of adverse effects.²⁹

RETINOPATHY

How should I manage retinopathy in patients with diabetes?

As with the management of DKD, it is important to optimize glycemic and BP control to reduce the risk, or slow the progression, of retinopathy. Intensive diabetes management, with the goal of achieving near-normal glycemic levels, has been shown in large prospective randomized studies to prevent or delay the onset and progression of diabetic retinopathy.^33,36 The presence of retinopathy is not a contraindication to aspirin therapy for ASCVD prevention, as aspirin does not increase the risk of retinal hemorrhage.

When should patients with diabetes be screened for retinopathy?

Patients with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years of the onset of diabetes. Those with type 2 diabetes should have such an exam shortly after diagnosis. The exam should be repeated annually; if there is no evidence of retinopathy, however, 2-year intervals may be considered.

PERIPHERAL NEUROPATHY

When and how should I screen patients with diabetes for neuropathy?

All patients should be screened for diabetic peripheral neuropathy (DPN) starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes, and continued at least annually thereafter. Assessment should include a detailed history and 10-g monofilament testing, as well as at least one of the following tests: pinprick, temperature, and vibration sensation.

It is important, too, to screen patients with more advanced diabetes for signs and symptoms of autonomic neuropathy. Signs and symptoms may include resting tachycardia, exercise intolerance, orthostatic hypotension, gastroparesis, constipation, impaired neurovascular function, and autonomic failure in response to hypoglycemia. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation.

How should I manage patients who have DPN?

Tight glycemic control is the only measure that has been shown to prevent or delay the development of DPN or cardiac autonomic neuropathy in patients with type 1 diabetes,^37,38 and to slow the progression of neuropathy in some patients with type 2 diabetes.³⁹

The FDA has approved pregabalin, duloxetine, and tapentadol for the treatment of pain associated with DPN. Tricyclic antidepressants, gabapentin, venlafaxine, carbamazepine, tramadol, and topical capsaicin, although not approved for the treatment of painful DPN, may also be effective in treating neuropathic pain.

For those with autonomic neuropathy, dietary changes and prokinetic agents such as erythromycin may alleviate gastroparesis. Due to extrapyramidal adverse effects, metoclopramide is reserved for the most severe and unresponsive cases. Recurrent urinary tract infections, pyelonephritis, incontinence, or palpable bladder should prompt an evaluation for bladder dysfunction. Controlling lipids and BP, quitting smoking, and making other lifestyle changes can reduce both the development and the progression of autonomic neuropathy.

The presence of retinopathy is not a contraindication to aspirin therapy for atherosclerotic cardiovascular disease prevention, as aspirin does not increase the risk of retinal hemorrhage.

FOOT CARE/PERIPHERAL ARTERIAL DISEASE

What does the ADA recommend regarding foot care for patients with diabetes?

The ADA’s standards recommend an annual comprehensive foot examination to identify risk factors predictive of ulcers and potential amputations. The exam should start with inspection and assessment of foot pulses and should seek to identify loss of peripheral sensation. The examination should include inspection of the skin, assessment of foot deformities, neurologic assessment including 10-g monofilament testing and pinprick or vibration testing or assessment of ankle reflexes, and vascular assessment, including pulses in the legs and feet.⁴⁰

It is also important to screen patients for peripheral arterial disease (PAD), with a comprehensive medical history and physical exam of pulses. Ankle-brachial index testing (ABI) should be performed in patients with signs or symptoms of PAD, including claudication or skin and hair changes in the lower extremities. ABI may be considered for all patients with diabetes starting at age 50 and in those younger than 50 years who have risk factors.⁴¹

Which patients with diabetes are at higher risk for foot complications?

The following are risk factors for foot complications: previous amputation, prior foot ulcer, peripheral neuropathy, foot deformity, peripheral vascular disease, visual impairment, peripheral neuropathy (especially if on dialysis), poor glycemic control, and smoking. Patients with high-risk foot conditions should be educated about their risk and appropriate management.

A well-fitted walking shoe that cushions the feet and redistributes pressure is one option to help patients. Patients with bony deformities may need extra wide or deep shoes and patients with more advanced disease may need custom-fitted shoes.

When should patients be referred to a foot specialist?

Refer patients to a foot care specialist for ongoing preventive care and lifelong surveillance if they smoke or have a history of lower-extremity complications, a loss of protective sensation, structural abnormalities, or PAD.

Prevention of diabetes, as well as early detection and treatment of both prediabetes and diabetes, is critical to the health of our country. Because evidence-based guidelines are key to our ability to effectively address the nation’s diabetes epidemic, the American Diabetes Association (ADA) updates its “Standards of Medical Care in Diabetes” annually to incorporate new evidence or clarifications.

The 2016 standards,¹ available at professional.diabetes.org/jfp, are a valuable resource. Among the latest revisions: an expansion in screening recommendations, a change in the age at which aspirin therapy for women should be considered, and a change in A1C goals for pregnant women with diabetes.

As members of the ADA’s primary care advisory group, we use a question and answer format in the summary that follows to highlight recent revisions and review other recommendations that are of particular relevance to physicians in primary care. It is important to note, however, that ADA recommendations are not intended to preclude clinical judgment and should be applied in the context of excellent medical care.

Diagnosis and screening

Have the 2016 ADA standards changed the way diabetes is diagnosed?

No. The criteria for a diagnosis of diabetes did not change. Diabetes and prediabetes are still screened for and diagnosed with any of the following: a fasting plasma glucose (FPG); a 2-hour 75-g oral glucose tolerance test (OGTT); a random plasma glucose >200 mg/dL with symptoms of hyperglycemia; or A1C criteria (TABLE 1).^1,2 The wording was changed, however, to make it clear that no one test is preferred over another for diagnosis.

Yes. In addition to screening asymptomatic adults of any age who are overweight or obese and have one or more additional risk factors for diabetes, the 2016 standards recommend screening all adults 45 years and older, regardless of weight.

Is an A1C <7% the recommended treatment goal for everyone with diabetes?

No. An A1C <7% is considered reasonable for most, but not all, nonpregnant adults. In the last few years, the ADA has focused more on individualized targets.

Tighter control (<6.5%)—which is associated with lower rates of eye disease, kidney disease, and nerve damage—may be appropriate for patients who have no significant hypoglycemia, no cardiovascular disease (CVD), a shorter duration of diabetes, or a longer expected lifespan.

Conversely, a higher target (<8%) may be appropriate for patients who are older, have longstanding diabetes, advanced macrovascular or microvascular disease, established complications, or a limited life expectancy.^3,4

The latest ADA revisions include an expansion in screening recommendations and changes in the age at which aspirin therapy for women should be considered and in A1C goals for pregnant women with diabetes.

Pregnancy. The 2016 standards have a new target for pregnant women with diabetes: The ADA previously recommended an A1C <6% for this patient population, but now recommends a target A1C between 6% and 6.5%. This may be tightened or relaxed, however, depending on individual risk of hypoglycemia.

In focusing on individualized targets and hypoglycemia avoidance, the ADA notes that attention must be paid to fasting, pre-meal, and post-meal blood glucose levels to achieve treatment goals. The 2016 standards emphasize the importance of patient-centered diabetes care, aligned with a coordinated, team-based chronic care model.

Diabetes self-management education and support is indicated for those who are newly diagnosed, and should be provided periodically based on glucose control and progression of the disease. All patients should receive education on hypoglycemia risk and treatment.

Prediabetes and prevention

What is prediabetes and what can I do to prevent patients with prediabetes from developing diabetes?

Patients with impaired glucose tolerance, impaired fasting glucose, or an A1C between 5.7% and 6.4% are considered to have prediabetes and are at risk for developing type 2 diabetes.

Family physicians should refer patients with prediabetes to intensive diet, physical activity, and behavioral counseling programs like those based on the Diabetes Prevention Program study (www.niddk.nih.gov/about-niddk/research-areas/diabetes/diabetes-prevention-program-dpp/Pages/default.aspx). Goals should include a minimum 7% weight loss and moderate-intensity physical activity, such as brisk walking, for at least 150 minutes per week.

For patients with diabetes, a sustained weight loss of 5% may improve glycemic control and reduce the need for medication.

Lifestyle modification programs have been shown to be very effective in preventing diabetes, with about a 58% reduction in the risk of developing type 2 diabetes after 3 years.⁵ The 2016 standards added a recommendation that physicians encourage the use of new technology, such as text messaging or smart phone apps, to support such efforts.

Should I consider initiating oral antiglycemics in patients with prediabetes?

Yes. Pharmacologic agents, including metformin, acarbose, and pioglitazone, have been shown to decrease progression from prediabetes to type 2 diabetes. Thus, antiglycemics should be considered for certain patients. Metformin is especially appropriate for women with a history of gestational diabetes, patients who are younger than 60 years, and those who have a body mass index (BMI) ≥35 kg/m².⁶

How often should I screen patients with prediabetes?

Patients with prediabetes should be screened annually. Such individuals should also be screened and treated for modifiable cardiovascular risk factors. There is strong evidence that the treatment of obesity can be beneficial for those at any stage of the diabetes spectrum.

© 2016 Joe Gorman

Obesity management

What do the 2016 ADA standards recommend for obese patients with diabetes?

With more than two-thirds of Americans either overweight or obese, the ADA added a new section on obesity management and calls on health care providers to:

• weigh patients and calculate and document their BMI at every visit, and
• counsel those who are overweight or obese on the benefits of even modest weight loss.

The ADA recommends a sustained weight loss of 5%, which can improve glycemic control and reduce the need for diabetes medications,^7-9 although weight loss of ≥7% is optimal. Physicians are also called on to assess each patient’s readiness to engage in therapeutic lifestyle change to maintain a modest weight loss.

Treatment for obesity can include therapeutic lifestyle change (reduction in calories, increase in physical activity) and behavioral therapy. For refractory patients, pharmacologic therapy and bariatric surgery may be considered.

Interventions should be high-intensity (≥16 sessions in 6 months) and focus on diet, physical activity, and behavioral strategies to achieve a 500 to 750 calorie deficit per day.¹⁰ Long-term (≥1 year) comprehensive weight maintenance programs should be prescribed for those who achieve short-term weight loss.^11,12 Such programs should provide at least monthly contact and encourage ongoing monitoring of body weight (weekly or more frequently), continued consumption of a reduced-calorie diet, and participation in high levels of physical activity (200 to 300 minutes per week).

Glycemic treatment

What are some of the key factors that distinguish the different type 2 diabetes medications from one another?

An increasing understanding of diabetes pathophysiology has led to a wider array of medications, making treatment more complex than ever. It is important for physicians to have a strong working knowledge of the various classes of antidiabetic agents and the subtleties between drugs in the same class to best individualize treatment.

Here are the highlights of each class of medication listed in the ADA/European Association for the Study of Diabetes algorithm for the management of type 2 diabetes,¹³ which is available at http://care.diabetesjournals.org/content/38/1/140/F2.large.jpg):

Metformin is the preferred initial medication for all patients who can tolerate it and have no contraindications. The drug is cost-effective, weight neutral, and has had positive cardiovascular and mortality outcomes in long-term studies. Adverse gastrointestinal (GI) effects, including nausea, diarrhea, and dyspepsia, are common but can be reduced with a slow titration of the drug. Metformin should be used with caution in those with renal disease. The dose should be reduced if the estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m² and the drug discontinued if eGFR <30 mL/min/1.73 m².

Sulfonylureas/meglitinides stimulate insulin secretion in a glucose-independent manner. They are cost-effective and have high efficacy early in the disease and with initial use, but the effect wanes as the disease progresses. This class of drugs is associated with weight gain and hypoglycemia. Second-generation sulfonylureas (glipizide, glimepiride) are recommended; meglitinides are more expensive than sulfonylureas.

Patients who fail to achieve or maintain their A1C goal after one year may need to begin insulin therapy.

Thiazolidinediones work to improve insulin sensitivity in the periphery and have a low risk of hypoglycemia. They have been associated with fluid retention, weight gain, and worsening of pre-existing congestive heart failure, but previous cardiovascular concerns (with rosiglitazone)¹⁴ and bladder cancer risks (with pioglitazone)^15-17 have been refuted. Thiazolidinediones are contraindicated in those with Class III and IV congestive heart failure, however, and patients taking them require careful monitoring for weight gain, fluid retention, and exacerbation of heart failure.

Dipeptidyl peptidase-4 inhibitors (DPP4Is) work to reduce the breakdown of endogenous incretin hormones. These oral agents increase insulin secretion in a glucose-dependent manner; more insulin is secreted when glucose is higher and less when glucose is closer to normal. This means that there is a much lower risk of hypoglycemia when a DPP4I is used as monotherapy.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs), which are injectable, also work via incretin hormones and stimulate insulin in a glucose-dependent manner. They are associated with weight loss and low rates of hypoglycemia. Adverse GI effects are common with this class of drugs, but can be reduced by titrating the medication and avoiding overeating. GLP-1RAs can be taken twice daily to once weekly, depending on the specific agent.

Sodium glucose transporter 2 inhibitors (SGLT2Is) are oral agents and the newest class of antidiabetes drugs. The drugs help block the reabsorption of glucose, thereby lowering glucose levels, blood pressure, and weight in many patients. The most common adverse effects are urinary tract and genital yeast infections. SGLT2Is should not be given to patients with advanced renal disease (chronic kidney disease Stages 3B-5) because they will not be effectively absorbed.

The US Food and Drug Administration (FDA) recently issued a warning about the risk of ketoacidosis with these agents,¹⁸ and patients should be advised to stop taking them and to seek immediate medical attention if they develop symptoms of ketoacidosis, such as excessive thirst, frequent urination, nausea and vomiting, abdominal pain, weakness or fatigue, shortness of breath, fruity-scented breath, or confusion.

Insulin is eventually needed by most patients with type 2 diabetes who live long enough to see the disease progress. The most common adverse effects are weight gain and hypoglycemia. There are many types of insulin, but only one that is delivered via inhalation—human insulin inhaled powder. Inhaled insulin, however, has the potential for adverse pulmonary effects, including cough and reduction of peak expiratory flow. Therefore, pulmonary function testing is recommended prior to its use.

Treatment goal attainment should be evaluated every 3 months, and treatment titrated at 3-month intervals if goals are not achieved. The ADA/European Association for the Study of Diabetes’ algorithm indicates that patients are likely to need insulin a year after diagnosis if their A1C goal has not been achieved or maintained.¹³

The following medications are not included in the algorithm but are included in the 2016 standards, and may be helpful for certain patients:

Alpha-glucosidase inhibitors delay the absorption of glucose from the proximal to distal GI tract, thereby reducing postprandial hyperglycemia. Flatulence and leakage of stool—the most common adverse effects—have limited their use in the United States.

Patients ≥40 years will need moderate- to high-intensity statin therapy to lower their atherosclerotic cardiovascular disease risk.

Bile acid sequestrants (colesevelam) treat both hyperlipidemia and diabetes. The medications work by reducing glucose absorption from the GI tract. They reduce postprandial hyperglycemia, with a low risk of hypoglycemia. Colesevelam’s use is limited, however, because of the number of pills needed (6 daily).

Bromocriptine affects satiety levels via the central nervous system, and is available in a specific formulation for the treatment of diabetes. “First-dose” hypotension, however, is an adverse effect of considerable concern.¹

Pramlintide, an injectable amylin mimetic given to patients on prandial insulin, can reduce postprandial glucose levels. The most common adverse effects are upper GI symptoms and hypoglycemia. Due to the adverse effects and the need for an injection with each meal, pramlintide is used infrequently.

Cardiovascular risk reduction

Has the ADA revised its recommendations for cardiovascular disease risk management?

Yes. There have been several changes. The first is in terminology, with atherosclerotic cardiovascular disease (ASCVD) replacing CVD alone. While new recommendations for statin therapy for adults older than 40 years (TABLE 2)¹ were also added, the emphasis remains on therapeutic lifestyle change as an effective treatment for hypertension. These modifications should include at least 150 minutes of moderate physical activity per week and, for most patients, a reduction in total calories, saturated fat, and sodium.

It is important to remind patients that to maximize the benefits in terms of treating hyperglycemia, hypertension, and dyslipidemia, such changes must be maintained over the long term.

Aspirin therapy. The ADA also revised its recommendation regarding aspirin therapy. Based on new evidence in the treatment of women with ASCVD risk, the standards now call for considering aspirin therapy (75-162 mg/d) in both women and men ≥50 years as a primary prevention strategy for those with type 1 or type 2 diabetes with a 10-year ASCVD risk of >10%. (The previous standards recommended this only for women older than 60 years.)

Antiplatelet therapy is now recommended for patients younger than 50 years with multiple risk factors, and as secondary prevention in those with a history of ASCVD.^19-21

Hypertension. The ADA’s recommendations for treating hypertension in patients with diabetes have not changed; the goal remains <140/<90 mm Hg. Lower targets may be appropriate for younger patients, those with albuminuria, and individuals with additional CVD risk factors; however, systolic pressure <130 mm Hg has not been shown to reduce CVD outcomes, and diastolic pressure <70 mm Hg has been associated with higher mortality.²²

Optimal medication and lifestyle therapy are important to achieve goals, with avoidance of undue treatment burden. Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), but not both, should be included as part of treatment. Other agents, such as a thiazide diuretic, may be needed to achieve individual goals. Serum creatinine/eGFR and serum potassium levels should be monitored with the use of diuretics.

Lipids. The 2016 standards include notable changes in lipid management. The ADA sees a role for ezetimibe for select patients, based on studies such as the IMPROVE IT trial²³ that included participants with diabetes. The ADA also added a table highlighting statin recommendations and delineating high and moderate-intensity statins (TABLE 3).¹ Those younger than 40 years with no other risk factors may not need a statin, but patients ages 40 or older will need moderate- to high-intensity statin therapy to effectively lower ASCVD risk.^24-28

These recommendations reflect a comprehensive plan to reduce ASCVD in this at-risk population, which should also include lifestyle modification, including smoking prevention and quit strategies, as needed.

Microvascular complications

DIABETIC KIDNEY DISEASE

How should I diagnose nephropathy?

The ADA changed the terminology, referring to “diabetic kidney disease” (DKD) rather than nephropathy to highlight the fact that the focus is on kidney disease directly linked to diabetes.

Other recommendations include an annual assessment of urinary albumin (eg, spot urine albumin-to-creatinine ratio and eGFR) for patients who have had type 1 diabetes for ≥5 years and all patients who have type 2 diabetes. Two out of 3 abnormal specimens collected within a 3- to 6-month period indicate the presence of albuminuria.

What can be done to prevent or slow the progression of DKD?

Optimal BP and glycemic control are key,^29-35 along with diet and medication. For patients with DKD, dietary protein intake should be 0.8 g/kg body weight per day. ACE inhibitors and ARBs have been shown to slow the decline in eGFR in patients with elevated urinary albumin excretion (≥30 mg/day).

The ADA sees a role for ezetimibe for select patients, based on studiessuch as the IMPROVE IT trial that included participants with diabetes.

However, neither an ACE inhibitor nor an ARB is recommended for the primary prevention of DKD in patients who have normal BP, normal urine albumin-to-creatinine ratio (<30 mg/g), and normal eGFR. In addition, combined use of an ACE inhibitor and an ARB should be avoided, as it provides no additional benefit and increases the risk of adverse effects.²⁹

RETINOPATHY

How should I manage retinopathy in patients with diabetes?

As with the management of DKD, it is important to optimize glycemic and BP control to reduce the risk, or slow the progression, of retinopathy. Intensive diabetes management, with the goal of achieving near-normal glycemic levels, has been shown in large prospective randomized studies to prevent or delay the onset and progression of diabetic retinopathy.^33,36 The presence of retinopathy is not a contraindication to aspirin therapy for ASCVD prevention, as aspirin does not increase the risk of retinal hemorrhage.

When should patients with diabetes be screened for retinopathy?

Patients with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years of the onset of diabetes. Those with type 2 diabetes should have such an exam shortly after diagnosis. The exam should be repeated annually; if there is no evidence of retinopathy, however, 2-year intervals may be considered.

PERIPHERAL NEUROPATHY

When and how should I screen patients with diabetes for neuropathy?

All patients should be screened for diabetic peripheral neuropathy (DPN) starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes, and continued at least annually thereafter. Assessment should include a detailed history and 10-g monofilament testing, as well as at least one of the following tests: pinprick, temperature, and vibration sensation.

It is important, too, to screen patients with more advanced diabetes for signs and symptoms of autonomic neuropathy. Signs and symptoms may include resting tachycardia, exercise intolerance, orthostatic hypotension, gastroparesis, constipation, impaired neurovascular function, and autonomic failure in response to hypoglycemia. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation.

How should I manage patients who have DPN?

Tight glycemic control is the only measure that has been shown to prevent or delay the development of DPN or cardiac autonomic neuropathy in patients with type 1 diabetes,^37,38 and to slow the progression of neuropathy in some patients with type 2 diabetes.³⁹

The FDA has approved pregabalin, duloxetine, and tapentadol for the treatment of pain associated with DPN. Tricyclic antidepressants, gabapentin, venlafaxine, carbamazepine, tramadol, and topical capsaicin, although not approved for the treatment of painful DPN, may also be effective in treating neuropathic pain.

For those with autonomic neuropathy, dietary changes and prokinetic agents such as erythromycin may alleviate gastroparesis. Due to extrapyramidal adverse effects, metoclopramide is reserved for the most severe and unresponsive cases. Recurrent urinary tract infections, pyelonephritis, incontinence, or palpable bladder should prompt an evaluation for bladder dysfunction. Controlling lipids and BP, quitting smoking, and making other lifestyle changes can reduce both the development and the progression of autonomic neuropathy.

The presence of retinopathy is not a contraindication to aspirin therapy for atherosclerotic cardiovascular disease prevention, as aspirin does not increase the risk of retinal hemorrhage.

FOOT CARE/PERIPHERAL ARTERIAL DISEASE

What does the ADA recommend regarding foot care for patients with diabetes?

The ADA’s standards recommend an annual comprehensive foot examination to identify risk factors predictive of ulcers and potential amputations. The exam should start with inspection and assessment of foot pulses and should seek to identify loss of peripheral sensation. The examination should include inspection of the skin, assessment of foot deformities, neurologic assessment including 10-g monofilament testing and pinprick or vibration testing or assessment of ankle reflexes, and vascular assessment, including pulses in the legs and feet.⁴⁰

It is also important to screen patients for peripheral arterial disease (PAD), with a comprehensive medical history and physical exam of pulses. Ankle-brachial index testing (ABI) should be performed in patients with signs or symptoms of PAD, including claudication or skin and hair changes in the lower extremities. ABI may be considered for all patients with diabetes starting at age 50 and in those younger than 50 years who have risk factors.⁴¹

Which patients with diabetes are at higher risk for foot complications?

The following are risk factors for foot complications: previous amputation, prior foot ulcer, peripheral neuropathy, foot deformity, peripheral vascular disease, visual impairment, peripheral neuropathy (especially if on dialysis), poor glycemic control, and smoking. Patients with high-risk foot conditions should be educated about their risk and appropriate management.

A well-fitted walking shoe that cushions the feet and redistributes pressure is one option to help patients. Patients with bony deformities may need extra wide or deep shoes and patients with more advanced disease may need custom-fitted shoes.

When should patients be referred to a foot specialist?

Refer patients to a foot care specialist for ongoing preventive care and lifelong surveillance if they smoke or have a history of lower-extremity complications, a loss of protective sensation, structural abnormalities, or PAD.

Prevention of diabetes, as well as early detection and treatment of both prediabetes and diabetes, is critical to the health of our country. Because evidence-based guidelines are key to our ability to effectively address the nation’s diabetes epidemic, the American Diabetes Association (ADA) updates its “Standards of Medical Care in Diabetes” annually to incorporate new evidence or clarifications.

The 2016 standards,¹ available at professional.diabetes.org/jfp, are a valuable resource. Among the latest revisions: an expansion in screening recommendations, a change in the age at which aspirin therapy for women should be considered, and a change in A1C goals for pregnant women with diabetes.

As members of the ADA’s primary care advisory group, we use a question and answer format in the summary that follows to highlight recent revisions and review other recommendations that are of particular relevance to physicians in primary care. It is important to note, however, that ADA recommendations are not intended to preclude clinical judgment and should be applied in the context of excellent medical care.

Diagnosis and screening

Have the 2016 ADA standards changed the way diabetes is diagnosed?

No. The criteria for a diagnosis of diabetes did not change. Diabetes and prediabetes are still screened for and diagnosed with any of the following: a fasting plasma glucose (FPG); a 2-hour 75-g oral glucose tolerance test (OGTT); a random plasma glucose >200 mg/dL with symptoms of hyperglycemia; or A1C criteria (TABLE 1).^1,2 The wording was changed, however, to make it clear that no one test is preferred over another for diagnosis.

Yes. In addition to screening asymptomatic adults of any age who are overweight or obese and have one or more additional risk factors for diabetes, the 2016 standards recommend screening all adults 45 years and older, regardless of weight.

Is an A1C <7% the recommended treatment goal for everyone with diabetes?

No. An A1C <7% is considered reasonable for most, but not all, nonpregnant adults. In the last few years, the ADA has focused more on individualized targets.

Tighter control (<6.5%)—which is associated with lower rates of eye disease, kidney disease, and nerve damage—may be appropriate for patients who have no significant hypoglycemia, no cardiovascular disease (CVD), a shorter duration of diabetes, or a longer expected lifespan.

Conversely, a higher target (<8%) may be appropriate for patients who are older, have longstanding diabetes, advanced macrovascular or microvascular disease, established complications, or a limited life expectancy.^3,4

The latest ADA revisions include an expansion in screening recommendations and changes in the age at which aspirin therapy for women should be considered and in A1C goals for pregnant women with diabetes.

Pregnancy. The 2016 standards have a new target for pregnant women with diabetes: The ADA previously recommended an A1C <6% for this patient population, but now recommends a target A1C between 6% and 6.5%. This may be tightened or relaxed, however, depending on individual risk of hypoglycemia.

In focusing on individualized targets and hypoglycemia avoidance, the ADA notes that attention must be paid to fasting, pre-meal, and post-meal blood glucose levels to achieve treatment goals. The 2016 standards emphasize the importance of patient-centered diabetes care, aligned with a coordinated, team-based chronic care model.

Diabetes self-management education and support is indicated for those who are newly diagnosed, and should be provided periodically based on glucose control and progression of the disease. All patients should receive education on hypoglycemia risk and treatment.

Prediabetes and prevention

What is prediabetes and what can I do to prevent patients with prediabetes from developing diabetes?

Patients with impaired glucose tolerance, impaired fasting glucose, or an A1C between 5.7% and 6.4% are considered to have prediabetes and are at risk for developing type 2 diabetes.

Family physicians should refer patients with prediabetes to intensive diet, physical activity, and behavioral counseling programs like those based on the Diabetes Prevention Program study (www.niddk.nih.gov/about-niddk/research-areas/diabetes/diabetes-prevention-program-dpp/Pages/default.aspx). Goals should include a minimum 7% weight loss and moderate-intensity physical activity, such as brisk walking, for at least 150 minutes per week.

For patients with diabetes, a sustained weight loss of 5% may improve glycemic control and reduce the need for medication.

Lifestyle modification programs have been shown to be very effective in preventing diabetes, with about a 58% reduction in the risk of developing type 2 diabetes after 3 years.⁵ The 2016 standards added a recommendation that physicians encourage the use of new technology, such as text messaging or smart phone apps, to support such efforts.

Should I consider initiating oral antiglycemics in patients with prediabetes?

Yes. Pharmacologic agents, including metformin, acarbose, and pioglitazone, have been shown to decrease progression from prediabetes to type 2 diabetes. Thus, antiglycemics should be considered for certain patients. Metformin is especially appropriate for women with a history of gestational diabetes, patients who are younger than 60 years, and those who have a body mass index (BMI) ≥35 kg/m².⁶

How often should I screen patients with prediabetes?

Patients with prediabetes should be screened annually. Such individuals should also be screened and treated for modifiable cardiovascular risk factors. There is strong evidence that the treatment of obesity can be beneficial for those at any stage of the diabetes spectrum.

© 2016 Joe Gorman

Obesity management

What do the 2016 ADA standards recommend for obese patients with diabetes?

With more than two-thirds of Americans either overweight or obese, the ADA added a new section on obesity management and calls on health care providers to:

• weigh patients and calculate and document their BMI at every visit, and
• counsel those who are overweight or obese on the benefits of even modest weight loss.

The ADA recommends a sustained weight loss of 5%, which can improve glycemic control and reduce the need for diabetes medications,^7-9 although weight loss of ≥7% is optimal. Physicians are also called on to assess each patient’s readiness to engage in therapeutic lifestyle change to maintain a modest weight loss.

Treatment for obesity can include therapeutic lifestyle change (reduction in calories, increase in physical activity) and behavioral therapy. For refractory patients, pharmacologic therapy and bariatric surgery may be considered.

Interventions should be high-intensity (≥16 sessions in 6 months) and focus on diet, physical activity, and behavioral strategies to achieve a 500 to 750 calorie deficit per day.¹⁰ Long-term (≥1 year) comprehensive weight maintenance programs should be prescribed for those who achieve short-term weight loss.^11,12 Such programs should provide at least monthly contact and encourage ongoing monitoring of body weight (weekly or more frequently), continued consumption of a reduced-calorie diet, and participation in high levels of physical activity (200 to 300 minutes per week).

Glycemic treatment

What are some of the key factors that distinguish the different type 2 diabetes medications from one another?

An increasing understanding of diabetes pathophysiology has led to a wider array of medications, making treatment more complex than ever. It is important for physicians to have a strong working knowledge of the various classes of antidiabetic agents and the subtleties between drugs in the same class to best individualize treatment.

Here are the highlights of each class of medication listed in the ADA/European Association for the Study of Diabetes algorithm for the management of type 2 diabetes,¹³ which is available at http://care.diabetesjournals.org/content/38/1/140/F2.large.jpg):

Metformin is the preferred initial medication for all patients who can tolerate it and have no contraindications. The drug is cost-effective, weight neutral, and has had positive cardiovascular and mortality outcomes in long-term studies. Adverse gastrointestinal (GI) effects, including nausea, diarrhea, and dyspepsia, are common but can be reduced with a slow titration of the drug. Metformin should be used with caution in those with renal disease. The dose should be reduced if the estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m² and the drug discontinued if eGFR <30 mL/min/1.73 m².

Sulfonylureas/meglitinides stimulate insulin secretion in a glucose-independent manner. They are cost-effective and have high efficacy early in the disease and with initial use, but the effect wanes as the disease progresses. This class of drugs is associated with weight gain and hypoglycemia. Second-generation sulfonylureas (glipizide, glimepiride) are recommended; meglitinides are more expensive than sulfonylureas.

Patients who fail to achieve or maintain their A1C goal after one year may need to begin insulin therapy.

Thiazolidinediones work to improve insulin sensitivity in the periphery and have a low risk of hypoglycemia. They have been associated with fluid retention, weight gain, and worsening of pre-existing congestive heart failure, but previous cardiovascular concerns (with rosiglitazone)¹⁴ and bladder cancer risks (with pioglitazone)^15-17 have been refuted. Thiazolidinediones are contraindicated in those with Class III and IV congestive heart failure, however, and patients taking them require careful monitoring for weight gain, fluid retention, and exacerbation of heart failure.

Dipeptidyl peptidase-4 inhibitors (DPP4Is) work to reduce the breakdown of endogenous incretin hormones. These oral agents increase insulin secretion in a glucose-dependent manner; more insulin is secreted when glucose is higher and less when glucose is closer to normal. This means that there is a much lower risk of hypoglycemia when a DPP4I is used as monotherapy.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs), which are injectable, also work via incretin hormones and stimulate insulin in a glucose-dependent manner. They are associated with weight loss and low rates of hypoglycemia. Adverse GI effects are common with this class of drugs, but can be reduced by titrating the medication and avoiding overeating. GLP-1RAs can be taken twice daily to once weekly, depending on the specific agent.

Sodium glucose transporter 2 inhibitors (SGLT2Is) are oral agents and the newest class of antidiabetes drugs. The drugs help block the reabsorption of glucose, thereby lowering glucose levels, blood pressure, and weight in many patients. The most common adverse effects are urinary tract and genital yeast infections. SGLT2Is should not be given to patients with advanced renal disease (chronic kidney disease Stages 3B-5) because they will not be effectively absorbed.

The US Food and Drug Administration (FDA) recently issued a warning about the risk of ketoacidosis with these agents,¹⁸ and patients should be advised to stop taking them and to seek immediate medical attention if they develop symptoms of ketoacidosis, such as excessive thirst, frequent urination, nausea and vomiting, abdominal pain, weakness or fatigue, shortness of breath, fruity-scented breath, or confusion.

Insulin is eventually needed by most patients with type 2 diabetes who live long enough to see the disease progress. The most common adverse effects are weight gain and hypoglycemia. There are many types of insulin, but only one that is delivered via inhalation—human insulin inhaled powder. Inhaled insulin, however, has the potential for adverse pulmonary effects, including cough and reduction of peak expiratory flow. Therefore, pulmonary function testing is recommended prior to its use.

Treatment goal attainment should be evaluated every 3 months, and treatment titrated at 3-month intervals if goals are not achieved. The ADA/European Association for the Study of Diabetes’ algorithm indicates that patients are likely to need insulin a year after diagnosis if their A1C goal has not been achieved or maintained.¹³

The following medications are not included in the algorithm but are included in the 2016 standards, and may be helpful for certain patients:

Alpha-glucosidase inhibitors delay the absorption of glucose from the proximal to distal GI tract, thereby reducing postprandial hyperglycemia. Flatulence and leakage of stool—the most common adverse effects—have limited their use in the United States.

Patients ≥40 years will need moderate- to high-intensity statin therapy to lower their atherosclerotic cardiovascular disease risk.

Bile acid sequestrants (colesevelam) treat both hyperlipidemia and diabetes. The medications work by reducing glucose absorption from the GI tract. They reduce postprandial hyperglycemia, with a low risk of hypoglycemia. Colesevelam’s use is limited, however, because of the number of pills needed (6 daily).

Bromocriptine affects satiety levels via the central nervous system, and is available in a specific formulation for the treatment of diabetes. “First-dose” hypotension, however, is an adverse effect of considerable concern.¹

Pramlintide, an injectable amylin mimetic given to patients on prandial insulin, can reduce postprandial glucose levels. The most common adverse effects are upper GI symptoms and hypoglycemia. Due to the adverse effects and the need for an injection with each meal, pramlintide is used infrequently.

Cardiovascular risk reduction

Has the ADA revised its recommendations for cardiovascular disease risk management?

Yes. There have been several changes. The first is in terminology, with atherosclerotic cardiovascular disease (ASCVD) replacing CVD alone. While new recommendations for statin therapy for adults older than 40 years (TABLE 2)¹ were also added, the emphasis remains on therapeutic lifestyle change as an effective treatment for hypertension. These modifications should include at least 150 minutes of moderate physical activity per week and, for most patients, a reduction in total calories, saturated fat, and sodium.

It is important to remind patients that to maximize the benefits in terms of treating hyperglycemia, hypertension, and dyslipidemia, such changes must be maintained over the long term.

Aspirin therapy. The ADA also revised its recommendation regarding aspirin therapy. Based on new evidence in the treatment of women with ASCVD risk, the standards now call for considering aspirin therapy (75-162 mg/d) in both women and men ≥50 years as a primary prevention strategy for those with type 1 or type 2 diabetes with a 10-year ASCVD risk of >10%. (The previous standards recommended this only for women older than 60 years.)

Antiplatelet therapy is now recommended for patients younger than 50 years with multiple risk factors, and as secondary prevention in those with a history of ASCVD.^19-21

Hypertension. The ADA’s recommendations for treating hypertension in patients with diabetes have not changed; the goal remains <140/<90 mm Hg. Lower targets may be appropriate for younger patients, those with albuminuria, and individuals with additional CVD risk factors; however, systolic pressure <130 mm Hg has not been shown to reduce CVD outcomes, and diastolic pressure <70 mm Hg has been associated with higher mortality.²²

Optimal medication and lifestyle therapy are important to achieve goals, with avoidance of undue treatment burden. Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), but not both, should be included as part of treatment. Other agents, such as a thiazide diuretic, may be needed to achieve individual goals. Serum creatinine/eGFR and serum potassium levels should be monitored with the use of diuretics.

Lipids. The 2016 standards include notable changes in lipid management. The ADA sees a role for ezetimibe for select patients, based on studies such as the IMPROVE IT trial²³ that included participants with diabetes. The ADA also added a table highlighting statin recommendations and delineating high and moderate-intensity statins (TABLE 3).¹ Those younger than 40 years with no other risk factors may not need a statin, but patients ages 40 or older will need moderate- to high-intensity statin therapy to effectively lower ASCVD risk.^24-28

These recommendations reflect a comprehensive plan to reduce ASCVD in this at-risk population, which should also include lifestyle modification, including smoking prevention and quit strategies, as needed.

Microvascular complications

DIABETIC KIDNEY DISEASE

How should I diagnose nephropathy?

The ADA changed the terminology, referring to “diabetic kidney disease” (DKD) rather than nephropathy to highlight the fact that the focus is on kidney disease directly linked to diabetes.

Other recommendations include an annual assessment of urinary albumin (eg, spot urine albumin-to-creatinine ratio and eGFR) for patients who have had type 1 diabetes for ≥5 years and all patients who have type 2 diabetes. Two out of 3 abnormal specimens collected within a 3- to 6-month period indicate the presence of albuminuria.

What can be done to prevent or slow the progression of DKD?

Optimal BP and glycemic control are key,^29-35 along with diet and medication. For patients with DKD, dietary protein intake should be 0.8 g/kg body weight per day. ACE inhibitors and ARBs have been shown to slow the decline in eGFR in patients with elevated urinary albumin excretion (≥30 mg/day).

The ADA sees a role for ezetimibe for select patients, based on studiessuch as the IMPROVE IT trial that included participants with diabetes.

However, neither an ACE inhibitor nor an ARB is recommended for the primary prevention of DKD in patients who have normal BP, normal urine albumin-to-creatinine ratio (<30 mg/g), and normal eGFR. In addition, combined use of an ACE inhibitor and an ARB should be avoided, as it provides no additional benefit and increases the risk of adverse effects.²⁹

RETINOPATHY

How should I manage retinopathy in patients with diabetes?

As with the management of DKD, it is important to optimize glycemic and BP control to reduce the risk, or slow the progression, of retinopathy. Intensive diabetes management, with the goal of achieving near-normal glycemic levels, has been shown in large prospective randomized studies to prevent or delay the onset and progression of diabetic retinopathy.^33,36 The presence of retinopathy is not a contraindication to aspirin therapy for ASCVD prevention, as aspirin does not increase the risk of retinal hemorrhage.

When should patients with diabetes be screened for retinopathy?

Patients with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years of the onset of diabetes. Those with type 2 diabetes should have such an exam shortly after diagnosis. The exam should be repeated annually; if there is no evidence of retinopathy, however, 2-year intervals may be considered.

PERIPHERAL NEUROPATHY

When and how should I screen patients with diabetes for neuropathy?

All patients should be screened for diabetic peripheral neuropathy (DPN) starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes, and continued at least annually thereafter. Assessment should include a detailed history and 10-g monofilament testing, as well as at least one of the following tests: pinprick, temperature, and vibration sensation.

It is important, too, to screen patients with more advanced diabetes for signs and symptoms of autonomic neuropathy. Signs and symptoms may include resting tachycardia, exercise intolerance, orthostatic hypotension, gastroparesis, constipation, impaired neurovascular function, and autonomic failure in response to hypoglycemia. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation.

How should I manage patients who have DPN?

Tight glycemic control is the only measure that has been shown to prevent or delay the development of DPN or cardiac autonomic neuropathy in patients with type 1 diabetes,^37,38 and to slow the progression of neuropathy in some patients with type 2 diabetes.³⁹

The FDA has approved pregabalin, duloxetine, and tapentadol for the treatment of pain associated with DPN. Tricyclic antidepressants, gabapentin, venlafaxine, carbamazepine, tramadol, and topical capsaicin, although not approved for the treatment of painful DPN, may also be effective in treating neuropathic pain.

For those with autonomic neuropathy, dietary changes and prokinetic agents such as erythromycin may alleviate gastroparesis. Due to extrapyramidal adverse effects, metoclopramide is reserved for the most severe and unresponsive cases. Recurrent urinary tract infections, pyelonephritis, incontinence, or palpable bladder should prompt an evaluation for bladder dysfunction. Controlling lipids and BP, quitting smoking, and making other lifestyle changes can reduce both the development and the progression of autonomic neuropathy.

The presence of retinopathy is not a contraindication to aspirin therapy for atherosclerotic cardiovascular disease prevention, as aspirin does not increase the risk of retinal hemorrhage.

FOOT CARE/PERIPHERAL ARTERIAL DISEASE

What does the ADA recommend regarding foot care for patients with diabetes?

The ADA’s standards recommend an annual comprehensive foot examination to identify risk factors predictive of ulcers and potential amputations. The exam should start with inspection and assessment of foot pulses and should seek to identify loss of peripheral sensation. The examination should include inspection of the skin, assessment of foot deformities, neurologic assessment including 10-g monofilament testing and pinprick or vibration testing or assessment of ankle reflexes, and vascular assessment, including pulses in the legs and feet.⁴⁰

It is also important to screen patients for peripheral arterial disease (PAD), with a comprehensive medical history and physical exam of pulses. Ankle-brachial index testing (ABI) should be performed in patients with signs or symptoms of PAD, including claudication or skin and hair changes in the lower extremities. ABI may be considered for all patients with diabetes starting at age 50 and in those younger than 50 years who have risk factors.⁴¹

Which patients with diabetes are at higher risk for foot complications?

The following are risk factors for foot complications: previous amputation, prior foot ulcer, peripheral neuropathy, foot deformity, peripheral vascular disease, visual impairment, peripheral neuropathy (especially if on dialysis), poor glycemic control, and smoking. Patients with high-risk foot conditions should be educated about their risk and appropriate management.

A well-fitted walking shoe that cushions the feet and redistributes pressure is one option to help patients. Patients with bony deformities may need extra wide or deep shoes and patients with more advanced disease may need custom-fitted shoes.

When should patients be referred to a foot specialist?

Refer patients to a foot care specialist for ongoing preventive care and lifelong surveillance if they smoke or have a history of lower-extremity complications, a loss of protective sensation, structural abnormalities, or PAD.