Vitiligo is an acquired idiopathic disease of unknown etiology. Characterized by depigmented maculae and melanocytic destruction, it usually presents in childhood or young adulthood. The incidence of vitiligo ranges from 0.5% to 2% globally and there is no racial or gender predilection.¹

Patients with vitiligo may exhibit pigmentary abnormalities of the iris and retina.² Noninflammatory depigmented lesions of the ocular fundus observed in vitiligo indicate a local loss of melanocytes.¹ The fact that melanocytes are present not only in the skin and roots of the hair but also in the uvea and stria vascularis of the inner ear may explain the ophthalmologic disorders that accompany vitiligo.³ The term glaucoma refers to a large number of diseases that share a common feature: a distinctive and progressive optic neuropathy that may derive from various risks and is associated with a gradual loss of the visual field. If the disorder is not diagnosed and treated properly it could cause blindness.

Glaucoma is classified on the basis of the underlying abnormality that causes intraocular pressure (IOP) to rise. Glaucoma is first divided into open-angle and angle-closure glaucoma; glaucoma associated with developmental anomalies is then subdivided according to specific alterations.⁴

A PubMed search of articles indexed for MEDLINE using the terms vitiligo and glaucoma revealed only 1 study examining the incidence of glaucoma in patients with vitiligo.⁵ In the study reported here, we determined the presence of and possible risk factors for glaucoma in patients with vitiligo who had presented to the dermatology polyclinic.

Methods

We registered 49 patients diagnosed with vitiligo by clinical and Wood light examination and 20 age- and sex-matched healthy controls. Patients who were using topical corticosteroid treatments for vitiligo lesions located on the face were excluded from the study due to the glaucoma-inducing effects of corticosteroids. Similarly, patients who received drugs with sympathetic and parasympathetic action that can cause glaucoma were excluded.

The patients received a comprehensive ophthalmologic examination that included visual acuity testing, refraction, IOP measurement, gonioscopy, and fundus examination. All patients and controls underwent visual field tests and optic nerve head analyses using a confocal scanning laser ophthalmoscope. Glaucoma was diagnosed based on fundus examination, IOP measurement, field of vision evaluation, and optic nerve head analysis.

Informed consent was obtained from all participants. The research protocol was approved by the university hospital ethics committee.

Results

The study registered a total of 49 patients with vitiligo (28 female; 21 male) and 20 healthy controls (10 female; 10 male) with a variety of demographic and clinical characteristics (Table 1).

Mean (SD) IOP values were 13.83 (2.84) mm Hg for the right eye and 13.89 (2.60) mm Hg for the left eye in the vitiligo group. Values were 14.35 (2.56) mm Hg and 14.95 (2.92) mm Hg, respectively, in the control group. The IOP differences between the 2 groups were not statistically significant (P>.05).

Nine patients (18.4%) in the vitiligo group were found to have signs of normal-tension glaucoma (NTG). Optic nerve damage and vision loss occurs in the presence of normal IOP in NTG. There were no signs of NTG in the control group. Normal-tension glaucoma was diagnosed in the vitiligo group based on glaucomatous optic disc appearance, visual field defects, and structural analysis of the entire optic nerve head in confocal scanning laser ophthalmoscope. The NTG difference between the vitiligo and control groups was statistically significant (P=.04).

In the vitiligo group, of the 9 patients who had NTG, 6 had periorbital vitiligo lesions; the remaining 3 had none. Although patients who had periorbital lesions had a higher rate of glaucoma relative to the patients without periorbital lesions, the difference was not statistically significant (P>.05).

No statistically significant differences (P>.05) were found between patients with vitiligo with and without glaucoma in terms of age, sex, disease duration, family history of vitiligo, presence or absence of periorbital involvement, manner of involvement, percentage of the involved body areas, and IOP (Table 1).

Comment

Glaucoma is characterized by increased IOP, visual field loss, and changes in the optic nerve head. Although elevated IOP is common in ocular hypertension as well as in glaucoma, there is no glaucomatous visual field loss in ocular hypertension. In NTG, on the other hand, glaucomatous visual field loss and optic nerve head changes occur without an increase in IOP.⁶ Normal-tension glaucoma is a particular type of open-angle glaucoma. It is believed that NTG and high-tension glaucoma induce optic nerve head damage through different means.⁷ Alternative theories have been put forth to account for the glaucomatous damage to the optic nerve head that occurs in NTG, despite normal or close to normal IOP. These theories include vascular disorders (eg, ischemia, which interrupts the orthograde or retrograde axonal transport), excessive accumulation of free radicals, triggering of apoptosis, and low resistance of lamina cribrosa.⁸

Although there are various studies exploring ocular symptoms in patients with vitiligo,^9-15 only 1 study has examined the incidence of glaucoma in this group of patients.⁵ Biswas et al¹¹ examined ocular signs in 100 patients with vitiligo and found that 23% of patients had hypopigmented foci in the iris, 18% had pigmentation in the anterior chamber, 11% had chorioretinal degeneration, 9% had hypopigmentation of the retinal pigment epithelium, 5% had uveitis, and 34% were evaluated as normal. In this study, the authors concluded that there was a strong relationship between vitiligo and eye diseases.¹¹ When Gopal et al⁹ compared the eye examinations of 150 vitiligo patients and 100 healthy controls, they found uveitis, iris, and retinal pigmentary abnormalities in 16% of the vitiligo patients (P<.001).

Rogosić et al⁵ examined the incidence of glaucoma in 42 patients with vitiligo and found primary open-angle glaucoma in 24 (57%) patients. The patients had a mean age of 56 years, mean disease duration of 13 years, and mean IOP of 18 mm Hg for the right eye and 17.5 mm Hg for the left eye. The incidence of glaucoma was significantly higher in patients with vitiligo (P<.001) and increased with disease duration.⁵

Similar studies, however, have failed to show a relationship between vitiligo and glaucoma. In a study that evaluated the retinal pigment epithelium and the optic nerve in patients with vitiligo, Perossini et al¹⁰ found that the fundus examination of the patients was perfectly normal.

In our study, we detected NTG in 18.4% of patients with vitiligo. We did not find a significant statistical difference between patients with and without glaucoma (Table 2). Rogosić et al⁵ found a significant relationship between age and glaucoma incidence, but we did not find such a relationship, which we believe is because the mean age of our patients was lower than the prior study.

In vitiligo, melanocytes are destroyed through an unknown mechanism. Although the cellular and molecular mechanisms causing melanocytic destruction have not yet been determined, various hypotheses have been put forward to explain the etiopathogenesis of vitiligo. Among these, the most commonly held hypotheses are the neural, self-destruction, and autoimmune hypotheses.¹⁶

Based on the observation that stress and serious trauma could precipitate or trigger the onset of vitiligo,¹⁶ the neural hypothesis holds that neurochemical mediators released from the edges of the nerve endings exert toxic effects on melanocytes. The fact that both melanocytes and choroidal pigment cells originate from the mesenchyme and dermatomal spreading of segmental vitiligo are arguments propounded in favor of this hypothesis.¹⁷

The self-destruction hypothesis suggests that the intrinsic protective mechanisms that normally enable melanocytes to eliminate toxic intermediate products or metabolites on the melanogenesis path have been impaired in patients with vitiligo.^18,19 There is evidence of increased oxidative stress over the whole epidermis of patients with vitiligo.²⁰ Thus, free radicals affect melanin and cause membrane damage via lipid peroxidation reactions.²¹

The autoimmune hypothesis proposes a clinical relationship between vitiligo and several diseases believed to be autoimmune. Because the macrophage infiltration observed in vitiligo lesions is more pronounced on the perilesional skin, this hypothesis holds that macrophages may play a role in melanocyte removal.²¹ The Koebner phenomenon observed in vitiligo lends support to the critical role of trauma in the etiopathogenesis of the disease.

Although we could not explain the co-presence of vitiligo and glaucoma, we believe that it may result from the fact that both diseases are observed in tissues that have the same embryologic origin and etiology, perhaps vascular or neural disorders, excessive accumulation of free radicals, or the triggering of apoptosis. Dermatologists should be alert to the presence of glaucoma in patients with vitiligo because glaucoma is an eye disease that progresses slowly and may lead to vision loss.

Vitiligo is an acquired idiopathic disease of unknown etiology. Characterized by depigmented maculae and melanocytic destruction, it usually presents in childhood or young adulthood. The incidence of vitiligo ranges from 0.5% to 2% globally and there is no racial or gender predilection.¹

Patients with vitiligo may exhibit pigmentary abnormalities of the iris and retina.² Noninflammatory depigmented lesions of the ocular fundus observed in vitiligo indicate a local loss of melanocytes.¹ The fact that melanocytes are present not only in the skin and roots of the hair but also in the uvea and stria vascularis of the inner ear may explain the ophthalmologic disorders that accompany vitiligo.³ The term glaucoma refers to a large number of diseases that share a common feature: a distinctive and progressive optic neuropathy that may derive from various risks and is associated with a gradual loss of the visual field. If the disorder is not diagnosed and treated properly it could cause blindness.

Glaucoma is classified on the basis of the underlying abnormality that causes intraocular pressure (IOP) to rise. Glaucoma is first divided into open-angle and angle-closure glaucoma; glaucoma associated with developmental anomalies is then subdivided according to specific alterations.⁴

A PubMed search of articles indexed for MEDLINE using the terms vitiligo and glaucoma revealed only 1 study examining the incidence of glaucoma in patients with vitiligo.⁵ In the study reported here, we determined the presence of and possible risk factors for glaucoma in patients with vitiligo who had presented to the dermatology polyclinic.

Methods

We registered 49 patients diagnosed with vitiligo by clinical and Wood light examination and 20 age- and sex-matched healthy controls. Patients who were using topical corticosteroid treatments for vitiligo lesions located on the face were excluded from the study due to the glaucoma-inducing effects of corticosteroids. Similarly, patients who received drugs with sympathetic and parasympathetic action that can cause glaucoma were excluded.

The patients received a comprehensive ophthalmologic examination that included visual acuity testing, refraction, IOP measurement, gonioscopy, and fundus examination. All patients and controls underwent visual field tests and optic nerve head analyses using a confocal scanning laser ophthalmoscope. Glaucoma was diagnosed based on fundus examination, IOP measurement, field of vision evaluation, and optic nerve head analysis.

Informed consent was obtained from all participants. The research protocol was approved by the university hospital ethics committee.

Results

The study registered a total of 49 patients with vitiligo (28 female; 21 male) and 20 healthy controls (10 female; 10 male) with a variety of demographic and clinical characteristics (Table 1).

Mean (SD) IOP values were 13.83 (2.84) mm Hg for the right eye and 13.89 (2.60) mm Hg for the left eye in the vitiligo group. Values were 14.35 (2.56) mm Hg and 14.95 (2.92) mm Hg, respectively, in the control group. The IOP differences between the 2 groups were not statistically significant (P>.05).

Nine patients (18.4%) in the vitiligo group were found to have signs of normal-tension glaucoma (NTG). Optic nerve damage and vision loss occurs in the presence of normal IOP in NTG. There were no signs of NTG in the control group. Normal-tension glaucoma was diagnosed in the vitiligo group based on glaucomatous optic disc appearance, visual field defects, and structural analysis of the entire optic nerve head in confocal scanning laser ophthalmoscope. The NTG difference between the vitiligo and control groups was statistically significant (P=.04).

In the vitiligo group, of the 9 patients who had NTG, 6 had periorbital vitiligo lesions; the remaining 3 had none. Although patients who had periorbital lesions had a higher rate of glaucoma relative to the patients without periorbital lesions, the difference was not statistically significant (P>.05).

No statistically significant differences (P>.05) were found between patients with vitiligo with and without glaucoma in terms of age, sex, disease duration, family history of vitiligo, presence or absence of periorbital involvement, manner of involvement, percentage of the involved body areas, and IOP (Table 1).

Comment

Glaucoma is characterized by increased IOP, visual field loss, and changes in the optic nerve head. Although elevated IOP is common in ocular hypertension as well as in glaucoma, there is no glaucomatous visual field loss in ocular hypertension. In NTG, on the other hand, glaucomatous visual field loss and optic nerve head changes occur without an increase in IOP.⁶ Normal-tension glaucoma is a particular type of open-angle glaucoma. It is believed that NTG and high-tension glaucoma induce optic nerve head damage through different means.⁷ Alternative theories have been put forth to account for the glaucomatous damage to the optic nerve head that occurs in NTG, despite normal or close to normal IOP. These theories include vascular disorders (eg, ischemia, which interrupts the orthograde or retrograde axonal transport), excessive accumulation of free radicals, triggering of apoptosis, and low resistance of lamina cribrosa.⁸

Although there are various studies exploring ocular symptoms in patients with vitiligo,^9-15 only 1 study has examined the incidence of glaucoma in this group of patients.⁵ Biswas et al¹¹ examined ocular signs in 100 patients with vitiligo and found that 23% of patients had hypopigmented foci in the iris, 18% had pigmentation in the anterior chamber, 11% had chorioretinal degeneration, 9% had hypopigmentation of the retinal pigment epithelium, 5% had uveitis, and 34% were evaluated as normal. In this study, the authors concluded that there was a strong relationship between vitiligo and eye diseases.¹¹ When Gopal et al⁹ compared the eye examinations of 150 vitiligo patients and 100 healthy controls, they found uveitis, iris, and retinal pigmentary abnormalities in 16% of the vitiligo patients (P<.001).

Rogosić et al⁵ examined the incidence of glaucoma in 42 patients with vitiligo and found primary open-angle glaucoma in 24 (57%) patients. The patients had a mean age of 56 years, mean disease duration of 13 years, and mean IOP of 18 mm Hg for the right eye and 17.5 mm Hg for the left eye. The incidence of glaucoma was significantly higher in patients with vitiligo (P<.001) and increased with disease duration.⁵

Similar studies, however, have failed to show a relationship between vitiligo and glaucoma. In a study that evaluated the retinal pigment epithelium and the optic nerve in patients with vitiligo, Perossini et al¹⁰ found that the fundus examination of the patients was perfectly normal.

In our study, we detected NTG in 18.4% of patients with vitiligo. We did not find a significant statistical difference between patients with and without glaucoma (Table 2). Rogosić et al⁵ found a significant relationship between age and glaucoma incidence, but we did not find such a relationship, which we believe is because the mean age of our patients was lower than the prior study.

In vitiligo, melanocytes are destroyed through an unknown mechanism. Although the cellular and molecular mechanisms causing melanocytic destruction have not yet been determined, various hypotheses have been put forward to explain the etiopathogenesis of vitiligo. Among these, the most commonly held hypotheses are the neural, self-destruction, and autoimmune hypotheses.¹⁶

Based on the observation that stress and serious trauma could precipitate or trigger the onset of vitiligo,¹⁶ the neural hypothesis holds that neurochemical mediators released from the edges of the nerve endings exert toxic effects on melanocytes. The fact that both melanocytes and choroidal pigment cells originate from the mesenchyme and dermatomal spreading of segmental vitiligo are arguments propounded in favor of this hypothesis.¹⁷

The self-destruction hypothesis suggests that the intrinsic protective mechanisms that normally enable melanocytes to eliminate toxic intermediate products or metabolites on the melanogenesis path have been impaired in patients with vitiligo.^18,19 There is evidence of increased oxidative stress over the whole epidermis of patients with vitiligo.²⁰ Thus, free radicals affect melanin and cause membrane damage via lipid peroxidation reactions.²¹

The autoimmune hypothesis proposes a clinical relationship between vitiligo and several diseases believed to be autoimmune. Because the macrophage infiltration observed in vitiligo lesions is more pronounced on the perilesional skin, this hypothesis holds that macrophages may play a role in melanocyte removal.²¹ The Koebner phenomenon observed in vitiligo lends support to the critical role of trauma in the etiopathogenesis of the disease.

Although we could not explain the co-presence of vitiligo and glaucoma, we believe that it may result from the fact that both diseases are observed in tissues that have the same embryologic origin and etiology, perhaps vascular or neural disorders, excessive accumulation of free radicals, or the triggering of apoptosis. Dermatologists should be alert to the presence of glaucoma in patients with vitiligo because glaucoma is an eye disease that progresses slowly and may lead to vision loss.

Vitiligo is an acquired idiopathic disease of unknown etiology. Characterized by depigmented maculae and melanocytic destruction, it usually presents in childhood or young adulthood. The incidence of vitiligo ranges from 0.5% to 2% globally and there is no racial or gender predilection.¹

Patients with vitiligo may exhibit pigmentary abnormalities of the iris and retina.² Noninflammatory depigmented lesions of the ocular fundus observed in vitiligo indicate a local loss of melanocytes.¹ The fact that melanocytes are present not only in the skin and roots of the hair but also in the uvea and stria vascularis of the inner ear may explain the ophthalmologic disorders that accompany vitiligo.³ The term glaucoma refers to a large number of diseases that share a common feature: a distinctive and progressive optic neuropathy that may derive from various risks and is associated with a gradual loss of the visual field. If the disorder is not diagnosed and treated properly it could cause blindness.

Glaucoma is classified on the basis of the underlying abnormality that causes intraocular pressure (IOP) to rise. Glaucoma is first divided into open-angle and angle-closure glaucoma; glaucoma associated with developmental anomalies is then subdivided according to specific alterations.⁴

A PubMed search of articles indexed for MEDLINE using the terms vitiligo and glaucoma revealed only 1 study examining the incidence of glaucoma in patients with vitiligo.⁵ In the study reported here, we determined the presence of and possible risk factors for glaucoma in patients with vitiligo who had presented to the dermatology polyclinic.

Methods

We registered 49 patients diagnosed with vitiligo by clinical and Wood light examination and 20 age- and sex-matched healthy controls. Patients who were using topical corticosteroid treatments for vitiligo lesions located on the face were excluded from the study due to the glaucoma-inducing effects of corticosteroids. Similarly, patients who received drugs with sympathetic and parasympathetic action that can cause glaucoma were excluded.

The patients received a comprehensive ophthalmologic examination that included visual acuity testing, refraction, IOP measurement, gonioscopy, and fundus examination. All patients and controls underwent visual field tests and optic nerve head analyses using a confocal scanning laser ophthalmoscope. Glaucoma was diagnosed based on fundus examination, IOP measurement, field of vision evaluation, and optic nerve head analysis.

Informed consent was obtained from all participants. The research protocol was approved by the university hospital ethics committee.

Results

The study registered a total of 49 patients with vitiligo (28 female; 21 male) and 20 healthy controls (10 female; 10 male) with a variety of demographic and clinical characteristics (Table 1).

Mean (SD) IOP values were 13.83 (2.84) mm Hg for the right eye and 13.89 (2.60) mm Hg for the left eye in the vitiligo group. Values were 14.35 (2.56) mm Hg and 14.95 (2.92) mm Hg, respectively, in the control group. The IOP differences between the 2 groups were not statistically significant (P>.05).

Nine patients (18.4%) in the vitiligo group were found to have signs of normal-tension glaucoma (NTG). Optic nerve damage and vision loss occurs in the presence of normal IOP in NTG. There were no signs of NTG in the control group. Normal-tension glaucoma was diagnosed in the vitiligo group based on glaucomatous optic disc appearance, visual field defects, and structural analysis of the entire optic nerve head in confocal scanning laser ophthalmoscope. The NTG difference between the vitiligo and control groups was statistically significant (P=.04).

In the vitiligo group, of the 9 patients who had NTG, 6 had periorbital vitiligo lesions; the remaining 3 had none. Although patients who had periorbital lesions had a higher rate of glaucoma relative to the patients without periorbital lesions, the difference was not statistically significant (P>.05).

No statistically significant differences (P>.05) were found between patients with vitiligo with and without glaucoma in terms of age, sex, disease duration, family history of vitiligo, presence or absence of periorbital involvement, manner of involvement, percentage of the involved body areas, and IOP (Table 1).

Comment

Glaucoma is characterized by increased IOP, visual field loss, and changes in the optic nerve head. Although elevated IOP is common in ocular hypertension as well as in glaucoma, there is no glaucomatous visual field loss in ocular hypertension. In NTG, on the other hand, glaucomatous visual field loss and optic nerve head changes occur without an increase in IOP.⁶ Normal-tension glaucoma is a particular type of open-angle glaucoma. It is believed that NTG and high-tension glaucoma induce optic nerve head damage through different means.⁷ Alternative theories have been put forth to account for the glaucomatous damage to the optic nerve head that occurs in NTG, despite normal or close to normal IOP. These theories include vascular disorders (eg, ischemia, which interrupts the orthograde or retrograde axonal transport), excessive accumulation of free radicals, triggering of apoptosis, and low resistance of lamina cribrosa.⁸

Although there are various studies exploring ocular symptoms in patients with vitiligo,^9-15 only 1 study has examined the incidence of glaucoma in this group of patients.⁵ Biswas et al¹¹ examined ocular signs in 100 patients with vitiligo and found that 23% of patients had hypopigmented foci in the iris, 18% had pigmentation in the anterior chamber, 11% had chorioretinal degeneration, 9% had hypopigmentation of the retinal pigment epithelium, 5% had uveitis, and 34% were evaluated as normal. In this study, the authors concluded that there was a strong relationship between vitiligo and eye diseases.¹¹ When Gopal et al⁹ compared the eye examinations of 150 vitiligo patients and 100 healthy controls, they found uveitis, iris, and retinal pigmentary abnormalities in 16% of the vitiligo patients (P<.001).

Rogosić et al⁵ examined the incidence of glaucoma in 42 patients with vitiligo and found primary open-angle glaucoma in 24 (57%) patients. The patients had a mean age of 56 years, mean disease duration of 13 years, and mean IOP of 18 mm Hg for the right eye and 17.5 mm Hg for the left eye. The incidence of glaucoma was significantly higher in patients with vitiligo (P<.001) and increased with disease duration.⁵

Similar studies, however, have failed to show a relationship between vitiligo and glaucoma. In a study that evaluated the retinal pigment epithelium and the optic nerve in patients with vitiligo, Perossini et al¹⁰ found that the fundus examination of the patients was perfectly normal.

In our study, we detected NTG in 18.4% of patients with vitiligo. We did not find a significant statistical difference between patients with and without glaucoma (Table 2). Rogosić et al⁵ found a significant relationship between age and glaucoma incidence, but we did not find such a relationship, which we believe is because the mean age of our patients was lower than the prior study.

In vitiligo, melanocytes are destroyed through an unknown mechanism. Although the cellular and molecular mechanisms causing melanocytic destruction have not yet been determined, various hypotheses have been put forward to explain the etiopathogenesis of vitiligo. Among these, the most commonly held hypotheses are the neural, self-destruction, and autoimmune hypotheses.¹⁶

Based on the observation that stress and serious trauma could precipitate or trigger the onset of vitiligo,¹⁶ the neural hypothesis holds that neurochemical mediators released from the edges of the nerve endings exert toxic effects on melanocytes. The fact that both melanocytes and choroidal pigment cells originate from the mesenchyme and dermatomal spreading of segmental vitiligo are arguments propounded in favor of this hypothesis.¹⁷

The self-destruction hypothesis suggests that the intrinsic protective mechanisms that normally enable melanocytes to eliminate toxic intermediate products or metabolites on the melanogenesis path have been impaired in patients with vitiligo.^18,19 There is evidence of increased oxidative stress over the whole epidermis of patients with vitiligo.²⁰ Thus, free radicals affect melanin and cause membrane damage via lipid peroxidation reactions.²¹

The autoimmune hypothesis proposes a clinical relationship between vitiligo and several diseases believed to be autoimmune. Because the macrophage infiltration observed in vitiligo lesions is more pronounced on the perilesional skin, this hypothesis holds that macrophages may play a role in melanocyte removal.²¹ The Koebner phenomenon observed in vitiligo lends support to the critical role of trauma in the etiopathogenesis of the disease.

Although we could not explain the co-presence of vitiligo and glaucoma, we believe that it may result from the fact that both diseases are observed in tissues that have the same embryologic origin and etiology, perhaps vascular or neural disorders, excessive accumulation of free radicals, or the triggering of apoptosis. Dermatologists should be alert to the presence of glaucoma in patients with vitiligo because glaucoma is an eye disease that progresses slowly and may lead to vision loss.

Clinical question: What is the harm associated with long-term beta-blocker therapy in patients with uncomplicated hypertension undergoing non-cardiac surgery?

Background: Given the recent concerns over the validity of prior studies, there is uncertainty about which patients benefit most from perioperative beta-blockade. Current guidelines suggest continuing beta-blockers in the perioperative period. More data are needed to delineate which patients maximally benefit from perioperative beta-blockade.

Study design: Association study.

Setting: Danish nationwide cohort of patients.

Synopsis: Study investigators included 55,320 uncomplicated hypertension (no cardiovascular, renal, or liver disease) patients >19 years of age on ≥2 antihypertensive drugs undergoing non-cardiac surgery. In the 14,664 patients who received beta-blockers, the rates of 30-day major adverse cardiovascular events (MACE; cardiovascular death, nonfatal ischemic stroke, and nonfatal myocardial infarction) and 30-day all-cause mortality were 1.32% and 1.93%, respectively. However, in the 40,676 patients who did not receive beta-blockers, 30-day MACEs and 30-day all-cause mortality rates were 0.84% and 1.32%, respectively (P<0.001). When looking at the individual MACEs, cardiovascular death was the only statistically significant event with higher incidence (0.9% versus 0.45%, P<0.001).

Combination therapy with beta-blocker and RAS inhibitor, calcium channel blockers, or thiazide was associated with statistically significant higher risks of MACEs and all-cause mortality when compared to the combination of RAS inhibitor plus thiazide. Men >70 years of age or undergoing urgent surgery had the highest risk of harm. This study was not a randomized control trial, so caution must be used when attributing causality to beta-blockers, MACEs, and all-cause mortality.

Bottom line: Antihypertensive regimens containing beta-blockers may increase risk of perioperative MACEs and all-cause mortality in patients with uncomplicated hypertension.

Citation: Jorgensen ME, Hlatky MA, Kober L, et al. β-blocker-associated risks in patients with uncomplicated hypertension undergoing noncardiac surgery. JAMA Intern Med. 2015;175(12):1923-1931.

Clinical question: What is the harm associated with long-term beta-blocker therapy in patients with uncomplicated hypertension undergoing non-cardiac surgery?

Background: Given the recent concerns over the validity of prior studies, there is uncertainty about which patients benefit most from perioperative beta-blockade. Current guidelines suggest continuing beta-blockers in the perioperative period. More data are needed to delineate which patients maximally benefit from perioperative beta-blockade.

Study design: Association study.

Setting: Danish nationwide cohort of patients.

Synopsis: Study investigators included 55,320 uncomplicated hypertension (no cardiovascular, renal, or liver disease) patients >19 years of age on ≥2 antihypertensive drugs undergoing non-cardiac surgery. In the 14,664 patients who received beta-blockers, the rates of 30-day major adverse cardiovascular events (MACE; cardiovascular death, nonfatal ischemic stroke, and nonfatal myocardial infarction) and 30-day all-cause mortality were 1.32% and 1.93%, respectively. However, in the 40,676 patients who did not receive beta-blockers, 30-day MACEs and 30-day all-cause mortality rates were 0.84% and 1.32%, respectively (P<0.001). When looking at the individual MACEs, cardiovascular death was the only statistically significant event with higher incidence (0.9% versus 0.45%, P<0.001).

Combination therapy with beta-blocker and RAS inhibitor, calcium channel blockers, or thiazide was associated with statistically significant higher risks of MACEs and all-cause mortality when compared to the combination of RAS inhibitor plus thiazide. Men >70 years of age or undergoing urgent surgery had the highest risk of harm. This study was not a randomized control trial, so caution must be used when attributing causality to beta-blockers, MACEs, and all-cause mortality.

Bottom line: Antihypertensive regimens containing beta-blockers may increase risk of perioperative MACEs and all-cause mortality in patients with uncomplicated hypertension.

Citation: Jorgensen ME, Hlatky MA, Kober L, et al. β-blocker-associated risks in patients with uncomplicated hypertension undergoing noncardiac surgery. JAMA Intern Med. 2015;175(12):1923-1931.

Clinical question: What is the harm associated with long-term beta-blocker therapy in patients with uncomplicated hypertension undergoing non-cardiac surgery?

Background: Given the recent concerns over the validity of prior studies, there is uncertainty about which patients benefit most from perioperative beta-blockade. Current guidelines suggest continuing beta-blockers in the perioperative period. More data are needed to delineate which patients maximally benefit from perioperative beta-blockade.

Study design: Association study.

Setting: Danish nationwide cohort of patients.

Synopsis: Study investigators included 55,320 uncomplicated hypertension (no cardiovascular, renal, or liver disease) patients >19 years of age on ≥2 antihypertensive drugs undergoing non-cardiac surgery. In the 14,664 patients who received beta-blockers, the rates of 30-day major adverse cardiovascular events (MACE; cardiovascular death, nonfatal ischemic stroke, and nonfatal myocardial infarction) and 30-day all-cause mortality were 1.32% and 1.93%, respectively. However, in the 40,676 patients who did not receive beta-blockers, 30-day MACEs and 30-day all-cause mortality rates were 0.84% and 1.32%, respectively (P<0.001). When looking at the individual MACEs, cardiovascular death was the only statistically significant event with higher incidence (0.9% versus 0.45%, P<0.001).

Combination therapy with beta-blocker and RAS inhibitor, calcium channel blockers, or thiazide was associated with statistically significant higher risks of MACEs and all-cause mortality when compared to the combination of RAS inhibitor plus thiazide. Men >70 years of age or undergoing urgent surgery had the highest risk of harm. This study was not a randomized control trial, so caution must be used when attributing causality to beta-blockers, MACEs, and all-cause mortality.

Bottom line: Antihypertensive regimens containing beta-blockers may increase risk of perioperative MACEs and all-cause mortality in patients with uncomplicated hypertension.

Citation: Jorgensen ME, Hlatky MA, Kober L, et al. β-blocker-associated risks in patients with uncomplicated hypertension undergoing noncardiac surgery. JAMA Intern Med. 2015;175(12):1923-1931.

Clinical question: What is the prevalence of depression or depressive symptoms in resident physicians?

Background: Depression in resident physicians can lead to poor-quality medical care, increased errors, and long-term morbidity. Prevalence of depression or depressive symptoms has varied in prior studies, and more data are needed to better understand the true prevalence.

Study design: Systematic review and meta-analysis.

Setting: Surgical and nonsurgical residency programs in North America, Asia, Europe, South America, and Africa

Synopsis: Thirty-one cross-sectional studies (9,447 individuals) and 23 longitudinal studies (8,113 individuals) from January 1963 to September 2015 were included in this analysis, with the majority using self-reporting to identify residents with depression or depressive symptoms. Overall prevalence of depression or depressive symptoms was 28.8%, with a range of 20.9% to 43.2%, depending on the screening tool (95% CI, 25.3%–32.5%; P<0.001). There was an increased prevalence in depression or depressive symptoms as the calendar year progressed (slope=0.5% per calendar year increase; 95% CI, 0.03%–0.09%), with no difference in prevalence rates between surgical versus nonsurgical residents, U.S. versus elsewhere, cross-sectional versus longitudinal, or interns versus upper-level residents.

Because studies were heterogeneous with respect to the screening tools and resident population, the prevalence of depression or depressive symptoms cannot be precisely determined.

Bottom line: Prevalence of depression or depressive symptoms ranged from 20.9% to 43.2%, with pooled prevalence of 28.8%, and increased with time.

Citation: Mata DA, Ramos MA, Bansal N, et al. Prevalence of depression and depressive symptoms among resident physicians: a systematic review and met-analysis. JAMA. 2015;314(22):2373-2383.

Clinical question: What is the prevalence of depression or depressive symptoms in resident physicians?

Background: Depression in resident physicians can lead to poor-quality medical care, increased errors, and long-term morbidity. Prevalence of depression or depressive symptoms has varied in prior studies, and more data are needed to better understand the true prevalence.

Study design: Systematic review and meta-analysis.

Setting: Surgical and nonsurgical residency programs in North America, Asia, Europe, South America, and Africa

Synopsis: Thirty-one cross-sectional studies (9,447 individuals) and 23 longitudinal studies (8,113 individuals) from January 1963 to September 2015 were included in this analysis, with the majority using self-reporting to identify residents with depression or depressive symptoms. Overall prevalence of depression or depressive symptoms was 28.8%, with a range of 20.9% to 43.2%, depending on the screening tool (95% CI, 25.3%–32.5%; P<0.001). There was an increased prevalence in depression or depressive symptoms as the calendar year progressed (slope=0.5% per calendar year increase; 95% CI, 0.03%–0.09%), with no difference in prevalence rates between surgical versus nonsurgical residents, U.S. versus elsewhere, cross-sectional versus longitudinal, or interns versus upper-level residents.

Because studies were heterogeneous with respect to the screening tools and resident population, the prevalence of depression or depressive symptoms cannot be precisely determined.

Bottom line: Prevalence of depression or depressive symptoms ranged from 20.9% to 43.2%, with pooled prevalence of 28.8%, and increased with time.

Citation: Mata DA, Ramos MA, Bansal N, et al. Prevalence of depression and depressive symptoms among resident physicians: a systematic review and met-analysis. JAMA. 2015;314(22):2373-2383.

Clinical question: What is the prevalence of depression or depressive symptoms in resident physicians?

Background: Depression in resident physicians can lead to poor-quality medical care, increased errors, and long-term morbidity. Prevalence of depression or depressive symptoms has varied in prior studies, and more data are needed to better understand the true prevalence.

Study design: Systematic review and meta-analysis.

Setting: Surgical and nonsurgical residency programs in North America, Asia, Europe, South America, and Africa

Synopsis: Thirty-one cross-sectional studies (9,447 individuals) and 23 longitudinal studies (8,113 individuals) from January 1963 to September 2015 were included in this analysis, with the majority using self-reporting to identify residents with depression or depressive symptoms. Overall prevalence of depression or depressive symptoms was 28.8%, with a range of 20.9% to 43.2%, depending on the screening tool (95% CI, 25.3%–32.5%; P<0.001). There was an increased prevalence in depression or depressive symptoms as the calendar year progressed (slope=0.5% per calendar year increase; 95% CI, 0.03%–0.09%), with no difference in prevalence rates between surgical versus nonsurgical residents, U.S. versus elsewhere, cross-sectional versus longitudinal, or interns versus upper-level residents.

Because studies were heterogeneous with respect to the screening tools and resident population, the prevalence of depression or depressive symptoms cannot be precisely determined.

Bottom line: Prevalence of depression or depressive symptoms ranged from 20.9% to 43.2%, with pooled prevalence of 28.8%, and increased with time.

Citation: Mata DA, Ramos MA, Bansal N, et al. Prevalence of depression and depressive symptoms among resident physicians: a systematic review and met-analysis. JAMA. 2015;314(22):2373-2383.

NEW YORK (Reuters Health) - A breakfast rich in whey protein may help people with type 2 diabetes manage their illness better, new research from Israel suggests.

"Whey protein, a byproduct of cheese manufacturing, lowers postprandial glycemia more than other protein sources," said lead author Dr. Daniela Jakubowicz from Wolfson Medical Center at Tel Aviv University."

We found that in type 2 diabetes, increasing protein content at breakfast has a greater impact on weight loss, glycated hemoglobin (HbA1C), satiety and postprandial glycemia when the protein source is whey protein, compared with other protein sources, such as eggs, tuna and soy," she told Reuters Health by email.

Dr. Jakubowicz and her group presented their findings April 1 at ENDO 2016, the annual meeting of the Endocrine Society, in Boston.

They randomly assigned 48 overweight and obese patients with type 2 diabetes to one of three isocaloric diets. Over 12 weeks, everyone ate a large breakfast, a medium-sized lunch and a small dinner, but the amount and source of each group's breakfast proteins differed.

At breakfast, the 17 participants in the whey group ate 36 g of protein as part of a whey protein shake consisting of 40% carbohydrate, 40% protein and 20% fat. The 16 participants in the high-protein group ate 36 g of protein in the form of eggs, tuna and cheese (40% carbs; 40% protein; 20% fat). The 15 in the high-carbohydrate group ate 13 g of protein in ready-to-eat cereals (65% carbs; 15% protein; 20% fat).

All three diets included a 660 kcal breakfast, a 567 cal lunch and a 276 cal dinner, with the same composition at lunch and dinner.

After 12 weeks, the participants in the whey protein group lost the most weight (7.6 kg vs. 6.1 kg for participants in the high-protein group and 3.5 kg for those in the high-carbohydrate group (p&lt;0.0001).

Participants on the whey protein diet were less hungry during the day and had lower glucose spikes after meals compared with those on the other two diets.

The drop in HbA1C was 11.5% in the whey group, 7.7% in the protein group and 4.6% in the carbohydrate group (p&lt;0.0001). Compared with the carbohydrate group, the percentage drop in HbA1c was greater by 41% in the protein group and by 64% in the whey group (p&lt;0.0001).

"Whey protein was consumed only at breakfast; however, the improvement of glucose, insulin and glucagon-like peptide 1 (GLP-1) was also observed after lunch and dinner. The mechanism of this persistent beneficial effect of whey protein needs further research," Dr. Jakubowicz said.

Co-author Dr. Julio Wainstein, also at Wolfson Medical Center, added by email, "Usually, patients with type 2 diabetes are treated with a combination of several antidiabetic drugs to achieve adequate glucose regulation and decrease HbA1c. Whey protein should be considered an important adjuvant in the management of type 2 diabetes."

"Furthermore," Dr. Wainstein added, "it is possible that by adding whey protein to the diet, glucose regulation might be achieved with less medication, which is a valuable advantage in type 2 diabetes treatment."

The study had no commercial funding, and the authors declared no conflicts of interest.

NEW YORK (Reuters Health) - A breakfast rich in whey protein may help people with type 2 diabetes manage their illness better, new research from Israel suggests.

"Whey protein, a byproduct of cheese manufacturing, lowers postprandial glycemia more than other protein sources," said lead author Dr. Daniela Jakubowicz from Wolfson Medical Center at Tel Aviv University."

We found that in type 2 diabetes, increasing protein content at breakfast has a greater impact on weight loss, glycated hemoglobin (HbA1C), satiety and postprandial glycemia when the protein source is whey protein, compared with other protein sources, such as eggs, tuna and soy," she told Reuters Health by email.

Dr. Jakubowicz and her group presented their findings April 1 at ENDO 2016, the annual meeting of the Endocrine Society, in Boston.

They randomly assigned 48 overweight and obese patients with type 2 diabetes to one of three isocaloric diets. Over 12 weeks, everyone ate a large breakfast, a medium-sized lunch and a small dinner, but the amount and source of each group's breakfast proteins differed.

At breakfast, the 17 participants in the whey group ate 36 g of protein as part of a whey protein shake consisting of 40% carbohydrate, 40% protein and 20% fat. The 16 participants in the high-protein group ate 36 g of protein in the form of eggs, tuna and cheese (40% carbs; 40% protein; 20% fat). The 15 in the high-carbohydrate group ate 13 g of protein in ready-to-eat cereals (65% carbs; 15% protein; 20% fat).

All three diets included a 660 kcal breakfast, a 567 cal lunch and a 276 cal dinner, with the same composition at lunch and dinner.

After 12 weeks, the participants in the whey protein group lost the most weight (7.6 kg vs. 6.1 kg for participants in the high-protein group and 3.5 kg for those in the high-carbohydrate group (p&lt;0.0001).

Participants on the whey protein diet were less hungry during the day and had lower glucose spikes after meals compared with those on the other two diets.

The drop in HbA1C was 11.5% in the whey group, 7.7% in the protein group and 4.6% in the carbohydrate group (p&lt;0.0001). Compared with the carbohydrate group, the percentage drop in HbA1c was greater by 41% in the protein group and by 64% in the whey group (p&lt;0.0001).

"Whey protein was consumed only at breakfast; however, the improvement of glucose, insulin and glucagon-like peptide 1 (GLP-1) was also observed after lunch and dinner. The mechanism of this persistent beneficial effect of whey protein needs further research," Dr. Jakubowicz said.

Co-author Dr. Julio Wainstein, also at Wolfson Medical Center, added by email, "Usually, patients with type 2 diabetes are treated with a combination of several antidiabetic drugs to achieve adequate glucose regulation and decrease HbA1c. Whey protein should be considered an important adjuvant in the management of type 2 diabetes."

"Furthermore," Dr. Wainstein added, "it is possible that by adding whey protein to the diet, glucose regulation might be achieved with less medication, which is a valuable advantage in type 2 diabetes treatment."

The study had no commercial funding, and the authors declared no conflicts of interest.

NEW YORK (Reuters Health) - A breakfast rich in whey protein may help people with type 2 diabetes manage their illness better, new research from Israel suggests.

"Whey protein, a byproduct of cheese manufacturing, lowers postprandial glycemia more than other protein sources," said lead author Dr. Daniela Jakubowicz from Wolfson Medical Center at Tel Aviv University."

We found that in type 2 diabetes, increasing protein content at breakfast has a greater impact on weight loss, glycated hemoglobin (HbA1C), satiety and postprandial glycemia when the protein source is whey protein, compared with other protein sources, such as eggs, tuna and soy," she told Reuters Health by email.

Dr. Jakubowicz and her group presented their findings April 1 at ENDO 2016, the annual meeting of the Endocrine Society, in Boston.

They randomly assigned 48 overweight and obese patients with type 2 diabetes to one of three isocaloric diets. Over 12 weeks, everyone ate a large breakfast, a medium-sized lunch and a small dinner, but the amount and source of each group's breakfast proteins differed.

At breakfast, the 17 participants in the whey group ate 36 g of protein as part of a whey protein shake consisting of 40% carbohydrate, 40% protein and 20% fat. The 16 participants in the high-protein group ate 36 g of protein in the form of eggs, tuna and cheese (40% carbs; 40% protein; 20% fat). The 15 in the high-carbohydrate group ate 13 g of protein in ready-to-eat cereals (65% carbs; 15% protein; 20% fat).

All three diets included a 660 kcal breakfast, a 567 cal lunch and a 276 cal dinner, with the same composition at lunch and dinner.

After 12 weeks, the participants in the whey protein group lost the most weight (7.6 kg vs. 6.1 kg for participants in the high-protein group and 3.5 kg for those in the high-carbohydrate group (p&lt;0.0001).

Participants on the whey protein diet were less hungry during the day and had lower glucose spikes after meals compared with those on the other two diets.

The drop in HbA1C was 11.5% in the whey group, 7.7% in the protein group and 4.6% in the carbohydrate group (p&lt;0.0001). Compared with the carbohydrate group, the percentage drop in HbA1c was greater by 41% in the protein group and by 64% in the whey group (p&lt;0.0001).

"Whey protein was consumed only at breakfast; however, the improvement of glucose, insulin and glucagon-like peptide 1 (GLP-1) was also observed after lunch and dinner. The mechanism of this persistent beneficial effect of whey protein needs further research," Dr. Jakubowicz said.

Co-author Dr. Julio Wainstein, also at Wolfson Medical Center, added by email, "Usually, patients with type 2 diabetes are treated with a combination of several antidiabetic drugs to achieve adequate glucose regulation and decrease HbA1c. Whey protein should be considered an important adjuvant in the management of type 2 diabetes."

"Furthermore," Dr. Wainstein added, "it is possible that by adding whey protein to the diet, glucose regulation might be achieved with less medication, which is a valuable advantage in type 2 diabetes treatment."

The study had no commercial funding, and the authors declared no conflicts of interest.

Micrograph showing

multiple myeloma

Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.

The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.

And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.

Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.

First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.

Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.

When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.

The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.

However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.

Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.

In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.

The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.

The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.

Micrograph showing

multiple myeloma

Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.

The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.

And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.

Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.

First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.

Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.

When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.

The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.

However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.

Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.

In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.

The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.

The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.

Micrograph showing

multiple myeloma

Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.

The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.

And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.

Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.

First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.

Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.

When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.

The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.

However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.

Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.

In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.

The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.

The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.

Red blood cells

The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.

Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with

erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.

In addition, researchers said there were no serious adverse events related to roxadustat.

Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.

The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.

Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.

In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.

The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.

Results

Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).

Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.

Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.

Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).

After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).

“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”

“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”

Treatment-emergent adverse events were reported in 80% of all patients.

The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).

Red blood cells

The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.

Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with

erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.

In addition, researchers said there were no serious adverse events related to roxadustat.

Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.

The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.

Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.

In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.

The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.

Results

Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).

Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.

Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.

Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).

After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).

“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”

“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”

Treatment-emergent adverse events were reported in 80% of all patients.

The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).

Red blood cells

The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.

Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with

erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.

In addition, researchers said there were no serious adverse events related to roxadustat.

Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.

The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.

Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.

In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.

The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.

Results

Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).

Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.

Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.

Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).

After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).

“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”

“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”

Treatment-emergent adverse events were reported in 80% of all patients.

The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).

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 [email protected].

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 [email protected].

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 [email protected].

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.

CASE 1 › Ms. T is an otherwise healthy 76 year old with a history of severe osteoarthritis (OA) in her right knee. She has participated in multiple rounds of physical therapy (PT) over the last 3 years. During the past year, she received 2 intra-articular corticosteroid injections, each of which provided only 3 to 4 weeks of pain relief, and one hyaluronic acid (HA) injection, which provided no benefit whatsoever.

Today, she describes her right knee pain as an 8 out of 10 and is frustrated by her lack of symptom relief. She was planning to have a total knee replacement and is a good surgical candidate, but recently found an article regarding platelet-rich plasma (PRP) injections for knee OA. She wants your opinion as to whether she should try this approach or proceed with surgery.

CASE 2 › Mr. H is a 44-year-old, right-handed dentist who has been suffering from right lateral epicondylitis for the past year. Although he has undergone PT and has been performing exercises at home since his symptoms began, he has not noticed a significant improvement. In the last 5 months, he has been out of work a total of 8 weeks due to the pain. He received one corticosteroid injection last month, which provided no improvement in symptoms. He is not interested in surgery, as he does not want to be out of work for a prolonged period of time.

He reports that one of his friends recently received a PRP injection for lateral epicondylitis and now feels great. He is aware that PRP injections are not covered by his health insurance and says he is willing to pay out of pocket if the treatment works. He wants to know if you recommend this course of action for his elbow pain.

How would you counsel each of these patients about the use of PRP injections for pain relief from their respective orthopedic conditions?

Musculoskeletal symptoms account for 10% to 28% of patients’ complaints to primary care physicians annually.¹ Treatment of both chronic tendinopathies and knee OA—2 of the most common causes of these complaints—typically follows a stepwise approach, beginning with anti-inflammatory and pain medications in addition to PT. Patients who fail to respond to these interventions are often treated with corticosteroid injections, and, in the case of knee OA, viscosupplementation (ie, HA injections) and braces. If these therapies fail, patients are often forced to choose between an invasive surgical procedure or continued pain and limited function.

Platelet-rich plasma is thought to tip the body’s response in favor of regeneration over destruction.

A number of physicians specializing in musculoskeletal medicine have turned to prolotherapy—specifically, dextrose prolotherapy (see “Prolotherapy: Can it help your patient?” J Fam Pract. 2015;64:763-768) and platelet-rich plasma (PRP) therapy—as an alternative treatment for chronic musculoskeletal conditions.

PRP has been used to enhance surgical healing and to treat muscle strains and chondropathies. It drew a great deal of attention in the media when it was used by such high-profile professional athletes as Tiger Woods and Kobe Bryant.

Although PRP therapy is not commonly reimbursed by health insurance companies because of a lack of large, definitive studies supporting its effectiveness, patients are paying anywhere from a few hundred to a few thousand dollars out of pocket for it. They’re doing so in the hope that it will treat their chronic musculoskeletal disorders or at least delay surgical procedures.

But what can these patients reasonably expect from this therapy?

The following review of the evidence for PRP in the treatment of knee OA and tendinopathies (including elbow epicondylitis, patellar tendinitis, and Achilles tendinitis) will help you counsel patients on its appropriate use.

What is PRP?

PRP is defined as a sample of autologous blood with concentrations of platelets above baseline values.² It is made through a one- or 2-stage centrifugation process in which the liquid and solid components of whole blood are separated, and then the liquid components are further separated into portions that are platelet-rich and platelet-poor.

Significant variability in preparation methods exists, resulting in more than 40 different products.² Some methods centrifuge only once, creating plasma that is separated from red and white blood cells, but without a huge shift in the concentration of platelets; some include white blood cells in the final preparation; and most have differing concentrations of platelets and various growth factors in the end product. Researchers have attempted to classify the various preparations by platelet concentration, inclusion or exclusion of white blood cells, and fibrin content, but no validated system yet exists. Thus, consistency in preparations is lacking.^3,4

PRP is rich not only in platelets, but also in a multitude of other growth factors. It is thought to improve healing by enhancing the body’s natural regenerative processes at the tissue level. In OA, for example, a complex balance of destructive and reparative processes is at play; PRP is thought to tip the body’s response in favor of regeneration over destruction. Similarly, chronic tendinopathy involves a process of destruction, reaction, healing, and degeneration; intervening at the correct point in this pathway with a boost to healing may help the body repair an otherwise diseased tendon.³

What does the evidence show?

Overall, basic science and preclinical research support “the promise” of PRP(strength of recommendation [SOR]: A).⁵ However, patient-centered evidence is lacking, and tremendous variability exists between studies, not only in terms of PRP preparation, but also with regard to:

• Protocol—Was ultrasound guidance used? Did the injection include needling of the tendon? What post-injection rehabilitation was followed?
• Patient population—What treatments were tried in the past? How chronic or severe was the problem?
• Study design—What was the comparison group? How were pain and function measured? Most studies have been small in size and have included various treatment modalities in addition to the PRP injection (most often PT).

Knee OA: PRP may provide short-term benefit, especially in younger patients

Researchers have conducted a number of studies evaluating PRP for knee OA.^6-12 Most have compared PRP to HA—another intra-articular injection that is plagued by mixed, limited, and poor-quality evidence. These trials have had varied results and do not consistently support PRP as superior to HA.

The most well-designed study to date demonstrated that PRP was superior to saline and as effective as HA.¹¹ In addition, the researchers found that a series of 3 PRP injections was superior to 3 injections of HA or only one injection of PRP.

One small randomized controlled trial (RCT) compared PRP injections to saline and found that PRP improved pain and function better than placebo at 6 weeks, 3 months, and 6 months; results appeared to deteriorate after that time period.⁶ Also, the findings suggested that PRP delivered the strongest benefit in younger patients who had less advanced OA.

In addition, a recent systematic review found short-term improvements in functional outcomes in patients treated with PRP injections vs those treated with HA injections and those treated with placebo.¹²

Basic science and preclinical research support “the promise” of platelet-rich plasma, but patient-centered evidence is lacking, and tremendous variability exists between studies.

But before experts can make any conclusive recommendations regarding the use of PRP for knee OA, standardized studies with larger numbers of participants and rigorous methodology must be designed. Notably, no evidence exists of significant harm resulting from PRP injection for knee OA. Therefore, given the mixed evidence in terms of efficacy, there may be a potential benefit to treatment with little negative consequence.

In 2013, the American Academy of Orthopaedic Surgeons (AAOS) stated that they were unable to recommend for or against PRP injection for patients with symptomatic OA of the knee because the evidence was inconclusive.¹³ At the same time, the AAOS was unable to recommend for or against corticosteroid injections, manual therapy, or bracing for knee OA, and recommended against HA injections.¹³ Recently, however, the American Medical Society for Sports Medicine (AMSSM) recommended that HA be used in appropriate patients with knee OA.¹⁴

Such disagreement indicates that evidence is lacking for many modalities employed in the management of knee OA, including the injection of corticosteroids, which is a frequent and generally accepted treatment. Compounding matters is that many of the original studies testing the efficacy of PRP injection in knee OA used HA injections as the comparison, and there is no agreement between AAOS and AMSSM as to its usefulness. Thus, the validity of using HA as a control is suspect.

Tendinopathies: PRP may have benefit, but more research is needed

A number of meta-analyses and systematic review articles have combined the results of studies involving PRP treatment for various tendinopathies.^3,15-17 While most found that PRP may have a benefit (although not long-lasting) and may be of use in attempts to avoid surgery or to return to a desired activity, all reported that more rigorous studies with standardized methodologies must be conducted before PRP can be conclusively recommended for any anatomic site.

Elbow epicondylitis (tennis elbow). The majority of tendinopathy studies have examined the effect of PRP on tennis elbow, although given the small study numbers (N=20-100), high risks of bias, and very different comparison groups, the data are extremely limited. Of the 4 randomized studies,^18-21 2 compared different PRP preparations to whole blood,^18,20 one compared PRP to both saline and corticosteroid,¹⁹ and one compared PRP to corticosteroid alone.²¹

The studies comparing PRP to whole blood found similar outcomes at most time points.^18,20 These studies were of extremely poor quality, and other review articles have defined whole blood as a type of PRP, so this comparison was somewhat inappropriate. One recently published meta-analysis, which included 10 studies comparing either PRP or whole blood to corticosteroid, found that PRP improved pain more than a corticosteroid.²²

The one study that included a comparison of PRP to placebo (saline) suffered from a high dropout rate, and the authors were not able to analyze the primary outcome data. At 3 months, the participants remaining in each group (PRP, saline, or corticosteroid) had similar pain and disability scores.¹⁹ Although the steroid group had improved from baseline at one month, there was no difference between the steroid group and placebo group at 3 months. The PRP group did not differ from the placebo group at any time point.

The study comparing PRP to corticosteroid alone found that PRP’s effects on pain and function exceeded those of the steroid. Specifically, the steroid group initially improved and then worsened, ending the study near their baseline pain and function scores.²¹ The PRP group, on the other hand, showed slow improvement throughout, ending the study with less pain and disability than when they started.

There is no evidence of significant harms associated with platelet-rich plasma treatment, but studies have lacked the power to detect rare but serious problems.

Patellar tendinitis (jumper’s knee). The majority of studies examining the effect of PRP on patellar tendinitis are non-randomized, non-comparative studies. Of the 2 small RCTs that were conducted, one compared PRP to extracorporeal shockwave therapy (ESWT),²³ and the other to dry needling.²⁴

In the ESWT study, there was a slight improvement in pain and function in the PRP group relative to the ESWT group at 6 and 12 months. In the other study, although the PRP group showed an improvement in recovery at 12 weeks relative to the dry needling group, there was no difference between such outcomes as pain and activity in the 2 groups at 26 weeks.

Worth noting here is that like the studies done on OA patients, the research involving patellar tendinitis also used comparative interventions (ESWT and dry needling) that lack high-quality evidence for their use. So whether these were appropriate comparisons is debatable.

Achilles tendinitis. Only one RCT (N=54) has evaluated PRP for the treatment of Achilles tendinitis.²⁵ This study, which compared PRP to saline, excluded patients who had previously completed a course of PT, yet both study groups participated in PT during the study. Although the trial found no difference between groups at any time point (both showed improvement), it was underpowered to detect any difference (positive or negative) between groups, given that most participants likely would have improved with PT anyway.²⁶

PRP has few harms or adverse effects

Most individual studies involving PRP have not reported on harms or side effects; the studies that have reported on them have generally found low rates (2%-5%) of only local, short-term adverse effects.¹⁵ One review article did find that increasing the number of PRP injections increased the rate of adverse effects; however, those effects still appeared to be mild and time-limited.¹⁰

One study reported that 33% (17/51) of patients experienced systemic adverse effects including syncope, dizziness, and nausea at the time of their PRP injection.⁶ Overall, there is no evidence of significant harms associated with PRP treatment, but available studies have lacked the power to detect rare but serious problems.

Looking to the future: Additional considerations

In order to properly evaluate this potentially promising method of care, future studies need to include appropriately chosen controls, specifically defined formulations of PRP, standardized protocols for the injection of PRP, standardized post-injection PT regimens, and patient populations that are clearly defined in terms of severity and chronicity of disease. Furthermore, studies must be rigorously designed in terms of randomization, blinding, and analysis. (Many studies done to date did not use an intention-to-treat protocol, for example). Higher-quality studies with larger numbers of participants are the only way to determine whether PRP is worth all the “buzz.”

Platelet-rich plasma is approved only for use in the operative setting to enhance bone graft handling properties. Office-based injections are an off-label use.

We should keep in mind, too, that the evidence for many of the other treatment options for both tendinopathy and knee OA are similarly problematic, and these modalities are even more widely used than PRP. Given the systemic problems associated with nonsteroidal anti-inflammatory drugs, concerns about possible tendon rupture with corticosteroid injections, and the time and compliance issues associated with PT, PRP may be a safer alternative to more traditional treatments.

An off-label use. PRP does not pass through the standard regulatory pathway of the US Food and Drug Administration (FDA). As a blood product, PRP falls under the regulatory purview of the FDA’s Center for Biologics Evaluation and Research, which has approved PRP only for use in the operative setting to enhance bone graft handling properties.²⁷ Therefore, office-based PRP injections are an off-label use of the treatment.

CASE 1 › You explain to Ms. T that PRP injections are not covered by insurance and that there is not a significant amount of evidence to indicate that an injection would appreciably improve her pain. She decides to proceed with a knee replacement and not to pursue a PRP injection.

CASE 2 › Given the time that Mr. H has invested in traditional conservative management strategies, his time away from work, and that he is not concerned with the out-of-pocket cost associated with PRP, you explain to him that there is some limited evidence that PRP might improve his symptoms. He decides that he would rather try a PRP injection than pursue surgery.

CORRESPONDENCE
Jordan White, MD, MPH, Department of Family Medicine, 111 Brewster Street, Pawtucket, RI 02860; [email protected].

CASE 1 › Ms. T is an otherwise healthy 76 year old with a history of severe osteoarthritis (OA) in her right knee. She has participated in multiple rounds of physical therapy (PT) over the last 3 years. During the past year, she received 2 intra-articular corticosteroid injections, each of which provided only 3 to 4 weeks of pain relief, and one hyaluronic acid (HA) injection, which provided no benefit whatsoever.

Today, she describes her right knee pain as an 8 out of 10 and is frustrated by her lack of symptom relief. She was planning to have a total knee replacement and is a good surgical candidate, but recently found an article regarding platelet-rich plasma (PRP) injections for knee OA. She wants your opinion as to whether she should try this approach or proceed with surgery.

CASE 2 › Mr. H is a 44-year-old, right-handed dentist who has been suffering from right lateral epicondylitis for the past year. Although he has undergone PT and has been performing exercises at home since his symptoms began, he has not noticed a significant improvement. In the last 5 months, he has been out of work a total of 8 weeks due to the pain. He received one corticosteroid injection last month, which provided no improvement in symptoms. He is not interested in surgery, as he does not want to be out of work for a prolonged period of time.

He reports that one of his friends recently received a PRP injection for lateral epicondylitis and now feels great. He is aware that PRP injections are not covered by his health insurance and says he is willing to pay out of pocket if the treatment works. He wants to know if you recommend this course of action for his elbow pain.

How would you counsel each of these patients about the use of PRP injections for pain relief from their respective orthopedic conditions?

Musculoskeletal symptoms account for 10% to 28% of patients’ complaints to primary care physicians annually.¹ Treatment of both chronic tendinopathies and knee OA—2 of the most common causes of these complaints—typically follows a stepwise approach, beginning with anti-inflammatory and pain medications in addition to PT. Patients who fail to respond to these interventions are often treated with corticosteroid injections, and, in the case of knee OA, viscosupplementation (ie, HA injections) and braces. If these therapies fail, patients are often forced to choose between an invasive surgical procedure or continued pain and limited function.

Platelet-rich plasma is thought to tip the body’s response in favor of regeneration over destruction.

A number of physicians specializing in musculoskeletal medicine have turned to prolotherapy—specifically, dextrose prolotherapy (see “Prolotherapy: Can it help your patient?” J Fam Pract. 2015;64:763-768) and platelet-rich plasma (PRP) therapy—as an alternative treatment for chronic musculoskeletal conditions.

PRP has been used to enhance surgical healing and to treat muscle strains and chondropathies. It drew a great deal of attention in the media when it was used by such high-profile professional athletes as Tiger Woods and Kobe Bryant.

Although PRP therapy is not commonly reimbursed by health insurance companies because of a lack of large, definitive studies supporting its effectiveness, patients are paying anywhere from a few hundred to a few thousand dollars out of pocket for it. They’re doing so in the hope that it will treat their chronic musculoskeletal disorders or at least delay surgical procedures.

But what can these patients reasonably expect from this therapy?

The following review of the evidence for PRP in the treatment of knee OA and tendinopathies (including elbow epicondylitis, patellar tendinitis, and Achilles tendinitis) will help you counsel patients on its appropriate use.

What is PRP?

PRP is defined as a sample of autologous blood with concentrations of platelets above baseline values.² It is made through a one- or 2-stage centrifugation process in which the liquid and solid components of whole blood are separated, and then the liquid components are further separated into portions that are platelet-rich and platelet-poor.

Significant variability in preparation methods exists, resulting in more than 40 different products.² Some methods centrifuge only once, creating plasma that is separated from red and white blood cells, but without a huge shift in the concentration of platelets; some include white blood cells in the final preparation; and most have differing concentrations of platelets and various growth factors in the end product. Researchers have attempted to classify the various preparations by platelet concentration, inclusion or exclusion of white blood cells, and fibrin content, but no validated system yet exists. Thus, consistency in preparations is lacking.^3,4

PRP is rich not only in platelets, but also in a multitude of other growth factors. It is thought to improve healing by enhancing the body’s natural regenerative processes at the tissue level. In OA, for example, a complex balance of destructive and reparative processes is at play; PRP is thought to tip the body’s response in favor of regeneration over destruction. Similarly, chronic tendinopathy involves a process of destruction, reaction, healing, and degeneration; intervening at the correct point in this pathway with a boost to healing may help the body repair an otherwise diseased tendon.³

What does the evidence show?

Overall, basic science and preclinical research support “the promise” of PRP(strength of recommendation [SOR]: A).⁵ However, patient-centered evidence is lacking, and tremendous variability exists between studies, not only in terms of PRP preparation, but also with regard to:

• Protocol—Was ultrasound guidance used? Did the injection include needling of the tendon? What post-injection rehabilitation was followed?
• Patient population—What treatments were tried in the past? How chronic or severe was the problem?
• Study design—What was the comparison group? How were pain and function measured? Most studies have been small in size and have included various treatment modalities in addition to the PRP injection (most often PT).

Knee OA: PRP may provide short-term benefit, especially in younger patients

Researchers have conducted a number of studies evaluating PRP for knee OA.^6-12 Most have compared PRP to HA—another intra-articular injection that is plagued by mixed, limited, and poor-quality evidence. These trials have had varied results and do not consistently support PRP as superior to HA.

The most well-designed study to date demonstrated that PRP was superior to saline and as effective as HA.¹¹ In addition, the researchers found that a series of 3 PRP injections was superior to 3 injections of HA or only one injection of PRP.

One small randomized controlled trial (RCT) compared PRP injections to saline and found that PRP improved pain and function better than placebo at 6 weeks, 3 months, and 6 months; results appeared to deteriorate after that time period.⁶ Also, the findings suggested that PRP delivered the strongest benefit in younger patients who had less advanced OA.

In addition, a recent systematic review found short-term improvements in functional outcomes in patients treated with PRP injections vs those treated with HA injections and those treated with placebo.¹²

Basic science and preclinical research support “the promise” of platelet-rich plasma, but patient-centered evidence is lacking, and tremendous variability exists between studies.

But before experts can make any conclusive recommendations regarding the use of PRP for knee OA, standardized studies with larger numbers of participants and rigorous methodology must be designed. Notably, no evidence exists of significant harm resulting from PRP injection for knee OA. Therefore, given the mixed evidence in terms of efficacy, there may be a potential benefit to treatment with little negative consequence.

In 2013, the American Academy of Orthopaedic Surgeons (AAOS) stated that they were unable to recommend for or against PRP injection for patients with symptomatic OA of the knee because the evidence was inconclusive.¹³ At the same time, the AAOS was unable to recommend for or against corticosteroid injections, manual therapy, or bracing for knee OA, and recommended against HA injections.¹³ Recently, however, the American Medical Society for Sports Medicine (AMSSM) recommended that HA be used in appropriate patients with knee OA.¹⁴

Such disagreement indicates that evidence is lacking for many modalities employed in the management of knee OA, including the injection of corticosteroids, which is a frequent and generally accepted treatment. Compounding matters is that many of the original studies testing the efficacy of PRP injection in knee OA used HA injections as the comparison, and there is no agreement between AAOS and AMSSM as to its usefulness. Thus, the validity of using HA as a control is suspect.

Tendinopathies: PRP may have benefit, but more research is needed

A number of meta-analyses and systematic review articles have combined the results of studies involving PRP treatment for various tendinopathies.^3,15-17 While most found that PRP may have a benefit (although not long-lasting) and may be of use in attempts to avoid surgery or to return to a desired activity, all reported that more rigorous studies with standardized methodologies must be conducted before PRP can be conclusively recommended for any anatomic site.

Elbow epicondylitis (tennis elbow). The majority of tendinopathy studies have examined the effect of PRP on tennis elbow, although given the small study numbers (N=20-100), high risks of bias, and very different comparison groups, the data are extremely limited. Of the 4 randomized studies,^18-21 2 compared different PRP preparations to whole blood,^18,20 one compared PRP to both saline and corticosteroid,¹⁹ and one compared PRP to corticosteroid alone.²¹

The studies comparing PRP to whole blood found similar outcomes at most time points.^18,20 These studies were of extremely poor quality, and other review articles have defined whole blood as a type of PRP, so this comparison was somewhat inappropriate. One recently published meta-analysis, which included 10 studies comparing either PRP or whole blood to corticosteroid, found that PRP improved pain more than a corticosteroid.²²

The one study that included a comparison of PRP to placebo (saline) suffered from a high dropout rate, and the authors were not able to analyze the primary outcome data. At 3 months, the participants remaining in each group (PRP, saline, or corticosteroid) had similar pain and disability scores.¹⁹ Although the steroid group had improved from baseline at one month, there was no difference between the steroid group and placebo group at 3 months. The PRP group did not differ from the placebo group at any time point.

The study comparing PRP to corticosteroid alone found that PRP’s effects on pain and function exceeded those of the steroid. Specifically, the steroid group initially improved and then worsened, ending the study near their baseline pain and function scores.²¹ The PRP group, on the other hand, showed slow improvement throughout, ending the study with less pain and disability than when they started.

There is no evidence of significant harms associated with platelet-rich plasma treatment, but studies have lacked the power to detect rare but serious problems.

Patellar tendinitis (jumper’s knee). The majority of studies examining the effect of PRP on patellar tendinitis are non-randomized, non-comparative studies. Of the 2 small RCTs that were conducted, one compared PRP to extracorporeal shockwave therapy (ESWT),²³ and the other to dry needling.²⁴

In the ESWT study, there was a slight improvement in pain and function in the PRP group relative to the ESWT group at 6 and 12 months. In the other study, although the PRP group showed an improvement in recovery at 12 weeks relative to the dry needling group, there was no difference between such outcomes as pain and activity in the 2 groups at 26 weeks.

Worth noting here is that like the studies done on OA patients, the research involving patellar tendinitis also used comparative interventions (ESWT and dry needling) that lack high-quality evidence for their use. So whether these were appropriate comparisons is debatable.

Achilles tendinitis. Only one RCT (N=54) has evaluated PRP for the treatment of Achilles tendinitis.²⁵ This study, which compared PRP to saline, excluded patients who had previously completed a course of PT, yet both study groups participated in PT during the study. Although the trial found no difference between groups at any time point (both showed improvement), it was underpowered to detect any difference (positive or negative) between groups, given that most participants likely would have improved with PT anyway.²⁶

PRP has few harms or adverse effects

Most individual studies involving PRP have not reported on harms or side effects; the studies that have reported on them have generally found low rates (2%-5%) of only local, short-term adverse effects.¹⁵ One review article did find that increasing the number of PRP injections increased the rate of adverse effects; however, those effects still appeared to be mild and time-limited.¹⁰

One study reported that 33% (17/51) of patients experienced systemic adverse effects including syncope, dizziness, and nausea at the time of their PRP injection.⁶ Overall, there is no evidence of significant harms associated with PRP treatment, but available studies have lacked the power to detect rare but serious problems.

Looking to the future: Additional considerations

In order to properly evaluate this potentially promising method of care, future studies need to include appropriately chosen controls, specifically defined formulations of PRP, standardized protocols for the injection of PRP, standardized post-injection PT regimens, and patient populations that are clearly defined in terms of severity and chronicity of disease. Furthermore, studies must be rigorously designed in terms of randomization, blinding, and analysis. (Many studies done to date did not use an intention-to-treat protocol, for example). Higher-quality studies with larger numbers of participants are the only way to determine whether PRP is worth all the “buzz.”

Platelet-rich plasma is approved only for use in the operative setting to enhance bone graft handling properties. Office-based injections are an off-label use.

We should keep in mind, too, that the evidence for many of the other treatment options for both tendinopathy and knee OA are similarly problematic, and these modalities are even more widely used than PRP. Given the systemic problems associated with nonsteroidal anti-inflammatory drugs, concerns about possible tendon rupture with corticosteroid injections, and the time and compliance issues associated with PT, PRP may be a safer alternative to more traditional treatments.

An off-label use. PRP does not pass through the standard regulatory pathway of the US Food and Drug Administration (FDA). As a blood product, PRP falls under the regulatory purview of the FDA’s Center for Biologics Evaluation and Research, which has approved PRP only for use in the operative setting to enhance bone graft handling properties.²⁷ Therefore, office-based PRP injections are an off-label use of the treatment.

CASE 1 › You explain to Ms. T that PRP injections are not covered by insurance and that there is not a significant amount of evidence to indicate that an injection would appreciably improve her pain. She decides to proceed with a knee replacement and not to pursue a PRP injection.

CASE 2 › Given the time that Mr. H has invested in traditional conservative management strategies, his time away from work, and that he is not concerned with the out-of-pocket cost associated with PRP, you explain to him that there is some limited evidence that PRP might improve his symptoms. He decides that he would rather try a PRP injection than pursue surgery.

CORRESPONDENCE
Jordan White, MD, MPH, Department of Family Medicine, 111 Brewster Street, Pawtucket, RI 02860; [email protected].

CASE 1 › Ms. T is an otherwise healthy 76 year old with a history of severe osteoarthritis (OA) in her right knee. She has participated in multiple rounds of physical therapy (PT) over the last 3 years. During the past year, she received 2 intra-articular corticosteroid injections, each of which provided only 3 to 4 weeks of pain relief, and one hyaluronic acid (HA) injection, which provided no benefit whatsoever.

Today, she describes her right knee pain as an 8 out of 10 and is frustrated by her lack of symptom relief. She was planning to have a total knee replacement and is a good surgical candidate, but recently found an article regarding platelet-rich plasma (PRP) injections for knee OA. She wants your opinion as to whether she should try this approach or proceed with surgery.

CASE 2 › Mr. H is a 44-year-old, right-handed dentist who has been suffering from right lateral epicondylitis for the past year. Although he has undergone PT and has been performing exercises at home since his symptoms began, he has not noticed a significant improvement. In the last 5 months, he has been out of work a total of 8 weeks due to the pain. He received one corticosteroid injection last month, which provided no improvement in symptoms. He is not interested in surgery, as he does not want to be out of work for a prolonged period of time.

He reports that one of his friends recently received a PRP injection for lateral epicondylitis and now feels great. He is aware that PRP injections are not covered by his health insurance and says he is willing to pay out of pocket if the treatment works. He wants to know if you recommend this course of action for his elbow pain.

How would you counsel each of these patients about the use of PRP injections for pain relief from their respective orthopedic conditions?

Musculoskeletal symptoms account for 10% to 28% of patients’ complaints to primary care physicians annually.¹ Treatment of both chronic tendinopathies and knee OA—2 of the most common causes of these complaints—typically follows a stepwise approach, beginning with anti-inflammatory and pain medications in addition to PT. Patients who fail to respond to these interventions are often treated with corticosteroid injections, and, in the case of knee OA, viscosupplementation (ie, HA injections) and braces. If these therapies fail, patients are often forced to choose between an invasive surgical procedure or continued pain and limited function.

Platelet-rich plasma is thought to tip the body’s response in favor of regeneration over destruction.

A number of physicians specializing in musculoskeletal medicine have turned to prolotherapy—specifically, dextrose prolotherapy (see “Prolotherapy: Can it help your patient?” J Fam Pract. 2015;64:763-768) and platelet-rich plasma (PRP) therapy—as an alternative treatment for chronic musculoskeletal conditions.

PRP has been used to enhance surgical healing and to treat muscle strains and chondropathies. It drew a great deal of attention in the media when it was used by such high-profile professional athletes as Tiger Woods and Kobe Bryant.

Although PRP therapy is not commonly reimbursed by health insurance companies because of a lack of large, definitive studies supporting its effectiveness, patients are paying anywhere from a few hundred to a few thousand dollars out of pocket for it. They’re doing so in the hope that it will treat their chronic musculoskeletal disorders or at least delay surgical procedures.

But what can these patients reasonably expect from this therapy?

The following review of the evidence for PRP in the treatment of knee OA and tendinopathies (including elbow epicondylitis, patellar tendinitis, and Achilles tendinitis) will help you counsel patients on its appropriate use.

What is PRP?

PRP is defined as a sample of autologous blood with concentrations of platelets above baseline values.² It is made through a one- or 2-stage centrifugation process in which the liquid and solid components of whole blood are separated, and then the liquid components are further separated into portions that are platelet-rich and platelet-poor.

Significant variability in preparation methods exists, resulting in more than 40 different products.² Some methods centrifuge only once, creating plasma that is separated from red and white blood cells, but without a huge shift in the concentration of platelets; some include white blood cells in the final preparation; and most have differing concentrations of platelets and various growth factors in the end product. Researchers have attempted to classify the various preparations by platelet concentration, inclusion or exclusion of white blood cells, and fibrin content, but no validated system yet exists. Thus, consistency in preparations is lacking.^3,4

PRP is rich not only in platelets, but also in a multitude of other growth factors. It is thought to improve healing by enhancing the body’s natural regenerative processes at the tissue level. In OA, for example, a complex balance of destructive and reparative processes is at play; PRP is thought to tip the body’s response in favor of regeneration over destruction. Similarly, chronic tendinopathy involves a process of destruction, reaction, healing, and degeneration; intervening at the correct point in this pathway with a boost to healing may help the body repair an otherwise diseased tendon.³

What does the evidence show?

Overall, basic science and preclinical research support “the promise” of PRP(strength of recommendation [SOR]: A).⁵ However, patient-centered evidence is lacking, and tremendous variability exists between studies, not only in terms of PRP preparation, but also with regard to:

• Protocol—Was ultrasound guidance used? Did the injection include needling of the tendon? What post-injection rehabilitation was followed?
• Patient population—What treatments were tried in the past? How chronic or severe was the problem?
• Study design—What was the comparison group? How were pain and function measured? Most studies have been small in size and have included various treatment modalities in addition to the PRP injection (most often PT).

Knee OA: PRP may provide short-term benefit, especially in younger patients

Researchers have conducted a number of studies evaluating PRP for knee OA.^6-12 Most have compared PRP to HA—another intra-articular injection that is plagued by mixed, limited, and poor-quality evidence. These trials have had varied results and do not consistently support PRP as superior to HA.

The most well-designed study to date demonstrated that PRP was superior to saline and as effective as HA.¹¹ In addition, the researchers found that a series of 3 PRP injections was superior to 3 injections of HA or only one injection of PRP.

One small randomized controlled trial (RCT) compared PRP injections to saline and found that PRP improved pain and function better than placebo at 6 weeks, 3 months, and 6 months; results appeared to deteriorate after that time period.⁶ Also, the findings suggested that PRP delivered the strongest benefit in younger patients who had less advanced OA.

In addition, a recent systematic review found short-term improvements in functional outcomes in patients treated with PRP injections vs those treated with HA injections and those treated with placebo.¹²

Basic science and preclinical research support “the promise” of platelet-rich plasma, but patient-centered evidence is lacking, and tremendous variability exists between studies.

But before experts can make any conclusive recommendations regarding the use of PRP for knee OA, standardized studies with larger numbers of participants and rigorous methodology must be designed. Notably, no evidence exists of significant harm resulting from PRP injection for knee OA. Therefore, given the mixed evidence in terms of efficacy, there may be a potential benefit to treatment with little negative consequence.

In 2013, the American Academy of Orthopaedic Surgeons (AAOS) stated that they were unable to recommend for or against PRP injection for patients with symptomatic OA of the knee because the evidence was inconclusive.¹³ At the same time, the AAOS was unable to recommend for or against corticosteroid injections, manual therapy, or bracing for knee OA, and recommended against HA injections.¹³ Recently, however, the American Medical Society for Sports Medicine (AMSSM) recommended that HA be used in appropriate patients with knee OA.¹⁴

Such disagreement indicates that evidence is lacking for many modalities employed in the management of knee OA, including the injection of corticosteroids, which is a frequent and generally accepted treatment. Compounding matters is that many of the original studies testing the efficacy of PRP injection in knee OA used HA injections as the comparison, and there is no agreement between AAOS and AMSSM as to its usefulness. Thus, the validity of using HA as a control is suspect.

Tendinopathies: PRP may have benefit, but more research is needed

A number of meta-analyses and systematic review articles have combined the results of studies involving PRP treatment for various tendinopathies.^3,15-17 While most found that PRP may have a benefit (although not long-lasting) and may be of use in attempts to avoid surgery or to return to a desired activity, all reported that more rigorous studies with standardized methodologies must be conducted before PRP can be conclusively recommended for any anatomic site.

Elbow epicondylitis (tennis elbow). The majority of tendinopathy studies have examined the effect of PRP on tennis elbow, although given the small study numbers (N=20-100), high risks of bias, and very different comparison groups, the data are extremely limited. Of the 4 randomized studies,^18-21 2 compared different PRP preparations to whole blood,^18,20 one compared PRP to both saline and corticosteroid,¹⁹ and one compared PRP to corticosteroid alone.²¹

The studies comparing PRP to whole blood found similar outcomes at most time points.^18,20 These studies were of extremely poor quality, and other review articles have defined whole blood as a type of PRP, so this comparison was somewhat inappropriate. One recently published meta-analysis, which included 10 studies comparing either PRP or whole blood to corticosteroid, found that PRP improved pain more than a corticosteroid.²²

The one study that included a comparison of PRP to placebo (saline) suffered from a high dropout rate, and the authors were not able to analyze the primary outcome data. At 3 months, the participants remaining in each group (PRP, saline, or corticosteroid) had similar pain and disability scores.¹⁹ Although the steroid group had improved from baseline at one month, there was no difference between the steroid group and placebo group at 3 months. The PRP group did not differ from the placebo group at any time point.

The study comparing PRP to corticosteroid alone found that PRP’s effects on pain and function exceeded those of the steroid. Specifically, the steroid group initially improved and then worsened, ending the study near their baseline pain and function scores.²¹ The PRP group, on the other hand, showed slow improvement throughout, ending the study with less pain and disability than when they started.

There is no evidence of significant harms associated with platelet-rich plasma treatment, but studies have lacked the power to detect rare but serious problems.

Patellar tendinitis (jumper’s knee). The majority of studies examining the effect of PRP on patellar tendinitis are non-randomized, non-comparative studies. Of the 2 small RCTs that were conducted, one compared PRP to extracorporeal shockwave therapy (ESWT),²³ and the other to dry needling.²⁴

In the ESWT study, there was a slight improvement in pain and function in the PRP group relative to the ESWT group at 6 and 12 months. In the other study, although the PRP group showed an improvement in recovery at 12 weeks relative to the dry needling group, there was no difference between such outcomes as pain and activity in the 2 groups at 26 weeks.

Worth noting here is that like the studies done on OA patients, the research involving patellar tendinitis also used comparative interventions (ESWT and dry needling) that lack high-quality evidence for their use. So whether these were appropriate comparisons is debatable.

Achilles tendinitis. Only one RCT (N=54) has evaluated PRP for the treatment of Achilles tendinitis.²⁵ This study, which compared PRP to saline, excluded patients who had previously completed a course of PT, yet both study groups participated in PT during the study. Although the trial found no difference between groups at any time point (both showed improvement), it was underpowered to detect any difference (positive or negative) between groups, given that most participants likely would have improved with PT anyway.²⁶

PRP has few harms or adverse effects

Most individual studies involving PRP have not reported on harms or side effects; the studies that have reported on them have generally found low rates (2%-5%) of only local, short-term adverse effects.¹⁵ One review article did find that increasing the number of PRP injections increased the rate of adverse effects; however, those effects still appeared to be mild and time-limited.¹⁰

One study reported that 33% (17/51) of patients experienced systemic adverse effects including syncope, dizziness, and nausea at the time of their PRP injection.⁶ Overall, there is no evidence of significant harms associated with PRP treatment, but available studies have lacked the power to detect rare but serious problems.

Looking to the future: Additional considerations

In order to properly evaluate this potentially promising method of care, future studies need to include appropriately chosen controls, specifically defined formulations of PRP, standardized protocols for the injection of PRP, standardized post-injection PT regimens, and patient populations that are clearly defined in terms of severity and chronicity of disease. Furthermore, studies must be rigorously designed in terms of randomization, blinding, and analysis. (Many studies done to date did not use an intention-to-treat protocol, for example). Higher-quality studies with larger numbers of participants are the only way to determine whether PRP is worth all the “buzz.”

Platelet-rich plasma is approved only for use in the operative setting to enhance bone graft handling properties. Office-based injections are an off-label use.

We should keep in mind, too, that the evidence for many of the other treatment options for both tendinopathy and knee OA are similarly problematic, and these modalities are even more widely used than PRP. Given the systemic problems associated with nonsteroidal anti-inflammatory drugs, concerns about possible tendon rupture with corticosteroid injections, and the time and compliance issues associated with PT, PRP may be a safer alternative to more traditional treatments.

An off-label use. PRP does not pass through the standard regulatory pathway of the US Food and Drug Administration (FDA). As a blood product, PRP falls under the regulatory purview of the FDA’s Center for Biologics Evaluation and Research, which has approved PRP only for use in the operative setting to enhance bone graft handling properties.²⁷ Therefore, office-based PRP injections are an off-label use of the treatment.

CASE 1 › You explain to Ms. T that PRP injections are not covered by insurance and that there is not a significant amount of evidence to indicate that an injection would appreciably improve her pain. She decides to proceed with a knee replacement and not to pursue a PRP injection.

CASE 2 › Given the time that Mr. H has invested in traditional conservative management strategies, his time away from work, and that he is not concerned with the out-of-pocket cost associated with PRP, you explain to him that there is some limited evidence that PRP might improve his symptoms. He decides that he would rather try a PRP injection than pursue surgery.

CORRESPONDENCE
Jordan White, MD, MPH, Department of Family Medicine, 111 Brewster Street, Pawtucket, RI 02860; [email protected].