Ajay Sood, MD

Insulin injection therapy is one of the most widely used health care interventions to manage both type 1 and type 2 diabetes mellitus (T1DM/T2DM). Globally, more than 150 to 200 million people inject insulin into their upper posterior arms, buttocks, anterior and lateral thighs, or abdomen.^1,2 In an ideal world, every patient would be using the correct site and rotating their insulin injection sites in accordance with health care professional (HCP) recommendations—systematic injections in one general body location, at least 1 cm away from the previous injection.² Unfortunately, same-site insulin injection (repeatedly in the same region within 1 cm of previous injections) is a common mistake made by patients with DM—in one study, 63% of participants either did not rotate sites correctly or failed to do so at all.

Insulin-resistant cutaneous complications may occur as a result of same-site insulin injections. The most common is lipohypertrophy, reported in some studies in nearly 50% of patients with DM on insulin therapy.⁴ Other common cutaneous complications include lipoatrophy and amyloidosis. Injection-site acanthosis nigricans, although uncommon, has been reported in 18 cases in the literature.

Most articles suggest that same-site insulin injections decrease local insulin sensitivity and result in tissue hypertrophy because of the anabolic properties of insulin and increase in insulin binding to insulin-like growth factor-1 (IGF-1) receptor.^5-20 The hyperkeratotic growth and varying insulin absorption rates associated with these cutaneous complications increase chances of either hyper- or hypoglycemic episodes in patients.^10,11,13 It is the responsibility of the DM care professional to provide proper insulin-injection technique education and perform routine inspection of injection sites to reduce cutaneous complications of insulin therapy. The purpose of this article is to (1) describe a case of acanthosis nigricans resulting from insulin injection at the same site; (2) review case reports in the literature describing injection-site acanthosis nigricans resulting from same-site insulin injections; (3) describe localized cutaneous complications associated with the use of insulin; and (4) discuss clinical implications and lessons learned from the literature.

Case Presentation

A 75-year-old patient with an 8-year history of T2DM, as well as stable coronary artery disease, atrial fibrillation, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and stage 3 chronic kidney disease, presented with 2 discrete abdominal hyperpigmented plaques. At the time of the initial clinic visit, the patient was taking metformin 1000 mg twice daily and insulin glargine 40 units once daily. When insulin was initiated 7 years prior, the patient received neutral protamine Hagedorn (NPH) insulin for the first year and transitioned to insulin glargine. After 4 years of insulin therapy, insulin aspart was added and discontinued after 2 years. The patient’s hemoglobin A_1c (HbA_1c) was 6.8%, suggesting good glycemic control.

fdp03907_epub1_f1f2.png

The patient reported 5 years of progressive, asymptomatic hyperpigmentation of the skin surrounding his insulin glargine injection sites and injecting in these same sites daily without rotation. He reported no additional skin changes or symptoms. He had noticed no skin changes while using NPH insulin during his first year of insulin therapy. On examination, the abdominal wall skin demonstrated 2 well-demarcated, nearly black, soft, velvety plaques, measuring 9 × 8 cm on the left side and 4 × 3.5 cm on the right, suggesting acanthosis nigricans (Figure 1A). The remainder of the skin examination, including the flexures, was normal. Of note, the patient received biweekly intramuscular testosterone injections in the gluteal region for secondary hypogonadism with no adverse dermatologic effects. A skin punch biopsy was performed and revealed epidermal papillomatosis and hyperkeratosis, confirming the clinical diagnosis of acanthosis nigricans (Figure 2).

After a review of insulin-injection technique at his clinic visit, the patient started rotating insulin injection sites over his entire abdomen, and the acanthosis nigricans partially improved. A few months later, the patient stopped rotating the insulin injection site, and the acanthosis nigricans worsened again. Because of worsening glycemic control, the patient was then started on insulin aspart. He did not develop any skin changes at the insulin aspart injection site, although he was not rotating its site of injection.

Subsequently, with reeducation and proper injection-site rotation, the patient had resolution of his acanthosis nigricans (Figure 1b).

Discussion

A review of the literature revealed 18 reported cases of acanthosis nigricans at sites of repeated insulin injection (Table).^5-20 Acanthosis nigricans at the site of insulin injection afflicts patients of any age, with cases observed in patients aged 14 to 75 years. Sixteen (84%) of 19 cases were male. Fourteen cases (73%) had T2DM; the rest of the patients had T1DM. The duration of insulin injection therapy prior to onset ranged from immediate to 13 years (median 4 years). Fourteen cases (73%) were reported on the abdomen; however, other sites, such as thighs and upper arm, also were reported. Lesions size varied from 12 to 360 cm². Two cases had associated amyloidosis. The average HbA_1c reported at presentation was 10%. Following insulin injection-site rotation, most of the cases reported improvement of both glycemic control and acanthosis nigricans appearance.

In the case described by Kudo and colleagues, a 59-year-old male patient with T2DM had been injecting insulin into the same spot on his abdomen for 10 years. He developed acanthosis nigricans and an amyloidoma so large and firm that it bent the needle when he injected insulin.¹¹

Most of the cases we found in the literature were after 2005 and associated with the use of human or analog insulin. These cases may be related to a bias, as cases may be easier to find in digital archives in the later years, when human or analog insulins have been in common use. Also noteworthy, in cases that reported dosage, most were not very high, and the highest daily dose was 240 IU/d. Ten reports of injection-site acanthosis nigricans were in dermatology journals; only 5 reports were in endocrinology journals and 3 in general medical journals, indicating possible less awareness of this phenomenon in other HCPs who care for patients with DM.

Complications of Same-Site Injections

Acanthosis nigricans. Commonly found in the armpits, neck folds, and groin, acanthosis nigricans is known as one of the calling cards for insulin resistance, obesity, and hyperinsulinemia.²¹ Acanthosis nigricans can be seen in people with or without DM and is not limited to those on insulin therapy. However, same-site insulin injections for 4 to 6 years also may result in injection-site acanthosis nigricans–like lesions because of factors such as insulin exposure at the local tissue level.¹⁶

Acanthosis nigricans development is characterized by hyperpigmented, hyperkeratotic, velvety, and sometimes verrucous plaques.⁶ Acanthosis nigricans surrounding repeated injection sites is hypothesized to develop as a result of localized hyperinsulinemia secondary to insulin resistance, which increases the stimulation of IGF, thereby causing epidermal hypertrophy.^5-20 If insulin injection therapy continues to be administered through the acanthosis nigricans lesion, it results in decreased insulin absorption, leading to poor glycemic control.¹³

Acanthosis nigricans associated with insulin injection is reversible. After rotation of injection sites, lesions either decrease in size or severity of appearance.^5-8,11 Also, by avoiding injection into the hyperkeratotic plaques and using normal subcutaneous tissue for injection, patients’ response to insulin improves, as measured by HbA_1c and by decreased daily insulin requirement.^{6-8,10,12,18-20}

Lipohypertrophy. This is characterized by an increase in localized adipose tissue and is the most common cutaneous complication of insulin therapy.² Lipohypertrophy presents as a firm, rubbery mass in the location of same-site insulin injections.²² Development of lipohypertrophy is suspected to be the result of either (1) anabolic effect of insulin on local adipocytes, promoting fat and protein synthesis; (2) an autoimmune response by immunoglobulin (Ig) G or IgE antibodies to insulin, immune response to insulin of different species, or to insulin injection techniques; or (3) repeated trauma to the injection site from repeated needle usage.^4,23

In a study assessing the prevalence of lipohypertrophy and its relation to insulin technique, 49.1% of participants with lipohypertrophy had glycemic variability compared with 6.5% of participants without lipohypertrophy.³ Johansson and colleagues described an impairment of insulin absorption in lipohypertrophic tissues, causing a 25% lower plasma insulin concentration compared with that of normal tissues.⁴ These findings suggest a significant effect of lipohypertrophy on insulin absorption—unnecessarily increasing insulin consumption and worsening glycemic control.

Primary prevention measures include injection site inspection and patient education about rotation and abstaining from needle reuse.²² If a patient already has signs of lipohypertrophy, data supports education and insulin injection technique practice as simple and effective means to reduce insulin action variability and increase glycemic control.²⁴

Lipoatrophy. Lipoatrophy is described as a local loss of subcutaneous adipose tissue often in the face, buttocks, legs and arm regions and can be rooted in genetic, immune, or drug-associated etiologies.²⁵ Insulin-induced lipoatrophy is suspected to be the result of tumor necrosis factor-α hyperproduction in reaction to insulin crystal presence at the injection site.^26,27 Overall, lipoatrophy development has decreased since the use of recombinant human insulin and analog insulin therapy.²⁸ The decrease is hypothesized to be due to increased subcutaneous tissue absorption rate of human insulin and its analog, decreasing overall adipocyte exposure to localized high insulin concentration.²⁷ Treatments for same-site insulin-derived lipoatrophy include changing injection sites and preparation of insulin.²⁶ When injection into the lipoatrophic site was avoided, glycemic control and lipoatrophy appearance improved.²⁶

Amyloidosis. Amyloidosis indicates the presence of an extracellular bundle of insoluble polymeric protein fibrils in tissues and organs.²⁹ Insulin-induced amyloidosis presents as a hard mass or ball near the injection site.²⁹ Insulin is one of many hormones that can form amyloid fibrils, and there have been several dozen cases reported of amyloid formation at the site of insulin injection.^29-31 Although insulin-derived amyloidosis is rare, it may be misdiagnosed as lipohypertrophy due to a lack of histopathologic testing or general awareness of the complication.²⁹

In a case series of 7 patients with amyloidosis, all patients had a mean HbA_1c of 9.3% (range, 8.5-10.2%) and averaged 1 IU/kg bodyweight before intervention.³⁰ After the discovery of the mass, participants were instructed to avoid injection into the amyloidoma, and average insulin requirements decreased to 0.48 IU/kg body weight (P = .40).³⁰ Patients with amyloidosis who rotated their injection sites experienced better glycemic control and decreased insulin requirements.³⁰

Pathophysiology of Localized Insulin Resistance

Insulin regulates glucose homeostasis in skeletal muscle and adipose tissue, increases hepatic and adipocyte lipid synthesis, and decreases adipocyte fatty acid release.³² Generalized insulin resistance occurs when target tissues have decreased glucose uptake in response to circulating insulin.³² Insulin resistance increases the amount of free insulin in surrounding tissues. At high concentrations, insulin fosters tissue growth by binding to IGF-1 receptors, stimulating hypertrophy and reproduction of keratinocytes and fibroblasts.³³ This pathophysiology helps explain the origin of localized acanthosis nigricans at same-site insulin injections.

Conclusions

Cutaneous complications are a local adverse effect of long-term failure to rotate insulin injection sites. Our case serves as a call to action for HCPs to improve education regarding insulin injection-site rotation, conduct routine injection-site inspection, and actively document cases as they occur to increase public awareness of these important complications.

If a patient with DM presents with unexplained poor glycemic control, consider questioning the patient about injection-site location and how often they are rotating the insulin injection site. Inspect the site for cutaneous complications. Of note, if a patient has a cutaneous complication due to insulin injection, adjust or decrease the insulin dosage when rotating sites to mitigate the risk of hypoglycemic episodes.

Improvement of glycemic control, cosmetic appearance of injection site, and insulin use all begin with skin inspection, injection technique education, and periodic review by a HCP.

Insulin injection therapy is one of the most widely used health care interventions to manage both type 1 and type 2 diabetes mellitus (T1DM/T2DM). Globally, more than 150 to 200 million people inject insulin into their upper posterior arms, buttocks, anterior and lateral thighs, or abdomen.^1,2 In an ideal world, every patient would be using the correct site and rotating their insulin injection sites in accordance with health care professional (HCP) recommendations—systematic injections in one general body location, at least 1 cm away from the previous injection.² Unfortunately, same-site insulin injection (repeatedly in the same region within 1 cm of previous injections) is a common mistake made by patients with DM—in one study, 63% of participants either did not rotate sites correctly or failed to do so at all.

Insulin-resistant cutaneous complications may occur as a result of same-site insulin injections. The most common is lipohypertrophy, reported in some studies in nearly 50% of patients with DM on insulin therapy.⁴ Other common cutaneous complications include lipoatrophy and amyloidosis. Injection-site acanthosis nigricans, although uncommon, has been reported in 18 cases in the literature.

Most articles suggest that same-site insulin injections decrease local insulin sensitivity and result in tissue hypertrophy because of the anabolic properties of insulin and increase in insulin binding to insulin-like growth factor-1 (IGF-1) receptor.^5-20 The hyperkeratotic growth and varying insulin absorption rates associated with these cutaneous complications increase chances of either hyper- or hypoglycemic episodes in patients.^10,11,13 It is the responsibility of the DM care professional to provide proper insulin-injection technique education and perform routine inspection of injection sites to reduce cutaneous complications of insulin therapy. The purpose of this article is to (1) describe a case of acanthosis nigricans resulting from insulin injection at the same site; (2) review case reports in the literature describing injection-site acanthosis nigricans resulting from same-site insulin injections; (3) describe localized cutaneous complications associated with the use of insulin; and (4) discuss clinical implications and lessons learned from the literature.

Case Presentation

A 75-year-old patient with an 8-year history of T2DM, as well as stable coronary artery disease, atrial fibrillation, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and stage 3 chronic kidney disease, presented with 2 discrete abdominal hyperpigmented plaques. At the time of the initial clinic visit, the patient was taking metformin 1000 mg twice daily and insulin glargine 40 units once daily. When insulin was initiated 7 years prior, the patient received neutral protamine Hagedorn (NPH) insulin for the first year and transitioned to insulin glargine. After 4 years of insulin therapy, insulin aspart was added and discontinued after 2 years. The patient’s hemoglobin A_1c (HbA_1c) was 6.8%, suggesting good glycemic control.

fdp03907_epub1_f1f2.png

The patient reported 5 years of progressive, asymptomatic hyperpigmentation of the skin surrounding his insulin glargine injection sites and injecting in these same sites daily without rotation. He reported no additional skin changes or symptoms. He had noticed no skin changes while using NPH insulin during his first year of insulin therapy. On examination, the abdominal wall skin demonstrated 2 well-demarcated, nearly black, soft, velvety plaques, measuring 9 × 8 cm on the left side and 4 × 3.5 cm on the right, suggesting acanthosis nigricans (Figure 1A). The remainder of the skin examination, including the flexures, was normal. Of note, the patient received biweekly intramuscular testosterone injections in the gluteal region for secondary hypogonadism with no adverse dermatologic effects. A skin punch biopsy was performed and revealed epidermal papillomatosis and hyperkeratosis, confirming the clinical diagnosis of acanthosis nigricans (Figure 2).

After a review of insulin-injection technique at his clinic visit, the patient started rotating insulin injection sites over his entire abdomen, and the acanthosis nigricans partially improved. A few months later, the patient stopped rotating the insulin injection site, and the acanthosis nigricans worsened again. Because of worsening glycemic control, the patient was then started on insulin aspart. He did not develop any skin changes at the insulin aspart injection site, although he was not rotating its site of injection.

Subsequently, with reeducation and proper injection-site rotation, the patient had resolution of his acanthosis nigricans (Figure 1b).

Discussion

A review of the literature revealed 18 reported cases of acanthosis nigricans at sites of repeated insulin injection (Table).^5-20 Acanthosis nigricans at the site of insulin injection afflicts patients of any age, with cases observed in patients aged 14 to 75 years. Sixteen (84%) of 19 cases were male. Fourteen cases (73%) had T2DM; the rest of the patients had T1DM. The duration of insulin injection therapy prior to onset ranged from immediate to 13 years (median 4 years). Fourteen cases (73%) were reported on the abdomen; however, other sites, such as thighs and upper arm, also were reported. Lesions size varied from 12 to 360 cm². Two cases had associated amyloidosis. The average HbA_1c reported at presentation was 10%. Following insulin injection-site rotation, most of the cases reported improvement of both glycemic control and acanthosis nigricans appearance.

In the case described by Kudo and colleagues, a 59-year-old male patient with T2DM had been injecting insulin into the same spot on his abdomen for 10 years. He developed acanthosis nigricans and an amyloidoma so large and firm that it bent the needle when he injected insulin.¹¹

Most of the cases we found in the literature were after 2005 and associated with the use of human or analog insulin. These cases may be related to a bias, as cases may be easier to find in digital archives in the later years, when human or analog insulins have been in common use. Also noteworthy, in cases that reported dosage, most were not very high, and the highest daily dose was 240 IU/d. Ten reports of injection-site acanthosis nigricans were in dermatology journals; only 5 reports were in endocrinology journals and 3 in general medical journals, indicating possible less awareness of this phenomenon in other HCPs who care for patients with DM.

Complications of Same-Site Injections

Acanthosis nigricans. Commonly found in the armpits, neck folds, and groin, acanthosis nigricans is known as one of the calling cards for insulin resistance, obesity, and hyperinsulinemia.²¹ Acanthosis nigricans can be seen in people with or without DM and is not limited to those on insulin therapy. However, same-site insulin injections for 4 to 6 years also may result in injection-site acanthosis nigricans–like lesions because of factors such as insulin exposure at the local tissue level.¹⁶

Acanthosis nigricans development is characterized by hyperpigmented, hyperkeratotic, velvety, and sometimes verrucous plaques.⁶ Acanthosis nigricans surrounding repeated injection sites is hypothesized to develop as a result of localized hyperinsulinemia secondary to insulin resistance, which increases the stimulation of IGF, thereby causing epidermal hypertrophy.^5-20 If insulin injection therapy continues to be administered through the acanthosis nigricans lesion, it results in decreased insulin absorption, leading to poor glycemic control.¹³

Acanthosis nigricans associated with insulin injection is reversible. After rotation of injection sites, lesions either decrease in size or severity of appearance.^5-8,11 Also, by avoiding injection into the hyperkeratotic plaques and using normal subcutaneous tissue for injection, patients’ response to insulin improves, as measured by HbA_1c and by decreased daily insulin requirement.^{6-8,10,12,18-20}

Lipohypertrophy. This is characterized by an increase in localized adipose tissue and is the most common cutaneous complication of insulin therapy.² Lipohypertrophy presents as a firm, rubbery mass in the location of same-site insulin injections.²² Development of lipohypertrophy is suspected to be the result of either (1) anabolic effect of insulin on local adipocytes, promoting fat and protein synthesis; (2) an autoimmune response by immunoglobulin (Ig) G or IgE antibodies to insulin, immune response to insulin of different species, or to insulin injection techniques; or (3) repeated trauma to the injection site from repeated needle usage.^4,23

In a study assessing the prevalence of lipohypertrophy and its relation to insulin technique, 49.1% of participants with lipohypertrophy had glycemic variability compared with 6.5% of participants without lipohypertrophy.³ Johansson and colleagues described an impairment of insulin absorption in lipohypertrophic tissues, causing a 25% lower plasma insulin concentration compared with that of normal tissues.⁴ These findings suggest a significant effect of lipohypertrophy on insulin absorption—unnecessarily increasing insulin consumption and worsening glycemic control.

Primary prevention measures include injection site inspection and patient education about rotation and abstaining from needle reuse.²² If a patient already has signs of lipohypertrophy, data supports education and insulin injection technique practice as simple and effective means to reduce insulin action variability and increase glycemic control.²⁴

Lipoatrophy. Lipoatrophy is described as a local loss of subcutaneous adipose tissue often in the face, buttocks, legs and arm regions and can be rooted in genetic, immune, or drug-associated etiologies.²⁵ Insulin-induced lipoatrophy is suspected to be the result of tumor necrosis factor-α hyperproduction in reaction to insulin crystal presence at the injection site.^26,27 Overall, lipoatrophy development has decreased since the use of recombinant human insulin and analog insulin therapy.²⁸ The decrease is hypothesized to be due to increased subcutaneous tissue absorption rate of human insulin and its analog, decreasing overall adipocyte exposure to localized high insulin concentration.²⁷ Treatments for same-site insulin-derived lipoatrophy include changing injection sites and preparation of insulin.²⁶ When injection into the lipoatrophic site was avoided, glycemic control and lipoatrophy appearance improved.²⁶

Amyloidosis. Amyloidosis indicates the presence of an extracellular bundle of insoluble polymeric protein fibrils in tissues and organs.²⁹ Insulin-induced amyloidosis presents as a hard mass or ball near the injection site.²⁹ Insulin is one of many hormones that can form amyloid fibrils, and there have been several dozen cases reported of amyloid formation at the site of insulin injection.^29-31 Although insulin-derived amyloidosis is rare, it may be misdiagnosed as lipohypertrophy due to a lack of histopathologic testing or general awareness of the complication.²⁹

In a case series of 7 patients with amyloidosis, all patients had a mean HbA_1c of 9.3% (range, 8.5-10.2%) and averaged 1 IU/kg bodyweight before intervention.³⁰ After the discovery of the mass, participants were instructed to avoid injection into the amyloidoma, and average insulin requirements decreased to 0.48 IU/kg body weight (P = .40).³⁰ Patients with amyloidosis who rotated their injection sites experienced better glycemic control and decreased insulin requirements.³⁰

Pathophysiology of Localized Insulin Resistance

Insulin regulates glucose homeostasis in skeletal muscle and adipose tissue, increases hepatic and adipocyte lipid synthesis, and decreases adipocyte fatty acid release.³² Generalized insulin resistance occurs when target tissues have decreased glucose uptake in response to circulating insulin.³² Insulin resistance increases the amount of free insulin in surrounding tissues. At high concentrations, insulin fosters tissue growth by binding to IGF-1 receptors, stimulating hypertrophy and reproduction of keratinocytes and fibroblasts.³³ This pathophysiology helps explain the origin of localized acanthosis nigricans at same-site insulin injections.

Conclusions

Cutaneous complications are a local adverse effect of long-term failure to rotate insulin injection sites. Our case serves as a call to action for HCPs to improve education regarding insulin injection-site rotation, conduct routine injection-site inspection, and actively document cases as they occur to increase public awareness of these important complications.

If a patient with DM presents with unexplained poor glycemic control, consider questioning the patient about injection-site location and how often they are rotating the insulin injection site. Inspect the site for cutaneous complications. Of note, if a patient has a cutaneous complication due to insulin injection, adjust or decrease the insulin dosage when rotating sites to mitigate the risk of hypoglycemic episodes.

Improvement of glycemic control, cosmetic appearance of injection site, and insulin use all begin with skin inspection, injection technique education, and periodic review by a HCP.

Insulin injection therapy is one of the most widely used health care interventions to manage both type 1 and type 2 diabetes mellitus (T1DM/T2DM). Globally, more than 150 to 200 million people inject insulin into their upper posterior arms, buttocks, anterior and lateral thighs, or abdomen.^1,2 In an ideal world, every patient would be using the correct site and rotating their insulin injection sites in accordance with health care professional (HCP) recommendations—systematic injections in one general body location, at least 1 cm away from the previous injection.² Unfortunately, same-site insulin injection (repeatedly in the same region within 1 cm of previous injections) is a common mistake made by patients with DM—in one study, 63% of participants either did not rotate sites correctly or failed to do so at all.

Insulin-resistant cutaneous complications may occur as a result of same-site insulin injections. The most common is lipohypertrophy, reported in some studies in nearly 50% of patients with DM on insulin therapy.⁴ Other common cutaneous complications include lipoatrophy and amyloidosis. Injection-site acanthosis nigricans, although uncommon, has been reported in 18 cases in the literature.

Most articles suggest that same-site insulin injections decrease local insulin sensitivity and result in tissue hypertrophy because of the anabolic properties of insulin and increase in insulin binding to insulin-like growth factor-1 (IGF-1) receptor.^5-20 The hyperkeratotic growth and varying insulin absorption rates associated with these cutaneous complications increase chances of either hyper- or hypoglycemic episodes in patients.^10,11,13 It is the responsibility of the DM care professional to provide proper insulin-injection technique education and perform routine inspection of injection sites to reduce cutaneous complications of insulin therapy. The purpose of this article is to (1) describe a case of acanthosis nigricans resulting from insulin injection at the same site; (2) review case reports in the literature describing injection-site acanthosis nigricans resulting from same-site insulin injections; (3) describe localized cutaneous complications associated with the use of insulin; and (4) discuss clinical implications and lessons learned from the literature.

Case Presentation

A 75-year-old patient with an 8-year history of T2DM, as well as stable coronary artery disease, atrial fibrillation, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and stage 3 chronic kidney disease, presented with 2 discrete abdominal hyperpigmented plaques. At the time of the initial clinic visit, the patient was taking metformin 1000 mg twice daily and insulin glargine 40 units once daily. When insulin was initiated 7 years prior, the patient received neutral protamine Hagedorn (NPH) insulin for the first year and transitioned to insulin glargine. After 4 years of insulin therapy, insulin aspart was added and discontinued after 2 years. The patient’s hemoglobin A_1c (HbA_1c) was 6.8%, suggesting good glycemic control.

fdp03907_epub1_f1f2.png

The patient reported 5 years of progressive, asymptomatic hyperpigmentation of the skin surrounding his insulin glargine injection sites and injecting in these same sites daily without rotation. He reported no additional skin changes or symptoms. He had noticed no skin changes while using NPH insulin during his first year of insulin therapy. On examination, the abdominal wall skin demonstrated 2 well-demarcated, nearly black, soft, velvety plaques, measuring 9 × 8 cm on the left side and 4 × 3.5 cm on the right, suggesting acanthosis nigricans (Figure 1A). The remainder of the skin examination, including the flexures, was normal. Of note, the patient received biweekly intramuscular testosterone injections in the gluteal region for secondary hypogonadism with no adverse dermatologic effects. A skin punch biopsy was performed and revealed epidermal papillomatosis and hyperkeratosis, confirming the clinical diagnosis of acanthosis nigricans (Figure 2).

After a review of insulin-injection technique at his clinic visit, the patient started rotating insulin injection sites over his entire abdomen, and the acanthosis nigricans partially improved. A few months later, the patient stopped rotating the insulin injection site, and the acanthosis nigricans worsened again. Because of worsening glycemic control, the patient was then started on insulin aspart. He did not develop any skin changes at the insulin aspart injection site, although he was not rotating its site of injection.

Subsequently, with reeducation and proper injection-site rotation, the patient had resolution of his acanthosis nigricans (Figure 1b).

Discussion

A review of the literature revealed 18 reported cases of acanthosis nigricans at sites of repeated insulin injection (Table).^5-20 Acanthosis nigricans at the site of insulin injection afflicts patients of any age, with cases observed in patients aged 14 to 75 years. Sixteen (84%) of 19 cases were male. Fourteen cases (73%) had T2DM; the rest of the patients had T1DM. The duration of insulin injection therapy prior to onset ranged from immediate to 13 years (median 4 years). Fourteen cases (73%) were reported on the abdomen; however, other sites, such as thighs and upper arm, also were reported. Lesions size varied from 12 to 360 cm². Two cases had associated amyloidosis. The average HbA_1c reported at presentation was 10%. Following insulin injection-site rotation, most of the cases reported improvement of both glycemic control and acanthosis nigricans appearance.

In the case described by Kudo and colleagues, a 59-year-old male patient with T2DM had been injecting insulin into the same spot on his abdomen for 10 years. He developed acanthosis nigricans and an amyloidoma so large and firm that it bent the needle when he injected insulin.¹¹

Most of the cases we found in the literature were after 2005 and associated with the use of human or analog insulin. These cases may be related to a bias, as cases may be easier to find in digital archives in the later years, when human or analog insulins have been in common use. Also noteworthy, in cases that reported dosage, most were not very high, and the highest daily dose was 240 IU/d. Ten reports of injection-site acanthosis nigricans were in dermatology journals; only 5 reports were in endocrinology journals and 3 in general medical journals, indicating possible less awareness of this phenomenon in other HCPs who care for patients with DM.

Complications of Same-Site Injections

Acanthosis nigricans. Commonly found in the armpits, neck folds, and groin, acanthosis nigricans is known as one of the calling cards for insulin resistance, obesity, and hyperinsulinemia.²¹ Acanthosis nigricans can be seen in people with or without DM and is not limited to those on insulin therapy. However, same-site insulin injections for 4 to 6 years also may result in injection-site acanthosis nigricans–like lesions because of factors such as insulin exposure at the local tissue level.¹⁶

Acanthosis nigricans development is characterized by hyperpigmented, hyperkeratotic, velvety, and sometimes verrucous plaques.⁶ Acanthosis nigricans surrounding repeated injection sites is hypothesized to develop as a result of localized hyperinsulinemia secondary to insulin resistance, which increases the stimulation of IGF, thereby causing epidermal hypertrophy.^5-20 If insulin injection therapy continues to be administered through the acanthosis nigricans lesion, it results in decreased insulin absorption, leading to poor glycemic control.¹³

Acanthosis nigricans associated with insulin injection is reversible. After rotation of injection sites, lesions either decrease in size or severity of appearance.^5-8,11 Also, by avoiding injection into the hyperkeratotic plaques and using normal subcutaneous tissue for injection, patients’ response to insulin improves, as measured by HbA_1c and by decreased daily insulin requirement.^{6-8,10,12,18-20}

Lipohypertrophy. This is characterized by an increase in localized adipose tissue and is the most common cutaneous complication of insulin therapy.² Lipohypertrophy presents as a firm, rubbery mass in the location of same-site insulin injections.²² Development of lipohypertrophy is suspected to be the result of either (1) anabolic effect of insulin on local adipocytes, promoting fat and protein synthesis; (2) an autoimmune response by immunoglobulin (Ig) G or IgE antibodies to insulin, immune response to insulin of different species, or to insulin injection techniques; or (3) repeated trauma to the injection site from repeated needle usage.^4,23

In a study assessing the prevalence of lipohypertrophy and its relation to insulin technique, 49.1% of participants with lipohypertrophy had glycemic variability compared with 6.5% of participants without lipohypertrophy.³ Johansson and colleagues described an impairment of insulin absorption in lipohypertrophic tissues, causing a 25% lower plasma insulin concentration compared with that of normal tissues.⁴ These findings suggest a significant effect of lipohypertrophy on insulin absorption—unnecessarily increasing insulin consumption and worsening glycemic control.

Primary prevention measures include injection site inspection and patient education about rotation and abstaining from needle reuse.²² If a patient already has signs of lipohypertrophy, data supports education and insulin injection technique practice as simple and effective means to reduce insulin action variability and increase glycemic control.²⁴

Lipoatrophy. Lipoatrophy is described as a local loss of subcutaneous adipose tissue often in the face, buttocks, legs and arm regions and can be rooted in genetic, immune, or drug-associated etiologies.²⁵ Insulin-induced lipoatrophy is suspected to be the result of tumor necrosis factor-α hyperproduction in reaction to insulin crystal presence at the injection site.^26,27 Overall, lipoatrophy development has decreased since the use of recombinant human insulin and analog insulin therapy.²⁸ The decrease is hypothesized to be due to increased subcutaneous tissue absorption rate of human insulin and its analog, decreasing overall adipocyte exposure to localized high insulin concentration.²⁷ Treatments for same-site insulin-derived lipoatrophy include changing injection sites and preparation of insulin.²⁶ When injection into the lipoatrophic site was avoided, glycemic control and lipoatrophy appearance improved.²⁶

Amyloidosis. Amyloidosis indicates the presence of an extracellular bundle of insoluble polymeric protein fibrils in tissues and organs.²⁹ Insulin-induced amyloidosis presents as a hard mass or ball near the injection site.²⁹ Insulin is one of many hormones that can form amyloid fibrils, and there have been several dozen cases reported of amyloid formation at the site of insulin injection.^29-31 Although insulin-derived amyloidosis is rare, it may be misdiagnosed as lipohypertrophy due to a lack of histopathologic testing or general awareness of the complication.²⁹

In a case series of 7 patients with amyloidosis, all patients had a mean HbA_1c of 9.3% (range, 8.5-10.2%) and averaged 1 IU/kg bodyweight before intervention.³⁰ After the discovery of the mass, participants were instructed to avoid injection into the amyloidoma, and average insulin requirements decreased to 0.48 IU/kg body weight (P = .40).³⁰ Patients with amyloidosis who rotated their injection sites experienced better glycemic control and decreased insulin requirements.³⁰

Pathophysiology of Localized Insulin Resistance

Insulin regulates glucose homeostasis in skeletal muscle and adipose tissue, increases hepatic and adipocyte lipid synthesis, and decreases adipocyte fatty acid release.³² Generalized insulin resistance occurs when target tissues have decreased glucose uptake in response to circulating insulin.³² Insulin resistance increases the amount of free insulin in surrounding tissues. At high concentrations, insulin fosters tissue growth by binding to IGF-1 receptors, stimulating hypertrophy and reproduction of keratinocytes and fibroblasts.³³ This pathophysiology helps explain the origin of localized acanthosis nigricans at same-site insulin injections.

Conclusions

Cutaneous complications are a local adverse effect of long-term failure to rotate insulin injection sites. Our case serves as a call to action for HCPs to improve education regarding insulin injection-site rotation, conduct routine injection-site inspection, and actively document cases as they occur to increase public awareness of these important complications.

If a patient with DM presents with unexplained poor glycemic control, consider questioning the patient about injection-site location and how often they are rotating the insulin injection site. Inspect the site for cutaneous complications. Of note, if a patient has a cutaneous complication due to insulin injection, adjust or decrease the insulin dosage when rotating sites to mitigate the risk of hypoglycemic episodes.

Improvement of glycemic control, cosmetic appearance of injection site, and insulin use all begin with skin inspection, injection technique education, and periodic review by a HCP.

While cardiovascular mortality rates have declined, heart disease continues to be the leading cause of death in the US, and the number of people with cardiovascular disease (CVD) is rising.¹ CVD is more prevalent among military veterans than it is among nonveterans aged ≥ 25 years, and veteran status is associated with higher risk of incident heart disease after controlling for socioeconomic status, other medical diseases, depression, and lifestyle.^2-4 Combat exposure, posttraumatic stress disorder (PTSD), and Purple Heart commendation are associated with higher rates of CVD, including adverse cardiovascular events.^5-7 Many patients seeking care in the Veterans Health Administration (VHA), including those who undergo cardiac catheterization, meet the criteria for multimorbidity (defined as having ≥ 2 chronic diseases⁸), which is common among veterans.^9,10 Multimorbidity presents a challenge for lifestyle intervention, as different diets may be prescribed to treat different conditions, such as Dietary Approaches to Stop Hypertension, and low-glycemic diet for diabetes mellitus (DM). Veterans with CVD are often clinically complex and may require more multifaceted secondary prevention programs.

During the coronavirus 2019 (COVID-19) pandemic, effective secondary prevention intervention is needed more than ever. Older age, CVD, and common comorbidities, including hypertension, DM, and obesity, place patients at the highest risk for severe COVID-19 infection.¹¹ COVID-19 social distancing encourages vulnerable populations to stay home, which can make engaging in any levels of physical activity more challenging. The International Food Council found that 85% of adults have made a change to their food consumption pattern, including eating more, during the COVID-19 pandemic.¹² Thus, secondary CVD prevention programs for veterans need to provide treatment that addresses these specific challenges and can be delivered via telehealth for continuity of care after disruption of traditional services.

Nutrition may be the most powerful Ornish ICR component. The initial RCT conducted by Ornish and colleagues included only stress management training and a whole-food, plant-based (WFPB) diet, including grains, legumes, vegetables, fruits, nuts, and seeds. The trial found 91% of participants experienced reduced angina after only 24 days.¹⁵ The only single-component intervention study resulting in partial reversal of atherosclerosis was a WFPB diet-only study, which documented regression of atherosclerotic plaques after 5 years, using coronary angiography in 73% of participants, with arrested progression in the other 27%.²² Participants reported no cardiovascular AEs after 12 years.²³ Furthermore, a number of other recent studies have demonstrated the benefits of WFPB diet-only interventions for type 2 DM (T2DM), hypertension, and obesity.^24-27 The Heart Disease Reversal Program (HDRP) was developed to create an interdisciplinary lifestyle intervention that emphasized nutrition for a broad population of veterans with atherosclerotic CVD, of varying levels of functional ability, to promote comprehensive CVD risk reduction and bring heart disease reversal intervention into routine clinical practice.

fdp03712558_f.png

Program Description 

The Mental Health, Cardiology, and Nutrition and Food services all approved the launch of HDRP. We contacted veterans by mail, and 11% expressed interest (Figure). Among patients who received the initial mailed letter (prior to our accepting staff referrals), only 5% of patients who enrolled in HDRP reported previously being told about or prescribed a WFPB diet by any health care provider (HCP). Currently, patients are primarily referred to HDRP by Cardiology, Primary Care, and Mental Health services.

Design

HDRP is an adaptation of interdisciplinary lifestyle interventions that have resulted in regression of atherosclerotic blockages confirmed with invasive coronary angiography.^15-17,22,28 HDRP currently is offered in a Behavioral Medicine Clinic at the Sacramento US Department of Veterans Affairs (VA) Medical Center (VAMC) in California. Program staff include a clinical health psychologist who organizes, coordinates, and act as the lead facilitator of the program; registered dietitians; clinical pharmacists; and a consulting physician. Patients engage in the 4-month core HDRP program in small cohorts (ie, 6-10 patients), and spouses/partners are highly encouraged to attend all sessions.

Components

Telephone screening. Patients are screened for the inclusion and exclusion criteria (Table 1). Patients engaging in a traditional CR program are included in the screening. Patients are informed that the program consists of lifestyle intervention, including emphasis on following a WFPB diet.

fdp03712558_t1.png

fdp03712558_t2.png

A psychologist delivers the physical activity component. Patients are encouraged to meet the American Heart Association/American College of Cardiology recommendations for aerobic exercise (at least 150 minutes of moderate intensity physical activity per week) through a walking program.³⁵ Patients with medical contraindications (eg, severe pain, mobility restrictions) are encouraged to follow the exercise/activity recommendations they had been given by their primary care provider (PCP), physical therapist, or other HCP.

A psychologist provides evidence-based cognitive behavioral stress management (CBSM) training, adapted from models developed for patients with stable ischemic heart disease, HIV/AIDS, and cancer.^36-38 CBSM is a psychotherapy grounded in stress/coping theory and cognitive behavioral theory of psychopathology that integrates cognitive restructuring, coping skills training, communication/assertiveness training, anger management, and mindfulness/acceptance-based approaches. Additional emphasis is placed on assisting patients’ adjustment to the lifestyle challenges for following a plant-based diet, dealing with food cravings and emotional eating, and connecting lifestyle change to patients’ deepest values and goals.

A clinical pharmacist conducts a medication reconciliation for each patient at baseline. The pharmacist consults with each patient’s PCP, cardiologist, and HDRP consulting physician, as needed, to ensure safe adjustments to medications. Pharmacists also provide education on medications at group sessions.

After completion of the 12-week core program, graduates are encouraged to attend the monthly graduates’ group indefinitely, and as often as they desire to promote maintenance of the disease reversal lifestyle. Patients are encouraged to complete our recommended fasting laboratory work every 3 to 6 months to facilitate maintenance of treatment gains.

Program Evaluation

Patients frequently reported that the group format was vital to their success. Patients requested a cooking class, yet we lacked a full teaching kitchen. Integrating plant-based meal samples at every session and cooking videos helped. Patients reported that 100% adherence to the WFPB diet led to significant changes in their food preferences, including a loss of interest in meat.³⁹ Patients encouraged us to keep the “disease reversal” language and focus. One veteran stated: “Disease reversal, that is the reason I called you when I got your letter.” Showing before and after images of coronary angiograms and cardiac positron emission tomography scans depicting regression of atherosclerotic plaque and restored myocardial perfusion were described as highly motivating and generated willingness to commit to a more aggressive lifestyle change.³¹

Patients routinely stated that they lacked understanding of their laboratory test results, which HDRP remedied. Some patients reported their adult children followed a plant-based diet, and our program resulted in a new commonality and source of bonding that was highly valued. Some patients reported that HDRP was helpful for controlling their COVID-19 anxiety and feeling in control of their health. Satisfaction surveys were completed by participants at the end of the core program, which demonstrated very high satisfaction with and acceptability of HDRP (Table 3).

fdp03712558_t3.png

COVID-19 Response

Face-to-face group appointments were converted to videoconferencing as a result of the COVID-19 pandemic. While HDRP always promoted the use of technology and mHealth tools, the pandemic led us to develop novel technology-based interventions.⁴⁰ One cohort transitioned from in-person to videoconferencing sessions, and 2 cohorts recently started this format and are ongoing. We have successfully used videoconferencing with Cisco Webex, the VA-approved backup platform, as we encountered technical barriers when using VA Video Connect. Program materials were shared electronically, and participants sent blood pressure/sugar logs by secure messaging. Guidance for online grocery shopping with home delivery was provided, and research on the benefits of the HDRP lifestyle on immune function was incorporated.

The stress management component incorporated coping with COVID-19, including normalizing common emotional difficulties with sheltering-in-place and quarantine, acknowledging and processing fear and anxiety related to being at very high risk for severe COVID-19. We presented heart disease reversal as an urgent and feasible goal during the pandemic both reducing risk of premature death and major adverse cardiovascular events in the long-term and also reducing personal risk of severe COVID complications. The new VA COVID Coach app was also presented as a resource. Reputable sources of COVID-19 and public health information were shared. Walking continued to be the primary recommended form of exercise, while indoor home exercise options were promoted during the periods of very poor air quality due to the widespread California fires and smoke.

Considering the research suggesting benefits of our intervention for treating T2DM,promoting sustained weight loss, and promoting comprehensive cardiometabolic risk reduction, we have begun accepting referrals for patients with any type of atherosclerotic CVD (eg, peripheral artery disease, carotid artery disease), patients with T2DM (without CVD), and patients with only a history of ischemic stroke or transient ischemic attack.^24-27 Vascular surgery has become a new referral source, primarily for patients with peripheral and carotid artery diseases. Finally, we are leveraging videoconferencing and accepting referrals across the VA Northern California Health Care System (VANCHCS)catchment (from the California-Oregon state border to the San Francisco Bay Area). This also helps address a long-standing problem with reaching the many rural veterans who live far from a VA clinic. We successfully implemented a consult/referral process within the EHR that is available to providers across VANCHCS.

Discussion

The efficacy and effectiveness of reversal programs are well established in intensive programs (eg, ICR), yet such programs have yet to be streamlined and disseminated broadly into routine clinical care. HDRP has endeavored to address this by emphasizing nutrition relative to other program components. We have learned that the words “disease reversal” are very often the reason patients initially reach out or accept referral to our program.

Consistent with past research on plant-based nutrition interventions, the group format was indispensable.⁴¹ Individual sessions with a clinical health psychologist enabled tailored feedback and education on how behavior changes could impact laboratory results and how certain psychosocial factors could support success. Participants reported that seeing significantly favorable laboratory results was highly motivating and confirmed the power of their lifestyle changes. Furthermore, a psychosocial health assessment with individual sessions promoted a tailored treatment plan with targeted clinical interventions, such as behavioral health education, motivational interviewing, and advanced methods, including cognitive behavioral therapy and techniques drawn from dialectical behavior therapy and acceptance and commitment therapy.

Veterans with multimorbidity face the difficult task of learning and maintaining a complex disease self-management program and implementing a lifestyle approach that is feasible, effective, promotes weight loss, and treats multiple conditions. HDRP is a model approach for this population, as demonstrated by a recent case report of a 65-year-old male veteran with atherosclerotic CVD, T2DM, hypertension, and myasthenia gravis who had 2 heart attacks within 2 months.⁴² His neurologic disease precluded significant physical activity. Although he achieved some initial weight loss through lifestyle changes, he continued to have daily angina despite optimal and aggressive cardiology management. After enrolling in HDRP and adopting the WFPB diet, the patient reported almost complete resolution of angina within 1 month, similar to that found in other studies.¹⁵

The literature suggests that concern over the acceptability of plant-based diets and patients’ ability to adhere to them long-term may be misplaced. A review paper on dietary interventions lasting > 1 year found that 51 to 61% of vegetarian and vegan study participants had maintained dietary adherence, while 20 to 55% of omnivorous diet intervention participants adhered to their study diets.⁴³ Remarkably, there were no statistically significant differences in the acceptability of the vegan, vegetarian, or omnivorous diets in the studies reviewed.⁴³ Recent dietary research also suggests that providing patients with higher goals (eg, adopting a vegan diet instead of only moderate dietary changes) results in greater weight loss and maintenance.²⁶ HDRP provides training on consumption of whole plant foods, which may offer patients a unique advantage for maximizing results and higher adherence over time.

Limitations

Hands-on cooking instruction was not provided at our VAMC. The total time of the intervention was significantly less in HDRP (25 hours) than it was for the Ornish ICR program (72 hours), which may hinder long-term adherence. Without an exercise facility, we were not able to provide more detailed exercise instruction and supervised exercise.

Program Improvements Planned

There are a number of improvements that are planned for HDRP. First, the program anticipates requesting medical clearance at the telephone screening stage for self-referred patients. Second, HDRP will provide regular presentations on the program to VAMC clinics and community-based outpatient clinics, including reminders about inclusion/exclusion criteria and the referral process, and to solicit feedback on processes. Third, we hope to routinely provide education and address common questions and concerns of HCPs, including expected results. Fourth, we would like to lengthen the patient commitment to HDRP (eg, 1- to 2-year commitment to the graduate group), consistent with other HDRPs.²⁸ Fifth, we hope to further integrate technology-based components to promote behavior change/maintenance, such as automated text messaging.

Conclusions

Although our patient population was self-selected for participation, early program evaluation demonstrates high acceptability. Very few patients had ever been told about a heart disease reversing lifestyle, and we found direct-to-patient clinical outreach an effective method for launching a disease reversal program (optimally timed with HCP presentations). Furthermore, the program is adaptable to current restrictions on in-person appointments due to the COVID-19 pandemic, and much more convenient for rural veterans who live far from any VA clinic. Being able to offer sustainable health care for individuals during unexpected public health crises is critically important. Additionally, treating veterans who are most vulnerable to pandemic illness due to existing medical conditions, such as CVD, should be a high priority. Last, HDRP also may represent a novel integrated treatment for COVID-19 anxiety and secondary CVD prevention, as lifestyle habits are optimized to improve chronic diseases that elevate risk for severe COVID-19 infection and mortality, as well as including coping strategies consistent with evidence-based psychotherapies for anxiety disorders.⁴⁴

We believe that beyond the clinical benefits to patients, there is significant value and benefit added to the health care system by offering an intervention within the “disease reversal” paradigm. Efforts of the health care team to reverse a disease can be considered the highest aim of medicine and health care.⁴⁵

Acknowledgments

This work was supported by the US Department of Veterans Affairs. We give special thanks to David M. Gellerman, MD, PhD, and David W. Schafer, PsyD, for providing Mental Health Service support for initiating the Heart Disease Reversal Program, and to Joseph Giorgio, PsyD (Program Manager, Integrated Care Program) for sustaining it. We thank Amogh Bhat, MD, Chief of Cardiology, for his continued support and partnership with the Cardiology Department. We express thanks to Stephanie Mohney, RDN (Chief, Nutrition and Food Service), Amy Klotz, RDN (Supervisory Dietician), Sian M. Carr-Lopez, PharmD (Associate Chief of Pharmacy, Primary Care), and Michelle Rand, PharmD, CACP (Anticoagulation Clinical Pharmacist-Supervisor) for their staff support of this interdisciplinary program. We thank the patients and their families for their participation in the program and commitment to the lifestyle changes. We also thank the following individuals for their contributions to this program: Lisa Wagaman, RDN, Karen Soong, PharmD, Sara S. Ali, PharmD, Suzan Hua, PharmD, and Stephen Cooperman.

While cardiovascular mortality rates have declined, heart disease continues to be the leading cause of death in the US, and the number of people with cardiovascular disease (CVD) is rising.¹ CVD is more prevalent among military veterans than it is among nonveterans aged ≥ 25 years, and veteran status is associated with higher risk of incident heart disease after controlling for socioeconomic status, other medical diseases, depression, and lifestyle.^2-4 Combat exposure, posttraumatic stress disorder (PTSD), and Purple Heart commendation are associated with higher rates of CVD, including adverse cardiovascular events.^5-7 Many patients seeking care in the Veterans Health Administration (VHA), including those who undergo cardiac catheterization, meet the criteria for multimorbidity (defined as having ≥ 2 chronic diseases⁸), which is common among veterans.^9,10 Multimorbidity presents a challenge for lifestyle intervention, as different diets may be prescribed to treat different conditions, such as Dietary Approaches to Stop Hypertension, and low-glycemic diet for diabetes mellitus (DM). Veterans with CVD are often clinically complex and may require more multifaceted secondary prevention programs.

During the coronavirus 2019 (COVID-19) pandemic, effective secondary prevention intervention is needed more than ever. Older age, CVD, and common comorbidities, including hypertension, DM, and obesity, place patients at the highest risk for severe COVID-19 infection.¹¹ COVID-19 social distancing encourages vulnerable populations to stay home, which can make engaging in any levels of physical activity more challenging. The International Food Council found that 85% of adults have made a change to their food consumption pattern, including eating more, during the COVID-19 pandemic.¹² Thus, secondary CVD prevention programs for veterans need to provide treatment that addresses these specific challenges and can be delivered via telehealth for continuity of care after disruption of traditional services.

Nutrition may be the most powerful Ornish ICR component. The initial RCT conducted by Ornish and colleagues included only stress management training and a whole-food, plant-based (WFPB) diet, including grains, legumes, vegetables, fruits, nuts, and seeds. The trial found 91% of participants experienced reduced angina after only 24 days.¹⁵ The only single-component intervention study resulting in partial reversal of atherosclerosis was a WFPB diet-only study, which documented regression of atherosclerotic plaques after 5 years, using coronary angiography in 73% of participants, with arrested progression in the other 27%.²² Participants reported no cardiovascular AEs after 12 years.²³ Furthermore, a number of other recent studies have demonstrated the benefits of WFPB diet-only interventions for type 2 DM (T2DM), hypertension, and obesity.^24-27 The Heart Disease Reversal Program (HDRP) was developed to create an interdisciplinary lifestyle intervention that emphasized nutrition for a broad population of veterans with atherosclerotic CVD, of varying levels of functional ability, to promote comprehensive CVD risk reduction and bring heart disease reversal intervention into routine clinical practice.

fdp03712558_f.png

Program Description 

The Mental Health, Cardiology, and Nutrition and Food services all approved the launch of HDRP. We contacted veterans by mail, and 11% expressed interest (Figure). Among patients who received the initial mailed letter (prior to our accepting staff referrals), only 5% of patients who enrolled in HDRP reported previously being told about or prescribed a WFPB diet by any health care provider (HCP). Currently, patients are primarily referred to HDRP by Cardiology, Primary Care, and Mental Health services.

Design

HDRP is an adaptation of interdisciplinary lifestyle interventions that have resulted in regression of atherosclerotic blockages confirmed with invasive coronary angiography.^15-17,22,28 HDRP currently is offered in a Behavioral Medicine Clinic at the Sacramento US Department of Veterans Affairs (VA) Medical Center (VAMC) in California. Program staff include a clinical health psychologist who organizes, coordinates, and act as the lead facilitator of the program; registered dietitians; clinical pharmacists; and a consulting physician. Patients engage in the 4-month core HDRP program in small cohorts (ie, 6-10 patients), and spouses/partners are highly encouraged to attend all sessions.

Components

Telephone screening. Patients are screened for the inclusion and exclusion criteria (Table 1). Patients engaging in a traditional CR program are included in the screening. Patients are informed that the program consists of lifestyle intervention, including emphasis on following a WFPB diet.

fdp03712558_t1.png

fdp03712558_t2.png

A psychologist delivers the physical activity component. Patients are encouraged to meet the American Heart Association/American College of Cardiology recommendations for aerobic exercise (at least 150 minutes of moderate intensity physical activity per week) through a walking program.³⁵ Patients with medical contraindications (eg, severe pain, mobility restrictions) are encouraged to follow the exercise/activity recommendations they had been given by their primary care provider (PCP), physical therapist, or other HCP.

A psychologist provides evidence-based cognitive behavioral stress management (CBSM) training, adapted from models developed for patients with stable ischemic heart disease, HIV/AIDS, and cancer.^36-38 CBSM is a psychotherapy grounded in stress/coping theory and cognitive behavioral theory of psychopathology that integrates cognitive restructuring, coping skills training, communication/assertiveness training, anger management, and mindfulness/acceptance-based approaches. Additional emphasis is placed on assisting patients’ adjustment to the lifestyle challenges for following a plant-based diet, dealing with food cravings and emotional eating, and connecting lifestyle change to patients’ deepest values and goals.

A clinical pharmacist conducts a medication reconciliation for each patient at baseline. The pharmacist consults with each patient’s PCP, cardiologist, and HDRP consulting physician, as needed, to ensure safe adjustments to medications. Pharmacists also provide education on medications at group sessions.

After completion of the 12-week core program, graduates are encouraged to attend the monthly graduates’ group indefinitely, and as often as they desire to promote maintenance of the disease reversal lifestyle. Patients are encouraged to complete our recommended fasting laboratory work every 3 to 6 months to facilitate maintenance of treatment gains.

Program Evaluation

Patients frequently reported that the group format was vital to their success. Patients requested a cooking class, yet we lacked a full teaching kitchen. Integrating plant-based meal samples at every session and cooking videos helped. Patients reported that 100% adherence to the WFPB diet led to significant changes in their food preferences, including a loss of interest in meat.³⁹ Patients encouraged us to keep the “disease reversal” language and focus. One veteran stated: “Disease reversal, that is the reason I called you when I got your letter.” Showing before and after images of coronary angiograms and cardiac positron emission tomography scans depicting regression of atherosclerotic plaque and restored myocardial perfusion were described as highly motivating and generated willingness to commit to a more aggressive lifestyle change.³¹

Patients routinely stated that they lacked understanding of their laboratory test results, which HDRP remedied. Some patients reported their adult children followed a plant-based diet, and our program resulted in a new commonality and source of bonding that was highly valued. Some patients reported that HDRP was helpful for controlling their COVID-19 anxiety and feeling in control of their health. Satisfaction surveys were completed by participants at the end of the core program, which demonstrated very high satisfaction with and acceptability of HDRP (Table 3).

fdp03712558_t3.png

COVID-19 Response

Face-to-face group appointments were converted to videoconferencing as a result of the COVID-19 pandemic. While HDRP always promoted the use of technology and mHealth tools, the pandemic led us to develop novel technology-based interventions.⁴⁰ One cohort transitioned from in-person to videoconferencing sessions, and 2 cohorts recently started this format and are ongoing. We have successfully used videoconferencing with Cisco Webex, the VA-approved backup platform, as we encountered technical barriers when using VA Video Connect. Program materials were shared electronically, and participants sent blood pressure/sugar logs by secure messaging. Guidance for online grocery shopping with home delivery was provided, and research on the benefits of the HDRP lifestyle on immune function was incorporated.

The stress management component incorporated coping with COVID-19, including normalizing common emotional difficulties with sheltering-in-place and quarantine, acknowledging and processing fear and anxiety related to being at very high risk for severe COVID-19. We presented heart disease reversal as an urgent and feasible goal during the pandemic both reducing risk of premature death and major adverse cardiovascular events in the long-term and also reducing personal risk of severe COVID complications. The new VA COVID Coach app was also presented as a resource. Reputable sources of COVID-19 and public health information were shared. Walking continued to be the primary recommended form of exercise, while indoor home exercise options were promoted during the periods of very poor air quality due to the widespread California fires and smoke.

Considering the research suggesting benefits of our intervention for treating T2DM,promoting sustained weight loss, and promoting comprehensive cardiometabolic risk reduction, we have begun accepting referrals for patients with any type of atherosclerotic CVD (eg, peripheral artery disease, carotid artery disease), patients with T2DM (without CVD), and patients with only a history of ischemic stroke or transient ischemic attack.^24-27 Vascular surgery has become a new referral source, primarily for patients with peripheral and carotid artery diseases. Finally, we are leveraging videoconferencing and accepting referrals across the VA Northern California Health Care System (VANCHCS)catchment (from the California-Oregon state border to the San Francisco Bay Area). This also helps address a long-standing problem with reaching the many rural veterans who live far from a VA clinic. We successfully implemented a consult/referral process within the EHR that is available to providers across VANCHCS.

Discussion

The efficacy and effectiveness of reversal programs are well established in intensive programs (eg, ICR), yet such programs have yet to be streamlined and disseminated broadly into routine clinical care. HDRP has endeavored to address this by emphasizing nutrition relative to other program components. We have learned that the words “disease reversal” are very often the reason patients initially reach out or accept referral to our program.

Consistent with past research on plant-based nutrition interventions, the group format was indispensable.⁴¹ Individual sessions with a clinical health psychologist enabled tailored feedback and education on how behavior changes could impact laboratory results and how certain psychosocial factors could support success. Participants reported that seeing significantly favorable laboratory results was highly motivating and confirmed the power of their lifestyle changes. Furthermore, a psychosocial health assessment with individual sessions promoted a tailored treatment plan with targeted clinical interventions, such as behavioral health education, motivational interviewing, and advanced methods, including cognitive behavioral therapy and techniques drawn from dialectical behavior therapy and acceptance and commitment therapy.

Veterans with multimorbidity face the difficult task of learning and maintaining a complex disease self-management program and implementing a lifestyle approach that is feasible, effective, promotes weight loss, and treats multiple conditions. HDRP is a model approach for this population, as demonstrated by a recent case report of a 65-year-old male veteran with atherosclerotic CVD, T2DM, hypertension, and myasthenia gravis who had 2 heart attacks within 2 months.⁴² His neurologic disease precluded significant physical activity. Although he achieved some initial weight loss through lifestyle changes, he continued to have daily angina despite optimal and aggressive cardiology management. After enrolling in HDRP and adopting the WFPB diet, the patient reported almost complete resolution of angina within 1 month, similar to that found in other studies.¹⁵

The literature suggests that concern over the acceptability of plant-based diets and patients’ ability to adhere to them long-term may be misplaced. A review paper on dietary interventions lasting > 1 year found that 51 to 61% of vegetarian and vegan study participants had maintained dietary adherence, while 20 to 55% of omnivorous diet intervention participants adhered to their study diets.⁴³ Remarkably, there were no statistically significant differences in the acceptability of the vegan, vegetarian, or omnivorous diets in the studies reviewed.⁴³ Recent dietary research also suggests that providing patients with higher goals (eg, adopting a vegan diet instead of only moderate dietary changes) results in greater weight loss and maintenance.²⁶ HDRP provides training on consumption of whole plant foods, which may offer patients a unique advantage for maximizing results and higher adherence over time.

Limitations

Hands-on cooking instruction was not provided at our VAMC. The total time of the intervention was significantly less in HDRP (25 hours) than it was for the Ornish ICR program (72 hours), which may hinder long-term adherence. Without an exercise facility, we were not able to provide more detailed exercise instruction and supervised exercise.

Program Improvements Planned

There are a number of improvements that are planned for HDRP. First, the program anticipates requesting medical clearance at the telephone screening stage for self-referred patients. Second, HDRP will provide regular presentations on the program to VAMC clinics and community-based outpatient clinics, including reminders about inclusion/exclusion criteria and the referral process, and to solicit feedback on processes. Third, we hope to routinely provide education and address common questions and concerns of HCPs, including expected results. Fourth, we would like to lengthen the patient commitment to HDRP (eg, 1- to 2-year commitment to the graduate group), consistent with other HDRPs.²⁸ Fifth, we hope to further integrate technology-based components to promote behavior change/maintenance, such as automated text messaging.

Conclusions

Although our patient population was self-selected for participation, early program evaluation demonstrates high acceptability. Very few patients had ever been told about a heart disease reversing lifestyle, and we found direct-to-patient clinical outreach an effective method for launching a disease reversal program (optimally timed with HCP presentations). Furthermore, the program is adaptable to current restrictions on in-person appointments due to the COVID-19 pandemic, and much more convenient for rural veterans who live far from any VA clinic. Being able to offer sustainable health care for individuals during unexpected public health crises is critically important. Additionally, treating veterans who are most vulnerable to pandemic illness due to existing medical conditions, such as CVD, should be a high priority. Last, HDRP also may represent a novel integrated treatment for COVID-19 anxiety and secondary CVD prevention, as lifestyle habits are optimized to improve chronic diseases that elevate risk for severe COVID-19 infection and mortality, as well as including coping strategies consistent with evidence-based psychotherapies for anxiety disorders.⁴⁴

We believe that beyond the clinical benefits to patients, there is significant value and benefit added to the health care system by offering an intervention within the “disease reversal” paradigm. Efforts of the health care team to reverse a disease can be considered the highest aim of medicine and health care.⁴⁵

Acknowledgments

This work was supported by the US Department of Veterans Affairs. We give special thanks to David M. Gellerman, MD, PhD, and David W. Schafer, PsyD, for providing Mental Health Service support for initiating the Heart Disease Reversal Program, and to Joseph Giorgio, PsyD (Program Manager, Integrated Care Program) for sustaining it. We thank Amogh Bhat, MD, Chief of Cardiology, for his continued support and partnership with the Cardiology Department. We express thanks to Stephanie Mohney, RDN (Chief, Nutrition and Food Service), Amy Klotz, RDN (Supervisory Dietician), Sian M. Carr-Lopez, PharmD (Associate Chief of Pharmacy, Primary Care), and Michelle Rand, PharmD, CACP (Anticoagulation Clinical Pharmacist-Supervisor) for their staff support of this interdisciplinary program. We thank the patients and their families for their participation in the program and commitment to the lifestyle changes. We also thank the following individuals for their contributions to this program: Lisa Wagaman, RDN, Karen Soong, PharmD, Sara S. Ali, PharmD, Suzan Hua, PharmD, and Stephen Cooperman.

While cardiovascular mortality rates have declined, heart disease continues to be the leading cause of death in the US, and the number of people with cardiovascular disease (CVD) is rising.¹ CVD is more prevalent among military veterans than it is among nonveterans aged ≥ 25 years, and veteran status is associated with higher risk of incident heart disease after controlling for socioeconomic status, other medical diseases, depression, and lifestyle.^2-4 Combat exposure, posttraumatic stress disorder (PTSD), and Purple Heart commendation are associated with higher rates of CVD, including adverse cardiovascular events.^5-7 Many patients seeking care in the Veterans Health Administration (VHA), including those who undergo cardiac catheterization, meet the criteria for multimorbidity (defined as having ≥ 2 chronic diseases⁸), which is common among veterans.^9,10 Multimorbidity presents a challenge for lifestyle intervention, as different diets may be prescribed to treat different conditions, such as Dietary Approaches to Stop Hypertension, and low-glycemic diet for diabetes mellitus (DM). Veterans with CVD are often clinically complex and may require more multifaceted secondary prevention programs.

During the coronavirus 2019 (COVID-19) pandemic, effective secondary prevention intervention is needed more than ever. Older age, CVD, and common comorbidities, including hypertension, DM, and obesity, place patients at the highest risk for severe COVID-19 infection.¹¹ COVID-19 social distancing encourages vulnerable populations to stay home, which can make engaging in any levels of physical activity more challenging. The International Food Council found that 85% of adults have made a change to their food consumption pattern, including eating more, during the COVID-19 pandemic.¹² Thus, secondary CVD prevention programs for veterans need to provide treatment that addresses these specific challenges and can be delivered via telehealth for continuity of care after disruption of traditional services.

Nutrition may be the most powerful Ornish ICR component. The initial RCT conducted by Ornish and colleagues included only stress management training and a whole-food, plant-based (WFPB) diet, including grains, legumes, vegetables, fruits, nuts, and seeds. The trial found 91% of participants experienced reduced angina after only 24 days.¹⁵ The only single-component intervention study resulting in partial reversal of atherosclerosis was a WFPB diet-only study, which documented regression of atherosclerotic plaques after 5 years, using coronary angiography in 73% of participants, with arrested progression in the other 27%.²² Participants reported no cardiovascular AEs after 12 years.²³ Furthermore, a number of other recent studies have demonstrated the benefits of WFPB diet-only interventions for type 2 DM (T2DM), hypertension, and obesity.^24-27 The Heart Disease Reversal Program (HDRP) was developed to create an interdisciplinary lifestyle intervention that emphasized nutrition for a broad population of veterans with atherosclerotic CVD, of varying levels of functional ability, to promote comprehensive CVD risk reduction and bring heart disease reversal intervention into routine clinical practice.

fdp03712558_f.png

Program Description 

The Mental Health, Cardiology, and Nutrition and Food services all approved the launch of HDRP. We contacted veterans by mail, and 11% expressed interest (Figure). Among patients who received the initial mailed letter (prior to our accepting staff referrals), only 5% of patients who enrolled in HDRP reported previously being told about or prescribed a WFPB diet by any health care provider (HCP). Currently, patients are primarily referred to HDRP by Cardiology, Primary Care, and Mental Health services.

Design

HDRP is an adaptation of interdisciplinary lifestyle interventions that have resulted in regression of atherosclerotic blockages confirmed with invasive coronary angiography.^15-17,22,28 HDRP currently is offered in a Behavioral Medicine Clinic at the Sacramento US Department of Veterans Affairs (VA) Medical Center (VAMC) in California. Program staff include a clinical health psychologist who organizes, coordinates, and act as the lead facilitator of the program; registered dietitians; clinical pharmacists; and a consulting physician. Patients engage in the 4-month core HDRP program in small cohorts (ie, 6-10 patients), and spouses/partners are highly encouraged to attend all sessions.

Components

Telephone screening. Patients are screened for the inclusion and exclusion criteria (Table 1). Patients engaging in a traditional CR program are included in the screening. Patients are informed that the program consists of lifestyle intervention, including emphasis on following a WFPB diet.

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A psychologist delivers the physical activity component. Patients are encouraged to meet the American Heart Association/American College of Cardiology recommendations for aerobic exercise (at least 150 minutes of moderate intensity physical activity per week) through a walking program.³⁵ Patients with medical contraindications (eg, severe pain, mobility restrictions) are encouraged to follow the exercise/activity recommendations they had been given by their primary care provider (PCP), physical therapist, or other HCP.

A psychologist provides evidence-based cognitive behavioral stress management (CBSM) training, adapted from models developed for patients with stable ischemic heart disease, HIV/AIDS, and cancer.^36-38 CBSM is a psychotherapy grounded in stress/coping theory and cognitive behavioral theory of psychopathology that integrates cognitive restructuring, coping skills training, communication/assertiveness training, anger management, and mindfulness/acceptance-based approaches. Additional emphasis is placed on assisting patients’ adjustment to the lifestyle challenges for following a plant-based diet, dealing with food cravings and emotional eating, and connecting lifestyle change to patients’ deepest values and goals.

A clinical pharmacist conducts a medication reconciliation for each patient at baseline. The pharmacist consults with each patient’s PCP, cardiologist, and HDRP consulting physician, as needed, to ensure safe adjustments to medications. Pharmacists also provide education on medications at group sessions.

After completion of the 12-week core program, graduates are encouraged to attend the monthly graduates’ group indefinitely, and as often as they desire to promote maintenance of the disease reversal lifestyle. Patients are encouraged to complete our recommended fasting laboratory work every 3 to 6 months to facilitate maintenance of treatment gains.

Program Evaluation

Patients frequently reported that the group format was vital to their success. Patients requested a cooking class, yet we lacked a full teaching kitchen. Integrating plant-based meal samples at every session and cooking videos helped. Patients reported that 100% adherence to the WFPB diet led to significant changes in their food preferences, including a loss of interest in meat.³⁹ Patients encouraged us to keep the “disease reversal” language and focus. One veteran stated: “Disease reversal, that is the reason I called you when I got your letter.” Showing before and after images of coronary angiograms and cardiac positron emission tomography scans depicting regression of atherosclerotic plaque and restored myocardial perfusion were described as highly motivating and generated willingness to commit to a more aggressive lifestyle change.³¹

Patients routinely stated that they lacked understanding of their laboratory test results, which HDRP remedied. Some patients reported their adult children followed a plant-based diet, and our program resulted in a new commonality and source of bonding that was highly valued. Some patients reported that HDRP was helpful for controlling their COVID-19 anxiety and feeling in control of their health. Satisfaction surveys were completed by participants at the end of the core program, which demonstrated very high satisfaction with and acceptability of HDRP (Table 3).

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COVID-19 Response

Face-to-face group appointments were converted to videoconferencing as a result of the COVID-19 pandemic. While HDRP always promoted the use of technology and mHealth tools, the pandemic led us to develop novel technology-based interventions.⁴⁰ One cohort transitioned from in-person to videoconferencing sessions, and 2 cohorts recently started this format and are ongoing. We have successfully used videoconferencing with Cisco Webex, the VA-approved backup platform, as we encountered technical barriers when using VA Video Connect. Program materials were shared electronically, and participants sent blood pressure/sugar logs by secure messaging. Guidance for online grocery shopping with home delivery was provided, and research on the benefits of the HDRP lifestyle on immune function was incorporated.

The stress management component incorporated coping with COVID-19, including normalizing common emotional difficulties with sheltering-in-place and quarantine, acknowledging and processing fear and anxiety related to being at very high risk for severe COVID-19. We presented heart disease reversal as an urgent and feasible goal during the pandemic both reducing risk of premature death and major adverse cardiovascular events in the long-term and also reducing personal risk of severe COVID complications. The new VA COVID Coach app was also presented as a resource. Reputable sources of COVID-19 and public health information were shared. Walking continued to be the primary recommended form of exercise, while indoor home exercise options were promoted during the periods of very poor air quality due to the widespread California fires and smoke.

Considering the research suggesting benefits of our intervention for treating T2DM,promoting sustained weight loss, and promoting comprehensive cardiometabolic risk reduction, we have begun accepting referrals for patients with any type of atherosclerotic CVD (eg, peripheral artery disease, carotid artery disease), patients with T2DM (without CVD), and patients with only a history of ischemic stroke or transient ischemic attack.^24-27 Vascular surgery has become a new referral source, primarily for patients with peripheral and carotid artery diseases. Finally, we are leveraging videoconferencing and accepting referrals across the VA Northern California Health Care System (VANCHCS)catchment (from the California-Oregon state border to the San Francisco Bay Area). This also helps address a long-standing problem with reaching the many rural veterans who live far from a VA clinic. We successfully implemented a consult/referral process within the EHR that is available to providers across VANCHCS.

Discussion

The efficacy and effectiveness of reversal programs are well established in intensive programs (eg, ICR), yet such programs have yet to be streamlined and disseminated broadly into routine clinical care. HDRP has endeavored to address this by emphasizing nutrition relative to other program components. We have learned that the words “disease reversal” are very often the reason patients initially reach out or accept referral to our program.

Consistent with past research on plant-based nutrition interventions, the group format was indispensable.⁴¹ Individual sessions with a clinical health psychologist enabled tailored feedback and education on how behavior changes could impact laboratory results and how certain psychosocial factors could support success. Participants reported that seeing significantly favorable laboratory results was highly motivating and confirmed the power of their lifestyle changes. Furthermore, a psychosocial health assessment with individual sessions promoted a tailored treatment plan with targeted clinical interventions, such as behavioral health education, motivational interviewing, and advanced methods, including cognitive behavioral therapy and techniques drawn from dialectical behavior therapy and acceptance and commitment therapy.

Veterans with multimorbidity face the difficult task of learning and maintaining a complex disease self-management program and implementing a lifestyle approach that is feasible, effective, promotes weight loss, and treats multiple conditions. HDRP is a model approach for this population, as demonstrated by a recent case report of a 65-year-old male veteran with atherosclerotic CVD, T2DM, hypertension, and myasthenia gravis who had 2 heart attacks within 2 months.⁴² His neurologic disease precluded significant physical activity. Although he achieved some initial weight loss through lifestyle changes, he continued to have daily angina despite optimal and aggressive cardiology management. After enrolling in HDRP and adopting the WFPB diet, the patient reported almost complete resolution of angina within 1 month, similar to that found in other studies.¹⁵

The literature suggests that concern over the acceptability of plant-based diets and patients’ ability to adhere to them long-term may be misplaced. A review paper on dietary interventions lasting > 1 year found that 51 to 61% of vegetarian and vegan study participants had maintained dietary adherence, while 20 to 55% of omnivorous diet intervention participants adhered to their study diets.⁴³ Remarkably, there were no statistically significant differences in the acceptability of the vegan, vegetarian, or omnivorous diets in the studies reviewed.⁴³ Recent dietary research also suggests that providing patients with higher goals (eg, adopting a vegan diet instead of only moderate dietary changes) results in greater weight loss and maintenance.²⁶ HDRP provides training on consumption of whole plant foods, which may offer patients a unique advantage for maximizing results and higher adherence over time.

Limitations

Hands-on cooking instruction was not provided at our VAMC. The total time of the intervention was significantly less in HDRP (25 hours) than it was for the Ornish ICR program (72 hours), which may hinder long-term adherence. Without an exercise facility, we were not able to provide more detailed exercise instruction and supervised exercise.

Program Improvements Planned

There are a number of improvements that are planned for HDRP. First, the program anticipates requesting medical clearance at the telephone screening stage for self-referred patients. Second, HDRP will provide regular presentations on the program to VAMC clinics and community-based outpatient clinics, including reminders about inclusion/exclusion criteria and the referral process, and to solicit feedback on processes. Third, we hope to routinely provide education and address common questions and concerns of HCPs, including expected results. Fourth, we would like to lengthen the patient commitment to HDRP (eg, 1- to 2-year commitment to the graduate group), consistent with other HDRPs.²⁸ Fifth, we hope to further integrate technology-based components to promote behavior change/maintenance, such as automated text messaging.

Conclusions

Although our patient population was self-selected for participation, early program evaluation demonstrates high acceptability. Very few patients had ever been told about a heart disease reversing lifestyle, and we found direct-to-patient clinical outreach an effective method for launching a disease reversal program (optimally timed with HCP presentations). Furthermore, the program is adaptable to current restrictions on in-person appointments due to the COVID-19 pandemic, and much more convenient for rural veterans who live far from any VA clinic. Being able to offer sustainable health care for individuals during unexpected public health crises is critically important. Additionally, treating veterans who are most vulnerable to pandemic illness due to existing medical conditions, such as CVD, should be a high priority. Last, HDRP also may represent a novel integrated treatment for COVID-19 anxiety and secondary CVD prevention, as lifestyle habits are optimized to improve chronic diseases that elevate risk for severe COVID-19 infection and mortality, as well as including coping strategies consistent with evidence-based psychotherapies for anxiety disorders.⁴⁴

We believe that beyond the clinical benefits to patients, there is significant value and benefit added to the health care system by offering an intervention within the “disease reversal” paradigm. Efforts of the health care team to reverse a disease can be considered the highest aim of medicine and health care.⁴⁵

Acknowledgments

This work was supported by the US Department of Veterans Affairs. We give special thanks to David M. Gellerman, MD, PhD, and David W. Schafer, PsyD, for providing Mental Health Service support for initiating the Heart Disease Reversal Program, and to Joseph Giorgio, PsyD (Program Manager, Integrated Care Program) for sustaining it. We thank Amogh Bhat, MD, Chief of Cardiology, for his continued support and partnership with the Cardiology Department. We express thanks to Stephanie Mohney, RDN (Chief, Nutrition and Food Service), Amy Klotz, RDN (Supervisory Dietician), Sian M. Carr-Lopez, PharmD (Associate Chief of Pharmacy, Primary Care), and Michelle Rand, PharmD, CACP (Anticoagulation Clinical Pharmacist-Supervisor) for their staff support of this interdisciplinary program. We thank the patients and their families for their participation in the program and commitment to the lifestyle changes. We also thank the following individuals for their contributions to this program: Lisa Wagaman, RDN, Karen Soong, PharmD, Sara S. Ali, PharmD, Suzan Hua, PharmD, and Stephen Cooperman.