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Food as Medicine: Diet’s Role in Parkinson’s Disease
For 15 years, John Duda, MD, national director of the VA Parkinson’s Disease Research, Education and Clinical Centers, has urged his patients to “keep waiting” for effective treatments to manage both motor and nonmotor symptoms of Parkinson’s disease.
However, Duda, who also serves as director of the Brain Wellness Clinic at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia, Pennsylvania, recognized the persistent lack of effective drugs to address these symptoms. This prompted him to consider what other evidence-based strategies he could use to support his patients.
“I recognized that nutritional approaches within a broader program that includes medication review, stress management, social connections, adequate sleep, and physical exercise could make a real difference,” he said.
Observational studies have shown an inverse association between dietary patterns and Parkinson’s disease risk, age of onset, symptom severity, and mortality rates — particularly with the Mediterranean diet (MeDi) and the MIND diet, which combines elements of MeDi and the Dietary Approaches to Stop Hypertension (DASH) diet. Although randomized controlled trials are still limited, the epidemiologic evidence supporting dietary interventions is “compelling,” said Duda.
For example, a cross-sectional study comparing 167 participants with Parkinson’s disease vs 119 controls showed that later age of Parkinson’s disease onset correlated with adherence to the MIND diet in women, with a difference of up to 17.4 years (P < .001) between low and high dietary tertiles.
The MeDi was correlated with later onset in men, with differences of up to 8.4 years (P = .002). As previously reported, a healthy diet emphasizing vegetables, fruits, nuts, and grains was inversely associated with prodromal features of Parkinson’s disease, including constipation, excessive daytime sleepiness, and depression. In addition, lower rates of Parkinson’s disease have been shown in populations following vegetarian and vegan dietary patterns.
Does Parkinson’s disease Start in the Gut?
Parkinson’s disease is characterized by decreased short-chain fatty acid–producing bacteria and increased pro-inflammatory species linked to intestinal inflammation and alpha-synuclein aggregation. “There are reasons to believe that a-synuclein accumulation may start in the gut,” Duda noted.
Numerous studies implicate gut microbiome dysbiosis as a pathogenic mechanism in Parkinson’s disease, with gastrointestinal symptoms often predating motor symptoms. Dysbiosis might result in a pro-inflammatory state potentially linked to the recurrent gastrointestinal symptoms. Fecal microbiota transplant may restore a healthier gut environment and beneficially affect Parkinson’s disease symptoms, he said.
Some of the benefits conferred by the MeDi and other healthy diets may be mediated by improving the gut microbiome. Duda cited a study that showed that a 14-day ovo-lacto vegetarian diet intervention and a daily fecal enema for 8 days improved not only the microbiome but also Movement Disorder Society Unified Parkinson’s Disease Rating Scale—part III scores.
Duda also reviewed the role of dietary interventions in addressing common Parkinson’s disease symptoms, such as orthostatic hypotension. He recommended that Parkinson’s disease patients with this condition should avoid eating large meals, increase dietary salt intake, increase fluid intake, and decrease alcohol intake.
Malnutrition affects close to 25% of those with Parkinson’s disease, which is partially attributable to diminished olfaction. Because the experience of taste is largely driven by a sense of smell, patients may be less interested in eating. Duda recommended increasing herbs, spices, and other flavors in food. High caloric–density foods, including nuts, nut butters, and seeds, can boost weight, he said. However, he added, any patient with significant weight loss should consult a nutritionist.
Constipation is one of the most debilitating symptoms of Parkinson’s disease, affecting up to 66% of patients. Duda advised increasing fluid intake, exercise, and dietary fiber and use of stool softeners and laxatives. The MeDi may reduce symptoms of constipation and have a beneficial effect on gut microbiota.
Coffee may be helpful for sleepiness in Parkinson’s disease and may also confer neuroprotective, motor, and cognitive benefits. As an adjuvant treatment, caffeine may alter levodopa pharmacokinetics, reduce dyskinesia, improve gait in patients with freezing and may even reduce the risk of developing Parkinson’s disease, with a maximum benefit reached at approximately three cups of coffee daily.
Problematic Foods
There is also a growing body of evidence regarding the deleterious effects of ultraprocessed foods (UPFs), Duda said. He noted that a recent systematic review and meta-analysis of 28 studies showed that higher UPF intake was significantly associated with an enhanced risk for Parkinson’s disease (relative risk, 1.56; 95% CI, 1.21-2.02). As previously reported, UPFs have been tied to a host of adverse neurologic outcomes, including cognitive decline and stroke.
Although protein is a necessary nutrient, incorporating it into the diet of Parkinson’s disease patients taking levodopa is complicated. Levodopa, a large neutral amino acid (LNAA), competes with other LNAAs for transport to the brain from the small intestine, Duda explained.
“Some people notice that carbidopa-levodopa doesn’t work as well if taken with a high-protein meal.” He recommended taking carbidopa-levodopa 30 minutes before or 60 minutes after meals.
Rebecca Gilbert, MD, PhD, chief mission officer of the American Parkinson’s Disease Association, said that patients with Parkinson’s disease might want to avoid eating protein during the day, concentrating instead on carbohydrates and vegetables and saving the protein for the evening, which is closer to bedtime. Some evidence also supports the use of protein redistribution diets to enhance the clinical response to levodopa and reduce motor fluctuations.
What About Supplements?
It’s “hard to prove that one specific supplement can be protective against Parkinson’s disease because diet consists of many different components and the whole diet may be worth more than the sum of its parts,” Gilbert said. The evidence for individual supplements “isn’t robust enough to say they prevent or treat Parkinson’s disease.”
Research on the role of specific nutrients in Parkinson’s disease is conflicting, with no clear evidence supporting or refuting their benefits. For example, a study that followed participants for about 30 years showed no link between reduced Parkinson’s disease risk and vitamin B or folate intake.
On the other hand, there is research suggesting that certain vitamins may help reduce Parkinson’s disease risk, although these nutrients do not operate in isolation. For instance, one recent study showed a connection between vitamins C and E and reduced Parkinson’s disease risk, but factors such as body mass index and coffee consumption appeared to influence the strength of this association.
Consuming polyunsaturated fatty acids along with reducing saturated fatty acid intake has been tied to a reduced risk for Parkinson’s disease.
Additionally, certain foods may offer protective effects, including green and black tea, with consumption of three or more cups per day associated with a delay in motor symptom onset by 7.7 years. Foods high in nicotine content, such as those from the Solanaceae family — including peppers, tomatoes, tomato juice, and potatoes — have also been linked to potential protective benefits.
Diets rich in antioxidants, including carotenoids, lutein, and vitamins E and C, have been robustly linked to a reduced risk for parkinsonism and progression of parkinsonian symptoms in older adults.
Increasing the intake of dietary flavonoids, particularly tea, berry fruits, apples, red wine, and oranges or orange juice, can reduce Parkinson’s disease risk. One study showed that male participants in the highest quintile of total flavonoid consumption had a 40% lower Parkinson’s disease risk compared with those in the lowest quintile. Another study showed that flavonoid-rich foods were also associated with a lower risk for death in patients with Parkinson’s disease.
Food as Medicine
Although recent research shows that the drug development pipeline for Parkinson’s disease is robust, with a wide variety of approaches being developed and evaluated in phase 1 and 2, investigators note that only a limited number of disease-modifying treatments are transitioning to phase 3.
Duda noted that phytochemicals incorporated into the diet might target some of the same mechanisms that are targets of these drugs in development.
“Flavonoids have been shown to stabilize alpha-synuclein in vitro,” he said. “Caffeine, curcumin, resveratrol, and eliminating meat and dairy inhibit mTOR [mammalian target of rapamycin], and mTOR inhibition results in increased autophagy that may help clear alpha-synuclein. Genestein, an isoflavone in soybeans, protects dopaminergic neurons by inhibiting microglia activation. Flavonoids inhibit inflammation by inhibiting release of NO [nitric oxide] and pro-inflammatory cytokines,” he noted.
Ongoing studies of dietary interventions for Parkinson’s disease are exploring various areas, including the potential role of the ketogenic diet in protecting the gut microbiome, optimizing protein intake for muscle preservation and sleep, the effects of psyllium and wheat bran on weight and constipation, and the impact of a gluten-free diet.
Practical Tips for Healthy Eating
Gilbert emphasized that there are no medications or interventions currently available that can delay a Parkinson’s disease diagnosis by up to 17 years, as some dietary patterns have been shown to do, and she noted that it’s not possible to replicate the MeDi diet in a pill. However, she recommended a practical approach to eating that includes a diet low in ultraprocessed foods and high in beneficial nutrients. She encouraged people to shop for “real food” and enjoy a variety of colorful fruits and vegetables.
Duda acknowledged that motivating patients to follow a healthy diet can be difficult. As a result, the focus often shifts to making small adjustments and modifications. For example, he suggested that instead of pairing meat with French fries, people could opt for vegetables or add greens to their meals. Similarly, instead of having eggs and bacon for breakfast, they might choose oatmeal.
Preparing whole-food, plant-based meals may take more time than patients are accustomed to, so Duda suggests that, if possible, patients involve loved ones in both the meal preparation and the meal itself. He explained that a healthy meal can become an opportunity for bonding and that the key is educating them about new meal-related concepts.
Duda reported no relevant financial relationships with the pharmaceutical or food industries. He has received compensation from the Physicians Committee for Responsible Medicine for his lecture delivered at the conference and research grant support from the VA, the National Institutes of Health, the Michael J. Fox Foundation, and the Department of Defense unrelated to this topic. Gilbert reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
For 15 years, John Duda, MD, national director of the VA Parkinson’s Disease Research, Education and Clinical Centers, has urged his patients to “keep waiting” for effective treatments to manage both motor and nonmotor symptoms of Parkinson’s disease.
However, Duda, who also serves as director of the Brain Wellness Clinic at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia, Pennsylvania, recognized the persistent lack of effective drugs to address these symptoms. This prompted him to consider what other evidence-based strategies he could use to support his patients.
“I recognized that nutritional approaches within a broader program that includes medication review, stress management, social connections, adequate sleep, and physical exercise could make a real difference,” he said.
Observational studies have shown an inverse association between dietary patterns and Parkinson’s disease risk, age of onset, symptom severity, and mortality rates — particularly with the Mediterranean diet (MeDi) and the MIND diet, which combines elements of MeDi and the Dietary Approaches to Stop Hypertension (DASH) diet. Although randomized controlled trials are still limited, the epidemiologic evidence supporting dietary interventions is “compelling,” said Duda.
For example, a cross-sectional study comparing 167 participants with Parkinson’s disease vs 119 controls showed that later age of Parkinson’s disease onset correlated with adherence to the MIND diet in women, with a difference of up to 17.4 years (P < .001) between low and high dietary tertiles.
The MeDi was correlated with later onset in men, with differences of up to 8.4 years (P = .002). As previously reported, a healthy diet emphasizing vegetables, fruits, nuts, and grains was inversely associated with prodromal features of Parkinson’s disease, including constipation, excessive daytime sleepiness, and depression. In addition, lower rates of Parkinson’s disease have been shown in populations following vegetarian and vegan dietary patterns.
Does Parkinson’s disease Start in the Gut?
Parkinson’s disease is characterized by decreased short-chain fatty acid–producing bacteria and increased pro-inflammatory species linked to intestinal inflammation and alpha-synuclein aggregation. “There are reasons to believe that a-synuclein accumulation may start in the gut,” Duda noted.
Numerous studies implicate gut microbiome dysbiosis as a pathogenic mechanism in Parkinson’s disease, with gastrointestinal symptoms often predating motor symptoms. Dysbiosis might result in a pro-inflammatory state potentially linked to the recurrent gastrointestinal symptoms. Fecal microbiota transplant may restore a healthier gut environment and beneficially affect Parkinson’s disease symptoms, he said.
Some of the benefits conferred by the MeDi and other healthy diets may be mediated by improving the gut microbiome. Duda cited a study that showed that a 14-day ovo-lacto vegetarian diet intervention and a daily fecal enema for 8 days improved not only the microbiome but also Movement Disorder Society Unified Parkinson’s Disease Rating Scale—part III scores.
Duda also reviewed the role of dietary interventions in addressing common Parkinson’s disease symptoms, such as orthostatic hypotension. He recommended that Parkinson’s disease patients with this condition should avoid eating large meals, increase dietary salt intake, increase fluid intake, and decrease alcohol intake.
Malnutrition affects close to 25% of those with Parkinson’s disease, which is partially attributable to diminished olfaction. Because the experience of taste is largely driven by a sense of smell, patients may be less interested in eating. Duda recommended increasing herbs, spices, and other flavors in food. High caloric–density foods, including nuts, nut butters, and seeds, can boost weight, he said. However, he added, any patient with significant weight loss should consult a nutritionist.
Constipation is one of the most debilitating symptoms of Parkinson’s disease, affecting up to 66% of patients. Duda advised increasing fluid intake, exercise, and dietary fiber and use of stool softeners and laxatives. The MeDi may reduce symptoms of constipation and have a beneficial effect on gut microbiota.
Coffee may be helpful for sleepiness in Parkinson’s disease and may also confer neuroprotective, motor, and cognitive benefits. As an adjuvant treatment, caffeine may alter levodopa pharmacokinetics, reduce dyskinesia, improve gait in patients with freezing and may even reduce the risk of developing Parkinson’s disease, with a maximum benefit reached at approximately three cups of coffee daily.
Problematic Foods
There is also a growing body of evidence regarding the deleterious effects of ultraprocessed foods (UPFs), Duda said. He noted that a recent systematic review and meta-analysis of 28 studies showed that higher UPF intake was significantly associated with an enhanced risk for Parkinson’s disease (relative risk, 1.56; 95% CI, 1.21-2.02). As previously reported, UPFs have been tied to a host of adverse neurologic outcomes, including cognitive decline and stroke.
Although protein is a necessary nutrient, incorporating it into the diet of Parkinson’s disease patients taking levodopa is complicated. Levodopa, a large neutral amino acid (LNAA), competes with other LNAAs for transport to the brain from the small intestine, Duda explained.
“Some people notice that carbidopa-levodopa doesn’t work as well if taken with a high-protein meal.” He recommended taking carbidopa-levodopa 30 minutes before or 60 minutes after meals.
Rebecca Gilbert, MD, PhD, chief mission officer of the American Parkinson’s Disease Association, said that patients with Parkinson’s disease might want to avoid eating protein during the day, concentrating instead on carbohydrates and vegetables and saving the protein for the evening, which is closer to bedtime. Some evidence also supports the use of protein redistribution diets to enhance the clinical response to levodopa and reduce motor fluctuations.
What About Supplements?
It’s “hard to prove that one specific supplement can be protective against Parkinson’s disease because diet consists of many different components and the whole diet may be worth more than the sum of its parts,” Gilbert said. The evidence for individual supplements “isn’t robust enough to say they prevent or treat Parkinson’s disease.”
Research on the role of specific nutrients in Parkinson’s disease is conflicting, with no clear evidence supporting or refuting their benefits. For example, a study that followed participants for about 30 years showed no link between reduced Parkinson’s disease risk and vitamin B or folate intake.
On the other hand, there is research suggesting that certain vitamins may help reduce Parkinson’s disease risk, although these nutrients do not operate in isolation. For instance, one recent study showed a connection between vitamins C and E and reduced Parkinson’s disease risk, but factors such as body mass index and coffee consumption appeared to influence the strength of this association.
Consuming polyunsaturated fatty acids along with reducing saturated fatty acid intake has been tied to a reduced risk for Parkinson’s disease.
Additionally, certain foods may offer protective effects, including green and black tea, with consumption of three or more cups per day associated with a delay in motor symptom onset by 7.7 years. Foods high in nicotine content, such as those from the Solanaceae family — including peppers, tomatoes, tomato juice, and potatoes — have also been linked to potential protective benefits.
Diets rich in antioxidants, including carotenoids, lutein, and vitamins E and C, have been robustly linked to a reduced risk for parkinsonism and progression of parkinsonian symptoms in older adults.
Increasing the intake of dietary flavonoids, particularly tea, berry fruits, apples, red wine, and oranges or orange juice, can reduce Parkinson’s disease risk. One study showed that male participants in the highest quintile of total flavonoid consumption had a 40% lower Parkinson’s disease risk compared with those in the lowest quintile. Another study showed that flavonoid-rich foods were also associated with a lower risk for death in patients with Parkinson’s disease.
Food as Medicine
Although recent research shows that the drug development pipeline for Parkinson’s disease is robust, with a wide variety of approaches being developed and evaluated in phase 1 and 2, investigators note that only a limited number of disease-modifying treatments are transitioning to phase 3.
Duda noted that phytochemicals incorporated into the diet might target some of the same mechanisms that are targets of these drugs in development.
“Flavonoids have been shown to stabilize alpha-synuclein in vitro,” he said. “Caffeine, curcumin, resveratrol, and eliminating meat and dairy inhibit mTOR [mammalian target of rapamycin], and mTOR inhibition results in increased autophagy that may help clear alpha-synuclein. Genestein, an isoflavone in soybeans, protects dopaminergic neurons by inhibiting microglia activation. Flavonoids inhibit inflammation by inhibiting release of NO [nitric oxide] and pro-inflammatory cytokines,” he noted.
Ongoing studies of dietary interventions for Parkinson’s disease are exploring various areas, including the potential role of the ketogenic diet in protecting the gut microbiome, optimizing protein intake for muscle preservation and sleep, the effects of psyllium and wheat bran on weight and constipation, and the impact of a gluten-free diet.
Practical Tips for Healthy Eating
Gilbert emphasized that there are no medications or interventions currently available that can delay a Parkinson’s disease diagnosis by up to 17 years, as some dietary patterns have been shown to do, and she noted that it’s not possible to replicate the MeDi diet in a pill. However, she recommended a practical approach to eating that includes a diet low in ultraprocessed foods and high in beneficial nutrients. She encouraged people to shop for “real food” and enjoy a variety of colorful fruits and vegetables.
Duda acknowledged that motivating patients to follow a healthy diet can be difficult. As a result, the focus often shifts to making small adjustments and modifications. For example, he suggested that instead of pairing meat with French fries, people could opt for vegetables or add greens to their meals. Similarly, instead of having eggs and bacon for breakfast, they might choose oatmeal.
Preparing whole-food, plant-based meals may take more time than patients are accustomed to, so Duda suggests that, if possible, patients involve loved ones in both the meal preparation and the meal itself. He explained that a healthy meal can become an opportunity for bonding and that the key is educating them about new meal-related concepts.
Duda reported no relevant financial relationships with the pharmaceutical or food industries. He has received compensation from the Physicians Committee for Responsible Medicine for his lecture delivered at the conference and research grant support from the VA, the National Institutes of Health, the Michael J. Fox Foundation, and the Department of Defense unrelated to this topic. Gilbert reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
For 15 years, John Duda, MD, national director of the VA Parkinson’s Disease Research, Education and Clinical Centers, has urged his patients to “keep waiting” for effective treatments to manage both motor and nonmotor symptoms of Parkinson’s disease.
However, Duda, who also serves as director of the Brain Wellness Clinic at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia, Pennsylvania, recognized the persistent lack of effective drugs to address these symptoms. This prompted him to consider what other evidence-based strategies he could use to support his patients.
“I recognized that nutritional approaches within a broader program that includes medication review, stress management, social connections, adequate sleep, and physical exercise could make a real difference,” he said.
Observational studies have shown an inverse association between dietary patterns and Parkinson’s disease risk, age of onset, symptom severity, and mortality rates — particularly with the Mediterranean diet (MeDi) and the MIND diet, which combines elements of MeDi and the Dietary Approaches to Stop Hypertension (DASH) diet. Although randomized controlled trials are still limited, the epidemiologic evidence supporting dietary interventions is “compelling,” said Duda.
For example, a cross-sectional study comparing 167 participants with Parkinson’s disease vs 119 controls showed that later age of Parkinson’s disease onset correlated with adherence to the MIND diet in women, with a difference of up to 17.4 years (P < .001) between low and high dietary tertiles.
The MeDi was correlated with later onset in men, with differences of up to 8.4 years (P = .002). As previously reported, a healthy diet emphasizing vegetables, fruits, nuts, and grains was inversely associated with prodromal features of Parkinson’s disease, including constipation, excessive daytime sleepiness, and depression. In addition, lower rates of Parkinson’s disease have been shown in populations following vegetarian and vegan dietary patterns.
Does Parkinson’s disease Start in the Gut?
Parkinson’s disease is characterized by decreased short-chain fatty acid–producing bacteria and increased pro-inflammatory species linked to intestinal inflammation and alpha-synuclein aggregation. “There are reasons to believe that a-synuclein accumulation may start in the gut,” Duda noted.
Numerous studies implicate gut microbiome dysbiosis as a pathogenic mechanism in Parkinson’s disease, with gastrointestinal symptoms often predating motor symptoms. Dysbiosis might result in a pro-inflammatory state potentially linked to the recurrent gastrointestinal symptoms. Fecal microbiota transplant may restore a healthier gut environment and beneficially affect Parkinson’s disease symptoms, he said.
Some of the benefits conferred by the MeDi and other healthy diets may be mediated by improving the gut microbiome. Duda cited a study that showed that a 14-day ovo-lacto vegetarian diet intervention and a daily fecal enema for 8 days improved not only the microbiome but also Movement Disorder Society Unified Parkinson’s Disease Rating Scale—part III scores.
Duda also reviewed the role of dietary interventions in addressing common Parkinson’s disease symptoms, such as orthostatic hypotension. He recommended that Parkinson’s disease patients with this condition should avoid eating large meals, increase dietary salt intake, increase fluid intake, and decrease alcohol intake.
Malnutrition affects close to 25% of those with Parkinson’s disease, which is partially attributable to diminished olfaction. Because the experience of taste is largely driven by a sense of smell, patients may be less interested in eating. Duda recommended increasing herbs, spices, and other flavors in food. High caloric–density foods, including nuts, nut butters, and seeds, can boost weight, he said. However, he added, any patient with significant weight loss should consult a nutritionist.
Constipation is one of the most debilitating symptoms of Parkinson’s disease, affecting up to 66% of patients. Duda advised increasing fluid intake, exercise, and dietary fiber and use of stool softeners and laxatives. The MeDi may reduce symptoms of constipation and have a beneficial effect on gut microbiota.
Coffee may be helpful for sleepiness in Parkinson’s disease and may also confer neuroprotective, motor, and cognitive benefits. As an adjuvant treatment, caffeine may alter levodopa pharmacokinetics, reduce dyskinesia, improve gait in patients with freezing and may even reduce the risk of developing Parkinson’s disease, with a maximum benefit reached at approximately three cups of coffee daily.
Problematic Foods
There is also a growing body of evidence regarding the deleterious effects of ultraprocessed foods (UPFs), Duda said. He noted that a recent systematic review and meta-analysis of 28 studies showed that higher UPF intake was significantly associated with an enhanced risk for Parkinson’s disease (relative risk, 1.56; 95% CI, 1.21-2.02). As previously reported, UPFs have been tied to a host of adverse neurologic outcomes, including cognitive decline and stroke.
Although protein is a necessary nutrient, incorporating it into the diet of Parkinson’s disease patients taking levodopa is complicated. Levodopa, a large neutral amino acid (LNAA), competes with other LNAAs for transport to the brain from the small intestine, Duda explained.
“Some people notice that carbidopa-levodopa doesn’t work as well if taken with a high-protein meal.” He recommended taking carbidopa-levodopa 30 minutes before or 60 minutes after meals.
Rebecca Gilbert, MD, PhD, chief mission officer of the American Parkinson’s Disease Association, said that patients with Parkinson’s disease might want to avoid eating protein during the day, concentrating instead on carbohydrates and vegetables and saving the protein for the evening, which is closer to bedtime. Some evidence also supports the use of protein redistribution diets to enhance the clinical response to levodopa and reduce motor fluctuations.
What About Supplements?
It’s “hard to prove that one specific supplement can be protective against Parkinson’s disease because diet consists of many different components and the whole diet may be worth more than the sum of its parts,” Gilbert said. The evidence for individual supplements “isn’t robust enough to say they prevent or treat Parkinson’s disease.”
Research on the role of specific nutrients in Parkinson’s disease is conflicting, with no clear evidence supporting or refuting their benefits. For example, a study that followed participants for about 30 years showed no link between reduced Parkinson’s disease risk and vitamin B or folate intake.
On the other hand, there is research suggesting that certain vitamins may help reduce Parkinson’s disease risk, although these nutrients do not operate in isolation. For instance, one recent study showed a connection between vitamins C and E and reduced Parkinson’s disease risk, but factors such as body mass index and coffee consumption appeared to influence the strength of this association.
Consuming polyunsaturated fatty acids along with reducing saturated fatty acid intake has been tied to a reduced risk for Parkinson’s disease.
Additionally, certain foods may offer protective effects, including green and black tea, with consumption of three or more cups per day associated with a delay in motor symptom onset by 7.7 years. Foods high in nicotine content, such as those from the Solanaceae family — including peppers, tomatoes, tomato juice, and potatoes — have also been linked to potential protective benefits.
Diets rich in antioxidants, including carotenoids, lutein, and vitamins E and C, have been robustly linked to a reduced risk for parkinsonism and progression of parkinsonian symptoms in older adults.
Increasing the intake of dietary flavonoids, particularly tea, berry fruits, apples, red wine, and oranges or orange juice, can reduce Parkinson’s disease risk. One study showed that male participants in the highest quintile of total flavonoid consumption had a 40% lower Parkinson’s disease risk compared with those in the lowest quintile. Another study showed that flavonoid-rich foods were also associated with a lower risk for death in patients with Parkinson’s disease.
Food as Medicine
Although recent research shows that the drug development pipeline for Parkinson’s disease is robust, with a wide variety of approaches being developed and evaluated in phase 1 and 2, investigators note that only a limited number of disease-modifying treatments are transitioning to phase 3.
Duda noted that phytochemicals incorporated into the diet might target some of the same mechanisms that are targets of these drugs in development.
“Flavonoids have been shown to stabilize alpha-synuclein in vitro,” he said. “Caffeine, curcumin, resveratrol, and eliminating meat and dairy inhibit mTOR [mammalian target of rapamycin], and mTOR inhibition results in increased autophagy that may help clear alpha-synuclein. Genestein, an isoflavone in soybeans, protects dopaminergic neurons by inhibiting microglia activation. Flavonoids inhibit inflammation by inhibiting release of NO [nitric oxide] and pro-inflammatory cytokines,” he noted.
Ongoing studies of dietary interventions for Parkinson’s disease are exploring various areas, including the potential role of the ketogenic diet in protecting the gut microbiome, optimizing protein intake for muscle preservation and sleep, the effects of psyllium and wheat bran on weight and constipation, and the impact of a gluten-free diet.
Practical Tips for Healthy Eating
Gilbert emphasized that there are no medications or interventions currently available that can delay a Parkinson’s disease diagnosis by up to 17 years, as some dietary patterns have been shown to do, and she noted that it’s not possible to replicate the MeDi diet in a pill. However, she recommended a practical approach to eating that includes a diet low in ultraprocessed foods and high in beneficial nutrients. She encouraged people to shop for “real food” and enjoy a variety of colorful fruits and vegetables.
Duda acknowledged that motivating patients to follow a healthy diet can be difficult. As a result, the focus often shifts to making small adjustments and modifications. For example, he suggested that instead of pairing meat with French fries, people could opt for vegetables or add greens to their meals. Similarly, instead of having eggs and bacon for breakfast, they might choose oatmeal.
Preparing whole-food, plant-based meals may take more time than patients are accustomed to, so Duda suggests that, if possible, patients involve loved ones in both the meal preparation and the meal itself. He explained that a healthy meal can become an opportunity for bonding and that the key is educating them about new meal-related concepts.
Duda reported no relevant financial relationships with the pharmaceutical or food industries. He has received compensation from the Physicians Committee for Responsible Medicine for his lecture delivered at the conference and research grant support from the VA, the National Institutes of Health, the Michael J. Fox Foundation, and the Department of Defense unrelated to this topic. Gilbert reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
As GLP-1 Use Surges, Clinicians Weigh Benefits and Risks
Rates of overweight and obesity have more than doubled in the United States during the last three decades, according to a new analysis. By 2050, it’s anticipated that 213 million adults (age, > 25 years) and 43 million children and adolescents will have overweight or obesity. The results led authors of a study to describe obesity as having reached a “crisis point” requiring urgent action and interventions.
Are glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed and prescribed for diabetes and now approved for weight loss, the answer?
Their popularity is certainly surging. Between the last 6 months of 2022 vs the last 6 months of 2024, the number of patients prescribed GLP-1 RAs increased by 132.6%. This is also reflected in a shift in public awareness, with a recent survey of US adults finding that 32% of respondents had heard “a lot” about these drugs, up from 19% in 2023.
GLP-1 RAs (including tirzepatide, which targets not only the GLP-1 receptor but also the glucose-dependent insulinotropic polypeptide receptor) have shown efficacy in weight loss. A 2022 review and meta-analysis of 22 trials (17,183 patients) found that 50.2% and 17.5% of those treated with GLP-1 RAs had a ≥ 5% and ≥ 10% weight loss, respectively, compared with placebo. A 2023 review of 41 trials (15,135 patients) found that compared with controls, GLP-1 RAs significantly reduced body weight, body mass index, waist circumference, and waist-to-hip ratio.
“GLP-1 RAs are great medications,” Andres Acosta, MD, PhD, director of the Precision Medicine for Obesity Laboratory, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. “We’ve been using them for almost two decades. But now there’s excitement about their utility in treating obesity.”
Treating the Four Categories of Obesity
Daniel Drucker, MD, senior investigator at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, is a pioneer in diabetes treatment and particularly in the development of GLP-1 RAs. Drucker told Medscape Medical News that despite the efficacy and enormous potential of GLP-1 RAs, “we know some people don’t lose much weight when taking these medicines and others don’t feel well and can’t take them.”
The number of individuals who don’t respond to or aren’t able to tolerate GLP-1 RAs “might be small — less than 10% of people who try to take them — but we don’t fully understand the differences in response across different individuals,” Drucker said.
Acosta agreed, adding that it’s “essential for us to identify who will be the best responders, as we do with medications for other conditions, such as cancer and cardiovascular disease.”
Acosta’s group has spent more than a decade engaged in efforts to identify unique characteristics among patients with obesity and has succeeded in identifying four obesity phenotypes.
“What matters in the space of GLP-1 is that using this classification, we can identify the best responders and those who don’t respond.”
The first phenotype, described as “Hungry Gut” (HG), includes patients with abnormal postprandial satiety. “Although they may be satiated at the end of a meal, they have accelerated gastric emptying and therefore feel hungry between meals and want to keep eating,” he said.
There are also patients who experience abnormal satiety during meals. According to Acosta, these are the patients who will return to the table for second and third helpings. “They don’t feel full and continue to eat more and more in a single sitting” — a phenomenon referred to as “Hungry Brain.”
The third phenotype — “Emotional Hunger” — consists of people who are “hedonic” about food or engage in emotional eating behavior, whereas in the fourth group, people have “an abnormal metabolism in which they don’t burn enough calories. They have an inefficient metabolic rate.” This latter phenomenon is called “Slow Burn.”
Acosta and colleagues randomized 312 patients attending a weight management center to phenotype-guided or non–phenotype-guided treatment with anti-obesity medications (phentermine, phentermine/topiramate, bupropion/naltrexone, lorcaserin, and liraglutide). The phenotype-guided approach was associated with a 1.75-fold greater weight loss after 1 year than the non–phenotype-guided approach (mean weight loss, 15.9% vs 9.0%, respectively).
GLP-1 RAs: Not One-Size-Fits-All
Acosta’s group has developed a genetic test that uses patients’ saliva to identify their obesity phenotype, with the aim of predicting the best responders to GLP-1 RAs. The test, MyPhenome genetic obesity test, is licensed by Acosta’s lab and available through Phenomix Sciences.
Acosta and colleagues presented their findings at the American Gastroenterological Association’s 2024 annual meeting regarding a machine-learning gene risk score (ML-GRS) they developed to predict HG, based on saliva and blood samples. Their genetic studies generated a ML-GRS that classified participants with obesity along a continuum from “HG Positive” (HG+) to “HG Negative” (HG−). Compared with the HG− participants, those who were HG+ had superior total body weight loss with semaglutide at 9 and 12 months. When used to predict response, the ML-GRS had an area under the curve of 0.76 (P = .04) and a positive predictive value of 0.95.
According to Acosta, HG+ patients are “the best responders to the GLP-1 RAs, although we don’t yet understand the mechanism of why they have the phenomenon of abnormal postprandial satiety. It may be an abnormal genetic pathway or abnormal secretion of GLP-1. More studies are needed.”
He noted that GLP-1 RAs “might also be helpful with the second [Hungry Brain] category, but these patients do better with phentermine-topiramate,” as demonstrated in a 2023 study conducted by Acosta and colleagues.
His group has also studied which lifestyle interventions are most effective for each phenotype. “When a unique lifestyle intervention targeting each phenotype was applied, patients lost more weight and had greater metabolic improvement,” he reported.
“Treating obesity no longer needs to be trial-and-error, but should be done using precision medicine because one size doesn’t fit all,” Acosta said.
Concerning Side Effects
The popular media has featured stories about individuals who took GLP-1 RAs for weight loss and experienced serious side effects, including a recent account of a British nurse who died after taking tirzepatide. As reported by the BBC, the nurse’s death certificate listed multiple organ failure, septic shock, and pancreatitis as the immediate causes of death, with the “use of prescribed tirzepatide” recorded as a contributing factor. The report went on to note that there were 23 suspected deaths in the United Kingdom tied to semaglutide since 2019.
Beyond brand-name products, there are also risks associated with GLP-1 RAs manufactured by compounding pharmacies. In early November, CNN reported that compounded semaglutide has been linked to at least 10 deaths. Because of a prior shortage of tirzepatide, the US Food and Drug Administration (FDA) had allowed compounding pharmacies to manufacture the drug. In October, the FDA clarified that it won’t take legal action against compounders, even now that the shortage has been resolved.
A pharmacovigilance study using the FDA Adverse Event Reporting System identified “potential safety signals of increased mortality and serious adverse event reporting” associated with certain GLP-1 RAs — especially in younger patients and women (P < .0001 for both groups).
The most common side effects reported with GLP-1 RAs are gastrointestinal events, such as nausea, diarrhea, constipation, and vomiting. Most occur during dose initiation and escalation and wane over the following weeks. However, studies have also reported severe side effects, including a higher risk for pancreatitis, bowel obstruction, and gastroparesis, as well as a significantly higher risk for gallbladder and biliary diseases. In fact, according to one study, patients with diabetes taking GLP-1 RAs reported gastrointestinal-related issues as a “prominent factor” in their decision to discontinue taking these medications.
Several types of cancer are potentially associated with GLP-1 RAs, but findings regarding this potential link have been inconsistent. In a recent review article, Drucker noted there were only inconsistent data linking GLP-1 RAs with thyroid cancer and medullary thyroid cancer and that their potential association with pancreatic has “not been supported by results from randomized controlled trials or real-world data.”
Concerns have been raised about loss of lean mass and muscle strength and function, especially in older individuals with obesity and advanced liver, cardiovascular, or kidney disease. However, as Drucker pointed out in his review article, muscle function may not correlate with the loss of lean mass. In fact, there are “consistent reductions” in lean mass after bariatric surgery, but “little evidence to date for impairment of muscle function.” He added that newer GLP-1 agents under development for obesity treatment are focusing on “developing complementary therapies that preferentially reduce adipose tissue, while sparing lean mass.”
As covered by Medscape Medical News, there have been reports of potential suicidal ideation associated with GLP-1 RAs. This triggered a 2023 review from the European Medicines Agency. However, recent results from a cohort study and a post hoc analysis of randomized controlled trials concluded that there is no evidence that these drugs increase suicidal ideation or behavior.
In early November, the FDA updated the labels for the GLP-1 RAs to include a warning regarding pulmonary aspiration during general anesthesia or deep sedation. Guidance from a group of societies, led by the American Society of Anesthesiologists, contains recommendations regarding nuances of addressing this concern in surgical patients taking these agents.
Not a Standalone Treatment
Marc-Andre Cornier, MD, professor of medicine, James A. Keating Endowed Chair in Diabetes, and director of the Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, told Medscape Medical News that GLP-1 RAs should not be viewed as cosmetic interventions but rather as medical treatments, “not only for weight loss but to reverse obesity-associated complications.”
Moreover, they should be used “as an adjunct to lifestyle changes,” emphasized Cornier. “We want our patients to have a high-quality diet with high protein content, fluid, vitamins, and minerals, and we want them to exercise.” Especially with the concern of potential loss of muscle mass with these agents, “resistance exercise might help mitigate that concern.”
Recently published recommendations can assist clinicians in guiding patients taking GLP-1 RAs to optimize nutrition. The recommendations note that patients should be referred to a registered dietitian to “complement and support” treatment with anti-obesity medications.
What Do Patients Want?
Despite the ever-rising popularity of GLP-1 RAs, a new national survey of over 2200 US adults conducted by the Physicians Committee for Responsible Medicine suggests that most Americans don’t want to use them. Among those who wanted to lose weight, almost three-quarters “disagreed” or “strongly disagreed” with the idea of taking a weight-loss injectable, and 68% of those who wanted to lose weight “agreed” or “strongly agreed” that they would be willing to try a plant-based diet, if it could lead to significant weight loss.
Moreover, many individuals treated with GLP-1 RAs discontinue their use, despite the probability of regaining the weight, according to a report that found only 46.3% of GLP-1 users were still taking the medications at 6 months and only 32.3% at 1 year. The authors commented that their real-world findings show a “substantially lower” 1-year persistence rate, compared with the rate reported in clinical trials. They suggest that the financial burden (> $12,000/year) may contribute to discontinuation.
Discontinuation of GLP-1 RAs can lead to worsening cardiometabolic parameters, with a potential increased risk for adverse outcomes; moreover, weight cycling (“yo-yo dieting”) carries its own risks. In light of these concerns, it’s particularly important to select appropriate patients and to determine whether potential short-term therapy has any enduring benefit.
Acosta agreed. “It’s exciting when looking at the data on how to find the best responders and who should make the effort to take these medications — not only in terms of side effects but also in terms of cost and which patients will receive maximum benefits and should be covered by insurance.”
Drucker has served as a consultant or speaker for Altimmune, Amgen, AstraZeneca, Arrowhead, Boehringer Ingelheim, Kallyope, Merck Research Laboratories, Novo Nordisk, Pfizer, and Zealand Pharma. He holds nonexercised options in Kallyope. Mount Sinai Hospital receives research support for investigator-initiated studies in the Drucker laboratory from Amgen, Novo Nordisk, Pfizer, and Zealand Pharma. Gila Therapeutics and Phenomix Sciences have licensed Acosta’s research technologies from University of Florida and Mayo Clinic. Acosta received consultant fees in the last 5 years from Rhythm Pharmaceuticals, Gila Therapeutics, Amgen, General Mills, Regeneron Pharmaceuticals, Boehringer Ingelheim, Novo Nordisk, Currax, Nestlé, Phenomix Sciences, Bausch Health, and Rare Disease. He received funding support from the National Institutes of Health, Vivus Pharmaceuticals, Novo Nordisk, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical, Rhythm Pharmaceuticals, Regeneron Pharmaceuticals, Boehringer Ingelheim, and Novo Nordisk. In the past, Cornier has served as a consultant for Novo Nordisk.
A version of this article first appeared on Medscape.com.
Rates of overweight and obesity have more than doubled in the United States during the last three decades, according to a new analysis. By 2050, it’s anticipated that 213 million adults (age, > 25 years) and 43 million children and adolescents will have overweight or obesity. The results led authors of a study to describe obesity as having reached a “crisis point” requiring urgent action and interventions.
Are glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed and prescribed for diabetes and now approved for weight loss, the answer?
Their popularity is certainly surging. Between the last 6 months of 2022 vs the last 6 months of 2024, the number of patients prescribed GLP-1 RAs increased by 132.6%. This is also reflected in a shift in public awareness, with a recent survey of US adults finding that 32% of respondents had heard “a lot” about these drugs, up from 19% in 2023.
GLP-1 RAs (including tirzepatide, which targets not only the GLP-1 receptor but also the glucose-dependent insulinotropic polypeptide receptor) have shown efficacy in weight loss. A 2022 review and meta-analysis of 22 trials (17,183 patients) found that 50.2% and 17.5% of those treated with GLP-1 RAs had a ≥ 5% and ≥ 10% weight loss, respectively, compared with placebo. A 2023 review of 41 trials (15,135 patients) found that compared with controls, GLP-1 RAs significantly reduced body weight, body mass index, waist circumference, and waist-to-hip ratio.
“GLP-1 RAs are great medications,” Andres Acosta, MD, PhD, director of the Precision Medicine for Obesity Laboratory, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. “We’ve been using them for almost two decades. But now there’s excitement about their utility in treating obesity.”
Treating the Four Categories of Obesity
Daniel Drucker, MD, senior investigator at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, is a pioneer in diabetes treatment and particularly in the development of GLP-1 RAs. Drucker told Medscape Medical News that despite the efficacy and enormous potential of GLP-1 RAs, “we know some people don’t lose much weight when taking these medicines and others don’t feel well and can’t take them.”
The number of individuals who don’t respond to or aren’t able to tolerate GLP-1 RAs “might be small — less than 10% of people who try to take them — but we don’t fully understand the differences in response across different individuals,” Drucker said.
Acosta agreed, adding that it’s “essential for us to identify who will be the best responders, as we do with medications for other conditions, such as cancer and cardiovascular disease.”
Acosta’s group has spent more than a decade engaged in efforts to identify unique characteristics among patients with obesity and has succeeded in identifying four obesity phenotypes.
“What matters in the space of GLP-1 is that using this classification, we can identify the best responders and those who don’t respond.”
The first phenotype, described as “Hungry Gut” (HG), includes patients with abnormal postprandial satiety. “Although they may be satiated at the end of a meal, they have accelerated gastric emptying and therefore feel hungry between meals and want to keep eating,” he said.
There are also patients who experience abnormal satiety during meals. According to Acosta, these are the patients who will return to the table for second and third helpings. “They don’t feel full and continue to eat more and more in a single sitting” — a phenomenon referred to as “Hungry Brain.”
The third phenotype — “Emotional Hunger” — consists of people who are “hedonic” about food or engage in emotional eating behavior, whereas in the fourth group, people have “an abnormal metabolism in which they don’t burn enough calories. They have an inefficient metabolic rate.” This latter phenomenon is called “Slow Burn.”
Acosta and colleagues randomized 312 patients attending a weight management center to phenotype-guided or non–phenotype-guided treatment with anti-obesity medications (phentermine, phentermine/topiramate, bupropion/naltrexone, lorcaserin, and liraglutide). The phenotype-guided approach was associated with a 1.75-fold greater weight loss after 1 year than the non–phenotype-guided approach (mean weight loss, 15.9% vs 9.0%, respectively).
GLP-1 RAs: Not One-Size-Fits-All
Acosta’s group has developed a genetic test that uses patients’ saliva to identify their obesity phenotype, with the aim of predicting the best responders to GLP-1 RAs. The test, MyPhenome genetic obesity test, is licensed by Acosta’s lab and available through Phenomix Sciences.
Acosta and colleagues presented their findings at the American Gastroenterological Association’s 2024 annual meeting regarding a machine-learning gene risk score (ML-GRS) they developed to predict HG, based on saliva and blood samples. Their genetic studies generated a ML-GRS that classified participants with obesity along a continuum from “HG Positive” (HG+) to “HG Negative” (HG−). Compared with the HG− participants, those who were HG+ had superior total body weight loss with semaglutide at 9 and 12 months. When used to predict response, the ML-GRS had an area under the curve of 0.76 (P = .04) and a positive predictive value of 0.95.
According to Acosta, HG+ patients are “the best responders to the GLP-1 RAs, although we don’t yet understand the mechanism of why they have the phenomenon of abnormal postprandial satiety. It may be an abnormal genetic pathway or abnormal secretion of GLP-1. More studies are needed.”
He noted that GLP-1 RAs “might also be helpful with the second [Hungry Brain] category, but these patients do better with phentermine-topiramate,” as demonstrated in a 2023 study conducted by Acosta and colleagues.
His group has also studied which lifestyle interventions are most effective for each phenotype. “When a unique lifestyle intervention targeting each phenotype was applied, patients lost more weight and had greater metabolic improvement,” he reported.
“Treating obesity no longer needs to be trial-and-error, but should be done using precision medicine because one size doesn’t fit all,” Acosta said.
Concerning Side Effects
The popular media has featured stories about individuals who took GLP-1 RAs for weight loss and experienced serious side effects, including a recent account of a British nurse who died after taking tirzepatide. As reported by the BBC, the nurse’s death certificate listed multiple organ failure, septic shock, and pancreatitis as the immediate causes of death, with the “use of prescribed tirzepatide” recorded as a contributing factor. The report went on to note that there were 23 suspected deaths in the United Kingdom tied to semaglutide since 2019.
Beyond brand-name products, there are also risks associated with GLP-1 RAs manufactured by compounding pharmacies. In early November, CNN reported that compounded semaglutide has been linked to at least 10 deaths. Because of a prior shortage of tirzepatide, the US Food and Drug Administration (FDA) had allowed compounding pharmacies to manufacture the drug. In October, the FDA clarified that it won’t take legal action against compounders, even now that the shortage has been resolved.
A pharmacovigilance study using the FDA Adverse Event Reporting System identified “potential safety signals of increased mortality and serious adverse event reporting” associated with certain GLP-1 RAs — especially in younger patients and women (P < .0001 for both groups).
The most common side effects reported with GLP-1 RAs are gastrointestinal events, such as nausea, diarrhea, constipation, and vomiting. Most occur during dose initiation and escalation and wane over the following weeks. However, studies have also reported severe side effects, including a higher risk for pancreatitis, bowel obstruction, and gastroparesis, as well as a significantly higher risk for gallbladder and biliary diseases. In fact, according to one study, patients with diabetes taking GLP-1 RAs reported gastrointestinal-related issues as a “prominent factor” in their decision to discontinue taking these medications.
Several types of cancer are potentially associated with GLP-1 RAs, but findings regarding this potential link have been inconsistent. In a recent review article, Drucker noted there were only inconsistent data linking GLP-1 RAs with thyroid cancer and medullary thyroid cancer and that their potential association with pancreatic has “not been supported by results from randomized controlled trials or real-world data.”
Concerns have been raised about loss of lean mass and muscle strength and function, especially in older individuals with obesity and advanced liver, cardiovascular, or kidney disease. However, as Drucker pointed out in his review article, muscle function may not correlate with the loss of lean mass. In fact, there are “consistent reductions” in lean mass after bariatric surgery, but “little evidence to date for impairment of muscle function.” He added that newer GLP-1 agents under development for obesity treatment are focusing on “developing complementary therapies that preferentially reduce adipose tissue, while sparing lean mass.”
As covered by Medscape Medical News, there have been reports of potential suicidal ideation associated with GLP-1 RAs. This triggered a 2023 review from the European Medicines Agency. However, recent results from a cohort study and a post hoc analysis of randomized controlled trials concluded that there is no evidence that these drugs increase suicidal ideation or behavior.
In early November, the FDA updated the labels for the GLP-1 RAs to include a warning regarding pulmonary aspiration during general anesthesia or deep sedation. Guidance from a group of societies, led by the American Society of Anesthesiologists, contains recommendations regarding nuances of addressing this concern in surgical patients taking these agents.
Not a Standalone Treatment
Marc-Andre Cornier, MD, professor of medicine, James A. Keating Endowed Chair in Diabetes, and director of the Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, told Medscape Medical News that GLP-1 RAs should not be viewed as cosmetic interventions but rather as medical treatments, “not only for weight loss but to reverse obesity-associated complications.”
Moreover, they should be used “as an adjunct to lifestyle changes,” emphasized Cornier. “We want our patients to have a high-quality diet with high protein content, fluid, vitamins, and minerals, and we want them to exercise.” Especially with the concern of potential loss of muscle mass with these agents, “resistance exercise might help mitigate that concern.”
Recently published recommendations can assist clinicians in guiding patients taking GLP-1 RAs to optimize nutrition. The recommendations note that patients should be referred to a registered dietitian to “complement and support” treatment with anti-obesity medications.
What Do Patients Want?
Despite the ever-rising popularity of GLP-1 RAs, a new national survey of over 2200 US adults conducted by the Physicians Committee for Responsible Medicine suggests that most Americans don’t want to use them. Among those who wanted to lose weight, almost three-quarters “disagreed” or “strongly disagreed” with the idea of taking a weight-loss injectable, and 68% of those who wanted to lose weight “agreed” or “strongly agreed” that they would be willing to try a plant-based diet, if it could lead to significant weight loss.
Moreover, many individuals treated with GLP-1 RAs discontinue their use, despite the probability of regaining the weight, according to a report that found only 46.3% of GLP-1 users were still taking the medications at 6 months and only 32.3% at 1 year. The authors commented that their real-world findings show a “substantially lower” 1-year persistence rate, compared with the rate reported in clinical trials. They suggest that the financial burden (> $12,000/year) may contribute to discontinuation.
Discontinuation of GLP-1 RAs can lead to worsening cardiometabolic parameters, with a potential increased risk for adverse outcomes; moreover, weight cycling (“yo-yo dieting”) carries its own risks. In light of these concerns, it’s particularly important to select appropriate patients and to determine whether potential short-term therapy has any enduring benefit.
Acosta agreed. “It’s exciting when looking at the data on how to find the best responders and who should make the effort to take these medications — not only in terms of side effects but also in terms of cost and which patients will receive maximum benefits and should be covered by insurance.”
Drucker has served as a consultant or speaker for Altimmune, Amgen, AstraZeneca, Arrowhead, Boehringer Ingelheim, Kallyope, Merck Research Laboratories, Novo Nordisk, Pfizer, and Zealand Pharma. He holds nonexercised options in Kallyope. Mount Sinai Hospital receives research support for investigator-initiated studies in the Drucker laboratory from Amgen, Novo Nordisk, Pfizer, and Zealand Pharma. Gila Therapeutics and Phenomix Sciences have licensed Acosta’s research technologies from University of Florida and Mayo Clinic. Acosta received consultant fees in the last 5 years from Rhythm Pharmaceuticals, Gila Therapeutics, Amgen, General Mills, Regeneron Pharmaceuticals, Boehringer Ingelheim, Novo Nordisk, Currax, Nestlé, Phenomix Sciences, Bausch Health, and Rare Disease. He received funding support from the National Institutes of Health, Vivus Pharmaceuticals, Novo Nordisk, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical, Rhythm Pharmaceuticals, Regeneron Pharmaceuticals, Boehringer Ingelheim, and Novo Nordisk. In the past, Cornier has served as a consultant for Novo Nordisk.
A version of this article first appeared on Medscape.com.
Rates of overweight and obesity have more than doubled in the United States during the last three decades, according to a new analysis. By 2050, it’s anticipated that 213 million adults (age, > 25 years) and 43 million children and adolescents will have overweight or obesity. The results led authors of a study to describe obesity as having reached a “crisis point” requiring urgent action and interventions.
Are glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed and prescribed for diabetes and now approved for weight loss, the answer?
Their popularity is certainly surging. Between the last 6 months of 2022 vs the last 6 months of 2024, the number of patients prescribed GLP-1 RAs increased by 132.6%. This is also reflected in a shift in public awareness, with a recent survey of US adults finding that 32% of respondents had heard “a lot” about these drugs, up from 19% in 2023.
GLP-1 RAs (including tirzepatide, which targets not only the GLP-1 receptor but also the glucose-dependent insulinotropic polypeptide receptor) have shown efficacy in weight loss. A 2022 review and meta-analysis of 22 trials (17,183 patients) found that 50.2% and 17.5% of those treated with GLP-1 RAs had a ≥ 5% and ≥ 10% weight loss, respectively, compared with placebo. A 2023 review of 41 trials (15,135 patients) found that compared with controls, GLP-1 RAs significantly reduced body weight, body mass index, waist circumference, and waist-to-hip ratio.
“GLP-1 RAs are great medications,” Andres Acosta, MD, PhD, director of the Precision Medicine for Obesity Laboratory, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. “We’ve been using them for almost two decades. But now there’s excitement about their utility in treating obesity.”
Treating the Four Categories of Obesity
Daniel Drucker, MD, senior investigator at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, is a pioneer in diabetes treatment and particularly in the development of GLP-1 RAs. Drucker told Medscape Medical News that despite the efficacy and enormous potential of GLP-1 RAs, “we know some people don’t lose much weight when taking these medicines and others don’t feel well and can’t take them.”
The number of individuals who don’t respond to or aren’t able to tolerate GLP-1 RAs “might be small — less than 10% of people who try to take them — but we don’t fully understand the differences in response across different individuals,” Drucker said.
Acosta agreed, adding that it’s “essential for us to identify who will be the best responders, as we do with medications for other conditions, such as cancer and cardiovascular disease.”
Acosta’s group has spent more than a decade engaged in efforts to identify unique characteristics among patients with obesity and has succeeded in identifying four obesity phenotypes.
“What matters in the space of GLP-1 is that using this classification, we can identify the best responders and those who don’t respond.”
The first phenotype, described as “Hungry Gut” (HG), includes patients with abnormal postprandial satiety. “Although they may be satiated at the end of a meal, they have accelerated gastric emptying and therefore feel hungry between meals and want to keep eating,” he said.
There are also patients who experience abnormal satiety during meals. According to Acosta, these are the patients who will return to the table for second and third helpings. “They don’t feel full and continue to eat more and more in a single sitting” — a phenomenon referred to as “Hungry Brain.”
The third phenotype — “Emotional Hunger” — consists of people who are “hedonic” about food or engage in emotional eating behavior, whereas in the fourth group, people have “an abnormal metabolism in which they don’t burn enough calories. They have an inefficient metabolic rate.” This latter phenomenon is called “Slow Burn.”
Acosta and colleagues randomized 312 patients attending a weight management center to phenotype-guided or non–phenotype-guided treatment with anti-obesity medications (phentermine, phentermine/topiramate, bupropion/naltrexone, lorcaserin, and liraglutide). The phenotype-guided approach was associated with a 1.75-fold greater weight loss after 1 year than the non–phenotype-guided approach (mean weight loss, 15.9% vs 9.0%, respectively).
GLP-1 RAs: Not One-Size-Fits-All
Acosta’s group has developed a genetic test that uses patients’ saliva to identify their obesity phenotype, with the aim of predicting the best responders to GLP-1 RAs. The test, MyPhenome genetic obesity test, is licensed by Acosta’s lab and available through Phenomix Sciences.
Acosta and colleagues presented their findings at the American Gastroenterological Association’s 2024 annual meeting regarding a machine-learning gene risk score (ML-GRS) they developed to predict HG, based on saliva and blood samples. Their genetic studies generated a ML-GRS that classified participants with obesity along a continuum from “HG Positive” (HG+) to “HG Negative” (HG−). Compared with the HG− participants, those who were HG+ had superior total body weight loss with semaglutide at 9 and 12 months. When used to predict response, the ML-GRS had an area under the curve of 0.76 (P = .04) and a positive predictive value of 0.95.
According to Acosta, HG+ patients are “the best responders to the GLP-1 RAs, although we don’t yet understand the mechanism of why they have the phenomenon of abnormal postprandial satiety. It may be an abnormal genetic pathway or abnormal secretion of GLP-1. More studies are needed.”
He noted that GLP-1 RAs “might also be helpful with the second [Hungry Brain] category, but these patients do better with phentermine-topiramate,” as demonstrated in a 2023 study conducted by Acosta and colleagues.
His group has also studied which lifestyle interventions are most effective for each phenotype. “When a unique lifestyle intervention targeting each phenotype was applied, patients lost more weight and had greater metabolic improvement,” he reported.
“Treating obesity no longer needs to be trial-and-error, but should be done using precision medicine because one size doesn’t fit all,” Acosta said.
Concerning Side Effects
The popular media has featured stories about individuals who took GLP-1 RAs for weight loss and experienced serious side effects, including a recent account of a British nurse who died after taking tirzepatide. As reported by the BBC, the nurse’s death certificate listed multiple organ failure, septic shock, and pancreatitis as the immediate causes of death, with the “use of prescribed tirzepatide” recorded as a contributing factor. The report went on to note that there were 23 suspected deaths in the United Kingdom tied to semaglutide since 2019.
Beyond brand-name products, there are also risks associated with GLP-1 RAs manufactured by compounding pharmacies. In early November, CNN reported that compounded semaglutide has been linked to at least 10 deaths. Because of a prior shortage of tirzepatide, the US Food and Drug Administration (FDA) had allowed compounding pharmacies to manufacture the drug. In October, the FDA clarified that it won’t take legal action against compounders, even now that the shortage has been resolved.
A pharmacovigilance study using the FDA Adverse Event Reporting System identified “potential safety signals of increased mortality and serious adverse event reporting” associated with certain GLP-1 RAs — especially in younger patients and women (P < .0001 for both groups).
The most common side effects reported with GLP-1 RAs are gastrointestinal events, such as nausea, diarrhea, constipation, and vomiting. Most occur during dose initiation and escalation and wane over the following weeks. However, studies have also reported severe side effects, including a higher risk for pancreatitis, bowel obstruction, and gastroparesis, as well as a significantly higher risk for gallbladder and biliary diseases. In fact, according to one study, patients with diabetes taking GLP-1 RAs reported gastrointestinal-related issues as a “prominent factor” in their decision to discontinue taking these medications.
Several types of cancer are potentially associated with GLP-1 RAs, but findings regarding this potential link have been inconsistent. In a recent review article, Drucker noted there were only inconsistent data linking GLP-1 RAs with thyroid cancer and medullary thyroid cancer and that their potential association with pancreatic has “not been supported by results from randomized controlled trials or real-world data.”
Concerns have been raised about loss of lean mass and muscle strength and function, especially in older individuals with obesity and advanced liver, cardiovascular, or kidney disease. However, as Drucker pointed out in his review article, muscle function may not correlate with the loss of lean mass. In fact, there are “consistent reductions” in lean mass after bariatric surgery, but “little evidence to date for impairment of muscle function.” He added that newer GLP-1 agents under development for obesity treatment are focusing on “developing complementary therapies that preferentially reduce adipose tissue, while sparing lean mass.”
As covered by Medscape Medical News, there have been reports of potential suicidal ideation associated with GLP-1 RAs. This triggered a 2023 review from the European Medicines Agency. However, recent results from a cohort study and a post hoc analysis of randomized controlled trials concluded that there is no evidence that these drugs increase suicidal ideation or behavior.
In early November, the FDA updated the labels for the GLP-1 RAs to include a warning regarding pulmonary aspiration during general anesthesia or deep sedation. Guidance from a group of societies, led by the American Society of Anesthesiologists, contains recommendations regarding nuances of addressing this concern in surgical patients taking these agents.
Not a Standalone Treatment
Marc-Andre Cornier, MD, professor of medicine, James A. Keating Endowed Chair in Diabetes, and director of the Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, told Medscape Medical News that GLP-1 RAs should not be viewed as cosmetic interventions but rather as medical treatments, “not only for weight loss but to reverse obesity-associated complications.”
Moreover, they should be used “as an adjunct to lifestyle changes,” emphasized Cornier. “We want our patients to have a high-quality diet with high protein content, fluid, vitamins, and minerals, and we want them to exercise.” Especially with the concern of potential loss of muscle mass with these agents, “resistance exercise might help mitigate that concern.”
Recently published recommendations can assist clinicians in guiding patients taking GLP-1 RAs to optimize nutrition. The recommendations note that patients should be referred to a registered dietitian to “complement and support” treatment with anti-obesity medications.
What Do Patients Want?
Despite the ever-rising popularity of GLP-1 RAs, a new national survey of over 2200 US adults conducted by the Physicians Committee for Responsible Medicine suggests that most Americans don’t want to use them. Among those who wanted to lose weight, almost three-quarters “disagreed” or “strongly disagreed” with the idea of taking a weight-loss injectable, and 68% of those who wanted to lose weight “agreed” or “strongly agreed” that they would be willing to try a plant-based diet, if it could lead to significant weight loss.
Moreover, many individuals treated with GLP-1 RAs discontinue their use, despite the probability of regaining the weight, according to a report that found only 46.3% of GLP-1 users were still taking the medications at 6 months and only 32.3% at 1 year. The authors commented that their real-world findings show a “substantially lower” 1-year persistence rate, compared with the rate reported in clinical trials. They suggest that the financial burden (> $12,000/year) may contribute to discontinuation.
Discontinuation of GLP-1 RAs can lead to worsening cardiometabolic parameters, with a potential increased risk for adverse outcomes; moreover, weight cycling (“yo-yo dieting”) carries its own risks. In light of these concerns, it’s particularly important to select appropriate patients and to determine whether potential short-term therapy has any enduring benefit.
Acosta agreed. “It’s exciting when looking at the data on how to find the best responders and who should make the effort to take these medications — not only in terms of side effects but also in terms of cost and which patients will receive maximum benefits and should be covered by insurance.”
Drucker has served as a consultant or speaker for Altimmune, Amgen, AstraZeneca, Arrowhead, Boehringer Ingelheim, Kallyope, Merck Research Laboratories, Novo Nordisk, Pfizer, and Zealand Pharma. He holds nonexercised options in Kallyope. Mount Sinai Hospital receives research support for investigator-initiated studies in the Drucker laboratory from Amgen, Novo Nordisk, Pfizer, and Zealand Pharma. Gila Therapeutics and Phenomix Sciences have licensed Acosta’s research technologies from University of Florida and Mayo Clinic. Acosta received consultant fees in the last 5 years from Rhythm Pharmaceuticals, Gila Therapeutics, Amgen, General Mills, Regeneron Pharmaceuticals, Boehringer Ingelheim, Novo Nordisk, Currax, Nestlé, Phenomix Sciences, Bausch Health, and Rare Disease. He received funding support from the National Institutes of Health, Vivus Pharmaceuticals, Novo Nordisk, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical, Rhythm Pharmaceuticals, Regeneron Pharmaceuticals, Boehringer Ingelheim, and Novo Nordisk. In the past, Cornier has served as a consultant for Novo Nordisk.
A version of this article first appeared on Medscape.com.
Interim guidance for CPR in patients with COVID-19
The American Heart Association (AHA) and seven other medical societies have issued interim guidance to inform treatment of victims of cardiac arrest with suspected or confirmed COVID-19, focusing on reducing provider exposure, and prioritizing oxygenation and ventilation strategies, goals of care, and appropriateness of resuscitation.
“We were very specific in calling this ‘interim guidance’ based on expert opinion because things are evolving so quickly and we are learning more and more every day as more and more patients with COVID-19 are taken care of,” corresponding author Comilla Sasson, MD, PhD, vice president, Emergency Cardiovascular Care (ECC) Science and Innovation, American Heart Association, told theheart.org | Medscape Cardiology.
“We wanted this to be a starting point for providing the clinical guidance that everyone is looking for and, as we collect more data, the guidance will change, as it has for CDC [Centers for Disease Control and Prevention] and WHO [World Health Organization],” she said.
“The guidance sought to balance the provision of timely, high-quality resuscitation to patients while simultaneously protecting rescuers,” she added.
The guidance was published online April 9 in Circulation. The AHA produced the guidelines in collaboration with the American Academy of Pediatrics, American Association for Respiratory Care, American College of Emergency Physicians, the Society of Critical Care Anesthesiologists, and the American Society of Anesthesiologists, with support from the American Association of Critical Care Nurses and National EMS Physicians.
Respiratory Etiologies
“We think of cardiac arrest in adults, especially as related to cardiac etiologies, but we are now thinking of it in COVID-19 more as hypoxemia or respiratory failure, which can predispose patients to cardiac arrest,” Sasson explained.
Healthcare workers are the “highest-risk profession” for contracting the COVID-19, with resuscitations carrying “added risk” for several reasons, the authors note.
Administering CPR involves performing numerous aerosol-generating procedures that can cause viral particles to remain suspended in the air and be inhaled by those nearby, with a half-life of approximately 1 hour, they point out.
Moreover, resuscitation efforts “require numerous providers to work in close proximity to one another and the patient,” and the high-stress emergent nature of these events may result in lapses in infection-control procedures.
The guidance is designed “to protect not only the patient but also the provider and involves strategies regarding oxygenation and ventilation that differ from what we’ve done in the past since we have a strong feeling that this is a different disease process that may require different approaches than what we’ve dealt with in the past,” Sasson commented.
Reducing Provider Exposure
Providers should don PPE to protect both themselves and their colleagues from unnecessary exposure, the authors advise, noting that recommendations for PPE standards may “vary considerably,” so health or emergency medical services (EMS) standards should be taken into account.
Moreover, it is important to allow only the most essential providers into the room or on the scene. In keeping with reducing the number of rescuers, the authors recommend replacing manual chest compressions with mechanical CPR devices for patients who meet height and weight criteria in settings with “protocols and expertise in place for their use.”
COVID-19 status should be communicated to any new providers prior to their arrival on the scene, the authors stress.
Oxygenation and Ventilation Strategies
“Reducing risk of aerosolization during the process of intubation is key,” Sasson emphasized.
For this reason, a high-efficiency particulate air HEPA filter (if available) should be attached to any manual or mechanical ventilation device, specifically in the path of exhaled gas, before any breaths are administered.
Moreover, it is important to intubate early with a cuffed tube and connect to a mechanical ventilator, if possible. The intubator should be engaged with the “highest chance of first-pass success,” and chest compression should be paused to intubate.
To further increase the chance of a successful first intubation, use of video laryngoscopy (if available) is helpful.
Additional guidance includes:
- Using a bag-mask device (or T-piece in neonates) with a HEPA filter and a tight seal prior to intubation
- Considering passive oxygenation with non-rebreathing face mask as an alternative to bag-mask device for short duration (in adults)
- Considering supraglottic airway if intubation is delayed
- Minimizing closed circuit disconnections.
Resuscitation Considerations
“One big take-home point of the guidance is to consider resuscitation appropriateness, starting with goals of care when the patient comes to us, and continuing or stopping resuscitation when needed, based on the discussion with the family as well as local protocol,” Sasson said.
A variety of factors need to be taken into account, including age, comorbidities, and illness severity to determine the appropriateness of resuscitation, and “the likelihood of success” must be balanced “against the risk to rescuers and patients from whom resources are being diverted,” the authors state.
An Array of Scenarios
“We divided bystander CPR into adults vs pediatrics and into those who are living with a person who is in cardiac arrest – because they have already been exposed [to COVID-19] – vs those who are not living with the patient,” Sasson reported. “We also addressed the role of lay bystanders.”
For lay rescuers:
- Household members should perform at least hands-only CPR, if willing and able to do so
- Use of a face mark or cloth covering of the mouth and nose of the rescuer and/or patient may reduce the risk of transmission to a nonhousehold member
- In children, lay rescuers should perform chest compressions and “consider mouth-to-mouth resuscitation,” especially if they are household members.
- If available, an automated external defibrillator should be used to assess and treat victims of out-of-hospital cardiac arrest (OHCA).
The authors offer additional guidance for in-hospital cardiac arrest (IHCA), including addressing advanced care directives, closing the door when possible to prevent airborne contamination of adjacent space, and considering leaving the patient on a mechanical ventilator with HEPA filter.
They additionally address the special needs of neonates, recommending the presence of a “skilled attendant prepared to resuscitate, irrespective of COVID-19 status,” and stressing the importance of PPE since the mother may be a “potential source of aerosolization for the neonatal team.” Additional measures include avoidance of routine airway suctioning and the use of endotracheal medications.
Critically ill pregnant women with COVID-19 are more vulnerable to acute decompensation because of the cardiopulmonary physiological changes associated with pregnancy, the authors note. Preparation for a potential perimortem delivery should take place after 4 minutes of resuscitation and be initiated early in the resuscitation algorithm so as to allow specialized obstetrical and neonatal teams with PPE to convene.
“We will be continually updating this guidance and we are encouraging people to ask questions,” Sasson summarized.
She noted that a hospital-based COVID-19 registry is being formed to collect “clinically relevant data” that will inform and update the current guidance.
Sasson reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper.
This article first appeared on Medscape.com.
The American Heart Association (AHA) and seven other medical societies have issued interim guidance to inform treatment of victims of cardiac arrest with suspected or confirmed COVID-19, focusing on reducing provider exposure, and prioritizing oxygenation and ventilation strategies, goals of care, and appropriateness of resuscitation.
“We were very specific in calling this ‘interim guidance’ based on expert opinion because things are evolving so quickly and we are learning more and more every day as more and more patients with COVID-19 are taken care of,” corresponding author Comilla Sasson, MD, PhD, vice president, Emergency Cardiovascular Care (ECC) Science and Innovation, American Heart Association, told theheart.org | Medscape Cardiology.
“We wanted this to be a starting point for providing the clinical guidance that everyone is looking for and, as we collect more data, the guidance will change, as it has for CDC [Centers for Disease Control and Prevention] and WHO [World Health Organization],” she said.
“The guidance sought to balance the provision of timely, high-quality resuscitation to patients while simultaneously protecting rescuers,” she added.
The guidance was published online April 9 in Circulation. The AHA produced the guidelines in collaboration with the American Academy of Pediatrics, American Association for Respiratory Care, American College of Emergency Physicians, the Society of Critical Care Anesthesiologists, and the American Society of Anesthesiologists, with support from the American Association of Critical Care Nurses and National EMS Physicians.
Respiratory Etiologies
“We think of cardiac arrest in adults, especially as related to cardiac etiologies, but we are now thinking of it in COVID-19 more as hypoxemia or respiratory failure, which can predispose patients to cardiac arrest,” Sasson explained.
Healthcare workers are the “highest-risk profession” for contracting the COVID-19, with resuscitations carrying “added risk” for several reasons, the authors note.
Administering CPR involves performing numerous aerosol-generating procedures that can cause viral particles to remain suspended in the air and be inhaled by those nearby, with a half-life of approximately 1 hour, they point out.
Moreover, resuscitation efforts “require numerous providers to work in close proximity to one another and the patient,” and the high-stress emergent nature of these events may result in lapses in infection-control procedures.
The guidance is designed “to protect not only the patient but also the provider and involves strategies regarding oxygenation and ventilation that differ from what we’ve done in the past since we have a strong feeling that this is a different disease process that may require different approaches than what we’ve dealt with in the past,” Sasson commented.
Reducing Provider Exposure
Providers should don PPE to protect both themselves and their colleagues from unnecessary exposure, the authors advise, noting that recommendations for PPE standards may “vary considerably,” so health or emergency medical services (EMS) standards should be taken into account.
Moreover, it is important to allow only the most essential providers into the room or on the scene. In keeping with reducing the number of rescuers, the authors recommend replacing manual chest compressions with mechanical CPR devices for patients who meet height and weight criteria in settings with “protocols and expertise in place for their use.”
COVID-19 status should be communicated to any new providers prior to their arrival on the scene, the authors stress.
Oxygenation and Ventilation Strategies
“Reducing risk of aerosolization during the process of intubation is key,” Sasson emphasized.
For this reason, a high-efficiency particulate air HEPA filter (if available) should be attached to any manual or mechanical ventilation device, specifically in the path of exhaled gas, before any breaths are administered.
Moreover, it is important to intubate early with a cuffed tube and connect to a mechanical ventilator, if possible. The intubator should be engaged with the “highest chance of first-pass success,” and chest compression should be paused to intubate.
To further increase the chance of a successful first intubation, use of video laryngoscopy (if available) is helpful.
Additional guidance includes:
- Using a bag-mask device (or T-piece in neonates) with a HEPA filter and a tight seal prior to intubation
- Considering passive oxygenation with non-rebreathing face mask as an alternative to bag-mask device for short duration (in adults)
- Considering supraglottic airway if intubation is delayed
- Minimizing closed circuit disconnections.
Resuscitation Considerations
“One big take-home point of the guidance is to consider resuscitation appropriateness, starting with goals of care when the patient comes to us, and continuing or stopping resuscitation when needed, based on the discussion with the family as well as local protocol,” Sasson said.
A variety of factors need to be taken into account, including age, comorbidities, and illness severity to determine the appropriateness of resuscitation, and “the likelihood of success” must be balanced “against the risk to rescuers and patients from whom resources are being diverted,” the authors state.
An Array of Scenarios
“We divided bystander CPR into adults vs pediatrics and into those who are living with a person who is in cardiac arrest – because they have already been exposed [to COVID-19] – vs those who are not living with the patient,” Sasson reported. “We also addressed the role of lay bystanders.”
For lay rescuers:
- Household members should perform at least hands-only CPR, if willing and able to do so
- Use of a face mark or cloth covering of the mouth and nose of the rescuer and/or patient may reduce the risk of transmission to a nonhousehold member
- In children, lay rescuers should perform chest compressions and “consider mouth-to-mouth resuscitation,” especially if they are household members.
- If available, an automated external defibrillator should be used to assess and treat victims of out-of-hospital cardiac arrest (OHCA).
The authors offer additional guidance for in-hospital cardiac arrest (IHCA), including addressing advanced care directives, closing the door when possible to prevent airborne contamination of adjacent space, and considering leaving the patient on a mechanical ventilator with HEPA filter.
They additionally address the special needs of neonates, recommending the presence of a “skilled attendant prepared to resuscitate, irrespective of COVID-19 status,” and stressing the importance of PPE since the mother may be a “potential source of aerosolization for the neonatal team.” Additional measures include avoidance of routine airway suctioning and the use of endotracheal medications.
Critically ill pregnant women with COVID-19 are more vulnerable to acute decompensation because of the cardiopulmonary physiological changes associated with pregnancy, the authors note. Preparation for a potential perimortem delivery should take place after 4 minutes of resuscitation and be initiated early in the resuscitation algorithm so as to allow specialized obstetrical and neonatal teams with PPE to convene.
“We will be continually updating this guidance and we are encouraging people to ask questions,” Sasson summarized.
She noted that a hospital-based COVID-19 registry is being formed to collect “clinically relevant data” that will inform and update the current guidance.
Sasson reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper.
This article first appeared on Medscape.com.
The American Heart Association (AHA) and seven other medical societies have issued interim guidance to inform treatment of victims of cardiac arrest with suspected or confirmed COVID-19, focusing on reducing provider exposure, and prioritizing oxygenation and ventilation strategies, goals of care, and appropriateness of resuscitation.
“We were very specific in calling this ‘interim guidance’ based on expert opinion because things are evolving so quickly and we are learning more and more every day as more and more patients with COVID-19 are taken care of,” corresponding author Comilla Sasson, MD, PhD, vice president, Emergency Cardiovascular Care (ECC) Science and Innovation, American Heart Association, told theheart.org | Medscape Cardiology.
“We wanted this to be a starting point for providing the clinical guidance that everyone is looking for and, as we collect more data, the guidance will change, as it has for CDC [Centers for Disease Control and Prevention] and WHO [World Health Organization],” she said.
“The guidance sought to balance the provision of timely, high-quality resuscitation to patients while simultaneously protecting rescuers,” she added.
The guidance was published online April 9 in Circulation. The AHA produced the guidelines in collaboration with the American Academy of Pediatrics, American Association for Respiratory Care, American College of Emergency Physicians, the Society of Critical Care Anesthesiologists, and the American Society of Anesthesiologists, with support from the American Association of Critical Care Nurses and National EMS Physicians.
Respiratory Etiologies
“We think of cardiac arrest in adults, especially as related to cardiac etiologies, but we are now thinking of it in COVID-19 more as hypoxemia or respiratory failure, which can predispose patients to cardiac arrest,” Sasson explained.
Healthcare workers are the “highest-risk profession” for contracting the COVID-19, with resuscitations carrying “added risk” for several reasons, the authors note.
Administering CPR involves performing numerous aerosol-generating procedures that can cause viral particles to remain suspended in the air and be inhaled by those nearby, with a half-life of approximately 1 hour, they point out.
Moreover, resuscitation efforts “require numerous providers to work in close proximity to one another and the patient,” and the high-stress emergent nature of these events may result in lapses in infection-control procedures.
The guidance is designed “to protect not only the patient but also the provider and involves strategies regarding oxygenation and ventilation that differ from what we’ve done in the past since we have a strong feeling that this is a different disease process that may require different approaches than what we’ve dealt with in the past,” Sasson commented.
Reducing Provider Exposure
Providers should don PPE to protect both themselves and their colleagues from unnecessary exposure, the authors advise, noting that recommendations for PPE standards may “vary considerably,” so health or emergency medical services (EMS) standards should be taken into account.
Moreover, it is important to allow only the most essential providers into the room or on the scene. In keeping with reducing the number of rescuers, the authors recommend replacing manual chest compressions with mechanical CPR devices for patients who meet height and weight criteria in settings with “protocols and expertise in place for their use.”
COVID-19 status should be communicated to any new providers prior to their arrival on the scene, the authors stress.
Oxygenation and Ventilation Strategies
“Reducing risk of aerosolization during the process of intubation is key,” Sasson emphasized.
For this reason, a high-efficiency particulate air HEPA filter (if available) should be attached to any manual or mechanical ventilation device, specifically in the path of exhaled gas, before any breaths are administered.
Moreover, it is important to intubate early with a cuffed tube and connect to a mechanical ventilator, if possible. The intubator should be engaged with the “highest chance of first-pass success,” and chest compression should be paused to intubate.
To further increase the chance of a successful first intubation, use of video laryngoscopy (if available) is helpful.
Additional guidance includes:
- Using a bag-mask device (or T-piece in neonates) with a HEPA filter and a tight seal prior to intubation
- Considering passive oxygenation with non-rebreathing face mask as an alternative to bag-mask device for short duration (in adults)
- Considering supraglottic airway if intubation is delayed
- Minimizing closed circuit disconnections.
Resuscitation Considerations
“One big take-home point of the guidance is to consider resuscitation appropriateness, starting with goals of care when the patient comes to us, and continuing or stopping resuscitation when needed, based on the discussion with the family as well as local protocol,” Sasson said.
A variety of factors need to be taken into account, including age, comorbidities, and illness severity to determine the appropriateness of resuscitation, and “the likelihood of success” must be balanced “against the risk to rescuers and patients from whom resources are being diverted,” the authors state.
An Array of Scenarios
“We divided bystander CPR into adults vs pediatrics and into those who are living with a person who is in cardiac arrest – because they have already been exposed [to COVID-19] – vs those who are not living with the patient,” Sasson reported. “We also addressed the role of lay bystanders.”
For lay rescuers:
- Household members should perform at least hands-only CPR, if willing and able to do so
- Use of a face mark or cloth covering of the mouth and nose of the rescuer and/or patient may reduce the risk of transmission to a nonhousehold member
- In children, lay rescuers should perform chest compressions and “consider mouth-to-mouth resuscitation,” especially if they are household members.
- If available, an automated external defibrillator should be used to assess and treat victims of out-of-hospital cardiac arrest (OHCA).
The authors offer additional guidance for in-hospital cardiac arrest (IHCA), including addressing advanced care directives, closing the door when possible to prevent airborne contamination of adjacent space, and considering leaving the patient on a mechanical ventilator with HEPA filter.
They additionally address the special needs of neonates, recommending the presence of a “skilled attendant prepared to resuscitate, irrespective of COVID-19 status,” and stressing the importance of PPE since the mother may be a “potential source of aerosolization for the neonatal team.” Additional measures include avoidance of routine airway suctioning and the use of endotracheal medications.
Critically ill pregnant women with COVID-19 are more vulnerable to acute decompensation because of the cardiopulmonary physiological changes associated with pregnancy, the authors note. Preparation for a potential perimortem delivery should take place after 4 minutes of resuscitation and be initiated early in the resuscitation algorithm so as to allow specialized obstetrical and neonatal teams with PPE to convene.
“We will be continually updating this guidance and we are encouraging people to ask questions,” Sasson summarized.
She noted that a hospital-based COVID-19 registry is being formed to collect “clinically relevant data” that will inform and update the current guidance.
Sasson reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper.
This article first appeared on Medscape.com.
More conflicting evidence on paclitaxel devices in PAD
The controversy regarding the safety of treating peripheral artery disease (PAD) with paclitaxel-coated devices has only deepened in the new year, with two recent studies suggesting opposite safety findings.
The debate began with a 2018 meta-analysis showing a late mortality signal associated with paclitaxel drug-coated balloons (DCBs) that sent reverberations through the interventional cardiology community (J Am Heart Assoc. 2018 Dec 18;7[24]:e011245).
Now, in a new meta-analysis involving eight randomized controlled trials (RCTs) and more than 1,400 patients with critical limb ischemia (CLI), the same researchers found significantly more early amputations and deaths in those treated with DCB below the knee, compared with conventional balloon angioplasty.
“The findings of our latest report add to previous evidence underpinning major safety concerns around use of paclitaxel in lower limb angioplasties – increased long-term patient mortality in cases of intermittent claudication,” lead author Konstantinos Katsanos MD, MSc, PhD, Patras University Hospital, Greece, said in an interview.
By contrast, a retrospective study of insurance claims in Germany showed no heightened mortality with paclitaxel-coated balloons and stents, compared with uncoated devices, in close to 38,000 patients with PAD.
On the contrary, use of paclitaxel-coated devices was associated with higher long-term survival, better amputation-free survival (AFS), and lower rates of major cardiovascular events in the treatment of chronic limb-threatening ischemia (CLTI).
These findings “emphasize the difference between population-based evidence and randomized trials,” lead author Christian-Alexander Behrendt, MD, University Medical Center Hamburg-Eppendorf, Germany, said in an interview.
Downstream “showers”
In the new meta-analysis led by Dr. Katsanos, published online Jan. 15, the 1,420 patients were treated with five different DCBs and 97% had CLI (J Vasc Intervent Radiol 2020 Feb;31[2]:202-12).
In up to 1-year follow-up, the paclitaxel DCB group had fewer target lesion revascularizations (TLR) than those of the uncoated device group (11.8% vs. 25.6%; risk ratio, 0.53; 95% confidence interval, 0.35-0.81) but worse AFS (13.7% vs. 9.4%; hazard ratio [HR], 1.52; 95% CI, 1.12-2.07).
The latter finding was driven by nonsignificant increased risks for all-cause death (odds ratio [OR], 1.39; 95% CI, 0.94-2.07) and major amputations (OR, 1.63; 95% CI, 0.92-2.90).
In dose-subgroup analyses, AFS was significantly worse in cases with high-dose (3.0-3.5 mcg/mm2) devices, but not in the single trial with a low-dose DCB (2.0 mcg/mm2).
“Considering the well-described downstream ‘showers’ of paclitaxel particles with current drug-coated balloons, we hypothesize that nontarget paclitaxel embolization is a plausible mechanism for distal foot and systemic toxicity,” Dr. Katsanos said.
Short time frame
Eric Secemsky, MD, of Harvard Medical School, and director of vascular intervention at Beth Israel Deaconess Medical Center, Boston, suggested in an interview that this theorized mechanism of harm in below-the-knee procedures could potentially shed light on a similar mechanism at play in above-the-knee procedures.
“We didn’t understand why people could potentially be dying in above-the-knee [procedures], and the suggestion here is that these devices might perhaps be causing particular embolization or maybe delayed wound healing,” Dr. Secemsky speculated.
However, “I don’t know that this is true, so I am cautious to say this is true,” he emphasized.
Dr. Secemsky said a strength of the Katsanos analysis is that the RCTs included more than 1,000 patients, but noted that it is hard to vet the quality and rigor of the data, as some of the studies have not yet been published. He also noted that paclitaxel-coated devices are not approved by the Food and Drug Administration in the United States for below-the-knee procedures.
Moreover, he continued, “two studies were driving the signal of harm: the IN.PACT DEEP, which included an iteration of their DCB that is no longer being tested; and the unpublished SINGA-PACLI trial. Those studies contributed most of the adverse events seen in this meta-analysis.”
In addition, the trials had different lengths of follow-up (6-12 months), he said. “Thus, the five trials with data available to 12 months are driving the 1-year findings, whereas three RCTs, including the primary RCT showing safety [Lutonix-BTK trial], only contribute data to 6 months.”
For this reason, “we are not too excited about this meta-analysis as of now, [because] all it tells us is that we need more data to support the safety of drug-coated devices in this population,” Dr. Secemsky said.
Dr. Katsanos explained that, “to address the differences in follow-up period and number of cases lost to follow-up, the primary endpoint was calculated on the log-hazard scale and expressed as a hazard ratio, as recommended for time-to-event outcomes.”
He highlighted that a short-term time frame of 6 months to 1 year was chosen “because it is clinically relevant to limb-threatening CLI.”
Sensitivity tests also “showed consistent direction and magnitude of the summary treatment effects in case of both AFS and freedom from TLR,” Dr. Katsanos emphasized.
Lower mortality, fewer amputations
The second study, published online Jan. 8, drew on health insurance claims in the German BARMER database to analyze 37,914 patients (mean age, 73.3 years, 49% female) and 21,546 propensity-score-matched patients with symptomatic CLTI or intermittent claudication (IC) with an index revascularization during 2010-2018 (Eur J Vasc Endovasc Surg. 2020 Jan 8. doi: 10.1016/j.ejvs.2019.12.034).
Patients were first stratified by CLTI or IC, and then by balloon vs. stent use. Paclitaxel-coated devices were then compared with uncoated devices within each stratum. The primary outcome was all-cause mortality at the end of follow-up.
From 2010 to 2018, the annual use of paclitaxel-coated devices increased dramatically from 3% to 39% in the CLTI group and from 4% to 48% in the IC group (P less than .001 for both).
A total of 2,454 deaths occurred within 5 years of follow-up (median, 2.7 years; longest, 8 years).
A Cox proportional hazards model (based on propensity-score-matched cohorts at 5 years) showed that, compared with uncoated devices, use of paclitaxel-coated devices in the CLTI group was associated with several improvements:
- Overall survival: HR, 0.83; 95% CI, 0.77-0.90.
- Amputation-free survival: HR, 0.85; 95% CI, 0.78-0.91.
- Major cardiovascular events: HR, 0.82; 95% CI, 0.77-0.88.
In the IC group, mortality was significantly better with DCB (HR, 0.87; 95% CI, 0.76-0.99) or a combination of DCB and drug-eluting stents (HR, 0.88; 95% CI, 0.80-0.98) than with uncoated devices, but similar for DES alone (HR, 0.91; 95% CI, 0.77-1.08).
No benefit was found for paclitaxel-coated devices in the IC group for AFS (HR, 0.91; 95% CI, 0.82-1.00) or major cardiovascular events (HR, 0.93; 95% CI, 0.87-1.00).
The authors acknowledge that “unmeasured confounding” may partly explain the results. It may be that patients revascularized with DCB or DES “are more likely to be treated in highly specialized trial centers with clear follow-up protocol.”
Moreover, these patients may have received “the best treatment,” including statin therapy, added Dr. Behrendt.
More evidence needed
Dr. Secemsky, who was not involved with either study, said the German investigators “did a wonderful job with this analysis in a large population of several thousand patients, showing nicely that after accounting for differences in comorbidities, the patients had no evidence of harm with [paclitaxel-coated] devices through 5 years.”
However, he cautioned, median follow-up time was just over 2 years. “Although the investigators had data all the way out to 5 years, over time, the number of patients contributing data became smaller, which results in more uncertainty with these longer-term findings,” he said. “As such, we still need to look at additional long-term data in this patient population to confirm the safety of these devices.”
At present, the “major consideration we want to address is whether it’s safe to use these devices, and we’re undertaking these analyses to examine safety, not to see if they improve mortality,” although the present study “has a suggestion of mortality benefit,” Dr. Secemsky said.
Dr. Katsanos added that paclitaxel-coated balloons “remain under investigation for below-knee arteries and critical limb ischemia,” with “a few randomized controlled trials on the way.”
“We need definitive evidence from high-quality multicenter controlled trials that these devices may improve wound healing and limb salvage without any systemic mortality risk,” he said.
Dr. Katsanos receives personal fees from Boston Scientific and Philips Healthcare. The study by Dr. Behrendt was part of the IDOMENEO project funded by the German Joint Federal Committee. Dr. Behrendt reports no relevant financial relationships. Dr. Secemsky reports institutional grants from Cook Medical, BD Bard, Medtronic, Beth Israel Deaconess Medical Center, and Boston Scientific, and reports consultancy for Cook Medical, BD Bard, and Medtronic.
This article first appeared on Medscape.com.
The controversy regarding the safety of treating peripheral artery disease (PAD) with paclitaxel-coated devices has only deepened in the new year, with two recent studies suggesting opposite safety findings.
The debate began with a 2018 meta-analysis showing a late mortality signal associated with paclitaxel drug-coated balloons (DCBs) that sent reverberations through the interventional cardiology community (J Am Heart Assoc. 2018 Dec 18;7[24]:e011245).
Now, in a new meta-analysis involving eight randomized controlled trials (RCTs) and more than 1,400 patients with critical limb ischemia (CLI), the same researchers found significantly more early amputations and deaths in those treated with DCB below the knee, compared with conventional balloon angioplasty.
“The findings of our latest report add to previous evidence underpinning major safety concerns around use of paclitaxel in lower limb angioplasties – increased long-term patient mortality in cases of intermittent claudication,” lead author Konstantinos Katsanos MD, MSc, PhD, Patras University Hospital, Greece, said in an interview.
By contrast, a retrospective study of insurance claims in Germany showed no heightened mortality with paclitaxel-coated balloons and stents, compared with uncoated devices, in close to 38,000 patients with PAD.
On the contrary, use of paclitaxel-coated devices was associated with higher long-term survival, better amputation-free survival (AFS), and lower rates of major cardiovascular events in the treatment of chronic limb-threatening ischemia (CLTI).
These findings “emphasize the difference between population-based evidence and randomized trials,” lead author Christian-Alexander Behrendt, MD, University Medical Center Hamburg-Eppendorf, Germany, said in an interview.
Downstream “showers”
In the new meta-analysis led by Dr. Katsanos, published online Jan. 15, the 1,420 patients were treated with five different DCBs and 97% had CLI (J Vasc Intervent Radiol 2020 Feb;31[2]:202-12).
In up to 1-year follow-up, the paclitaxel DCB group had fewer target lesion revascularizations (TLR) than those of the uncoated device group (11.8% vs. 25.6%; risk ratio, 0.53; 95% confidence interval, 0.35-0.81) but worse AFS (13.7% vs. 9.4%; hazard ratio [HR], 1.52; 95% CI, 1.12-2.07).
The latter finding was driven by nonsignificant increased risks for all-cause death (odds ratio [OR], 1.39; 95% CI, 0.94-2.07) and major amputations (OR, 1.63; 95% CI, 0.92-2.90).
In dose-subgroup analyses, AFS was significantly worse in cases with high-dose (3.0-3.5 mcg/mm2) devices, but not in the single trial with a low-dose DCB (2.0 mcg/mm2).
“Considering the well-described downstream ‘showers’ of paclitaxel particles with current drug-coated balloons, we hypothesize that nontarget paclitaxel embolization is a plausible mechanism for distal foot and systemic toxicity,” Dr. Katsanos said.
Short time frame
Eric Secemsky, MD, of Harvard Medical School, and director of vascular intervention at Beth Israel Deaconess Medical Center, Boston, suggested in an interview that this theorized mechanism of harm in below-the-knee procedures could potentially shed light on a similar mechanism at play in above-the-knee procedures.
“We didn’t understand why people could potentially be dying in above-the-knee [procedures], and the suggestion here is that these devices might perhaps be causing particular embolization or maybe delayed wound healing,” Dr. Secemsky speculated.
However, “I don’t know that this is true, so I am cautious to say this is true,” he emphasized.
Dr. Secemsky said a strength of the Katsanos analysis is that the RCTs included more than 1,000 patients, but noted that it is hard to vet the quality and rigor of the data, as some of the studies have not yet been published. He also noted that paclitaxel-coated devices are not approved by the Food and Drug Administration in the United States for below-the-knee procedures.
Moreover, he continued, “two studies were driving the signal of harm: the IN.PACT DEEP, which included an iteration of their DCB that is no longer being tested; and the unpublished SINGA-PACLI trial. Those studies contributed most of the adverse events seen in this meta-analysis.”
In addition, the trials had different lengths of follow-up (6-12 months), he said. “Thus, the five trials with data available to 12 months are driving the 1-year findings, whereas three RCTs, including the primary RCT showing safety [Lutonix-BTK trial], only contribute data to 6 months.”
For this reason, “we are not too excited about this meta-analysis as of now, [because] all it tells us is that we need more data to support the safety of drug-coated devices in this population,” Dr. Secemsky said.
Dr. Katsanos explained that, “to address the differences in follow-up period and number of cases lost to follow-up, the primary endpoint was calculated on the log-hazard scale and expressed as a hazard ratio, as recommended for time-to-event outcomes.”
He highlighted that a short-term time frame of 6 months to 1 year was chosen “because it is clinically relevant to limb-threatening CLI.”
Sensitivity tests also “showed consistent direction and magnitude of the summary treatment effects in case of both AFS and freedom from TLR,” Dr. Katsanos emphasized.
Lower mortality, fewer amputations
The second study, published online Jan. 8, drew on health insurance claims in the German BARMER database to analyze 37,914 patients (mean age, 73.3 years, 49% female) and 21,546 propensity-score-matched patients with symptomatic CLTI or intermittent claudication (IC) with an index revascularization during 2010-2018 (Eur J Vasc Endovasc Surg. 2020 Jan 8. doi: 10.1016/j.ejvs.2019.12.034).
Patients were first stratified by CLTI or IC, and then by balloon vs. stent use. Paclitaxel-coated devices were then compared with uncoated devices within each stratum. The primary outcome was all-cause mortality at the end of follow-up.
From 2010 to 2018, the annual use of paclitaxel-coated devices increased dramatically from 3% to 39% in the CLTI group and from 4% to 48% in the IC group (P less than .001 for both).
A total of 2,454 deaths occurred within 5 years of follow-up (median, 2.7 years; longest, 8 years).
A Cox proportional hazards model (based on propensity-score-matched cohorts at 5 years) showed that, compared with uncoated devices, use of paclitaxel-coated devices in the CLTI group was associated with several improvements:
- Overall survival: HR, 0.83; 95% CI, 0.77-0.90.
- Amputation-free survival: HR, 0.85; 95% CI, 0.78-0.91.
- Major cardiovascular events: HR, 0.82; 95% CI, 0.77-0.88.
In the IC group, mortality was significantly better with DCB (HR, 0.87; 95% CI, 0.76-0.99) or a combination of DCB and drug-eluting stents (HR, 0.88; 95% CI, 0.80-0.98) than with uncoated devices, but similar for DES alone (HR, 0.91; 95% CI, 0.77-1.08).
No benefit was found for paclitaxel-coated devices in the IC group for AFS (HR, 0.91; 95% CI, 0.82-1.00) or major cardiovascular events (HR, 0.93; 95% CI, 0.87-1.00).
The authors acknowledge that “unmeasured confounding” may partly explain the results. It may be that patients revascularized with DCB or DES “are more likely to be treated in highly specialized trial centers with clear follow-up protocol.”
Moreover, these patients may have received “the best treatment,” including statin therapy, added Dr. Behrendt.
More evidence needed
Dr. Secemsky, who was not involved with either study, said the German investigators “did a wonderful job with this analysis in a large population of several thousand patients, showing nicely that after accounting for differences in comorbidities, the patients had no evidence of harm with [paclitaxel-coated] devices through 5 years.”
However, he cautioned, median follow-up time was just over 2 years. “Although the investigators had data all the way out to 5 years, over time, the number of patients contributing data became smaller, which results in more uncertainty with these longer-term findings,” he said. “As such, we still need to look at additional long-term data in this patient population to confirm the safety of these devices.”
At present, the “major consideration we want to address is whether it’s safe to use these devices, and we’re undertaking these analyses to examine safety, not to see if they improve mortality,” although the present study “has a suggestion of mortality benefit,” Dr. Secemsky said.
Dr. Katsanos added that paclitaxel-coated balloons “remain under investigation for below-knee arteries and critical limb ischemia,” with “a few randomized controlled trials on the way.”
“We need definitive evidence from high-quality multicenter controlled trials that these devices may improve wound healing and limb salvage without any systemic mortality risk,” he said.
Dr. Katsanos receives personal fees from Boston Scientific and Philips Healthcare. The study by Dr. Behrendt was part of the IDOMENEO project funded by the German Joint Federal Committee. Dr. Behrendt reports no relevant financial relationships. Dr. Secemsky reports institutional grants from Cook Medical, BD Bard, Medtronic, Beth Israel Deaconess Medical Center, and Boston Scientific, and reports consultancy for Cook Medical, BD Bard, and Medtronic.
This article first appeared on Medscape.com.
The controversy regarding the safety of treating peripheral artery disease (PAD) with paclitaxel-coated devices has only deepened in the new year, with two recent studies suggesting opposite safety findings.
The debate began with a 2018 meta-analysis showing a late mortality signal associated with paclitaxel drug-coated balloons (DCBs) that sent reverberations through the interventional cardiology community (J Am Heart Assoc. 2018 Dec 18;7[24]:e011245).
Now, in a new meta-analysis involving eight randomized controlled trials (RCTs) and more than 1,400 patients with critical limb ischemia (CLI), the same researchers found significantly more early amputations and deaths in those treated with DCB below the knee, compared with conventional balloon angioplasty.
“The findings of our latest report add to previous evidence underpinning major safety concerns around use of paclitaxel in lower limb angioplasties – increased long-term patient mortality in cases of intermittent claudication,” lead author Konstantinos Katsanos MD, MSc, PhD, Patras University Hospital, Greece, said in an interview.
By contrast, a retrospective study of insurance claims in Germany showed no heightened mortality with paclitaxel-coated balloons and stents, compared with uncoated devices, in close to 38,000 patients with PAD.
On the contrary, use of paclitaxel-coated devices was associated with higher long-term survival, better amputation-free survival (AFS), and lower rates of major cardiovascular events in the treatment of chronic limb-threatening ischemia (CLTI).
These findings “emphasize the difference between population-based evidence and randomized trials,” lead author Christian-Alexander Behrendt, MD, University Medical Center Hamburg-Eppendorf, Germany, said in an interview.
Downstream “showers”
In the new meta-analysis led by Dr. Katsanos, published online Jan. 15, the 1,420 patients were treated with five different DCBs and 97% had CLI (J Vasc Intervent Radiol 2020 Feb;31[2]:202-12).
In up to 1-year follow-up, the paclitaxel DCB group had fewer target lesion revascularizations (TLR) than those of the uncoated device group (11.8% vs. 25.6%; risk ratio, 0.53; 95% confidence interval, 0.35-0.81) but worse AFS (13.7% vs. 9.4%; hazard ratio [HR], 1.52; 95% CI, 1.12-2.07).
The latter finding was driven by nonsignificant increased risks for all-cause death (odds ratio [OR], 1.39; 95% CI, 0.94-2.07) and major amputations (OR, 1.63; 95% CI, 0.92-2.90).
In dose-subgroup analyses, AFS was significantly worse in cases with high-dose (3.0-3.5 mcg/mm2) devices, but not in the single trial with a low-dose DCB (2.0 mcg/mm2).
“Considering the well-described downstream ‘showers’ of paclitaxel particles with current drug-coated balloons, we hypothesize that nontarget paclitaxel embolization is a plausible mechanism for distal foot and systemic toxicity,” Dr. Katsanos said.
Short time frame
Eric Secemsky, MD, of Harvard Medical School, and director of vascular intervention at Beth Israel Deaconess Medical Center, Boston, suggested in an interview that this theorized mechanism of harm in below-the-knee procedures could potentially shed light on a similar mechanism at play in above-the-knee procedures.
“We didn’t understand why people could potentially be dying in above-the-knee [procedures], and the suggestion here is that these devices might perhaps be causing particular embolization or maybe delayed wound healing,” Dr. Secemsky speculated.
However, “I don’t know that this is true, so I am cautious to say this is true,” he emphasized.
Dr. Secemsky said a strength of the Katsanos analysis is that the RCTs included more than 1,000 patients, but noted that it is hard to vet the quality and rigor of the data, as some of the studies have not yet been published. He also noted that paclitaxel-coated devices are not approved by the Food and Drug Administration in the United States for below-the-knee procedures.
Moreover, he continued, “two studies were driving the signal of harm: the IN.PACT DEEP, which included an iteration of their DCB that is no longer being tested; and the unpublished SINGA-PACLI trial. Those studies contributed most of the adverse events seen in this meta-analysis.”
In addition, the trials had different lengths of follow-up (6-12 months), he said. “Thus, the five trials with data available to 12 months are driving the 1-year findings, whereas three RCTs, including the primary RCT showing safety [Lutonix-BTK trial], only contribute data to 6 months.”
For this reason, “we are not too excited about this meta-analysis as of now, [because] all it tells us is that we need more data to support the safety of drug-coated devices in this population,” Dr. Secemsky said.
Dr. Katsanos explained that, “to address the differences in follow-up period and number of cases lost to follow-up, the primary endpoint was calculated on the log-hazard scale and expressed as a hazard ratio, as recommended for time-to-event outcomes.”
He highlighted that a short-term time frame of 6 months to 1 year was chosen “because it is clinically relevant to limb-threatening CLI.”
Sensitivity tests also “showed consistent direction and magnitude of the summary treatment effects in case of both AFS and freedom from TLR,” Dr. Katsanos emphasized.
Lower mortality, fewer amputations
The second study, published online Jan. 8, drew on health insurance claims in the German BARMER database to analyze 37,914 patients (mean age, 73.3 years, 49% female) and 21,546 propensity-score-matched patients with symptomatic CLTI or intermittent claudication (IC) with an index revascularization during 2010-2018 (Eur J Vasc Endovasc Surg. 2020 Jan 8. doi: 10.1016/j.ejvs.2019.12.034).
Patients were first stratified by CLTI or IC, and then by balloon vs. stent use. Paclitaxel-coated devices were then compared with uncoated devices within each stratum. The primary outcome was all-cause mortality at the end of follow-up.
From 2010 to 2018, the annual use of paclitaxel-coated devices increased dramatically from 3% to 39% in the CLTI group and from 4% to 48% in the IC group (P less than .001 for both).
A total of 2,454 deaths occurred within 5 years of follow-up (median, 2.7 years; longest, 8 years).
A Cox proportional hazards model (based on propensity-score-matched cohorts at 5 years) showed that, compared with uncoated devices, use of paclitaxel-coated devices in the CLTI group was associated with several improvements:
- Overall survival: HR, 0.83; 95% CI, 0.77-0.90.
- Amputation-free survival: HR, 0.85; 95% CI, 0.78-0.91.
- Major cardiovascular events: HR, 0.82; 95% CI, 0.77-0.88.
In the IC group, mortality was significantly better with DCB (HR, 0.87; 95% CI, 0.76-0.99) or a combination of DCB and drug-eluting stents (HR, 0.88; 95% CI, 0.80-0.98) than with uncoated devices, but similar for DES alone (HR, 0.91; 95% CI, 0.77-1.08).
No benefit was found for paclitaxel-coated devices in the IC group for AFS (HR, 0.91; 95% CI, 0.82-1.00) or major cardiovascular events (HR, 0.93; 95% CI, 0.87-1.00).
The authors acknowledge that “unmeasured confounding” may partly explain the results. It may be that patients revascularized with DCB or DES “are more likely to be treated in highly specialized trial centers with clear follow-up protocol.”
Moreover, these patients may have received “the best treatment,” including statin therapy, added Dr. Behrendt.
More evidence needed
Dr. Secemsky, who was not involved with either study, said the German investigators “did a wonderful job with this analysis in a large population of several thousand patients, showing nicely that after accounting for differences in comorbidities, the patients had no evidence of harm with [paclitaxel-coated] devices through 5 years.”
However, he cautioned, median follow-up time was just over 2 years. “Although the investigators had data all the way out to 5 years, over time, the number of patients contributing data became smaller, which results in more uncertainty with these longer-term findings,” he said. “As such, we still need to look at additional long-term data in this patient population to confirm the safety of these devices.”
At present, the “major consideration we want to address is whether it’s safe to use these devices, and we’re undertaking these analyses to examine safety, not to see if they improve mortality,” although the present study “has a suggestion of mortality benefit,” Dr. Secemsky said.
Dr. Katsanos added that paclitaxel-coated balloons “remain under investigation for below-knee arteries and critical limb ischemia,” with “a few randomized controlled trials on the way.”
“We need definitive evidence from high-quality multicenter controlled trials that these devices may improve wound healing and limb salvage without any systemic mortality risk,” he said.
Dr. Katsanos receives personal fees from Boston Scientific and Philips Healthcare. The study by Dr. Behrendt was part of the IDOMENEO project funded by the German Joint Federal Committee. Dr. Behrendt reports no relevant financial relationships. Dr. Secemsky reports institutional grants from Cook Medical, BD Bard, Medtronic, Beth Israel Deaconess Medical Center, and Boston Scientific, and reports consultancy for Cook Medical, BD Bard, and Medtronic.
This article first appeared on Medscape.com.