Modulators

In 1989, researchers discovered the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. CFTR regulates the proper flow of water and chloride in and out of cells lining the lungs and other organs.2 Mutations in the CFTR gene result in either a defective protein or no protein at all being produced, and this defect can lead to multiorgan health concerns.2

In recent years, CF clinic teams added highly effective modulator therapy (HEMT) to the cystic fibrosis (CF) treatment plan to help regulate the proper flow of water and chloride in and out of cells lining the lungs and other organs. CFTR modulators include  –elexacaftor, tezacaftor, and ivacaftor (ETI)– known as TrikaftaTM. Other modulators include Kalydeco™ (ivacaftor), Orkambi™ (lumacaftor and ivacaftor), and Symdeco™ (tezacaftor and ivacaftor). Despite side effects, modulators have significantly improved individuals’ pulmonary health and quality of life.3

Nutrition

Because of pancreatic insufficiency, many CF patients experienced malnutrition in the past. Treatment plans often included the “Legacy CF Diet” (a high-fat, high-calorie diet) because weight gain was associated with better health outcomes.4 Researchers and clinicians theorized that the Legacy CF Diet would “offset the negative energy expenditure created by malabsorption, increased work of breathing, inflammation, pancreatic insufficiency, and pulmonary exacerbations.”5 Because past studies typically recommended a high-energy diet with higher fat and protein intake, clinical management did not adequately focus on patients’ food choices, dietary needs, and eating habits.6 As Dr. A. Uluer has stated, the “historical CF diet previously focused on nutrition-poor foods, saturated fats, and excessive sugar.”7 

A changing dynamic around nutrition in the age of HEMT necessitates that researchers and clinicians reconsider past nutritional guidelines. Even before HEMT, Jimenez et al. argued that an “increased lifespan and decreased symptoms” amongst patients with CF demands that providers reconsider the historical CF diet.8 Since poor childhood eating habits can impact adult eating behaviors, “it is likely that people with CF will have difficulty transitioning to a lower-calorie diet after a lifetime of consuming high-calorie, high-fat foods.”3 Nutritional needs should be assessed on an individual basis, factoring in which and what dose modulator the individual is taking, their current health status, and their socio-economic background. The Academy for Nutrition and Dietetics: 2020 Cystic Fibrosis Evidence Analysis Center Evidence-based Nutrition Practice Guideline considers the use of ETI on patients’ weight and provides detailed provisions for providers to follow in both CF pediatric and adult nutrition care.9 

Weight

Data has shown that the number of patients with CF who are obese or overweight has doubled in the past 20 years.10 In the age of HEMT, this trend has become exacerbated.4 Leonard et al. hypothesize that “HEMT likely contributes to an increase in weight by reducing energy expenditure for breathing, improving smell/taste, enhancing appetite, optimizing fat absorption/intestinal pH increasing fat mass and presenting the need to take the medication with fatty foods.”1 The CF Foundation has not formally updated the CF Nutrition Guidelines since obesity and overweight have emerged as significant issues or since highly effective CFTR modulators recently became available for about 90% of the CF population.4 However, the Academy of Nutrition and Dietetics has.9 Litvin et al., in their article, “Energy balance and obesity in individuals with cystic fibrosis” (2019), have also provided excellent clinical practice points for CF teams to take into consideration, featured in Figure 1.11

Researchers must continue to understand the impact of weight gain and obesity on patients’ short and long-term health. Being overweight or obese in the general population can cause health complications like diabetes, cardiovascular disease, sleep apnea, and other comorbidities. Clinic teams are now focusing on diet quality as a way to promote optimal health outcomes and prevent other chronic lifestyle diseases in CF.9,12

Understanding Diet Recommendations

The evolving landscape of treatment for CF patients has made it difficult for doctors and researchers to recommend an appropriate diet for patients with CF. Nutrition for patients with CF has long been a focal point in clinical management. Because the CF Foundation Patient Registry data (CFFPR) showed a strong positive correlation between nutritional measures (e.g., BMI) and lung function, the CF Foundation set BMI goals above the 50th percentile for children and ≥22 kg/m2 for adult females and ≥23 kg/m2 for adult males with CF.13 Because of the history of malnutrition in the CF population and its effects on lung function, most nutritional interventions focused on increasing BMI.  CF Centers often prioritized nutrition and weight gain, even as they saw patients exceeding the 50th percentile in BMI.3 Yet a recent 2021 article by Kutney et al. cites studies that people with a BMI above 25 kg/m² do not generally show improvements in FEV₁.13  

Further, recent discussions in the CF world are re-examining the wisdom of using BMI as the proper measure for patients with CF.  BMI, for instance, does not account for bone mass, muscle, fat, or a genetic predisposition to the normal metabolic process in the body. Neither does it encompass various cultural eating habits. As such, there are increasing calls to replace BMI with other measures.14 Until evidence-based guidance on dietary recommendations for CF patients is available, clinic teams need to personalize nutritional recommendations using an individual’s clinical data and the patient’s weight goals.1

While significant changes in weight and BMI have been seen with ETI, it is vital to investigate the height, weight, and body mass index in people with CF (PwCF) on HEMT. HEMT likely contributes to an increase in weight by reducing the energy expenditure for breathing. It improves smell/taste, enhances appetite, and optimizes fat absorption/intestinal pH.15,16 Weight gain also results from the need to take modulators with food that has fat.1 There is an ongoing study [STRONG study, NCT05639556; Strength and Muscle Related Outcomes for Nutrition and Lung Function in CF; https://www.scholars.northwestern.edu/en/projects/strength-and-muscle-related-outcomes-for-nutrition-and-lung-funct] that seeks to compare markers of body composition with sarcopenia (loss of bone mass) using DXA scans. The study will look at nutritional and body composition measures and link them to the clinical outcomes of patients with various pulmonary function.17 Long-term studies like this one will increase knowledge about the effect of HEMT on patients’ nutritional status. It will also answer questions about whether weight gain from HEMT eventually plateaus–signaling a metabolic equilibrium– or if weight gain continues to rise, which would pose a risk for obesity.16  

Scientific knowledge about nutrition and CF is rapidly changing, particularly since weight gain and obesity are becoming a significant issue.18 This is due, in part, to a rise in obesity in patients with CF, which mirrors the obesity epidemic in the US.18 According to Petersen et al., “the causes of excess weight gain in CF are multifactorial, including: adherence to the high-fat legacy diet, reduced exercise tolerance, therapeutic advances, and general population trends.”19  Individuals are now instructed to follow a high-energy, low-calorie diet but are having difficulty transitioning to it. 

As of 2023, researchers are starting to study the effects of ivacaftor on weight gain. For instance, in 2021, King explored the relationship between lung function and weight among patients with the G551D mutation treated with ivacaftor.20 Patients gained significant weight in the first month and an additional five months of treatment. Mean weight increases were primarily composed of fat mass, with only small gains in fat-free mass in the first month of ivacaftor and after six months. Minimal body composition changes occurred once patients were stabilized on ivacaftor; weight, fat mass, and fat-free mass plateaued by two years.20 Petersen’s retrospective study, conducted in 2021 at the Washington University Adult Cystic Fibrosis Center, examined the effect of ETI on body weight and cardiometabolic parameters (n=134).19 The study looked at outpatient records, focusing on body weight, BMI, and blood pressure measures from the preceding year and the year following the initiation of ETI. The researchers measured other metabolic parameters, cardiometabolic risk factors at baseline, and each participant’s most recent follow-up.19 Results showed an association between ETI use and BMI increases. Significant increases in blood pressure and hyperlipidemia also occurred. The researchers concluded that widespread use of ETI may increase the incidence of overnutrition in the CF population.19 Leonard et al. have confirmed this finding of hypertension among PwCF, stating that “7.2% of adult pwCF had a diagnosis of hypertension” in 2021.1 They also showed a growing incidence of hypertension and metabolic syndrome in CF patients on ETI.1,19,21 Bailey, Litvin, and Yoon reported additional outcomes. They found patients experience a decrease in resting energy expenditure, an improvement in intestinal absorption, and an increase in caloric intake.4,11,18  To be sure, more extensive studies are needed to examine the relationship between body composition and fat distribution changes on CFTR modulators, unintended weight gain, and rates and mechanisms of becoming overweight and obese on these drugs.4  

Treatment Options

Changing their eating habits is problematic for patients used to the Legacy diet. The Endocrine Society recommends pharmacologic therapy for adults with a BMI ≥ 27 kg/m2 who have co-morbidities and a BMI ≥ 30 kg/m2 for those without co-morbidities.3 Providers must balance a patient’s weight reduction needs and the metabolic benefits of a lower BMI with the risk of a lower BMI on lung function.3 

Changing one’s diet is typically the first approach recommended for treating obesity. Reducing calories by 500–1000 kcal/day can usually produce a healthy weight loss of 1-2 lbs per week.3 Calorie reduction requires adding a food diary or a mobile phone app to track food choices and caloric intake to patients’ treatment regimens. Such tracking may be a struggle for people with CF due to a lack of time, daily treatment regimens, and other activities. 

With weight gain from HEMT, PwCF may experience weight stigma. Care teams need to acknowledge the mental impacts of undesired weight gain on patients’ body image and consider using WNAs (weight-neutral approaches) to lifestyle interventions.1 The latter should include discussing diet with the care team, modifying behavior (e.g., adding regular exercise to address a sedentary lifestyle), and nutritional education or re-education. 

Some patients may prefer to reflect on other health markers rather than BMI or weight, like lower blood pressure or cholesterol or less pain when considering their motivations for weight loss. Bailey and colleagues cite the HAES (Health at Every Size) approach as optimal, especially for patients with a history of disordered eating or body image issues: Instead of promoting weight loss, the Health at Every Size (HAES®) approach focuses on improving physical, behavioral, and psychological profiles.4 This weight-inclusive model emphasizes accepting one’s body and optimizing one’s relationship with food (see the Body Image chapter for body image and eating disorders). Though HAES is a weight-neutral program, it can improve quality of life, heart health, heightened physical activity, improved diet quality,  lower BMI and waist circumference, and facilitate fat loss.4  

Healthy Eating

The traditional American diet is known for being rich in saturated fats, additives, and preservatives. It also frequently includes refined carbohydrates and fats. It commonly causes addictive-like eating behaviors, including eating fats and sugars, which induces cravings and overeating. Eating nutrient-rich, fresh foods can retrain the brain and the foods it craves. Below are types of diets from around the world that center on nutrient-dense and high-quality foods. People who eat these diets have been shown to live longer, healthier lives, and so they may be appropriate for individuals with CF.

• Mediterranean Diet – Whole grains, legumes, fresh fruits, and fresh vegetables are produced locally. Fish and poultry are consumed in moderation (2-3 times/week), but meat, sugar, and salt are saved for special occasions.
• Traditional Okinawa Diet – This diet is a low-calorie, nutrient-dense diet. It focuses on fresh fruits and vegetables with moderate seafood and lean meat. The idea is to eat enough food to feel 80% full.
• Nordic Diet – Rich in root vegetables, whole-grain bread, and oily fish, the Nordic diet is high in fiber and protein but low in sugar. Meat dishes and processed dairy products are limited, but fermented milk and cheese are common ingredients.
• West African – Centered on lean meat, vegetables, and cereal staples, the West African diet is low in calories and nearly devoid of processed foods. This diet focuses on traditional preparations of foods like fresh fruit, fresh vegetables, whole grains, and fish.

Some people with CF have specific dietary needs, like being gluten-free or restrictions on dairy. Modifying one’s diet usually occurs by making small changes over time. 

Some helpful tips include: 

• Focus on plant-based foods such as legumes, beans, fruits, vegetables, nuts, seeds, and healthy fats. Enjoy fresh, in-season produce and fish, and use lean meat as sparingly as possible.
• Make breakfast your largest meal and eat smaller meals in the afternoon and evening. Limit your portions and stop eating when your stomach feels about 80% full.
• Consume as little added sugar as possible. Most of your daily intake is from natural sugars found in fruits and vegetables. Save sweets for occasional treats.
• Choose whole, natural foods that have not been processed or altered. Eat as much locally produced, in-season food as you possibly can. And use cooking methods that preserve the nutritional integrity of the raw ingredients.
• Drink plenty of water and reduce or stop drinking soft drinks and/or sugary drinks like some fruit juices. 
• Eat processed foods (cereals, crackers, chips, granola bars, etc.) in moderation. 
• Try to avoid canned fruits and vegetables. If you can’t find fresh, then frozen is the next best choice.
• Green tea and black coffee are ok to drink. 
• Be careful with dairy products, such as cheese, which can be high in fat and calories. When eating dairy, stick to Greek yogurts and low-fat or plant-based milks.

Structural and Social Determinants of Health Influencing Nutrition 

Eating fresh food is essential for losing weight and maintaining health. Yet broader, structural, and social factors such as affordability and low socio-economic status may make doing this particularly difficult for patients.

Affording healthy food while managing the expensive costs of CF drugs on a limited budget is a major barrier to losing weight and maintaining a healthy lifestyle. According to the Cystic Fibrosis Foundation (CFF), 71% of people with CF experience financial hardship due to medical bills.1 To better understand the impacts of financial hardships on the lives of those with CF, the CFF asked researchers from the Milken Institute School of Public Health at George Washington University to conduct the 2019 CF Health Insurance Survey.22 This online survey offered nine questions on various social determinants of health. Results showed that 38% of non-elderly adults with CF in the U.S. were on Social Security Insurance (SSI) or Social Security Disability Insurance (SSDI). Eight out of ten respondents indicated that their finances negatively impacted their quality of life. These researchers found that food insecurity in the CF community was three times the national average. Over 25% of CF patients participate in the Supplemental Nutrition Assistance Program (SNAP, aka food stamps).22 As a result of the findings, more CF centers are screening for food insecurity to help social workers identify those experiencing food insecurity that can impact their nutritional health.22 

According to the U.S. Department of Agriculture (USDA), food-insecure households have “limited or uncertain access to adequate food.”23 “Limited access to healthy food correlates with other unmet needs that indicate poverty. Poverty and food insecurity are both associated with obesity in the general population.”24

Lower incomes, like those on disability in the CF community, often force CF patients to live in neighborhoods with limited access to healthy food options.13 Further, food prices can dictate patient purchase decisions because boxed meals or low nutrient-dense foods are often cheaper than fresh fruits, vegetables, and protein sources. According to Bailey, a reliance upon high-calorie foods for CF patients who are food insecure or live in food deserts could increase the risk of becoming overweight or obese.4 As community members continue using HEMT, this risk may increase. 

Many sites offer discounted foods delivered to one’s home, and many of these sites accept a flexible spending account card, a health savings account card, and a supplemental nutrition assistance program electronic benefit transfer card. Here is a list of sites that may offer options:

• Thrive Market: https://thrivemarket.com
• Imperfect Foods: www.imperfectfoods.com
• Boxed: www.boxed.com
• Amazon Fresh if you are a Prime member: www.amazon.com
• Walmart Grocery: www.walmart.com
• Misfits Market: https://www.misfitsmarket.com
• The Hungry Root: www.hungryroot.com

Local food banks can also offer fresh fruits, vegetables, and meats to those facing financial hardships. CF social workers can help patients find resources in their local area.

Conclusion

Since the introduction of HEMT, there has been a significant increase in the life expectancy of PwCF. Addressing lifestyle changes, such as eating habits and exercise, has become a key component of CF care to combat the incidence of weight gain and address the comorbidities that come with living longer.

According to the 2022 CF Patient Registry, 82% of PwCF use HEMT, and 40.9% of all PwCF are within the BMI ranges that the CDC characterizes as overweight or obese.25 While some of the prevalence of obesity can be attributed to factors beyond HEMT (e.g., personal eating habits, financial stressors, and national trends), CF clinic teams should emphasize preventing weight-related comorbidities in their nutritional counseling and individualized dietary recommendations. 

Patients can also modify their diet by controlling portion sizes and eating fresh foods as much as possible. They can also increase their exercise if they have gained weight on ETIs. While these changes might be challenging, taking steps to better manage weight gain is important to stave off diseases associated with being overweight or obese, like cardiovascular disease, high cholesterol, diabetes, and fatigue, among others.

Leonard et al. developed an assessment tool that can help CF clinic providers. “An Interprofessional Team’s role in weight management and food insecurity assessment” addresses the potential roles of the patient and provider. 

An Interprofessional Team’s role in weight management and food insecurity assessment

Leonard A, Bailey J, Bruce A, et al. Nutritional considerations for a new era: A CF foundation position paper. J Cyst Fibros. doi:10.1016/j.jcf.2023.05.010

Photos courtesy of: https://www.istockphoto.com