Jay H. Shubrook, DO, FAAFP, FACOFP

Type 2 diabetes (T2D) has become a noncommunicable pandemic. Approximately 14.7% of the US adult population has diabetes.¹ Additionally, nearly 25% of the geriatric population has diabetes and nearly 50% has prediabetes.² Needless to say, most practices, regardless of specialty, see many patients with diabetes. We have made major advances in diabetes treatments, yet diabetes mellitus is still the leading cause of legal blindness, nontraumatic amputation, and end-stage renal disease requiring dialysis.³ 

While the prevalence of diabetes in adults is concerning, what is even more startling is the significant increase of T2D within the pediatric population. It was not too long ago that we considered T2D an “adult-only” disease. Now, 24% of children with diabetes have T2D, and 18% of adolescents have prediabetes.^4,5 This is not the end of the story. Recent studies have identified that the earlier you are diagnosed with T2D, the less responsive you are to diabetes treatments—and the disease will progress more rapidly to complications. 
 

We know that pediatric patients are not little adults. There are important physiologic and metabolic differences in our younger patients. The RISE study found that adolescents have lower insulin sensitivity than adults.^4,6 The pancreatic beta cells are more responsive at first and there is less clearance by the liver, which may indeed make insulin resistance worse. Finally, pancreatic beta cell function declines more rapidly in adolescents than in adults.^4,6 These physiologic changes can be even worse during puberty. The hormonal changes seen in puberty accelerate and amplify insulin secretion and worsen insulin resistance, which can result in hyperglycemia in those at risk.^7,8

The other complicating factor is the rapid rise in obesity in Americans. While childhood obesity is not quite at adult levels, it is a major risk factor for adult obesity. The prevalence of obesity in childhood was recently estimated to be 19.7% and is still on the rise.⁹ Obesity can be diabetogenic as we see an increase in visceral obesity. This triggers an inflammatory response that leads to worsening systemic insulin resistance and lipotoxicity from elevated circulating free fatty acids.⁸ 

Lifestyle and behavioral factors are also important in adolescents with T2D. While they are more independent than younger children, they are still largely dependent on the foods that are available in their home. Family food choices have a major impact on our youth. Further, the foods that our adolescents eat outside the home are more likely to be fast food or ultra-processed foods, which have been shown to contribute to obesity and T2D. 

Family history is a strong predictor of risk for T2D. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort, 89.4% of pediatric participants had a first-degree relative or grandparent with T2D.¹⁰ This highlights the importance of both genetic risk and living environment as risks for T2D. 

The American Diabetes Association recommends that all children with specific risk factors be screened for diabetes starting at the age 10 years or at puberty, whichever comes first.¹¹ The screening tests recommended for diabetes are currently the same as for adults, yet there are few data supporting this regimen. To diagnose diabetes, you can use any of the following screening tests: fasting glucose, glucose tolerance, or glycated hemoglobin (HbA1c).¹ 

Risk Factors That Should Prompt Diabetes Screening¹¹

Screening is recommended in children who are overweight (≥85%) or obese (≥95%) and who also have ≥1 of the following risk factors:

• Family history of T2D in a first- or second-degree relative
• Maternal history of gestational diabetes
• Low birth weight for gestational age
• Physical signs of insulin resistance or related conditions (eg, hypertension, dyslipidemia, polycystic ovary syndrome)
• High-risk race/ethnicity (Native American, African American, Pacific Islander, Latino)

Diagnostic Criteria for Diabetes Mellitus¹¹

A childhood or adolescent T2D diagnosis should be taken seriously and communicated to the patient and family in a timely manner. Treatment should start immediately. There are several factors that make managing T2D in adolescents more challenging. Children do not control key aspects of their life, including nutrition and, often, free time activity. There are a lot of social pressures to be “normal,” and having a chronic disease will definitely make the child feel “different” and potentially feel socially isolated. There are high rates of mood disorders in children with diabetes, which can make self-management even harder.¹²

As mentioned above, treatment should begin immediately upon diagnosis. This is because T2D in younger people tends to be more progressive and less responsive to treatment options, and patients are much more likely to develop.^1,13,14 These same complications can be seen in adult patients, but in younger patients they develop earlier in the disease; specifically, renal and neurologic complications occur at even higher rates.¹⁴ 

The initial treatment should include both family-based therapeutic lifestyle changes (ie, nutrition, physical activity intervention) and medication.¹¹ There are fewer US Food and Drug Administration–approved medication options for children and adolescents, and those treatments that have been approved are less durable in this population. 

Metformin and insulin are the most-used medications, but their initiation is often delayed, as therapeutic lifestyle change is tried first. This has not been shown to be an effective strategy and may even undermine the value of therapeutic lifestyle change if the family is told later that medication may still need to be added. 

Recent studies have shown the benefit of select glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as important therapeutic tools to treat T2D in adolescence. Dulaglutide, exenatide, and liraglutide have been shown to be safe and effective in trials for adolescents with T2D.^15-17 These agents reduce glucose and body weight and may be important tools to help reduce extra glycemic risks (eg, cardiovascular disease, kidney disease), but they have not been studied for this purpose yet. 

Further, there is good support for the use of bariatric surgery for adolescents. While this is a relatively new treatment option, early and mid-term results are favorable compared with medication-based strategies.¹⁸ Further studies are needed to determine the long-term benefits.

Take home points:

1. T2D is becoming increasingly common in our youth.
2. T2D, when diagnosed earlier in life, is more progressive, less responsive to treatment options, and associated with earlier complications.
3. New studies support the use of novel therapies such as GLP-1 RAs and metabolic surgery in this age group.

Dr. Shubrook and Dr. Antonia M. Molinari have written a comprehensive review on treatment options and current guidelines for the management of T2D in the pediatric population, which can supply further information.¹⁹ 

Type 2 diabetes (T2D) has become a noncommunicable pandemic. Approximately 14.7% of the US adult population has diabetes.¹ Additionally, nearly 25% of the geriatric population has diabetes and nearly 50% has prediabetes.² Needless to say, most practices, regardless of specialty, see many patients with diabetes. We have made major advances in diabetes treatments, yet diabetes mellitus is still the leading cause of legal blindness, nontraumatic amputation, and end-stage renal disease requiring dialysis.³ 

While the prevalence of diabetes in adults is concerning, what is even more startling is the significant increase of T2D within the pediatric population. It was not too long ago that we considered T2D an “adult-only” disease. Now, 24% of children with diabetes have T2D, and 18% of adolescents have prediabetes.^4,5 This is not the end of the story. Recent studies have identified that the earlier you are diagnosed with T2D, the less responsive you are to diabetes treatments—and the disease will progress more rapidly to complications. 
 

We know that pediatric patients are not little adults. There are important physiologic and metabolic differences in our younger patients. The RISE study found that adolescents have lower insulin sensitivity than adults.^4,6 The pancreatic beta cells are more responsive at first and there is less clearance by the liver, which may indeed make insulin resistance worse. Finally, pancreatic beta cell function declines more rapidly in adolescents than in adults.^4,6 These physiologic changes can be even worse during puberty. The hormonal changes seen in puberty accelerate and amplify insulin secretion and worsen insulin resistance, which can result in hyperglycemia in those at risk.^7,8

The other complicating factor is the rapid rise in obesity in Americans. While childhood obesity is not quite at adult levels, it is a major risk factor for adult obesity. The prevalence of obesity in childhood was recently estimated to be 19.7% and is still on the rise.⁹ Obesity can be diabetogenic as we see an increase in visceral obesity. This triggers an inflammatory response that leads to worsening systemic insulin resistance and lipotoxicity from elevated circulating free fatty acids.⁸ 

Lifestyle and behavioral factors are also important in adolescents with T2D. While they are more independent than younger children, they are still largely dependent on the foods that are available in their home. Family food choices have a major impact on our youth. Further, the foods that our adolescents eat outside the home are more likely to be fast food or ultra-processed foods, which have been shown to contribute to obesity and T2D. 

Family history is a strong predictor of risk for T2D. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort, 89.4% of pediatric participants had a first-degree relative or grandparent with T2D.¹⁰ This highlights the importance of both genetic risk and living environment as risks for T2D. 

The American Diabetes Association recommends that all children with specific risk factors be screened for diabetes starting at the age 10 years or at puberty, whichever comes first.¹¹ The screening tests recommended for diabetes are currently the same as for adults, yet there are few data supporting this regimen. To diagnose diabetes, you can use any of the following screening tests: fasting glucose, glucose tolerance, or glycated hemoglobin (HbA1c).¹ 

Risk Factors That Should Prompt Diabetes Screening¹¹

Screening is recommended in children who are overweight (≥85%) or obese (≥95%) and who also have ≥1 of the following risk factors:

• Family history of T2D in a first- or second-degree relative
• Maternal history of gestational diabetes
• Low birth weight for gestational age
• Physical signs of insulin resistance or related conditions (eg, hypertension, dyslipidemia, polycystic ovary syndrome)
• High-risk race/ethnicity (Native American, African American, Pacific Islander, Latino)

Diagnostic Criteria for Diabetes Mellitus¹¹

A childhood or adolescent T2D diagnosis should be taken seriously and communicated to the patient and family in a timely manner. Treatment should start immediately. There are several factors that make managing T2D in adolescents more challenging. Children do not control key aspects of their life, including nutrition and, often, free time activity. There are a lot of social pressures to be “normal,” and having a chronic disease will definitely make the child feel “different” and potentially feel socially isolated. There are high rates of mood disorders in children with diabetes, which can make self-management even harder.¹²

As mentioned above, treatment should begin immediately upon diagnosis. This is because T2D in younger people tends to be more progressive and less responsive to treatment options, and patients are much more likely to develop.^1,13,14 These same complications can be seen in adult patients, but in younger patients they develop earlier in the disease; specifically, renal and neurologic complications occur at even higher rates.¹⁴ 

The initial treatment should include both family-based therapeutic lifestyle changes (ie, nutrition, physical activity intervention) and medication.¹¹ There are fewer US Food and Drug Administration–approved medication options for children and adolescents, and those treatments that have been approved are less durable in this population. 

Metformin and insulin are the most-used medications, but their initiation is often delayed, as therapeutic lifestyle change is tried first. This has not been shown to be an effective strategy and may even undermine the value of therapeutic lifestyle change if the family is told later that medication may still need to be added. 

Recent studies have shown the benefit of select glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as important therapeutic tools to treat T2D in adolescence. Dulaglutide, exenatide, and liraglutide have been shown to be safe and effective in trials for adolescents with T2D.^15-17 These agents reduce glucose and body weight and may be important tools to help reduce extra glycemic risks (eg, cardiovascular disease, kidney disease), but they have not been studied for this purpose yet. 

Further, there is good support for the use of bariatric surgery for adolescents. While this is a relatively new treatment option, early and mid-term results are favorable compared with medication-based strategies.¹⁸ Further studies are needed to determine the long-term benefits.

Take home points:

1. T2D is becoming increasingly common in our youth.
2. T2D, when diagnosed earlier in life, is more progressive, less responsive to treatment options, and associated with earlier complications.
3. New studies support the use of novel therapies such as GLP-1 RAs and metabolic surgery in this age group.

Dr. Shubrook and Dr. Antonia M. Molinari have written a comprehensive review on treatment options and current guidelines for the management of T2D in the pediatric population, which can supply further information.¹⁹ 

Type 2 diabetes (T2D) has become a noncommunicable pandemic. Approximately 14.7% of the US adult population has diabetes.¹ Additionally, nearly 25% of the geriatric population has diabetes and nearly 50% has prediabetes.² Needless to say, most practices, regardless of specialty, see many patients with diabetes. We have made major advances in diabetes treatments, yet diabetes mellitus is still the leading cause of legal blindness, nontraumatic amputation, and end-stage renal disease requiring dialysis.³ 

While the prevalence of diabetes in adults is concerning, what is even more startling is the significant increase of T2D within the pediatric population. It was not too long ago that we considered T2D an “adult-only” disease. Now, 24% of children with diabetes have T2D, and 18% of adolescents have prediabetes.^4,5 This is not the end of the story. Recent studies have identified that the earlier you are diagnosed with T2D, the less responsive you are to diabetes treatments—and the disease will progress more rapidly to complications. 
 

We know that pediatric patients are not little adults. There are important physiologic and metabolic differences in our younger patients. The RISE study found that adolescents have lower insulin sensitivity than adults.^4,6 The pancreatic beta cells are more responsive at first and there is less clearance by the liver, which may indeed make insulin resistance worse. Finally, pancreatic beta cell function declines more rapidly in adolescents than in adults.^4,6 These physiologic changes can be even worse during puberty. The hormonal changes seen in puberty accelerate and amplify insulin secretion and worsen insulin resistance, which can result in hyperglycemia in those at risk.^7,8

The other complicating factor is the rapid rise in obesity in Americans. While childhood obesity is not quite at adult levels, it is a major risk factor for adult obesity. The prevalence of obesity in childhood was recently estimated to be 19.7% and is still on the rise.⁹ Obesity can be diabetogenic as we see an increase in visceral obesity. This triggers an inflammatory response that leads to worsening systemic insulin resistance and lipotoxicity from elevated circulating free fatty acids.⁸ 

Lifestyle and behavioral factors are also important in adolescents with T2D. While they are more independent than younger children, they are still largely dependent on the foods that are available in their home. Family food choices have a major impact on our youth. Further, the foods that our adolescents eat outside the home are more likely to be fast food or ultra-processed foods, which have been shown to contribute to obesity and T2D. 

Family history is a strong predictor of risk for T2D. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort, 89.4% of pediatric participants had a first-degree relative or grandparent with T2D.¹⁰ This highlights the importance of both genetic risk and living environment as risks for T2D. 

The American Diabetes Association recommends that all children with specific risk factors be screened for diabetes starting at the age 10 years or at puberty, whichever comes first.¹¹ The screening tests recommended for diabetes are currently the same as for adults, yet there are few data supporting this regimen. To diagnose diabetes, you can use any of the following screening tests: fasting glucose, glucose tolerance, or glycated hemoglobin (HbA1c).¹ 

Risk Factors That Should Prompt Diabetes Screening¹¹

Screening is recommended in children who are overweight (≥85%) or obese (≥95%) and who also have ≥1 of the following risk factors:

• Family history of T2D in a first- or second-degree relative
• Maternal history of gestational diabetes
• Low birth weight for gestational age
• Physical signs of insulin resistance or related conditions (eg, hypertension, dyslipidemia, polycystic ovary syndrome)
• High-risk race/ethnicity (Native American, African American, Pacific Islander, Latino)

Diagnostic Criteria for Diabetes Mellitus¹¹

A childhood or adolescent T2D diagnosis should be taken seriously and communicated to the patient and family in a timely manner. Treatment should start immediately. There are several factors that make managing T2D in adolescents more challenging. Children do not control key aspects of their life, including nutrition and, often, free time activity. There are a lot of social pressures to be “normal,” and having a chronic disease will definitely make the child feel “different” and potentially feel socially isolated. There are high rates of mood disorders in children with diabetes, which can make self-management even harder.¹²

As mentioned above, treatment should begin immediately upon diagnosis. This is because T2D in younger people tends to be more progressive and less responsive to treatment options, and patients are much more likely to develop.^1,13,14 These same complications can be seen in adult patients, but in younger patients they develop earlier in the disease; specifically, renal and neurologic complications occur at even higher rates.¹⁴ 

The initial treatment should include both family-based therapeutic lifestyle changes (ie, nutrition, physical activity intervention) and medication.¹¹ There are fewer US Food and Drug Administration–approved medication options for children and adolescents, and those treatments that have been approved are less durable in this population. 

Metformin and insulin are the most-used medications, but their initiation is often delayed, as therapeutic lifestyle change is tried first. This has not been shown to be an effective strategy and may even undermine the value of therapeutic lifestyle change if the family is told later that medication may still need to be added. 

Recent studies have shown the benefit of select glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as important therapeutic tools to treat T2D in adolescence. Dulaglutide, exenatide, and liraglutide have been shown to be safe and effective in trials for adolescents with T2D.^15-17 These agents reduce glucose and body weight and may be important tools to help reduce extra glycemic risks (eg, cardiovascular disease, kidney disease), but they have not been studied for this purpose yet. 

Further, there is good support for the use of bariatric surgery for adolescents. While this is a relatively new treatment option, early and mid-term results are favorable compared with medication-based strategies.¹⁸ Further studies are needed to determine the long-term benefits.

Take home points:

1. T2D is becoming increasingly common in our youth.
2. T2D, when diagnosed earlier in life, is more progressive, less responsive to treatment options, and associated with earlier complications.
3. New studies support the use of novel therapies such as GLP-1 RAs and metabolic surgery in this age group.

Dr. Shubrook and Dr. Antonia M. Molinari have written a comprehensive review on treatment options and current guidelines for the management of T2D in the pediatric population, which can supply further information.¹⁹ 

An estimated 93.3 million Americans (roughly 40% of the US population) were obese in 2015-2016, and most of them had at least 1 chronic disease.¹ As a result, patient education focused on lifestyle modification, including healthy nutrition and physical activity, has become an integral part of our everyday practice.

At the same time, the most recent dietary guidelines recommend that added sugar make up < 10% of daily calories.² In the United States, low-calorie food and beverages containing non-nutritive sweeteners (NNSs; TABLE^3-8) have become a popular means of keeping the sweetness in our diet without the health ramifications associated with sugar. These NNSs (aka, artificial sweeteners, high-intensity sweeteners, and non-caloric sweeteners) are ubiquitous in soft drinks, processed grains (including breads, cereals, and granola bars), and dairy products (including yogurts, flavored milk, and ice cream). As examples, NNSs are present in 42% of flavored waters, 33% of yogurts, and all diet beverages.^9,10 They can even be found in medications, multivitamins, toothpaste, and mouthwash.

Business is booming

Global NNS consumption has been growing more than 5% per year, meaning that by 2020, NNSs are expected to be a $2.2 billion industry.¹¹ One study using data from the National Health and Nutrition Examination Survey (NHANES) found that the use of NNSs in the United States increased from 21.1% in 2003 to 24.9% in 2009-2010 among adults and increased from 7.8% to 18.9% over the same time period among children.¹²

The main increase in the consumption of NNSs across all age groups has been via the consumption of beverages. Approximately 11% of healthy weight, 19% of overweight, and 22% of obese adults consume diet beverages.^13,14 Consumption of diet beverages or NNSs increases with age¹² and is especially common among women with higher levels of education and income.¹⁵

However, concerns remain about the safety of these agents and their effect on weight, appetite, and the body’s glycemic response. This article reviews the available research and current recommendations regarding the use of NNSs.

WHAT EFFECT DO NNSs HAVE ON WEIGHT?

The data on NNSs and weight are inconsistent. One randomized controlled trial(RCT) compared weight loss over the course of 1 year (12-week weight loss phase; 9-month weight maintenance phase) when 303 participants consumed either water or drinks sweetened with NNSs.¹⁶ Weight loss was significantly greater in the NNS drink group when compared with the water group.¹⁶

Observational studies have revealed similar findings.^17,18 Data from NHANES revealed that US adults (n = 14,098) during 2 nonconsecutive 24-hour dietary recall periods demonstrated lower total energy (calorie) intake if they consumed NNSs vs no NNSs.¹⁹ Another study using 2011-2016 NHANES data on adolescents (n = 7026) found no difference in energy intake between those who consumed beverages containing NNSs vs those who consumed beverages containing sugar.²⁰

Continue to: Other lines of investigation...

Other lines of investigation, including animal studies, have shown that long-term use of NNSs is associated with numerous metabolic derangements including weight gain.²¹ The negative effects of NNSs appear to be the greatest in males and those who are obese and have high-calorie diets.²¹

A 2017 meta-analysis concluded that evidence from RCTs does not support a benefit of NNSs on weight management, and that routine consumption of NNSs may be associated with increased body mass index (BMI) and cardiometabolic risk.²² Another systematic review and meta-analysis found that there was a higher pooled risk for obesity among those who drank beverages containing NNSs vs those who drank sugar-containing beverages.²³

Based on the most current literature, we conclude that NNSs are not beneficial for weight loss. While there is concern about weight gain through psychological effects (stimulation of sweetness receptors without satiety), further well-designed research is needed to explore whether this concern has merit.

WHAT IS THE EFFECT OF NNSs ON APPETITE?

There appears to be no effect. While original studies seemed to indicate there was an effect, later studies leaned to the contrary.

Consumption of diet beverages or non- nutritive sweeteners increases with age and is especially common among women with higher levels of education and income.

The notion that NNSs might enhance appetite and food intake was advanced in the 1980s by John Blundell and his research team.²⁴ The hypothesis was that since NNSs uncouple sweet taste and calories, they do not exert the normal post-ingestive inhibitory influence that real sugar does. This, in turn, disrupts appetite control mechanisms.^25-27

Continue to: However, subsequent research studies...

However, subsequent research studies found no relationship between the use of NNSs and appetite.^28-30 Mattes and colleagues hypothesized that such a difference in findings could result from the fact that earlier studies focused on isolating NNSs from other energy-yielding products, which emphasized an association with heightened hunger.²⁹ Subsequent studies showed that when NNSs were incorporated into energy-yielding products, there was no association between NNSs and increased hunger or appetite.

DO NNSs INCREASE THE RISK FOR TYPE 2 DIABETES MELLITUS?

The data are mixed. One study of women participating in the Nurses’ Health Study II showed that those who consumed caffeinated, artificially-sweetened beverages had a 35% higher risk of developing type 2 diabetes mellitus (T2DM); however, this risk was no longer significant after adjusting for BMI and energy intake.³¹

The Health Professionals Follow-Up Trial studied more than 40,000 men for more than 20 years and found that NNS consumption increased the risk of developing T2DM by 40%.³² However, this finding lost statistical significance after adjusting for BMI.³²

These results make it difficult to determine whether there is any association between NNSs and T2DM; rather NNS-containing beverages are likely consumed more often by those who have higher BMIs and by those trying to lose weight.

A 2017 randomized crossover study involving 10 healthy men looked at the effects of a variety of caloric and non-caloric sweeteners on 24-hour glucose profiles and found no differences.³³ Another study, a randomized, double-blind, crossover trial involving 60 non-obese adults without diabetes who did not consume NNSs, randomized the participants one-to-one to drink either 2 cans per day of either a beverage containing aspartame and acesulfame K or an unsweetened, no-calorie beverage for 12 weeks.³⁴

Continue to: After a 4-week washout period...

After a 4-week washout period, the participants then switched to the opposite beverage for 12 weeks. The study concluded that consumption of 2 cans of a beverage containing aspartame and acesulfame K over 12 weeks had no significant effect on insulin sensitivity or secretion in nondiabetic adults.³⁴

Similar results were obtained from a study involving 100 non-obese adults.³⁵ The researchers found that aspartame ingested at 2 different doses (350 or 1050 mg/d) in beverages over 12 weeks had no effect on a 240-minute oral glucose tolerance test, blood pressure, appetite, or body weight.³⁵

A 2016 systematic review critically evaluated the effect of NNSs on both glucose absorption and appetite.³⁶ The review included 14 observational prospective trials, 28 RCTs, and 2 meta-analyses. The sweeteners studied included aspartame, sucralose, saccharin, acesulfame K, and stevia.³⁶ The studies were focused largely on single-exposure outcomes (20 trials), but a minority of the studies (8 trials) looked at longer exposures from 1 to 18 weeks. Only some of the studies controlled for critical variables, such as BMI. In the end, there was no consistent pattern of increased or decreased risk for insulin resistance or diabetes.³⁶

Two meta-analyses tried to determine if an association exists between consumption of beverages containing NNSs and the development of T2DM.^37,38 The first meta-analysis with 4 studies showed a slight, but significant, relative risk (RR) of 1.13 (95% confidence interval [CI], 1.02-1.25) for those who consumed beverages containing NNSs.³⁷ In the second meta-analysis (10 studies), NNS consumption had an RR of 1.48 (95% CI, 1.35-1.62), but the risk was lower (and no longer significant) after adjusting for BMI.³⁸ A study of 98 Hispanic adolescents who were overweight or obese found that chronic users (n = 9) of NNSs had higher HbA1c levels 1 year later than did controls (n = 75) and people who initiated use of NNSs between the baseline and 1-year visit (n = 14).³⁹

The American Diabetes Association (ADA) and American Heart Association joint position statement on NNSs, first published in 2012, says that NNSs can be utilized to reduce caloric and carbohydrate consumption for overall diabetes control and to obtain a healthy body weight.⁴⁰ These principles were reaffirmed in the ADA Standards of Care in 2019.⁴¹

Continue to: The 2015 US Scientific Reports on Dietary Guidelines...

The 2015 US Scientific Reports on Dietary Guidelines provided a consensus statement saying, “Future experimental studies should examine the relationship between artificially sweetened soft drinks and biomarkers of insulin resistance and other diabetes markers.”⁴²

DO NNSs HAVE ANY ADVERSE HEALTH EFFECTS?

Maybe. Many individuals avoid NNSs due to fear of developing cancer. While rat studies have previously shown a dose-dependent increased risk of developing cancer, epidemiologic studies in humans have not confirmed an association.⁴³ The National Cancer Institute reports that carcinogenicity studies of NNSs have not shown an association with cancer in humans.⁴⁴

A prospective study—the Nurses’ Health Study, which followed over 88,000 women for 24 years—found that consumption of > 2 diet sodas per day was associated with an increased risk for coronary heart disease (CHD) and chronic kidney disease (CKD) compared with consumption of < 1 diet soda per month.⁴⁵ However, other prospective studies have shown that these specific negative health effects may not be present when controlling for weight.^45,46

While the prospective studies found some associations between medical conditions (eg, CHD and CKD) and NNS consumption, the literature is limited to intake from beverages and does not include NNS-containing foods. More studies are needed to determine the relationship between NNSs and potential adverse health events, since the current literature is observational and cannot predict causation.

Patients at risk for, or who have been diagnosed with, type 2 diabetes mellitus can include non-nutritive sweeteners in their diet without fear of disturbing their glycemic levels.

A 2019 study explored the associations between long-term consumption of sugar-sweetened beverages and artificially sweetened beverages (ASBs) and the risk of mortality in the United States.⁴⁷ This study included 37,716 men from the Health Professionals Follow-up Study and 80,647 women from the Nurses’ Health Study. Subjects who had the highest consumption of ASBs had higher risks for total and cardiovascular disease mortality.⁴⁷ Cohort-specific analyses showed that an association between ASB consumption and mortality was observed in the participants from the Nurses’ Health Study but not in those from the Health Professionals Follow-up Study, warranting further investigation.⁴⁷ Cancer mortality and ASB consumption were not shown to have an association in this study.

Continue to: WHY ARE THE DATA INCONCLUSIVE?

Nutritional studies are hard to complete accurately outside of the laboratory setting. Also, the science of NNSs is new and evolving.

With regard to obesity and NNSs, it is possible that findings have been due to reverse causation. People who are overweight or obese are more likely to consume low-calorie foods and beverages; they are also at greater risk for developing diseases, such as T2DM.^48,49

HOW SAFE ARE NNSs?

They appear to be safe, but more data are needed. Each of the 7 FDA-approved NNSs has passed extensive laboratory, animal, and human testing, and appears to cause no harm in the human body when consumed.⁴⁹ But clearly the data are incomplete. As we continue to gain a greater understanding of the metabolism of NNSs, we may need to revisit the issue of safety.

ARE THERE ANY NNSs THAT SOME PEOPLE SHOULD AVOID?

Yes. People with phenylketonuria, who have difficulty metabolizing phenylalanine (a component of aspartame), should avoid consumption of aspartame.⁵⁰

Reverse causation may be at work with obesity and non-nutritive sweeteners. That is, people who are overweight or obese are more likely to consume low-calorie foods and beverages.

In addition, NNSs have been found to be present in breast milk.⁵¹ While the significance of this finding is yet to be determined, we warn against the use of NNSs by women who are breastfeeding.⁵¹

WHAT EFFECT—IF ANY—DO NNSs HAVE ON GUT MICROBIOTA?

We don’t know. Disruptions in the gut microbiome have been linked to numerous metabolic abnormalities, including obesity, insulin resistance, and diabetes, as well as cardiovascular disorders.^52,53 Diet is a main determinant of balance in the gut microbiota.⁵⁴ The gut microbiota are centrally involved in energy harvest, and studies have suggested that low gut bacterial diversity is associated with increased adiposity, insulin resistance, and low-grade inflammation.^55-60 Whether NNSs have a relationship with abnormal changes in gut microbiota requires further study.

CORRESPONDENCE
Clipper F. Young, PharmD, MPH, CDE, BC-ADM, BCGP, Touro University California, College of Osteopathic Medicine, 1310 Club Drive, Vallejo, CA 94592; Clipper.young@tu.edu.

An estimated 93.3 million Americans (roughly 40% of the US population) were obese in 2015-2016, and most of them had at least 1 chronic disease.¹ As a result, patient education focused on lifestyle modification, including healthy nutrition and physical activity, has become an integral part of our everyday practice.

At the same time, the most recent dietary guidelines recommend that added sugar make up < 10% of daily calories.² In the United States, low-calorie food and beverages containing non-nutritive sweeteners (NNSs; TABLE^3-8) have become a popular means of keeping the sweetness in our diet without the health ramifications associated with sugar. These NNSs (aka, artificial sweeteners, high-intensity sweeteners, and non-caloric sweeteners) are ubiquitous in soft drinks, processed grains (including breads, cereals, and granola bars), and dairy products (including yogurts, flavored milk, and ice cream). As examples, NNSs are present in 42% of flavored waters, 33% of yogurts, and all diet beverages.^9,10 They can even be found in medications, multivitamins, toothpaste, and mouthwash.

Business is booming

Global NNS consumption has been growing more than 5% per year, meaning that by 2020, NNSs are expected to be a $2.2 billion industry.¹¹ One study using data from the National Health and Nutrition Examination Survey (NHANES) found that the use of NNSs in the United States increased from 21.1% in 2003 to 24.9% in 2009-2010 among adults and increased from 7.8% to 18.9% over the same time period among children.¹²

The main increase in the consumption of NNSs across all age groups has been via the consumption of beverages. Approximately 11% of healthy weight, 19% of overweight, and 22% of obese adults consume diet beverages.^13,14 Consumption of diet beverages or NNSs increases with age¹² and is especially common among women with higher levels of education and income.¹⁵

However, concerns remain about the safety of these agents and their effect on weight, appetite, and the body’s glycemic response. This article reviews the available research and current recommendations regarding the use of NNSs.

WHAT EFFECT DO NNSs HAVE ON WEIGHT?

The data on NNSs and weight are inconsistent. One randomized controlled trial(RCT) compared weight loss over the course of 1 year (12-week weight loss phase; 9-month weight maintenance phase) when 303 participants consumed either water or drinks sweetened with NNSs.¹⁶ Weight loss was significantly greater in the NNS drink group when compared with the water group.¹⁶

Observational studies have revealed similar findings.^17,18 Data from NHANES revealed that US adults (n = 14,098) during 2 nonconsecutive 24-hour dietary recall periods demonstrated lower total energy (calorie) intake if they consumed NNSs vs no NNSs.¹⁹ Another study using 2011-2016 NHANES data on adolescents (n = 7026) found no difference in energy intake between those who consumed beverages containing NNSs vs those who consumed beverages containing sugar.²⁰

Continue to: Other lines of investigation...

Other lines of investigation, including animal studies, have shown that long-term use of NNSs is associated with numerous metabolic derangements including weight gain.²¹ The negative effects of NNSs appear to be the greatest in males and those who are obese and have high-calorie diets.²¹

A 2017 meta-analysis concluded that evidence from RCTs does not support a benefit of NNSs on weight management, and that routine consumption of NNSs may be associated with increased body mass index (BMI) and cardiometabolic risk.²² Another systematic review and meta-analysis found that there was a higher pooled risk for obesity among those who drank beverages containing NNSs vs those who drank sugar-containing beverages.²³

Based on the most current literature, we conclude that NNSs are not beneficial for weight loss. While there is concern about weight gain through psychological effects (stimulation of sweetness receptors without satiety), further well-designed research is needed to explore whether this concern has merit.

WHAT IS THE EFFECT OF NNSs ON APPETITE?

There appears to be no effect. While original studies seemed to indicate there was an effect, later studies leaned to the contrary.

Consumption of diet beverages or non- nutritive sweeteners increases with age and is especially common among women with higher levels of education and income.

The notion that NNSs might enhance appetite and food intake was advanced in the 1980s by John Blundell and his research team.²⁴ The hypothesis was that since NNSs uncouple sweet taste and calories, they do not exert the normal post-ingestive inhibitory influence that real sugar does. This, in turn, disrupts appetite control mechanisms.^25-27

Continue to: However, subsequent research studies...

However, subsequent research studies found no relationship between the use of NNSs and appetite.^28-30 Mattes and colleagues hypothesized that such a difference in findings could result from the fact that earlier studies focused on isolating NNSs from other energy-yielding products, which emphasized an association with heightened hunger.²⁹ Subsequent studies showed that when NNSs were incorporated into energy-yielding products, there was no association between NNSs and increased hunger or appetite.

DO NNSs INCREASE THE RISK FOR TYPE 2 DIABETES MELLITUS?

The data are mixed. One study of women participating in the Nurses’ Health Study II showed that those who consumed caffeinated, artificially-sweetened beverages had a 35% higher risk of developing type 2 diabetes mellitus (T2DM); however, this risk was no longer significant after adjusting for BMI and energy intake.³¹

The Health Professionals Follow-Up Trial studied more than 40,000 men for more than 20 years and found that NNS consumption increased the risk of developing T2DM by 40%.³² However, this finding lost statistical significance after adjusting for BMI.³²

These results make it difficult to determine whether there is any association between NNSs and T2DM; rather NNS-containing beverages are likely consumed more often by those who have higher BMIs and by those trying to lose weight.

A 2017 randomized crossover study involving 10 healthy men looked at the effects of a variety of caloric and non-caloric sweeteners on 24-hour glucose profiles and found no differences.³³ Another study, a randomized, double-blind, crossover trial involving 60 non-obese adults without diabetes who did not consume NNSs, randomized the participants one-to-one to drink either 2 cans per day of either a beverage containing aspartame and acesulfame K or an unsweetened, no-calorie beverage for 12 weeks.³⁴

Continue to: After a 4-week washout period...

After a 4-week washout period, the participants then switched to the opposite beverage for 12 weeks. The study concluded that consumption of 2 cans of a beverage containing aspartame and acesulfame K over 12 weeks had no significant effect on insulin sensitivity or secretion in nondiabetic adults.³⁴

Similar results were obtained from a study involving 100 non-obese adults.³⁵ The researchers found that aspartame ingested at 2 different doses (350 or 1050 mg/d) in beverages over 12 weeks had no effect on a 240-minute oral glucose tolerance test, blood pressure, appetite, or body weight.³⁵

A 2016 systematic review critically evaluated the effect of NNSs on both glucose absorption and appetite.³⁶ The review included 14 observational prospective trials, 28 RCTs, and 2 meta-analyses. The sweeteners studied included aspartame, sucralose, saccharin, acesulfame K, and stevia.³⁶ The studies were focused largely on single-exposure outcomes (20 trials), but a minority of the studies (8 trials) looked at longer exposures from 1 to 18 weeks. Only some of the studies controlled for critical variables, such as BMI. In the end, there was no consistent pattern of increased or decreased risk for insulin resistance or diabetes.³⁶

Two meta-analyses tried to determine if an association exists between consumption of beverages containing NNSs and the development of T2DM.^37,38 The first meta-analysis with 4 studies showed a slight, but significant, relative risk (RR) of 1.13 (95% confidence interval [CI], 1.02-1.25) for those who consumed beverages containing NNSs.³⁷ In the second meta-analysis (10 studies), NNS consumption had an RR of 1.48 (95% CI, 1.35-1.62), but the risk was lower (and no longer significant) after adjusting for BMI.³⁸ A study of 98 Hispanic adolescents who were overweight or obese found that chronic users (n = 9) of NNSs had higher HbA1c levels 1 year later than did controls (n = 75) and people who initiated use of NNSs between the baseline and 1-year visit (n = 14).³⁹

The American Diabetes Association (ADA) and American Heart Association joint position statement on NNSs, first published in 2012, says that NNSs can be utilized to reduce caloric and carbohydrate consumption for overall diabetes control and to obtain a healthy body weight.⁴⁰ These principles were reaffirmed in the ADA Standards of Care in 2019.⁴¹

Continue to: The 2015 US Scientific Reports on Dietary Guidelines...

The 2015 US Scientific Reports on Dietary Guidelines provided a consensus statement saying, “Future experimental studies should examine the relationship between artificially sweetened soft drinks and biomarkers of insulin resistance and other diabetes markers.”⁴²

DO NNSs HAVE ANY ADVERSE HEALTH EFFECTS?

Maybe. Many individuals avoid NNSs due to fear of developing cancer. While rat studies have previously shown a dose-dependent increased risk of developing cancer, epidemiologic studies in humans have not confirmed an association.⁴³ The National Cancer Institute reports that carcinogenicity studies of NNSs have not shown an association with cancer in humans.⁴⁴

A prospective study—the Nurses’ Health Study, which followed over 88,000 women for 24 years—found that consumption of > 2 diet sodas per day was associated with an increased risk for coronary heart disease (CHD) and chronic kidney disease (CKD) compared with consumption of < 1 diet soda per month.⁴⁵ However, other prospective studies have shown that these specific negative health effects may not be present when controlling for weight.^45,46

While the prospective studies found some associations between medical conditions (eg, CHD and CKD) and NNS consumption, the literature is limited to intake from beverages and does not include NNS-containing foods. More studies are needed to determine the relationship between NNSs and potential adverse health events, since the current literature is observational and cannot predict causation.

Patients at risk for, or who have been diagnosed with, type 2 diabetes mellitus can include non-nutritive sweeteners in their diet without fear of disturbing their glycemic levels.

A 2019 study explored the associations between long-term consumption of sugar-sweetened beverages and artificially sweetened beverages (ASBs) and the risk of mortality in the United States.⁴⁷ This study included 37,716 men from the Health Professionals Follow-up Study and 80,647 women from the Nurses’ Health Study. Subjects who had the highest consumption of ASBs had higher risks for total and cardiovascular disease mortality.⁴⁷ Cohort-specific analyses showed that an association between ASB consumption and mortality was observed in the participants from the Nurses’ Health Study but not in those from the Health Professionals Follow-up Study, warranting further investigation.⁴⁷ Cancer mortality and ASB consumption were not shown to have an association in this study.

Continue to: WHY ARE THE DATA INCONCLUSIVE?

Nutritional studies are hard to complete accurately outside of the laboratory setting. Also, the science of NNSs is new and evolving.

With regard to obesity and NNSs, it is possible that findings have been due to reverse causation. People who are overweight or obese are more likely to consume low-calorie foods and beverages; they are also at greater risk for developing diseases, such as T2DM.^48,49

HOW SAFE ARE NNSs?

They appear to be safe, but more data are needed. Each of the 7 FDA-approved NNSs has passed extensive laboratory, animal, and human testing, and appears to cause no harm in the human body when consumed.⁴⁹ But clearly the data are incomplete. As we continue to gain a greater understanding of the metabolism of NNSs, we may need to revisit the issue of safety.

ARE THERE ANY NNSs THAT SOME PEOPLE SHOULD AVOID?

Yes. People with phenylketonuria, who have difficulty metabolizing phenylalanine (a component of aspartame), should avoid consumption of aspartame.⁵⁰

Reverse causation may be at work with obesity and non-nutritive sweeteners. That is, people who are overweight or obese are more likely to consume low-calorie foods and beverages.

In addition, NNSs have been found to be present in breast milk.⁵¹ While the significance of this finding is yet to be determined, we warn against the use of NNSs by women who are breastfeeding.⁵¹

WHAT EFFECT—IF ANY—DO NNSs HAVE ON GUT MICROBIOTA?

We don’t know. Disruptions in the gut microbiome have been linked to numerous metabolic abnormalities, including obesity, insulin resistance, and diabetes, as well as cardiovascular disorders.^52,53 Diet is a main determinant of balance in the gut microbiota.⁵⁴ The gut microbiota are centrally involved in energy harvest, and studies have suggested that low gut bacterial diversity is associated with increased adiposity, insulin resistance, and low-grade inflammation.^55-60 Whether NNSs have a relationship with abnormal changes in gut microbiota requires further study.

CORRESPONDENCE
Clipper F. Young, PharmD, MPH, CDE, BC-ADM, BCGP, Touro University California, College of Osteopathic Medicine, 1310 Club Drive, Vallejo, CA 94592; Clipper.young@tu.edu.

An estimated 93.3 million Americans (roughly 40% of the US population) were obese in 2015-2016, and most of them had at least 1 chronic disease.¹ As a result, patient education focused on lifestyle modification, including healthy nutrition and physical activity, has become an integral part of our everyday practice.

At the same time, the most recent dietary guidelines recommend that added sugar make up < 10% of daily calories.² In the United States, low-calorie food and beverages containing non-nutritive sweeteners (NNSs; TABLE^3-8) have become a popular means of keeping the sweetness in our diet without the health ramifications associated with sugar. These NNSs (aka, artificial sweeteners, high-intensity sweeteners, and non-caloric sweeteners) are ubiquitous in soft drinks, processed grains (including breads, cereals, and granola bars), and dairy products (including yogurts, flavored milk, and ice cream). As examples, NNSs are present in 42% of flavored waters, 33% of yogurts, and all diet beverages.^9,10 They can even be found in medications, multivitamins, toothpaste, and mouthwash.

Business is booming

Global NNS consumption has been growing more than 5% per year, meaning that by 2020, NNSs are expected to be a $2.2 billion industry.¹¹ One study using data from the National Health and Nutrition Examination Survey (NHANES) found that the use of NNSs in the United States increased from 21.1% in 2003 to 24.9% in 2009-2010 among adults and increased from 7.8% to 18.9% over the same time period among children.¹²

The main increase in the consumption of NNSs across all age groups has been via the consumption of beverages. Approximately 11% of healthy weight, 19% of overweight, and 22% of obese adults consume diet beverages.^13,14 Consumption of diet beverages or NNSs increases with age¹² and is especially common among women with higher levels of education and income.¹⁵

However, concerns remain about the safety of these agents and their effect on weight, appetite, and the body’s glycemic response. This article reviews the available research and current recommendations regarding the use of NNSs.

WHAT EFFECT DO NNSs HAVE ON WEIGHT?

The data on NNSs and weight are inconsistent. One randomized controlled trial(RCT) compared weight loss over the course of 1 year (12-week weight loss phase; 9-month weight maintenance phase) when 303 participants consumed either water or drinks sweetened with NNSs.¹⁶ Weight loss was significantly greater in the NNS drink group when compared with the water group.¹⁶

Observational studies have revealed similar findings.^17,18 Data from NHANES revealed that US adults (n = 14,098) during 2 nonconsecutive 24-hour dietary recall periods demonstrated lower total energy (calorie) intake if they consumed NNSs vs no NNSs.¹⁹ Another study using 2011-2016 NHANES data on adolescents (n = 7026) found no difference in energy intake between those who consumed beverages containing NNSs vs those who consumed beverages containing sugar.²⁰

Continue to: Other lines of investigation...

Other lines of investigation, including animal studies, have shown that long-term use of NNSs is associated with numerous metabolic derangements including weight gain.²¹ The negative effects of NNSs appear to be the greatest in males and those who are obese and have high-calorie diets.²¹

A 2017 meta-analysis concluded that evidence from RCTs does not support a benefit of NNSs on weight management, and that routine consumption of NNSs may be associated with increased body mass index (BMI) and cardiometabolic risk.²² Another systematic review and meta-analysis found that there was a higher pooled risk for obesity among those who drank beverages containing NNSs vs those who drank sugar-containing beverages.²³

Based on the most current literature, we conclude that NNSs are not beneficial for weight loss. While there is concern about weight gain through psychological effects (stimulation of sweetness receptors without satiety), further well-designed research is needed to explore whether this concern has merit.

WHAT IS THE EFFECT OF NNSs ON APPETITE?

There appears to be no effect. While original studies seemed to indicate there was an effect, later studies leaned to the contrary.

Consumption of diet beverages or non- nutritive sweeteners increases with age and is especially common among women with higher levels of education and income.

The notion that NNSs might enhance appetite and food intake was advanced in the 1980s by John Blundell and his research team.²⁴ The hypothesis was that since NNSs uncouple sweet taste and calories, they do not exert the normal post-ingestive inhibitory influence that real sugar does. This, in turn, disrupts appetite control mechanisms.^25-27

Continue to: However, subsequent research studies...

However, subsequent research studies found no relationship between the use of NNSs and appetite.^28-30 Mattes and colleagues hypothesized that such a difference in findings could result from the fact that earlier studies focused on isolating NNSs from other energy-yielding products, which emphasized an association with heightened hunger.²⁹ Subsequent studies showed that when NNSs were incorporated into energy-yielding products, there was no association between NNSs and increased hunger or appetite.

DO NNSs INCREASE THE RISK FOR TYPE 2 DIABETES MELLITUS?

The data are mixed. One study of women participating in the Nurses’ Health Study II showed that those who consumed caffeinated, artificially-sweetened beverages had a 35% higher risk of developing type 2 diabetes mellitus (T2DM); however, this risk was no longer significant after adjusting for BMI and energy intake.³¹

The Health Professionals Follow-Up Trial studied more than 40,000 men for more than 20 years and found that NNS consumption increased the risk of developing T2DM by 40%.³² However, this finding lost statistical significance after adjusting for BMI.³²

These results make it difficult to determine whether there is any association between NNSs and T2DM; rather NNS-containing beverages are likely consumed more often by those who have higher BMIs and by those trying to lose weight.

A 2017 randomized crossover study involving 10 healthy men looked at the effects of a variety of caloric and non-caloric sweeteners on 24-hour glucose profiles and found no differences.³³ Another study, a randomized, double-blind, crossover trial involving 60 non-obese adults without diabetes who did not consume NNSs, randomized the participants one-to-one to drink either 2 cans per day of either a beverage containing aspartame and acesulfame K or an unsweetened, no-calorie beverage for 12 weeks.³⁴

Continue to: After a 4-week washout period...

After a 4-week washout period, the participants then switched to the opposite beverage for 12 weeks. The study concluded that consumption of 2 cans of a beverage containing aspartame and acesulfame K over 12 weeks had no significant effect on insulin sensitivity or secretion in nondiabetic adults.³⁴

Similar results were obtained from a study involving 100 non-obese adults.³⁵ The researchers found that aspartame ingested at 2 different doses (350 or 1050 mg/d) in beverages over 12 weeks had no effect on a 240-minute oral glucose tolerance test, blood pressure, appetite, or body weight.³⁵

A 2016 systematic review critically evaluated the effect of NNSs on both glucose absorption and appetite.³⁶ The review included 14 observational prospective trials, 28 RCTs, and 2 meta-analyses. The sweeteners studied included aspartame, sucralose, saccharin, acesulfame K, and stevia.³⁶ The studies were focused largely on single-exposure outcomes (20 trials), but a minority of the studies (8 trials) looked at longer exposures from 1 to 18 weeks. Only some of the studies controlled for critical variables, such as BMI. In the end, there was no consistent pattern of increased or decreased risk for insulin resistance or diabetes.³⁶

Two meta-analyses tried to determine if an association exists between consumption of beverages containing NNSs and the development of T2DM.^37,38 The first meta-analysis with 4 studies showed a slight, but significant, relative risk (RR) of 1.13 (95% confidence interval [CI], 1.02-1.25) for those who consumed beverages containing NNSs.³⁷ In the second meta-analysis (10 studies), NNS consumption had an RR of 1.48 (95% CI, 1.35-1.62), but the risk was lower (and no longer significant) after adjusting for BMI.³⁸ A study of 98 Hispanic adolescents who were overweight or obese found that chronic users (n = 9) of NNSs had higher HbA1c levels 1 year later than did controls (n = 75) and people who initiated use of NNSs between the baseline and 1-year visit (n = 14).³⁹

The American Diabetes Association (ADA) and American Heart Association joint position statement on NNSs, first published in 2012, says that NNSs can be utilized to reduce caloric and carbohydrate consumption for overall diabetes control and to obtain a healthy body weight.⁴⁰ These principles were reaffirmed in the ADA Standards of Care in 2019.⁴¹

Continue to: The 2015 US Scientific Reports on Dietary Guidelines...

The 2015 US Scientific Reports on Dietary Guidelines provided a consensus statement saying, “Future experimental studies should examine the relationship between artificially sweetened soft drinks and biomarkers of insulin resistance and other diabetes markers.”⁴²

DO NNSs HAVE ANY ADVERSE HEALTH EFFECTS?

Maybe. Many individuals avoid NNSs due to fear of developing cancer. While rat studies have previously shown a dose-dependent increased risk of developing cancer, epidemiologic studies in humans have not confirmed an association.⁴³ The National Cancer Institute reports that carcinogenicity studies of NNSs have not shown an association with cancer in humans.⁴⁴

A prospective study—the Nurses’ Health Study, which followed over 88,000 women for 24 years—found that consumption of > 2 diet sodas per day was associated with an increased risk for coronary heart disease (CHD) and chronic kidney disease (CKD) compared with consumption of < 1 diet soda per month.⁴⁵ However, other prospective studies have shown that these specific negative health effects may not be present when controlling for weight.^45,46

While the prospective studies found some associations between medical conditions (eg, CHD and CKD) and NNS consumption, the literature is limited to intake from beverages and does not include NNS-containing foods. More studies are needed to determine the relationship between NNSs and potential adverse health events, since the current literature is observational and cannot predict causation.

Patients at risk for, or who have been diagnosed with, type 2 diabetes mellitus can include non-nutritive sweeteners in their diet without fear of disturbing their glycemic levels.

A 2019 study explored the associations between long-term consumption of sugar-sweetened beverages and artificially sweetened beverages (ASBs) and the risk of mortality in the United States.⁴⁷ This study included 37,716 men from the Health Professionals Follow-up Study and 80,647 women from the Nurses’ Health Study. Subjects who had the highest consumption of ASBs had higher risks for total and cardiovascular disease mortality.⁴⁷ Cohort-specific analyses showed that an association between ASB consumption and mortality was observed in the participants from the Nurses’ Health Study but not in those from the Health Professionals Follow-up Study, warranting further investigation.⁴⁷ Cancer mortality and ASB consumption were not shown to have an association in this study.

Continue to: WHY ARE THE DATA INCONCLUSIVE?

Nutritional studies are hard to complete accurately outside of the laboratory setting. Also, the science of NNSs is new and evolving.

With regard to obesity and NNSs, it is possible that findings have been due to reverse causation. People who are overweight or obese are more likely to consume low-calorie foods and beverages; they are also at greater risk for developing diseases, such as T2DM.^48,49

HOW SAFE ARE NNSs?

They appear to be safe, but more data are needed. Each of the 7 FDA-approved NNSs has passed extensive laboratory, animal, and human testing, and appears to cause no harm in the human body when consumed.⁴⁹ But clearly the data are incomplete. As we continue to gain a greater understanding of the metabolism of NNSs, we may need to revisit the issue of safety.

ARE THERE ANY NNSs THAT SOME PEOPLE SHOULD AVOID?

Yes. People with phenylketonuria, who have difficulty metabolizing phenylalanine (a component of aspartame), should avoid consumption of aspartame.⁵⁰

Reverse causation may be at work with obesity and non-nutritive sweeteners. That is, people who are overweight or obese are more likely to consume low-calorie foods and beverages.

In addition, NNSs have been found to be present in breast milk.⁵¹ While the significance of this finding is yet to be determined, we warn against the use of NNSs by women who are breastfeeding.⁵¹

WHAT EFFECT—IF ANY—DO NNSs HAVE ON GUT MICROBIOTA?

We don’t know. Disruptions in the gut microbiome have been linked to numerous metabolic abnormalities, including obesity, insulin resistance, and diabetes, as well as cardiovascular disorders.^52,53 Diet is a main determinant of balance in the gut microbiota.⁵⁴ The gut microbiota are centrally involved in energy harvest, and studies have suggested that low gut bacterial diversity is associated with increased adiposity, insulin resistance, and low-grade inflammation.^55-60 Whether NNSs have a relationship with abnormal changes in gut microbiota requires further study.

CORRESPONDENCE
Clipper F. Young, PharmD, MPH, CDE, BC-ADM, BCGP, Touro University California, College of Osteopathic Medicine, 1310 Club Drive, Vallejo, CA 94592; Clipper.young@tu.edu.

Travel, once reserved for wealthy vacationers and high-level executives, has become a regular experience for many people. The US Travel and Tourism Overview reported that US domestic travel climbed to more than 2.25 billion person-trips in 2017.¹ The US Centers for Disease Control and Prevention (CDC) and the US Travel Association suggest that, based on this frequency and the known rate of diabetes, 17 million people with diabetes travel annually for leisure and 5.6 million for business, and these numbers are expected to increase.²

It stands to reason that as the number of people who travel continues to increase, so too will the number of patients with diabetes seeking medical travel advice. Despite resources available to travelers with diabetes, researchers at the 2016 meeting of the American Diabetes Association noted that only 30% of patients with diabetes who responded to a survey reported being satisfied with the resources available to help them manage their diabetes while traveling.² This article discusses how clinicians can help patients manage their diabetes while traveling, address common travel questions, and prepare patients for emergencies that may arise while traveling.

PRE-TRIP PREPARATION

Provider visit before travel: Checking the bases

Advise patients to schedule an appointment 4 to 6 weeks before their trip.³ At this appointment, give the patient a healthcare provider travel letter (Figure 1) and prescriptions that the patient can hand-carry en route.³ The provider letter should state that the patient has diabetes and should list all supplies the patient needs. The letter should also include specific medications used by the patient and the devices that deliver these medications, eg, Humalog insulin and U-100 syringes⁴ to administer insulin, as well as any food and medication allergies.

Prescriptions should be written for patients to use in the event of an emergency during travel. Prescriptions for diabetes medications should be written with generic names to minimize confusion for those traveling internationally. Additionally, all prescriptions should provide enough medication to last throughout the trip.⁴

Advise patients that rules for filling prescriptions may vary between states and countries.³ Also, the strength of insulin may vary between the United States and other countries. Patients should understand that if they fill their insulin prescription in a foreign country, they may need to purchase new syringes to match the insulin dose. For example, if patients use U-100 syringes and purchase U-40 insulin, they will need to buy U-40 syringes or risk taking too little of a dose.

Remind patients that prescriptions are not necessary for all diabetes supplies but are essential for coverage by insurance companies. Blood glucose testing supplies, ketone strips, and glucose tablets may be purchased in a pharmacy without a prescription. Human insulin may also be purchased over the counter. However, oral medications, glucagon, and analog insulins require a prescription. We suggest that patients who travel have their prescriptions on file at a chain pharmacy rather than an independent one. If they are in the United States, they can go to any branch of the chain pharmacy and easily fill a prescription.

Work with the patient to compile a separate document that details the medication dosing, correction-scale instructions, carbohydrate-to-insulin ratios, and pump settings (basal rates, insulin sensitivity, active insulin time).⁴ Patients who use an insulin pump should record all pump settings in the event that they need to convert to insulin injections during travel.⁴ We suggest that all patients with an insulin pump have an alternate insulin method (eg, pens, vials) and that they carry this with them along with basal insulin in case the pump fails. This level of preparation empowers the patient to assume responsibility for his or her own care if a healthcare provider is not available during travel.

Like all travelers, patients with diabetes should confirm that their immunizations are up to date. Encourage patients to the CDC’s page (wwwnc.cdc.gov/travel) to check the list of vaccines necessary for their region of travel.^4,5 Many special immunizations can be acquired only from a public health department and not from a clinician’s office.

Additionally, depending on the region of travel, prescribing antibiotics or antidiarrheal medications may be necessary to ensure patient safety and comfort. We also recommend that patients with type 1 diabetes obtain a supply of antibiotics and antidiarrheals because they can become sick quickly.

Packing with diabetes: Double is better

The American Diabetes Association recommends that patients pack at least twice the medication and blood-testing supplies they anticipate needing.³ Reinforce to patients the need to pack all medications and supplies in their carry-on bag and to keep this bag in their possession at all times to avoid damage, loss, and extreme changes in temperature and air pressure, which can adversely affect the activity and stability of insulin.

Ask patients about the activities they plan to participate in and how many days they will be traveling, and then recommend shoes that will encourage appropriate foot care.⁴ Patients with diabetes should choose comfort over style when selecting footwear. All new shoes should be purchased and “broken in” 2 to 3 weeks before the trip. Alternating shoes decreases the risk of blisters and calluses.⁴

Emergency abroad: Planning to be prepared

It is crucial to counsel patients on how to respond in an emergency.

Encourage patients with diabetes, especially those who use insulin, to obtain a medical identification bracelet, necklace, or in some cases, a tattoo, that states they use insulin and discloses any allergies.³ This ensures that emergency medical personnel will be aware of the patient’s condition when providing care. Also suggest that your patients have emergency contact information available on their person and their cell phone to expedite assistance in an emergency (Table 2).

Urge patients to determine prior to their departure if their health coverage will change once they leave the state or the country. Some insurance companies require patients to go to a specific healthcare system while others regulate the amount of time a patient can be in the hospital before being transferred home. It is important for patients to be aware of these terms in the event of hospitalization.⁴ Travel insurance should be considered for international travel.

AIRPORT SECURITY: WHAT TO EXPECT WITH DIABETES

The American Diabetes Association works with the US Transportation Security Administration (TSA) to ensure that passengers with diabetes have access to supplies. Travelers with diabetes are allowed to apply for an optional disability notification card, which discreetly informs officers that the passenger has a condition or device that may affect screening procedures.⁶

The TSA suggests that, before going through airport screening, patients with diabetes separate their diabetes supplies from their luggage and declare all items.⁶ Including prescription labels for medications and medical devices helps speed up the security process. Advise patients to carry glucose tablets and other solid foods for treating hypoglycemia when passing through airport security checkpoints.⁷

Since 2016, the TSA has allowed all diabetes-related supplies, medications, and equipment, including liquids and devices, through security after they have been screened by the x-ray scanner or by hand.⁷ People with diabetes are allowed to carry insulin and other liquid medications in amounts greater than 3.4 ounces (100 mLs) through airport security checkpoints.

Insulin can pass safely through x-ray scanners, but if patients are concerned, they may request that their insulin be inspected by hand.⁷ Patients must inform airport security of this decision before the screening process begins. A hand inspection may include swabbing for explosives.

Patients with an insulin pump and a continuous glucose monitoring device may feel uncomfortable during x-ray screening and special security screenings. Remind patients that it is TSA policy that patients do not need to disconnect their devices and can request screening by pat-down rather than x-ray scanner.⁶ It is the responsibility of the patient to research whether the pump can pass through x-ray scanners.

All patients have the right to request a pat-down and can opt out of passing through the x-ray scanner.⁶ However, patients need to inform officers about a pump before screening and must understand that the pump may be subject to further inspection. Usually, this additional inspection includes swabbing the patient’s hands to check for explosive material and a simple pat-down of the insulin pump.⁷

IN-FLIGHT TIPS

Time zones and insulin dosing

Diabetes management is often based on a 24-hour medication schedule. Travel can disrupt this schedule, making it challenging for patients to determine the appropriate medication adjustments. With some assistance, the patient can determine the best course of action based on the direction of travel and the number of time zones crossed.

According to Chandran and Edelman,⁷ medication adjustments are needed only when the patient is traveling east or west, not north or south. As time zones change, day length changes and, consequently, so does the 24-hour regimen many patients follow. As a general rule, traveling east results in a shortened day, requiring a potential reduction in insulin, while traveling west results in a longer day, possibly requiring an increase in insulin dose.⁷ However, this is a guideline and may not be applicable to all patients.⁷

Advise patients to follow local time to administer medications beginning the morning after arrival.⁷ It is not uncommon, due to changes in meal schedules and dosing, for patients to experience hyperglycemia during travel. They should be prepared to correct this if necessary.

Patients using insulin injections should plan to adjust to the new time zone as soon as possible. If the time change is only 1 or 2 hours, they should take their medications before departure according to their normal home time.⁷ Upon arrival, they should resume their insulin regimen based on the local time.

Westward travel. If the patient is traveling west with a time change of 3 or more hours, additional changes may be necessary. Advise patients to take their insulin according to their normal home time before departure. The change in dosing and schedule will depend largely on current glucose control, time of travel, and availability of food and glucose during travel. Encourage patients to discuss these matters with you in advance of any long travel.

Eastward travel. When the patient is traveling east with a time change greater than 3 hours, the day will be consequently shortened. On the day of travel, patients should take their morning dose according to home time. If they are concerned about hypoglycemia, suggest that they decrease the dose by 10%.⁶ On arrival, they should adhere to the new time zone and base insulin dosing on local time.

Advice for insulin pump users. Patients with an insulin pump need make only minimal changes to their dosing schedule. They should continue their routine of basal and bolus doses and change the time on their insulin pump to local time when they arrive. Insulin pump users should bring insulin and syringes as backup; in the event of pump malfunction, the patient should continue to use the same amount of bolus insulin to correct glucose readings and to cover meals.⁷ As for the basal dose, patients can administer a once-daily injection of long-acting insulin, which can be calculated from their pump or accessed from the list they created as part of their pre-travel preparation.⁷

Advice for patients on oral diabetes medications

If a patient is taking an oral medication, it is less crucial to adhere to a time schedule. In fact, in some cases it may be preferable to skip a dose and risk slight hyperglycemia for a few hours rather than take medication too close in time and risk hypoglycemia.⁷

Remind patients to anticipate a change in their oral medication regimen if they travel farther than 5 time zones.⁷ Encourage patients to research time changes and discuss the necessary changes in medication dosage on the day of travel as well as the specific aspects of their trip. A time-zone converter can be found at www.timeanddate.com.⁸

Insulin 101

Storing insulin at the appropriate temperature may be a concern. Insulin should be kept between 40°F and 86°F (4°C–30°C).⁴ Remind patients to carry their insulin with them at all times and to not store it in a car glove compartment or backpack where it can be exposed to excessive sun. The Frio cold pack (ReadyCare, Walnut Creek, CA) is a helpful alternative to refrigeration and can be used to cool insulin when hiking or participating in activities where insulin can overheat. These cooling gel packs are activated when exposed to cold water for 5 to 7 minutes⁵ and are reusable.

Alert patients that insulin names and concentrations may vary among countries. Most insulins are U-100 concentration, which means that for every 1 mL of liquid there are 100 units of insulin. This is the standard insulin concentration used in the United States. There are U-200, U-300, and U-500 insulins as well. In Europe, the standard concentration is U-40 insulin. Syringe sizes are designed to accommodate either U-100 or U-40 insulin. Review these differences with patients and explain the consequences of mixing insulin concentration with syringes of different sizes. Figure 2 shows how to calculate equivalent doses.

Resort tips: Food, drinks, and excursions

A large component of travel is indulging in local cuisine. Patients with diabetes need to be aware of how different foods can affect their diabetes control. Encourage them to research the foods common to the local cuisine. Websites such as Calorie King, MyFitnessPal, Lose it!, and Nutrition Data can help identify the caloric and nutritional makeup of foods.⁹

Advise patients to actively monitor how their blood glucose is affected by new foods by checking blood glucose levels before and after each meal.⁹ Opting for vegetables and protein sources minimizes glucose fluctuations. Remind patients that drinks at resorts may contain more sugar than advertised. Patients should continue to manage their blood glucose by checking levels and by making appropriate insulin adjustments based on the readings. We often advise patients to pack a jar of peanut butter when traveling to ensure a ready source of protein.

Patients who plan to participate in physically challenging activities while travelling should inform all relevant members of the activity staff of their condition. In case of an emergency, hotel staff and guides will be better equipped to help with situations such as hypoglycemia. As noted above, patients should always carry snacks and supplies to treat hypoglycemia in case no alternative food options are available during an excursion. Also, warn patients to avoid walking barefoot. Water shoes are a good alternative to protect feet from cuts and sores.

Patients should inquire about the safety of high-elevation activities. With many glucose meters, every 1,000 feet of elevation results in a 1% to 2% underestimation of blood glucose,¹⁰ which could result in an inaccurate reading. If high-altitude activities are planned, advise patients to bring multiple meters to cross-check glucose readings in cases where inaccuracies (due to elevation) are possible.

Travel, once reserved for wealthy vacationers and high-level executives, has become a regular experience for many people. The US Travel and Tourism Overview reported that US domestic travel climbed to more than 2.25 billion person-trips in 2017.¹ The US Centers for Disease Control and Prevention (CDC) and the US Travel Association suggest that, based on this frequency and the known rate of diabetes, 17 million people with diabetes travel annually for leisure and 5.6 million for business, and these numbers are expected to increase.²

It stands to reason that as the number of people who travel continues to increase, so too will the number of patients with diabetes seeking medical travel advice. Despite resources available to travelers with diabetes, researchers at the 2016 meeting of the American Diabetes Association noted that only 30% of patients with diabetes who responded to a survey reported being satisfied with the resources available to help them manage their diabetes while traveling.² This article discusses how clinicians can help patients manage their diabetes while traveling, address common travel questions, and prepare patients for emergencies that may arise while traveling.

PRE-TRIP PREPARATION

Provider visit before travel: Checking the bases

Advise patients to schedule an appointment 4 to 6 weeks before their trip.³ At this appointment, give the patient a healthcare provider travel letter (Figure 1) and prescriptions that the patient can hand-carry en route.³ The provider letter should state that the patient has diabetes and should list all supplies the patient needs. The letter should also include specific medications used by the patient and the devices that deliver these medications, eg, Humalog insulin and U-100 syringes⁴ to administer insulin, as well as any food and medication allergies.

Prescriptions should be written for patients to use in the event of an emergency during travel. Prescriptions for diabetes medications should be written with generic names to minimize confusion for those traveling internationally. Additionally, all prescriptions should provide enough medication to last throughout the trip.⁴

Advise patients that rules for filling prescriptions may vary between states and countries.³ Also, the strength of insulin may vary between the United States and other countries. Patients should understand that if they fill their insulin prescription in a foreign country, they may need to purchase new syringes to match the insulin dose. For example, if patients use U-100 syringes and purchase U-40 insulin, they will need to buy U-40 syringes or risk taking too little of a dose.

Remind patients that prescriptions are not necessary for all diabetes supplies but are essential for coverage by insurance companies. Blood glucose testing supplies, ketone strips, and glucose tablets may be purchased in a pharmacy without a prescription. Human insulin may also be purchased over the counter. However, oral medications, glucagon, and analog insulins require a prescription. We suggest that patients who travel have their prescriptions on file at a chain pharmacy rather than an independent one. If they are in the United States, they can go to any branch of the chain pharmacy and easily fill a prescription.

Work with the patient to compile a separate document that details the medication dosing, correction-scale instructions, carbohydrate-to-insulin ratios, and pump settings (basal rates, insulin sensitivity, active insulin time).⁴ Patients who use an insulin pump should record all pump settings in the event that they need to convert to insulin injections during travel.⁴ We suggest that all patients with an insulin pump have an alternate insulin method (eg, pens, vials) and that they carry this with them along with basal insulin in case the pump fails. This level of preparation empowers the patient to assume responsibility for his or her own care if a healthcare provider is not available during travel.

Like all travelers, patients with diabetes should confirm that their immunizations are up to date. Encourage patients to the CDC’s page (wwwnc.cdc.gov/travel) to check the list of vaccines necessary for their region of travel.^4,5 Many special immunizations can be acquired only from a public health department and not from a clinician’s office.

Additionally, depending on the region of travel, prescribing antibiotics or antidiarrheal medications may be necessary to ensure patient safety and comfort. We also recommend that patients with type 1 diabetes obtain a supply of antibiotics and antidiarrheals because they can become sick quickly.

Packing with diabetes: Double is better

The American Diabetes Association recommends that patients pack at least twice the medication and blood-testing supplies they anticipate needing.³ Reinforce to patients the need to pack all medications and supplies in their carry-on bag and to keep this bag in their possession at all times to avoid damage, loss, and extreme changes in temperature and air pressure, which can adversely affect the activity and stability of insulin.

Ask patients about the activities they plan to participate in and how many days they will be traveling, and then recommend shoes that will encourage appropriate foot care.⁴ Patients with diabetes should choose comfort over style when selecting footwear. All new shoes should be purchased and “broken in” 2 to 3 weeks before the trip. Alternating shoes decreases the risk of blisters and calluses.⁴

Emergency abroad: Planning to be prepared

It is crucial to counsel patients on how to respond in an emergency.

Encourage patients with diabetes, especially those who use insulin, to obtain a medical identification bracelet, necklace, or in some cases, a tattoo, that states they use insulin and discloses any allergies.³ This ensures that emergency medical personnel will be aware of the patient’s condition when providing care. Also suggest that your patients have emergency contact information available on their person and their cell phone to expedite assistance in an emergency (Table 2).

Urge patients to determine prior to their departure if their health coverage will change once they leave the state or the country. Some insurance companies require patients to go to a specific healthcare system while others regulate the amount of time a patient can be in the hospital before being transferred home. It is important for patients to be aware of these terms in the event of hospitalization.⁴ Travel insurance should be considered for international travel.

AIRPORT SECURITY: WHAT TO EXPECT WITH DIABETES

The American Diabetes Association works with the US Transportation Security Administration (TSA) to ensure that passengers with diabetes have access to supplies. Travelers with diabetes are allowed to apply for an optional disability notification card, which discreetly informs officers that the passenger has a condition or device that may affect screening procedures.⁶

The TSA suggests that, before going through airport screening, patients with diabetes separate their diabetes supplies from their luggage and declare all items.⁶ Including prescription labels for medications and medical devices helps speed up the security process. Advise patients to carry glucose tablets and other solid foods for treating hypoglycemia when passing through airport security checkpoints.⁷

Since 2016, the TSA has allowed all diabetes-related supplies, medications, and equipment, including liquids and devices, through security after they have been screened by the x-ray scanner or by hand.⁷ People with diabetes are allowed to carry insulin and other liquid medications in amounts greater than 3.4 ounces (100 mLs) through airport security checkpoints.

Insulin can pass safely through x-ray scanners, but if patients are concerned, they may request that their insulin be inspected by hand.⁷ Patients must inform airport security of this decision before the screening process begins. A hand inspection may include swabbing for explosives.

Patients with an insulin pump and a continuous glucose monitoring device may feel uncomfortable during x-ray screening and special security screenings. Remind patients that it is TSA policy that patients do not need to disconnect their devices and can request screening by pat-down rather than x-ray scanner.⁶ It is the responsibility of the patient to research whether the pump can pass through x-ray scanners.

All patients have the right to request a pat-down and can opt out of passing through the x-ray scanner.⁶ However, patients need to inform officers about a pump before screening and must understand that the pump may be subject to further inspection. Usually, this additional inspection includes swabbing the patient’s hands to check for explosive material and a simple pat-down of the insulin pump.⁷

IN-FLIGHT TIPS

Time zones and insulin dosing

Diabetes management is often based on a 24-hour medication schedule. Travel can disrupt this schedule, making it challenging for patients to determine the appropriate medication adjustments. With some assistance, the patient can determine the best course of action based on the direction of travel and the number of time zones crossed.

According to Chandran and Edelman,⁷ medication adjustments are needed only when the patient is traveling east or west, not north or south. As time zones change, day length changes and, consequently, so does the 24-hour regimen many patients follow. As a general rule, traveling east results in a shortened day, requiring a potential reduction in insulin, while traveling west results in a longer day, possibly requiring an increase in insulin dose.⁷ However, this is a guideline and may not be applicable to all patients.⁷

Advise patients to follow local time to administer medications beginning the morning after arrival.⁷ It is not uncommon, due to changes in meal schedules and dosing, for patients to experience hyperglycemia during travel. They should be prepared to correct this if necessary.

Patients using insulin injections should plan to adjust to the new time zone as soon as possible. If the time change is only 1 or 2 hours, they should take their medications before departure according to their normal home time.⁷ Upon arrival, they should resume their insulin regimen based on the local time.

Westward travel. If the patient is traveling west with a time change of 3 or more hours, additional changes may be necessary. Advise patients to take their insulin according to their normal home time before departure. The change in dosing and schedule will depend largely on current glucose control, time of travel, and availability of food and glucose during travel. Encourage patients to discuss these matters with you in advance of any long travel.

Eastward travel. When the patient is traveling east with a time change greater than 3 hours, the day will be consequently shortened. On the day of travel, patients should take their morning dose according to home time. If they are concerned about hypoglycemia, suggest that they decrease the dose by 10%.⁶ On arrival, they should adhere to the new time zone and base insulin dosing on local time.

Advice for insulin pump users. Patients with an insulin pump need make only minimal changes to their dosing schedule. They should continue their routine of basal and bolus doses and change the time on their insulin pump to local time when they arrive. Insulin pump users should bring insulin and syringes as backup; in the event of pump malfunction, the patient should continue to use the same amount of bolus insulin to correct glucose readings and to cover meals.⁷ As for the basal dose, patients can administer a once-daily injection of long-acting insulin, which can be calculated from their pump or accessed from the list they created as part of their pre-travel preparation.⁷

Advice for patients on oral diabetes medications

If a patient is taking an oral medication, it is less crucial to adhere to a time schedule. In fact, in some cases it may be preferable to skip a dose and risk slight hyperglycemia for a few hours rather than take medication too close in time and risk hypoglycemia.⁷

Remind patients to anticipate a change in their oral medication regimen if they travel farther than 5 time zones.⁷ Encourage patients to research time changes and discuss the necessary changes in medication dosage on the day of travel as well as the specific aspects of their trip. A time-zone converter can be found at www.timeanddate.com.⁸

Insulin 101

Storing insulin at the appropriate temperature may be a concern. Insulin should be kept between 40°F and 86°F (4°C–30°C).⁴ Remind patients to carry their insulin with them at all times and to not store it in a car glove compartment or backpack where it can be exposed to excessive sun. The Frio cold pack (ReadyCare, Walnut Creek, CA) is a helpful alternative to refrigeration and can be used to cool insulin when hiking or participating in activities where insulin can overheat. These cooling gel packs are activated when exposed to cold water for 5 to 7 minutes⁵ and are reusable.

Alert patients that insulin names and concentrations may vary among countries. Most insulins are U-100 concentration, which means that for every 1 mL of liquid there are 100 units of insulin. This is the standard insulin concentration used in the United States. There are U-200, U-300, and U-500 insulins as well. In Europe, the standard concentration is U-40 insulin. Syringe sizes are designed to accommodate either U-100 or U-40 insulin. Review these differences with patients and explain the consequences of mixing insulin concentration with syringes of different sizes. Figure 2 shows how to calculate equivalent doses.

Resort tips: Food, drinks, and excursions

A large component of travel is indulging in local cuisine. Patients with diabetes need to be aware of how different foods can affect their diabetes control. Encourage them to research the foods common to the local cuisine. Websites such as Calorie King, MyFitnessPal, Lose it!, and Nutrition Data can help identify the caloric and nutritional makeup of foods.⁹

Advise patients to actively monitor how their blood glucose is affected by new foods by checking blood glucose levels before and after each meal.⁹ Opting for vegetables and protein sources minimizes glucose fluctuations. Remind patients that drinks at resorts may contain more sugar than advertised. Patients should continue to manage their blood glucose by checking levels and by making appropriate insulin adjustments based on the readings. We often advise patients to pack a jar of peanut butter when traveling to ensure a ready source of protein.

Patients who plan to participate in physically challenging activities while travelling should inform all relevant members of the activity staff of their condition. In case of an emergency, hotel staff and guides will be better equipped to help with situations such as hypoglycemia. As noted above, patients should always carry snacks and supplies to treat hypoglycemia in case no alternative food options are available during an excursion. Also, warn patients to avoid walking barefoot. Water shoes are a good alternative to protect feet from cuts and sores.

Patients should inquire about the safety of high-elevation activities. With many glucose meters, every 1,000 feet of elevation results in a 1% to 2% underestimation of blood glucose,¹⁰ which could result in an inaccurate reading. If high-altitude activities are planned, advise patients to bring multiple meters to cross-check glucose readings in cases where inaccuracies (due to elevation) are possible.

Travel, once reserved for wealthy vacationers and high-level executives, has become a regular experience for many people. The US Travel and Tourism Overview reported that US domestic travel climbed to more than 2.25 billion person-trips in 2017.¹ The US Centers for Disease Control and Prevention (CDC) and the US Travel Association suggest that, based on this frequency and the known rate of diabetes, 17 million people with diabetes travel annually for leisure and 5.6 million for business, and these numbers are expected to increase.²

It stands to reason that as the number of people who travel continues to increase, so too will the number of patients with diabetes seeking medical travel advice. Despite resources available to travelers with diabetes, researchers at the 2016 meeting of the American Diabetes Association noted that only 30% of patients with diabetes who responded to a survey reported being satisfied with the resources available to help them manage their diabetes while traveling.² This article discusses how clinicians can help patients manage their diabetes while traveling, address common travel questions, and prepare patients for emergencies that may arise while traveling.

PRE-TRIP PREPARATION

Provider visit before travel: Checking the bases

Advise patients to schedule an appointment 4 to 6 weeks before their trip.³ At this appointment, give the patient a healthcare provider travel letter (Figure 1) and prescriptions that the patient can hand-carry en route.³ The provider letter should state that the patient has diabetes and should list all supplies the patient needs. The letter should also include specific medications used by the patient and the devices that deliver these medications, eg, Humalog insulin and U-100 syringes⁴ to administer insulin, as well as any food and medication allergies.

Prescriptions should be written for patients to use in the event of an emergency during travel. Prescriptions for diabetes medications should be written with generic names to minimize confusion for those traveling internationally. Additionally, all prescriptions should provide enough medication to last throughout the trip.⁴

Advise patients that rules for filling prescriptions may vary between states and countries.³ Also, the strength of insulin may vary between the United States and other countries. Patients should understand that if they fill their insulin prescription in a foreign country, they may need to purchase new syringes to match the insulin dose. For example, if patients use U-100 syringes and purchase U-40 insulin, they will need to buy U-40 syringes or risk taking too little of a dose.

Remind patients that prescriptions are not necessary for all diabetes supplies but are essential for coverage by insurance companies. Blood glucose testing supplies, ketone strips, and glucose tablets may be purchased in a pharmacy without a prescription. Human insulin may also be purchased over the counter. However, oral medications, glucagon, and analog insulins require a prescription. We suggest that patients who travel have their prescriptions on file at a chain pharmacy rather than an independent one. If they are in the United States, they can go to any branch of the chain pharmacy and easily fill a prescription.

Work with the patient to compile a separate document that details the medication dosing, correction-scale instructions, carbohydrate-to-insulin ratios, and pump settings (basal rates, insulin sensitivity, active insulin time).⁴ Patients who use an insulin pump should record all pump settings in the event that they need to convert to insulin injections during travel.⁴ We suggest that all patients with an insulin pump have an alternate insulin method (eg, pens, vials) and that they carry this with them along with basal insulin in case the pump fails. This level of preparation empowers the patient to assume responsibility for his or her own care if a healthcare provider is not available during travel.

Like all travelers, patients with diabetes should confirm that their immunizations are up to date. Encourage patients to the CDC’s page (wwwnc.cdc.gov/travel) to check the list of vaccines necessary for their region of travel.^4,5 Many special immunizations can be acquired only from a public health department and not from a clinician’s office.

Additionally, depending on the region of travel, prescribing antibiotics or antidiarrheal medications may be necessary to ensure patient safety and comfort. We also recommend that patients with type 1 diabetes obtain a supply of antibiotics and antidiarrheals because they can become sick quickly.

Packing with diabetes: Double is better

The American Diabetes Association recommends that patients pack at least twice the medication and blood-testing supplies they anticipate needing.³ Reinforce to patients the need to pack all medications and supplies in their carry-on bag and to keep this bag in their possession at all times to avoid damage, loss, and extreme changes in temperature and air pressure, which can adversely affect the activity and stability of insulin.

Ask patients about the activities they plan to participate in and how many days they will be traveling, and then recommend shoes that will encourage appropriate foot care.⁴ Patients with diabetes should choose comfort over style when selecting footwear. All new shoes should be purchased and “broken in” 2 to 3 weeks before the trip. Alternating shoes decreases the risk of blisters and calluses.⁴

Emergency abroad: Planning to be prepared

It is crucial to counsel patients on how to respond in an emergency.

Encourage patients with diabetes, especially those who use insulin, to obtain a medical identification bracelet, necklace, or in some cases, a tattoo, that states they use insulin and discloses any allergies.³ This ensures that emergency medical personnel will be aware of the patient’s condition when providing care. Also suggest that your patients have emergency contact information available on their person and their cell phone to expedite assistance in an emergency (Table 2).

Urge patients to determine prior to their departure if their health coverage will change once they leave the state or the country. Some insurance companies require patients to go to a specific healthcare system while others regulate the amount of time a patient can be in the hospital before being transferred home. It is important for patients to be aware of these terms in the event of hospitalization.⁴ Travel insurance should be considered for international travel.

AIRPORT SECURITY: WHAT TO EXPECT WITH DIABETES

The American Diabetes Association works with the US Transportation Security Administration (TSA) to ensure that passengers with diabetes have access to supplies. Travelers with diabetes are allowed to apply for an optional disability notification card, which discreetly informs officers that the passenger has a condition or device that may affect screening procedures.⁶

The TSA suggests that, before going through airport screening, patients with diabetes separate their diabetes supplies from their luggage and declare all items.⁶ Including prescription labels for medications and medical devices helps speed up the security process. Advise patients to carry glucose tablets and other solid foods for treating hypoglycemia when passing through airport security checkpoints.⁷

Since 2016, the TSA has allowed all diabetes-related supplies, medications, and equipment, including liquids and devices, through security after they have been screened by the x-ray scanner or by hand.⁷ People with diabetes are allowed to carry insulin and other liquid medications in amounts greater than 3.4 ounces (100 mLs) through airport security checkpoints.

Insulin can pass safely through x-ray scanners, but if patients are concerned, they may request that their insulin be inspected by hand.⁷ Patients must inform airport security of this decision before the screening process begins. A hand inspection may include swabbing for explosives.

Patients with an insulin pump and a continuous glucose monitoring device may feel uncomfortable during x-ray screening and special security screenings. Remind patients that it is TSA policy that patients do not need to disconnect their devices and can request screening by pat-down rather than x-ray scanner.⁶ It is the responsibility of the patient to research whether the pump can pass through x-ray scanners.

All patients have the right to request a pat-down and can opt out of passing through the x-ray scanner.⁶ However, patients need to inform officers about a pump before screening and must understand that the pump may be subject to further inspection. Usually, this additional inspection includes swabbing the patient’s hands to check for explosive material and a simple pat-down of the insulin pump.⁷

IN-FLIGHT TIPS

Time zones and insulin dosing

Diabetes management is often based on a 24-hour medication schedule. Travel can disrupt this schedule, making it challenging for patients to determine the appropriate medication adjustments. With some assistance, the patient can determine the best course of action based on the direction of travel and the number of time zones crossed.

According to Chandran and Edelman,⁷ medication adjustments are needed only when the patient is traveling east or west, not north or south. As time zones change, day length changes and, consequently, so does the 24-hour regimen many patients follow. As a general rule, traveling east results in a shortened day, requiring a potential reduction in insulin, while traveling west results in a longer day, possibly requiring an increase in insulin dose.⁷ However, this is a guideline and may not be applicable to all patients.⁷

Advise patients to follow local time to administer medications beginning the morning after arrival.⁷ It is not uncommon, due to changes in meal schedules and dosing, for patients to experience hyperglycemia during travel. They should be prepared to correct this if necessary.

Patients using insulin injections should plan to adjust to the new time zone as soon as possible. If the time change is only 1 or 2 hours, they should take their medications before departure according to their normal home time.⁷ Upon arrival, they should resume their insulin regimen based on the local time.

Westward travel. If the patient is traveling west with a time change of 3 or more hours, additional changes may be necessary. Advise patients to take their insulin according to their normal home time before departure. The change in dosing and schedule will depend largely on current glucose control, time of travel, and availability of food and glucose during travel. Encourage patients to discuss these matters with you in advance of any long travel.

Eastward travel. When the patient is traveling east with a time change greater than 3 hours, the day will be consequently shortened. On the day of travel, patients should take their morning dose according to home time. If they are concerned about hypoglycemia, suggest that they decrease the dose by 10%.⁶ On arrival, they should adhere to the new time zone and base insulin dosing on local time.

Advice for insulin pump users. Patients with an insulin pump need make only minimal changes to their dosing schedule. They should continue their routine of basal and bolus doses and change the time on their insulin pump to local time when they arrive. Insulin pump users should bring insulin and syringes as backup; in the event of pump malfunction, the patient should continue to use the same amount of bolus insulin to correct glucose readings and to cover meals.⁷ As for the basal dose, patients can administer a once-daily injection of long-acting insulin, which can be calculated from their pump or accessed from the list they created as part of their pre-travel preparation.⁷

Advice for patients on oral diabetes medications

If a patient is taking an oral medication, it is less crucial to adhere to a time schedule. In fact, in some cases it may be preferable to skip a dose and risk slight hyperglycemia for a few hours rather than take medication too close in time and risk hypoglycemia.⁷

Remind patients to anticipate a change in their oral medication regimen if they travel farther than 5 time zones.⁷ Encourage patients to research time changes and discuss the necessary changes in medication dosage on the day of travel as well as the specific aspects of their trip. A time-zone converter can be found at www.timeanddate.com.⁸

Insulin 101

Storing insulin at the appropriate temperature may be a concern. Insulin should be kept between 40°F and 86°F (4°C–30°C).⁴ Remind patients to carry their insulin with them at all times and to not store it in a car glove compartment or backpack where it can be exposed to excessive sun. The Frio cold pack (ReadyCare, Walnut Creek, CA) is a helpful alternative to refrigeration and can be used to cool insulin when hiking or participating in activities where insulin can overheat. These cooling gel packs are activated when exposed to cold water for 5 to 7 minutes⁵ and are reusable.

Alert patients that insulin names and concentrations may vary among countries. Most insulins are U-100 concentration, which means that for every 1 mL of liquid there are 100 units of insulin. This is the standard insulin concentration used in the United States. There are U-200, U-300, and U-500 insulins as well. In Europe, the standard concentration is U-40 insulin. Syringe sizes are designed to accommodate either U-100 or U-40 insulin. Review these differences with patients and explain the consequences of mixing insulin concentration with syringes of different sizes. Figure 2 shows how to calculate equivalent doses.

Resort tips: Food, drinks, and excursions

A large component of travel is indulging in local cuisine. Patients with diabetes need to be aware of how different foods can affect their diabetes control. Encourage them to research the foods common to the local cuisine. Websites such as Calorie King, MyFitnessPal, Lose it!, and Nutrition Data can help identify the caloric and nutritional makeup of foods.⁹

Advise patients to actively monitor how their blood glucose is affected by new foods by checking blood glucose levels before and after each meal.⁹ Opting for vegetables and protein sources minimizes glucose fluctuations. Remind patients that drinks at resorts may contain more sugar than advertised. Patients should continue to manage their blood glucose by checking levels and by making appropriate insulin adjustments based on the readings. We often advise patients to pack a jar of peanut butter when traveling to ensure a ready source of protein.

Patients who plan to participate in physically challenging activities while travelling should inform all relevant members of the activity staff of their condition. In case of an emergency, hotel staff and guides will be better equipped to help with situations such as hypoglycemia. As noted above, patients should always carry snacks and supplies to treat hypoglycemia in case no alternative food options are available during an excursion. Also, warn patients to avoid walking barefoot. Water shoes are a good alternative to protect feet from cuts and sores.

Patients should inquire about the safety of high-elevation activities. With many glucose meters, every 1,000 feet of elevation results in a 1% to 2% underestimation of blood glucose,¹⁰ which could result in an inaccurate reading. If high-altitude activities are planned, advise patients to bring multiple meters to cross-check glucose readings in cases where inaccuracies (due to elevation) are possible.