Exploring The Use Of Adjunctive Therapies In Type 1 Diabetes

Mariel Lechner, ASN, BSN, RN

Abstract

Recently, the likelihood of an individual with type 1 diabetes being overweight or obese has risen. Mottalib et al. described when people with type 1 diabetes begin to show clinical signs of type 2 diabetes such as insulin resistance and obesity, it is referred to as double diabetes. One factor associated with this trend includes intensive insulin therapy throughout diabetes care. Healthcare providers recommend health promotion behaviors, such as making healthy food choices and partaking in regular exercise. However, people with type 1 diabetes/double diabetes may need additional intervention besides health-promotion behaviors to help them lose weight. An emerging trend that can assist people with type 1 diabetes with losing weight and achieve glycemic goals includes adjunctive pharmacological treatments. Preliminary research demonstrated type 1 diabetes individuals who used these agents experienced lowered HbA1C levels and lost weight compared with using insulin therapy alone. Although there are potential adverse effects of using antihyperglycemic therapies, Diabetes Care and Education Specialists (DCESs) appraise further research by collaborating with colleagues and other experts while applying the standards of DSMES. This will help DCESs in offering the most up-to-date and individualized information for people with type 1 diabetes. In conclusion, antihyperglycemics can improve the quality of life among this individual population by assisting individuals in losing weight and reducing the frequency of glycemic variability episodes.

Introduction

Many healthcare providers recommend participating in health promotion behaviors for people with type 1 diabetes. These behaviors include making healthy food choices and partaking in regular exercise to maintain a healthy weight. Isaacs and colleagues discussed that despite these approaches, current treatments such as routine administration of exogenous insulin can contribute to weight gain. According to Lane, weight gain can occur in people with type 1 diabetes when they titrate insulin to maintain glucose levels within a precise physiologic range. Also, routine administration of exogenous insulin can result in glycemic variability when either too much or not enough insulin is taken during meals which results in adverse effects of hypo/hyperglycemia. Isaacs and colleagues reported 47.8% of people with type 1 diabetes are obese. People with type 1 diabetes may need additional help to lose weight when a healthy diet and exercise are not enough. Overweight and obesity further increase the risk of cardiovascular disease in people with type 1 diabetes; therefore, adjunctive pharmacological treatments, such as antihyperglycemic medications, may be a preferable approach.

Isaacs and colleagues mentioned people with type 1 diabetes are interested in using adjunctive agents for managing weight because there are currently not enough options in pharmacological therapies to help overweight individuals with diabetes lose weight. In recent times, the likelihood of an individual with type 1 diabetes being overweight or obese has risen. Mottalib et al. discussed how double diabetes is when individuals with type 1 diabetes experience obesity and insulin resistance, clinical manifestations of type 2 diabetes. This phenomenon occurs because when the proinflammatory condition associated with metabolic syndrome leads to increased glycemic variability; double diabetes develops, necessitating higher daily insulin dosages. However, it is essential to note that increased insulin dosage as a result of IR can lead to more weight gain, worsening the situation. A prospective study from Conway et al supported this statement when they identified two factors that can result in increased rates of obesity in people with diabetes: intensive insulin therapy during follow-up care and an HBA1C that has an abrupt baseline. The same study demonstrates a potential link between the two factors and the incidence rates of obesity through research data. Karras and colleagues displayed trends that the overweight population in type 1 diabetes has increased by 47% with 22.7% of this population reported having a BMI indicating they are obese (BMI equal to or greater than 30kg/m2). Karras and colleagues displayed trends that the overweight population in type 1 diabetes has increased by 47% with 22.7% of this population reported having an elevated BMI (BMI equal to or greater than 30 kg/m2). Karras and colleagues also demonstrated this potential link by documenting that only 7% of people with T1D were taking three or more daily injections at baseline (1986-1988); however, it sharply rose to 82% when the follow-up period ended (2004-2007).

In their Standards of Medical Care, the ADA recommends metformin over pramlintide as evidenced by it is currently utilized more frequently for people with T1D that overweight or obese. The Standards also present the option of adding glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) to insulin therapy, which has resulted in minor reductions in A1C (0.2%) and a body weight reduction of 3 kg compared with insulin therapy alone. Although the use of SGLT-2 inhibitors in type 1 diabetes has an increased risk of ketoacidosis, these drugs, when used alongside insulin treatment have been linked with lower HBA1C values and body weight compared with insulin by itself. While the risks and benefits of adjunctive agents' continue to be evaluated, Harris et al mentioned only pramlintide is approved as an adjunct for people with type 1 diabetes.

Factors for weight gain in people with type 1 diabetes

Multiple factors influence weight gain in those with type 1 diabetes. By identifying and quantifying elements linked to obesity and overweight in the diabetes population, providers can consider other causes of weight gain besides biological and behavioral factors (e.g., symptoms, diet, physical activity). Examples of factors as well as how they contribute to individuals with type 1 diabetes gaining weight are listed below:

Social Determinants of Health

According to Healthy People 2030, Social Determinants Of Health (SDOH) are the conditions in which one resides, studies, plays, worships, and ages. SDOHs are categorized into five domains that include:

Economic stability.
Education access and quality.
Healthcare access and quality.
Neighborhood and the built environment.
Social and community context.

Hill, Nielsen, and Fox (2013) pointed out SDOH can be seen as the most powerful influencers and best predictors of health outcomes at both the individual and population levels. Also, they influence diabetes-related outcomes in biological and behavioral aspects.

Hill-Briggs and associates found that a lack of social support for people with type 1 diabetes has been associated with higher mortality and diabetes-related consequences. In contrast, better social support has been linked to better diabetes management and higher quality of life. Lack of social support can contribute to weight gain because some people with diabetes do not have the ability to gather with health professionals and others in similar situations to share ideas and learn frequently. Otherwise, a lack of social support can result in the individual "jumping off course" in health-promotion behaviors and partaking in self-destructive behaviors (e.g., not exercising and consuming unhealthy foods). People with type 1 diabetes living in resource-deprived environments defined by poverty, a lack of education, or quality healthcare can significantly impact their health. For instance, Hill, Nielsen, and Fox (2013) discussed that the struggle to make ends meet causes significant levels of chronic stress in those experiencing poverty, triggering psychological and biological responses. Notably, people experiencing high levels of chronic stress experience elevated blood pressure, cortisol, blood glucose levels, and a reduced ability to adapt to future stresses appropriately.

Additionally, individuals may partake in self-destructive behaviors and decisions (e.g., substance misuse and abuse and unhealthy eating) to cope with feelings of chronic stress such as anxiety and melancholy. It is also to cope with the fact that type 1 diabetes is a chronic illness that will require lifelong administration of exogenous insulin. Therefore, obesity will most likely result from these physiologic reactions, compounded by negative psychological responses. Hill, Nielsen, and Fox (2013) implied that the effects of poverty might be exacerbated for those living with diabetes because diabetes-care expenditures consume a more significant portion of one's income, making diabetes care a personal financial burden. Also, an individual already living in poverty lacks the resources (safe housing, healthy food, and healthcare services) needed to manage diabetes, reducing an individual's productivity or impeding educational attainment if left untreated. This is evident by how Hill-Briggs and associates pointed out that low income is linked to a higher risk of diabetes-related ketoacidosis and higher HbA1c levels in adolescents and adults with T1DM, especially among racial/ethnic minority youth with lower SES. Otherwise, diabetes heightens the cycle of poverty most people experience that is unlikely to be broken without outside intervention.

Disordered Eating

Larrañaga, Docet, García-Mayor, people with type 1 diabetes are at higher risk of developing disordered eating behaviors (DEB) because they experience numerous eating-related irregularities by carefully choosing their foods or exercise to regulate weight and overcome body dissatisfaction. Hence, researchers found a risk factor that can contribute to DEB includes those who eat according to a predefined meal plan rather than in response to internal hunger and fullness cues; researchers proposed that a disregard for internal cues may contribute to dysregulation nutrition in those susceptible. It is essential to note that eating disorders (ED) and diabetes exist because both conditions are most prevalent from childhood to young adulthood. Binge-eating disorder (BED) and night-eating syndrome (NES) are two eating disorders linked to being overweight or obese.

First, Binge-Eating Disorder (BED) is a DEB in which individuals attempt to numb emotions with food. According to McCuen-Wurst, Ruggieri, and Allison, a diagnosis of BED is made when individuals report eating a considerable amount of food in a short time (in comparison to what others might consume in a comparable setting), as well as losing control over their eating habit during this time. They also mentioned at least three of the following features must also be present:

Eating food considerably faster than usual.
Eating food until uncomfortably full.
Consuming vast amounts of food while not hungry.
Eating alone to avoid shame.
Feeling disgusted, sad, or guilty after the eating event.

The diagnosis also requires that the binge episodes cause a significant level of distress and occur at least once a week for at least three months (on average). Finally, the disorder must not be accompanied by regular compensatory behavior, nor should binge eating occur only during a bulimia nervosa or anorexia nervosa episode. It is vital to note BED is linked to a higher risk of physical comorbidities such as diabetes, hypertension, obesity, persistent headaches, and other types of chronic pain, in addition to psychological issues. This is evident by how people with BED are 3–6 times more likely to be obese than those who do not have an eating problem. Additionally, the implied connection between BED and metabolic syndrome is based on how BED is highly linked to diabetes (fivefold higher risk) and components of the metabolic syndrome (twofold increased risk) than previously proposed.

Meanwhile, Night Eating Syndrome (NES) is another DEB that people are experiencing; they get up and consume a meal or snack to help them fall asleep again. According to McCuen-Wurst, Ruggieri, and Allison, a diagnosis of NES is made when an individual consumes excessive food consumption after dinnertime (I.e., evening hyperphagia) or eating after waking up (I.e., nocturnal ingestions). Other indications of NES include Morning anorexia, a solid need to eat between supper and sleep and during the night, sleep onset and maintenance insomnia, frequently depressed mood or mood deteriorating in the evening, and the idea that one cannot get back to sleep without eating. However, it is essential to note that individuals must be aware of and recollect the eating events to be diagnosed with NES. Previous research indicated that 9.7% of people with diabetes have NES, and those who exhibit night-eating symptoms have elevated A1C levels and two or more diabetes-related comorbidities. McCuen-Wurst, Ruggieri, and Allison pointed out unstable blood glucose levels due to night eating. This could be due to the meal choices chosen by people who eat late at night, such as high carbohydrate and high-fat items, which raise the risk of metabolic syndrome when regular eating patterns are disrupted during the day.

Although these are two distinct DEB, both BED and NES have similarities that should be noted. For instance, both the causes of binge-eating disorder and night-eating syndrome remain unknown but, factors such as dieting, genetics, and coexisting psychological issues seem to play a role in DEB development. People with BED and NES also experience the health consequence of being vitamin and mineral deficient, as much of the food they consume is high in fat and sugar, both of which have little nutritional value. Larrañaga, Docet, García-Mayor also discussed DEB such as BED and NES had been linked to worse metabolic regulation, more frequent episodes of insulin resistance, and the beginning of diabetes-related problems earlier than predicted. Perhaps, individuals may benefit from using antihyperglycemics as an adjunctive therapy because antihyperglycemics help individuals lose weight by reducing plasma levels appetite-stimulating hormones (e.g., ghrelin).

Sustainability of Weight Changes

Previous research proposes sustainability of weight changes is influenced by body composition and age-related risks of weight loss. Before discussing how these two factors influence the sustainability of weight changes, a brief description of body composition and age-related risks of weight loss is needed. Body composition determines how much of a person's overall weight consists of lean mass (muscles, bones, connective tissue, and water) and fat. Al-Goblin, Al-Alfi, and Khan listed puberty, pregnancy, and the aging process as examples of age-related risks of weight loss because weight gain typically occurs during these stages of life. Weight gain can occur through an increase in the secretion of appetite hormones, extra fluid (water) in the body, slowing of metabolism or, an increase in fat mass and decrease in muscle mass. Al-Sofiani ME, Ganji SS, Kalyani emphasized the aging process as an influencer to sustainability in weight changes by revealing differences in the pattern of body composition changes in adults based on diabetes status. This suggests that metabolically unhealthy body composition (I.e., increased body fat) in people with diabetes may be a risk factor for diabetes development and a consequence of the disease. Researchers also discovered that loss in lean body mass has profound health implications such as impairs long-term sustainability by lowering resting energy expenditure/metabolism, tiredness, neuromuscular function decreases, and injury risk. Willoughby, Hewlings, and Kalman highlighted a metabolic drop that happens following LBM loss which leads to a body fat overshoot, or a re-absorption of fat mass, leading to unfavorable, compounded changes in body composition.

Additionally, the increased incidence of type 1 diabetes can be attributed to weight growth and body mass. Al-Goblin, Al-Alfi, and Khan described the "accelerator theory,” which stated that gaining weight in young age groups increases the likelihood of getting type 1 diabetes, and an inverse association between BMI and age at diagnosis is noted. It is also crucial to consider that diabetes can be detected in young children as they acquire weight because gaining weight increases insulin resistance, resulting in type 1 diabetes in those genetically susceptible. In summary, Antihyperglycemic treatment may improve individuals with type 1 diabetes health outcomes by evaluating its effect on body composition.

Additional Benefits of using adjunctive therapies for weight loss among people with T1D

There are additional benefits of using adjunctive therapies among this population. For instance, individuals with type 1 diabetes and obesity have an increased risk of inflammation and can experience insulin resistance as a result of hyperinsulinemia associated with intense titration of insulin therapy. Therefore, people with type 1 diabetes who take pharmacological adjunctive treatments can experience reduced insulin doses, increased glycemic stability, lowered HbA1C levels, and potentially reduced incidence of microvascular and macrovascular complications. Therefore, using antihyperglycemics as adjunctive pharmacological therapies may have the potential to decrease mortality and morbidity gaps associated with type 1diabetes.

In addition to weight loss, another advantage to reducing insulin doses is cost savings without having to ration insulin. Insulin rationing can lead to life-threatening complications, whereas adjunctive pharmacological therapies can help people with type 1 diabetes lose weight, lower insulin doses, and save money. On the other hand, reducing insulin doses through introducing adjunctive pharmacological therapies, such as antihyperglycemics, could allow people with T1D to manage their diabetes without facing financial hardships.

Drawbacks of using adjunctive therapies for weight loss among people with T1D

Currently, pramlintide is the only medication that has been approved in the United States for clinical use as adjunctive therapy in T1D. Isaacs and colleagues discussed the disadvantages of using pramlintide including side effects, price, administration route, and repeated dosing. Having to add three injections per day for people who are already on multiple injections might be too much. Harris and colleagues (2018) discussed the risks of serious and potentially life-threatening complications such as lower limb amputation when using canagliflozin. Some of these adjunctive medications can cause severe hypoglycemia when taken alone (DPP-4 inhibitors, GLP-1 RA agonists, Amylin analogues, and SGLT-2 inhibitors), which could greatly increase the risk of hypoglycemia when combined with insulin. Gastrointestinal symptoms such as nausea, vomiting, and diarrhea are other reported side effects experienced by people who take adjunctive pharmacological therapies. It is also vital to note the increased risk of ketoacidosis with SGLT-2 inhibitors used adjunctively with insulin.

Appraising and applying evidence of adjunctive therapies for weight loss

DCES(s) consider adjunctive therapies for weight loss in their patients with type 1 diabetes through education and support. DCESs collaborate with colleagues and other experts and monitor the current literature to provide the most up-to-date and individualized information for patients. After monitoring recent literature, DCES(s) can refer individuals to resources such as the Diabetes Daily website. The Diabetes Daily website has a section dedicated to providing information about medications that can potentially be utilized as adjunctive pharmacological therapies such as SGLT2 inhibitors and GLP-1 agonists. DCESs can also recommend online forums where individuals can talk to others who are using antihyperglycemics as an adjunctive therapy such as the JDRF Type One Nation forum called "Metformin, SGLT-2 or GLT-1 Experiences". Diabetes UK Blogs, is another online resource that has an array of forums focusing on adjunctive medication.

Other roles of the DCES

One of the pillars of Diabetes Self-Management Education and Support (DSMES) is person-centered care. Therefore, one-way DCES(s) can provide a person-centered care approach by developing a unique DSMES plan. DCES (s) develop a unique DSMES plan by gathering feedback on the benefits and risks of using adjunctive therapies through surveys, conference calls, reading patient forums, or face-to-face meetings. It is essential to note that DCES (s) can also gather information through conducting a comprehensive assessment. During these interactions, questions may pertain to overall service design, accessibility, participation, or sustainability of using adjunctive therapies for weight loss in the type 1 diabetes population. Diabetes care and education providers may also look into if there is a need for new resources or altering of existing services regarding adjunctive therapies for weight loss in those with type 1 diabetes. Additionally, DCES may collect information such as age, weight, onset and history of type 1 diabetes, medication history, ethnicity, and other information through either their health records at the facility you work in or the state department health records. Based on the information gathered, the individual and the DSMES team will discuss ideas that address the advantages and disadvantages of using adjunctive pharmacological treatments for weight loss. Therefore, DCES(s) create solutions when individuals decide if they are interested in taking antihyperglycemics alongside their insulin after understanding the benefits and risks. Lastly, DCES(s) can advocate and collaborate with other DSMES providers for future research that focuses on the risks and benefits of using these medications in overweight and obese people with type 1 diabetes.

Steps for providers when proposing off-label use of DM medications

There are a few things to keep in mind when considering the off-label use of type 2 diabetes drugs (antihyperglycemics) in people with type 1 diabetes. Before suggesting or informing a person with type 1 diabetes about supplementary medicines, practitioners should consider the following questions (FDA, 2018):

What research has been done to support the use of supplementary therapies in type 1 diabetes, and what research has not been done?
What are the advantages and disadvantages of using antihyperglycemics to treat type 1 diabetes?
Will these medications be covered by their health insurance to treat type 1 diabetes?
Am I comfortable recommending antihyperglycemics as supplementary therapy off-label?

It's important to highlight that these are just a few of the many considerations providers should make before suggesting off-label use. Following the consideration of these questions, clinicians must provide information and education about off-label usage of type 1 diabetes. According to Hoskins (2019), providers might provide information on how to use antihyperglycemics properly, the risks and advantages of utilizing these medications as a supplementary therapy, and the expected versus unfavorable effects of type 2 diabetes medications. Providers should also educate PWDs about the clinical signs of diabetes-related ketoacidosis (DKA) and when to cease taking antihyperglycemics if they have doubts or concerns and are sick or diagnosed with DKA. Providers should also determine whether the PWD is prepared to take responsibility by attentively following the provider's recommendations for supplementary therapy.

Providers can use shared decision-making, collaboration, and therapeutic communication when advocating off-label usage of type 2 diabetes drugs. Furey and Wilkins (2016) proposed a three-step communication model for shared decision-making, along with examples of how providers could put it into practice:

They inform persons with type 1 diabetes about treatments other than insulin therapy that can help them regulate their blood glucose levels (choice talk).

1- Option talk (the step in which participants are informed about their choices): According to providers, the number of approved supplementary medications for type 1 diabetes is limited. Then, despite the lack of FDA approval in type 1 diabetes, practitioners can describe the risks, advantages, and off-label uses of antihyperglycemics and outline the scientific and practice standards that guide these treatments. Using decision support tools such as reliable websites, handouts, or movies is another alternative conversation method. Increased comprehension, more accurate perception of risks and benefits, and higher participation in decision-making and decision-talk have all resulted from decision support aids.

2- Decision talk (step in which participants are backed in weighing their options and making a decision): providers must allow enough time for people to make a decision. It is worth noting that participants may need more than one visit to feel supported in the deliberation process.

3- The last step entails providers ensuring individuals with diabetes understand what they learned about off-label use of antihyperglycemics. Using the teach-back method is a simple yet, effective way to assess comprehension of patient education and clarify any misinformation the person with diabetes may have or reinforce educational concepts.

Summary

One option to assist people with type 1 diabetes with losing weight and achieving glycemic goals includes the use of adjunctive pharmacological treatments. While there are potential adverse effects associated with using these therapies, they can enhance the quality of life among this individual population. Comprehensive assessment, education, and follow-up by DCESs will be necessary as further research emerges regarding utilizing adjunctive pharmacological treatments for weight loss in people with T1D.

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