The evolving role of therapeutic nutrition

According to the Public Health Agency of Canada, 44% of adults 20 years of age or older have at least one chronic condition, and more than two-thirds of deaths result from four groups of chronic diseases: cardiovascular, cancer, type 2 diabetes and respiratory illness.1, 2 These diseases share preventable risk factors; unhealthy diet is one of the most important. Obesity has also become a major public health issue, affecting an estimated 7.3 million Canadian adults in 2018, while another 9.9 million adults are classed as overweight.3 As the incidence of obesity, type 2 diabetes and other metabolically-based chronic diseases skyrocket, healthcare providers have been part of many strategies to arrest this devastating trend. More recently, there is growing public interest in exploring a “food first” therapeutic nutrition approach to actively treating these diseases, and growing evidence to support the use of personalized therapeutic nutrition to achieve remission as a clinical goal. Pharmacists will increasingly encounter patients using therapeutic nutrition strategies to manage various diseases. To help pharmacists better prepare for their role in assisting these patients, this article describes energy metabolism, what therapeutic nutrition is and its evidence base. It also discusses the pharmacist’s role in supporting therapeutic nutrition, with a focus on making adjustments to diabetes and antihypertensive medications. Energy metabolism To understand the basis of therapeutic nutrition, pharmacists should first appreciate the fundamentals of energy metabolism. It is now understood that chronic overnutrition is a primary driver of metabolic dysfunction and that adipose tissue plays an important role. In response to persistent excess energy, adipose tissue expansion can lead to adipocyte hypertrophy, followed by accumulation of ectopic fat in the liver, muscle and pancreas. Left unchecked, this dysfunctional adipose tissue results in activation of inflammatory pathways through the production of hormones and proinflammatory cytokines.4, 5 Muscle tissue also plays a central role in metabolism and glucose homeostasis. Muscle is normally a reservoir for glucose, with insulin signalling allowing the storage of glucose in the form of glycogen. When muscle insulin resistance or sarcopenia (a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength) is present, this reservoir for glucose is lost. As subcutaneous fat storage is exceeded and blood glucose can no longer be effectively deposited in muscle, the liver turns excess blood glucose into liver fat. Increased visceral fat in the liver leads to increased very low-density lipoprotein (VLDL) production and decreased sensitivity of hepatocytes to insulin. This hepatic insulin resistance leads to a lack of suppression of endogenous glucose production, resulting in excess glucose production and increased blood glucose. This increase in plasma glucose leads to more basal insulin secretion, hepatic fat deposition and VLDL secretion.6, 7 In the pancreas, increased plasma VLDL leads to increased triglyceride deposition in the islet cells and worsening beta-cell responsiveness to glucose. Hepatic insulin resistance in combination with pancreatic beta-cell hyporesponsiveness results in increased postprandial glucose, and a further increase in basal insulin secretion. This produces a vicious cycle of hyperinsulinemia and insulin resistance. Both are present, and are key players in metabolic dysfunction (see Figure 1).6 What is personalized therapeutic nutrition? \Personalized therapeutic nutrition is an individually tailored nutritional intervention designed to manage or reverse patientspecific metabolic dysfunctions, medical conditions or their associated symptoms. Using an evidence-based approach, it focuses on active treatment of chronic disease as opposed to primary prevention. The goal is to support people to take a “food first” approach to treating chronic disease. It includes a variety of eating patterns that are individualized based on the condition being treated. This approach also considers a person’s needs, preferences, motivation and degree of insulin resistance, and focuses on patient safety by preparing health practitioners to recognize and manage risks associated with potential overmedication. Personalized therapeutic nutrition provides a new option for managing metabolically-based chronic diseases and should be offered as a first-line treatment for interested patients.8 Evidence for therapeutic nutrition KEY CLINICAL STUDIES Over the last decade or more, nutrition science literature has been expanding on the effects of various dietary patterns on weight loss and metabolic risk factors for chronic diseases (see Table 1).9, 10, 11 The following studies highlight some of the most promising research in this emerging field. The PURE (Prospective Urban Rural Epidemiology) study,12 one of the largest dietary studies in the world, provided a unique opportunity to examine the impact of diet on total mortality and cardiovascular disease in some settings where overnutrition is common, and others where poverty is widespread and under-nutrition is of greater concern. Although the results were confounded by different degrees of social–economical development in the various countries, the main messages for nutritional advice were to follow health dietary patterns and to reduce consumption of processed red meats, sugar-sweetened foods and beverages, and refined grains. A systematic review examined dietary patterns in the management of type 2 diabetes.13 It assessed published randomized trials of six months or longer involving lowcarbohydrate, macrobiotic, vegan, vegetarian, Mediterranean and intermittent fasting diets, compared to low-fat diets and the effects on glycemic control, weight and lipids. Despite the recognized need for more long-term trials in this area, the vegan, vegetarian and Mediterranean dietary patterns helped to control glycemic markers in patients with type 2 diabetes. Diabetes reversal and remission have been the focus of several studies. The Diabetes Remission Clinical Trial (DiRECT trial) was an open-label cluster-randomized trial from 49 practices in the UK; it included patients aged 20–65 with type 2 diabetes for less than six years, with a body mass index (BMI) of 27–45 and not receiving insulin. The intervention was comprised of withdrawing all antidiabetes and antihypertensive drugs on Day 1 of the weight management program and using a total diet replacement low-calorie formula for three to five months followed by a supported long-term weight-loss maintenance program. At one year, 68 (46%) of 149 intervention participants were in diabetes remission and 36 (24%) had achieved at least a 15 kg weight loss. Two followup studies from the DiRECT trial looked at the durability of diabetes remission and predictors of remission. Both studies found sustained remission in one-third of people with type 2 diabetes at two years.16, 17 A UK study examined the use of a low-energy total diet replacement in diabetes patients on insulin and showed significant reductions in body weight, insulin usage and insulin doses at 12 months.(18) The mean weight loss at 12 months was 9.8 kg (intervention group) versus 5.6 kg (control group). Glycated hemoglobin (A1C) fell by 0.43% in the intervention group and 0.09% in the control group. One-third of patients were no longer using insulin at the 12-month mark. A series of US studies by Virta Health used a very low carbohydrate diet with continuous remote monitoring in patients with type 2 diabetes.11 It found lower A1C, improved insulin resistance, reduction in diabetes medications, sustained loss of body weight, improvements in triglycerides, and reductions in blood pressure, inflammation and rates of metabolic syndrome. At two years, more than half of the treatment patients met the criteria for diabetes reversal and a significant portion of those individuals also had partial or complete diabetes remission.19 GUIDELINES AND RECOMMENDATIONS In early 2019, the American Diabetes Association (ADA) released its nutrition therapy consensus report for adults with diabetes or prediabetes.20 The report recognizes that there is no “one-size-fits-all” approach to managing diabetes and that nutrition therapy must be individualized. Notably, the consensus report also included a new section on low carbohydrate diets, which concluded that they are effective for weight loss, and may result in lower glucose levels and reduce the need for diabetes medications.20, 21 The 2021 ADA Standards of Medical Care in Diabetes recognize low carbohydrate nutritional therapy as a viable option for the management of type 2 diabetes.22 In 2021, the British Dietetic Association published a review of available clinical trials and practice audit data relating to dietary changes and remission of type 2 diabetes. The paper concluded that currently available evidence suggests that a range of dietary approaches, including low-energy diets and low-carbohydrate diets, can be used to support the achievement of euglycemia and potentially lead to diabetes remission. The paper recommended that healthcare professionals discuss dietary options with all people living with type 2 diabetes.23 A guidance document regarding low carbohydrate diets for adults living with diabetes was published by Diabetes Canada in 2020.24 It recommends that patients with diabetes should receive support in their choice of healthy eating patterns based on their goals and preferences. It also recommends that “healthy low- or very low-carbohydrate diets can be considered for type 1 and type 2 diabetes, with the benefits of weight loss, improved A1C levels, reduced insulin requirements, less glucose variability and/or reduced need for antihyperglycemic therapies.” In addition to a review of the evidence of low-carbohydrate and very low-carbohydrate diets for type 1 and 2 diabetes, the document discusses the cautions and safety of antihyperglycemic therapies during carbohydrate restriction and the risk of hypoglycemia. Pharmacist’s role in supporting therapeutic nutrition Pharmacists must consider key pharmaceutical care components and safety considerations for managing patients who are using therapeutic nutrition.25 When patients choose to follow various dietary meal plans, metabolic status may change quickly, and pharmacists need to identify and prioritize medication adjustments for disease states in response to the improvement seen in metabolic status. When following a therapeutic nutrition approach, diabetes and hypertension are two disease states that may require the pharmacist’s immediate attention, especially if the patient is using a very low calorie or very low carbohydrate approach. Various tools and strategies are available in the published literature to deprescribe medications in specific disease states. As members of a patient’s healthcare team, pharmacists are in an ideal position to create a medication plan that considers medication safety, and priorities for deprescribing and medication monitoring. Communicating the medication safety plan to patients and appropriate members of the patient’s healthcare team is a key step in the process. DIABETES MEDICATION ADJUSTMENT Pharmacists play a critical role in monitoring diabetes medications to ensure safety with therapeutic nutrition changes. Monitoring frequency depends on the medication(s) used. Determining a baseline blood glucose level is an important starting point for all medications. Oral medications that cause significant hypoglycemia will require blood glucose monitoring at least daily. Insulin monitoring should be (at a minimum) based on the number of doses of insulin prescribed.25, 26, 27, 28 Diabetes medications have many different mechanisms of action and differ in their risk-to-benefit profile. When considering safety and appropriateness of type 2 diabetes medications for patients using lower carbohydrate or lower calorie diets, the pharmacist must consider three key questions:28 Is there a risk of the drug causing hypoglycemia or other adverse effects? What degree of carbohydrate restriction is the patient using with the therapeutic nutrition approach? What are the benefits vs risks of continuing the medication once the carbohydrates are reduced? The greatest risk of hypoglycemia exists with sulfonylureas, repaglinide (a meglitinide) and exogenous insulin. These medications will need to be reduced or stopped based on individual patient circumstances and their current carbohydrate intake. Various algorithms have been published that can aid pharmacists in insulin dose adjustments.18, 25, 27, 28, 29, 30 The following are key points to note for other diabetes medications: Sodium-glucose cotransporter-2 (SGLT2) inhibitors may cause euglycemic ketoacidosis when used alone or with insulin. The risk of euglycemic ketoacidosis is further increased if the patient chooses to follow a lowcarbohydrate nutritional approach. It may be appropriate to stop SGLT2 inhibitors with low-carbohydrate diets if the patient does not have any cardiovascular risks or does not require the renal protective effects of the SGLT2 inhibitor. Thiazolidinediones (e.g., pioglitazone) may cause weight gain and do not cause hypoglycemia. These agents may be stopped as soon as blood glucose levels allow. Acarbose, an alpha-glucosidase inhibitor, can usually be stopped as this drug provides little to no benefit if there is low starch or sugar ingestion. Metformin reduces liver glucose output and may help to lower insulin resistance in the muscles and adipose tissue. It is safe to continue as it may offer clinical benefits in some patients. Metformin is also not associated with hypoglycemia when used alone and may facilitate minor weight loss. Glucagon-like peptide-1 (GLP-1) agonists (e.g., liraglutide) are safe to continue when starting a lower carbohydrate therapeutic nutrition approach. GLP-1 agonists increase satiety, slow gastric emptying and provide cardiovascular benefits. Dipeptidyl peptidase 4 (DPP4) inhibitors do not cause hypoglycemia alone and may be safely continued until blood glucose levels are in control. Figure 2 has a useful tool summarizing this information.25, 30, 31 ANTIHYPERTENSIVE MEDICATION ADJUSTMENT Low-carbohydrate diets have many benefits in managing hypertension. They promote fluid loss, lower insulin levels and reduce blood pressure. Dehydration is a risk with low carbohydrate diets if water and sodium are not replaced.27 As with drugs for diabetes, the pharmacist must consider a number of different factors when adjusting antihypertensive medications. This includes considering the patient’s initial blood pressure, blood pressure goal and whether they are monitoring their blood pressure, comorbidities and compelling indications for certain antihypertensive therapies, and side effect profiles of the various drugs. Because lower-carbohydrate diets result in water and sodium loss and subsequent blood pressure reductions, it is important to monitor for dehydration and symptoms of low sodium (e.g., weakness, dizziness, “brain fog,” headaches). Fluid correction often happens naturally within four to seven days after starting this dietary pattern. Leg cramps are often related to low magnesium or potassium levels, as initial effects of low-carbohydrate diets can cause electrolyte loss through natriuresis and require sodium, potassium and magnesium supplementation. For this reason, diuretics are often the first antihypertensive therapies to be stopped when a lowcarbohydrate diet is started.25, 26, 27, 30 Pharmacists can play a key role in teaching patients how to use blood pressure machines and to monitor for symptoms of dehydration and low sodium. With every 4.5–9 kg (10–20 pound) weight loss, patients may get a 5–20 mmHg drop in systolic and diastolic blood pressure.32 ADJUSTING OTHER MEDICATIONS Other medical conditions that may improve over a longer period of time with therapeutic nutrition approaches include dyslipidemia, gastroesophageal reflux disease (GERD), polycystic ovary syndrome (PCOS), psychiatric disorders and insomnia.33 Often, patients may discontinue dyslipidemia medication once cholesterol levels normalize.25, 27, 30 Patients on H2-receptor antagonists or proton pump inhibitors for GERD may gradually reduce their doses by half before discontinuing.25, 30 Patients with PCOS may see a return of fertility, so contraception may be required.33 Patients with insomnia or depression may see a positive change in sleep patterns and mood.25, 33 Team approach to therapeutic nutrition As the healthcare system evolves to include more team-based care, the implementation of a therapeutic nutrition approach requires optimization of the skills of many healthcare providers. For example, physicians who lack confidence to prescribe a therapeutic nutrition approach or deprescribe medications can still support their patients’ interests through a collaborative care team or provide leadership within a multidisciplinary team. Registered dietitians, while professionally prepared to recommend and supervise nutrition therapy, may be less accessible due to limited availability or insurance restrictions. Team-based approaches can improve this type of access issue. Advanced practice nurses, health coaches and other allied health providers with training in personalized therapeutic nutrition can be a cost-effective, more accessible support option, and many motivated empowered patients make great team leaders for their own care. Community pharmacists are also critical members of a patient’s healthcare team. They are very accessible, can be trained to monitor side effects of therapeutic nutrition, and their professional scope of practice uniquely allows them to advise physicians on deprescribing protocols and proactively address any patient safety concerns. Pharmacists wishing to learn more about personalized therapeutic nutrition can consult the resources in Box 1. ADJUSTING OTHER MEDICATIONS Other medical conditions that may improve over a longer period of time with therapeutic nutrition approaches include dyslipidemia, gastroesophageal reflux disease (GERD), polycystic ovary syndrome (PCOS), psychiatric disorders and insomnia.33 Often, patients may discontinue dyslipidemia medication once cholesterol levels normalize.25, 27, 30 Patients on H2-receptor antagonists or proton pump inhibitors for GERD may gradually reduce their doses by half before discontinuing.25, 30 Patients with PCOS may see a return of fertility, so contraception may be required.33 Patients with insomnia or depression may see a positive change in sleep patterns and mood.25, 33 Team approach to therapeutic nutrition As the healthcare system evolves to include more team-based care, the implementation of a therapeutic nutrition approach requires optimization of the skills of many healthcare providers. For example, physicians who lack confidence to prescribe a therapeutic nutrition approach or deprescribe medications can still support their patients’ interests through a collaborative care team or provide leadership within a multidisciplinary team. Registered dietitians, while professionally prepared to recommend and supervise nutrition therapy, may be less accessible due to limited availability or insurance restrictions. Team-based approaches can improve this type of access issue. Advanced practice nurses, health coaches and other allied health providers with training in personalized therapeutic nutrition can be a cost-effective, more accessible support option, and many motivated empowered patients make great team leaders for their own care. Community pharmacists are also critical members of a patient’s healthcare team. They are very accessible, can be trained to monitor side effects of therapeutic nutrition, and their professional scope of practice uniquely allows them to advise physicians on deprescribing protocols and proactively address any patient safety concerns. Pharmacists wishing to learn more about personalized therapeutic nutrition can consult the resources in Box 1. Summary Pharmacists can have a huge impact in medication management, deprescribing and medication safety. As highly trained medication experts, they can use a therapeutic nutrition approach to actively support a patient’s journey towards diabetes reversal and remission, and management of other chronic diseases. Karen Riley is a consultant pharmacist and pharmacist training lead for the Institute for Personalized Therapeutic Nutrition, B.C., and a Professor at Lambton College, Sarnia, ON. Sean McKelvey (smckelvey@therapeuticnutrition.org) is a pharmacist and chief executive officer for the Institute for Personalized Therapeutic Nutrition. Barb Reece is a registered nurse, educator and senior healthcare consultant. As chief operating officer for the Institute for Personalized Therapeutic Nutrition, she guides development of the Institute’s interdisciplinary training initiatives. References Public Health Agency of Canada. Executive summary: integrated pan-Canadian healthy living strategy 2005. http://www.phac-aspc.gc.ca/hp-ps/hl-mvs/ipchlsspimmvs/sum-res-eng.php (accessed October 6, 2021). Public Health Agency of Canada. Prevalence of chronic diseases among Canadian adults. https://www.canada.ca/en/public-health/services/chronicdiseases/prevalence-canadian-adults-infographic-2019.html (accessed October 6, 2021). Statistics Canada. Overweight and obese adults, 2018. https://www150.statcan. gc.ca/n1/pub/82-625-x/2019001/article/00005-eng.htm (accessed October 26, 2021). 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The evolving role of therapeutic nutrition

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