C L I N I C A L F E AT U R E S

Nutritional Management of Type 2 Diabetes Mellitus and Obesity and Pharmacologic Therapies to Facilitate Weight Loss Postgraduate Medicine Downloaded from informahealthcare.com by National Taiwan University on 06/29/15 For personal use only.

DOI: 10.3810/pgm.2014.01.2734

Marion L. Vetter, MD, RD 1,2 Anastassia Amaro, MD 2 Sheri Volger, RD, MS 2,3 Center for Weight and Eating Disorders, Department of Psychiatry, Perelman School of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA; 2 Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA; 3 Wyeth Nutrition at Nestle S.A., King of Prussia, PA 1

Abstract: Diet plays an integral role in the treatment of type 2 diabetes mellitus (T2DM). Unfortunately, many patients with T2DM do not have access to a registered dietitian or ­certified diabetes educator, and rates of physician counseling about diet remain low. This article provides an overview of the current recommendations for the nutritional management of T2DM, which are endorsed by the American Diabetes Association (ADA). Medical nutrition therapy, which provides a flexible and individualized approach to diet, emphasizes the total number (rather than the type) of carbohydrate consumed. Because fat intake also affects glycemia and cardiovascular risk, a reduction in daily mono- and polyunsaturated fat intake is recommended for most patients with T2DM. Weight loss plays an important adjunct role in treating patients with T2DM, because the majority of individuals with T2DM are overweight or obese. Patient lifestyle modification, which encompasses diet, physical activity, and behavioral therapy, can be used to facilitate weight loss in conjunction with several different dietary approaches. These include low-carbohydrate, low-fat, low-glycemic index, and Mediterranean diets. Studies have demonstrated that modest weight loss (5%–10% of body weight) is associated with significant improvements in patient measures of glycemic control, lipids, blood pressure, and other cardiovascular risk factors. Furthermore, a modest weight loss of as little as 4.5 kg can result in reducing the glycated hemoglobin level by approximately 0.5%. Pharmacologic agents, when combined with these approaches, may further augment weight loss. Familiarity with these principles can help physicians provide dietary counseling to their patients with T2DM and obesity. Keywords: medical nutrition therapy; pharmacotherapy; diabetes; obesity

Introduction

Correspondence: Marion L. Vetter, MD, 3535 Market St, Suite 3108, Philadelphia, PA 19104. Tel: 215-360-8965 E-mail: [email protected]

Obesity affects 35.9% of US adults and dramatically increases the risk of type 2 diabetes mellitus (T2DM).1,2 Currently, . two thirds of the 23 million US adults who have T2DM are obese.3,4 In conjunction with dietary management, exercise, and pharmacotherapy, weight loss plays an integral role in the management of T2DM. The term medical nutrition therapy (MNT) was introduced by the American Dietetic Association in 1994 to describe the process of providing individualized nutrition reco­ mmendations to patients that took their lifestyle and treatment goals into account.5 The effectiveness of MNT is well established,6–8 particularly if delivered within 1 year of diagnosis of T2DM.8 However, many patients do not have access to a registered dietitian or a certified diabetes educator. Rates of nutrition counseling from health care providers also remain low, which makes it particularly challenging for many patients to receive adequate education about the dietary management of diabetes.9–11 This article reviews current nutritional recommendations for the management of T2DM and ­obesity, using a case-based approach to illustrate questions that frequently arise during

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dietary counseling. Given the beneficial effects of weight loss on glycemia, behavioral and pharmacologic therapies for weight management (and their subsequent effects on glycemic control) are also briefly discussed.

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Case Study

A 48-year-old African-American woman named D.B. was diagnosed with T2DM approximately 2 years ago. She also has a history of hypertension and hyperlipidemia, for which she takes lisinopril 10 mg once daily and simvastatin 40 mg once daily. She is currently taking metformin 1000 mg twice daily and sitagliptin 100 mg once daily, but her glycated hemoglobin (HbA1c) level is still above target at 8.0%. She checks her blood sugars once a day (in the morning), but has been resistant to more frequent monitoring. Her current weight is 222 lbs and her body mass index is 38.5 kg/m2. When given the option of starting an additional antidiabetes medication, she states that she would like to try dietary modification first. She acknowledges that she has not really paid much attention to her diet in the past and requests guida­nce about carbohydrate intake. Specifically, she asks how many grams of carbohydrates should be consumed daily and whether different types of carbohydrate have differential effects on her blood glucose values.

Recommendations for Macronutrient Intake for Diabetes Carbohydrates

Postprandial glucose levels are primarily determined by the amount of carbohydrate consumed, rather than the type of carbohydrate (ie, sugar, starches, or dietary fiber).12,13 The Recommended Dietary Allowance for carbohydrates is 130 g/d, which is based on the average minimum amount of glucose used by the brain.14 The median intake of carbohydrates for US adults is 220 to 330 g/d for men and 180 to 230 g/d for women, with a recommended acceptable range of 45% to 65% of total caloric intake14; a serving of carbohydrate is typically 15 g (ie, a slice of bread).15 The American ­Diabetes Association (ADA) recommends a consistent distribution of carbohydrates throughout the day, with a target intake of 45 to 60 g/meal.16 Carbohydrate intake may be monitored by counting the number of grams of carbohydrate, using carbohydrate exchanges, or by experience-based estimation.16 Although the Diabetes Control and Complications Trial firmly established the efficacy of carbohydrate counting in type 1 diabetes mellitus (T1DM),17 it is less clear for individuals with T2DM. 140

Types of Carbohydrate Not all types of carbohydrates are fully metabolized to blood glucose.12 Added sugars, including sucrose and high-fructose corn syrup (HFCS), are digested, absorbed, and fully metabolized in a similar manner to naturally occurring mono- and disaccharides. In contrast, # half of the carbohydrate content of dietary fiber is metabolized to glucose as discussed in a later section. Sucrose Restricted sucrose intake was recommended for many years on the assumption that sugars are more rapidly digested and absorbed than starches. However, several randomized trials have found no difference in the glycemic response when sucrose is substituted for equal amounts of other types of carbohydrates in individuals with T1DM or T2DM. 18–22 Although it is possible to substitute sucrose for other sources of carbohydrates,12 it is important to emphasize that consumption of sugars, sugary beverages, and prepared foods with a high sucrose content tend to be high in calories and low in micronutrients (ie, vitamins, minerals, and trace elements). High-Fructose Corn Syrup High-fructose corn syrup, an artificial sweetener that contains 50% fructose and 50% glucose, is typically found in soft drinks, sauces, salad dressings, and many processed foods. Fructose, from either sugar or high-fructose corn syrup, has been implicated in a growing number of health issues over the past decade.23 Several meta-analyses have shown associations between the consumption of sugar-sweetened beverages and obesity24,25 and an increased risk of diabetes,26 but convincing evidence of a direct link remains lacking. Most of these effects have been attributed to the increased caloric intake associated with HFCS-containing foods, rather than HFCS itself.27 In terms of glycemic effects, HFCS has also been shown to decrease insulin sensitivity in both animal and human models.28 Unlike sucrose, fructose does not undergo firstpass metabolism by the liver.28 Instead, fructose is rapidly metabolized by hepatic fructose kinase C, leading to the generation of substrates for de novo lipogenesis. Fructoseinduced lipotoxicity (and other alterations in lipid metabolism) are believed to mediate some of the adverse effects of fructose and HFCS on insulin sensitivity. Although the ADA neither recommends for or against the use of HFCS, many foods that contain this additive tend to be calorie-dense and limited consumption is recommended.27

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Nutritional Management of T2DM and Obesity

Dietary Fiber Dietary fiber is not digested by enzymes in the small intestine and does not contribute to the immediate glucose supply.12 Soluble fibers, which are derived from whole-grain products and fruit (pectin), are fermented in the colon and delay the digestion and absorption of carbohydrates.29,30 Insoluble fiber (such as wheat bran) has bulking action and may improve glycemia by decreasing the production of short chain fatty acids in the colon, which decrease hepatic insulin ­sensitivity.31 The term net carbohydrates has been used to account for the fact that certain carbohydrates are only partially converted to glucose, whereas others are not converted at all (such as insoluble fiber).25 Net carbohydrates can be calculated in food items that contain $ 5 g of fiber/serving by subtracting half of the total number of grams of dietary fiber from the total number of grams of carbohydrates.12 Several randomized controlled trials (RCTs) have evaluated the effect of varying the amount of dietary fiber (while controlling the total amount of dietary carbohydrate) on glycemic control in individuals with metabolic syndrome, T1DM, and T2DM.31–33 High-fiber diets contain approximately 50  g per day, as compared with the average daily intake of 15 g for US adults.32 A recent meta-analysis that included 15 studies reported a nonsignificant mean reduction in fasting blood glucose of 15 mg/dL with a high-fiber diet.34 High-fiber diets also had very m ­ odest effects on HbA1c, resulting in a mean difference in HbA1c  ­reduction of 0.3%, compared with lower fiber diets. Individuals with T2DM are encouraged to consume a variety of fiber-containing foods, such as legumes, fiberrich cereals ($  5  g fiber/serving), fruits, vegetables, and whole grains.16 Similar to recommendations for the general population, the ADA recommends that patients with T2DM consume 14 g of fiber per 1000 kcal.

Case Study (Continued)

D.B. also asks whether fat can adversely affect her blood sugars and whether certain fats are “healthier” than others.

Fat

Dietary fat and free fatty acids (FAs) are known to impair insulin sensitivity and to enhance hepatic glucose production, which may contribute to the development of hyperglycemia.35,36 These adverse effects are thought to be mediated through alterations in cell membrane composition, lipogenic gene expression, and enzyme activity.37 Because individuals with T2DM are at increased risk for coronary heart disease, the amount and type of fat consumed also has important implications for cardiovascular risk reduction.38

Effects of Specific Types of Fat on Cardiovascular Risk Factors and Insulin Sensitivity Saturated FAs Saturated FAs, which are found predominantly in animal products, are one of the principal determinants of low-density lipoprotein cholesterol (LDL-C) levels. Saturated fats have also been found to decrease insulin sensitivity.37 Given the known association of saturated fats and cardiovascular disease in individuals without diabetes mellitus, the ADA ­currently recommends that saturated fat be restricted to , 7% of total energy intake.16 Trans FAs Trans FAs, or trans fats, are formed during the process that converts vegetable oils into semi-solid fats for use in margarines, commercial cooking, and manufacturing processes. Trans fats have been shown to increase both LDL-C and triglyceride levels and to reduce levels of high-density lipoprotein cholesterol (HDL-C).39 In addition to inducing an atherogenic dyslipidemia, trans FAs may also promote inflammatory cytokines and induce endothelial dysfunction. Even a low consumption of trans fats (1%–3% of total caloric intake) appears to substantially increase the risk of coronary heart disease.40–42 Few studies have examined the effects of trans fats on insulin sensitivity, but animal studies suggest that it may impair adipocyte membrane fluidity and insulin sensitivity, possibly through downregulation of the peroxisome proliferator-activated receptor-γ located in adipose tissue.43 The ADA currently recommends minimal intake of trans FAs.16 Polyunsaturated FAs Polyunsaturated FAs include the omega-3 FAs, which are found in fish and canola oil, and the omega-6 FAs, which are found in vegetable oils. A systematic review that included 23 RCTs of omega-3 supplementation (with a mean of 3.5 g/d in a total of 1075 participants with T2DM), found significant reductions in triglyceride levels and very low LDL-C levels in participants.44 Although LDL-cholesterol levels increased slightly with omega-3 supplementation, the increase was not significant in subgroup analyses. Omega-3 supplementation did not have any effect on fasting glucose, insulin, or HbA1c levels. In the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, a large RCT that included 12 536 patients with prediabetes or T2DM who were at increased cardiovascular risk, supplementation of omega-3 FAs did not prevent death or reduce cardiovascular outcomes in patients compared with placebo.45

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Omega-6 FAs may have beneficial effects on insulin sensitivity. A recent randomized controlled crossover study (that included .  50% of participants with obesity and/or T2DM) found that an omega-6 polyunsaturated FA–rich diet improved insulin sensitivity (as assessed by a euglycemic clamp) within 5 weeks compared with a diet that was high in saturated FAs.46 The omega-6 FAs are thought to decrease insulin resistance by acting as a ligand for peroxisome proliferator-activated receptors.47 Monounsaturated FAs Oleic acid, which is contained in olive oil, is the predominant source of monounsaturated fatty acids (MUFAs) in many diets. A recent meta-analysis found that a high-MUFA intake improved fasting glucose, triglyceride, total cholesterol, and HDL-C levels, but not HbA1c or LDL-C concentrations.48 A further discussion of MUFAs is provided in the section called Mediterranean Diets.

Protein

Dietary protein also plays a role in carbohydrate metabolism. Amino acids directly contribute to the de novo synthesis of glucose through gluconeogenesis and also participate in the recycling of glucose carbon via the glucose-alanine cycle.49 Although specific amino acids, including glycine, leucine, and arginine, stimulate insulin release, the net impact of amino acids on glucose homeostasis remains unclear. Discrepant effects of amino acids on glycemia have been reported in the literature.50,51 The range of dietary protein intake appropriate for individuals with T2DM was recently summarized in a meta-analysis and a systematic review.52,53 Discrepant effects of high-protein diets (defined as $ 30% of total energy intake) have been reported on HbA1c levels, but high-protein diets appear to improve $ 1 cardiovascular risk factor.53 The ADA recommends using an individualized approach with respect to protein intake, with patient factors such as cardiometabolic risk and renal function to be taken into consideration.54 The ADA recommends reducing protein intake to between 0.8 to 1.0 g/kg/d during the earlier stages of chronic kidney disease and to 0.8 g/kg/d in patients with more advanced renal dysfunction.16

Approaches to Facilitate Weight Loss The Effects of Weight Loss on Diabetes Mellitus

Most individuals with T2DM are overweight or obese, and weight reduction is associated with significant improvements in insulin sensitivity.55 Weight loss confers the greatest 142

b­ enefit for individuals with prediabetes56,57 or shortly after the onset of T2DM, when insulin resistance is the predominant mechanism of impaired glycemia.58 Additional defects in patients with T2DM include inappropriate suppression of glucagon and a diminished incretin response.59 As the disease progresses and patient β-cell function becomes more impaired, weight loss has a more modest effect on glycemic control.60,61 Bariatric surgery studies provide the most compelling ­evidence for this phenomenon. Despite the very significant weight loss induced by bariatric procedures, individuals with longstanding diabetes (. 5 years in d­ uration), insulin dependence, body mass index  ,  45  kg/m2, and a baseline HbA1c level . 7.9% are less likely to experience diabetes mellitus remission.62,63 Nonetheless, weight loss remains an important component in the treatment of longstanding T2DM in patients and is associated with a significant reduction in the number of antidiabetes medications (many of which tend to promote weight gain) and cardiovascular risk factors.64,65 A modest weight loss of 5% to 10% of body weight confers significant improvements in glycemic control, lipemia, and blood pressure.65 For every 4.5-kg loss in weight, patient HbA1c levels may be reduced by 0.5%.66

Macronutrient Distribution

The optimal distribution of dietary macronutrients (ie, carbo­ hydrate, protein, and fat) for the management of diabetes mellitus and weight loss has not been established.16 Isocaloric diets (ie, equivalent in caloric content) of varying macronutrient composition have been found to induce similar weight loss (regardless of the distribution of carbohydrates, fat, and protein),67 and no particular dietary approach has been found to be more efficacious than others in terms of promoting ­optimal glycemic control or weight loss in patients.52 An energyreduced diet should be recommended to facilitate weight loss. Individualization of the macronutrient composition depends on the metabolic status of the patient (eg, lipid profile and renal function) or food preferences.16 For most patients, the optimal diet is the one to which individuals have the best adherence.68

Approaches to Weight Management Lifestyle Modification

Patient lifestyle modification, which encompasses diet, physical activity, and behavioral therapy, serves as the cornerstone for any dietary approach to diabetes mellitus and weight management.69 Common techniques include self-monitoring (keeping records of food intake and physical activity), modifying cues that elicit unwanted eating (stimulus control),

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Nutritional Management of T2DM and Obesity

problem solving, and relapse prevention. Self-monitoring increases individuals’ awareness of their behavior (such as overeating), the circumstances that trigger the behavior, and patterns of behavior.70 Food records also serve to increase awareness of the calorie content and portion sizes of commonly consumed foods, which may account for the finding that maintenance of daily food records is associated with greater initial weight loss.71 Lifestyle modification programs typically induce a weight loss of 8% to 10% in the first 6 to 12 months, resulting in clinically important health benefits.71 A 5% reduction in body weight has been associated with a 0.5% decrease in patient HbA1c levels.72 Unfortunately, most individuals regain one third of the weight loss during the next year and return to their baseline weight within 3 to 5 years.73 Weight regain can be minimized by frequent self-monitoring,74 as well as with ongoing contact that is delivered face to face, via the Internet, or by telephone.75 The Look AHEAD (Action for Health in Diabetes) study, an RCT that included 5145 overweight participants with T2DM, was designed to assess whether weight reduction (achieved through lifestyle modification) also reduced cardiovascular morbidity and mortality.76 Participants were randomly assigned to either of 2 conditions: intensive lifestyle intervention (ILI), which included group and individual meetings; or diabetes mellitus support and education. In September 2012, the Look AHEAD trial was halted early, with a median of 9.6 years of follow-up, on the basis of futility.77 Although weight loss was greater in the ILI group than in the support and education group throughout the study (8.6% vs 0.7% at 1 year; 6.0% vs 3.5% at study end), it did not reduce the rate of cardiovascular events.78 However, ILI produced greater reductions in HbA1c levels and greater initial reductions in sleep apnea,79 urinary incontinence,80 and depression,81 and improvements in quality of life,82 physical functioning,83 and mobility.84 The study will continue as an observational trial to identify longer-term effects of the intervention.

Case Study (Continued)

Several friends and family members have recommended a variety of diets to D.B., including the South Beach diet, the Eat Right for Your Blood Type diet, the Scarsdale diet, and the cabbage soup diet. She asks if 1 of the diets is “optimal” to help regulate her blood sugar levels.

Dietary Approaches

A variety of dietary approaches can be used to meet the recommendations provided above.

Low-Carbohydrate Diets

Multiple studies have investigated the effects of a reduced carbohydrate intake on glycemia, weight, and other metabolic outcomes. However, efforts to compare findings from studies have been limited by the lack of a consistent definition of low-carbohydrate intake. Low-carbohydrate diets typically include an absolute carbohydrate intake of 50 to 100 g daily,85,86 or less than 40% of total calories derived from carbohydrates.87 Most low-carbohydrate diets permit unrestricted intake of fat and calories, although unsaturated fats are emphasized rather than saturated or trans fats.86 Low-carbohydrate diets are associated with more rapid and greater short-term weight loss than low-fat diets in both individuals with and without T2DM.88–91 However, longer duration studies (# 12 months) have consistently shown that weight loss is not maintained with a low-carbohydrate diet, and by 12 months weight change is equivocal between dietary groups.92–95 Longer term studies (# 4 years) show no detrimental effects on cardiovascular risk factors.96–98 A recent meta-analysis that included 23 RCTs of 6-month duration or more found that low-carbohydrate and low-fat diets were equally effective at reducing body weight and waist circumference.99 Low-carbohydrate diets have also been associated with short-term improvements in glycemic parameters in individuals with diabetes mellitus. Two meta-analyses100,101 and a recent ADA systematic review102 reported greater reductions in HbA1c levels and lower doses of antidiabetes medications in individuals with T2DM who were assigned to a low-carbohydrate diet, compared with conventional higher carbohydrate diets. However, the beneficial effects on improved glycemic control generally did not persist after 1 year and were likely attributable to weight loss.102 Limitations of these studies include significant loss to follow-up (many had completion rates , 70%), small samples sizes, and significant heterogeneity with respect to carbohydrate intake. The ADA acknowledges that lower carbohydrate diets are probably effective in the management of T2DM, but cautions that such diets may eliminate foods that are important sources of energy, fiber, vitamins, and minerals.16,103 Additionally, the ADA recommends that lipid profile, renal function, and protein intake (in patients with nephropathy) be monitored in patients who follow a low-carbohydrate diet.103

Low-Glycemic Diets

The physical properties of food, the rate of intestinal hydrolysis, and other dietary factors also affect the glycemic response.12 The glycemic index (GI) is a ranking that was

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developed to compare the postprandial glucose response of different carbohydrates.104 The GI is defined as the incremental increase in plasma glucose (above baseline) that is observed 2 hours after ingesting a known amount of carbohydrate of an individual food. This value is then compared with the response to a reference food (glucose or white bread) containing an equivalent amount of carbohydrate. High-GI foods, such as highly processed, starchy foods, tend to induce a higher peak glucose level than low-GI foods, which include lentils, beans, oats, and non-starchy vegetables. The glycemic load is the amount of carbohydrate multiplied by its GI. Use of the GI in clinical practice remains controversial. The GI of foods can be substantially altered by the presence of other macronutrients in the meal or by cooking methods.12 Moreover, the GI for any particular food is subject to significant variation, both within and between individuals.105 These factors limit the applicability of the GI in the real-world setting. Studies that have investigated the effects of low- versus high-GI diets on indices of glycemic control have reported discrepant findings. A recent Cochrane review that included 402  individuals with T1DM and T2DM reported significant improvements in glycemic control on a low-GI diet, as compared with a high-GI diet.106 Low-glycemic diets resulted in a mean pooled HbA1c level reduction of 0.5%. However, many of the studies included in the systematic review were short term, ranging from 4 to 6 months, and included small numbers of participants. More recently, Jenkins and colleagues107 found, in a 6-month RCT that compared a low-glycemic-index diet and a high-fiber cereal diet among 210 participants with T2DM, that HbA1c levels were significantly decreased in the low-glycemic group compared with the high-cereal fiber group (−0.5% vs −0.2%; P , 0.001), even after controlling for change in body weight. High-density lipoprotein cholesterol also increased in the low-glycemic-index group, whereas it decreased in the high-cereal fiber group (P = 0.005). Two relatively long-term studies found no difference in weight loss or HbA1c levels at 12 months between participants with T2DM assigned to a low-glycemic diet versus an ADA diet,108 or to diets of varying carbohydrate content.94

Fat-Restricted Diets

Low-fat diets, which contain  , 30% of calories from fat, have been conventionally endorsed as a dietary strategy for the management of T2DM (and have often served as the control group in many of the dietary studies reviewed in this article). Low-fat diets, in combination with caloric ­reduction, can induce weight loss and may help to reduce CVD risk 144

in ­individuals with T2DM.109 In a systematic review that included 5 studies evaluating low-fat diets versus moderate-fat or low-carbohydrate diets (although not necessarily mutually exclusive) in individuals with T2DM, greater weight loss was achieved in general in the low-fat groups.110 Although the patient level of HbA1c was reported in some studies, the improvements were very slight, and the quality of the trials included were judged to be at high risk of being biased. Many of the included studies were limited by small sample size, heterogeneity in fat intake, and differences in fat quality.

Mediterranean Diets

Mediterranean diets emphasize the moderate consumption of fats (30%–40% of daily energy intake, primarily from MUFAs such as olive oil), legumes, fruits, vegetables, nuts, whole grains, fish, and moderate consumption of wine. Many studies have demonstrated that a Mediterranean diet pattern has beneficial effects on cardiovascular health,111–113 and recent research has focused on its effect on diabetes mellitus. Several RCTs have investigated the effects of a Mediterranean diet, as compared with other commonly used diets, on glycemic parameters in participants with T2DM.96,114–116 In the Prevención con Dieta Mediterránea (PREDIMED) study, Estruch and colleagues114 randomly assigned 772 participants at high risk for cardiovascular disease (including 421 with T2DM) to 1 of 2 Mediterranean diets (supplemented with either 1 L/week of virgin olive oil or 30 g/d of tree nuts) or to a low-fat diet for 3 months. Compared with the low-fat diet, the Mediterranean diets were associated with greater reductions in fasting glucose and lipid levels, insulin resistance, blood pressure, and inflammatory markers. Longer duration studies have also shown a sustained benefit on glycemic control. Esposito and colleagues116 randomly assigned 215 participants with newly diagnosed T2DM to a Mediterranean or low-fat diet for 52 weeks. Significant reductions in fasting glucose and HbA1c levels were observed in the Mediterranean group compared with the low-fat group (−21 mg/dL and −0.6%, respectively). Similarly, Shai and colleagues96 reported a higher decrease in fasting plasma glucose in a subsample of participants with diabetes mellitus who followed a Mediterranean diet compared with patients following a low-carbohydrate or low-fat diet. A recent meta-analysis that included a total of 20 RCTs (total of 3073 individuals with T2DM) found that lowcarbohydrate, low-GI, Mediterranean, and high-protein diets were effective in improving glycemic indices and various markers of cardiovascular risk in individuals with T2DM.

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Nutritional Management of T2DM and Obesity

Per the most recent ADA guidelines, any of these approaches may effectively enhance glycemic control and weight loss in patients over the short term (# 2 years).103

Case Study (Continued)

D.B. asks whether any supplements would be helpful in regulating her blood sugars. She also mentions that she has heard that cinnamon has some glucose-lowering effects.

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Chromium, Antioxidants, and Supplements

Oxidative stress is involved in the pathogenesis of both cardio­ vascular disease and diabetes123 and the protective role of

c­ ertain supplements and antioxidants has garnered ­considerable ­interest. Selected supplements are reviewed in Table 1. Given the lack of clear evidence and the fact that a ­balanced diet provides adequate levels of essential vitamins and minerals, both the ADA and the American Heart Association (AHA) recommend against routine supplementation of antioxidants or the use of herbal products.12,122

Case Study (Continued)

Initially, D.B. is very motivated and records her food intake and activities daily. She also reduces her portion sizes and tries to make better food choices. She loses 10 lbs (4.5% weight loss) during the next 3 months and her HbA1c level decreases

Table 1.  Effects of Selected Supplements on Glycemic Control in Patients With T2DM Supplement

Purported effects

Evidence

Limitations of studies

Recommendations for use

Chromium picolinate117

May potentiate the action of insulin by augmenting its signaling pathway

May play a role in insulin sensitivity via the induction of the P13K/AKT pathway (mediator of insulin signaling and glucose disposal)

Vitamin D119

May stimulate postprandial insulin release

Systematic review and meta-analysis (4 studies; N = 233) found no significant change in HbA1c levels with vitamin D supplementation

Vitamin E120

May have a protective effect on islet β-cells by reducing cytotoxicity mediated by cytokines and their products and possibly by enhancing insulin action

Systematic review (8 RCTs; N = 418) found no beneficial effect of vitamin E supplementation on HbA1c levels (WMD -0.17%; 95% CI; -0.49 to 0.16)

Cinnamon121

Cinnamaldehydea may exert insulinotropic effects

Fenugreek122

May delay gastric emptying and slow CHO absorption; glucose transport may be inhibited because of fiber content

Systematic review and meta-analysis (10 RCTs; N = 543) found no significant effect of cinnamon on HbA1c levels; cinnamon was associated with significant reductions in total cholesterol, LDL-C, triglyceride, and FPG levels (WMD –25 mg/dl; 95% CI –40.5 to –8.7 mg/dL) Meta-analysis (4 RCTs; N = 51) found beneficial effects on FPG and PPGb

Considerable heterogeneity in study populations and in the range of chromium dose/ formulation; short duration of studies Considerable heterogeneity in study populations and in the range of zinc dose/formulation; confounding effects of other concomitant medications; short duration of studies Considerable heterogeneity in study populations and in the range of vitamin D dose/ formulation; small sample sizes; loss to follow-up Considerable heterogeneity in study populations, duration of T2DM, level of glycemic control, and antioxidant status; small sample sizes; confounding effects of concomitant medications noted Considerable heterogeneity in study populations and in the range of cinnamon dose/ formulation; short duration of studies

Not recommended by the ADA

Zinc118

Systematic review (7 studies) found no significant effect of chromium supplementation on HbA1c levels (WMD -0.33%; 95% CI; -0.72 to 0.06) Meta-analysis (8 studies; N = 408) reported a trend toward significant reduction in HbA1c levels (–0.64%; P = 0.072)

Considerable heterogeneity in study populations; generally poor quality studies with very small sample size

Not recommended by the ADA

Not recommended by the ADA

Not recommended by the ADA

Not recommended by the ADA

Not recommended by the ADA

Active ingredient in cinnamon. Pooled estimates were not provided. Abbreviations: ADA, American Diabetes Association; CHO, carbohydrate; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; PPG, postprandial glucose; RCT, randomized clinical trial; T2DM, type 2 diabetes mellitus; WMD, weighted mean difference. a

b

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146

Dose and dosing recommendations

Selective 5-HT2c receptor agonists Lorcaserin • Start 10 mg BID and (Belviq) re-evaluate after 12 wks. If decrease in weight is , 5%, discontinue drug. Adrenergic agents Phentermine •  15, 30, or 37.5 mg QD (Adipex, Suprenza)

• 120 mg TID with meals (or OTC as Alli in 60 mg dose). • Recommend restricting fat intake to , 30% of calories from fat throughout the day and , 15 g per meal. • Recommend taking a daily multivitamin containing fatsoluble vitamins $ 2 hours before or after orlistat. Combination agents Phentermine and • Start at 3.75/23 mg QD topiramate for 14 d, and increase to (Qsymia) 7.5/46 mg if tolerated. If weight loss of $ 3.0% is not achieved, the drug can be discontinued or dose can increase to 15/92 mg QD. If $ 5% weight loss is not achieved after an additional 12 wks of treatment, discontinue drug.

Lipase inhibitors Orlistat (Xenical, Alli)

Nonproprietary drug name (proprietary name)

•  0.9% reduction129

•  Effect not reported

• 3.2 kg placebosubtracted weight loss at 52 wks129

• 3.6 kg placebosubtracted weight loss in studies ranging from 2–24 wks130

•  Increased BP • Tachycardia • Palpitations • Insomnia

• Headache •  Mood disturbances • Memory and attention disturbances

•  0.2–0.4% reduction128 • Headache • Paresthesias •  Dry mouth • Constipation • Upper respiratory tract infections • Nasopharyngitis • Mood and sleep disturbances • Memory and attention disturbances •  Elevated CR level •  Metabolic acidosis

• 6.7–8.8 kg placebosubtracted weight loss at 52 wks128

•  Fatty and oily stool •  Fecal urgency •  Fecal incontinence • Decreased absorption of fat-soluble vitamins

Side effects

•  0.5% reduction127

Corresponding change in HbA1c levels

• 2.0 kg placebosubtracted weight loss in studies ranging from 12–57 wks127

Effects on weight

FDA recommendations for weight loss use

•  Cardiovascular disease •  Uncontrolled hypertension • Hyperthyroidism

• Concurrent use of other serotonergic or antidopaminergic agents • Pregnancy

•  Cardiovascular disease •  Uncontrolled hypertension • Hyperthyroidism • Glaucoma •  Pregnancy (fetal toxicity)

• Approved for short-term weight loss (, 12 weeks)

• Approved for long-term weight loss

• Approved for long-term weight loss

• Can reduce the absorption of amiodarone, • Approved for levothyroxine, and cyclosporine long-term weight • Can potentiate effect of warfarin (use with loss caution in patients taking these medications)

Contraindications (absolute and relative)

Table 2.  Selected Pharmacotherapy for Obesity Evaluated in Clinical Trials and Antidiabetic Medications That Potentially Promote Weight Loss

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• 10, 20, 40 mg QD (recommend taking in the morning to avoid insomnia)

•  75 mg QD

•  200 or 400 mg QD

 Acarbose (Precose)

25 mg with meals

Antidiabetic medications Metformin •  5 00, 850, or 1000 mg (Glucophage) QD or BID

Zonisamide

Antiepileptic medications Topiramate • 96–200 mg daily (dose (Topamax) used in clinical trials for weight loss)

SSRIs Fluoxetine (Prozac)

Diethylpropion

•  Effect not reported

•  0.4% reduction132

•  0.8% reduction131

•  N  ot significantly •  1.0% reduction134 different than placebo in trials ranging from 12–32 wks134 •  1.0 kg placebo•  0.6% reduction135 subtracted weight loss in trials ranging from 24–52 wks in patients with DM concurrently treated with metformin and a sulfonylurea135

• 0.4 and 3.3 kg placebo-subtracted weight loss for low and high dose at 52 wks, respectively (individuals with DM excluded)133

• 5.3 kg placebosubtracted weight loss in studies ranging from 16–44 wks132

• 4.3 kg placebosubtracted weight loss in studies ranging from 8–26 wks131

• 3.0 kg placebo•  Effect not reported subtracted weight loss in trials ranging from 6–52 wks (individuals with DM excluded)130,131

• Nausea •  Abdominal pain • Loose stools or diarrhea • Diarrhea •  Abdominal pain • Flatulence

• Paresthesias • Headache • Somnolence • Difficulty with memory and concentration • Constipation •  Increased nervousness • Sweating • Tremors • Fatigue • Insomnia • Hypersomnia • Gastrointestinal side effects

• Insomnia • Sweating •  Dry mouth • Constipation

• Dizziness • Headache • Insomnia • Restlessness •  Mild increase in BP • Palpitations •  Mild tachycardia • Gastrointestinal side effects

•  Concurrent use of MAOIs • Renal impairment (not recommended if serum Cr level . 1.4 mg/dL for women and . 1.5 mg/dL for men) • Renal impairment (not recommended if serum Cr level . 2.0 mg/dL)

•  Hypersensitivity to sulfonamides

• Glaucoma •  Use with caution in hepatic impairment

•  Concurrent use of MAOIs

•  Cardiovascular disease •  Severe hypertension • Hyperthyroidism • Glaucoma •  Concurrent use of MAOIs

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(Continued )

• Approved for the treatment of T2DM

• Approved for the treatment of T2DM

• Not approved for weight loss (used off-label)

• Not approved for weight loss (used off-label)

• Not approved for weight loss (used off-label)

• Not approved for weight loss (used off-label)

Nutritional Management of T2DM and Obesity

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148 • Nausea • Hypoglycemia with concomitant use of other hypoglycemia agents • Insomnia •  Dry mouth • Constipation • Pancreatitis • Nausea • Hypoglycemia (especially in patients treated concurrently with insulin)

•  Hyperkalemia •  Genitourinary infection

•  0.3% reduction138

•  0 .70%–0.95% reduction140

Side effects

•  0 .6%–1.2% reduction from trials of exenatide and liraglutide137

Corresponding change in HbA1c levels

•  A  pproved for the treatment of T2DM

•  A  pproved for the treatment of T2DM

FDA recommendations for weight loss use

•  Absence of long-term efficacy and safety data •  A  pproved for •  Discontinue canagliflozin if eGFR is the treatment persistently , 45 mL/min/1.73 m2 of T2DM

•  U  se with caution in combination with glucose-lowering agents and/or insulin

•  U  se with caution in combination with glucose-lowering agents and/or insulin. •  Family or personal history of C cell thyroid tumors (ie, medullary thyroid cancer) or MEN-2

Contraindications (absolute and relative)

Abbreviations: BID, twice daily; BP, blood pressure; Cr, creatinine; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; MAOI, monoamine oxidase inhibitor; MEN-2, multiple endocrine neoplasia-2; OTC, over the counter; QD, once daily; SSRI, selective serotonin reuptake inhibitor; SGLT-2, sodium-glucose cotransporter-2; TID, 3 times daily; T2DM, type 2 diabetes mellitus.

SGLT-2 inhibitors Canagliflozin (Invokana)

Pramlintide (Symlin)

•  E xenatide (immediate •  2 .0 kg placeborelease): 5–10 μg injected subtracted weight subcutaneously BID loss in studies •  E xenatide (extended ranging from release): 2 mg once per wk 20–52 wks (pooled •  L iraglutide: 0.6–1.8 mg estimates of trials injected subcutaneously QD of exenatide and (trials investigating liraglutide liraglutide)136 to treat obesity have used 3.0 mg QD) •  1 20–150 μg injected •  2 .2 kg placebo2–3 times daily (higher subtracted weight doses used in studies for the loss in studies treatment of obesity) ranging from 16–52 wks in patients with DM who concurrently received insulin138 •  1 00–300 mg QD before first •  2 –3 kg placebomeal subtracted weight loss in 26-wk monotherapy trial139

GLP-1 receptor agonists (Byetta, Bydureon,Victoza)

Effects on weight

Dose and dosing recommendations

Nonproprietary drug name (proprietary name)

Table 2.  (Continued )

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Nutritional Management of T2DM and Obesity

by 0.4%. However, D.B. soon tires of daily monitoring and stops recording her food intake. During the next month, she regains 5 lbs. When D.B. returns for follow-up, she asks if she would be a candidate for weight loss medication.

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Pharmacotherapy for Weight Loss

Weight loss, which plays an integral role in diabetes mellitus management, has profound effects on insulin sensitivity. In order to maximize initial weight lost and minimize weight regain in patients, pharmacotherapy can be used in combination with continued lifestyle modification. Health care providers should also be mindful of the potential weight effects when selecting pharmacologic treatments for diabetes mellitus.124 Several agents, including glucagon-like peptide-1, mimetics, and sodium glucose cotransporter 2 inhibitors, promote weight loss. In contrast, sulfonylureas, meglitinides, thiazolidinediones, and insulin tend to induce weight gain. A more detailed discussion of the weight effects of the ­various classes of antidiabetes medications is beyond the scope of this article, but is discussed elsewhere.124 At present, only 3  medications—orlistat, phentermine/ topiramate, and lorcaserin—are approved by the US Food and Drug Administration (FDA) for long-term weight loss (Table 2). All of these medications, when combined with lifestyle modification, induced losses of approximately 5% to 10% of initial patient body weight in 1- to 2-year trials.125–128 These losses were associated with significant improvements in seve­ ral metabolic outcomes and CVD risk factors in patients.

Conclusion

Medical nutrition therapy is an integral component in the management of diabetes mellitus. Current nutrition recommendations favor a flexible and individualized approach, with an emphasis on the total number of carbohydrates consumed. Weight loss plays an important adjunct role, and studies have demonstrated that modest weight loss (5%–10% of body weight) is associated with significant improvements in glycemic and lipid parameters, decreased insulin resistance, and reduced blood pressure. Optimal macronutrient distribution and dietary patterns for the management of T2DM and obesity have not been established, and low-carbohydrate, low-fat, Mediterranean, or low-GI diets may be effective. Behavioral modification, with or without pharmacotherapy, can be used to facilitate weight loss in patients.

Conflict of Interest Statement

Marion L. Vetter, MD, RD, has been employed by BristolMyers Squibb in research on pharmacotherapy for patients

with diabetes mellitus. Anastassia Amaro, MD, and Sheri Volger, RD, MS, have no conflicts of interest to disclose.

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© Postgraduate Medicine, Volume 126, Issue 1, January 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Nutritional management of type 2 diabetes mellitus and obesity and pharmacologic therapies to facilitate weight loss.

Diet plays an integral role in the treatment of type 2 diabetes mellitus (T2DM). Unfortunately, many patients with T2DM do not have access to a regist...
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