DM Treatment

All rights reserved: reproduction in whole or part not permitted.
All permission requests to reproduce or adapt published

material must be directed to the journal office in Conshohocken, PA, no other persons or offices are authorized to act on our behalf.
Reprints:
reprints@postgradmed.com permissions@postgradmed.com
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
Therapiesto Facilitate Weight Loss
DOI: 10.3810/pgm.2014.01.2734
Marion L. Vetter, MD, RD 1,2

Anastassia Amaro, MD 2
Sheri Volger, RD, MS 2,3
1
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.,
Kingof Prussia, PA
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 4.5kg 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: Marion.Vetter@uphs.upenn.edu
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 23million 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,68 particularly if delivered within
1year 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.911 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
Postgraduate Medicine, Volume 126, Issue 1, January 2014, ISSN 0032-5481, e-ISSN 1941-9260 139
ResearchSHARE: www.research-share.com Permissions: permissions@postgradmed.com Reprints: reprints@postgradmed.com
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.
Vetter etal
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.
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 10mg once daily and simvastatin 40mg
once daily. She is currently taking metformin 1000mg twice
daily and sitagliptin 100mg 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 222lbs and her body mass index is 38.5kg/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
130g/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 330g/d for men and 180 to
230g/d for women, with a recommended acceptable range
of 45% to 65% of total caloric intake14; a serving of carbohydrate is typically 15g (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 60g/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. 1822
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
Postgraduate Medicine, Volume 126, Issue 1, January 2014, ISSN 0032-5481, e-ISSN 1941-9260
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 $5g of fiber/serving by subtracting half
of the total number of grams of dietary fiber from the total
number of grams of carbohydrates.12
Several randomized controlled trials (RCTs) have evaluated the effect of varying the amount of dietary fiber (while
controlling the total amount of dietary carbohydrate) on glycemic control in individuals with metabolic syndrome, T1DM,
and T2DM.3133 High-fiber diets contain approximately 50 g
perday, as compared with the average daily intake of 15g for
US adults.32 A recent meta-analysis that included 15studies
reported a nonsignificant mean reduction in fasting blood glucose of 15mg/dL with a high-fiber diet.34 High-fiber diets also
had very m
odest effects on HbA1c, resulting in a mean difference
in HbA1c reduction of 0.3%, compared with lower fiber diets.
Individuals with T2DM are encouraged to consume a
variety of fiber-containing foods, such as legumes, fiberrich cereals ($ 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 14g of fiber per 1000kcal.
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.4042
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- 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
23RCTs of omega-3supplementation (with a mean of 3.5g/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-3supplementation, the increase was not
significant in subgroup analyses. Omega-3supplementation
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
Vetter etal
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 FArich 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
Afurther 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 1.0g/kg/d during the earlier
stages of chronic kidney disease and to 0.8g/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 enefitfor 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 -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),
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 12months, 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.
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
100g 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.8891 However, longer
duration studies (#12months) have consistently shown
that weight loss is not maintained with a low-carbohydrate
diet, and by 12months weight change is equivocal between
dietary groups.9295 Longer term studies (#4 years) show
no detrimental effects on cardiovascular risk factors.9698
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
Vetter etal
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 2hours 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 6months, 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 210participants 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 12months 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 5studies 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,111113
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.96,114116 In
the Prevencin con Dieta Mediterrnea (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 1L/week of virgin olive oil or 30g/d of tree nuts) or to
a low-fat diet for 3months. 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
(21mg/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 3073individuals 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.
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
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.
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 Table1.
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
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 10lbs (4.5% weight
loss) during the next 3months 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

(4studies; N = 233) found no significant
change in HbA1c levels with vitamin D
supplementation
Vitamin E120
May have a protective effect

on islet -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
ofstudies
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
in study populations, duration
of T2DM, level of glycemic
control, and antioxidant status;
small sample sizes; confounding
effects of concomitant
medications noted
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)
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
146
Dose and dosing

recommendations
Selective 5-HT2c receptor agonists

Lorcaserin
Start 10 mg BID and
(Belviq)
re-evaluate after 12 wks.
Ifdecrease 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 14d, and increase to
(Qsymia)
7.5/46mg 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

loss in studies
ranging from
224wks130
Increased BP
Tachycardia
Palpitations
Insomnia
Headache
Mood disturbances
Memory and attention
disturbances
0.20.4% reduction128 Headache

Paresthesias
Dry mouth
Constipation
Upper respiratory tract
infections
Nasopharyngitis
Mood and sleep
disturbances
Memory and attention
disturbances
Elevated CR level
Metabolic acidosis
6.78.8 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

loss in studies
ranging from
1257wks127
Effects on weight
FDA
recommendations
for weight loss use
Cardiovascular disease
Uncontrolled hypertension
Hyperthyroidism
Concurrent use of other serotonergic or

antidopaminergic agents
Pregnancy
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
Vetter etal
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
96200 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
1232 wks134
1.0 kg placebo 0.6% reduction135
subtracted weight
loss in trials ranging
from 2452 wks in
patients with DM
concurrently treated
with metformin and
asulfonylurea135
0.4 and 3.3 kg

placebo-subtracted
weight loss for low
and high dose at
52wks, respectively
(individuals with
DMexcluded)133

loss in studies
ranging from
1644wks132

lossin studies
ranging from
826wks131
3.0 kg placebo Effect not reported

subtracted weight
loss in trials ranging
from 652wks
(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
Severe hypertension
Hyperthyroidism
Glaucoma
(Continued)
Approved for
the treatment
ofT2DM
Approved for
the treatment
ofT2DM
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)
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
thetreatment
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
ofT2DM
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)
orMEN-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): 510 g injected
subtracted weight
subcutaneously BID
loss in studies
E xenatide (extended
ranging from
release): 2 mg once per wk
2052wks (pooled
L iraglutide: 0.61.8 mg
estimates of trials
injected subcutaneously QD
of exenatide and
(trials investigating liraglutide
liraglutide)136
to treat obesity have used
3.0mg QD)
1 20150 g injected
2 .2 kg placebo23 times daily (higher
subtracted weight
doses used in studies for the
loss in studies
treatment of obesity)
ranging from
1652wks in
patients with DM
who concurrently
received insulin138
1 00300 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)
Vetter etal
by 0.4%. However, D.B. soon tires of daily monitoring and

stops recording her food intake. During the next month, she
regains 5lbs. When D.B. returns for follow-up, she asks if
she would be a candidate for weight loss medication.
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 2inhibitors,
promote weight loss. In contrast, sulfonylureas, meglitinides,
thiazolidinediones, and insulin tend to induce weight gain.
Amore 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 medicationsorlistat, phentermine/
topiramate, and lorcaserinare approved by the US Food
and Drug Administration (FDA) for long-term weight loss
(Table2). 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.125128 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.
References
1. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity
and trends in the distribution of body mass index among US adults,
19992010. JAMA. 2012;307(5):491497.
2. Geiss LS, Pan L, Cadwell B, Gregg EW, Benjamin SM, EngelgauMM.
Changes in incidence of diabetes in U.S. adults, 19972003. Am J Prev
Med. 2006;30(5):371377.
3. Kramer H, Cao G, Dugas L, Luke A, Cooper R, Durazo-ArvizuR.
Increasing BMI and waist circumference and prevalence of obesity among adults with type 2 diabetes: the National Health and
Nutrition Examination Surveys. J Diabetes Complications. 2010;
24(6):368374.
4. Centers for Disease Control and Prevention. National diabetes fact
sheet: national estimates and general information on diabetes and
prediabetes in the United States, 2011. Atlanta, GA: U.S. Department
of Health and Human Services, Centers for Disease Control and
Prevention, 2011.
5. Franz MJ, Boucher JL, Green-Pastors J, Powers MA. Evidence-based
nutrition practice guidelines for diabetes and scope and standards of
practice. J Am Diet Assoc. 2008;108(4suppl 1):S52S58.
6. Franz MJ, Monk A, Barry B, etal. Effectiveness of medical nutrition
therapy provided by dietitians in the management of non-insulindependent diabetes mellitus: a randomized controlled trial. J Am Diet
Assoc. 1995;95(9):10091017.
7. Miller CK, Edwards L, Kissling G, Sanville L. Nutrition education
improves metabolic outcomes among older patients with diabetes
mellitus: results from a randomized controlled trial. Prev Med. 2002;
34(2):252259.
8. Franz M, Powers MA, Leontos C, etal. The evidence for medical nutrition therapy for type 1 and type 2 diabetes in adults. J Am Diet Assoc.
2010;110(12):18521889.
9. Peek ME, Tang H, Alexander GC, Chin MH. National prevalence of
lifestyle counseling or referral among African-Americans and whites
with diabetes. J Gen Intern Med. 2007;23(11):18581864.
10. Meigs JB, Stafford RS, Randall S. Cardiovascular disease prevention
practices by U.S. physicians for patients with diabetes. J Gen Intern
Med. 2000;15(4):220228.
11. Marrero DG, Kraft SK, Mayfield J, Wheeler ML, Fineberg N. Nutrition
management of type 2 diabetes by primary care physicians: reported
use and barriers. J Gen Intern Med. 2000;15(11):818821.
12. Wheeler ML, Pi-Sunyer FX. Carbohydrate issues: type and amount.
J Am Diet Assoc. 2008;108(4suppl 1):S34S39.
13. Kelley DE. Sugars and starch in nutritional management of diabetes
mellitus. Am J Clin Nutr. 2003;78(4):858S864S.
14. Institute of Medicine, Food and Nutrition Board. Dietary Reference
Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol,
Protein, and Amino Acids. Washington, DC: National Academies Press;
2005.
15. Kulkarni KD. Carbohydrate counting: a practical meal-planning option
for people with diabetes. Clin Diabetes. 2005;23(3):120122.
16. American Diabetes Association. Nutrition recommendations and interventions for diabetes. A position statement of the American Diabetes
Association. Diabetes Care. 2008;31(suppl 1):S61S78.
17. Anderson EJ, Richardson M, Castle G, etal. Nutrition interventions
for intensive therapy in the Diabetes Control and Complications Trial.
The DCCT Research Group. J Am Diet Assoc. 1993;93(7):768772.
18. Brand-Miller JC, Stockmann K, Atkinson F, Petocz P, Denyer G.
Glycemic index, postprandial glycemia, and the shape of the curve
in healthy subjects: an analysis of more than 1000 foods. Am J Clin
Nutr. 2009;89(1):97105.
19. Abraira C, Derler J. Large variations of sucrose in constant carbohydrate diets in type II diabetes. Am J Med. 1988;84(2):193200.
Vetter etal
20. Rickard KA, Cleveland JF, Loghmani ES, Fineberg NS, FreidenbergGR.
Similar glycemic responses to high vs moderate sucrose-containing
foods in test meals for adolescents with type 1 diabetes and fasting
euglycemia. J Am Diet Assoc. 2001;101(10):12021205.
21. Bantle JP, Swanson JE, Thomas W, Laine DC. Metabolic effects of
dietary sucrose in type II diabetic subjects. Diabetes Care. 1993;
16(9):13011305.
22. Malerbi DA, Paiva ES, Duarte AL, Wajchenberg BL. Metabolic effects
of dietary sucrose and fructose in type 2 diabetic subjects. Diabetes
Care. 1996;19(11):12491256.
23. Bray GA. Potential health risks from beverages containing fructose
found in sugar or high fructose corn syrup. Diabetes Care. 2013;
36(1):1112.
24. Vartanian LR, Schwartz MB, Brownell KD. Effects of soft drink
consumption on nutrition and health: a systematic review and metaanalysis. Am J Public Health. 2007;97(4):667675.
25. Olsen NJ, Heitmann BL. Intake of calorically sweetened beverages
and obesity. Obes Rev. 2009;10(1):6875.
26. Malik VS, Popkin BM, Bray GA, Despres JP, Willett WC, Hu FB.
Sugar-sweetened beverages and risk of metabolic syndrome and type 2
diabetes: a meta-analysis. Diabetes Care. 2010;33(11):24772483.
27. Franz M. High-fructose corn syrup. Whats all the fuss about? Diabetes
Self Manag. 2011;28(3):3334, 3637.
28. Stanhope KL, Schwarz JM, Havel PJ. Adverse metabolic effects of
dietary fructose: results from recent epidemiological, clinical, and
mechanistic studies. Curr Opin Lipidol. 2013;24(3):198206.
29. Anderson JW, Baird P, Davis RH, etal. Health benefits of dietary fiber.
Nutr Rev. 2009;67(4):188205.
30. Steemburgo T, DallAlba V, Almeida JC, Zelmanovitz T, Gross JL,
de Azevedo MJ. Intake of soluble fibers has a protective role for the
presence of metabolic syndrome in patients with type 2 diabetes. Eur
J Clin Nutr. 2009;63(1):127133.
31. Weickert MO, Roden M, Isken F, etal. Effects of supplemented isoene
rgetic diets differing in cereal fiber and protein content on insulin sensitivity in overweight humans. Am J Clin Nutr. 2011;94(2):459471.
32. ONeil C, Nicklas T, Zanovec M, Cho S. Fiber consumption and
metabolic syndrome in adults: results from NHANES 19992004.
FASEB J. 2009;23(1):LB491.
33. Chandalia M, Garg A, Lutjohann D, von Bergmann K, GrundySM,
B rinkley LJ. Beneficial effects of high dietary fiber intake in
patients withtype 2 diabetes mellitus. N Engl J Med. 2001;342(19):
13921398.
34. Post RE, Mainous AG 3rd, King DE, Simpson KN. Dietary fiber for
the treatment of type 2 diabetes mellitus: a meta-analysis. J Am Board
Fam Med. 2012;25(1):1623.
35. Rebrin K, Steil GM, Mittelman SD, Bergman RN. Causal linkage
between insulin suppression of lipolysis and suppression of liver
glucose output in dogs. J Clin Invest. 1996;98(3):741749.
36. Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev.
2007;87(2):507520.
37. Risrus U. Fatty acids and insulin sensitivity. Curr Opin Clin Nutr
Metab Care. 2008;11(2):100105.
38. Haffner SM, Lehto S, Rnnemaa T, Pyrl K, Laakso M. Mortality
from coronary heart disease in subjects with type 2 diabetes and in
nondiabetic subjects with and without prior myocardial infarction.
NEngl J Med. 1998;339(4):229234.
39. Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH.
A prospective study of cholesterol, apolipoproteins, and the risk of
myocardial infarction. N Engl J Med. 1991;325(6):373381.
40. Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, WillettWC.
Trans fatty acids and cardiovascular disease. N Engl J Med.
2006;354(15):16011613.
41. Oomen CM, Ocke MC, Feskens EJ, van Erp-Baart MA, Kok FJ,
Kromhout D. Association between trans fatty acid intake and 10-year
risk of coronary heart disease in the Zutphen Elderly Study: a prospective population-based study. Lancet. 2001;357(9258):746751.
150
42. Oh K, Hu FB, Manson JE, Stampfer MJ, Willett WC. Dietary fat intake
and risk of coronary heart disease in women: 20 years of follow-up of
the Nurses Health Study. Am J Epidemiol. 2005;161(7):672679.
43. Risrus U. Trans fatty acids and insulin resistance. Atheroscler Suppl.
2006;7(2):3739.
44. Hartweg J, Perera R, Montori V, Dinneen S, Neil HA, Farmer A.
Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes.
Cochrane Database Syst Rev. 2008;(1):CD003205.
45. The ORIGIN Trial Investigators. N-3 fatty acids and cardiovascular
outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):
309318.
46. Rizkalla SW, Taghrid L, Laromiguiere M, et al. Improved plasma
glucose control, whole-body glucose utilization and lipid profile on
a low-glycemic diet in type 2 diabetic men: a randomized controlled
trial. Diabetes Care. 2004;27(8):18661872.
47. Summers LK, Fielding BA, Bradshaw HA, et al. Substituting
dietary saturated fat with polyunsaturated fat changes abdominal
fat distribution and improves insulin sensitivity. Diabetologia.
2002;45(3):369377.
48. Garg A. High-monounsaturated-fat diets for patients with diabetes m
ellitus: a meta-analysis. Am J Clin Nutr. 1998;67(suppl3):
577S582S.
49. Layman DK, Clifton P, Gannon MC, Krauss RM, Nuttall FQ. Protein
in optimal health: heart disease and type 2 diabetes. Am J Clin Nutr.
2008;87(5):1571S1575S.
50. Ferranini E, Bevilacqua S, Lanzone L, etal. Metabolic interactions
of amino acids and glucose in healthy humans. Diabetes Nutr Metab.
1988;3:175186.
51. Krezowski PA, Nuttall FQ, Gannon MC, Bartosh NH. The effect of
protein ingestion on the metabolic response to oral glucose in normal
individuals. Am J Clin Nutr. 1986;44(6):847856.
52. Ajala O, Enlgish P, Pinkney J. Systematic review and meta-analysis
of different dietary approaches to the management of type 2 diabetes.
Am J Clin Nutr. 2013;97(3):505516.
53. Wheeler ML, Dunbar SA, Jaacks LM, et al. Macronutrients, food
groups, and eating patterns in the management of diabetes: a systematic
review of the literature, 2010. Diabetes Care. 2012;35(2):434445.
54. Beasley JM, Wylie-Rosett J. The role of dietary proteins among persons
with diabetes. Curr Atheroscler Rep. 2013;15(9):348.
55. Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL. Effects
of weight loss on regional fat distribution and insulin sensitivity in
obesity. Diabetes. 1999;48(4):839847.
56. Diabetes Prevention Program Research Group. Reduction in the
incidence of type 2 diabetes with lifestyle intervention or metformin.
N Engl J Med. 2002;346(6):393403.
57. Tuomilehto J, Lindstrom J, Eriksson JG. Prevention of type 2 diabetes
mellitus by changes in lifestyle among subjects with impaired glucose
tolerance. N Engl J Med. 2001;344(18):13431350.
58. Eriksson J, Franssila-Kallunki A, Ekstrand A, etal. Early metabolic
defects in persons at increased risk for non-insulin dependent diabetes
mellitus. N Engl J Med. 1989;321(6):337343.
59. DeFronzo RA. From the triumvirate to the ominous octet: a new
paradigm for the treatment of type 2 diabetes. Diabetes. 2009;
58(4):773795.
60. Watts NB, Spanheimer RG, DiGirolamo M, etal. Prediction of glucose
response to weight loss in patients with non-insulin dependent diabetes.
Arch Intern Med. 1990;150(4):803806.
61. Wolf AM, Conaway MR, Crowther JQ, et al. Translating lifestyle
intervention to practice in obese patients with type 2 diabetes: Improving Control with Activity and Nutrition (ICAN) study. Diabetes Care.
2004;27(7):15701576.
62. Schauer PR, Burguera B, Ikramuddin S, etal. Effect of laparoscopic
Roux-en-Y gastric bypass on type 2 diabetes mellitus. Ann Surg.
2003;238(4):467484.
63. Schernthaner G, Brix JM, Kopp HP, Schernthaner GH. Cure of type2
diabetes by metabolic surgery? A critical analysis of the evidence in
2010. Diabetes Care. 2011;34(suppl 2):S355S360.

64. Redmon JB, Raatz SK, Kwong CA, Swanson JE, Thomas W, BantleJP.
Pharmacologic induction of weight loss to treat type 2 diabetes. Diabetes Care. 1999;22(6):896903.
65. Klein S, Sheard NF, Pi-Sunyer X, Daly A, Wylie-Rosett J, KulkarniK,
etal. Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies:
astatement of the American Diabetes Association, the North American
Association for the Study of Obesity, and the American Society for
Clinical Nutrition. Diabetes Care. 2004;27(8):20672073.
66. Fujioka K, Seaton TB, Rowe E, Jelinek CA, Rakin P, Lebovitz HE,
etal. Weight loss with sibutramine improves glycaemic control and
other parameters in obese patients with type 2 diabetes. Diabetes Obes
Metab. 2000;2(3):175187.
67. Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, etal.
Comparison of weight-loss diet with different compositions of fat,
protein, and carbohydrates. N Engl J Med. 2009;360(9):859873.
68. Dansinger ML, Gleason JA, Griffiths JL, Selker HP, Schaefer EJ.
Comparison of the Atkins, Ornish, Weight Watchers, and the Zone
diets for weight loss and heart disease risk reduction: a randomized
trial. JAMA. 2005;293(1):4353.
69. Wadden TA, Butryn ML, Wilson C. Lifestyle modification for the
management of obesity. Gastroenterology. 2007;132(6):22262238.
70. Wadden TA, Crerand CE, Brock J. Behavioral treatment of obesity.
Psychiatr Clin North Am. 2005;28(1):151170.
71. Wing RR, Marquez B. Behavioral aspects of weight loss in type 2
diabetes. Curr Diab Rep. 2008;8(2):126131.
72. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight
loss inimproving cardiovascular risk factors in overweight and
obese individuals with type 2 diabetes. Diabetes Care. 2011;34(7):
14811486.
73. Wadden TA, Phelan S. Behavioral assessment of the obese patient.
In: Wadden TA, Stunkard AJ, eds. Handbook of Obesity Treatment.
New York: Guilford Press; 2002:186226.
74. Wing RR, Tate DF, Gorin AA, Raynor HA, Fava JL. A selfregulation program for maintenance of weight loss. N Engl J Med.
2006;355(15):15631571.
75. Turk MW, Yang K, Hravnak M, Sereika SM, Ewing LJ, Burke LE.
Randomized clinical trials of weight-loss maintenance: a review.
JCardiovasc Nurs. 2009;24(1):5880.
76. Ryan DH, Espeland MA, Foster GD, Haffner SM, Hubbard VS,
Johnson KC, etal; Look AHEAD Research Group. Look AHEAD
(Action for Health in Diabetes): design and methods for a clinical
trial for the prevention of cardiovascular disease in type 2 diabetes.
Control Clin Trials. 2003;24(5):610628.
77. Weight loss does not lower heart disease risk from type 2 diabetes
[press release]. Bethesda, MD: US Department of Health and Human
Services; October 19, 2012. http://www.nih.gov/news/health/oct2012/
niddk-19.htm.
78. Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, etal.
Cardiovascular effects of intensive lifestyle intervention in type 2
diabetes. N Engl J Med. 2013;369(2):145154.
79. Foster GD, Borradaile KE, Sanders MH, Millman R, Zammit G,
Newman AB, etal. A randomized study on the effect of weight loss on
obstructive sleep apnea among obese patients with type 2 diabetes: the
Sleep AHEAD study. Ann Intern Med. 2009;169(17):16191626.
80. Phelan S, Kanaya AM, Subak LL, Hogan PE, Espeland MA,
WingRR, etal. Weight loss prevents urinary incontinence in women
with type 2 diabetes: results from the Look AHEAD trial. J Urol.
2012;187(3):939944.
81. Faulconbridge LF, Wadden TA, Rubin RR, Wing RR, Walkup MP,
Fabricatore AN, etal. One-year changes in symptoms of depression
and weight in overweight/obese individuals with type 2 diabetes in
the Look AHEAD study. Obesity. 2012;20(4):783793.
82. Williamson DA, Rejeski L, Lang W, Van Dorsten B, Fabricatore AN,
Toledo K. Impact of a weight management program on health-related
quality of life in overweight adults with type 2 diabetes. Arch Intern
Med. 2009;169(2):163171.
83. Foy C, Lewis CE, Hairston KG, etal. Intensive lifestyle intervention
improves physical function among obese adults with knee pain:
findings from the Look AHEAD trial. Obesity. 2011;19(1):8393.
84. Rejeski WJ, Ip EH, Bertoni AG, Bray GA, Evans G, Gregg EW, etal.
Lifestyle change and mobility in obese adults with type 2 diabetes.
NEngl J Med. 2012;366(13):12091217.
85. Volek JS, Feinman RD. Carbohydrate restriction improves features of
the metabolic syndrome. Metabolic syndrome may be defined by the
response to carbohydrate restriction. Nutr Metab (Lond). 2005;2:31.
86. Samaha FF, Foster GD, Makris AP. Low-carbohydrate diets, obesity,
and metabolic risk factors for cardiovascular disease. Curr Atheroscler
Rev. 2007;9(6):441447.
87. Wylie-Rosett J, Aebersold K, Conlon B, Isasi CR, Ostrovsky NW.
Health effects of low-carbohydrate diets: where should new research
go? Curr Diab Rep. 2013;13(2):271278.
88. Dyson PA. A review of low and reduced carbohydrate diets and weight
loss in type 2 diabetes. J Hum Nutr Diet. 2008;21(6):530538.
89. Samaha FF, Iqbal N, Seshadri P, Chicano KL, Daily DA, McGrory J,
etal. A low-carbohydrate as compared with a low-fat diet in severe
obesity. N Engl J Med. 2003;348(21):20742081.
90. Gannon MC, Nuttall FQ. Effect of a high-protein, low-carbohydrate
diet on blood glucose control in people with type 2 diabetes. Diabetes.
2004;53(9):23752382.
91. Dyson PA, Beatty S, Matthews DR. A low-carbohydrate diet
is more effective in reducing body weight than healthy eating
behaviors in both diabetic and non-diabetic subjects. Diabet Med.
2007;24(12):14301435.
92. Stern L, Iqbal N, Seshadri P, Chicano KL, Daily DA, McGrory J, etal.
The effects of low-carbohydrate versus conventional weight loss diets
in severely obese adults: one-year follow-up of a randomized trial.
Ann Intern Med. 2004;140(10):778785.
93. Brinkworth GD, Noakes M, Parker B, Foster P, Clifton PM. Longterm effects of advice to consume a high-protein, low-fat diet rather
than a conventional weight loss diet, in obese adults with type 2
diabetes: one-year follow-up of a randomised trial. Diabetologia.
2004;47(10):16771686.
94. Wolever TM, Gibbs AL, Mehling C, Chiasson JL, Connelly PW,
JosseRG, etal. The Canadian trial of carbohydrates in diabetes (CCD),
a 1-y controlled trial of low-glycemic index dietary carbohydrate in
type 2 diabetes: no effect on glycated hemoglobin but reduction in
c-reactive protein. Am J Clin Nutr. 2008;87(1):114125.
95. Davis NJ, Tomuta N, Schechter C, Isasi CR, Segal-Isaacson CJ, Stein D,
etal. Comparative study of the effects of a 1-year dietary intervention
of a low-carbohydrate diet versus a low-fat diet on weight and glycemic
control in type 2 diabetes. Diabetes Care. 2009;32(7):11471152.
96. Shai I, Schwarzfuchs D, Henkin Y, Shahar DR, Witkow S, GreenbergI,
etal. Weight loss with a low-carbohydrate, Mediterranean, or low-fat
diet. N Engl J Med. 2008;359(3):229241.
97. Schwarzfuchs D, Golan R, Shai I. Four-year follow-up after two-year
dietary interventions. N Engl J Med. 2012;367(14):13731374.
98. Vetter ML, Iqbal N, Dalton-Bakes C, Volger S, Wadden TA. Long-term
effects of low-carbohydrate versus low-fat diets in obese persons. Ann
Intern Med. 2010;152(5):334335.
99. Hu T, Mills KT, Yao L, Demanelis K, Eloustaz M, Yancy WS Jr, etal.
Effects of low-carbohydrate diets versus low-fat diets on metabolic
risk factors: a meta-analysis of randomized controlled clinical trials.
Am J Epidemiol. 2012;176(suppl 7):S44S54.
100. Kirk JK, Graves DE, Craven TE, Lipkin EW, Austin M, MargolisKL.
Restricted-carbohydrate diets in patients with type 2 diabetes: ametaanalysis. J Am Diet Assoc. 2008;108(1):91100.
101. Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Sato M, etal. Influence of
fat and carbohydrate proportion son the metabolic profile in patients with
type 2 diabetes: a meta-analysis. Diabetes Care. 2009;32(5):959965.
102. Wheeler ML, Dunbar SA, Jaacks LM, Karmally W, Mayer-Davis EJ,
Wylie-Rosett J, etal. Macronutrients, food groups, and eating patterns
in the management of diabetes: a systematic review of the literature.
Diabetes Care. 2012;35(2):434445.
Vetter etal
103. American Diabetes Association. Standards of medical care in diabetes
2013. Diabetes Care. 2013;36(suppl 1):S11S66.
104. Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, BaldwinJM,
etal. Glycemic index of foods: a physiological basis for carbohydrate
exchange. Am J Clin Nutr. 1981;34(3):362366.
105. Ludwig DS. The glycemic index: physiological mechanisms relating
to obesity, diabetes, and cardiovascular disease. JAMA. 2002;287(18):
24142423.
106. Thomas D, Elliott EJ. Low glycaemic index, or low glycaemic load,
diets for diabetes mellitus (review). Cochrane Database Syst Rev.
2009;(1):CD006296.
107. Jenkins DJ, Kendall CW, McKeown-Eyssen G, etal. Effect of a
low-glycemic index or a high-cereal fiber diet on type 2 diabetes.
Arandomized trial. JAMA. 2008;300(23):27422753.
108. Ma Y, Olendzki B, Merriam PA, Chiriboga DE, Culver AL, Li W, etal.
A randomized clinical trial comparing low-glycemic index versus ADA
dietary education among individuals with type 2 diabetes. Nutrition.
2008;24(1):4556.
109. Davis N, Forbes B, Wylie-Rosett J. Nutritional strategies in type 2
diabetes. Mt Sinai J Med. 2009;76(3):257268.
110. Nield L, Moore HJ, Hooper L, Cruickshank JK, Vyas A, WhittakerV,
etal. Dietary advice for the treatment of type 2 diabetes mellitus in
adults. Cochrane Database Syst Rev. 2007;(3):CD004097.
111. Fung TT, Rexrode KM, Mantzoros CS, Manson JE, Willet WC, Hu FB.
Mediterranean diets and incidence of and mortality from coronary heart
disease and stroke in women. Circulation. 2009;119(8):10931100.
112. Knoops KT, de Groot LC, Kromhout D, Perrin AE, Moreiras-VarelaO,
Menotti A, etal. Mediterranean diet, lifestyle factors, and 10-year
mortality in elderly European men and women: the HALE project.
JAMA. 2004;292(12):14331439.
113. Mitrou PN, Kipnis V, Tiebaut AC, etal. Mediterranean dietary
pattern and prediction of all-cause mortality in a U.S. population:
results from the NIH-AARP Diet and Health Study. Arch Intern Med.
2007;167(22):24612468.
114. Estruch R, Martinez-Gonzlez MA, Corella D, Salas-Salvado J, RuizGuiterrez V, Covas MI, etal. Effects of a Mediterranean-style diet
on cardiovascular risk factors: a randomized trial. Ann Intern Med.
2006;145(1):111.
115. Shah M, Adams-Huet B, Brinkley L, Grundy SM, Garg A. Lipid, glycemic,
and insulin responses to meals rich in saturated, cis-monounsaturated,
andpolyunsaturated (n-3 and n-6) fatty acids in subjects with type 2
diabetes. Diabetes Care. 2007;30(12):29932998.
116. Esposito K, Maiorino MI, Ciotola M, Di Palo C, Scognamiglio P,
Gicchino M, etal. Effects of a Mediterranean-style diet on the need
for antihyperglycemic drug therapy in patients with newly diagnosed
type 2 diabetes. A randomized trial. Ann Intern Med. 2009;151(5):
306314.
117. Abdollahi M, Farshchi A, Nikfar S, Seyedifar M. Effect of chromium onglucose and lipid profiles in patients with type 2 diabetes:
a meta-analysis of randomized trials. J Pharm Pharm Sci. 2013;
16(1):99114.
118. Capdor J, Foster M, Petocz P, Samman S. Zinc and glycemic control:
a meta-analysis of randomized, placebo-controlled supplementation
trials in humans. J Trace Elem Med Biol. 2013;27(2):137142.
119. George PS, Pearson ER, Witham MD. Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic
review and meta-analysis. Diabet Med. 2012;29(8):e142e150.
120. Suksomboon N, Poolsup N, Sinprasert S. Effects of vitamin E
supplementation on glycaemic control in type 2 diabetes: a systematic review of randomized controlled trials. J Clin Pharm Ther.
2011;36(1):5363.
121. Allen RW, Schwartzman E, Baker WL, Coleman CI, Phung OJ.
Cinnamon use in type 2 diabetes: an updated systematic review and
meta-analysis. Ann Fam Med. 2013;11(5):452459.
152
122. Yeh GY, Eisenberg DM, Kaptchuk TJ, Phillips RS. Systematic review
of herbs and dietary supplements for glycemic control in diabetes.
Diabetes Care. 2003;26(4):12771294.
123. Unger J. Reducing oxidative stress in patients with type 2 diabetes
mellitus: a primary care call to action. Insulin. 2008;3:176184.
124. Nadeau DA. Physiologic and weight-focused treatment strategies
for managing type 2 diabetes mellitus: the metformin, glucagon-like
peptide-1 receptor agonist, and insulin (MGI) approach. Postgrad
Med. 2013;125(3):112126.
125. Lee M, Aronne LJ. Weight management for type 2 diabetes
mellitus: global cardiovascular risk reduction. Am J Cardiol.
2007;99(4A):68B79B.
126. Rucker D, Padwal R, Li SK, Curioni C, Lau DC. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ.
207;335(7629):11941199.
127. Norris SL, Zhang X, Avenell A, Gregg E, Schmid CH, Lau J. Pharmacotherapy for weight loss in adults with type 2 diabetes. Cochrane
Database Syst Rev. 2005;1:CD004096.
128. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose,
controlled-release phentermine plus topiramate combination on
weight and associated comorbidities in overweight and obese adults
(CONQUER): a randomized, placebo-controlled, phase 3 trial. Lancet.
2011;377(9776):13411352.
129. Chan EW, He Y, Chui CS, Wong AY, Lau WC, Wong IC. Efficacy and
safety of lorcaserin in obese adults: a meta-analysis of 1-year randomized controlled trials (RCTs) and narrative review on short-term RCTs.
Obes Rev. 2013;14(5):383392.
130. Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR,
etal. Meta-analysis: pharmacologic treatment of obesity. Ann Intern
Med. 2005;142(7):532546.
131. Ye Z, Chen L, Yang Z, etal. Metabolic effects of fluoxetine in adults
with type 2 diabetes: a meta-analysis of randomized placebo controlled
trials. PLoS One. 2011;6(7):e21551.
132. Kramer CK, Leitao CB, Pinto LC, Canani LH, Azevedo MJ, GrossJL.
Efficacy and safety of topiramate on weight loss: a meta-analysis of
randomized controlled trials. Obes Rev. 2011;12(5):e338e347.
133. Gadde KM, Kopping MF, Wagner HR, Yonish GM, Allison DB,
BrayGA. Zonisamide for weight reduction in obese adults: a 1-year randomized controlled trial. Arch Intern Med. 2012;172(20):15571564.
134. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M,
MoherD. Metformin monotherapy for type 2 diabetes mellitus.
Cochrane Database Syst Rev. 2005;3:CD002966.
135. Gross JL, Kramer CK, Leitao CB, Hawkins N, Viana LV, Schaan BD,
etal. Effect of antihyperglycemic agents added to metformin and a
sulfonylurea on glycemic control and weight gain in type 2 diabetes:
a network meta-analysis. Ann Intern Med. 2011;154(10):672679.
136. Vilsbll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects
of glucagon-like peptide-1 receptor agonists on weight loss: a systematic review and meta-analyses of randomized controlled trials. BMJ.
2012;344:d7771.
137. Shyangdan DS, Royle PL, Clar C, Sharma P, Waugh NR. Glucagonlike peptide analogues for type 2 diabetes: a systematic review and
meta-analysis. BMC Endocr Disord. 2010;10:20.
138. Singh-Franco D, Perez A, Harrington C. The effect of pramlintide
acetate on glycemic control and weight in patients with type 2 diabetes
mellitus and in obese patients without diabetes: a systematic review
and meta-analysis. Diabetes Obes Metab. 2011;13(2):169180.
139. Stenlof K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, etal.
Efficacy and safety of canagliflozin monotherapy in subjects with
type 2 diabetes mellitus inadequately controlled with diet and exercise.Diabetes Obes Metab. 2013;15(4):372382.
140. Clar C, Gill JA, Court R, Waugh N. Systematic review of SGLT2
receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ
Open. 2012;2(5):e001007.

DM Treatment

Caricato da

Informazioni sul documento

Titolo originale

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

DM Treatment

Caricato da

Copyright:

Formati disponibili

All rights reserved: reproduction in whole or part not permitted.

All permission requests to reproduce or adapt published

Nutritional Management of Type 2 Diabetes

Marion L. Vetter, MD, RD 1,2

Correspondence: Marion L. Vetter, MD,

dietary counseling. Given the beneficial effects of weight

A 48-year-old African-American woman named D.B. was

Postprandial glucose levels are primarily determined by the

Nutritional Management of T2DM and Obesity

Case Study (Continued)

Effects of Specific Types of Fat on Cardiovascular

Omega-6 FAs may have beneficial effects on insulin

Dietary protein also plays a role in carbohydrate metabolism.

Approaches to Facilitate Weight Loss

Most individuals with T2DM are overweight or obese, and

b enefitfor individuals with prediabetes56,57 or shortly after the

The optimal distribution of dietary macronutrients (ie, carbo

Approaches to Weight Management

Nutritional Management of T2DM and Obesity

problem solving, and relapse prevention. Self-monitoring

Case Study (Continued)

Several friends and family members have recommended a

A variety of dietary approaches can be used to meet the

Multiple studies have investigated the effects of a reduced

developed to compare the postprandial glucose response of

Low-fat diets, which contain ,30% of calories from fat,

in individuals with T2DM.109 In a systematic review that

Mediterranean diets emphasize the moderate consumption

Nutritional Management of T2DM and Obesity

Per the most recent ADA guidelines, any of these approaches

Case Study (Continued)

D.B. asks whether any supplements would be helpful in

Chromium, Antioxidants, and

Oxidative stress is involved in the pathogenesis of both cardio

c ertain supplements and antioxidants has garnered considerable

Case Study (Continued)

Initially, D.B. is very motivated and records her food intake

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

May potentiate the action

May play a role in insulin

May stimulate postprandial

Systematic review and meta-analysis

May have a protective effect

Systematic review (8 RCTs; N = 418)

Cinnamaldehydea may exert

May delay gastric emptying

Systematic review and meta-analysis

Systematic review (7 studies) found

Active ingredient in cinnamon.

Dose and dosing

Selective 5-HT2c receptor agonists

120 mg TID with meals (or

Effect not reported

3.2 kg placebosubtracted weight

3.6 kg placebosubtracted weight

0.20.4% reduction128 Headache

6.78.8 kg placebosubtracted weight

Fatty and oily stool

2.0 kg placebosubtracted weight

Concurrent use of other serotonergic or

Can reduce the absorption of amiodarone,

Effect not reported

0.4 and 3.3 kg

120 mg TID with meals (or

3.2 kg placebosubtracted weight

3.6 kg placebosubtracted weight

6.78.8 kg placebosubtracted weight

2.0 kg placebosubtracted weight

Concurrent use of other serotonergic or

Can reduce the absorption of amiodarone,

0.4 and 3.3 kg

5.3 kg placebosubtracted weight

4.3 kg placebosubtracted weight

3.0 kg placebo Effect not reported

Not approved for

Not approved for

Not approved for

Not approved for