DM treatment

8/10/2019 DM treatment

1/14

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

Postgraduate Medic ine, Volume 126, Issue 1, January 2014, ISSN 0032-5481, e-ISSN 1941-9260 139ResearchSHARE: 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 DiabetesMellitus and Obesity and Pharmacologic

Therapies to Facilitate Weight Loss

Marion L. Vetter, MD, RD1,2

Anastassia Amaro, MD2

Sheri Volger, RD, MS2,3

1Center for Weight and EatingDisorders, Department of Psychiatr y,Perelman School of Medicine,

Hospital of the University ofPennsylvania, Philadelphia, PA;2Division of Endocrinology, Diabetes,and Metabolism, Department ofMedicine, Perelman School ofMedicine, Hospital of the Universityof Pennsylvania, Philadelphia, PA;3Wyeth Nutrition at Nestle S.A.,King of Prussia, PA

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

DOI: 10.3810/pgm.2014.01.2734

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 certied

diabetes educator, and rates of physician counseling about diet remain low. This article pro-

vides 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 exible 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 modication, 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 signicant

improvements in patient measures of glycemic control, lipids, blood pressure, and other car-

diovascular 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 prin-

ciples can help physicians provide dietary counseling to their patients with T2DM and obesity.

Keywords:medical nutrition therapy; pharmacotherapy; diabetes; obesity

IntroductionObesity affects 35.9% of US adults and dramatically increases the risk of type 2 diabetes

mellitus (T2DM).1,2Currently,two thirds of the 23 million US adults who have T2DM

are obese.3,4In 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,68particularly if delivered within

1 year of diagnosis of T2DM.8However, many patients do not have access to a registered

dietitian or a certied 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. 911This

article reviews current nutritional recommendations for the management of T2DM and

obesity, using a case-based approach to illustrate questions that frequently arise during

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.

Re

[email protected] permissions@postgradme


2/14

Vetter et al

140 Postgraduate Medicine , Volume 126, Issue 1, January 2014, ISSN 0032-5481, e-ISSN 1941-9260ResearchSHARE: www.research-share.com Permissions: [email protected] Reprints: [email protected]


dietary counseling. Given the benecial effects of weight

loss on glycemia, behavioral and pharmacologic therapies

for weight management (and their subsequent effects on

glycemic control) are also briey discussed.

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

diagnosed with T2DM approximately 2 years ago. She alsohas 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 antidiabe-

tes medication, she states that she would like to try dietary

modication rst. She acknowledges that she has not reallypaid much attention to her diet in the past and requests

guidance about carbohydrate intake. Specically, 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 forMacronutrient Intake for DiabetesCarbohydratesPostprandial glucose levels are primarily determined by the

amount of carbohydrate consumed, rather than the type of

carbohydrate (ie, sugar, starches, or dietary ber).12,13The

Recommended Dietary Allowance for carbohydrates is

130 g/d, which is based on the average minimum amount

of glucose used by the brain.14The median intake of carbo-

hydrates 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 carbohy-

drate is typically 15 g (ie, a slice of bread).15The American

Diabetes Association (ADA) recommends a consistent dis-

tribution 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.16Although

the Diabetes Control and Complications Trial firmly

established the efcacy of carbohydrate counting in type 1

diabetes mellitus (T1DM),17it is less clear for individuals

with T2DM.

Types of Carbohydrate

Not all types of carbohydrates are fully metabolized to blood

glucose.12Added sugars, including sucrose and high-fructose

corn syrup (HFCS), are digested, absorbed, and fully metabo-

lized in a similar manner to naturally occurring mono- and

disaccharides. In contrast,half of the carbohydrate content

of dietary ber 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 con-

sumption of sugars, sugary beverages, and prepared foodswith 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 articial 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.23Several meta-analyses have shown

associations between the consumption of sugar-sweetened

beverages and obesity24,25and 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.28Unlike sucrose, fructose does not undergo rst-

pass metabolism by the liver.28Instead, fructose is rapidly

metabolized by hepatic fructose kinase C, leading to the

generation of substrates for de novo lipogenesis. Fructose-

induced lipotoxicity (and other alterations in lipid metabo-

lism) 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


3/14

Nutritional Management of T2DM and Obesity



Dietary Fiber

Dietary ber is not digested by enzymes in the small intestine

and does not contribute to the immediate glucose supply.12

Solublebers, which are derived from whole-grain products

and fruit (pectin), are fermented in the colon and delay the

digestion and absorption of carbohydrates.29,30Insoluble fber

(such as wheat bran) has bulking action and may improve gly-

cemia by decreasing the production of short chain fatty acidsin the colon, which decrease hepatic insulin sensitivity.31

The term net carbohydrateshas 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 ber).25Net carbohydrates can be calculated in food

items that contain5 g of ber/serving by subtracting half

of the total number of grams of dietary ber from the total

number of grams of carbohydrates.12

Several randomized controlled trials (RCTs) have evalu-

ated the effect of varying the amount of dietary ber (while

controlling the total amount of dietary carbohydrate) on gly-cemic control in individuals with metabolic syndrome, T1DM,

and T2DM.3133High-ber diets contain approximately 50 g

per day, as compared with the average daily intake of 15 g for

US adults.32A recent meta-analysis that included 15 studies

reported a nonsignicant mean reduction in fasting blood glu-

cose of 15 mg/dL with a high-ber diet.34High-ber diets also

had very modest effects on HbA1c

, resulting in a mean difference

in HbA1c

reduction of 0.3%, compared with lower ber diets.

Individuals with T2DM are encouraged to consume a

variety of ber-containing foods, such as legumes, ber-

rich cereals (5 g ber/serving), fruits, vegetables, and

whole grains.16Similar to recommendations for the general

population, the ADA recommends that patients with T2DM

consume 14 g of ber 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.

FatDietary fat and free fatty acids (FAs) are known to impair

insulin sensitivity and to enhance hepatic glucose pro-

duction, which may contribute to the development of

hyperglycemia.35,36These adverse effects are thought to be

mediated through alterations in cell membrane composition,

lipogenic gene expression, and enzyme activity.37Because

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 Specic 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.37Given the

known association of saturated fats and cardiovasculardisease in individuals without diabetes mellitus, the ADA

currently recommends that saturated fat be restricted to7%

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 pro-

cesses. Trans fats have been shown to increase both LDL-C

and triglyceride levels and to reduce levels of high-density

lipoprotein cholesterol (HDL-C).39In addition to inducingan atherogenic dyslipidemia, trans FAs may also promote

inammatory 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 uidity and insulin sensitivity,

possibly through downregulation of the peroxisome prolifer-

ator-activated receptor-located in adipose tissue.43The ADA

currently recommends minimal intake of trans FAs.16

Polyunsaturated FAs

Polyunsaturated FAs include the omega-3 FAs,which are

found in sh 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 signicant

reductions in triglyceride levels and very low LDL-C levels

in participants.44Although LDL-cholesterol levels increased

slightly with omega-3 supplementation, the increase was not

signicant 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 Inter-

vention (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


4/14

Vetter et al



Omega-6 FAs may have benecial 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.46The omega-6 FAs are thought to decrease

insulin resistance by acting as a ligand for peroxisomeproliferator-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.

ProteinDietary 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 specic 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 individu-

als with T2DM was recently summarized in a meta-analysis and

a systematic review.52,53Discrepant effects of high-protein diets

(dened as30% of total energy intake) have been reported

on HbA1c

levels, but high-protein diets appear to improve1

cardiovascular risk factor.53The 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.54The 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 LossThe Effects of Weight Loss on DiabetesMellitusMost individuals with T2DM are overweight or obese, and

weight reduction is associated with signicant improve-

ments in insulin sensitivity.55Weight loss confers the greatest

benet for individuals with prediabetes56,57or shortly after the

onset of T2DM, when insulin resistance is the predominant

mechanism of impaired glycemia.58Additional defects in

patients with T2DM include inappropriate suppression of

glucagon and a diminished incretin response.59As the dis-

ease progresses and patient -cell function becomes more

impaired, weight loss has a more modest effect on glyce-

mic control.60,61Bariatric surgery studies provide the mostcompelling evidence for this phenomenon. Despite the very

signicant weight loss induced by bariatric procedures, indi-

viduals with longstanding diabetes (5 years in duration),

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 compo-

nent in the treatment of longstanding T2DM in patients and

is associated with a signicant reduction in the number of

antidiabetes medications (many of which tend to promote

weight gain) and cardiovascular risk factors.64,65A modestweight loss of 5% to 10% of body weight confers signicant

improvements in glycemic control, lipemia, and blood pres-

sure.65For every 4.5-kg loss in weight, patient HbA1c

levels

may be reduced by 0.5%.66

Macronutrient DistributionThe optimal distribution of dietary macronutrients (ie, carbo-

hydrate, protein, and fat) for the management of diabetes

mellitus and weight loss has not been established.16Isocaloric

diets (ie, equivalent in caloric content) of varying macronutri-

ent composition have been found to induce similar weight

loss (regardless of the distribution of carbohydrates, fat, and

protein),67and no particular dietary approach has been found to

be more efcacious than others in terms of promoting optimal

glycemic control or weight loss in patients.52An energy-

reduced diet should be recommended to facilitate weight loss.

Individualization of the macronutrient composition depends on

the metabolic status of the patient (eg, lipid prole and renal

function) or food preferences.16For most patients, the optimal

diet is the one to which individuals have the best adherence.68

Approaches to Weight ManagementLifestyle ModicationPatient lifestyle modication, which encompasses diet, physi-

cal activity, and behavioral therapy, serves as the cornerstone

for any dietary approach to diabetes mellitus and weight

management.69Common techniques include self-monitoring

(keeping records of food intake and physical activity),

modifying cues that elicit unwanted eating (stimulus control),


5/14




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.70Food records also serve to increase

awareness of the calorie content and portion sizes of com-

monly consumed foods, which may account for the nding

that maintenance of daily food records is associated with

greater initial weight loss.71

Lifestyle modication programs typically induce a weight

loss of 8% to 10% in the rst 6 to 12 months, resulting in

clinically important health benets.71A 5% reduction in body

weight has been associated with a 0.5% decrease in patient

HbA1c

levels.72Unfortunately, most individuals regain one

third of the weight loss during the next year and return to

their baseline weight within 3 to 5 years.73Weight regain

can be minimized by frequent self-monitoring,74as 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 reduc-

tion (achieved through lifestyle modication) also reduced

cardiovascular morbidity and mortality.76Participants were

randomly assigned to either of 2 conditions: intensive lifestyle

intervention (ILI), which included group and individual meet-

ings; 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.77Although

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,79urinary incontinence,80and depression,81and

improvements in quality of life,82physical functioning,83and

mobility.84The 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 ApproachesA variety of dietary approaches can be used to meet the

recommendations provided above.

Low-Carbohydrate DietsMultiple studies have investigated the effects of a reduced

carbohydrate intake on glycemia, weight, and other meta-

bolic outcomes. However, efforts to compare ndings from

studies have been limited by the lack of a consistent deni-

tion of low-carbohydrate intake. Low-carbohydrate diets

typically include an absolute carbohydrate intake of 50 to

100 g daily,85,86or less than 40% of total calories derivedfrom carbohydrates.87Most 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.8891However, 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.9295Longer term studies (4 years) show

no detrimental effects on cardiovascular risk factors.9698A 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 benecial effects on

improved glycemic control generally did not persist after 1

year and were likely attributable to weight loss.102Limitations

of these studies include signicant loss to follow-up (many

had completion rates70%), small samples sizes, and sig-

nicant 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, ber, vitamins, and minerals.16,103 Additionally,

the ADA recommends that lipid prole, renal function, and

protein intake (in patients with nephropathy) be monitored

in patients who follow a low-carbohydrate diet.103

Low-Glycemic DietsThe physical properties of food, the rate of intestinal hydro-

lysis, and other dietary factors also affect the glycemic

response.12The glycemic index(GI) is a ranking that was


6/14

Vetter et al



developed to compare the postprandial glucose response of

different carbohydrates.104The GI is dened as the incre-

mental increase in plasma glucose (above baseline) that is

observed 2 hours after ingesting a known amount of carbo-

hydrate 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 inducea higher peak glucose level than low-GI foods, which include

lentils, beans, oats, and non-starchy vegetables. Theglycemic

loadis 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.12Moreover,

the GI for any particular food is subject to signicant variation,

both within and between individuals.105These 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 reporteddiscrepant ndings. A recent Cochrane review that included

402 individuals with T1DM and T2DM reported signi-

cant 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-ber cereal

diet among 210 participants with T2DM, that HbA1clevels

were signicantly decreased in the low-glycemic group

compared with the high-cereal ber group (0.5% vs 0.2%;

P0.001), 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 ber 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,108or to diets of

varying carbohydrate content.94

Fat-Restricted DietsLow-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

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.110Although

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. Manyof the included studies were limited by small sample size,

heterogeneity in fat intake, and differences in fat quality.

Mediterranean DietsMediterranean 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, sh, and moderate consumption of wine.

Many studies have demonstrated that a Mediterranean diet

pattern has benecial effects on cardiovascular health,111113

and recent research has focused on its effect on diabetesmellitus.

Several RCTs have investigated the effects of a Mediter-

ranean diet, as compared with other commonly used diets, on

glycemic parameters in participants with T2DM.96,114116In

the Prevencin con Dieta Mediterrnea (PREDIMED) study,

Estruch and colleagues114randomly 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 reduc-

tions in fasting glucose and lipid levels, insulin resistance,

blood pressure, and inammatory markers.

Longer duration studies have also shown a sustained ben-

et on glycemic control. Esposito and colleagues116randomly

assigned 215 participants with newly diagnosed T2DM to

a Mediterranean or low-fat diet for 52 weeks. Signicant

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 low-

carbohydrate, low-GI, Mediterranean, and high-protein diets

were effective in improving glycemic indices and various

markers of cardiovascular risk in individuals with T2DM.


7/14




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.

Chromium, Antioxidants, andSupplementsOxidative stress is involved in the pathogenesis of both cardio-

vascular disease and diabetes123 and the protective role of

certain 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 Associa-

tion (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

picolinate117May potentiate the action

of insulin by augmenting its

signaling pathway

Systematic review (7 studies) found

no signicant effect of chromium

supplementation on HbA1clevels

(WMD 0.33%; 95%

CI; 0.72 to 0.06)

Considerable heterogeneity

in study populations and in

the range of chromium dose/

formulation; short duration

of studies

Not recommended

by the ADA

Zinc118 May play a role in insulin

sensitivity via the induction

of the P13K/AKT pathway

(mediator of insulin signaling

and glucose disposal)

Meta-analysis (8 studies; N =408)

reported a trend toward signicant

reduction in HbA1clevels (0.64%;

P=0.072)

Considerable heterogeneity in

study populations and in the

range of zinc dose/formulation;

confounding effects of other

concomitant medications; short

duration of studies

Not recommended

by the ADA

Vitamin D119 May stimulate postprandial

insulin release

Systematic review and meta-analysis

(4 studies; N =233) found no signicant

change in HbA1clevels with vitamin D

supplementation

Considerable heterogeneity in

study populations and in the

range of vitamin D dose/

formulation; small sample sizes;

loss to follow-up

Not recommended

by the ADA

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 benecial effect of vitamin E

supplementation on HbA1clevels

(WMD 0.17%; 95% CI; 0.49 to 0.16)


in study populations, duration

of T2DM, level of glycemic

control, and antioxidant status;

small sample sizes; confounding

effects of concomitant

medications noted

Not recommended

by the ADA

Cinnamon121 Cinnamaldehydeamay exert

insulinotropic effects

Systematic review and meta-analysis

(10 RCTs; N =543) found no

signicant effect of cinnamon on

HbA1clevels; cinnamon was associated

with signicant reductions in total

cholesterol, LDL-C, triglyceride, and

FPG levels (WMD 25 mg/dl;

95% CI 40.5 to 8.7 mg/dL)


in study populations and in

the range of cinnamon dose/

formulation; short duration

of studies

Not recommended

by the ADA

Fenugreek122 May delay gastric emptying

and slow CHO absorption;

glucose transport may be

inhibited because of ber

content

Meta-analysis (4 RCTs; N =51) found

benecial effects on FPG and PPGbConsiderable heterogeneity

in study populations; generally

poor quality studies with very

small sample size

Not recommended

by the ADA

aActive ingredient in cinnamon.bPooled 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.


8/14


9/14


10/14

Vetter et al



Table2.(Continued)

Nonproprietary

drugname

(proprietary

name)

Doseand

dosing

recommendations

Effectsonweight

Corresponding

changeinHbA1c

levels

Sideeffects

Contraindications

(absoluteandrelative)

FDA

recommendations

forweightlossuse

GLP-1receptor

agonists(Byetta,

Bydureon,Victoza)

Exenatide(immediate

release):510ginjected

subcutaneouslyBID

Exenatide(extended

release):2mgonceperwk

Liraglutid

e:0.61.8mg

injectedsubcutaneouslyQD

(trialsinv

estigatingliraglutide

totreatobesityhaveused

3.0mgQ

D)

2.0kgplacebo-

subtractedweight

lossinstudies

rangingfrom

2052wks(pooled

estimatesoftrials

ofexenatideand

liraglutide)136

0.6%1.2%reduction

fromtrialsof

exenatideand

liraglutide137

Nausea

Hypoglycemiawith

concomitantuseof

otherhypoglycemia

agents

Insomnia

Drymouth

Constipation

Pancreatitis

Usewithcautionincombinationwith

glucose-loweringagentsand/orinsulin.

FamilyorpersonalhistoryofCcellthyroid

tumors(ie,medullarythyroidcancer)

orMEN-2

Approvedfor

thetreatment

ofT2DM

Pramlintide

(Symlin)

120150

ginjected

23timesdaily(higher

dosesusedinstudiesforthe

treatmen

tofobesity)

2.2kgplacebo-

subtractedweight

lossinstudies

rangingfrom

1652wksin

patientswithDM

whoconcurrently

receivedinsulin138

0.3%reduction138

Nausea

Hypoglycemia

(especiallyinpatients

treatedconcurrently

withinsulin)

Usewithcautionincombinationwith

glucose-loweringagentsand/orinsulin

Approvedfor

thetreatment

ofT2DM

SGLT-2inhibitors

Canag

lioz

in

(Invokana)

100

300

mg

QD

be

fore

rst

meal

23kgplacebo-

subtractedweight

lossin26-wk

monotherapytrial139

0.70%0.95%

reduction140

Hyperkalemia

Genitourinaryinfection

Absenceo

flong-t

erm

efcacyan

dsafety

data

Discontinuecanag

lioz

inife

GFRis

persistently4

5mL/min/1.73m2

Approvedfor

thetreatment

ofT2DM

Abbreviations:

BID

,tw

ice

da

ily;

BP,b

loo

dpressure;

Cr,creatin

ine;

DM

,diabetesme

llitus;eG

FR

,est

imate

dg

lomeru

lar

ltrationrate;

GLP

-1,g

lucag

on-l

ikepepti

de-1

;MAOI,monoam

ineox

idase

inhibitor;

MEN

-2,m

ultipleen

docrine

neoplasia-2;OTC,overthecounter;Q

D,oncedaily;SSRI,selectiveserotoninreuptakeinhibitor;SGLT-2,sodium-glucosecotransporter-2;TID,3timesdaily;T2DM,type2diabetesmellitus.


11/14




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.

Pharmacotherapy for Weight LossWeight loss, which plays an integral role in diabetes mellitus

management, has profound effects on insulin sensitivity. Inorder to maximize initial weight lost and minimize weight

regain in patients, pharmacotherapy can be used in combi-

nation with continued lifestyle modication. Health care

providers should also be mindful of the potential weight

effects when selecting pharmacologic treatments for diabetes

mellitus.124Several 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 ofthis 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

(Table 2). All of these medications, when combined with life-

style modication, induced losses of approximately 5% to 10%

of initial patient body weight in 1- to 2-year trials.125128These

losses were associated with signicant improvements in seve-

ral metabolic outcomes and CVD risk factors in patients.

ConclusionMedical nutrition therapy is an integral component in the

management of diabetes mellitus. Current nutrition recom-

mendations favor a exible 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 signicant improvements in

glycemic and lipid parameters, decreased insulin resistance,

and reduced blood pressure. Optimal macronutrient distribu-

tion 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 modication, with or without pharmacotherapy,

can be used to facilitate weight loss in patients.

Conict of Interest Statement

Marion L. Vetter, MD, RD, has been employed by Bristol-

Myers Squibb in research on pharmacotherapy for patients

with diabetes mellitus. Anastassia Amaro, MD, and Sheri

Volger, RD, MS, have no conicts 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, Engelgau MM.

Changes in incidence of diabetes in U.S. adults, 19972003.Am J PrevMed. 2006;30(5):371377.

3. Kramer H, Cao G, Dugas L, Luke A, Cooper R, Durazo-Arvizu R.

Increasing BMI and waist circumference and prevalence of obe-

sity 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(4 suppl 1):S52S58.

6. Franz MJ, Monk A, Barry B, et al. Effectiveness of medical nutritiontherapy provided by dietitians in the management of non-insulin-

dependent 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, et al. The evidence for medical nutri-

tion 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, Mayeld 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(4 suppl 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 inter-

ventions for diabetes. A position statement of the American DiabetesAssociation.Diabetes Care. 2008;31(suppl 1):S61S78.

17. Anderson EJ, Richardson M, Castle G, et al. 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 carbohy-

drate diets in type II diabetes.Am J Med. 1988;84(2):193200.


12/14

Vetter et al



20. Rickard KA, Cleveland JF, Loghmani ES, Fineberg NS, Freidenberg GR.

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 fructosefound 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 meta-

analysis.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, et al. Health benets of dietary ber.

Nutr Rev. 2009;67(4):188205.

30. Steemburgo T, DallAlba V, Almeida JC, Zelmanovitz T, Gross JL,

de Azevedo MJ. Intake of soluble bers 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, et al. Effects of supplemented isoene-

rgetic diets differing in cereal ber and protein content on insulin sen-

sitivity 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, Grundy SM,

Brinkley LJ. Beneficial effects of high dietary fiber intake in

patients with type 2 diabetes melli tus.N Engl J Med. 2001;342(19):

13921398.

34. Post RE, Mainous AG 3rd, King DE, Simpson KN. Dietary ber 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 metabo-

lism and the pathogenesis of insulin resistance. Physio l 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.

N Engl 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, Willett WC.

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 prospec-

tive population-based study.Lancet. 2001;357(9258):746751.

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 prole 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 diabe-

tes mellitus: a meta-analysis. Am J Clin Nutr. 1998;67(suppl 3):

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, et al. Metabolic interactionsof 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, et al. 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, et al. 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: Improv-

ing Control with Activity and Nutrition (ICAN) study.Diabetes Care.

2004;27(7):15701576.

62. Schauer PR, Burguera B, Ikramuddin S, et al. 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 type 2

diabetes by metabolic surgery? A critical analysis of the evidence in

2010.Diabetes Care. 2011;34(suppl 2):S355S360.


13/14




64. Redmon JB, Raatz SK, Kwong CA, Swanson JE, Thomas W, Bantle JP.

Pharmacologic induction of weight loss to treat type 2 diabetes.Dia-

betes Care. 1999;22(6):896903.

65. Klein S, Sheard NF, Pi-Sunyer X, Daly A, Wylie-Rosett J, Kulkarni K,

et al. Weight management through lifestyle modication for the pre-

vention and management of type 2 diabetes: rationale and strategies:

a statement 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,

et al. Weight loss with sibutramine improves glycaemic control andother 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, et al.

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, Grifths 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 modication 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. Benets of modest weight

loss in improving 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 self-

regulation 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.

J Cardiovasc Nurs. 2009;24(1):5880.

76. Ryan DH, Espeland MA, Foster GD, Haffner SM, Hubbard VS,

Johnson KC, et al; 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, et al.

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, et al. 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,

Wing RR, et al. Weight loss prevents urinary incontinence in womenwith 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, et al. 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, et al. Intensive lifestyle intervention

improves physical function among obese adults with knee pain:

ndings from the Look AHEAD trial. Obesity. 2011;19(1):8393.

84. Rejeski WJ, Ip EH, Bertoni AG, Bray GA, Evans G, Gregg EW, et al.

Lifestyle change and mobility in obese adults with type 2 diabetes.

N Engl J Med. 2012;366(13):12091217.

85. Volek JS, Feinman RD. Carbohydrate restriction improves features of

the metabolic syndrome. Metabolic syndrome may be dened 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 AtherosclerRev. 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,

et al. 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, et al.

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. Long-

term 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,

Josse RG, et al. 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,

et al. 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, Greenberg I,

et al. 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, et al.

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, Margolis KL.

Restricted-carbohydrate diets in patients with type 2 diabetes: a meta-

analysis.J Am Diet Assoc. 2008;108(1):91100.

101. Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Sato M, et al. Inuence of

fat and carbohydrate proportion son the metabolic prole 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, et al. Macronutrients, food groups, and eating patterns

in the management of diabetes: a systematic review of the literature.

Diabetes Care. 2012;35(2):434445.


14/14

Vetter et al


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, Baldwin JM,

et al. 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, et al. Effect of a

low-glycemic index or a high-cereal ber diet on type 2 diabetes.

A randomized trial.JAMA. 2008;300(23):27422753.

108. Ma Y, Olendzki B, Merriam PA, Chiriboga DE, Culver AL, Li W, et al.

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, Whittaker V,

et al. 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-Varela O,

Menotti A, et al. 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, et al. 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, Ruiz-

Guiterrez V, Covas MI, et al. 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,

and polyunsaturated (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, et al. 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 chro-

mium on glucose and lipid proles 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 supple-

mentation 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 sys-

tematic 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.

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(4 A):68B79B.

126. Rucker D, Padwal R, Li SK, Curioni C, Lau DC. Long term pharma-

cotherapy 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. Phar-

macotherapy 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. Efcacy and

safety of lorcaserin in obese adults: a meta-analysis of 1-year random-

ized 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,

et al. Meta-analysis: pharmacologic treatment of obesity.Ann Intern

Med. 2005;142(7):532546.

131. Ye Z, Chen L, Yang Z, et al. Metabolic effects of uoxetine 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, Gross JL.

Efcacy 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,

Bray GA. Zonisamide for weight reduction in obese adults: a 1-year ran-

domized controlled trial.Arch Intern Med. 2012;172(20):15571564.

134. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M,

Moher D. 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,

et al. 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 system-

atic review and meta-analyses of randomized controlled trials.BMJ.

2012;344:d7771.

137. Shyangdan DS, Royle PL, Clar C, Sharma P, Waugh NR. Glucagon-

like 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, et al.

Efcacy and safety of canagliozin monotherapy in subjects with

type 2 diabetes mellitus inadequately controlled with diet and exer-

cise.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

Documents

Transcript of DM treatment