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Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Managing Type 2 Diabetes: Balancing HbA1c and Body Weight

Annie A. Mavian DO, Stephan Miller PhD & Robert R. Henry MD

To cite this article: Annie A. Mavian DO, Stephan Miller PhD & Robert R. Henry MD (2010) Managing Type 2 Diabetes: Balancing HbA1c and Body Weight, Postgraduate Medicine, 122:3, 106-117

To link to this article: http://dx.doi.org/10.3810/pgm.2010.05.2148

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106 © Postgraduate Medicine, Volume 122, Issue 3, May 2010, ISSN – 0032-5481, e-ISSN – 1941-9260

C L I N I C A L F O C U S : D I A B E T E S

Managing Type 2 Diabetes: Balancing HbA 1c

and Body Weight

Abstract: Most patients with type 2 diabetes present with comorbid overweight or obesity. Reaching and maintaining acceptable glycemic control is more diffi cult in overweight and obese

patients, and these conditions are associated with increased risk for cardiovascular and other

diseases. Glycemic management for these patients is complicated by the fact that insulin and

many of the oral medications available to treat type 2 diabetes produce additional weight gain.

However, an increasing number of therapeutic options are available that are weight neutral or

lead to weight loss in addition to their glycemic benefi ts. This article evaluates the evidence

from clinical trials regarding the relative glycemic benefi ts, measured in terms of glycated

hemoglobin change, versus the impact on body weight of each medication currently approved

for type 2 diabetes. In general, the sulfonylureas, thiazolidinediones, and D-phenylalanine

derivatives have been shown to promote weight gain. The dipeptidyl peptidase-4 inhibitors are

weight neutral, while the biguanides, incretin mimetics, and amylin mimetics promote weight

loss. Trials examining the glycemic benefi ts of the weight loss agents orlistat and sibutramine

are also examined. Awareness of this evidence base can be used to inform medication selection

in support of weight management goals for patients with type 2 diabetes.

Keywords: type 2 diabetes; overweight; obesity; glycemic control

Introduction The prevalence of obesity and the prevalence of diabetes have risen markedly in the

United States.1–3 Overweight and obesity are associated not only with diabetes, high

blood pressure, high cholesterol, asthma and arthritis, but also overall fair or poor

health.3 Furthermore, overweight and obesity are independent risk factors of cardio-

vascular disease in patients with type 2 diabetes.4 The majority of patients with type

2 diabetes are overweight or obese at the time of diagnosis, and treatment with many

oral hypoglycemic agents and insulin are known to have weight gain as an adverse

effect. In addition, compared with non-obese patients, obese patients are less able to

maintain initial improvements in glycated hemoglobin A 1c

(HbA 1c

) levels with anti-

diabetic therapy.5 Studies have shown that weight loss is associated with improved

insulin resistance, resulting in better glycemic control,6 and that weight reductions in

post-gastric bypass patients are associated with a decrease in the use of antidiabetic

medications.7

The purpose of this article is to review the effects of currently US Food and Drug

Administration (FDA)-approved non-insulin diabetes medications on HbA 1c

and body

weight in type 2 diabetes. Selected studies include those with the following features:

a monotherapy arm, measurements of both HbA 1c

and weight, conducted within the

last 6 years, duration of � 18 weeks, and � 50 patients. Exceptions were made if the

drug was used only in combination and if no monotherapy studies had been conducted

in the past 6 years. Selected studies of drugs approved for the treatment of obesity

will also be considered. This article will discuss the key features of the studies listed

Annie A. Mavian, DO1

Stephan Miller, PhD2

Robert R. Henry, MD1

1Division of Endocrinology, Diabetes, and Metabolism, University of California San Diego and Veterans Affairs San Diego Healthcare System, San Diego, CA; 2Amylin Pharmaceuticals, Inc., San Diego, CA

Correspondence: Robert R. Henry, MD, Professor of Medicine, University of California San Diego, Chief, Division of Endocrinology, Diabetes, and Metabolism, Veterans Affairs San Diego Healthcare System, San Diego, CA. Tel: 858-522-8585 x3648 Fax: 858-642-6242 E-mail: [email protected]

Global reprints distributed only by Postgraduate Medicine USA. No part of Postgraduate Medicine may be reproduced or transmitted in any form without written permission from the publisher. All permission requests to reproduce or adapt published material must be directed to the journal office in Berwyn, PA, no other persons or offices are authorized to act on our behalf. Requests should include a statement describing how material will be used, the complete article citation, a copy of the figure or table of interest as it appeared in the journal, and a copy of the “new” (adapted) material if appropriate

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Balancing Glycemic Control and Body Weight

Table 1. Antidiabetic and Weight Loss Agents and Their Effect on HbA 1c and Body Weight

Agent Ref Study Duration

Subjects Doses Baseline HbA

1c (%)

Δ HbA 1c

(%)

Δ Weight (kg)

Adverse Events (% of subjects)

Sulfonylureas

Tolbutamide 12 24 wks 66 250–1000 mg TID 6.95 −0.93 +1.8 10% nausea 34% fl atulence

Chloropropamide 11 10 y 619 100–500 mg/day 6.3 6.7a +2.6b 1.0% major hypo/y

Glyburide ( glibenclamide)

11 10 y 615 2.5–5 mg/day 6.3 7.2a +1.7 b 1.4% major hypoglycemia/y

13 20 wks 160 2.5–10 mg/day 8.21 −1.24 +1.7 6.3% any hypoglycemia 4.4% diarrhea

19 4 y, median 1441 2.5–7.5 mg BID 7.4 +0.24/yr +1.6 1.8% serious CV events 38.7% any hypoglycemia

Glipizide 14 12 wks 119 5–20 mg/day 7.8 −0.76 +0.9 17% hypoglycemia

15 18 wks 84 15 mg BID 8.9 −0.4 −0.4 No hypoglycemia 13% URI 13% diarrhea

Glimepiride 16 52 wks 123 2–8 mg/day 8.45 −0.68 +0.79 31% any hypoglycemia 17% peripheral edema

Thiazolidinediones

Rosiglitazone 18 24 wks 238 8 mg QD 8.7 −1.3 +1.6 1 subject mild hypoglycemia 7.5% nasopharyngitis 4.1% peripheral edema

19 4 y, median 1456 4 mg QD−4 mg BID

7.4 +0.07/yr +0.7 3.4% serious CV events 9.8% any hypoglycemia

Pioglitazone 20 34.5 mos, mean

2605 15–45 mg QD 7.8 −0.8 +3.6 28% any hypoglycemia

21 24 wks 161 30 mg QD 8.7 −1.4 +1.5 1 subject mild hypoglycemia 4.1% edema

D-phenylalanine derivatives

Nateglinide 25,26 24 wks 179 120 mg 8.3 −0.5 +0.9 12.8% any hypoglycemia 27 28 wks 150 120 mg 8.4 −0.7 +0.53 0.7% confi rmed hypoglycemia

Meglitinides

Repaglinide 29 24 wks 63 4 mg/meal 9.3 −0.17 +1.6 6% mild hypoglycemia

Biguinides

Metformin 31 29 wks 143 850–2550 mg/day 8.4 −1.4 −0.6 8% severe diarrhea 4% severe nausea � 2% any hypoglycemia

31 29 wks 210 500–2500 mg/day 8.9 −0.4 −3.8 2% any hypoglycemia

32 32 wks 272 500–3000 mg/day 7.2 −0.38 −1.9 4% m/m hypoglycemia

19 4 y, median 1454 500 mg to 1 g BID 7.4 +0.14/yr −2.9 3.2% serious CV 11.6% any hypoglycemia

�-Glucosidase inhibitors

Acarbose 12 24 wks 67 200 mg TID 6.88 −0.54 −1.4 80% fl atulence 27% diarrhea

36 24 wks 220 Up to 300 mg/day 8.6 −1.3 −1.7 25.5% GI adverse events No hypoglycemia

Miglitol 37 36 wks 82 100 mg TID 8.2 +0.02 −0.42 71% GI adverse events 8.5% m/m hypoglycemia

(Continued)

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108 © Postgraduate Medicine, Volume 122, Issue 3, May 2010, ISSN – 0032-5481, e-ISSN – 1941-9260

Mavian et al

Table 1 (Continued)

Agent Ref Study Duration

Subjects Doses Baseline HbA

1c (%)

Δ HbA 1c

(%)

Δ Weight (kg)

Adverse Events (% of subjects)

Incretin mimetics

Exenatide 40 24 wks 232 10 μg BID 7.8 −0.9 −3.1 13% nausea 4% m/m hypoglycemia

42 30 wks 147 10 μg BID 8.3 −1.5 −3.6 34.5% nausea 15.4% minor hypoglycemiad

45 26 wks 231 10 μg BID 8.1 −0.79 −2.87 28% nausea 34% minor hypoglycemia 2 episodes major hypoglycemiad

EQW 42 30 wks 148 2 mg QW 8.3 −1.9 −3.7 26.4% nausea 14.5% minor hypoglycemiad

43 52 wks 128 2 mg QW 8.3 −2 −4.5 8.6% diarrheae 7.0% nausea

Liraglutide 44 52 wks 746 1.8 mg QD 8.3 −1.14 −2.45 29% nausea 8% minor hypoglycemia

45 26 wks 233 1.8 mg QD 8.2 −1.12 −3.24 25.5% nausea 26% minor hypoglycemia

Amylinomimetics

Pramlintide 47 52 wks 166 120 μg BID 9.0 −0.62 −1.4 0.3 event rate/patient-year severe hypoglycemia 2% nausea

48 6 mos 166 120 μg BID or TID 8.3 −0.56 −2.8 12% any hypoglycemia 29.5% nausea

DPP-4 inhibitors

Sitagliptin 50 24 wks 238 200 mg QD 8.08 −0.76 −0.1 0.8% m/m hypoglycemia 16.4% GI adverse event

51 24 wks 175 100 mg QD 8.87 −0.66 0.0 0.6% m/m hypoglycemia 16.4% GI adverse event

Saxagliptin 52 24 wks 98 10 mg QD 7.9 −0.54 −0.1 8.2% m/m hypoglycemia 6.1% diarrhea

Lipase Inhibitors

Orlistat 53 1 y 266 120 mg TID 9.01 −0.62 −3.89 80% GI adverse event 17% any hypoglycemia

54 1 y 250 120 mg TID 8.87 −0.75 −4.7 83% GI adverse event 10% m/m hypoglycemia

56 12 mos 71 120 mg TID 7.1 −0.8 −11c 34% GI adverse event

Reuptake Inhibitors

Sibutramine 55 12 mos 62 20 mg QD 9.14 −0.32 −8.0 Increased mean heart rate and blood pressure

56 12 mos 70 10 mg QD 7.0 −0.9 −10.4c Increased blood pressure in 1 subject

aMedian over 10 years; bWeight gain in addition to that with conventional therapy; cWeight change calculated from reported BMI change; dPrimarily in patients with concommitant SU use; eAdverse events from week 30 to week 52. Abbreviations: BID, twice daily; BMI, body mass index; CV, cardivascular; EQW, exenatide once weekly; GI, gastrointestinal symptoms; m/m, mild-to-moderate intensity; QD, once daily; TID, 3 times daily; URI, upper respiratory infection.

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Balancing Glycemic Control and Body Weight

in Table 1, with emphasis on select studies. Table 1 can be

referenced for an overview of baseline HbA 1c

, change in

HbA 1c

, change in body weight, and adverse events.

Antihyperglycemic Agents Associated with Weight Gain Sulfonylureas The sulfonylureas (SUs) are a class of antihyperglycemic

agents that improve plasma glucose levels by stimulating

insulin secretion from pancreatic β-cells. Because their specifi c action on insulin is independent of plasma glucose

concentrations, hypoglycemia is a common adverse

effect.8–10 The SUs are indicated as adjuncts to diet or diet

and exercise. The UK Prospective Diabetes Study compared

SUs and insulin with conventional diabetes dietary treat-

ment.11 Patients were randomized to receive either the fi rst-

generation SU chlorpropamide 100 to 500 mg daily (n = 619), the second-generation SU glyburide (glibenclamide) 2.5 to

20 mg daily (n = 615), insulin (n = 911), or conventional treatment with diet (n = 896). Over the course of 10 years, the median HbA

1c was 6.7% in the chlorpropamide group, 7.2%

in the glyburide group, and 7.1% in the insulin group, com-

pared with 7.9% in the conventional treatment group. Weight

gain was observed in all treatment groups and was greater

with chlorpropamide, glibenclamide, and insulin than with

conventional therapy. The chlorpropamide group gained

2.6 kg, the glyburide group gained 1.7 kg, and the insulin

group gained 4 kg more than the conventional treatment

group, which gained approximately 2.5 kg.11

The fi rst-generation SU tolbutamide was studied in a

multicenter, 24-week, placebo-controlled trial comparing

acarbose, tolbutamide, and tolbutamide plus acarbose.12

Patients in the tolbutamide group achieved an HbA 1c

reduction of 0.93% from a baseline of 6.95%, and the acar-

bose group achieved an HbA 1c

reduction of 0.54% from a

baseline of 6.88%. The combination of tolbutamide plus

acarbose produced an HbA 1c

reduction of 1.32% from a

baseline of 6.73%. Treatment with tolbutamide alone resulted

in a 1.8-kg weight gain. Acarbose alone produced a weight

loss of 1.4 kg and appeared to counteract the weight gain

effects of tolbutamide, resulting in a weight increase of only

0.19 kg when the 2 agents were used in combination.

Garber et al13 compared the second-generation SU

glyburide in combination with metformin to monotherapy

with either glyburide or metformin alone in a double-blind,

parallel-group, placebo-controlled multicenter study, in

which 806 subjects were randomized to placebo, glybu-

ride 2.5 mg, metformin 500 mg, glyburide/metformin

(1.25 mg/250 mg), or glyburide/metformin (2.5 mg/500 mg).

At 20 weeks of therapy HbA 1c

was reduced by 1.03% in

the metformin group, 1.24% in the glyburide group, 1.48%

in the glyburide/metformin (1.25 mg/250 mg) group, and

1.53% in the glyburide/metformin (2.5 mg/500 mg) group.

An overall weight gain was observed in all glyburide

treatment arms, whereas weight reduction was achieved

in both the placebo and metformin groups. The glyburide/

metformin (1.25 mg/250 mg) group demonstrated a 1.4-kg

weight gain, the glyburide/metformin (2.5 mg/500 mg) group

a 1.9-kg weight gain, and a 1.7-kg weight gain occurred in

the glyburide monotherapy group. In contrast, the metformin

and placebo groups achieved weight reductions from baseline

of 0.6 kg and 0.7 kg, respectively.

Variable effects on weight gain have been demonstrated

with the second-generation SU glipizide. Scott et al14 com-

pared glipizide monotherapy with sitagliptin in a 12-week

double-blind, placebo-controlled study of 743 patients with

type 2 diabetes inadequately controlled with diet and exer-

cise. Patients were randomized to receive placebo, glipizide,

or 1 of 4 doses of sitagliptin twice daily (5 mg, 12.5 mg,

25 mg, or 50 mg). Glipizide was initiated at 5 mg per day

with optional titration up to 20 mg depending on glycemic

control. At 12 weeks, the greatest HbA 1c

reduction was

in the glipizide treatment group (0.76%) compared with

reductions with sitagliptin ranging from 0.15% (2.5 mg) to

0.54% (50 mg) and an HbA 1c

increase in the placebo group

of 0.23%. However, the HbA 1c

reduction with glipizide was

accompanied by a 0.9-kg weight increase, whereas weight

was unchanged in the sitagliptin-treated groups relative to

baseline or placebo.

Goldstein et al15 evaluated glipizide alone and in

combination with metformin in a double-blind, parallel-

group, controlled study of patients who were failing

monotherapy with SUs alone. Subjects were random-

ized to receive glipizide 30 mg (n = 84), metformin 500 mg (n = 76), or glipizide/metformin 5/500 mg (n = 87) over an 18-week course of treatment. The doses were titrated to a maximum dose of glipizide

30 mg, metformin 2000 mg, and metformin/glipizide

20/2000 mg daily. Mean baseline HbA 1c

measurements

were in the range of 8.6% to 8.9% for all 3 groups. At

18 weeks, a greater reduction in HbA 1c

was achieved

in the combination metformin/glipizide group (1.3%)

than with either metformin (0.2%) or glipizide alone

(0.4%). Weight reduction occurred in all 3 arms of

the study, with the greatest reduction observed in the

metformin monotherapy arm (2.7 kg). Weight reduction

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110 © Postgraduate Medicine, Volume 122, Issue 3, May 2010, ISSN – 0032-5481, e-ISSN – 1941-9260

Mavian et al

was smaller in the glipizide-treated arms (0.4 kg with

glipizide monotherapy and 0.3 kg in the metformin/

glipizide arm).

Tan et al16 compared pioglitazone with the third-

generation SU glimepiride. This was a multicenter, 52-week,

double-blind, parallel-group study that randomized patients

to either glimepiride 2 mg daily (n = 123) or pioglitazone 15 mg (n = 121) with titration up to a maximum of 8 mg and 45 mg, respectively, to achieve glycemic targets. The

HbA 1c

decreased by 0.68% from a baseline of 8.45% in the

glimepiride group, while the pioglitazone group achieved

a 0.78% reduction from a baseline of 8.54%. Both groups

experienced weight gain from baseline (1.49 kg in the pio-

glitazone group and 0.79 kg in the glimepiride group).

The clinical trials conducted over the past several years

have consistently shown that while treatment with SUs

improves HbA 1c

, they are often accompanied by signifi cant

weight gain,12–14,16 with the exception of 1 glipizide study

discussed above.15 Weight gain with SUs may be a direct

result of improved insulin secretion and the anabolic effects

of insulin, while weight gain with thiazolidinediones (TZDs)

is partly related to fl uid retention and increased fat mass.

Thiazolidinediones Thiazolidinediones, including rosiglitazone, pioglitazone,

and troglitazone, are agonists of peroxisome proliferator-

activated receptors, which are found primarily in adipose

tissue and the liver and, at lower levels, in skeletal muscle.

Thiazolidinediones improve insulin resistance and insulin

sensitivity by increasing insulin-stimulated glucose disposal

and suppressing hepatic glucose production.17 Thiazolidin-

ediones are approved for use as monotherapy or in combina-

tion with an SU, metformin, or insulin when a single agent

(plus diet and exercise) does not provide adequate control.

Rosenstock et al18 compared vildagliptin with rosiglitazone

monotherapy in a 24-week, double-blind, randomized trial.

Patients were randomized to receive vildagliptin 100 mg

(n = 459) or rosiglitazone 8 mg daily (n = 238). In patients receiving rosiglitazone, there was an HbA

1c reduction of 1.3%

versus 1.1% reduction in the vildagliptin group. The average

body weight in the vildagliptin group did not change signifi -

cantly from a baseline of 91.2 kg, whereas the rosiglitazone

group had a statistically signifi cant weight increase of 1.6 kg

from a baseline of 93.1 kg.

A Diabetes Outcome Progression Trial (ADOPT)

compared monotherapy with rosiglitazone, metformin, and

glyburide as initial therapy in patients who were diagnosed

with type 2 diabetes within the last 3 years and were treatment

naïve.19 The median duration of this study was 4 years, and

the primary endpoint was time to monotherapy failure,

defi ned as a fasting plasma glucose level of � 180 mg/dL.

This was a double-blind, randomized, controlled trial with

4360 patients. Subjects were randomized to receive daily

doses of rosiglitazone 4 mg (n = 1456), metformin 500 mg (n = 1454), or glyburide 2.5 mg (n = 1441). Doses were titrated upwards to maximums of rosiglitazone 4 mg twice

daily, metformin 1 g twice daily, and glyburide 7.5 mg

twice daily. At 5 years, 15% of the patients treated with

rosiglitazone monotherapy met the criteria for monotherapy

failure, compared with 21% in the metformin group and

34% in the glyburide group. Secondary outcomes included

changes in HbA 1c

and body weight. After 4 years, 40% of the

rosiglitazone group achieved an HbA 1c

of � 7%, compared

with 36% of the metformin group and 26% of the glyburide

group. However, the rosiglitazone group experienced the

greatest weight gain, 4.8 kg after 5 years, compared with a

weight reduction of 2.9 kg in the metformin group. Weight

gain was more modest in the glyburide group (1.6 kg after

1 year) and relatively stable thereafter.19

The PROactive Study evaluated macrovascular events

in patients who were randomized to receive pioglitazone

45 mg (n = 2605) or placebo (n = 2633) in addition to their existing medication(s).20 This prospective trial had

an average observation time of 34.5 months until the fi nal

visit, at which time patients in the pioglitazone group had an

HbA 1c

reduction of 0.8% and the placebo group had a 0.3%

reduction. The improvement in the HbA 1c

was accompanied

by a 3.6-kg weight gain in the pioglitazone group, whereas

a 0.4-kg weight loss was observed in the placebo group.

Despite this weight gain, pioglitazone treatment was associ-

ated with a small reduction in risk of myocardial infarction,

stroke, and all-cause mortality.

The clinical trials discussed above consistently

demonstrated weight gain associated with rosiglitazone

or pioglitazone treatment. Another 24-week, multicenter,

randomized, double-blind, active-controlled study compared

pioglitazone monotherapy with vildagliptin monotherapy and

combinations of both drugs in subjects with a mean baseline

HbA 1c

of 8.7%. Patients in the pioglitazone (n = 161, 30 mg) and vildagliptin (n = 154, 100 mg) monotherapy groups had HbA

1c reductions of 1.4% and 1.1%, respectively,

compared with vildagliptin/pioglitazone 100/30 mg

(n = 148) and vildagliptin/pioglitazone 50/15 mg (n = 144), which achieved reductions of 1.9% and 1.7%, respectively.

Body weight did not change signifi cantly from baseline in the

vildagliptin monotherapy group (−0.3 kg) but increased in the

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Balancing Glycemic Control and Body Weight

pioglitazone monotherapy group by 1.5 kg and increased by

1.4 kg and 2.1 kg in the low-dose and high-dose combination

vildagliptin/pioglitazone groups, respectively.21

While TZDs improve HbA 1c

by improving insulin

sensitivity and peripheral glucose disposal, they also

have signifi cant effects on overall body weight by increasing

fat mass and fl uid retention. Thiazolidinedione use is usually

associated with an increase in subcutaneous adipose tissue,

while visceral adiposity decreases or remains unchanged.22,23

This is in contrast to the typical pattern of weight gain pro-

duced with some other classes of antidiabetic medication,

which includes an increase in the mass of metabolically more

toxic visceral adipose tissue. Because of the differential effect

on fat stores, it has been suggested that TZD-mediated weight

gain may be less detrimental than weight gain produced with

other agents, or may even be benefi cial.24 Further, weight gain

can be minimized or prevented by concomitant use of modest

caloric restriction and/or by co-administration of metformin

or glucagon-like peptide-1 (GLP-1) agonists.

D-phenylalanine Derivatives Nateglinide is an amino acid derivative that lowers blood

glucose levels by stimulating insulin secretion from the

pancreas.25 Nateglinide is indicated as an adjunct to diet and

exercise either alone or in combination with metformin or a

TZD. Nateglinide monotherapy (n = 179) was compared with metformin monotherapy (n = 178), combination nateglinide/ metformin (n = 172), and placebo (n = 172) in a 24-week double-blind, placebo-controlled study. Patients were

randomized to nateglinide 120 mg before meals, metformin

500 mg after the start of each meal, the combination of

nateglinide/metformin 120/500 mg, or placebo. After

24 weeks of therapy, HbA 1c

changes from baseline were

−0.5% in the nateglinide monotherapy group, −0.8% in the metformin group, −1.4% in the combination group, and +0.5% in the placebo group. All groups had a baseline HbA

of 8.3% to 8.4%. There were no signifi cant changes in weight

from baseline in any of the active treatment groups, although

the nateglinide monotherapy experienced a small weight gain

(� 1 kg).25,26 In another trial, Rosenstock et al27 evaluated

nateglinide, troglitazone, and the combination of nateglinide

and troglitazone in a 28-week, double-blind, randomized,

multicenter study with a 4-week, single-blind placebo, run-

in and a 24-week, double-blind, active treatment period.

Patients were randomized to nateglinide 120 mg, troglitazone

600 mg, nateglinide/troglitazone 120 mg/600 mg, or placebo.

By the end of week 24, HbA 1c

was increased by 0.3% in

the placebo group, but decreased by 0.7%, 1%, and 1.8%

in the nateglinide, troglitazone, and combination groups,

respectively, from a mean baseline HbA 1c

of 8.1% to 8.4%.

Mean body weight was increased by 0.53, 0.50, and 2.31 kg

in the nateglinide, troglitazone, and combination treatment

groups, respectively. Weight gain in the combination group

was greater than twice the amount compared with either

nateglinide or troglitazone monotherapy groups.

Meglitinides Repaglinide is currently the only FDA-approved drug in the

meglitinide class. It has a similar mechanism of action to

that of SUs, in that it is a glucose-independent secretagogue.

It works by inducing insulin secretion from pancreatic β-cells with a rapid onset of action for a short duration. Thus, the most

common adverse event is mild-to-moderate hypoglycemia.28

Repaglinide is indicated for use as monotherapy in conjunction

with diet and exercise or in combination with metformin or

a TZD. In a 24-week, randomized, multicenter, open-label,

parallel-group study, repaglinide plus rosiglitazone was

compared with repaglinide and rosiglitazone monotherapy in

patients with mean baseline HbA 1c

of 9% to 9.3% (N = 252).29 At the end of the 24 weeks, the mean change in HbA

1c in

the repaglinide monotherapy group alone was a decrease of

0.17% compared with 0.56% with rosiglitazone and 1.43%

with repaglinide/rosiglitazone therapy. The small HbA 1c

reduction with repaglinide monotherapy was accompanied

by a weight gain of 1.6 kg. Greater weight gain was noted

in the rosiglitazone monotherapy group (2.3 kg) and with

combination therapy (4.4 kg).29 Similar to the results in the

clinical trial evaluating nateglinide in combination with

troglitazone,27 greater weight gain was observed when repa-

glinide was used in combination with a TZD.

Antihyperglycemic Agents That Promote Weight Loss or Are Weight Neutral Biguanides Metformin hydrochloride is an antihyperglycemic agent

that improves both basal and postprandial plasma glucose

concentrations. Its mechanisms of action include decreasing

hepatic glucose production, decreasing intestinal absorp-

tion of glucose and improving hepatic, and to a lesser

extent, peripheral insulin sensitivity. Because insulin

secretion is unchanged by metformin, hypoglycemia is

uncommon.30 In contrast to most of the agents available,

metformin is approved for use in children as well as adults.

In 2 randomized, placebo-controlled, 29-week multicenter

trials, DeFronzo et al31 evaluated the effi cacy of metformin

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in moderately obese, non–insulin-dependent patients with

diabetes who were poorly controlled with diet alone or with

diet plus an SU. In protocol 1, the patients were instructed

to follow a low-calorie diet that consisted of 20% fewer

calories than the patient’s calculated daily caloric expen-

diture. After this initial phase, patients were randomized to

receive placebo (n = 146) or metformin (n = 143) starting at 850 mg once daily and uptitrating to 2550 mg daily. By

29 weeks, the HbA 1c

decreased by 1.4% from a baseline of

8.2% in the metformin group and increased by 0.4% from

a baseline of 8.4% in the placebo group. Weight reduction

was observed in both treatment groups, resulting in a 0.6-

kg weight loss in the metformin group and a 1.1-kg weight

loss in the placebo group (P = 0.21). In protocol 2, patients were instructed to follow a weight-maintaining diet. Prior

to randomization, patients were either continued on or were

started on glyburide. Patients who were on another SU were

switched to glyburide. During the active phase, patients were

randomized to glyburide (n = 209), metformin (n = 210), or a metformin/glyburide combination (n = 213). The initial starting dose of metformin was 500 mg daily and uptitrated

to 2500 mg daily, while glyburide was initiated at 10 mg

daily and uptitrated to 20 mg daily. At 29 weeks, the patients

achieved an HbA 1c

reduction of 1.7% from a baseline of 8.8%

in the combination group, compared with a 0.2% reduction

from a baseline of 8.5% in the glyburide group and 0.4%

reduction from a baseline of 8.9% in the metformin group.

There was a weight reduction of 3.8 kg in the metformin

group, an increase of 0.4 kg in the combination treatment

group, and no signifi cant weight change in the glyburide

group, suggesting that the SU offset the weight loss produced

by metformin.

Similar results were achieved in another clinical trial

comparing metformin monotherapy with metformin in

combination with TZDs. In a multicenter, randomized, double-

blind, parallel-group, dose-escalation study, metformin alone

was compared with metformin plus rosiglitazone.32 Two-

hundred seventy-two patients were randomized to metformin

alone, while 254 patients received metformin plus rosigli-

tazone. At the end of 32 weeks, the metformin group achieved

an HbA 1c

reduction from 7.2% to 6.8%. The combination

treatment group achieved an HbA 1c

reduction from 7.2% to

6.7%. Furthermore, a weight reduction of 1.9 kg was achieved

in the metformin group, whereas the combination group had

no signifi cant weight reduction. Two small studies have

demonstrated that the use of metformin in conjunction with

insulin allowed a reduction in insulin dose and either attenu-

ated insulin-induced weight gain33 or promoted weight loss.34

α-Glucosidase Inhibitors The α-glucosidase inhibitors (including acarbose and miglitol) work by delaying enzymatic breakdown of carbohydrates by

inhibiting pancreatic α -amylase and α -glucoside hydrolase, delaying absorption of and thereby lowering postprandial

blood glucose levels.35 A recent article by Pan et al36 com-

pared vildagliptin 100 mg daily (n = 440) and acarbose 300 mg daily (n = 220) monotherapy in a 24-week, random- ized, double-blind, parallel-group study. At the end of the

24-week treatment, there was an HbA 1c

reduction of 1.3% in

the acarbose group and a 1.4% reduction in the vildagliptin

group from a mean baseline HbA 1c

of 8.6%. Body weight

reductions of 1.7 and 0.4 kg were achieved in the acarbose

group and vildagliptin group, respectively.

Similarly, benefi cial effects on weight were also achieved

with another α-glucosidase inhibitor, miglitol, which was evaluated alone and in combination with metformin in a

randomized, double-blind, placebo-controlled study for

36 weeks. Patients were randomized to placebo (n = 83), miglitol monotherapy 100 mg 3 times daily (n = 82), metformin monotherapy 500 mg (n = 83), or metformin/ miglitol combination therapy (n = 76). Miglitol was started at 25 mg 3 times daily for 4 weeks, and uptitrated to 50 mg

3 times daily for 8 weeks, and fi nally increased to 100 mg

3 times daily until the end of the study. Metformin was

administered 500 mg 3 times daily throughout the study.

At the end of the study, HbA 1c

increased by 0.38% in the

placebo group, while it remained unchanged in the miglitol

monotherapy group. In contrast, patients in the metfor-

min plus miglitol group achieved an HbA 1c

reduction of

1.39%, signifi cantly greater than in the metformin mono-

therapy group, which achieved an HbA 1c

reduction of 0.85%.

Body weight reductions of 0.42 and 0.69 kg were noted in the

miglitol monotherapy group and placebo group, respectively,

while the metformin monotherapy group and miglitol plus

metformin group had greater weight reductions of 0.79 kg

and 1.87 kg, respectively.37

Incretin Mimetics Incretin mimetics augment the glucoregulatory functions of

GLP-1, a natural hormone secreted by L-cells of the ileum in

response to food intake. Agonists of GLP-1 enhance glucose-

dependent insulin secretion by the pancreatic β-cell, suppress inappropriately elevated glucagon secretion, slow gastric

emptying, and suppress appetite.38,39 Exenatide, the fi rst agent

in this class, is a synthetic form of exendin-4, an incretin-

mimetic peptide originally identifi ed in the saliva of the lizard

Heloderma suspectum. Exenatide was initially approved in

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Balancing Glycemic Control and Body Weight

2005 for use only in combination with metformin, an SU,

a TZD, a combination of metformin and an SU, or a com-

bination of metformin and a TZD. However, exenatide has

recently received a monotherapy indication as well for use in

conjunction with diet and exercise. Exenatide monotherapy

was evaluated in a 24-week, double-blind, placebo-controlled

study of patients (N = 232) with suboptimal glycemic control using diet and exercise alone.40 Patients were randomized

to receive placebo, exenatide 5 μg twice daily, or exenatide

10 μg twice daily. At 24 weeks, HbA 1c

decreased by 0.7%

and 0.9% in the 5 μg and 10 μg exenatide treatment groups,

respectively, while the placebo group experienced 0.2%

reduction in HbA 1c

. Weight loss from baseline was 2.8 kg

with the 5 μg exenatide treatment and 3.1 kg with the 10 μg

treatment, signifi cantly greater in each case than with placebo

(1.4 kg). It has been reported that exenatide is also associated

with weight loss in patients using insulin;41 however, this

combination is not FDA approved.

A long-acting, extended-release formulation of exena-

tide is approaching a regulatory decision with the FDA.

This formulation consists of the same exenatide molecu-

lar entity embedded in injectable microspheres, which

slowly degrade over time, allowing once-weekly dosing.

A monotherapy trial of exenatide once weekly is in prog-

ress, but a 30-week open-label study has been published

in which 295 patients were randomized to receive either

exenatide 2 mg once weekly or exenatide 10 μg twice daily

in addition to preexisting therapy with metformin, an SU,

a TZD, or a combination of any 2 of these agents.42 At

30 weeks, HbA 1c

had decreased 1.9% with exenatide once

weekly compared with 1.5% with exenatide twice daily.

Similar weight loss over this time was experienced by

both groups, resulting in a 3.7-kg reduction with exenatide

once weekly and a 3.6-kg reduction with exenatide twice

daily. A second stage of this trial examined the durabil-

ity of the improvements with exenatide once weekly and

demonstrated that patients continuing through 52 weeks

(n = 128) experienced a mean HbA 1c

reduction of 2% and

a mean weight reduction of 4.5 kg.43

Liraglutide, an analog of human GLP-1, was recently

approved by the FDA and the European Medicines

Agency (EMEA) for the treatment of type 2 diabetes with

once-daily dosing. Liraglutide can be used as monotherapy,

but is not recommended as a fi rst-line therapy because of

uncertainty over the clinical relevance of thyroid cancer

fi ndings in rodents.39 Monotherapy with liraglutide was

evaluated in comparison with glimepiride in a 52-week,

double-blind study of 746 patients with early type 2 dia-

betes.44 Patients were randomized to once-daily liraglu-

tide 1.2 mg, liraglutide 1.8 mg, or glimepiride 8 mg. At

52 weeks HbA 1c

had decreased 0.84% and 1.14% in the

1.2 mg and 1.8 mg liraglutide treatment groups, respec-

tively, and by 0.51% in the glimepiride group. Weight

loss over 52 weeks was 2.05 kg with liraglutide 1.2 mg

and 2.45 kg with liraglutide 1.8 mg in contrast to a gain

of 1.12 kg with glimepiride. Liraglutide and exenatide

twice daily have been compared in a recently published

26-week, open-label trial of patients (N = 464) on back- ground therapies of metformin, or a SU, or both agents.45

Patients were randomized to receive either liraglutide

1.8 mg once daily or exenatide 10 μg twice daily while

maintaining pre-study doses of oral antidiabetic drugs.

At 26 weeks, the liraglutide group experienced a 1.12%

reduction in HbA 1c

accompanied by a 3.24-kg weight loss

while the exenatide twice daily group experienced a 0.79%

HbA 1c

reduction and a weight loss of 2.87 kg.

Amylin Mimetics Pramlintide is an analog of the naturally occurring pancreatic

hormone amylin that slows gastric emptying rate, suppresses

postprandial glucagon secretion, and increases satiety.46

It is approved for use in conjunction with mealtime insulin by

patients with type 1 or type 2 diabetes. In a 52-week, double-

blind, placebo-controlled, parallel-group multicenter study,

656 patients were randomized to receive placebo, pramlintide

60 μg 3 times daily, 90 μg twice daily, or pramlintide 120 μg

twice daily as an adjunct to insulin therapy in patients with

type 2 diabetes.47 The greatest effi cacy was achieved with

the 120 μg twice-daily treatment, which resulted in a mean

HbA 1c

reduction of 0.68% at 26 weeks, maintained through

52 weeks (0.62% reduction). In addition to the HbA 1c

reduc-

tion, patients in the pramlintide 120 μg group had a mean

weight loss of 1.4 kg compared with a 0.7-kg weight gain

for patients in the placebo group.

Weight reduction was successfully demonstrated in

another study involving patients with type 2 diabetes on

pramlintide. Karl et al48 studied pramlintide as an adjunct

to insulin in 166 overweight or obese patients (mean BMI,

39 kg/m2) with type 2 diabetes in an open-label clinical

practice study. Pramlintide 120 μg was added as an adjunct

to mealtime insulin, and insulin doses were initially reduced

by 30% to 50% and then optimized for glycemic control.

Most of the patients were on multiple daily injections or

on continuous subcutaneous insulin infusion. In addition,

more than half of the patients were also on oral antidiabetic

agents. At 3 and 6 months, there were HbA 1c

reductions of

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114 © Postgraduate Medicine, Volume 122, Issue 3, May 2010, ISSN – 0032-5481, e-ISSN – 1941-9260

Mavian et al

0.66% and 0.56%, respectively, from a baseline of 8.3%. In

addition, reductions in body weight at 3 and 6 months were

2.3 kg and 2.8 kg, respectively.

DPP-4 Inhibitors This class of drug augments the effect of endogenous GLP-1

by inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme that

deactivates GLP-1.49 The 2 FDA-approved members of this

class, sitagliptin and saxagliptin, are approved as adjuncts

to diet and exercise either as monotherapy or in combina-

tion with metformin, SUs, or TZDs. The next 2 studies

consistently demonstrate that sitagliptin was not associated

with signifi cant weight changes. A double-blind, placebo-

controlled 24-week study examined 741 patients with type

2 diabetes randomized to receive either placebo, sitagliptin

100 mg, or sitagliptin 200 mg once daily.50 At 24 weeks,

HbA 1c

was reduced by 0.61% with sitagliptin 100 mg and

by 0.76% with sitagliptin 200 mg. In contrast, there were

no signifi cant body weight changes at 24 weeks with either

sitagliptin dose, whereas the placebo group experienced a

weight loss of 1.1 kg. Goldstein et al51 evaluated sitagliptin

in combination with metformin in a 24-week, double-blind,

placebo-controlled, parallel-group study of 1091 patients

who were randomized to daily sitagliptin/metformin

100/1000 mg, sitagliptin/metformin 100/2000 mg, metfor-

min 1000 mg, metformin 2000 mg, sitagliptin 100 mg, or

placebo. At the end of the 24-week study, the HbA 1c

reduction

was 1.9% for sitagliptin/metformin 100/2000 mg, 1.40% for

sitagliptin/metformin 100/1000 mg, 1.13% for metformin

2000 mg monotherapy, 0.82% with metformin 1000 mg

monotherapy, and 0.66% with sitagliptin 100 mg mono-

therapy. Body weight reductions ranging from 0.6 to 1.3 kg

were observed in all the groups, except in the sitagliptin

monotherapy group, which did not change from baseline.

Saxagliptin is the second medication in the DPP-4 class

to be FDA approved and it is also not associated with weight

gain. Saxagliptin monotherapy was evaluated in a 24-week,

double-blind, placebo-controlled trial of 401 treatment-naïve

patients with type 2 diabetes randomized to receive 2.5 mg,

5 mg, 10 mg, or placebo once daily.52 At 24 weeks, HbA 1c

reductions from a mean baseline of 7.9% were 0.43%, 0.46%,

and 0.54% for the saxagliptin 2.5 mg, 5 mg, and 10 mg

treatment groups, respectively. In contrast, there was a small

increase in HbA 1c

(0.19%) in the placebo group over this

period. In addition the placebo group experienced a small

weight reduction (1.4 kg), as did the saxagliptin 2.5 mg

treatment group (1.2 kg). Weight was unchanged with 5 mg

and 10 mg of saxagliptin.

Weight Loss Therapies as Diabetes Treatments Many patients with type 2 diabetes have an existing weight

problem at diagnosis, and a number of antidiabetic agents

commonly used to control glucose concentrations facilitate

weight gain. Given these facts, therapeutic agents that target

weight loss represent another approach to the control of type 2

diabetes, and some medications approved for weight loss

have also been studied for management of type 2 diabetes.

Orlistat Orlistat is a lipase inhibitor that inhibits the absorption of

dietary fats. Orlistat was evaluated in a multicenter, double-

blind, placebo-controlled trial of overweight or obese adults

with type 2 diabetes (mean baseline body weight, 102 kg;

HbA 1c

, 9%) treated with insulin alone or combined with

oral agents.53 Patients were randomized to receive either

orlistat 120 mg 3 times daily (n = 266) or placebo (n = 269) in concert with a reduced-calorie diet for 1 year. Thirty-three

percent of subjects treated with orlistat lost � 5% of their

baseline body weight compared with only 13% of patients

treated with placebo. Absolute weight reductions of 3.9 kg

and 1.3 kg were achieved in the orlistat group and placebo

groups, respectively. At the end of 52 weeks, the weight

loss was accompanied by an HbA 1c

reduction of 0.62% in

the orlistat group, while the placebo group had a reduction

of 0.27%. Gastrointestinal adverse events and hypoglycemia

were reported more frequently with orlistat treatment (80%

and 17%, respectively) than with placebo (62% and 10%,

respectively).

Improvement in HbA 1c

and weight loss was also achieved

in another study by Miles et al54 where orlistat was evaluated

as an add-on for patients failing metformin in a 1-year

multicenter, randomized, double-blind, placebo-controlled

trial comparing 120 mg orlistat 3 times daily (n = 250) with placebo (n = 254) in combination with a reduced-calorie diet. After 1 year of treatment, weight loss from baseline was

4.7 kg in the orlistat group (baseline, 102.1 kg) and 1.8 kg

in the placebo group (baseline, 101.1 kg). The study also

showed improvement in HbA 1c

of 0.75% from a baseline

of 8.87% in the orlistat group compared with 0.41% from a

baseline of 8.79% in the placebo group.

Sibutramine Sibutramine is a serotonin and norepinephrine reuptake inhib-

itor that acts centrally to enhance satiety and is FDA approved

for the treatment of obesity. Of note, sibutramine should not

be used in patients with a history of cardiovascular disease

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Balancing Glycemic Control and Body Weight

because of an increased risk of heart attack and stroke associ-

ated with sibutramine therapy. Several studies have examined

the effects of sibutramine in type 2 diabetes. A 12-month,

randomized, prospective, placebo-controlled, double-blind

study compared once-daily sibutramine at 15 mg (n = 68) and 20 mg (n = 62) with placebo (n = 64) in patients with type 2 diabetes on metformin.55 After 12 months, the patients

treated with sibutramine at 15 mg and 20 mg lost 5.5 kg

and 8 kg, respectively, (mean baseline, 104 kg), whereas no

signifi cant weight loss was observed in the placebo group.

A loss of � 5% of baseline body weight was observed in

46% of patients treated with sibutramine 15 mg and 65% of

patients treated with sibutramine 20 mg. A loss of � 10%

of baseline body weight was observed in 14% and 27% of

the patients in the 15 mg and 20 mg groups, respectively. At

the end of the study, there were small reductions in HbA 1c

the overall treatment groups (0.56% with sibutramine 15 mg

and 0.32% with sibutramine 20 mg). In addition, reduction

in HbA 1c

correlated with amount of weight loss with a 0.7%

reduction in HbA 1c

in subjects who had lost 5% to 10% of

their body weight and a 1.2% reduction in those who lost

� 10% of their body weight.

The metabolic effects of orlistat and sibutramine were

compared in obese patients with type 2 diabetes in a mul-

ticenter, double-blind, controlled trial in which subjects

were randomized to orlistat 120 mg 3 times daily (n = 71) or sibutramine 10 mg daily (n = 70).56 At baseline, patients had glycemic control with diet alone or diet plus oral

antidiabetes agents and were asked to follow an American

Diabetes Association-recommended diet with a 600 kcal per

day defi cit. At 12 months, there was a mean BMI reduction

from a baseline of 33.6 kg/m² to 29.7 kg/m² in the orlistat

group (P � 0.01) and from 33.1 kg/m² to 29.5 kg/m² in the

sibutramine group (P � 0.01). In addition, there were signifi -

cant HbA 1c

reductions in both the orlistat group (7.1%– 6.3%)

and the sibutramine group (7%–6.1%).

Summary The management of type 2 diabetes should not only facilitate

glycemic control resulting in improved HbA 1c

, but should

also take into consideration the effects of medication on

weight. The classes of diabetes drugs discussed previously

achieve HbA 1c

reduction by different mechanisms of action

and have a variety of effects on body weight. The SUs, TZDs,

D-phenylalanines, and meglitinides have variable effects

on weight gain, while biguanides, �-glucosidase inhibitors,

incretin mimetics, DPP-4 inhibitors, and amylin mimetics

tend to be weight neutral or induce weight loss (Table 2).

The weight loss medications orlistat and sibutramine are also

associated with reduction of HbA 1c

The management of type 2 diabetes requires a multidisci-

plinary approach that targets the treatment of not only blood

glucose levels, but also associated cardiovascular risk factors,

including dyslipidemia, blood pressure, infl ammation, and

hypercoagulability.57 Weight reduction has been shown to

improve glycemic control and reduce cardiovascular risk

factors independent of drug effect, whereas weight gain can

exacerbate insulin resistance and worsen glycemic control.

Weight gain can also worsen hypertension and increase

cardiovascular risk factors. Unfortunately, many antihyper-

glycemic agents and insulin promote weight gain, and this

information should be factored into the risk/benefi t analysis

in selecting medications. Before 1995, the only available

drugs for diabetes management in the United States were

insulin and SUs. However, over the past decade we have seen

an increased selection of available antidiabetic agents that

improve glycemic control and are also weight neutral or even

promote weight loss.58 Future studies are needed to defi ne

whether additional metabolic and cardiovascular benefi ts are

derived from agents with these properties.

Table 2. Summary of the Effect on Body Weight of Antidiabetic Medications

Effect on Weight Medication Class Medication Example

Weight gain Sulfonylureas Tolbutamide

Chloropropamide

Glyburide

Glimepiride

Glipizide

Thiazolidinediones Rosiglitazone

Pioglitazone

D-phenylalanine derivatives

Nateglinide

Meglitinides Repaglinide

Weight neutral DPP-4 inhibitors Sitagliptin

Saxagliptin

Vildagliptina

Weight loss Biguinides Metformin

Alpha-glucosidase inhibitors

Acarbose

Miglitol

Incretin mimetics Exenatide

Liraglutide

Amylin mimetics Pramlintide

aVildagliptin is EMEA-approved Abbreviations: DPP-4, dipeptidyl peptidase-4; EMEA, European Medicines Agency.

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Mavian et al

Acknowledgments Publication expenses for this article were defrayed by Amylin

Pharmaceuticals.

Confl ict of Interest Statement Annie A. Mavian, DO discloses no confl icts of interest.

Stephan Miller, PhD discloses a confl icct of interest with

Amylin Pharmaceuticals. Robert R. Henry, MD discloses

confl icts of interest with Amylin Pharmaceuticals, Astra-

Zeneca, Bristol-Myers Squibb, Daiichi Sankyo, Dainippon

Sumitomo, Eli Lilly and Company, GlaxoSmithKline, Isis,

Merck, Novartis, Novo Nordisk, Roche, sanofi -aventis, and

Takeda.

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