Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance in Obese Subjects With and Without Pre-Diabetes (original) (raw)

To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG).

RESEARCH DESIGN AND METHODS

Obese subjects (n = 152; age 46 ± 12 years, female 82%, weight 108.6 ± 23.0 kg, BMI 39.6 ± 7.0 kg/m2, IGT or IFG 25%) were randomized to receive exenatide (n = 73) or placebo (n = 79), along with lifestyle intervention, for 24 weeks.

RESULTS

Exenatide-treated subjects lost 5.1 ± 0.5 kg from baseline versus 1.6 ± 0.5 kg with placebo (exenatide − placebo, P < 0.001). Placebo-subtracted difference in percent weight reduction was −3.3 ± 0.5% (P < 0.001). Both groups reduced their daily calorie intake (exenatide, −449 cal; placebo, −387 cal). IGT or IFG normalized at end point in 77 and 56% of exenatide and placebo subjects, respectively.

CONCLUSIONS

Exenatide plus lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG.

Several well-designed trials have demonstrated that weight reduction can reduce diabetes risk (1,,–4). However, with only lifestyle modification, even modest weight loss is difficult to achieve over time (5,6); therefore, optimal pharmacologic strategies for treating obesity are being developed. This study explored exenatide in combination with lifestyle modification as treatment for weight loss in nondiabetic obese subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or impaired fasting glucose (IFG).

RESEARCH DESIGN AND METHODS

Obese adult subjects with a BMI ≥30 kg/m2 were included. Subjects with type 2 diabetes, previous use of glucose-lowering medications for >3 months, or unstable body weight before screening were excluded. At screening, subjects received an oral glucose tolerance test to stratify into subgroups: NGT, IGT (fasting glucose <7 mmol/l and 2-h postprandial glucose ≥7.8 and <11.1 mmol/l), or IFG (fasting glucose 6.1–6.9 mmol/l and 2-h postprandial glucose <7.8 mmol/l). Subjects then participated in a 1-week single-blind placebo lead-in period before randomization to exenatide (10 μg with a 4-week 5-μg dose-initiation period) or placebo administered before morning and evening meals. A structured program of diet and physical activity was implemented through week 24. Subjects fasted overnight, and study drug was withheld before oral glucose tolerance test assessments. A follow-up visit was conducted 4 weeks after study completion.

The primary end point was the effect of exenatide on body weight. Secondary end points included assessment of change in glucose and lipid concentrations, A1C, blood pressure, physical activity, and food intake. Primary analyses were based on the intent-to-treat sample and a mixed-model repeated-measures ANCOVA. Least squares means were produced to estimate the magnitudes of treatment effects.

RESULTS

Of 322 participants screened, 163 were randomized, 152 received at least one dose of study drug (intent-to-treat sample), 102 completed treatment through 24 weeks, and 96 completed a follow-up visit after being off the study drug for ∼4 weeks. Average BMI was 39.6 ± 7.0 kg/m2, and 38 subjects had IGT or IFG at baseline. The withdrawal rate was 34% for exenatide and 32% for placebo; baseline characteristics were comparable to completers. Adverse events accounted for nine withdrawals (five related to nausea) with exenatide and three with placebo.

Mean baseline body weight was 109.5 ± 2.7 and 107.6 ± 2.6 kg with exenatide and placebo, respectively. Exenatide-treated subjects lost 5.1 ± 0.5 kg from baseline versus 1.6 ± 0.5 kg with placebo (Figure 1: exenatide − placebo, P < 0.001). A placebo-subtracted difference in percentage weight reduction was first observed at week 4 (−0.9 ± 0.4%, P = 0.03) and remained at week 24 (−3.3 ± 0.5%, P < 0.001). Subjects who returned after being off the study drug for ∼4 weeks sustained weight loss with increases of only 0.5 kg in both groups. A greater percentage of exenatide-treated subjects experienced ≥5% body weight reduction at 24 weeks compared with placebo (32 vs. 17%, respectively; P = 0.039). Exenatide-treated subjects who did (n = 18) or did not (n = 55) experience nausea had mean body weight reductions at 24 weeks (nausea: −3.8 ± 1.2 kg; no nausea: −4.1 ± 0.8 kg).

Figure 1

Changes in body weight over 24 weeks in nondiabetic obese subjects treated with lifestyle intervention and randomized to exenatide or placebo. ○, Placebo (n = 78); ▲, exenatide (n = 73). Results derived from mixed-model repeated-measures analysis and presented as least squares means ± SE. Change from baseline: *P < 0.001, †P < 0.05.

Figure 1

Close modal

Most subjects with IGT or IFG normalized glucose tolerance at end point (exenatide 77%, placebo 56%). Five participants (three exenatide, two placebo) developed type 2 diabetes during the study, three of which (two exenatide, one placebo) had IGT or IFG at baseline. Both groups significantly (P < 0.05) reduced their daily calorie intake (exenatide −449 ± 64 calories; placebo −387 ± 63 calories). Significant baseline–to–end point changes were not observed for A1C, fasting glucose, oral glucose tolerance test, and physical activity. Similar changes in lipid concentrations and blood pressure were observed in both treatment groups.

No deaths, serious adverse events, or hypoglycemia were observed during the study. Nausea was experienced by 25 and 4% and diarrhea by 14 and 3% of exenatide- and placebo-treated subjects, respectively. The majority of adverse events were mild or moderate in severity.

CONCLUSIONS

GLP-1 receptor agonists are among the few treatments for type 2 diabetes in which significant weight loss was recognized as an added value. This study of exenatide, combined with a pragmatic lifestyle intervention, was designed to evaluate the potential for weight loss in obese (mean baseline BMI 39.6 kg/m2) nondiabetic subjects in clear need of therapeutic intervention, as recommended by current guidelines (7,8). Exenatide treatment plus lifestyle modification was associated with significantly greater mean percent reduction in body weight (treatment difference, −3.3%) than lifestyle modification alone. The placebo-subtracted change in weight (−3.5 kg) was similar to the change observed with liraglutide at the 2.4-mg dose (9). It is unknown if higher doses of exenatide might achieve greater weight reductions than those observed in the present study.

Although we did not evaluate possible mechanisms to explain the substantial weight loss observed, GLP-1 receptor agonism may activate central pathways mediating satiety- and nausea-regulating mechanisms (10,11). The finding that weight loss in exenatide-treated subjects with type 2 diabetes is sustained in the absence of continued nausea (12) supports a satiety-related mechanism (10,13).

Normalization of glucose tolerance and reduction of caloric intake favored subjects treated with exenatide. The current findings warrant further studies to explore the potential role of GLP-1 receptor agonists for the treatment of obese subjects with IGT or IFG. Exenatide, in addition to lifestyle modification, has potential as a treatment for obesity in subjects at high risk for developing type 2 diabetes. Because of the high recidivism observed with weight loss interventions, sustained weight loss demonstrated in long-term studies is a key issue for future anti-obesity research.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Acknowledgments

This study was supported by Eli Lilly and Company and Amylin Pharmaceuticals. J.R., L.J.K., and S.S. are clinical trial investigators for Eli Lilly and Company and Amylin Pharmaceuticals. M.T., J.H.H., and J.N. are employees of Eli Lilly and Company. K.W. is an employee of Amylin Pharmaceuticals. Eli Lilly and Company and Amylin Pharmaceuticals are involved in the development of exenatide. J.R. has served on advisory boards and received honorarium or consulting fees from Pfizer, Roche, sanofi-aventis, Novo Nordisk, Eli Lilly, MannKind, GlaxoSmithKline, Takeda, Daiichi Sankyo, Forest, Johnson & Johnson, Novartis, Boehringer Ingelheim, and Amylin and has received research grants from Merck, Pfizer, sanofi-aventis, Novo Nordisk, Roche, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Johnson & Johnson, Daiichi Sankyo, MannKind, and Boehringer Ingelheim. S.S. has conducted clinical trials and/or provided consultation for Abbott, Amgen, Astra-Zeneca, Aventis, Becton-Dickson, Bristol-Myers, Dexcom, Forest Lab, Genentech, GlaxoSmithKline, Johnson & Johnson, LifeScan, Medisense, Medtronic, Merck, Novartis, Novo Nordisk, Proctor & Gamble, Pfizer, Roche, Solvay, and Takeda. L.J.K. has received research/grant support from Eli Lilly, Novo Nordisk, GlaxoSmithKline, Boehringer Ingelheim, Forest Research, and Merck. No other potential conflicts of interest relevant to this article were reported.

Parts of this study were presented in abstract form at the 3rd International Congress on Pre-diabetes and Metabolic Syndrome, Nice, France, 1–4 April 2009, and the Endocrine Society's Annual Meeting, Washington, D.C., 10–13 June 2009.

We thank the subjects, investigators, and their staff for participating in this study. We also thank Dr. Dachuang Cao for providing statistical support. Additional study investigators were as follows: L. Thurman, P. Campbell, K. Charani, W. Figueroa, C. Fogarty, A. Gupta, R. Khairi, L. Kirby, E. Ross, T. Smith, M. Cox, and K. Hoppock.

References

Knowler

Barrett-Connor

Fowler

Hamman

Lachin

Walker

Nathan

Diabetes Prevention Program Research Group

Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin

N Engl J Med

2002

;

346

393

–

403

Lindström

Louheranta

Mannelin

Rastas

Salminen

Eriksson

Uusitupa

Tuomilehto

Finnish Diabetes Prevention Study Group

Lifestyle intervention and 3-year results on diet and physical activity

Diabetes Care

2003

;

3230

–

3236

Lindström

Ilanne-Parikka

Peltonen

Aunola

Eriksson

Hemiö

Hämäläinen

Härkönen

Keinänen-Kiukaanniemi

Laakso

Louheranta

Mannelin

Paturi

Sundvall

Valle

Uusitupa

Tuomilehto

Finnish Diabetes Prevention Study Group

Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study

Lancet

2006

;

368

1673

–

1679

Pan

Wang

Yang

Lin

Xiao

Cao

Liu

Jiang

Wang

Zheng

Zhang

Bennett

Howard

Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study

Diabetes Care

1997

;

537

–

544

Nathan

Buse

Davidson

Ferrannini

Holman

Sherwin

Zinman

American Diabetes Association, European Association for Study of Diabetes

Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes

Diabetes Care

2009

;

193

–

203

Norris

Zhang

Avenell

Gregg

Schmid

Kim

Lau

Efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes mellitus: a meta-analysis

Arch Intern Med

2004

;

164

1395

–

1404

Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. National Institutes of Health

Obes Res

1998

;

51S

–

209S

Snow

Barry

Fitterman

Qaseem

Weiss

Clinical Efficacy Assessment Subcommittee of the American College of Physicians

Pharmacologic and surgical management of obesity in primary care: a clinical practice guideline from the American College of Physicians

Ann Intern Med

2005

;

142

525

–

531

Astrup

Rössner

Van Gaal

Rissanen

Niskanen

Al Hakim

Madsen

Rasmussen

Lean

NN8022-1807 Study Group

Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study

Lancet

2009

;

374

1606

–

1616

Mack

Moore

Jodka

Bhavsar

Wilson

Hoyt

Roan

Laugero

Parkes

Young

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Int J Obes (Lond)

2006

;

1332

–

1340

Nauck

Unraveling the science of incretin biology

Am J Med

2009

;

122

–

S10

Klonoff

Buse

Nielsen

Guan

Bowlus

Holcombe

Wintle

Maggs

Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years

Curr Med Res Opin

2008

;

275

–

286

Edwards

Stanley

Davis

Brynes

Frost

Seal

Ghatei

Bloom

Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers

Am J Physiol Endocrinol Metab

2001

;

281

E155

–

E161

2010

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Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance in Obese Subjects With and Without Pre-Diabetes (original) (raw)

RESEARCH DESIGN AND METHODS

RESULTS

CONCLUSIONS

Acknowledgments

References

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