Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes

Priscilla Hollander, Alok K Gupta, Raymond Plodkowski, Frank Greenway, Harold Bays, Colleen Burns, Preston Klassen, Ken Fujioka, COR-Diabetes Study Group, Laura Akright, Mira Baron, Harold Bays, Jolene Berg, Bruce Berwald, James Borders, Robert Buynak, Marc Capobianco, Harold Cathcart, Joseph Cleaver, Milissa Cooper, Martin Conway, Adnan Dahdul, Matthew Davis, Steven Duckor, John Ervin, David Fitz-Patrick, Larry Gilderman, Gopalakrishna Gollapudi, Alok Gupta, Forrest Hanke, Howard Harris, Lydie Hazan, Priscilla Hollander, Adesh Jain, Boris Kerzner, Lawrence Koehler, Ildiko Kovacs, Richard A Krause, Diane Krieger, Judy Loper, Norman Lunde, Barbara McGuire, Richard Mills, Sunder Mudaliar, Troy Oxner, Naynesh Patel, Angel Pietri, Sanford N Plevin, Raymond Plodkowski, George Raad, Eric Ross, Robert Schrieman, Sherwyn Schwartz, Stan Self, Stephan Sharp, Diane Smith, Timothy Smith, Philip Snell, Joseph Soufer, Louise Taber, Andrew Thieneman, Joseph Tibaldi, Paul Tung, James Vogt, Claire Waltman, Mervyn Weerasinghe, Daniel Weiss, Troy Williams, Kevin Wingert, Douglas Young, Douglas Zmolek, Priscilla Hollander, Alok K Gupta, Raymond Plodkowski, Frank Greenway, Harold Bays, Colleen Burns, Preston Klassen, Ken Fujioka, COR-Diabetes Study Group, Laura Akright, Mira Baron, Harold Bays, Jolene Berg, Bruce Berwald, James Borders, Robert Buynak, Marc Capobianco, Harold Cathcart, Joseph Cleaver, Milissa Cooper, Martin Conway, Adnan Dahdul, Matthew Davis, Steven Duckor, John Ervin, David Fitz-Patrick, Larry Gilderman, Gopalakrishna Gollapudi, Alok Gupta, Forrest Hanke, Howard Harris, Lydie Hazan, Priscilla Hollander, Adesh Jain, Boris Kerzner, Lawrence Koehler, Ildiko Kovacs, Richard A Krause, Diane Krieger, Judy Loper, Norman Lunde, Barbara McGuire, Richard Mills, Sunder Mudaliar, Troy Oxner, Naynesh Patel, Angel Pietri, Sanford N Plevin, Raymond Plodkowski, George Raad, Eric Ross, Robert Schrieman, Sherwyn Schwartz, Stan Self, Stephan Sharp, Diane Smith, Timothy Smith, Philip Snell, Joseph Soufer, Louise Taber, Andrew Thieneman, Joseph Tibaldi, Paul Tung, James Vogt, Claire Waltman, Mervyn Weerasinghe, Daniel Weiss, Troy Williams, Kevin Wingert, Douglas Young, Douglas Zmolek

Abstract

Objective: To assess the efficacy and safety of 32 mg naltrexone sustained-release (SR)/360 mg bupropion SR (NB) in overweight/obese individuals with type 2 diabetes with or without background oral antidiabetes drugs.

Research design and methods: This was a 56-week, double-blind, placebo-controlled study in which 505 patients received standardized lifestyle intervention and were randomized 2:1 to NB or placebo. Coprimary end points were percent weight change and achievement of ≥5% weight loss. Secondary end points included achievement of HbA1c <7% (53 mmol/mol), achievement of weight loss ≥10%, and change in HbA1c, waist circumference, fasting blood glucose, and lipids.

Results: In the modified intent-to-treat population (54% female, 80% Caucasian, and mean age 54 years, weight 106 kg, BMI 37 kg/m(2), and HbA1c 8.0% [64 mmol/mol]), NB resulted in significantly greater weight reduction (-5.0 vs. -1.8%; P < 0.001) and proportion of patients achieving ≥5% weight loss (44.5 vs. 18.9%, P < 0.001) compared with placebo. NB also resulted in significantly greater HbA1c reduction (-0.6 vs. -0.1% [6.6 vs. 1.1 mmol/mol]; P < 0.001), percent of patients achieving HbA1c <7% (53 mmol/mol) (44.1 vs. 26.3%; P < 0.001), and improvement in triglycerides and HDL cholesterol compared with placebo. NB was associated with higher incidence of nausea (42.3 vs. 7.1%), constipation (17.7 vs. 7.1%), and vomiting (18.3 vs. 3.6%). No difference was observed between groups in the incidence of depression, suicidal ideation, or hypoglycemia.

Conclusions: NB therapy in overweight/obese patients with type 2 diabetes induced weight loss, which was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes.

Figures

Figure 1
Figure 1
A: Body weight change from baseline in the mITT LOCF population. Data are LS mean ± SE. Placebo, n = 159; NB, n = 265. ***P < 0.001 vs. placebo; except for change from baseline to week 56 end point for mITT LOCF population, P values are nominal (i.e., not adjusted for multiple comparisons) and associated with exploratory analyses. B: Body weight change from baseline to week 56 end point; placebo, n = 100; NB, n = 175. ***P < 0.001 vs. placebo; except for ≥5% weight loss category for the mITT-LOCF population, P values are nominal (i.e., not adjusted for multiple comparisons) and associated with exploratory analyses. C: Change in HbA1c from baseline to week 56 end point; placebo, n = 137; NB, n = 222. **P < 0.01 vs. placebo; ***P < 0.001 vs. placebo; the mITT LOCF population consists of patients who had a baseline measurement and at least one postbaseline measurement while on study drug. The last observation on study drug was carried forward. The completer population comprised all randomized patients with a baseline measurement and a 56-week measurement while on the study drug.

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