Cardiovascular Effects of the New Weight Loss Agents

Journal of the American College of Cardiology

Volumn 68, Issue 8, 2016, Pages 849-859

  Vorsanger, Matthew H ^a   Subramanyam, Pritha ^b   Weintraub, Howard S ^a   Lamm, Steven H ^a   Underberg, James A ^a   Gianos, Eugenia ^a   Goldberg, Ira J ^a   Schwartzbard, Arthur Z ^a  

^a NEW YORK UNIVERSITY MEDICAL CENTER   (United States)

^b MOUNT SINAI HOSPITAL   (United States)

Author keywords

cardiovascular disease; obesity; pharmacology; prevention; risk factors

Indexed keywords

AMFEBUTAMONE; ANTIOBESITY AGENT; LIRAGLUTIDE; NALTREXONE; PHENTERMINE PLUS TOPIRAMATE;

ANTIDIABETIC ACTIVITY; BLOOD PRESSURE; CARDIOMETABOLIC RISK; CARDIOVASCULAR DISEASE; CARDIOVASCULAR EFFECT; DISEASE COURSE; DRUG SAFETY; HEART RATE; HUMAN; INFLAMMATION; OBESITY; OUTCOME ASSESSMENT; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; UNCERTAINTY; WEIGHT REDUCTION; CARDIOVASCULAR DISEASES; COMPLICATION; LIFESTYLE; RISK FACTOR;

ANTI-OBESITY AGENTS; CARDIOVASCULAR DISEASES; HUMANS; LIFE STYLE; OBESITY; RISK FACTORS;

EID: 84990198496     PISSN: 07351097     EISSN: 15583597     Source Type: Journal    
DOI: 10.1016/j.jacc.2016.06.007     Document Type: Review

References (106)

1. 1 Ogden, C.L., Carroll, M.D., Kit, B.K., et al. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 311 (2014), 806–814.
2. 2 Jensen, M.D., Ryan, D.H., Apovian, C.M., et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. [Published correction appears in: J Am Coll Cardiol 2014;63:3029–30] J Am Coll Cardiol 63 (2014), 2985–3023.
3. 3 Nakamura, K., Fuster, J.J., Walsh, K., Adipokines: a link between obesity and cardiovascular disease. J Cardiol 63 (2014), 250–259.
4. 4 Hall, J.E., do Carmo, J.M., da Silva, A.A., et al. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ Res 116 (2015), 991–1006.
5. 5 Klop, B., Elte, J.W., Cabezas, M.C., Dyslipidemia in obesity: mechanisms and potential targets. Nutrients 5 (2013), 1218–1240.
6. 6 Felber, J.P., Golay, A., Pathways from obesity to diabetes. Int J Obes Relat Metab Disord 26 (2002), S39–S45.
7. 7 Romero-Corral, A., Caples, S.M., Lopez-Jimenez, F., et al. Interactions between obesity and obstructive sleep apnea: implications for treatment. Chest 137 (2010), 711–719.
8. 8 Samad, F., Ruf, W., Inflammation, obesity, and thrombosis. Blood 122 (2013), 3415–3422.
9. 9 Drew, B.S., Dixon, A.F., Dixon, J.B., Obesity management: update on orlistat. Vasc Health Risk Manag 3 (2007), 817–821.
10. 10 Taylor, J.R., Dietrich, E., Powell, J., Lorcaserin for weight management. Diabetes Metab Syndr Obes 6 (2013), 209–216.
11. 11 Sweeting, A.N., Tabet, E., Caterson, I.D., et al. Management of obesity and cardiometabolic risk - role of phentermine/extended release topiramate. Diabetes Metab Syndr Obes 7 (2014), 35–44.
12. 12 Astrup, A., Carraro, R., Finer, N., et al., NN8022-1807 Investigators. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 36 (2012), 843–854.
13. 13 Wadden, T.A., Foreyt, J.P., Foster, G.D., et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity (Silver Spring) 19 (2011), 110–120.
14. 14 James, W.P., Caterson, I.D., Coutinho, W., et al., SCOUT Investigators. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 363 (2010), 905–917.
15. 15 Mark, E.J., Patalas, E.D., Chang, H.T., et al. Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. [Published correction appears in: N Engl J Med 1997;337:1483] N Engl J Med 337 (1997), 602–606.
16. 16 Connolly, H.M., Crary, J.L., McGoon, M.D., et al. Valvular heart disease associated with fenfluramine-phentermine. [Published correction appears in: N Engl J Med 1997;337:1783] N Engl J Med 337 (1997), 581–588.
17. 17 Lovshin, J.A., Drucker, D.J., Incretin-based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol 5 (2009), 262–269.
18. 18 Cervera, A., Wajcberg, E., Sriwijitkamol, A., et al. Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab 294 (2008), E846–E852.
19. 19 Secher, A., Jelsing, J., Baquero, A.F., et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest 124 (2014), 4473–4488.
20. 20 Skibicka, K.P., The central GLP-1: implications for food and drug reward. Front Neurosci, 7, 2013, 181.
21. 21 Vilsbøll, T., Christensen, M., Junker, A.E., et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ, 344, 2012, d7771.
22. 22 Wadden, T.A., Hollander, P., Klein, S., et al., NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 37 (2013), 1443–1451.
23. 23 Pi-Sunyer, X., Astrup, A., Fujioka, K., et al., SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 373 (2015), 11–22.
24. 24 Davies, M.J., Bergenstal, R., Bode, B., et al., NN80220-1922 Study Group. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE Diabetes Randomized Clinical Trial. JAMA 314 (2015), 687–699.
25. 25 Liraglutide (Saxenda) [package insert], 2014, Novo Nordisk Pharmaceutical Industries, Inc., Bagsvaerd, Denmark.
26. 26 Seino, Y., Rasmussen, M.F., Zdravkovic, M., et al. Dose-dependent improvement in glycemia with once-daily liraglutide without hypoglycemia or weight gain: a double-blind, randomized, controlled trial in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract 81 (2008), 161–168.
27. 27 Zinman, B., Gerich, J., Buse, J.B., et al., LEAD-4 Study Investigators. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 32 (2009), 1224–1230.
28. 28 Garber, A., Henry, R., Ratner, R., et al., LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 373 (2009), 473–481.
29. 29 Marre, M., Shaw, J., Brändle, M., et al., LEAD-1 SU study group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med 26 (2009), 268–278.
30. 30 Nauck, M., Frid, A., Hermansen, K., et al. Long-term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study. Diabetes Obes Metab 15 (2013), 204–212.
31. 31 Russell-Jones, D., Vaag, A., Schmitz, O., et al., Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met+SU Study Group. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia 52 (2009), 2046–2055.
32. 32 Buse, J.B., Rosenstock, J., Sesti, G., et al., LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 374 (2009), 39–47.
33. 33 Frier, B.M., Schernthaner, G., Heller, S.R., Hypoglycemia and cardiovascular risks. Diabetes Care 34 (2011), S132–S137.
34. 34 Sun, F., Chai, S., Li, L., et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss in patients with type 2 diabetes: a systematic review and network meta-analysis. J Diabetes Res, 2015, 2015, 157201.
35. 35 Fonseca, V.A., Devries, J.H., Henry, R.R., et al. Reductions in systolic blood pressure with liraglutide in patients with type 2 diabetes: insights from a patient-level pooled analysis of six randomized clinical trials. J Diabetes Complications 28 (2014), 399–405.
36. 36 von Scholten, B.J., Lajer, M., Goetze, J.P., et al. Time course and mechanisms of the anti-hypertensive and renal effects of liraglutide treatment. Diabet Med 32 (2015), 343–352.
37. 37 Florentin, M., Liberopoulos, E.N., Elisaf, M.S., Sibutramine-associated adverse effects: a practical guide for its safe use. Obes Rev 9 (2008), 378–387.
38. 38 Díaz-Soto, G., de Luis, D.A., Conde-Vicente, R., et al. Beneficial effects of liraglutide on adipocytokines, insulin sensitivity parameters and cardiovascular risk biomarkers in patients with Type 2 diabetes: a prospective study. Diabetes Res Clin Pract 104 (2014), 92–96.
39. 39 Suzuki, D., Toyoda, M., Kimura, M., et al. Effects of liraglutide, a human glucagon-like peptide-1 analogue, on body weight, body fat area and body fat-related markers in patients with type 2 diabetes mellitus. Intern Med 52 (2013), 1029–1034.
40. 40 Kahal, H., Aburima, A., Ungvari, T., et al. The effects of treatment with liraglutide on atherothrombotic risk in obese young women with polycystic ovary syndrome and controls. BMC Endocr Disord, 15, 2015, 14.
41. 41 Rizzo, M., Abate, N., Chandalia, M., et al. Liraglutide reduces oxidative stress and restores heme oxygenase-1 and ghrelin levels in patients with type 2 diabetes: a prospective pilot study. J Clin Endocrinol Metab 100 (2015), 603–606.
42. 42 Smilowitz, N.R., Donnino, R., Schwartzbard, A., Glucagon-like peptide-1 receptor agonists for diabetes mellitus: a role in cardiovascular disease. Circulation 129 (2014), 2305–2312.
43. 43 Chen, W.R., Shen, X.Q., Zhang, Y., et al. Effects of liraglutide on left ventricular function in patients with non-ST-segment elevation myocardial infarction. Endocrine 52 (2016), 516–526.
44. 44 Marso, S.P., Lindsey, J.B., Stolker, J.M., et al. Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. Diab Vasc Dis Res 8 (2011), 237–240.
45. 45 Margulies K, Anstrom KJ, Redfield MM, et al. A randomized trial of liraglutide for high-risk heart failure patients with reduced ejection fraction (FIGHT). Paper presented at: American Heart Association Scientific Sessions; November 8, 2015; Orlando, FL.
46. 46 Marso, S.P., Poulter, N.R., Nissen, S.E., et al., LEADER Trial Investigators. Design of the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial. Am Heart J 166 (2013), 823–830.e5.
47. 47 Marso, S.P., Daniels, G.H., Brown-Frandsen, K., et al., LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med, 2016 Jun 13 [E-pub ahead of print].
48. 48 U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research. FDA Briefing Document NDA 200063 Contrave (Naltrexone 4 mg, 8 mg/Bupropion HCL 90 mg extended release tablet). 2010 Advisory Committee—December 7, 2010. 2010, U.S. Food and Drug Administration, Rockville, MD.
49. 49 Billes, S.K., Sinnayah, P., Cowley, M.A., Naltrexone/bupropion for obesity: an investigational combination pharmacotherapy for weight loss. Pharmacol Res 84 (2014), 1–11.
50. 50 Cone, R.D., Anatomy and regulation of the central melanocortin system. Nat Neurosci 8 (2005), 571–578.
51. 51 Cowley, M.A., Smart, J.L., Rubinstein, M., et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411 (2001), 480–484.
52. 52 Bronstein, D.M., Day, N.C., Gutstein, H.B., et al. Pre- and posttranslational regulation of β-endorphin biosynthesis in the CNS: effects of chronic naltrexone treatment. J Neurochem 60 (1993), 40–49.
53. 53 Greenway, F.L., Whitehouse, M.J., Guttadauria, M., et al. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring) 17 (2009), 30–39.
54. 54 Malcolm, R., O'Neil, P.M., Sexauer, J.D., et al. A controlled trial of naltrexone in obese humans. Int J Obes 9 (1985), 347–353.
55. 55 Maggio, C.A., Presta, E., Bracco, E.F., et al. Naltrexone and human eating behavior: a dose-ranging inpatient trial in moderately obese men. Brain Res Bull 14 (1985), 657–661.
56. 56 Greenway, F.L., Dunayevich, E., Tollefson, G., et al., NB-201 Study Group. Comparison of combined bupropion and naltrexone therapy for obesity with monotherapy and placebo. J Clin Endocrinol Metab 94 (2009), 4898–4906.
57. 57 Atkinson, R.L., Berke, L.K., Drake, C.R., et al. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther 38 (1985), 419–422.
58. 58 Anderson, J.W., Greenway, F.L., Fujioka, K., et al. Bupropion SR enhances weight loss: a 48-week double-blind, placebo-controlled trial. Obes Res 10 (2002), 633–641.
59. 59 Jain, A.K., Kaplan, R.A., Gadde, K.M., et al. Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obes Res 10 (2002), 1049–1056.
60. 60 Gadde, K.M., Parker, C.B., Maner, L.G., et al. Bupropion for weight loss: an investigation of efficacy and tolerability in overweight and obese women. Obes Res 9 (2001), 544–551.
61. 61 Apovian, C.M., Aronne, L., Rubino, D., et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity (Silver Spring) 21 (2013), 935–943.
62. 62 Hollander, P., Gupta, A.K., Plodkowski, R., et al., COR-Diabetes Study Group. 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. Diabetes Care 36 (2013), 4022–4029.
63. 63 Greenway, F.L., Fujioka, K., Plodkowski, R.A., et al., COR-I Study Group. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 376 (2010), 595–605.
64. 64 Contrave [package insert], 2014, Takeda Pharmaceuticals America, Inc., Deerfield, IL.
65. 65 Thase, M.E., Haight, B.R., Johnson, M.C., et al. A randomized, double-blind, placebo-controlled study of the effect of sustained-release bupropion on blood pressure in individuals with mild untreated hypertension. J Clin Psychopharmacol 28 (2008), 302–307.
66. 66 Tek, C., Guloksuz, S., Srihari, V.H., et al. Investigating the safety and efficacy of naltrexone for anti-psychotic induced weight gain in severe mental illness: study protocol of a double-blind, randomized, placebo-controlled trial. BMC Psychiatry, 13, 2013, 176.
67. 67 Kane, S., Altschuler, E.L., Kast, R.E., Crohn's disease remission on bupropion. Gastroenterology, 125, 2003, 1290.
68. 68 Kast, R.E., Altschuler, E.L., Tumor necrosis factor-alpha in hepatitis B: potential role for bupropion. J Hepatol 39 (2003), 131–133.
69. 69 Wilcox, C.S., Oskooilar, N., Erickson, J.S., et al. An open-label study of naltrexone and bupropion combination therapy for smoking cessation in overweight and obese subjects. Addict Behav 35 (2010), 229–234.
70. 70 Toll, B.A., Leary, V., Wu, R., et al. A preliminary investigation of naltrexone augmentation of bupropion to stop smoking with less weight gain. Addict Behav 33 (2008), 173–179.
71. 71 Suter, P.M., Häsler, E., Vetter, W., Effects of alcohol on energy metabolism and body weight regulation: is alcohol a risk factor for obesity?. Nutr Rev 55 (1997), 157–171.
72. 72 Rösner, S., Hackl-Herrwerth, A., Leucht, S., et al. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev, 2010, CD001867.
73. 73 McElroy, S.L., Guerdjikova, A.I., Kim, D.D., et al. Naltrexone/Bupropion combination therapy in overweight or obese patients with major depressive disorder: results of a pilot study. Prim Care Companion CNS Disord, 15(3), 2013.
74. 74 Jefferson, J.W., Bupropion extended-release for depressive disorders. Expert Rev Neurother 8 (2008), 715–722.
75. 75 Surtees, P.G., Wainwright, N.W., Luben, R.N., et al. Depression and ischemic heart disease mortality: evidence from the EPIC-Norfolk United Kingdom prospective cohort study. Am J Psychiatry 165 (2008), 515–523.
76. 76 Orexigen Therapeutics, Inc. Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors (The LIGHT Study). ClinicalTrials.gov [Internet], 2016, National Library of Medicine, Bethesda, MD Available at: https://clinicaltrials.gov/ct2/show/NCT01601704 Accessed June 13, 2016.
77. 77 Silverman E. Fat Chance: FDA Chastises Orexigen for Disclosing Interim Trial Data. Wall Street Journal, March 4, 2015. Available at: http://blogs.wsj.com/pharmalot/2015/03/04/fat-chance-fda-chastises-orexigen-for-disclosing-interim-trial-data/. Accessed June 13, 2016.
78. 78 Beilfuss L. Orexigen Terminates Required Study for Diet Drug Contrave. Wall Street Journal, May 12, 2015. Available at: http://www.wsj.com/articles/orexigen-terminates-required-study-for-diet-drug-contrave-1431443914. Accessed June 13, 2016.
79. 79 Silverman E. Orexigen Data is ‘Unreliable and Premature:’ FDA's Jenkins Explains. The Wall Street Journal, March 6, 2015. Available at: http://blogs.wsj.com/pharmalot/2015/03/06/orexigen-data-is-unreliable-and-premature-fdas-jenkins-explains/. Accessed June 13, 2016.
80. 80 Nissen, S.E., Wolski, K.E., Prcela, L., et al. Effect of naltrexone-bupropion on major adverse cardiovascular events in overweight and obese patients with cardiovascular risk factors: a randomized clinical trial. JAMA 315 (2016), 990–1004.
81. 81 Shukla, A.P., Buniak, W.I., Aronne, L.J., Treatment of obesity in 2015. J Cardiopulm Rehab Prev 35 (2015), 81–92.
82. 82 Rothman, R.B., Baumann, M.H., Dersch, C.M., et al. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39 (2001), 32–41.
83. 83 Munro, J.F., MacCuish, A.C., Wilson, E.M., et al. Comparison of continuous and intermittent anorectic therapy in obesity. Br Med J 1 (1968), 352–354.
84. 84 Phentermine hydrochloride [package insert], 2010, Qualitest Pharmaceutical, Inc., Huntsville, AL.
85. 85 Husum, H., Van Kammen, D., Termeer, E., et al. Topiramate normalizes hippocampal NPY-LI in flinders sensitive line ‘depressed’ rats and upregulates NPY, galanin, and CRH-LI in the hypothalamus: implications for mood-stabilizing and weight loss-inducing effects. Neuropsychopharmacology 28 (2003), 1292–1299.
86. 86 Richard, D., Ferland, J., Lalonde, J., et al. Influence of topiramate in the regulation of energy balance. Nutrition 16 (2000), 961–966.
87. 87 Bray, G.A., Hollander, P., Klein, S., et al. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 11 (2003), 722–733.
88. 88 Wilding, J., Van Gaal, L., Rissanen, A., et al., OBES-002 Study Group. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord 28 (2004), 1399–1410.
89. 89 Rosenstock, J., Hollander, P., Gadde, K.M., et al. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. Diabetes Care 30 (2007), 1480–1486.
90. 90 Stenlöf, K., Rössner, S., Vercruysse, F., et al. Topiramate in the treatment of obese subjects with drug-naive type 2 diabetes. Diabetes Obes Metab 9 (2007), 360–368.
91. 91 Toplak, H., Hamann, A., Moore, R., et al. Efficacy and safety of topiramate in combination with metformin in the treatment of obese subjects with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Int J Obes (Lond) 31 (2007), 138–146.
92. 92 Tonstad, S., Tykarski, A., Weissgarten, J., et al. Efficacy and safety of topiramate in the treatment of obese subjects with essential hypertension. Am J Cardiol 96 (2005), 243–251.
93. 93 Topamax [package insert], 2014, Janssen Pharmaceuticals, Inc., Titusville, NJ.
94. 94 Allison, D.B., Gadde, K.M., Garvey, W.T., et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) 20 (2012), 330–342.
95. 95 Gadde, K.M., Allison, D.B., Ryan, D.H., et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 377 (2011), 1341–1352.
96. 96 Garvey, W.T., Ryan, D.H., Look, M., et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 95 (2012), 297–308.
97. 97 Aronne, L.J., Wadden, T.A., Peterson, C., et al. Evaluation of phentermine and topiramate versus phentermine/topiramate extended-release in obese adults. Obesity (Silver Spring) 21 (2013), 2163–2171.
98. 98 Qsymia [package insert]. Mountain View, CA: Vivus, Inc.; 2012–2014.
99. 99 Garvey, W.T., Ryan, D.H., Bohannon, N.J., et al. Weight-loss therapy in type 2 diabetes: effects of phentermine and topiramate extended release. Diabetes Care 37 (2014), 3309–3316.
100. 100 Garvey, W.T., Ryan, D.H., Henry, R., et al. Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release. Diabetes Care 37 (2014), 912–921.
101. 101 Winslow, D.H., Bowden, C.H., DiDonato, K.P., et al. A randomized, double-blind, placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of obstructive sleep apnea in obese adults. Sleep 35 (2012), 1529–1539.
102. 102 Shantha, G.P., Kumar, A.A., Kahan, S., et al. Association between glycosylated hemoglobin and intentional weight loss in overweight and obese patients with type 2 diabetes mellitus: a retrospective cohort study. Diabetes Educ 38 (2012), 417–426.
103. 103 Neter, J.E., Stam, B.E., Kok, F.J., et al. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 42 (2003), 878–884.
104. 104 Dattilo, A.M., Kris-Etherton, P.M., Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr 56 (1992), 320–328.
105. 105 Sjoberg, N., Brinkworth, G.D., Wycherley, T.P., et al. Moderate weight loss improves heart rate variability in overweight and obese adults with type 2 diabetes. J Appl Physiol (1985) 110 (2011), 1060–1064.
106. 106 Pontiroli, A.E., Merlotti, C., Veronelli, A., et al. Effect of weight loss on sympatho-vagal balance in subjects with grade-3 obesity: restrictive surgery versus hypocaloric diet. Acta Diabetol 50 (2013), 843–850.