What Physicians Need to Know About Obesity Medication and Side Effects

MAY 31, 2017
Yasmine S. Ali, MD
With the global epidemic of obesity showing no signs of waning, physicians should be aware of
the cardiac side effects of weight-loss drugs.
Some obesity medications have been infamously removed from the market due to their adverse cardiac side effects. Perhaps most notable among them was the drug known as fen-phen, a combination of fen uramine and phentermine, which was withdrawn from the US market in the late 1990s because of the cardiac valvulopathy associated with fenfluramine.1 Although the currently available and approved obesity drugs appear to be much safer, they still have significant cardiac side effects—both adverse and beneficial. This article will review 3 commonly used agents with known cardiometabolic profiles.
The FDA approved the combination of naltrexone and bupropion for obesity treatment in 2014. Naltrexone had already been approved for monotherapy for alcohol dependence and opioid addiction, and bupropion had prior approval for the treatment of depression, smoking cessation, and seasonal affective disorder.2 The mechanism of action for this combination is related to central effects on satiety.
Naltrexone/bupropion has several effects on cardiometabolic variables and, notably, is contraindicated in patients with uncontrolled hypertension, although it can be prescribed to patients with other known forms of cardiovascular disease.3
In phase III trials, naltrexone/bupropion was noted to have effects on glucose metabolism that ranged from neutral to slightly favorable, as evidenced by a reduction in hemoglobin A1c (HbA1c) by as much as 0.5%.4,5
Overall, regarding this combination’s effects on lipids, the results of the phase III trials were favorable, with decreases in low-density lipoprotein cholesterol (LDL-C) by 1 mg/dL to 4 mg/dL and in triglycerides by 11 mg/dL to 15 mg/dL. High-density lipoprotein cholesterol (HDL-C) was also seen to increase by 3 mg/dL to 5 mg/dL in patients taking naltrexone/bupropion.4,5
However, the effects of this combination on blood pressure are rather unfavorable, as are its effects on heart rate.3 In the phase III trials, systolic blood pressure increased 1.1 mm Hg to 2.6 mm Hg, while heart rate increased 0.8 to 1.1 beats per minute.4,5  This is consistent with previous findings for bupropion monotherapy, believed to be mediated by its influence on dopamine and norepinephrine pathways.3,6
Overall, the phase III trials for naltrexone/bupropion enrolled a total of 4536 patients, who were followed for a mean of 56 weeks, and in this population, the rates of cardiovascular events in both the placebo and control groups were generally very low. However, the phase III trials were not specifically powered to assess cardiovascular outcomes, and further FDA-mandated trials to address this issue are underway.3
Liraglutide was approved by the FDA specifically for weight loss in December 2014. It was previously approved for the treatment of type 2 diabetes (T2D) based on the Liraglutide Effect and Action in Diabetes (LEAD) trials, in which it was also found to result in significant weight loss.7 The mechanism of liraglutide’s favorable effect on weight is complicated and believed to be due to its actions on central pathways involving hunger and satiety.3,8-10
Obviously, with its approval as a medication for T2D, liraglutide has a favorable effect on glycemic indices. In the phase III LEAD studies, treatment with liraglutide resulted in HbA1c reductions ranging from 0.33% to 1.85%.3
Regarding lipid effects, liraglutide was found in a meta-analysis of 35 trials to have several favorable results, with mean decreases of 6.2 mg/dL in total cholesterol, 4.6 mg/dL in LDL-C, and 23 mg/dL in triglycerides. However, there was also a mean decrease in HDL-C of 0.4 mg/dL.11
Liraglutide has also been found to have favorable effects on blood pressure, resulting in a systolic blood pressure reduction of approximately 2.8 mm Hg in a patient-level meta-analysis of the LEAD trials.3,2
Perhaps most remarkably, trials specifically examining hard cardiovascular outcomes have found that liraglutide is effective in reducing a composite primary endpoint of major cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.13
The combination of phentermine/topiramate, approved by the FDA in July 2012, represented the first such approval of a medication for the long-term management of obesity. Phentermine is a sympathomimetic amine that blocks norepinephrine reuptake and thereby increases energy expenditure and suppresses appetite,14 while topiramate is approved as an antiepileptic agent.
As might be expected due to the inclusion of phentermine in this combination, heart rate was found to increase as much as 1.8 beats per minute; however, systolic blood pressure generally decreased in clinical trials with this combination, in the range of a 1.1 mm Hg to 3.8 mm Hg reduction.15,16 Notably, the labeling information for phentermine/topiramate recommends against its use in patients with recent or unstable cardiac syndromes.3
Phentermine/topiramate was also found to have a favorable effect on HDL-C and triglycerides, with an increase from 2 mg/dL to 4 mg/dL for HDL-C and a reduction of 17 mg/dL to 24 mg/dL for triglycerides; its effect on LDL-C was neutral.15,16
Of the weight-loss medications with extensively studied cardiometabolic effects, liraglutide is remarkable in its favorable effects on hard cardiovascular outcomes as well as markers of cardiovascular risk. Given its proven history of effectiveness in T2D treatment, it would seem to be a drug of choice in patients with T2D who are also in need of obesity treatment beyond what they have been able to accomplish with therapeutic lifestyle changes.
Development of further antiobesity agents is to be expected, and cardiovascular effects and outcomes should continue to be monitored. ■ 
1. Centers for Disease Control and Prevention (CDC). Cardiac valvulopathy associated with exposure to fenfluramine or dexfenuramine: US Department of Health and Human Services Interim Public Health Recommendations, November 1997. MMWR Morb Mortal Wkly Rep. 1997;46(45):1061-1066.
2.US 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. https://www.fda.gov/downloads/advisorycommitteesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm235671.pdf. Accessed May 2, 2017.
3. Vorsanger MH, Subramanyam P, Weintraub HS, et al. Cardiovascular effects of the new weight loss agents. J Am Coll Cardiol. 2016;68(8):849-859. doi: 10.1016/j.jacc.2016.06.007.
4. Wadden TA, Foreyt JP, Foster GD, et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity (Silver Spring). 2011;19(1):110-120. doi: 10.1038/oby.2010.14.
5. Apovian CM, 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). 2013;21(5):935-943. doi: 10.1002/oby.20309.
6. Thase ME, Haight BR, Johnson MC, 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. 2008;28(3):302-307. doi: 10.1097/JCP.0b013e318172424e.
7. Vilsbøll T, Christensen M, Junker AE, et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomized controlled trials. BMJ. 2012;344:d7771. doi: https://doi.org/10.1136/bmj.d7771.
8. Secher A, Jelsing J, Baquero AF, et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest. 2014;124(10):4473-4488. doi: 10.1172/JCI75276.
9. Skibicka KP. The central GLP-1: implications for food and drug reward. Front Neurosci. 2013;7:181. doi: 10.3389/fnins.2013.0018.
10. Kanoski SE, Hayes MR, Skibicka KP. GLP-1 and weight loss: unraveling the diverse neural circuitry. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R885-895. doi: 10.1152/ajpregu.00520.2015.
11. 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. doi: 10.1155/2015/157201.
12. Fonseca VA, Devries JH, Henry RR, 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. 2014;28(3):399-405. doi: 10.1016/j.jdiacomp.2014.01.009.
13. Trujillo JM, Wettergreen SA, Nuffer WA, Ellis SL, McDermott MT. Cardiovascular outcomes of new medications for type 2 diabetes. Diabetes Technol Ther. 2016;18(12):749-758.
14. Rothman RB, Baumann MH, Dersch CM, et al. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse. 2001;39(1):32-41.
15. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20(2):330-342. doi: 10.1038/oby.2011.330.
16. 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 randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341-1352. doi: 10.1016/S0140-6736(11)60205-5.

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