Drugs Under Development for Cardiovascular Risk

Evidence-Based Diabetes Management, May/June , Volume 19, Issue SP5

Cardiometabolic risk, also known as metabolic syndrome, is a collection of risk factors that increase a person’s risk of developing cardiovascular (CV) disease and type 2 diabetes mellitus (T2DM). In 2009, over one-third of the US population over the age of 20 years met the criteria for having metabolic syndrome as defined by the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP/ATP III).1 Metabolic syndrome prevalence increases with age and body mass index (BMI).1 NCEP/ATP III classified abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance with or without glucose intolerance, and proinflammatory and prothrombotic states as factors contributing to the development of CV disease.2 Due to the nature of the orementioned risk factors, management of cardiometabolic risk may involve both therapeutic lifestyle changes (weight loss and physical activity) and pharmacotherapy to address non-lipid and lipid risk factors.2 The ultimate goal of both of these treatment modalities is to lower T2DM and CV risk. Pharmacologic subcutaneagents used to decrease risk may include drugs for dyslipidemia and tihypertensives, as well as drugs to assist with weight loss (Table). Lipids

Dyslipidemia is defined as elevated total cholesterol, elevated low-density lipoprotein cholesterol (LDL-C), or decreased high-density lipoprotein cholesterol (HDL-C). According to NCEP/ATP III reduction of LDL-C should be the primary goal of lipid management. Once goal LDL-C is achieved, focus should shift to the management of metabolic syndrome, which includes therapeutic lifestyle changes and treatment of non-HDLC. NCEP/ATP III does not specify HDL goals; however, studies suggest increasing HDL-C decreases CV risk.2 The mainstay of LDL-C-lowering therapy has been statins since the approval of the first in-class statin, lovastatin, in the late 1980s.3 Apolipoprotein B (apoB) plays an integral role in very-low-density lipoprotein (VLDL) biosynthesis, which is a precursor to LDL-C. Increased levels have been correlated with atherosclerotic disease progression, thus making it a favorable pharmacologic target.4 Antisense oligonucleotides (ASO) are single-strand synthetic analogues of nucleic acids 8 to 50 nucleotides long, which bind via hybridization to a target ribonucleic acid. ASOs targeting apoB decrease

both LDL production and progression of atherosclerosis.4,5 In an animal model of LDL receptor—deficient mice, ISIS 147764 demonstrated LDL-lowering effects of 60% to 90% in addition to decreased aortic atherosclerosis.4

Mipomersen, another ASO also targeting apoB, is delivered via subcutaneagents ous injection.6 Mipomersen received orphan status from the US Food and Drug Administration (FDA) in January for the treatment of homozygous familial hypercholesterolemia (HoFH); however, phase II randomized placebo-controlled trials (RCTs) have also been conducted in patients with hypercholesterolemia.5,7 Data from a small phase II dose escalation study demonstrated reduction of LDL-C ranging from 15% to 71%. Of particular note, reduction percentages seen with the higher doses exceeded reported reductions achieved by atorvastatin and rosuvastatin, the 2 most potent statins available on the market. Higher reductions in apoB levels when compared with statins were also observed. Adverse effects (AEs) occurring in greater than 10% of patients included injection site reaction, headache, nasopharyngitis, fatigue, myalgia, flu-like illness, increase in hepatic enzymes, back pain, nausea, and listlessness. Of these AEs, injection site reaction and headache were the most prevalent.6 A phase II study evaluating the effects of mipomersen in patients intolerant to high-dose statins has been completed but results have not been published.8 The results of a phase III study evaluating the effect of a mipomersen 200-mg weekly subcutaneous injection versus placebo in patients on maximally tolerated statin therapy and another hypolipdemic agent demonstrated a reduction in LDL-C from 276 mg/dL at baseline to 174 mg/dL. No statistical information was provided.9

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are another novel class being investigated. PCSK9 is a serine protease that binds to the LDL receptor. LDL receptors with this protease attached are then degraded, thus decreasing the number of LDL receptors available on hepatocytes. Consequently, LDL-C levels increase. This effect has been observed in genetics studies performed in individuals with increased PCSK9 function, making this a potential target for patients with elevated LDLC. 10 AMG-145 is a human monoclonal antibody to PSCK9 that inhibits PSCK9’s interaction with LDL receptors and is also administered via subcutaneous injection. AMG-145 was studied in low cardiac risk patients who had not previously been on any lipid-altering medications. Patients received placebo, ezetimibe monotherapy, or varying doses of AMG-145. At week 12, when compared with placebo, significant reductions in LDL-C were seen with all doses of AMG-145. An almost 15% greater reduction in LDL was also observed when comparing AMG-145 with ezetimibe, a statistically significant reduction. Injection site reaction occurred in 6% of the patients receiving AMG-145.10 LAPLACE-TIMI 57, a phase II RCT, evaluated AMG-145 in patients taking a statin with or without ezetimibe. LDL-C concentration at week 12 was reduced 42% to 66% in patients receiving the drug every 2 weeks and 42% to 50% in patients receiving the drug every 4 weeks. AMG-145 was well tolerated in this study.11 REGN-727/SAR-236553, another monoclonal antibody to PCSK9, was evaluated in a phase II study in patients with heterozygous fain milial hypercholesterolemia. Six weeks before randomization, patients received a daily statin dose with or without ezetimibe. At week 12, REGN-727 resulted in a least squares mean reduction of 29% to 68% compared with 11% with placebo. The greatest reduction was seen with REGN 727 150 mg every 2 weeks. At week 12, 94% of patients receiving this dose achieved an LDL less than 100 mg/dL while 81% of patients achieved an LDL-C less than 70 mg/dL. Gastrointestinal disorders and injection site reactions were the most common AEs reported.12 REGN 727 was also evaluated in combination with atorvastatin in patients with LDL-C greater than or equal to 100 mg/dL. Results from this study were in favor of the combination. After 8 weeks of treatment, the least-squares mean (± SE) difference in LDL cholesterol from baseline was −55.9 ± 4.9 when comparing participants receiving atorvastatin 80 mg plus REGN 727 and those only taking atorvastatin 80 mg.13

A third novel pharmacologic class targeting apoB is the microsomal triglyceride transfer protein (MTP) inhibitors. MTP transfers lipid molecules onto apoB; therefore inhibition of these proteins will lead to decreased production of chylomicrons and VLDL cholesterol, and ultimately, LDL-C.14 Unfortunately another lipid effect of this class is decreased HDL levels with a 5% to 10% reduction reported in studies.14 As with mipomersen, the MTP inhibitor lomitapide was provided with FDA orphan status at the end of 2012.15 A phase III single-arm, open-label study evaluated the effects of lomitapide in patients with difficult to treat HoFH already receiving lipid-lowering therapy and apheresis. Other lipid-lowering medications were continued throughout the study. After 26 weeks of therapy, an observed reduction in LDL-C levels of 50% was observed with a median dose of lomitapide 40 mg daily. At week 56, LDL-C levels were reduced 44% from baseline and at week 78 a reduction of 38% was observed.16 Although lomitapide is not FDA approved for patients other than those with HoFH, studies in other patients are being evaluated. A phase II RCT compared lomitapide monotherapy, ezetimibe monotherapy, and lomitapide plus ezetimibe in patients with LDL-C greater than 130 or 160 mg/dL, depending on risk factors. The lomitapide monotherapy dose was escalated over 12 weeks. LDL-C reduction of 20% to 22% was seen with ezetimibe alone, 19% to 30% with lomitapide alone, and 35% to 46% with combination therapy. Elevated transaminases and gastrointestinal effects were associated with lomitapide in both studies.14,16 Increases fain hepatic fat were also noted in the HoFH study; however, the clinical significance of this is currently unknown.16 Another MTP inhibitor in development is SLx-4090. In mice fed a high-fat diet, LDL-C and triglycerides reductions were observed without elevations in transaminases or hepatic fat, making this a promising agent.17 Findings from a phase II study evaluating the effects of SLx-4090 on LDL-C in combination with statin therapy have not been reported.18

Another class of interest for dyslipidemia treatment is the cholesteryl ester transfer protein (CETP) inhibitors. Although Pfizer halted studies of the first CETP inhibitor, torcetrapib, due to increased cardiovascular events and death associated with its use despite excellent increases in HDL in 2006, newer agents have demonstrated promising results with fewer AEs.19 CETP is responsible for assisting the exchange of cholesteryl esters and triglycerides between HDL-C and apoB containing lipoprotein particles including LDL-C and VLDL-C.19,20 Inhibition of CETP leads to increases in HDL-C, which may eventually lead to decreases in cardiovascular risk.19

Anacetrapib and evacetrapib are 2 CETP inhibitors currently in development, with anacetrapib being the more potent. Data from a double-blind RCT investigating the efficacy and safety of anacetrapib in patients with coronary heart disease (CHD) or at high risk for CHD with an LDL-C level of 50 to 100 mg/dL on a statin showed an almost 40% decrease in LDL-C and a 139% increase in HDL-C after 24 weeks of therapy.21 Effects on blood pressure, electrolyte levels, or serum aldosterone levels were not detected, unlike with torcetrapib. Additionally, anacetrapib did not have the same rate of CV events seen with torcetrapib.21 Two phase III studies are currently open to accrual, including the REVEAL study, which is evaluating anacetrapib’s effect on major coronary events.22,23 Evacetrapib is another CETP inhibitor under development. A phase II RCT demonstrated reductions of LDLC by 11% to 14% and increases of HDL by 79% to 89% in patients taking evacetrapib 100 mg with either atorvastatin, simvastatin, or rosuvastatin.24 As with anacetrapib, a phase III study is recruiting patients to determine its effect on cardiovascular outcomes.25

Weight

According to the American Heart Association, almost 155 million Americans are overweight or obese.26 With this rising trend in the United States, the development of anti-obesity medications is important. Although dietary changes along with exercise are the mainstay of therapy, medications to be used as an adjunct to these lifestyle changes may be useful to some patients. Before the summer of 2012, when lorcaserin and topiramate/phentermine were approved, no new anti-obesity medications had been FDA approved since orlistat in 1998.27 Currently, several other drugs are being evaluated for their weight loss effect. Not all of the agents under development are novel therapeutic classes. For example, one agent currently in phase III studies is a combination of a sustained-release formulation of the antidepressant bupropion with naltrexone.28 Hypothalamus neurons known as pro-opiomelancortin (POMC) neurons send signals resulting in a anorexigenic ouput, making these neurons a potential target for weight loss drugs.29 One proposed mechanism for bupropion-induced weight loss is due to the effect of dopamine and norepinephrine on POMC signaling. Reports of bupropion monotherapy for weight loss indicate therapy results in a modest weight loss with patients plateauing within several months.29 Naltrexone, an opioid receptor antagonist, has demonstrated minimal weight loss when used alone. Investigators hypothesized that the addition of these 2 agents may result in a clinically significant weight loss effect because of the effect naltrexone may have on POMC signaling. Researchers have proposed that POMC stimulation results in the activation of a negative feedback system and they have demonstrated that opioids inhibit POMC neurons. The rationale for combining these 2 agents is that naltrexone would disrupt the feedback loop that occurs as a result of POMC activation.29 Results of a phase II RCT comparing naltrexone/bupropion with placebo in patients with a BMI of 30 to 40 kg/m2 showed participants had a 6% to 6.5% weight loss from baseline at 24 weeks (weight loss in intention-to-treat population was 3.5%-4.6%).The most common AE in patients receiving naltrexone/bupropion was nausea.30 Data froma larger phase III study demonstrated results consistent with the previous trial. Weight was reduced by 5% to 6% in patients with a BMI of 27 to 45 kg/m2 taking naltrexone/bupropion. A higher dose of naltrexone resulted in a greater reduction. Again, the most common AE was nausea.31 Presently, 2 phase III studies with naltrexone/bupropion are ongoing, one of which is intended to provide insight regarding the effect of the drug on major adverse cardiovascular events.32

Bupropion in combination with zonisamide is another weight loss drug being developed. Zonisamide, an antiepileptic drug, is thought to further increase POMC stimulation. Results of a phase IIb study showed that at 24 weeks patients’ weight decreased 9.9% frombaseline compared with 1.7% with placebo. Almost 83% of patients decreased their weight by 5% of their baseline weight. Headache, insomnia, and nausea were the most commonly reported AEs.34 According to the manufacturer’swebsite, phase III studies are still in the planning stages.

Fumagillin is a potent and selective inhibitor of methionine aminopeptidase 2, which was isolated from thefungus aspergillus fumigatus.35,36 Discovery of beloranib, a synthetic fumagillin analogue, began by investigatingits anti-angiogenic effects in cancer.In animal studies subcutaneous or intravenous administration of low-dosebeloranib reduced food intake, body weight, and adipocyte size.36 Researchers conducted an RCT to determine the safety, tolerability, and pharmacologyof beloranib in women with a BMIof 32 to 45 kg/m2. Patients received 1 of 3 doses of beloranib or placebo as a twice-weekly intravenous infusion for 4 weeks. A dose-dependent weight loss was observed in patients receiving beloranib, with higher doses leading to a rapid and consistent weight loss of 1 kilogram per week. AEs observed in this study included nausea, dizziness, and migraines, with nausea being the most frequent. Nausea and infrequent episodes of vomiting had no effect on weight loss.36 An ongoing phase II study will evaluate the safety and tolerability of twice-weekly beloranib injectionsby evaluating parameters such as AEs,physical exams, electrocardiograms, vital signs, and laboratory values.37

Blood Pressure

Elevated blood pressure, another component of cardiometabolic disease, has been associated with myocardial infarction, stroke, and heart failure. Despite the fact that almost 1 out of every 3 Americans over the age of 20 years has elevated blood pressure, novel agents to aid in treatment of this condition have been scarce.38

Neprilysin is a new pharmacologic target which has been identified to help in the development of new drugs to treat hypertension. When neprilysin is inhibited, this results in increased concentration of natriuretic peptides. Clinically significant reductions in blood pressure are not seen with only neprilysin inhibition, potentially due to he fact that neprilysin is responsible for the breakdown of certain vasoconstrictors, including angiotensin II.39 By SelectionsFromFDLIUpdate combining neprilysin inhibition with an inhibitor of the renin-angiotensin-aldosterone system, blood pressure—lowering effects may be more pronounced.39 LCZ 696, a dual-acting angiotensin II receptorand neprilysin inhibitor (ARNI), is currently in phase III trials. A proof of concept study comparing varying doses of LCZ-696 with varying doses of the angiotensin receptor blocker valsartan in patients with mean diastolic blood pressure of 90 to 109 mm Hg over 8 weeks demonstrated significant reductions in blood pressure. The change in placebo-subtracted mean systolic and diastolic blood pressures was greater with LCZ-696 (systolic blood pressure:—6 to –12 mm Hg vs –5 to –6 mm Hg, diastolic blood pressure: –3 to –7 mm Hg vs –2 to –4 mm Hg). The results were statistically significant with the 2 highest doses of CZ696.39 Ongoing or proposed phase III studies with LCZ696 include studies evaluating the effects of neprilysinmonotherapy in elderly patients, LCZ-696 compared with olmesartan, and LCZ696 plus amlodipine.40

Conclusion

Patients with cardiometabolic risk have increased healthcare utilization and costs compared with patients without similar risk. One US study estimated that patients with cardiometabolic risk factors have annual healthcare costs totaling $2000 more than those without such risks.40 With cardiometabolic syndrome reaching epidemic proportions in the United States, the impact on overallhealthcare costs is staggering. A large percentage of the costs comes from prescription drugs. While the mainstayof treatment remains lifestyle changes including diet and exercise, goals are often not met with these alone. Pharmacologic intervention remains a key approach to managing this cluster of related disease states. Focus on decreasing LDL, increasing HDL, weight loss, and lowering blood pressure and blood glucose are imperative mechanisms to decrease the risk factors that lead to CV disease. A number of novel agentshave achieved significant results in decreasing cardiometabolic risk factors; however, it is too soon to determine the role they will play in clinical practice. While the costs of these agents are notyet known, several of them are injectabledrugs and others are suggested incombination therapies. Both of thesesuggest a more expensive approachthan what is currently available. Lessexpensive agents will likely remain the mainstay of treatment. The more costly agents should be reserved for those patients who cannot tolerate currently available medications, or for those whoare unable to meet the goals with standard regimens. However, the impressive results seen in the treatment of dyslipidemia may have promise in the area of first-line treatment, with the main drawbacks being their route of administration and cost. Depending on the results of outcome trials, prescribers may choose these agents over oral medicationsin those patients with severe disease.

Author Affiliation: At the time of submission, the author was assistant professor of pharmacy practice, University of Louisiana at Monroe College of Pharmacy, Baton Rouge Campus, Baton Rouge Louisiana

Funding Source: None

1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.Circulation. 2002;106(2):3143.

2. Ervin RB. Prevalence of metabolic syndrome among adults 20 years of age and over, by sex,age, race and ethnicity, and body mass index:United States, 2003-2006. National health statistics reports; no 13. Hyattsville, MD: National Center for Health Statistics; 2009.

3. Junod SW. Statins: a success story involving FDA, academia, and industry. http://www.fda.gov/AboutFDA/WhatWeDo/History /ProductRegulation/SelectionsFromFDLIUpdatecombiningSeriesonFDAHistory/ucm082054.htm. Published April 2009. Accessed March 29, 2013.

4. Mullick AE, Fu W, Graham MJ, et al. Antisense oligonucleotide reduction of apoB-ameliorated atherosclerosis in LDL receptor- deficient mice. JLipid Res. 2011;52(5):885-896.

5. Joy TR. Novel therapeutic agents for lowering low density lipoprotein cholesterol. Pharmacol Ther. 2012;135(1):31-43.

6. Akdim F, Tribble DL, Flaim JD, et al. Efficacy of apolipoprotein B synthesis inhibition in subjectswith mild-to-moderate hyperlipidaemia. Eur Heart J. 2011;32(21):2650-2659.

7. FDA approves new orphan drug for rare cholesterol disorder [press release]. FDA website.http://www.fda.gov/NewsEvents /Newsroom/PressAnnouncements/ucm337195.htm. Silver Springs, MD: 2013. Published January 29, 2013.Accessed March 23, 2013.

8. Safety and efficacy study of ISIS 301012 (mipomersen) administration in high risk statinintolerant subjects (ASSIST). http://www.clinicaltrials.gov/ct2/show/study/NCT00707746?term=mipomersen&rank=15. Updated February 2013. Accessed March 23, 2013.

9. Safety and efficacy of mipomersen in patients with severe hypercholesterolemia on a maximally tolerated lipid-lowering regimen and who are not on apheresis. http://www.clinicaltrials.gov/ct2/show/study/NCT00794664?term=mipomersen&rank=8§=X0125. Updated February 2013. Accessed March 23, 2013.

10. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind,placebo-controlled, phase 2 study. Lancet. 2012;380(9858):1995-2006.

11. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients withhypercholesterolaemia (LAPLACE-TIMI 57): arandomised, placebo-controlled, dose-ranging,phase 2 study. Lancet. 2012;380(9858):2007-2017.

12. Stein EA, Gipe D, Bergeron J, et al Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012;380(9836):29-36.

13. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367(20):1891-1900.

14.Samaha FF, McKenney J, Bloedon LT, Sasiela WJ, Rader DJ. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2008;5(8):497-505.

15. FDA approves new orphan drug for rare cholesterol disorder [press release]. FDA website.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333285.htm. Silver34. Rohn J. Newsmaker: zafgen. Nat Biotechnol. 2011;29(12):1068.

Springs, MD. Published December 26, 2012. Accessed March 29, 2013.

16. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet.2013;381(9860):40-46.

17. Kim E, Campbell S, Schueller O. A small-molecule inhibitor of enterocytic microsomal triglyceridetransfer protein, SLx-4090: biochemical, pharmacodynamic, pharmacokinetic, and safety profile. J Pharmacol Exp Ther. 2011;337(3):775-785.

18. Comparison of Slx-4090 with statin therapy versus statin alone in reducing LDL-C in patients with hyperlipidemia. http://www.clinicaltrials.gov/ct2/show/NCT00810979?term=slx4090&rank=2. Updated December 2009. Accessed March 25, 2013.

19. Goldberg AS, Hegele RA. Cholesteryl ester transfer protein inhibitors for dyslipidemia: focus on dalcetrapib. Drug Des Devel Ther. 2012;6:251-259.

20. Davidson M, Liu SX, Barter P, et al. Measurement of LDL-C after treatment with the CETPinhibitor anacetrapib. J Lipid Res. 2013;54(2):467-472.

21. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363 (25):2406-2415.

22. A study of the safety and efficacy of anacetrapib (MK-0859) when added to ongoing statin therapy (MK-0859-021 AM1). http://www.clinicaltrials.gov/ct2/show/NCT01717300?term=anacetrapib&recr=Open&rank=1. Updated May 2013. Accessed May 16, 2013.

23. REVEAL: randomized evaluation of the effects of anacetrapib through lipid modification. http:// www.clinicaltrials.gov/ct2/show/NCT01252953?term=anacetrapib&recr=Open&rank=3. Updated January 2013. Accessed March 29, 2013.

24. Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011;306(19):2099-2109.

25. A study of evacetrapib in high risk vascular disease (ACCELERATE). http://www.clinicaltrials .gov/ct2/show/NCT01687998?term=evacetrapib&recr=Open&rank=3. Updated May 14, 2013. Accessed May 16, 2013.

26. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, et al; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127:e6-e245.

27. Orexigen Therapeutics, Inc. Contrave. http://www.orexigen.com/product-candidates/contrave.html. Published 2013. Accessed March 29,2013.

28. Greenway FL, Whitehouse MJ, Guttadauria M, et al. Rational design of a combination medication for the treatment of obesity. Obesity. 2009;17(1):30-39.

29. Greenway FL, Dunayevich E, Tollefson G, et al. Comparison of combined bupropion and naltrexone therapy for obesity with monotherapy and placebo. J Clin Endocrinol Metab. 2009;94(12): 4898-4906.

30. Greenway FL, Fujioka K, Plodkowski RA, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebocontrolled, phase 3 trial. Lancet. 2010;376(9741):595-605.

31. Method of use study assessing the effect of naltrexone sustained release (SR)/bupropion SR on body weight and cardiovascular risk factors in overweight and obese subjects. http://www.clinicaltrials.gov/ct2/show/NCT01764386?term=bupropion+naltrexone&rank=7. Updated February 2013. Accessed March 29, 2013.

32. Cardiovascular outcomes study of naltrexone SR/bupropion SR in overweight and obese subjects on cardiovascular risk factors (the LIGHT study). http://www.clinicaltrials.gov/ct2/show/ NCT01601704?term=bupropion+naltrexone&rank=13. Updated February 2013. Accessed March 29, 2013.

33. Orexigen Therapeutics, Inc. Empatic. http://www.orexigen.com/product-candidates/empatic.html. Published 2013. Accessed March 29, 2013.

34. Rohn J. Newsmaker: zafgen. Nat Biotechnol. 2011;29(12):1068.

35. Hughes TE, Kim DD, Marjason J, et al. Ascending dose controlled trial of beloranib, a novel obesity treatment for safety, tolerability and weight loss in obese women [published online March 20, 2013]. Obesity (Silver Spring).

36. An efficacy, safety, and pharmacokinetic study of beloranib (SGN-440 for injectablesuspension) in obese subjects. http://www.clinicaltrials.gov/ct2/show/NCT01666691?term=beloranib+obesity&rank=1. Accessed March 27, 2013.

37. High blood pressure: statistical fact sheet- 2013 update. http://www.heart.org/idc/groups/heart-public/@wcm/@sop/@smd/documents/downloadable/ucm_319587.pdf. Published March 2013. Accessed March 29, 2013.

38. Ruilope LM, Dukat A, Böhm M, at al. Bloodpressure reduction with LCZ696, a novel dualacting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebocontrolled, active comparator study. Lancet.2010;375(9722):1255-1266.

39. LCZ696. http://www.clinicaltrials.gov/ct2/results?term=LCZ696+blood+pressure&Search=Search. Updated December 2012. Accessed March28, 2013.

40. Boudreau DM, Malone DC, Raebel MA, et al. Health care utilization and costs by metabolic syndrome risk factors. Metab Syndr Relat Disord. 2009;7(4):305-314.

Author Disclosure: The author reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. Authorship Information: Concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.