Medical scholars on both sides of the very public dispute over new disease prevention guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA) expected controversy.

Major revisions to treatment protocols typically generate at least some points of genuine dispute, leaving individual professionals to weigh the evidence for themselves until new research and analysis answers questions definitively.

In this particular case, the points of actual contention are few, though serious. The vast majority of the guidelines, along with the vast majority of the procedures for creating them, have won widespread support among those who study atherosclerotic cardiovascular disease. Indeed, even the most famous critics of the new recommendations have praised them for their emphasis

on preventing stroke as well as heart disease, their efforts to differentiate risk by race and gender, and their efforts to translate research into suggestions

• Studies correlating low-density lipoprotein (LDL) cholesterol and disease find no specific thresholds separating safety from danger, so the guidelines omit any mention of specific LDL targets along the lines of <70 mg/dL or <100 mg/dL.

• Drug trials have found that many nonstatin medications can lower LDL levels, but no such drug has demonstrated the ability to lower the risk of stroke or heart disease like statins, which is why the new guidelines rarely recommend considering them, not even for statin-intolerant patients with dangerous LDL levels.

• Trials of statins, on the other hand, have distinctly demonstrated that they prevent strokes and myocardial infarction associated with hypertension, diabetes, and other risk factors beyond LDL levels; thus, the new guidelines suggest statins for many patients with healthy cholesterol profiles.

• Analyses that found no evidence of benefit to statins given to older patients have also been incorporated into the new guidelines, which do not recommend them for patients over age 75 years. Such recommendations have raised objections among conservative clinicians who think the changes too radical and from people who wanted more emphasis on lifestyle and less on medication.

Among thought leaders, however, all the suggestions above have received a warm reception. The only real controversial points are formulas that combine nearly a dozen factors to estimate each patient’s 10-year risk of atherosclerotic cardiovascular disease and a recommendation that any patient whose calculated 10-year risk exceeds 7.5% consider statin therapy.

A viewpoint article published by The Lancet on November 19, 2013, just a few days after the ACC and AHA unveiled the new guidelines, began the debate on both those points, starting with the decision to base discussions about statin use on a combined calculation. “No trial of statin therapy has ever used a global risk prediction score as an enrollment criterion, so basing prescriptions on such a metric might be difficult to defend in an evidence-based climate,” wrote Paul Ridker, MD, and Nancy Cook, PhD, both professors at Harvard University’s Brigham & Women’s Hospital.

“In addition, trial data contradict statements that high absolute risk always predicts statin efficacy… The CORONA

 trials enrolled individuals with very high vascular risk in the settings of heart failure or renal failure and found no evidence of event reduction with statin therapy despite large reductions in LDL cholesterol.”

Other critics have expressed particular frustration that high risk scores generated almost entirely by a patient’s age can easily cross the 7.5% threshold and thus trigger serious consideration of statin therapy.

 After all, they argue, no trial has ever found that statins prevent atherosclerotic cardiovascular disease associated with aging.

Donald Lloyd-Jones, MD, ScM, who co-chaired the risk assessment work group, thinks many of the critics simply misunderstand, or haven’t read, the guidelines. “The guidelines don’t order anyone to use statins. They merely indicate when it makes sense for doctors and patients to consider statins because there is evidence of benefit for patients in those groups,” said Lloyd-Jones, Eileen M. Foell Professor and chairman of the Department of Preventive Medicine at Northwestern University’s Fienberg School of Medicine.

“If your total 10-year risk is lower than 7.5%, the costs associated with statins may outweigh the benefits for many patients, so there may be no reason to use them. Once your risk exceeds 7.5%, though, it may make sense to use them, depending on why your risk exceeds 7.5%.

“If hypertension or diabetes or high LDL contributes to your risk, then statins probably make sense. If age is your only risk factor, then statins may not make sense and these guidelines aren’t pushing statins on you. I just don’t understand how anyone who had bothered to read the documents in full rather than news reports could think otherwise.”

The other major criticism of the guidelines concerns the accuracy of the risk calculator and, again, traces its origin to the Lancet piece. In it, Ridker and Cook report on their efforts to validate the risk calculator on 3 large medical data sets: the Women’s Health Study (WHS), the Physicians’ Health Study (PHS), and the Women’s Health Initiative Observation Study (WHI-OS).

The risk calculator received the initial information from each cohort participant and made predictions that Ridker and Cook then compared against actual patient results. The calculator overestimated risk by 75% to 150% in all 3 cohorts, Ridker and Cook wrote, predicting roughly double the actual amount of observed disease across the 3 groups. “It is possible that as many as 40—50% of the 33 million middle-aged Americans targeted by the new ACC/AHA guidelines for statin therapy do not actually have risk thresholds that exceed the 7.5% threshold suggested for treatment. Miscalibration to this extent should be reconciled and addressed in additional external validation cohorts before these new prediction models are widely implemented.”

Those charges have made much news, but the risk calculator’s creators and backers stand firmly behind their work.

To build the calculator, the ACC/AHA committee started with a list of factors proved to increase the risk of atherosclerotic cardiovascular disease and found several major medical cohorts that collected all the relevant data on large numbers of typical American patients for at least a decade: the Framingham Heart Study, Atherosclerosis Risk in Communities, Coronary Artery Risk Development in Young Adults, and the Cardiovascular Health Study.

They then crunched untold billions of numbers until they had the tool that best translated starting-point risk factors into accurate projections of actual disease occurrence. After finalizing the calculator, the committee attempted to validate it just as Ridker and Cook later did, by seeing how its predictions matched reality among patients in other cohorts, namely the Multiethnic Study of Atherosclerosis and Reasons for Geographic and Racial Differences in Stroke studies. These validation efforts also found that the calculator systematically overestimated risk. The overestimates tended to be small for people at low risk, but often exceeded 50% for patients at higher risk.

Committee members began to investigate and quickly found a plausible explanation for the error: many of the patients with high initial risk in both cohorts had started taking statins, which had prevented many of them suffering the strokes and heart problems that the calculator predicted. They suspect the same explanation would account for some of the overestimation that Ridker and Cook found and that missing data, along with the unusual patient populations of the WHS, PHS and WHI-OS cohorts, would explain most of the rest.

“We considered using all 3 of those cohorts, either to build or test the risk calculators, but we decided against it on grounds that they lacked the data needed to be helpful and could well end up being misleading,” said David Goff, MD, PhD, FACP, FAHA, dean of the Colorado School of Public Health and co-chair of the Risk Assessment Committee.

The data shortfalls ranged from the duration of patients’ records (less than a decade) to the information recorded (incomplete accounts of some risk factors and medications) to the way the information was collected (often selfreported). The patient populations of all 3 cohorts posed even greater concerns. Neither WHS nor PHS nor WHI-OS tracks anything like a normal cross-section of Americans. All 3 abound with the sort of affluent and educated patient who consistently enjoys far better health than poorer people with ostensibly similar medical starting points.

Barring both a decision by Ridker and Cook to hand over all their data and calculations and the discovery that Ridker and Cook devised a very clever way to compensate for the unusually healthy patient populations, Goff and his colleagues see little reason to scrap a risk calculator that, they say, works on normal populations better than any other available tool.

That said, the ACC-AHA committee did take a step to guard against the possibility of systematic risk overestimation. It decided to raise the risk threshold for the consideration of statin therapy from the 5% that many felt the evidence supported to the 7.5% that made the final cut. “It’s basically impossible to believe the calculator massively overestimates the number of patients who should consider statins when you look at the big picture,” said Goff. “The risk calculator would suggest that about a third of Americans aged 40 to 75 are at enough risk to consider statins. In reality, about a third of all Americans will die from heart disease or stroke and 60% of us will have a major vascular event.”

The controversies over the risk calculator and other aspects of the new guidelines have themselves sparked a sort of meta-controversy, not about the actual guidelines but about the process of their creation. A number of critics have suggested the very existence of serious criticisms, even if the critics turn out to be wrong, indicates that the guideline committees failed to create the sort of bulletproof process that guarantees accurate recommendations and their rapid acceptance.

“Every time a controversy plays out like this, it hurts patients. Many people will leap from the assertion that this calculator recommends statins too frequently to the conclusion that they should always refuse to use statins,” said Steven Nissen, MD, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic. “The committees should have taken extra steps, like independent peer review for previously unpublished material, to avoid controversies that could set us back years.”

But avoiding controversy has proved very difficult for many bodies that have written guidelines in the past. Debate still rages about the US Preventive Services Task Force (USPSTF) recommendation that women under 50 years not get routine yearly mammograms,

 and it is beginning to heat up over new suggestions on when to treat high blood pressure.

There is, unfortunately, no widely accepted blueprint for writing comprehensive and accurate guidelines beyond a brief primer from the Institutes of Medicine (IOM).

 Still, the ACC/AHA committees think they created a strong process for tracking down relevant research, evaluating its merit, resolving apparent conflicts, acknowledging hazy areas, and translating it all into easily understood recommendations. Indeed, the process has won the groups praise from the IOM, which is trying to update and expand its guidelines for writing guidelines.

“They were talking about guideline writing committees that had designed good processes,” Lloyd-Jones said. “And they used us as their example.” 

1. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease [published online November 20, 2013]. Lancet. 2013;382(9907):1762-1765. doi:10.1016/S0140.

2. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicenter randomized placebo-controlled trial. Lancet. 2004;364(9435):685-696.

3. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinaviran Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOTLLA): a multicenter randomised controlled trial. Lancet. 2003;361(9364):1149-1158.

4. Kjekshus J, Dunselman P, Blideskog M, et al. A statin treatment of heart failure? controlled rosuvastatin multinational study in heart failure (CORONA): Study design and baseline  haracteristics. European Journal of Heart Failure. 2005;7(6):1059-1069.

5. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients underdoing hemodialysis. N Eng J Med. 2009;360(14):1395-1407.

6. Husten L. Controversy erupts over accuracy of cardiovascular risk calculator for guidelines. Forbes website. http://www.forbes.com/sites/larryhusten/2013/11/18/controversy-eruptsover-accuracy-of-cardiovascular-risk-calculatorfor-guidelines/. Published November 18, 2013. Accessed January 8, 2014.

7. Mammogram rate did not decline in U.S. after controversial recommendations. Science Daily. http://www.sciencedaily.com/releases/2013/04/130419080010.htm. Published April 19, 2013. Accessed January 8, 2014.

8. Burling S. New blood pressure guidelines raise concern among heart-health groups. Washington Post. December 26, 2013. http://www.washingtonpost.com/national/health-science/new-blood-pressure-guidelines-raise-concernamong-heart-health-groups/2013/12/26/eaa6c73e-6e3d-11e3-b405-7e360f7e9fd2_story.html. Accessed January 8, 2014.

9. Clinical guidelines we can trust. Institute of Medicine. http://www.iom.edu/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust/Report-Brief.aspx. Published March 23, 2011. Accessed January 8, 2014.

Articles

Evidence-Based Diabetes Management

Understanding the Role of Big Data in the CV Risk Calculator Controversy

Obesity continues to be a growing health concern. The number of adults classified by the Centers for Disease Control and Prevention (CDC) as being overweight or obese, with a body mass index (BMI) of 25 kg/m2 or higher, is almost 155 million; those considered obese (BMI ≥30.0 kg/m2) number 79 million. If left unchecked, obesity-related healthcare costs could top $950 billion by 2030.

 Based on the number of people affected and the associated cost, stakeholders are taking steps to reduce this burden. However, challenges remain (see Highlight Box).

Until 2012, the US Food and Drug Administration (FDA) had not approved a drug to treat obesity since orlistat won approval 13 years ago.

 Safety concerns had limited the number of drugs available to treat obesity, and safety continues to remain a concern. Lorcaserin, marketed as Belviq by Arena Pharmaceuticals, and phentermine/topiramate extended release, marketed as Qsymia by Vivus Inc, were both approved in 2012 to treat obesity alongside a reduced-calorie diet and exercise.

Both drugs have FDA-approved labeling stating the drugs should be discontinued if 5% weight loss is not achieved after 12 weeks of therapy.

 The nonincretin medications that are currently in phase III development have mechanisms of action similar to antiobesity drugs that are currently available. Only 1 drug in phase II development has a mechanism of action that does not involve the central nervous system (CNS).

 Currently, the only nonincretin product in phase III development in the United States is a combination of bupropion and naltrexone being developed by Orexigen. If approved, it will be marketed as Contrave. Both components of this centrally acting agent affect the pro-opiomelanocortin (POMC) neurons (Figure). So far, this agent has had a bumpy road to approval.

The FDA initially rejected Orexigen’s new drug application (NDA) in January 2011, indicating a concern about the product’s cardiovascular safety. The pivotal study cited in the initial filing was a phase III trial of 1496 patients who were enrolled for 56 weeks of treatment with bupropion/naltrexone or placebo. Fifty-four percent of patients in each treatment arm completed the study. Weight loss was significantly greater at 28 weeks in the bupropion/naltrexone group compared with the placebo group, and the same result was seen at 56 weeks (6.5% vs 1.9%, P <.001; 6.4% vs 1.2%, P <.001; respectively).

 More patients dropped out of the study due to adverse events in the treatment group than in the placebo group (241 vs 68 patients). Nausea, headache, and constipation were the most frequently reported adverse events. Serious adverse events were reported in 2.1% of the treatment group and 1.4% in the placebo group. A myocardial infarction was reported by a patient in the treatment group with active coronary artery disease, and 1 patient in the treatment group who did not have a history of seizures suffered one during the study.

In its complete response letter, the FDA mandated in 2011 that Orexigen conduct a randomized, double-blind, placebo-controlled trial to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects does not adversely affect the drug’s benefit risk profile.

 To address these concerns, the Light Study was designed and approved by the FDA.

The study began in June 2012 and is expected to be completed in the second quarter of 2017. The FDA proposed that findings from the interim analysis report compiled by the Light Study’s independent data monitoring committee be the basis for the NDA resubmission filing. The primary outcome measure of the Light Study is the length of time to the first confirmed occurrence of a major cardiovascular event in a 4-year period.

 The secondary outcomes measures are also related to safety issues. On November 25, 2013, Orexigen announced that the interim results of the Light Study had been successful, and on December 11, 2013, it resubmitted its NDA filing with approval aimed for June 2014.

In February 2013, Orexigen initiated another study, the Ignite Study, to assess the percent change in body weight during a 26-week time period. The secondary outcomes measures include both efficacy and safety measures.

 The company anticipates that the study will be completed in December 2014.

A lipase inhibitor dubbed cetilistat, to be marketed as Cametor by Takeda, is in phase III trials in Japan. A 12-week study compared cetilistat with orlistat, both given 3 times daily, demonstrated similar weight reduction results compared with a placebo. With cetilistat treatment, weight reduction was 3.85 kg (P = .01) in those receiving an 80-mg dose and 4.32 kg (P = .0002 in the placebo comparison) in those receiving a 120-mg dose. The weight reduction was 3.78 kg (P = .008) in the 120-mg orlistat group. There were fewer discontinuations in the cetilistat group than in the orlistat group; the discontinuations due to adverse events in the cetilistat were similar to those patients receiving placebo.

 Norgine, a European company, is developing the product for approval by regulatory agencies outside of Japan and is currently seeking partnerships for such programs.

 A drug with a new mechanism of action for treating obesity is beloranib. The drug is a methionine aminopeptidase 2 (MetAP2) inhibitor that targets imbalances in fat metabolism that are present in patients with obesity.

 Specifically, it reduces the production of new fatty acid molecules by the liver and also helps to convert stored fats into useful energy. Results announced by Zafgen Inc on November 15, 2013, showed significant weight loss and improvements in cardiometabolic risk markers in 147 obese patients over a 12-week period. Study participants taking 0.6 mg, 1.2 mg, or 2.4 mg of the drug lost, on average, 5.5 kg, 6.9 kg, and 10.9 kg, respectively, compared with 0.4 kg for those on a placebo. No serious adverse events deemed related to the drug were reported.

 Both components of a new combination drug that will be marketed as Empatic (bupropion SR 360 mg/zonisamide SR 360 mg) affect the CNS. It has shown favorable weight-loss effects. Bupropion increases dopamine levels, while zonisamide increases dopamine and serotonin neurotransmission.

 After 24 weeks of treatment, patients in the treatment group had a mean weight loss of 7.5% vs 1.4% in the placebo group (no P value given). The combination drug was also compared with its components. Greater mean weight loss was seen with the combination drug (7.5% for combination, 2.3% for bupropion, and 5.3% for zonisamide; P <.001). The most commonly reported adverse events were headache, insomnia, and nausea as would be expected with drugs affecting the CNS.

 A melanocortin-4 receptor (MC4R) agonist, RM-493 modulates leptin-receptor signaling, resulting in decreased appetite; it has also been implicated as a common genetic variant in obesity is in early phase II trials.

 Results for weight loss in humans have been mixed.

 Adverse events observed have included nausea, diarrhea, and loose stools, and skin rash, but it was considered well tolerated overall.

 Potential unwanted adverse effects may be increased blood pressure and heart rate as well as penile erection, as MC4 agonists stimulate the sympathetic nervous system.

 Tesofensine inhibits dopamine, norepinephrine, and serotonin uptake. Initial development of the drug was for Parkinson disease and Alzheimer disease; however, researchers discovered weight loss was associated with its use without changing blood pressure.

 In a trial of 203 patients, participantswere assigned to either restrict their diets or take tesofensine in doses of 0.25 mg, 0.5 mg, or 1 mg for 24 weeks. Those in the diet-restricted group lost 2% of their body weight, whereas those in the tesofensine groups lost a mean of 4.5%, 9.2%, and 10.6%, respectively, more body weight greater than did the control group (all P = .0001). Significant increases in diastolic or systolic blood pressure were not observed in the 0.25-mg and 0.5-mg groups, but an increased heart rate (7.4 beats/min) was seen in the 0.5-mg group (P = .0001). The most frequently observed adverse events were dry mouth, nausea, constipation, diarrhea, and insomnia.

There are only a few nonincretin drugs in the pipeline for the treatment of obesity. This is disappointing because of the enormous health and financial consequences of obesity. However, it appears that there is beginning to be a convergence of thinking about the importance of addressing obesity in the United States. The government and the AMA appear ready to accept the challenge of reducing obesity. As demand for drugs increases, pharmaceutical and biotechnology companies will undoubtedly respond with new therapeutic entities to treat overweight and obese patients.

It will be up to patients, employers, insurers, and health plans as to whether we proceed on a course to address the challenge.

 The federal Health Care and Education Reconciliation Act of 2010 included provisions relative to the treatment and insurance coverage of conditions related to obesity.

All Medicaid and Medicare beneficiaries as well as those patients with private insurance will be eligible to receive preventative services for obesity as recommended by the US Preventive Services Task Force (USPSTF). Private insurers will be required to pay medical claims for preexisting conditions identified as obesity or an obesity-caused comorbid condition.

 In June 2012, the USPSTF, an independent panel of experts, recommended that doctors screen all patients for obesity. They also recommended that clinicians should refer patients with BMI ≥ 30 kg/m

 to an intensive, multicomponent behavioral intervention program. However, the USPSTF did not identify programs that meet the criteria for an intensive, multicomponent behavioral intervention that helps patients lose weight.

To date, Medicare part D does not cover obesity drugs. Under Medicaid, only 10 states provided coverage of obesity drugs for adults as found by a survey in 2008.

 Due to this legislation and recommendations of the USPSTF, the US Secretary of Health and Human Services (HHS) may develop rules and regulations to address or expand coverage of services related to the treatment of obesity.

 Most state insurance laws do not include language about the coverage of obesity treatments. A survey of state insurance laws in 2008 found that relative to obesity, 6 states required or explicitly allowed coverage of certain obesity treatments in their group markets. For individual markets, only 5 states had language about coverage in the policies.

 Obesity treatments included bariatric surgery and drugs. A retrospective study conducted by the Veterans Affairs medical centers could further deemphasize coverage for bariatric surgery. The analyses of 850 veterans (mean age 49.5 years) showed that after a mean follow-up of 6.7 years, bariatric surgery did not reduce mortality compared with usual care.

 In June 2013, the American Medical Association (AMA) recognized obesity as a disease. This policy acknowledges that obesity is a complex issue that requires a range of medical interventions to advance obesity treatments and prevention.

To date, the American Heart Association and American Diabetes Association have not updated their guidelines on obesity to include drugs for the treatment of obesity.

Although employers are aware of the financial impact of obesity, they generally consider obesity as a lifestyle choice rather than a disease. Some offer onsite weight-control programs or health coaches, and some have modified cafeteria menus. Health risk assessments and financial incentives associated with healthcare premiums are also strategies being utilized to “encourage” employees to adhere to a healthy weight-friendly lifestyle.

 As noted, government agencies (Centers for Medicare & Medicaid Services for Medicare Part D and Medicaid in most states) do not broadly provide drug coverage for obesity drugs. The stance of managed care organizations (MCOs) is similar. A survey conducted in early 2013 found that nearly half of surveyed MCOs and medical directors do not cover drugs for obesity.

 Reasons for not covering these drugs include: safety, long-term efficacy, no improvement in cardiovascular outcomes, and the perception that these are “lifestyle”

drugs that are used for cosmetic reasons.

 Express Scripts, one of the largest pharmacy benefit management companies, added phentermine/topiramate extended release (Qsymia) to its national formulary in 2012 with availability only through its mail order service.

 Of course, employers and health plans will be the determining factor as to whether they offer the drug to their patients. Also in 2012, Aetna added locaserin and phentermine/topiramate in a clinical policy bulletin describing the insurer’s approach to weight reduction.

 This weight reduction policy bulletin included all drugs approved by the FDA for obesity.

1. Statistical Fact Sheet 2013 Update: Overweight & Obesity. American Heart Association website. http://www.heart.org/idc/groups/heart-public/@wcm/@sop/@smd/documents/downloadable/ucm_319588.pdf. Accessed October 1, 2013.

2. Orlistat (marketed as Alli and Xenical) information. US Food and Drug Administration website.http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm180076.htm. Updated June 17, 2013. Accessed October 1, 2013.

3. FDA approves Belviq to treat some overweight or obese adults [press release]. Silver Spring, MD: US Food and Drug Administration; June 27, 2012. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm309993.htm. Accessed September 30, 2013.

4. FDA approves weight-management drug Qsymia [press release]. Silver Spring, MD: US Food and Drug Adminstration; July 17, 2012. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm. Accessed September 30, 2013.

5. Apovian CM, Aronne L, Rubin D. et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity. 2013;21:935-943.

6. FDA issues complete response to new drug application for Contrave for the management of obesity [press release]. San Diego, CA: Orexigen website; February 1, 2011. http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-news Article&id=1522207. Accessed September 29, 2013.

7. Cardiovascular outcomes study of naltrexone SR/bupropion SR in overweight and obese subjects with cardiovascular risk factors (The Light Study). US National Institutes of Health. http://clinicaltrials.gov/ct2/show/NCT01601704?term=Light+study&rank=2. Published May 6, 2013. Accessed September 29, 2013.

8. Orexigen resubmits Contrave new drug application [press release]. San Diego, CA: Orexigen website; December 11, 2013. http://ir.orexigen .com/phoenix.zhtml?c=207034&p=irol-newsArticle_print&ID=1883850&highlight=. Accessed December 31, 2013.

9. 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. US National Institutes of Health. http://clinicaltrials.gov/ct2/show/NCT01764386?term=Ignite+study&rank=1. Published February 8, 2013. Accessed September 29, 2013.

10. Kopelman P, Groot GH, Rissanen A, et al. Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics; comparison with orlistat (Xenical). Obesity. 2010;18:108-115.

11. Partnering opportunities. Norgine website. www.norgine.com/pages/partnering/opportunities.html. Accessed September 30, 2013.

12. Chugh PK, Sharma S. Recent advances in the pathophysiology and pharmacological treatment of obesity. J Clin Pharm Ther. 2012;37:525-535. 13. Zafgen announces new weight loss and safety data from phase 2 study of beloranib in obesity at Obesity Week 2013 [press release]. Atlanta, GA: November 15, 2013. http://www.zafgen.com/zafgen/newsroom/news-details?ID=d0dbc3b2-5885-6f14-8089-ff0000fc4595 Accessed December 31, 2013.

14. Orexigen therapeutics phase 2b trial for Empatic meets primary efficacy endpoint demonstrating significantly greater weight loss versus comarators in obese patients [press release]. San Diego, CA:Orexigen website; September 30, 2009. http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1336796&highlight=. Accessed September 30, 2013.

15. Adan RAH. Mechanisms underlying current and future antiobesity drugs. Trends Neurosci. 2013;36:133-140.

16. Misra M. Obesity pharmacotherapy: current perspectives and future directions. Current Cardiology Reviews. 2013;9:33-54.

17. Krishna R, Bumbiner B, Stevens C, et al. Potent and selective agonism of the malanocortin receptor 4 with MK-0493 does not induce weight loss in obese human subjects—energy intake predicts lack of weight loss efficacy. Clin Pharmacol Ther. 2009;86:659-666.

18. Schakenbach J. BioFlash Newsletter. http://www.bizjournals.com/boston/blog/bioflash/2013/01/rhythm-begins-phase-2-trials-for.html?page=all. Published January 4, 2013. Accessed October 3, 2013.

19. Khan A, Raza S, Khan Y, et al. Current updates in the medical management of obesity. Recent Pat Endocr Metab Immune Drug Discov.2012;6:1-12.

20. Astrup A, Meier DH, Mikkelsen BO, et al. Weight loss produced by tesofensine in patients with Parkinson’s or Alzheimer’s disease. Obesity. 2008;16:1363-1369.

21. Astrup A, Madsbbad S, Breum L, et al. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients:a randomized, double-blind, placebo-controlled trial. Lancet. 2008;372:1906-1913.

22. Downey M. What does health care reform mean for obesity? the Downey Obesity Report. http://www.downeyobesityreport.com/2010/03/what-does-health-care-reform-mean-forobesity/. Published March 23, 2010. Accessed October 3, 2013.

23. US Preventive Services Task Force Recommendation. Statement Screening for and Management of Obesity in Adults. http://www.uspreventiveservicestaskforce.org/uspstf11/obeseadult/obesers.htm. Published June 2012. Accessed October 3, 2013.

24. Lee JS, Sheer JLO, Lopez N, et al. Coverage of obesity treatment: a state-by-state analysis of Medicaid and state insurance laws. Public Health Reports. 2010;125:596-604.

25. Maciejewski ML, Livingston ED, Smith VA, et al. Survival among high-risk patients after bariatric surgery. JAMA. 2011;305:2419-2426.

Nonincretin Drugs in Later-Stage Development

Glycemic control in diabetes mellitus has been shown in landmark studies to keep circulatory, renal, and ophthalmologic complications at bay. However, once these patients with diabetes mellitus show signs of kidney dysfunction, clinicians must be vigilant for a host of other potential problems.

According to the latest National Health and Nutrition Examination Surveys (NHANES), 40% of patients with diabetes had self-reported chronic signs, kidney disease (CKD), with a 3.5-fold increased likelihood of CKD compared with the general population (Figure 1).

 At the recent 2013 annual meeting of the American Heart Association, investigators took a closer look at addressing 2 of the more troubling problems associated with diabetes and renal disease. The microvascular abnormalities seen in patients with diabetes, which involve the kidneys and the retina, are thought to be linked through microalbuminuria (or moderately increased albumin levels). The presence of microalbuminuria is considered a sign of early diabetes-related CKD, but it is also associated with cardiovascular disease in both patients with diabetes and those without.

 Microalbuminuria seen in these diabetes-related microvascular abnormalities may be connected with coronary bed microvascular irregularities, which can result in dysrhythmia.

Therefore, the possible relationship of retinopathy, coupled with microalbuminur, ia, as well as retinal vascular were studied by researchers from the United States and Singapore.

 By studying the general population over a 14-year span, researchers sought to determine the frequency of atrial fibrillation (AF) and microalbuminuria in those with retinopathy.

At baseline, 7.1% of the 10,009 study population had retinopathy (retinal microaneurysms, 4%; retinal hemorrhage, 3%), while microalbuminuria was seen in 7.2% of the cohort. After a mean follow-up of 13.6 years, the researchers found that AF had occurred in 11.0% (1100 individuals).

The AF incidence rates were highest for patients with retinopathy and microalbuminuria and lowest for those without either potential risk factor (Table). When the investigators analyzed the cumulative incidence of AF by albumin to creatinine ratio (either <30 or ≥30), as well as retinal vascular they found that the incidence of AF increased rapidly after year 3 only in patients with both microalbuminuria and retinopathy. After adjusting for age, race, and sex, they calculated a hazard ratio for AF (with 95% confidence intervals) of 1.86 (1.54—2.24) when subjects with retinopathy were compared with those without. When they adjusted for cardiovascular risk factors, such as diabetes, high blood pressure, and prevalent heart disease, the hazard ratio for AF was 1.37 (1.12–1.67).

Even though a nonlinear connection was revealed between AF and a narrowing of retinal venous circulation, the researchers could not find a correlation with other retinal microvascular signs, such as retinal arterial circulatory narrowing or focal-generalized narrowing. Independent and interactive indications of microvessel disease in kidneys and retina, concluded the investigators,

can cause a greater risk of AF. They speculated that systems such as endothelial dysfunction, atrial fibrosis, cardiac remodeling, and autonomic dysfunction may play a role in this association. However, further study will be needed to elucidate this relationship.

New Treatment for Patients With CKD and Resistant Hypertension

The link between the renal and circulatory systems is well-known, as the renin-angiotensin-aldosterone hormonal axis regulates the balance between blood pressure and fluid in the body. The kidney plays a critical role, as it can actively remove water from the circulation, reducing blood pressure. When the system is overactive, hypertension is the result.

Patients with diabetes mellitus are at risk for both CKD and hypertension, and often the renin-angiotensin—aldosterone system is the culprit.

 Antihypertensive agents have long been dominated by drugs that influence this hormonal axis, including diuretics, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers. However, few new antihypertensive modalities have been introduced in recent years, and patients with refractory hypertension could benefit from new treatment approaches.

 This is especially true for patients who are taking several blood pressure medications and still are not attaining adequate control. Experts believe that perhaps one-fifth of all patients with hypertension fall into that resistant-to-treatment category.

One promising approach may not be pharmacologic in nature. Catheter-based renal denervation (Figure 2) may offer several benefits, including improved glucose metabolism.

 German researchers performed a pilot study using renal denervation as a novel antihypertensive therapy for individuals with treatment-resistant hypertension.

 They also examined whether renal denervation in these patients with CKD slowed the decline in renal function. The 15 patients in the study group, with a mean age of 66 years, were taking at least 3 antihypertensive medications, with the mean 5.8 agents. However, they had not reached a blood pressure of < 140/90 mm Hg). The study subjects all had stage 3 or 4 CKD. Eleven patients also had concomitant type 2 diabetes mellitus (T2DM).

Each patient underwent catheter-based renal denervation. After 1 year, significant reductions were achieved in blood pressure: Mean systolic blood pressure decreased from 167 ± 22 mm Hg at baseline to 141 ± 11 mm Hg (P = .004). Diastolic pressure fell as well, although this decrease did not attain statistical significance (78 ± 13 at baseline vs. 73 ± 9 mm Hg after 1 year [P = .079]). Significant reductions were also observed in average systolic 24-hour ambulatory blood pressure (13 mm Hg decrease, P = .028) and average aortic systolic blood pressure (24 mm Hg decrease, P = .001).

The mean estimated glomerular filtration rate (eGFR) decline before the renal denervation was —5.6 mL/min/173 m²/yr. After the therapy, eGFR was steady or increased (baseline: 47.0 ± 11 vs. 1 yr: 49.2 ± 14 mL/min/1.73 m²). A significant difference was seen in eGFR before and after renal denervation (–5.6 ± 4.4 vs 2.2 ± 8.0 mL/min/173 m²/yr; P = .021).

The researchers reported that none of the 15 study participants needed dialysis after the procedure or experienced a doubling of their serum creatinine levels during the 1-year follow-up.

This pilot study demonstrated that patients with resistant hypertension may benefit from interventional treatment using renal denervation, according to the researchers. They emphasize that this procedure shows the potential to mitigate the deterioration in renal function in these patients with CKD as well as treatment-resistant hypertension.

1. 2013 Atlas of CKD and ESRD. US Renal Data System 2013 (http://www.usrds.org/atlas.aspx). Accessed January 6, 2014.

2. McCollough DK, Bakris GL. Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus. Up to Date. http://www.uptodate.com/contents/moderately-increasedalbuminuria-microalbuminuria-in-type-2-diabetesmellitus. Updated November 2013. Accessed January 5, 2013.

3. Agarwal S, Shah T, Lopez F, et al. Retinal microvascular abnormalities, albuminuria, and atrial fibrillation incidence: The ARIC Study. Presented at the 2013 Scientific Sessions of the American Heart Association. November 16-20, 2013; Dallas, TX.

4. Lim HS, MacFadyen RJ, Lip GY. Diabetes mellitus, the renin-angiotensin-aldosterone system, and the heart. Arch Intern Med. 2004;164(16):1737-1748.

5. Monge M, Lorthioir A, Bobrie G, Azizi M. New drug therapies interfering with the reninangiotensin-aldosterone system for resistant hypertension. J Renin Angiotensin Aldosterone Syst. 2013;14(4):285-289.

6. Krum H, Granger CB. Catheter-based renal denervation: Current status and future applications. Medscape Cardiology. http://www.medscape.org/viewarticle/742356_transcript. Published June 10, 2011. Accessed January 6, 2014.

7. Mahfoud F, Schlaich M, Kindermann I, et al. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation. 2011;123(18)

8. Schmieder REE, Mahfoud F, Schmid A, et al. Does renal denervation stop renal function decline in treatment-resistant hypertension? Results of a pilot study. Presented at the 2013 Scientific Sessions of the American Heart Association. November 16-20, 2013; Dallas, TX.

Attacking Complications to Kidney Problems in Diabetes: Atrial Fibrillation and Resistant Hypertension

This month, the federal panel charged with offering guidance on what Americans should eat will try to make up for lost time, when it meets January 13-14, 2014, in Bethesda, Maryland, to hear comments from the public.

In June 2013, the Dietary Guidelines Advisory Committee (DGAC), a 15-member group that includes experts in nutrition, epidemiology, obesity, cancer prevention, cardiovascular disease, and pediatric health, kicked off the process that will end with the publication of the 2015 Dietary Guidelines for Americans. A meeting planned for early October was canceled due to the government shutdown, making for a full January agenda.

US dietary guidelines have been issued every 5 years since 1980 and are now mandated by Congress. The lengthy process that creates them invites plenty of scrutiny. Given the stakes, lobbyists for the food industry and nutrition advocates alike prepare well in advance for the meetings. Even though the 2010 process produced innocuous sounding edicts like “Avoid oversized portions” and “Drink water instead of sugary drinks,” it also produced highly specific instructions that caused an overhaul of school lunch programs.

Dietary Guidelines for Americans drives regulations from the US Department of Agriculture (USDA) and the US Food and Drug Administration (FDA). Besides school lunches, the guidelines dictate the shape of huge programs, such as meals for the military and values in the Supplemental Nutrition Assistance Program (SNAP).

Interest in the guidelines has increased with first lady Michelle Obama’s focus on childhood obesity, especially given the fallout from the 2010 report. That process, which straddled the end of the Bush Administration and President Barack Obama’s first 2 years, resulted in the well-publicized scrapping of the “food pyramid” for “MyPlate,” a visual representation that won some praise for promoting fruit and vegetable consumption but was seen by others as a concession to the food industry, with too much emphasis on protein and dairy.

 Companion legislation passed in 2010 overhauled school lunches, removing popular fried foods, imposing calorie caps, and inviting complaints from around the country that districts were losing money when students refused to eat the healthier fare.

The guidelines’ role in reining in obesity was highlighted when the last edition was issued. “The 2010 Dietary Guidelines are being released at a time when the majority of adults and 1 in 3 children is overweight or obese, and this is a crisis we can no longer ignore,” US Agriculture Secretary Tom Vilsack said at the time.

 In a process outlined by statute, Vilsack’s department took the lead on the 2010 report, while the Department of Health and Human Services (HHS), led by Secretary Kathleen Sebelius, will be the lead agency this time. Staff from both departments have input, although HHS will be responsible for incorporating DGAC’s recommendations into the final report.

The 2015 panel is composed almost entirely of new members, led by Chair Barbara Millen, DrPH, RD, who is a professor at the Boston University School of Medicine. Millen is also founder and president of Millennium Prevention, Inc, a startup with significant funding from the National Institutes of Health (NIH) that develops web-based and mobile applications to encourage healthy ifestyles.

 Including Millen, the panel includes 5 registered dieticians, as well as 3 members affiliated with cancer centers: Lucile Adams-Campbell, PhD, professor of oncology at the Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; Marian Neuhouser, PhD, RD, of the Cancer Prevention Program at the Fred Hutchinson Cancer Research Center in Seattle, Washington; and Steven Clinton, MD, PhD, of the Ohio State University Comprehensive Cancer Center.

Members of the committee contacted this fall by Evidence-Based Diabetes Management referred all questions back to agency staff, saying they could not discuss the process prior to making recommendations. Thus, gaining a sense of the committee’s output requires a look at what topics panelists are prioritizing. This reading of the tea leaves can cause intense reaction to developments that are seen as fodder for the committee’s work. For example, a May 2013 report from the Institute of Medicine (IOM) that clarified recommendations on salt intake provoked such outcry that IOM President Harvey V. Fineberg issued a letter critiquing press coverage.

Registered dietician Lori Kaley, MS, RD, LD, MSB, writing for Fooducate, a nutrition website that claims it is not “funded or influenced” by the food or supplement industry, in July 2013 took note of the items labeled “high priority” or “new” by one of the panel’s original working groups.

 High-priority items included sodium, omega-3 fatty acids (seafood), fortified foods and beverages, trans fatty acids, processed meats, dairy, and whole fruit and juice. New topics included food and cognitive function, nutrient “overconsumption,” supplements and athletic performance, sugar-sweetened beverages—the term for soda&mdash;and finally, “gene-food interactions.”

A notice on the committee’s website states that the subcommittee structure has been revamped since June, and 5 new subcommittees have been created.

The largest, with 8 members, covers “Dietary Patterns, Foods and Nutrients, and Health Outcomes.” There is also a committee dealing with sustainability in the food supply, a topic listed on this month’s agenda.

 What might that cover? In September 2013, the committee received comments from experts at Johns Hopkins’ Center for a Livable Future, which is among the groups asking the committee to reframe recommendations on seafood: consumers, they argue, are consuming so many big fish and shrimp that supplies are dwindling, and the public should be steered toward sardines and other items “lower on the food chain.”

Inclusion of soda is significant given the attention it received in June 2013 at the American Diabetes Association 73rd Scientific Sessions, where researcher Kimber Stanhope, PhD, RD, openly asked whether the panel would have the fortitude to do something about soda during its deliberations.

 New York City’s new mayor, Bill de Blasio, has vowed to follow through on soda restrictions, and Mexico — now the world’s most obese nation – just imposed a soda tax.

Also, it’s not known how the Dietary Guidelines for Americans will interact with the Affordable Care Act, and its call for healthcare providers and insurers to be rewarded based on population health. HHS will issue the final guidelines around the same time that those who fail to sign up for health insurance will face stiffer penalties in 2015.

1. Dietary Guidelines Advisory Committee. 2015 Dietary Guidelines for Americans website. www.dietaryguidelines.gov. Updated December 18, 2013. Accessed January 1, 2014.

2. US Dept of Agriculture. 2010 Dietary Guidelines for Americans. http://www.cnpp.usda.gov/DGAs2010-PolicyDocument.htm. Published January 31, 2011. Accessed December 31, 2013.

3. US Dept of Agriculture. MyPlate, Dietary Guidelines and General Nutrition. USDA Resource Library. http://snap.nal.usda.gov/resource-library/eat-healthy-every-day/myplate-dietary-guidelinesand-general-nutrition. Updated December 23, 2013. Accessed January 1, 2014.

4. Harvard School of Public Health. Healthy Eating Plate vs. USDA’s MyPlate. HSPH website. http://www.hsph.harvard.edu/nutritionsource/healthyeating-plate-vs-usda-myplate/. Accessed January 1, 2014.

5. Michelle Obama-touted federal healthy lunch program leaves bad taste in some school districts’ mouths. CBS News website. August 30, 2013. http://www.cbsnews.com/news/michelle-obama-touted-federal-healthy-lunchprogram-leaves-bad-taste-in-some-school-districtsmouths/. Accessed December 31, 2013.

6. USDA and HHS announce new dietary guidelines to help Americans make healthier good choices and confront obesity epidemic [press release]. Washington, DC: US Dept HHS News; January 31, 2011. http://www.hhs.gov/news/press/2011pres/01/20110131a.html. Accessed December 31, 2013.

7. E-mail from Tara Broido, MPH, deputy director of communications, Office of the Assistant Secretary for Health, US Dept of Health and Human Services. July 15, 2013.

8. US Dept of Health and Human Services. HHS and USDA announce the appointment of the 2015 Dietary Guidelines Advisory Committee [press release]. Washington, DC: US Dept of HHS News; May 31, 2013. http://www.hhs.gov/news/press/2013pres/05/20130531a.html2015. Accessed July 15, 2013.

9. Millennium Prevention. Extension Engine, Health + Technology website. http://extensionengine .com/health/?page_id=103. Accessed December 31, 2013.

10. Center for Science in the Public Interest. Institute of Medicine chief knocks press coverage of salt report. https://www.cspinet.org/new/201306171.html. Published June 17, 2013. Accessed January 1, 2014.

11. Kaley L. The 2015 Dietary Guidelines for Americans: here’s how you can help improve them. http://blog.fooducate.com/2013/07/29/the-2015-dietary-guidelines-for-americans-hereshow-you-can-help-improve-them/. Published July 29, 2013. Accessed December 31, 2013.

12. Fry JP, Love DC, Nachman KE, Lawrence RS. Letter to 2015 Dietary Guidelines Advisory Committee. Center for Livable Future website. http://www.jhsph.edu/research/centers-and-institutes/johns-hopkins-center-for-a-livable-future/_pdf/projects/ffp/farm_bill/CLF-public-commentseafood-DGAC_2013.pdf. Published September 25, 2013. Accessed December 31, 2013.

13. Stanhope KL. Symposium speaker, Dietary sweeteners—research, recommendations and the real world. 73rd Scientific Sessions of the American Diabetes Association; June 23, 2013; Chicago, Ill.

14. Page P. Will NYC’s new mayor follow through on soda limits? Am J Manag Care 2013;19(SP11):SP318,SP405-SP406.

Dietary Guidelines Panel to Take Input From Public

The movement toward payment for quality took both forward and backward steps as 2013 ended. Positive signs in reimbursement were offset by another delay in a permanent fix to Medicare’s Sustainable Growth Rate (SGR), although Congress does appear ready to resolve this matter in early 2014.

For clinicians involved in the care of patients with cardiometabolic conditions, the news was mixed, as was reaction from professional associations that represent those involved in diabetes care. On November 27, 2013, the Centers for Medicare & Medicaid Services (CMS) unveiled a 2014 Medicare physician fee schedule that featured allowances for care outside of face-to-face visits, starting in 2015.

“Healthcare is changing, and part of the delivery system reform is recognizing this and making sure payment systems account for these changes,” CMS Principal Deputy Administrator Jonathan Blum said in a prepared statement. “We believe that successful efforts to improve chronic care management for these patients could improve the quality of care while simultaneously decreasing costs, through reductions in hospitalizations, use of post-acute care services, and emergency department visits.”

On the plus side, the new CMS rules will permit payments for telephonic health services in rural areas where shortages of qualified professionals have been identified.

 But the 2014 schedule, released the day before Thanksgiving, kept cuts under SGR that Congress was working to eliminate, prompting strong reactions from the American Medical Association (AMA) and the American Academy of Family Physicians (AAFP).

AAFP Presdient Reid Blackwelder, MD, released a response stating the 2014 schedule reflects the flawed SGR formula that dictates Medicare payment for physician services. “That formula must be repealed, and the AAFP urges Congress to act quickly to do so.”

 Congress did act, but not with the permanent remedy for SGR which was outlined in a proposal unveiled October

30, 2013. Instead, the bipartisan budget deal signed by President Barack Obama December 26, 2013, contains a 3-month “patch” similar to others approved year after year, which delays the harsh effects of SGR without unraveling a mechanism critics say has never kept pace with the cost of care.

The short-term fix is also a mixed bag: while it technically includes a 0.5% “raise,” it also locks in other cuts imposed by the federal sequester and retains them in place for up to a decade.

Whether SGR reform will happen in the first quarter of 2014 remains to be seen. Proposals discussed in the fall combined long-term rate freezes with movements toward rewards for quality care.

 Reaction from professional associations was mixed, with AMA making an initial endorsement of the plan—with the hope of doing something to scrap SGR&mdash;while urging Congress to reconsider rate freezes on the heels of previous reimbursement cuts.

Dubbed the Pathway for SGR Reform Act of 2013, this amendment passed the House on December 12, 2013, and the Senate 6 days later. The Congressional Budget Office estimated that the temporary fix would cost $3.3 billion in 2014 and a total of $7.3 billion through 2023. It would be paid for by cutting Medicaid payments for hospital-based charity care and to long-term care hospitals.

The problem with SGR dates to 1997, when Congress created the formula in an effort to control spending. The formula was supposed to set realistic yearly and cumulative spending targets; if the cost of care exceeded the target in any given year, rates would be cut the following year to make up the difference. However, inaccurate forecasts meant actual Medicare Part B spending has exceeded the target for more than a decade.

AMA President Ardis Hoven, MD, told MedPage Today after the October 30, 2013, announcement that, each year, the “sword of Damocles” would hang over physicians’ heads as they waited for Congress to pass legislation to thwart the automatic cuts.

 Yet the longer Congress failed to fix SGR, the worse the problem grew.

How big is the problem? Estimates for getting rid of SGR included $377 billion for 2012 and $139 billion for 2013, and there are no good answers on how to address the problem. When asked how the repeal would be funded, AMA’s Hoven said, “I don’t think we really know.”

 Some accounts attribute the shrinking SGR shortfall to the fact that physicians have already sustained so many cuts.

Endocrinologists and family physicians involved in diabetes care have been especially attuned to efforts by Congress to reform reimbursement formulas. In a September 2013 interview with Evidence-Based Diabetes Management, George Grunberger, MD, said the existing reimbursement scheme fails to reward knowledge-based specialties and was driving endocrinologists out of the profession.

 Severe shortages of these critical specialists have resulted, at the very time when epidemics of obesity and cardiometabolic disease mean endocrinologists are needed more than ever.

January 2014

Understanding the Role of Big Data in the CV Risk Calculator Controversy

Nonincretin Drugs in Later-Stage Development

Attacking Complications to Kidney Problems in Diabetes: Atrial Fibrillation and Resistant Hypertension

Dietary Guidelines Panel to Take Input From Public

In Diabetes Care, Mixed News on Payment Reform

The JNC 8 Hypertension Guidelines: An In-Depth Guide

Nutritional Supplements and Cardiovascular Health

Dangerous Liaisons: Obesity and Diabetes

Neuroscience Study Uncovers New Player in Obesity

Understanding the Connections Between Race and Bariatric Surgery

Getting an Earlier Diagnosis of Diabetes Starts With Better Screening

Daschle: What Lies Ahead for Healthcare and Health Reform

Moving Toward Value-Based Care in Diabetes: Stakeholders Weigh In

New Possibilities in Primary Care and Reimbursement

Making ACOs Work Amid the Changing Healthcare Landscape

In Controlling Diabetes and Obesity, Employers Have Opportunities