EVERY DAY, APPROXIMATELY 500 Americans lose a limb and join millions of others who will struggle with a lifetime of high medical bills, disability, and significant barriers to participating in their communities.

The greatest risk factor for developing this condition—which is completely preventable if caught early&mdash;is diabetes, the prevalence of which is at an all-time high.

Within the Medicare program, African Americans living with diabetes are nearly 3 times as likely to experience limb loss as other beneficiaries; the disparity is even worse in certain regions, such as the rural Southeast.

 Meanwhile, Hispanics are between 50% and 75% more likely than whites to undergo an amputation,

Americans—especially those living in rural Western regions&mdash;are substantially more likely to receive a diagnosis of diabetes and undergo an amputation than their white counterparts.

The good news is that we already have the capability to identify and treat vascular diseases before they progress to the point of amputation. And we have the technical know-how to bring the right care to the right people. What’s missing is a comprehensive, national strategy that integrates public awareness, increased screening and arterial testing for those determined to be at risk, and improved multidisciplinary care with new patient safety measures. 

With as many as 18 million Americans at risk for limb loss due to peripheral artery disease (PAD)

 and the unprecedented prevalence of diabetes, we clearly need more effective public awareness.

 This applies to patients, who should receive better education about the risks of PAD, as well as providers, who should have better incentives to perform standard arterial testing on at-risk patients. In this regard, CMS should take cues from the previously successful Fistula First Breakthrough Initiative, which significantly increased the  percentage of patients with end-stage renal disease receiving fistulas by setting standards for the entire field.

 Implementing a similar amputation reduction initiative, with a specific focus on providers in minority communities, could raise the benchmark across the whole spectrum of cardiovascular care providers.

Based on the US Preventive Services Task Force assigned grade of I, or insufficient evidence, there is great room for improvement in PAD screening the general US population and in identifying disease in asymptomatic, at-risk populations. Despite guidelines issued by the American College of Cardiology and American Heart Association that recommend screening of at-risk patients—those who are over age 65, have a history of diabetes, smoking, and/or PAD, or have received a diagnosis of other vascular disease

—we know that screenings are not taking place among these patient groups, therefore increasing the likelihood for advanced disease and limb loss.

But awareness is not enough if arterial testing remains underutilized. According to a 2014 study, more than 30% of patients who underwent a nontraumatic amputation had no arterial testing the prior year to evaluate whether they would be a potential candidate for revascularization or another intervention.

 Providers should make screening mandatory for all at-risk patients, and no amputation should occur unless a patient receives an invasive angiogram or other arterial vascular evaluation first. A 2011 analysis of more than a million Medicare patients with critical limb ischemia (CLI) found that this practice reduced the odds of amputation among patients with CLI by 90%.

 At some centers—particularly The Surgical

Clinic in Nashville, Tennessee, and Martin Memorial Hospital in Stuart, Florida—an angiogram before an amputation is routine. Both centers saw significant declines in their nontraumatic amputation rates since implementing this requirement.

Improved Quality Measures and Multidisciplinary Care

Many facilities remain out of reach for patients living in underserved communities, which have populations that are disproportionately African American, Hispanic, and Native American. Reaching these communities requires that care be improved in other settings and that CMS promote policies to encourage more providers to coordinate care.

Quality measures for facilities that accept Medicare are also improving. As recently as this year, CMS approved 2 new cardiovascular-related measures as Qualified Clinical Data Registries (QCDRs), which will track the rates of noninvasive vascular testing prior to revascularization for patients with CLI or who have claudication. Because they are applicable

to all specialties that provide revascularization care, these measures are expected to give investigators greater insight into the decision-making process that precedes an amputation.

However, there is room for CMS to go further. The CardioVascular Coalition’s most recent Quality Measures Working Group recommends that CMS implement an additional measure to track use of a patient safety survey prior to undergoing a nontraumatic amputation. Facilities would be required to go through a Safe Surgery Checklist with patients before proceeding with an amputation and report the results as part of Medicare’s QCDR program.

Better measures like these have the potential to improve care quality and save money. Research shows that patients who avoid amputation have a higher quality of life afterward and experience fewer adverse effects associated with limb loss—such as depression and disability.

 And, according to an analysis by Avalere Health, cutting the number of Medicare patients with major amputations in half could save the program $2 billion over 10 years.

 could save the program $2 billion over 10 years.

When considering all these factors, it is clear that opportunities exist for improving how both PAD and CLI are screened, diagnosed, and treated among the Medicare population, particularly minorities who are at greatest risk. The progress made in the field of vascular care indicates that there is no good reason any amputation should occur when limb preservation is a possibility. This is why the CardioVascular Coalition is calling for a national Sprint to Zero initiative that seeks to eliminate senseless amputations through increased awareness, higher screening rates, and the use of a multidisciplinary approach that will ensure no amputation is performed on a patient without arterial testing.

Jeffrey Carr, MD, FACC, FSCAI, is an interventional cardiologist and endovascular specialist. He is the founding and immediate past president of the Outpatient Endovascular and Interventional Society, a multispecialty medical society. He is also the physician lead for the CardioVascular Coalition, a group dedicated to raising awareness for peripheral artery

disease and amputation prevention. Dr Carr is in practice at Cardiovascular Associates of East Texas.

1. Ziegler&#8208;Graham K, MacKenzie EJ, Ephraim PL, Travison TG, Brookmeyer R. Estimating the Prevalence of Limb Loss in the United States: 2005 to 2050. 

. 2008;89(3):422&#8208;429. doi: 10.1016/j.apmr.2007.11.005.

2. Centers for Disease Control and Prevention. National diabetes statistics report, 2017. https://cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Published July 17, 2017. Accessed November 9, 2017.

3. Goodney PP, Dzebisashvili N, Goodman DC, Bronner KK; Dartmouth Atlas of Health Care. Variation in the care of surgical conditions: diabetes and peripheral arterial disease. www.dartmouthatlas.org/downloads/reports/Diabetes_report_10_14_14.pdf. Published October 2014. Accessed November 9, 2017.

4. Mustapa J, Fisher BT, Rizzo JA, et al. Racial disparities in amputation rates for the treatment of peripheral artery disease (PAD) using the healthcare cost and utilization project (HCUP) database. Presented at: ISPOR 21st Annual International Meeting; May 21-25, 2016; Washington, DC. cardiovascularcoalition.com/wp-content/uploads/2016/11/CSI-Racial-Disparities-African-Americans-Hispanics-ISPOR-POSTER-2016.pdf. Accessed November 9, 2017.

5. Rizzo, JA, Chen J, Laurich C, et al. Racial disparities in amputation rates among Native Americans with peripheral artery disease: analysis of the health care cost and utilization project database (HCUP). 

. 2016;19(3):55. doi: 10.1016/j.jval.2016.03.140.

6. Aggarwal S, Loomba RS, Arora R. Preventive aspects in peripheral artery disease. 

. 2012;6(2):53-70. doi: 10.1177/1753944712437359.

7. Fistula First Catheter Last. ESRD NCC website. esrdncc.org/en/fistula-first-catheter-last. Accessed November 26, 2017.

8. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. 

. 2017;69(11):1465-508. doi: 10.1016/j.jacc.2016.11.008.

9. Vemulapalli S, Greiner MA, Jones WS, Patel MR, Hernandez AF, Curtis LH. Peripheral arterial testing before lower extremity amputation among Medicare beneficiaries, 2000 to 2010. 

. 2014;7(1):142-150. doi:10.1161/CIRCOUTCOMES.113.000376.

10. Henry AJ, Hevelone ND, Belkin M, Nguyen LL. Socioeconomic and hospital-related predictors of amputation for critical limb ischemia. 

. 2011;53(2):330-339.e1. doi: 10.1016/j.jvs.2010.08.077.

11. Fisher BT, Hannan S, Martinsen BJ. Team-based approach for the treatment of arterial wounds reduces amputation rates in critical limb ischemia patients. 

. 2016;9(4):S34-S35. doi: 10.1016/j.jcin.2015.12.155. 

12. Sanguily J, Martinsen BJ, Igyarto Z, Pham MT. Reducing amputation rates in critical limb ischemia patients via a limb salvage program: a retrospective analysis. 

13. Yost M. Cost-benefit analysis of critical limb ischemia in the era of the ACA. Endovascular Today. evtoday.com/2014/05/cost-benefit-analysis-of-criticallimb-ischemia-in-the-era-of-the-affordable-care-act. Published May 2014. Accessed November 9, 2017.

14. Avalere Health, May 2015 analysis of CY2011-CY2013 Medicare claims. Data on file.

Articles

Evidence-Based Diabetes Management

CMS can take steps to raise awareness, including a specific quality measure, to ensure that testing occurs prior to nontraumatic amputation. 

“Sprint to Zero“: A Strategy to Address High Rates of Nontraumatic Amputations in Minority Communities

Ten years ago, a stunning article in the 

 linked a blockbuster diabetes drug—rosiglitazone&mdash;with a higher risk of heart attacks.

 The FDA soon required expansive cardiovascular (CV) outcomes trials for new glucose-lowering therapies, to make sure they did not raise the risk of heart attacks, strokes, or early death.

But what about heart failure? Even though 25% of patients who develop heart failure have diabetes, and these patients tend to be far sicker and costlier to health systems,

 the FDA’s 2008 guidance focused on atherosclerotic CV disease, which occurs when plaque accumulates and hardens the arteries. Heart failure, in which the heart fails to adequately pump blood throughout the body, was not a primary endpoint in the wave of trials that followed.

To Eldrin F. Lewis, MD, MPH, a CV disease and transplant specialist at Brigham and Women’s Hospital and an associate professor at Harvard Medical School, this was a missed opportunity. In an interview with 

™), Lewis said heart failure specialists tried to sound the alarm.

Since the FDA didn’t request it, 100% of the clinical trials did not include heart failure as part of the primary composite endpoint,” he said. “And for years, we in the heart failure community have been saying, ‘This is a problem; this is a problem.’”

Science has brought others around, however. The first surprise came in 2013, when a safety trial found an unexpected increase in hospitalization for heart failure for the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin.

 The big shock came in September 2015, when the EMPA-REG OUTCOME trial reported that the sodium-glucose cotransporter-2 (SGLT2) inhibitor empaglifozin, sold as Jardiance, caused a 38% reduction in CV death.

 Meanwhile, a secondary endpoint showed a 32% reduction in hospitalization for heart failure among a study population with longstanding diabetes and established CV disease.

Since then, 2 more type 2 diabetes drugs—the SGLT2 inhibitors canaglifozin,

 sold as Invokana, and the glucagonlike peptide-1 (GLP-1) receptor agonist liraglutide,

 sold as Victoza—have shown cardioprotective efects; results from CANVAS for canaglifozin showed a 33% risk reduction for hospitalization for heart failure.

As the results generate waves at the FDA and among payers, heart failure is having its moment.

Diabetes specialists appeared at this year’s meeting of the American College of Cardiology (ACC) to tout upcoming trials, called EMPEROR HF, that will study empaglifozin in heart failure patients. And Lewis was part of a panel of CV specialists at the American Diabetes Association (ADA) who called for more attention to heart failure, including clinical trials with heart failure as a primary endpoint.

Separate EMPEROR trials, for EMPaglifozin outcome tRial in Patients With ChrOnic heaRt Failure, will study the SGLT2 inhibitor empaglifozin in patients with preserved and reduced ejection fraction (EF).

 Sponsored by Boehringer Ingelheim and Eli Lilly, the trials are currently recruiting patients and will not be completed before 2020. But a separate trial based on claims data, called CVD-REAL, drew notice at this year’s ACC and ADA meetings when results showed the drug class might be able to prevent heart failure in a broad population.

Lewis, whose research includes work on preventing disease progression and on patient quality of life, is excited about the possibility that at long last, strategies will be found to prevent heart failure, especially in high-risk patients with diabetes. Attitudes are shifting not only because of trial data but also because payment reform has compelled health systems to think differently about patients with diabetes and heart failure.

“The management of diabetes is a team effort. We have to work with nutritionists; we have to work with psychiatrists, if patients have depression; with endocrinologists; with cardiologists; and with pharmacists to come up with strategies to optimize management of both,” he said. “These patients are often depressed because they get frustrated that they can’t do a lot of things they want to do. And they want information to try to prevent future adverse events.” What follows are excerpts from the 

™:Why has it taken so long for heart failure among patients with diabetes to receive the attention it’s receiving now?

: The main reason that it’s taken a while is that the understanding of diabetes and how it relates to cardiovascular disease was that diabetes was a coronary heart disease risk equivalent. That’s been considered standard for a long time. As a consequence, I think there’s been a lot of emphasis on reducing coronary heart disease—heart attacks, unstable angina, and stroke&mdash;kind of an atherosclerotic cardiac event.

Because of that understanding—and we understand the impact of diabetes on the pathophysiology of atherosclerosis&mdash;translational research [has focused on] linking the presence of diabetes, or poor glucose control, with atherosclerotic events and models. The focus for patient education, clinical trials, and public health prevention has been on reducing atherosclerotic-related events, or atherosclerotic cardiovascular disease.

What we’ve noticed in the heart failure community all along is that in almost every predictor that you evaluate for the development of heart failure, diabetes is one of the most important risk fac-tors. In fact, if you take away hypertension, diabetes would probably be the number 2 risk factor for heart failure development.

The reason I think we are seeing attention to heart failure now is 2-fold:

•  First, we have 2 trials looking at SGLT2 inhibitors [empaglifozin and canaglifozin] that show a reduction in heart failure events in patients with diabetes. So people are saying, “Oh, that’s interesting. We need to pay more attention to heart failure.”

 •  Conversely, because there is a single DPP-4 inhibitor agent [saxagliptin] that led to an increased signal of risk for heart failure, there’s now concern for the safety of therapies for heart failure in addition to overall atherosclerotic cardiovascular disease.

™: The EMPEROR HF clinical trials are just getting under way. What interests you about these trials?

: The EMPEROR trials are exciting for 2 reasons. First, they are looking at patients with heart failure—both a reduced and a preserved EF population. I don’t think you can take data from a high-risk cardiovascular disease trial, such as EMPA-REG and CANVAS, and then extrapolate that to a heart failure population because the heart failure patients have higher risk, and they have other factors that can influence hospitalizations for heart failure. So I think it’s interesting and important to look in both the reduced and preserved EF population to examine the use of empaglifozin in this population, to see whether the findings of EMPA-REG and CANVAS can be reproduced in a heart failure population.

The second interesting thing for me is that these trials will be looking at patients without type 2 diabetes. I’m really intrigued to look at the use of this agent in non-diabetes patients. One of the thoughts that I have is: You have a drug that happens to lower glucose, but it has non-glucose-lowering properties that may lead to an improvement of cardiovascular risk. And if that’s the case, then we can still use empaglifozin and other SGLT2 inhibitors to treat type 2 diabetes, but we can consider using them in non-diabetes patients as well. The question I would have is, whether the mechanism of action for reduction of cardiovascular risk is glucose related or not, I think it doesn’t matter—at the end of the day, you want to see how people do. You want to reduce the morbidity and mortality associated with the complications of diabetes.

™: The CVD-REAL trial, while not a randomized clinical trial, suggested there may be potential for SGLT2 inhibitors to be used for prevention. Depending on what we see in the EMPEROR trials, do you see potential for more widespread use of SGLT2 inhibitors—as well as earlier use in the disease life cycle? Is that a possibility? 

I think that’s a possibility. I give a little pause in terms of applying it generally, but for the moderate to high-risk population with cardiovascular disease, it looks like there is a benefit. I think the CVD-REAL trial supports the fact that, one, there is early use of SGLT2 inhibitors, and two, it looks like from a large set of payer data that the use of SGLT2 inhibitors—regardless of why&mdash;has translated into some improved outcomes in the real world. I’m encouraged by that, and I actually see that we’ll be using more SGLT2 inhibitors fairly rapidly.

™: Has the payment reform movement—and particularly the focus on hospital readmissions&mdash; caused health systems to pay more attention to heart failure, given the high rate of readmissions and the costs associated with this condition? 

I think so. In general, heart failure patients are complicated. The mean age of patients is in the early 70s, and so there may not be as much interest in general in the typical heart failure patient, unfortunately. The older heart failure patients come with a lot of comorbid illnesses—chronic kidney disease, COPD [chronic obstructive pulmonary disease], hypertension, end-stage renal disease&mdash;multisystem organ failure. They have frailty, sarcopenia, etc. When these patients come in, they are complicated, and sometimes we cannot dramatically improve them. They are expensive for the hospital system because of the comorbid conditions. As a consequence, there hasn’t been as much focus from mainstream cardiology on heart failure management. We traditionally had readmission rates within 30 days of higher than 30%, with the thinking, “These are complicated patients, and you can’t reduce it.”

When third-party payers started saying there will be a penalty associated with 30-day all-cause readmission, all of a sudden there’s an interest in the hospital systems’ coming up with strategies to reduce readmissions.

With ACOs [accountable care organizations], where everyone must share in coming up with efficiency measures, that alone has incentivized hospital systems to come up with strategies to prevent hospitalizations for heart failure. And the negative incentives from third-party payers to prevent readmissions will also offer a reason to provide necessary resources to prevent readmissions.

hat we’ve noticed since a lot of these changes have occurred is that you have seen a reduction in readmissions—down to the 24% range instead of well over 30%. And we’re starting to better understand why these patients are hospitalized in the first place.

™: Preventing disease progression and hospital admissions is the goal. But we hear that when physicians try to start patients on newer therapies, such as SGLT2 inhibitors, earlier in the life cycle of the disease, payers often say no. How can we address these challenges going forward? 

There will be challenges—payer restrictions are problematic. The tricky part is, it’s hard to know whether we’re receiving them early enough because we don’t have enough trials to inform us about the timing and the impact of the tiered approach. Metformin still becomes the foundation of diabetes management. Most primary care physicians and endocrinologists would start metformin first. There hasn’t been a head-to-head trial that asks, “In newly diagnosed diabetes, should we start metformin or an SGLT2 inhibitor?” Once we have that information, it will be easier to go away from the current guidelines. The guidelines say, “Start with metformin and then expand.”

In terms of restrictions—and I don’t have data, this is strictly my opinion&mdash;if you have a prior authorization that is required, a busy clinician will often find that hurdle somewhat challenging. You have to slow down, complete the form, and sometimes have to do a peer-to-peer review, which takes additional time. If you’re a busy clinician, it becomes challenging in between seeing your 45 to 50 patients. Prior authorization can be enough of a hurdle to reduce utilization.

Unfortunately, we don’t have primary data that evaluate primary care clinicians on why they haven’t started a new therapy. Say you have patient A, who clearly qualifies for initiating an SGLT2 inhibitor; their A1C [glycated hemoglobin] is uncontrolled. And the clinician chooses not to [prescribe the drug]. The question is to go back to the provider and ask, “Why didn’t you do it?” That kind of information would be very helpful. Sometimes it’s lack of knowledge; sometimes it’s the hurdle.

In terms of the knowledge, the other tricky part is, who manages the diabetes? Diabetes and heart failure can both be managed by a specialist; you can have an endocrinologist managing diabetes, a cardiologist or heart specialist managing the heart failure. But in the real world, about 80% of heart failure patients are managed by their primary care doctor. For diabetes, I would assume it would be a relatively high number as well. If you’re a primary care doctor who has 15 minutes to deal with all the problems that a patient has, in addition to diabetes and heart failure, it becomes challenging to not only have the knowledge gap reduced, so that they understand: This is a drug that can be used to treat diabetes, and here’s a novel drug to treat heart failure. But they have to understand when you would use an SGLT2 inhibitor, versus a DPP-4 inhibitor, versus a GLP-1 receptor agonist, versus using insulin initially. So, these algorithms can be complex, and for heart failure, it’s even more complex.

I think the future of diabetes and heart failure management rests with electronic health records [EHRs] with logic built in—to help trigger the primary care doctor to identify patients who might benefit from some of these more novel therapies. Once a new guideline comes out, you build that into the EHR decision-making process.

™: Are we doing enough to prevent heart failure in patients with diabetes? Do we need to do more? 

Given that diabetes is the number 2 risk factor for heart failure, we have to. Especially in patients who have what I call the trifecta—hyper tension, diabetes, and preexisting atherosclerotic cardiovascular disease&mdash;those are very high-risk populations. Lipid lowering is important, as well, in these patients, but we need some type of precision medicine approach to managing the prevention of heart failure. If you look at the natural history of patients after they develop heart failure, you’re looking at a median survival of 5 years; at best, the median survival is 8 years, if we include the asymptomatic patients.

We should absolutely come up with strategies to prevent heart failure—and that’s what excites me about the SGLT2 inhibitors. I’m waiting to see the additional trials come out to add to our understanding, but the fact that we have 2 trials that have reduced not only mortality but also reduced heart failure is very important.&ensp;

1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes [published correction appears in 

2007;356(24):2457-2471. doi: 10.1056/NEJMoa072761.

2. FDA guidance for industry. Diabetes mellitus: Developing drugs and therapeutic biologicals for treatment and prevention. US Food and Drug Administration. fda.gov/downloads/Drugs/.../Guidances/ucm071624.pdf. February 2008, Draft. Accessed October 15, 2017.

3. Caffrey M, Szwed A. Heart failure needs more attention in diabetes drug trials, expert says. 

 website. ajmc.com/conferences/ada-2017/Heart-Failure-Needs-More-Attention-in-Diabetes-Drug-Trials-Expert-Says. Published June 11, 2017. Accessed October 15, 2017.

4. Scirica BM, Bhatt DL, Braunwald E, et al, for the SAVOR-TIMI 53 Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. 

. 2013;369(14):1317-1326. doi: 10.1056/NEJMoa1307684.

5.  Zinman B, Wanner C, Lachin JM, et al, for the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. 

. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.

6. Neal B, Perkovic V, Mahaffey KW, et al, for the CANVAS Program Collaorative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. 

. 2017; 377(7):644-657. doi: 10.1056/NEJMoa1611925.

7. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. 

8. EMPagliflozin outcomE tRial in Patients With chrOnic HeaRt Failure With Reduced Ejection Fraction) EMPEROR-Reduced. www.clinicaltrials.gov/ct2/show/NCT03057977. Updated October 4, 2017. Accessed October 15, 2017.

9. EMPagliflozin outcomE tRial in Patients With chrOnic HeaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved). www.clinicaltrials.gov/ct2/show/NCT03057951. Updated October 4, 2017. Accessed October 15, 2017.

10. Caffrey M. Can SGLT2 inhibitors prevent heart failure in a broad population? 

 website. www.ajmc.com/conferences/acc-2017/can-sglt2-inhibitors-prevent-heart-failure-in-a-broad-population-results-from-a-real-world-study. Published March 19, 2017. Accessed October 15, 2017.

11. Kosiborod M, Cavender MA, Fu AZ, et al; CVD-REAL Investigators and Study Group. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL Study. 

2017;136(3):249-259. doi: 10.1161/CIRCULATIONAHA.117.029190.

The payment reform movement has changed the thinking about what can be done for patients with diabetes and heart failure, for the good of patients.

Eldrin F. Lewis, MD, MPH, on Heart Failure's Place in Diabetes Drug Trials, and the Promise of SGLT2s in Prevention

IN 1979, THE FRAMINGHAM STUDY told us that people with diabetes are at least twice as likely to develop cardiovascular disease (CVD), putting them at risk for early death from cardiovascular (CV) causes. Since that time, those of us in diabetes care have searched for the right combination of lifestyle management, therapy, and other tools to change this fact. We’ve made progress, but it remains true that people with diabetes die of heart disease at much higher rates than others, and we don’t entirely understand why.

Although we know many of the risk factors that are responsible for diabetes being a cardiovascular risk equivalent, the traditional risk factors (hypertension, hyperlipidemia, and obesity) do not fully explain why the risk of a myocardial infarction (MI) in a patient with diabetes is roughly the same as a typical post-MI patient without diabetes. Precision medicine should be able to identify new risk factors and predictors of coronary disease—the leading cause of mortality for people with diabetes. We must account not only for genetic and environmental factors but also for behavioral and socioeconomic diferences, which can predict how well a patient will be able to follow a regimen for the long haul.

We continue to learn. Data gathered a decade ago during Action to Control Cardiovascular Risk in Diabetes (ACCORD) are providing new insights and resolving a puzzle: why did patients at high risk of CVD who had extremely tight glycemic control have a higher rate of fatal heart attacks? Why did they fare worse than their counterparts in standard care? Are there new risk factors that might explain this surprising diference? In other words, those in the group with the most tightly controlled diabetes were less likely to have a heart attack, but if they had one, it was more likely to be fatal.

Last month, scientists led by Joslin Diabetes Center published a paper in Diabetes Care that that fnds genetic links between glucagon-like peptide-1 (GLP-1) and CV mortality. The team showed how patients in the ACCORD study with a genetic variant associated with CV mortality saw their fasting GLP-1 levels drop while undergoing strict glycemic control. For those without the variant, GLP-1 levels were stable.

The implications of this fnding are potentially signifcant. We already know that GLP-1 agonists can reduce cardiovascular events in people with diabetes. Several GLP-1 receptor agonists have been approved based on their ability to promote insulin production, and 2 have already shown CV benefts in clinical trials. One (liraglutide) received FDA approval in August for a cardiovascular indication with the recently approved semaglutide likely to follow. Furthermore, the genetic variant found in the ACCORD population may repre sent a new risk factor in explaining the high risk of CVD in individuals with diabetes.

Along with GLP-1 agonists, a second glucose lowering medication, has been shown to decrease cardiovascular events: SGLT2 inhibitors. As we review the fndings of the cardiovascular outcomes trials for 2 of the approved sodium glucose co-transporter-2 (SGLT2) inhibitors, there the belief is that they cause diuresis and volume contraction to produce benefts for patients with congestive heart failure, leading to fewer hospitalizations.

Both examples are of interest to payers, who are interested in getting the right drugs to the right patients, and who want proof that therapies can reduce costs in high-risk populations. The surprising results with SGLT2 inhibitors have sparked a new round of trials to resolve the unanswered questions about their role in heart failure, in patients with and without diabetes.

For all the promise of new therapies, however, the basics of care coordination and meeting patients where they are cannot be overlooked. For patients who live with diabetes and heart disease day after day, the financial cost and personal toll are considerable. At Joslin, sharing these lessons along with the latest science is essential to what we do every day.

Dr Gabbay is senior vice president and chief medical officer, Joslin Diabetes Center. He is editor in chief of 

For Those With Diabetes and CV Risk, Personalized Care Matters

WE ARE IN a unique time in healthcare. Although there are periodic crises of cost in medicine, this time we have a convergence on quality that has produced a consensus around 3 things: quality measures, the ability to measure quality in a granular fashion, and the desire for patient-oriented outcomes. This convergence has created a sharper focus on accountability for quality. Combining these new foci has resulted in a drive to improve the value proposition of medicine in America.

Currently we spend more than $3 trillion annually

 on care that is highly variable in terms of quality, clinical outcomes, and cost; diferences in spending can be 10-fold or greater.

Given that we are paying a signifcant premium for healthcare relative to other industrialized nations, there should be a more consistently excellent product.

So, as healthcare providers and healthcare payers are under intense scrutiny to reliably deliver measurably better health, they are looking to all elements of the health supply chain to deliver that value.

At the same time, the cost to bring a therapy through the FDA-approval process keeps rising, and pressure from generics and alternative medications is growing. Increased sophistication of the mechanisms of action of these new drugs, along with expectations from venture capital frms and shareholders, has pushed the overall cost of pharmaceuticals past what we spend on physicians in the United States. Today, pharmaceutical spending is second only to the spend on hospitals.

This has led to potential innovation in the pricing and positioning of new million-dollar therapies, as the drive to deliver true value for patients/plan members intensifes.

For many years, payers and, to some extent, providers have been shifting from traditional fee-for-service care toward models that reward results. Tentative steps such as paying for process metric achievement for primary care physicians to more quality gated gainsharing models have given way to far more performance risk sharing, where providers are focused on total medical expense budgets or partial capitation agreements. Some states, such as California and Maryland, have even more advanced models. Despite these advances, the share of healthcare spending tied to these new models remains small and the pressure to develop ways to drive quality improvement as a cost-saving measure continues to mount.

Additionally, as new and very expensive therapies are developed, the desire to ensure efcacy at these prices is even greater. The need to show that a medication can change a disease trajectory and afect an outcome that patients, providers, payers, and employers (or whoever the ultimate payers is) care about is paramount.

This begs the question: what does each group care about? The simple answer is that each stakeholder cares about many things and many concerns overlap

 care about the impact on their lives and functional status. They care what a drug costs them out of pocket, and they care somewhat about the overall cost.

 have similar concerns, but they focus more on cost than individual responsibility.

 care about tho same outcomes as patients and employers, but with a greater focus on medical quality in addition to impact, and are interested in intermediate outcome measures far more than patients.

 care about medical quality and increasingly about total cost, but they also worry about the customer service experience of members and how drug costs afect employers.

The other important consideration is the time horizon of the impact. For patients, it is their lifetime; for employers, the duration of employment; for payers, the period of coverage; and for providers, the length of time they spend caring for each patient. These diferent time horizons create additional challenges in thinking through how to create a successful value equation.

The ideal is a program that improves medical quality in a way that is visible and important to patients and lowers the total cost of care in a year or less (for Medicaid, perhaps in a month or less). This is very hard to create. Readmission reductions programs are a great example: They have a big impact and quickly and defnitively impact cost. Medical quality is often more about the reliable delivery of the best care.

This creates a real challenge for pharma. While most drugs take considerable time to afect outcomes that matter to patients and translate into cost reductions, the impact on medical quality may come quickly. In diabetes, for example, although many medications have been shown to reduce glycated hemoglobin levels within several months, which makes doctors happy, they take far longer to impact heart attack rates, which is a measure that patients can appreciate. Insurers, meanwhile, often don’t see value until an avoided heart attack translates into lower costs for patients—who are not admitted for the heart attacks they don’t have. And the employer won’t see the impact until enough employees avoid heart attacks to actually bring down future rate increases. This is a signifcant issue now that some drugs cost hundreds, thousands, or tens of thousands of dollars per month.

For patients with diabetes, thus far, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, evolocumab (Repatha) has been shown to reduce cardiovascular (CV) events (eg, hospitalization, heart attack and stroke), which is an incredibly important outcome for a patient. This happens in a clinically relevant time horizon (median 26 months), which is important for patients and their employers and from a public policy standpoint. Politicians have chosen to weigh in on mandating coverage of even marginally efective treatments (Ornish intensive cardiac rehab for Medicare for instance) and a case could be made that the evidence is powerful. However, insurers will be challenged by creating appropriate rules so that this medication is used only for those patients who will truly beneft because of implementation issues.

Clearly, reducing CV events will be important for both quality and cost. However, since many patients are currently well treated with much less expensive medications, and many more could be if they were maximally managed, there is a risk that patients will receive these $14,000-per-year drugs when they really do not need them.

If patients are exposed to side efects and complications of PCSK9 inhibitors, this would impact the cost savings they create. Additionally, all cause morbidities and mortality and cost need to be considered. Reducing CV complications alone is not enough.

An analysis of the total medical expense would be helpful and key to the real value equation. Understanding the quality improvements, both on CV outcomes and overall health, is the frst step. We need to know mortality impact, morbidity impact, and utilization impact to measure the positive effects. We also need to know the full cost, not just of the medication, but of managing the complications, the natural course of progression, and the cost of monitoring. From an employer and patient perspec tive, the lost work time and other “life” efects are very important but largely invisible to the insurer and to the physician.

There’s also the challenge of defning a realistic comparator. Total medical expense, a likely best candidate, is often harder to determine than it would first appear—and absent a solid comparator&mdash;the relative impact is impossible to judge. Pharma has ofered several interesting ideas for how this might be managed:

 We are now well past the era of using volume discounts to help control costs. The goal today is controlling the total cost of care, especially pharmaceutical costs, which have outpaced the overall medical spend. Some have looked at rebates or refunds if certain complications occur, such as heart attacks.

 The challenge is that these practices do not necessarily support the optimal use of the medication, that they encourage widespread marketing to the lowest-risk patients to ensure complications do not occur too frequently. This also does not get at the underlying issue: the therapy may simply cost too much. Offering a 30% reduction for certain patients on a drug that is 50% overvalued does not control costs.

 The idea of not charging patients who do not respond to a treatment is another approach. This model is uniquely suited to the high-cost specifc-use medications being introduced in cancer care; it would fail for other drug classes where determining response is more difficult. To truly develop comprehensive accountability, a program that includes annual total cost of care and trend impact is needed. The challenge here is that there are many factors outside of a specifc disease and certainly beyond a drug’s impact that afect the total cost of care. Many pharmaceutical companies have developed or partnered with others to provide wrap-around services to improve adherence and modify lifestyle—offering stress reduction treatments or help with exercise and diet to support improved outcomes and reduced healthcare utilization. However, these services may interfere with similar programs at the health plan or provider level. Also, these programs are either not explicitly tied to cost or only focus on the cost of the specifc diagnosis or disease state. This makes perfect sense from a pharmaceutical and provider perspective. However, from the payer, employer, and patient perspectives, programs that reduce CV costs and utilization but raise costs in other areas are not helpful. Proving causality or even an indirect relationship between the two is even harder.

For this approach, a collaboration between physicians, other providers, and drug manufacturers would help with the all-encompassing nature of total medical expenses. However, this only becomes practical for companies that have medications for multiple disease states and systems that have large numbers of patients. For insurers, this works only if the same pharma—provider coalitions care for a signifcant number of their members. The practical application of these global innovations is challenging.

What can we really do? How can we move forward? It is clear that there is no silver bullet to improving quality while driving down cost in healthcare; in the pharmaceutical arena, as well. A tailored approach blending all the ideas will be necessary. We also need to look for related areas in which we can eliminate non—value-added costs from the system. Examples include site-of-service issues, where the infusion location often translates into a 2- to 10-fold cost difference, or cost-plus-percentage markups for medications that work well when medications are priced in the hundreds of dollars but fail when prices reach $500,000. These are simple changes that can impact cost that do not really create accountability but do rationalize the overall pharmaceutical spend.

Creating a direct link between the impact of the proper use of the medication and the corresponding price paid is critical to the long-term success of healthcare. The keys are:

Reaching agreement among payers, providers, and pharma on a process for measuring the direct and long-term impacts, quality, utilization, and cost of new therapies.

Agreeing on a process to ensure selection of the optimal patients for each new therapy, along with a mechanism to create accountability for patient selection.

For many, the idea of a rebate for treatment failures or complications makes sense; for others, the idea of overall cost of care for a specifc disease category on an annual basis works; for still others, By working through these areas and tailoring the methodology to the disease state and specifc medication profle, we can best make lasting progress to drive quality improvement to reduce total cost of care rather than just cutting a few dollars today.

Dr Graf is vice president and chief medical officer, Horizon Blue Cross Blue Shield of New Jersey. 

1. National Health Expenditure fact sheet. Centers for Medicare & Medicaid Services website. cms.gov/research-statistics-data-and-systems/statistics-trends-and-reports/nationalhealthexpenddata/nhe-fact-sheet.html. Updated June 14, 2017. Accessed November 24, 2017.

2. Pritchard D, Petrilla A, Hallinan S, Taylor DH, Schabert VF, Dubois RW. What contributes most to high healthcare costs? Healthcare spending in high resource patients. 

. 2016;22(2):102-109. doi: 10.18553/jmcp.2016.22.2.102.

3. Squires D, Anderson C. US health care from a global perspective: spending, use of services, prices, and health in 13 countries. The Commonwealth Fund website. commonwealthfund.org/publications/issue-briefs/2015/oct/us-health-care-from-a-global-perspective. Published October 8, 2015. Accessed October 16, 2017.

4. Glied S, Ma S, Solís-Román C. Where the money goes: the evolving expenses of the US health care system. 

. 2016;35(7):1197-1203. doi: 10.1377/hlthaff.2015.1356.

5. Keshavan M. We may soon have our first $1 million drug. Who will pay for it? And how? 

. October 13, 2017. statnews.com/2017/10/13/gene-therapy-pricing/. Accessed November 24, 2017.

6. Blumenthal D, Abrams MK. Tailoring complex care management for high-need, high-cost patients. 

. 2016;316(16):1657-1658. doi: 10.1001/jama.2016.12388.

7. Davidson SM, Shwartz M, Stafford RS. The feasibility and value of new measures showing patterns of quality for patients with three chronic conditions.

. 2008;31(1):37-51. doi: 10.1097/01.JAC.0000304096.59205.e0.

8. Blumenthal D. Value-based drug pricing: watch out for side effects. The Commonwealth Fund website. commonwealthfund.org/publications/blog/2016/jul/value-based-drug-pricing. Published July 21, 2016. Accessed October 16, 2017.

9. Silow-Carroll S, Alteras T. Value-driven health care purchasing: four states that are ahead of the curve. The Commonwealth Fund website. commonwealthfund.org/publications/fund-reports/2007/aug/value-driven-health-care-purchasing--four-states-that-are-ahead-of-the-curve. Published August 1, 2007. Accessed October 16, 2017.

10. Mittler JN, O’Hora JL, Harvey JB, Press MJ, Volpp KG, Scanlon DP. Turning readmission reduction policies into results: some lessons from a multistate initiative to reduce readmissions. 

. 2013;16(4):255-260. doi: 10.1089/pop.2012.0087.

11. Sabatine MS, Giugliano RP, Keech AC, et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. 

. 2017;376(18):1713-1722. doi: 10.1056/NEJMoa1615664.

12. Hernandez I. Outcomes-based pricing for PCSK9 inhibitors. 

. ajmc.com/contributor/inmaculada-hernandez-pharmd/2017/09/outcomes-based-pricing-for-pcsk9-inhibitors. Published September 24, 2017. Accessed November 24, 2017.

13. Carroll J. Heart attack while on Repatha? Amgen will give you your money back. 

. March 20, 2017. endpts.com/heart-attack-while-on-repatha-amgen-will-give-you-your-money-back/. Accessed November 24, 2017.

A chief medical officer for a major payer outlines the challenges making sure that certain high-cost therapies are directed to the patients who need them.

Moving Pharma Contracting Into the Era of Accountability

LARGE CARDIOVASCULAR OUTCOMES trials (CVOTs), designed to show how new diabetes medications afect the incidences of cardiovascular (CV) death, heart attacks, and strokes, also provide limited insight into another area: microvascular complications, such as renal neuropathy and retinopathy.

The data, however, do not tell a consistent story. Glucagon-like peptide 1 (GLP-1) receptor agonists may reduce the overall risk of kidney problems, but at least 1 medication in the class was associated with proliferative retinopathy progression in trial patients. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, on the other hand, appear to reduce the overall risk of kidney problems more than any of the GLP-1 agonists, all without any reported short-term efect on retinopathy. However, the SGLT2 inhibitor, canaglifozin—but no other drug from this class to date&mdash;is associated with a higher risk of amputation compared with placebo, although overall rates were small. As for dipeptidyl peptidase-4 (DPP-4) inhibitors, there’s no evidence that they have any particular infuence on any microvascular outcome (although these outcomes were not rigorously evaluated with these agents in CVOTs).

The strength for all of these vascular fndings is far from conclusive, but according to John B. Buse, MD, PhD, there’s more evidence of renal protection, particularly for the SGLT2 inhibitors, than damage elsewhere. The ease of measuring creatinine levels ensures that most CVOTs collect regular data on every patient’s kidney function, but no CVOT has regularly measured circulation to the eyes and extremities, so the outcome data have come from the very few patients whose adverse events required surgical procedures.

“The CVOTs to date haven’t made any efort to systematically measure neuropathy or retinopathy in all patients, and there just aren’t enough surgeries to use them as proxies. I suspect the association between some drugs and increased surgeries may stem from the suddenness with which they lower blood sugar,” said Buse, a distinguished professor at the University of North Carolina (UNC) School of Medicine who has participated in several CVOTs. “Previous work has shown that fasting blood sugar reductions can exacerbate preexisting eye problems, even though lower blood sugar reduces long-term complications, so doctors might want to take the precaution of starting small and gradually increasing the dose, particularly in poorly controlled patients who already have eye damage. For patients with clinical CV disease, the benefts on heart attack, stroke, and CV death far exceeds these small risks.

“The evidence on kidney function is much more robust, and it shows that both GLP-1 agonists and SGLT2 inhibitors tend to improve outcomes. That said, the fndings are not yet strong enough that they should be a major consideration in drug selection,” said Buse, who is also the chief of UNC Health Care’s Division of Endocrinology and head of its diabetes center. “The main consideration is still what it has always been: getting the patient’s A1C [glycated hemoglobin] to target levels of blood sugar control with whatever combination of medications works best for each patient.”

The LEADER trial, which randomized 9340 patients between liraglutide (Victoza) and placebo and followed them for a median period of 3.8 years, made headlines by finding that the GLP-1 analogue was associated with lower rates of stroke, myocardial infarction, and CV death. Less publicized was the fact that liraglutide use was associated with a signifcant reduction in nephropathy events, which were defned as “a new onset of persistent macroalbuminuria or persistent doubling of serum creatinine level and creatinine clearance per MDRD<45 mL/min/1.73m

[Modifcation of Diet in Renal Disease Study equation] or the need for continuous renal-replacement therapy (in the absence of an acute reversible cause) or death due to renal disease.” There were 1.5 such events per 100 patient-years in the liraglutide group and 1.9 per 100 patient-years in the placebo group (HR, 0.78; 95% CI, 0.67-0.92; P = .003). There was no signifcant diference in retinopathy between the 2 groups and no specifc attempt to measure neuropathy by amputations or other vascular outcomes.

The SUSTAIN-6 trial, which randomized 3297 patients among placebo and 2 doses of semaglutide (a longer-acting version of liraglutide), found that the GLP-1 agonist resulted in signifcantly less nephropathy than placebo (defned as in the LEADER trial) and signifcantly more proliferative retinopathy progression (defined as “the need for retinal photocoagulation or treatment with intravitreal agents or vitreous hemorrhage or diabetes-related blindness). Neuropathy events were detected in 62 semaglutide patients and 100 placebo patients (HR, 0.64; 95% CI, 0.46-0.88; P = .005). Retinopathy was detected in 50 semaglutide patients and 26 placebo patients (HR, 1.76; 95% CI, 1.11-2.78; P = .02).

The ELIXA trial, which randomized 6068 patients between lixisenatide (Adlyxin) and placebo, found that the albumin/creatine ratio in urine samples rose 26% in lixisenatide users (to 11.9 mg/g) and 32% in placebo users (to 13.4 mg/g). Renal and urinary adverse events were also found in fewer lixisenatide patients (12) than placebo patients (20). Neither result rose to the level of signifcance, however, and there were no data on retinopathy or neuropathy.

The EXSCEL trial, which randomized 14,752 patients between weekly exenatide (Byetta) and placebo, did not report any microvascular data in the main paper.

The EMPA-REG OUTCOME trial, which randomized 7020 patients among 2 doses of the SGLT2 inhibitor, empaglifozin (Jardiance), and placebo, also found evidence of CV beneft, but the initial write-up provided no signifcant microvascular data. The rate of kidney failure was lower in empaglifozin users than in the placebo group (5.2% vs 6.6%, respectively), but the diference was not signifcant. The study did not publish any comparative data related to neuropathy or retinopathy.

The CANVAS program, which followed 10,142 patients who were randomized between canaglifozin (Invokana) and placebo for a mean period of more than 3 years, also found better renal outcomes in the canaglifozin group than in the placebo group. There was a 40% reduction in combined endpoint of estimated glomerular fltration rate, the need for renal-replacement therapy, or death from renal causes (HR of canaglifozin was signifcantly associated with increased risk of lower extremity amputation. There were 6.3 amputations (mostly toes or metatarsals) per 1000 patient-years in the canaglifozin group and 3.4 amputations per 1000 patient-years in the placebo group (HR, 1.97; 95% CI, 1.41-2.75).

The EXAMINE trial, which followed 5380 patients randomized between alogliptin (Nesina) and placebo, tracked kidney function over a median period of 18 months and found no signifcant diference between the 2 arms. The study paper did not disclose any data about retinopathy or neuropathy.

The SAVOR-TIMI-53 trial, which randomized 16,492 patients between saxagliptin and placebo, did not reveal meaningful diferences in signifcant renal events. The study authors did not disclose data on less serious kidney problems or on neuropathy or retinopathy.

The TECOS trial, which randomized 14,671 patients between sitagliptin (Januvia) and placebo, reported on several types of microvascular outcomes but found little diference between the medication and placebo. Renal failure occurred in 1.4% (100) of sitagliptin patients and 1.5% (111) of placebo patients, which was not a signifcant diference. Similar numbers of sitagliptin and placebo patients also experienced peripheral arterial disease (2.7% [197] vs 2.9% [209]), amputation (0.8% [60] vs 0.9% [66]), diabetic neuropathy (4.1% [303 vs 3.8% [281]), diabetic blindness (0.3% [24] vs 0.3% [25]), and retinopathy (2.8% [205] vs 2.2% [158]).

Physicians should have more microvascular outcome data to guide their decisions. Another major CVOT, the DECLARE-TIMI-58 trial of dapaglifozin (Farxiga), is expected to report results in 2019. Researchers, moreover, are mining the huge amounts of data generated by existing CVOTs to find additional results. All of the initial papers focused very heavily on the CV outcomes such trials are designed to measure.)

Researchers have already mined data from the EMPA-REG trial for more information about empaglifozin and renal function, and they have found that SGLT2 inhibitor use is associated with slower progression of kidney disease and fewer renal events. New or worsening nephropathy occurred in 525 of 4124 (12.7%) empaglifozin patients and 388 of 2061 (18.8%) placebo patients (HR, 0.61; 95% CI, 0.53-0.70; P <.001).

Evidence is more robust on kidney function but not sufficient to make drug decisions, one expert said. A whole separate trial, called CREDENCE, is examining renal function in patients taking canagliflozin.

December 2017

“Sprint to Zero“: A Strategy to Address High Rates of Nontraumatic Amputations in Minority Communities

Eldrin F. Lewis, MD, MPH, on Heart Failure's Place in Diabetes Drug Trials, and the Promise of SGLT2s in Prevention

For Those With Diabetes and CV Risk, Personalized Care Matters

Moving Pharma Contracting Into the Era of Accountability

As Trials Report Cardiovascular Outcomes Data, What About Microvascular Results?

Perspectives of a Lipidologist: LDL Cholesterol Testing, PCSK9 Inhibitors

The CVD-Real Trial: What Can Real-World Evidence Tell Us About Primary Prevention?

Medical World News: Business Updates

Medical World News: Regulatory Updates