To show why diabetes has become a public health crisis, Peter Butler, MD, the renowned endocrinologist from the University of California at Los Angeles (UCLA), tells the story with pictures: The food portions are bigger. The amount of time spent in front of screens last longer. The distances we commute are farther. Too much eating and sitting do not add up to good health, he explained, creating a $327 billion tab for diabetes just in the United States.

What’s worse, Butler said, “We’ve exported our lifestyle,” making diabetes, driven by rising obesity rates, a growing global threat. In 2018, the journal 

 estimated there are 500 million cases of type 2 diabetes (T2D) worldwide, and rates are comparable between wealthy and poor countries.

“Clearly, we have to take care of people and manage it,” he said.

To understand the challenges that health systems face—and what must be done do to meet them&mdash;Butler, the division chief of endocrinology and director of the Larry Hillblom Islet Research Center at UCLA, hosted the April 17, 2019, session of the Institute for Value-Based Medicine®, “Diabetes Management: Advances in Treatment and Management to Reduce Cost and Improve Outcomes.” The session, presented by 

®, explored how investing in better interventions—from newer therapies to improved monitoring to more attention to the whole person&mdash;leads to better health and saves money in the long run.

An all-star lineup joined Butler at the Loews Santa Monica Hotel: Anne L. Peters, MD, professor of medicine at the Keck School of Medicine at the University of Southern California (USC) and director of the USC Clinical Diabetes Programs; Karol E. Watson, MD, PhD, FACC, director of the UCLA Barbra Streisand Women’s Heart Health Program, codirector of the UCLA Program in Preventive Cardiology, and director of the UCLA Cardiology Fellowship; and Sachin H. Jain, MD, MBA, president and chief executive officer for CareMore Health.

Getting Empagliflozin on Formulary: A Case for Cost-Effectiveness

Peters is not a typical diabetes expert. Besides being involved in cutting-edge research in both drug and device development, she splits her time between patients on both the west side of Los Angeles County, where most patients have health coverage, and the east side, where she said, “there are some of the saddest stories you’ve ever seen.”

Her service on the county’s Department of Health Services formulary committee offera a front-row seat for debates about price and value. “One of the things I know the most about is cost,” Peters said. She’s had to make the case that certain therapies that may have higher acquisition costs ultimately save money by preventing complications that occur when diabetes is not well controlled.

She is not a fan of insulin or sulfonylureas, but she recognizes that both will stay on formulary in T2D for now. But Peters succeeded in getting empagliflozin on the Los Angeles County formulary 2 years before the EMPA-REG OUTCOME trial results were reported.

She told the IVBM attendees how she convinced the committee that the sodium glucose cotransporter 2 (SGLT2) inhibitor was keeping patients out of the hospital for heart failure—a result that has been borne out across the class in multiple studies.

With empagliflozin, she said, “You get an immediate benefit.” For low-income patients especially, that makes a difference. “Heart failure is so hard for these patients. It’s heartbreaking. They don’t have the home environments where they can deal with sodium and everything else that would really make their lives better.”

Overall, avoidable complications persist in diabetes. Peters said only 14.3% of adults with diabetes reach all of their targets—not just glycated hemoglobin (A1C), but also blood pressure (BP) and cholesterol,

 and there are serious knowledge gaps among primary care physicians. “I’ve asked some of my best internist friends, ‘What do you do after metformin?’ And most of them look at me blankly. That is not a good start. We’ve made the algorithm too complicated.”

Diabetes causes suffering, Peters said, such as blindness, kidney failure, amputations, and tooth loss. “There’s an increased risk of depression and a whole host of other things,” she said. “Diabetes is not your friend, but my feeling is, if you take care of it well, none of this stuff has to happen. It’s the taking care of it well that matters, and that means access to healthcare, which I think is the most important part of all of this.”

 it’s essential to achieve and maintain glycemic control. “A 45-year-old who gets diabetes is someone who is going to live long enough to get complications,” she said. This is what costs the health system money. Patients classified as obese, in particular, incur high costs from joint replacements and sleep apnea. “But more than that, their lived experience is miserable.”

Even when patients get outstanding care, they remain at high risk for heart attacks. “Every time I hear a patient of mine [died suddenly], I race back to their chart to make sure I didn’t miss something,” Peters said. “One of the reasons I’m so passionate about this is that most of my patients are really well risk-modified, and they still die. “I know we’re all going to die,” Peters said. “But I’d prefer it not be in your 50s and 60s.”

Which New Therapy Makes Sense in Type 2 Diabetes?

Metformin remains the first therapy patients take when T2D is diagnosed. Now that SGLT2 inhibitors have been shown to have cardiovascular benefits, Peters said, there’s an argument to be made that they should be foundational for patients with T2D with comorbid cardiovascular disease. The question becomes: Which of the newer T2D therapies should come next? First Peters, and then Watson, reviewed evidence from a key set of studies—the cardiovascular outcomes trials (CVOTs)&mdash;that have fundamentally changed treatment of T2D and brought cardiologists into the mix in the treatment of this condition.

As Watson later explained, in 2008, the FDA began requiring CVOTs to show that new glucose-lowering therapies at least did not cause harm—meaning

they did not cause heart attacks, strokes, or other events—to patients with T2D.

Watson shared how the 2015 announcement of the EMPA-REG OUTCOME results3—that the SGLT2 inhibitor had reduced hospitalization for heart failure by 35% and all-cause mortality by 32%&mdash;hit like a thunderclap. That set off the wave of rethinking among both endocrinologists and cardiologists that culminated with the American College of Cardiologists’ (ACC) 2018 Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease.

CVOTs for 2 classes of therapy—SGLT2 inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists&mdash;have shown results with cardiovascular benefits. Peters reviewed the results and the criteria physicians should consider in deciding which class makes sense for a patient: 

Patients at risk of heart failure would likely benefit from an SGLT2 inhibitor. 

There are established cut points for estimated glomerular filtration rate to consider when prescribing an SGLT2 inhibitor, and patients with amputation risk should avoid canagliflozin, given the results of CANVAS.

If patients have a compelling need to minimize hypoglycemia and they need to lose weight, a GLP-1 receptor agonist is a good choice.

A1C Is No Longer the Measurement That Matters

Peters concluded with a discussion about moving away from A1C as the holy grail of measuring glycemic control. Use of continuous glucose monitoring (CGM) systems has highlighted the importance of time in range—which tells patients and physicians what percentage of time a person’s blood glucose stays out of hypo- or hyperglycemia, or between 70-180 mg/dL. Time in range, she said, is a much better indicator of a person’s likelihood of developing microsvascular and macrovascular

complications. With the availability of factory-calibrated systems, such as Dexcom’s G6 and Abbott’s Freestyle Libre, or the Eversense implant that requires no day-to-day involvement from the patient, a more complete picture emerges of the importance of maintaining glycemic control.

“The thing we know from these devices is that probably the A1C is a useless number,” Peters said. The next step is moving toward consistency in CGM reports, more like those that come from an electrocardiogram. Use of CGM allows physicians to demonstrate to insurers that even if a patient’s A1C seems normal, if time in range is volatile, a person with diabetes needs the glycemic control that an SGLT2 inhibitor provides to avoid long-term complications.

Peters expects that re-examining data from landmark studies like the Diabetes Complications and Control Trial will show the link between time in range and retinopathy or nephropathy. Thus, using CGM “will help us find the patients who need more or less help.”

“But it’s going to take a lot of teaching to get people to understand CGM,” she said. 

For Cardiologists, “This Is Your Lane”

For years, Watson explained, the success that cardiologists saw in managing lipids and high blood pressure—due in large part to improved therapies&mdash;wasn’t repeated when it came to diabetes. “Peter and I and Anne and I have patients in common, who, despite perfect lipids and blood pressure, were still having events, which is heartbreaking,” she said.

“We know cardiovascular disease is the leading cause of death and morbidity for patients with diabetes, and it costs a lot of money,” Watson said. “And we know that it comes with a lot of co-existing risk factors like hypertension or dyslipidemia, but it doesn’t matter…I can get their lipids perfect, I can get their blood pressure perfect, and diabetes itself is going to confer increased risk.”

But getting cardiologists involved in diabetes care, to encourage them to target this risk with antihyperglycemic agents, represents a change in thinking. And this was the point of ACC’s Expert Consensus Pathway document. “It’s one of the most revolutionary documents that ACC has ever released,” she said. “We’re trying to get cardiologists to understand: This is your lane.”

Watson said the document has 3 essential points: (1) Cardiologists should screen for T2D, (2) they should treat the risk factors, and (3) they should treat with antihyperglycemic agents, specifically SGLT2 inhibitors and GLP-1 receptor agonists. “We understood that when we put out this document, cardiologists would need a lot of hand-holding.”

The document further identified empagliflozin as the preferred SGLT2 inhibitor, and liraglutide as the preferred GLP-1 receptor agonist; as Peters did, Watson identified SGLT2 inhibitors as the preferred class for those at risk of heart failure. If patients have osteoporosis, are overweight, or are at risk for amputation, GLP-1 receptor agonists may be the better choice.

SGLT2 inhibitors, Watson noted, compare favorably in treating heart failure to many drugs developed specifically to target this condition; several trials are studying this class in heart failure for patients with and without diabetes. The first studies will report findings in 2020.

 “I’m putting my money on the agents,” she said.

Prescribing antihyperglycemic agents is just one area where cardiologists have shifted their thinking in light of new evidence, Watson said. Besides ACC’s Expert Consensus Pathway, updated primary prevention guidelines

Watson said the ASCEND trial results, which showed that taking aspirin for primary prevention reduced vascular events but was offset 1:1 by bleeding risk, was “the nail in the coffin” for giving aspirin to older adults who do not have coronary heart disease.

 Under the new primary prevention guideline, ACC has sharply curtailed who is recommended to receive daily aspirin. 

New guidelines adopted in 2017 by ACC and the American Heart Association redefined what constitutes high BP and lowered the threshold for treatment, based on the SPRINT study results.

 BP ≤120/80 mm Hg or below is considered normal. Systolic BP >120 and ≤130 mm Hg is elevated; stage 1 high BP is defined as systolic BP >130 and ≤139 mm Hg or diastolic BP >80 and ≤89 mm Hg. Stage 2 high BP is defined as systolic BP <140 mm Hg or diastolic BP <90 mm Hg.

 Watson was an author on the 2013 guidelines that identified 4 groups that need statins: (1) patients who have had an event, (2) patients with low-density lipoprotein (LDL) cholesterol above 190 mg/dL, (3) patients with diabetes, and (4) very-high-risk primary prevention patients, based on age and other factors.

The idea of cardiologists screening for diabetes and treating risk factors is new, but necessary, Watson said. “If we don’t do something to improve outcomes in patients with diabetes, they’re going to keep having events, and that’s why cardiologists are going to become diabetologists.”

Organizing Healthcare Delivery Around the Whole Patient

So, if every patient just gets the right medication, we can solve this problem called diabetes, right? If only.

CareMore’s Jain reminded the providers gathered at the session of a disturbing fact: “We are developing 21st century medicine with a 19th century delivery model,” he said. The idea that closing the gaps in healthcare is as simple as making patients better consumers might make sense to economists and people who don’t practice medicine, Jain said. Then he shared an anecdote that illustrated how the solutions being developed for consumers don’t always match the needs—or desires&mdash;of the people who use the most healthcare.

Early in his career, Jain served in the Office of the National Coordinator (ONC) for Health Information Technology. So, when he was home visiting his family recently, his mother asked him to put that experience to use and set up all her patient portals with her doctors. The bell went off that so much money and time has been expended on something that has very little value for his mother. “There is the false idea that people want to use this stuff,” he said, that patients are going to order healthcare the way they order things on Amazon.

Patients with chronic disease, the kind of patients that CareMore sees, are likely not using this type of technology in a meaningful way. The health system held a town hall with them at a hotel and listened to what the patients had to say.

“Healthcare should anticipate and deliver on people’s needs,” he said. Instead of giving them choices they don’t understand, healthcare should understand that expertise matters and that the cheapest solution may not be the best one. The idea that poor people need “skin in the game” to responsibly use healthcare is also out of touch. “People should not pay out of pocket for the things they need,” he said. “We should not have co-pays for the things that people need to live,” such as insulin.

If health systems want to keep patients from returning to the hospital, then things like using Lyft to get them home, ensuring there’s a healthy meal waiting for them when they arrive, making sure they have social contacts, and confirming that they see the same doctor for follow-up care all matter.

CareMore has pioneered services like toenail clippings because they offer regular touch points with the healthcare system, Jain said. When the average daily cost of a hospital bed in Los Angeles County is $3500 to $4000, he said, “You can buy a lot of prevention” by focusing on cost avoidance. 

CareMore integrates dental coverage and uses a patient’s time in the chair to check on other vital signs. Its Togetherness Program touches at-risk seniors who either live alone or need support to adhere to medications or get engaged in community or fitness programs. 

How does CareMore do it? The fully integrated care and delivery system for Medicare and Medicaid patients is fully at risk, because as Jain puts it, CareMore’s way of doing things would not be possible in “our broken fee-for-service delivery system.”

“We believe risk is freedom,” he said.

So, when Butler asked how to explain why the field of diabetes has better drugs than ever, but the average A1C is not better than it was 10 years ago, Jain said the need to reinvent the delivery system is the issue.

“A lot of the talk in health policy is around delivery science,” he said. “A lot of what we need is more common sense. Radical common sense.”

1. American Diabetes Association. Economic costs of diabetes in the US in 2017. Diabetes Care. 2018;41(5):917-928. doi: 10.2337/dci18-0007.

2. Kaiser AB, Zhang N, van der Pluijm W. Global prevalence of type 2 diabetes over the next ten years (2018-2028). Diabetes. 2018;67(suppl 1). doi: 10.2337/db18-202-LB.

3. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2126. doi: 10.1056/NEJMoa1504720.

Articles

Evidence-Based Diabetes Management

The Los Angeles gathering of the Institute for Value-Based Medicine focused on the need to intervene early in the course of diabetes, so that patients can avoid long-term complications. Over the past decade, cardiovascular outcomes trials for glucose-lowering therapies have revealed unexpected benefits, offering new opportunities for cardiologists. 

Managing Costs in Diabetes Means Intervening Early to Avoid Complications Later, Experts Say

The evidence for optimal management of diabetes continues to evolve at a feverish pace. Since the FDA introduced its guidance on evaluating the cardiovascular risk of new diabetes drugs in 2008, investigators have made significant progress in amassing evidence that therapeutic agents reduce the risk of major clinical end points.

 These clinical advances are best represented by data from pivotal trials demonstrating a reduction in major adverse cardiovascular events (MACE) associated with both the sodium glucose cotransporter type 2 (SGLT2) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists in particular. The dipeptidyl peptidase 4 (DPP-4) inhibitors have not been shown in major investigations to increase cardiovascular risk. Large, prospective, cardiovascular outcomes studies have demonstrated the efficacy of various agents from the SGLT2 inhibitor and GLP-1RA classes in reducing MACE, including EMPA-REG OUTCOME (empagliflozin),

 In fact, the American Diabetes Association (ADA)'s 

—2019 has incorporated the evidence from these studies to guide clinicians on which therapies may be optimal in patients with established  atherosclerotic cardiovascular disease or other comorbidities, such as chronic kidney disease (CKD).

Numerous opportunities remain to advance the science regarding optimization of diabetes treatment in reducing the risk of microvascular and macrovascular manifestations of diabetes. Further, investigators have presented several studies at the ADA's 79th Scientific Sessions, June 7-11, 2019, in San Francisco, California (see 

). Some of the Scientific Sessions presentations demonstrating results from these anticipated outcomes studies are highlighted below.

Investigators have conducted a number of trials to evaluate the effects of the SGLT2 inhibitors in slowing the progression of CKD as well as the progression of kidney

disease as a secondary outcome. In a post hoc analysis of the EMPA-REG OUTCOME trial, renal outcomes associated with empagliflozin—including incident or worsening nephropathy or progression to macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy, and death from renal disease&mdash;were evaluated.

A total of 7020 patients received at least 1 dose of study medication, with the following outcomes: 

• Incident or worsening nephropathy occurred in 525 of the 4124 patients (12.7%) receiving empagliflozin and in 388 of 2061 patients (18.8%) receiving placebo (hazard ratio [HR] for empagliflozin, 0.61; 95% CI, 0.53-0.70; 

• Progression to macroalbuminuria occurred in 459 of 4091 patients (11.2%) receiving empagliflozin compared with 330 of 2033 (16.2%) in the placebo group,

representing a 38% reduction in risk of progression of kidney disease (HR for empagliflozin, 0.62; 95% CI, 0.54-0.72; 

• A doubling of serum creatinine occurred in 70 of the 4645 patients (1.5%) receiving empagliflozin compared with 60 of 2323 (2.6%) in the placebo group, representing

a relative risk reduction of 44% (HR for empagliflozin, 0.56; 95% CI, 0.39-0.79; 

Furthermore, the EMPA-REG OUTCOME analysis demonstrated additional reductions in the need for renal replacement therapy initiation (13 of 4687 patients [0.3%] receiving empagliflozin vs 14 of 2333 [0.6%] receiving placebo; relative risk reduction, 55%), though renal disease led to more deaths in the empagliflozin arm (3 in the empagliflozin group [0.1%] vs none in the placebo group, [0.0%]).

 Results of this analysis have suggested beneficial renal outcomes attributed to treatment with empagliflozin, independent of cardiovascular risk reduction. 

Investigators have also evaluated renal outcomes associated with dapagliflozin therapy in a post hoc pooled analysis of 2 phase 3 clinical trials in patients with type 2 diabetes and uncontrolled hypertension.

 The analysis included data from 356 patients (dapagliflozin, n = 167; placebo, n = 189) with microalbuminuria or macroalbuminuria at baseline. Patients randomized to receive dapagliflozin experienced a greater reduction in albuminuria at 12 weeks, based on  urine albumin/creatinine ratio, compared with those receiving placebo (absolute difference, —33.2%; 95% CI, –45.4 to –18.2). Investigators also observed a decrease in estimated glomerular filtration rate (eGFR) in patients receiving dapagliflozin (–2.80 mL/min/1.73 m2 at 12-week follow-up; 95% CI, –5.43 to –0.16), which was reversed after stopping therapy.

Whether the reduction in renal outcomes is a class-wide effect remains unknown, so the presentation of key findings and data analysis from the CREDENCE trial were a highlight of the 79th Scientific Sessions. This is the first randomized, prospective, double-blind, placebo-controlled, multicenter, parallel-group trial specifically powered to evaluate the effects of canagliflozin on major renal outcomes. Its primary end point is time to first occurrence of any event in the primary composite end point (end-stage kidney disease, doubling of serum creatinine, renal or cardiovascular death) in patients with diabetes, CKD (defined as an eGFR of 30 to less than 90

mL/min/1.73 m2), and macroalbuminuria, who are receiving a maximally tolerated angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

The recent publication of the CREDENCE findings has shed light on these potential benefits and, importantly, helped to show that these benefits may represent a class-wide effect. Notably, the CREDENCE trial was concluded after an interim analysis, as its prespecified efficacy objectives had been met. Patients treated with canagliflozin

had an average event reduction of 30% for the composite primary end point, and from a safety perspective, CREDENCE did not identify a higher risk of fractures or amputation in the canagliflozin group. The risk of diabetic ketoacidosis was significantly higher in patients treated with canagliflozin compared with placebo (2.2 vs 0.2 events per 1000 patientyears, respectively), though this is not a surprising finding for an SGLT2 inhibitor.

Investigators also presented the results from the CARMELINA trial, published earlier this year, at the 79th Scientific Sessions. The major study evaluated the effect of linagliptin compared with placebo on the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in patients with elevated baseline cardiovascular and renal risk. Background standard-of-care diabetes management was offered to the 6979 patients in both treatment arms (linagliptin, n = 3494; placebo, n = 3485), though the use of DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists was disallowed via predefined exclusion criteria. For the 3-point MACE primary outcome, linagliptin (12.4%) was shown to be noninferior to placebo (12.1%) groups (HR, 1.02; 95% CI, 0.89-1.17; 

 <.001 for noninferiority). Subsequent testing for superiority for this primary outcome was not statistically significant (

 = 0.74). Similarly, the secondary composite outcome of time to first occurrence of end-stage renal disease, death due to renal failure, or sustained decrease in eGFR by 40% from baseline was not statistically different between the linagliptin (9.4%) and placebo (8.8%) groups (HR, 1.04; 95% CI, 0.89-1.22; 

 = 0.62).11 Although some exploratory outcomes of CARMELINA showed promise (eg, reduction in albuminuria progression) in the linagliptin arm, the overall results are not likely practice changing to the same degree as the cardiovascular and renal outcomes trials conducted with other pharmacotherapy options in other antidiabetic drug classes.

Beyond these trials, several additional study announcements included the role of vitamin D in diabetes prevention, the role of lifestyle intervention in preventing diabetes, the possible use of SGLT2 inhibitors in managing type 1 diabetes, and the efficacy and safety of an oral semaglutide formulation. Further, additional safety data are necessary to inform and elucidate risks associated with both drug classes (euglycemic diabetic ketoacidosis and amputation risk with SGLT2 inhibitor use and cancer risks associated with GLP-1 receptor agonists and DPP-4 inhibitors) and provide clarification on risk factors associated with these specific adverse events. In the meantime, the growing body of outcomes data related to cardiovascular and, now, renal outcomes has begun to shed some light on the potential role of multiple

pharmacotherapy options in the individualized management of diabetic patients. 

Joseph Cruz, PharmD, BCPS, a graduate of the Ernest Mario School of Pharmacy (EMSOP) at Rutgers University, completed an American Society of Health-System Pharmacists—accredited PGY-1 pharmacy residency and a PGY-2 drug information specialty residency at Robert Wood Johnson University Hospital.

Mary Barna Bridgeman, PharmD, BCPS, BCGP, is a graduate of EMSOP. She completed a phar macy residency at Robert Wood Johnson University Hospital and is a clinical professor in the Department of Pharmacy Practice and Administration at Rutgers University. She maintains volunteer faculty appointments in the Department of Medicine, Rutgers—Robert Wood Johnson Medical School, and in the Physician Assistant Program, Rutgers School of Health Professions, in addition to her practice site in internal medicine at Robert Wood Johnson University Hospital.

1. Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. FDA website. www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf. Published December 2008. Accessed March 26, 2019.

2. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.

3. Neal B, Perkovic V, Maheffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.

4. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee, LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/NEJMoa1603827.

5. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. doi: 10.1056/NEJMoa1607141.

6. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(suppl 1):S90-S102. doi: 10.2337/dc19-S009.

7. Wanner C, Inzucchi SE, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323-334. doi: 10.1056/NEJMoa1515920.

8. Heerspink HJ, Johnsson E, Gaulse-Nilsson I, Cain VA, Sjöström CD. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab. 2016;18(6):590-597. doi: 10.1111/dom.12654.

9. Jardine MJ, Mahaffey KW, Neal B, et al; CREDENCE study investigators. The canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017;46(6):462-472. doi: 10.1159/000484633.

10. Perkovic V, Jardine MJ, Neal B, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy [published online April 14, 2019]. N Engl J Med. doi: 10.1056/ NEJMoa1811744.

11. Rosenstock J, Perkovic V, Johansen OE, et al; CARMELINA Investigators. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019;321(1):69-79. doi: 10.1001/jama.2018.18269.

Two doctors of pharmacy review the impact of recent outcomes trials for newer classes of type 2 diabetes therapy.

Outcomes Trials Set Stage for Future of Diabetes Management in Patients With Renal Disease

Over the past decade, results from cardiovascular outcomes trials (CVOTs) for glucose-lowering therapies have had an enormous impact on people with type 2 diabetes (T2D). The first wave of findings reported on major adverse cardiovascular events (MACE) that were the focus of the FDA’s 2008 guidance requiring the studies.

 In November 2018, the DECLARE-TIMI trial reported results for dapagliflozin, the sodium glucose cotransporter 2 (SGLT2) inhibitor sold as Farxiga by AstraZeneca.

 Those results showed that dapagliflozin significantly reduced the risk of hospitalization for heart failure and appeared to slow the loss of kidney function.

That second finding reflects a major focus in a new wave of findings for SGLT2 inhibitors. The first dedicated renal outcomes trial reported results in April,

 and more are on the way. (Upcoming dedicated trials also will examine the effects of SGLT2 inhibitors on heart failure.) Finding ways to prevent the loss of renal function, including the need for dialysis, is a priority of managed care. Doing so would not only improve quality of life for patients but also bring savings for Medicare—the annual cost of a year of dialysis is estimated at $89,000.

 vice president of US cardiovascular and metabolic diseases at AstraZeneca, to discuss lessons from the CVOTs, the new focus on renal outcomes, and what’s next for SGLT2 inhibitors.

As a class, SGLT2 inhibitors are proving to have many benefits beyond lowering blood glucose for patients with T2D. For the past 4 years, much of t he focus at major scientific meetings has been on CVOT results—reduction in major cardiovascular events. But those results also contained evidence that the class also had the ability to play a major role in preventing the slow progression to debilitating conditions like kidney failure. Can you discuss why the renal benefits of SGLT2 inhibitors are getting more attention now?

 The primary focus of cardiovascular safety and the reduction in major cardiovascular events by SGLT2 inhibitors stems from cardiovascular outcomes trials that were mandated following the 2008 guidance from the FDA to confirm these medicines were safe from a cardiovascular perspective.

 With this in mind, it’s easy to see why confirming the CV safety and efficacy of these medicines was established as the primary objectives of these trials and therefore were the first topics of scientific discussion.

We have always known that patients with diabetes have an increased risk of renal complications. In fact, diabetes is the leading cause of kidney disease, and  approximately 1 in 4 adults with diabetes has kidney disease.

 Although the initial SGLT2 inhibitor CVOTs were focused on CV outcomes, secondary analyses were included to assess renal impact. These secondary analyses generated interesting hypotheses about SGLT2s and their impact on renal outcomes. As a result of these findings, AstraZeneca is prospectively evaluating these hypotheses in a large randomized clinical trial known as Dapa-CKD,

 a study evaluating the effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with chronic kidney disease (CKD).

Can you discuss the new indication that dapagliflozin received from the FDA and why this is important?

The FDA approved an updated label for Farxiga that expands who may benefit from the medicine—specifically, for patients with T2D and moderate renal impairment [CKD with an estimated glomerular filtration rate (eGFR) of 45-59 mL/min/1.73 m

 The updated label lowers the eGFR threshold to 45 mL/min/1.73 m

Because patients may be affected by metabolic and renal complications that are interrelated, it’s important to have information about how these medicines work in patients with both conditions included in the prescribing information for [dapagliflozin].

 was announced, AstraZeneca added a primary end point to its CVOT, the DECLARE-TIMI trial, which has reported results at meetings for the American Heart Association and American College of Cardiology. Can you discuss this decision and the importance of this additional primary end point?

Every time you conduct a clinical trial, you ask a specific question and receive an answer, but each trial also generates new hypotheses and therefore questions that need to be answered by a subsequent clinical trial. The benefit of being the third CVOT is that we were able to take some of the questions generated by the results of the other CVOTs and prospectively study them in DECLARE. In DECLARE, the study design was adjusted to include coprimary end points of MACE as

well as the composite of hospitalization for heart failure or CV death, because we believed understanding the impact on hospitalizations for heart failure would be especially important—particularly because 1 out of every 3 patients with diabetes will go on to have heart failure, heart failure is the first cardiac complication for most patients, and the mortality rates for heart failure are quite high.

With more than 17,000 patients in 33 counties, DECLARE provides a broad representation of type 2 diabetes patients with cardiovascular risk factors and established cardiovascular disease, offers a rich body of scientific evidence for this patient population, and the benefit was seen in the broadest patient population to date, making it highly relevant to the real-world clinical setting.

 the first trial evaluating the effect of an SGLT2 inhibitor on the incidence of worsening heart failure or cardiovascular death in patients with chronic heart failure and  with and without T2D, is expected to read out this year.] 

What is the significance of the American Diabetes Association (ADA) releasing a midyear guideline update to include new evidence on 

The addition of new data that feature the most up-to-date research on CV and renal risk reduction in patients with type 2 diabetes for the SGLT2 inhibitor class in the ADA 

 [Standards of Medical Care in Diabetes] helps empower healthcare professionals to provide evidence-based care to their patients and help improve outcomes. Heart failure is the No. 1 cardiac complication in patients with type 2 diabetes.

We just had the first of the new wave of reported results from renal outcomes trials, and Dapa-CKD will be complete in 2020. Significantly, half of these patients do not have diabetes. Is there anything you can tell us about the study so far?

The Dapa-CKD trial is designed to evaluate the effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with CKD and includes both patients with and without type 2 diabetes. It is a randomized, multicenter, event-driven, double-blind, placebo-controlled study involving 4000 patients with CKD. The

primary outcome is defined as the composite of time to first occurrence of ≥50% sustained decline in eGFR, reaching end stage renal disease (ESRD) or CV death or renal death. ESRD is defined as sustained eGFR <15 mL/min/1.73m2, chronic dialysis treatment or receiving a renal transplant.

Dapa-CKD is expected to read out in 2020.

Given the extreme burdens for patients, high mortality rates for those who begin dialysis, the diminished quality of life, and the cost to Medicare, how do the potential renal benefits of SGLT2 inhibitors compare with the CV benefits?

It is probably too early to make a definitive statement about this. What we know is that the risk of developing renal impairment or CKD is high among patients with diabetes, and the SGLT2 class of medicines has generated some interesting and promising hypotheses about how they may affect the kidney. As we continue to evaluate the potential benefits of SGLT2 inhibitors, we believe these treatments could become innovative options that may address cardiorenal risks for patients with diabetes.

1. US Food and Drug Administration. Guidance for Industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf. Published December 2008. Accessed March 26, 2019.

2. Wiviott SD, Raz I, Bonaca MP, et al; DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;390(4):347-357. doi: 10.1056/NEJMoa1812389.

3. Perkovic V, Jardine MJ, Neal B, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy [published online April 14, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1811744.

4. The Kidney Project. Statistics. University of California at San Francisco website. https://pharm.ucsf.edu/kidney/need/statistics. Accessed June 6, 2019.

5. Diabetic Kidney Disease. National Institute of Diabetes and Digestive and Kidney Diseases website. niddk.nih.gov/health-information/diabetes/overview/preventing-problems/diabetic-kidney-disease. Updated February 2017. Accessed June 6, 2019.

6. A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (Dapa-CKD). clinicaltrials.gov/ct2/show/NCT03036150. Updated April 29, 2019. Accessed June 6, 2019.

7. US FDA approves expanded Farxiga and Xigduo XR labels for use in patients with type 2 diabetes and moderate renal impairment [press release]. Wilmington, DE: AstraZeneca; February 27, 2019. businesswire. com/news/home/20190227005113/en/FDA-Approves-Expanded-FARXIGA-XIGDUO-XR-Labels. Accessed June 6, 2016.

8. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720.

9. Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF). clinicaltrials.gov/ct2/show/NCT03036124. Updated April 19, 2019. Accessed June 6, 2016.

10. American Diabetes Association issues critical updates to 2019 Standards of Medical Care in Diabetes [press release]. Arlington VA: American Diabetes Association; March 27, 2019. diabetes.org/newsroom/press-releases/2019/ada-issues-critical-updates-to-2019-standardsof-care.html. Accessed June 6, 2016.

A discussion with Naeem Khan, MD, vice president of US cardiovascular and metabolic diseases at AstraZeneca, on lessons from the wave of cardiovascular outcomes trials, the new focus on renal outcomes, and what’s next for SGLT2 inhibitors.

AstraZeneca's Khan Discusses Dapagliflozin and Cardiovascular, Renal Outcomes in Diabetes Care

CREDENCE, the first of a coming wave of dedicated renal outcomes trials for sodium glucose cotransporter 2 (SGLT2) inhibitors, has reported 2 sets of results that

suggest there is more news to come for the drug class that has already changed diabetes care since reaching the market in 2013.

Investigators for CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), reported on April 14, 2019, that canagliflozin cut the risk of renal failure or death by 30% in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD).

 These results, unveiled at the International Society of Nephrology 2019 World Congress of Nephrology in Melbourne, Australia, were simultaneously reported in the 

Canagliflozin is sold as Invokana by Janssen Pharmaceutical Companies of Johnson and Johnson.

The findings prompted the American Diabetes Association (ADA) to update its 

 in 2 chapters that deal with cardiovascular (CV) disease and risk management

 and microvascular complications and foot care.

Then, on June 11, 2019, during the Scientific Sessions in San Francisco, California, CREDENCE coprincipal investigator Kenneth Mahaffey, MD, of Stanford University Medical Center, shared additional data on what the results mean for primary and secondary prevention—namely, how well canagliflozin prevented renal decline in individuals with T2D who had been diagnosed with CV disease or had experienced an event (secondary prevention) as well as those who had neither (primary prevention).

After a series of CV outcomes trials (CVOTS) showed a class effect for CV benefits for SGLT2 inhibitors,

 there was plenty of interest at the 79th Scientific Sessions not only for CREDENCE, but also for secondary findings on renal outcomes from the CVOTS for rival drugs. Other manufacturers have their own dedicated renal outcomes trials in process: AstraZeneca has Dapa-CKD for dapagliflozin (Farxiga),

 due to report in November 2020, and Boehringer Ingelheim and Eli Lilly have sponsored EMPA-KIDNEY for empagliflozin (Jardiance), due to report in June 2022.

 Various dedicated trials exploring the therapeutic value of SGLT2 inhibitors

in heart failure for patients with and without diabetes are also under way.

SGLT2 inhibitors lower blood glucose by targeting a protein that affects reuptake of glucose by the kidneys back into the bloodstream. Patients who take these drugs excrete glucose out of the body through the urine, and this unique system for discharging extra blood glucose accounts for the drugs’ protective effects on the renal system. As described by Christoph Wanner, MD, in a 2017 article, “The potential mechanisms responsible are likely multifactorial, and direct renovascular and hemodynamic effects are postulated to play a central role.”

Although an early completion date of CREDENCE had suggested positive results,

 the magnitude of the benefit surprised some. While moderating a press briefing at the 79th Scientific Sessions, Robert H. Eckel, MD, of the University of Colorado, exclaimed, “CREDENCE—that just knocks your socks off, doesn’t it?”

Initial Findings Show No Amputation Risk 

Phase 3 results reported in Melbourne show that CREDENCE easily achieved its primary end point; compared with placebo, canagliflozin reduced a composite of (1) the progression to end-stage renal disease (ESRD), defined as the need for chronic dialysis or renal transplant; (2) doubling of serum creatinine; and (3) renal or CV death.

 This was not unexpected, given the June 2018 announcement that the trial was ending early after independent evaluators determined the primary end point had been met.

CREDENCE did not show the elevated risk of lower extremity amputation seen in CANVAS,

 the CVOT for canagliflozin that caused the FDA to issue a boxed warning, even though the same trial found benefits that led to an indication for lower risk of CV events.

 When asked if these results would prompt the drug maker to seek removal of the warning, Janssen officials said in an email that the new data are “reassuring” because they “show no imbalance” in either fractures or amputations between the canagliflozin or placebo arms; the company will be working with the FDA, “to reflect these safety findings in the Invokana label.”

Janssen is seeking an additional indication for canagliflozin, based on the CREDENCE findings.

CREDENCE was a double-blind trial that randomized 4401 patients with a median follow-up of 2.62 years. Patients had a mean age of 63 years (± 9.2 years) and had lived with T2D for an average of 15.8 years (± 8.6 years). All patients had an estimated glomerular filtration rate (eGFR) of 30 to <90 mL per minute per 

 of body surface area and albuminuria. All were being treated with standard of care, renin-angiotensin system blockade.

• The relative risk (RR) of the primary outcome was 30% lower for those taking 100 mg of canagliflozin compared with placebo; event rates were 43.2 and 61.2 per 1000 patient-years (hazard ratio [HR], 0.70; 95% CI, 0.59-0.82; 

• The RR for the renal-specific elements of the primary end point—excluding CV death&mdash;was 34% lower for those taking canagliflozin (HR, 0.66; 95% CI, 0.53-0.81; 

• The RR of ESRD was 32% lower for those taking canagliflozin (HR, 0.68; 95% CI, 0.54-0.86; 

• Among secondary end points, the risks of CV death, myocardial infarction, or stroke (HR, 0.80; 95% CI, 0.67-0.95; 

 = .01) and for hospitalization for heart failure (HR, 0.61; 95% CI, 0.47-0.80; P <.001) was lower among those taking canagliflozin. The authors wrote that these measures may have been limited when the trial ended early, but they were consistent with other randomized controlled trials and real-world studies in SGLT2 inhibitors.

No significant differences were seen in rates of amputations or fractures. In amputation, the HR was 1.11 (95% CI, 0.79-1.56) and in adjudicated fractures, the HR was 0.98 (95% CI, 0.70-1.37). 

Lower limb amputation rates were 12.3 for canagliflozin versus 11.2 for placebo per 1000 patient-years. There has been much speculation about whether the amputation findings in CANVAS were due to the makeup of the study population. Authors in CREDENCE wrote that the population in this trial was at high risk for CV events, and they discussed the disparity from the CANVAS findings.

“Whether the increased risk of lower limb amputation in the CANVAS Program was due to differing trial populations or protocols or to chance remains unclear,”

they wrote. “The overall safety profile in our trial is otherwise consistent with the known adverse effects associated with canagliflozin.”

A Breakthrough With Potential Savings to the Health System

“Canagliflozin is the first medical breakthrough in nearly 20 years proven to slow the progression of chronic kidney disease in patients with diabetes at high risk of developing kidney failure,” the study’s lead author, Vlado Perkovic, MBBS, PhD, FASN, FRACP, said in a statement.

Perkovic, who is cochair of the CREDENCE Steering Committee and executive director of The George Institute for Global Health, Australia, said, “These impressive results from the CREDENCE study have significant clinical implications for preventing kidney failure and improving health for millions of people living with chronic kidney disease and type 2 diabetes.”

Researchers and physicians familar with the CREDENCE trial have hinted as far back as the summer of 2017 that the renal outcomes suggested in CANVAS-R (the renal component of CANVAS) would be fully demonstrated in these results.18 With T2D being the top cause of kidney failure, a treatment to prevent patients with T2D from needing dialysis or transplant would potentially save millions of dollars for Medicare. A 2018 report from the US Renal Data System (USRDS) found that 1% of the patients in Medicare have ESRD, but they account for 7% of Medicare fee-for-service costs.

reported that empagliflozin reduced the risk of CV death in 2015, it “changed the landscape in diabetes management,” as Julie R. Ingelfinger, MD, and Clifford J. Rosen, MD, wrote in their editorial that accompanied publication of the study.

 EMPA-REG OUTCOME and subsequent CVOTs showed that SGLT2 inhibitors reduced the risk of hospitalization for heart failure, suggesting that the drugs were not only beneficial to patients, but could also reduce one of the high-cost items in healthcare, just as health systems were being graded on their ability to avoid repeat hospitalizations for this condition. 

SGLT2 inhibitors have been shown to reduce hypertension and promote modest weight loss. Existing evidence showing prevention of renal decline last month prompted the American College of Cardiology and the American Heart Association to include the class, with glucagon-like peptide-1 receptor agonists, in an updated primary prevention guideline.

 Ingelfinger and Rosen wrote that, although several T2D medications show benefits beyond lowering blood glucose, “the SGLT2 inhibitors appear to be the most promising.”

CREDENCE shows that canagliflozin has the potential to achieve savings in an area of huge importance to policy makers. Few items tax the health system as much as ESRD, which affects 750,000 individuals in the United States. The USRDS estimates the cost of a year of dialysis at $89,000 per patient

, and, as Ingelfinger and Rosen wrote, the ranks in need of dialysis and kidney transplants are growing due to rising levels of obesity.

 They noted that the investigators estimate that among

 would need to be treated with canagliflozin to avoid dialysis or transplant, doubling the serum creatinine level, or renal or CV death.

 Dialysis and kidney transplant care are so costly that patients with CKD who reach this stage automatically qualify for Medicare at any age; most Medicare Advantage plans do not accommodate these patients unless they have a special needs plan that handles ESRD.

Presentations at 2 major scientific conferences showed that the SGLT2 inhibitor cut the risk of renal failure or death by 30% and had renal benefits for patients with and without previous cardiovascular disease.

June 2019

Managing Costs in Diabetes Means Intervening Early to Avoid Complications Later, Experts Say

Outcomes Trials Set Stage for Future of Diabetes Management in Patients With Renal Disease

AstraZeneca's Khan Discusses Dapagliflozin and Cardiovascular, Renal Outcomes in Diabetes Care

CREDENCE: First Renal Outcomes Trial Finds Canagliflozin Cuts Risk of Renal Failure, Death; Prompts ADA Updates

From the Editor-in-Chief: Evolving Role of T2D Therapy, From Secondary to Primary Prevention

2019 ADA Coverage: Renal Outcomes