Mary Caffrey

Cardiologists should consider screening patients who have 

 (HF), diabetic kidney disease (DKD), or atherosclerotic cardiovascular disease (ASCVD) for 

 (T2D) once a year if they meet the criteria for prediabetes, according to an updated American College of Cardiology (ACC) document on new drug classes developed for T2D that have shown a range of benefits in cardiovascular care.

Regular screening is just one recommendation in the 2020 Expert Consensus Decision Pathway (ECDP) on Novel Therapies for Cardiovascular Risk Reduction With Type 2 Diabetes, published today in the 

Journal of the American College of Cardiology. 

It comes nearly 2 years after the inaugural document discussed 2 groups of therapies—sodium glucose co-transporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists—that have transformed T2D treatment and are now changing the way physicians prevent heart and renal failure.

“An important paradigm shift in the care of patients with diabetes and cardiovascular disease is underway,” Sandeep R. Das, MD, MPH, FACC, co-chair of writing committee for the ECDP, 

. “Patients and physicians can now choose from a number of medications that have important proven benefits on cardiovascular and renal outcomes, in addition to their effects on blood glucose.”

Among key updates in the 2020 ACC pathway:

The authors say the need for patients to get started on SGLT2 inhibitors or GLP-1 RAs upon discharge after a heart attack “must be weighed” when hospitals decide what drugs to put on formulary.

, which singled out one therapy from each class as “preferred,” the 2020 version makes no such distinctions, but some approved drugs in each class are not discussed in language on therapy initiation.

Both the SGLT2 inhibitor and GLP-1 RA classes were first approved to lower blood glucose, but they were found to have other benefits, including the ability to prevent heart attacks, strokes, renal decline, or cardiovascular death; or to reduce heart failure for hospitalization. The benefits were revealed in the first wave of cardiovascular outcomes trials, which were required by FDA and led to publication of the initial pathway in 

Since then, leaders of ACC have sought to educate members about the value of prescribing these drug classes in patients with heart failure or who have demonstrated ASCVD. However, cardiologists sometimes have resisted using drugs that were first approved for diabetes, in part because they don’t want to “own” responsibility for a patient’s glycated hemoglobin level (A1C), a quality measure that can get reported to Medicare.

In a forthcoming interview to be published with 

®, Darren K. McGuire, MD, MHSc¸ of UT Southwestern Medical Center, said there’s been a rapid embrace of new evidence among the fellows he trains at the cardiology clinic at Parkland Hospital in Dallas, Texas. But among cardiologists generally, he said uptake has been “dismal.”

“It’s important that we disconnect the benefits of both the SGLT2 inhibitors and the GLP-1 receptor agonists. The cardiovascular benefits that have been demonstrated are completely independent of glucose control,” McGuire said, and guidelines in both the United States and Europe reflect this.

 glucose control,” he said. “You simply use the risk of the patient to prescribe the medication. It’s not that you’re forgetting the glucose control. That’s still going to be left up to the providers who’ve been managing it all along, but we’ll be adding these.”

September will mark 5 years since the scientific community was stunned with results from the EMPA-REG OUTCOME trial, which was the first to show a drug to lower blood glucose, empagliflozin, could also provide cardiovascular (CV) benefits. The race was on among competitors in the 2 emerging drug classes to show which individual therapy was more likely to reduce heart attacks, CV death, or heart or renal failure. In the 2018 pathway, the ACC authors singled out empagliflozin (Jardiance, Eli Lilly/Boehringer Ingelheim) among the SGLT2 inhibitors and liraglutide (Victoza, Novo Nordisk) among the GLP-1 RAs as “preferred,” on the strength of CV outcomes trial results reported at that time.

 Since then, more clinical trial findings have been reported, and this has increased available data across the 2 classes for the ECDP Writing Committee and the Solution Set Oversight Committee to evaluate. Among the newer studies, the 

 found that the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) reduced the risk of worsening HF or CV death for patients with HF with reduced ejection fraction (HFrEF), regardless of diabetes status. 

 found that the SGLT2 inhibitor canagliflozin (Invokana, Janssen) could reduce the risk of renal decline or renal death in patients with T2D and chronic kidney disease (CKD).

More recently, the DAPA-CKD trial was stopped early, and sponsors of the EMPEROR-Reduced trial for empagliflozin in HRrEF say it has achieved all primary and secondary endpoints.

Among the treatment recommendations, the authors write:

An SGLT2 inhibitor with demonstrated CV benefit is recommended for patients with T2D and HF, especially reduced ejection fraction (HFrEF).

Diagnosis of T2D, when ASCVD, DKD, or HFrEF is present, or a diagnosis of ASCVD when any of the other conditions are present, “offers the opportunity to begin the patient-clinician discussion” about taking an SGLT2 inhibitor.

GLP-1 RAs are recommended for those patients with established or very high risk ASCVD.

Decisions on prescribing these medications for CV or kidney risk reduction “should not be contingent” on a patient’s A1C level; however, the document stops short of saying metformin is not needed, and in fact, says most patients will likely take it.

In the new pathway, authors write, “Although canagliflozin, dapagliflozin, and empagliflozin have differences in their FDA-approved CV indications, they appear to have broadly similar CV and renal benefits.”

Among the GLP-1 RAs, the authors write, “data support the use of dulaglutide, liraglutide or injectable semaglutide as having demonstrated CV benefit to reduce the risk of [major adverse cardiovascular events].” Based on 

, dulaglutide (Trulicity, Lilly) won a label indication for reduction of MACE in patients with and without established CV disease. This class is also considered more effective for weight loss, ranging from 2% to 4%of total body weight for dulaglutide, exenatide, and liraglutide. The authors note that existing studies suggest that the GLP-1 RA class may offer “modest renal benefits,” but this has not been confirmed in a trial with a primary renal outcome.

The document gives dosing recommendations; with GLP-1 RAs, generally, physicians should start on a low dose and titrate up to avoid gastrointestinal reactions. With SGLT2 inhibitors, cardiologists should use the lowest dose tested in CV and renal outcomes trials.

Authors speak to recent concerns about diabetic ketoacidosis among users of SGLT2 inhibitors outside a clinical trial setting, and note that physicians should advise patients about the dangers of dehydration with a drug whose mechanism of action leads to volume depletion—the drugs expel excess blood glucose through the urine.

The authors discuss whether the 2 classes should be used together; they note there is guideline support for this, “even though such combination therapy has not been studied for CV risk reduction.” Patient out-of-pocket costs might be a factor here, they note.

Among other questions: What is the role for these drug classes among patients “who do not have DKD or established ASCVD but are at high risk?” How should drugs be prioritized and sequenced? How do these therapies fit it with others, such as icosapent ethyl (Vascepa), PCSK9 inhibitors, and antiplatelet therapies?

The cardiologists’ role with T2D patients requires working with others, said Brendan M. Everett, MD, MPH, FACC, co-chair of the writing committee. “We should consider thesenew medications important tools to reduce cardiovascular morbidity and mortality in patients,” with T2D, he said. “We can work together with our patients and other members of the care team to decide whether the patient would benefit from these therapies, and to initiate therapy if appropriate.”

Ras DR, Everett BM, co-chairs, for the Writing Committee of the American College of Cardiology Solution Set Oversight Committee. 2020 Expert Consensus Decision Pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes. Published online August 5, 2020. 

Articles

The American College of Cardiology updates guidance on prescribing SGLT2 inhibitors and GLP-1 receptor agonists to patients with type 2 diabetes and cardiovascular disease or CV risk.

New Renal, HF Results Seen in 2020 ACC Pathway on CV Risk Reduction 

Reimbursements that HHS imposed for certain medications administered in outpatient clinics of 340B hospitals were based on a “reasonable interpretation of the Medicare statute” and can remain, a 3-judge panel of the US Court of Appeals for the District of Columbia ruled July 31, 2020.

The 2-1 reverses a District Court level ruling that HHS, through CMS, exceeded its authority when it imposed a 28.5% rate cut for a category of outpatient drugs used by hospitals enrolled in the discount program, which was created to support safety net hospitals serving Medicaid patients.

The American Hospital Association (AHA) and 2 allies in the effort to restore 340B cuts issued a statement that suggests they will challenge the ruling. “We will continue to fight for our hospitals and their patients, and we call on CMS to reverse this harmful policy to ensure hospitals can continue to provide the services people need the most,” read the statement from AHA, America’s Essential Hospitals and the American Association of Medical Colleges.2

Hospital groups have the right to seek a ruling by an 

The ruling is the latest twist in a battle over the 340B program, which even critics say started with good intentions but evolved into a way for hospitals to employ drug discounts beyond their walls that underwrite other operating costs.

Under the 340B program, pharmaceutical manufacturers must allow discounts for certain drugs to qualifying hospitals—which lets the hospital pay between 20% and 50% below the average sales price, while Medicare reimburses at the normal rate. When discounts under 340B were applied to certain Medicare Part B drugs given in the outpatient setting—whose reimbursements were calculated by specific formulas—it allowed hospitals to effectively make a profit off them, or at least CMS saw it this way, the appellate ruling said. Thus, in 2017, the Trump administration sought to narrow the gap between drug payments in 340B and those in Medicare Part B.

Critics of the program say the 340B “discount” gets made up in the form of higher overall costs, and the pricing dynamics hurt seniors who are forced to pay a higher co-payment tied to a drug’s pre-discount price.

For several years, providers such as the Community Oncology Alliance have argued that the program’s expansion into outpatient clinics came at their expense, since non-hospital clinics could not compete on drug prices. These providers have been aided by reports from the Government Accountability Organization, including a 

 that found poor oversight of the program and that some hospitals were getting discounts for which they did not qualify.


“[The] court decision is another major victory for President Trump’s agenda of lower drug prices and better healthcare for all Americans,” HHS Secretary Alex Azar said in a statement. “Since HHS took the action that the court affirmed … we have saved more than $4.8 billion in lower drug costs and reinvested these savings in the Medicare program.”

However, hospitals affected by the cuts have argued the lost revenue will impair their ability to provide critical services, and as they have stepped up that case as the coronavirus disease 2019 (COVID-19) pandemic has put unprecedented strain on large hospitals, including academic medical centers.

“These cuts of nearly 30% have caused real and lasting pain to safety-net hospitals and the patients they serve,” Maureen Testoni, president and CEO of advocacy group 340B Health, said in a statement. “Keeping these cuts in place will only deepen the damage of forced cutbacks in patient services and cancellations of planned care expansions.”

Even as the matter has worked its way through the courts, HHS has continued to include the cuts in annual payment rules, and at least one observer wrote that it will interesting to see what happens next, given that hospital interests are waiting on an update to the Part B hospital outpatient prospective payment system (HOPPS) for 2021.

“Despite the lower court decision, CMS doubled down and maintained the cuts in the 2020 HOPPS rule while the government pursued its appeal,” wrote 

In making its ruling, the DC Circuit panel relied on the same case as the District Court, but came up with a different interpretation, Kirschenbaum noted. While the lower court found that CMS had exceeded its authority, the 2 judges on the panel ruled found otherwise.

Writing for the panel, Chief Judge Padmanabhan Srikanth Srinivasan said, “Was HHS obligated to continue reimbursing 340B hospitals for [outpatient drugs] in amounts substantially exceeding their costs to obtain the drugs, with the resulting effects that concerned the agency on out-of-pocket copayments owed by Medicare beneficiaries? We think the agency was not compelled to continue doing so.”

1. American Hospital Association et al v. Alex M. Azar II, et al. 19-5048-1854504 [2020] (US Circuit Court of Appeals, January 11, 2018). Accessed July 31, 2020. 

https://www.cadc.uscourts.gov/internet/opinions.nsf/B8E3F76510742B95852585B600531146/$file/19-5048-1854504.pdf

2. Statement on 340B court decision: AHA, AAMC, and America’s Essential Hospitals. News release. Published and accessed July 31, 2020. 

https://www.aha.org/press-releases/2020-07-31-statement-340b-court-decision-aha-aamc-and-americas-essential-hospitals

3. HHS Secretary Price: Trump administration taking action on drug prices. News release. Published July 13, 2017. Accessed August 2, 2020. 

https://www.hhs.gov/about/news/2017/07/13/hhs-secretary-price-trump-administration-taking-action-drug-prices.html

4. Government Accountability Office. Increased oversight needed to ensure nongovernmental hospitals meet eligibility requirements. GAO website. Published January 10, 2020. Accessed August 3, 2020. 

5. HHS Secretary Azar statement on court victory for President Trump’s drug-pricing agenda. News release. Published and accessed July 31, 2020.

https://www.hhs.gov/about/news/2020/07/31/hhs-secretary-azar-statement-court-victory-president-trumps-drug-pricing-agenda.html

6. Daly R. Hospitals decry appeals court decision upholding 340B cuts. HFMA website. Published and accessed August 3, 2020. 

https://www.hfma.org/topics/news/2020/08/hospitals-decry-appeals-court-decision-upholding-340b-cuts.html

7. Kirschenbaum AM. DC Circuit reverses lower court, clearing way for CMS cuts in drug payment to 340B hospitals. FDA Law Blog. Published and accessed August 3, 2020. 

http://www.fdalawblog.net/2020/08/d-c-circuit-reverses-lower-court-clearing-the-way-for-cms-cuts-in-drug-payment-to-340b-hospitals/

The ruling reversed a lower court ruling regarding the drug discount program for hospitals that serve patients covered by Medicaid.

Hospitals Vow to Fight Court of Appeals 340B Ruling

On July 31, FDA approved tafasitamab-cxix to be used in combination with lenalidomide for second-line treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), meeting the needs of patients who are not eligible for an autologous stem cell transplant.

Tafasitamab, to be sold as Monjuvi by MorphoSys and Incyte, is a humanized Fc-modified cytolytic CD19 monoclonal antibody being studied in several B-cell malignancies. As described in the journal 

 the treatment uses Xencor’s proprietary Xmab technology, which deploys a different technique to boost affinity for the antigen and make various receptors especially capable of binding to it. In 2018, authors in 

described how this sets off particularly effective processes that target cancer cells and regulate cell death.

Approval was based on phase 2 results for 80 patients in the 

, which reported an update May 2019 at the American Society of Clinical Oncology, with final results published last month in 

Results submitted to FDA showed an overall response rate of 55%, including a compete response rate of 37% and a partial response rate of 18%. Median duration of response was 21.7 months. Common adverse events included neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, pyrexia, peripheral edema, respiratory tract infection, and decreased appetite.

Among non-Hodgkin lymphomas, DLBCL is the most common subtype, accounting for 22% of cases in the United States and 40% worldwide, with about 18,000 US cases per year. People are at higher risk if they have HIV, an autoimmune disease, or if they have had an organ transplant. More common in older people, DLBCL can be very aggressive. Although well-known treatments have been developed, there are gaps—and a notable one is when DLBCL cannot be kept in remission after chemotherapy but the patient is not eligible for an autologous stem cell transplant. Some of these patients have had chimeric antigen receptor (CAR) T-cell therapy, but this process is costly with significant side effects.

“The FDA approval of Monjuvi in combination with lenalidomide helps address an urgent unmet medical need for patients with relapsed or refractory DLBCL in the United States,” Hervé Hoppenot, CEO of Incyte, said 

. “At Incyte we are committed to advancing patient care and are proud to bring this new and much-needed targeted therapeutic option to appropriate patients and the clinical community.”

FDA had previously granted the combination Fast Track and Breakthrough Therapy Designation in this indication.

A new treatment option is approved for patients with a common form of non-Hodgkin lymphoma who cannot have an autologous stem cell transplant.

Tafasitamab Combination Approved for Adults With R/R DLBCL

AstraZeneca reported July 30 that osimertinib, sold as Tagrisso, has been granted Breakthrough Therapy Designation (BTD) from FDA for adjuvant treatment of patients with early-stage, 

m) non–small cell lung cancer (NSCLC), following surgery for completely tumor resection.

The action follows a presentation during the 2020 American Society of Clinical Oncology (ASCO) virtual meeting of the 

, which showed that treatment with osimertinib reduced the risk of disease recurrence or death by 79% (hazard ratio .21, 95% CI 0.16-0.28; 

 < .0001) in a key secondary end point. The ADAURA trial was stopped in April 2020 after an independent monitoring committee called for the trial to be unblinded 2 years early based on a determination of overwhelming efficacy.

Osimertinib, a third-generation, irreversible 

 tyrosine kinase inhibitor, is already the preferred option for patients with advanced 

m NSCLC. Following presentation of the ADAURA results, both the study’s lead author and commentators said osimertinib should also become the treatment of choice for patients with 

m who are treated after surgery for early-stage, localized disease (stage IB-IIIA). The 

m genetic driver is seen in 10% to 15% of NSCLC cases in the United States and up to 40% of cases in Asia.

With current treatments, nearly half of patients diagnosed in stage IB experience disease recurrence, and more than three-fourths of patients diagnosed in stage IIIA experience recurrence within 5 years.

"Patients with early-stage 

m lung cancer often experience recurrence even after successful surgery and adjuvant chemotherapy, yet there are currently no approved targeted treatments to improve outcomes," José Baselga, executive vice president for Oncology R&D at AstraZeneca, said 

. "The phase 3 ADAURA trial with Tagrisso demonstrated an unprecedented level of clinical benefit in these patients, and we are working closely with the FDA to deliver this potentially curative treatment to patients as quickly as possible."

BTD is a process that expedites review of drugs that may offer substantial improvement over available therapy on clinical end points that include irreversible morbidity or mortality or serious symptoms.

The ADAURA trial was stopped in April 2020 after an independent monitoring committee called for the trial to be unblinded 2 years early based on a determination of overwhelming efficacy.

Author | Mary Caffrey

Articles

New Renal, HF Results Seen in 2020 ACC Pathway on CV Risk Reduction

Hospitals Vow to Fight Court of Appeals 340B Ruling

Tafasitamab Combination Approved for Adults With R/R DLBCL

Osimertinib Granted Breakthrough Status for Early-Stage, EGFR-Mutated NSCLC Patients After Surgery