The antidiabetic drugs that have recently shown efficacy for reducing cardiovascular-disease events in patients with type 2 diabetes have prompted some cardiologists to start acting a bit more like diabetologists.

The dramatic reduction in cardiovascular death and heart failure hospitalization seen during treatment with empagliflozin (Jardiance) in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial, for example, has prompted some cardiologists in the year since the first EMPA-REG report to become active prescribers of the drug to their patients who have type 2 diabetes and cardiovascular disease. The same evidence has driven other cardiologists who may not feel fully comfortable prescribing an antidiabetic drug on their own to enter into active partnerships with endocrinologists to work as a team to put diabetes patients with cardiovascular disease on empagliflozin.

“I hear from more cardiologists who are prescribing empagliflozin, but there still is considerable resistance for prescribing it for several reasons; the primary reason is that they don’t want to be involved in managing diabetes,” David Fitchett, MD, said during an interview at the annual congress of the European Society of Cardiology (ESC). That’s understandable because “most cardiologists do not want to serve as the primary care physician for patients with diabetes, but the least cardiologists can do is prescribe [diabetes] agents with benefits” documented for cardiovascular-disease endpoints, specifically the sodium-glucose cotransporter (SGLT)-2 inhibitor empagliflozin and the glucagon-like peptide (GLP)-1 analogue liraglutide (Victoza), which showed significant benefit for reducing the rate of cardiovascular death, nonfatal MI, or nonfatal stroke in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial (N Engl J Med. 2016;375:311-22). (Reduction in adverse cardiovascular disease outcomes were also shown in patients with type 2 diabetes as a result of treatment with semaglutide, another GLP-1 analogue not yet approved for U.S. marketing).

Endocrinologists generally agree that the recent positive cardiovascular results from large antidiabetic drug trials are repositioning these drugs in the antihyperglycemic algorithm. They see this new glycemic activism by some cardiologists as encouraging but also potentially problematic if physicians not experienced in glycemic control start unilaterally tinkering with a patient’s antidiabetic regimen.

In Dr. Fitchett’s practice, “if a patient with type 2 diabetes has an endocrinologist, then I will send a letter to that physician saying I think the patient should be on one of these drugs,” empagliflozin or liraglutide, he said. “If the patient is being treated by a primary care physician, then I will prescribe empagliflozin myself because most primary care physicians are not willing to prescribe it. I think more and more cardiologists are doing this. The great thing about empagliflozin and liraglutide is that they do not cause hypoglycemia and the adverse effect profiles are relatively good. As long as drug cost is not an issue, then as cardiologists we need to adjust glycemia control with cardiovascular benefit as we did years ago with statin treatment,” explained Dr. Fitchett, a cardiologist at St. Michael’s Hospital in Toronto and a senior collaborator and coauthor on the EMPA-REG study.

When results from the 4S [Scandinavian Simvastatin Survival Study] came out in 1994, proving that long-term statin treatment was both safe and increased survival in patients with coronary heart disease, “cardiologists took over lipid management from endocrinologists,” he recalled. “We now have a safe and simple treatment for glucose lowering that also cuts cardiovascular disease events, so cardiologists have to also be involved, at least to some extent. Their degree of involvement depends on their practice and who provides a patient’s primary diabetes care,” he said.

Cardiologists vary on empagliflozin

Other cardiologists are mixed in their take on personally prescribing antidiabetic drugs to high-risk patients with type 2 diabetes. Greg C. Fonarow, MD, has also aggressively taken to empagliflozin over the past year, especially for his patients with heart failure or at high risk for developing heart failure. The EMPA-REG results showed that empagliflozin’s potent impact on reducing cardiovascular death in patients linked closely with a reduction in heart failure hospitalizations. In his recent experience, endocrinologists as well as other physicians who care for patients with type 2 diabetes “are often reluctant to make any changes [in a patient’s hypoglycemic regimen], and in general they have not gravitated toward the treatments that have been shown to improve cardiovascular outcomes and instead focus solely on a patient’s hemoglobin A_1c,” Dr. Fonarow said in an interview at the recent annual meeting of the Heart Failure Society of America.

He said he prescribes empagliflozin to patients with type 2 diabetes if they are hospitalized for heart failure or as outpatients, and he targets it to patients diagnosed with heart failure – including heart failure with preserved ejection fraction – as well as to patients with other forms of cardiovascular disease, closely following the EMPA-REG enrollment criteria. It’s too early in the experience with empagliflozin to use it preferentially in diabetes patients without cardiovascular disease or patients who in any other way fall outside the enrollment criteria for EMPA-REG, he said.

“I am happy to consult with their endocrinologist, or I tell patients to discuss this treatment with their endocrinologist. If the endocrinologist prescribes empagliflozin, great; if not, I feel an obligation to provide the best care I can to my patients. This is not a hard medication to use. The safety profile is good. Treatment with empagliflozin obviously has renal-function considerations, but that’s true for many drugs. The biggest challenge is what is covered by the patient’s insurance. We often need preauthorization.

“So far I have seen excellent responses in patients for both metabolic control and clinical responses in patients with heart failure. Their symptoms seem to improve,” said Dr. Fonarow, professor of medicine and co-chief of cardiology at the University of Southern California , Los Angeles.

While Dr. Fonarow cautioned that he also would not start empagliflozin in a patient with a HbA_1c below 7%, he would seriously consider swapping out a patient’s drug for empagliflozin if it were a sulfonylurea or a dipeptidyl peptidase-4 inhibitor. He stopped short of suggesting a substitution of empagliflozin for metformin. In Dr. Fonarow’s opinion, the evidence for empagliflozin is also “more robust” than it has been for liraglutide or semaglutide. With what’s now known about the clinical impact of these drugs, he foresees a time when a combination between a SGLT-2 inhibitor, with its effect on heart failure, and a GLP-1 analogue, with its effect on atherosclerotic disease, may seem an ideal initial drug pairing for patients with type 2 diabetes and significant cardiovascular disease risk, with metformin relegated to a second-line role.

Other cardiologists endorsed a more collaborative approach to prescribing empagliflozin and liraglutide.

“Seeing the complexity of the landscape” with more than one drug now showing some sort of clear cardiovascular benefit, “it is critically important for cardiologists to collaborate with diabetologists and endocrinologists, as well as primary care physicians, to give care based on the best available data,” said Robert J. Mentz, MD, a cardiologist and heart failure specialist at Duke University in Durham, N.C., who was an EMPA-REG investigator. “It should be collaborative to personalize the care as best we can, working together to get patients on the right drugs that improve outcomes and not just lower HbA_1c. I see these collaborations happening now, but much more needs to be done.”

Another team-approach advocate is Robert O. Bonow, MD, cardiologist and professor of medicine at Northwestern University in Chicago. “Cardiologists are comfortable prescribing metformin and telling patients about lifestyle, but when it comes to newer antidiabetic drugs, that’s a new field, and a team approach may be best,” he said in an interview. “If possible, a cardiologist should have a friendly partnership with a diabetologist or endocrinologist who is expert in treating diabetes.” Many cardiologists now work in and for hospitals, and easy access to an endocrinologist is probably available, he noted.

Other cardiologists suggested even more restraint. “We’re hopeful that the benefits of empagliflozin will translate info practice, but we are not yet sure whom to treat,” and the EMPA-REG results “need further validation,” said Biykem Bozkurt, MD, professor of medicine at Baylor College of Medicine and chief of cardiology at the VA Medical Center in Houston. “My preference is to use empagliflozin [only] in patients at risk for heart failure. We’ve been burned before” with harm from new treatments for patients with established heart failure, she warned during a talk at the Heart Failure Society of America meeting.

But new analyses of the EMPA-REG data reported by Dr. Fitchett at the ESC congress showed that empagliflozin treatment exerted a similar benefit of reduced cardiovascular death regardless of whether patients had prevalent heart failure at entry into the study, incident heart failure during follow-up, or no heart failure of any sort.

Impact of heart failure in EMPA-REG

Roughly 10% of the 7,020 patients enrolled in EMPA-REG had heart failure at the time they entered the trial. During a median follow-up of just over 3 years, the incidence of new-onset heart failure – tallied as either a new heart failure hospitalization or a clinical episode deemed to be heart failure by an investigator – occurred in 4.6% of patients on empagliflozin and in 6.5% of patients in the placebo arm, a 1.9-percentage-point difference and a 30% relative risk reduction linked with empagliflozin use, Dr. Fitchett reported.

The main EMPA-REG outcome was a composite of cardiovascular death, nonfatal MI, and nonfatal stroke. This positive outcome in favor of empagliflozin treatment was primarily driven by a difference in the rate of cardiovascular death. In the new analysis, the relative reduction in cardiovascular deaths with empagliflozin compared with placebo was 29% among patients with prevalent heart failure at baseline, 35% among those who had an incident heart failure hospitalization during follow-up, 27% among patients with an incident heart failure episode diagnosed by an investigator during follow-up, 33% among the combined group of trial patients with any form of heart failure at trial entry or during the trial (those with prevalent heart failure at baseline plus those with an incident event), and 37% among the large number of patients in the trial who remained free from any indication of heart failure during follow-up.

In short, treatment with empagliflozin “reduced cardiovascular mortality by the same relative amount” regardless of whether patients did or did not have heart failure during the trial,” Dr. Fitchett concluded.

Additional secondary analyses from EMPA-REG reported at the ESC congress in August also documented that the benefit from empagliflozin treatment was roughly the same regardless of the age of patients enrolled in the trial and regardless of patients’ blood level of LDL cholesterol at entry into the study. These findings provide “confidence in the consistency of the effect” by empagliflozin, Dr. Fitchett said.

The endocrinologists’ view

“Any effort that widens the number of appropriate patients who receive antidiabetic medications is welcome,” said Paul S. Jellinger, MD, reflecting the view of all endocrinologists asked about it. They also all agreed with Dr. Jellinger when he added that antidiabetic drugs, particularly the newer drugs, “have important subtleties and warnings that must be clearly understood,” and endocrinologists are the best source for that information.

“Most cardiologists are not thoroughly familiar with the full palette of medications for hyperglycemia. Selection of medication should not be made solely on the basis of results from a cardiovascular outcomes trial,” said Helena W. Rodbard, MD, a clinical endocrinologist in Rockville, Md.

Cardiologists “do not necessarily know the adverse effects and appropriate dosing” for antidiabetic drugs; a better approach would be a cardiologist and endocrinologist working together, said Philip Levy, MD, a clinical endocrinologist with Banner-University Medical Center in Phoenix.

“The EMPA-REG OUTCOMES and LEADER results are very exciting and encouraging. When all other factors are equal, the cardiovascular results could sway the decision about which medication to use. But an endocrinologist is in the best position to balance the many factors when choosing combination therapy and to set a target level for HbA_1c, fasting blood glucose, and postprandial glucose, and to adjust therapy to minimize the risk of hypoglycemia,” Dr. Rodbard said in an interview.

The role for a cardiologist “depends on who is treating the patient,” said Richard Hellman, MD, a clinical endocrinologist in North Kansas City, Mo. If the patient is also seen by an endocrinologist, “I’d like to think the endocrinologist has a plan for glycemic control. I wouldn’t object if the cardiologist sent a note” explaining why adding a drug like empagliflozin to a patient’s regimen might be a good idea. Dr. Hellman said he has received notes like this.

He called empagliflozin a drug with “interesting promise,” especially for patients with incipient heart failure. The extra cardiovascular benefit from the GLP-1 analogues is “less settled,” although the liraglutide and semaglutide trial results are important and mean these drugs need more consideration and study. The EMPA-REG results were more clearly positive, he said.

“We are now much more comfortable using empagliflozin in patients with cardiovascular risk, especially for heart failure,” Dr. Hellman said in an interview. Metformin remains the first-line drug for most patients, but empagliflozin is an appropriate drug to add for selected patients with high cardiovascular risk.

“Metformin is still the initial drug” for most patients with type 2 diabetes, echoed Dr. Levy. Drugs like empagliflozin and liraglutide are usually used in combination with metformin.

“Like many endocrinologists, I have for some time used the oral SGLT-2 inhibitors and GLP-1 analogues in combination with metformin. It made sense before the recent cardiovascular data appeared, and it makes even more sense now,” said Dr. Jellinger, professor of clinical medicine and an endocrinologist at the University of Miami.

“Endocrinologists and diabetologists are aware that cardiologists have been taking a larger role in the care of patients with diabetes,” noted Dr. Rodbard. “I favor cardiologists and endocrinologists working in concert to improve the care of patients with diabetes.”

“Over the next few years, we will need to decide whether to treat patients with type 2 diabetes with an agent with proven benefits,” said Dr. Fitchett. “Until the results from EMPA-REG and the LEADER trial came out, there was no specific glucose-lowering agent that also reduced cardiovascular events. Some cardiologists might ask when they should get involved in managing patients with type 2 diabetes. What I would do for patients with a history of cardiovascular disease who develop new type 2 diabetes is start empagliflozin as their first drug,” Dr. Fitchett said, though he admitted that no evidence yet exists to back that approach.

The EMPA-REG trial was sponsored by Boehringer Ingelheim and by Eli Lilly, the companies that market empagliflozin. The LEADER trial was sponsored in part by Novo Nordisk, the company that markets liraglutide. Dr. Fitchett and Dr. Mentz were both researchers for EMPA-REG. Dr. Fitchett has been a consultant to AstraZeneca, Merck, and Amgen. Dr. Mentz has been an adviser to Boehringer Ingelheim. Dr. Fonarow has been an adviser to Amgen, Janssen, Novartis, and ZS Pharma. Dr. Bozkurt had no disclosures. Dr. Bonow has been a consultant to Gilead. Dr. Jellinger has been a speaker on behalf of Boehringer-Ingelheim, Novo Nordisk, Merck, and Janssen. Dr. Rodbard has been a consultant to or speaker for several drug companies including Boehringer-Ingelheim, Eli Lilly, and Novo Nordisk. Dr. Levy has been a speaker on behalf of Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and AstraZeneca. Dr. Hellman had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Diabetes drugs with cardiovascular benefits broaden cardiology’s turf