SAN DIEGO — The recent results of large outcomes trials showing cardiovascular benefit with type 2 diabetes drugs must be properly incorporated into treatment guidelines, such as those issued by the American Diabetes Association and other national guidelines all over the world, implores one expert.
"This is a very big deal. I think it's time now to apply the evidence and incorporate it into the guidelines for cardiologists, and endocrinologists and professional societies have to take the lead," cardiologist Steve Nissen, MD, of the Cleveland Clinic, Ohio, told a packed auditorium here at the American Diabetes Association (ADA) 2017 Scientific Sessions yesterday.
And, he emphasized, for this to happen, "we need close collaboration between cardiologists and diabeto-endocrinologists. We take care of the same patients, so coming together to determine how best to treat these patients is incredibly important."
The past few years have illustrated "a triumph of evidence-based medicine," he stressed, "and now it's very important for changes in the guidelines to reflect contemporary knowledge, but we will still have a way to go with that. We've got to overcome clinical inertia," he stressed.
Referring specifically to landmark results with the sodium-glucose cotransporter-2 (SGLT-2) empagliflozin (Jardiance, Boehringer Ingelheim) in EMPA-REG OUTCOME and the glucagonlike peptide-1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) in LEADER — which both showed impressive reductions in cardiovascular end points in patients with type 2 diabetes at high risk of cardiovascular events, he said that the most important outcome seen in both of these trials was the reduction in cardiovascular death.
"The one thing we want to do for our patients, whether they have heart disease or diabetes [or both], is to keep them alive," Dr Nissen asserted.
But if the results of these trials are not rapidly translated into changes in guidelines, there is a danger that the same thing that happened with statins will happen in diabetes, he said, noting, "It took years for the adoption of the pivotal trial results with statins, it was just too slow."
And he stressed that, since statins, "it's been hard to come up with therapies that reduce cardiovascular death. And now we have the most robust results with diabetes drugs on the end point that is toughest to achieve — death."
CV-Outcomes Trials Show Not All Drugs in Class Are the Same
Dr Nissen explained how, prior to the current crop of CV-outcomes trials, there had historically been little progress in preventing diabetes patients from dying from cardiovascular disease — the biggest killer in this condition.
While nondiabetic patients saw tumbling death rates from CVD in past decades, the rate had stagnated among diabetes patients and even increased in women with diabetes, he explained.
"It's taken some shock waves to wake the medical community from a 50-year slump — the realization that merely lowering blood glucose is not a guarantee of improving health outcomes [in diabetes]," he added.
He then went on to outline the history behind the cardiovascular-outcomes trials for diabetes drugs, which were mandated by the FDA in 2008 as a result of the rosiglitazone debacle — in which Dr Nissen played a key role.
"There was a lot of pushback, a lot of whining, when we first suggested these CV-outcomes trials," he noted. "But we've gotten some really big bonuses from doing them. These drugs are not all the same. and before we label something as a 'class effect,' we have to look carefully. We only find out what they actually do when we study them."
And while he acknowledged that the aim of the cardiovascular-outcomes trials was initially to demonstrate lack of CV harm with diabetes drugs, there was some anticipation of positive effects, he said.
For example, with the dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs, when these were introduced, "people said it's going to be a revolution. Every single [prior analysis] suggested DPP-4 inhibitors would lower CV outcomes," he told the audience.The effect was on glucose and neutral effects on CVD.
But this didn't turn out to be the case.
In fact, the results of the first CV-outcomes trials with the DPP-4 inhibitors saxagliptin (Onglyza, AstraZeneca) and alogliptin (Nesina, Takeda) — SAVOR-TIMI 53 and EXAMINE — "actually showed a significantly increased risk for hospitalization for heart failure with the respective drugs, a completely unexpected finding," he noted.
"We would never have found out this problem had we not done the trials," he asserted.
And a third outcomes trial with the DPP-4 inhibitor sitagliptin (Januvia, Merck), TECOS, while not showing any increase in heart-failure hospitalization, did not improve CV outcomes — it was neutral — and so "that was a third disappointment for DPP-4 inhibitors."
But patience paid off in the end, said Dr Nissen.
"We always had an ambitious agenda and we [eventually] got some really big bonuses. EMPA-REG is, in my opinion, a breakthrough study."
However, as people wait with bated breath here for the results of the second CV-outcomes trial with a SGLT2 inhibitor, CANVAS with canagliflozin, he reiterated that it's always important to wait for the results from each study.
For example, whereby LEADER with liraglutide showed cardiovascular benefit (as did SUSTAIN-6 with the investigational GLP-1 agonist semaglutide), another trial, ELIXA, with the GLP-1 agonist lixisenatide, was neutral.
"When you do large outcomes trials, you get surprises. The most important message I can give you [for each agent] is wait for the data."
American Diabetes Association 2017 Scientific Sessions. June 11, 2017; San Diego, California. Presentation 1-AC-SY13
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