CV Comparisons Between New and Older Diabetes Drugs Needed

Miriam E Tucker

March 13, 2017

The lack of cardiovascular-end-point data for widely used older generic type 2 diabetes drugs presents a conundrum that the US Food and Drug Administration (FDA) should address, argues endocrinologist and health policy expert James Flory, MD, of Weill Cornell Medical College, New York.

"As data on metformin remain limited and data on newer drugs accumulate, a dilemma has emerged. There is no longer more evidence for the cardiovascular benefit of metformin than there is for some of the newer second-line drugs," Dr Flory writes in a "Viewpoint" column published in the March issue of JAMA Internal Medicine.

Since 2008, the US Food and Drug Administration has required randomized clinical trials assessing cardiovascular safety for all new type 2 diabetes drugs entering the US market.

But the requirement was never applied to drugs already available and in many cases generic, including metformin, the recommended first-line treatment for type 2 diabetes, and sulfonylureas — still widely used as second-line agents — as well as thiazolidinediones (TZDs).

With recent trials showing cardiovascular benefit for some newer drugs, such as EMPA-REG OUTCOME with the sodium-glucose cotransporter 2 (SGLT-2) inhibitor empagliflozin (Jardiance, Lilly/Boehringer Ingelheim) and LEADER, with the glucagonlike peptide 1 (GLP-1) receptor agonist liraglutide (Victoza, Novo Nordisk) in patients at high risk of cardiovascular disease (CVD), Dr Flory suggests that efforts should be made to gather similar outcomes data for metformin and sulfonylureas.

One way to address this quandary would be for the newer drugs to be compared directly with the older drugs (active-controlled trial design), rather than being tested against a placebo arm, he says.

However, in an interview with Medscape Medical News, Dr Flory acknowledged that stating the problem is easier than finding a solution. "Giving a precise prescription for action isn't easy to do. There isn't a good premarket mechanism to produce the kind of research we really need to compare the effectiveness of drugs. Payers don't ask for it, and patients aren't in a position to ask for it."

The US National Institutes of Health (NIH) might be able to conduct such a trial, but its resources are limited. What's left, Dr Flory says, is the financial incentive the FDA still exerts for manufacturers to conduct trials to obtain new indications for their drugs, such as the one empagliflozin recently received for reducing mortality due to cardiovascular disease in patients with type 2 diabetes and existing cardiovascular disease, on the basis of the EMPA-REG data.

Designing Trials With Active Control Arms Will Be Tricky

Thus, he says, the FDA could revise its guidance to recommend that cardiovascular-safety studies include an active-control arm — currently placebo is listed as equally acceptable.

The agency could go on to indicate that it would be unlikely to approve new cardiovascular-benefit indications for novel diabetes drugs unless they were first compared with both metformin and placebo in cardiovascular-outcomes trials.

"It makes sense to see if there's anything FDA can do to realign the incentives a little bit," he explained.

In the cardiovascular-outcomes studies to date, the active (new) drug is normally given on top of standard therapy for type 2 diabetes (but excluding any agents in the same class as the one being tested), and then this arm is compared with placebo plus standard therapy.

"Standard" therapy for diabetes will almost always include metformin because it is already recommended and accepted as first-line therapy for type 2 diabetes, and it may also include sulfonylureas. This therefore creates difficulty in designing a head-to-head trial comparing it with another agent.

"I think you have to think creatively how to do that. One option might be to compare a GLP-1 receptor agonist with aggressive uptitration of metformin," for example, he suggested.

Another possibility might be to conduct a trial in patients who are newly diagnosed with type 2 diabetes at the time they have a cardiovascular event. In that scenario, he said, it would be "reasonable" to randomize to either metformin or a GLP-1 receptor agonist initially as first-line.

"There's arguably now equipoise. There hasn't been a study of metformin for cardiovascular protection right after a CV event.…I personally would want a whole committee to make this decision, but I think that would be a reasonable and ethical study," Dr Flory said.

Still a Role for Sulfonylureas

As for sulfonylureas, they're currently still considered acceptable and widely used as second-line agents despite their known risks for hypoglycemia and weight gain and the suggestion of cardiovascular harm.

Nonetheless, Dr Flory believes that sulfonylureas still have a role and therefore head-to-head trials including sulfonylureas may be justified, particularly for individuals with high HbA1c levels who are at low risk for hypoglycemia.

Indeed, there is currently an ongoing cardiovascular-outcomes trial comparing the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (Tradjenta, Lilly/BI) against the sulfonylurea glimepiride, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA), due to be completed in February 2019.

Moreover, he noted, "in the real world there's tremendous pressure from formularies to keep patients using sulfonylureas.…[Low] cost is a legitimate reason to use sulfonylureas if you have to."  

Tolerability and Cost of Metformin Keep It First

Dr Flory didn't mention cost in his commentary, because the FDA officially doesn't use it in its deliberations, but he told Medscape Medical News that the low cost of metformin and its relative tolerability should keep it as first-line until proven otherwise.

"I think metformin is great.…If a patient doesn't fit very neatly into one of the high-risk populations studied in the newest trials, I would still work to get metformin on board first, especially in patients at generally low cardiovascular risk.

"Metformin just has so many advantages in terms of tolerability and cost, I don't think the evidence yet warrants pushing to one of the new agents first."

And he stressed the fact that cost can't be overlooked, especially now with the uncertainty in healthcare.

"There's so much more cost-sharing now for patients. If you put them on a new agent, they're going to try hard to take it, and it could potentially cost them their rent money. You have to have a really good reason to do that."

On December 12, 2016, after the Viewpoint was accepted for publication, Dr Flory became a consultant to Sidley Austin and Pepper Hamilton, law firms retained by Boehringer Ingelheim and Eli Lilly to advise them about litigation involving empagliflozin.

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JAMA Intern Med. 2017;177:301-302. Editorial


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