New Diabetes Trials Reassure but Don't Guide Gliptin Use

Miriam E. Tucker

September 06, 2013

New results from two cardiovascular safety studies of the dipeptidyl peptidase-4 (DPP-4) inhibitors saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) and alogliptin ( Nesina, Takeda Pharmaceuticals) provide some reassurance about the use of these agents, known as gliptins, in treating patients with type 2 diabetes but also raise questions about the overall benefit of the drug class, say diabetes experts.

The new trials were conducted to fulfill the 2008 US Food and Drug Administration (FDA) requirement for cardiovascular safety studies in all diabetes drugs — prompted at the time by widely publicized concerns about rosiglitazone (Avandia, GlaxoSmithKline) .

However, the 2 studies do nothing to fill the most glaring knowledge gap in the management of type 2 diabetes that exists today: how best to determine, for a given patient, the next drug to add after metformin, say the doctors approached by Medscape Medical News this week.

Thankfully a new trial, Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), is under way that should help answer this question, although it will be some time before the results of this are known.

In the meantime, they disagree on whether these FDA-mandated studies are worth it, with one expert arguing that the money could be better spent.

Safety Studies Provide No Clues About Benefits, Next Steps

The 2 new trials, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus — TIMI 53 (SAVOR-TIMI 53) and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) were both reported September 2 at the European Society of Cardiology (ESC) 2013 Congress and were simultaneously published online in the New England Journal of Medicine (here and here). These are some of the first results to report from these FDA-mandated cardiovascular safety studies for diabetes drugs, but a whole host of similar trials with different agents are set to report over the next few years.

In EXAMINE, which enrolled 5380 patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with alogliptin as compared with placebo in a follow-up out to 40 months.

In SAVOR-TIMI 53, which enrolled 16,492 high-risk patients, rates of ischemic events were not increased at a median follow-up of 2.1 years, but hospitalization for heart failure was significantly higher with saxagliptin (3.5% vs 2.8%; hazard ratio, 1.27; P = .007), as were hypoglycemic events (15.3% vs 13.4%; P < .001)

Both gliptins reduced hemoglobin A1c by about 0.3% points (compared with placebo and added to metformin and a variety of other nonincretin glucose-lowering agents), yet neither drug demonstrated a cardiovascular benefit, despite the suggestion from previous meta-analyses that there might be one (Postgrad Med. 2010;122:16-27).

Asked for his thoughts, David M. Nathan, MD, from the Diabetes Center at Massachusetts General Hospital and professor of medicine at Harvard Medical School, Boston, stressed the original intent of these trials: "We need to keep in mind that these are safety studies. These are not designed to look at benefit of lower hemoglobin A1c or even the specific benefits of the drug.

"They're designed for the most part to look at the noninferiority of adding these drugs, compared with adding other diabetes drugs, on the risk for heart disease," Dr. Nathan told Medscape Medical News.

George Grunberger, MD, from Wayne State University School of Medicine, Detroit, Michigan, and Oakland University William Beaumont Medical School, Rochester, Michigan, and vice-president of the American Association of Clinical Endocrinologists (AACE), agrees but says the findings still leave diabetologists mostly in the dark about choice of therapy.

"Doctors can take some solace from the fact that it doesn't seem that these drugs hurt. But they provide absolutely zero guidance about what to do… Physicians use drugs for diabetes to lower A1c to below 6.5% or 7%. These drugs didn't really accomplish that," he told Medscape Medical News,

Doctors can take some solace from the fact that it doesn't seem that these drugs hurt. But they provide absolutely zero guidance about what to do. Dr. George Grunberger

Elizabeth Seaquist, MD, professor of medicine at the University of Minnesota, Minneapolis, and holder of the Pennock Family Chair in Diabetes Research, said: "I think there's a concern by many practitioners about new medications and wanting to be sure they're very safe before they give them to their patients. This helps with that," she said.

But, added Dr. Seaquist, who is also president-elect, medicine and science, of the American Diabetes Association, "The heart-failure signal is certainly something to pay attention to. We're going to have to keep an eye on that. The challenge is these are high-risk patients. We expect some heart failure, but of course we want to be sure that it's not something to do with the drug."

Both Dr. Grunberger and Dr. Seaquist stressed they were providing their own opinions and not speaking on behalf of their respective organizations.

What's the Risk/Benefit for the DPP-4 Inhibitors?

Dr. Nathan told Medscape Medical News that there was no reason to think the DPP-4 inhibitors would reduce heart disease if one assumes glucose-lowering to be the mechanism for such a proposed benefit.

"These are not heart-disease drugs. These are diabetes drugs. That needs to be kept clearly in mind. The lowering of A1c with this particular class of drugs is pretty weak… We lower A1c to prevent eye disease, kidney disease, and nerve disease, not heart disease."

He pointed out that the studies that have shown a cardiovascular benefit for glucose-lowering — the United Kingdom Prospective Diabetes Study (UKPDS) being the landmark among them — looked at newly diagnosed type 2 patients who did not have significant cardiovascular disease at baseline and followed them for far longer than the studies now being conducted to fulfill FDA requirements.

Moreover, the UKPDS achieved a 1%-point difference in A1c levels between the intensive and conventional control groups using metformin and sulfonylureas, compared with just a 0.3% difference with the DPP-4 inhibitors.

The new CV safety studies need to enroll high-risk patients to ensure that enough events occur within the study period, he notes.

Thus, the 2 new DPP4 inhibitor studies are "not powerful enough and not long enough and picked the highest-risk group. Once heart disease is this far advanced, whether or not you can do anything about it by lowering glucose is a real question."

I don't see a big role for [gliptins]. They're weak and expensive. Dr. David M. Nathan

Dr. Nathan said he doesn't use DPP-4 inhibitors. "My personal opinion is, I don't see a big role for them. They're weak and expensive. I don't quite get it. I take the cost of these drugs seriously into account. Even though the patients may not be seeing the cost, as a community and a society we're all seeing the costs of some of these drugs."

And, he added that the heart-failure signal with saxagliptin is "kind of interesting, because this is not a class of drug that was thought to contribute to heart failure. Why this is happening is not clear at all. It's a signal that is of concern."

Also speaking to the heart-failure finding, Dr. Grunberger told Medscape Medical News, "It's a potential signal. I don't think it's a reason not to prescribe the drug, but hopefully there will be an observational follow-up. The absolute risk appears to be very small, and patients were on a variety of other drugs. Just like any signal, it needs to be pursued in a controlled fashion."

In a statement issued to Medscape Medical News, Bristol-Myers Squibb spokesperson Ken Dominski said: "The finding in SAVOR was specific to hospitalization for heart failure, not heart failure alone… The imbalance in hospitalization for heart failure requires further analysis before any recommendations can be made to investigators, prescribers or patients, and health authorities. We are doing additional analyses of SAVOR with the Thrombolysis in Myocardial Infarction [TIMI] study group to more completely understand this observation. We anticipate further information will be presented by TIMI at upcoming scientific meetings later this year or early next year."

All 3 diabetes experts told Medscape Medical News that they were less concerned about the hypoglycemia finding in SAVOR-TIMI 53, since it would be expected that any glucose-lowering drug added to insulin or sulfonylureas might have that effect.

Should the FDA Rethink Its CV Safety Study Requirement?

Dr. Grunberger believes that the 2 new studies call into question the wisdom of the FDA cardiovascular safety study requirement, given that there were no CV safety signals in premarket testing of the DPP-4 inhibitors, and even the concerns about rosiglitazone that prompted the rule have now been mostly alleviated.

"I believe the FDA requirement is misguided and nonsensical. It's a total waste of time and money. Not because it's bad to prove safety, but I look at the opportunity cost. The hundreds of millions of dollars poured into these studies could have been spent directly to help my patients who can't afford the drugs" or for drug discovery, added Dr. Grunberger, who is also chair of the Grunberger Diabetes Institute, Bloomfield Hills, Michigan.

I believe the FDA requirement is misguided and nonsensical. Dr. George Grunberger

But Dr. Seaquist sees the FDA requirement a bit differently. "If a signal is found that's frightening, they've made the right decision. If no signal is found, then people wonder if it's worth it. People with diabetes are at great risk for CV events. I think we have to be very cautious that we're not putting them at greater risk with medications."

She acknowledged that the studies are "very expensive, take a long time, and keep drugs off the market" for lengthy periods that could otherwise be available for people to use. Ultimately, though, "safety is really critical, and that's what the FDA is charged to watch for. At this point, I wouldn't change [the CV study requirement], but I think it's something that people need to talk about."

Dr. Seaquist added that another notable finding from these 2 studies is the lack of an increased risk for pancreatitis with either drug. While the concern there has been more with the glucagonlike peptide–1 receptor (GLP-1) agonists, there had also been discussion about such a risk with the DPP-4 inhibitors. "Some people lump them together," she noted.

So, Which Drug After Metformin?

One thing all 3 experts agree on is that these 2 new studies do very little to inform physicians about which glucose-lowering drug should be used next in patients who don't achieve target A1c levels with metformin alone. Nor do any other studies thus far, for that matter.

What's embarrassing is here we have one of the most common diseases in the world, yet we don't have a clue. Dr. David M. Nathan

"What's embarrassing is here we have one of the most common diseases in the world, yet we don't have a clue… There's no financial incentive for the companies to do this kind of study," Dr. Nathan told Medscape Medical News.

Indeed, Dr. Grunberger noted, the AACE Comprehensive Diabetes Management Algorithm 2013, for which he served on the writing committee, was purposely not called a "guideline" because there are no randomized, head-to-head studies on which to base the medication recommendations. Rather, it was almost entirely based on expert opinion given the data that have been published for individual drugs.

In the algorithm, the DPP-4 inhibitors are listed as third-choice options after metformin and GLP-1 receptor agonists for mono- and dual therapy and farther down the list in triple-therapy scenarios.

Dr. Grunberger points out that the new SAVOR-TIMI 53 and EXAMINE data don't really inform the AACE algorithm because the patient populations had long-standing diabetes with complications, and were already on multiple antidiabetic agents, whereas the algorithm was intended to guide management of newly diagnosed patients.

But there is a study just getting off the ground that aims to answer the next-drug question: GRADE, funded by the National Institutes of Health. This will be enrolling 5000 metformin-treated patients with type 2 diabetes of less than 5 years' duration, who will be randomized to receive 1 of 4 major classes of glucose-lowering drugs: sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, or insulin.

We're trying to recruit new type 2s on metformin less than 5 years…send them to us! Dr. Elizabeth Seaquist

The main study outcome will be time to primary failure, defined as an HbA1c of 7% or greater over an anticipated mean observation period of 4.8 years (range, 4 to 7 years).

The four drugs will also be compared with respect to selected microvascular complications, cardiovascular disease risk factors, adverse effects, tolerability, quality of life, and cost-effectiveness.

"This is meant to be a definitive study. Hopefully, there won't be a million new drugs on the market by the time we finish, but we don't see the drugs we're studying as going out of phase," Dr. Nathan said.

Dr. Seaquist, who is the GRADE principal investigator at the University of Minnesota, had a favor to ask of Medscape readers: "We're trying to recruit new type 2s on metformin less than 5 years…send them to us!"

Dr. Nathan has no disclosures. Dr. Grunberger receives research support from Amylin, Novo-Nordisk, and Eli Lilly and is on the speakers' bureau for Novo-Nordisk, Sanofi, Lilly, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Merck, and Takeda. Dr. Seaquist has done consulting for Sanofi, Merck, and AMG Medical, a small company that is developing a glucagon product, and has a research grant from Lilly.

New England Journal of Medicine. Published online September 2, 2013. EXAMINE article SAVOR-TIMI 53 article


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