BARCELONA, Spain — Results from the cardiovascular-safety trials of the type 2 diabetes drugs, EXAMINE with alogliptin (Nesina, Takeda Pharmaceuticals) and SAVOR-TIMI 53 with saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca), were presented again and discussed in depth by the diabetes community at the European Association for the Study of Diabetes (EASD) 2013 Meeting last week.

The diabetes conference was seen as the perfect forum for further analysis, now that the results of SAVOR and EXAMINE have sunk in and people have had time to slice, dice, and digest the data. The results of the 2 trials were first presented at the European Society of Cardiology (ESC) meeting last month and published online in the New England Journal of Medicine along with an editorial; the papers will appear in the print publication of the journal this week.

Endocrinologists already polled by Medscape Medical News have said the 2 new 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. And while reassuring on many safety issues, the "signal" for heart-failure hospitalization seen with saxagliptin in SAVOR is concerning and requires further investigation, they said.

Thus, it was predictable that there would be a heated discussion about this topic at the EASD meeting, fueled by some post hoc heart-failure data from EXAMINE, with experts there concluding that, for the time being, until more data become available, the drug class should probably not be prescribed to type 2 diabetes patients with existing heart failure.

But that aside, there is much other useful information to be gleaned from these 2 new trials regarding this relatively new class of dipeptidyl peptidase-4 (DPP-4) inhibitors (or "gliptins") for diabetologists, cardiologists, and primary-care/family physicians alike, attendees heard in Barcelona.

Despite the fact there was disappointment that the studies did not demonstrate a cardiovascular benefit of the gliptins, the audience was reminded that the trials were in fact Food and Drug Administration (FDA)–mandated to simply rule out cardiovascular harm in the wake of the rosiglitazone (Avandia, GlaxoSmithKline) furor.

Although there had been some signs that cardiovascular benefits might pan out in these intermediate-term trials (duration 1.5 to 2 years), it is now becoming clear that the best way to reduce the risks for a cardiac or vascular event in type 2 diabetes are the tried and tested methods of reducing blood pressure, prescribing statins, and stopping people from smoking, commentators stressed.

Reducing HbA1c in this patient population should therefore translate into microvascular benefits, but not macrovascular ones, they noted. To this end, saxagliptin was linked to less progression to microalbuminuria in SAVOR, an end point that has not yet been analyzed in EXAMINE.

Overall, doctors said the findings were somewhat reassuring outside of the worry about heart failure. The DPP-4 inhibitors showed no increased risk for pancreatitis or pancreatic cancer — another issue that has caused concern; both drugs reduced progression to use of insulin; and they have a neutral effect on weight gain, with little in the way of hypoglycemia (with the exception of saxagliptin combined with sulfonylureas).

That said, there is no getting away from the fact that the drugs only provide a "modest" reduction in blood sugar, the experts said, although there is some indication that the antihyperglycemic effects of gliptins may be stronger in certain patient groups, such as those in whom HbA1c is difficult to control.

Modest Glycemic Effects of Gliptins

The relatively small HbA1c-lowering effect of saxagliptin and alogliptin in SAVOR and EXAMINE, averaging only 0.3 to 0.4 percentage points, was a topic of much discussion at the EASD meeting.

In a press conference, the endocrinologist study investigators and other commentators were asked how they would justify the use of gliptins with such weak HbA1c-lowering effects to payers, who might question their added value over older antihyperglycemic agents.

They stressed first that it is important to understand that both SAVOR and EXAMINE allowed additional antihyperglycemic therapy at the discretion of the treating physician, and that this was employed more frequently in the "placebo" or control patients than in the active-treatment groups.

Prof. Naveed Sattar, from the University of Glasgow, Scotland, who was not involved in either trial but was asked by the EASD to provide commentary, said, "I don't think the message was clear…that the patients in the placebo arm could titrate and were encouraged to titrate and that message is important."

Press conference moderator Dr. Cornelius J. Tack, MD, PhD, of Radboud University Nijmegen, the Netherlands, agreed, saying the placebo arms were not really placebo, as patients "were treated with additional drugs for diabetes."

Nevertheless, "This is not a revolution; these drugs lower HbA1c modestly but seem to do it relatively safely except for the heart-failure signal, which we need to investigate a bit more," Dr. Sattar surmised.

Ultimately, they do "what it says on the tin, they lower sugar," he said, adding, "I'm pleased to see weight neutrality, and hypoglycemia rates are relatively low, and I'm not too concerned about them." Nor is there any real signal for pancreatitis or pancreatic cancer, he added, which he called "reassuring."

He noted that he would be keenly awaiting patient quality-of-life data from EXAMINE and SAVOR to see how things such as lack of weight gain and less hypoglycemia affected these outcomes.

Dr. Simon Heller

EXAMINE investigator Simon Heller, MD, from the University of Sheffield, United Kingdom, concurred: "You have to decide whether a 0.4% difference in HbA1c is worthwhile or not. It's modest but it's certainly relevant, and it comes without classical side effects [that put people off] — weight gain and hypoglycemia. These are really important issues."

However, he added, "I accept that prescribing advisors who aren't diabetologists might be…resistant…but you have to ask, 'What you would want to be on? What would you want a family member to receive?' These are useful drugs. They are incrementally important, and they will have a place in therapy."

Dr. Sattar stressed, however, that a related class of drugs may pan out to be better. "There is more hope with the [injectable glucagon-like peptide 1] GLP-1 agonists, they lower sugar more" and induce weight loss, he observed.

Glycemic Control Will Lower Microvascular, Not CV, Events

Some studies have shown a cardiovascular benefit for glucose-lowering, including the landmark United Kingdom Prospective Diabetes Study (UKPDS), which looked at newly diagnosed type 2 patients who did not have significant cardiovascular disease at baseline and followed them for far longer than either EXAMINE or SAVOR.

The 10-year results of UKPDS showed a reduction in risk for myocardial infarction between the intensive and conventional glycemic control groups (using metformin and sulfonylureas), but the difference in HbA1c levels between the treatment groups in these trials was greater than that seen in EXAMINE and SAVOR, at 1 percentage point.

However, the patient populations in SAVOR and EXAMINE were different, doctors at EASD stressed; those in SAVOR had an average diabetes duration of 10 years and either a history of cardiovascular disease or were at high risk for it. And EXAMINE tested the sickest population yet in such a trial — type 2 diabetes patients who had had a myocardial infarction or unstable angina within the past 3 months.

Co–primary investigator of EXAMINE, cardiologist Dr.William White, from the Pat and Jim Calhoun Cardiology Center at the University of Connecticut Health Center, Farmington, pointed out that other recent studies, such as ACCORD and ADVANCE, "have not necessarily shown a favorable impact of intensive glycemic control on macrovascular events" in type 2 diabetes patients at high risk for cardiovascular disease.

And Dr. Sattar said the expectation that either of these gliptins was going to show vascular benefit in such study populations was totally unrealistic — "a very modest reduction in glucose is not going to change CV risk," he observed.

"What it tells us is that while we aim for less than 7% [HbA1c] in patients with heart disease, I don't think we should go there, I think we should relax our targets," he urged.

"We should reaffirm the point that if you've got diabetes and heart disease, don't go for strict levels like less than 7%, be happy with levels between 7% and 8%. It's about individualizing therapy, relaxing HbA1c targets. To get too low can potentially cause harm."

Dr. Heller agreed. "I think it's a really important message that it's about individualizing therapy, discussing it with patients; they also have a choice to make."

Instead, "If you want to reduce cardiovascular events in patients with diabetes, the best way is to…[get] the cholesterol to target, get the BP to target, and stop them smoking," Dr. Sattar urged.

"These drugs [gliptins] do very little else beyond reducing glucose. They don't change BP and they don't change lipids, they just change sugar. That might not be a bad thing necessarily, because we need things that lower sugar for microvascular benefit. But cardiovascular disease mortality has come down over the past 2 decades because we're picking up disease earlier, and we are treating aggressively with statins at diagnosis, we're treating [high] blood pressure, and we're cutting smoking."

Dr.Heller concurred: "When treating macrovascular disease, it is easier to give a statin, and more effective."

Is There a Role for Gliptins in Harder-to-Treat Patients?

Dr. Itamar Raz

Meanwhile, endocrinologist Itamar Raz, MD, co–primary investigator of SAVOR, from Hadassah University Hospital, Jerusalem, Israel, noted that the antihyperglycemic effects of gliptins appear to be stronger in certain patient groups, such as those in whom HbA1c is difficult to control.

"For example, in SAVOR, HbA1c lowering was dependent on starting levels, with those with higher levels, eg, greater than 8.5%, generally seeing a bigger [HbA1c-lowering] effect [of saxagliptin] without hypoglycemia," he noted.

"And if you look at ACCORD, what it showed was that the main problem was…mortality in patients with high HbA1c and hypoglycemia but [in whom] you could not reduce HbA1c by more than 0.5%. We show here that we actually have a drug that, if you add it to insulin, you can reduce HbA 1c by 0.7 or 0.8% without increasing hypoglycemia.

"So this might be a very good answer for those patients that you cannot manage in spite of the fact that you give them all the therapies you can, but for some reason you cannot bring them to control," Dr.Raz observed.

For this reason, the gliptins could be a useful addition to the armamentarium of nonendocrinologists, he suggested. "When your patient has HbA1c greater than 8% and you cannot reduce it, or when you control him he develops hypoglycemia, you send him to the specialist. [Gliptins] can solve many patient problems, and you won't need to send patients to specialists, so I see many good signs here for family physicians and for cardiologists," he concluded.

Dr. Sattar has reported no relevant financial relationships. Dr. White and Dr.Heller are investigators in EXAMINE. Dr. Tack reports having participated on advisory boards of AstraZeneca/Bristol-Myers Squibb, Johnson & Johnson, MSD, and Takeda and having received research grants from and lectured for Novo Nordisk. Dr. Raz reports being on the advisory board for Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, MSD, and Eli Lilly; consulting for Bristol-Myers Squibb/AstraZeneca, Johnson & Johnson, and Eli Lilly; and being on the speakers' bureau for Eli Lilly, Novo Nordisk, AstraZeneca, Roche, and Johnson & Johnson.

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