Saxagliptin lowered HbA1c, improved microvascular disease

Issue: October 2013

Data from the SAVOR-TIMI 53 trial showed that saxagliptin lowered HbA1c, improved microvascular disease and did not affect the pancreas, according to experts who presented safety data relevant to endocrinologists from the trial at the ongoing EASD 2013 meeting.

Perspective from Naveed Sattar, MBChB, MRCP

“SAVOR TIMI 53 confirms the overall safety profile of saxagliptin in patients with long disease duration, broad HbA1c levels between 6% and 12%, various antidiabetic medications except incretin therapy, concomitant cardiovascular disease and other medical comorbidities,” Itamar Raz, MD, head of the diabetes unit, department of medicine, Hadassah University Medical Center, Jerusalem, said in a press conference. “The most interesting is that, all together, you can say that this is a safe drug.”

The double blind study that looked at 16,492 patients randomly assigned to saxagliptin (Onglyza, Bristol-Myers Squibb) 5 mg per day or placebo was designed with the primary endpoints of CV death, myocardial infarction and ischemic stroke, but offers additional information for endocrinologists treating patients with diabetes. After 1,040 events occurred, the trial ended. Median duration was 2.1 years.

“In spite of the fact that the principal investigators were supposed to bring patients to target HbA1c in both arms, you can see that when we added saxagliptin, we always have a better blood glucose control, which gets better and better as HbA1c gets higher and higher,” Raz said.

Mean HbA1C was lower in saxagliptin vs. placebo (7.6% vs. 7.9% at 1 year, and 7.5% vs. 7.8% at 2 years). Similarly, attainment of HbA1c <7% was higher with saxagliptin vs. placebo (38.4% vs. 27.5% of patients at 1 year, and 40% vs. 30% at 2 years).

Deepak L. Bhatt

“It’s important to realize that these changes in glycemic control were in the context of a 23% reduction in the intensification of anti-hyperglycemic medications with saxagliptin compared to control, [and] … a 30% reduction in the initiation of insulin therapy for more than 3 months with saxagliptin compared to control,” Deepak L. Bhatt, MD, MPH, professor of medicine at Harvard Medical School said in his presentation.

Besides glucose control, Raz said 13% of patients with microalbuminuria (30-300 mg/g) progressed to microalbuminuria (>300 mg/g) when treated with saxagliptin as compared with 16% of placebo-treated patients. Improvement from microalbuminuria to normoalbuminuria (<30 mg/g) was seen in 11% of saxagliptin-treated patients and 9% of placebo-treated patients.

“We are not even sure that the effect that we got was related to blood glucose control because this was not so very impressive,” Raz said. “So, it seems that this drug, by different mechanisms, can have a protective effect on the kidney.”

Raz said more patients treated with saxagliptin were classified as having any level of hypoglycemia (15.3% vs. 13.4% in the placebo group, P=.001), most of these being minor. Saxagliptin significantly increased the risk for major hypoglycemia in patients treated with sulfonylurea and a baseline HbA1c <7%, he said.

Lastly, Raz said saxagliptin showed no signs of pancreatic risk from pancreatitis or pancreatic cancer. Data showed five cases of pancreatic cancer in the saxagliptin group and 12 cases in the placebo group.

Of 63 reported cases of pancreatitis, an external committee confirmed 24 cases in saxagliptin-treated patients and 21 in placebo-treated patients (P=.77); 17 vs. nine were acute (P=.17); and two vs. six (P=.18) were chronic. Raz said of these pancreatitis cases, 61.5% of patients in the saxagliptin group and 48% of patients in the placebo group continued treatment.

“In 2-year follow-up, we don’t see any signs that these drugs will cause or will accelerate cancer,” he said. “Any way we look at it, it doesn’t seem that there is any increase in risk from pancreatitis.”

For more information:

Bhatt D.

Raz I. Both presented at: 49th Annual Meeting of the European Association for the Study of Diabetes; Sept. 24-27, 2013; Barcelona, Spain.

Disclosure: The study was funded by AstraZeneca and Bristol-Myers Squibb. Raz reports serving on an advisory board, consulting and is on the speakers’ bureau for AstraZeneca/Bristol-Myers Squibb. Bhatt reports relationships with various pharmaceutical and device companies.

Perspective

Naveed Sattar, MBChB, MRCP

We’re in a brave new world with diabetes. The FDA 2008 guidelines have provided us a new approach to diabetes drugs. You’ve seen in the recent history in trials that we now know that drugs that lower sugar will not necessarily mean that they will lower cardiovascular disease or mortality. And, actually, they may increase these things, particularly mortality.

As a result of that, the FDA has mandated every new diabetes drug requires a clinical endpoint trial. That has caused a lot of heartache, money, effort, but actually has led us to realize truths sooner than we would have otherwise.

In some ways, the designs of these two studies were forced by the FDA. They were forced by the need for expediency and they were forced, in a way, to manage the costs because you need huge numbers nowadays to do these trials, in part, because CV mortality rates have come down substantially in patients with diabetes already. To get the right power, you need big studies.

So both studies were designed with a hope for superiority but in a way they could pull out if there was no evidence that was going to happen earlier … and that’s what happened in both cases. …

The no vascular benefit, the noninferiority, is going to disappoint a lot of physicians out there. Why? It’s because there was meta-analysis of all these Phase 3, 2b studies suggesting that these drugs are going to prevent CV disease. So lots of people in the audience were expecting these drugs to prevent vascular disease in a short time and that didn’t happen.

We’re faced with this falling reality that in order to reduce CV events in a modest, medium or long-term in patients with diabetes one has to treat them with statins, get the cholesterol to target, the BP to target and stop smoking. And that reducing glucose … in a small, modest amount … is not going to change CV risk reduction.

These drugs do very little else beyond reducing glucose. … They don’t change blood pressure. They don’t change lipids. They just change sugar. That might not be a bad thing, necessarily because we need things to lower sugar, but CVD mortality has come down in recent decades because we’re picking up the disease earlier. We’re treating aggressively with statins at diagnosis; we’re treating BP; and we’re cutting smoking. Those are the major reasons. And glucose reduction is probably at a much more modest, long-term effect but it won’t be picked up in 1.5 to 2 year trials. …

These trials have allowed us to get closer to truth quicker. They provide robust evidence on speculation, whether it was good or bad. … The trials have gotten us there quicker than we would have. … They’ve also picked up things that we wouldn’t have picked up unless we do the big trials – potentially a HF signal, which I think has to be taken seriously.

Naveed Sattar, MBChB, MRCP

Institute of Cardiovascular and Medical Sciences

BHF Glasgow Cardiovascular Research Centre

Disclosures: Endocrine Today could not confirm Sattar’s financial relationships at the time of press