No Cancer Signal with Saxagliptin at 2 Years in SAVOR-TIMI 53

Marlene Busko

June 06, 2015

BOSTON — Use of saxagliptin (Onglyza, AstraZeneca), a dipeptidyl peptidase-4 (DPP-4) inhibitor for type 2 diabetes, was not associated with an increase in cancer incidence or cancer-related death during 2 years of follow-up in patients with a high risk of cardiovascular disease who participated in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-TIMI 53 trial.

In the more than 16,000 patients who were randomized to saxagliptin or to placebo, there were 688 cancers during the follow-up period, equally distributed in both patient groups, in this prespecified secondary analysis.

"But, of course, the findings are limited by the relatively small number of individual cancer types and the short duration of follow-up," Dr Lawrence A Leiter (University of Toronto, Ontario) acknowledged, presenting these findings at the American Diabetes Association (ADA) 2015 Scientific Sessions.

In response to a question from a member of the audience, Dr Leiter admitted that "in just 2.1 years, we would have been very surprised had we seen any [between group] difference" in the incidence of cancer.

Session chair Dr Anthony L McCall (University of Virginia, Charlottesville) speculated that the detected cancers were probably preexisting malignancies, an observation that Dr Leiter agreed with.

Increased, Decreased, or No Influence on Cancer Risk?

Although patients with type 2 diabetes have an increased risk of cancer, the role of antiglycemic agents on this risk is unclear, Dr Leiter said.

"Among established antihyperglycemic agents there have been reports demonstrating increased, decreased, or no influence on cancer risk and malignancy death," he said, adding that earlier concerns that DPP-4 inhibitors increased the likelihood of pancreatic cancer have not been confirmed.

Very few large, randomized controlled trials have examined the effect of taking specific antihyperglycemic agents on risk of cancer.

To look into this, Dr Leiter and colleagues analyzed data from SAVOR-TIMI, which randomized 16,413 patients who had type 2 diabetes and established cardiovascular disease (80% of patients) or multiple cardiovascular risk factors (20% of patients) to saxagliptin (5 mg/day or 2.5 mg/day with renal impairment; n = 8280) or placebo (n = 8173).

The patients had a mean age of 65 and had had diabetes for an average of 12 years; a third were women. At baseline, they had an HbA1c level of 8.0%, and roughly 69% were also taking metformin and 40% were taking a sulfonylurea.

The primary end point was cardiovascular death, MI, or ischemic stroke. "This was a cardiovascular-event–driven study, and the required number of events occurred after a median follow-up of 2.1 years, so at that point the study was completed," Dr Leiter explained. Saxagliptin met the primary end point of noninferiority but not superiority vs placebo.

In the current study, the researchers looked at the incidence of 12 main types of cancer — melanoma and prostate, skin, lung, hematologic, hepatic and biliary, thyroid, breast, gastrointestinal tract, urinary tract and bladder, colon, and pancreatic cancer—plus other cancers.

After 2.1 years, 362 patients (53%) in the placebo group and 326 patients (47%) in the saxagliptin group had at least one cancer (HR 0.89, P = .13).

There were more cases of colon cancer in the patients who received placebo (31) vs saxagliptin (16), but "I would not overinterpret this result, given the small number of events," Dr Leiter cautioned.

Patients who developed cancer were more likely to be older males with significantly lower HbA1c levels, diastolic blood pressure, and estimated glomerular filtration rate, without established atherosclerosis.

A similar number of patients in the placebo and saxagliptin groups were taking insulin, metformin, sulfonylurea, thiazolidinediones, aspirin, an ACE inhibitor, an angiotensin-receptor blocker (ARB), a beta-blocker, or a calcium-channel blocker. However, slightly more patients who developed cancer were taking a statin (83 patients vs 78 patients; P = .004), "but very importantly, this was not corrected for differences in baseline characteristics," Dr Leiter said.

More men than women had cancer, but the number of cancers were similar in the placebo and saxagliptin arms for each gender.

Not surprisingly, there were increasing numbers of cancer with increasing age.

However, duration of diabetes did not predict the likelihood of developing cancer. Among patients younger than 65 and those who had had diabetes for less than 5 years, there were significantly fewer cancers in patients taking saxagliptin, "but once again, I would not overinterpret [these findings], given the small number of cancers," Dr Leiter warned.

In multivariable modeling, patients who were male, had dyslipidemia, or were current smokers were more likely to develop cancer.

There were a similar number of cancer-associated deaths in the saxagliptin group (53) and the placebo group (59).

Thus, "stratification by gender, age, race and ethnicity, diabetes duration, baseline HbA1c, and pharmacotherapy did not reveal any clinically meaningful differences between the two study arms," he summarized.

Although the study was powered to detect a difference in cardiovascular outcomes, it "probably had a reasonable power" to detect a difference in cancer, Dr Leiter noted. There were about 1300 cardiovascular events and about 700 cancers in the whole cohort, again "highlighting the fact that cancer is a complication of diabetes," he concluded.

The study was funded by AstraZeneca. Dr Leiter is on the advisory panel and the speaker's bureau for and has received research support from AstraZeneca, as well as from other pharmaceutical companies.

American Diabetes Association 2015 Scientific Sessions; June 5, 2015; Boston, Massachusetts. Abstract 11-OR

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