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BOSTON -- The diabetes drug sitagliptin (Januvia) did not increase the risk of cardiovascular events when compared with placebo, but it didn't lower the risk either, researchers reported here.

The primary outcome, a composite of cardiovascular outcomes, occurred in 11.4% of the patients on sitagliptin (4.06 per 100 person-years) and in 11.6% of the patients on placebo (4.17 per 100 person-years) in the trial of the drug, a dipeptidyl peptidase 4 inhibitor (DPP-4). Those on sitagliptin had a hazard ratio of 0.98 (95% CI 0.88-1.09; P<0.001 for noninferiority), according to the study of more than 14,000 patients with an average follow-up of 3.0 years.

In addition, rates of hospitalization did not differ between the two groups, said , from the University of Oxford, the study's lead investigator. The study was presented at a session here at the American Diabetes Association annual meeting and simultaneously published in the on June 8.

"We feel that this very adequately addresses the question, and puts to bed the question, that there is any cardiovascular risk with sitagliptin," said Holman in a press conference preceding the release of the results. There have also been concerns that DPP-4 inhibitors are associated with pancreatitis and pancreatic cancer, but the rates of both were low and did not differ significantly by group.

"From a safety point of view, we saw a very low rate of acute pancreatitis," he said. "There were no new data to suggest that we should be overly concerned."

The Trial

The trial -- called the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) -- was the third large, long-term trial of a DPP-4 inhibitor, following SAVOR-TIMI 53 and EXAMINE, where there were concerns of an increased risk of heart failure.

But the top line results reported earlier this year made it clear that there was no difference in the placebo and sitagliptin groups when it came to cardiovascular safety. , at the Joslin Diabetes Center in Boston, said that it's important to realize the context of the study.

"The regulatory environment was really looking for safety information," and not at efficacy of lowering glucose levels, she said in an interview with 番茄社区app. "These trials were not constructed as glucose lowering or glucose target trials -- the message is not that it doesn't show that treating diabetes is effective or not effective."

The trial was conducted as glycemic equipoise, meaning that other drugs were used in the trial to manage diabetes so that the differences in glucose levels in the two treatment arms were actually quite small. "The finding that you could use the sitagliptin in comparison with placebo including other drugs to use to treat diabetes is quite reassuring," Goldfine added.

The study was conducted at 673 sites in 38 different countries. All patients had type 2 diabetes and cardiovascular disease, were at least 50 years old, and had a glycated hemoglobin level of 6.5% to 8.0% when treated with antihyperglycemic agents like metformin, pioglitazone, or sulfonylurea, or with insulin. They were assigned 1:1 to either sitagliptin or placebo, in addition to usual care.

Patients were excluded if they had taken a DPP-4 inhibitor, a glucagon-like peptide-1 receptor agonist, or a thiazolidinedione other than pioglitazone in the last 3 months. Those with a history of two or more episodes of severe hypoglycemia during the past 12 months were also excluded, as were those who had an estimated glomerular filtration rate of less than 30 mL/min/1.73 m² of body-surface area at baseline.

Patients who had two or more episodes of severe hypoglycemia during the trial were required to discontinue the medication. The primary outcome was defined as the first confirmed event of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina, according to the study.

The secondary outcome was the same as the first with the exception of hospitalization for unstable angina. Other secondary outcomes included death from any cause and hospitalization for heart failure. An independent classification committee also looked at other health outcomes like death, acute pancreatitis, and cancers.

The Results

At 4 months, the mean glycated hemoglobin values were 0.4 percentage points lower in the sitagliptin group, the study found. But that difference narrowed over the rest of the study period. There was an overall least-squares mean difference of -0.29% in the sitagliptin group (95% CI -0.32 to -0.27).

Patients in the sitagliptin group received fewer additional antihyperglycemic agents than did those in the placebo group (1,591 versus 2,046 patients; HR 0.72, 95% CI 0.68-0.77; P<0.001). They were also less likely to start long-term insulin therapy (542 patients versus 744 patients; HR 0.70, 95% CI 0.63-0.79; P<0.001).

"We feel very confidently that this drug can be used very safely in patients with cardiovascular disease," said co-author , at the Duke Clinical Research Institute, at the press conference. He added that there "wasn't even a hint" that sitagliptin raised the risk of cardiovascular events.

There was no difference in the secondary composite cardiovascular analysis (HR 0.99, 95% CI 0.89-1.11; P<0.001) for noninferiority or in the intention-to-treat analysis (HR 0.99, 95% CI 0.89-1.10; P=0.84) for superiority.

Death from all causes occurred in 547 patients in the sitagliptin group (7.5%, 2.48 per 100 person-years) and in 537 patients in the placebo group (7.3%, 2.45 per 100 person-years; HR 1.01, 95% CI 0.90-1.14; P=0.88 in the intention-to-treat analysis).

Researchers also performed subgroup analyses of major prespecified primary cardiovascular outcomes. "No significant interactions were observed apart from body mass index," noted the study.

There was no significant difference between the sitagliptin group and the placebo group when it came to the overall incidence of infections, cancer, renal failure, or severe hypoglycemia. Acute pancreatitis events were rare in both groups, but there were more in the sitagliptin group (23 versus 12 in the placebo group; P=0.07 in the intention-to-treat analysis and P=0.12 in the per-protocol analysis).

On the other hand, there were more pancreatic cancers in the placebo group than in the sitagliptin group (nine events versus 14 events; P=0.32 in the intention-to-treat analysis and P=0.85 in the per-protocol analysis).

, at University of Colorado's School of Medicine, in Aurora, said that the results are decisive enough to make him feel confident when prescribing sitagliptin to patients. But he added that there are reasons why physicians might not prescribe DPP-4 inhibitors to their patients.

"When we make a decision clinically about how to treat our patients, we begin to individualize goals for treatment," he said. Those include length of diabetes, comorbidities, other risk factors, tolerance to the medication, and cost. That last factor is especially important when it comes to DPP-4 inhibitors, which are expensive, he added.

Goldfine said that researchers will be further parsing the data over the coming months to look for differences in subgroups.

"They will be analyzing the data to determine whether or not there are subgroups who responded differently, more favorably, less favorably, to the drug, although they have done an initial evaluation of this, and all of the subgroups look like they're having similar equipoise in their response rates," she said.

Limitations of the study include a relatively short follow-up time. In addition, those with severe renal insufficiency were excluded, and there were potential biases due to the confounding effects on cardiovascular outcomes, such as the small differences in hemoglobin levels between the groups and the greater use of anti-hyperglycemic agents in the placebo group.

"The opportunistic approach to data collection, apart from the selected values for glycated hemoglobin, resulted in limited acquisition of data regarding the ratio of urinary albumin to creatinine," wrote the authors.

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