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Vascular Outcomes Trials Confirm Safety of DPP-4 Inhibitors for the Treatment of Type 2 Diabetes Mellitus

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 35th Annual Congress of the European Society of Cardiology (ESC)

Amsterdam, Netherlands / August 31-September 4, 2013

Amsterdam - Both of the first two trials in a series to confirm the cardiovascular safety of dipeptidyl peptidase-4 (DPP-4) inhibitors met their primary end point. Although there are important differences in the design and information generated by the two trials, they encourage DPP-4 inhibitors to be moved forward in the treatment algorithm for glycemic control in patients with type 2 diabetes mellitus (T2DM). Although neither DPP-4 trial was associated with a cardioprotective effect, which each trial design was designed to capture if non-inferiority was met, both expanded available data to rule out any causal relationship with uncommon adverse events, including pancreatitis, for which scattered case reports had raised initial concern. The larger of the two trials was particularly reassuring not only as a result of a longer follow-up but because the patients randomized were more representative of those encountered in typical practice. 

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Two large placebo-controlled trials with DPP-4 inhibitors have fulfilled a mandate from the U.S. Food and Drug Administration (FDA) to demonstrate cardiovascular (CV) safety for anti-diabetic therapies. They are the first such studies to be completed since the mandate was invoked. The largest of the two trials, called SAVOR-TIMI 53 (Bhatt et al. ESC 2013 Abstract 2753), was conducted with saxagliptin, which was the first and remains one of the most widely prescribed DPP-4 inhibitors worldwide. The second, called EXAMINE (White et al. ESC 2013 Abstract 2571), was conducted with alogliptin, a relatively new DPP-4 inhibitor not yet available in Canada.

“In both trials, the data show clearly that the primary hypothesis [of CV safety] was met,” reported Dr. Eugene Braunwald, Brigham and Women’s Hospital, Harvard Medical School, Boston.

The reassuring safety data generated from these two studies are expected to further encourage early use of DPP-4 inhibitors, which are effective for blood glucose control and impose a relatively low risk of weight gain and hypoglycemia. The safety data are particularly welcome in the wake of a recent meta-analysis that associated sulfonylureas with an increased risk of stroke and overall mortality (Monani et al. Diabetes Obes Metab 2013;epub ahead of print April 17).

Reassuring Safety Data

Of the two studies, SAVOR-TIMI 53, which randomized 16,492 T2DM patients to saxagliptin or placebo, is considered the more important. Relative to EXAMINE, which randomized 5380 patients to alogliptin or placebo, SAVOR-TIMI 53 enrolled a broader high risk population including those with a history of CV disease and those with multiple risk factors. More representative than that of EXAMINE, which required patients to have had an acute coronary syndrome (ACS) within 90 days of enrollment. SAVOR-TIMI 53 also had a mean follow-up of 2.1 years, while the median follow-up in EXAMINE was only 18 months.

Over the course of SAVOR-TIMI 53, the event curves for the primary composite end point of CV death, myocardial infarction, or ischemic stroke were essentially superimposable, producing a highly significant (P<0.001) non-inferiority for the primary end point, which was the FDA mandate being fulfilled by this study. The hazard ratio (HR) was 1.00 (95% confidence interval (CI) of 0.89-1.12). A secondary end point that added hospitalization for unstable angina, congestive heart failure, or revascularization to the events included in the primary end point produced the same degree of significance for non-inferiority (HR 1.02; 95% CI 0.94-1.11; P<0.001).

When individual end points were evaluated separately, there were no significant differences except an excess of hospitalization for heart failure on saxagliptin (HR 1.27; 95% CI 1.07-1.51; P=0.007). The risk was concentrated in those with a history of heart failure and elevated brain natriuretic peptide (BNP) levels, but even in this group, saxagliptin was not associated with an increased risk of the primary outcome.

In regard to non-CV safety, there were no differences between the active treatment and placebo arms in a long list of events, including cancer (P=0.15), bone fracture (P=0.1), severe infection (P=0.79), and pancreatitis (P=0.77). Minor hypoglycemia events did occur more frequently on saxagliptin (14.2% vs. 12.5%; P=0.002) but the increased relative rate of major hypoglycemia events was of borderline significance (2.1% vs. 1.7%; P=0.047), and there was no significant difference in hospitalization for hypoglycemia (0.6% vs. 0.5%; P=0.33). Microalbuminuria was more likely to worsen on placebo (16% vs. 15%) and improve on saxagliptin (11% vs. 9%).

Continued Efficacy

It is notable that mean HbA1c levels were significantly improved in the group who received the DPP-4 inhibitor relative to placebo at 1 year, 2 years, and the end of study (P<0.001) even though patients in both groups were permitted additional anti-diabetes drug as needed. At 2 years, 40% of those randomized to saxagliptin versus 30% of those randomized to placebo (P<0.001) had HbA1c <7.0%.

Although Dr. Braunwald called the CV safety of DPP-4 inhibitors “good news,” he acknowledged that he had anticipated an overall CV benefit, which was a prespecified study end point for both studies once non-inferiority had been established. The speculation that DDP-4 inhibitors are cardioprotective was based on a previously published hypothesis-generating meta-analysis which associated this class of drug with a 52% (P<0.001) relative reduction in risk of an adverse CV event (Patil et al. Am J Cardiol 2012’;110:826-33).

EXAMINE used the same primary end point for an ACS population. Again, the non-inferiority of the active therapy for CV safety was confirmed by the similar event curves for the primary composite end point (HR 0.96; 95% CI 0.96-1.16; P<0.001). A broader composite secondary end point that included urgent revascularization also produced similar results. Again, as in SAVOR-TIMI 53, there were no significant differences in rates of a long list of non-CV events, including pancreatitis.

Reconsidering Sulfonylureas

More large CV outcome studies with DPP-4 inhibitors are coming, including TECOS with sitagliptin and CAROLINA with linagliptin, as well as similarly designed CV safety studies for glucagon-like peptide-1 (GLP-1) agonists. While data suggesting a cardioprotective benefit independent of glycemic control would have been welcome, the CV safety in these first 2 trials (SAVOR-TIMI 53 and EXAMINE) provide reassurance for moving these therapies in front of sulfonylureas, which are being challenged by experts for their long-term safety in regard to beta cell function and vascular risk.

“If sulfonylureas were evaluated today, they would not be approved by either the FDA or the EMA [European Medicines Agency],” observed Dr. Eduardo Mannucci, Careggi Teaching Hospital, Florence, Italy. He cited several studies documenting the long-term risks of these agents, including evidence of an increased risk of vascular complications, which have drawn increased attention since the FDA mandate has intensified interest in evidence of CV safety with anti-diabetes therapies. As CV disease is by far the most important cause of death in patients with T2DM, he believes the current emphasis of using therapies that do not exacerbate CV risk is appropriate.

A similar point was made by Dr. Lawrence Leiter, University of Toronto, who suggested that both DPP-4 inhibitors and GLP-1 agonists have drawn attention as a more attractive add on therapy in the context of increasing concern about the relative disadvantages of sulfonylureas. Relative to sulfonylureas, agents in both classes are associated with a relatively low risk of hypoglycemia, a neutral effect on body weight, and appear to provide a more physiological action of glycemic control.

Several experts, including Dr. Leiter, suggested that neither SAVOR-TIMI 53 nor EXAMINE have fully ruled out the possibility of a cardioprotective effect from DPP-4 inhibitors. In particular, one concern is that the duration of follow-up was insufficient to permit a vascular protective effect to be observed, particularly for the lower risk patients randomized in SAVOR-TIMI 53. It is also possible that cardioprotection requires these drugs to be initiated at an earlier stage of atherosclerosis. Dr. Jaime Davidson, Endocrinologist, University of Texas Southwestern Medical Center, Dallas, noted that the mortality curves showing benefit from a multi-risk intervention program in STENO 2 (Gaede et al. N Engl J Med 2008;358;580-91) did not diverge for almost 8 years.


The first in a series of large studies conducted to demonstrate CV safety with DPP-4 inhibitors met their primary end point. The placebo-controlled studies with saxagliptin and alogliptin employed a non-inferiority design to demonstrate a neutral effect on CV risk in high-risk patients. Although these studies differed in size and enrolled somewhat different high-risk populations, they not only provide a large body of evidence of CV safety but expand evidence that agents within this class pose a low risk of non-CV adverse events and possess several attributes that make them versatile for early diabetes control.

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